Stem Cell Treatment for Erectile Dysfunction

Stem Cell Treatment for Erectile Dysfunction

STEM CELL TREATMENT ERECTILE DYSFUNCTION

Stem Cell Treatment for Erectile Dysfunction

  • Erectile Dysfunction is a sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance.

  • Stem Cell Treatmentst aims to effect the Calcium-sensitive potassium channel and therefore help increase the flow of blood into the Corpus.

STEM CELL TREATMENT ERECTILE DYSFUNCTIONA penile erection is the hydraulic effect of blood entering and being retained in sponge-like bodies within the penis. The process is often initiated as a result of sexual arousal, when signals are transmitted from the brain to nerves in the penis. Erectile dysfunction is indicated when an erection is difficult to produce. There are various circulatory causes, including alteration of the voltage-gated potassium channel, as in arsenic poisoning from drinking water.

The most important organic causes are cardiovascular disease and diabetes, neurological problems (for example, trauma from prostatectomy surgery), hormonal insufficiencies (hypogonadism) and drug side effects.

Psychological impotence is where erection or penetration fails due to thoughts or feelings (psychological reasons) rather than physical impossibility; this is somewhat less frequent but often can be helped. Notably in psychological impotence, there is a strong response to placebo treatment. Erectile dysfunction, tied closely as it is about ideas of physical well being, can have severe psychological consequences.

Stem Cell Treatment for Erectile Dysfunction

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Related Articles Difference of opinion - Is There a Space to Improve the Treatment of Erectile Dysfunction in the Next Years? Opinion: YES. Int Braz J Urol. 2015 Sep-Oct;41(5):830-1 Authors: Althof SE PMID: 26689506 [PubMed - indexed for MEDLINE]
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Related Articles Intracavernous delivery of clonal mesenchymal stem cells rescues erectile function in the streptozotocin-induced diabetic mouse. Andrology. 2016 Jan;4(1):172-84 Authors: Ryu JK, Kim DH, Song KM, Ryu DS, Kim SN, Shin DH, Yi T, Suh JK, Song SU Abstract The major hurdle for the clinical application of stem cell therapy is the heterogeneous nature of the isolated cells, which may cause different treatment outcomes. The aim of this study was to examine the effectiveness of mouse clonal bone marrow-derived stem cells (BMSCs) obtained from a single colony by using subfractionation culturing method for erectile function in diabetic animals. Twelve-week-old C57BL/6J mice were divided into four groups: controls, diabetic mice, and diabetic mice treated with a single intracavernous injection of PBS (20 μL) or clonal BMSCs (3 × 10(5) cells/20 μL). Clonal BMSCs were isolated from 5-week-old C3H mice. Two weeks after treatment, erectile function was measured by electrical stimulation of the cavernous nerve. The penis was stained with antibodies to PECAM-1, smooth muscle α-actin, neuronal nitric oxide synthase (nNOS), neurofilament, and phosphorylated endothelial NOS (phospho-eNOS). We also performed Western blot for phospho-eNOS, and eNOS in the corpus cavernosum tissue. Local delivery of clonal BMSCs significantly restored cavernous endothelial and smooth muscle cell contents, and penile nNOS and neurofilament contents, and induced eNOS phosphorylation (Ser1177) in diabetic mice. Intracavernous injection of clonal BMSCs induced significant recovery of erectile function, which reached 80-90% of the control values. Clonal BMSCs successfully restored erectile function through dual angiogenic and neurotrophic effects in diabetic mice. The homogenous nature of clonal mesenchymal stem cells may allow their clinical applications and open a new avenue through which to treat diabetic erectile dysfunction. PMID: 26711324 [PubMed - indexed for MEDLINE]
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Related Articles Determining the Feasibility of Managing Erectile Dysfunction in Humans With Placental-Derived Stem Cells. J Am Osteopath Assoc. 2016 Jan;116(1):e1-5 Authors: Levy JA, Marchand M, Iorio L, Cassini W, Zahalsky MP Abstract INTRODUCTION: Stem cell therapy is thought to improve wound healing and promote vasculogenesis and has also been investigated as a treatment for patients with erectile dysfunction (ED), which is usually caused by a microvascular disease such as diabetes mellitus or hypertension. OBJECTIVE: To determine the feasibility and effects of using placental matrix-derived mesenchymal stem cells (PM-MSCs) in the treatment of patients with ED. METHODS: Participants were recruited from a private practice urology in Coral Springs, Florida. Each patient received an injection of PM-MSCs and was followed up with at 6 weeks, 3 months, and 6 months to assess peak systolic velocity (PSV), end diastolic velocity, stretched penile length, penile width, and erectile function status based on the International Index of Erectile Function questionnaire. RESULTS: Eight patients were injected with PM-MSCs. At the 6-week follow-up, PSV ranged from 25.5 cm/s to 56.5 cm/s; at 3 months, PSV ranged from 32.5 cm/s to 66.7 cm/s. Using unpaired t tests, the increase in PSV was statistically significant (P<.05). At 6 months, PSV ranged from 50.7 cm/s to 73.9 cm/s (P<.01). Changes in measured end diastolic velocity, stretched penile length, penile width, and International Index of Erectile Function scores were not statistically significant. At the 6-week follow-up, 2 patients for whom previous oral therapies failed had the ability to sustain erections on their own. At the 3-month follow-up, 1 additional patient was able to achieve erections on his own. CONCLUSION: To our knowledge, this is one of the first human studies to report on the feasibility of using stem cell therapy to treat patients with ED. The results indicate that this treatment may be beneficial, and further investigations with larger sample sizes should be conducted. (ClinicalTrials.gov number NCT02398370). PMID: 26745574 [PubMed - indexed for MEDLINE]
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Related Articles Dual Strategy With Oral Phosphodiesterase Type 5 Inhibition and Intracavernosal Implantation of Mesenchymal Stem Cells Is Superior to Individual Approaches in the Recovery of Erectile and Cavernosal Functions After Cavernous Nerve Injury in Rats. J Sex Med. 2016 Jan;13(1):1-11 Authors: Martínez-Salamanca JI, Zurita M, Costa C, Martínez-Salamanca E, Fernández A, Castela A, Vaquero J, Carballido J, Angulo J Abstract INTRODUCTION: Novel effective therapeutic strategies are necessary for treating erectile dysfunction secondary to cavernous nerve injury (CNI). AIM: To functionally evaluate the benefits of long-term oral treatment with a phosphodiesterase type 5 inhibitor on the potential capacity of intracavernosal cell therapy to recover erectile function after CNI. METHODS: Bilateral crush CNI (BCNI) was produced in anesthetized male rats. After BCNI, rats were treated with the phosphodiesterase type 5 inhibitor tadalafil (TAD; 5 mg/kg/d orally; BCNI + TAD), a single intracavernosal injection of bone marrow-derived mesenchymal stem cells (BMSCs; BCNI + BMSC), or dual therapy (BCNI + BMSC + TAD). Ex vivo function of the corpus cavernosum (CC) and in vivo intracavernosal pressure responses to CN electrical stimulation were evaluated 4 weeks after BCNI. Trichrome staining and terminal 2'-deoxyuridine-5'-triphosphate nick-end labeling assay were used for fibrosis and apoptosis determination, respectively, in the CC. MAIN OUTCOME MEASURES: In vivo erectile responses in anesthetized rats, ex vivo evaluation of endothelium-dependent relaxation, neurogenic relaxation and neurogenic contraction in CC strips, and histologic evaluation of fibrosis and apoptosis in cavernosal tissue. RESULTS: BCNI resulted in a marked decrease of erectile responses that were partly recovered in the BCNI + TAD and BCNI + BMSC groups. Complete recovery of erectile function was achieved only in the BCNI + BMSC + TAD group. Endothelium-dependent and nitric oxide donor-induced relaxations of the CC were not altered by BCNI or the treatments. BCNI resulted in enhanced neurogenic adrenergic contractions and impaired nitrergic relaxations of the CC. The BCNI + TAD group displayed diminished neurogenic contractions, whereas the BCNI + TAD and BCNI + BMSC groups showed partly recovered nitrergic responses. In the BCNI + BMSC + TAD group, neurogenic contractions were decreased and nitrergic relaxations were normalized. Cavernosal apoptosis and fibrosis were similarly prevented in the BCNI + TAD, BCNI + BMSC, and BCNI + BMSC + TAD groups. CONCLUSION: A dual strategy combining the intracavernosal injection of BMSCs and oral administration of TAD was superior to individual approaches in normalizing neurogenic control of cavernosal tone and preserving erectile function after CNI, suggesting the potential of this dual strategy in the future management of erectile dysfunction after radical prostatectomy. PMID: 26755080 [PubMed - indexed for MEDLINE]
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Related Articles Adipose Tissue-Derived Stem Cells for the Treatment of Erectile Dysfunction. Curr Urol Rep. 2016 Feb;17(2):14 Authors: Gokce A, Peak TC, Abdel-Mageed AB, Hellstrom WJ Abstract Although a spectrum of options is available for erectile dysfunction (ED) treatment, ED in diabetics, post-prostatectomy patients, and those with Peyronie's disease (PD) may be more severe in degree and less likely to respond to conventional medical therapies. Unfortunately, there have been limited breakthroughs in therapeutic options for severe ED during the past decade. However, one of the more fascinating strategies in preclinical development to treat ED is stem cell transplantation. Depending on the cell type, recent research has demonstrated that with transplantation, these stem cells can exert a paracrine effect on surrounding penile tissues and differentiate into smooth muscle, endothelium, and neurons. Adipose tissue-derived stem cells (ADSCs) have become a valuable resource because of their abundance and ease of isolation. It is evident that ADSCs may provide a realistic, therapeutic modality for the treatment of ED. In this review, we will cover the literature that has evaluated ADSCs in the treatment of ED. PMID: 26757908 [PubMed - indexed for MEDLINE]
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Related Articles Advances in stem cell research for the treatment of male sexual dysfunctions. Curr Opin Urol. 2016 Mar;26(2):129-39 Authors: Soebadi MA, Moris L, Castiglione F, Weyne E, Albersen M Abstract PURPOSE OF REVIEW: To summarize recent literature on basic stem cell research in erectile dysfunction in cavernous nerve injury, aging, diabetes, and Peyronie's disease and to provide a perspective on clinical translation of these cellular therapies. RECENT FINDINGS: Stem cell research has been concentrated on mesenchymal stem (stromal) cells from bone marrow and adipose tissue. Application of both cell types has produced positive effects on erectile function in various animal models of erectile dysfunction. In acute animal models, such as cavernous nerve injury-induced erectile dysfunction and chemically induced Peyronie's disease, engraftment and differentiation have not been observed, and stem cells are believed to interact with the host tissue in a paracrine fashion, whereas in chronic disease models some evidence suggests both engraftment and paracrine factors may support improved function. Clinical trials are now investigating therapeutic efficacy of cellular therapy, whereas the first safety studies in humans have recently been published. SUMMARY: Evidence from preclinical studies has established stem cells as a potential curative treatment for erectile dysfunction and early phase clinical trials are currently performed. PMID: 26759972 [PubMed - indexed for MEDLINE]
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Related Articles A Rare Consequence of Chronic Graft Versus Host Disease - Peyronie's Disease. Arch Cancer Res. 2015;3(2): Authors: Jain NA, Venkatesan K, Anandi P, Ito S, Kumar D, Lu K, Battiwalla M, Barrett AJ Abstract Chronic graft versus host disease (GvHD) after allogeneic stem cell transplantation (SCT) may involve any organ system, but male genital involvement is rare. Peyronie's Disease (PD) is an acquired, localized fibrotic disorder of the tunica albuginea, which leads to penile deformity, pain, and eventually to erectile dysfunction. We report the case of a 52 year old African American male with Acute Myeloid Leukemia who underwent human leucocyte antigen (HLA) matched sibling allogeneic peripheral blood SCT. His post transplant course was complicated by development of acute and multi-organ chronic GvHD requiring prolonged immunosuppression. He developed progressive dorsal curvature of the penis with erections within 1 year of ultra low dose interleukin -2 (IL2) treatment for his chronic GvHD but concealed symptoms for several months. Color Doppler Duplex ultrasound evaluation of the erect penis revealed a 75-degree curvature and appropriate hemodynamic response to prostaglandin injection. He underwent successful incision and grafting of the penile plaque. There is no significant residual curvature and is now able to engage in intercourse. A strong temporal association between GVHD (or its treatment) and Peyronie's is documented here. Awareness of the possible link between PD and chronic GVHD is required in this era of rapid growth in numbers of SCT. PMID: 26770907 [PubMed]
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Related Articles Neurotrophic Effect of Adipose Tissue-Derived Stem Cells on Erectile Function Recovery by Pigment Epithelium-Derived Factor Secretion in a Rat Model of Cavernous Nerve Injury. Stem Cells Int. 2016;2016:5161248 Authors: Chen X, Yang Q, Zheng T, Bian J, Sun X, Shi Y, Liang X, Gao G, Liu G, Deng C Abstract The paracrine effect is the major mechanism of stem cell therapy. However, the details of the effect's mechanism remain unknown. The aim of this study is to investigate whether adipose tissue-derived stem cells (ADSCs) can ameliorate cavernous nerve injury-induced erectile dysfunction (CNIED) rats and to determine its mechanism. Twenty-eight days after intracavernous injection of 5-ethynyl-2-deoxyuridine- (EdU-) labeled ADSCs, the erectile function of all the rats was evaluated by intracavernosal pressure (ICP). The ADSCs steadily secreted detectable pigment epithelium-derived factor (PEDF) in vitro. The expression of PEDF increased in the penis of the bilateral cavernous nerve injury (BCNI) group for 14 days and then gradually decreased. On day 28 after the intracavernous injection, the ADSCs group exhibited a significantly increased ICP compared with the phosphate buffered saline- (PBS-) treated group. Moreover, the neuronal nitric oxide synthase (nNOS) and S100 expression in penile dorsal nerves and the smooth muscle content to collagen ratio in penile tissues significantly increased. Furthermore, elevated PEDF, p-Akt, and p-eNOS were identified in the ADSCs group. This study demonstrated that intracavernous injection of ADSCs improved erectile function, repaired the nerve, and corrected penile fibrosis. One potential mechanism is the PEDF secretion of ADSCs and subsequent PI3K/Akt pathway activation. PMID: 26783403 [PubMed]
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Related Articles Effects of adipose-derived stem cells plus insulin on erectile function in streptozotocin-induced diabetic rats. Int Urol Nephrol. 2016 May;48(5):657-69 Authors: Zhou F, Hui Y, Xu Y, Lei H, Yang B, Guan R, Gao Z, Xin Z, Hou J Abstract PURPOSE: Erectile dysfunction (ED) is a distressing complication in men with diabetes mellitus (DM). This study aimed to investigate the effects of adipose-derived stem cells (ADSCs) plus insulin on ED in streptozotocin (STZ)-induced diabetic rats. METHODS: Forty-five eight-week-old male Sprague-Dawley rats received intraperitoneal injection of STZ (60 mg/kg). Eight weeks after the induction, the determined diabetic rats were randomly distributed into four groups: rats in DM + PBS group received a one-time intracavernous (IC) injection of phosphate-buffered saline (PBS) solution, DM + ADSCs group received IC injection of ADSCs, DM + Insulin group received subcutaneous injection of neutral protamine Hagedorn twice a day, and DM + ADSCs + Insulin group received both ADSCs and neutral protamine Hagedorn treatments. Another 10 normal rats were served as control group and received IC injection of PBS. Four weeks after the treatments, intracavernous pressure, histopathological changes in penis, functional proteins of ADSCs, and penis were measured. RESULTS: We found that ADSCs expressed vascular endothelial growth factor, TIMP metallopeptidase inhibitor 1 (TIMP-1), and lipopolysaccharide-inducible CXC chemokine (LIX). ADSC injection partially restored cavernous endothelium and smooth muscle contents and nNOS-positive nerves, and reduced apoptosis in penis compared with PBS-treated diabetic rats. Insulin treatment could further modulate inflammatory response and reduce advanced glycation end-product accumulation in penis. CONCLUSIONS: Better than single therapy, ADSCs combined with insulin ameliorate ED and pathological changes in diabetic rats to near-normal levels. PMID: 26820518 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cell therapy in treatment of erectile dysfunction: Autologous or allogeneic cell sources? Int J Urol. 2016 Apr;23(4):348-9 Authors: Kadihasanoglu M, Ozbek E PMID: 26822742 [PubMed - indexed for MEDLINE]
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Related Articles A survey of fertility and sexual health following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia. Br J Haematol. 2016 Feb;172(4):592-601 Authors: Dyer G, Gilroy N, Bradford J, Brice L, Kabir M, Greenwood M, Larsen SR, Moore J, Hertzberg M, Kwan J, Brown L, Hogg M, Huang G, Tan J, Ward C, Kerridge I Abstract Four hundred and twenty-one adult allogeneic haematopoietic stem cell transplant (HSCT) survivors participated in a cross-sectional study to assess sexual dysfunction and infertility post-transplant. Survey instruments included the Sydney Post-Blood and Marrow Transplant (BMT) Survey, Functional Assessment of Cancer Treatment (FACT) - BMT, the Depression, Anxiety, Stress Scales (DASS 21), the Chronic Graft-versus-Host Disease (cGVHD) Activity Assessment- Patient Self Report (Form B), the Lee cGVHD Symptom Scale and The Post-Traumatic Growth Inventory. Most HSCT survivors reported sexual difficulties (51% of males; 66% of females). Men reported erectile dysfunction (79%) and decreased libido (61·6%) and women reported loss of libido (83%), painful intercourse (73%) and less enjoyment of sex (68%). Women also commonly reported vaginal dryness (73%), vaginal narrowing (34%) and vaginal irritation (26%). Woman had much higher rates of genital cGvHD than men (22% vs. 5%). Age and cGVHD were significantly associated with sexual dysfunction. Few survivors had children following transplant (3·3%). However, for those of reproductive age at HSCT, 22% reported trying to conceive, with 10·3% reporting success. This study is the largest to date exploring sexual function in survivors of allo-HSCT. This data provides the basis for health service reform to better meet the needs of HSCT survivors, including evidence to support counselling and education both pre- and post-transplant. PMID: 26847746 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cell-based gene therapy for erectile dysfunction. Int J Impot Res. 2016 May;28(3):81-7 Authors: Kim JH, Lee HJ, Song YS Abstract Despite the overwhelming success of PDE5 inhibitor (PDE5I), the demand for novel pharmacotherapeutic and surgical options for ED continues to rise owing to the increased proportion of elderly individuals in the population, in addition to the growing percentage of ED patients who do not respond to PDE5I. Surgical treatment of ED is associated with many complications, thus warranting the need for nonsurgical therapies. Moreover, none of the above-mentioned treatments essentially corrects, cures or prevents ED. Although gene therapy is a promising option, many challenges and obstacles such as local inflammatory response and random transgene expression, in addition to other safety issues, limit its use at the clinical level. The use of stem cell therapy alone also has many shortcomings. To overcome these inadequacies, many scientists and clinicians are investigating new gene and stem cell therapies. PMID: 26888355 [PubMed - indexed for MEDLINE]
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Related Articles [Spanish consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria]. Med Clin (Barc). 2016 Mar 18;146(6):278.e1-7 Authors: Villegas A, Arrizabalaga B, Bonanad S, Colado E, Gaya A, González A, Jarque I, Núñez R, Ojeda E, Orfao A, Ribera JM, Vicente V, Urbano-Ispizua Á, Grupo de Trabajo de HPN de la Sociedad Española de Hematología y Hemoterapia Abstract Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder of the haematopoietic progenitor cells due to a somatic mutation in theX-linked phosphatidylinositol glycan class A gene. The disease is characterized by intravascular haemolytic anaemia, propensity to thromboembolic events and bone marrow failure. Other direct complications of haemolysis include dysphagia, erectile dysfunction, abdominal pain, asthenia and chronic renal failure (65% of patients). The disease appears more often in the third decade of life and there is no sex or age preference. Detection of markers associated with glucosyl phosphatidyl inositol deficit by flow cytometry is currently used in the diagnosis of PNH. For years, transfusions have been the mainstay of therapy for PNH. A breakthrough in treatment has been the approval of the humanized monoclonal antibody eculizumab, which works by blocking the C5 complement protein, preventing its activation and therefore haemolysis. Several studies have confirmed that treatment with eculizumab avoids or decreases the need for transfusions, decreases the probability of thrombosis, improves the associated symptomatology and the quality of life in patients with PNH, showing an increase in survival. Because of rapid advances in the knowledge of the disease and its treatment, it may become necessary to adapt and standardize clinical guidelines for the management of patients with PNH. PMID: 26895645 [PubMed - indexed for MEDLINE]
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Related Articles Transplantation of Human Urine-Derived Stem Cells Transfected with Pigment Epithelium-Derived Factor to Protect Erectile Function in a Rat Model of Cavernous Nerve Injury. Cell Transplant. 2016 11;25(11):1987-2001 Authors: Yang Q, Chen X, Zheng T, Han D, Zhang H, Shi Y, Bian J, Sun X, Xia K, Liang X, Liu G, Zhang Y, Deng C Abstract The aim of this study was to investigate whether intracavernous injection of urine-derived stem cells (USCs) or USCs genetically modified with pigment epithelium-derived factor (PEDF) could protect the erectile function and cavernous structure in a bilateral cavernous nerve injury-induced erectile dysfunction (CNIED) rat model. USCs were cultured from the urine of six healthy male donors. Seventy-five rats were randomly divided into five groups ( n = 15 per group): sham, bilateral cavernous nerve (CN) crush injury (BCNI), USC, USCGFP+, and USCGFP/PEDF+ groups. The sham group received only laparotomy without CN crush injury and intracavernous injection with phosphate-buffered saline (PBS). All of the other groups were subjected to BCNI and intracavernous injection with PBS, USCs, USCsGFP+, or USCsGFP/PEDF+, respectively. The total intracavernous pressure (ICP) and the ratio of ICP to mean arterial pressure (ICP/MAP) were recorded. The penile dorsal nerves, the endothelium, and the smooth muscle were assessed within the penile tissue. The USC and USCGFP/PEDF+ groups displayed more significantly enhanced ICP and ICP/MAP ratio ( p < 0.05) 28 days after cell transplantation. Immunohistochemistry (IHC) and Western blot analysis demonstrated that the protection of erectile function and the cavernous structure by USCsGFP/PEDF+ was associated with an increased number of nNOS-positive fibers within the penile dorsal nerves, improved expression of endothelial markers (CD31 and eNOS) and a smooth muscle marker (smoothelin), an enhanced smooth muscle to collagen ratio, decreased expression of transforming growth factor-β1 (TGF-β1), and decreased cell apoptosis in the cavernous tissue. The paracrine effect of USCs and USCsGFP/PEDF+ prevented the destruction of erectile function and the cavernous structure in the CNIED rat model by nerve protection, thereby improving endothelial cell function, increasing the smooth muscle content, and decreasing fibrosis and cell apoptosis in the cavernous tissue. PMID: 27075964 [PubMed - indexed for MEDLINE]
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Related Articles What is the current role of intracavernosal injection in management of erectile dysfunction? Int J Impot Res. 2016 May;28(3):88-95 Authors: El-Sakka AI Abstract The emerging of intracavernosal injection (ICI) of vasoactive materials was a major breakthrough in the treatment of erectile dysfunction (ED). However, the current state and future direction of ICI role in the armamentarium of diagnosis, prevention and treatment of ED are not well defined. The aim of this study was to address the current place of ICI in the armamentarium of ED diagnosis and treatment. An English-language MEDLINE review for the utilization of 'intracavernosal injection & erectile dysfunction' was performed from 1990 to present time. Four hundred forty-eight articles were analyzed and classified according to the current utilization of ICI in the following conditions; diagnosis of ED, phosphodiesterase-5 inhibitor (PDE5I) non-responders, diabetes, post radical prostatectomy (RP), stem cells and gene therapy, new intracavernosal drugs, adverse effects and couple satisfaction. This paper is not a standard systematic review; it is eventually a literature review of original peer-reviewed manuscripts and clinical trials reported in Medline. The comprehensive analyses of all the reviewed data were not possible as the level of evidence for utility of ICI in each topic was not available. Current date have established the role of ICI of vasoactive materials as a very common alternative domain in treatment of severe ED particularly in diabetic patients, post-RP, PDE5I non-responders. Further, new studies have denoted the potential future role of intracavernosal treatment for ED in the era of stem cells and gene therapy. ICI of vasoactive material continues to be a highly effective and safe treatment tool for men with wide varieties of ED etiologies. Several experimental and clinical studies are currently investigating new ICI materials. Hopefully in the near future, we might witness evolved molecules and innovative strategies that could help to treat ED patients with different etiologies. PMID: 27076113 [PubMed - indexed for MEDLINE]
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Related Articles Safety and Potential Effect of a Single Intracavernous Injection of Autologous Adipose-Derived Regenerative Cells in Patients with Erectile Dysfunction Following Radical Prostatectomy: An Open-Label Phase I Clinical Trial. EBioMedicine. 2016 Mar;5:204-10 Authors: Haahr MK, Jensen CH, Toyserkani NM, Andersen DC, Damkier P, Sørensen JA, Lund L, Sheikh SP Abstract BACKGROUND: Prostate cancer is the most common cancer in men, and radical prostatectomy (RP) often results in erectile dysfunction (ED) and a substantially reduced quality of life. The efficacy of current interventions, principal treatment with PDE-5 inhibitors, is not satisfactory and this condition presents an unmet medical need. Preclinical studies using adipose-derived stem cells to treat ED have shown promising results. Herein, we report the results of a human phase 1 trial with autologous adipose-derived regenerative cells (ADRCs) freshly isolated after a liposuction. METHODS: Seventeen men suffering from post RP ED, with no recovery using conventional therapy, were enrolled in a prospective phase 1 open-label and single-arm study. All subjects had RP performed 5-18 months before enrolment, and were followed for 6 months after intracavernosal transplantation. ADRCs were analyzed for the presence of stem cell surface markers, viability and ability to differentiate. Primary endpoint was the safety and tolerance of the cell therapy while the secondary outcome was improvement of erectile function. Any adverse events were reported and erectile function was assessed by IIEF-5 scores. The study is registered with ClinicalTrials.gov, NCT02240823. FINDINGS: Intracavernous injection of ADRCs was well-tolerated and only minor events related to the liposuction and cell injections were reported at the one-month evaluation, but none at later time points. Overall during the study period, 8 of 17 men recovered their erectile function and were able to accomplish sexual intercourse. Post-hoc stratification according to urinary continence status was performed. Accordingly, for continent men (median IIEFinclusion = 7 (95% CI 5-12), 8 out of 11 men recovered erectile function (IIEF6months = 17 (6-23)), corresponding to a mean difference of 0.57 (0.38-0.85; p = 0.0069), versus inclusion. In contrast, incontinent men did not regain erectile function (median IIEF1/3/6 months = 5 (95% CI 5-6); mean difference 1 (95% CI 0.85-1.18), p > 0.9999). INTERPRETATION: In this phase I trial a single intracavernosal injection of freshly isolated autologous ADRCs was a safe procedure. A potential efficacy is suggested by a significant improvement in IIEF-5 scores and erectile function. We suggest that ADRCs represent a promising interventional therapy of ED following prostatectomy. FUNDING: Danish Medical Research Council, Odense University Hospital and the Danish Cancer Society. PMID: 27077129 [PubMed - indexed for MEDLINE]
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Related Articles Stem Cell Therapy for Diabetic Erectile Dysfunction in Rats: A Meta-Analysis. PLoS One. 2016;11(4):e0154341 Authors: Li M, Li H, Ruan Y, Wang T, Liu J Abstract INTRODUCTION: Stem cell therapy is a novel method for the treatment of diabetic erectile dysfunction (ED). Many relative animal studies have been done to evaluate the efficacy of this therapy in rats. AIMS: This meta-analysis was performed to compare the efficacy of different stem cell therapies, to evaluate the influential factors and to determine the optimal stem cell therapeutic strategy for diabetic ED. METHODS: We searched the studies analyzing the efficacy of stem cell therapy for diabetic ED in rats published before September 30, 2015 in PubMed, Web of Science and EBSCO. A random effects meta-analysis was conducted to assess the outcomes of stem cell therapy. Subgroup analysis was also performed by separating these studies based on their different characteristics. Changes in the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP) and in the structure of the cavernous body were compared. RESULTS: 10 studies with 302 rats were enrolled in this meta-analysis. Pooled analysis of these studies showed a beneficial effect of stem cell therapy in improving erectile function of diabetic rats (SMD 4.03, 95% CI = 3.22 to 4.84, P< 0.001). In the stem cell therapy group, both the smooth muscle and endothelium content were much more than those in control group. There was also significant increase in the expression of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS), the ratio of smooth muscle to collagen, as well as the secretion of vascular endothelial growth factor (VEGF). Besides, apoptotic cells were reduced by stem cell treatment. The subgroup analysis indicated that modified stem cells were more effective than those without modification. CONCLUSIONS: Our results confirmed that stem cell therapy could apparently improve the erectile function of diabetic rats. Some specific modification, especially the gene modification with growth factors, could improve the efficacy of stem cell therapy. Stem cell therapy has potential to be an effective therapeutic strategy for diabetic ED. PMID: 27111659 [PubMed - indexed for MEDLINE]
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Related Articles Implanted Muscle-Derived Stem Cells Ameliorate Erectile Dysfunction in a Rat Model of Type 2 Diabetes, but Their Repair Capacity Is Impaired by Their Prior Exposure to the Diabetic Milieu. J Sex Med. 2016 05;13(5):786-97 Authors: Kovanecz I, Vernet D, Masouminia M, Gelfand R, Loni L, Aboagye J, Tsao J, Rajfer J, Gonzalez-Cadavid NF Abstract INTRODUCTION: Muscle-derived stem cells (MDSCs) and other SCs implanted into the penile corpora cavernosa ameliorate erectile dysfunction in type 1 diabetic rat models by replenishing lost corporal smooth muscle cells (SMCs) and decreasing fibrosis. However, there are no conclusive data from models of type 2 diabetes (T2D) and obesity. AIM: To determine whether MDSCs from obese Zucker (OZ) rats with T2D at an early stage of diabetes (early diabetic SCs isolated and cultured in low-glucose medium [ED-SCs]) counteract corporal veno-occlusive dysfunction and corporal SMC loss or lipo-fibrosis when implanted in OZ rats at a late stage of diabetes and whether MDSCs from these OZ rats with late diabetes (late diabetic SCs isolated and cultured in high-glucose medium [LD-SC]) differ from ED-SCs in gene transcriptional phenotype and repair capacity. METHODS: ED-SCs and LD-SCs were compared by DNA microarray assays, and ED-SCs were incubated in vitro under high-glucose conditions (ED-HG-SC). These three MDSC types were injected into the corpora cavernosa of OZ rats with late diabetes (OZ/ED, OZ/LD, and OZ/ED-HG rats, respectively). Untreated OZ and non-diabetic lean Zucker rats functioned as controls. Two months later, rats were subjected to cavernosometry and the penile shaft and corporal tissues were subjected to histopathology and DNA microarray assays. MAIN OUTCOME MEASURES: In vivo erectile dysfunction assessment by Dynamic Infusion Cavernosometry followed by histopathology marker analysis of the penile tissues. RESULTS: Implanted ED-SCs and ED-HG-SCs improved corporal veno-occlusive dysfunction, counteracted corporal decreases in the ratio of SMCs to collagen and fat infiltration in rats with long-term T2D, and upregulated neuronal and endothelial nitric oxide. LD-SCs acquired an inflammatory, pro-fibrotic, oxidative, and dyslipidemic transcriptional phenotype and failed to repair the corporal tissue. CONCLUSION: MDSCs from pre-diabetic rats injected into the corpora cavernosa of rats with long-term T2D improve corporal veno-occlusive dysfunction and the underlying histopathology. In contrast, MDSCs from rats with long-term uncontrolled T2D are imprinted by the hyperglycemic and dyslipidemic milieu with a noxious phenotype associated with an impaired tissue repair capacity. SCs affected by diabetes could lack tissue repair efficacy as autografts and should be reprogrammed in vitro or substituted by SCs from allogenic non-diabetic sources. PMID: 27114192 [PubMed - indexed for MEDLINE]
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Related Articles Clinical applications of low-intensity pulsed ultrasound and its potential role in urology. Transl Androl Urol. 2016 Apr;5(2):255-66 Authors: Xin Z, Lin G, Lei H, Lue TF, Guo Y Abstract Low-intensity pulsed ultrasound (LIPUS) is a form of ultrasound that delivered at a much lower intensity (<3 W/cm(2)) than traditional ultrasound energy and output in the mode of pulse wave, and it is typically used for therapeutic purpose in rehabilitation medicine. LIPUS has minimal thermal effects due to its low intensity and pulsed output mode, and its non-thermal effects which is normally claimed to induce therapeutic changes in tissues attract most researchers' attentions. LIPUS have been demonstrated to have a rage of biological effects on tissues, including promoting bone-fracture healing, accelerating soft-tissue regeneration, inhibiting inflammatory responses and so on. Recent studies showed that biological effects of LIPUS in healing morbid body tissues may be mainly associated with the upregulation of cell proliferation through activation of integrin receptors and Rho/ROCK/Src/ERK signaling pathway, and with promoting multilineage differentiation of mesenchyme stem/progenitor cell lines through ROCK-Cot/Tpl2-MEK-ERK signaling pathway. Hopefully, LIPUS may become an effective clinical procedure for the treatment of urological diseases, such as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), erectile dysfunction (ED), and stress urinary incontinence (SUI) in the field of urology. It still needs an intense effort for basic-science and clinical investigators to explore the biomedical applications of ultrasound. PMID: 27141455 [PubMed]
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Related Articles Superparamagnetic iron oxide nanoparticle targeting of adipose tissue-derived stem cells in diabetes-associated erectile dysfunction. Asian J Androl. 2017 Jul-Aug;19(4):425-432 Authors: Zhu LL, Zhang Z, Jiang HS, Chen H, Chen Y, Dai YT Abstract Erectile dysfunction (ED) is a major complication of diabetes, and many diabetic men with ED are refractory to common ED therapies. Adipose tissue-derived stem cells (ADSCs) have been shown to improve erectile function in diabetic animal models. However, inadequate cell homing to damaged sites has limited their efficacy. Therefore, we explored the effect of ADSCs labeled with superparamagnetic iron oxide nanoparticles (SPIONs) on improving the erectile function of streptozotocin-induced diabetic rats with an external magnetic field. We found that SPIONs effectively incorporated into ADSCs and did not exert any negative effects on stem cell properties. Magnetic targeting of ADSCs contributed to long-term cell retention in the corpus cavernosum and improved the erectile function of diabetic rats compared with ADSC injection alone. In addition, the paracrine effect of ADSCs appeared to play the major role in functional and structural recovery. Accordingly, magnetic field-guided ADSC therapy is an effective approach for diabetes-associated ED therapy. PMID: 27157506 [PubMed - indexed for MEDLINE]
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Related Articles Erectile dysfunction. Nat Rev Dis Primers. 2016 02 04;2:16003 Authors: Yafi FA, Jenkins L, Albersen M, Corona G, Isidori AM, Goldfarb S, Maggi M, Nelson CJ, Parish S, Salonia A, Tan R, Mulhall JP, Hellstrom WJ Abstract Erectile dysfunction is a multidimensional but common male sexual dysfunction that involves an alteration in any of the components of the erectile response, including organic, relational and psychological. Roles for nonendocrine (neurogenic, vasculogenic and iatrogenic) and endocrine pathways have been proposed. Owing to its strong association with metabolic syndrome and cardiovascular disease, cardiac assessment may be warranted in men with symptoms of erectile dysfunction. Minimally invasive interventions to relieve the symptoms of erectile dysfunction include lifestyle modifications, oral drugs, injected vasodilator agents and vacuum erection devices. Surgical therapies are reserved for the subset of patients who have contraindications to these nonsurgical interventions, those who experience adverse effects from (or are refractory to) medical therapy and those who also have penile fibrosis or penile vascular insufficiency. Erectile dysfunction can have deleterious effects on a man's quality of life; most patients have symptoms of depression and anxiety related to sexual performance. These symptoms, in turn, affect his partner's sexual experience and the couple's quality of life. This Primer highlights numerous aspects of erectile dysfunction, summarizes new treatment targets and ongoing preclinical studies that evaluate new pharmacotherapies, and covers the topic of regenerative medicine, which represents the future of sexual medicine. PMID: 27188339 [PubMed - indexed for MEDLINE]
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Related Articles The Effects of Adipose-Derived Stem Cells in a Rat Model of Tobacco-Associated Erectile Dysfunction. PLoS One. 2016;11(6):e0156725 Authors: Huang YC, Kuo YH, Huang YH, Chen CS, Ho DR, Shi CS Abstract Tobacco use is associated with erectile dysfunction (ED) via a number of mechanisms including vascular injury and oxidative stress in corporal tissue. Adipose derived stem cells (ADSC) have been shown to ameliorate vascular/corporal injury and oxidative stress by releasing cytokines, growth factors and antioxidants. We assessed the therapeutic effects of intracavernous injection of ADSC in a rat model of tobacco-associated ED. Thirty male rats were used in this study. Ten rats exposed to room air only served as negative controls. The remaining 20 rats were passively exposed to cigarette smoke (CS) for 12 weeks. At the 12-week time point, ADSC were isolated from paragonadal fat in all rats. Amongst the 20 CS exposed rats, 10 each were assigned to one of the two following conditions: (i) injection of phosphate buffered saline (PBS) into the corpora cavernosa (CS+PBS); or (ii) injection of autologous ADSC in PBS into the corpora cavernosa (CS+ADSC). Negative control animals received PBS injection into the corpora cavernosa (normal rats [NR] + PBS). After injections all rats were returned to their previous air versus CS exposure state. Twenty-eight days after injection, all rats were placed in a metabolic cage for 24-hour urine collection to be testing for markers of oxidative stress. After 24-hour urine collection all 30 rats also underwent erectile function testing via intracavernous pressure (ICP) testing and were then sacrificed. Corporal tissues were obtained for histological assessment and Western blotting. Mean body weight was significantly lower in CS-exposed rats than in control animals. Mean ICP, ICP /mean arterial pressure ratio, serum nitric oxide level were significantly lower in the CS+PBS group compared to the NR+PBS and CS+ADSC groups. Urine markers for oxidative stress were significantly higher in the CS+PBS group compared to the NR+PBS and CS+ADSC groups. Mean expression of corporal nNOS and histological markers for endothelial and smooth muscle cells was significantly lower, and tissue apoptotic index significantly higher, in the CS+PBS group compared to the NR+PBS and CS+ADSC groups. Our findings confirm that chronic tobacco exposure causes ultrastructural damage to the corporal tissue and increases systemic oxidative stress states. Treatment with ADSC ameliorates these adverse effects and holds promise as a potential therapy for tobacco-related ED. PMID: 27257818 [PubMed - indexed for MEDLINE]
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Related Articles Bone marrow-derived mesenchymal stromal cell therapy in a rat model of cavernous nerve injury: Preclinical study for approval. Cytotherapy. 2016 07;18(7):870-80 Authors: You D, Jang MJ, Kim BH, Choi KR, Lee C, Song G, Shin HC, Jeong IG, Suh N, Kim YM, Ahn TY, Kim CS Abstract BACKGROUND AIMS: Although clinical studies using stem cells to treat erectile dysfunction have been performed or are ongoing, there is little consensus on the optimal protocol. We aimed to develop a protocol optimizing human bone marrow-derived mesenchymal stromal cell (hBMSC) therapy in a rat model of cavernous nerve injury. METHODS: We performed, in order, a dose-finding study, a toxicokinetic study of hBMSCs, and a study to determine the timing and number of cell injections. RESULTS: From the dose-finding study, 1 × 10(6) cells were selected as the dose per hBMSC injection. From the toxicokinetic study, 14 days was selected as the interval between repeat treatments. In the final study, the ratio of maximal intracavernous pressure to mean arterial pressure was significantly lower in the control group than in the sham group (23.4% vs. 55.1%, P <0.001). An immediate single injection of hBMSCs significantly improved erectile function compared with the control group (39.8%, P = 0.035), whereas a delayed single injection showed improvement with a marginal trend (38.1%, P = 0.079). All histomorphometric changes were significantly more improved in the immediate or delayed single injection groups than in the control group. Repeat treatments did not provide any benefit for the recovery of erectile function and histomorphometric changes. CONCLUSIONS: Intracavernous injection of 1 × 10(6) hBMSCs results in a recovery of penile erection and histomorphometric changes in a rat model of cavernous nerve injury, even when treatment was delayed until 4 weeks after cavernous nerve injury. PMID: 27260208 [PubMed - indexed for MEDLINE]
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Related Articles Therapeutic effects of adipose-derived stem cells-based microtissues on erectile dysfunction in streptozotocin-induced diabetic rats. Asian J Androl. 2017 Jan-Feb;19(1):91-97 Authors: Zhou F, Hui Y, Xin H, Xu YD, Lei HE, Yang BC, Guan RL, Li M, Hou JQ, Xin ZC Abstract This study aimed to explore the therapeutic effects of adipose-derived stem cells (ADSCs)-based microtissues (MTs) on erectile dysfunction (ED) in streptozotocin (STZ)-induced diabetic rats. Fifty-six 8-week-old Sprague-Dawley rats received intraperitoneal injection of STZ (60 mg kg-1 ), and 8 weeks later, the determined diabetic rats randomly received intracavernous (IC) injection of phosphate buffer solution (PBS), ADSCs, or MTs. Another eight normal rats equally got IC injection of PBS. MTs were generated with a hanging drop method, and the injected cells were tracked in ADSC- and MT-injected rats. Four weeks after the treatments, intracavernous pressure (ICP), histopathological changes in corpus cavernosum (CC), and functional proteins were measured. Rat cytokine antibody array was used to detect ADSCs or MTs lysate. The results showed that MTs expressed vascular endothelial growth factor (VEGF), nerve growth factor (NGF), and tumor necrosis factor-stimulated gene-6 (TSG-6). MTs injection had a higher retention than ADSCs injection and MTs treatment improved ICP, neuronal nitric oxide synthase (nNOS) expression, smooth muscle, and endothelial contents in diabetic rats, ameliorated local inflammation in CC better. Thus, our findings demonstrate that IC injection of MTs improves erectile function and histopathological changes in STZ-induced diabetic rats and appears to be more promising than traditional ADSCs. The underlying mechanisms involve increased cell retention accompanied with neuroprotection and anti-inflammatory behaviors of the paracrine factors. PMID: 27345005 [PubMed - indexed for MEDLINE]
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Related Articles Periprostatic implantation of neural differentiated mesenchymal stem cells restores cavernous nerve injury-mediated erectile dysfunction. Am J Transl Res. 2016;8(6):2549-61 Authors: Fang JF, Jia CC, Zheng ZH, Ye XL, Wei B, Huang LJ, Wei HB Abstract Mesenchymal stem cells (MSCs) have been utilized to restore erectile function in animal models of cavernous nerve injury (CNI). However, transplantation of primary MSCs may lead to unpredictable therapeutic outcomes. In this study, we investigated the efficiency of neural differentiated MSCs (d-MSCs) on the restoration of erectile function in CNI rats. Rat bone marrow MSCs (r-BM-MSCs) were treated with all-trans retinoic acid to induce neural differentiation. Rats were divided into five groups: a sham operation group; a bilateral CNI group that received an intracavernous injection of r-BM-MSCs (IC group); and three groups that received periprostatic implantation of either r-BM-MSCs (IP group), d-MSCs (IP-d group), or PBS (PBS group). The data revealed that IP injection of d-MSCs ameliorated erectile function in a similar manner to an IC injection of MSCs and enhanced erectile function compared to an IP injection of MSCs. An in vivo time course of d-MSCs survival revealed that PKH26-labled d-MSCs were detectable either within or surrounding the cavernous nerve tissue. In addition, the expression of caspase-3 significantly increased in the PBS group and decreased after treatment with MSCs, especially in the IC and IP-d groups. Furthermore, the expression levels of neurotrophic factors increased significantly in d-MSCs. This study demonstrated that periprostatic implantation of d-MSCs effectively restored erectile function in CNI rats. The mechanism might be ascribed to decreases in the frequency of apoptotic cells, as well as paracrine signaling by factors derived from d-MSCs. PMID: 27398139 [PubMed]
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Related Articles Combination of low-energy shock-wave therapy and bone marrow mesenchymal stem cell transplantation to improve the erectile function of diabetic rats. Asian J Androl. 2017 Jan-Feb;19(1):26-33 Authors: Shan HT, Zhang HB, Chen WT, Chen FZ, Wang T, Luo JT, Yue M, Lin JH, Wei AY Abstract Stem cell transplantation and low-energy shock-wave therapy (LESWT) have emerged as potential and effective treatment protocols for diabetic erectile dysfunction. During the tracking of transplanted stem cells in diabetic erectile dysfunction models, the number of visible stem cells was rather low and decreased quickly. LESWT could recruit endogenous stem cells to the cavernous body and improve the microenvironment in diabetic cavernous tissue. Thus, we deduced that LESWT might benefit transplanted stem cell survival and improve the effects of stem cell transplantation. In this research, 42 streptozotocin-induced diabetic rats were randomized into four groups: the diabetic group (n = 6), the LESWT group (n = 6), the bone marrow-derived mesenchymal stem cell (BMSC) transplantation group (n = 15), and the combination of LESWT and BMSC transplantation group (n = 15). One and three days after BMSC transplantation, three rats were randomly chosen to observe the survival numbers of BMSCs in the cavernous body. Four weeks after BMSC transplantation, the following parameters were assessed: the surviving number of transplanted BMSCs in the cavernous tissue, erectile function, real-time polymerase chain reaction, and penile immunohistochemical assessment. Our research found that LESWT favored the survival of transplanted BMSCs in the cavernous body, which might be related to increased stromal cell-derived factor-1 expression and the enhancement of angiogenesis in the diabetic cavernous tissue. The combination of LESWT and BMSC transplantation could improve the erectile function of diabetic erectile function rats more effectively than LESWT or BMSC transplantation performed alone. PMID: 27427555 [PubMed - indexed for MEDLINE]
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Related Articles Innovative trends and perspectives for erectile dysfunction treatment: A systematic review. Arab J Urol. 2016 Jun;14(2):84-93 Authors: Ismail EA, El-Sakka AI Abstract OBJECTIVE: To review contemporary knowledge concerning the innovative trends and perspectives in the treatment of erectile dysfunction (ED). METHODS: Medline was reviewed for English-language journal articles between January 2000 and March 2016, using the terms 'erectile dysfunction treatments', 'new trends' and 'perspectives'. In all, 114 original articles and 16 review articles were found to be relevant. Of the 76 cited papers that met the inclusion criteria, 51 papers had level of evidence of 1a-2b, whilst 25 had level of evidence of 3-4. Criteria included all pertinent review articles, randomised controlled trials with tight methodological design, cohort studies, and retrospective analyses. We also manually reviewed references from selected articles. RESULTS: Several interesting studies have addressed novel phosphodiesterase type 5 inhibitors (PDE5Is), orodispersible tablets, their recent chronic use, and combination with other agents. A few controlled studies have addressed herbal medicine as a sole or additional treatment for ED. Experimental studies and exciting review papers have addressed stem cells as novel players in the field of ED treatment. Other recent articles have revised the current status of low-intensity extracorporeal shockwave therapy in the field of ED. A few articles without long-term data have addressed new technologies that included: external penile support devices, penile vibrators, tissue engineering, nanotechnology, and endovascular tools for ED treatment. CONCLUSIONS: The current treatment of ED is still far from ideal. We expect to see new drugs and technologies that may revolutionise ED treatment, especially in complex cases. PMID: 27493808 [PubMed]
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Related Articles Advances in the treatment of erectile dysfunction: what's new and upcoming? F1000Res. 2016;5: Authors: Patel CK, Bennett N Abstract Erectile dysfunction adversely affects up to 20% of all men and is the most commonly treated sexual disorder. The public health implications of this condition are significant and represent a challenge for our healthcare system. The physiological pathways responsible for erections have been extensively studied, and much advancement has been made since the introduction of phosphodiesterase 5 inhibitors. Newer agents, such as dopaminergic and melanocortin receptor agonists, which target central erectogenic pathways, are under investigation. Newer formulations and delivery methods of existing medications such as alprostadil will also be introduced in the near future. Furthermore, low-intensity shockwave lithotripsy and stem cell regenerative techniques are innovative approaches to the treatment of erectile dysfunction. PMID: 27516878 [PubMed]
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Related Articles Beneficial effect of PEDF-transfected ADSCs on erectile dysfunction in a streptozotocin-diabetic rat model. Cell Tissue Res. 2016 Dec;366(3):623-637 Authors: Lu J, Xin Z, Zhang Q, Cui D, Xiao Y, Zhuo J, Sun F, Xia S, Shao Y Abstract Diabetes mellitus (DM) is an important risk factor for erectile dysfunction. Adipose-derived stem cells (ADSCs) are essential for maintaining erectile function but their function is impaired during hyperglycemia. To evaluate the effects of pigment epithelium-derived factor (PEDF)-transfected ADSCs on the restoration of erectile function ADSCs and PEDF-transfected ADSCs were exposed to normal or high glucose levels for 72 h and the effects on cell survival and protein expression were determined. For in vivo studies, rats with streptozocin-induced DM were intravenously injected with ADSCs or PEDF-transfected ADSCs. Two weeks later, the intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured to assess erectile function, and penile tissues were harvested for further evaluation. PEDF overexpression in ADSCs protected cells against hyperglycemia-induced apoptosis (as determined by a TUNEL assay), increasing the expression of neurotrophic factors and decreasing the expression of inflammatory cytokines and oxidative stress-related proteins (as determined by western blotting and ELISA). In DM rats, transplantation with PEDF-transfected ADSCs effectively restored erectile function, as determined by the ICP/MAP ratio, compared with untreated ADSCs. PEDF overexpression also resulted in higher survival rates and decreased apoptosis of ADSCs. Promotion of neurotrophic factor expression and suppression of inflammatory cytokines and oxidative stress-related proteins were also observed after transplantation of PEDF-transfected ADSCs. Thus, our results demonstrate that transplantation of ADSCs restored erectile function in a rat model of DM, attenuating the negative effects of hyperglycemia. These findings indicate the therapeutic potential of ADSCs for treating erectile dysfunction and the additional benefits of PEDF overexpression. PMID: 27655233 [PubMed - indexed for MEDLINE]
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Related Articles [Microstructural changes of the corpus cavernosum in hypoxia-induced erectile dysfunction]. Zhonghua Nan Ke Xue. 2016 Oct;22(10):932-937 Authors: Deng JK, Tan Y Abstract Hypoxia is an independent risk factor of erectile dysfunction (ED), and the mechanisms of hypoxia causing ED are varied and complicated. Traditional studies related are concentrated on the changes of the corpus cavernosal endothelium and hormone levels in the body but have failed to achieve notable breakthroughs. Recent researches have demonstrated that such alterations in the corpus cavernosal microstructure as decreased corpus cavernosum smooth muscle cells of the contractile phenotype and fibrillation of the corpus cavernosum may be two important factors of hypoxia-induced ED. This review gives a brief introduction of the management of hypoxia-induced ED with the strategies of intervening in the corpus cavernosal microstructural changes, such as gene therapy, stem cell therapy, and induction of cell autophagy. PMID: 29278477 [PubMed - indexed for MEDLINE]
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Related Articles Re: The Effects of Adipose-Derived Stem Cells in a Rat Model of Tobacco-Associated Erectile Dysfunction. J Urol. 2016 11;196(5):1587-1588 Authors: Seftel AD PMID: 27751499 [PubMed - indexed for MEDLINE]
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Related Articles Treatment of diabetes mellitus-induced erectile dysfunction using endothelial progenitor cells genetically modified with human telomerase reverse transcriptase. Oncotarget. 2016 Jun 28;7(26):39302-39315 Authors: Zhang Y, Chen Z, Wang T, Yang J, Li R, Wang S, Liu J, Ye Z Abstract The efficacy of treatments for diabetes mellitus-induced erectile dysfunction (DMED) is quite poor, and stem cell therapy is emerging as a useful method. In this study, we used endothelial progenitor cells (EPCs) overexpressing human telomerase reverse transcriptase (hTERT) for the treatment of DMED. Rat EPCs were transfected with hTERT (EPCs-hTERT). EPCs-hTERT secreted more growth factors and demonstrated enhanced proliferation and resistance to oxidative stress. Twenty-four male DMED rats were subjected to four treatments: DMED (DMED group), EPCs (EPCs group), EPCs transduced with control lentivirus (EPC-control group) and EPCs-hTERT (EPCs-hTERT group). A group of healthy rats were used as the normal control group. The erectile function in the EPCs-hTERT group was markedly increased compared with the EPCs and EPCs-control groups. The EPCs-hTERT group exhibited more growth factors, smooth muscle content and retained stem cells in penile tissues. The degree of apoptosis and collagen/smooth muscle ratio in penile tissues of the EPCs-hTERT group was considerably reduced. Endothelial nitric oxide synthase (eNOS) expression increased significantly in the EPCs-hTERT group. Taken together, these data showed that the enhanced paracrine effect, resistance to oxidative stress and proliferation of EPCs-hTERT may contribute to the improvements of erectile function in DMED rats. PMID: 27283992 [PubMed - indexed for MEDLINE]
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Related Articles Stem cells and vascular regenerative medicine: A mini review. Clin Hemorheol Microcirc. 2016;64(4):613-633 Authors: Stoltz JF, Bensoussan D, De Isla N, Zhang L, Han Z, Magdalou J, Huselstein C, Ye JS, Leballe B, Decot V, Reppel L Abstract Most human tissues do not regenerate spontaneously, which is why "cell therapy" are promising alternative treatments. The Principe is simple: patients' or donors' cells are collected and introduced into the injured tissues or organs directly or in a porous 3D material, with or without modification of their properties. This concept of regenerative medicine is an emerging field which can be defined as "the way to improve health and quality of life by restoring, maintaining, or enhancing tissue and organ functions".There is an extraordinarily wide range of opportunities for clinical applications: artheropathies, diabetes, cartilage defects, bone repair, burns, livers or bladder regeneration, organs reconstruction (lung, heart, liver ...) neurodegenerative disorders, sepsis ...  Different stem cells (SC) with different potential can be used and characterised (totipotent, mesenchymal of different origins, especially those present in tissues...). Today it is undeniable that cells like bone marrow, adipose tissue or Wharton Jelly stem cells, are of potential interest for clinical applications because they are easily separated and prepared and no ethical problems are involved in their use.In this paper some potential clinical applications in the vascular field are considered: peripheral arteriopathy in diabetic patients, cardiac insufficiency, traitment of erectile dysfunction, or organ regeneration with liver as example. But the regeneration of tissue or organ is and will remain a challenge for the future development of cell therapy. Many problems remain to be solved that could lead to the development of innovative strategies to facilitate cell differentiation, increase the yield of cells and ensure a standardised product, overcome the risks of teratogenic effects and/or immune reactions, enable grafting via direct cell or biotissue transplantation and avoid legal issues involved in national regulations. PMID: 27791997 [PubMed - indexed for MEDLINE]
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Related Articles Current Perspectives on Stem Cell Therapy for Erectile Dysfunction. Sex Med Rev. 2016 07;4(3):247-256 Authors: Peak TC, Anaissie J, Hellstrom WJ Abstract INTRODUCTION: Erectile dysfunction (ED) is a common sexual disorder that affects the lives of millions of male patients and their partners. Various medical and surgical therapies exist, with the most common being oral intake of phosphodiesterase 5 inhibitors. One therapeutic strategy in preclinical development to treat ED is stem cell transplantation. AIM: To examine the studies that have investigated stem cells for the treatment of ED. METHODS: A literature review was performed through PubMed focusing on stem cells and ED. MAIN OUTCOME MEASURES: An assessment of different types of stem cells and how they may be applied therapeutically in the treatment of ED. RESULTS: The stem cell types that have been investigated for the treatment of ED include bone marrow-derived mesenchymal, adipose-derived, muscle-derived, testes, urine-derived, neural crest, and endothelial progenitor. Depending on the cell type, research has demonstrated that with transplantation, stem cells exert a paracrine effect on penile tissue, and can differentiate into smooth muscle, endothelium, and neurons. CONCLUSION: Multiple stem cell lines are currently being studied for their potential to treat ED. To date, stem cells have proven safe and effective in both animal and human models of ED. More research is needed to understand their full therapeutic potential. PMID: 27871958 [PubMed - indexed for MEDLINE]
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Related Articles Antiplasmodial activity of Heinsia crinita (Rubiaceae) and identification of new iridoids. J Ethnopharmacol. 2017 Jan 20;196:261-266 Authors: Tshisekedi Tshibangu P, Mutwale Kapepula P, Kabongo Kapinga MJ, Tujibikila Mukuta A, Kalenda DT, Tchinda AT, Mouithys-Mickalad AA, Jansen O, Cieckiewicz E, Tits M, Angenot L, Frédérich M Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Heinsia crinita is used in traditional medicine for the treatment of febrile illness and erectile dysfunction. Its stem bark powder is found in some peripheral markets in the Democratic Republic of the Congo (DRC) as a remedy against malaria. Investigations were conducted on crude extracts of leaves, fruits and stem barks in view to validate their use and to determine which plant part possesses the best antiplasmodial properties. MATERIALS AND METHODS: Different plant parts were extracted with methanol, ethanol and dichloromethane. Based on the preliminary assays, the dichloromethane extract of the stem bark was subjected to fractionation using preparative HPLC system and column chromatography. This step led to the isolation of two new iridoids which had their structures elucidated by NMR, UV, MS and FT-IR spectroscopic techniques. Extracts and pure compounds were tested in vitro against the 3D7 strain of Plasmodium falciparum. The inhibition of the parasite growth was evaluated in vitro by colorimetric method (p-LDH assay) and their cytotoxicity evaluated in vitro against the human non-cancer fibroblast cell line (WI38) through WST1 assay. The in vivo antiplasmodial activity was assessed by the inhibition of Plasmodium berghei growth in infected mice treated with the ethanol extract of H. crinita stem bark at the concentrations of 200 and 300mg/Kg/day per os, using a protocol based on the 4-d suppressive test of Peters and compared to a non-treated negative control group of mice (growth =100%). Finally the antioxidant activity of the same extract was evaluated using ABTS, DPPH and cell-based assays. RESULTS: A moderate in vitro antiplasmodial activity was observed for the dichloromethane extract of the stem bark of H. crinita (IC50 =29.2±1.39µg/mL) and for the two new iridoids, lamalbide 6, 7, 8- triacetate (IC50 =16.39±0.43µg/mL) as well as for its aglycone lamiridosin 6, 7, 8-triacetate (IC50 =0.44.56±1.12µg/mL). The ethanolic stem bark extract (200 and 300mg/kg/day, oral route) showed a moderate in vivo antimalarial activity in Plasmodium berghei-infected mice with 27.84±2.75% and 48.54±3.76% of inhibition of the parasite growth, respectively (p<0.01).). This extract displayed high cellular antioxidant activity using dichlorofluorescein-diacetate (DCFDA) on HL-60 monocytes. These crude extracts and pure compounds tested at the higher concentration of 100µg/mL did not show any cytotoxicity against WI38 cells. CONCLUSIONS: The results showed that H. crinita extracts possess antimalarial activity and contain some unusual iridoids with moderate antiplasmodial activity, therefore justifying to some extent its traditional use by the local population in DRC for this purpose. This is the first report of the isolation and antiplasmodial activity of these two new iridoids. PMID: 27890637 [PubMed - indexed for MEDLINE]
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Related Articles B Cell Lymphoma-2-Modified Bone Marrow-Derived Mesenchymal Stem Cells Transplantation for the Treatment of Diabetes Mellitus-Induced Erectile Dysfunction in a Rat Model. Urol Int. 2017;98(3):358-366 Authors: Sun X, Luo LH, Feng L, Li DS, Zhong KZ Abstract OBJECTIVE: The study aimed to explore the effects of B cell lymphoma-2 (Bcl-2)-modified bone marrow-derived mesenchymal stem cells (BMSCs) transplantation for the treatment of diabetes mellitus-induced erectile dysfunction (DMED) in a rat model. METHODS: The DMED rat model was successfully established. Thirty-six DMED rats were assigned into the Bcl-2-BMSCs, null-BMSCs, BMSCs and phosphate buffered saline (PBS) groups. Meanwhile, 9 normal rats injected with PBS were taken as the normal control group. RESULTS: In the Bcl-2-BMSCs group, the average times of erection, rate of erection, peak intra-cavernous pressure (ICP) and peak ICP/mean arterial pressure were higher than those in the null-BMSCs, BMSCs and PBS groups, but were lower than those in the normal control group. In the Bcl-2-BMSCs group, capillary vessels and Bcl-2 mRNA and protein expressions were similar to those in the normal control group, while they were higher than those in other groups. CONCLUSION: These findings indicate that Bcl-2-modified BMSC transplantation could improve erectile function in DMED rats. PMID: 27894122 [PubMed - indexed for MEDLINE]
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Related Articles Purified Human Skeletal Muscle-Derived Stem Cells Enhance the Repair and Regeneration in the Damaged Urethra. Transplantation. 2017 10;101(10):2312-2320 Authors: Nakajima N, Tamaki T, Hirata M, Soeda S, Nitta M, Hoshi A, Terachi T Abstract BACKGROUND: Postoperative damage of the urethral rhabdosphincter and nerve-vascular networks is a major complication of radical prostatectomy and generally causes incontinence and/or erectile dysfunction. The human skeletal muscle-derived stem cells, which have a synchronized reconstitution capacity of muscle-nerve-blood vessel units, were applied to this damage. METHODS: Cells were enzymatically extracted from the human skeletal muscle, sorted using flow cytometry as CD34/45 (Sk-34) and CD29/34/45 (Sk-DN/29) fractions, and separately cultured/expanded in appropriate conditions within 2 weeks. Urethral damage was induced by manually removing one third of the wall of the muscle layer in nude rats. A mixture of expanded Sk-34 and Sk-DN/29 cells was applied on the damaged portion for the cell transplantation (CT) group. The same amount of media was used for the non-CT (NT) group. Urethral pressure profile was evaluated via electrical stimulation to assess functional recovery. Cell engraftments and differentiations were detected using immunohistochemistry and immunoelectron microscopy. Expression of angiogenic cytokines was also analyzed using reverse transcriptase-polymerase chain reaction and protein array. RESULTS: At 6 weeks after transplantation, the CT group showed a significantly higher functional recovery than the NT group (70.2% and 39.1%, respectively; P < 0.05). Histological analysis revealed that the transplanted human cells differentiated into skeletal muscle fibers, nerve-related Schwann cells, perineuriums, and vascular pericytes. Active paracrine angiogenic cytokines in the mixed cells were also detected with enhanced vascular formation in vivo. CONCLUSIONS: The transplantation of Sk-34 and Sk-DN/29 cells is potentially useful for the reconstitution of postoperative damage of the urethral rhabdosphincter and nerve-vascular networks. PMID: 28027190 [PubMed - indexed for MEDLINE]
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Related Articles Stem Cells in Male Sexual Dysfunction: Are We Getting Somewhere? Sex Med Rev. 2017 04;5(2):222-235 Authors: Soebadi MA, Milenkovic U, Weyne E, Castiglione F, Albersen M Abstract INTRODUCTION: Stem cells for sexual disorders are steadily being introduced into clinical trials. Two conditions of importance are the main target for this line of treatment, especially when regarding the wide array of translational and basic science highlighting the potential advantages of regenerative therapy: erectile dysfunction (ED) and more recently Peyronie disease (PD). Cellular therapy offers a treatment modality that might reverse disease progression. It would be used in a curative setting, in contrast to other pharmaceutical agents that are currently available. AIM: To review basic preclinical studies and recent clinical trials of stem cells on ED and PD. METHODS: A search of the medical literature for the following terms was performed using PubMed: stem cells, cellular therapy, erectile dysfunction, Peyronie's disease, and clinical trial. MAIN OUTCOME MEASURES: A non-systematic narrative review and critical reflection on preclinical and clinical studies administering stem cells for ED and PD in animal models and human subjects. RESULTS: Numerous studies have confirmed the beneficial functional effects of stem cell injection in established animal models on ED and PD. Various stem cell types have been adopted, from embryonic to adult mesenchymal cell types. Each cell type offers distinctive advantages and disadvantages. Diverse administrations of stem cells were investigated, with insignificant variability in the ultimate results. Stem cells appear to have a pronounced paracrine effect, rather than the classic engraftment and differentiation hypothesis. Phase 1 clinical trials using stem cells have not reported any severe adverse events in animals. However, these results cannot be extrapolated to draw any conclusions about efficacy in human patients. CONCLUSION: Stem cells have an established efficacy in preclinical studies and early clinical trials. Studies are currently being published demonstrating the safety of intrapenile injection of autologous bone marrow- and adipose tissue-derived stem cells. Soebadi MA, Milenkovic U, Weyne E, et al. Stem Cells in Male Sexual Dysfunction: Are We Getting Somewhere? Sex Med Rev 2017;5:222-235. PMID: 28041853 [PubMed - indexed for MEDLINE]
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Related Articles The Current Status of Stem-Cell Therapy in Erectile Dysfunction: A Review. World J Mens Health. 2016 Dec;34(3):155-164 Authors: Reed-Maldonado AB, Lue TF Abstract Stem cells are undifferentiated cells that are capable of renewal and repair of tissue due to their capacity for division and differentiation. The purpose of this review is to describe recent advances in the use of stem cell (SC) therapy for male erectile dysfunction (ED). We performed a MEDLINE database search of all relevant articles regarding the use of SCs for ED. We present a concise summary of the scientific principles behind the usage of SC for ED. We discuss the different types of SCs, delivery methods, current pre-clinical literature, and published clinical trials. Four clinical trials employing SC for ED have been published. These articles are summarized in this review. All four report improvements in ED after SC therapy. SC therapy remains under investigation for the treatment of ED. It is reassuring that clinical trials thus far have reported positive effects on erectile function and few adverse events. Safety and methodical concerns about SC acquisition, preparation and delivery remain and require continued investigation prior to wide-spread application of these methods. PMID: 28053944 [PubMed]
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Related Articles Intracavernous Injection of Human Umbilical Cord Blood Mononuclear Cells Improves Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats. J Sex Med. 2017 01;14(1):50-58 Authors: Cengiz T, Kaya E, Oral DY, Ozakca I, Bayatli N, Karabay AZ, Ensari TA, Karahan T, Yilmaz E, Gur S Abstract INTRODUCTION: Erectile dysfunction (ED) worsens in men with diabetes. Human umbilical cord blood (HUCB), because of its widespread availability and low immunogenicity, is a valuable source for stem cell-based therapies. AIM: To determine the effect of intracavernous injection of HUCB mononuclear cells (MNCs) on ED in rats with diabetes induced by streptozotocin. METHODS: Thirty adult male Sprague-Dawley rats were equally divided into three groups: (i) control, (ii) diabetes induced by streptozotocin (35 mg/kg intravenously for 8 weeks), and (iii) diabetic rats treated with MNCs (1 × 106 cells by intracavernosal injection). The HUCB-MNCs isolated by the Ficoll-Hypaque technique were obtained from eight healthy donors and administered to diabetic rats after 4 weeks. MAIN OUTCOME MEASURES: The ratio of intracavernosal pressure to mean arterial pressure ratio; the protein expression of endothelial and neuronal markers, such as von Willebrand factor, neuronal nitric oxide synthase, hypoxia-inducible factor-1α, and vascular endothelium growth factor; and the relative area of smooth muscle to collagen using western blotting and Masson trichrome staining were determined. RESULTS: Diabetic rats demonstrated a significantly decreased ratio of intracavernosal pressure to mean arterial pressure (0.26 ± 0.04; P < .01) and treatment with MNCs restored erectile function in diabetic rats (0.67 ± 0.05) compared with control rats (0.56 ± 0.02). In bath studies, neurogenic relaxant and contractile responses were significantly decreased in diabetic cavernosal tissues, which were restored by treatment. The ratio of smooth muscle to collagen was partly recovered by treatment, whereas von Willebrand factor levels were not altered in any group. Neuronal nitric oxide synthase and vascular endothelium growth factor levels were decreased, which were not restored by treatment. Increased hypoxia-inducible factor-1α protein expression in the diabetic group was completely normalized in MNC-treated diabetic samples. CONCLUSION: These results suggest that HUCB-MNC treatment can enhance the recovery of erectile function and promote numerous activities such the contribution of the hypoxia-inducible factor-1α and von Willebrand factor pathway to the neurogenic erectile response of diabetic rats. HUCB-MNCs in the healing process could involve an adaptive regenerative response and appear to be a potential candidate for cell-based therapy in ED of men with diabetes. It is evident that HUCB could provide a realistic therapeutic modality for the treatment of diabetic ED. PMID: 28065360 [PubMed - indexed for MEDLINE]
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Related Articles Erectile dysfunction treatment and traditional medicine-can East and West medicine coexist? Transl Androl Urol. 2017 Feb;6(1):91-100 Authors: Lee JK, Tan RB, Chung E Abstract Erectile dysfunction (ED) is a common sexual problem affecting many men irrespective of cultures, beliefs and nationalities. While medical therapy for ED has been revolutionized by the advent of oral phosphodiesterase type 5 inhibitors and intracavernosal injection of vasoactive agents, recent technological advances such stem cell therapy, low intensity shock wave and newer generation of penile prosthesis implant offer hope to men who do not respond to conventional medical therapy. In contrast, traditional and complementary medicine (TCM) focuses on the restoration and better overall bodily regulation with the use of various herbal and animal products as well as exercises to invigorate qi (energy) in vital organs. Western medicine involves an analysis of ED symptom and underlying causes that contribute to ED, while TCM emphases the concept of holism and harmonization of body organs to achieve natural sexual life. The following article reviews our current understanding regarding the philosophical approach, and evaluates the evidence surrounding various ED therapies between mainstream Western Medicine and TCM. PMID: 28217454 [PubMed]
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Related Articles [Using cell technologies to treat urologic diseases]. Urologiia. 2016 Aug;(3):85-91 Authors: Glybochko PV, Olefir YV, Alyaev YG, Butnaru DV, Bezrukov EA, Chaplenko AA, Zharikova TM Abstract Stem and progenitor cells being introduced into the body have the ability to stimulate regeneration of tissues and organs by differentiating into specialized cells. Stem cell therapy is used in urology to treat various disorders, including erectile dysfunction, urinary incontinence, Peyronies disease, and male infertility. This review presents the results of international preclinical and clinical research on stem cell based medications for treating the above diseases. The most promising appears to be the use of adipose tissue-derived mesenchymal stem cells. PMID: 28247636 [PubMed - indexed for MEDLINE]
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Related Articles In Situ Activation of Penile Progenitor Cells With Low-Intensity Extracorporeal Shockwave Therapy. J Sex Med. 2017 04;14(4):493-501 Authors: Lin G, Reed-Maldonado AB, Wang B, Lee YC, Zhou J, Lu Z, Wang G, Banie L, Lue TF Abstract BACKGROUND: We previously reported that progenitor cells, or stem cells, exist within penile tissue. We hypothesized that acoustic wave stimulation by low-intensity extracorporeal shockwave therapy (Li-ESWT) would activate local stem or progenitor cells within the penis, producing regenerative effects. AIMS: To study the feasibility of in situ penile progenitor cell activation by Li-ESWT. METHODS: We performed a cohort analysis of young and middle-age male Sprague-Dawley rats treated with 5-ethynyl-2'-deoxyuridine (EdU) pulse followed by Li-ESWT. In addition, Li-ESWT was applied to cultured Schwann cells and endothelial cells to study the molecular mechanism involved in cell proliferation. Thirty minutes before Li-ESWT, each rat received an intraperitoneal injection of EdU. Li-ESWT was applied to the penis at very low (0.02 mJ/mm2 at 3 Hz for 300 pulses) or low (0.057 mJ/mm2 at 3 Hz for 500 pulses) energy levels. The endothelial and Schwann cells were treated with very low energy (0.02 mJ/mm2 at 3 Hz for 300 pulses) in vitro. OUTCOMES: At 48 hours or 1 week after Li-ESWT, penile tissues were harvested for histologic study to assess EdU+ and Ki-67+ cells, and cell proliferation, Ki-67 expression, Erk1/2 phosphorylation, translocation, and angiogenesis were examined in cultured Schwann and endothelial cells after Li-ESWT. RESULTS: Li-ESWT significantly increased EdU+ cells within penile erectile tissues (P < .01) at 48 hours and 1 week. There were more cells activated in young animals than in middle-age animals, and the effect depended on dosage. Most activated cells were localized within subtunical spaces. In vitro studies indicated that Li-ESWT stimulated cell proliferation through increased phosphorylation of Erk1/2. CLINICAL TRANSLATION: The present results provide a possible explanation for the clinical benefits seen with Li-ESWT. STRENGTHS AND LIMITATIONS: The main limitation of the present project was the short period of study and the animal model used. Li-ESWT could be less effective in improving erectile function in old animals because of the decreased number and quality of penile stem or progenitor cells associated with aging. CONCLUSION: Li-ESWT activation of local penile progenitor cells might be one of the mechanisms that contribute to the beneficial effects of shockwave treatment for erectile dysfunction, which represents a non-invasive alternative to exogenous stem cell therapy. Lin G, Reed-Maldonado AB, Wang B, et al. In Situ Activation of Penile Progenitor Cells With Low-Intensity Extracorporeal Shockwave Therapy. J Sex Med 2017;14:493-501. PMID: 28258952 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell therapies in post-prostatectomy erectile dysfunction: a critical review. Can J Urol. 2017 Feb;24(1):8609-8619 Authors: Mangır N, Türkeri L Abstract INTRODUCTION: Erectile dysfunction (ED) is still a common complication of radical prostatectomy. Current treatments of ED are mainly symptomatic. Mesenchymal stem cells (MSCs) have been widely investigated as a potential curative treatment. Although MSC therapy consistently improved erectile functions in the pre-clinical studies the initial expectations seem to be unmet. The aim of this study is to critically review the existing studies on use of stem cells in post-prostatectomy ED and understand factors that preclude clinical translation of the available evidence. MATERIALS AND METHODS: A literature search for all pre-clinical and clinical studies investigating MSCs in the treatment of post-prostatectomy ED published between January 2009 and March 2016 was performed using the PubMed database. RESULTS: A total of 24 pre-clinical studies investigated MSC based treatments in cavernous nerve injury (CNI) rodent models. In the majority of these studies intracavernous injection of MSCs at the time injury improved erectile functions. There is less data on the efficacy of MSCs when applied in a chronic disease state. Allogeneic or xenogeneic MSCs were similarly effective with limited data on immunologic response. There is a lack of conclusive data on in vivo fate of MSCs and the best route of MSC administration. CONCLUSION: MSC therapy consistently improved erectile functions after CNI. There seems to be a consensus on the disease model used and outcome evaluation however further studies focusing on immunologic response to MSCs, their mechanism of action and in vivo fate are needed before their widespread use in clinic. PMID: 28263125 [PubMed - indexed for MEDLINE]
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Related Articles Effect of icariin in combination with daily sildenafil on penile atrophy and erectile dysfunction in a rat model of bilateral cavernous nerves injury. Andrology. 2017 05;5(3):598-605 Authors: Xu Y, Xin H, Wu Y, Guan R, Lei H, Fu X, Xin Z, Yang Y Abstract The commonly utilized phosphodiesterase type 5 inhibitors do not lead to satisfactory penile erection after radical prostatectomy mainly because of insufficient nitric oxide drive from the damaged cavernous nerves. The aim of this study was to assess the efficacy and mechanisms of icariin in combination with daily sildenafil on neurogenic erectile dysfunction and penile atrophy in a rat model of bilateral cavernous nerves injury. Sixty male Sprague-Dawley rats injected with 5-ethynyl-2-deoxyuridine (50 mg/kg) at postnatal day 1 for the purpose of tracking endogenous stem cells in penis. Forty-eight rats of bilateral cavernous nerves injury were randomized equally into gavage feeding of vehicle, sildenafil (10 mg/kg), icariin (1.5 mg/kg) and sildenafil + icariin, respectively. Twelve sham-operated rats served as control. The intracavernous pressure and mean arterial pressure was measured and mid-penile cross sections were histologically examined 5 weeks after surgery. Western blotting of cavernous tissue protein was also performed. Animals treated with sildenafil + icariin had significantly higher mean intracavernous pressure/mean arterial pressure ratio relative to other rats with bilateral cavernous nerves injury (p < 0.05). The circumference and mean cross-sectional area of the paired corpus cavernosum were effectively preserved in the sildenafil + icariin. Treatment with sildenafil + icariin significantly increased the cavernous cyclic guanosine monophosphate concentration compared with the icariin group (p < 0.05). In addition, the numbers of neuronal nitric oxide synthase-positive nerves and 5-ethynyl-2-deoxyuridine-positive cells co-expressing S100 in the icariin-treated groups were greater compared with the bilateral cavernous nerves injury control group (p < 0.05). These data suggest that the combined use of icariin and daily sildenafil holds promise as a potential therapy for neurogenic erectile dysfunction in the future. The underlying mechanisms appears to involve two aspects: (i) icariin promotes differentiation of endogenous stem cells to Schwann cells, which help to repair the damaged neural pathway for erection; (ii) on this basis, sildenafil can further improve penile engorgement through the cyclic guanosine monophosphate-dependent smooth muscle relaxation. PMID: 28296277 [PubMed - indexed for MEDLINE]
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Related Articles Combination of mesenchymal stem cell injection with icariin for the treatment of diabetes-associated erectile dysfunction. PLoS One. 2017;12(3):e0174145 Authors: Wang X, Liu C, Xu Y, Chen P, Shen Y, Xu Y, Zhao Y, Chen W, Zhang X, Ouyang Y, Wang Y, Xie C, Zhou M, Liu C Abstract The present study was aimed to examine whether icariin, a traditional Chinese medicine, could improve therapeutic effects of adipose derived mesenchymal stem cells (ADSCs) for diabetes-associated erectile dysfunction (DMED). DMED were induced in rats by intraperitoneal injection of streptozotocin and confirmed by erectile function measurement. Then, rats of diabetic ED were randomly divided to receive the treatment of saline, ADSCs, icariin or ADSCs combined with icariin respectively. Compared with the treatment by ADSCs or icariin alone, intracavernosum injection of ADSCs combined with the following daily gastric gavage of icariin significantly augmented the value of ICP and ICP/MAP (p<0.01). Meanwhile, the survival of transplanted ADSCs was much improved due to the application of icariin. Similarly, immunofluorescent staining analysis demonstrated that the improved erectile tissue structure by combination of ADSCs and icariin was significantly associated with the increased expression of endothelial markers (vWF) (p<0.01) and smooth muscle markers (α-SMA) (p<0.01). Furthermore, the structure changes in corpus cavernosum were further confirmed by the Masson's trichrome staining. To explore the possible mechanism underlying icariin-enhanced therapeutic efficacy of MSCs, we employed an in vitro testing system by introducing H2O2 to imitate oxidative stress condition considering the oxidative environment faced by engrafted ADSCs and anti-oxidative capacity of icariin. In vitro, we found that the addition of icariin considerably reduced the apoptosis of ADSCs, and attenuated the intracellular reactive oxygen species (ROS), the superoxidase dismutase (SOD) activity and the lactate dehydrogenase (LDH). Subsequently, we examined the expression of apoptosis-related proteins and explored the potential signaling pathway through which icariin promoted the survival of ADSCs against oxidative stress. It was demonstrated that icariin significantly inhibited the upregulation of apoptosis-related proteins under oxidative condition, including Bax and cleaved caspase-3, while promoted the expression of anti-apoptotic factor BCL2. These effects were accompanied with the activation of signal molecules, PI3K/Akt and STAT3. The further signal protein inhibition assays exhibited that the suppression of STAT3 abrogated the icariin-mediated anti-apoptotic effects observed above, while did not influence the expression of PI3K/Akt. However, PI3K inhibition could abrogate icariin-mediated STAT3 activation and achieved a similar effect as STAT3 inhibition. Our results suggested that icariin was an effective adjuvant for enhancing ADSC-based therapy of DMEM, which may be ascribed to their protection of ADSCs against oxidative stress via the regulation of PI3K/Akt-STAT3 signal pathway. PMID: 28350842 [PubMed - indexed for MEDLINE]
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Related Articles Stem-cell therapy for erectile dysfunction. Biomed Mater Eng. 2017;28(s1):S81-S85 Authors: Yiou R Abstract Stem cell-based therapies have been recently investigated in the field of organic erectile dysfunctions, such as those associated with diabetes or the treatment of prostate cancer. The overall aim is to repair the repair the underlying penile cellular damage. Here, we review the rationale behind the use of stem cells injection in post-radical prostatectomy erectile dysfunction (pRP-ED).Radical prostatectomy for prostate cancer induces complex neurologic and vascular injuries that cause one of the most difficult-to-treat forms of erectile dysfunction. Evidence from animal models replicating pRP-ED suggests that intracavernous injection of autologous bone marrow mononuclear cells (BM-MNCs) may represent the first curative approach. Several clinical trials are ongoing and two of them have been completed with encouraging results. PMID: 28372281 [PubMed - indexed for MEDLINE]
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Related Articles Adipose tissue-derived stem cell therapy for erectile dysfunction in rats: a systematic review and meta-analysis. Int Urol Nephrol. 2017 Jul;49(7):1127-1137 Authors: Hou QL, Ge MY, Zhang CD, Tian DD, Wang LK, Tian HZ, Wang WH, Zhang WD Abstract OBJECTIVE: We aimed to systematically assess the effect of adipose tissue-derived stem cell (ADSC) therapy and its influential factors on the treatment of erectile dysfunction (ED) in rats. METHODS: Two authors independently searched for published studies through PubMed and EMBASE from study inception until August 31, 2016. A meta-analysis was used to combine the effect estimate from the published studies. A subgroup analysis was performed to identify the effect of some influential factors. The pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated by a fixed-effects or random-effects model analysis. RESULTS: Twenty studies with a total of 248 rats were included in this meta-analysis. The pooled analysis showed that ADSC therapy significantly increased the ratio of intracavernous pressure and mean arterial pressure (ICP/MAP; SMD 3.46, 95% CI 2.85-4.06; P < 0.001) compared to control therapy. The levels of neuronal nitric oxide synthase (nNOS; SMD 6.37, 95% CI 4.35-8.39; P < 0.001), the cavernous smooth muscle content (CSMC; SMD 3.65, 95% CI 2.65-4.65; P < 0.001), the ratio of cavernous smooth muscle and collagen (CSM/collagen; SMD 4.16, 95% CI 2.59-5.72; P < 0.001), and the cyclic guanosine monophosphate (cGMP; SMD 7.12, 95% CI 2.76-11.48; P = 0.001) were higher following ADSC therapy than following control therapy. Subgroup analysis showed that ADSCs modified by growth or neurotrophic factors significantly recovered erectile function (P < 0.001) compared with ADSC therapy. CONCLUSION: The adequate data indicated that ADSC therapy recovered erectile function and regenerated cavernous structures in ED rats, and ADSCs modified by some growth and neurotrophic factors accelerated the recovery of erectile function and cavernous structures in ED rats. PMID: 28417342 [PubMed - indexed for MEDLINE]
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Related Articles In vitro and in vivo investigation of natural compounds from seed extract of Mucuna pruriens lacking l-DOPA for the treatment of erectile dysfunction. Asian Pac J Trop Med. 2017 Mar;10(3):238-252 Authors: Duangnin N, Phitak T, Pothacharoen P, Kongtawelert P Abstract OBJECTIVE: To investigate the biological effects of the Mucuna pruriens (M. pruriens) seed extracts that lacked l-DOPA, which was formerly reported as the active ingredient, on erectile dysfunction (ED) both in vitro and in vivo. METHODS: Seed of M. pruriens plant that cultivated in Mae Taeng District, Chiang Mai Province, Thailand, was collected. Component of its seeds were extracted and isolated into 2 fractions using methanol, polar and nonpolar. Each fraction was investigated for phytochemicals using gas chromatography and mass spectroscopy and was screened for biological activity in vitro using three different cell lines. The most biological active fraction was used to treat both streptozotocin (STZ)-induced diabetes mellitus-erectile dysfunction (DM-ED) male Wistar rats and normal rats (n = 6 per groups) to compare the effect on sexual behavior parameters, including number of intromission, mounting and ejaculation, with that of rats given Sildenafil by individually pairing with their female counterparts. Penile tissues and serums were collected to determine histological structure, related gene expression and biomolecules. RESULTS: The phytochemicals of the polar fraction were possibly catechol and its derivatives plus polyphenols, whereas the nonpolar fraction consisted of lipid derivatives. l-DOPA was not detected in either of the extracts. The polar fraction was able to up-regulate the expression of ED-related genes including eNOS and nNOS in vitro which subsequently promotes nitric oxide production and maintains intracellular cyclic guanosine monophosphate levels. When administrated to DM-ED rats, the polar extract significantly improved all sexual behavior parameters in DM-ED rats compared to untreated group (18.3 ± 1.8 to 10.8 ± 2.9 for intromission, 9.8 ± 2.2 to 5.7 ± 1.3 for mounting, and 1.8 ± 0.6 to 0.2 ± 0.4 for ejaculation). That effect might due to the ability of the extract to stimulate the expression of eNOS and nNOS which results in nitric oxide production and subsequently maintains cyclic guanosine monophosphate levels in penile tissue. Moreover, this extract may also prevent penile tissue deterioration due to diabetes. CONCLUSIONS: The polar extract of M. pruriens seed can be used for ED therapy, especially in patients with metabolic diseases including diabetes. The action of the extract might be due to catechol and its derivatives and polyphenols. PMID: 28442107 [PubMed - in process]
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Related Articles Drugs in preclinical to phase II clinical development for the treatment of erectile dysfunction. Expert Opin Investig Drugs. 2017 Jun;26(6):669-675 Authors: Smith-Harrison L, Starke NR, Smith RP, Kovac JR Abstract INTRODUCTION: Erectile function is an important aspect in the quality of life of many men. For men with erectile dysfunction (ED), a spectrum of treatment options exists. Novel therapies for ED are currently being developed in order to delay surgical placement of a penile prosthesis - the final step in the management of treatment-refractory ED. Areas covered: This review examines innovative treatments such as alternative vasoactive agents, trophic factors and bio-compounds as well as gene and stem cell therapy. All therapies are currently in some phase of development for the management of ED. Using the MedLine and FDA Clinical Trials Registry, recent developments in treatment of ED were queried. Expert opinion: Recent studies have demonstrated the potential for multiple, novel therapies in the treatment of ED. Much of the work requires further experimentation in large-scale, blinded, placebo-controlled studies. This will require a concerted effort to bring these products to market. PMID: 28460540 [PubMed - indexed for MEDLINE]
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Related Articles Myostatin, a profibrotic factor and the main inhibitor of striated muscle mass, is present in the penile and vascular smooth muscle. Int J Impot Res. 2017 Sep;29(5):194-201 Authors: Kovanecz I, Masouminia M, Gelfand R, Vernet D, Rajfer J, Gonzalez-Cadavid NF Abstract Myostatin is present in striated myofibers but, except for myometrial cells, has not been reported within smooth muscle cells (SMC). We investigated in the rat whether myostatin is present in SMC within the penis and the vascular wall and, if so, whether it is transcriptionally expressed and associated with the loss of corporal SMC occurring in certain forms of erectile dysfunction (ED). Myostatin protein was detected by immunohistochemistry/fluorescence and western blots in the perineal striated muscles, and also in the SMC of the penile corpora, arteries and veins, and aorta. Myostatin was found in corporal SMC cultures, and its transcriptional expression (and its receptor) was shown there by DNA microarrays. Myostatin protein was measured by western blots in the penile shaft of rats subjected to bilateral cavernosal nerve resection (BCNR), that were left untreated, or treated (45 days) with muscle-derived stem cells (MDSC), or concurrent daily low-dose sildenafil. Myostatin was not increased by BCNR (compared with sham operated animals), but over expressed after treatment with MDSC. This was reduced by concurrent sildenafil. The presence of myostatin in corporal and vascular SMC, and its overexpression in the corpora by MDSC therapy, may have relevance for the stem cell treatment of corporal fibrosis and ED. PMID: 28539643 [PubMed - indexed for MEDLINE]
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Related Articles Telomerase reverse transcriptase genetically modified adipose tissue derived stem cells improves erectile dysfunction by inhibiting oxidative stress and enhancing proliferation in rat model. Biomed Pharmacother. 2017 Aug;92:595-605 Authors: Wu XJ, Shen WH, He P, Zhou XZ, Zhi Y, Dai Q, Chen ZW, Zhou ZS Abstract Erectile dysfunction (ED) is considered to be incapable of obtaining or/and keeping a sufficient erection function to receive the satisfactory during the sexual intercourse. This study aims to investigate the effects of telomerase reverse transcriptase (hTERT) modified adipose tissue derived stem cells (ADSCs) autologously injected into cavernosa of the ED rats on erectile function. The ADSCs were isolated form the rat subcutaneous adipose tissue sample, and identified by examining the CD29 and CD44 molecule. The ED model was established by using 100μg/kg apomorphine (APO). The adenovirus expressing rat hTERT (Ade-hTERT vector) was established, and transfected into ADSCs and injected into ED rat model, respectively. Telomerase activity, cell growth, cell apoptosis were analyzed by using TRAP ELISA assay, CCK8 assay and flow cytometry assay, respectively. The trophic growth factors were examined by using enzyme-linked immunosorbent assay (ELISA). The mRNA and proteins were detected by using semi-quantitative PCR and western blot assay, respectively. Ade-hTERT vector was highly expressed in both ADSCs and ED rat mode. The hTERT expression enhanced the telomerase activity, inhibits cell apoptosis and enhances proliferation of ADSCs (P<0.05). hTERT expression triggers the secretory function of ADSCs and induces differentiative potential of ADSCs. hTERT expression inhibits apoptosis and increases eNOS and nNOS levels in older ED rats compared to the Ade-vector injected ED rats (P<0.05). In conclusion, the hTERT modification could enhance the ADSCs proliferation, and hTERT modified ADSCs could increase the anti-oxidative stress capacity in the ED rat model. PMID: 28577498 [PubMed - indexed for MEDLINE]
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Related Articles Radiation-induced erectile dysfunction: Recent advances and future directions. Adv Radiat Oncol. 2016 Jul-Sep;1(3):161-169 Authors: Mahmood J, Shamah AA, Creed TM, Pavlovic R, Matsui H, Kimura M, Molitoris J, Shukla H, Jackson I, Vujaskovic Z Abstract Prostate cancer is one of the most prevalent cancers and the second leading cause of cancer-related deaths in men in the United States. A large number of patients undergo radiation therapy (RT) as a standard care of treatment; however, RT causes erectile dysfunction (radiation-induced erectile dysfunction; RiED) because of late side effects after RT that significantly affects quality of life of prostate cancer patients. Within 5 years of RT, approximately 50% of patients could develop RiED. Based on the past and current research findings and number of publications from our group, the precise mechanism of RiED is under exploration in detail. Recent investigations have shown prostate RT induces significant morphologic arterial damage with aberrant alterations in internal pudendal arterial tone. Prostatic RT also reduces motor function in the cavernous nerve which may attribute to axonal degeneration may contributing to RiED. Furthermore, the advances in radiogenomics such as radiation induced somatic mutation identification, copy number variation and genome-wide association studies has significantly facilitated identification of biomarkers that could be used to monitoring radiation-induced late toxicity and damage to the nerves; thus, genomic- and proteomic-based biomarkers could greatly improve treatment and minimize arterial tissue and nerve damage. Further, advanced technologies such as proton beam therapy that precisely target tumor and significantly reduce off-target damage to vital organs and healthy tissues. In this review, we summarize recent advances in RiED research and novel treatment modalities for RiED. We also discuss the possible molecular mechanism involved in the development of RiED in prostate cancer patients. Further, we discuss various readily available methods as well as novel strategies such as stem cell therapies, shockwave therapy, nerve grafting with tissue engineering, and nutritional supplementations might be used to mitigate or cure sexual dysfunction following radiation treatment. PMID: 28740886 [PubMed]
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Related Articles Recent advances in the treatment of erectile dysfunction. Postgrad Med J. 2017 Nov;93(1105):679-685 Authors: Mobley DF, Khera M, Baum N Abstract Erectile dysfunction (ED) is one of the most common conditions affecting middle-aged and older men. Nearly every primary care physician, internist and geriatrician will be called upon to manage this condition or to make referrals to urologists, endocrinologists and cardiologists who will assist in the treatment of ED. This article will briefly discuss the diagnosis and management of ED. In addition, emerging concepts in ED management will be discussed, such as the use of testosterone to treat ED, the role of the endothelium in men with ED and treating the partner of the man with ED. Finally, future potential therapies for ED will be discussed. PMID: 28751439 [PubMed - indexed for MEDLINE]
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Related Articles Intracavernous Injections of Bone Marrow Mononucleated Cells for Postradical Prostatectomy Erectile Dysfunction: Final Results of the INSTIN Clinical Trial. Eur Urol Focus. 2017 12;3(6):643-645 Authors: Yiou R, Hamidou L, Birebent B, Bitari D, Le Corvoisier P, Contremoulins I, Rodriguez AM, Augustin D, Roudot-Thoraval F, de la Taille A, Rouard H Abstract We recently reported stage I of a phase 1/2 clinical trial of cell therapy to treat postradical prostatectomy erectile dysfunction (INSTIN, INtra-cavernous STem-cell INjection clinical trial, NCT01089387). In this first stage, four doses of intracavernous autologous bone marrow mononuclear cells (BM-MNCs) were tested in 12 patients. Here, we report the results of stage II, in which six additional patients received the optimal dose identified in stage I (109 BM-MNCs), and the long-term results in the 12 patients included in stage I. The objectives were to assess the safety and efficacy of this new treatment. In stage II, no patients had side effects, and the erectile function improvements were similar to those seen in stage I: after 6 months, significant improvements versus baseline were noted in International Index of Erectile Function-15 intercourse satisfaction (7.8±3.1 vs 2.2±3.4, p=0.033) and erectile function (18±8.3 vs 3.7±4.1, p=0.035) domains. In stage I patients, after a mean follow-up of 62.1±11.7 mo, there were no prostate cancer recurrences, and erectile function scores were somewhat lower compared with the 1-yr time point. These findings suggest that intracavernous BM-MNC injections are safe and improve erectile function. The decline in erectile function over time suggests a need for assessing repeated injections. PATIENT SUMMARY: We report a phase 1/2 pilot clinical trial of cell therapy consisting in intracavernous injection of bone marrow mononuclear cells to treat postradical prostatectomy erectile dysfunction. Erectile function was improved after 6 mo in the patients given 1×109 cells. No serious side effects (life threatening or requiring hospitalisation) occurred after a mean follow-up of 62.1 mo in the first 12 patients. PMID: 28753830 [PubMed - in process]
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Related Articles Adipose-Derived Stem Cell-Derived Exosomes Ameliorate Erectile Dysfunction in a Rat Model of Type 2 Diabetes. J Sex Med. 2017 Sep;14(9):1084-1094 Authors: Chen F, Zhang H, Wang Z, Ding W, Zeng Q, Liu W, Huang C, He S, Wei A Abstract BACKGROUND: The efficacy of adipose-derived stem cells (ADSCs) in alleviating erectile dysfunction (ED) of diabetic rats has been demonstrated mainly through a paracrine effect. However, exosomes (EXOs), which are important bioactive substance vectors secreted by ADSCs, have never been associated with ED. AIM: To investigate the effect of ADSC-derived EXOs on erectile function in a type 2 diabetic ED rat model. METHODS: EXOs were isolated from the supernatants of cultured ADSCs by ultracentrifugation. We constructed a type 2 diabetic rat model using a high-fat diet and low-dose streptozotocin administered by intraperitoneal injection. In total, 24 diabetic rats were randomly assigned to three groups and were treated with an intracavernous injection of ADSC-derived EXOs, ADSCs, or phosphate buffered saline. Another eight age-matched rats underwent sham operation and composed the normal control group. OUTCOMES: Intracavernous pressure and mean arterial pressure testing and histologic and western blot analyses were performed 4 weeks after the intracavernous injection. RESULTS: ADSC-derived EXOs and ADSCs administered by intracavernous injection led to an increase in the ratio of intracavernous pressure to mean arterial pressure compared with that for phosphate buffered saline treatment. Histologic and western blot analyses demonstrated an increased ratio of smooth muscle to collagen, increased expression of an endothelial marker (CD31), a smooth muscle marker (α-smooth muscle actin), and antiapoptotic protein Bcl-2 and decreased the expression of the apoptotic protein cleaved caspase-3 and apoptosis of endothelial and smooth muscle cells in the corpus cavernosum tissue after EXO or ADSC injection compared with values for the phosphate buffered saline treatment. CLINICAL TRANSLATION: The present results are expected to provide a scientific foundation for clinical application in the near future. STRENGTHS AND LIMITATIONS: Although the results demonstrated that intracavernous injection of ADSC-derived EXOs could ameliorate ED of diabetic rats, the optimum dose and times of injection remain for further study. CONCLUSIONS: ADSC-derived EXOs, similarly to ADSCs, were capable of rescuing corpus cavernosum endothelial and smooth muscle cells by inhibiting apoptosis and thus promoting the recovery of erectile function in type 2 diabetic rats. Chen F, Zhang H, Wang Z, et al. Adipose-Derived Stem Cell-Derived Exosomes Ameliorate Erectile Dysfunction in a Rat Model of Type 2 Diabetes. J Sex Med 2017;14:1084-1094. PMID: 28781215 [PubMed - indexed for MEDLINE]
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Related Articles Neuroprotective and Nerve Regenerative Approaches for Treatment of Erectile Dysfunction after Cavernous Nerve Injury. Int J Mol Sci. 2017 Aug 18;18(8): Authors: Campbell JD, Burnett AL Abstract Erectile dysfunction (ED) is a significant cause of reduced quality of life in men and their partners. Cavernous nerve injury (CNI) during pelvic surgery results in ED in greater than 50% of patients, regardless of additional patient factors. ED related to CNI is difficult to treat and typically poorly responsive to first- and second-line therapeutic options. Recently, a significant amount of research has been devoted to exploring neuroprotective and neuroregenerative approaches to salvage erectile function in patients with CNI. In addition, therapeutic options such as neuregulins, immunophilin ligands, gene therapy, stem cell therapy and novel surgical strategies, have shown benefit in pre-clinical, and limited clinical studies. In the era of personalized medicine, these new therapeutic technologies will be the future of ED treatment and are described in this review. PMID: 28820434 [PubMed - indexed for MEDLINE]
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Related Articles Transplantation of adipose tissue-derived stem cell-derived exosomes ameliorates erectile function in diabetic rats. Andrologia. 2018 Mar;50(2): Authors: Zhu LL, Huang X, Yu W, Chen H, Chen Y, Dai YT Abstract Mesenchymal stem cells (MSCs) have been considered as an attractive tool for the therapy of diseases. Accumulating evidence indicates that the healing effects of MSCs are mainly related to paracrine action rather than transdifferentiation. Exosomes excreted from MSCs have emerged as physiologically relevant and powerful components of the MSC secretome. However, whether MSC-derived exosomes can improve erectile function of streptozotocin-induced diabetic rats and its mechanism remains unknown. Our previous work showed that adipose tissue-derived stem cells (ADSCs) transplantation could increase endothelial and smooth muscle contents and improve erectile function of diabetic rats. In this study, ADSC-derived exosomes (ADSC-Exo) exhibited in vitro proangiogenic properties, induced the proliferation of endothelial cells and restored erectile function in vivo, as well as decreased fibrosis of corpus cavernosum. In further experiments, we found that ADSC-Exo contained some proangiogenic (miR-126, miR-130a and miR-132) microRNAs and an antifibrotic microRNA family (miR-let7b and miR-let7c). Thus, it is reasonable to postulate that ADSC-Exo transports key functional miRNAs to target cells in a specific manner to improve functional recovery or to activate endogenous repair mechanisms. This proof-of-concept study provides a novel approach for the treatment of diabetic erectile dysfunction. PMID: 29057541 [PubMed - indexed for MEDLINE]
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Related Articles Effects of Next-Generation Low-Energy Extracorporeal Shockwave Therapy on Erectile Dysfunction in an Animal Model of Diabetes. World J Mens Health. 2017 Dec;35(3):186-195 Authors: Jeong HC, Jeon SH, Qun ZG, Kim KS, Choi SW, Bashraheel F, Bae WJ, Kim SJ, Cho HJ, Ha US, Hong SH, Lee JY, Moon DG, Kim SW Abstract PURPOSE: Gene therapy, stem cell therapy, and low-energy extracorporeal shockwave therapy (ESWT) have been investigated as treatments for refractory erectile dysfunction (ED), but inconclusive evidence has been obtained. We investigated the effect of a next-generation electromagnetic cylinder ESWT device on an animal model of ED. MATERIALS AND METHODS: Diabetes mellitus (DM)-induced rats were divided into 3 groups: group 1, control; group 2, DM; and group 3, DM+ESWT. Rats were treated with ESWT 3 times a week for 2 weeks. After the treatment course, intracavernous pressure was measured and the corpus cavernosum and cavernous nerve were evaluated. RESULTS: In the DM group, all parameters predicted to be significantly lower in the ED model had statistically significantly decreased (p<0.01). As a measurement of erectile function, intracavernous pressure was evaluated. The DM+ESWT group exhibited significantly restored erectile function compared to the DM group (p<0.05). Moreover, ESWT treatment restored smooth muscle content, as assessed by Masson's trichrome staining (p<0.05). Finally, corporal tissue and the dorsal nerve were evaluated by immunohistochemistry, Western blotting, and ELISA. After ESWT treatment, vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), platelet endothelial cell adhesion molecule-1, cyclic guanosine monophosphate, and neuronal nitric oxide synthase (nNOS) expression levels were restored to levels in the DM group (p<0.05). CONCLUSIONS: Electromagnetic cylinder ESWT device resulted in increased VEGF, nNOS, and eNOS expression; reduced smooth muscle atrophy; and increased endothelial cell regeneration in a DM-associated ED model. Our data suggest that safe and effective application could be possible in future clinical studies. PMID: 29164834 [PubMed]
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Related Articles [Treatment by stem cell therapy of erectile dysfunction of diabetic origin: State of the art]. Prog Urol. 2018 Feb;28(2):74-84 Authors: El Osta R, Decot V, Bensoussan D, Stoltz JF, Eschwege P, Hubert J Abstract PURPOSE: Review of various publications on stem cell therapy to treat erectile dysfunction of diabetic origin. MATERIAL AND METHODS: Bibliographic search in PUBMED performed using the keywords cell therapy strain/erectile dysfunction associated with diabetes. Among the 51 articles obtained from the PUBMED research, we selected 16 articles for their specificity of studying erectile dysfunction (DE) related to diabetes. RESULTS: Different types of stem cells have been studied: adipose derived mesenchymal stem cells/bone marrow derived mesenchymal stem cells as well as progenitor endothelial cells. The experimental protocols are quite similar from one study to the next with nevertheless some specifications concerning the studied cells and the monitoring of the latter. Intracavernous pressure (ICP) measured after the injection of stem cells into the corpus cavernosum was always significantly higher than the control populations. The addition of certain growth factors to stem cells by gene transfection improve the efficacy of the cells. No ideal tracking markers of the cells have been identified. CONCLUSION: The positive effect of the injection of stem cells on the ICP belongs to the cellular trans-differentiation effect but especially to the paracrine effects which have not yet been completely elucidated. PMID: 29170014 [PubMed - indexed for MEDLINE]
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Related Articles In Situ Activation and Preservation of Penile Progenitor Cells Using Icariside II in an Obesity-Associated Erectile Dysfunction Rat Model. Stem Cells Dev. 2018 02 01;27(3):207-215 Authors: Ruan Y, Lin G, Kang N, Tamaddon A, Zhou J, Wang B, Wang HS, Wang G, Banie L, Xin Z, Liu J, Lue TF Abstract Obesity-associated erectile dysfunction (ED) involves pathologic change that may be related to deficit of the penile endogenous stem/progenitor cells. Therefore, an in-depth study of the penile stem/progenitor cells in the pathogenesis of ED is warranted. For this study, eight Zucker Lean (ZUC-Leprfa 186; ZL group) and 16 Zucker Fatty (ZUC-Leprfa 185; ZF) male rats received an intraperitoneal injection of 5-ethynyl-2-deoxyuridine (EdU) to track endogenous stem cells. Twelve weeks later, the ZF rats were randomized to gavage feeding with 1.5 mg/kg/day of icariside II (ZF + ICA II group) or the solvent (ZF group). Treatment lasted 4 weeks and was followed by a 1-week washout period. ZF rats had impaired erectile function with related pathologic changes compared with ZL rats. ICA II treatment restored erectile function and prevented smooth muscle atrophy, endothelial dysfunction, and lipid accumulation compared with no treatment. EdU label-retaining cell levels were higher in the ZF + ICA II group compared with the ZF group. Histone 3 phosphorylation at Ser 10, a specific mitotic cell marker, was additionally used to identify dividing cells. ICA II activated more penile stem cells to proliferate in ZF rats compared with ZL rats. These results suggest that ZF rats can be used as a model for obesity-associated ED and that ICA II improves erectile function and pathologic changes through endogenous progenitor cell preservation and proliferation. PMID: 29179669 [PubMed - indexed for MEDLINE]
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Related Articles Use of amnion chorion and umbilical cord grafts in conjunction with penile implant procedures. Transl Androl Urol. 2017 Nov;6(Suppl 5):S900-S902 Authors: Kramer AC Abstract Biologics have increased in popularity lately as a novel and exciting new therapy for men with a spectrum of sexual dysfunction ailments-ranging from erectile dysfunction, Peyronie's disease, and ejaculatory disorders. In this series, sequential patients were analyzed who received biologic materials at the time of their penile implant surgery, with various metrics assessed. The information gathered includes recovery time, need for postoperative analgesics, and satisfaction with the final outcome. In this study, early metrics appear to point to improved outcomes in select criteria. Further study will need to address whether treatment with biologics has broader appeal, but in the penile implant patient, the surgery seems to be augmented with the placement of biologic material into the surgical wound. PMID: 29238669 [PubMed]
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Related Articles TNF-α antagonism with etanercept enhances penile NOS expression, cavernosal reactivity, and testosterone levels in aged rats. Can J Physiol Pharmacol. 2018 Feb;96(2):200-207 Authors: Demirtaş Şahin T, Yazir Y, Utkan T, Gacar G, Furat Rençber S, Gocmez SS Abstract Erectile dysfunction (ED) has been reported to be associated with inflammation. This study investigated the effects of tumor necrosis factor alpha (TNF-α) inhibitor etanercept on penile neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) expressions, testosterone concentrations, neurogenic and endothelium-dependent relaxations of corpus cavernosum (CC), and circulating and cavernosal levels of inflammatory markers in aged rats. Animals were separated into control, aged, and etanercept-treated aged groups. Aged rats displayed significantly increased serum and cavernosal TNF-α, C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule (ICAM-1) levels, and decreased penile nNOS and eNOS expressions and serum testosterone levels compared with controls. In etanercept-treated aged group, NOS expressions were similar to that of the control group. The circulating and cavernosal concentrations of TNF-α, CRP, MCP-1, ICAM-1, and testosterone were also normalized by etanercept. Neurogenic and endothelium-dependent relaxant responses significantly decreased in aged rats and etanercept treatment markedly improved these relaxation responses. Our findings indicate that aging decreases penile NOS expression, neurogenic and endothelium-dependent relaxations of CC, and also suppresses serum testosterone levels by inducing inflammatory response that may contribute to the development of ED. TNF-α antagonism may be a novel strategy to treat aging-associated ED. PMID: 29260891 [PubMed - indexed for MEDLINE]
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Related Articles Re: Combination of Mesenchymal Stem Cell Injection with Icariin for the Treatment of Diabetes-Associated Erectile Dysfunction. J Urol. 2017 Aug;198(2):238 Authors: Seftel AD PMID: 29370619 [PubMed - in process]
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Related Articles [New approaches for recovery of erectile function in patients after radical prostatectomy]. Urologiia. 2017 Dec;(6):138-143 Authors: Epifanova MV, Chalyi ME, Gvasaliya BR, Eremin II, Pulin AA, Nadelyaeva II, Artemenko SA, Galitskaya DA, Repin AM Abstract Prostate cancer (PCa) is one of the most common maligmancies and causes of death among men. Radical prostatectomy (RP) is optimal and recommended treatment modality for localized prostate cancer. More than half of all men undergoing surgery experience problems with erectile function and existing treatments do not provide a positive effect. Thus, there is a need for new approaches to the restoration of erectile function in patients after RP. One of these is the use of cell technologies, namely the stromal-vascular fraction and autologous platelet-rich plasma. This review examines the results of preclinical and clinical studies investigating the efficacy and safety of these treatment options in erectile dysfunction. PMID: 29376611 [PubMed - indexed for MEDLINE]
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Related Articles Improvement of penile neurogenic and endothelial relaxant responses by chronic administration of resveratrol in rabbits exposed to unpredictable chronic mild stress. Int J Impot Res. 2018 Aug;30(4):163-170 Authors: Yazir Y, Utkan T, Şahin TD, Gocmez SS Abstract Chronic stress is an important public health problem known as a risk factor for depression, cognitive deficits, and also erectile dysfunction (ED). Resveratrol, a plant polyphenol, was reported to activate constitutive endothelial nitric oxide synthase (eNOS). Although resveratrol has been proven to exert beneficial effects on the unpredictable chronic mild stress (UCMS)-induced decline in cognitive functions, its potential protecting effect on the penile tissue subjected to UCMS was in fact not investigated. Therefore, restorative effects of resveratrol on neurogenic and endothelium-dependent relaxations were evaluated in the corpus cavernosum of rabbits exposed to UCMS. Eighteen male New Zealand white rabbits were assigned into three groups (n = 6 in each group): controls; UCMS; and UCMS rabbits treated with resveratrol (20 mg/kg/day, i.p.) for 12-week period of stress induction. UCMS was induced by a couple of defined adverse conditions applied in a shuffled order for 12 weeks. Neurogenic and endothelium-dependent relaxations of corpus cavernosum were assessed by using organ bath studies. Both the electrical field stimulation (EFS)-induced neurogenic and carbachol-induced endothelium-dependent relaxant responses significantly decreased in physiological stress and resveratrol treatment exhibited a marked improvement in these relaxation responses in vitro. Our results indicated that chronic psychological stress could lead to ED by reducing neurogenic and endothelium-dependent relaxations and resveratrol prevents impairment of the functional responses, suggesting a potential new treatment approach for treatment of ED during psychological stress. PMID: 29382932 [PubMed - in process]
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Related Articles LncRNA MIAT facilitated BM-MSCs differentiation into endothelial cells and restored erectile dysfunction via targeting miR-200a in a rat model of erectile dysfunction. Eur J Cell Biol. 2018 Apr;97(3):180-189 Authors: Wang H, Ding XG, Yang JJ, Li SW, Zheng H, Gu CH, Jia ZK, Li L Abstract BACKGROUND: Bone-marrow derived mesenchymal stem cells (BM-MSCs) implantation effectively restored rats' erectile dysfunction (ED). Long noncoding RNA (LncRNA)-myocardial infarction-associated transcript (MIAT) has been reported to play an important role in regulating endothelial cells (ECs) function via vascular endothelial growth factor (VEGF) that induced BM-MSCs differentiation into ECs. However, the molecular functions and biological roles of lncRNA MIAT in ED remained unclear. METHODS: The rat model of ED was established. Quantitative real-time PCR (qRT-PCR) and western blotting were used to detect the expression of lncRNA MIAT, von Willebrand factor (vWF), vascular endothelial cadherin (VE-cadherin), endothelial NO synthase (eNOS) and VEGF following BM-MSCs transfection. Erectile function was evaluated by intra-cavernous pressure/mean artery pressure (ICP/MAP). Furthermore, RNA immunoprecipitation (RIP) assay and RNA pull down as well as luciferase reporter assay were carried out to examine the interaction among lncRNA MIAT, miR-200a and VEGF. RESULTS: BM-MSCs restored ED by upregulating lncRNA MIAT. LncRNA MIAT was upregulated in a time-dependent manner during BM-MSCs differentiation into ECs. LncRNA MIAT regulated VEGF via targeting miR-200a, thereby promoting BM-MSCs differentiation into ECs. LncRNA MIAT knockdown in vivo abolished the effect of BM-MSCs on ED. CONCLUSION: LncRNA MIAT promoted BM-MSCs differentiation into ECs and restored ED via miR-200a. PMID: 29486902 [PubMed - indexed for MEDLINE]
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Related Articles Combined Transplantation of Mesenchymal Stem Cells and Endothelial Progenitor Cells Restores Cavernous Nerve Injury-Related Erectile Dysfunction. J Sex Med. 2018 Mar;15(3):284-295 Authors: Fang JF, Huang XN, Han XY, Ouyang X, Fan L, Zhao X, Chen ZH, Wei HB Abstract BACKGROUND: Whether combined transplantation of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) is more effective than transplantation of a single cell type in the restoration of erectile function is unknown. AIM: To investigate the effect of combined transplantation of MSCs and EPCs on restoration of erectile function in rats with cavernous nerve injury (CNI). METHODS: MSCs were isolated from human bone marrow and EPCs were isolated from human umbilical cord blood. MSCs and EPCs were identified by flow cytometry and in vitro differentiation or immunofluorescence staining. 25 8-week-old male Sprague-Dawley rats were allocated to 1 of 5 groups: sham operation group, bilateral CNI group receiving periprostatic implantation of MSCs plus EPCs, MSCs, EPCs, or phosphate buffered saline (control group). 2 weeks after CNI and treatment, erectile function of rats was measured by electrically stimulating the CN. The penis and major pelvic ganglia were harvested for histologic examinations. RNA and protein levels of neurotrophin factors (vascular endothelial growth factor, nerve growth factor, and brain-derived neurotrophic factor) in mono- or coculture MSCs and EPCs were assessed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. OUTCOMES: Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. Histologic examinations of the penis and major pelvic ganglia and RNA and protein levels of neurotrophin factors in MSCs and EPCs were performed. RESULTS: MSCs and EPCs expressed the specified cell markers and exhibited the typical appearance and characteristics. Treatments using MSCs and/or EPCs could increase endothelial and smooth muscle contents of the corpus cavernosum, decrease caspase-3 expression and increase penile neuronal nitric oxide synthase expression, and restore the neural component of the major pelvic ganglia in rats with CNI. Combined transplantation of MSCs and EPCs had a better effect on improving erectile function than single transplantation of MSCs or EPCs. Expression levels of vascular endothelial growth factor and nerve growth factor in coculture MSCs and EPCs were significantly higher than those of primary MSCs or EPCs. CLINICAL TRANSLATION: Combined transplantation of MSCs and EPCs was more effective in restoring erectile function in CNI-related erectile dysfunction models. STRENGTHS AND LIMITATIONS: The study, for the 1st time, proved that combined transplantation of MSCs and EPCs was more effective in restoring erectile function in rats with CNI. The rat model might not represent the human condition. CONCLUSION: Combined periprostatic transplantation of MSCs and EPCs could restore erectile function in rats with CNI more effectively. MSCs might restore CN fibers by secreting neurotrophin factors such as vascular endothelial growth factor and nerve growth factor, and EPCs could enhance the paracrine activity of MSCs. Fang J-f, Huang X-n, Han X-y, et al. Combined Transplantation of Mesenchymal Stem Cells and Endothelial Progenitor Cells Restores Cavernous Nerve Injury-Related Erectile Dysfunction. J Sex Med 2018;15:284-295. PMID: 29502978 [PubMed - in process]
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Related Articles Recovery from hypogonadism and male health in adult allogeneic stem cell transplantation. Eur J Haematol. 2018 Jun;100(6):584-591 Authors: Schneidewind L, Neumann T, Probst KA, Schmidt CA, Krüger W Abstract OBJECTIVE: There is a substantial lack of data about men`s health in adult allogeneic stem cell transplantation. METHODS: We conducted prospective unicentric non-interventional clinical study on men's health with a follow-up time of 1 year. RESULTS: Between 11/2013 and 12/2015, we were able to include 27 patients. AML was the most frequent underlying disease (25.9%), and we mainly used intermediate intense conditioning protocols (77.8%). Erectile dysfunction, loss of libido, and loss of efficiency were the most frequent symptoms of hypogonadism. At inclusion of the study, hypogonadism was already frequent. Primary hypogonadism was found in eight cases (29.6%) and secondary hypogonadism in one case (3.7%). We did not observe hypogonadism 6 months after inpatient treatment anymore, but there might still be the impairment of fertility because of still rising FSH levels at the end of the observation period. There were no significant associations of hypogonadism with myeloablative conditioning or kind of donor. Interestingly, there is a significant association with nicotine abuse (P = .049). CONCLUSIONS: On the whole, male hypogonadism was found in one-third of the patients who underwent allogeneic stem cell transplantation. PMID: 29509972 [PubMed - indexed for MEDLINE]
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Related Articles Molecular mechanisms underlying therapeutic potential of pericytes. J Biomed Sci. 2018 Mar 09;25(1):21 Authors: Harrell CR, Simovic Markovic B, Fellabaum C, Arsenijevic A, Djonov V, Volarevic V Abstract BACKGROUND: Pericytes are multipotent cells present in every vascularized tissue in the body. Despite the fact that they are well-known for more than a century, pericytes are still representing cells with intriguing properties. This is mainly because of their heterogeneity in terms of definition, tissue distribution, origin, phenotype and multi-functional properties. The body of knowledge illustrates importance of pericytes in the regulation of homeostatic and healing processes in the body. MAIN BODY: In this review, we summarized current knowledge regarding identification, isolation, ontogeny and functional characteristics of pericytes and described molecular mechanisms involved in the crosstalk between pericytes and endothelial or immune cells. We highlighted the role of pericytes in the pathogenesis of fibrosis, diabetes-related complications (retinopathy, nephropathy, neuropathy and erectile dysfunction), ischemic organ failure, pulmonary hypertension, Alzheimer disease, tumor growth and metastasis with the focus on their therapeutic potential in the regenerative medicine. The functions and capabilities of pericytes are impressive and, as yet, incompletely understood. Molecular mechanisms responsible for pericyte-mediated regulation of vascular stability, angiogenesis and blood flow are well described while their regenerative and immunomodulatory characteristics are still not completely revealed. Strong evidence for pericytes' participation in physiological, as well as in pathological conditions reveals a broad potential for their therapeutic use. Recently published results obtained in animal studies showed that transplantation of pericytes could positively influence the healing of bone, muscle and skin and could support revascularization. However, the differences in their phenotype and function as well as the lack of standardized procedure for their isolation and characterization limit their use in clinical trials. CONCLUSION: Critical to further progress in clinical application of pericytes will be identification of tissue specific pericyte phenotype and function, validation and standardization of the procedure for their isolation that will enable establishment of precise clinical settings in which pericyte-based therapy will be efficiently applied. PMID: 29519245 [PubMed - indexed for MEDLINE]
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Related Articles Pilot study of a multimodal intervention to enhance sexual function in survivors of hematopoietic stem cell transplantation. Cancer. 2018 Jun 01;124(11):2438-2446 Authors: El-Jawahri A, Fishman SR, Vanderklish J, Dizon DS, Pensak N, Traeger L, Greer JA, Park ER, Markovitz N, Waldman L, Hunnewell C, Saylor M, Driscoll J, Li Z, Spitzer TR, McAfee S, Chen YB, Temel JS Abstract BACKGROUND: Although sexual dysfunction is common after hematopoietic stem cell transplantation (HCT), interventions to address sexual function are lacking. METHODS: We conducted a pilot study to assess the feasibility and preliminary efficacy of a multimodal intervention to address sexual dysfunction in allogeneic HCT survivors. Transplant clinicians screened HCT survivors ≥3 months post-HCT for sexual dysfunction causing distress. Those who screened positive attended monthly visits with a trained transplant clinician who: 1) performed an assessment of the causes of sexual dysfunction; 2) educated and empowered the patient to address his or her sexual concerns; and 3) implemented therapeutic interventions targeting the patient's needs. Feasibility was defined as having approximately 75% of patients who screened positive agreeing to participate and 80% attending at least 2 intervention visits. We administered the Patient-Reported Outcomes Measurement Information System (PROMIS) sexual function and satisfaction measure, the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), and the Hospital Anxiety and Depression Scale (HADS) to evaluate sexual function, quality of life (QOL), and mood, respectively, at baseline and 6 months postintervention. RESULTS: Approximately 33.1% of patients (50 of 151 patients) screened positive for sexual dysfunction causing distress and 94.0% (47 of 50 patients) agreed to participate, with 100% attending 2 intervention visits. Participants reported improvements in satisfaction (P<.0001) and interest in sex (P<.0001), as well as orgasm (P<.0001), erectile function (P<.0001), vaginal lubrication (P = .0001), and vaginal discomfort (P = .0005). At baseline, approximately 32.6% of participants were not sexually active, compared with 6.5% after the intervention (P = .0005). Participants reported improvement in their QOL (P<.0001), depression (P = .0002), and anxiety (P = .0019). CONCLUSIONS: A multimodal intervention to address sexual dysfunction integrated within the transplant clinic is feasible with encouraging preliminary efficacy for improving sexual function, QOL, and mood in HCT survivors. Cancer 2018;124:2438-46. © 2018 American Cancer Society. PMID: 29537491 [PubMed - in process]
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Related Articles The effect of low-intensity extracorporeal shockwave therapy in an obesity-associated erectile dysfunction rat model. BJU Int. 2018 Jul;122(1):133-142 Authors: Ruan Y, Zhou J, Kang N, Reed-Maldonado AB, Tamaddon A, Wang B, Wang HS, Wang G, Banie L, Lin G, Liu J, Lue TF Abstract OBJECTIVES: To investigate the feasibility of the Zucker fatty (ZF) rat as a model for research in to obesity-associated erectile dysfunction (OAED) and to determine the effect of low-intensity extracorporeal shockwave therapy (Li-ESWT) on penile tissue and function in these rats. MATERIALS AND METHODS: Eight new-born male Zucker lean (ZL group) rats (ZUC-Leprfa 186) and 16 new-born male ZF rats (ZUC-Leprfa 185) were injected with 5-ethynyl-2'-deoxyuridine (EdU) at birth to identify and monitor endogenous stem cells. Insulin tolerance testing was performed at 10 weeks of age. Beginning at 12 weeks of age, eight ZF rats were kept as controls, and the remaining eight ZF rats were treated with Li-ESWT (0.02 mJ/mm2 , 3 Hz, 500 pulses; ZF + SW group) twice a week for 4 weeks. Following a 1-week washout period, erectile function was evaluated by measuring intracavernosal pressure (ICP) and mean arterial pressure (MAP). Penile tissues were then harvested for histological study to assess smooth muscle/collagen content and endothelium content in the corpora cavernosum. LipidTOX™ staining was used to evaluate lipid accumulation. EdU, as a marker of cell activation, and phosphorylated histone 3 (H3P), as a marker of cell mitosis, were also assessed. RESULTS: The ICP/MAP indicated that erectile function was severely impaired in the ZF group as compared with the ZL group. In the ZF + SW group, erectile function was significantly improved (P < 0.05). Muscle atrophy was seen in the ZF group, while Li-ESWT increased the muscle content in ZF + SW group. Moreover, the penile endothelium was damaged in the ZF group, and Li-ESWT enhanced the regeneration of endothelial cells (P < 0.01) in the ZF + SW group. Lipid accumulation was seen in the penile tissue of ZF rats. Li-ESWT significantly reduced both the amount and the distribution pattern of LipidTOX, suggesting decreased overall lipid infiltration. Furthermore, Li-ESWT increased EdU-positive cells and markedly enhanced the phosphorylation level of H3P at Ser-10 in the ZF + SW group. Most H3P-positive cells were located within smooth muscle cells, with some located in the endothelium suggesting that these tissues are the reservoirs of penile stem/progenitor cells. CONCLUSION: ZF rats can serve as an animal model in which to study OAED. This study reveals that obesity impairs erectile function by causing smooth muscle atrophy, endothelial dysfunction, and lipid accumulation in the corpus cavernosum. Li-ESWT restored penile haemodynamic parameters in the ZF rats by restoring smooth muscle and endothelium content and reducing lipid accumulation. The underlying mechanism of Li-ESWT appears to be activation of stem/progenitor cells, which prompts cellular proliferation and accelerates penile tissue regeneration. Our findings are of interest, not just as a validation of this emerging treatment for erectile dysfunction, but also as a novel and potentially significant method to modulate endogenous stem/progenitor cells in other disease processes. PMID: 29573106 [PubMed - in process]
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Related Articles Adipose-derived stem cells improve erectile function partially through the secretion of IGF-1, bFGF, and VEGF in aged rats. Andrology. 2018 May;6(3):498-509 Authors: Yang J, Zhang Y, Zang G, Wang T, Yu Z, Wang S, Tang Z, Liu J Abstract Adipose-derived stem cells (ADSCs) have recently been considered as a promising therapy for erectile dysfunction (ED). However, the mechanism of ADSC-based therapy is unclear. Insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) secreted by ADSCs were assessed in vitro. Sixteen 24-month-old male Sprague-Dawley rats were used for comparative analysis of 2-week treatment with labeled ADSCs or PBS. Eight additional 5-month-old rats were used as a young rat group. At 2 weeks post-transplantation, all rats were analyzed for erectile function, cavernous IGF-1, bFGF and VEGF levels, and penile histology. Conditioned medium and co-culture systems were used in cell experiments to detect how growth factors act on corpus cavernosum smooth muscle cells (CCSMCs) under oxidative stress conditions via crystal violet staining and immunofluorescence staining. We found that ADSCs secreted significantly higher IGF-1, bFGF, and VEGF levels in culture medium compared with basal medium. Compared with young rats, untreated aged rats had significantly lower Max ICP/MAP and ADSC treatment significantly increased the ratio. Immunofluorescence staining demonstrated a small number of labeled ADSCs in the corpus cavernosum. The untreated aged rats showed significantly decreased cavernous IGF-1, bFGF, and VEGF levels and significantly decreased contents of cavernous smooth muscle and endothelium compared with young rats. ADSC treatment partially normalized these alterations. In cell experiments, the groups receiving growth factor neutralizing antibody separately or combined had significantly decreased numbers of CCSMCs compared with control groups. These results indicated that ADSC treatment may improve aging-related ED partially through the secretion of IGF-1, bFGF, and VEGF. PMID: 29603682 [PubMed - in process]
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Related Articles Suppression of Cavernosal Fibrosis in a Rat Model. Sex Med Rev. 2018 Oct;6(4):572-582 Authors: Cho MC, Song WH, Paick JS Abstract INTRODUCTION: Cavernosal fibrosis is an important pathologic condition leading to erectile dysfunction (ED). The etiologies of cavernosal fibrosis include aging, diabetes mellitus, castration, cavernosal nerve injury during radical prostatectomy, hypertension, and Peyronie disease. AIMS: To summarize published studies investigating suppression of cavernosal fibrosis in rat models of ED of various etiologies. METHODS: A literature search was conducted using PubMed. Relevant studies were identified using search terms such as erectile dysfunction, penis, fibrosis, and rat models. MAIN OUTCOME MEASURES: We reviewed representative literature studies on the mechanisms and suppression of cavernosal fibrosis in rat models of ED. RESULTS: The underlying mechanisms and potential therapeutic strategies suggested thus far for cavernosal fibrosis in rat models of ED were as follows. For age-related ED involving oxidative stress and tumor growth factor-β1 (TGF-β1)-driven pathways such as RhoA-ROCK1-LIMK2-cofilin or p42-44 and mitogen-activated protein kinase, proposed therapeutic strategies included phosphodiesterase type 5 inhibitors (PDE5Is), kallikrein-kinin system stimulators, and calorie restriction. For diabetes-related ED involving angiotensin-II- and TGF-β1-driven Smad and non-Smad pathways, TGF-β1-Wnt10b, and histone deacetylase (HDAC)-TGF-β1 pathways, positive therapeutic results were obtained with PDE5Is, TGF-β1 antagonists, HDAC inhibitors, antioxidants, sphingosine-1-phosphate receptor modulators (fingolimod), angiotensin-II antagonists, stem cell therapy, and antidiabetic drugs. For cavernosal nerve injury-associated ED involving TGF-β1-driven pathways (Smad or RhoA-ROCK1-LIMK2-cofilin), Sonic hedgehog signaling, angiotensin-II-Smad, and HDAC4-TGF-β1-Smad signaling triggered by cavernosal hypoxia, PDE5Is, angiotensin-II antagonists, stem cell therapy, HDAC inhibitors, Sonic hedgehog administration, ROCK inhibitors, and LIMK2 inhibitors have shown positive results. For testosterone deficiency-associated ED, TGF-β1-driven pathways were found to be responsive to testosterone supplementation. For hypertensive ED, positive therapeutic results were obtained with angiotensin-II antagonists. For Peyronie disease involving TGF-β1 or myostatin signaling, proposed therapeutic strategies included intra-tunical injection of TGF-β receptor inhibitors or adipose tissue-derived stem cells and HDAC2 small hairpin RNA. CONCLUSION: Several signaling pathways appear to be responsible for the development of cavernosal fibrosis related to ED of various etiologies. Some therapeutic success has been achieved in animal models, but further research focusing on mechanism-specific targeted therapies is needed. Cho MC, Song WH, Paick J-S. Suppression of Cavernosal Fibrosis in a Rat Model. Sex Med Rev 2018;6:572-582. PMID: 29631978 [PubMed - in process]
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Related Articles Stem Cell Therapy for Erectile Dysfunction. Sex Med Rev. 2018 Apr 06;: Authors: Matz EL, Terlecki R, Zhang Y, Jackson J, Atala A Abstract INTRODUCTION: The prevalence of erectile dysfunction (ED) is substantial and continues to rise. Current therapeutics for ED consist of oral medications, intracavernosal injections, vacuum erection devices, and penile implants. While such options may manage the disease state, none of these modalities, however, restore function. Stem cell therapy has been evaluated for erectile restoration in animal models. These cells have been derived from multiple tissues, have varied potential, and may function via local engraftment or paracrine signaling. Bone marrow-derived stem cells (BMSC) and adipose-derived stem cells (ASC) have both been used in these models with noteworthy effects. AIM: Herein, we will review the pathophysiology of ED, animal models, current and novel stem-cell based therapeutics, clinical trials and areas for future research. METHODS: The relevant literature and contemporary data using keywords, "stem cells and erectile dysfunction" was reviewed. MAIN OUTCOME MEASURE: Examination of evidence supporting the association between erectile dysfunction and adipose derived stem cells, bone marrow derived stem cells, placental stem cells, urine stem cells and stem cell therapy respectively. RESULTS: Placental-derived stem cells and urine-derived stem cells possess many similar properties as BMSC and ASC, but the methods of acquisition are favorable. Human clinical trials have already demonstrated successful use of stem cells for improvement of erectile function. CONCLUSION: The future of stem cell research is constantly being evaluated, although, the evidence suggests a place for stem cells in erectile dysfunction therapeutics. Matz EL, Terlecki R, Zhang Y, et al. Stem Cell Therapy for Erectile Dysfunction. Sex Med Rev 2018;XX:XXX-XXX. PMID: 29631980 [PubMed - as supplied by publisher]
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Related Articles [Immediate and delayed intracavernous injection of bone marrow mesenchymal stem cells to improve erectile function in rats with cavernous nerve injury]. Zhonghua Nan Ke Xue. 2017 May;23(5):392-398 Authors: Sun C, Zhu WD, Liu J, Jiang H, Chen M Abstract Objective: To explore the effects of immediate and delayed intracavernous injection of bone marrow mesenchymal stem cells (BM-MSCs) on neurogenic erectile dysfunction (NED) induced by bilateral cavernous nerve injury in Sprague-Dawley (SD) rats. METHODS: BM-MSCs isolated from male SD rats were cultured and identified. Twenty-eight 8-week-old male SD rats were randomly divided into four groups, sham operation, NED model control, BM-MSCs immediate, and BM-MSCs delayed, and NED models were established in the latter three groups by crushing the bilateral cavernous nerves. The rats in the sham operation and model control groups were injected intracavernously with placebo while those in the latter two with BM-MSCs immediately or 2 weeks after modeling. At 12 weeks after operation, the penile function of the rats was assessed according to the penile intracavernous pressure (ICP), mean arterial pressure (MAP), and ICP/MAP ratio obtained from different groups of rats. Then, all the animals were sacrificed and the penile cavernosal tissue collected for histological analysis. RESULTS: At 12 weeks after modeling, both ICP and ICP/MAP were significantly increased in the BM-MSCs immediate and delayed groups as compared with those in the model control (P <0.05), and so were the ratio of smooth muscle to collagen (P <0.05) and the smooth muscle content in the corpus cavernosum (P <0.05), and the number of neurofilament (NF)-positive nerve fibers (P <0.05) and the expression of neuronal nitric oxide synthase (nNOS) in the dorsal nerves of the midshaft penis (P <0.05). CONCLUSIONS: Intracavernous injection of BM-MSCs can improve erectile function in rats with bilateral cavernous nerve injury by elevating the smooth muscle-collagen ratio and smooth muscle content in the corpus cavernosum and thus preventing its fibrosis as well as by increasing the number of NF-positive nerve fibers and expression of nNOS in the penile dorsal nerves. PMID: 29717827 [PubMed - indexed for MEDLINE]
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Related Articles [Adipose-derived stem cells for the treatment of penile erectile dysfunction: An update]. Zhonghua Nan Ke Xue. 2017 Jun;23(6):561-565 Authors: Wang Y, Wang YM, Chen C, Wang YC, Song NH Abstract Adipose-derived stem cells (ADSCs) are pluripotent stem cells isolated from the adipose tissue and have the potential for self-renewal and multi-directional differentiation into neurogenic cells, smooth muscle cells, endothelial cells, and so on. Erectile dysfunction (ED) is a common male sexual dysfunction that has a negative impact on the lives of the patients and their partners. Current treatments of ED include surgery and medication, with oral 5-phosphodiesterase inhibitors as the first-line drugs. However, a small number of the patients are not sensitive to these therapies and cannot be improved or cured pathologically. So far, animal experiments and preclinical trials have confirmed the safety and efficacy of ADSCs, which act on ED though paracrine mechanisms. This review summarizes the advances in the recent 5 years in the studies of ADSCs for the treatment of ED. PMID: 29722950 [PubMed - indexed for MEDLINE]
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Related Articles [Prevention and treatment of erectile dysfunction after prostatectomy: An update]. Zhonghua Nan Ke Xue. 2017 Jul;23(7):656-662 Authors: Xu P, Wang YH Abstract Prostate cancer has the highest incidence among malignant tumors of the urinary system in China. Radical prostatectomy (RP) is the most effective treatment for localized prostate cancer with a good long-term prognosis. Erectile dysfunction (ED) is a common complication after RP, which seriously affects the patient's quality of life. With the rising incidence and early diagnosis of prostate cancer, the proportion of young cases of RP is increasing, and so is the importance of the treatment of post-RP ED. The restoration of erectile function after RP is closely related to the timing of penile rehabilitation as well as to pre- and intra-operative measures such as surgical strategies and methods. Common options for the treatment of post-RP ED include oral medication of phosphodiesterase type 5 inhibitors, application of vasoactive substances in the urethra or corpus cavernosum, use of vacuum erection devices, and implantation of penile prosthesis. Stem cell therapy, nerve transplantation, low-intensity extracorporeal shockwave therapy, and erythropoietin have shown great potential in penile rehabilitation after RP. At present, the stress is placed on the remission of symptoms in the treatment of ED. Stem cell therapy may reverse the cause of disease or cure ED by reversing its pathophysiological changes. A series of clinical trials of stem cell therapy are underway and have preliminarily confirmed the safety of stem cell therapy and proved that it can improve erectile function in patients with post-RP ED. This review focuses on the progress in the prevention and treatment of ED after RP. PMID: 29723462 [PubMed - indexed for MEDLINE]
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Related Articles Icariside II Promotes the Differentiation of Adipose Tissue-Derived Stem Cells to Schwann Cells to Preserve Erectile Function after Cavernous Nerve Injury. Mol Cells. 2018 Jun;41(6):553-561 Authors: Zheng T, Zhang TB, Wang CL, Zhang WX, Jia DH, Yang F, Sun YY, Ding XJ, Wang R Abstract Icariside II (ICA II) is used in erectile dysfunction treatment. Adipose tissue-derived stem cells (ADSCs) are efficient at improving erectile function. This study aimed to explore the action mechanism of ADSCs in improving erectile function. ADSCs were isolated from the adipose tissues of rats. Cell proliferation was determined using the Cell Counting Kit-8 (CCK-8) assay. The expressions of mRNA and protein were determined separately through qRT-PCR and western blot. The endogenous expressions of related genes were regulated using recombinant plasmids and cell transfection. A Dual-Luciferase Reporter Assay was performed to determine the interaction between miR-34a and STAT3. Rat models with bilateral cavernous nerve injuries (BCNIs) were used to assess erectile function through the detection of mean arterial pressure (MAP) and intracavernosal pressure (ICP). ICA II promoted ADSCs' proliferation and differentiation to Schwann cells (SCs) through the inhibition of miR-34a. Suppressed miR-34a promoted the differentiation of ADSCs to SCs by upregulating STAT3. ICA II promoted the differentiation of ADSCs to SCs through the miR-34a/STAT3 pathway. The combination of ICA II and ADSCs preserved the erectile function of the BCNI model rats. ADSCs treated with ICA II markedly preserved the erectile function of the BCNI model rats, which was reversed through miR-34a overexpression. ICA II promotes the differentiation of ADSCs to SCs through the miR-34a/STAT3 pathway, contributing to erectile function preservation after the occurrence of a cavernous nerve injury. PMID: 29902838 [PubMed - indexed for MEDLINE]
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Related Articles The Use of Stromal Vascular Fraction in the Treatment of Male Sexual Dysfunction: A Review of Preclinical and Clinical Studies. Sex Med Rev. 2018 Jun 27;: Authors: Haney NM, Gabrielson A, Kohn TP, Hellstrom WJG Abstract INTRODUCTION: Stem cell therapy using stromal vascular fraction (SVF) is a promising treatment modality. SVF is comprised of a mixture of adipose-derived stem cells, endothelial precursor cells, and immune modulatory cells that act synergistically to facilitate angiogenesis and epithelial cell differentiation. This makes SVF an attractive option for men's sexual disorders that require reconstitution of vasculature and endothelial lining, namely erectile dysfunction (ED) and Peyronie's disease (PD). AIM: The objective of this study was to compare and contrast the available literature regarding the use of SVF in the treatment of male sexual dysfunction. METHODS: A literature review was performed in PubMed with the keywords "stromal vascular fraction" and/or "erectile dysfunction" and/or "Peyronie's disease" and/or "sexual dysfunction." MAIN OUTCOME MEASURES: The main outcome measure for preclinical studies was erectile function, as measured by changes in intracavernous pressures, and results of histopathologic analysis of corporal tissue. Clinical endpoint analysis in humans included various patient questionnaires. RESULTS: For ED, there were 5 preclinical studies included in the analysis, with 1 Phase 1 clinical trial in humans. Major limitations of both the preclinical and clinical studies included the absence of SVF component analysis, and short duration of follow-up. Despite a paucity of preclinical studies, there was a single clinical study assessing the efficacy of combination SVF and shock wave therapy in the treatment of PD. Limitations of this study included an absence of a control group and the use of subjective data. CONCLUSION: Preclinical and clinical data in the use of SVF for the treatment of male sexual dysfunction is deficient. Even though multiple medicinal disciplines are studying the use of SVF on a myriad of pathologies, further investigative work elucidating the mechanism and potential adverse effects of SVF need to be performed before clinical trials are undertaken. Haney NM, Gabrielson A, Kohn TP, Hellstrom WJG. The Use of Stromal Vascular Fraction in the Treatment of Male Sexual Dysfunction: A Review of Preclinical and Clinical Studies. Sex Med Rev 2018;XX:XXX-XXX. PMID: 29960873 [PubMed - as supplied by publisher]
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Related Articles Phase I and phase II clinical trials for the treatment of male sexual dysfunction-a systematic review of the literature. Expert Opin Investig Drugs. 2018 Jul;27(7):583-593 Authors: Capogrosso P, Montorsi F, Salonia A Abstract INTRODUCTION: The prevalence of sexual dysfunctions has increased over the last decades; despite a number of available treatments for erectile dysfunction (ED), premature ejaculation (PE), and Peyronie's disease (PD), still several unmet therapeutic needs deserve to be fulfilled. The aim of this review is to detail on phase I and II clinical trials investigating novel medical treatments for ED, PE, and PD. Areas covered: We conducted a systematic review of the literature including both published and ongoing phase I and II registered trials focused on medical treatment of ED, PE, and PD during the last 5 years. A total of 35 trials have been identified. Most studies (63%) investigated ED treatments and 26% were still ongoing. Stem cells (SCs) therapy was assessed in 28% of trials. Expert opinion: SCs therapy represent a promising treatment for ED although only few patients have been treated to date. Likewise, the oral selective oxytocin receptor antagonists for treating PE showed excellent safety profile and deserve further investigations in phase III trials. Preliminary results of novel topical treatments for PD with fibrinolytic and antiinflammatory drugs are encouraging, but urgently need to be confirmed in large placebo-controlled trials. PMID: 29969332 [PubMed - indexed for MEDLINE]
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Related Articles Nanotechnology-assisted adipose-derived stem cell (ADSC) therapy for erectile dysfunction of cavernous nerve injury: In vivo cell tracking, optimized injection dosage, and functional evaluation. Asian J Androl. 2018 Sep-Oct;20(5):442-447 Authors: Wu H, Tang WH, Zhao LM, Liu DF, Yang YZ, Zhang HT, Zhang Z, Hong K, Lin HC, Jiang H Abstract Stem cell therapy is a potentially promising option for erectile dysfunction; however, its risk of tumorigenicity is a clinical hurdle and the risk is positively related to the number of injected cells. Our previous study showed that nanotechnology improved adipose-derived stem cell (ADSC) therapy for erectile dysfunction of cavernous nerve injury (CNI) by attracting cells in the corpus cavernosum. These results indicated the possibility of using a reduced dosage of ADSCs for intracavernous injection. In this exploratory study, we used lower dosage (2 × 105 cells) of ADSCs for intracavernous injection (ICI) and the nanotechnology approach. Intracavernous pressure and mean arterial pressure were measured at day 28 to assess erectile function. The low-dose ADSC therapy group showed favorable treatment effects, and nanotechnology further improved these effects. In vivo imaging of ICI cells revealed that the fluorescein signals of NanoShuttle-bound ADSCs (NanoADSCs) were much stronger than those of ADSCs at days 0, 1, and 3. Both immunofluorescence and Western blot analysis showed a significant increase in smooth muscle, endothelium, and nerve tissue in the ADSC group compared to that in the CNI group; further improvement was achieved with assisted nanotechnology. These findings demonstrate that nanotechnology can be used to further improve the effect of small dosage of ADSCs to improve erectile function. Abundant NanoADSCs remain in the corpus cavernosum in vivo for at least 3 days. The mechanism of erectile function improvement may be related to the regeneration of the smooth muscle, endothelium, and nerve tissues. PMID: 30004040 [PubMed - in process]
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Related Articles Exosomes derived from mesenchymal stem cells exert therapeutic effect in a rat model of cavernous nerves injury. Andrology. 2018 Jul 16;: Authors: Li M, Lei H, Xu Y, Li H, Yang B, Yu C, Yuan Y, Fang D, Xin Z, Guan R Abstract Postradical prostatectomy erectile dysfunction (pRP-ED) is a major health issue. There has been a shortage of an effective treatment method until now. In this study, a total of 48 adult male Sprague-Dawley (SD) rats were randomly equally divided into four groups, including group 1-sham surgery with cavernous nerve exposure plus vehicle, group 2-bilateral cavernous nerve injury (BCNI) plus vehicle, group 3-BCNI plus adipose-derived mesenchymal stem cells (ADSCs)-derived exosomes (ADSC-Exo), and group 4-BCNI plus bone marrow-derived mesenchymal stem cell (BMSCs)-derived exosomes (BMSC-Exo). Twenty-one days following surgery, erectile function was measured before tissue harvest. Histologic and Western blot analyses were then performed. Exosomes were capable of internalization into human umbilical vein endothelial cells (HUVEC) in vitro and could be detected in the corpus cavernosum in vivo. The nNOS expression in the penile dorsal nerves (DN) and major pelvic ganglion (MPG), protein level of neurofilament in the DN, endothelial markers vWF, alpha smooth muscle actin (α-SMA), the ratio of smooth muscle to collagen content were obviously lower in BCNI group compared with the sham group, while ADSC-Exo and BMSC-Exo groups resulted in significant restoration of the above histopathological changes. Moreover, BCNI treated with ADSC-Exo or BMSC-Exo had significantly higher mean intracavernous pressure/mean arterial pressure ratio compared with BCNI group. The results demonstrated that both ADSC-Exo and BMSC-Exo treatment could significantly alleviate pathological changes and improve the erectile function in BCNI-related rats. Exosomes derived from ADSCs and BMSCs may be a potential agent for pRP-ED treatment. PMID: 30009463 [PubMed - as supplied by publisher]
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Related Articles Down-regulation of lncRNA MEG3 promotes endothelial differentiation of bone marrow derived mesenchymal stem cells in repairing erectile dysfunction. Life Sci. 2018 Sep 01;208:246-252 Authors: Sun X, Luo LH, Feng L, Li DS Abstract AIMS: In the treatment of diabetes mellitus associated erectile dysfunction (DMED), the intracavernous and periprostatic implantations of bone marrow derived mesenchymal stem cells (BM-MSCs) represent the new therapeutic approaches with great applied prospect. However, the specific mechanisms of BM-MSCs protecting erectile function remain largely unknown. MATERIALS AND METHODS: The DMED rats were induced and the erectile function was assessed in the models with or without BM-MSCs implantation using intracavernous pressure (ICP)/mean arterial pressure (MAP) ratio. The differentiation of BM-MSCs toward endothelial cells (ECs) was induced by exogenous vascular endothelial growth factor (VEGF) in vitro. RNA pull-down and RIP assays were performed to explore the interaction between MEG3 and FOXM1 protein. KEY FINDINGS: Intracavernous implantation of BM-MSCs effectively improved the erectile function of DMED rats, which was accompanied by a significant decrease in the expression of MEG3 in the corpus cavernosum tissues. Also, our study revealed that MEG3 expression was significantly down-regulated during the endothelial differentiation of BM-MSCs in vitro. The down-regulation of MEG3 was further confirmed to be conducive to the differentiation of BM-MSCs toward ECs. More importantly, MEG3 promoted the degradation of FOXM1 protein via facilitating FOXM1 ubiquitination, thereby decreasing VEGF expression, which ultimately regulated the endothelial differentiation of BM-MSCs. SIGNIFICANCE: Taken together, our findings presented the vital role of MEG3 in the repairing processes of BM-MSCs for erectile function and provided new mechanistic insights into the BM-MSCs-mediated DMED repairing. PMID: 30012476 [PubMed - indexed for MEDLINE]
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Related Articles Restorative effect of resveratrol on expression of endothelial and neuronal nitric oxide synthase in cavernous tissues of chronic unpredictable mild stress-exposed rats: an impact of inflammation. Int J Impot Res. 2018 Nov;30(6):318-326 Authors: Yazir Y, Demirtaş Şahin T, Furat Rençber S, Gacar G, Halbutoğulları ZS, Utkan T, Aricioglu F Abstract We investigated the effect of resveratrol on endothelial and neuronal nitric oxide synthase (eNOS and nNOS) expression in the corpus cavernosum from chronic unpredictable mild stress (CUMS)-exposed rats in order to examine possible role of proinflammatory cytokines, which might play a role on erectile dysfunction (ED). Rats were randomly and equally divided into four groups such as control, control+resveratrol, CUMS and CUMS + resveratrol (20 mg/kg/day, i.p/8 weeks). Sucrose intake and forced swimming tests were used to evaluate depressive-like behaviors. nNOS, eNOS expressions, inflammatory markers, corticosterone and testosterone levels were analyzed either in blood samples and/or penile tissues. CUMS-exposed rats displayed depressive-like behaviors, reduced penile nNOS and eNOS expressions, and serum testosterone levels and enhanced serum and penile tissue levels of proinflammatory markers compared to controls. Resveratrol reversed depressive-like behaviors and suppressed serum and penile levels of proinflammatory markers, increased nNOS and eNOS expressions and testosterone levels in CUMS-exposed rats. Resveratrol exerted antidepressant-like effects and protected the development of CUMS-induced impairment of cavernosal eNOS and nNOS expressions associated with ED, which might be related to its anti-inflammatory action. PMID: 30050074 [PubMed - in process]
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Related Articles Depression induced by chronic stress leads to penile cavernosal dysfunction: protective effect of anti-TNF-α treatment. Can J Physiol Pharmacol. 2018 Sep;96(9):933-942 Authors: Demirtaş Şahin T, Yazir Y, Utkan T, Gacar G, Halbutoğulları ZS, Gocmez SS Abstract Psychological stress may lead to erectile dysfunction (ED), and inflammation has been evaluated as a major contributing factor. The goal of this study was to investigate the effects of etanercept (ETN), an anti-tumor necrosis factor α (TNF-α) protein, on cavernosal function in the unpredictable chronic mild stress (UCMS) rat model of depression. Animals were divided into 4 groups: animals not exposed to UCMS, animals not exposed to UCMS and treated with ETN, animals exposed to UCMS, and animals treated with ETN while exposed to UCMS. UCMS significantly impaired the neurogenic and endothelium-dependent relaxation responses; reduced cavernosal endothelial nitric oxide (NO) synthase (eNOS) and neuronal NO synthase (nNOS) expressions; decreased testosterone levels; enhanced systemic levels of corticosterone, TNF-α, interleukin 1β (IL-1β), interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule 1 (ICAM-1); and also increased cavernosal levels of TNF-α, IL-1β, and IL-6 in rats. ETN administration restored NO-mediated neurogenic and endothelium-dependent relaxation responses of the corpus cavernosum, increased cavernosal eNOS and nNOS expressions, enhanced testosterone levels, and decreased corticosterone levels in UCMS-exposed rats. Also, systemic inflammatory markers and cavernosal proinflammatory cytokine levels were reduced by ETN. Our results demonstrate the role of TNF-α-mediated inflammation in the development of depression and ED in rats exposed to chronic stress. PMID: 30052465 [PubMed - indexed for MEDLINE]
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Related Articles Pharmacotherapy for erectile dysfunction in diabetic males. Expert Opin Pharmacother. 2018 Aug;19(12):1345-1356 Authors: El-Sakka AI Abstract INTRODUCTION: Numerous studies have highlighted the intimate association between erectile dysfunction (ED) and diabetes mellitus (DM). However, the true pathogenesis of ED among diabetic men has not yet been fully discovered. The treatment of ED in diabetic patients remains an interesting area of research. The last two decades have witnessed phenomenal advances in the management of ED with the efficacy of pharmacotherapy for ED in diabetic patients encouraging, especially with introduction of innovative conservative tools for treatment. Areas covered: The aim of this review is to discuss the currently available information on ED pharmacotherapy in diabetic males and provide an expert perspective on the current treatment strategies. Expert opinion: Conservative treatment remains the initial step for the treatment of ED in diabetic patients. This kind of therapy consists of different modalities including: oral treatments, intracavernosal pharmacotherapy, and evolving modalities such as soluble guanylate cyclase activators, stem cells (SCs), and alternative treatments such as herbal treatment and transdermal/topical pharmacotherapy. However, it should be noted that the currently available pharmacotherapy is still far from ideal. One hopes to witness new drugs and technologies that may revolutionize ED treatment in the future, especially in such complex cases as DM. PMID: 30106605 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell therapy in erectile dysfunction: science fiction or realistic treatment option? Hormones (Athens). 2018 Sep;17(3):315-320 Authors: Vakalopoulos I, Memmos D, Mykoniatis I, Toutziaris C, Dimitriadis G Abstract Stem cell therapy has become a subject of great interest to researchers worldwide. One of the medical conditions being studied for possible treatment with the use of stem cells is erectile dysfunction, and particularly organic and post-radical prostatectomy erectile dysfunction. However, is stem cell therapy a viable treatment option for erectile dysfunction? The current body of literature provides a wide array of clinical trials performed on animal models simulating different types of human erectile dysfunction. Unfortunately, only a handful of studies have been performed on human patients and almost all of them were phase 1 studies limited by the small sample size. This review aims to summarize the available evidence on the use of stem cell therapy for the treatment of erectile dysfunction and also to provide an overview of upcoming and ongoing clinical trials in this field. PMID: 30132303 [PubMed - in process]
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Related Articles Safety and Potential Therapeutic Effect of Two Intracavernous Autologous Bone Marrow Derived Mesenchymal Stem Cells injections in Diabetic Patients with Erectile Dysfunction: An Open Label Phase I Clinical Trial. Urol Int. 2018;101(3):358-365 Authors: Al Demour S, Jafar H, Adwan S, AlSharif A, Alhawari H, Alrabadi A, Zayed A, Jaradat A, Awidi A Abstract OBJECTIVES: This open label, phase I clinical trial (NCT02945462) using 2 consecutive intracavernous autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) for the first time in the treatment of diabetic patients with erectile dysfunction (ED). The primary outcome is to assess the safety and tolerability of intracavernous autologous BM-MSCs, the secondary outcome is to assess efficacy of the procedure. PATIENTS AND METHODS: Four diabetic patients with refractory ED were included. Two consecutive intracavernous autologous BM-MSC injections were performed. Tolerability was assessed immediately and at 24 h, safety was evaluated for 2 years. Efficacy was assessed using International Index of Erectile Function-15 (IIEF-15) and Erection Hardness Score (EHS) for 12 months. RESULTS: procedure was well tolerated and no patients reported significant adverse effects. There was significant improvement of IIEF-15 and EHS; IIEF-15 (p = 0.04), Erectile Function (p = 0.03), Sexual Desire (p = 0.04), Intercourse Satisfaction (p = 0.04), and Overall Satisfaction (p = 0.04). CONCLUSION: This is the first human study with proven tolerability, safety and efficacy of intracavernous autologous BM-MSC injections for treatment of diabetic patients with ED. PMID: 30173210 [PubMed - in process]
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Related Articles [Protective effect of urine-derived stem cells on erectile dysfunction in rats with cavernous nerve injury]. Zhonghua Nan Ke Xue. 2018 Jun;24(6):483-490 Authors: Chen WM, Yang QY, Bian J, Han DY, Lai DH, Sun XZ, Deng CH Abstract Objective: To investigate the protective effect of human urine-derived stem cells (USCs) on erectile function and cavernous structure in rats with cavernous nerve injury (CNI). METHODS: Sixty adult male SD rats with normal sexual function were randomly divided into four groups of equal number: sham operation, bilateral CNI (BCNI) model control, phosphate buffered saline (PBS), and USC. The BCNI model was established in the latter three groups of rats by clamping the bilateral cavernous nerves. After modeling, the rats in the PBS and USC groups were treated by intracavernous injection of PBS at 200 μl and USCs at 1×106/200 μl PBS respectively for 28 days. Then, the maximum intracavernous pressure (mICP) and the ratio of mICP to mean arterial pressure (mICP/MAP) of the rats were calculated by electrical stimulation of the major pelvic ganglions, the proportion of nNOS- or NF200-positive nerve fibers in the total area of penile dorsal nerves determined by immunohistochemical staining, the levels of endothelial cell marker eNOS, smooth muscle marker α-SMA and collagen I detected by Western blot, and the smooth muscle to collagen ratio and the cell apoptosis rate in the corpus cavernosum measured by Masson staining and TUNEL, respectively. RESULTS: After 28 days of treatment, the rats in the USC group, as compared with those in the PBS and BCNI model control groups, showed significant increases in the mICP ([81 ± 9.9] vs [31 ± 8.3] and [33 ± 4.2] mmHg, P <0.05), mICP/MAP ratio (0.72 ± 0.05 vs 0.36 ± 0.03 and 0.35 ± 0.04, P <0.05), the proportions of nNOS-positive nerve fibers ([11.31 ± 4.22]% vs [6.86 ± 3.08]% and [7.29 ± 4.84]% , P <0.05) and NF200-positive nerve fibers in the total area of penile dorsal nerves ([27.31 ± 3.12]% vs [17.38 ± 2.87]% and [19.49 ± 4.92]%, P <0.05), the eNOS/GAPDH ratio (0.52 ± 0.08 vs 0.31 ± 0.06 and 0.33 ± 0.07, P <0.05), and the α-SMA/GAPDH ratio (1.01 ± 0.09 vs 0.36 ± 0.05 and 0.38 ± 0.04, P <0.05), but a remarkable decrease in the collagen I/GAPDH ratio (0.28 ± 0.06 vs 0.68 ± 0.04 and 0.70 ± 0.10, P <0.05). The ratio of smooth muscle to collagen in the corpus cavernosum was significantly higher in the USC than in the PBS and BCNI model control groups (17.91 ± 2.86 vs 7.70 ± 3.12 and 8.21 ± 3.83, P <0.05) while the rate of cell apoptosis markedly lower in the former than in the latter two (3.31 ± 0.83 vs 9.82 ± 0.76, P <0.01; 3.31 ± 0.83 vs 9.75 ± 0.91, P <0.05). CONCLUSIONS: Intracavernous injection of USCs can protect the erectile function of the rat with cavernous nerve injury by protecting the nerves, improving the endothelial function, alleviating fibrosis and inhibiting cell apoptosis in the cavernous tissue. PMID: 30173451 [PubMed - in process]
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Related Articles Stem cell in urology-are we at the cusp of a new era? Transl Androl Urol. 2018 Aug;7(4):653-658 Authors: Panda A Abstract Stem cell therapy can potentially disrupt conventional medicine as we practice it today. Stem cells can self-renew and differentiate and by this, repair and in certain conditions regenerate damaged tissue. In the past two decades, there has been significant research into its value in several chronic urological conditions for which conventional therapy is unsatisfactory. Stem cell therapy has been tried on animal models of bladder dysfunction, stress urinary incontinence (SUI), erectile dysfunction and urethral injury and certain preclinical studies have had very encouraging results. Yet despite this explosion of knowledge about the nature and value of stem cells, translation of research into the clinical domain has been slow. In addition, lack of regulation of stem cell therapy has resulted in indiscriminate, unscientific administration of stem cell therapy to patients. This review looks into the advances in the use of stem cells in urological practice, the recent regulatory guidelines that have been introduced and what the future holds for this exciting branch. PMID: 30211055 [PubMed]
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Related Articles Efficient Promotion of Autophagy and Angiogenesis Using Mesenchymal Stem Cell Therapy Enhanced by the Low-Energy Shock Waves in the Treatment of Erectile Dysfunction. Stem Cells Int. 2018;2018:1302672 Authors: Zhu GQ, Jeon SH, Bae WJ, Choi SW, Jeong HC, Kim KS, Kim SJ, Cho HJ, Ha US, Hong SH, Lee JY, Kwon EB, Kim SW Abstract Background: Mesenchymal stem cell therapy (MSCT) and defocused low-energy shock wave therapy (ESWT) has been shown to ameliorate erectile dysfunction (ED). However, the interactions and effects of action between MSCT and ESWT remain poorly understood. In this study, we investigated the mechanisms of combination therapy with MSCT and ESWT in a rat model of diabetic ED. Materials and Methods: Eight-week-old male Sprague-Dawley rats were randomly divided into 2 parts. Diabetic rats induced by streptozotocin (65 mg/kg) were randomly divided into 4 groups: (1) DM control group, (2) DM + ESWT group, (3) DM + MSCT group, and (4) DM + ESWT + MSCT group. The sham group was a normal control group (without streptozotocin). MSCT and (or) ESWT were, respectively, administered to each group according to the proposal for 8 weeks. Immediately after recording of intracavernous pressure (ICP), the penis was then harvested for histologic analysis, ELISA, and Western blotting. Results: The ratio of ICP/MAP was significantly higher in the DM + ESWT + MSCT group than in ESWT or MSCT treated group (P < 0.05). Also, the treatment stimulated angiogenesis and vasodilatation in the corpus cavernosum (P < 0.05). ESWT increased the quantity of MSCs in the corpus cavernosum and also induced MSCs to express more VEGF in vitro and vivo (P < 0.05) which activated the PI3K/AKT/mTOR and NO/cGMP signaling pathways in the corpus cavernosum. The combination approach stimulated autophagy and decreased apoptosis in the corpus cavernosum. NGF and BDNF expressions were higher in the DM + ESWT + MSCT group than in the DM control group (P < 0.01). Furthermore, the treatment promoted the MSC recruitment by inducing penile tissues to express more PECAM and SDF-1. Conclusions: Combination of LI-ESWT and MSCT can get a better result than a single treatment by expressing more VEGF which can take part in autophagy by triggering the PI3K/AKT/mTOR signaling pathway. This cooperative therapy would provide a new research direction in ED treatment for the future. PMID: 30228820 [PubMed]
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Related Articles MSC-derived exosomes ameliorate erectile dysfunction by alleviation of corpus cavernosum smooth muscle apoptosis in a rat model of cavernous nerve injury. Stem Cell Res Ther. 2018 Sep 26;9(1):246 Authors: Ouyang X, Han X, Chen Z, Fang J, Huang X, Wei H Abstract BACKGROUND: This study investigated the therapeutic effects of MSC-derived exosomes (MSC-Exos) on erectile function in a rat model of cavernous nerve injury (CNI). METHODS: MSCs were isolated from rat bone marrow and exosomes were isolated from the supernatants by ultracentrifugation. The tissue explant adherent method was used to isolate and culture corpus cavernosum smooth muscle cells (CCSMCs). MSCs and CCSMCs were identified by flow cytometry, in vitro differentiation or immunofluorescence staining. Thirty-two 10-week-old male Sprague Dawley (SD) rats were divided into four groups: a sham operation group and bilateral CNI groups that received intracavernosal (IC) injection of either PBS, MSCs or MSC-Exos. Four weeks after CNI and treatment, the erectile function of the rats was measured by electrically stimulating the cavernous nerve. The penile tissues were harvested for blinded histologic analysis and western blotting. H2O2 was used to induce apoptosis in the CCSMCs, and a flow cytometer was used to measure the cell viability of the CCSMCs treated with or without exosomes in vitro. RESULTS: Recovery of erectile function was observed in the MSC-Exos group. The MSC-Exos treatment significantly enhanced smooth muscle content and neuronal nitric oxide synthase in the corpus cavernosum. The ratio of smooth muscle to collagen in the corpus cavernosum was significantly improved in the MSC-Exos treatment group compared to the PBS vehicle group. WB confirmed these biological changes. Cell viability of the CCSMCs was increased in the MSC-Exos-treated groups, and caspase-3 expression was decreased after the MSC-Exos treatment in vivo and in vitro. CONCLUSIONS: Exosomes isolated from MSCs culture supernatants by ultracentrifugation could ameliorate CNI-induced ED in rats by inhibiting apoptosis in CCSMCs, with similar potency to that observed in the MSCs-treated group. Therefore, this cell-free therapy has great potential for application in the treatment of CNI-induced ED for replacing cell therapy. MSC-derived exosomes ameliorate erectile dysfunction in a rat model of cavernous nerve injury. PMID: 30257719 [PubMed - in process]
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Related Articles Intratunical Injection of Stromal vascular fraction prevents Fibrosis in a Rat Model of Peyronie's Disease. BJU Int. 2018 Sep 29;: Authors: Castiglione F, Hedlund P, Weyne E, Hakim L, Montorsi F, Salonia A, Bivalacqua TJ, De Ridder D, Milenkovic U, Ralph D, Garaffa G, Muneer A, Joniau S, Albersen M, Trauma and Reconstructive Urology Working Party of the European Association of Urology (EAU) Young Academic Urologists (YAU) Abstract OBJECTIVE: Previous studies have shown that the injection of adipose tissue-derived stem cells (ADSCs) into the tunica albuginea (TA) during the active phase of the Peyronie's disease (PD) prevents the development of fibrosis and elastosis in the TA and corpus cavernosum The aim of this study was to investigate whether local injection of autologous adipose stromal vascular fraction (SVF) can prevent the development of fibrosis and elastosis in the TA using a rat model of acute phase of the Peyronie's disease (PD) METHODS: A total of 24 male 12-wk-old Sprague-Dawley rats were divided in three equal groups: sham, PD without treatment (TGFB) and PD treated with SVF (SVF) 1 day after disease induction. Sham rats underwent 2 injections of vehicle into the TA one day apart. TGFB rats underwent TGF- β1 injection and injection of vehicle one day later. SVF rats underwent TGF-β1 injection followed by SVF one day later. One month after treatment all rats underwent measurement of intracorporal pressure (ICP) and mean arterial (MAP) pressure during electrostimulation of the cavernous nerve. Following euthanasia, penises were again harvested for histology and Western blot. RESULTS: Erectile function was moderately reduced in the TGFB group and was significantly improved after SVF treatment (p < 0.05). PD animals developed areas of fibrosis with a significant upregulation of collagen III, Collagen I and elastin protein expression. These fibrotic changes were prevented when treated with SVF. CONCLUSIONS: Local injection of SVF may represent a treatment for the acute phase of PD. This article is protected by copyright. All rights reserved. PMID: 30267556 [PubMed - as supplied by publisher]
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Related Articles Advances in gene therapy for erectile dysfunction: promises and challenges. Curr Gene Ther. 2018 Oct 04;: Authors: Yu B, Wu C, Li T, Qin F, Yuan J Abstract Erectile dysfunction (ED) is a major health problem in men. Over the past few decades, oral phosphodiesterase type 5 (PDE5) inhibitors have been adopted as the recommended strategy to treat ED in the majority of cases. However, these oral medications require on-demand access and are not effective in some hard-to-treat populations. Other alternative treatments are also not satisfactory. In recent years, a novel therapeutic approach against ED, gene therapy, has shown great potential in preclinical models designed to provide long-term improvement of erectile function and the underlying conditions. Gene therapy refers to the use of viral and non-viral vectors to deliver therapeutic genes to tissues via direct or transduced cell-mediated approaches. With the growing knowledge of the molecular mechanisms involved in the pathophysiology of ED, a number of therapeutic gene strategies have been extensively tested and proven to be effective in many animal models. However, only few of them have been evaluated in clinical trials. Safety concerns are the major obstacles to be addressed before clinical application can be considered. In this review, we summarize the advancements in gene therapy for ED treatment, with an emphasis on the emerging stem cell-based approaches, as well as other combinational strategies. The challenges facing its future application for ED treatment are also discussed. PMID: 30289066 [PubMed - as supplied by publisher]
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Related Articles Erectile dysfunction treated with intracavernous stem cells: A promising new therapy? Rev Int Androl. 2018 Jul - Sep;16(3):119-127 Authors: Gómez-Guerra LS, Robles-Torres JI, Garza-Bedolla A, Mancías-Guerra C Abstract In the past decades, great interest has been shown in the development of new therapies for erectile dysfunction. Stem cell therapy has generated promising results in numerous preclinical trials in animal models, which is why has led to the development of the first clinical trials in humans. The main cause involved in the pathophysiology of erectile dysfunction is vascular damage related to endothelial and neuronal injury. The interest in stem cell therapy is justified by their capability to differentiate into specific damaged tissues, including endothelium and nervous tissue, and induction of the host own cell proliferation. Despite the great effort of the many studies carried out to date, knowledge about biological effects, therapeutic efficacy and safety of stem cells therapy for erectile dysfunction is still very limited. PMID: 30300133 [PubMed - in process]
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Related Articles Advances in stem cell therapy for erectile dysfunction. Expert Opin Biol Ther. 2018 Nov;18(11):1137-1150 Authors: Gur S, Abdel-Mageed AB, Sikka SC, Hellstrom WJG Abstract INTRODUCTION: Stem cell (SC) application is a promising area of research in regenerative medicine, with the potential to treat, prevent, and cure disease. In recent years, the number of studies focusing on SCs for the treatment of erectile dysfunction (ED) and other sexual dysfunctions has increased significantly. Areas covered: This review includes critical ED targets and preclinical studies, including the use of SCs and animal models in diabetes, aging, cavernous nerve injury, and Peyronie's disease. A literature search was performed on PubMed for English articles. Expert opinion: Combination treatment offers better results than monotherapy to improve pathological changes in diabetic ED. Regenerative medicine is a promising approach for the maintenance of sexual health and erectile function later in life. Cavernous nerve regeneration and vascular recovery employing SC treatment may be focused on radical prostatectomy-induced ED. Notwithstanding, there are a number of hurdles to overcome before SC-based therapies for ED are considered in clinical settings. Paracrine action, not cellular differentiation, appears to be the principal mechanism of action underlying SC treatment of ED. Intracavernosal injection of a single SC type should be the choice protocol for future clinical trials. PMID: 30301368 [PubMed - in process]
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Related Articles Engineered Mesenchymal Stem Cells Expressing Stromal Cell-derived Factor-1 Improve Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats. Int J Mol Sci. 2018 Nov 23;19(12): Authors: Jeon SH, Zhu GQ, Bae WJ, Choi SW, Jeong HC, Cho HJ, Ha US, Hong SH, Lee JY, Kwon EB, Kim HJ, Lee SM, Kim HY, Kim SW Abstract Effective therapies for erectile dysfunction (ED) associated with diabetes mellitus (DM) are needed. In this study, the effects of stromal cell-derived factor-1 (SDF-1)-expressing engineered mesenchymal stem cells (SDF-1 eMSCs) and the relevant mechanisms in the corpus cavernosum of a streptozotocin (STZ)-induced DM ED rat model were evaluated. In a randomized controlled trial, Sprague⁻Dawley (SD) rats (n = 48) were divided into four groups (n = 12/group): Normal (control), DM ED (diabetes induced by STZ), DM ED + BM-MSC (treated with bone marrow [BM]-derived MSCs), and DM ED + SDF-1 eMSC (treated with SDF-1-expressing BM-MSCs). After four weeks, intracavernosal pressure (ICP), an indicator of erectile function, was 0.75 ± 0.07 in the normal group, 0.27 ± 0.08 in the DM ED group, 0.42 ± 0.11 in the DM ED + BM-MSC group, and 0.58 ± 0.11 in the DM ED + SDF-1 eMSC group. BM-MSCs, especially SDF-1 eMSCs, improved ED (p < 0.05). SDF-1 eMSC treatment improved the smooth muscle content in the corpus cavernosum (p < 0.05). As SDF-1 expression increased, ED recovery improved. In the SDF-1 eMSC group, levels of neuronal nitric oxide synthase (nNOS) and phosphorylated endothelial NOS (p-eNOS) were higher than those in other groups (p < 0.05). In addition, high stromal cell-derived factor-1 (SDF-1) expression was associated with increased vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in DM ED rats (p < 0.05). Higher levels of phosphorylated protein kinase B (p-AKT)/protein kinase B (AKT) (p < 0.05) and B-cell lymphoma-2 (Bcl-2) and lower levels of the apoptosis factors Bcl2-associated x (Bax) and caspase-3 were observed in the MSC-treated group than in the DM ED group (p < 0.05). SDF-1 eMSCs showed beneficial effects on recovery from erectile function. PMID: 30477146 [PubMed - in process]
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Related Articles Long-Term Therapeutic Effect of Cell Therapy on Improvement in Erectile Function in a Rat Model with Pelvic Neurovascular Injury. BJU Int. 2018 Nov 30;: Authors: Gu X, Hua S, Ethan M, Zhong L, Long T, Clouse C, Li W, Chen D, Chung H, Murphy S, Yoo J, Lin G, Lu T, Atala A, John J, Zhang Y Abstract OBJECTIVE: To determine the long-term therapeutic effect among three types of human cell types on erectile function recovery in a rodent model of dual neurovascular injured erectile dysfunction (NVED). MATERIALS AND METHODS: A dual NVED model was established in athymic rats by crushing the bilateral cavernous nerves and ligations of the bilateral internal pudendal nerve-vessel bundles. At the time of defect creation, three different types of human cell populations (2.5x106 cells/0.2 ml), umbilical vein endothelial cells (UVEC), adipose derived stem cells (ADSC) and amniotic fluid derived stem cells (AFSC), were injected intracavernously into the penile tissue. Normal saline (NS) injection (0.2mL) served as a control group. Erectile function and histomorphological analyses of penile tissues were assessed 12 weeks after defect creation and cell or saline injection. RESULTS: The ratio of intracavernous pressure to mean artery pressure (functional indicator) significantly increased in the cell therapy groups, compared to the NS injection control group (p<0.05). Immunofluorescence staining showed increased numbers of cells expressing biomarkers of endothelial, smooth muscle, and nerve cells within the penile tissue in the cell therapy groups when compared to the NS injection control group. CONCLUSIONS: Cell therapy enhanced erectile function and ameliorated the histological changes 12 weeks after pelvic neurovascular injury in vivo, indicating that cell therapy may improve the long-term outcomes in neurogenic, myogenic and vascular tissue regeneration in the treatment of NVED. This article is protected by copyright. All rights reserved. PMID: 30499626 [PubMed - as supplied by publisher]
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Related Articles Un homme sur cinq en souffre. Rev Prat. 2017 Jun;67(6):616-622 Authors: Huyghe É Abstract News in erectile dysfunction. Erectile dysfunction (ED) is the most commonly treated sexual disorder affecting up to 20% of all men. As ED adversely affects the lives of millions of men, the public health implications of this condition are significant and represent a challenge for our healthcare system. Several options are available for treating ED : oral pharmacotherapy with phosphodiesterase 5 (PDE5) inhibitors represent so far the first-line option for many patients with ED. They are effective in three quarters of patients, with a similar response rate with the 4 available molecules (sildenafil, vardenafil, tadalafil and avanafil). Recently, an alprostadil cream (Vitaros) combining the active molecule with a skin enhancer has been allowed for usage in France. Low systemic adverse effects (3%), together with a high efficacy (up to 83%) make it a possible first-line therapeutic option for patients with ED who are reluctant to take systemic treatments. The intra-cavernous injections of alprostadil, the vacuum, and ultimately the penile implant (reserved for ED refractory to other treatments) remain effective therapeutic options that must be discussed with the patient. Other therapeutic options are currently under investigation, such as low-intensity shockwave lithotripsy, dopaminergic and melanocortin receptor agonists, which target central erectogenic pathways, soluble guanylate cyclases, rho-kinase inhibitors, and maxi-k channel activators that act peripherally. Newer formulations of existing medications, such as alprostadil and PDE5 inhibitors are also developed. Finally, stem cell regenerative techniques and gene therapy are promising new approaches to the treatment of erectile dysfunction. Most of these novel drugs have yet to reach Phase III studies. However, it is likely that in years to come, patients will be selectively treated with these novel agents as a monotherapy or in combination with others acting in a synergistic manner. PMID: 30512730 [PubMed]
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