Treatment Of Diabetic Erectile Dysfunction Research Articles

Differential Gene Expression in the Penile Cavernosum of Streptozotocin-Induced Diabetic Rats.

Men with diabetes mellitus (DM) often present with severe erectile dysfunction (ED). This ED is less responsive to current pharmacological therapies. If we know the upregulated or downregulated genes of diabetic ED, we can inhibit or enhance the expression of such genes through RNA or gene overexpression. To investigate gene changes associated with ED in type 1 DM, we examined the alterations of gene expression in the cavernosum of streptozotocin-induced diabetic rats. Specifically, we considered 11,636 genes (9,623 upregulated and 2,013 downregulated) to be differentially expressed in the diabetic rat cavernosum group (n=4) compared to the control group (n=4). The analysis of differentially expressed genes using the gene ontology (GO) classification indicated that the following were enriched: downregulated genes such as cell cycle, extracellular matrix, glycosylphosphatidylinositol-anchor biosynthesis and upregulated genes such as calcium signaling, neurotrophin signaling, apoptosis, arginine and proline metabolism, gap junction, transforming growth factor-β signaling, tight junction, vascular smooth muscle contraction, and vascular endothelial growth factor (VEGF) signaling. We examined a more than 2-fold upregulated or downregulated change in expression, using real time polymerase chain reaction. Analysis of differentially expressed genes, using the GO classification, indicated the enrichment. Of the 41,105 genes initially considered, statistical filtering of the array analysis showed 9,623 upregulated genes and 2,013 downregulated genes with at least 2-fold changes in expression (P<0.05). With Bonferroni correction, SLC2A9 (solute carrier family 2 member 9), LRRC20 (leucine rick repeat containing 20), PLK1 (polo like kinase 1), and AATK (apoptosis-associated tyrosine kinase) were all 2-fold changed genes. This study broadens the scope of candidate genes that may be relevant to the pathophysiology of diabetic ED. In particular, their enhancement or inhibition could represent a novel treatment for diabetic ED.

Comprehensive analysis of biological landscape of oxidative stress-related genes in diabetic erectile dysfunction.

Oxidative stress plays a pivotal role in the pathogenesis of diabetic erectile dysfunction, while specific mechanisms have not been illuminated. The study aims to reveal the genetic expression patterns of oxidative stress in diabetic erectile dysfunction. Transcriptome data of diabetic erectile dysfunction and oxidative stress-related genes (OSRGs) in the Gene Expression Omnibus database were downloaded and analyzed based on differential expression. Functional enrichment analyses were conducted to clarify the biological functions. A protein interaction framework was established, and significant gene profiles were validated in the cavernous endothelial cells, clinical patients, and rat models. A miRNA-OSRGs network was predicted and validated. The results were analyzed using Student's t-test. The analysis screened 203 differentially expressed OSRGs (p < 0.05), which had a close association with oxidoreductase activities, glutathione metabolism, and autophagy. A four-gene signature comprised of EPS8L2 (p = 0.044), GSTA3 (p = 0.015), LOX (p < 0.001) and MGST1 (p = 0.002) was well validated and regarded as the hub OSRGs. Compared with the control group, notable increases and decreases were observed in the expressions of GSTA3 (3.683 ± 0.636 vs. 0.416 ± 0.507) and LOX (2.104 ± 1.895 vs. 18.804 ± 2.751) in the validated diabetic erectile dysfunction group. The hub OSRGs-related miRNAs participated in smooth muscle cell proliferation. Besides, miR-125a-3p (p = 0.034) and miR-138-2-3p (p = 0.012) were validated as promising oxidative stress-related miRNA biomarkers. Our findings revealed the genetic alternations of oxidative stress in diabetic erectile dysfunction. These results will be instructive to explore the molecular landscape and the potential treatment for diabetic erectile dysfunction.

Traditional chinese medicine to prevent and treat diabetic erectile dysfunction.

Diabetic erectile dysfunction (DED) is one of the most common complications of diabetes mellitus. However, current therapeutics have no satisfactory effect on DED. In recent years, traditional Chinese medicine (TCM) has shown good effects against DED. By now, several clinical trials have been conducted to study the effect of TCM in treating DED; yet, the underlying mechanism is not fully investigated. Therefore, in this review, we briefly summarized the pathophysiological mechanism of DED and reviewed the published clinical trials on the treatment of DED by TCM. Then, the therapeutic potential of TCM and the underlying mechanisms whereby TCM exerts protective effects were summarized. We concluded that TCM is more effective than chemical drugs in treating DED by targeting multiple signaling pathways, including those involved in oxidation, apoptosis, atherosclerosis, and endothelial function. However, the major limitation in the application of TCM against DED is the lack of a large-scale, multicenter, randomized, and controlled clinical trial on the therapeutic effect, and the underlying pharmaceutical mechanisms also need further investigation. Despite these limitations, clinical trials and further experimental studies will enhance our understanding of the mechanisms modulated by TCM and promote the widespread application of TCM to treat DED.

Low-Intensity Pulsed Ultrasound Enhanced Adipose-Derived Stem Cell-Mediated Angiogenesis in the Treatment of Diabetic Erectile Dysfunction through the Piezo-ERK-VEGF Axis.

Objectives Erectile dysfunction is a major comorbidity of diabetes. Stem cell transplantation is a promising method to treat diabetic erectile dysfunction. In this study, we evaluated whether low-intensity pulsed ultrasound (LIPUS) could enhance the efficacy of adipose-derived stem cells (ADSCs) and investigated the underlying molecular mechanism. Materials and methods. Sixty 8-week-old male Sprague–Dawley rats were randomly divided into the normal control (NC) cohort or the streptozocin-induced diabetic ED cohort, which was further subdivided into DM, ADSC, LIPUS, and ADSC+LIPUS groups. Rats in the ADSC or ADSC+LIPUS group received ADSC intracavernosal injection. Rats in the LIPUS or ADSC+LIPUS group were treated with LIPUS. The intracavernous pressure (ICP) and mean arterial pressure (MAP) were recorded at Day 28 after injection. The corpus cavernosum tissues were harvested and subjected to histologic analysis and ELISA. The effects of LIPUS on proliferation and cytokine secretion capacity of ADSCs were assessed in vitro. RNA sequencing and bioinformatic analysis were applied to predict the mechanism involved, and western blotting and ELISA were used for verification. Results Rats in the ADSC+LIPUS group achieved significantly higher ICP and ICP/MAP ratios than those in the DM, ADSC, and LIPUS groups. In addition, the amount of cavernous endothelium and cGMP level also increased significantly in the ADSC+LIPUS group. In vitro experiments demonstrated that LIPUS promoted proliferation and cell cycle progression in ADSCs. The excretion of cytokines such as CXCL12, FGF2, and VEGF was also enhanced by LIPUS. Bioinformatic analysis based on RNA sequencing indicated that LIPUS stimulation might activate the MAPK pathway. We confirmed that LIPUS enhanced ADSC VEGF secretion through the Piezo-ERK pathway. Conclusion LIPUS enhanced the curative effects of ADSCs on diabetic erectile dysfunction through the activation of the Piezo-ERK-VEGF pathway. ADSC transplantation combined with LIPUS could be applied as a synergistic treatment for diabetic ED.

NLRP3 downregulation enhances engraftment and functionality of adipose-derived stem cells to alleviate erectile dysfunction in diabetic rats.

BackgroundThe transplantation of adipose-derived stem cells (ASCs) is a most promising treatment for diabetic erectile dysfunction (DMED). However, the effect of high glucose on the post-transplantation survival of stem cells limits the efficacy of ASCs transplantation. Prolonging the survival time of ASCs in vivo after transplantation is a key issue in the utilization of ASCs for DMED. Herein, we aimed to investigate the therapeutic effect of ASCs by downregulating NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) as well as its mechanism of action in DMED.MethodsASCs were obtained by isolating subcutaneous fat from SD rats and were identified using lipogenic and osteogenic differentiation assays, as well as flow cytometric analysis. The shNLRP3 lentivirus with the best downregulating effect was screened, and shNLRP3 lentivirus (LV-shNLRP3) was transfected into ASCs (ASCsshNLRP3) to detect apoptosis and the reactive oxygen species (ROS) levels in each group under high glucose conditions. In DMED rats, ASCsLV-shNLRP3, ASCsLV-control, or phosphate buffered saline (PBS) were administrated via intra-cavernous injection, and normal rats served as normal controls. One week post-injection, animal imaging was performed to track the ASCs. Four weeks post-injection, erectile function was evaluated by measuring the intra-cavernosal pressure and mean arterial pressure. Corpus cavernosum pyroptosis and endothelial function were examined by western blotting and immunofluorescence.ResultsNLRP3-mediated pyroptosis might be a pathogenic mechanism of ED and DMED. ASCs were isolated successfully. Thereafter, the LV-shNLRP3 with the highest transfection efficiency was selected and used to modify ASCs successfully. LV-shNLRP3 could protect ASCs paracrine function under hyperglycemia through anti-apoptosis and anti-ROS deposition mechanisms. Furthermore, ASCsLV-shNLRP3 showed an advantage in the suppression of pyroptosis compared to ASCsLV-control. The ASCsLV-shNLRP3 group had improved cavernous endothelial function and smooth muscle injury, thus reversing erectile function, and was superior to the ASCsLV-control group.ConclusionsNLRP3 Inflammasome-mediated pyroptosis might be involved in DMED formation. Intra-cavernous injection of ASCsLV-shNLRP3 could suppress cavernosal pyroptosis, contributing to improved erectile function in DMED rats.

Progress and prospect of stem cell therapy for diabetic erectile dysfunction.

Diabetic erectile dysfunction (DED) is a common complication of diabetes mellitus, significantly impairing the quality of life of patients. The conventional clinical treatment still has limitations. Stem cells (SCs), as a type of cells with multidirectional or directional differentiation capability and sustainable self-renewal potential, are widely used in regenerative medicine and tissue engineering. With the continuous update of regenerative medicine theory and the success of animal experiments, SCs as a treatment for male erectile dysfunction, especially DED, have attracted widespread attention because of curable possibility. This review focus on the current progress in the clinical application of SC treatment for DED. Moreover, we summarize the development prospects of SCs in the field of DMED therapy.

Artificial intelligence based identification of the functional role of hirudin in diabetic erectile dysfunction treatment

Diabetic erectile dysfunction (DED) hugely affected the patients' sexual life quality. However, there are no satisfactory therapeutic methods and intervention targets for this subtype of erectile dysfunction (ED). Inspired by the clinical practice of traditional Chinese medicine (TCM), we found that hirudin, the main active ingredient in the leech, could ameliorate the ED symptoms of the DED mouse model. To further reveal the underlying mechanism of hirudin, we designed a novel strategy to discover potential targets based on the diagnostic system of TCM, and found that myeloperoxidase (MPO) was a promising target of hirudin. Hirudin directly interacts with MPO and inhibits its activity, thus further decreases the content of oxidized low-density lipoprotein (ox-LDL) in serum. Our results demonstrated that the hirudin could ameliorate the symptoms of DED, and revealed the underlying mechanism of hirudin in regulating the activity of MPO.

Injectable and self-healing hydrogel as a stem cells carrier for treatment of diabetic erectile dysfunction.

Diabetic erectile dysfunction has witnessed extensive preclinical and clinical explorations of intracavernous injection of stem cells therapy. However, intracavernous injection of stem cells for diabetic erectile dysfunction is challenged by rapid diffusion from cavernous sinus. Here, we found that a benzaldehyde terminated poly (ethylene glycol)/glycol chitosan (CHO-PEG/GCS) hydrogel with injectability and self-healability served as a stem cell carrier to prolong cell retention in corpus cavernosum. It was able to gelate under physiological condition and encapsulate adipose stem cells (ASCs) without reducing proliferation after injection. Encapsulated labelled ASCs presented higher fluorescence than non-encapsulated ones in the region of penis at 14days after intracavernous injection in male rats. CHO-PEG/GCS hydrogel enhanced ASCs to ameliorate diabetes-induced fibrosis and apoptosis of CD31-positive endothelial cells, α-SMA-positive smooth muscle and NeuN-positive neural fibers 12weeks post-operation. It also synergized with ASCs to elevate cGMP level and promote erectile function. CHO-PEG/GCS hydrogel serves as a promising stem cell carrier in conditions requiring injection and in situ gelation to prolong cell retention.

Erectile dysfunction in diabetes mellitus: A review

The International Diabetes Federation estimates that globally there are 425 million people with diabetes. Estimates of the prevalence of erectile dysfunction (ED) in men with diabetes range from 20% to 85% in different studies. Among men with ED, those with diabetes are likely to experience the problem 10–15 years earlier than men without diabetes. This review aims to provide an update of the epidemiology, pathophysiology and management of ED in diabetes patients in India. The proposed mechanisms of ED in diabetic patients include elevated advanced glycation end-products and increased levels of oxygen-free radicals, impaired nitric oxide (NO) synthesis, increased endothelin B receptor binding sites and ultrastructural changes, upregulated RhoA/Rho-kinase pathway, NO-dependent selective nitrergic nerve degeneration and impaired cyclic guanosine monophosphate-dependent kinase-1. Modifiable risk factors for ED include smoking, lack of physical activity, wrong diets, overweight or obesity, metabolic syndrome and excessive alcohol consumption. Therefore, the promotion of healthful lifestyles would yield great benefits in reducing the burden of ED. The treatment of diabetic ED is multimodal. The treatment of the underlying hyperglycaemia and comorbidities is of utmost importance to prevent the progression of the disease. The peripherally acting oral phosphodiesterase type 5 inhibitors are the mainstay of oral medical treatment of ED in diabetics. Vacuum erection devices are an additional a non-invasive treatment option. The local administration of vasoactive medication through urethral suppository or intracorporal injection can be effective with minimal side-effects.

Comparison of Improving Effects for Diabetic Erectile Dysfunction according to the Anti-Glycemic Agents: Phlorizin and Insulin.

PurposeTo compare the improving effects of diabetic erectile dysfunction with two anti-glycemic agents; phlorizin and insulin.Materials and MethodsSixty Sprague-Dawley rats were divided into four groups (n=15 in each group): normal control (C), untreated diabetic rats (D), and diabetic rats treated by phlorizin (P) or insulin (I). Ten weeks after the diabetic induction using an injection of streptozotocin (55 mg/kg), four weeks of diabetic control was conducted. Erectile response, Western blot, and immunohistochemistry were assessed.ResultsDuring the experiment, the C-group showed continuous weight gain, while the other groups suffered from weight loss. After start of diabetic control, the body weight of I-group was increased; whereas, there was no meaningful change in the P-group. Meanwhile, comparable blood glucose levels were achieved in the P- and I-groups. The erectile response was markedly decreased in the D-group, whereas the P- and I-groups were similar as good as the C-group. In addition, D-group showed the significant decrease in the cavernosal smooth muscle content and increased apoptosis. Platelet endothelial cell adhesion molecule-1 protein expression, phosphorylation of endothelial nitric oxide synthase and myosin phosphatase target subunit 1 were significantly distorted in the D-group, while the P- and I-groups were comparable with the C-group.ConclusionsPhlorizin treatment resulted in the improvement of erectile function as same as insulin despite the lack of anabolic weight gains. These results suggest that control of blood glucose level rather than a type of anti-glycemic agents is more important for the prevention and treatment of diabetic erectile dysfunction

Pancreatic kininogenase improves erectile function in streptozotocin-induced type 2 diabetic rats with erectile dysfunction.

Erectile dysfunction (ED) associated with type 2 diabetes is a severe problem that requires effective treatment. Pancreatic kininogenase (PK) has the potential to improve the erectile function of ED patients. This study aims to investigate the effect of PK on erectile function in streptozotocin-induced type 2 diabetic ED rats. To achieve this goal, we divided male Sprague–Dawley rats into five groups. One group was not treated, and the other four groups were treated with saline, sildenafil, PK or sildenafil, and PK, respectively, for 4 weeks after the induction of type 2 diabetic ED. Then, intracavernous pressure under cavernous nerve stimulation was measured, and penile tissue was collected for further study. Endothelial nitric oxide synthase levels, smooth muscle content, endothelium content, cyclic guanosine monophosphate (cGMP) levels in the corpus cavernosum, and neuronal nitric oxide synthase levels in the dorsal penile nerve were measured. Improved erectile function and endothelium and smooth muscle content in the corpus cavernosum were observed in diabetic ED rats. When treating diabetic ED rats with PK and sildenafil at the same time, a better therapeutic effect was achieved. These data demonstrate that intraperitoneal injection of PK can improve erectile function in a rat model of type 2 diabetic ED. With further research on specific mechanisms of erectile function improvement, PK may become a novel treatment for diabetic ED.

Transplantation of adipose tissue-derived stem cell-derived exosomes ameliorates erectile function in diabetic rats.

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.

Stem Cell Therapy for Diabetic Erectile Dysfunction in Rats: A Meta-Analysis.

IntroductionStem 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.AimsThis 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.MethodsWe 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.Results10 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.ConclusionsOur 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.

A review of the efficacy and safety of mirodenafil in the management of erectile dysfunction.

Erectile dysfunction (ED) is a common disorder that can jeopardize quality of life and the partnership of patients and their sexual partners. The advent of oral phosphodiesterase type 5 inhibitors (PDE5Is) has revolutionized a treatment for ED, and they are recognized as the first-line therapy for ED, regardless of its etiology. Mirodenafil, a second-generation PDE5I, has biochemical profiles such as high affinity for PDE5 and high selectivity for PDE5 over other PDE isoforms, compared to other existing PDE5Is such as sildenafil, vardenafil and tadalafil. Available evidence has suggested that doses of 50 and 100 mg mirodenafil effectively improve ED [with improvements in the erectile function domain of the International Index of Erectile Function (IIEF-EF) scores, positive responses to questions 2 of the Sexual Encounter Profiles (SEP2) and questions 3 of the Sexual Encounter Profiles (SEP3): 7.6-11.6 points, 27.72-38.98% and 44.20-67.33%, respectively] in a broad range of patient populations with ED of a variety of underlying etiologies, severities and ages, without any serious treatment-related adverse effects. In the treatment of diabetic ED, a traditionally difficult-to-treat population, 100 mg mirodenafil has been reported to offer favorable efficacy (with improvements in the IIEF-EF scores, and positive responses to the SEP2 and the SEP3: 9.3 points, 36.1% and 61.8%, respectively) and tolerability (mild adverse effects of less than 19.6%), which are comparable with results from clinical studies on other PDE5Is. Mirodenafil appears to be effective, safe and well tolerated in men with both ED and hypertension or lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) who are taking concomitant antihypertensive medications or α1-blockers. Furthermore, recent evidence has indicated that mirodenafil may be a potential option for chronic dosing in the treatment of ED despite its short half-life (T 1/2). Most of the available clinical studies have reported that adverse effects (up to 53.7%) caused by 50 and 100 mg mirodenafil are mild or moderate in severity, with headache (1.8-14.8%) and flushing (6.7-24.1%) being the most common. Due to the pharmacodynamic profiles of mirodenafil, its tolerability is expected to be somewhat better than those of the other PDE5Is. However, further well designed studies with larger cohorts of different ethnicities, flexible dosing schedules and long-term follow up are necessary to confirm the favorable efficacy and tolerability profiles of mirodenafil for the treatment of ED.

ROS activates JNK-mediated autophagy to counteract apoptosis in mouse mesenchymal stem cells in vitro.

Transplantation of mesenchymal stem cells (MSCs) for the treatment of diabetic erectile dysfunction (ED) is hampered by apoptosis of the transplanted cells. In diabetic ED, there is increased oxidative stress and decreased NO in the corpora cavernosa, and reactive oxygen species (ROS) induce apoptosis of the transplanted cells. In this study we examined whether and how autophagy was involved in ROS-induced apoptosis of MSCs. Mouse C3H10 MSCs were treated with H2O2 to simulate the high oxidative condition in diabetic ED. Cell viability was measured using MTT assay. Apoptosis was analyzed by flow cytometry. Apoptosis- and autophagy-related proteins were detected with Western blot assays. Intracellular autophagosome accumulation was studied using transmission electron microscopy. Treatment of MSCs with H2O2 (50-400 μmol/L) inhibited the cell viability in concentration- and time-dependent manners. Furthermore, H2O2 (300 μmol/L) induced apoptosis, as well as activated autophagy in MSCs. Pretreatment with lysosome inhibitor chloroquine (10 μmol/L) or PI3K inhibitor 3-methyladenine (5 mmol/L) significantly enhanced H2O2-induced cell death. Pretreatment with JNK inhibitor SP600125 (10 μmol/L) abrogated H2O2-induced accumulation of LC3-II, and attenuated H2O2-induced reduction of Bcl-2 levels in MSCs. ROS induce autophagy to counteract apoptosis in MSCs by activation of JNK. Thus, augmentation of autophagy may reduce apoptosis, prolonging MSC survival and improving MSC-based therapeutic efficacy for diabetic ED.

AB157. Treatment of diabetic erectile dysfunction by using endothelial progenitor cells genetically modified by human telomerase reverse transcriptase

ObjectiveErectile dysfunction (ED) is one of the most common complications of diabetes mellitus (DM). Under the background that effectivity of treatments for diabetic ED are quite poor, stem cell therapy is emerging a useful method. The aim of this study is to evaluate the possibility and mechanism of treatment of diabetic ED with endothelial progenitor cells (EPCs) genetically modified by human telomerase reverse transcriptase (hTERT).MethodsRat EPCs were isolated and transfected with hTERT (EPCs-hTERT). The paracrine characters and resistance to oxidative stress of EPCs-hTERT was determined in vitro. Thirty SD male rats were divided into five groups: diabetic ED rats, diabetic ED rats treated with EPCs, diabetic ED rats treated with EPCs-control, diabetic ED rats treated with EPCs-hTERT, normal control rats. Diabetes was induced by intraperitoneal injection of streptozotocin. After 8 weeks, diabetic ED rats were selected by apomorphine (APO) test. After injection of EPCs for 2 weeks, intracavernosal pressure (ICP) was measured by means of electrical stimulation for each group. Concentration of growth factors, the amount of EPCs and endothelium/smooth muscle content were evaluated in vivo.ResultsEPCs-hTERT showed stable expression of hTERT at the level of, mRNA and protein for more than 40 passages. EPCs-hTERT could paracrine more VEGF, HGF and bFGF. EPCs’ ability of resistance to oxidative stress was dramatically improved by tranfection of hTERT. ICP/mean arterial pressure (MAP) ratio induced by electrical stimulation in diabetic ED treated with EPCs-hTERT was markably higher than diabetic ED rats treated with EPCs or EPCs-control. Immunofluorescence demonstrated that more cells survived in penile tissues after implantation of EPC-hTERT. More growth factors were detected, and the endothelium/smooth muscle content was increase in penile tissues.ConclusionsThe paracrine effect and resistance to oxidative stress of EPCs-hTERT contributed to the improvement of erection of diabetic ED rats.

A comprehensive review of erectile dysfunction in men with diabetes.

Erectile dysfunction (ED) is more common in men with diabetes (DM). Dependent on the selected population, age, DM type and duration, the prevalence of diabetic ED (DED) varies from 32 to 90%. In 12-30% of men ED is the first sign of diabetes, diagnosed later. Today men with diabetes live longer than ever, and develop more late diabetic complications. Having in mind also the global ageing of the world population all this data suggests an increasing number of men with DED in the future. The main factors playing in the complex pathogenesis of DED are diabetic neuropathy (oxidative stress, polyol pathway, advanced glycation end-products, nerve growth factor deficiency, dysfunction of protein kinase C, tissue remodeling, etc.), macrovascular arterial disease (endothelial dysfunction, abnormal collagen deposition and smooth muscle degeneration, dyslipidemia, arterial hypertension, veno-occlusive dysfunction, etc.), hypogonadism, structural remodeling of the corporeal tissue, psychogenic components and adverse drug reactions. The diagnostic process is based on the results of questionnaires, neurological, vascular (Doppler) and other more rarely used investigations.Because of the complex pathogenesis of DED diabetic men represent a "difficult" treatment group. The difficulties are from the "beginning", because patients do not talk about their problem spontaneously, and doctors do not ask about it. The treatment of DED should be team work, preferably including also specialists in sexual medicine. Psychological support and counseling of the couple is necessary in most cases. The general measures include implementation of a healthier lifestyle, improved glycemic-, lipids-, and arterial pressure control, and careful re-evaluation of the concomitant medications. The specific treatment includes as first line therapy the inhibitors of phosphodiesterase type 5 (PDE-5) with lesser effectiveness compared to non-DM men. There are rare studies with selected diabetic populations and even less with head-to-head comparisons between the PDE-5 inhibitors. Men with DM have a higher prevalence of hypogonadism. Testosterone replacement therapy should be started in symptomatic men with proven hypogonadism and no contraindications. Vacuum constriction devices and intracavernous or intraurethral applications of vasoactive drugs are the second line therapy. Vascular surgery rarely comes into consideration. The penile implant is the last and effective option in men with severe DED.

The effects of long-term administration of tadalafil on STZ-induced diabetic rats with erectile dysfunction via a local antioxidative mechanism

Type 5 phosphodiesterase inhibitors (PDE5Is) are well known being effective via the nitric oxide and cyclic guanosine monophosphate (NO-cGMP) pathway and are widely used in the treatment of diabetic erectile dysfunction (ED). However, it is unclear whether other pathways may be involved in the treatment of diabetic ED with PDE5Is. The purpose of this study was to clarify the role of antioxidants in diabetic ED treatment through the long-term administration of PDE5Is. Three groups of Sprague-Dawley rats were utilized: Group N, the normal control; Group D, streptozotocin (STZ)-induced diabetic rats as a control; and Group D+T, STZ-induced diabetic rats who received oral administration of tadalafil for 8 weeks. Erectile function was assessed by intracavernous pressure (ICP) and mean arterial pressure (MAP) during electrical stimulation of the cavernous nerve before euthanasia. The levels of malondialdehyde (MDA), superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) of cavernous tissue were assessed by biochemical analysis. The morphology of mitochondria was observed by electron microscopy. The ICP/MAP ratio was higher in Group D+T than in Group D (P<0.05). The levels of MDA decreased and the activities of SOD increased in Group D+T in comparison with Group D (P<0.05). The mitochondrial membrane potential level of cavernous tissue in diabetic rats was partially recovered by tadalafil treatment for 8 weeks. The morphology changes of mitochondria were also remarkably ameliorated in Group D+T. Collectively, the long-term administration of tadalafil in diabetic rats partially reduced oxidative stress lesions of the penis via a local antioxidative stress pathway. Long-term dosages of tadalafil given once daily beginning soon after the onset of diabetes may aid in preventing rats from developing diabetic ED.

AB196. The long-term administration of tadalafil on STZ-induced diabetic rats with erectile dysfunction via local antioxidative mechanism

ObjectiveTo clarify the antioxidation role in diabetic ED treatment by a long-term administration of PDE5I.MethodsThree groups of Sprague-Dawley rats were utilized: group N, normal control; group D, streptozotocin (STZ) induced diabetic rats as control; group D + T, STZ induced diabetic rats by the intragastric administration with tadalafil for 8 weeks.ResultsICP/MAP ratio was significantly higher in group D + T than in group D. The levels of MDA decreased remarkably and the activities of SOD increased significantly of group D + T, compared with group D. The level of mitochondrial membrane potential of cavernous tissue of diabetic rats was partly recovered by tadalafil treatment for 8 weeks. The morphology changes of mitochondria were also ameliorated in group D + T.ConclusionsThe long-term administration of tadalafil on diabetic rats is proven to partly lessen the oxidative stress lesion of the penis via a local antioxidative stress pathway. Early long-term dosages of tadalafil once daily maybe partly prevent rats from diabetic erectile dysfunction. To our knowledge, this is the first report to reveal the new mechanism on long-term treatment of tadalafil in diabetic ED.

Hydrogen therapy may be a promising, safe and effective treatment for diabetic erectile dysfunction: a hypothesis

Inhalation of hydrogen gas has been proven to be an effective treatment for ischemiareperfusion injury by selectively reducing hydroxyl and peroxynitrite radicals. There has been considerable evidence of hydrogen’s protective effect against diseases related to oxidative injury, such as the ischemia-reperfusion injury of the brain, liver and heart. More and more studies suggest that radical oxygen species (ROS) play an important role in the development of diabetic erectile dysfunction (ED) and antioxidants can markedly decrease the production of ROS and improve the erectile function. We hypothesize that hydrogen therapy may be a promising, safe and effective treatment for diabetic ED by reducing the production of ROS.