Diabetes Mellitus-induced Erectile Dysfunction Research Articles

Increased serum asprosin is correlated with diabetes mellitus-induced erectile dysfunction

ObjectiveAsprosin, a newly identified adipokine, is pathologically increased in type 2 diabetes. The aim of this study is to see whether serum asprosin concentrations are linked to diabetes mellitus-induced erectile dysfunction (DMED).Methods90 male patients with type 2 diabetes were included. According to the International Index of Erectile Function (IIEF-5) score, they were classified into two groups: 45 type 2 diabetes patients without erectile dysfunction (DM group) (IIEF-5 > 21),45 patients with diabetes induced erectile dysfunction (DMED group) (IIEF-5 ≤ 21)0.45 healthy male volunteers with normal blood glucose, IIEF-5 score > 21 points, and age matched with the DMED group were included as the control group. Anthropometric and biochemical variables were determined in all participants.ResultsWhen compared to the controls, T2DM ( Type 2 Diabetes Mellitus)patients had higher serum asprosin levels. The DMED group had significantly higher serum asprosin than the T2DM groups(p < 0.001). After adjusting for multiple variables considered traditional risk factors for ED(erectile dysfunction), Asprosin can still be used as an independent risk factor for ED; The ROC(Receive Operating Characteristic Curve) indicates that asprosin has good sensitivity (97.8%) and specificity (62.2%) in predicting ED, with an area under the curve of 0.843.Correlation analysis shows that asprosin is negatively correlated with SOD(superoxide dismutase ) and positively correlated with MDA (malondialdehyde).ConclusionSerum asprosin concentrations are increased in patients with DMED. Also, asprosin is correlated with oxidative stress indexes (MDA, SOD).

(059) Effects of a Red-Light–Controllable Nitric Oxide Donor, NORD-1, on Diabetes Mellitus-Induced Erectile Dysfunction in Rats

Abstract Introduction Diabetes mellitus (DM) often causes erectile dysfunction (ED). Phosphodiesterase-5 inhibitor has limited effects on diabetes mellitus-induced erectile dysfunction (DMED). One contributing factor to this reduced effect is the decreased production of nitric oxide owing to neuropathy and endothelial impairment. To address this issue, we developed a red-light–controllable nitric oxide donor, NORD-1, that successfully enhanced erectile function in intact and cavernous nerve injury model rats. Objective In this study, we investigated whether NORD-1 and red-light irradiation could improve DMED in rats. Methods Seven-week-old Sprague–Dawley male rats were used. Rats in the DM and sham groups were intravenously administered streptozotocin 50 mg/kg and saline, respectively. One week after treatment, the blood glucose levels of rats in the DM group were found to be over 250 mg/dL. Five weeks after the treatment, we performed a functional study using the measurements of intracavernous pressure (ICP) under the stimulation of the cavernous nerve. The study was performed before and after NORD-1 treatment, both with and without light irradiation. Additionally, we performed an isometric tension study using corpus cavernosum from rats treated with either NORD-1 or a control compound, SiR650. Results The ICP/MAP ratio of the DM group was significantly lower than that of the sham group before and after NORD-1 treatment without light irradiation (both P&amp;lt;0.05). However, after NORD-1 treatment with light irradiation, the ICP/MAP ratios of the Sham and DM groups were substantially enhanced compared with that before and after NORD-1 treatment without light irradiation (all P&amp;lt;0.05). The ICP/MAP ratio of the DM group was similar to that of the Sham group under the normal condition before NORD-1 treatment by light irradiation. Moreover, systemic blood pressure was not affected by NORD-1 and light irradiation. In the isometric tension study, rat corpus cavernosum from rats treated with SiR650 showed no changes under red light in both the Sham and DM groups. However, the corpus cavernosum from rats treated with NORD-1 was strongly relaxed by red light in both groups. Conclusions NORD-1 and red-light irradiation could improve DMED in STZ-induced DM rats without lowering blood pressure. Disclosure No.

Bibliometric and Visualization Analysis of Stem Cell Therapy for Erectile Dysfunction.

As a common male disease, erectile dysfunction (ED) seriously affects the physical and mental health of patients. In recent years, studies have continued to point out the great potential of stem cell therapy (SCT) in the treatment of ED. The purpose of this study is to comprehensively analyze the research of SCT for ED and understand the development trends and research frontiers in this field. Publications regarding SCT and ED were retrieved and collected from the Web of Science Core Collection. CiteSpace and VOSviewer software were then utilized for bibliometric and visualization analysis. A total of 524 publications were eventually included in this study. The annual number of publications in this field was increasing year by year. China and the USA were the two most productive countries. Lin GT, Lue TF and Lin CS, and the University of California San Francisco where they worked were the most productive research group and institution, respectively. The journal with the largest number of publications was The Journal of Sexual Medicine, and the following were mostly professional journals of urology and andrology. Diabetes mellitus-induced ED and cavernous nerve injury-related ED were the two most commonly constructed models of ED in studies. Concerning the types of stem cells, mesenchymal stem cells derived from adipose and bone marrow were most frequently used. Moreover, future research would mainly focus on exosomes, tissue engineering technology, extracorporeal shockwave therapy, and clinical translation. The research of SCT for ED will receive increasing global attention in the future. Our study provided bibliometric and visualization analysis of published literature, helping researchers understand the global landscape and frontiers in this field. More preclinical and clinical studies should be conducted to more deeply explore the underlying mechanisms of treatment and promote clinical translation.

MiRNA-100 ameliorates diabetes mellitus-induced erectile dysfunction by modulating autophagy, anti-inflammatory, and antifibrotic effects.

Diabetes mellitus-induced erectile dysfunction (DMED) has become a common disease in adult men that can seriously reduce the quality of life of patients, and new therapies are urgently needed. miRNA-100 has many targets and can induce autophagy and reduce fibrosis by inhibiting the mTOR pathway and the TGF-β pathway. However, no research has been conducted with miR-100 in the field of DMED, and the specific mechanism of action is still unclear. To ascertain the effects of miR-100 on corpus cavernosum tissue of DMED rats and vascular endothelial cells in a high glucose environment and to elucidate the relevant mechanisms in autophagy, fibrosis and inflammation to find a new approach for the DMED therapy. Thirty rats were divided into three groups: the control group, the DMED group, and the DMED + miR-100 group. Using intraperitoneal injections of streptozotocin, all rats except the control group were modeled with diabetes mellitus, which was verified using the apomorphine (APO) test. For rats in the DMED + miR-100 group, rno-miR-100-5p agomir (50nmol/kg, every 2 days, 6 times in total) was injected via the tail vein. After 13weeks, the erectile function of each rat was assessed using cavernous manometry, and the corpus cavernosum tissue was harvested for subsequent experiments. For cellular experiments, human coronary microartery endothelial cells (HCMEC) were divided into four groups: the control group, the high-glucose (HG, 40mM) group, the HG + mimic group, and the HG + inhibitor group. The cells were cultured for 6 days and collected for subsequent experiments 2 days after transfection. Diabetic modeling impaired the erectile function in rats, and miR-100 reversed this effect. By measuring autophagy-related proteins such as mTOR/Raptor/Beclin1/p62/LC3B, we found that miR-100 could suppress the expression of mTOR and induce autophagy. The analysis of the eNOS/NO/cGMP axis function indicated that impaired endothelial function was improved by miR-100. By evaluating the TGF-β1/CTGF/Smad2/3 and NF-κB/TNF-α pathways, we found that miR-100 could lower the level of inflammation and fibrosis, which contributed to the improvement of the erectile function. Cellular experiments can be used as supporting evidence for these findings. MiR-100 can improve the erectile function by inhibiting mTOR and thus inducing autophagy, improving the endothelial function through the eNOS/NO/cGMP axis, and exerting antifibrotic and anti-inflammatory effects, which may provide new ideas and directions for the treatment of DMED.

Fermented Gynochthodes officinalis (F.C.How) Razafim. & B.Bremer alleviates diabetic erectile dysfunction by attenuating oxidative stress and regulating PI3K/Akt/eNOS pathway.

As a traditional Chinese medicine, Gynochthodes officinalis (F.C.How) Razafim. & B.Bremer (G. officinalis) has been historically as tonics to treat impotence. Fermentation is an ancient processing method for traditional Chinese medicine. Whether fermentation affects the therapeutic effects of G. officinalis on diabetic erectile dysfunction has so far remained unknown. In this research, we aim to determine the effect of fermented or unfermented G. officinalis root extract on diabetes mellitus-induced erectile dysfunction (DMED) and the potential mechanisms. Candida sp. B5, Lactobacillus sp. Y5 and Lactobacillus sp. R2 are applied for the fermentation of G. officinalis. The optimum fermentation conditions of G. officinalis are investigated. Sprague-Dawley rats were used to establish a diabetic erectile dysfunction model, treated with different concentrations of fermented or unfermented G. officinalis, to compare the effect of fermented or unfermented G. officinalis on DMED and explore underlying mechanisms by assessment of intracavernous pressure, ELISA, Western blot, Masson's trichrome staining, and immunofluorescence. The corpus cavernosum smooth muscle cells (CCSMCs) and Schwann cells were isolated and used to investigate the effect of fermented or unfermented G. officinalis on hydrogen peroxide (H2O2)-induced apoptosis. The results reveal the optimum fermentation conditions of G. officinalis using Lactobacillus sp. Y5 were determined to be 35°C, the ratio of solid to liquid 1:10, and six days of fermentation. The fermentation increases the abundance of major active ingredients within G. officinalis. After fermented or unfermented G. officinalis treatment for eight weeks by oral gavage at a dose of 100mgkg-1 or 300mgkg-1, the results show that the fermentation enhances the effect of G. officinalis on diabetic erectile dysfunction detected by intracavernous pressure. The protein expressions of the PI3K/Akt/eNOS pathway were upregulated in diabetic rats after fermented or unfermented G. officinalis treatment, while the level of oxidative stress was significantly reduced. Meanwhile, Masson's trichrome staining also displayed an improvement in the ratio of smooth muscle to collagen. In vitro experiments confirmed that fermented or unfermented G. officinalis protected CCSMCs and Schwann cells from apoptosis. In contrast, fermented G. officinalis showed a fortified protective effect over unfermented G. officinalis. Our findings suggest that fermentation can increase the composition of main active ingredients in G. officinalis and enhance its role in diabetic erectile dysfunction. It augurs the potential therapeutic application of fermented G. officinalis well for treating diabetic erectile dysfunction.

MP27-09 OXYMATRINE IMPROVES ERECTILE FUNCTION THROUGH SUPPRESSION OF INFLAMMATION AND FIBROSIS IN DIABETIC RATS

You have accessJournal of UrologyCME1 Apr 2023MP27-09 OXYMATRINE IMPROVES ERECTILE FUNCTION THROUGH SUPPRESSION OF INFLAMMATION AND FIBROSIS IN DIABETIC RATS Wenchao Xu, Hao Li, Taotao Sun, Jiaxin Wang, Tao Wang, and Jihong Liu Wenchao XuWenchao Xu More articles by this author , Hao LiHao Li More articles by this author , Taotao SunTaotao Sun More articles by this author , Jiaxin WangJiaxin Wang More articles by this author , Tao WangTao Wang More articles by this author , and Jihong LiuJihong Liu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003255.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Diabetic mellitus-induced erectile dysfunction (DMED) responds poorly to phosphodiesterase type 5 inhibitors (PDE5i). Oxymatrine (OMT) has broad-spectrum anti-inflammatory and anti-fibrosis effects, but whether it improves the erectile function of diabetic populations through the above-mentioned mechanism is unclear. We intend to explore the role of OMT in the treatment of DMED. METHODS: A rat model of DMED was constructed by a single intraperitoneal injection of 1% streptozotocin solution. Thirty-two DMED rats were randomly divided into control group, DMED group, DMED + OMT-Low (50 mg/kg/day) group and DMED + OMT-High (100 mg/kg/day) group. Erectile function was evaluated by measuring intracavernosal pressure (ICP) and mean arterial pressure (MAP). The penile shafts were collected for subsequent molecular biological and histological analysis. RESULTS: ICP/MAP indicated that the erectile function of rats in the DMED model group was severely impaired, which was rescued in the DMED + OMT-Low and DMED + OMT-High groups. Rats in the DMED model group can highly express inflammatory indicators NF-kb, TNF-α and fibrosis-related proteins TGF-beta, CTGF, and Smad 2/3. The above-mentioned penile inflammation and fibrosis changes can be inhibited by OMT. Meanwhile, our results also showed that after OMT treatment, the NO/cGMP pathway was promoted and the RhoA/ROCK pathway was inhibited in the corpus cavernosum of DMED rats. CONCLUSIONS: OMT suppresses inflammation and fibrosis in the corpus cavernosum of diabetic rats to improve erectile function. OMT could improve penile erection by influencing endothelial and smooth muscle function. Our study provides new insight into the therapeutic effect of OMT and preclinical evidence for a potential treatment strategy for DMED. Source of Funding: This research was funded by grants from the National Natural Science Foundation of China (No. 82001536 and No.81873831) and the Fundamental Research Funds for the Central Universities (HUST: YCJJ202201021) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e365 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Wenchao Xu More articles by this author Hao Li More articles by this author Taotao Sun More articles by this author Jiaxin Wang More articles by this author Tao Wang More articles by this author Jihong Liu More articles by this author Expand All Advertisement PDF downloadLoading ...

MP79-07 EFFECT OF NEAR-INFRARED LASER TREATMENT ON IMPROVING ERECTILE FUNCTION IN RATS WITH DIABETES MELLITUS

You have accessJournal of UrologyCME1 Apr 2023MP79-07 EFFECT OF NEAR-INFRARED LASER TREATMENT ON IMPROVING ERECTILE FUNCTION IN RATS WITH DIABETES MELLITUS Lin Yang, Guoxiong Liu, Dali Jiang, Guiting Lin, Hengtong Fan, Zejun Ren, Bing Yang, Liyue Mu, Tom F Lue, and Dalin He Lin YangLin Yang More articles by this author , Guoxiong LiuGuoxiong Liu More articles by this author , Dali JiangDali Jiang More articles by this author , Guiting LinGuiting Lin More articles by this author , Hengtong FanHengtong Fan More articles by this author , Zejun RenZejun Ren More articles by this author , Bing YangBing Yang More articles by this author , Liyue MuLiyue Mu More articles by this author , Tom F LueTom F Lue More articles by this author , and Dalin HeDalin He More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003356.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Diabetes mellitus induced erectile dysfunction (DMED) is difficult to treat. The oxidative stress (OS) created by DM is a major cause of injuries to the corpus cavernosum (CC), thereby resulting in ED. Near-infrared (NIR) laser has already been shown to be effective in treating multiple brain disorders due to its anti-OS effect. In this study we want to investigate whether an NIR laser improves the erectile function of DMED rats through its anti-OS effect. METHODS: Knowing its advantage of reasonable deep tissue penetration and good photo activation on mitochondria, a NIR laser with wavelength of 808nm was used in the experiment. Since the internal and external CC was covered by different tissue layers, the laser penetration rates of the internal and external CC were measured separately. Different radiant exposure settings were applied: in the initial experiment, 40 male SD rats were randomly assigned to five groups, normal controls (NC), and STZ-induced DM rats that 10 weeks later received various radiant exposures (J/cm2) from the NIR laser (DM0J, DM1J, DM2J, and DM4J) in the subsequent 2 weeks. Erectile function was then assessed 1 week after NIR treatment. It was found the initial radiant-exposure setting was not optimal according to the Arndt–Schulz rule. We followed with a second experiment using a different radiant exposure setting. Forty male rats were randomly divided into five groups (NC, DM0J, DM4J, DM8J, and DM16J), and the NIR laser was again applied according the new setting and erectile function was assessed as in the first experiment. Histologic, biochemical analyses and proteomic were then conducted. RESULTS: Recovery of erectile function of varying degrees was observed in the NIR treatment groups, and radiant exposure of 4 J/cm2 achieved optimal results. The NIR4J group showed improvement in mitochondrial function and in morphology in DM rats, and it was found that OS levels were significantly reduced by NIR exposure. The tissue structure of the CC was also improved by NIR exposure. The proteomics analysis confirming multiple biologic processes had been changed by DM and NIR. CONCLUSIONS: NIR laser activated mitochondria, improved OS, repaired the damage to penile CC tissue structures caused by DM, and improved erectile function in DM rats. These results thus raise the possibility that human patients with DMED may respond to NIR therapy in a manner that parallels the responses we observed in animal study. Source of Funding: Key R&D Plan of Shaanxi Province (2022SF-531) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1143 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Lin Yang More articles by this author Guoxiong Liu More articles by this author Dali Jiang More articles by this author Guiting Lin More articles by this author Hengtong Fan More articles by this author Zejun Ren More articles by this author Bing Yang More articles by this author Liyue Mu More articles by this author Tom F Lue More articles by this author Dalin He More articles by this author Expand All Advertisement PDF downloadLoading ...

Current status and prospects of diabetes mellitus induced erectile dysfunction: A bibliometric and visualization study.

The prevalence of diabetes mellitus-induced erectile dysfunction (DMED) has recently increased, which has prompted numerous DMED studies. Here, we conduct a bibliometric analysis of relevant literature in the field of DMED and to discuss the research hotspots and future development directions. The Web of Science Core Collection database was searched for literature on DMED, and literature characterization including the number of articles, journals, countries/regions, institutions, authors, keywords, and other information was performed using VOS viewer and CiteSpace software. In addition, Pajek software was used for visual map adjustment, and GraphPad Prism was used to generate line graphs. A total of 804 articles concerning DMED were included in this study. The Journal of Sexual Medicine issued the most documents(92 articles). The United States and China were in the leading position in the field of DMED research, and cross-institutional collaboration on DMED research worldwide needs to be further strengthened. Ryu JK were the authors with the highest number of documents issued (22 articles) while Bivalacqua TJ was the author with the most co-citated(249 co-citated). The keywords analysis shows that the main research hotspots in the field of DMED were mechanism discussions and disease treatment and management. Global research on DMED is expected to increase further. The investigation of the mechanism of DMED and the exploration of new therapeutic means and targets are the focus of future research.

Effect of near-infrared laser treatment on improving erectile function in rats with diabetes mellitus.

Diabetes mellitus-induced erectile dysfunction is difficult to treat. The oxidative stress created by diabetes mellitus is a major cause of injuries to the corpus cavernosum, thereby resulting in erectile dysfunction. Near-infrared laser has already been shown to be effective in treating multiple brain disorders because of its antioxidative stress effect. To investigate whether a near-infrared laser improves the erectile function of diabetes mellitus-induced erectile dysfunction rats through its antioxidative stress effect. Knowing its advantage of reasonable deep tissue penetration and good photoactivation on mitochondria, a near-infrared laser with wavelength of 808nm was used in the experiment. Since the internal and external corpus cavernosum were covered by different tissue layers, the laser penetration rates of the internal and external corpus cavernosum were measured separately. Different radiant exposure settings were applied: in the initial experiment, 40 male Sprague-Dawley rats were randomly assigned to five groups, normal controls, and streptozotocin-induced diabetes mellitus rats that 10weeks later received various radiant exposures (J/cm2 ) from the near-infrared laser (DM0J(DM+NIR 0 J/cm2 ), DM1J, DM2J, and DM4J) in the subsequent 2weeks. Erectile function was then assessed 1week after near-infrared treatment. It was found that the initial radiant exposure setting was not optimal according to the Arndt-Schulz rule. We performed a second experiment using a different radiant exposure setting. Forty male rats were randomly divided into five groups (normal controls, DM0J, DM4J, DM8J, and DM16J), and the near-infrared laser was again applied according to the new setting, and erectile function was assessed as in the first experiment. Histologic, biochemical, and proteomic analyses were then conducted. Recovery of erectile function of varying degrees was observed in the near-infrared treatment groups, and radiant exposure of 4 J/cm2 achieved optimal results. The DM4J group showed improvement in mitochondrial function and morphology in diabetes mellitus rats, and it was found that oxidative stress levels were significantly reduced by near-infrared exposure. The tissue structure of the corpus cavernosum was also improved by near-infrared exposure. The proteomics analysis confirming multiple biologic processes were changed by diabetes mellitus and near-infrared. Near-infrared laser activated mitochondria, improved oxidative stress, repaired the damage to penile corpus cavernosum tissue structures caused by diabetes mellitus, and improved erectile function in diabetes mellitus rats. These results thus raise the possibility that human patients with diabetes mellitus-induced erectile dysfunction may respond to near-infrared therapy in a manner that parallels the responses we observed in animal study.

Comparison of characteristics between Chinese diabetes mellitus-induced erectile dysfunction populations and non-diabetes mellitus-induced erectile dysfunction populations: A cross-sectional study.

Erectile dysfunction (ED) is a common disease in adult men, and diabetes is an independent risk factor for ED. However, there are few reports on the distinction between diabetes mellitus-induced erectile dysfunction (DMED) and non-DMED features, as well as ED features of varying severity in the two groups. A total of 365 ED patients treated at two clinics in China from 2019 to 2022 were included. Questionnaires of the International Index of Erectile Function (IIEF-5), Erectile Hardness Score (EHS), Premature Ejaculation Diagnostic Tool (PEDT), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder-7 (GAD-7) were administered to the patients. They were divided into three groups according to the IIEF-5 score: 5-7 for severe ED, 8-11 for moderate ED, and 12-21 for mild ED. In addition, the patient's age, weight, height, fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), total testosterone (TT) and other indicators were also collected. Statistical analysis was performed using SPSS 26, comparing all parameters between groups. Age (P<0.001), height (P=0.009), body mass index (BMI) (P=0.002), PEDT (P<0.001), FBG (P<0.001), FSH (P<0.001), TG (P<0.001), TT (P<0.001) and triglyceride-glucose index (TyG) (P<0.001) were significantly different between diabetic ED and nondiabetic ED subjects. The trend test in the nondiabetic ED population found a negative correlation between the IIEF-5 score and PHQ-9 (P for trend=0.15). Multivariate ordinal logistic regression in the diabetic ED population showed that elevated LH OR=11.37 (95% CI: 0.966, 3.897) and elevated PRL OR=4.10 (95% CI: 0.410, 2.411) were associated with an increased risk of more severe ED. The aetiology, demographic parameters, degree of premature ejaculation, and related biochemical tests were significantly different between the DMED and non-DMED populations.

Low-Intensity Pulsed Ultrasound Counteracts Advanced Glycation End Products-Induced Corpus Cavernosal Endothelial Cell Dysfunction via Activating Mitophagy

Injury to corpus cavernosal endothelial cells (CCECs) is an important pathological basis of diabetes mellitus-induced erectile dysfunction (DMED), while low-intensity pulsed ultrasound (LIPUS) has been shown to improve erectile function in DMED. To further understand its therapeutic mechanism of action, in this study, we first demonstrated increased apoptosis and shedding in the CCECs of DMED patients, accompanied by significant mitochondrial injury by immunohistochemistry and electron microscopy of corpus cavernosum tissue. Next, we used advanced glycation end products (AGEs) to simulate the diabetic environment in vitro and found that AGES damaged mitochondria and inhibited angiogenesis in CCECs in a dose-dependent manner, while LIPUS treatment significantly reversed its effects. Mechanistic studies based on transcriptome sequencing showed that LIPUS significantly up-regulated LC3 and PARKIN protein levels in mitochondria, promoted mitophagy, and affected mitochondrial dynamics and reactive oxygen species (ROS) production. In addition, the protective effects of LIPUS were abrogated when mitophagy was inhibited by 3-methyladenine. In summary, LIPUS exerted potent inhibitory effects on AGES-induced CCEC failure via mitophagy, providing a theoretical basis for DMED treatment that encompasses the protection of endothelial structure and function.

Saxagliptin alleviates erectile dysfunction through increasing stromal cell-derived factor-1 in diabetes mellitus.

Diabetes mellitus-induced erectile dysfunction (DMED) is one of the complications of diabetes and has a poor response to phosphodiesterase type 5 inhibitor, the first-line treatment for ED. Saxagliptin (Sax), a dipeptidyl peptidase-4 inhibitor (DPP-4i), has been officially used in the treatment of type 2 diabetes. Stromal cell-derived factor-1 (SDF-1) is one of the important substrates of DPP-4, and has been proven to be beneficial for several DM complications. However, it is unknown whether Sax contributes to the management of DMED. To explore the effect and possible underlying mechanisms of Sax in the treatment of DMED. The model of DM was established by intraperitoneal injection of streptozotocin. All rats were divided into three groups (n=8 per group): control group, DMED group and DMED+Sax group. In cellular experiments, the corpus cavernosum smooth muscle cells (CCSMCs) were exposed to high glucose (HG), and treated with Sax and AMD3100 (SDF-1 receptor inhibitor). The penile tissue and CCSMCs were harvested for detection. We found that erectile function was impaired in DMED rats compared with the control group, which was partially relieved by Sax. Decreased expression of DPP-4 and increased level of SDF-1 were also observed in DMED+Sax group, together with elevation of PI3K/AKT pathway and inhibition of endothelial dysfunction, oxidative stress and apoptosis in corpus cavernosum. Moreover, Sax could also regulate oxidative stress and apoptosis in CCSMCs under HG condition, which was blocked in part by AMD3100. Sax could alleviate DMED through increasing SDF-1 and PI3K/AKT pathway, in company with moderation of endothelial dysfunction, oxidative stress and apoptosis. Our findings indicated that DPP-4 is may be beneficial to the management of DMED.

GPX4 Alleviates Diabetes Mellitus-Induced Erectile Dysfunction by Inhibiting Ferroptosis.

Pharmacological therapy of diabetes mellitus-induced erectile dysfunction (DMED) is intractable owig to the poor response to phosphodiesterase type 5 inhibitors (PDE5i). The surge in the number of diabetic patients makes it extremely urgent to find a novel therapy for DMED. Ferroptosis is a recently discovered form of cell death evoked by lipid peroxidation and is related to several diabetic complications. GPX4, an important phospholipid hydroperoxidase, can alleviate ferroptosis and maintain redox balance via reducing lipid peroxides. However, whether GPX4 can be a prospective target of DMED needs to be determined. Fifty rats were randomly divided into control group, DMED group, DMED + negative control group (DMED + NC group), DMED + low-dose group (1 × 106 infectious units), and DMED + high-dose group (2 × 106 infectious units). Erectile function was assessed 4 weeks after intracavernous injection of GPX4 or negative control lentivirus. The penile shafts were collected for subsequent molecular biological and histological analysis. The results demonstrated that erectile function of the rats in DMED and DMED + NC groups was extremely impaired and was improved in a dose-dependent manner with GPX4 lentivirus (GPX4-LV) injection. Additionally, upregulation of the ACSL4-LPCAT3-LOX pathway, iron overload, oxidative stress, fibrosis, and decreased endothelial and smooth muscle cell numbers were observed in the corpus cavernosum of DMED group. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway was inhibited, and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was promoted in DMED rats. The above histologic alterations and related molecular changes were alleviated after GPX4-LV injection. The results revealed that GPX4 improved erectile function by modulating ferroptosis during DMED progression. This finding is of paramount significance in deciphering the molecular mechanism of hyperglycemia-induced ferroptosis, thereby providing a prospective target for preventing the development of DMED.

Ferroptosis is involved in corpus cavernosum smooth muscle cells impairment in diabetes mellitus-induced erectile dysfunction.

Erectile dysfunction (ED) is a common andrological disorder that tends to afflict diabetic patients, among others. Pharmacological therapy of diabetes mellitus-induced ED (DMED) is ineffective, as it is linked with smooth muscle cell loss in the corpus cavernosum. Ferroptosis is a recently identified kind of cell death evoked by lipid peroxidation, and it is connected with a number of diabetic complications. To investigate the role of ferroptosis in DMED. We established the rat model of DMED and conducted a combined analysis of RNA sequencing (RNA-seq) and Gene Expression Omnibus (GEO) data to identify differentially expressed genes (DEGs). Next, DMED disease targets were determined by cross-referencing DEGs and DMED-related genes in the DisGeNET, GenCLiP3, and GeneCards databases. Additionally, these targets were analyzed using "clusterProfiler" in R utilizing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations. Immunohistochemistry (IHC) staining of rat penile tissues was used to validate several targets. Notably, the Cell Counting Kit-8 assay, Western blotting, oxidative stress (OS) level, and iron concentration were tested in corpus cavernosum smooth muscle cells (CCSMCs) stimulated with high glucose (HG), and treated with Ferrostatin-1 (Fer-1). Sixty-nine disease targets of DMED were identified. According to KEGG analysis, these targets were primarily enriched in the ferroptosis pathway. Additionally, IHC results revealed that the expression of GPX4, SLC7A11, and ACSL4 was deregulated in the DMED group compared to the control group. Significantly, HG decreased cell viability and increased OS and iron levels in CCSMCs, which could be reversed by Fer-1 treatment. Our study revealed that ferroptosis may indeed exist in DMED. GPX4, SLC7A11, and ACSL4 all have a role in controlling the viability of CCSMCs, making them potential therapeutic targets.

Ganoderma lucidum polysaccharide ameliorated diabetes mellitus-induced erectile dysfunction in rats by regulating fibrosis and the NOS/ERK/JNK pathway

BackgroundDiabetes mellitus-induced erectile dysfunction (DMED) is a frequent complication of diabetes mellitus (DM), with limited therapy at present. This study aimed to explore the role and mechanism of Ganoderma lucidum polysaccharide (GLP) on DMED.MethodsDMED was induced in the experimental rats [male 12-week-old Sprague-Dawley (SD) rats] by treatment with streptozotocin (60 mg/kg) and apomorphine (APO). Next, rats in the GLP low dose (GLP-L)/GLP high dose (GLP-H) groups were treated with GLP (100 or 400 mg/kg/d, respectively) for 8 weeks. Subsequently, erectile function was assessed by APO and electrostimulation of the cavernous nerve (CN). Serum or penile testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and cyclic guanosine monophosphate (cGMP) contents were evaluated by enzyme-linked immunosorbent assay (ELISA). The levels of oxidative stress indicators in the corpus cavernosum (CC) were measured by corresponding kits, and histological changes in the CC were observed by hematoxylin-eosin (HE) and Masson staining. Additionally, the apoptosis index, caspase-3, caspase-9, and eNOS expression, and mitochondrial membrane potential (MMP) were also detected. Furthermore, quantitative polymerase chain reaction (qPCR) and western blot assays were conducted to determine the NOS, TGF-β1 mRNA expression, ERK1/2, eNOS, JNK phosphorylation, and arginase II protein expression.ResultsThe erectile function test revealed that erectile dysfunction (ED) was alleviated in the DMED rats following treatment with GLP. Moreover, GLP upregulated the T and cGMP content, improved the oxidative stress and histological injuries of CC, and also inhibited the apoptosis and MMP loss of penile tissues in DMED rats. Furthermore, GLP treatment enhanced the mRNA expression of NOS and TGF-β1 and suppressed the phosphorylation of ERK1/2, eNOS, and JNK, as well as the protein expression of arginase II in DMED rats.ConclusionsGLP ameliorated DMED by repairing the CC pathological damage and upregulating NOS expression and ERK/JNK phosphorylation, indicating that GLP may be a candidate drug for DMED therapy.

The Efficacy of Li-ESWT Combined With VED in Diabetic ED Patients Unresponsive to PDE5is: A Single-Center, Randomized Clinical Trial.

IntroductionPhosphodiesterase type 5-inhibitors (PDE5is) are the first-line treatment for patients with diabetes mellitus-induced erectile dysfunction (DMED), however, some patients are non-responser to PDE5is. We performed a perspective, randomized, comparative study to explore the efficacy of low intensity extracorporeal shock wave treatment (Li-ESWT) combined with vacuum erectile device (VED) in the treatment of DMED patients who were unresponsive to PDE5is.MethodsOne hundred and five eligible patients were randomly divided into three groups: group A (VED), group B (Li-ESWT) and group C (VED plus Li-ESWT). Follow-up was conducted at 4 weeks, 8 weeks and 12 weeks after the end of treatment. The erectile function was estimated by the international index of erectile function-erectile function domain (IIEF-EF), erection hardness score (EHS), sexual encounter profile questions 2 and 3 (SEP2 and SEP3) and global assessment question 1 and 2 (GAQ1 and GAQ2) before and after treatment. The changes of five points in IIEF-EF were calculated as the minimal clinical important difference (MCID), which was considered as the main index of efficacy.ResultsThe MCID was achieved in 14.7%, 14.7% and 17.6% patients in group A at the follow up on 4 weeks, 8 weeks and 12 weeks, respectively (36.4%, 39.4% and 36.4% in group B; 36.4%, 51.5%, and 66.7% in group C). There were significant differences in the percentage of MCID cases between group A and group C at the follow up on 12 weeks (P<0.001), as well as that between group B and group C (P=0.014). Additionally, comparison in MCID within group C showed that there were significant differences between 4 weeks and 12 weeks follow-up (P=0.014).ConclusionOur findings indicated the combined therapy Li-ESWT and VED was more beneficial to shift turn PDE5is non-responders to responders for moderate patients with DMED than VED or Li-ESWT monotherapy. Moreover, this study provided evidence that patients with DMED who failed after taking oral PDE5is could attempt to opt for an alternative physicotherapy (Li-ESWT or VED) prior to more invasive alternatives.

Non-Coding RNAs: New Dawn for Diabetes Mellitus Induced Erectile Dysfunction.

Erectile dysfunction (ED) is a common sexual dysfunction in males, with multifactorial alterations which consist of psychological and organic. Diabetes mellitus (DM) induced erectile dysfunction (DMED) is a disconcerting and critical complication of DM, and remarkably different from non-diabetic ED. The response rate of phosphodiesterase type 5 inhibitor (PDE5i), a milestone for ED therapy, is far from satisfactory in DMED. Unfortunately, the contributing mechanisms of DMED remains vague. Hence, It is urgent to seek for novel prospective biomarkers or targets of DMED. Numerous studies have proved that non-coding RNAs (ncRNAs) play essential roles in the pathogenesis process of DM, which comprise of long non-coding RNAs (lncRNAs) and small non-coding RNAs (sncRNAs) like microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs) and circular RNAs (circRNAs). However, the implications of ncRNAs in DMED are still understudied. This review highlights the pathophysiology of DMED, summarizes identified mechanisms of ncRNAs associated with DMED and covers the topic of perspectives for ncRNAs in DMED.

Paeonol ameliorates diabetic erectile dysfunction by inhibiting HMGB1/RAGE/NF-kB pathway.

The management of diabetes mellitus-induced erectile dysfunction (DMED) is progressively becoming tricky due to the surge in the number of patients and the poor efficiency of phosphodiesterase type 5 inhibitors in DMED. Paeonol (Pae), as a traditional Chinese medicine, has been more and more widely used in the treatment of diabetic complications. However, whether Pae could be a potential therapeutic drug of DMED needs to be further evaluated. To investigate the pharmacological effect and possible mechanism of Pae in the treatment of DMED. Intraperitoneal streptozotocin injection and an apomorphine test were used to construct the model of DMED. Seventeen DMED rats were divided into two groups: DMED group (n=8) and DMED+Pae group (Pae; 100mg/kg/d; oral administration; n=9). In addition, there were still 10 normal age-matched male rats as control group. Four weeks later, the cavernous nerve electric stimulation was carried out to measure the erectile response. Moreover, the corpus cavernosum smooth muscle cells (CCSMCs) were primarily isolated and exposed to high glucose (HG) stimulation, Pae treatment and glycyrrhizin (GL; the selective inhibitor of HMGB1). After an incubation for 1week, the CCSMCs were harvested for detection. The impairment of erectile function was observed in DMED rats compared with control samples, accompanied by the upregulation of HMGB1/RAGE/NF-κB Pathway. The lower nitric oxide and cGMP level and the higher level of inflammation, fibrosis, and apoptosis were also observed in DMED rats. It showed contrast that Pae treatment could improve the erectile function, as well as histologic alteration and related molecular changes. In addition, Pae could downregulate the HMGB1/RAGE/NF-κB pathway to regulate the apoptosis and inflammation levels of CCSMCs in high-glucose conditions, which is similar to the results of GL treatment. Pae alleviated ED in DMED rats, likely by inhibiting HMGB1/RAGE/NF-κB Pathway, inflammatory, apoptosis, and fibrotic activity, and moderating endothelial dysfunction. Our study provide evidence for a potential new therapy for DMED.

Trigonella foenum-graecum L. and Psoralea corylifolia L. Improve Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats through Suppression of Oxidative Stress.

Background Diabetes mellitus-induced erectile dysfunction (DMED) is one of the most common complications of diabetes and is mainly attributed to oxidative stress. Hu-Lu-Ba-Wan (HLBW) is a classic Chinese formulation consisting of Trigonella foenum-graecum L. (TFG) and Psoralea corylifolia L. (PC). HLBW has been used not only for the treatment of diabetes but also for the treatment of erectile dysfunction in clinics. This study aimed to explore the efficacy and underlying mechanism of HLBW in ameliorating erectile function in streptozotocin-induced diabetic rats. Methods The diabetic model was established by tail vein injection of streptozotocin (26 mg/kg), and then DMED rats screened by the apomorphine test were randomly divided into two groups: the model group and the HLBW group. The rats in the HLBW group were administered HLBW granules daily for 12 weeks. Fasting blood glucose and fasting insulin were tested by a commercial kit. Intracavernous pressure (ICP) and mean arterial pressure (MAP) were measured by cavernous nerve electrostimulation before the rats were killed. Erectile function was evaluated with ICP/MAP. The markers of oxidative stress in the corpus cavernosum (CC) were assayed by assay kits. Apoptosis in cavernosal tissue was detected by Western blotting (WB). The expression levels of vascular endothelial marker (vWF), α-smooth muscle actin (α-SMA), endothelial nitric oxide synthase (eNOS), and NADPH oxidase subunit P47phox were determined by WB and PCR. Furthermore, the structure of the CC was further confirmed by Masson's trichrome staining. Results The results showed that HLBW significantly reduced blood glucose and increased insulin sensitivity. HLBW reduced oxidative stress and apoptosis. In addition, we observed that the expression levels of vWF, α-SMA, and eNOS as well as the ratio of smooth muscle to collagen increased in the HLBW group. Conclusions Our results demonstrated that HLBW could reduce oxidative stress damage in CC to improve diabetes mellitus-induced erectile dysfunction in rats by inhibiting NADPH oxidase.

Angiotensin-(1−7) improves diabetes mellitus-induced erectile dysfunction in rats by regulating nitric oxide synthase levels

This study explores the role of inducible nitric oxide synthase (iNOS) in the pathogenesis of diabetes mellitus-induced erectile dysfunction (DMED) and the effect of angiotensin 1–7 (Ang- [1–7]) on NOS levels. A type 2 diabetes mellitus (DM) rat model was established. Erectile function was assessed by measuring intracavernous pressure and mean arterial pressure after electrical stimulation. The expression of iNOS, endothelial NOS (eNOS), eNOS phosphorylated at Ser 1177 (p-eNOS [Ser 1177]), and AKT/p-AKT in corpus cavernosum smooth muscle cells (CCSMCs) was measured by Western blotting and immunofluorescence. The plasma levels of NO, SOD, malondialdehyde, and peroxynitrite were calculated. Intracellular calcium content was determined by flow cytometry. DMED rats exhibited decreased erectile function and severe oxidative stress. Ang-(1−7) treatment improved erectile response and suppressed oxidative stress by upregulating p-eNOS/eNOS and downregulating iNOS levels. Silencing iNOS in CCSMCs decreased oxidative stress and intracellular calcium levels induced by high glucose. In turn, iNOS overexpression increased oxidative stress and intracellular calcium level. Treatment with the MAS receptor antagonist A779 and the Akt antagonist LY294002 reversed the effects of Ang-(1−7) on iNOS. Ang-(1−7) improved DMED through the MAS/AKT signaling pathway.