Diabetes-induced Erectile Dysfunction Research Articles

MicroRNA-148a-3p in pericyte-derived extracellular vesicles improves erectile function in diabetic mice by promoting cavernous neurovascular regeneration

BackgroundTo investigate the regulatory role of microRNA (miR)-148a-3p in mouse corpus cavernous pericyte (MCPs)-derived extracellular vesicles (EVs) in the treatment of diabetes-induced erectile dysfunction (ED).MethodsMouse corpus cavernous tissue was used for MCP primary culture and EV isolation. Small-RNA sequencing analysis was performed to assess the type and content of miRs in MCPs-EVs. Four groups of mice were used: control nondiabetic mice and streptozotocin-induced diabetic mice receiving two intracavernous injections (days − 3 and 0) of phosphate buffered saline, MCPs-EVs transfected with reagent control, or MCPs-EVs transfected with a miR-148a-3p inhibitor. miR-148a-3p function in MCPs-EVs was evaluated by tube-formation assay, migration assay, TUNEL assay, intracavernous pressure, immunofluorescence staining, and Western blotting.ResultsWe extracted EVs from MCPs, and small-RNA sequencing analysis showed miR-148a-3p enrichment in MCPs-EVs. Exogenous MCPs-EV administration effectively promoted mouse cavernous endothelial cell (MCECs) tube formation, migration, and proliferation, and reduced MCECs apoptosis under high-glucose conditions. These effects were significantly attenuated in miR-148a-3p-depleted MCPs-EVs, which were extracted after inhibiting miR-148a-3p expression in MCPs. Repetitive intracavernous injections of MCPs-EVs improved erectile function by inducing cavernous neurovascular regeneration in diabetic mice. Using online bioinformatics databases and luciferase report assays, we predicted that pyruvate dehydrogenase kinase-4 (PDK4) is a potential target gene of miR-148a-3p.ConclusionsOur findings provide new and reliable evidence that miR-148a-3p in MCPs-EVs significantly enhances cavernous neurovascular regeneration by inhibiting PDK4 expression in diabetic mice.

Pentaclethra macrophylla leaves reduce blood glucose level, improve sexual behavior and modulate critical enzymes associated with diabetes-erectile dysfunction morbidity in rats.

This research work studied the phenolic composition of Pentaclethra macrophylla (PM), the inclusion of dietary supplementation of PM leaves on sexual functions and its connection to inhibit enzymes (arginase and phosphodiesterase-5) and nitric oxide level, linked to type 2 diabetes-induced erectile dysfunction in rats. Gallic acid, chlorogenic and ellagic acids, Kaempferol, and epicatechin etc. was spotted with High performance liquid chromatography-diode array detector from PM extract. Twenty-five (25) rats were used for the study. Five rats were placed with basal diet; diets not supplemented with PM leaves (normal rat group) while twenty rats were made diabetic by feeding them with high fat diet for two weeks, prior to single injection with 35 mg/kg of streptozotocin (STZ). After checking with glucometer, experimental animals with blood glucose level >250 mg/dL were accepted as diabetic. The diabetic rats were subsequently divided into four groups of five rats each (n=5). The diabetic rats were placed on basal diet, or diets supplemented with PM leaves (10 % or 5 % inclusion) or sildenafil citrate (SC). The result revealed that PM supplemented diets caused significant (p<0.05) reduction in blood glucose level, and augmented erectile function by inhibiting arginase and PDE5 activities as well as enhancing nitric oxide level. In conclusion, dietary inclusion of PM leavescould serve as a potent nutraceutical source in hyperglycemia induced erectile dysfunction management.

(226) Mito-Q, a Mitochondrial-targeted Antioxidant, Partially Improves Relaxation of the Corpus Cavernosum in Aged Diabetic Mice

Abstract Introduction Erectile dysfunction is associated with increased contraction and decreased relaxation of the corpus cavernosum (CC). Excessive reactive oxygen species produced by mitochondria play a key role in aging- and diabetes-induced erectile dysfunction. Erectile dysfunction is associated with increased contraction and decreased relaxation of the corpus cavernosum. Mitochondrial deterioration is part of normal physiological aging, and it plays a role in the pathogenesis of age-related disorders by producing reactive oxygen species (ROS). It is also known that excessive ROS produced by mitochondria plays a key role in aging- and diabetes-induced erectile dysfunction. Objective We aimed to test the hypothesis that in vitro inhibition of mitochondrial oxidative stress improves the reactivity of the CC. Methods To test this hypothesis, the CC of young (3 to 4-month-old) and old (10 to 14-month-old) male lean and diabetic (dbdb-/-) mice were mounted in myographs. Concentration-response curves to acetylcholine (ACh 1 nM – 30 uM) and relaxation induced by electrical field stimulation (EFS – 1, 2, 4, 8 and 16 Hz) were obtained. All curves were repeated after 30 minutes of incubation with the antioxidant Mito-Q (100 nM). Results Results: Relaxation to ACh was significantly reduced in the CC of diabetic mice (Lean: 87 ± 8% vs dbdb-/-: 60 ± 6%). Similarly, aged lean mice presented impaired relaxation to ACh (Lean old: 54 ± 6%) while old diabetic mice displayed a further decrease in the relaxing response to ACh (35 ± 6%). After 30 minutes of incubation with Mito-Q, the relaxation produced by ACh was improved in the CC of the aged lean mice (62 ± 3%) and aged diabetic mice (44 ± 1%). Relaxing responses to EFS were significantly decreased in obese and aged mice compared to the lean young animals. However, no improvement in the relaxing response to EFS was seen after incubation with Mito-Q. Conclusions Impairment in the endothelium-dependent relaxation of the CC induced by aging and diabetes is associated with increased production of mitochondrial reactive oxygen species. The use of the mitochondrial-targeted antioxidant Mito-Q improved at least in part the relaxation of the CC in both aged and diabetic mice. Disclosure No

Extracellular Matrix and Protein Phosphorylation Dysregulation Related to Diabetes-Induced Erectile Dysfunction

Diabetes can cause erectile dysfunction (ED) in more than half of male patients. However, the mechanisms underlying diabetes-induced erectile dysfunction (DED) remain unknown. This study is aimed at systematically analyzing the cellular and molecular mechanisms leading to DED using bioinformatic analysis and providing molecular targets for predicting and treating DED. In total, we identified 800 DEGs in the DED samples compared with those in the control group. The 407 upregulated DEGs were mainly enriched in glucose and lipid metabolism-related pathways, and the 393 downregulated DEGs were primarily enriched in tissue development and structure. Dysregulated extracellular matrix genes (especially collagen and elastin) may be closely related to damage to the erectile function of the corpus cavernosum. Sixteen hub genes and 24 modules were detected with hub genes and MCODE analysis. The consensus sequence AAA (G/C) AAA was observed at the promoter sites of most genes that were enriched in the “posttranslational protein phosphorylation” pathway. These genes had abundant phosphorylation sites. Furthermore, 20 TFs targeting DEGs were identified using ChEA3 tool. In conclusion, our research comprehensively and systematically describes the molecular characteristics of DED and suggests that dysregulated extracellular matrix genes and protein phosphorylation may play critical roles in DED. Therefore, they may be potential markers for diagnosing and treating DED.

Effect of formulated polyherbal tea blends on erectile function biomarkers in streptozotocin (STZ)-induced diabetic Male Rats

This study determined the effect of polyherbal tea blend (PTB) from Roselle (Hibiscus sabdariffa) Calyx, Soursop (Annona. Muricata), and Moringa (Moringa oleifera) leave on fasting blood glucose level (FBGL), glycated hemoglobin, insulin, and enzymes [arginase, angiotensin-I converting enzyme, thiobarbituric acid reactive species, phosphodiesterase-5 (PDE-5), and purinergic and antioxidant enzymes] related to erectile dysfunction (ED) in the penile homogenate of diabetes mellitus (DM) rats’ model. The samples were prepared and blended in the ratio of 2:2:6 and bagged to contain 1 gram. The sweetening/sweetening (S/US- PTB) teabags, were infused with 20 ml of boiled water for 5 (S/US-PTB-5) and 10 (S/US-PTB-10) min, respectively. The animals were made diabetic [except the normal control (NC) group] with streptozotocin intraperitoneally, and grouped into NC, DM, DM+Acarbose (ACA), DM+S-PTB-5, DM+S-PTB-10, DM+US-PTB-5, and DM+US-PTB-10. The result revealed that the PTB decreased FBGL and related enzymes, but improved insulin level and antioxidant status in the diabetes-induced ED (DMED), while the S/US-PTB-10 appeared better. Since the formulated PTB is in line with the therapeutic effect, the tea can be used as a therapeutic agent for managing not only diabetes but also DMED. However, sexual behavior, clinical trials, and phytochemical screening of the PTB should be carried out.

A study of diabetes-induced erectile dysfunction treated with human umbilical cord mesenchymal stem cells.

The present study aimed to assess the value of human umbilical cord mesenchymal stem cells (hUC-MSCs) for the treatment of diabetes-induced erectile dysfunction (DMED). We established a type 1 diabetes model through intra-abdominal streptozotocin injection. After 10 weeks, an apomorphine test was performed to screen the rats for erectile dysfunction (ED). The rats were divided into three groups: normal control group (n=10), DMED group (n=9) and DMED+hUC-MSC group (n=9). After 4 weeks of hUC-MSC therapy, erectile function was evaluated by intracavernous pressure measurements, and penile tissue collagen and smooth muscle were examined by haematoxylin-eosin and Masson's trichrome staining. In addition, western blotting, immunohistochemistry and RT-PCR analysis of TLR4, VEGF and eNOS were performed. The results showed that hUC-MSC treatment restored erectile function (p < .05) and reversed the smooth muscle/collagen ratio changes of DMED rats (p < .05). Furthermore, hUC-MSC treatment inhibited the expression of TLR4 (p < .05) and enhanced VEGF and eNOS expression (p < .05). In conclusion, hUC-MSC treatment restored the erectile function of diabetic rats by inhibiting TLR4, improving corpora cavernosa fibrosis, and increasing VEGF and eNOS expression.

Berberine modulates crucial erectogenic biomolecules and alters histological architecture in penile tissues of diabetic rats.

Berberine is an isoquinoline alkaloid, found in several plants. Diabetes induces erectile dysfunction (ED) via reduction in some hormones and enzymes implicated in sexual function. This study aimed to investigate the role of berberine on crucial biomolecules linked to penile function in diabetic rats. Sixty-three (63) adult male rats were used and distributed into nine groups (each=7). Group I-IV normal rats administered with citrate buffer (pH 4.5), sildenafil citrate (SD, 5.0mg/kg), 50 and 100mg/kg of berberine, respectively, via oral gavage. Rats in groups V-IX were diabetic rat with ED treated with buffer, SD, 50 and 100mg/kg of berberine, and acarbose (25mg/kg ACA) respectively. The result revealed that histological architecture in penile tissues were altered in diabetic groups treated with berberine, sildenafil citrate and acarbose when compared to the diabetic control group. Treatment with berberine, increased testosterone, luteinizing hormone and follicle-stimulating hormone in diabetic rat with ED. Also, reduced prolactin level and acetylcholinesterase, angiotensin-1 converting enzyme, adenosine deaminase and arginase activities were observed in berberine treated diabetic rat with ED. Molecular docking analysis revealed that berberine had strong binding affinities for these enzymes. Thus, berberine could represent a potential therapeutic agent for diabetes-induced ED.

GYY4137 attenuates functional impairment of corpus cavernosum and reduces fibrosis in rats with STZ-induced diabetes by inhibiting the TGF-β1/Smad/CTGF pathway

Erectile dysfunction (ED) is a common diabetic complication. Recent evidence has illuminated the role of hydrogen sulfide (H2S) as a dynamic mediator of the erection process. H2S is a potent endogenous relaxant gas. It has been shown to relax human and animal penile tissue in vitro and induce erection in animals in vivo. The reported penile expression of H2S-synthesizing enzymes also supports the potential role of the endogenous L-cysteine/H2S pathway in penile homeostasis. Several pathological changes take place in the diabetic penile tissue, including inflammation, oxidative stress, neuropathy and fibrosis of the corpus cavernosum (CC), the major erectile structure of the penis. The present study is experimental and has been performed in the diabetic rat model. The study will investigate the role of H2S as a potential protective mediator against diabetes-induced structural and functional alterations in the CC by examining if it: (1) reduces corporal contraction and/or enhances corporal relaxation following pharmacological stimulation, (2) attenuates fibromuscular changes in diabetic CC, and (3) whether there is a link with H2S plasma/urine level and CC tissue generation, as well as studying the expression of some proteins in the transforming growth factor (TGF)-β1-associated pathway. The major findings of the study reveal that- compared to the nondiabetic controls - the diabetic animals CC showed: (1) augmented contraction and attenuated relaxation in response to phenylephrine and carbachol, respectively, (2) marked fibromuscular degeneration with a significantly lower smooth muscle/collagen ratio and upregulation of TGF-β-1/Smad/CTGF fibrosis signaling pathway, (3) reduced H2S plasma and urinary levels and cavernosal tissue generation. Chronic GYY4137 treatment prevented most of these pathological changes in diabetic CC, thus may be considered a potential new strategy for the prevention and/or treatment of diabetes-induced ED.

Berberine mitigates diabetes-induced erectile dysfunction in rats through modulation of antioxidant status and critical enzyme activity

Berberine mitigates diabetes-induced erectile dysfunction in rats through modulation of antioxidant status and critical enzyme activity

Effect of leech-centipede medicine on improving erectile function in diabetes-induced erectile dysfunction rats via PDE5 signalling pathway-related molecules

Context The leech and centipede granules have good curative effects on many diabetic vascular diseases, including diabetes-induced erectile dysfunction (DIED). Objective To explore the effect of leech and centipede on erectile function in rats with diabetes-induced erectile dysfunction and its possible mechanism. Materials and methods Thirty male Sprague–Dawley DIED rats were randomly divided into the model group (Group M), low-dose group (Group DD), high-dose group (Group DG) and tadalafil group (Group T) (n = 6); diabetic rats were induced by streptozotocin. Apomorphine was used to induce diabetic erectile dysfunction. The ‘leech-centipede’ granules (0.15 and 0.6 g/kg) were intragastrically administered in the DD and DG groups for 8 weeks. Blood glucose, serum insulin, testosterone, cGMP levels and protein expression changes were measured in each group. Results After 8 weeks, the erectile function of rats in the DG group significantly improved (1.26 ± 0.73). Penis tissue cGMP levels were higher in the DG group (1.48 ± 0.11) than in the M group (0.58 ± 0.15). Protein and mRNA expression levels of NOS were significantly higher (0.77 ± 0.05; 0.61 ± 0.02) but those of PDE5 (0.43 ± 0.05; 0.61 ± 0.03) were lower in the DG group than in the M group (0.37 ± 0.06; 0.51 ± 0.01; 0.78 ± 0.06; 0.81 ± 0.04). Conclusion The leech-centipede can improve erectile dysfunction in DIED rats by regulating the expression of cGMP, NOS, and PDE5-related molecules in the PDE5 pathway. This study provides a potential mechanism for the treatment of DIED with leech-centipede.

Effects of Cultured Cordycep militaris on Sexual Performance and Erectile Function in Streptozotocin-Induced Diabetic Male Rats.

Cordyceps militaris (CM), a valuable edible and medicinal fungus, has been used as traditional medicine to treat health conditions, as well as hyposexuality in Asian societies for over a century. Due to the high demand, several artificial cultivation methods have been developed for their biological activities. In this study, CM was cultured on medium that contained white rice and silkworm pupae, and the levels of cordycepin and adenosine, as well as its aphrodisiac effects in diabetes-induced erectile dysfunction (DIED), were evaluated. Diabetic rats were induced by streptozotocin (STZ) injection and administered orally with CM (0.1, 0.5, and 1.0 g/kg BW/day) for 3 weeks. Diabetic rats in negative and positive control groups received vehicle and sildenafil citrate (5 mg/kg), respectively. Results showed the changes in mating behaviour in which mount latency and intromission latency were significantly increased in diabetic rats, compared with the normal control group. Diabetic rats also showed a significant reduction in intracavernosal pressure (ICP) response to cavernous nerve stimulation, sperm count, testosterone level, penile nitric oxide synthase (NOS), and testicular superoxide dismutase (SOD) activities, when compared to the normal control group. Administration of CM (0.1, 0.5, and 1.0 g/kg BW/day) reversed the effects of diabetes on the mating behaviour, and the ICP responses to electrical stimulation. Moreover, the levels of penile NOS, testicular SOD activities, testosterone, and sperm count were significantly increased, and testicular malondialdehyde (MDA) levels were significantly decreased in these treated diabetic rats. Diabetic rats treated with sildenafil showed a significant induction in intromission frequency and NOS and SOD activities, as well as a marked increase in ICP responses. These results suggest that CCM exerts its aphrodisiac effect, possibly through activating testosterone production and suppressing oxidative stress to enhance erectile function in diabetic rats.

Gene expression profiling of mouse cavernous endothelial cells for diagnostic targets in diabetes-induced erectile dysfunction.

PurposeTo investigate potential target genes associated with the diabetic condition in mouse cavernous endothelial cells (MCECs) for the treatment of diabetes-induced erectile dysfunction (ED).Materials and MethodsMouse cavernous tissue was embedded into Matrigel, and sprouted cells were subcultivated for other studies. To mimic diabetic conditions, MCECs were exposed to normal-glucose (NG, 5 mmoL) or high-glucose (HG, 30 mmoL) conditions for 72 hours. An RNA-sequencing assay was performed to evaluate gene expression profiling, and RT-PCR was used to validate the sequencing data.ResultsWe isolated MCECs exposed to the two glucose conditions. MCECs showed well-organized tubes and dynamic migration in the NG condition, whereas tube formation and migration were significantly decreased in the HG condition. RNA-sequencing analysis showed that MCECs had different gene profiles in the NG and HG conditions. Among the significantly changed genes, which we classified into 14 major gene categories, we identified that aging-related (9.22%) and angiogenesis-related (9.06%) genes were changed the most. Thirteen genes from the two gene categories showed consistent changes on the RNA-sequencing assay, and these findings were validated by RT-PCR.ConclusionsOur gene expression profiling studies showed that Cyp1a1, Gclm, Igfbp5, Nqo1, Il6, Cxcl5, Olr1, Ctgf, Hbegf, Serpine1, Cyr61, Angptl4, and Loxl2 may play a critical role in diabetes-induced ED through aging and angiogenesis signaling. Additional research is necessary to help us understand the potential mechanisms by which these genes influence diabetes-induced ED.

Harnessing Stem Cell Potential for the Treatment of Erectile Function in Men with Diabetes Mellitus: From Preclinical/Clinical Perspectives to Penile Tissue Engineering.

According to the World Health Organization, more than 150 million people are diabetic, and this number will increase twofold by the year 2025. Diabetes-related complications affect all body organ systems, including the penis. Diabetes-induced Erectile Dysfunction (ED) is caused by neuropathy of the penile nerves and vasculopathy involving the smooth muscle and endothelium of the corpus cavernosum. This study aims to present an overview of Stem Cell (SC) research in diabetic animal models of ED, focusing on the function, signaling, and niches that have a prominent role in the regeneration of cavernosal cells and penile tissues. We highlight common erectile pathologies caused by diabetes and review relevant preclinical trials. We also discuss paracrine mechanisms of various SC therapies involved in the repair of endothelial cells and cavernous nerves in these diabetic models. A PubMed search was performed, with dates ranging from inception until Mar 31, 2019. This review provides a comprehensive evaluation of the various strategies that have been investigated for improving SC delivery methods, through preclinical literature and published clinical trials regarding ED in men with diabetes. Various cell-type applications have benefited erectile function in diabetic models of ED. This review examines the progress and remaining challenges in diabetes-related SC research regarding ED. Moving forward, it is only with a combined effort of basic biology and translational work that the potential of SC-based therapies in diabetes in ED can be realized.

Moringa oleifera leaf and seed inclusive diets influenced the restoration of biochemicals associated with erectile dysfunction in the penile tissue of STZ-induced diabetic male rats treated with/without Acarbose drug.

We aim to evaluate the effect of Moringa leaf (ML) and seed (MS) inclusive diets on critical biomarkers [acetylcholinesterase (AChE), monoamine oxidase (MAO), angiotensin-I converting enzyme (ACE), adenosine deiminase (ADA) and arginase activities, and thiobarbituric acid reactive species (TBARS) level] associated with erectile dysfunction (ED) in the penile tissue of diabetic male rats treated with/without Acarbose (ACA). About 60mg/kg BW streptozotocin (STZ)-induced diabetic rats were fed with ML and MS inclusive diets and cotreated with ACA for 14days. The result indicated that AChE, MAO, ADA, ACE, and arginase activities, as well as TBARS level were (p<.05) restored in the diabetic rats fed with ML/MS inclusive diets treated with/without ACA compared to the untreated diabetic rats. In conclusion, the combination therapy of ML/MS inclusive diets plus ACA could be explored toward the management of diabetic-induced ED. PRACTICAL APPLICATIONS: We discovered in this study, treatments of diabetic rats with ACA and co-fed with 2% and 4% of Moringa leaf and seed inclusive diets for 14days, could be of great benefit toward the management of ED caused by diabetes, as evidenced by the expression of some ED-related biomarkers in the penile tissue of diabetes male rats, compared to that of ACA treated alone. Thus, it seems reasonable to explore the effect of food-drug interaction on the large-scale clinical trial to manage diabetes complications, such as the potential effect of Moringa leaf and seed inclusive diets co-administered with ACA for the holistic management of diabetes-induced erectile dysfunction (ED).

The beneficial effect of clove essential oil and its major component, eugenol, on erectile function in diabetic rats.

Diabetic men are at a higher risk of erectile dysfunction (ED). A tropical plant, clove (Syn. Eugenia caryophyllata, Caryophyllus aromaticus L., Syzygium aromaticum (L.) Merr. & L.M. Perry) from the Myrtaceae family has displayed aphrodisiac activity. The present research aimed to investigate the impacts of clove essential oil (CEO) and the ingredient of CEO, eugenol (E) on ED in diabetic rats. We divided Sprague-Dawley rats into control and diabetic groups. Erectile function was evaluated before and after CEO and E intracavernosal injection. CEO- and E-induced relaxation responses were investigated in isolated corpus cavernosum (CC) usingvarious inhibitors. The intracavernous administration of CEO and E restored erectile responses in diabetic rats. CEO and E induced remarkable relaxation in all groups. CEO- and E-induced relaxation responses were partially inhibited after pre-contraction with KCl. Tetraethylammonium and glibenclamide inhibited the relaxation response to CEO. Glibenclamide inhibited maximum relaxation to E. The inhibitors of nitric oxide synthase (NOS), soluble guanylyl cyclase and nifedipine did not change CEO- and E-induced relaxation responses. The current results suggest that CEO and the major compound of the essential oil, E improved diabetes-induced ED in rats, and CEO caused CC relaxation via K+ channels independently NO signalling pathway.

Intracavernosal Adeno-Associated Virus-Mediated S100A1 Gene Transfer Enhances Erectile Function in Diabetic Rats by Promoting Cavernous Angiogenesis via VEGF-A/VEGFR2 Signaling

IntroductionNovel therapeutic targets for diabetes-induced erectile dysfunction (DED) are urgently needed. Previous studies have proved that S100A1, a small Ca2+-binding protein, is a pluripotent regulator of cardiovascular pathophysiology. Its absence is associated with endothelial dysfunction, the central event linking cardiovascular changes in diabetes. However, the role of S100A1 in DED remains unknown. AimTo explore the effect and underlying mechanisms of S100A1 in restoring erectile function in type I diabetic rat model. MethodsDiabetes was induced by intraperitoneal injection of streptozotocin and then screened by apomorphine (APO) to confirm erectile dysfunction. Rats that met the criteria of penile erection were marked as APO-positive; otherwise, the result was APO-negative. In experiment 1, S100A1 gene expression alterations in the corpus cavernosum in moderate and established stages of DED were analyzed. In experiment 2, S100A1 and control GFP gene were delivered into the corpus cavernosum in APO-negative rats by adeno-associated virus (AAV) serotype 9. Erectile function was assessed at 4 weeks after gene therapy. Main Outcome MeasuresErectile response, histologic and molecular alterations. ResultsS100A1 protein was localized to the area surrounding the cavernosal sinusoids in the penis, and it was gradually downregulated synchronized with the progression of DED. Compared with an injection of AAV-GFP, a single injection of AAV-S100A1 significantly restored erectile function in diabetic rats. S100A1 overexpression significantly upregulated the expression of endogenous VEGF-A, promoted VEGFR2 internalization, and subsequently triggered the protein kinase B–endothelial nitric oxide synthase pathway in diabetic erectile tissues. Marked increases in nitric oxide and endothelial content were noted in AAV-S100A1-treated diabetic rats. Clinical ImplicationsLocal S100A1 overexpression may be an alternative therapy for DED and should be further investigated by future clinical studies. Strength & LimitationsThis is the first study demonstrating the angiogenic role of S100A1 in DED, but does not preclude the contribution of the effects of S100A1 in other tissues such as the neuronal tissue on the functional effects observed in erectile responses. ConclusionThe decreased expression of S100A1 during hyperglycemia might be important in the development of erectile dysfunction. S100A1 may play a potential role in restoring erectile function in rats with DED through modulating cavernous angiogenesis.Yu Z, Zhang Y, Tang Z, et al. Intracavernosal Adeno-Associated Virus-Mediated S100A1 Gene Transfer Enhances Erectile Function in Diabetic Rats by Promoting Cavernous Angiogenesis via VEGF-A/VEGFR2 Signaling. J Sex Med 2019;16:1344–1354.

Low-Intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction in Diabetic Patients.

The cause of erectile dysfunction (ED) in diabetic patients is complex and involves both neurogenic and vasculogenic components and is often hard to treat. To study the effect of low-intensity extracorporeal shock wave therapy (Li-ESWT) therapy on a subgroup of diabetic patients with ED who are responders (PDE5I-R) and non-responders (PDE5I-NR) to phosphodiesterase 5 inhibitors (PDE5I). Analysis of pooled data from 5 double-blind, sham-controlled trials was performed. In this sub-analysis, of 350 patients in the PDE5I-R group and with vasculogenic ED, we found 61 patients with diabetes mellitus who underwent LI-ESWT. Another 48 patients (of 53) belonged to the PDE5I-NR group. Baseline efficacy was evaluated with the International Index of Erectile Function-Erectile Function domain questionnaire (IIEF-EF) for the PDE5I-R and with Erection Hardness Score, IIEF-EF, and flow-mediated dilation technique for the PDE5I-NR. Change in the IIEF-EF score after treatment of diabetes-induced ED with Li-ESWT in the PDE5i-R group vs the PDE5i-NR group. LI-ESWT therapy was found to be effective in both subgroups of diabetic patients. Minimally clinical important difference in IIEF-EF score was achieved in 50%, 79.5%, 77.3%, and 65.9% of the subjects in the active group in after the sixth shockwave (SW) treatment evaluation (just before initiating the seventh SW session) and at 1 month, 6 months, and 12 months after the last SW treatment, respectively. The difference among the groups was significant (P < .05) after the sixth treatment and in all the follow-up periods. In the PDE5I-NR group, 55% of the active group were converted to PDE5I-5-R after LI-ESWT. The difference between the active and sham groups was statistically significant in all the tested measures (P < .001). LI-ESWT is safe and effective for the treatment of ED in PDE5I-R and PDE5I-NR groups. Spivak L, Shultz T, Appel B, etal. Low-Intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction in Diabetic Patients. Sex Med Rev 2021;9:619-627.

Potential of phloroglucinol to improve erectile dysfunction associated with streptozotocin-induced diabetes in rats

ObjectiveDiabetes is a common metabolic disease with several complications in its patients. Often, people living with diabetes develop erectile dysfunction (ED). The primary aim of this work was to investigate the effect of phloroglucinol in diabetes-induced ED in rats. MethodsMale Wistar rats were given 52 mg/kg of streptozotocin, by intraperitoneal injection, to induce diabetes and ED. Subsequently, animals were grouped into three groups: group 1, diabetic control; group 2, low-dose phloroglucinol (150 mg/kg body weight); and group 3, high-dose phloroglucinol (250 mg/kg body weight). A group of six normal rats served as a normal control. The rats were treated with phloroglucinol for six weeks and then were assessed for treatment effects. Sexual behavior, glycosylated hemoglobin A1c (HbA1c) values, serum testosterone, serum nitric oxide (NO), blood pressure and sperm count were measured after the end of treatment. ResultsAfter a 6-week treatment period, the high dose of phloroglucinol significantly decreased HbA1c values in diabetic rats. Rats treated with phloroglucinol had increased serum testosterone, NO and sperm count. Animals treated with 250 mg/kg phloroglucinol performed similar to normal rats in the sexual behavioral study, suggesting the reversal of complications of ED. Conversely, a decrease in the blood pressure in treated groups was observed. ConclusionThe results highlight the protective effect of phloroglucinol in diabetes-induced ED in rats warranting further studies.

Nerve Growth Factor Improves the Outcome of Type 2 Diabetes-Induced Hypotestosteronemia and Erectile Dysfunction.

Hypotestosterone and erectile dysfunction (ED) occur frequently in males with type 2 diabetes. It is still clinically challenging to manage diabetes-induced ED. Here, we conducted a 2-arm randomized clinical study and in vitro cell line experiments to investigate the effects of nerve growth factor (NGF) on serum testosterone and ED in diabetic males with sensorimotor polyneuropathy and to identify its underlying mechanisms. The analyses of serum total testosterone (TT) and free testosterone (FT), and 5-item version of the International Index of Erectile Function (IIEF-5) score at baseline and after treatment show increases in TT (3.90 nmol/L, 95% confidence interval [CI]: 3.13-4.66 nmol/L vs 1.21 nmol/L [95% CI: 0.57-1.85 nmol/L]), FT (3.79 pg/mL [95% CI: 3.05-4.54 pg/mL] vs 1.27 pg/mL [95% CI: 0.85-1.70 pg/mL]), and IIEF-5 score (1.84 [95% CI: 1.21-2.47] vs 0.24 [95% CI: -0.24 to 0.73]) in the NGF treatment compared controls ( P < .005). In mouse Leydig cells, NGF significantly ameliorated the hyperglycemia-induced downregulation of steroidogenic acute regulatory protein and cytochrome P450 11A1 ( P < .05). Thus, NGF treatment effectively improves type 2 diabetes-induced hypotestosterone and ED outcome through a mechanism that includes upregulation of key enzymes in testosterone biosynthesis.

Combination of stromal vascular fraction and Ad-COMP-Ang1 gene therapy improves long-term therapeutic efficacy for diabetes-induced erectile dysfunction

Men with diabetic erectile dysfunction (ED) respond poorly to the currently available oral phosphodiesterase-5 inhibitors. Therefore, functional therapies for diabetic ED are needed. Stromal vascular fraction (SVF) and the adenovirus-mediated cartilage oligomeric matrix angiopoietin-1 (Ad-COMP-Ang1) gene are known to play critical roles in penile erection. We previously reported that SVF and Ad-COMP-Ang1 have only a short-term effect in restoring erectile function. Further improvements to ED therapy are needed for long-lasting effects. In the present study, we aimed to test if the combination of SVF and Ad-COMP-Ang1 could extend the erection effect in diabetic ED. We found that the combination therapy showed a long-term effect in restoring erectile function through enhanced penile endothelial and neural cell regeneration. Combination therapy with SVF and Ad-COMP-Ang1 notably restored cavernous endothelial cell numbers, pericyte numbers, endothelial cell–cell junctions, decreased cavernous endothelial cell permeability, and promoted neural regeneration for at least 4 weeks in diabetic mice. In summary, this is an initial description of the long-term effect of combination therapy with SVF and Ad-COMP-Ang1 in restoring erectile function through a dual effect on endothelial and neural cell regeneration. Such combination therapy may have therapeutic potential for the treatment of diabetic ED.