Diabetic Erectile Dysfunction Research Articles

A systematic review of intracavernosal injection of mesenchymal stem cells for diabetic erectile dysfunction

BACKGROUND As current erectile dysfunction (ED) treatments are limited, other treatment such as stem cells should be explored. Hence, this study aimed to review the sources, method of administration, and therapeutic effect of mesenchymal stem cells (MSCs) for diabetic ED treatment.
 METHODS All relevant articles regarding the use of MSCs for diabetic ED were searched in PubMed and Google Scholar databases from December 15, 2019 to January 1, 2020 published in the past 10 years. The keywords were “mesenchymal stem cells” and “diabetic ED”. The selection and critical appraisal of the studies were discussed. Diabetic ED was evaluated for functional and structural outcome. Functional outcome in animal studies was assessed by intracavernosal pressure/mean arterial pressure (ICP/MAP) ratio, meanwhile the structural outcome was done microscopically. In human study, the assessments were done using international index of erectile function score (IIEF-5) to erection hardness score and penile Doppler ultrasonography.
 RESULTS There were 10 animal studies and 3 human studies. The studies used MSCs from adipose (n = 6), bone marrow (n = 4), placenta (n = 1), umbilical cord (n = 1), and muscle tissue (n = 1). The MSCs were administrated through intracavernosal injection in all studies. In all animal studies, functional outcome was improved, shown in higher ICP/MAP ratio. Microscopically, there were an increase of cavernosal endothelial cells, vascular endothelial growth factor, nitric oxide synthase, and smooth muscle cells. In human studies, IIEF-5 and erection hardness score were improved. Peak systolic velocity was also higher.
 CONCLUSIONS MSCs may be a promising therapy for diabetic ED; however, long-term safety concerns still need further investigations.

Erectile Dysfunction in Type-2 Diabetes Mellitus Patients: Predictors of Early Detection and Treatment

Purpose: To identify risk factors and potential predictors of erectile dysfunction (ED) in type-2 diabetes mellitus (T2DM) patients for early detection and treatment. Methods: A retrospective cohort was used to assess the clinical data of 105 diabetic patients with ED from May 2019 to April 2020 age-matched to 105 diabetic patients without ED. Potential risk factors that could contribute to ED were compared between the groups. Erectile function was evaluated using the International Index of Erectile Function-5 questionnaire. Results: There were higher rates of diabetic peripheral neuropathy (p = 0.036) and retinopathy (p < 0.001), longer duration of diabetes (p < 0.001), lower estimated glomerular filtration rate (p = 0.010) values, and higher uric acid (p < 0.001) and C-reactive protein (p = 0.001) levels in the ED group compared to the non-ED group. Multivariate logistic analysis identified uric acid, diabetic retinopathy, and T2DM course as independent predictors of diabetic ED. Diabetics with retinopathy and T2DM for ≥49 months were 3.028 and 3.860 times more likely to have ED, respectively. Uric acid values ≥392.5 μmol/L were associated with 18.638 times greater risk of having ED, though the values were within normal range. Conclusion: In T2DM patients, higher uric acid (≥392.5 μmol/L), longer diabetes duration (≥49 months), and the presence of diabetic retinopathy were important and reliable predictors for diabetic ED. For patients who have high risk factors for developing ED, diligent screening and early treatment are necessary.

Human umbilical cord Wharton's jelly-derived mesenchymal stem cell transplantation could improve diabetic intracavernosal pressure.

Mesenchymal stem cells (MSCs) secrete various cytokines with angiogenic and neuroprotective effects. This study aimed to assess the effects of human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on diabetes-related intracavernosal pressure (ICP) impairment in rats. hWJ-MSCs were isolated from human umbilical cord Wharton's jelly and transplanted into the corpus cavernosum of streptozotocin (STZ)-induced diabetic rats by unilateral injection. The erectile function was evaluated at 4 weeks, as well as the expression levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), endothelial nitric oxide synthase (eNOS), and insulin-like growth factor 1 (IGF1). STZ-induced diabetic rats showed impaired ICP, which was significantly improved by hWJ-MSC treatment. VEGF, eNOS, IGF1, and bFGF expression levels were higher in hWJ-MSC injection sites than those in control ones in STZ-induced diabetic rats. These results suggest that hWJ-MSC transplantation might improve diabetic erectile dysfunction through increased production of paracrine growth factors, highlighting a novel potential therapeutic option for erectile dysfunction.

CRISPR/Cas9-mediated TEAD1 knockout induces phenotypic modulation of corpus cavernosum smooth muscle cells in diabetic rats with erectile dysfunction

To construct a corpus cavemosum smooth muscle cell (CCSMCs) line with TEAD1 knockout from diabetic rats with erectile dysfunction (ED) using CRISPR/Cas9 technology and explore the role of TEAD1 in phenotypic modulation of CCSMCs in diabetic rats with ED. Models of diabetic ED were established in male Sprague-Dawley rats by intraperitoneal injection of streptozotocin. CCSMCs from the rat models were primarily cultured and identified with immunofluorescence assay. Three sgRNAs (sgRNA-1, sgRNA-2 and sgRNA-3) were transfected via lentiviral vectors into 293T cells to prepare the sgRNA-Cas9 lentivirus. CCSMCs from diabetic rats with ED were infected by the lentivirus, and the cellular expression of TEAD1 protein was detected using Western blotting. In CCSMCs infected with the sgRNA-Cas9 lentivirus (CCSMCs-sgRNA-2), or the empty lentiviral vector (CCSMCs-sgRNA-NC) and the blank control cells (CCSMCs-CK), the expressions of cellular phenotypic markers SMMHC, calponin and PCNA at the mRNA and protein levels were detected using real-time fluorescence quantitative RT-PCR (qRT-PCR) and Western blotting, respectively. The primarily cultured CCSMCs from diabetic rats with ED showed a high α-SMA-positive rate of over 95%. The recombinant lentivirus of TEAD1-sgRNA was successfully packaged, and stable TEAD1-deficient CCSMC lines derived from diabetic rat with ED were obtained. Western blotting confirmed that the protein expression of TEAD1 in TEAD1-sgRNA-2 group was the lowest (P < 0.05), and this cell line was used in subsequent experiment. The results of qRT-PCR and Western blotting showed significantly up-regulated expressions of SMMHC and calponin (all P < 0.05) and down-regulated expression of PCNA (all P < 0.05) at both the mRNA and protein levels in TEAD1-deficient CCSMCs from diabetic rats with ED. We successfully constructed a stable CCSMCs line with CRISPR/Cas9-mediated TEAD1 knockout from diabetic rats with ED. TEAD1 gene knockout can induce phenotype transformation of the CCSMCs from diabetic rats with ED from the synthetic to the contractile type.

The Experience of Indonesian Men Living with Type-2 Diabetes Mellitus and Erectile Dysfunction: A Semi-structured Interview Study

Erectile dysfunction (ED) in men living with Type-2 Diabetes Mellitus (T2DM) in Indonesia is rarely discussed. This study explored the lived experiences of young- to middle-aged Indonesian men living with T2DM and ED to identify the related healthcare support they received from their local public health center. A qualitative-descriptive approach was used to elicit the experiences of twelve men with T2DM who were recruited from a public health center in Surabaya. Using guiding questions, individual interviews were audio recorded, transcribed verbatim, translated to English and then thematically analyzed. Most men in this study experienced ED, with participants’ responses to ED ranging from acceptance to feeling afraid to acknowledge ED to their wife or displaying anger towards their wife. Despite reporting they needed information about ED related to T2DM, participants reported an absence of discussion about ED with health professionals during regular T2DM appointments. Men reported not raising the issue themselves as they felt ashamed or embarrassed. Some men engaged in high-risk self-management behaviors, such as using off-street medications to try and fix their ED while others sought other forms of intimacy with their wife. This study’s findings present previously unreported healthcare experiences of Indonesian men with T2DM and ED. Although routinely visiting healthcare professionals in public health settings for T2DM management, the men in this study did not receive assessment or healthcare around ED. The men would have appreciated the opportunity to discuss their ED and explore treatment options. Future studies are recommended to explore how men with T2DM and ED, and their wives, can be supported by healthcare professionals to improve health and wellbeing outcomes.

Effect of physical exercise combined with shockwave therapy on erectile dysfunction in diabetic patients.

The aim of the study was to evaluate whether physical exercise (PE) in addition to extracorporeal shockwave therapy (ESWT) is more effective in improving erectile function as compared to ESWT and PE alone in diabetic patients with erectile dysfunction (ED). Forty-five patients with type 2 diabetes mellitus (DM) and ED were divided into three equal groups: group 1 (ESWT group) received treatment with ESWT twice weekly for 6 weeks, comprising 3000 shockwaves at an energy density of 0.25 mJ/mm2 and an emission frequency of 6 Hz; group 2 (PE group) received treatment with physical exercise three times per week for 12 weeks; and group 3 (combined group) was treated using physical exercise in the form of the program followed by the PE group, plus ESWT in the form of the same parameter and protocol as that of the ESWT group. Treatment outcomes were measured by International Index of Erectile Function-5 (IIEF-5) score variations recorded at 4 and 12 weeks after the end of treatment with respect to the baseline. The mean IIEF-5 scores significantly improved in all groups at the 4-week follow-up without intergroup differences. At the 12-week follow-up, the mean IIEF-5 improvement and durability were significantly higher among patients in combined groups. The combined approach of ESWT and PE provides significant advantages in erectile dysfunction improvement and durability as compared to ESWT or PE alone in diabetic patients with ED.

Caspase Signaling in ED Patients and Animal Models

BackgroundCurrent treatments for erectile dysfunction (ED) are ineffective in prostatectomy and diabetic patients due to cavernous nerve (CN) injury, which causes smooth muscle apoptosis, penile remodeling, and ED. Apoptosis can occur via the intrinsic (caspase 9) or extrinsic (caspase 8) pathway. AimWe examined the mechanism of how apoptosis occurs in ED patients and CN injury rat models to determine points of intervention for therapy development. Methods and OutcomesImmunohistochemical and western analyses for caspase 3-cleaved, caspase-8 and caspase-9 (pro and active forms) were performed in corpora cavernosal tissue from Peyronie’s, prostatectomy and diabetic ED patients (n = 33), penis from adult Sprague Dawley rats that underwent CN crush (n = 24), BB/WOR diabetic and control rats (n = 8), and aged rats (n = 9). ResultsCaspase 3-cleaved was observed in corpora cavernosa from Peyronie’s patients and at higher abundance in prostatectomy and diabetic tissues. Apoptosis takes place primarily through the extrinsic (caspase 8) pathway in penis tissue of ED patients. In the CN crushed rat, caspase 3-cleaved was abundant from 1–9 days after injury, and apoptosis takes place primarily via the intrinsic (caspase 9) pathway. Caspase 9 was first observed and most abundant in a layer under the tunica, and after several days was observed in the lining of and between the sinuses of the corpora cavernosa. Caspase 8 was initially observed at low abundance in the rat corpora cavernosa and was not observed at later time points after CN injury. Aged and diabetic rat penis primarily exhibited intrinsic mechanisms, with diabetic rats also exhibiting mild extrinsic activation. Clinical translationKnowing how and when to intervene to prevent the apoptotic response most effectively is critical for the development of drugs to prevent ED, morphological remodeling of the corpora cavernosa, and thus, disease management. Strengths and limitationsAnimal models may diverge from the signaling mechanisms observed in ED patients. While the rat utilizes primarily caspase 9, there is a significant flux through caspase 8 early on, making it a reasonable model, as long as the timing of apoptosis is considered after CN injury. ConclusionsApoptosis takes place primarily through the extrinsic caspase 8 dependent pathway in ED patients and via the intrinsic caspase 9 dependent pathway in commonly used CN crush ED models. This is an important consideration for study design and interpretation that must be taken into account for therapy development and testing of drugs, and our therapeutic targets should ideally inhibit both apoptotic mechanisms.Martin S, Harrington DA, Ohlander S, et al. Caspase Signaling in ED Patients and Animal Models. J Sex Med 2021;18:711–722.

Effect of low-intensity extracorporeal shock wave therapy on diabetic erectile dysfunction: Randomised control trial.

This study aimed to assess the effectiveness of low-intensity extracorporeal shockwave therapy (Li-ESWT) in the management of erectile dysfunction in diabetic patients with mixed vasculogenic and neurogenic causes as confirmed by nerve conduction and Doppler studies. This randomised controlled trial included 42 patients 41-55years of age with a confirmed diagnosis of erectile dysfunction and diabetic polyneuropathy. They were randomly allocated to one of two groups: shock wave group (n=21) treated with Li-ESWT plus pelvic floor muscle training and control Group (n=21) treated with pelvic floor muscle exercise and sham therapy by a shock wave. The erectile function was scored according to the five-item version of the International Index of Erectile Function (IIEF-5). Colour-coded duplex sonography was used for the evaluation of penile perfusion of the two cavernous arteries. The assessment was done before and three months after treatment. IIEF-EF increased significantly in the study group (p<.001), but not in the control group (p=.194). Peak systolic velocity increased significantly in the two groups; however, the post-treatment peak systolic velocity was significantly higher in the study group compared to the control group (p<.001, for both arteries).

Vasohibin-1 rescues erectile function through up-regulation of angiogenic factors in the diabetic mice

Neovascularization of the erectile tissue emerges as a beneficial curative approach to treat erectile dysfunction (ED). Here we for the first time report the unexpected role of vasohibin-1 (VASH1), mainly known as an anti-angiogenic factor, in restoring erectile function in diabetic mice. A diabetic patient has lower cavernous VASH1 expression than in the potent man. VASH1 was mainly expressed in endothelial cells. There were significant decreases in cavernous endothelial cell and pericyte contents in VASH1 knockout mice compared with those in wild-type mice, which resulted in impairments in erectile function. Intracavernous injection of VASH1 protein successfully restored erectile function in the diabetic mice (~ 90% of control values). VASH1 protein reinstated endothelial cells, pericytes, and endothelial cell–cell junction proteins and induced phosphorylation of eNOS (Ser1177) in the diabetic mice. The induction of angiogenic factors, such as angiopoietin-1 and vascular endothelial growth factor, is responsible for cavernous angiogenesis and the restoration of erectile function mediated by VASH1. Altogether, these findings suggest that VASH1 is proangiogenic in diabetic penis and is a new potential target for diabetic ED.

Mellituslu Erkek Hastalarda Akut-Kronik Glisemik Oran ile Erektil Disfonksiyon Arasındaki İlişkinin Değerlendirilmesi: Retrospektif, Olgu-Kontrol Çalışması

Objective: The aim of this study was to investigate the possible association between the acute to chronic (A/C) glycemic ratio and the presence of erectile dysfunction (ED) in diabetic men. Material and Methods: A total of 104 diabetic men, 45 of whom had ED while 59 did not, were retrospectively enrolled in this study. Clinical examination and laboratory analyses including A/C glycemic ratio, serum fasting glucose, hemoglobin A1c, lipid profile, and total testosterone were analyzed. Results: The total testosterone levels were lower in the diabetic ED patients compared to the non-ED diabetic participants (4.49 ng/dL vs 4.80 ng/dL, respectively). However, the difference was not statistically significant (p=0.093). Mean high-density lipoprotein cholesterol levels were significantly lower in the diabetic ED patients than in the controls (40±9 mg/dL vs 44±10 mg/dL; respectively; p=0.030). Although the median A/C glycemic ratios were higher in the diabetic ED patients (1.28±0.23 vs. 1.18±0.32), no statistical significant differences were noted between the two groups (p=0.054) Conclusion: The strong relationship between diabetes mellitus (DM) and ED demands caution since DM is a common disease in the population. We believe that developing biomarkers for the early diagnosis of ED will help provide treatment and improve the life quality of patients. Although we could not find a statistical relationship between the A/C glycemic ratio and ED in our study results, we think that further welldesigned prospective studies are needed in this area.

Reviewing the evidence for shockwave- and cell-based regenerative therapies in the treatment of erectile dysfunction.

Erectile dysfunction (ED) is both a common and complex disease process. Existing ED treatments do not always achieve adequate results. There is clinical interest in employing regenerative therapies, including low-intensity extracorporeal shockwave therapy (Li-ESWT), platelet rich plasma (PRP), and stem cell therapy (SCT), in the treatment of ED as adjunct or alternative treatments. Here, we present evidence for emerging shockwave- and cell-based regenerative therapies for the treatment of ED following a thorough review of the existing PubMed literature pertaining to Li-ESWT, PRP, and SCT in relation to the treatment of ED. Li-ESWT causes microtrauma in tissue that hypothetically upregulates angiogenesis and recruits stem cells. Several large-scale systematic reviews and meta-analyses have reported that Li-ESWT improved ED in humans. Additionally, evidence has commenced to show that Li-ESWT may be effective against two recognized and complex etiologies of ED: diabetic and neurogenic. PRP delivers an autologous sample rich in growth factors to damaged tissue. Animal model studies have demonstrated improved erectile function recovery as well as preservation of cavernous nerve axons. Studies with PRP in humans are limited. SCT utilizes the regenerative potential of stem cells for healing of damaged tissue. In the treatment of ED, SCT has been used in the setting of diabetic and post-prostatectomy ED. Results of human studies are varied, although SCT treatments did result in increased erectile rigidity with some patients recovering the ability to achieve penetration. While these regenerative therapies show potential to augment the current treatment regimen for ED, there is a paucity of evidence to support the safety and efficacy of these treatments. Further research is necessary to define the role of these alternative therapies in the treatment of ED.

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.

Analysis of cardiovascular risks for erectile dysfunction in Chinese patients with type 2 diabetes mellitus lacking clinical symptoms of cardiovascular diseases.

BackgroundErectile dysfunction (ED) is common but usually underdiagnosed in diabetics. The correlation between different vascular lesions and ED in diabetics without clinical cardiovascular symptoms is unknown. The aim was to explore the association between cardiovascular risks and ED in Chinese type 2 diabetic men lacking clinical performance.MethodsErectile function of patients with type 2 diabetes was assessed by the 5-item International Index of Erectile Function (IIEF-5) questionnaire. The data of clinical characteristics and vascular lesions at carotid and lower limb sites assessed by the Doppler ultrasound were collected to evaluate diabetes- metabolic indices. Univariate and multivariate analyses were conducted to find statistical correlation between cardiovascular risks and diabetic ED.ResultsA total of 71.21% reported suffering from ED. Lower limb plaques were more common (45.38%) than carotid district (35.62%) in diabetes. Men with ED had higher carotid intima-media thickness (IMT) (P<0.001) and the presence of lower limb plaques (P<0.001) compared with men without ED. After adjusting for age, diabetic duration, blood pressure (BP) and antidiabetic medication, carotid IMT greater than 0.75 mm (P<0.001) and the presence of lower limb plaques (P=0.051) remained associated with the presence of ED and its severity. Compared with isolated atherosclerosis at carotid or lower limb district, vascular lesions at any site and both sites were more correlative with ED presence (all P<0.001).ConclusionsThe prevalence of ED is high among Chinese diabetic men. A higher carotid IMT and the presence of lower limb plaques indicate a tight correlation between peripheral atherosclerosis and diabetic ED. ED may be the only clinical association of symptomatic cardiovascular diseases (CVDs) in diabetes. It is significant to screen ED to prevent the further development of severe symptomatic CVDs.

Effects of "metabolic memory" on erectile function in diabetic men: A retrospective case-control study.

This study was performed to explore the effects of metabolic memory on diabetic erectile dysfunction (ED), especially the severity and response to treatment. Through medical records and follow-up by telephone, 67 patients meeting the criteria with a clinical diagnosis of ED and a diabetic history of more than 5years were enrolled for erectile function analysis. They were divided into a glycemic control group, a glycemic non-control group and a metabolic memory group according to glycemic levels and treatments for diabetes in the past 5years, and they were treated with phosphodiesterase type 5 (PDE5) inhibitors for 4weeks. Erectile function and efficacy were assessed by the International Index for Erectile Function (IIEF), the Erection Hardness Score (EHS), and the Sexual Encounter Profile (SEP). The patients in the glycemic control group performed better in erectile function than those in the other groups. The patients in the glycemic control group received a significantly greater score on both the EHS and the five domains of the IIEF than did the patients in the glycemic non-control group and the metabolic memory group (all P<.001). There were also statistically significant differences favoring the glycemic control group (P<.05) in SEP2 and SEP3 success rates. However, there were no significant differences between the metabolic memory group and the glycemic non-control group in these erectile function assessments (P>.05). Significant negative correlations were seen between HbA1c levels at the time of consultation and the scores on the IIEF-EF and the EHS (Pearson r-values of -0.338 with P=.005 and -0.273 with P=.025, respectively). HbA1c levels at the first diagnosis of diabetes mellitus (DM) were also significantly negatively correlated with scores on the IIEF-EF and the EHS with greater Pearson correlation coefficients (Pearson r-values of -0.478 with P<.001 and -0.392 with P=.001, respectively). Significant improvements on each of the erectile function assessments were observed among diabetic patients with ED, but no significant difference in efficacy was observed between each group. The phenomenon of metabolic memory did have a significant influence on ED in men with diabetes, associated with the severity of ED but not the response to medical treatment. Early hyperglycemia exposure would have long-term disadvantageous effects on erectile function in diabetic patients with ED, which would be sustained even after the patients achieve better glycemic control. In this report, we looked at the erectile functions of 67 patients with a clinical diagnosis of ED and a diabetic history of more than 5years. We found that early hyperglycemia exposure would have long-term disadvantageous effects on erectile function in diabetic patients with ED, which would be sustained even after the patients achieve better glycemic control. We further found that the effects were associated with the severity of ED but not the response to medical treatment in men with diabetes.

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.

Effect of leech-centipede medicine on improving erectile function in DIED rats via PKC signalling pathway-related molecules

Ethnopharmacological relevanceLeeches (pinyin name Shui Zhi; Latin scientific name Hirudo; Hirudinea; Hirudinidae) and centipedes (pinyin name Wu Gong; Latin scientific name Scolopendridae; Chilopoda; Scolopendridae) are traditional Chinese medicines, and they belong to the family entomology. A combination of leech and centipede is used as an effective medicine to promote blood circulation and remove blood stasis in traditional Chinese medicine, and “leech-centipede” medicine has been used in many prescriptions to treat diabetic vascular disease, including diabetic erectile dysfunction (DIED). However, its specific mechanism remains unclear and requires in-depth study. Aim of the studyThis study aimed to investigate the mechanism of “leech-centipede” medicine to improve erectile dysfunction-associated diabetes by detecting PKC pathway-related molecules. Materials and methodsThe active ingredients of “leech-centipede” medicine were identified using high performance liquid chromatography (HPLC). Fifty male SPF rats were injected with streptozotocin to induce the DM model. Eight weeks later, the DMED model was validated with apomorphine. The DIED rats were divided into five groups—T,P,DD,DZ, and DG—and were separately treated with tadalafil, pathway inhibitor LY333531 and low-, medium-, and high-dose “leech-centipede” medicine for 8 weeks. After treatment, the blood glucose level was measured, erectile function with apomorphine was assessed, the LOX-1, sE-selectin, sICAM-1, SOD, and MDA in serum was evaluated by enzyme-linked immunosorbent assay, and flow cytometry was performed. After the collection of penile tissue, the related protein and mRNA expression was assessed by Western blotting and PCR, and the tissue and ultrastructure were analysed by HE staining, immunohistochemistry and scanning electron microscopy. ResultsAfter treatment, the erectile function of rats was significantly improved in the T,P,DD,DZ, and DG groups compared with that in the model group. Thus, “leech-centipede” medicine can significantly reduce the levels of LOX-1, sE-selectin, sICAM-1, EMPs and CD62P to protect vascular endothelial function and anti-platelet activation, improving DIED rat erectile function. Additionally, “leech-centipede” medicine can increase SOD expression and decrease MDA expression, reducing the possibility of oxidative stress injury in DIED rats and improving the antioxidant capacity. Moreover, “leech-centipede” therapy can dramatically reduce the protein and mRNA expression of DAG, PKCβ, NF-κB, and ICAM-1, improve vascular endothelial injury in DIED rats and inhibit abnormal platelet activation. Conclusion“leech-centipede” medicine can improve erectile dysfunction by inhibiting the expression of PKC pathway-related molecules in DIED rats and protects endothelial function and anti-platelet activation.

Serum leptin level in diabetic patients with erectile dysfunction

Background: Erectile dysfunction (ED) is a common sexual problem affecting men. Diabetes mellitus (DM) is one of the most common comorbidities of ED. Leptin is a 167-amino-acid peptide that is mainly expressed in white adipose tissue but is also found in a variety of tissues. Objective: To estimate serum level of leptin in diabetic patients with ED and correlate level of serum leptin in diabetic patients with severity and origin of ED. Patients and methods: Cross-sectional descriptive study was conducted on 64 individual male; 34 diabetic patients of both types of DM with ED and 30 non diabetic normal erectile function as control. All patients were evaluated clinically by history included IIEF-5 score and examination. Assessment of serum leptin level, HbA1c, cholesterol, triglycerides was done and penile duplex study was done only for diseased patients. Results: Serum leptin significantly increased in cases than control (P <0.001). Also, there was increased in diabetic men vasculogenic ED either arterial, venous or mixed (P =0.047). Serum leptin was correlated with the severity of ED (P =0.046). Conclusion: Leptin may play an important biomarker as a cost-effective method for diagnosis and assessment of severity of vasculogenic ED in DM and as a good predictor for ED occurrence.

Prevalence and Factors Associated with Quality of Life among Diabetic Men Living with Erectile Dysfunction

Diabetic erectile dysfunction (DED) is one of the most frequently occurring complications of diabetes mellitus (DM) in men, and past studies have usually overlooked the effect DED has on quality of life (QoL). The objectives of this study are to determine the prevalence of DED and to investigate QoL, and the factors that influence QoL, in Thai men who are living with DED. Five hundred and eighty-two Thai men living with diabetes who enrolled in the diabetic and general medical outpatient clinic at a tertiary hospital in the northern part of Thailand were surveyed to determine the prevalence of DED, as well as QoL and its influencing factors, for men living with DED. The average age of the men was 58.2 years old (±SD = 10.1, range = 34.3 - 80 years old). DED was found in 417 out of the 582 men (71.5 %). The International Index of Erectile Function (IIEF-5) mean score was 17.03 (±SD = 3.47). The QoL was found to be at a moderate level (= 95.42 ±SD = 11.39). The QoL domains found to be at a good level were the psychological (= 23.84 ±SD = 3.42) and environmental domains (= 31.4 ±SD = 3.98), while domains found to be at a moderate level were the social relationships (= 10.77 ±SD = 1.93) and physical domains (= 24.9 ±SD = 3.13). The mean score of the QoL of men living with DED was lower than that of men without DED. The most important factor associated with poor QoL was severity of DED, while men who have a good QoL tend to have a higher education level and more frequent sexual intercourse (p &lt; 0.05). The study showed that the prevalence of erectile dysfunction in Thai men living with DED was high. DED has a moderate impact on QoL, especially on the social relationship domain. The results suggest the importance of screening for DED in clinical settings for early detection of, and creating supportive strategies for treating men with, diabetes mellitus.

Erectile dysfunction is associated with defective L-cysteine/hydrogen sulfide pathway in human corpus cavernosum and penile arteries

H2S signaling was proposed to participate in erectile physiology. L-cysteine (CYS)/H2S pathway stimulation causes cGMP-dependent relaxation of human corpus cavernosum (HCC) and penile arteries (HPRA). The aim was to evaluate the impact of ED on CYS/H2S pathway at functional and molecular level in human penile vascular tissues. NaHS- and CYS-induced responses were evaluated in HCC and HPRA from organ donors without ED (NoED, n = 29) and from ED patients undergoing penile prosthesis insertion (n = 45). cGMP accumulation and cystathionine β-synthase and cystathionine γ-lyase expression were also determined.NaHS-induced relaxations were slightly but significantly impaired in HCC but not in HPRA from ED patients. In contrast, CYS-induced relaxations were markedly impaired in HCC (Emax 67.6 ± 4.9% vs 46.2 ± 4.6%, P < 0.01) and HPRA (Emax 80.8 ± 4.0% vs 48.1 ± 8.6%, P < 0.05) from men with ED. Impairment of CYS-induced responses was observed even after separating diabetic ED patients. In HPRA from ED patients, CYS- but not NaHS-induced vasodilation was significantly associated to endothelial function measured as vasodilatory capacity of acetylcholine (ACh) in these preparations (r2 = 0.481, P < 0.01). Impairment of CYS-induced relaxations was related to significant reduction in CYS-induced accumulation of cGMP in cavernosal tissue. Furthermore, the expression of H2S synthesizing enzymes was significantly reduced in HCC from ED patients with respect to NoED. This was confirmed by immunofluorescence in HCC and HPRA sections. ED involves impairment of CYS/H2S pathway in penile vascular tissues associated with decreased expression of H2S generating enzymes, CBS and CSE. These evidences support a therapeutic potential for modulation of CYS/H2S signaling in the management of ED.

Probucol enhances the therapeutic efficiency of mesenchymal stem cells in the treatment of erectile dysfunction in diabetic rats by prolonging their survival time via Nrf2 pathway

BackgroundIntracavernous injection of mesenchymal stem cells (MSCs) is a promising method for diabetic mellitus-induced erectile dysfunction (DMED), but short survival time of MSCs in cavernous is a fatal defect for therapy. This study investigated therapeutic efficiency and potential mechanism of probucol combined with MSCs.MethodsIn vivo study, a total of forty-eight 10-week-old male Sprague-Dawley (SD) rats were used. Twelve rats received intraperitoneal injection of PBS as the sham group; the rest received intraperitoneal injection of 60 mg/kg streptozotocin to establish DM models. DM rats were randomly divided into three groups: received intracavernosal (IC) injection of either PBS (DM group), MSCs (M group), or administrated probucol after intracavernosal injection of MSCs (P + M group). Erectile function was assessed by electrical stimulation of the cavernous nerves with real-time intracavernous pressure measurement. After euthanasia, penile tissue was investigated for histologic examination and Western blotting. In in vitro experiment, H2O2 was used to create oxidative stress environment to detect changes in cell viability. CCK8 was used to measure cell viability of MSCs treated with or without probucol. Intracellular ROS changes were detected by flow cytometry. Autophagy and apoptosis were detected by Western blotting and confocal microscopy.ResultsRecovery of erectile function was observed in the P + M group. The combination therapy decreased fibrosis and increased endothelial function compared with MSC therapy alone. Western blotting results confirmed the increased expression of Nrf2 and HO-1 in cavernous body. H2O2 induced high oxidative stress and reduced cell viability in vitro, which was gradually reversed with increased concentration of probucol. H2O2 reduced Nrf2 expression, which was reversed by probucol’s intervention. Furthermore, the expression of Bax, Caspase3, and Cleaved-Caspase3 decreased, and the expression of Bcl-2 increased in a dose-dependent manner because of probucol’s intervention. In addition, Beclin1 and LC3II both increased in a dose-dependent manner. Meanwhile, the expression of P62 decreased. In the study of autophagy flux, we found probucol did not block it.ConclusionProbucol enhanced therapeutic efficiency of MSCs in DMED by prolonging their survival time, which mediated through improving the transplanted microenvironment of MSCs, increasing self-antioxidant ability of MSCs, strengthening protective autophagy, and inhibiting apoptosis of MSCs via Nrf2 pathway.Graphical abstractSchematic model showing combined probucol and MSCs to improve DMED. Probucol increases self-antioxidant ability of MSCs, strengthening protective autophagy and inhibiting apoptosis via Nrf2/HO-1 and Nrf2/autophagy pathways.