Restoring erectile function by combined treatment with JNK inhibitor and HDAC inhibitor in a rat model of cavernous nerve injury.

BACKGROUND: The main pathophysiologic conditions of erectile dysfunction (ED) after radical prostatectomy are considered to be corporal fibrosis and apoptosis induced by cavernosal nerve (CN) injury. OBJECTIVES: In a rat model of CN crush injury (CNCI), we investigated whether combination treatment with JNK inhibitor (JNKi), SP600125, and HDAC inhibitor (HDACi), suberoylanilide-hydroxamic-7 acid (SAHA), for 2 weeks after CNCI would restore erectile function by suppressing fibrosis and apoptosis through normalization of JNK and HDAC pathways. MATERIALS AND METHODS: Seventy 12-week-old rats were randomly divided into five groups: Sham surgery, CNCI alone, CNCI treated with daily intraperitoneal injection of 10 mg/kg JNKi, CNCI treated with daily oral administration of 25.0 mg/kg HDACi, and CNCI daily treated with a combination. Two weeks after CNCI, we investigated the erectile response to electrostimulation and conducted histological staining, caspase-3 activity assay, and western blot analysis. RESULTS: CNCI alone resulted in significantly reduced intracavernosal pressure/mean arterial pressure (MAP) and area under the curve/MAP, decreased smooth muscle (SM)/collagen ratio and SM content, higher caspase-3 activity, and increased protein levels of total HDAC3, transforming growth factor (TGF)-ß, fibronectin, and c-Jun phosphorylation, compared with the Sham surgery. The CNCI groups exposed to JNKi, HDACi or both showed improvements in erectile-responses and SM/collagen ratio, compared to the CNCI alone. The combined treatment showed additional improvement in erectile responses at 1.0V stimulation and in SM/collagen ratio compared to the single agent treatment. SM content, caspase-3 activity, and c-Jun phosphorylation improved in the two CNCI groups exposed to JNKi. The two CNCI groups exposed to HDACi showed normalization of protein levels of HDAC3, fibronectin, and TGF-ß. DISCUSSION AND CONCLUSIONS: The combined administration of JNKi and HDACi during the acute phase after CNCI in rats can preserve ED by suppressing cavernosal fibrosis and apoptosis by normalizing the HDAC/TGF-ß and JNK pathways.

Pfaffia glomerata hydroalcoholic extract stimulates penile tissue in adult Swiss mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Roots of Pfaffia glomerata are used in traditional medicine as aphrodisiacs and sexual stimulants. AIM OF THE STUDY: The aim of this study was to evaluate the action of the hydroalcoholic extract from the roots of Pfaffia glomerata on the Leydig cells, cavernous bodies and other penile constituents, as well as on serum testosterone and 17ß-estradiol levels of adult mice. MATERIALS AND METHODS: Mature male Swiss mice were divided into 6 groups: control (water), sildenafil citrate, 3 groups receiving daily doses of P. glomerata extract (100, 200 and 400 mg/kg) and one group receiving intermittent doses of P. glomerata (200 mg/kg/3-3d). RESULTS: The proportions of blood vessels, lymphatic space and estradiol levels were increased. On the other hand, reduction of testosterone levels due to Leydig cells death was observed. As for penile parameters, volumetric proportions of cavernous bodies, collagen and nitric oxide were increased, while smooth muscle content was decreased. CONCLUSIONS: Despite that the long term intake of P. glomerata extract was related to a stimulant action, reduction on Leydig cell viability induced decreased testosterone production.

Keloidal penile fibrosis: improvements with Centellicum® (Centella asiatica) and Pycnogenol® supplementation: a pilot registry.

BACKGROUND: The aim of this pilot study was to evaluate the effects of Pycnogenol® and CA (Centellicum®) on penile fibrosis and on associated signs and symptoms. METHODS: A group of 82 subjects with penile nodules and plaques was included in this registry study and followed up for 3 months; 32 were managed with standard management (SM) only. Twenty-four were managed with CA (Centellicum®: 3 capsules/day: 675 mg/day) in association with SM, and 26 subjects were managed with Pycnogenol® (150 mg/day) + CA (Centellicum® at the same dosage as in group 2) and SM. RESULTS: Subjects in the 3 groups were comparable, including the distribution of plaques. The occurrence of any previous catheterizations was also comparable. Safety and tolerability were optimal, no subjects had to stop supplementation. The percentage of subjects with improved symptoms evaluated with a Visual Analogue Scale line was significantly higher with both supplements in comparison with SM (P<0.05). The combined management with Pycnogenol® and Centellicum® was superior to the other 2 managements (P<0.05). Erectile function assessed by the Index of Erectile Fuction questionnaire (IIEF) was significantly higher with the combination Pycnogenol®+Centellicum (P<0.05). The number of plaques and microplaques, the average total sectional area of the plaques in each subject and the grey scale median were all better improved with the combination. Both supplementations were superior to SM at 12 weeks (P<0.05). Oxidative stress resulted significantly better (P<0.05) with the combination. All blood tests were normal at inclusion and at 12 weeks. The minimal, penile curvature at baseline was reduced in both the supplement groups at 12 weeks more than in the SM group (P<0.05). CONCLUSIONS: In conclusion Centellicum and Pycnogenol® appear to improve penile fibrosis reducing the keloidal aspects of penile plaques.

Management of post-circumcision necrosis of the penis: the medicolegal aspect.

PURPOSE: To perform a medical evaluation of penile necrosis causes and treatment approaches by examining patients who had penile necrosis after circumcision surgery. METHODS: A total of 24 patients with penile necrosis after circumcision surgery, who presented at various hospitals in Turkey between September 2003 and April 2013 and whose cases were being reviewed at the Institution of Forensic Medicine with regard to malpractice, were evaluated retrospectively. RESULTS: The mean age of the patients was 5 ± 3.7 years, and the mean time of the necrosis diagnosis after circumcision was 5.2 ± 6.3 days. In etiologic terms, the predictive factors were monopolar cautery use in ten (41.6%) patients, post-circumcision infection in eight (33.3%), compartment syndrome due to post-circumcision dressing in three (12.5%), local anesthetic agent used for dorsal nerve blockage in two (8.3%), and methemoglobinemia in one (4.1%) patient. The first approaches to necrosis treatment were surgical intervention in 15 (62.5%) patients, hyperbaric oxygen treatment (HBOT) in 6 (25%), the conservative approach in 2 (8.3%), and HBOT plus surgical intervention in 1 (4.1%) patient. CONCLUSION: Penile necrosis is a preventable complication that requires early intervention. The current study will be helpful in preventing penile necrosis and in guiding surgeons in approaches following its occurrence.

Intratunical injection of autologous adipose stromal vascular fraction reduces collagen III expression in a rat model of chronic penile fibrosis.

Previous studies have shown that the injection of adipose stem cells and stromal vascular fraction(SVF) into the tunica albuginea (TA) during the inflammatory phase in a rat model of Peyronie's disease(PD) prevented the development of TA fibrosis. Our aim was to investigate whether local injection of SVF can reduce established fibrosis in a rat model of chronic phase of PD. Eighteen-male 12-wk-old Sprague-Dawley rats were divided in three equal groups: sham, PD without treatment (PD) and PD treated with SVF(PD-SVF). Sham rats underwent 2 injections of vehicle into the TA one month apart. PD rats underwent TGF-ß1 injection and injection of vehicle one month later. PD-SVF rats underwent TGF-ß1 injection followed by SVF (1-million cells) one month later. One month after the last treatment, the animals, n = 6 rats per group, underwent measurement of intracorporal and mean arterial pressure during electrostimulation of the cavernous nerve. Following euthanasia, penises were harvested for in-vitro study. Erectile function was not statistically significantly different between groups. PD animals developed subtunical areas of fibrosis and elastosis with upregulation of collagen III protein. These fibrotic changes were reversed after injection of SVF. We provide evidence that local injection of SVF reverses TA fibrosis in a rat model of chronic phase of PD.

Successful replantation of amputated penis with adjuvant hyperbaric oxygen therapy.

Successful penile replantations are rarely reported in the literature and are associated with significant complications. We present a case of a patient who auto-amputated his penis. Delayed microvascular replantation was performed approximately 14 hours following injury. He was treated with a phosphodiesterase inhibitor postoperatively, and adjuvant hyperbaric oxygen (HBO2) therapy was started 58 hours after replantation; 20 treatments at 2.4 atmospheres absolute (ATA), twice daily for eight days, followed by once daily for four days. Perfusion of the replanted penis was serially assessed using fluorescent angiography. With some additional surgical procedures including a split- thickness skin graft to the shaft due to skin necrosis he has made a complete recovery with return of normal urinary and sexual function. This unusual case illustrates the potential benefit of HBO2 therapy in preserving viability of a severed body part. Fluorescent angiography may have potential utility in monitoring efficacy of HBO2.

Antioxidant Mechanism of Xiaojin Pill () for Treatment of Peyronie's Disease in Rats Based on Matrix Metalloproteinases.

OBJECTIVE: To evaluate the effects of Xiaojin Pill () in the treatment of Peyronie's disease (PD) in a rat model. METHODS: Twenty-four male Sprague-Dawley rats were randomly divided into four groups with 6 in each: sham operation, PD model, vehicle control and Xiaojin Pill groups. The rats in the sham operation group received penile tunica albsginea (TA) injection with 50 µL vehicle, while the rats in the other 3 groups received 50 µL penile TA injection of 50 µg transforming growth factor (TGF)-ß1. Forty-two days after the injection, rats in the vehicle control and Xiaojin Pill groups received 0.5 mL water and Xiaojin Pill solution (107 mg/kg of body weight), respectively by gavage for 28 days, while those in the sham operation and PD model groups did not receive any intervention. After intervention, the expressions of matrix metalloproteinase 2/9 (MMP2/9), nitric oxidesynthase (NOS), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured. RESULTS: Rats in the PD model and vehicle control groups presented obvious fibrosis in corpus cavernosum (CC) and demonstrated a significantly increased expressions of MMP2 and MMP9 in the CC compared with the sham operation group (all P<0.01). In contrast, the expressions of MMP2 and MMP9 in the Xiaojin Pill group were significantly down-regulated (both P<0.01). In addition, the levels of NOS and MDA in CC were significantly increased while the activity of SOD was decreased in the PD model and vehicle control groups compared with the sham operation group (all P<0.01). After Xiaojin Pill treatment, the levels of MDA, NOS and SOD appeared to be corrected (all P<0.01). CONCLUSIONS: Xiaojin Pill could reduce fibrosis in the CC by decreasing the expressions of MMPs, NOS and MDA, and by increasing the activity of SOD. Therefore, Xiaojin Pill might be a therapeutic option for PD.

Orange peels modulate antioxidant markers and key enzymes relevant to erection in the penile tissue of paroxetine-treated rats.

In comparison to other antidepressant drugs, erectile dysfunction (ED) is more pronounced in paroxetine use. On the other hand, orange (Citrus sinensis) peels commonly consumed in various forms are used in folkloric medicine for ED management. Thus, this study evaluated the effect of orange peels infusion on sexual behaviour, nitric oxide (NO) level and some enzymes (arginase, phosphodiesterase-5 [PDE-5], acetylcholinesterase [AChE] and adenosine deaminase [ADA]) in paroxetine-treated rats. Erectile dysfunction was induced with paroxetine (10 mg/kg body weight). The animals were grouped into five (n = 6): normal rats; paroxetine-induced rats; paroxetine-induced rats treated with sildenafil citrate (5 mg/kg); paroxetine-induced rats treated with orange peels infusion (50 mg/kg); Paroxetine induced rats treated with orange peel infusions (100 mg/kg). The results revealed a significant decrease in sexual behaviour, NO level and the activities of antioxidant enzymes, while there was a significant increase in arginase, PDE-5, AChE and ADA activities in paroxetine-induced rats. However, orange peel infusions ameliorated erectile dysfunction in paroxetine-treated rats. This study showed some possible biochemical basis underlying the use of orange peels infusion in erectile dysfunction management.

The effects of single versus combined therapy using LIM-kinase 2 inhibitor and type 5 phosphodiesterase inhibitor on erectile function in a rat model of cavernous nerve injury-induced erectile dysfunction.

We aimed to determine whether combination of LIM-kinase 2 inhibitor (LIMK2i) and phosphodiesterase type-5 inhibitor (PDE5i) could restore erectile function through suppressing cavernous fibrosis and improving cavernous apoptosis in a rat model of cavernous nerve crush injury (CNCI). Seventy 12-week-old Sprague-Dawley rats were equally distributed into five groups as follows: (1) sham surgery (Group S), (2) CNCI (Group I), (3) CNCI treated with daily intraperitoneal administration of 10.0 mg kg-1 LIMK2i (Group I + L), (4) daily oral administration of 20.0 mg kg-1 udenafil, PDE5i (Group I + U), and (5) combined administration of 10.0 mg kg-1 LIMK2i and 20.0 mg kg-1 udenafil (Group I + L + U). Rats in Groups I + L, I + U, and I + L + U were treated with respective regimens for 2 weeks after CNCI. At 2 weeks after surgery, erectile response was assessed using electrostimulation. Penile tissues were processed for histological studies and western blot. Group I showed lower intracavernous pressure (ICP)/mean arterial pressure (MAP), lower area under the curve (AUC)/MAP, decreased immunohistochemical staining for alpha-smooth muscle (SM) actin, higher apoptotic index, lower SM/collagen ratio, increased phospho-LIMK2-positive fibroblasts, decreased protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) phosphorylation, increased LIMK2/cofilin phosphorylation, and increased protein expression of fibronectin, compared to Group S. In all three treatment groups, erectile responses, protein expression of fibronectin, and SM/collagen ratio were improved. Group I + L + U showed greater improvement in erectile response than Group I + L. SM content and apoptotic index in Groups I + U and I + L + U were improved compared to those in Group I. However, Group I + L did not show a significant improvement in SM content or apoptotic index. The number of phospho-LIMK2-positive fibroblasts was normalized in Groups I + L and I + L + U, but not in Group I + U. Akt/eNOS phosphorylation was improved in Groups I + U and I + L + U, but not in Group I + L. LIMK2/cofilin phosphorylation was improved in Groups I + L and I + L + U, but not in Group I + U. Our data indicate that combined treatment of LIMK2i and PDE5i immediate after CN injury could improve erectile function by improving cavernous apoptosis or eNOS phosphorylation and suppressing cavernous fibrosis. Rectification of Akt/eNOS and LIMK2/cofilin pathways appears to be involved in their improvement.

CO2 laser treatment for pearly penile papules - personal experience.

Pearly penile papules (PPP) are physiological lesions in the epithelium of the corona of the glans penis which extend to its neck. These lesions may also appear on both sides of the frenulum. Although they are not pathological, the lesions frequently cause concern or embarrassment/discomfort in patients. They are the most common reason for seeing a dermatologist. There are several methods of treatment for PPP such as cryosurgery, electrocoagulation, treatment with CO2, Er:YAG, or pulsed dye lasers. This paper describes the authors' experience in removing PPP with a CO2 laser.

Priapism caused by "Rhino 7 Platinum 3000" an over-the-counter male enhancement supplement.

Male enhancement and erectile dysfunction supplements are typically non-Food and Drug Administration (FDA) approved and readily available for purchase by anyone. Longstanding priapism is a significant potential side effect. A 25-year-old man presented with a 48-h priapism after taking Rhino 7 Platinum 3000. He required bilateral corpo-glanular shunting to alleviate his priapism. On initial 2-week follow-up, he had significant fibrosis of the corporal bodies bilaterally and had been unable to achieve an erection. There are few studies performed and few case reports regarding the roles of various supplements in causing priapism. We are unaware of any studies regarding Rhino 7 Platinum 3000. Interestingly, since our initial contact with the FDA Safety Reporting Portal, multiple investigations of Rhino products have demonstrated that sildenafil is a non-labeled ingredient. Given the lack of FDA oversight of many other supplements similar to this one, patients must be wary that the ingredients listed may not be comprehensive and that serious side effects can occur.

Lymphangioma Circumscriptum Post Radiotherapy for Penile Cancer Treated with CO2 Laser.

Lymphangioma circumscriptum (LC) is a rare, benign condition, predominantly characterized by the malformation of lymphatic skin vessels. Its onset may be congenital or due to secondary causes such as radiotherapy, infections, or surgical procedures. We present the case of a 55-year-old patient with a pathologic history of squamous cell carcinoma of the penis followed by radical penectomy. Due to metastasis to the locoregional lymph nodes, the entire affected area was subsequently treated with radiation therapy, receiving a total dose of 55.8 Gray. Eight years after this treatment, translucent vesicles filled with a clear liquid appeared on the scrotum. Histopathology confirmed the diagnosis of LC and therapy with CO2 laser was applied, resulting in a favorable outcome. LC of the scrotum may present a long-term radiotherapy-induced complication of this site. Our clinical experience showed that the CO2 laser was the therapy of choice as the vesicles entirely disappeared and healed as white scar-like lesions.

Role of Jun amino-terminal kinase (JNK) in apoptosis of cavernosal tissue during acute phase after cavernosal nerve injury.

The present study aimed to identify which mitogen-activated protein kinase (p38 or Jun amino-terminal kinase [JNK]) was involved in cavernosal apoptosis during the acute phase after cavernosal nerve crush injury (CNCI) in rats to ameliorate apoptosis of cavernosal tissue, such as smooth muscle (SM). A total of twenty 10-week-old male Sprague-Dawley rats were divided equally into two groups: sham surgery (S) and CNCI (I). The I group approximated the clinical situation of men undergoing radical prostatectomy using two 60-second compressions of both CNs with a microsurgical vascular clamp. At 2-week postinjury, erectile response was assessed using electrostimulation. Penile tissues were harvested for immunohistochemistry analysis of alpha-SM actin (α-SMA), western blot analysis, and double immunofluorescence analysis of α-SMA and phosphorylated p38 or JNK, as well as double immunofluorescent of TUNEL and phosphorylated p38 or JNK. At 2-week postinjury, the I group had a significantly lower intracavernous pressure (ICP)/mean arterial pressure (MAP) and a lower area under the curve (AUC)/MAP than the S group. The I group also exhibited decreased immunohistochemical staining of α-SMA, an increase in the number of SM cells positive for phosphorylated JNK, an increased number of apoptotic cells positive for phosphorylated JNK, and increased JNK phosphorylation compared with the S group. However, there was no significant difference in p38 phosphorylation expression or the number of SM cells positive for phosphorylated p38 between the two groups. In conclusion, our data suggest that JNK, not p38, is involved in cavernosal apoptosis during the acute phase after partial CN damage.

Differences in Survival Associated with Performance of Lymph Node Dissection in Patients with Invasive Penile Cancer: Results from the National Cancer Database.

PURPOSE: Inguinal lymphadenectomy remains under performed in patients with invasive penile cancer. Using a large national cancer registry we assessed temporal trends in inguinal lymphadenectomy performance and evaluated the impact of the procedure on survival in patients in whom inguinal lymphadenectomy was an absolute indication (T1b-4 N0/x-1) according to NCCN® (National Comprehensive Cancer Network®) Guidelines®. MATERIALS AND METHODS: We queried the National Cancer Database for all cases of nonmetastatic, T1b-4 N0/x-1 squamous cell carcinoma of the penis from 2004 to 2014. Multivariable logistic regression models adjusting for patient, demographic, and clinicopathological characteristics were used to examine the association between available covariates and receipt of inguinal lymphadenectomy. Cox proportional hazards regression analysis was then done to assess the impact of clinical and pathological variables on overall survival. Propensity score weighted analysis was performed to assess the effect of inguinal lymphadenectomy on overall survival. RESULTS: A total of 2,224 patients met analysis criteria, of whom 606 (27.2%) underwent inguinal lymphadenectomy. Following adjustment the procedure was more likely in younger patients, those who presented with palpable adenopathy (cN1), those treated at an academic facility and those with a more contemporary diagnosis. On survival analysis controlling for all known and measured confounders inguinal lymphadenectomy was associated with improved overall survival (HR 0.79, 95% CI 0.74-0.84, p <0.001). CONCLUSIONS: At hospitals that report to the National Cancer Database the overall rate of inguinal lymphadenectomy in patients with invasive penile cancer was only 27.2%. Inguinal lymphadenectomy was associated with increased overall survival, justifying the procedure as an important quality metric for performance reporting in patients with invasive penile cancer.

Successful downstaging of locally recurrent penile squamous cell carcinoma with neoadjuvant nanosomal docetaxel lipid suspension (NDLS) based regimen followed by curative surgery.

Penile squamous cell carcinoma (pSCC) is a relatively rare disease in Western world but is a significant health problem in developing countries like India. We report here a case of successful multimodality management of recurrent pSCC with pelvic lymphadenopathy in a 56-year-old male patient with poorly controlled diabetes. The patient presented with ulceroproliferative growth over the residual penile stump clinically involving root of penis and with right pelvic lymphadenopathy. The patient had a history of partial penectomy done elsewhere 20 months ago. In view of the comorbidities, locally recurrent disease and presence of right Iliac lymphadenopathy, the patient was treated with nanosomal docetaxel lipid suspension (NDLS), cisplatin and 5-fluorouracil (TPF regimen) in the neoadjuvant setting followed by staged surgical resection. This is the first case report showing successful treatment of recurrent pSCC with NDLS-based TPF regimen in the neoadjuvant setting followed by staged surgery in a patient with poorly controlled diabetes.

Zoon Balanitis Revisited: Report of Balanitis Circumscripta Plasmacellularis Resolving With Topical Mupirocin Ointment Monotherapy.

INTRODUCTION: Zoon balanitis is an idiopathic benign inflammatory condition of the glans penis and prepuce. A patient with biopsy confirmed diagnosis of Zoon balanitis who was successfully treated with topical mupirocin ointment monotherapy is described.

METHOD: A search using PubMed database was performed using the following terms: Zoon balanitis (cases, diagnosis, treatment of), balanitis circumscripta plasmacellularis, and mupirocin. Relevant papers and their reference citations were reviewed and evaluated.

RESULTS: The gold standard of treatment for Zoon balanitis has previously been circumcision. More recently, topical calcineurin inhibitors have been shown to be effective. Our patient had successful resolution of his Zoon balanitis after 3 months of mupirocin ointment monotherapy.

DISCUSSION: Zoon balanitis is a benign inflammatory dermatosis. Previous successful treatment modalities include circumcision, phototherapy, laser therapy, and topical calcineurin inhibitors. Topical mupirocin ointment twice daily resulted in resolution of Zoon balanitis in our patient. Additional evaluation of mupirocin ointment as a therapeutic agent should be considered as a potential first-line therapy in patients with Zoon balanitis.

J Drugs Dermatol. 2017;16(3):285-287.

Effect of Testosterone on the Phenotypic Modulation of Corpus Cavernosum Smooth Muscle Cells in a Castrated Rat Model.

OBJECTIVE: To investigate the effect of testosterone (T) on the phenotypic modulation of corpus cavernosum smooth muscle (CCSM) cells in a castrated rat model. MATERIALS AND METHODS: Thirty male Sprague-Dawley rats were randomly divided into 3 groups: control, castration, and castration with T supplementation (castration + T). Erectile function, histologic change, and biochemical markers were assessed for phenotypic modulation of CCSM cells in corporal tissue. Moreover, the primary rat CCSM cells were isolated and examined by Western blot analysis. RESULTS: Our data showed that serum T level, mean weight of the body, erectile function, and smooth muscle-to-collagen ratio were significantly decreased in the castration group compared with those in the control and castration + T groups. The expressions of CCSM cells' phenotypic markers, such as α-smooth muscle actin, calponin, and smooth muscle myosin heavy chain 11, were markedly lower, whereas osteopontin protein expression was significantly higher in castrated rats than in control and castrated + T rats. In addition, the immunofluorescence staining of α-smooth muscle actin and calponin markedly decreased in the primary CCSM cells of the castrated rats compared with the intensity of the control and the castration + T rats. CONCLUSION: CCSM cells undergo phenotype modulation in castrated rats, whereas T reversed the alterations. T may play a key role in the phenotype modulation of CCSM cells.

Reduced corporal fibrosis to protect erectile function by inhibiting the Rho-kinase/LIM-kinase/cofilin pathway in the aged transgenic rat harboring human tissue kallikrein 1.

Our previous studies have demonstrated that erectile function was preserved in aged transgenic rats (TGR) harboring the human tissue kallikrein 1 (hKLK1), while the molecular level of hKLK1 on corporal fibrosis to inhibit age-related erectile dysfunction (ED) is poorly understood. Male wild-type Sprague-Dawley rats (WTR) and TGR harboring the hKLK1 gene were fed to 4- or 18-month-old and divided into three groups: young WTR (yWTR) as the control, aged WTR (aWTR), and aged TGR (aTGR). Erectile function of all rats was assessed by cavernous nerve electrostimulation method. Masson's trichrome staining was used to evaluate corporal fibrosis in the corpus cavernosum. We found that the erectile function of rats in the aWTR group was significantly lower than that of other two groups. Masson's trichrome staining revealed that compared with those of the yWTR and aTGR groups, the ratio of smooth muscle cell (SMC)/collagen (C) was significantly lower in the aWTR group. Immunohistochemistry and Western blotting analysis were performed, and results demonstrated that expression of α-SMA was lower, while expressions of transforming growth factor-ß 1 (TGF-ß1), RhoA, ROCK1, p-MYPT1, p-LIMK2, and p-cofilin were higher in the aWTR group compared with those in other two groups. However, LIMK2 and cofilin expressions did not differ among three groups. Taken together, these results indicated that the RhoA/ROCK1/LIMK/cofilin pathway may be involved in the corporal fibrosis caused by advanced age, and hKLK1 may reduce this corporal fibrosis by inhibiting the activation of this pathway to ameliorate age-related ED.

Hyperlipidemia impairs erectile function in rats by causing cavernosal fibrosis.

Men with hyperlipidemia are more likely to have erectile dysfunction (ED) than those without hyperlipidemia, but the mechanisms are not fully understood. The aim of this study was to investigate the underlying mechanism of ED caused by hyperlipidemia. Fourteen 8-week-old Sprague-Dawley rats were randomly divided into two groups: a control group and a hyperlipidemia group (fed chow containing 4% cholesterol and 1% cholic acid). After 6 months, we assessed erectile function by performing cavernous nerve electrostimulation followed by intracavernosal pressure/mean arterial pressure measurements, as well as plasma lipid profile assessment in all rats. A transferase-mediated nick end labeling (TUNEL) assay, immunohistochemical staining and Western blotting were performed to determine the levels of apoptosis, autophagy and fibrosis in the penile tissue. Compared with the control group, the hyperlipidemia group exhibited: (i) increased plasma lipid levels; (ii) decreased erectile function; (iii) a decreased smooth muscle/collagen ratio; (iv) increased fibrosis; (v) increased apoptosis and decreased autophagy. Overall, hyperlipidemia may attenuate erectile function in rats by causing of cavernosal fibrosis.