Efficacy of Chinese Herbal Medicine Formula in the Treatment of Mild to Moderate Erectile Dysfunction: Study Protocol for a Multi-Center, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.

Introduction: Erectile dysfunction (ED) is a prevalent condition in urology, primarily managed with PDE5 inhibitors (PDE5Is). However, approximately 20% of patients do not experience improvement in overall sexual satisfaction (OS) after taking PDE5Is. Among these, traditional Chinese medicine (TCM) has emerged as a complementary approach, with formulas like Hongjing I granules (HJIG) showing promise in preliminary studies. This study aims to rigorously evaluate the effectiveness and safety of HJIG in mild to moderate ED cases, assessing improvement in both sexual function and TCM pattern alignment. Methods: This study is a randomized, double-blind, placebo-controlled multicentre trial. Recruitment will be conducted from patients who have a strong willingness to try using only traditional Chinese medicine treatment (This is very common in traditional Chinese medicine hospitals.). A total of 100 patients diagnosed with mild to moderate ED caused by qi deficiency and blood stasis will be recruited and randomly assigned to receive one of two treatments: HJIG (N = 50) or placebo (N = 50). Patients will receive 8 weeks of treatment and a 16-week follow-up starting from the fourth week of treatment. Outcome measures, including the International Index of Erectile Function-Erectile Function domain (IIEF-EF) score, Sexual Encounter Profile (SEP), and Traditional Chinese Medicine symptom score, will be evaluated. Discussion: The expected outcome of this trial is that the use of the herbal formula HIJG alone can improve overall sexual satisfaction (OS) in patients with mild to moderate ED, while also improving their traditional Chinese medicine symptom scores. This will provide evidence-based support for the use of Chinese medicine in the treatment of ED in China. Trial Registration: Chinese Clinical Trial Registry, ChiCTR2000041127, Registered on 19 December 2020, https://www.chictr.org.cn/showproj.html?proj=46469. Trial Status: Recruitment began in March 2021, therefore 80 patients have been recruited. It is expected to finish recruiting in December 2023.

Protective Effects of Total Flavonoids from Lysimachia christinae on Calcium Oxalate-Induced Oxidative Stress in a Renal Cell Line and Renal Tissue.

Oxidative stress (OS) in renal tubular epithelial cells (RTECs) is induced by calcium oxalate (CaOx) stones and plays an important role in the pathology of CaOx nephrolithiasis. The nuclear factor-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important endogenous antioxidant pathway. Flavonoids are compounds with 2-phenylchromone as the basic mother nucleus and are natural antioxidant components of Lysimachia christinae. Our previous studies demonstrated that the total flavonoids from L. christinae (TFL) reduced calcium and oxalic acid concentrations in urine, thus inhibiting CaOx stone formation. We also showed that TFL can reduce OS in renal tissue. However, whether TFL inhibit the formation of CaOx stones through the Nrf2/ARE pathway requires further investigation. Here, we found that TFL protected against injury to a renal cell line and renal tissue, reduced CaOx-induced OS in renal tissue, and reduced CaOx crystal formation. In addition, TFL significantly increased nuclear Nrf2 and the expression of the downstream antioxidant genes heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO-1). Furthermore, TFL increased superoxide dismutase (SOD) activity and decreased the malondialdehyde (MDA) content, thereby alleviating OS in RTECs. Silencing Nrf2 expression blocked the protective effect of TFL on CaOx-induced OS. Taken together, our findings indicate that TFL reduce CaOx-induced OS in renal tissue by activating the Nrf2/ARE pathway.

In vivo and in vitro protective effects of the Wuzi Yanzong pill against experimental spermatogenesis disorder by promoting germ cell proliferation and suppressing apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Wuzi Yanzong pill (WZYZP) is a classical traditional Chinese medicine (TCM) formula originated from the Tang dynasty. WZYZP has a long history of use for reinforcing kidney and alleviating male infertility in China. AIM OF THE STUDY: The effect of WZYZP on male infertility and the mechanism underlying this effect was not clarified clearly. Therefore, this study aimed to investigate the protective effect of WZYZP in experimental spermatogenesis disorder via in vivo and in vitro studies, to promote the use of this formula for the treatment of spermatogenesis disorder. MATERIAL AND METHODS: Male SD rats were exposed to tripterygium glycosides to induce experimental spermatogenesis disorder, and WZYZP was subsequently administrated at different dosages for treatment. Sperm counts, sperm motility, and serum hormone levels were detected. HE staining and TUNEL staining were performed to evaluate the pathological lesions and apoptosis of testes, respectively. Next, germ cells were isolated from spermatogenesis disorder-model rats and treated with WZYZP- containing serum at different concentrations. CCK-8 assay and flow cytometry assay were performed to detect cell proliferation and apoptosis. Immunofluorescence assay, qRT-PCR and Western blotting analyses were performed to detect the expression of Beclin 1, LC3 and TGF-ß-PI3k/AKT-mTOR pathway - related factors, including TGF-ß, PI3K, AKT, mTOR, 4 EBP-1 and p70S6K. RESULTS: In vivo experiments showed that WZYZP protected against spermatogenesis disorder in model rats by improving sperm count and motility, as well as restoring serum hormone levels. HE and TUNEL staining demonstrated that the pathological injuries and cell apoptosis in testes of the model rats were alleviated by WZYZP treatment. Moreover, in vitro experiments of germ cells isolated from spermatogenesis disorder-model rats showed that WZYZP treatment increased the cell proliferation, inhibited cell apoptosis and autophagy. qRT-PCR and Western blotting assay results showed that this protective effect was associated with the regulation of the TGF-ß/PI3K/AKT/mTOR signaling pathway. The expression levels of p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, 4 EBP-1 and p70S6K were increased, while TGF-ß was inhibited in the WZYZP treated groups. CONCLUSION: The results showed that WZYZP could protect against experimental spermatogenesis disorder by increasing the germ cell proliferation and inhibiting their apoptosis. Our support the clinical use of this formula for the management of spermatogenesis disorder.

Tocopheryl quinone improves non-alcoholic steatohepatitis (NASH) associated dysmetabolism of glucose and lipids by upregulating the expression of glucagon-like peptide 1 (GLP-1) via restoring the balance of intestinal flora in rats.

CONTEXT: Glucagon-like peptide 1 (GLP-1) and α-tocopheryl quinone can promote the growth of intestinal flora and affect the pathogenesis of non-alcoholic steatohepatitis (NASH). OBJECTIVE: This study determines the molecular mechanism of the effect of tocopheryl quinone in the treatment of high cholesterol and cholate diet (HFCC)-induced NASH. MATERIALS AND METHODS: Thirty-two male Sprague Dawley (SD) rats grouped as lean control (LC), LC + tocopheryl quinone (1 mL of 3 × 106 dpm tocopheryl quinone via i.p. injection), HFCC (5.1 kcal/g of fat diet), and HFCC + tocopheryl quinone. Profiles of intestinal flora were assessed by 16S ribosomal ribonucleic acid-based analysis. Levels and activity of GLP-1, interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) in intestinal tissues were detected by immunohistochemistry (IHC), Western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS: HFCC rats presented higher levels of cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL), while tocopheryl quinone reversed the effects of HFCC. HFCC dysregulated malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), Vitamin E, 12-hydroxyeicosatetraenoic acid (12-HETE), 13-hydroxyoctadecadienoic acid (13-HODE) and nuclear factor kappa B (NF-κB), and the effects of HFCC were reversed by the treatment of tocopheryl quinone. Also, GLP-1 in the HFCC group was down-regulated while the IL-6 and TNF-α activity and endotoxins were all up-regulated. HFCC significantly decreased the number and diversity of bacteria, whereas tocopheryl quinone substantially restored the balance of intestinal flora and promoted the growth of both Bacteroides and Lactobacilli in vitro. DISCUSSION AND CONCLUSIONS: α-Tocopheryl quinone relieves HFCC-induced NASH via regulating oxidative stress, GLP-1 expression, intestinal flora imbalance, and the metabolism of glucose and lipids.

Neuroprotective effect of Hongjing I granules on erectile dysfunction in a rat model of bilateral cavernous nerve injury.

Neurogenic erectile dysfunction (NED) is an inevitable postoperative disease of cavernous nerve injury which will lead to various pathophysiological changes in the corpus cavernosum and dorsal penile nerve caused by radical prostatectomy (RP). Although serval years of clinical application of HJIG I granules (HJIG), an innovative formulation, has demonstrated its reliable clinical efficacy against NED, the mechanism of HJIG remains unclear. This study aimed to assess the neuroprotective effect of HJIG, to repair damaged nerves in a rat model of bilateral cavernous nerve injury (BCNI) in vivo and their effects on neurites of major pelvic ganglia (MPG) regeneration and Schwann cells (SCs) proliferation in vitro. Rats were divided into five groups randomly: normal control (NC), BCNI-induced ED model (M), M + low-dose HJIG (HL), M + medium-dose HJIG (HM), and M + high-dose HJIG (HH). All groups were treated with normal saline or the relevant drug for 28 consecutive days after a standard NED animal model. Our data revealed that administration of HJIG improved NED that was detected by intracavernous pressure (ICP) in a dose-dependent manner. The haematoxylin-eosin (HE) and Immunofluorescence (IF) staining demonstrated that HJIG ameliorate the shape of penis and induced the protein synthesis of GAP43, NF200, S100, and nNOS. NF200 and S100 level were also detected by western blotting. Moreover, HJIG (0.78 mg/mL) markedly increased SCs viability and promoted neurites regeneration of MPG. These findings provide new insights into the NED therapy by HJIG.

Urothelial carcinoma of the bladder with abundant myxoid stroma: A case report and literature review.

INTRODUCTION: Abundant myxoid stroma rarely occurs in urothelial carcinomas (UCs). We report an 83-year-old woman with UC of the urinary bladder with abundant myxoid stroma. We summarized the clinicopathological features, immunophenotype, diagnosis, and differential diagnosis of this type of bladder cancer, in order to improve the understanding of surgeons and pathologists. PATIENT CONCERNS: An 83-year-old female presented with hematuria and frequent micturition, without odynuria, hypogastralgia, or fever. DIAGNOSIS: The computed tomography scan demonstrated extensive tumors in the anterior wall of the bladder and a soft tissue shadow anterior to the sacrum. Cystoscopy showed massive wide-based tumors located on the anterior and lateral walls of the bladder, with no tumor involving the bladder neck. Multiple punch biopsies were performed, the histologic evaluation of which revealed a poorly differentiated invasive UCs with myxoid stroma. INTERVENTIONS: The patient underwent a laparoscopic radical cystectomy and cutaneous ureterostomy. OUTCOMES: The patient discharged without any complications. Histologic evaluation revealed an invasive UC; the most prominent feature was an abundant myxoid stroma that covered approximately 80% of the lesion and the tumor cells were arranged in cords, small nests, or a sheet-like structure. Immunohistochemically, the tumor cells were positive for CK19, CK20, VEGF, EGFR, p63, 34ßE12, MUC1, GATA3, uroplakin3, and TopII (rate = 15%), while the Ki-67 proliferation index was 10%. The myxoid stroma in the mesenchyme stained positively with AB-PAS and colloidal iron, and some tumor cells stained positive for colloidal iron. Considering the histologic, histochemical, and immunohistochemical findings, a diagnosis of UC with abundant myxoid stroma was made. After surgery, the regular follow-up was continued in clinic, and there was no recurrence for 2 years. CONCLUSION: Morbidity associated with UC with abundant myxoid stroma is very low. The diagnosis mainly depends on histopathological and immunohistochemical findings.

Effect of HongJing I in Treating Erectile Function and Regulating RhoA Pathway in a Rat Model of Bilateral Cavernous Nerve Injury.

HongJing I (HJI), a traditional Chinese herbal formula, has been confirmed to be effective for the clinical treatment of erectile dysfunction (ED). However, the mechanism of action of HJI remains unclear. Here, we aimed to investigate the effect and underlying mechanisms of HJI against ED in a rat model of bilateral cavernous nerve injury (BCNI). Rats were divided into five groups: normal control (NC), BCNI-induced ED model (M), M + low-dose HJI (HL), M + medium-dose HJI (HM), and M + high-dose HJI (HH). All groups were treated with normal saline or the relevant drug for 28 consecutive days after inducing BCNI-ED. At the end of the treatment period, the intracavernous pressure (ICP) was recorded, and histological examination was conducted using Masson's trichrome staining. Immunofluorescence staining and western blotting were applied to detect the changes in fibrosis protein and Ras homolog A (RhoA), Rho-associated protein kinase 1 (ROCK1), and ROCK2 expression. We found that HJI effectively improved the ICP in the treatment groups. In addition, RhoA, ROCK1, and ROCK2 expression levels were increased upon BCNI-ED induction, and HJI successfully inhibited cavernosum fibrosis and the activation of RhoA/ROCK2 signaling. Overall, these results suggest that the effects of HJI in attenuating ED may be caused, at least in part, by the suppression of RhoA/ROCK2 signaling and alleviation of fibrosis. However, the precise mechanism surrounding this requires further investigation in future studies.

PDGF-mediated PI3K/AKT/ß-catenin signaling regulates gap junctions in corpus cavernosum smooth muscle cells.

Erectile dysfunction (ED) is the most common sexual disorder that men report to healthcare providers. Gap junctions (GJs) are thought to be responsible for synchronous shrinkage of corpus cavernosum smooth muscle cells (CCSMCs), and play thus an important role in the maintenance of an erection. Hypoxia has been suggested as a pathological mechanism underlying ED. Here we demonstrate that hypoxia increased the expression of platelet-derived growth factor (PDGF) and the main GJ component connexin (Cx)43 in CCSMCs. Inhibiting PDGF receptor (PDGFR) activity decreased Cx43 expression. Treatment with different concentrations of PDGF increased the levels of phosphorylated protein kinase B (AKT), ß-catenin, and Cx43, whereas inhibition of PDGFR or activation of phosphatidylinositol 3 kinase (PI3K)/AKT signaling altered ß-catenin and Cx43 expression. Meanwhile, silencing ß-catenin resulted in the downregulation of Cx43. These results demonstrate that PDGF secretion by CCSMCs and vascular endothelial cells is enhanced under hypoxic conditions, leading to increased Cx43 expression through PI3K/AKT/ß-catenin signaling and ultimately affecting GJ function in ED. Thus, targeting this pathway is a potential therapeutic strategy for the treatment of ED.

The Protective Effect of Salidroside on Hypoxia-Induced Corpus Cavernosum Smooth Muscle Cell Phenotypic Transformation.

Salidroside, a major active ingredient isolated from Rhodiola rosea, has a long application in Chinese medical history. It has widely demonstrated effects on fatigue, psychological stress, and depression and exhibits potential antihypoxia activity. Emerging evidence shows that hypoxia is an important independent risk factor for erectile dysfunction (ED). The aim of this study was to clarify the effect of salidroside on hypoxia-induced phenotypic transformation of corpus cavernosum smooth muscle cells (CCSMCs). Our results showed that salidroside decreased the hypoxia-induced expression of collagen and content of vimentin, a corpus cavernosum smooth muscle synthetic protein, in vitro. Simultaneously, salidroside increased expression of the CCSMC contractile proteins, α-smooth muscle actin (α-SMA) and desmin. In vivo, similarly, the expressions of collagen and hypoxia-inducible factor-1α were increased in bilateral cavernous neurectomy (BCN) rats while they were decreased in the salidroside group. Among the phenotypic proteins, α-SMA and desmin increased and vimentin decreased after treating BCN rats with salidroside compared with the BCN alone group. Overall, our results demonstrate that salidroside has the ability to oppose hypoxia and can inhibit the CCSMC phenotypic transformation induced by hypoxia. Salidroside may provide a new treatment method for ED.

The platelet-derived growth factor receptor/STAT3 signaling pathway regulates the phenotypic transition of corpus cavernosum smooth muscle in rats.

Erectile dysfunction (ED) is a common clinical disease that is difficult to treat. We previously found that hypoxia modulates the phenotype of primary corpus cavernosum smooth muscle cells (CCSMCs) in rats, but the underlying molecular mechanism is still unknown. Platelet-derived growth factor receptor (PDGFR)-related signaling pathways are correlated with cell phenotypic transition, but research has been focused more on vascular smooth muscle and tracheal smooth muscle and less on CCSMCs. Here, we investigated the role of PDGFR-related signaling pathways in penile CCSMCs, which were successfully isolated from rats and cultured in vitro. PDGF-BB at 5, 10, or 20 ng/ml altered CCSMC morphology from the original elongated, spindle shape to a broader shape and promoted the synthetic phenotype and expression of the related proteins vimentin and collagen-I, while inhibiting the contractile phenotype and expression of the related proteins smooth muscle (SM) α-actin (α-SMA) and desmin. Inhibition of PDGFR activity via siRNA or the PDGFR inhibitor crenolanib inhibited vimentin and collagen-I expression, increased α-SMA and desmin expression, and considerably inhibited serine-threonine protein kinase (AKT) and signal transducer and activator of transcription 3 (STAT3) phosphorylation. STAT3 knockdown promoted the contractile phenotype, inhibited vimentin and collagen-I expression, and increased α-SMA and desmin expression, whereas AKT knockdown did not affect phenotype-associated proteins. STAT3 overexpression in CCSMC cells weakened the suppressive effect of PDGFR inhibition on the morphology and phenotypic transformation induced by PDGF-BB. Through activation of the PDGFR/STAT3 signaling pathway, PDGF promoted the synthetic phenotype transition; thus, regulation of this pathway might contribute to ED therapy.

The Tumor Necrosis Factor-α-308 and -238 Polymorphisms and Risk of Hepatocellular Carcinoma for Asian Populations: A Meta-Analysis.

BACKGROUND: Tumor necrosis factor-α (TNF-α) has been suggested to play a very important role in the development and progression of hepatocellular carcinoma (HCC). Many studies have identified the associations of TNF-α-308 and -238 polymorphisms with HCC risk, but the results remain controversial. AIM: We conducted this meta-analysis to evaluate the associations between TNF-α-308 and -238 polymorphisms and HCC susceptibility. METHODS: PubMed, Embase, and China National Knowledge Infrastructure electronic databases were searched for all articles on associations between TNF-α-308 and -238 polymorphisms and HCC risk in Asians through September 30, 2013. Odds ratios (ORs) and their 95% CIs were calculated to assess the strength of this association. RESULTS: A total of 17 case-control studies were identified in our meta-analysis. For the TNF-α-308 G/A polymorphism, 14 studies containing 3154 cases and 3767 controls were included. Overall, the frequency of the A allele was higher in patients with HCC than in the healthy controls (10.2% vs 7.5%), and the A allele and allele carrier were significantly associated with increased risk of HCC in a random effects model (A vs G: OR = 1.57; 95% CI, 1.22-2.01; P = 0.0004; AA + AG vs GG: OR = 1.62; 95% CI, 1.18-2.22; P = 0.003). For the TNF-α-238 polymorphism, 10 research articles were identified. No association was found between the TNF-α-238 G/A polymorphism and risk of HCC in any genetic models (P > 0.05). The sensitivity analysis further strengthened the overall correlations. CONCLUSIONS: Our meta-analysis proved that the TNF-α-308 G/A polymorphism is associated with increased susceptibility to HCC. However, the TNF-α-238 G/A polymorphism is not significantly associated with risk of HCC in Asian populations. Further studies with large sample sizes are needed to confirm these associations among other populations.

Disposable circumcision suture device: clinical effect and patient satisfaction.

In our experience patients undergoing circumcision are mostly concerned about pain and penile appearances. We conducted a prospective randomized trial to assess the benefits of a new disposable circumcision suture device (DCSD). A total of 942 patients were equally divided into three groups (conventional circumcision, Shang ring and disposable suture device group). Patients in the DCSD group were anesthetized with compound 5% lidocaine cream, the others with a 2% lidocaine penile block. Operation time, intra-operative blood loss, incision healing time, intra-operative and post-operative pain, the penile appearance and overall satisfaction degree were measured. Operation time and intra-operative blood loss were significantly lower in the Shang ring and suture device groups compared to the conventional group (P < 0.001). Intra-operative pain was less in the suture device group compared with the other two groups (P < 0.001); whereas post-operative pain was higher in the conventional group compared to the other two groups (P < 0.001). Patients in the suture device (80.57%) and Shang ring (73.57%) groups were more satisfied with penile appearances compared with the conventional circumcision group (20.06%, P < 0.05). Patients in suture device group also healed markedly faster than the conventional group (P < 0.01). The overall satisfaction rate was better in the suture device group (78.66%) compared with the conventional (47.13%) and Shang ring (50.00%) groups (P < 0.05). The combination of DCSD and lidocaine cream resulted in shorter operation and incision healing times, reduced intra-operative and post-operative pain and improved patient satisfaction with the cosmetic appearances.