Chlorogenic acid can improve spermatogenic dysfunction in rats with varicocele by regulating mitochondrial homeostasis and inhibiting the activation of NLRP3 inflammasomes by oxidative mitochondrial DNA and cGAS/STING pathway.

In recent years, Varicocele (VC) has been recognized as a common cause of male infertility that can be treated by surgery or drugs. How to reduce the damage of VC to testicular spermatogenic function has attracted extensive attention in recent years. Among them, overexpressed ROS and high levels of inflammation may play a key role in VC-induced testicular damage. As the key mediated innate immune pathways, cGAS-STING shaft under pathological conditions, such as in cell and tissue damage stress can be cytoplasmic DNA activation, induce the activation of NLRP3 inflammatory corpuscle, triggering downstream of the inflammatory cascade reaction. Chlorogenic acid (CGA), as a natural compound from a wide range of sources, has strong anti-inflammatory and antioxidant activities, and is a potential effective drug for the treatment of varicocele infertility. The aim of this study is to investigate the role of CGA in the spermatogenic dysfunction of the rat testis induced by VC and the potential mechanisms. The results of this study have shown that CGA gavage treatment ameliorated the pathological damage of seminiferous tubules, increased the number of sperm in the lumen, and increased the expression levels of Occludin and ZO-1, which indicated the therapeutic effect of CGA on spermatogenic dysfunction in the testis of VC rats. Meanwhile, the damage of mitochondrial structure was alleviated and the expression levels of ROS, NLRP3 and pro-inflammatory cytokines (IL-1ß, IL-6, IL-18) were significantly reduced in the testicular tissues of model rats after CGA treatment. In addition, we demonstrated for the first time the high expression status of cGAS and STING in testicular tissues of VC model rats, and this was ameliorated to varying degrees after CGA treatment. In conclusion, this study suggests that CGA can improve the spermatogenic function of the testis by reducing mitochondrial damage and inhibiting the activation of the cGAS-STING axis, inhibiting the activation of the NLRP3 inflammasome, and improving the inflammatory damage of the testis, highlighting the potential of CGA as a therapeutic agent for varicocele infertility.

Network pharmacology and in vivo experiment-based strategy for investigating the mechanism of chronic prostatitis/chronic pelvic pain syndrome in QianLieJinDan tablets.

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urinary system disease that is prone to recurrence. It typically leads to varying degrees of pelvic pain and discomfort, as well as symptoms related to the urinary system in affected patients. QianLieJinDan tablets (QLJD), a traditional Chinese medicine, have shown promising therapeutic effects on CP/CPPS in clinical practice, but the underlying mechanisms of QLJD in treating CP/CPPS have not been determined. Objective: To reveal the phytochemical characterization and multitarget mechanism of QLJD on CP/CPPS. Methods: The concentrations of the components of QLJD were determined using UHPLC-Q Exactive Orbitrap-MS. Utilizing network pharmacology approaches, the potential components, targets, and pathways involved in the treatment of CP/CPPS caused by QLJD were screened. Molecular docking calculations were employed to assess the affinity between the components of the QLJD and potential targets, revealing the optimal molecular conformation and binding site. Finally, the therapeutic efficacy and potential underlying mechanisms of QLJD were investigated through pharmacological experiments. Results: In this study, a total of 35 components targeting 29 CP-related genes were identified, among which quercetin, baicalin, icariin, luteolin, and gallic acid were the major constituents. Enrichment analysis revealed that the potential targets were involved mainly in the regulation of cytokines, cell proliferation and apoptosis, and the oxidative stress response and were primarily associated with the cytokine‒cytokine receptor interaction pathway, the IL-17 signaling pathway, the Th17 cell differentiation pathway, and the JAK-STAT signaling pathway. In vivo experiments demonstrated that QLJD effectively attenuated the infiltration of CD3+ T cells and the expression of ROS in a CP/CPPS model rat prostate tissue. Furthermore, through the inhibition of IL-6 and STAT3 expression, QLJD reduced the differentiation of Th17 cells, thereby ameliorating pathological injury and prostatic index in prostate tissue. Conclusion: The potential of QLJD as an anti-CP/CPPS agent lies in its ability to interfere with the expression of IL-6 and STAT3, inhibit Th17 cell differentiation, reduce inflammatory cell infiltration in rat prostate tissue, and alleviate oxidative stress damage through its multi-component, multi-target, and multi-pathway effects.

Mailuoshutong pill for varicocele-associated male infertility-Phytochemical characterisation and multitarget mechanism.

Background: Varicocele (VC) is a relatively common and treatable cause of male infertility. Mailuoshutong pill (MLST), a traditional Chinese patent medicine, is widely used for treating varicose vein disease, but the underlying mechanism of MLST on varicocele-associated male infertility is unclear. Objective: To reveal the phytochemical characterisation and multitarget mechanism of MLST on varicocele-associated male infertility. Methods: The components in MLST were determined using UHPLC-MS/MS. Through network analysis, we constructed the "Drug-Components-Targets-Disease" network and predicted the potential biological functions and signaling pathways of MLST. Finally, the therapeutic effects and potential mechanisms of MLST were discovered by pharmacological experiments. Results: By network analysis, the "Drug-Components-Targets-Disease" network was constructed, 62 components such as apigenin, limonin, kaempferol, and obacunoic acid may be the main active components of MLST for varicocele-associated male infertility, 28 targets such as VEGFA, PIK3CA, AKT1, and MTOR are considered as hub targets, signaling pathways such as HIF-1, Estrogen, PI3K/Akt, and mTOR may be key pathways for MLST against varicocele-associated male infertility. Through pharmacological experiments, we found that MLST ameliorated VC-induced testicular atrophy. Further histomorphology showed that MLST reduced VC-induced damage to testicular spermatogonia and seminiferous tubule, while MLST reduced ROS and MDA levels and increased antioxidant enzymes (GSH, GSH-Px, SOD, and CAT) levels. TUNEL staining and immunofluorescence showed that MLST reduced VC-induced apoptosis in testicular tissue, decreased BAX, and increased BCL2. Western blot results showed that MLST decreased the phosphorylation of PI3K, AKT, and mTOR proteins, and decreased the expression of HIF1α. Conclusion: The phytochemical characterisation and multitarget mechanism of MLST on varicocele-associated male infertility were discovered using network analysis and pharmacological experiments. We verified that MLST can inhibit the activation of the PI3K/Akt/mTOR signaling pathway, reduce the expression of HIF1α, and further attenuate VC-induced oxidative stress and apoptosis in the testis. These findings provide evidence for the therapeutic role of MLST in varicocele-associated male infertility.

The efficacy and safety of immune checkpoint inhibitors in metastatic castration-resistant prostate cancer: A systematic review and meta-analysis.

BACKGROUND: We aim to assess the efficacy and safety profiles of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer using a meta-analysis. METHODS: We extracted and examined data from phase I, II and III clinical trials from PubMed, Embase, Web of Science, and Cochrane Library, which included patients with metastatic castration-resistant prostate cancer who were treated with immune checkpoint inhibitors. We performed a meta-analysis to investigate several indexes of efficacy and safety, including the objective response rate, 1-year overall survival (OS) rate, prostate-specific antigen response rate, and adverse event rate of immune checkpoint inhibitors. The material data were calculated and pooled using The R Project for Statistical Computing and STATA 12.0 software. RESULTS: We identified 12 clinical trials in our study. We assessed the pooled frequencies of all-grade AEs and grade ≥ 3 AEs first and showed 0.82 (95% CI: 0.74-0.91, I2 = 94%, P < .01) and 0.42 (95% CI: 0.33-0.54, I2 = 96%, P < .01), respectively. The objective response rate was 0.10 (95% CI: 0.04-0.19, I2 = 70%, P < .01), and the 1-year OS and prostate-specific antigen response rate were 0.55 (95% CI: 0.45-0.67, I2 = 93%, P < .01) and 0.18 (95% CI: 0.16-0.20, I2 = 43%, P = .03), respectively. CONCLUSION: The immune checkpoint inhibitors therapy was well tolerated and showed potential to improve tumor responses in patients with metastatic castration-resistant prostate cancer.

Reasons and treatment strategy for discontinuation of dapoxetine treatment in premature ejaculation patients in China: A retrospective observational study.

To assess dapoxetine discontinuation rates and the reasons for discontinuation in Chinese men with premature ejaculation (PE). Information on 906 PE outpatients was obtained from the hospital information system (HIS) in 2019. Of these, 150 patients were chosen. We analysed the dapoxetine discontinuation rate and the reasons for discontinuation over a 12-week follow-up period. The mean age of all patients was 33.6 years (range = 18-55), the mean PE duration was 12.36 ± 9.45 months. The 5-item International Index of Erectile Function (IIEF-5) score was 21.51 ± 3.80. A total of 37.3% of all the patients remained on the treatment until the 12th week. The cumulative discontinuation rates at the 4th, 8th and 12th weeks were 12%, 41.3% and 62.7%, respectively. The discontinuation rates for all the patients in weeks 0-4, weeks 4-8 and weeks 8-12 were 19.1%, 46.8% and 34.0%, respectively. After 4 weeks, the discontinuation rates dropped sharply. The reasons for patients' discontinuation were as follows: overexpectation of efficacy (30.9%), relapsing after drug withdrawal (26.6%), high cost (25.5%), side effects (9.6%), fear of drug addiction (4.3%), failure of follow-up (2.1%) and choosing other treatments (1.1%). The dapoxetine treatment discontinuation rate was very high. The main reasons for discontinuation were overexpectation of efficacy and high cost.

Effect of Baduanjin exercise on cervical spondylosis: A protocol for the systematic review of randomized controlled trials.

BACKGROUND: The study aims to evaluate the effectiveness and safety of Baduanjin exercise for patients with cervical spondylosis (CS). METHODS: We will retrieve a randomized controlled trial of Baduanjin for CS from the following electronic databases establishment to May 2021: The Cochrane Library, MEDLINE, EMBASE, Web of Science, Springer, World Health Organization International Clinical Trials Registry Platform (ICTRP), China National Knowledge Infrastructure (CNKI), Wan-fang database, Chinese Scientific Journal Database (VIP), Chinese Biomedical Literature Databases (CBM), and other databases. Two independent researchers will operate article retrieval, duplication removing, screening, quality evaluation, and data analyses by Review Manager (V.5.3.5). Meta-analyses, subgroup analysis, and/or descriptive analysis will be performed based on the included data conditions. RESULTS: The results of this study will provide researchers in the field of CS with a current synthesis of high-quality evidence. CONCLUSION: This conclusion of this study will provide the evidence of whether Baduanjin is an effective and safe intervention for patients with CS. PROSPERO REGISTRATION NUMBER: CRD42020211019.