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.

Efficacy and safety of Chinese herbal medicine for chronic prostatitis associated with damp-heat and blood-stasis syndromes: a meta-analysis and literature review.

OBJECTIVE: The aim of this meta-analysis and systematic review is to evaluate the safety and efficacy of Chinese herbal medicine (CHM) for chronic prostatitis (CP) associated with damp-heat and blood-stasis syndromes. METHODS: An electronic search of 13 databases up to May 2016 was screened to identify randomized controlled trials comparing the safety and efficacy of CHM for the treatment of CP associated with damp-heat and blood-stasis syndromes. Studies reporting on effective rates, adverse events, National Institutes of Health chronic prostatitis symptom index (NIH-CPSI) scores, and symptom index of Chinese medicine for chronic prostatitis (SI-CM) scores as outcomes were included in the analysis. Data were analyzed by fixed- or random-effect models using the Review Manager software. RESULTS: Thirteen articles with the modified Jadad score ≥4 were identified. It was found that CHM was superior to placebo in increasing the efficacy (odds ratio: 6.72, 95% confidence interval [CI]: 2.78-9.48, P<0.00001) and reducing the SI-CM scores (standardized mean difference: -1.08, 95% CI: -1.35 to -0.81, P<0.00001). Oral CHMs were significantly more effective than placebo at reducing NIH-CPSI scores, with a mean difference of -1.39 (95% CI: -1.87 to -0.92, P<0.00001). Nevertheless, no significant differences were found between Prostant and placebo (standardized mean difference: -0.23, 95% CI: -0.46 to 0.01, P=0.06). The frequency of adverse events associated with oral CHM was similar to that associated with placebo (risk ratio: 1.36, 95% CI: 0.72-2.55, P=0.34) and less than that associated with Prostant (risk ratio: 1.63, 95% CI: 1.14-2.34, P=0.008). CONCLUSION: Our novel analysis demonstrates that CHM ranks highest in terms of improvement of CP associated with damp-heat and blood-stasis syndromes. While Prostant showed some efficacy in this disorder, it was associated with a smaller reduction in NIH-CPSI scores. In conclusion, CHM monotherapy is safe and effective for the treatment of CP associated with damp-heat and blood-stasis syndromes.

Role of removing stasis and reducing heat formula in clearance of proximal ureteral calculi after ureteroscopic Ho:YAG laser lithotripsy: a prospective randomized study.

OBJECTIVE: To prospectively evaluate the efficacy of Removing Stasis and Reducing Heat Formula in accelerating calculus clearance and improving lower urinary tract symptoms of patients with proximal ureteral calculi after ureteroscopic Ho:YAG laser lithotripsy. METHODS: A total of 138 patients with proximal ureteral calculi underwent ureteroscopic Ho:YAG laser lithotripsy by a single endocrinologist. Stone size varied from 10 to 15 mm. After operation, the patients were randomly divided into three groups: the control group (group A), tamsulosin group (group B), and Removing Stasis and Reducing Heat Formula group (group C). The treatment lasted for 4 weeks or until stone clearance. The primary and secondary outcomes of the three groups at follow-up were assessed. RESULTS: Of the 131 patients available for follow-up, 44 cases were in the group A, 45 in the group B, and 42 in the group C, respectively. The stone free rate at 2 weeks in the groups B and C were significantly higher than that in the group A (95.56%, 97.62% vs. 79.55%; all P<0.05). The ureteral colic rate and mean time of fragment expulsion were significantly reduced in the groups B (4.44% and 7.86±4.99 days) and C (2.43% and 6.76±4.37 days) compared with the group A (22.73% and 11.54±9.89 days, all P<0.05). On the day of double-J ureteric stent removal, the group C differed significantly from the group A in the total International Prostate Symptom Score, irritative subscore, obstructive subscore, and quality of life score (all P<0.05). CONCLUSION: Removing Stasis and Reducing Heat Formula in the medical expulsive therapy might be an effective modality for patients with calculus in the proximal uretera after ureteroscopic Ho:YAG laser lithotripsy.