We conducted a network meta-analysis of randomized trials to assess the effect of different exercises on the renal and cardiovascular function of patients with chronic kidney disease not receiving dialysis. The PubMed, Embase, Web of science, COCHRANE LIBRARY, Trials, CNKI, WANFANG DATA and VIP were searched. The standardized mean difference (SMD), with a 95

ObjectiveChronic kidney disease (CKD) is a major global health problem. In clinical practice, the Chinese patent herbal medicine Jianpi-Yishen (JPYS) formula is commonly used to treat CKD. However, the molecular mechanisms by which JPYS targets and modulates the host immune response remain unclear.MethodsThis study utilized network pharmacology, RNA sequencing (RNA-seq), and metabolic analyses using in vivo and in vitro models to investigate the impact of the JPYS formula on inflammation and the immune system. Specifically, the study focused on macrophage polarization and metabolic changes that may slow down the progression of CKD.ResultsA total of 14,946 CKD-related targets were identified from the GeneCards and Online Mendelian Inheritance in Man (OMIM) databases through network pharmacology analyses. 227 potential targets of the JPYS formula were predicted using the TCMSP database. Additionally, network diagram demonstrated that 11 targets were associated with macrophage activity. In vivo studies indicated that the JPYS formula could reduce blood urea nitrogen and serum creatinine in adenine-induced CKD rats. Furthermore, the formula inhibited inflammatory damage and abnormal macrophage infiltration in this CKD model. RNA-seq, proteomic and metabolic analyses identified the regulation of amino acid metabolism by betaine, specifically referring to glycine, serine, and threonine metabolism, as a key target of the JPYS formula in slowing the progression of CKD. In addition, in vitro studies suggested that JPYS may enhance tryptophan metabolism in M1 macrophage polarization and betaine metabolism in M2 macrophage polarization.ConclusionsThe JPYS formula has been shown to have beneficial impact on CKD; a key mechanism is the mitigation of inflammatory damage through the interaction between amino acid metabolism and macrophage polarization. Of specific importance in this context are the roles of tryptophan in M1 polarization and betaine in M2 polarization.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) worldwide. Early detection is critical for the risk stratification and early intervention of progressive DKD. Serum creatinine (sCr) and urine output are used to assess kidney function, but these markers are limited by their delayed changes following kidney pathology, and lacking of both sensitivity and accuracy. Hence, it is essential to illustrate potential diagnostic indicators to enhance the precise prediction of early DKD. A total of 194 Chinese individuals include 30 healthy participants (Stage 0) and 164 incidents with type 2 diabetes (T2D) spanning from DKD's Stage 1a to 4 were recruited and their serums were subjected for untargeted metabolomic analysis. Random forest (RF), a machine learning approach, together with univariate linear regression (ULR) and multivariate linear regression (MvLR) analysis were applied to characterize the features of untargeted metabolites of DKD patients and to identify candidate DKD biomarkers. Our results indicate that 2-(α-D-mannopyranosyl)-L-tryptophan (ADT), succinyladenosine (SAdo), pseudouridine and N,N,N-trimethyl-L-alanyl-L-proline betaine (L-L-TMAP) were associated with the development of DKD, in particular, the latter three that were significantly elevated in Stage 2-4 T2D incidents. Each of the four metabolites in combination with sCr achieves better performance than sCr alone with area under the receiver operating characteristic curve (AUC) of 0.81-0.91 in predicting DKD stages. An average of 3.9 years follow-up study of another cohort including 106 Stage 2-3 patients suggested that "urinary albumin-to-creatinine ratio (UACR) + ADT + SAdo" can be utilized for better prognosis evaluation of early DKD (average AUC = 0.9502) than UACR without sexual difference.

Ethnopharmacological relevance Jian-Pi-Yi-Shen (JPYS) formula is an effective herbal therapy against renal injury, and JPYS has been clinically applied to ameliorate chronic kidney disease (CKD) and CKD-associated anemia. Increasing evidence supports the link between renal fibrosis and anemia in CKD. JPYS possessed anti-fibrosis effects in experimental CKD. Nevertheless, research on the mechanisms of JPYS in ameliorating renal anemia (RA) through suppressing renal fibrosis remains to be clarified. Aim of the study Our study here was carried out to investigate the mechanisms of JPYS in protecting against RA. Materials and methods An adenine-induced anemia model in rats with CKD at three different time points was established, and bio-samples taken from each group were analyzed. Biochemical analysis was employed to detect kidney function and hematological parameters. Masson staining was used to evaluate renal fibrosis of rats. Western blot and immunohistochemistry were utilized to evaluate the expressions of fibrotic markers, erythropoietin (EPO) and hypoxia inducible factor-2α (HIF-2α) in the kidneys of rats. Subsequently, transcriptomic analysis was conducted to disclose the possible mechanisms of JPYS in treating RA. Finally, the expression levels of key targets were analyzed and validated by using western blot and enzyme-linked immunosorbent assay (ELISA). Results JPYS treatment improved kidney function, suppressed renal fibrosis and enhanced hematological parameters in CKD rats. Moreover, JPYS treatment restored the increased expression levels of fibrotic markers and the declined EPO with time dependence. In parallel, data indicated JPYS treatment stimulated the translocation of HIF-2α into nucleus in the renal interstitium and thus promoted the expression of EPO. Transcriptomic profiling disclosed that activations of both nuclear factor kappa B (NF-κB) and transforming growth factor-β (TGF-β)/Smad pathways were closely associated with RA. Ultimately, experimental validation results presented that the increased expressions of target proteins from the above-mentioned two pathways in the kidneys were decreased significantly after JPYS treatment. Conclusion Our findings suggest that JPYS may improve RA by alleviating renal fibrosis, and the mechanisms of which involve in inhibiting the NF-κB and TGF-β/Smad pathways.

The integrated analysis of host metabolome and intestinal microbiome is an opportunity to explore the complex therapeutic mechanisms of traditional Chinese medicines. Currently, researchers mainly employ various statistical correlation analytical methods to investigate metabolome-microbiome correlations. However, these conventional correlation techniques often focus on statistical correlations and their biological meanings are always ignored, especially the functional relevance between them. Here, we developed a novel enzyme-based functional correlation (EBFC) algorithm to further improve the interpretability and the identified scope of microbe-metabolite correlations based on the conventional Spearman’s analysis. The proposed EBFC algorithm is successfully utilized to reveal the therapeutic mechanisms of Jian-Pi-Yi-Shen (JPYS) formula on the treatment of adenine-induced chronic kidney disease (CKD) rats. JPYS, a TCM formula for treating CKD, has beneficial clinical effects. We tentatively revealed the potential mechanism of JPYS for treating CKD rats from the perspective of the serum metabolome, gut microbiome, and their interactions. Specifically, 11 metabolites and 19 bacterial genera in the CKD rats were significantly regulated to approaching normal status after JPYS treatment, suggesting that JPYS could ameliorate the pathological symptoms of CKD rats by reshaping the disturbed metabolome and gut microbiota. Further correlation analysis between the significantly perturbed metabolites, microbiota, and the related enzymes provided more strong evidence for the study of host metabolism-microbiota interactions and the therapeutic mechanism of JPYS on CKD rats. In conclusion, these findings will help us to deeply understand the pathogenesis of CKD and provide new insights into the therapeutic mechanism of JPYS.

Ethnopharmacological relevance: The JinChan YiShen TongLuo (JCYSTL) formula, a traditional Chinese medicine (TCM), has been used clinically for decades to treat diabetic nephropathy (DN). TCM believes that the core pathogenesis of DN is "kidney deficiency and collateral obstruction," and JCYSTL has the effect of "tonifying kidney and clearing collateral," thus alleviating the damage to kidney structure and function caused by diabetes. From the perspective of modern medicine, mitochondrial damage is an important factor in DN pathogenesis. Our study suggests that the regulation of mitophagy and mitochondrial function by JCYSTL may be one of the internal mechanisms underlying its good clinical efficacy. Aim of the study: This study aimed to investigate the mechanisms underlying the renoprotective effects of JCYSTL. Materials and methods: Unilateral nephrectomy combined with low-dose streptozotocin intraperitoneally injected in a DN rat model and high glucose (HG) plus hypoxia-induced HK-2 cells were used to explore the effects of JCYSTL on the HIF-1 alpha/mitophagy pathway, mitochondrial function and apoptosis. Results: JCYSTL treatment significantly decreased albuminuria, serum creatinine, blood urea nitrogen, and uric acid levels and increased creatinine clearance levels in DN rats. In vitro, , medicated serum containing JCYSTL formula increased mitochondrial membrane potential (MMP); improved activities of mitochondrial respiratory chain complexes I, III, and IV; decreased the apoptotic cell percentage and apoptotic protein Bax expression; and increased anti-apoptotic protein Bcl-2 expression in HG/hypoxia-induced HK-2 cells. The treatment group exhibited increased accumulation of PINK1, Parkin, and LC3-II and reduced P62 levels in HG/hypoxia-induced HK-2 cells, whereas in PINK1 knockdown HK-2 cells, JCYSTL did not improve the HG/hypoxia-induced changes in Parkin, LC3-II, and P62. When mitophagy was impaired by PINK1 knockdown, the inhibitory effect of JCYSTL on Bax and its promoting effect on MMP and Bcl-2 disappeared. The JCYSTL-treated group displayed significantly higher HIF-1 alpha expression than the model group in vivo, , which was comparable to the effects of FG-4592 in DN rats. PINK1 knockdown did not affect HIF-1 alpha accumulation in JCYSTL-treated HK-2 cells exposed to HG/ hypoxia. Both JCYSTL and FG-4592 ameliorated mitochondrial morphological abnormalities and reduced the mitochondrial respiratory chain complex activity in the renal tubules of DN rats. Mitochondrial apoptosis signals in DN rats, such as increased Bax and Caspase-3 expression and apoptosis ratio, were weakened by JCYSTL or FG4592 administration. Conclusion: This study demonstrates that the JCYSTL formula activates PINK1/Parkin-mediated mitophagy by stabilizing HIF-1 alpha to protect renal tubules from mitochondrial dysfunction and apoptosis in diabetic conditions, presenting a promising therapy for the treatment of DN.

Ethnopharmacological relevanceThe JinChan YiShen TongLuo (JCYSTL) formula, a traditional Chinese medicine (TCM), has been used clinically for decades to treat diabetic neuropathy (DN). TCM believes that the core pathogenesis of DN is “kidney deficiency and collateral obstruction," and JCYSTL has the effect of “tonifying kidney and clearing collateral," thus alleviating the damage to kidney structure and function caused by diabetes. From the perspective of modern medicine, mitochondrial damage is an important factor in DN pathogenesis. Our study suggests that the regulation of mitophagy and mitochondrial function by JCYSTL may be one of the internal mechanisms underlying its good clinical efficacy.Aim of the studyThis study aimed to investigate the mechanisms underlying the renoprotective effects of JCYSTL.Materials and methodsUnilateral nephrectomy combined with low-dose streptozotocin intraperitoneally injected in a DN rat model and high glucose (HG) plus hypoxia-induced HK-2 cells were used to explore the effects of JCYSTL on the HIF-1α/mitophagy pathway, mitochondrial function and apoptosis.ResultsJCYSTL treatment significantly decreased albuminuria, serum creatinine, blood urea nitrogen, and uric acid levels and increased creatinine clearance levels in DN rats. In vitro, medicated serum containing JCYSTL formula increased mitochondrial membrane potential (MMP); improved activities of mitochondrial respiratory chain complexes I, III, and IV; decreased the apoptotic cell percentage and apoptotic protein Bax expression; and increased anti-apoptotic protein Bcl-2 expression in HG/hypoxia-induced HK-2 cells. The treatment group exhibited increased accumulation of PINK1, Parkin, and LC3-II and reduced P62 levels in HG/hypoxia-induced HK-2 cells, whereas in PINK1 knockdown HK-2 cells, JCYSTL did not improve the HG/hypoxia-induced changes in Parkin, LC3-II, and P62. When mitophagy was impaired by PINK1 knockdown, the inhibitory effect of JCYSTL on Bax and its promoting effect on MMP and Bcl-2 disappeared. The JCYSTL-treated group displayed significantly higher HIF-1α expression than the control group in vivo, which was comparable to the effects of FG-4592 in DN rats. PINK1 knockdown did not affect HIF-1α accumulation in JCYSTL-treated HK-2 cells exposed to HG/hypoxia. Both JCYSTL and FG-4592 ameliorated mitochondrial morphological abnormalities and reduced the mitochondrial respiratory chain complex activity in the renal tubules of DN rats. Mitochondrial apoptosis signals in DN rats, such as increased Bax and Caspase-3 expression and apoptosis ratio, were weakened by JCYSTL or FG-4592 administration.ConclusionThis study demonstrates that the JCYSTL formula activates PINK1/Parkin-mediated mitophagy by stabilizing HIF-1α to protect renal tubules from mitochondrial dysfunction and apoptosis in diabetic conditions, presenting a promising therapy for the treatment of DN.

Introduction Triptolide (TPL) is a promising plant-derived compound for clinical therapy of multiple human diseases; however, its application was limited considering its toxicity. Methods To explore the underlying molecular mechanism of TPL nephrotoxicity, a network pharmacology based approach was utilized to predict candidate targets related with TPL toxicity, followed by deep RNA-seq analysis to characterize the features of three transcriptional elements include protein coding genes (PCGs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) as well as their associations with nephrotoxicity in rats with TPL treatment. Results & Discussion Although the deeper mechanisms of TPL nephrotoxcity remain further exploration, our results suggested that c-Jun is a potential target of TPL and Per1 related circadian rhythm signaling is involved in TPL induced renal toxicity.

Chronic kidney disease (CKD) is a serious health threat worldwide. Defective mitophagy has been reported to induce mitochondrial dysfunction, which is closely associated with CKD pathogenesis. Honokiol (HKL) is a bioactive component of Magnolia officinalis that has multiple efficacies. Our study aimed to investigate the effect of HKL on a CKD rat model and explore the possible mechanisms of mitophagy mediated by Bcl-2 interacting protein 3 and BNIP3-like (NIX) (also known as the BNIP3/NIX pathway) and FUN14 domain-containing 1 (the FUNDC1 pathway) and the role of the AMP-activated protein kinase (AMPK) pathway. A CKD rat model was established by feeding the animals dietary adenine (0.75

Ethnopharmacological relevance: Jian-Pi-Yi-Shen (JPYS) is a herbal decoction being used to relieve the symptoms of chronic kidney disease (CKD) and its complications, including anemia, for over twenty years. Nonetheless, it is unclear how JPYS influences renal anemia and iron metabolism. Aim of the study: An analysis of network pharmacology, chemical profiling, and in vivo experiments was conducted to identify the impact of JPYS on JAK2-STAT3 pathway and iron utilization in renal anemia and CKD. Materials and methods: The chemical properties of JPYS and its exposed ingredients were detected in vivo. And based on the aforesaid chemical compounds, the potential targets and signaling pathways of JPYS for renal anemia treatment were predicted by network pharmacology. Afterward, an adenine-feeding animal model of CKD-related anemia was developed to verify the mechanism by which JPYS modulates iron recycling to treat renal anemia. Renal injury was estimated by serum creatinine (Scr), blood urea nitrogen (BUN), histopathological examinations and fibrosis degree. Western blot, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry approaches were utilized to assess the levels of JAK2, STAT3 and iron metabolism-related factors. Results: There were 164 active ingredients identified in JPYS, including prototypes and metabolites in vivo were identified in JPYS, and 21 core targets were found through network pharmacology based on topological characteristics. Combined with the core targets and pathway enrichment analysis, the majority of the candidate targets were associated with the JAK2-STAT3 signaling pathways. Experimental results indicated that JPYS treatment significantly decreased the expression of BUN and Scr, restored renal pathological damage, downregulated fibrosis degree, and improved hematological parameters such as red blood cell, hemoglobin and hematocrit in CKD rats. Furthermore, JPYS significantly restored iron metabolism from dysregulation by increasing the levels of iron and ferritin in the serum, inhibiting the production of hepcidin in liver and serum, and regulating transferrin receptor 1 in bone marrow. Meanwhile, the expression of JAK2 and STAT3 was suppressed by JPYS treatment. Conclusions: Based on these results, JPYS reduces hepcidin levels by inhibiting the activation of JAK2-STAT3 signaling, thereby protecting against iron deficiency anemia.

Aims:This study aimed to evaluate the effects of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) on iron metabolism and inflammation in dialysis-dependent chronic kidney disease (DD-CKD) patients. Methods:PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov websites were searched for randomized controlled trials (RCTs) investigating HIF-PHIs versus ESAs for DD-CKD patients. Key findings:Twenty studies with 14,737 participants were included in the meta-analysis, which demonstrated no significant difference in the effect of transferrin saturation and ferritin between HIF-PHIs and the ESAs group (MD, 0.65; 95%CI, -0.45 to 1.75; very low certainty; SMD, -0.03; 95% CI, -0.13 to 0.07; low certainty). However, HIF-PHIs significantly increased the iron (MD, 2.30; 95% CI, 1.40 to 3.20; low certainty), total iron-binding capacity (SMD, 0.82; 95% CI, 0.66 to 0.98; low certainty), and transferrin (SMD, 0.90; 95%CI, 0.74 to 1.05; moderate certainty) levels when compared with the ESAs group. In contrast, the hepcidin level and dosage of intravenous iron were significantly decreased in the HIF-PHIs group compared with the ESAs group (MD, -15.06, 95%CI, -21.96 to -8.16; low certainty; MD, -18.07; 95% CI, -30.05 to -6.09; low certainty). The maintenance dose requirements of roxadustat were independent of baseline CRP or hsCRP levels with respect to the effect on inflammation. Significance:HIF-PHIs promote iron utilization and reduce the use of intravenous iron therapy. Furthermore, HIF-PHIs, such as roxadustat, maintain the erythropoietic response independent of the inflammatory state. Thus, HIF-PHIs may be an alternative treatment strategy for anemia in DD-CKD patients, where ESA is hyporesponsive due to iron deficiency and inflammation.

脾与肾一司后天,一主先天,互为根本,共同参于水液的代谢、精微的封藏和精血的生化等.在生理上协调互济,病理上相互影响.多年来,从脾论治肾脏病成为临床上最受重视的治疗方法.故本期肾海探骊论坛特邀国内肾病领域的中医、中西医结合肾病专家李顺民、孙升云、占永立、刘伟敬和刘玉宁教授就脾之生理、病理及其治疗思路多角度探讨肾脏病从脾论治.本期论坛由论坛主席刘玉宁教授主持.

《金匮要略》(以下简称《金匮》)条文相比《伤寒论》更为简略,理解晦涩,虽该书成书久远,但对肾病的诊治仍具有临床指导意义.中医治疗讲究因时、因地、因人制宜,岭南具有其独特的气候、地理位置,当地人体质具有"上焦多浮热"、"中虚多湿蕴"、"下元多寒湿"的特点[1] ,笔者旨在立足于经典,结合岭南医学临床诊治特色及文献梳理,进一步探讨中医药治疗肾病的思路与方法.

Polycystic ovary syndrome (PCOS) is a universal endocrine and metabolic disorder prevalent in reproductive aged women. PCOS is often accompanied with insulin resistance (IR) which is an essential pathological factor. Although there is no known cure for PCOS, cangfudaotan (CFDT) decoction is widely used for the treatment of PCOS; nevertheless, the underlying mechanism is not clear. In this study, 40 Sprague-Dawley (SD) rats (female) were randomized to 4 groups, namely the control group, PCOS group, PCOS+CFDT group, and PCOS+metformin group. The rats in the control group were fed a normal-fat diet, intraperitoneally injected with 0.5% carboxymethyl cellulose (CMC, 1 mL/kg/d) for 21 days and orally given saline (1 mL/kg/d) for the next 4 weeks. The rats in the PCOS group, PCOS+CFDT group, and PCOS+Metformin group were fed a high-fat diet (HFD) and intraperitoneally injected with letrozole (1.0 mg/kg) for 21 days. During this period, we recorded the body weight, estrous cycles, and rate of pregnancy in all rats. We also observed the ovarian ultrastructure. Blood glucose indices, serum hormones, and inflammatory factors were also recorded. Then, we detected apoptotic and mitochondrial function, and observed mitochondria in ovarian granular cells by transmission electron microscopy. We also detected genes of ASK1/JNK pathway at mRNA and protein levels. The results showed that CFDT alleviated pathohistological damnification and apoptosis in PCOS rat model. In addition, CFDT improved ovarian function, reduced inflammatory response, inhibited apoptosis of granular cells, and inhibited the operation of ASK1/JNK pathway. These findings demonstrate the occurrence of ovary mitochondrial dysfunction and granular cell apoptosis in PCOS. CFDT can relieve mitochondria-dependent apoptosis by inhibiting the ASK1/JNK pathway in PCOS rats.

目的:应用网络药理技术从氨基酸代谢调控角度分析黄芪甲苷抗糖尿病肾损害网络分子机制.方法:基于前期代谢组学筛选出的与糖尿病肾病进展相关的氨基酸.使用KEGG、PubChem、TCMSP数据库,检索并提取氨基酸及黄芪甲苷的有效靶标基因,采用KEGG pathway数据库进行通路分析;应用Cytoscape绘制黄芪甲苷、氨基酸基因靶标蛋白互作网络图,并提取核心基因靶标.Cytoscape3.7.1软件内在的ClueGO应用进行疾病进展相关氨基酸基因靶标的通路、生物过程、细胞定位、分子功能进行富集分析,并绘制网络图.结果:本研究共分析了 10个与糖尿病肾病进展密切相关的氨基酸,提取基因靶标82个,参与KEGG通路62条.提取黄芪甲苷基因靶标24个.通过构建PPI网络,拟合黄芪甲苷和氨基酸基因靶标网络,提取核心靶标39个.富集分析结果表明黄芪甲苷和氨基酸核心基因靶标参与调控细胞应激、转录生长因子调控、蛋白质去乙酰化、RNA聚合酶调控、DNA结合调节、细胞周期调控、碳水化合物分解、糖酵解、细胞增殖染色质重塑等生物过程;涉及的细胞定位包括细胞周期蛋白、RNA聚合酶体复合物、常染色质、转录抑制因子、ATP酶复合物、PcG蛋白复合物、组蛋白甲基转移酶、组蛋白去乙酰化酶、SWI/SNF超家族复合物、Sin3复合物、CHD复合物;参与的分子功能有调控组蛋白去乙酰化、DNA转录因子结合、RNA聚合酶结合、转录因子活化、染色质DNA结合、泛素蛋白连接、p53连接、糖皮质受体结合等;核心基因靶标涉及的KEGG通路以调控细胞周期、癌症、自噬通路相关通路为主.结论:黄芪甲苷可能通过调节糖代谢、蛋白、DNA的转录后修饰,在细胞增殖、细胞周期、氧化应激、细胞自噬等多个分子功能层面实施保护糖尿病肾病肾脏的功能.

"肺与大肠相表里"是中医学理论的基本内容,其核心是肺与大肠作为一个整体而相互关联.近代生物学研究显示:肠道微生态与呼吸道微生态相互影响,肠道微生物组稳态失衡进而导致呼吸道微生态组稳态失衡,即"肠病及肺",故中医临床往往以"肺肠同治"法进行治疗.西医研究结果显示糖尿病患者往往合并肠道微生物组稳态失衡,而肺作为一个毛细血管密集的脏器,是糖尿病的重要靶器官.因此通过研究近年来的文献资料,结合肠道微生物组这一热点,探讨"肺与大肠相表里"在糖尿病肺损伤中的生物学基础,进而丰富中医藏象理论内涵,为防治糖尿病肺损伤提供新思路.

Traditional Chinese medicine (TCM) is an important complementary and alternative branch of chronic kidney disease (CKD) therapy. Jian-Pi-Yi-Shen formula (JPYSF) is a TCM formula used for treating CKD with good efficacy. However, the underlying mechanisms of JPYSF in treating CKD remain to be elucidated. The purpose of the present study was to investigate the renoprotective effect and potential mechanism of JPYSF in treating CKD. CKD rat model was induced by feeding a diet containing 0.75% w/w adenine for 4 weeks. JPYSF was given by gavage every day, starting from the 3rd week of the adenine-containing diet and continuing for 4 weeks at the dose of 10.89 g/kg. Renal injury was evaluated by serum creatinine (Scr), blood urea nitrogen (BUN), histopathology, and fibrotic markers expression. Serum levels of tryptophan metabolites were detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Aryl hydrocarbon receptor (AHR) signaling was tested by Western blot analysis. The results found that JPYSF treatment significantly lowered Scr and BUN levels, improved renal pathological injury, and down-regulated fibrotic markers expression in CKD rats. Furthermore, JPYSF significantly reduced the levels of 10 tryptophan metabolites in the serum of CKD rats and restored the level of tryptophan. Additionally, the kidney expression of AHR signaling was enhanced in CKD rats and was further suppressed in JPYSF treated rats. These results suggested that JPYSF protected against adenine-induced CKD via modulating tryptophan metabolism and AHR activation.

Abnormal ovarian function is the main manifestation of female reproductive toxicity. Granulosa cells (GCs) play an important role in determining the fate of follicles and are the main effector cells of the female reproductive system. Excessive apoptosis of GCs leads to pathological folliculogenesis and further reproductive damage. However, drugs available for treatment of female reproductive toxicity are limited. Recent studies have confirmed that various natural products and bioactive ingredients of traditional Chinese medicine (TCM) can inhibit apoptosis of GCs and protect ovarian function. In this review, the mechanisms underlying the proapoptotic and antiapoptotic effects of natural products and bioactive ingredients of TCM on the proliferation, function, and apoptosis of GCs are summarized based on the findings of reports published over the past 10 years as reference for the treatment of female reproductive toxicity.

目的 探讨二甲双胍与膈下逐瘀汤联合用药治疗肥胖型多囊卵巢综合征(PCOS)不孕症患者的疗效,并观察记录患者的免疫功能、阴道菌群变化及其妊娠情况.方法 选取2017年9月至2019年11月深圳市中医院妇科门诊收治的肥胖型PCOS不孕症患者130例(118例顺利完成临床研究),随机分为对照组60例与观察组58例.对照组患者给予二甲双胍单药治疗,观察组患者在对照组基础上采用膈下逐瘀汤,连续进行为期3个月的治疗.比较两组患者治疗前后胰岛素抵抗指标C肽、空腹血浆胰岛素(FINS)、胰岛β细胞功能指数(HOMA-β)、胰岛素抵抗指数(HOMA-IR)、叉头框蛋白P3(FoxP3)、转化生长因子-β1(TGF-β1)、白细胞介素-17(IL-17)、白细胞介素-10(IL-10)、阴道菌群的变化情况,并统计患者的妊娠率.结果 治疗后两组患者TGF-β1、IL-10与FoxP3的mRNA表达水平明显高于治疗前(P<0.05),且观察组TGF-β1、IL-10与FoxP3的mRNA表达水平高于对照组(P<0.05);治疗后两组患者IL-17水平低于治疗前(P<0.05),且观察组IL-17水平低于对照组(P<0.05).治疗后两组患者CP、FINS、HOMA-IR低于治疗前(P<0.05),且观察组CP、FINS、HOMA-IR低于对照组(P<0.05).观察组排卵率及临床妊娠率高于对照组,差异有统计学意义(P<0.05).治疗后两组患者滴虫、假丝酵母菌检出率及菌群失调率、阴道清洁度(Ⅲ+Ⅳ度)低于治疗前(P<0.05),且观察组低于对照组(P<0.05).结论 膈下逐瘀汤联合二甲双胍可以显著改善胰岛素抵抗、调节T细胞免疫应答、纠正阴道微生物稳态失衡,对PCOS患者具有较好的疗效.

As a widely applied traditional Chinese medicine (TCM), Jian-Pi-Yi-Shen (JPYS) decoction maybe applied in curing premature ovarian failure (POF) besides chronic kidney disease (CKD). In vivo experiments, 40 female SD (8-week-old) rats were randomized into four groups, namely, control group (negative control), POF model group, JPYS treatment group, and triptorelin treatment group (positive control). JPYS group was treated with JPYS decoction (oral, 11 g/kg) for 60 days, and the triptorelin group was treated with triptorelin (injection, 1.5 mg/kg) for 10 days before the administration of cyclophosphamide (CTX) (50 mg/kg body weight) to establish POF model. We examined apoptosis, mitochondrial function, and target gene (ASK1/JNK pathway and mitochondrial fusion/fission) expression. In vitro experiments, the KGN human granulosa cell line was used. Cells were pretreated with CTX (20, 40, and 60 μg/mL) for 24 h, followed by JPYS-containing serum (2, 4, and 8 %) for 24 h. Thereafter, these cells were employed to assess apoptosis, mitochondrial function, and target gene levels of protein and mRNA. In vivo, JPYS alleviated injury and suppressed apoptosis in POF rats. In addition, JPYS improved ovarian function. JPYS inhibit apoptosis of granulosa cells through improving mitochondrial function by activating ASK1/JNK pathway. In vitro, JPYS inhibited KGN cell apoptosis through inhibited ASK1/JNK pathway and improved mitochondrial function. The effects of GS-49977 were similar to those of JPYS. During POF, mitochondrial dysfunction occurs in the ovary and leads to granulosa cell apoptosis. JPYS decoction improves mitochondrial function and alleviates apoptosis through ASK1/JNK pathway.