Exploring the therapeutic mechanism of Yuebi decoction on nephrotic syndrome based on network pharmacology and experimental study.

OBJECTIVE: This study aimed to explore the material basis of YBD and its possible mechanisms against NS through network pharmacology, molecular docking, and in vivo experiment. METHODS: Active ingredients and potential targets of YBD were obtained through TCMSP and SwissTargetPrediction. NS-related targets were obtained from GeneCards, PharmGKB, and OMIM databases. The herb-ingredient-target network and PPI network were constructed by Cytoscape 3.9.1 and STRING database. GO and KEGG analyses were performed by DAVID database and ClueGO plugin. The connection between main active ingredients and core targets were revealed by molecular docking. To ascertain the effects and molecular mechanisms of YBD, a rat model was established by PAN. RESULTS: We collected 124 active ingredients, 269 drug targets, and 2089 disease targets. 119 overlapping were screened for subsequent analysis. PPI showed that AKT1, STAT3, TRPC6, CASP3, JUN, PPP3CA, IL6, PTGS2, VEGFA, and NFATC3 were potential therapeutic targets of YBD against NS. Through GO and KEGG analyses, it showed the therapeutic effect of YBD on NS was closely involved in the regulation of pathways related to podocyte injury, including AGE-RAGE signaling pathway in diabetic complications and MAPK signaling pathway. Five key bioactive ingredients of YBD had the good affinity with the core targets. the experiment confirmed the renoprotective effects of YBD through reducing podocyte injury. Furthermore, YBD could downregulate expressions of PPP3CA, STAT3, NFATC3, TRPC6, and AKT1 in rats. CONCLUSIONS: YBD might be a potential drug in the treatment of NS, and the underlying mechanism is closely associated with the inhibition of podocyte injury.

Potential Molecular Mechanisms of Ephedra Herb in the Treatment of Nephrotic Syndrome Based on Network Pharmacology and Molecular Docking.

Objective: To explore the possible mechanisms of Ephedra herb (EH) in the treatment of nephrotic syndrome (NS) by using network pharmacology and molecular docking in this study. Methods: Active ingredients and related targets of EH were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and the gene names corresponding to the proteins were found through the UniProt database. Then, target genes related to NS were screened out from GeneCards, PharmGKB, and OMIM databases. Next, the intersection targets were obtained successfully through Venn diagram, which were also seen as key target genes of EH and NS. Cytoscape 3.9.0 software was used to construct the effective "active ingredient-target" network diagram, and "drug-ingredient-target-disease (D-I-T-D)" network diagram. After that, the STRING database was used to construct a protein-protein interaction (PPI) network. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment involved in the targets were performed by the DAVID database and ClueGO plugin in Cytoscape. Finally, AutoDockTools software was used for molecular docking to verify the binding strength between main active ingredients and key target proteins. Results: A total of 22 main active ingredients such as quercetin, kaempferol, luteolin, and naringenin were obtained, which could act on 105 targets related to NS. Through PPI network, 53 core targets such as AKT1, TNF, IL6, VEGFA, and IL1B were found, which might play a crucial role in the treatment of NS. Meanwhile, these targets were significantly involved in PI3K-Akt signaling pathway, TNF signaling pathway, AGE-RAGE signaling pathway, hepatitis B, and pathways in cancer through GO and KEGG enrichment analysis. The docking results indicated that active ingredients such as kaempferol, luteolin, quercetin, and naringenin all had good binding to the target protein AKT1 or TNF. Among them, luteolin and naringenin binding with AKT1 showed the best binding energy (-6.2 kcal/mol). Conclusion: This study indicated that the potential mechanism of EH in treating NS may be related to PI3K-Akt signaling pathway, TNF signaling pathway, and AGE-RAGE signaling pathway, which provided better approaches for exploring the mechanism in treating NS and new ideas for further in vivo and in vitro experimental verifications.

Recent Advances in Traditional Chinese Medicine for Treatment of Podocyte Injury.

Podocyte is also called glomerular epithelial cell, which has been considered as the final gatekeeper of glomerular filtration barrier (GFB). As a major contributor to proteinuria, podocyte injury underlies a variety of glomerular diseases and becomes the challenge to patients and their families in general. At present, the therapeutic methods of podocyte injury mainly include angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, steroid and immunosuppressive medications. Nevertheless, the higher cost and side effects seriously disturb patients with podocyte injury. Promisingly, traditional Chinese medicine (TCM) has received an increasing amount of attention from different countries in the treatment of podocyte injury by invigorating spleen and kidney, clearing heat and eliminating dampness, as well enriching qi and activating blood. Therefore, we searched articles published in peer-reviewed English-language journals through Google Scholar, PubMed, Web of Science, and Science Direct. The protective effects of active ingredients, herbs, compound prescriptions, acupuncture and moxibustion for treatment of podocyte injury were further summarized and analyzed. Meanwhile, we discussed feasible directions for future development, and analyzed existing deficiencies and shortcomings of TCM in the treatment of podocyte injury. In conclusion, this paper shows that TCM treatments can serve as promising auxiliary therapeutic methods for the treatment of podocyte injury.

Chinese Herbal Injections for Primary Nephrotic Syndrome in Adults: A Systematic Review and Network Meta-Analysis.

Primary nephrotic syndrome (PNS) is a common renal disease that presents with heavy proteinuria and hypoalbuminemia. Despite notable advances in its treatment, some patients show poor responses and clinical outcomes when treated with conventional Western medicine (WM). Chinese herbal injections (CHIs) have been reported to have beneficial effects for PNS. The aim of the present study was to comprehensively determine the efficacy and safety of CHIs for PNS in adults using a network meta-analysis approach. PubMed, Embase, the Cochrane library, and four Chinese databases were systematically searched to identify randomized controlled trials (RCTs) using CHIs for treatment of PNS published before June 1, 2019. Quality assessment of the identified RCTs was performed according to the Cochrane Handbook. Pooled odds ratios (OR) or mean differences (MD) with corresponding 95% confidence intervals (CI) were calculated for discrete or continuous variables, respectively. The primary outcome was complete/total remission and secondary outcomes were serum albumin and urinary protein excretion. The surface under the cumulative ranking curve (SUCRA) value and cluster analyses were used to rank treatment by probability. Eighty-five studies involving 11 CHIs and 5801 subjects were included. Compared with WM alone, CHI plus WM showed an improved complete/total remission rate as well as higher serum albumin and lower 24-hour urinary protein excretion, except in the following: Yinxingye injection plus WM did not improve the total remission rate, and Dengzhanhua or Xueshuantong injection plus WM did not lower the 24-hour urinary protein excretion. Either Danhong (DH) or Dengzhanhua (DZH) injection plus WM was the preferable treatment for PNS based on SUCRA and cluster analyses of clinical remission and adverse events. However, considering that literature in this area is limited, these results need further validation. CHIs administered as adjuvants to WM showed favourable outcomes for PNS. DH + WM and DZH + WM might be the potential optimal therapies for PNS.

Efficacy and Safety of Immunosuppressive Monotherapy Agents for IgA Nephropathy: A Network Meta-Analysis.

Background: The efficacy and safety of immunosuppressive monotherapy agents were evaluated for immunoglobulin A nephropathy (IgAN) using a network meta-analysis approach. Methods: Randomized controlled trials (RCTs) published prior to October 1, 2019, using immunosuppressive agents for treating IgAN, were systematically searched in PubMed, Embase, Cochrane Library, and Web of Science databases. Relative risks (RRs) or standard mean differences with 95% confidence intervals (CIs) were estimated using the random-effects model. The primary outcomes were clinical remission, end-stage renal disease (ESRD), and serious adverse events (SAEs). The secondary outcomes were urinary protein excretion and serum creatinine. Results: Twenty-five RCTs with 2,005 participants were deemed eligible. Six medications were evaluated: corticosteroids, mycophenolate mofetil (MMF), tacrolimus (TAC), cyclosporine, leflunomide, and hydroxychloroquine (HCQ). Steroids (RR 1.50, 95% CI 1.17-1.93), MMF (RR 2.05, 95% CI 1.15-3.65), TAC (RR 3.67, 95% CI 1.06-12.63), and HCQ (RR 3.25, 95% CI 1.05-10.09) significantly improved clinical remission rates compared to supportive care alone. Only steroids reduced the risk of ESRD (RR 0.35, 95% CI 0.12-0.98); however, there were significantly more SAEs than in the control group (RR 2.90, 95% CI 1.37-6.13). No significantly different effects in serum creatinine levels were found among the therapies. MMF showed no significant improvement in remission when excluding studies with a follow-up of fewer than 2 years in the sensitivity analysis (RR 1.41, 95% CI 0.40-4.92). The effect of TAC in the decrease of proteinuria was reversed after discontinuing medication for 3 months; the long-term effects of HCQ could not be evaluated due to the short follow-up duration. Conclusion: Corticosteroids might induce remission and increase renal survival in IgAN; however, adverse reactions should be taken into consideration. MMF, TAC, and HCQ might improve the remission of proteinuria when treating IgAN, but showed no superiority compared to steroids, and the long-term effects require further study.