Sanqi Qushi Granule Alleviates Proteinuria and Podocyte Damage in NS Rat: A Network Pharmacology Study and in vivo Experimental Validation.

Background: Nephrotic syndrome (NS) and its numerous complications remain the leading causes of morbidity and mortality globally. Sanqi Qushi granule (SQG) is clinically effective in NS. However, its potential mechanisms have yet to be elucidated. Methods: A network pharmacology approach was employed in this study. Based on oral bioavailability and drug-likeness, potential active ingredients were picked out. After acquiring overlapping targets for drug genes and disease-related genes, a component-target-disease network and protein-protein interaction analysis (PPI) were constructed using Cytoscape, followed by GO and KEGG enrichment analyses. Adriamycin was injected into adult male Sprague-Dawley (SD) rats via the tail vein to establish NS model. Kidney histology, 24-hr urinary protein level, creatinine (Cr), blood urea nitrogen (BUN), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL-C) level were assessed. Western blotting, immunohistochemistry, and TUNEL staining were applied. Results: In total, 144 latent targets in SQG acting on NS were screened by a network pharmacology study, containing AKT, Bax, and Bcl-2. KEGG enrichment analysis suggested that PI3K/AKT pathway was enriched primarily. In vivo validation results revealed that SQG intervention ameliorated urine protein level and podocyte lesions in the NS model. Moreover, SQG therapy significantly inhibited renal cells apoptosis and decreased the ratio of Bax/Bcl-2 protein expression. Moreover, we found that Caspase-3 regulated the PI3K/AKT pathway in NS rats, which mediated the anti-apoptosis effect. Conclusion: By combining network pharmacology with experimental verification in vivo, this work confirmed the treatment efficacy of SQG for NS. SQG protected podocyte from injury and inhibited kidney apoptosis in NS rats via the PI3K/AKT pathway at least partially.

A Network Pharmacology-Based Approach to Investigating the Mechanisms of Fushen Granule Effects on Intestinal Barrier Injury in Chronic Renal Failure.

PURPOSE: Fushen Granule (FSG) is a Chinese medicine prepared by doctors for treating patients with chronic renal failure, which is usually accompanied by gastrointestinal dysfunction. Here, we explore the protective effect of FSG on intestinal barrier injury in chronic renal failure through bioinformatic analysis and experimental verification. METHODS: In this study, information on the components and targets of FSG related to CRF is collected to construct and visualize protein-protein interaction networks and drug-compound-target networks using network pharmacological methods. DAVID is used to conduct gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Then, it is validated by in vitro experiments. In this study, the human intestinal epithelial (T84) cells are used and divided into four groups: control group, model group, FSG low-dose group, and FSG high-dose group. After the experiment, the activity of T84 cells is detected by a MTT assay, and the expressions of tight junction protein ZO-1, claudin-1, nuclear factor erythroid 2-related factor (Nrf2), heme oxygenase-1 (HO-1), malondialdehyde (MDA), and cyclooxygenase-2 (COX-2) are examined by immunofluorescence and/or western blotting. RESULTS: Eighty-six potential chronic renal failure-related targets are identified by FSG; among them, nine core genes are screened. Furthermore, GO enrichment analysis shows that the cancer-related signaling pathway, the PI3K-Akt signaling pathway, the HIF1 signaling pathway, and the TNF signaling pathway may play key roles in the treatment of CRF by FSG. The MTT method showed that FSG is not cytotoxic to uremic toxin-induced injured T84 cells. The results of immunofluorescence and WB indicate that compared with the control group, protein expressions level of ZO-1, claudin-1, and Nrf2 in T84 cells is decreased and protein expressions level of HO-1, MDA, and COX-2 is increased after urinary toxin treatment. Instead, compared with the model group, protein expressions level of ZO-1, claudin-1, and Nrf2 in T84 cells is increased and protein expressions level of HO-1, MDA, and COX-2 is decreased after FSG treatment. CONCLUSION: FSG had a protective effect on urinary toxin-induced intestinal epithelial barrier injury in chronic renal failure, and its mechanism may be related to the upregulation of Nrf2/HO-1 signal transduction and the inhibition of tissue oxidative stress and inflammatory responses. Screening CRF targets and identifying the corresponding FSG components by network pharmacological methods is a practical strategy to explain the mechanism of FSG in improving gastrointestinal dysfunction in CRF.

Efficacy of Chinese Herbal Injections for the Treatment of Primary Nephrotic Syndrome: A Bayesian Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Considering the adverse reactions and side effects of immunosuppressive and cytotoxic drugs for the treatment of Primary Nephrotic Syndrome (PNS) and the extensive exploration of Chinese herbal injections (CHIs), systematic evaluation of the efficacy of different CHIs in the treatment of PNS is a key imperative. In this study, we performed a network meta-analysis to investigate the efficacy of CHIs in the treatment of PNS. METHODS: A systematic literature review including studies published from the establishment of each database to May 28, 2020, was conducted in PubMed, the Cochrane Library, Embase, Web of Science, the Chinese Biological Medicine Literature Service System (CBM), the China National Knowledge Infrastructure (CNKI) database, the Chinese Scientific Journal Database (VIP), and the Wanfang Database (WF).Two evaluators independently screened the literature, extracted data and the Cochrane Reviewer's Handbook 5.1 method was used to evaluate the quality of included studies. The differences in efficacy of different CHIs were compared and ranked using Stata 16.0 software. Surface under the cumulative ranking curve (SUCRA) probability values were applied to rank the examined treatments. Clustering analysis was performed to compare the effects of CHIs between two different outcomes. RESULTS: A total of 41 eligible randomized controlled trials involving 2879 patients and nine CHIs were included. Nine CHIs were Xiangdan injection (XDI), Huangqi injection (HQI), Shenkang injection (SKI), Danshen injection (DSI), Yinxingdamo injection (YXI), Dengzhanhuasu injection (DZI), Danhong injection (DHI), Shuxuetong injection (SXI), Chuanxiongqin injection (CXI). The results of the network meta-analysis showed that: with Western medical (WM) treatment as a co-intervention, in terms of improving the total clinical effectiveness and serum albumin level, DHI was the most likely to be the best choice for treatment (SUCRA = 82.2%); YXI had the highest probability of being the best option in terms of reducing 24-h urinary protein excretion (SUCRA = 97.8%); in cholesterol-lowering comparisons, the SUCRA value allows for the most likely to be the best treatment is DZI (SUCRA = 84.5%). SXI was the most effective CHIs in terms of lowering serum triglycerides (SUCRA = 85.6%), whereas on the reducing fibrinogen side, the efficacy of CXI was significant (SUCRA = 67.6%). The result cluster analysis indicated that YXI and DHI were the best interventions with respect to total clinical effectiveness, 24-h urinary protein excretion and serum albumin. CONCLUSIONS: CHIs were found to be superior to WM alone in the treatment of PNS and may be beneficial for patients with PNS. WM+YXI and WM+DHI had the potential to be the best CHI with respect to the total clinical effectiveness, 24-h urinary protein excretion and serum albumin. However, more well-designed randomized controlled trials are still warranted.