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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.
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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.
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PURPOSE: Hirudin, a polypeptide structure containing 65 amino acids, is a potent natural thrombin inhibitor with anticoagulant property extracted from Hirudo medicinalis. It has been reported to have anti-inflammatory and antifibrotic property. Here we explored the renoprotective effect of hirudin on unilateral ureteral obstruction (UUO) induced renal interstitial fibrosis (RIF). METHODS: Rats were randomly divided into five groups: sham group, UUO alone group, and three UUO + hirudin-treatment groups (10, 20, or 40 IU/kg/d, for 14 continuous days). At the end of the experiment period, animals were sacrificed. Pathologic changes in renal specimens were observed using hematoxylin and eosin (HE) staining and Masson staining. The expressions of collagen III (Col III), fibronectin (FN), α-smooth muscle actin (α-SMA), protease-activated receptor 1 (PAR-1), and proteins in the TGF-ß1/Smad and NF-κB pathways in renal tissues were examined by immunohistochemistry and/or Western blotting. RESULTS: HE and Masson staining showed that hirudin-treated UUO rats had lower extent of renal injury and deposition of extracellular matrix (ECM) in renal interstitium than those in the UUO group. The results of immunohistochemistry and WB indicated decreased protein expressions of Col III, FN, α-SMA, PAR-1, and inflammatory markers such as tumor necrosis factor-α and interleukin-6 after hirudin treatment. Furthermore, hirudin reduced the expressions of transforming growth factor ß1 (TGF-ß1), phosphorylated-Smad2, and phosphorylated-Smad3 in the UUO model. In parallel, we found inhibited nuclear factor-κB (NF-κB) signaling after hirudin treatment, with downregulated protein expressions of P65, phosphorylated-P65, and phosphorylated-iκBα and increased iκBα. CONCLUSION: Hirudin improves kidney injury and suppresses inflammatory response and ECM accumulation in UUO rats; its underlying mechanism may be associated with the inhibition of TGF-ß1/Smad and NF-κB signaling.