Background: Hirudin has been widely used in the treatment of antifibrosis. Previous studies have shown that hirudin can effectively improve the clinical remission rate of chronic kidney disease. However, the mechanism of its renal protection has not been systematically investigated.Methods: In this study, the reliability of UUO-induced renal interstitial fibrosis was evaluated by histopathological verification. High-throughput transcriptome sequencing was used to elucidate the molecular mechanism of hirudin, differentially expressed mRNAs were identified, and their functions were analyzed by GO analysis and GSEA. In addition, the RNA-seq results were validated by in vitro and vivo experiments.Results: We found 322 identical differential expressed genes (IDEs) in the UUO hirudin-treated group compared with the sham group. Functional enrichment analysis indicated that cellular amino acid metabolic processes were the most obvious enrichment pathways in biological processes. In terms of molecular functional enrichment analysis, IDEs were mainly enriched in coenzyme binding, pyridoxal phosphate binding and other pathways. In addition, microbody is the most obvious pathway for cellular components. A total of 115 signaling pathways were enriched, and AMPK, JAK-STAT, and PI3K-Akt signaling pathways were the important signaling pathways enriched. We found that PI3K, p-Akt, and mTOR expression were significantly reduced by hirudin treatment. In particular, our results showed that hirudin could induce a decrease in the expression of autophagy-related proteins such as P62, LC3, Beclin-1 in TGF-β1-induced NRK-52E cells.Conclusion: Our results suggest that hirudin may protect the kidney by ameliorating renal autophagy impairment through modulating the PI3K/Akt pathway.
For Chronic Kidney Disease (CKD), the study of microRNA as a biomarker has become an exciting area, so we carried out a meta-analysis to investigate the potential diagnostic values of miRNAs in CKD. We searched Pubmed, Cochrane Library, Embase, and Web of science databases to identify relevant publications published from the establishment of the database to April 30, 2021. We included a total of 26 articles containing 56 studies. There were 4,098 patients with CKD and 2,450 patients without CKD. We found that the overall sensitivity and specificity of miRNAs in CKD diagnosis were 0.86 (95% CI: 0.83–0.89) and 0.79 (95% CI: 0.75–0.83), respectively. In addition, we plotted the summary receiver operator characteristic (SROC) curve to assess diagnostic accuracy, with the area under the curve (AUC) of 0.90 (95% CI: 0.87–0.92). Subgroup analysis showed that sensitivity, specificity, and AUC of miRNAs in plasma and serum were 0.84, 0.78, 0.88; and 0.79, 0.76, 0.83, respectively, while miRNAs in urine were 0.89 for sensitivity, 0.82 for specificity, and 0.92 for AUC. Moreover, we found that the panel of microRNAs (miRNAs) could improve the pooled sensitivity (0.88, 0.81, and 0.91 for sensitivity, specificity, and AUC, respectively). We believe that miRNAs have great potential to become an effective diagnostic biomarker for CKD. Panels of miRNA have higher accuracy than single miRNAs. Additionally, miRNAs in both blood and urine have significant accuracy in the diagnosis of CKD; nevertheless, urine is superior.
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%);
Fibrosis is a pathological manifestation of wound healing that replaces dead/damaged tissue with collagen-rich scar tissue to maintain homeostasis, and complications from fibrosis contribute to nearly half of all deaths in the industrialized world. Ageing is closely associated with a progressive decline in organ function, and the prevalence of tissue fibrosis dramatically increases with age. Despite the heavy clinical and economic burden of organ fibrosis as the population ages, to date, there is a paucity of therapeutic strategies that are specifically designed to slow fibrosis. Aryl hydrocarbon receptor (AhR) is an environment-sensing transcription factor that exacerbates aging phenotypes in different tissues that has been brought back into the spotlight again with economic development since AhR could interact with persistent organic pollutants derived from incomplete waste combustion. In addition, gut microbiota dysbiosis plays a pivotal role in the pathogenesis of numerous diseases, and microbiota-associated tryptophan metabolites are dedicated contributors to fibrogenesis by acting as AhR ligands. Therefore, a better understanding of the effects of tryptophan metabolites on fibrosis modulation through AhR may facilitate the exploitation of new therapeutic avenues for patients with organ fibrosis. In this review, we primarily focus on how tryptophan-derived metabolites are involved in renal fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis and cardiac fibrosis. Moreover, a series of ongoing clinical trials are highlighted.
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.
Background: Diabetic nephropathy (DN) is one of the common complications of diabetes, it can cause a disproportionate burden. Leeches are widely used to treat DN in China, and hirudin is the main component of leeches. However, its pharmacological mechanisms and molecular targets are unclear. This work aimed to explore new biomarkers of DN and reveal the mechanism of hirudin in DN. Methods: Expression microarray datas between kidney tissues of DN and control individuals were obtained from the GEO database, and differentially expressed genes were identified as DN-related targets using the robust rank aggregation analysis. The SEA, GeneCards and SwissTargetPrediction databases were used to predict targets of hirudin. A protein-protein interaction network of DN-hirudin was conducted by Cytoscape software. GO and KEGG pathway enrichment analyses were carried out to explore the involved pharmacological mechanism of hirudin in treatment of DN. And molecular docking was adopted to predict the hub targets of hirudin. Results: A total of 30 significant DEGs (16 up- and 14 down-regulated) were identified. ATF3, SLC22A8 and TGF-Β1 are likely as new biomarkers of DN. The 42 candidate targets were identifyed in PPI network. GO analysis revealed that these targets were enriched with ubiquitin protein ligase, transcription factor binding and nuclear transport. The KEGG pathways were enriched, including AGE-RAGE signaling pathway in diabetic complications, PI3K-Akt signaling pathway, Focal adhesion. The docking results showed that hirudin could easily dock with ITGA4, EGFR and ESR1. Conclusion: Our study demonstrates that hirudin is involved in DN therapy through a multi-targeted, multi-pathway approach. It provides a basis for further research on its mechanism of action.
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