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      Yishen Xiezhuo formula ameliorates the development of cisplatin-induced acute kidney injury by attenuating renal tubular epithelial cell senescence

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          Abstract

          Background

          Although cisplatin (DDP) is an important clinical anti-tumor drug, its use is limited by its nephrotoxicity. How to avoid the renal injury incurred by platinum drugs and improve the clinical efficiency of platinum drugs use has become an urgent clinical problem. Previous studies have verified that Chinese medicine has definite effects on acute kidney injury (AKI). Yishen Xiezhuo formula (YSXZ) is a traditional Chinese medicine (TCM) compound which is an effective clinical drug for AKI, but its mechanism remains unclear.

          Methods

          In our research, an AKI model was induced by DDP in human renal tubular epithelial cell (HKC) lines in the in vitro study. The mechanism of the YSXZ on cell senescence was analyzed by Cell Counting Kit-8 (CCK-8), senescence-associated β-galactosidase (SA-β-Gal) staining, western blot, flow cytometry, and enzyme-linked immunosorbent assay (ELISA). Network pharmacology was used to analyze the role of YSXZ against AKI.

          Results

          Compared with the control group, the cells in the DDP intervention group were significantly senescent. Compared with DDP group, YSXZ decreased the number of SA-β-Gal-positive senescence cells, down regulated the expression of senescence-related proteins, reduced the release of senescence-related secreted phenotypic factors, and reversed the phenomenon of cell cycle S-phase arrest. Network pharmacology and experimental studies showed that the mitogen-activated protein kinase ( MAPK) signaling pathway played a central role.

          Conclusions

          Our present results suggested that YSXZ ameliorated the development of DDP-induced AKI by attenuating renal tubular epithelial cell (RTEC) senescence via alleviating the activation of MAPK pathway.

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          The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible

          Damian Szklarczyk, John Morris, Helen Cook … (2016)
          A system-wide understanding of cellular function requires knowledge of all functional interactions between the expressed proteins. The STRING database aims to collect and integrate this information, by consolidating known and predicted protein–protein association data for a large number of organisms. The associations in STRING include direct (physical) interactions, as well as indirect (functional) interactions, as long as both are specific and biologically meaningful. Apart from collecting and reassessing available experimental data on protein–protein interactions, and importing known pathways and protein complexes from curated databases, interaction predictions are derived from the following sources: (i) systematic co-expression analysis, (ii) detection of shared selective signals across genomes, (iii) automated text-mining of the scientific literature and (iv) computational transfer of interaction knowledge between organisms based on gene orthology. In the latest version 10.5 of STRING, the biggest changes are concerned with data dissemination: the web frontend has been completely redesigned to reduce dependency on outdated browser technologies, and the database can now also be queried from inside the popular Cytoscape software framework. Further improvements include automated background analysis of user inputs for functional enrichments, and streamlined download options. The STRING resource is available online, at http://string-db.org/.
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            TCMSP: a database of systems pharmacology for drug discovery from herbal medicines

            Jinlong Ru, Peng Li, Jinan Wang … (2014)
            Background Modern medicine often clashes with traditional medicine such as Chinese herbal medicine because of the little understanding of the underlying mechanisms of action of the herbs. In an effort to promote integration of both sides and to accelerate the drug discovery from herbal medicines, an efficient systems pharmacology platform that represents ideal information convergence of pharmacochemistry, ADME properties, drug-likeness, drug targets, associated diseases and interaction networks, are urgently needed. Description The traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) was built based on the framework of systems pharmacology for herbal medicines. It consists of all the 499 Chinese herbs registered in the Chinese pharmacopoeia with 29,384 ingredients, 3,311 targets and 837 associated diseases. Twelve important ADME-related properties like human oral bioavailability, half-life, drug-likeness, Caco-2 permeability, blood-brain barrier and Lipinski’s rule of five are provided for drug screening and evaluation. TCMSP also provides drug targets and diseases of each active compound, which can automatically establish the compound-target and target-disease networks that let users view and analyze the drug action mechanisms. It is designed to fuel the development of herbal medicines and to promote integration of modern medicine and traditional medicine for drug discovery and development. Conclusions The particular strengths of TCMSP are the composition of the large number of herbal entries, and the ability to identify drug-target networks and drug-disease networks, which will help revealing the mechanisms of action of Chinese herbs, uncovering the nature of TCM theory and developing new herb-oriented drugs. TCMSP is freely available at http://sm.nwsuaf.edu.cn/lsp/tcmsp.php.
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              Network pharmacology: the next paradigm in drug discovery.

              Andrew Hopkins (2008)
              The dominant paradigm in drug discovery is the concept of designing maximally selective ligands to act on individual drug targets. However, many effective drugs act via modulation of multiple proteins rather than single targets. Advances in systems biology are revealing a phenotypic robustness and a network structure that strongly suggests that exquisitely selective compounds, compared with multitarget drugs, may exhibit lower than desired clinical efficacy. This new appreciation of the role of polypharmacology has significant implications for tackling the two major sources of attrition in drug development--efficacy and toxicity. Integrating network biology and polypharmacology holds the promise of expanding the current opportunity space for druggable targets. However, the rational design of polypharmacology faces considerable challenges in the need for new methods to validate target combinations and optimize multiple structure-activity relationships while maintaining drug-like properties. Advances in these areas are creating the foundation of the next paradigm in drug discovery: network pharmacology.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Ann Transl Med
                Journal ID (iso-abbrev): Ann Transl Med
                Journal ID (publisher-id): ATM
                Title: Annals of Translational Medicine
                Publisher: AME Publishing Company
                ISSN (Print): 2305-5839
                ISSN (Electronic): 2305-5847
                Publication date (Print and electronic): December 2022
                Publication date (Print): December 2022
                Volume: 10
                Issue: 24
                Electronic Location Identifier: 1392
                Affiliations
                [1]deptDepartment of Nephrology, Integrated Hospital of Traditional Chinese Medicine , Southern Medical University , Guangzhou, China
                Author notes

                Contributions: (I) Conception and design: Q Zhang, X Nie; (II) Administrative support: J Qi, Q Luo; (III) Provision of study materials or patients: M Wu; (IV) Collection and assembly of data: L Zhang; (V) Data analysis and interpretation: Q Zhang, L Qin; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

                Correspondence to: Xiaoli Nie. Department of Nephrology, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China. Email: nxl117@ 123456163.com .
                Article
                Publisher ID: atm-10-24-1392
                DOI: 10.21037/atm-22-5415
                PMC ID: 9843381
                PubMed ID: 36660714
                SO-VID: c7f91325-95c1-430d-ae34-d2284220278b
                Copyright © 2022 Annals of Translational Medicine. All rights reserved.
                License:

                Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

                History
                Date received : 30 September 2022
                Date accepted : 20 December 2022
                Categories
                Subject: Original Article

                Keywords: yishen xiezhuo formula (ysxz),cisplatin (ddp),acute kidney injury (aki),cell senescence,network pharmacology
                Data availability:
                Keywords: yishen xiezhuo formula (ysxz), cisplatin (ddp), acute kidney injury (aki), cell senescence, network pharmacology

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