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    • An Herbal Formulation “shenshuaifu Granule” Alleviates Cisplatin-Induced Nephrotoxicity by Suppressing Inflammation and Apoptosis Through Inhibition of the TLR4/MyD88/NF-κB Pathway

    Xiaoming Jin,Riming He,Jiahui Liu,Yuzhi Wang,Zhongtang Li,Beibei Jiang,Jiandong Lu,Shudong Yang

    Journal of Ethnopharmacology（2023）SCI 2区SCI 1区

    Guangzhou Univ Chinese Med | Nanjing Univ Chinese Med

    Cited 2|Views28
    Abstract
    Ethnopharmacological relevance: Shenshuaifu Granule (SSF) is an in-hospital preparation approved by the Guangdong Food and Drug Administration of China. It has been clinically used against kidney diseases for more than 20 years with a definite curative effect. Aim of the study: Cisplatin (CDDP) is a first-line chemotherapeutic drug in clinical practice, primarily excreted by the kidney with nephrotoxicity as a common side effect. Approximately 5-20% of cancer patients develop acute kidney injury (AKI) after chemotherapy; however, prevention and control strategies are currently unavailable. Therefore, it is important to identify safe and effective drugs that can prevent the nephrotoxicity of CDDP. SSF is an herbal formulation with 8 herbs, and has been used to protect the kidney in China. Nonetheless, its mech-anism in relieving CDDP nephrotoxicity remains unclear. Therefore, this work attempt to prove that SSF can alleviate CDDP nephrotoxicity. We also explore its mechanism. Materials and methods: First, Thin Layer Chromatography (TLC) of a few herbs in SSF were performed for quality control. Several open-access databases were used to identify the active ingredients of SSF, their corresponding targets, and CDDP-induced nephrotoxicity targets. We performed Protein-Protein Interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Next, the results of network pharmacology were validated using CDDP-induced nephrotoxicity mouse models. Renal function in the mice was assessed by analyzing the levels of serum creatinine (Scr) and blood urea nitrogen (BUN). On the other hand, renal damage was assessed by determining the level of tubular injury and apoptotic cells using Periodic acid-Schiff (PAS) staining and Terminal Dutp Nick End-Labeling (TUNEL) staining, respectively. The expression of inflammatory and apoptotic-related targets including IL-1??, IL-6, TNF-??, Cox-2, Bax, Bcl-2, Cleaved-caspase 3, and Cleaved-caspase 9 was determined using Western Blot (WB) and Immunohistochemistry (IHC). Furthermore, WB was used to analyze the expression of proteins associated with the TLR4/MyD88/NF-xB pathway in the kidneys of mice with CDDP-induced nephrotoxicity. Finally, molecular docking simulations were performed to evaluate the binding abilities between major active ingredients of SSF and core targets. Result: Through network pharmacology, we identified 127 active ingredients of SSF and their corresponding 134 targets. Additional screening identified 14 active ingredients and 17 targets for further analysis. In biological process (BP), the targets were enriched in inflammation and apoptosis, among others. In KEGG terms, they were enriched in apoptosis and NF-xB pathways. Animal experiments revealed that SSF significantly reduced the levels of Scr and BUN and prevented renal tubular damage in mice treated with CDDP. In addition, SSF inhibited inflammation and apoptosis by targeting the TLR4/MyD88/NF-xB pathway. Molecular docking revealed good binding capacities of active ingredients and core targets.
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    Cisplatin-induced nephrotoxicity,A herbal formulation,Inflammation,Apoptosis,The TLR4,MyD88,NF-xB pathway
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    【要点】：本研究发现中药制剂“肾衰复颗粒”（SSF）能通过抑制TLR4/MyD88/NF-κB通路缓解顺铂（CDDP）诱导的肾毒性，减少炎症和细胞凋亡。
    

    【方法】：研究采用网络药理学结合实验验证的方法，首先通过数据库分析确定SSF中的活性成分及其作用靶点，并通过蛋白质-蛋白质相互作用（PPI）、基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析探索其作用机制。
    

    【实验】：实验在CDDP诱导的肾毒性小鼠模型上进行，通过检测血清肌酐（Scr）和血尿素氮（BUN）水平评估小鼠肾功能，通过PAS染色和TUNEL染色评估肾损伤程度，通过Western Blot（WB）和免疫组化（IHC）检测炎症和凋亡相关指标，并通过分子对接模拟评价SSF主要活性成分与核心靶点的结合能力。结果显示SSF能显著降低Scr和BUN水平，防止肾小管损伤，并通过作用于TLR4/MyD88/NF-κB通路抑制炎症和凋亡。