Unveiling the Renoprotective Mechanisms of Schisandrin B in Ischemia-Reperfusion Injury Through Transcriptomic and Pharmacological Analysis.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-09-21 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S489458

Changhong Xu, Yun Deng, Jiangwei Man, Huabin Wang, Tuanjie Che, Liyun Ding, Li Yang

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Abstract

Objective: This study investigates the targets, pathways, and mechanisms of Schisandrin B (Sch B) in alleviating renal ischemia-reperfusion injury (RIRI) using RNA sequencing and network pharmacology.

Methods: The effects of Sch B on RIRI were assessed using hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining, along with measurements of blood creatinine and urea nitrogen (BUN). Differential gene expression in mouse models treated with RIRI and Sch B+RIRI was analyzed through RNA-Seq. Key processes, targets, and pathways were examined using network pharmacology techniques. The antioxidant capacity of Sch B was evaluated using assays for reactive oxygen species (ROS), mitochondrial superoxide, and JC-1 membrane potential. Molecular docking was employed to verify the interactions between key targets and Sch B, and the expression of these targets and pathway was confirmed using qRT-PCR, Western blot, and immunofluorescence.

Results: Sch B pre-treatment significantly reduced renal pathological damage, inflammatory response, and apoptosis in a mouse RIRI model. Pathological damage scores dropped from 4.33 ± 0.33 in the I/R group to 2.17 ± 0.17 and 1.5 ± 0.22 in Sch B-treated groups (p < 0.01). Creatinine and BUN levels were also reduced (from 144.6 ± 21.05 µmol/L and 53.51 ± 2.34 mg/dL to 50.44 ± 5.61 µmol/L and 17.18 ± 0.96 mg/dL, p < 0.05). Transcriptomic analysis identified four key targets (AKT1, ALB, ACE, CCL5) and the PI3K/AKT pathway. Experimental validation confirmed Sch B modulated these targets, reducing apoptosis and oxidative stress, and enhancing renal recovery.

Conclusion: Sch B reduces oxidative stress, inflammation, and apoptosis by modulating key targets such as AKT1, ALB, ACE, and CCL5, while activating the PI3K/AKT pathway, leading to improved renal recovery in RIRI.

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通过转录组学和药理学分析揭示五味子素 B 在缺血再灌注损伤中的肾脏保护机制

研究目的本研究采用 RNA 测序和网络药理学方法研究五味子素 B（Sch B）缓解肾缺血再灌注损伤（RIRI）的靶点、途径和机制：方法：使用苏木精-伊红（HE）和周期性酸-希夫（PAS）染色法以及血肌酐和尿素氮（BUN）测量法评估 Sch B 对 RIRI 的影响。通过 RNA-Seq 分析了接受 RIRI 和 Sch B+RIRI 治疗的小鼠模型的差异基因表达。利用网络药理学技术对关键过程、靶点和通路进行了研究。使用活性氧（ROS）、线粒体超氧化物和 JC-1 膜电位检测法评估了 Sch B 的抗氧化能力。利用分子对接验证了关键靶点与 Sch B 之间的相互作用，并通过 qRT-PCR、Western 印迹和免疫荧光证实了这些靶点和通路的表达：结果：在小鼠 RIRI 模型中，Sch B 预处理明显减轻了肾脏病理损伤、炎症反应和细胞凋亡。病理损伤评分从 I/R 组的 4.33 ± 0.33 降至 Sch B 治疗组的 2.17 ± 0.17 和 1.5 ± 0.22（p < 0.01）。肌酐和 BUN 水平也有所降低（从 144.6 ± 21.05 µmol/L 和 53.51 ± 2.34 mg/dL 降至 50.44 ± 5.61 µmol/L 和 17.18 ± 0.96 mg/dL，p < 0.05）。转录组分析确定了四个关键靶点（AKT1、ALB、ACE、CCL5）和 PI3K/AKT 通路。实验验证证实，Sch B 可调节这些靶点，减少细胞凋亡和氧化应激，促进肾功能恢复：Sch B通过调节AKT1、ALB、ACE和CCL5等关键靶点，减少了氧化应激、炎症和细胞凋亡，同时激活了PI3K/AKT通路，从而改善了RIRI患者的肾功能恢复。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.