Total alkaloids of Aconitum carmichaelii Debx alleviate cisplatin-induced acute renal injury by inhibiting inflammation and oxidative stress related to gut microbiota metabolism

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2024-10-09 DOI:10.1016/j.phymed.2024.156128

Xi Yang , Yijing Xin , Yanzhi Gu , Youlei Wang , Xingjiang Hu , Guanghui Ying , Qiao Zhang , Xuelin He

{"title":"Total alkaloids of Aconitum carmichaelii Debx alleviate cisplatin-induced acute renal injury by inhibiting inflammation and oxidative stress related to gut microbiota metabolism","authors":"Xi Yang , Yijing Xin , Yanzhi Gu , Youlei Wang , Xingjiang Hu , Guanghui Ying , Qiao Zhang , Xuelin He","doi":"10.1016/j.phymed.2024.156128","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Cisplatin-induced acute kidney injury (AKI) is a complex and serious clinical issue, representing a major cause of hospital-acquired AKI. Alkaloids are the main active constituents of <em>Aconitum carmichaelii</em> Debx, which exhibit protective effects in several kidney disease models and against other acute organ injuries. However, its activity and mechanism of action in AKI treatment remain unclear.</div></div><div><h3>Purpose</h3><div>This study aimed to elucidate the effect of <em>Aconitum carmichaelii</em> Debx (ACA) in a model of cisplain-induced AKI and comprehensively investigate its underlying mechanisms.</div></div><div><h3>Methods</h3><div>The major alkaloids in ACA were analyzed using high-performance liquid chromatography. Blood urea nitrogen (BUN) and serum creatine levels were measured using automated biochemical instruments. 16S rRNA sequencing, short-chain fatty acid (SCFA) analysis, fecal microbiota transplantation (FMT), non-targeted metabolomics, and transcriptomics were performed to systematically identify prospective biomarkers after ACA treatment. Anti-inflammatory and anti-oxidative stress activities were monitored using ELISA and western blotting.</div></div><div><h3>Results</h3><div>Four main compounds (fuziline, neoline, talatisamine, and songorine) were identified in ACA. ACA significantly alleviated cisplatin-induced AKI by reducing (BUN) and serum creatine levels and improving histopathological scores. Moreover, ACA balanced cisplatin-mediated confoundments in microbial composition and function, including decreasing the levels of <em>Escherichia-Shigella, Clostridium,</em> and <em>Ruminococcus</em>, as well as increasing <em>Ligilactobacillus, Anaerotruncus, Bacteroides</em> and <em>Desulfovibrio</em> levels, accompanied by uremic toxin reduction, and augmenting serum SCFAs. The FMT experiments further confirmed that ACA exerts anti-AKI effects by affecting gut microbiota. A multi-omics study has shown that ACA regulates glutathione and tryptophan metabolism and mediates pathways that trigger inflammatory responses. Finally, ACA reduced serum levels of inflammatory factors (IL-1β, IL-6, and TNF-α), restored enzymes of the antioxidative system (SOD and CAT) and GSH values, and decreased monoester diterpene alkaloid levels in the kidney by inhibiting the expression of NF-κB pathway-related proteins and increasing Nrf2/HO-1 pathway-related protein expression.</div></div><div><h3>Conclusion</h3><div>ACA protects against cisplatin-induced AKI through its anti-inflammatory and antioxidant functions, which may be associated with the restoration of gut microbiota metabolism. ACA is a potential drug for AKI and other forms of organ damage related to the disruption of the gut microbiota.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"135 ","pages":"Article 156128"},"PeriodicalIF":6.7000,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytomedicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0944711324007852","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Cisplatin-induced acute kidney injury (AKI) is a complex and serious clinical issue, representing a major cause of hospital-acquired AKI. Alkaloids are the main active constituents of Aconitum carmichaelii Debx, which exhibit protective effects in several kidney disease models and against other acute organ injuries. However, its activity and mechanism of action in AKI treatment remain unclear.

Purpose

This study aimed to elucidate the effect of Aconitum carmichaelii Debx (ACA) in a model of cisplain-induced AKI and comprehensively investigate its underlying mechanisms.

Methods

The major alkaloids in ACA were analyzed using high-performance liquid chromatography. Blood urea nitrogen (BUN) and serum creatine levels were measured using automated biochemical instruments. 16S rRNA sequencing, short-chain fatty acid (SCFA) analysis, fecal microbiota transplantation (FMT), non-targeted metabolomics, and transcriptomics were performed to systematically identify prospective biomarkers after ACA treatment. Anti-inflammatory and anti-oxidative stress activities were monitored using ELISA and western blotting.

Results

Four main compounds (fuziline, neoline, talatisamine, and songorine) were identified in ACA. ACA significantly alleviated cisplatin-induced AKI by reducing (BUN) and serum creatine levels and improving histopathological scores. Moreover, ACA balanced cisplatin-mediated confoundments in microbial composition and function, including decreasing the levels of Escherichia-Shigella, Clostridium, and Ruminococcus, as well as increasing Ligilactobacillus, Anaerotruncus, Bacteroides and Desulfovibrio levels, accompanied by uremic toxin reduction, and augmenting serum SCFAs. The FMT experiments further confirmed that ACA exerts anti-AKI effects by affecting gut microbiota. A multi-omics study has shown that ACA regulates glutathione and tryptophan metabolism and mediates pathways that trigger inflammatory responses. Finally, ACA reduced serum levels of inflammatory factors (IL-1β, IL-6, and TNF-α), restored enzymes of the antioxidative system (SOD and CAT) and GSH values, and decreased monoester diterpene alkaloid levels in the kidney by inhibiting the expression of NF-κB pathway-related proteins and increasing Nrf2/HO-1 pathway-related protein expression.

Conclusion

ACA protects against cisplatin-induced AKI through its anti-inflammatory and antioxidant functions, which may be associated with the restoration of gut microbiota metabolism. ACA is a potential drug for AKI and other forms of organ damage related to the disruption of the gut microbiota.

查看原文本刊更多论文

Aconitum carmichaelii Debx的总生物碱通过抑制与肠道微生物群代谢有关的炎症和氧化应激，减轻顺铂诱导的急性肾损伤。

背景：顺铂诱发的急性肾损伤（AKI）是一个复杂而严重的临床问题，是医院获得性急性肾损伤的主要原因。生物碱是 Aconitum carmichaelii Debx 的主要活性成分，在多种肾病模型和其他急性器官损伤中显示出保护作用。目的：本研究旨在阐明 Aconitum carmichaelii Debx（ACA）在顺铂诱导的 AKI 模型中的作用，并全面研究其潜在机制：方法：采用高效液相色谱法分析 Aconitum carmichaelii Debx（ACA）中的主要生物碱。方法：使用高效液相色谱法分析 ACA 中的主要生物碱，并使用自动生化仪器测量血尿素氮（BUN）和血清肌酸水平。通过16S rRNA测序、短链脂肪酸（SCFA）分析、粪便微生物群移植（FMT）、非靶向代谢组学和转录组学来系统鉴定ACA治疗后的前瞻性生物标记物。使用酶联免疫吸附试验（ELISA）和免疫印迹法监测抗炎和抗氧化应激活性：结果：在 ACA 中发现了四种主要化合物（fuziline、neoline、talatisamine 和 songorine）。ACA 通过降低（BUN）和血清肌酸水平以及改善组织病理学评分，明显缓解了顺铂诱导的 AKI。此外，ACA 还平衡了顺铂介导的微生物组成和功能混乱，包括降低了志贺氏菌、梭状芽孢杆菌和反刍球菌的水平，提高了半乳杆菌、厌氧菌、乳酸菌和脱硫弧菌的水平，同时降低了尿毒症毒素，增加了血清 SCFAs。FMT实验进一步证实，ACA通过影响肠道微生物群发挥抗AKI作用。一项多组学研究表明，ACA 可调节谷胱甘肽和色氨酸的代谢，并介导引发炎症反应的途径。最后，ACA 通过抑制 NF-κB 通路相关蛋白的表达和增加 Nrf2/HO-1 通路相关蛋白的表达，降低了血清中炎症因子（IL-1β、IL-6 和 TNF-α）的水平，恢复了抗氧化系统酶（SOD 和 CAT）和 GSH 值，并降低了肾脏中单酯二萜生物碱的水平：ACA通过抗炎和抗氧化功能保护顺铂诱导的AKI，这可能与肠道微生物群代谢的恢复有关。ACA 是治疗 AKI 和其他与肠道微生物群破坏有关的器官损伤的潜在药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.