Water extract from Herpetospermum pedunculosum attenuates oxidative stress and ferroptosis induced by acetaminophen via regulating Nrf2 and NF-κB pathways

Jintao Li; Qiuxia Lu; Meihao Peng; Jiaqing Liao; Bowen Zhang; Di Yang; Peng Huang; Yixi Yang; Qi Zhao; Bo Han; Jian Li

doi:10.1016/j.jep.2022.116069

Water extract from Herpetospermum pedunculosum attenuates oxidative stress and ferroptosis induced by acetaminophen via regulating Nrf2 and NF-κB pathways

J Ethnopharmacol. 2023 Apr 6:305:116069. doi: 10.1016/j.jep.2022.116069. Epub 2022 Dec 24.

Authors

Jintao Li¹, Qiuxia Lu², Meihao Peng¹, Jiaqing Liao¹, Bowen Zhang², Di Yang², Peng Huang³, Yixi Yang², Qi Zhao², Bo Han⁴, Jian Li⁵

Affiliations

¹ Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Pharmacy, Chengdu University, Chengdu, 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China.
² Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China.
³ Tibet Rhodiola Pharmaceutical Holding Company, Lhasa, Tibet, 850000, China.
⁴ State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. Electronic address: hanbo@cdutcm.edu.cn.
⁵ Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China; School of Basic Medical Sciences, Chengdu University, Chengdu, 610106, China; Institute of Cancer Biology and Drug Discovery, Chengdu University, Chengdu, 610106, China. Electronic address: lijian01@cdu.edu.cn.

PMID: 36572326
DOI: 10.1016/j.jep.2022.116069

Abstract

Ethnopharmacological relevance: The seeds of Herpetospermum pedunculosum seeds is a traditional Tibetan medicine possessing hepatoprotective effect, but their protective effect on APAP-induced liver injury has not yet been explored.

Aim of the study: This study aimed at exploring the protective effect and mechanism of the water extract from the seeds of Herpetospermum pedunculosum (HPWE) on APAP-induced liver injury in vitro and in vivo.

Materials and methods: In vitro and in vivo models of liver injury were established by APAP treatment of BRL-3A cells or mice. The effect and mechanism of action of HPWE were explored by using cell viability assay, ELISA, immunofluorescence assay, RT-qPCR, histological observation and immunohistochemistry staining, western blotting and high-content imaging system.

Results: In vitro experiments showed that HPWE treatment significantly promoted the cell viability, decreased ALT/AST level, and inhibited the ROS accumulation induced by APAP. Furthermore, HPWE and Fer-1 alleviated erastin-induced cell ferroptosis, upregulated GPX4 and SLC7A11 expression, and reduced lipid peroxides production. Further study showed that APAP could also downregulate the expression of GPX4 and SLC7A11, causing cell ferroptosis, and HPWE and Fer-1 counteracted this process. Our in vivo experiments showed that pretreatment with HPWE in APAP-treated mice significantly alleviated the serum ALT/AST level, decreased necrotic cells and inflammatory cell infiltration, upregulated the expression of GPX4 and SLC7A11. Further, it was demonstrated that HPWE treatment downregulated Nrf2 and its downstream target genes, i.e. HO-1 and NQO1 expression at the mRNA and protein levels. HPWE treatment also inhibited the activation of NF-κB p65 and downregulated its target genes, i.e. TNF-α and IL-1β, expression.

Conclusion: The present study showed that HPWE could relieve oxidative stress and ferroptosis via activating Nrf2 signaling pathway and inhibiting NF-κB mediated pathway.

Keywords: Acetaminophen; Ferroptosis; Herpetospermum pedunculosum seeds; Nrf2; Oxidative stress.

MeSH terms

Acetaminophen / toxicity
Animals
Chemical and Drug Induced Liver Injury* / drug therapy
Chemical and Drug Induced Liver Injury* / metabolism
Chemical and Drug Induced Liver Injury* / prevention & control
Chemical and Drug Induced Liver Injury, Chronic* / metabolism
Ferroptosis*
Liver
Mice
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism
NF-kappa B / metabolism
Oxidative Stress

Substances

Acetaminophen
NF-E2-Related Factor 2
NF-kappa B
Nrf1 protein, mouse