Multimodal modulation of hepatic ischemia/reperfusion-induced injury by phytochemical agents: A mechanistic evaluation of hepatoprotective potential and safety profiles

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Multimodal modulation of hepatic ischemia/reperfusion-induced injury by phytochemical agents: A mechanistic evaluation of hepatoprotective potential and safety profiles

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https://doi.org/10.1016/j.intimp.2024.112445

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Highlights

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  Ischemia reperfusion, linked to early/late graft rejection after liver transplant, liver failure after many liver surgeries.

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  Phytochemical agents exhibited potential protection against hepatic ischemia reperfusion injury.

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  Benefits of phytochemicals worked via normalization of anxious oxidative profile, apoptotic, and inflammatory markers.

Abstract

Background

Hepatic ischemia–reperfusion (I/R) injury is a clinically fundamental phenomenon that occurs through liver resection surgery, trauma, shock, and transplantation.

Aims of the review

This review article affords an expanded and comprehensive overview of various natural herbal ingredients that have demonstrated hepatoprotective effects against I/R injury through preclinical studies in animal models.

Materials and methods

For the objective of this investigation, an extensive examination was carried out utilizing diverse scientific databases involving PubMed, Google Scholar, Science Direct, Egyptian Knowledge Bank (EKB), and Research Gate. The investigation was conducted based on specific identifiable terms, such as hepatic ischemia/reperfusion injury, liver resection and transplantation, cytokines, inflammation, NF-kB, interleukins, herbs, plants, natural ingredients, phenolic extract, and aqueous extract.

Results

Bioactive ingredients derived from ginseng, curcumin, resveratrol, epigallocatechin gallate, quercetin, lycopene, punicalagin, crocin, celastrol, andrographolide, silymarin, and others and their effects on hepatic IRI were discussed. The specific mechanisms of action, signaling pathways, and clinical relevance for attenuation of liver enzymes, cytokine production, immune cell infiltration, oxidative damage, and cell death signaling in rodent studies are analyzed in depth. Their complex molecular actions involve modulation of pathways like TLR4, NF-κB, Nrf2, Bcl-2 family proteins, and others.

Conclusion

The natural ingredients have promising values in the protection and treatment of various chronic aggressive clinical conditions, and that need to be evaluated on humans by clinical studies.

Introduction

Ischemia-reperfusion (I/R) injury is distinguished by clinical tissue deterioration caused when blood supply is disrupted and later restored, initiating oxidative stress, inflammation, and cell death cascades. This phenomenon mainly occurs in several vascular pathologies such as, solid organ transplantation, stroke, myocardial infarction, surgical resection, and trauma prompting considerable research into protective strategies [1]. During liver surgery and transplantation, periods of vascular inflow occlusion followed by reperfusion are often necessary maneuvers to minimize blood loss. However, they subject the liver to I/R injury which leads to graft dysfunction or organ failure [2]. Specifically, the pathophysiology involves hypoxic injury from ischemia, followed by a surge of reactive oxygen species (ROS) upon reoxygenation that damages cellular components through lipids’ peroxidation, protein denaturation, and nucleic acid damage [1]. This also activates Kupffer cells and promotes infiltration of neutrophils and T-cells, releasing cytokines and further amplifying inflammation and injury [1].

Considerable research has focused on strategies to mitigate hepatic I/R damage given its clinical significance. Therapeutic hypothermia, ischemic preconditioning, pharmacological agents, and gene therapy approaches have shown promising results. Additionally, an emerging body of literature has revealed the cytoprotective impacts of natural herbal products against I/R injury through a multiplicity of mechanisms, presenting an attractive adjuvant therapy option. Natural compounds contain a diversity of phytochemicals which often work synergistically to exert therapeutic anti-inflammatory, antioxidant, and anti-apoptotic activities with less toxicity compared to synthetic drugs [3]. This article review provides a novel, comprehensive overview of the natural herbal ingredients studied for attenuating hepatic I/R injury through preclinical animal models. Their mechanisms of action, relevant signaling pathways, and prospects for clinical translation will be discussed in-depth.

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