Diosmin Alleviates Doxorubicin-Induced Liver Injury via Modulation of Oxidative Stress-Mediated Hepatic Inflammation and Apoptosis via NfkB and MAPK Pathway: A Preclinical Study.

Abdullah F Alasmari,Adel Alghamdi,Youssef Sari,Fawaz Alasmari,Faleh Alqahtani,Nemat Ali,Mohammed Alswayyed,Ibrahim A Al-Alallah,Hassan M Hakami,Sami I Alzarea,Meshal K Alyousef,Metab Alharbi

doi:10.3390/antiox10121998

Abstract

Hepatotoxicity caused by chemotherapeutic drugs (e.g., doxorubicin) is of critical concern in cancer therapy. This study focused on investigating the modulatory effects of diosmin against doxorubicin-induced hepatotoxicity in Male Wistar rats. Male Wistar rats were randomly divided into four groups: Group I was served as control, Group II was treated with doxorubicin (20 mg/kg, intraperitoneal, i.p.), Group III was treated with a combination of doxorubicin and low-dose diosmin (100 mg/kg orally), and Group IV was treated with a combination of doxorubicin and high-dose diosmin (200 mg/kg orally) supplementation. A single dose of doxorubicin (i.p.) caused hepatic impairment, as shown by increases in the concentrations of serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Doxorubicin produced histological abnormalities in the liver. In addition, a single injection of doxorubicin increased lipid peroxidation and reduced glutathione, catalase, and superoxide dismutase (SOD) levels. Importantly, pre-treatment with diosmin restored hepatic antioxidant factors and serum enzymatic activities and reduced the inflammatory and apoptotic-mediated proteins and genes. These findings demonstrate that diosmin has a protective effect against doxorubicin-induced hepatotoxicity.

Highlights

We revealed that a single injection of DOX dose induced hepatic injury, as evidenced by the increase in serum ALT, AST, and alkaline phosphatase (ALP) concentrations (Figure 1A–C)
Our findings demonstrated that gene expressions of superoxide dismutase (SOD) and HO-1 were downregulated in Dox-exposed animals as compared to control group, which was consistent with earlier reports [48,49]
We showed that activation of p-p38 mitogen-activated protein kinases (MAPKs) is a potent enhancer of reactive oxygen species (ROS)

Summary

Introduction

Doxorubicin (DOX) is an anticancer agent and is considered an effective anthracycline antibiotic. It has been effective in both solid and hematological cancers [1,2]. DOX could negatively affect non-cancer cells; its clinical practice is limited. In the context of its mechanical action, DOX has more capabilities to target cancer cell growth and inhibit free radical production and DNA intercalation, as shown in in-vitro and in-vivo systems [3,4]. As shown by redox signaling on mitochondria and drastic generation of superoxide radicals and ROS, causing oxidative stress [5,6]. The liver has been studied as a preeminent metabolic organ for DOX and has been considered the Antioxidants 2021, 10, 1998.

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Discussion

Conclusion