Carnosic Acid, a Natural Diterpene, Attenuates Arsenic-Induced Hepatotoxicity via Reducing Oxidative Stress, MAPK Activation, and Apoptotic Cell Death Pathway.

Sonjit Das,Shovonlal Bhowmick,Niloy Bhattacharjee,Jatin Kalita,Swarnalata Joardar,Prasenjit Manna,Achintya Saha,Ritu Khanra,Vincenzo De Feo,Tarun K Dua,Supratim Ray,Saikat Dewanjee

doi:10.1155/2018/1421438

Abstract

The present studies have been executed to explore the protective mechanism of carnosic acid (CA) against NaAsO2-induced hepatic injury. CA exhibited a concentration dependent (1–4 μM) increase in cell viability against NaAsO2 (12 μM) in murine hepatocytes. NaAsO2 treatment significantly enhanced the ROS-mediated oxidative stress in the hepatic cells both in in vitro and in vivo systems. Significant activation of MAPK, NF-κB, p53, and intrinsic and extrinsic apoptotic signaling was observed in NaAsO2-exposed hepatic cells. CA could significantly counteract with redox stress and ROS-mediated signaling and thereby attenuated NaAsO2-mediated hepatotoxicity. NaAsO2 (10 mg/kg) treatment caused significant increment in the As bioaccumulation, cytosolic ATP level, DNA fragmentation, and oxidation in the liver of experimental mice (n = 6). The serum biochemical and haematological parameters were significantly altered in the NaAsO2-exposed mice (n = 6). Simultaneous treatment with CA (10 and 20 mg/kg) could significantly reinstate the NaAsO2-mediated toxicological effects in the liver. Molecular docking and dynamics predicted the possible interaction patterns and the stability of interactions between CA and signal proteins. ADME prediction anticipated the drug-likeness characteristics of CA. Hence, there would be an option to employ CA as a new therapeutic agent against As-mediated toxic manifestations in future.

Highlights

Arsenic (As) is a toxic metalloid, which raises much disquiet in the health standpoints for human and animals [1]
carnosic acid (CA), bovine serum albumin (BSA), Dulbecco’s modified Eagle’s medium (DMEM), fetal bovine serum (FBS), Bradford reagent, and collagenase type I were procured from Sigma-Aldrich Chemical Company, MO, USA
The present study demonstrated that NaAsO2 can elicit hepatocellular apoptosis by triggering NF-κB, mitogen-activated protein kinases (MAPK), p53, and intrinsic and extrinsic apoptotic signaling

Summary

Introduction

Arsenic (As) is a toxic metalloid, which raises much disquiet in the health standpoints for human and animals [1]. Industrial outcomes can cause the release and mobilization of As to soil, water, and air in various forms [2, 3]. Inorganic trivalent arsenicals (arsenites, AsO2−) are most potent toxicants [5]. Drinking water contaminated with arsenites is thought to be the major root of As calamity affecting >140 million people in ∼70 countries [4]. As is absorbed through the gastrointestinal tract and bioaccumulated into various organs [6]. It can enter into the body through the respiratory system and dermis [7]. Earlier investigations revealed that As reduces mitochondrial integrity, resulting in random formation of superoxide radical which subsequently potentiates a cascade of radical reactions and enhances the secondary generation of other

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