Vitis vinifera polyphenols from seedless black fruit act synergistically to suppress hepatotoxicity by targeting necroptosis and pro-fibrotic mediators

Abstract

Human is subjected from his surrounding to various hepatotoxins, which aggravates his liver. nowadays, natural polyphenols have attracted great interest in health improvement, especially liver health. the present research, therefore, assessed the hepatotherapeutic potency of the isolated polyphenols (VVF1) from seedless (pulp and skin) black Vitis vinifera (VV) against CCl 4 -induced hepatotoxicity in vitro and in vivo. Further, VVF1 was fractionated into resveratrol-enriched (VVF2) and phenolics-enriched (VVF3) fractions to study (in vitro) the possible synergism of their coexistence. The highest content of phenolics in VVF1 displayed in vitro synergistic antioxidant and anti-hepatotoxic activities comparing to VVF2, VVF3, and silymarin (SM, reference drug). More importantly, it exhibited multiple in vivo regulatory functions via diminishing oxidative stress and inflammation, which in turn decreased necroptosis and pro-fibrotic mediators (mixed lineage kinase domain-like protein (MLKL), collagen type I alpha 1 chain (COL1A1), and transforming growth factor (TGF)-β1). In addition to these novel findings, VVF1 had higher anti-hepatotoxic potency than that of SM in most of the studied parameters. The histopathological analysis confirmed the improving role of VVF1 in the serious hepatic damage induced by ccl 4 . Thus, the synergistic functions of VVF1 polyphenols could be a promising new anti-hepatotoxic agent for targeting both necroptotic and profibrotic mediators.The liver is the largest organ of the body and the main defense organ against environmental and metabolic toxins. Administration of certain medicinal, chemical, or industrial agents can induce hepatotoxicity. Due to the conversion of these hepatotoxins into reactive metabolites by the hepatic cytochrome P450 (CYP) metabolizing enzymes 1 . Carbon tetrachloride (CCl 4 ) is a well-known hepatotoxin that caused liver cell damage by inducing hepatic oxidative stress, inflammation, and necroptosis 2,3 . Necroptosis is a pathophysiological process called programmed necrosis and combines the features of both necrosis and apoptosis-dependent inflammatory cell death. Hence, it is a highly regulated process involving specific molecules (e.g., pro-necroptotic mixed lineage kinase domain-like protein (MLKL) and at the same time associated with a membrane integrity defect 4 . All of these damage effects lead to hepatic steatosis, fibrosis, cirrhosis, and may develop into hepatocellular carcinoma if the hepatotoxin persist 2,3 .Medicinal plants have crucial roles in health care and improving multiple human disorders. Grape (Vitis vinifera, VV) is one of the medicinal plants used in folk medicine and belongs to the Vitaceae family with a woody climbing vine and large leaves 5 . It can grow all over the world "non-climacteric fruit" and is considered to be the most broadly planted fruit crop and the most consumed fruits worldwide. The VV is rich in sugars, organic open Scientific RepoRtS | (2020) 10:2452 | https://doi.org/10.1038/s41598-020-59489-z www.nature.com/scienti...

The synergistic hepatoprotective potential of Beta vulgaris juice and 2,3- dimercaptosuccinic acid in lead-intoxicated rats via improving the hepatic oxidative and inflammatory stress

“…The obtained synergism between DMSA and BVJ may be related to their antioxidant properties. As several studies have shown synergistic antioxidant and anti-inflammatory impacts after the combination of different antioxidant extracts or drug and extract [18,34,53]. However, the exact mechanism for this synergism needs further investigations and analyses.…”

WITHDRAWN: The Amelioration Role of Acacia Senegal on the Systemic Oxidative Stress and Necroinflammation Induced by Carbon Tetrachloride in Rats

“…This can be due to the liver's metabolism, which is caused by CYP2E1. This catabolic process resulted in the formation of CCl 3 *, which converted to the additional reactive trichloromethyl peroxyl radical (CCl 3 OO*), following its combination with oxygen 2,24 . Formation of these radicals will augment the ROS level in the liver and induce a disruption of its redox state and in turn, cause the occurrence of the oxidative stress, leading to hepatic damage.…”

“…The presence of these compounds explains the current outcomes about the antioxidant activities of AS in vitro through scavenging the ABTS, NO, and lipid peroxide radicals. Hence, the antioxidant activities of the phenolic acids and reducing sugars were reported extensively in the previous researches 2,19,20 .…”

“…Oxidative stress exhibits an asymmetry between the exposure to the reactive oxygen species (ROS) and the ability of the physiological system to directly scavenge the reactive intermediates or adjust the outcome's damage 1 . Disturbances in the normal redox state of cells can produce lethal results by building ROS that damage all cell parts, involving lipids, proteins, and DNA 1,2 . ROS performs a crucial role in the pathogenesis of various human organs, including liver, heart, lung, spleen, and kidney 3,4 .…”

“…CCl 4 is incorporated with its quick break by cytochrome P450 (CYP2E1) in liver cells, providing trichloromethyl radicals (CCl 3 *) driving lipid peroxidation and subsequent membrane impairment 4,9 . In addition to this, CCl 4 caused the activation of hepatic Kupffer cells that generate in ammatory mediators and ROS, yielding an ending in hepatic parenchymal cells' distress 2,10 . CCl 4 can also induce similar damage to other organs such as kidney, lung, and spleen 11 .…”