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 CCl4-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 CCl4. Thus, the synergistic functions of VVF1 polyphenols could be a promising new anti-hepatotoxic agent for targeting both necroptotic and profibrotic mediators.
Highlights
Human is subjected from his surrounding to various hepatotoxins, which aggravates his liver
Necroptosis is a pathophysiological process called programmed necrosis and combines the features of both necrosis and apoptosis-dependent inflammatory cell death. 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]
The results found that VVF1, which represents the highest yield, had the greatest phenolic content compared to VVF2 and VVF3
Summary
Human is subjected from his surrounding to various hepatotoxins, which aggravates his liver. 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) 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). The current study evaluated the targeting ability of these extracted polyphenols to CCl4-induced necroptotic and pro-fibrotic mediators, which had not been previously published These mediators (including, pro-oxidants, pro-inflammatory, pro-necroptotic MLKL protein, TGF-β and collagen type I alpha 1 chain (COL1A1) have been studied here because of their critical role in liver damage. After the most effective isolated fraction was highlighted by the in vitro study, it was studied in vivo to provide more convincing evidence of its effectiveness
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