Terminalia Chebula provides protection against dual modes of necroptotic and apoptotic cell death upon death receptor ligation

Abstract

Death receptor (DR) ligation elicits two different modes of cell death (necroptosis and apoptosis) depending on the cellular context. By screening a plant extract library from cells undergoing necroptosis or apoptosis, we identified a water extract of Terminalia chebula (WETC) as a novel and potent dual inhibitor of DR-mediated cell death. Investigation of the underlying mechanisms of its anti-necroptotic and anti-apoptotic action revealed that WETC or its constituents (e.g., gallic acid) protected against tumor necrosis factor-induced necroptosis via the suppression of TNF-induced ROS without affecting the upstream signaling events. Surprisingly, WETC also provided protection against DR-mediated apoptosis by inhibition of the caspase cascade. Furthermore, it activated the autophagy pathway via suppression of mTOR. Of the WETC constituents, punicalagin and geraniin appeared to possess the most potent anti-apoptotic and autophagy activation effect. Importantly, blockage of autophagy with pharmacological inhibitors or genetic silencing of Atg5 selectively abolished the anti-apoptotic function of WETC. These results suggest that WETC protects against dual modes of cell death upon DR ligation. Therefore, WETC might serve as a potential treatment for diseases characterized by aberrantly sensitized apoptotic or non-apoptotic signaling cascades.

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

“…However, few studies have investigated the influence of phenolic compounds on necroptosis. Recently, the protective effect of certain phenolic-containing extract against necroptosis was explored 44 . In contrast, gallic acid proved its efficiency in the induction of necroptosis-dependent death in the activating HSC and was considered as a new therapeutic strategy for the avoidance of hepatic fibrosis 45 .…”

A systems pharmacology approach to identify the autophagy-inducing effects of Traditional Persian medicinal plants

“…It is being known as the “king of medicines” in Tibet 144 , Terminalia chebula Retz. contains several natural products, such as punicalagin and geraniin, which have shown the ability to induce autophagy 92 , 144 . In regard to Coriandrum sativum L. (coriander), Cocos nucifera L. (Coconut), and Cichorium intybus L. (Chicory), the direct evidence on their inducing effect on autophagy is scarce.…”

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“…Odor Based: Anthrones, flavonoids, and coumarins are centered on tricyclic ketones Table 5 131 . Geraniin is the chemical constituent of TCF that offered significant antioxidant activity 132 indicating either the quantity/potency. Biosynthesis of the terpenophenols, the Cannabinoid from marijuana 133 is from the substrate geranyl pyro/diphosphate (Vijaya refers to both cannabis and TCFs) Table 5.…”