RETRACTED: Melatonin attenuates TNF‐α‐mediated hepatocytes damage via inhibiting mitochondrial stress and activating the Akt‐Sirt3 signaling pathway

Abstract

The role of mitochondrial dysfunction and its molecular mechanism in inflammationinduced acute liver failure (ALF) remain unknown. Despite the numerous studies performed to date, very few therapies are available for inflammation-induced ALF.Therefore, our study is aimed to explore the regulatory effects of mitochondrial stress and the Akt-Sirt3 pathway on the development of TNF-α-induced hepatocyte death and assess the therapeutic effects of melatonin on the damaged liver. Our results exhibited that TNF-α treatment induced hepatocyte damage in vitro; the effect of which was dose-dependently inhibited by melatonin. At the molecular level, TNF-α-treated hepatocytes expressed lower levels of Sirt3 and subsequently exhibited mitochondrial stress. Interestingly, melatonin treatment improved mitochondrial bioenergetics, reduced mitochondrial oxidative stress, reversed mitochondrial dynamics, and repressed mitochondrial apoptosis by reversing the decrease in Sirt3 expression after TNF-α challenge. In addition, we found that melatoninregulated Sirt3 expression in a manner dependent on the Akt pathway. Blockade of the Akt pathway abolished the protective exerted by melatonin on mitochondria and hepatocyte under TNF-α treatment. In conclusion, TNF-α promotes hepatocyte apoptosis by inducing mitochondrial stress. However, melatonin significantly increases the activity of the Akt/Sirt3 axis and consequently maintains mitochondrial homeostasis, restoring hepatocyte viability in an inflammatory environment. Thus, the information compiled here might provide important perspectives for the use of melatonin in the clinic for preventive and therapeutic applications in patients with ALF based on its anti-inflammatory and mitochondria-protective effects. K E Y W O R D Sacute liver failure, Akt pathway, hepatocyte death, melatonin, mitochondria, Sirt3

Melatonin Attenuates Sepsis-Induced Small-Intestine Injury by Upregulating SIRT3-Mediated Oxidative-Stress Inhibition, Mitochondrial Protection, and Autophagy Induction

“…Melatonin targets mitochondria and functions as an apex antioxidant ( 45 ), and besides being taken up by cells from the circulation, melatonin might be produced in mitochondria ( 45 ). Melatonin can attenuate TNF-α-mediated hepatocyte damage through SIRT3-mediated mitochondrial-stress inhibition ( 18 ), and counteracts mitochondrial dysfunction in the skeletal muscle of septic mice ( 46 ). Furthermore, SIRT3-mediated mitophagy protects tumor cells against apoptosis under hypoxia ( 46 ).…”

“…It has been revealed that melatonin treatment elevates the expression and activity of SIRT1 in various animal/cell sepsis models, and alleviates sepsis-induced brain and liver injury, as well as cardiac dysfunction (10,(13)(14)(15)(16). Moreover, melatonin can activate SIRT3 to reduce oxidative stress (17) and inflammation (18), induce autophagy (18), and preserve mitochondrial function (19,20). Its effect on sepsis is also reportedly related to the regulation of other SIRTs, including SIRT2 (21,22), SIRT4 (23), and SIRT6 (24).…”

Mechanism of glycyrrhizin on ferroptosis during acute liver failure by inhibiting oxidative stress

“…LPS or TNF-α alone cause a lower specific damage to hepatocytes (21). Previous studies have shown that D-GalN can be used as a sensitizer in LPS-induced liver injury; specifically, uridine triphosphate is depleted by the galactose pathway, which inhibits protein synthesis, resulting in ROS-mediated liver damage (22–24). Therefore, LPS can be used in combination with D-GalN to induce ALF in animal models (25,26) and TNF-α combined with D-GalN can be used to create an L02 cell injury model (27); these models have been widely used to explore and develop new liver protection agents for the treatment of ALF.…”

Mechanistic insight into the gut microbiome and its interaction with host immunity and inflammation

“…It can damage the integrity, increase the permeability of the intestinal barrier, and promote the secrete of proinflammatory cytokine to amplify the inflammatory response ( Nguyen et al., 2018 ). TNF-α combines with TNF receptor 1, which is a membrane receptor, and leads to apoptosis by activating the TNF receptor 2 associated death domain protein, Fas-associated death domain protein (FADD), FADD like IL-1β converting enzyme, caspase-3, and caspase-9 ( Song et al., 2019 ). Furthermore, intestinal flora can convert tryptophan to indole-3-formaldehyde which can alleviate the mouse dermatitis through suppressing the cytokine secretion of Th2 cells ( Gostner et al, 2016 ).…”