Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice

Zhang, Wen-xuan; He, Ben; Ying, Wantao; Qiao, Jianfeng; Peng, Zhenyu

doi:10.1016/j.lfs.2018.11.055

Cited by 110 publications

(89 citation statements)

References 39 publications

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“…Abnormally activated mTOR appears to be an important driver of both autophagy and apoptosis, as autophagy is closely related to the alteration of apoptosis [41]. Similarly, melatonin significantly improved cardiac function, decreased CK-MB levels, and inhibited cardiomyocyte apoptosis, while inhibition of SIRT1 using EX527 abolished melatonin's cardioprotection during sepsis [42]. Generally, SIRT1 inhibition attenuated the protective effects of Dex against MI/R injury.…”

Section: Discussionmentioning

confidence: 98%

Dexmedetomidine postconditioning suppresses myocardial ischemia/reperfusion injury by activating the SIRT1/mTOR axis

Zhang

Wang

et al. 2020

Bioscience Reports

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Myocardial ischemia/reperfusion (MI/R) triggers a complicated chain of inflammatory reactions. Dexmedetomidine (Dex) has been reported to be important in myocardial disorders. We evaluated the role of Dex in MI/R injury via the silent information regulator factor 2-related enzyme 1 (SIRT1)/mammalian target of rapamycin (mTOR) signaling pathway. First, Dex was immediately injected into rat models of MI/R injury during reperfusion. After Evans Blue-triphenyl tetrazolium chloride (TTC) and Hematoxylin–Eosin (H-E) staining, MI/R injury was observed. The extracted serum and myocardial tissues were used to detect oxidative stress and the inflammatory response. Western blot analysis was performed to evaluate MI/R autophagy and the levels of proteins associated with the SIRT1/mTOR axis. The effects of the combination of Dex and SIRT1 inhibitor EX527 on MI/R injury and autophagy were evaluated. Finally, the mechanism of Dex was tested, and autophagy levels and the levels of proteins associated with the SIRT1/mTOR signaling pathway were assessed in MI/R rats. The results of the present study suggested that Dex relieved MI/R injury, reduced cardiomyocyte apoptosis, oxidative stress and inflammatory reactions, up-regulated the SIRT1/mTOR axis and decreased overautophagy in MI/R rats. SIRT1 inhibitor EX527 attenuated the protective effects of Dex. Our study demonstrated that Dex alleviated MI/R injury by activating the SIRT1/mTOR axis. This investigation may offer new insight into the treatment of MI/R injury.

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Section: Discussionmentioning

confidence: 98%

Dexmedetomidine postconditioning suppresses myocardial ischemia/reperfusion injury by activating the SIRT1/mTOR axis

Zhang

Wang

et al. 2020

Bioscience Reports

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“…Melatonin has been shown to have beneficial effects in the treatment of sepsis and inflammation (22, 23, 30, 43, 44). Treatment with melatonin contributed to the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) pathway, which are essential components of inflammasomes (45).…”

Section: Discussionmentioning

confidence: 99%

“…Treatment with melatonin contributed to the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) pathway, which are essential components of inflammasomes (45). Moreover, melatonin regulates apoptosis and autophagy in tissue, further contributing to the protection against sepsis (22). The apoptosis, inflammation, and tissue damage in CLP mice are mediated by polymicrobial infection (46).…”

Section: Discussionmentioning

confidence: 99%

“…Melatonin induces an anti-inflammatory response and an anti-oxidant effect, which decreases the production of pro-inflammatory cytokines and the release of nitric oxide (NO) (20, 21, 24). The anti-inflammatory properties of melatonin offer therapeutic protection in animal sepsis models, such as lipopolysaccharide (LPS)-induced septic shock in mice (22, 25, 26), peritonitis-induced sepsis in rats (20, 21), and cecal ligation puncture (CLP)-induced polymicrobial sepsis model (27–29). Moreover, melatonin also shows anti-apoptotic effects by inhibiting inflammasome and mitochondrial dysfunction in polymicrobial sepsis models (30, 31).…”

Section: Introductionmentioning

confidence: 99%

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Protective Effect of Melatonin Against Polymicrobial Sepsis Is Mediated by the Anti-bacterial Effect of Neutrophils

Zhang

Kwak

et al. 2019

Front. Immunol.

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Sepsis is an infection- or toxin-mediated systemic inflammatory syndrome. Previous studies have shown that melatonin, the primary hormone produced by the pineal gland, attenuates the effect of polymicrobial infection-mediated septic shock in animals. However, the mechanism of the anti-septic effect of melatonin during polymicrobial infection has not been well-studied. In this study, we investigated how melatonin protects mice from polymicrobial sepsis. Melatonin treatment inhibited peripheral tissue inflammation and tissue damage in a cecal ligation puncture (CLP)-induced polymicrobial sepsis model, consequently reducing the mortality of the mice. We found that macrophages and neutrophils expressed melatonin receptors. Upon depletion of neutrophils, melatonin-induced protection against polymicrobial infection failed in the mice, but melatonin treatment in macrophage-depleted mice attenuated the mice mortality resulting from polymicrobial sepsis. Moreover, melatonin treatment promoted the development of the neutrophil extracellular trap (NET), which contributed to anti-bacterial activity during polymicrobial infection, whereas the phagocytic activities of neutrophils were inhibited by melatonin. The data from this study support previously unexplained antiseptic effects of melatonin during a polymicrobial infection and could be potentially useful for human patients with sepsis.

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“…Thus, therapeutic approaches should aim at regulating and subsiding the neuroinflammation as well as the accumulation of oxidative stress via stimulating the antioxidant enzymes. Melatonin acts as an endogenous potent antioxidant, free radical scavenger, and a regulator of endogenous antioxidant enzymes in various pathological and disease conditions (Huang et al, 2015;Yu et al, 2019;Zhang et al, 2019). Melatonin has been associated with the activation of various antioxidant systems and thus helps in maintaining a homeostatic environment in the brain.…”

Section: A B Cmentioning

confidence: 99%

A Potent Antioxidant Endogenous Neurohormone Melatonin, Rescued MCAO by Attenuating Oxidative Stress-Associated Neuroinflammation

Alattar²,

Tan³

et al. 2020

Front. Pharmacol.

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Ischemic stroke is an acute neurological syndrome either due to permanent or temporary obstruction of blood. Such obstruction immediately triggers abrupt pathological cascading processes, which collectively lead to neuronal cell death. Oxidative stress and neuroinflammation in ischemic stroke are critical regulating events that ultimately lead to neuronal death. Complicated interplay exists between the two processes which occur through several stages. Most often, oxidative stress precedes the inflammatory mechanisms and includes several interconnected cascades that underlie the ischemic stroke pathology. In continuation of the previously published data, here, we further ruled out the protective role of melatonin in focal cerebral ischemic injury model. Administration of 5 mg/kg dose of melatonin 30 min prior to ischemia reduced brain infarction associated with sequentially rescued neuronal apoptosis. Furthermore, melatonin attenuated neuroinflammatory markers and reactive oxygen species (ROS), induced by ischemic stroke, via halting the key players of mitogen stress family (p38/JNK). Besides, melatonin modulated the endogenously produced antioxidant enzyme, thioredoxin (Trx) pathway. These broader therapeutic efficacies of melatonin suggest that melatonin could be further investigated for its diverse therapeutic actions with multiple targets in recovering, preventing and halting the detrimental outcomes of MCAO, such as elevated oxidative stress, neuroinflammation, and neurodegeneration.

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Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice

Cited by 110 publications

References 39 publications

Dexmedetomidine postconditioning suppresses myocardial ischemia/reperfusion injury by activating the SIRT1/mTOR axis

Dexmedetomidine postconditioning suppresses myocardial ischemia/reperfusion injury by activating the SIRT1/mTOR axis

Protective Effect of Melatonin Against Polymicrobial Sepsis Is Mediated by the Anti-bacterial Effect of Neutrophils

A Potent Antioxidant Endogenous Neurohormone Melatonin, Rescued MCAO by Attenuating Oxidative Stress-Associated Neuroinflammation

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