Melatonin protects against focal cerebral ischemia-reperfusion injury in diabetic mice by ameliorating mitochondrial impairments: involvement of the Akt-SIRT3-SOD2 signaling pathway

Liu, Lian; Cao, Qian; Gao, Wenwei; Li, Bingyu; Xia, Zhongyuan; Zhao, Bo

doi:10.18632/aging.203137

Cited by 25 publications

(18 citation statements)

References 83 publications

(104 reference statements)

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“…Cytochrome c release and mitochondrial membrane disruption are intracellular events associated with apoptosis and often act as direct apoptotic drivers 42 . Our data suggest that PCC1 treatment enhanced cytochrome c release from mitochondria to the surrounding cytoplasmic space (Fig.…”

Section: Resultsmentioning

confidence: 99%

The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice

et al. 2021

Nat Metab

137

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Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction. In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate or prevent age-related pathologies.

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Section: Resultsmentioning

confidence: 99%

The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice

et al. 2021

Nat Metab

137

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“…Melatonin appears to increase the activity of antioxidant enzymes such as SOD and GPX, through Sirtuin (SIRT)-3 [ 175 ]. Resveratrol is a phytoalexin derived from grapes [ 176 ], likely acting via several mechanisms: the downregulation of NOX expression and activity, mitochondrial O 2 •− reduction [ 177 , 178 ], and increased PON1 activity ( Figure 4 A).…”

Section: Pharmacological Interventionsmentioning

confidence: 99%

Role of Oxidative Stress in the Pathogenesis of Atherothrombotic Diseases

Petrucci

Rizzi

Hatem³

et al. 2022

Antioxidants

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Oxidative stress is generated by the imbalance between reactive oxygen species (ROS) formation and antioxidant scavenger system’s activity. Increased ROS, such as superoxide anion, hydrogen peroxide, hydroxyl radical and peroxynitrite, likely contribute to the development and complications of atherosclerotic cardiovascular diseases (ASCVD). In genetically modified mouse models of atherosclerosis, the overexpression of ROS-generating enzymes and uncontrolled ROS formation appear to be associated with accelerated atherosclerosis. Conversely, the overexpression of ROS scavenger systems reduces or stabilizes atherosclerotic lesions, depending on the genetic background of the mouse model. In humans, higher levels of circulating biomarkers derived from the oxidation of lipids (8-epi-prostaglandin F2α, and malondialdehyde), as well as proteins (oxidized low-density lipoprotein, nitrotyrosine, protein carbonyls, advanced glycation end-products), are increased in conditions of high cardiovascular risk or overt ASCVD, and some oxidation biomarkers have been reported as independent predictors of ASCVD in large observational cohorts. In animal models, antioxidant supplementation with melatonin, resveratrol, Vitamin E, stevioside, acacetin and n-polyunsaturated fatty acids reduced ROS and attenuated atherosclerotic lesions. However, in humans, evidence from large, placebo-controlled, randomized trials or prospective studies failed to show any athero-protective effect of antioxidant supplementation with different compounds in different CV settings. However, the chronic consumption of diets known to be rich in antioxidant compounds (e.g., Mediterranean and high-fish diet), has shown to reduce ASCVD over decades. Future studies are needed to fill the gap between the data and targets derived from studies in animals and their pathogenetic and therapeutic significance in human ASCVD.

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“…Many studies have confirmed the ability of melatonin to reduce damage to key mitochondrial constituents including proteins of the ETC and the mitochondrial genome [65,168,169], which normally appears under conditions of high oxidative stress. Melatonin's ability to stimulate mitochondrial superoxide dismutase 2 (SOD2) follows its deacetylation signaled by upregulation of the major mitochondrial deacetylase, SIRT3 [168,170,171].…”

Section: Melatonin In Mitochondria: Relation To Oxidative Stress and ...mentioning

confidence: 99%

Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells

Reíter

Sharma

Rosales-Corral

et al. 2021

IJMS

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Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount synthesized by the pineal gland is less than 5% of the total. Melatonin produced in mitochondria influences glucose metabolism in all cells. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production, as acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic glycolysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology.

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Melatonin protects against focal cerebral ischemia-reperfusion injury in diabetic mice by ameliorating mitochondrial impairments: involvement of the Akt-SIRT3-SOD2 signaling pathway

Cited by 25 publications

References 83 publications

The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice

The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice

Role of Oxidative Stress in the Pathogenesis of Atherothrombotic Diseases

Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells

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