BI1 alleviates cardiac microvascular ischemia‐reperfusion injury via modifying mitochondrial fission and inhibiting XO/ROS/F‐actin pathways

Journal of Cellular Physiology, Journal Year: 2018, Volume and Issue: 234(4), P. 5056 - 5069

Published: Sept. 7, 2018

Abstract Pathogenesis of cardiac microvascular ischemia‐reperfusion (IR) injury is associated with excessive mitochondrial fission. However, the upstream mediator fission remains obscure. Bax inhibitor 1 (BI1) linked to multiple functions, and there have been no studies investigating contribution BI1 on in setting IR injury. This study was undertaken establish action reperfusion figure out whether sustained endothelial viability via inhibiting Our observation indicated that downregulated reperfused hearts overexpression attenuated Mechanistically, elevated levels xanthine oxidase (XO), an effect followed by increased reactive oxygen species (ROS) production. Subsequently, oxidative stress mediated F‐actin depolymerization latter promoted Aberrant caused dysfunction ultimately activated apoptosis cells. By comparison, repressed XO expression thus neutralized ROS, interrupting F‐actin‐mediated The inhibitory viability, reversed barrier integrity, inflammation response, maintained microcirculation patency. Altogether, we conclude essential maintaining homeostasis alleviating Deregulated XO/ROS/F‐actin pathways plays a causative role development

Language: Английский

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Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury

Journal of Pineal Research, Journal Year: 2019, Volume and Issue: 67(1)

Published: March 23, 2019

Accumulated pieces of evidence have proved the beneficial effects melatonin on myocardial ischemia/reperfusion (MI/R) injury, and these were largely dependent membrane receptor activation. In humans other mammals, there are two types receptors, including 1 (MT1, 1a or MTNR1A) (MT2, 1b MTNR1B) subtypes. However, which mediates melatonin-conferred cardioprotection remains unclear. this study, we employed both loss-of-function gain-of-function approaches to reveal answer. Mice (wild-type; MT1 MT2 silencing by in vivo minicircle vector; those overexpressing AAV9 vector) exposed MI/R injury. Both present wild-type myocardium. MT2, but not MT1, was essentially upregulated after Melatonin administration significantly reduced injury improved cardiac function Mechanistically, treatment suppressed MI/R-initiated oxidative stress nitrative stress, alleviated endoplasmic reticulum mitochondrial inhibited apoptosis. These actions absent MT2-silenced heart, subtype. Furthermore, AAV9-mediated cardiomyocyte-specific overexpression mitigated dysfunction, accompanied significant amelioration dysfunction. protected primary cardiomyocytes against hypoxia/reoxygenation via MT2/Notch1/Hes1/RORα signaling. Our study presents first direct that subtype, is a novel endogenous protective Medications specifically targeting may hold promise fighting ischemic heart disease.

Language: Английский

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Melatonin alleviates cognition impairment by antagonizing brain insulin resistance in aged rats fed a high‐fat diet

Journal of Pineal Research, Journal Year: 2019, Volume and Issue: 67(2)

Published: May 3, 2019

Abstract Brain insulin resistance, induced by neuroinflammation and oxidative stress, contributes to neurodegeneration, that is, processes are associated with Aβ accumulation TAU hyperphosphorylation. Here, we tested the effect of chronic administration melatonin (MLT) on brain resistance cognition deficits caused a high‐fat diet (HFD) in aged rats. Results showed MLT supplementation attenuated peripheral lowered hippocampal stress levels. Activated microglia astrocytes levels TNF‐α HFD‐fed rats were reduced treatment. Melatonin also prevented HFD‐induced increases beta‐amyloid (Aβ) phosphorylation hippocampus. In addition, impairments signaling elicited long‐term HFD restored treatment, as confirmed ex vivo stimulation. Importantly, reversed cognitive decline measured water maze test, normalized LTP CREB activity BDNF well cholinergic neuronal Collectively, these findings indicate may exhibit substantial protective effects cognition, via restoration signaling.

Language: Английский

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The Crosstalk between Melatonin and Sex Steroid Hormones

Neuroendocrinology, Journal Year: 2021, Volume and Issue: 112(2), P. 115 - 129

Published: March 26, 2021

Melatonin, an indolamine mainly released from the pineal gland, is associated with many biological functions, namely, modulation of circadian and seasonal rhythms, sleep inducer, regulator energy metabolism, antioxidant, anticarcinogenic. Although several pieces evidence also recognize influence melatonin in reproductive physiology, crosstalk between sex hormones not clear. Here, we review effects differences circulating levels update current knowledge on link melatonin. Furthermore, explore gonadal steroidogenesis hormonal control females. The literature shows that despite strong impact profiles melatonin, reports are still considerably ambiguous, these may arise factors, like use contraceptive pills, status, deprivation. there has been inconclusive debate about characteristics reciprocal relationship hormones. In this regard, for role brought by research affects multiple transduction pathways modulate Sertoli cell physiology consequently spermatogenesis, estrogen progesterone production. From outcome our research, it possible to conclude understanding correlation crucial correction complications occurring during pregnancy, preeclampsia, climacteric symptoms.

Language: Английский

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RAB7 activity is required for the regulation of mitophagy in oocyte meiosis and oocyte quality control during ovarian aging

Autophagy, Journal Year: 2021, Volume and Issue: 18(3), P. 643 - 660

Published: July 7, 2021

There is increasing evidence that mitophagy, a specialized form of autophagy to degrade and clear long-lived or damaged mitochondria, impaired in aging age-related disease. Previous study has demonstrated the obesity-exposed oocytes accumulate transmit mitochondria due an inability activate mitophagy. However, it remains unknown whether mitophagy functions oocyte what's regulatory mechanism aging. In study, when fully grown were treated with CCCP, uncoupling agent induce we found activation PRKN-mediated pathway accompanied blockage meiosis at metaphase I stage. Our result then its association decreased activity RAB7 all observed defects CCCP could be effectively rescued by microinjection mRNA encoding active RAB7Q67L treatment activator ML098. Further indicated PRKN protein level as rate-limiting factor facilitate degradation GEF (guanine nucleotide exchange factor) complex CCZ1-MON1 through ubiquitin-proteasome system. GV collected during ovarian aging, increase PINK1 proteins significant decrease which resulted mitophagosome formation accumulation mitochondria. The retardation female fertility was improved after vivo Thus, required maintain balance between chromosome stability good candidate ameliorate deterioration quality.Abbreviations: ATG9: related 9A; ATP: adenosine triphosphate; CALCOCO2/NDP52: calcium binding coiled-coil domain 2; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CCZ1: CCZ1 vacuolar trafficking biogenesis associated; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GAPs: GTPase-activating proteins; GEF: guanine factor; GV: germinal vesicle; GVBD: vesicle breakdown; LAMP1: lysosomal-associated membrane 1; MI: stage meiosis; MII: II Mito: MitoTracker; mtDNA: mitochondrial DNA; MON1: MON1 homolog, secretory OPTN: optineurin; PINK1: PTEN induced putative kinase PRKN: parkin RBR E3 ubiquitin ligase; RAB7: RAB7, member RAS oncogene family; ROS: reactive oxygen species; TEM: transmission electron microscopy; TOMM20/TOM20: translocase outer 20; TUBB: tubulin, beta; UB: ubiquitin.

Language: Английский

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