Pre-ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings.
TL;DR: There is strong evidence that pre‐ischemia melatonin administration significantly protects against cerebral IR injury through inhibiting ER stress‐dependent autophagy, especially among the population with high risk of cerebral ischemic stroke.
Abstract: Melatonin has demonstrated a potential protective effect in central nervous system. Thus, it is interesting to determine whether pre-ischemia melatonin administration could protect against cerebral ischemia/reperfusion (IR)-related injury and the underlying molecular mechanisms. In this study, we revealed that IR injury significantly activated endoplasmic reticulum (ER) stress and autophagy in a middle cerebral artery occlusion mouse model. Pre-ischemia melatonin treatment was able to attenuate IR-induced ER stress and autophagy. In addition, with tandem RFP-GFP-LC3 adeno-associated virus, we demonstrated pre-ischemic melatonin significantly alleviated IR-induced autophagic flux. Furthermore, we showed that IR induced neuronal apoptosis through ER stress related signalings. Moreover, IR-induced autophagy was significantly blocked by ER stress inhibitor (4-PBA), as well as ER-related signaling inhibitors (PERK inhibitor, GSK; IRE1 inhibitor, 3,5-dibromosalicylaldehyde). Finally, we revealed that melatonin significantly alleviated cerebral infarction, brain edema, neuronal apoptosis, and neurological deficiency, which were remarkably abolished by tunicamycin (ER stress activator) and rapamycin (autophagy activator), respectively. In summary, our study provides strong evidence that pre-ischemia melatonin administration significantly protects against cerebral IR injury through inhibiting ER stress-dependent autophagy. Our findings shed light on the novel preventive and therapeutic strategy of daily administration of melatonin, especially among the population with high risk of cerebral ischemic stroke.
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TL;DR: A crosstalk between autophagy, necroptosis, and apoptosis that contribute to ischemic stroke is proposed and the interactions between Autophagy and oxidative stress, mitochondrial dysfunction and endoplasmic reticulum stress are discussed.
259 citations
TL;DR: The determined factors that control the changeover switch between ER stress‐mediated autophagy and ER‐phagy are largely obscure, which may be associated with the type of cells and the extent of stimulation.
Abstract: Endoplasmic reticulum (ER) stress, a common cellular stress response, is closely related to the activation of autophagy that is an important and evolutionarily conserved mechanism for maintaining cellular homeostasis. Autophagy induced by ER stress mainly includes the ER stress-mediated autophagy and ER-phagy. The ER stress-mediated autophagy is characterized by the generation of autophagosomes that include worn-out proteins, protein aggregates, and damaged organelles. While the autophagosomes of ER-phagy selectively include ER membranes, and the double membranes also derive, at least in part, from the ER. The signaling pathways of IRE1α, PERK, ATF6, and Ca2+ are necessary for the activation of ER stress-mediated autophagy, while the receptor-mediated selective ER-phagy degrades the ER is Atg40/FAM134B. The ER stress-mediated autophagy and ER-phagy not only have differences, but also have connections. The activation of ER-phagy requires the core autophagy machinery, and the ER-phagy may be a branch of ER stress-mediated autophagy that selectively targets the ER. However, the determined factors that control the changeover switch between ER stress-mediated autophagy and ER-phagy are largely obscure, which may be associated with the type of cells and the extent of stimulation. This review summarized the crosstalk between ER stress-mediated autophagy and ER-phagy and their signaling networks. Additionally, we discussed the possible factors that influence the type of autophagy induced by ER stress.
224 citations
Cites background from "Pre-ischemia melatonin treatment al..."
...Feng et al. (2017) established the mouse model of the transient middle cerebral artery occlusion (MCAO) and observed that the expression of ER stress markers increased, along with the increased of autophagy markers (ratio of LC3II/I and Beclin-1), which represented the activation of ER stress and…...
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TL;DR: It is confirmed that OPA1‐related mitochondrial fusion/mitophagy is actually modulated by melatonin in the setting of cardiac ischemia‐reperfusion (I/R) injury and manipulation of the AMPK‐OPA1‐mitochondrial fusion/Mitophagy axis via melatonin may be a novel therapeutic approach to reduce cardiac I/R injury.
Abstract: Optic atrophy 1 (OPA1)-related mitochondrial fusion and mitophagy are vital to sustain mitochondrial homeostasis under stress conditions. However, no study has confirmed whether OPA1-related mitochondrial fusion/mitophagy is activated by melatonin and, consequently, attenuates cardiomyocyte death and mitochondrial stress in the setting of cardiac ischemia-reperfusion (I/R) injury. Our results indicated that OPA1, mitochondrial fusion, and mitophagy were significantly repressed by I/R injury, accompanied by infarction area expansion, heart dysfunction, myocardial inflammation, and cardiomyocyte oxidative stress. However, melatonin treatment maintained myocardial function and cardiomyocyte viability, and these effects were highly dependent on OPA1-related mitochondrial fusion/mitophagy. At the molecular level, OPA1-related mitochondrial fusion/mitophagy, which was normalized by melatonin, substantially rectified the excessive mitochondrial fission, promoted mitochondria energy metabolism, sustained mitochondrial function, and blocked cardiomyocyte caspase-9-involved mitochondrial apoptosis. However, genetic approaches with a cardiac-specific knockout of OPA1 abolished the beneficial effects of melatonin on cardiomyocyte survival and mitochondrial homeostasis in vivo and in vitro. Furthermore, we demonstrated that melatonin affected OPA1 stabilization via the AMPK signaling pathway and that blockade of AMPK repressed OPA1 expression and compromised the cardioprotective action of melatonin. Overall, our results confirm that OPA1-related mitochondrial fusion/mitophagy is actually modulated by melatonin in the setting of cardiac I/R injury. Moreover, manipulation of the AMPK-OPA1-mitochondrial fusion/mitophagy axis via melatonin may be a novel therapeutic approach to reduce cardiac I/R injury.
212 citations
TL;DR: The data show that high-fat-mediated liver damage is associated with Sirt3 downregulation, which is followed by ERK-CREB pathway inactivation and Bnip3-mediated inhibition of mitophagy, causing hepatocytes to undergo mitochondria-dependent cell death.
Abstract: Increased mitochondrial damage is related to the progression of a diet-induced nonalcoholic fatty liver disease. The aim of our study is to investigate the role of Sirtuin 3 (Sirt3) in treating nonalcoholic fatty liver disease with a focus on mitophagy and the ERK-CREB pathway. Our data indicated that Sirt3 was downregulated in liver tissue in response to chronic HFD treatment. Interestingly, re-introduction of Sirt3 protected hepatic function, attenuated liver fibrosis, alleviated the inflammatory response, and prevented hepatocyte apoptosis. Molecular investigations demonstrated that lipotoxicity was associated with an increase in mitochondrial apoptosis as evidenced by reduced mitochondrial potential, augmented ROS production, increased cyt-c leakage into the nucleus, and activated caspase-9 apoptotic signalling. Additionally, Sirt3 overexpression protected hepatocytes against mitochondrial apoptosis via promoting Bnip3-required mitophagy. Functional studies showed that Sirt3 reversed Bnip3 expression and mitophagy activity via the ERK-CREB signalling pathway. Blockade of the ERK-CREB axis repressed the promotive effects of Sirt3 on Bnip3 activation and mitophagy augmentation, finally negating the anti-apoptotic influences of Sirt3 on hepatocytes in the setting of high-fat-stress. Collectively, our data show that high-fat-mediated liver damage is associated with Sirt3 downregulation, which is followed by ERK-CREB pathway inactivation and Bnip3-mediated inhibition of mitophagy, causing hepatocytes to undergo mitochondria-dependent cell death. Based on this, strategies for enhancing Sirt3 activity and activating the ERK-CREB-Bnip3-mitophagy pathways could be used to treat nonalcoholic fatty liver disease.
211 citations
Cites background from "Pre-ischemia melatonin treatment al..."
...Nonalcoholic fatty liver disease (NAFLD) encompasses a broad spectrum, including simple steatosis, nonalcoholic steatohepatitis (NASH) with fibrosis, cirrhosis, and probably hepatocellular carcinoma [1,2]....
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...S population is obese, and 75% of these obese individuals have NAFLD [3,4]....
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...Pathogenically, increased free fatty acid levels have been associated with the development and progression of NAFLD [5]....
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...Approximately 30% of the U.S population is obese, and 75% of these obese individuals have NAFLD [3,4]....
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TL;DR: The research progress related to IR injury is summarized, the possible mechanisms responsible for the myocardial benefits of melatonin against reperfusion injury are listed and the prospect of the use ofmelatonin in clinical application is discussed.
Abstract: Acute myocardial infarction (MI) is a major cause of mortality and disability worldwide. In patients with MI, the treatment option for reducing acute myocardial ischemic injury and limiting MI size is timely and effective myocardial reperfusion using either thombolytic therapy or primary percutaneous coronary intervention (PCI). However, the procedure of reperfusion itself induces cardiomyocyte death, known as myocardial reperfusion injury, for which there is still no effective therapy. Recent evidence has depicted a promising role of melatonin, which possesses powerful antioxidative and anti-inflammatory properties, in the prevention of ischemia-reperfusion (IR) injury and the protection against cardiomyocyte death. A number of reports explored the mechanism of action behind melatonin-induced beneficial effects against myocardial IR injury. In this review, we summarize the research progress related to IR injury and discuss the unique actions of melatonin as a protective agent. Furthermore, the possible mechanisms responsible for the myocardial benefits of melatonin against reperfusion injury are listed with the prospect of the use of melatonin in clinical application.
198 citations
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TL;DR: In this paper, the authors evaluated rapid endovascular treatment in addition to standard care in patients with acute ischemic stroke with a small infarct core, a proximal intracranial arterial occlusion, and moderate-to-good collateral circulation.
Abstract: Among patients with a proximal vessel occlusion in the anterior circulation, 60 to 80% of patients die within 90 days after stroke onset or do not regain functional independence despite alteplase treatment. We evaluated rapid endovascular treatment in addition to standard care in patients with acute ischemic stroke with a small infarct core, a proximal intracranial arterial occlusion, and moderate-to-good collateral circulation. Methods We randomly assigned participants to receive standard care (control group) or standard care plus endovascular treatment with the use of available thrombectomy devices (intervention group). Patients with a proximal intracranial occlusion in the anterior circulation were included up to 12 hours after symptom onset. Patients with a large infarct core or poor collateral circulation on computed tomography (CT) and CT angiography were excluded. Workflow times were measured against predetermined targets. The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. A proportional odds model was used to calculate the common odds ratio as a measure of the likelihood that the intervention would lead to lower scores on the modified Rankin scale than would control care (shift analysis). Results The trial was stopped early because of efficacy. At 22 centers worldwide, 316 participants were enrolled, of whom 238 received intravenous alteplase (120 in the intervention group and 118 in the control group). In the intervention group, the median time from study CT of the head to first reperfusion was 84 minutes. The rate of functional independence (90-day modified Rankin score of 0 to 2) was increased with the intervention (53.0%, vs. 29.3% in the control group; P<0.001). The primary outcome favored the intervention (common odds ratio, 2.6; 95% confidence interval, 1.7 to 3.8; P<0.001), and the intervention was associated with reduced mortality (10.4%, vs. 19.0% in the control group; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 3.6% of participants in intervention group and 2.7% of participants in control group (P = 0.75). Conclusions Among patients with acute ischemic stroke with a proximal vessel occlusion, a small infarct core, and moderate-to-good collateral circulation, rapid endovascular treatment improved functional outcomes and reduced mortality. (Funded by Covidien and others; ESCAPE ClinicalTrials.gov number, NCT01778335.)
4,739 citations
TL;DR: In this article, the authors examined the incidence and size of infarction after occlusion of different portions of the rat middle cerebral artery (MCA) in order to define the reliability and predictability of this model of brain ischemia.
Abstract: We have examined the incidence and size of infarction after occlusion of different portions of the rat middle cerebral artery (MCA) in order to define the reliability and predictability of this model of brain ischemia. We developed a neurologic examination and have correlated changes in neurologic status with the size and location of areas of infarction. The MCA was surgically occluded at different sites in six groups of normal rats. After 24 hr, rats were evaluated for the extent of neurologic deficits and graded as having severe, moderate, or no deficit using a new examination developed for this model. After rats were sacrificed the incidence of infarction was determined at histologic examination. In a subset of rats, the size of the area of infarction was measured as a percent of the area of a standard coronal section. Focal (1-2 mm) occlusion of the MCA at its origin, at the olfactory tract, or lateral to the inferior cerebral vein produced infarction in 13%, 67%, and 0% of rats, respectively (N = 38) and produced variable neurologic deficits. However, more extensive (3 or 6 mm) occlusion of the MCA beginning proximal to the olfactory tract--thus isolating lenticulostriate end-arteries from the proximal and distal supply--produced infarctions of uniform size, location, and with severe neurologic deficit (Grade 2) in 100% of rats (N = 17). Neurologic deficit correlated significantly with the size of the infarcted area (Grade 2, N = 17, 28 +/- 5% infarction; Grade 1, N = 5, 19 +/- 5%; Grade 0, N = 3, 10 +/- 2%; p less than 0.05). We have characterized precise anatomical sites of the MCA that when surgically occluded reliably produce uniform cerebral infarction in rats, and have developed a neurologic grading system that can be used to evaluate the effects of cerebral ischemia rapidly and accurately. The model will be useful for experimental assessment of new therapies for irreversible cerebral ischemia.
2,490 citations
TL;DR: In this article, the lumenal domains of transmembrane protein kinases (PERK and IRE1) were found to be functionally interchangeable in mediating an ER stress response and that in unstressed cells, both L1 and L2 domains formed a stable complex with the ER chaperone BiP.
Abstract: PERK and IRE1 are type-I transmembrane protein kinases that reside in the endoplasmic reticulum (ER) and transmit stress signals in response to perturbation of protein folding. Here we show that the lumenal domains of these two proteins are functionally interchangeable in mediating an ER stress response and that, in unstressed cells, both lumenal domains form a stable complex with the ER chaperone BiP. Perturbation of protein folding promotes reversible dissociation of BiP from the lumenal domains of PERK and IRE1. Loss of BiP correlates with the formation of high-molecular-mass complexes of activated PERK or IRE1, and overexpression of BiP attenuates their activation. These findings are consistent with a model in which BiP represses signalling through PERK and IRE1 and protein misfolding relieves this repression by effecting the release of BiP from the PERK and IRE1 lumenal domains.
2,365 citations
01 Jan 2000
TL;DR: It is shown that the lumenal domains of these two proteins are functionally interchangeable in mediating an ER stress response and that, in unstressed cells, both lumenAL domains form a stable complex with the ER chaperone BiP.
Abstract: PERK and IRE1 are type-I transmembrane protein kinases that reside in the endoplasmic reticulum (ER) and transmit stress signals in response to perturbation of protein folding. Here we show that the lumenal domains of these two proteins are functionally interchangeable in mediating an ER stress response and that, in unstressed cells, both lumenal domains form a stable complex with the ER chaperone BiP. Perturbation of protein folding promotes reversible dissociation of BiP from the lumenal domains of PERK and IRE1. Loss of BiP correlates with the formation of highmolecular-mass complexes of activated PERK or IRE1, and overexpression of BiP attenuates their activation. These findings are consistent with a model in which BiP represses signalling through PERK and IRE1 and protein misfolding relieves this repression by effecting the release of BiP from the PERK and IRE1 lumenal domains. onditions that alter protein folding in the ER elicit two principal cellular responses. The first involves upregulation of genes encoding chaperones and other proteins that prevent polypeptide aggregation and participate in polypeptide folding, post-translational assembly of protein complexes and protein degradation 1
2,332 citations
TL;DR: It is found that the autophagy system is activated as a novel signaling pathway in response to ER stress and played important roles in cell survival after ER stress.
Abstract: Eukaryotic cells deal with accumulation of unfolded proteins in the endoplasmic reticulum (ER) by the unfolded protein response, involving the induction of molecular chaperones, translational attenuation, and ER-associated degradation, to prevent cell death. Here, we found that the autophagy system is activated as a novel signaling pathway in response to ER stress. Treatment of SK-N-SH neuroblastoma cells with ER stressors markedly induced the formation of autophagosomes, which were recognized at the ultrastructural level. The formation of green fluorescent protein (GFP)-LC3-labeled structures (GFP-LC3 “dots”), representing autophagosomes, was extensively induced in cells exposed to ER stress with conversion from LC3-I to LC3-II. In IRE1-deficient cells or cells treated with c-Jun N-terminal kinase (JNK) inhibitor, the autophagy induced by ER stress was inhibited, indicating that the IRE1-JNK pathway is required for autophagy activation after ER stress. In contrast, PERK-deficient cells and ATF6 knockdown cells showed that autophagy was induced after ER stress in a manner similar to the wild-type cells. Disturbance of autophagy rendered cells vulnerable to ER stress, suggesting that autophagy plays important roles in cell survival after ER stress.
1,757 citations