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Coronary heart disease (CHD) is one of the main causes of death worldwide. In the past few decades, several in-depth research on the pathological mechanisms and effective treatment methods for CHD have been conducted. At present, the intervention of a variety of therapeutic drugs and treatment technologies have greatly reduced the burden on global public health. However, severe arrhythmia and myocardial fibrosis accompanying CHD in the later stages need to be addressed urgently. Mitochondria are important structural components for energy production and the main sites for aerobic respiration in cells. Mitochondria are involved in arrhythmia, myocardial fibrosis, and acute CHD and play a crucial role in regulating myocardial ischemia/hypoxia. Mitochondrial dysfunction or mitophagy disorders (including receptor-dependent mitophagy and receptor-independent mitophagy) play an important role in the pathogenesis of CHD, especially mitophagy. Mitophagy acts as a “mediator” in the inflammatory damage of cardiomyocytes or vascular endothelial cells and can clear mitochondria or organelles damaged by inflammation under normal conditions. We reviewed experimental advances providing evidence that mitochondrial homeostasis or mitochondrial quality control are important in the pathological mechanism of CHD. Further, we reviewed and summarized relevant regulatory drugs that target mitochondrial function and quality control.

Lysosomal dysfunction has been found in many pathological conditions, and methods to improve lysosomal function have been reported to be protective against infarcted hearts. However, the mechanisms underlying lysosomal dysfunction caused by ischemic injury are far less well-established. The retromer complex is implicated in the trafficking of cation-independent mannose 6-phosphate receptor (CI-MPR), which is an important protein tag for the proper transport of lysosomal contents and therefore is important for the maintenance of lysosomal function. In this study, we found that the function of retrograde transport in cardiomyocytes was impaired with ischemia/hypoxia (I/H) treatment, which resulted in a decrease in CI-MPR and an abnormal distribution of lysosomal cathepsins. I/H treatment caused a reduction in TBC1D5 and a blockade of the Rab7 membrane cycle, which impeded retromer binding to microtubules and motor proteins, resulting in an impairment of retrograde transport and a decrease in CI-MPR. We also established that TBC1D5 was an important regulator of the distribution of lysosomal cathepsins. Our findings shed light on the regulatory role of retromer in ischemic injury and uncover the regulatory mechanism of TBC1D5 over retromer.

This study aimed to investigate the usefulness of the thyroid-related hormones as markers of acute systemic hypoxia/ischemia to identify deaths caused by asphyxiation due to neck compression in human autopsy cases. The following deaths from pathophysiological conditions were examined: mechanical asphyxia and acute/subacute blunt head injury; acute/subacute non-head blunt injury; sharp instrument injury as the hemorrhagic shock condition; drowning as alveolar injury; burn; and death due to cardiac dysfunction. Blood samples were collected from the left and right cardiac chambers and iliac veins, and serum triiodothyronine (T3), thyroxine (T4), thyroglobulin (Tg), and thyroid-stimulating hormone (TSH) levels were measured using electrochemiluminescence immunoassays. Two types of thyroid cell lines were used to confirm independent thyroid function under the condition of hypoxia (3% O2). The human thyroid carcinoma cell line (HOTHC) cell line derived from human anaplastic thyroid carcinoma and the UD-PTC (sample of the second resection papillary thyroid carcinoma) cell line derived from human thyroid papillary adenoma, which forms Tg retention follicles, were used to examine the secretion levels of T3, T4, and Tg hormones. The results showed a strong correlation between T3 and T4 levels in all blood sampling sites, while the TSH and Tg levels were not correlated with the other markers. Serum T3 and T4 levels were higher in cases of mechanical asphyxia and acute/subacute blunt head injury, representing hypoxic and ischemic conditions of the brain as compared to those in other causes of death. In the thyroid gland cell line, T4, T3, and Tg levels were stimulated after exposure to hypoxia for 10–30 min. These findings suggest that systemic advanced hypoxia/ischemia may cause a rapid and TSH-independent release of T3 and T4 thyroid hormones in autopsy cases. These findings demonstrate that increased thyroid-related hormone (T3 and T4) levels in the pathophysiological field may indicate systemic hypoxia/ischemia. [ABSTRACT FROM AUTHOR]

Background Myocardial injury caused by microvascular obstruction (MVO) is characterized by persistent ischemia/hypoxia (IH) of cardiomyocytes after microembolization. Autophagy and Egr-1 were closely associated with various cardiovascular diseases, including MVO. Bim and Beclin-1 are the important genes for autophagy and apoptosis. We aimed to explore whether the Egr-1/Bim/Beclin-1 pathway is involved in regulating autophagy and apoptosis in IH-exposed cardiomyocytes. Methods Neonatal rat cardiomyocytes exposed to the IH environment in vitro were transfected with lentivirus expressing Egr-1 or Egr-1 shRNA, or further treated with 3-methyladenine (3-MA). The expressions of autophagy and apoptosis-associated genes were evaluated using RT-qPCR and Western blots assays. Autophagic vacuoles and autophagic flux were detected by transmission electron microscopy (TEM) and confocal microscope, respectively. Cell injury was assessed by lactate dehydrogenase (LDH) leakage, and apoptosis was determined by flow cytometry. Results IH exposure elevated Egr-1 and Bim expressions, and decreased Beclin-1 expression in rat cardiomyocytes. Egr-1 overexpression in IH-exposed cardiomyocytes significantly up-regulated the levels of Egr-1 and Bim, and down-regulated the level of Beclin-1. Egr-1 knockdown resulted in down-regulated expressions of Egr-1 and Bim, as well as up-regulated expression of Beclin-1. In addition, Egr-1 knockdown induced autophagy was suppressed by 3-MA treatments. TEM and autophagic flux experiments also confirmed that Egr-1 inhibited autophagy progression in IH-exposed cardiomyocytes. Egr-1 suppression protected cardiomyocytes from IH-induced injury, as evidenced by the positive correlations between Egr-1 expression and LDH leakage or apoptosis index in IH-exposed cardiomyocytes. Conclusions IH-induced cardiomyocyte autophagy and apoptosis are regulated by the Egr-1/Bim/Beclin-1 pathway, which is a potential target for treating cardiomyocyte injury caused by MVO in the IH environment. [ABSTRACT FROM AUTHOR]

Background: Autophagy plays an important role in cardiovascular disease. Controversy still exists regarding the effect of autophagy on ischemic/hypoxic myocardium. Cardiac shock wave therapy (CSWT) is an effective alternative treatment for refractory ischemic heart disease. Whether CSWT can regulate cardiomyocyte autophagy under hypoxic conditions is not clear. We established a myocardial hypoxia model using the H9c2 cell line and performed shock waves (SWs) treatment to evaluate the effect of SW on autophagy. Methods: The H9c2 cells were incubated under hypoxic conditions, and SW treatment was then performed at energies of 0.02, 0.05, or 0.10 mJ/mm2. The cell viability and intracellular ATP level were examined. Western blot analysis was used to assess the expression of LC3B, AMPK, mTOR, Beclin-1, Sirt1, and HIF-1α. Autophagic vacuoles were visualized by monodansylcadaverine staining. Results: After the 24-hour hypoxic period, cardiomyocyte viability and ATP levels were decreased and autophagy was significantly increased in H9c2 cells. SW treatment with an energy of 0.05 mJ/mm2 significantly increased the cellular viability, ATP level, LC3B-II/I, and number of autophagic vacuoles. In addition, phosphorylated AMPK and Sirt1 were increased and phosphorylated mTOR and HIF-1α were decreased after SW treatment. Conclusion: SW treatment can potentially promote cardiomyocyte autophagy during hypoxia and protect cardiomyocyte function by regulating the AMPK/mTOR pathway.

Background: Previous studies have demonstrated that Cardiac Shock Wave Therapy (CSWT) improves myocardial perfusion and cardiac function in a porcine model of chronic myocardial ischemia and also ameliorates myocardial ischemia in patients with severe coronary artery disease (CAD). Apoptosis plays a key role in ischemic myocardial pathogenesis. However, it remains unclear whether CSWT is beneficial for ischemia/hypoxia (I/H)-induced myocardial cell apoptosis and by which mechanism CSWT could improve heart function. We put forward the hypothesis that CSWT might protect heart function during ischemia/hypoxia by decreasing apoptosis. Methods: We generated ischemia/hypoxia (I/H)-induced apoptosis in the H9c2 myoblast cell line to examine the CSWT function and possible mechanisms. H9c2 cells were treated under hypoxic serum-starved conditions for 24 h and then treated with or without CSWT (500 shots, 0.06, 0.09, 0.12mJ/mm2). The apoptotic cell rate was determined by flow cytometry assay, cell viability was examined by the MTT assay, nuclear fragmentation was detected by Hoechst 33342 staining, and the mitochondrial-mediated intrinsic pathway of apoptosis was assessed by the expression of Bax and Bcl-2 protein and Caspase3 activation. Results: First, apoptosis could be induced by ischemia/hypoxia in H9c2 cells. Second, CSWT attenuates the cell death and decreases the H9c2 cell apoptosis rate induced by ischemia and hypoxia. Third, CSWT suppresses the expression of apoptosis molecules that regulate the intrinsic pathway of apoptosis in H9c2 cells. Fourth, CSWT increases the phosphorylation of AKT, which indicates the activation of the PI3K-AKT pathway. Conclusions: These results indicate that CSWT exerts a protective effect against I/H-induced cell death, potentially by preventing the activation of components of the mitochondrial-dependent intrinsic apoptotic pathway. We also demonstrate that the PI3K-Akt pathway may be involved in the CSWT effects on apoptosis.

Background: Autophagy plays an important role in cardiovascular disease. Controversy still exists regarding the effect of autophagy on ischemic/hypoxic myocardium. Cardiac shock wave therapy (CSWT) is an effective alternative treatment for refractory ischemic heart disease. Whether CSWT can regulate cardiomyocyte autophagy under hypoxic conditions is not clear. We established a myocardial hypoxia model using the H9c2 cell line and performed shock waves (SWs) treatment to evaluate the effect of SW on autophagy. Methods: The H9c2 cells were incubated under hypoxic conditions, and SW treatment was then performed at energies of 0.02, 0.05, or 0.10 mJ/mm2. The cell viability and intracellular ATP level were examined. Western blot analysis was used to assess the expression of LC3B, AMPK, mTOR, Beclin-1, Sirt1, and HIF-1α. Autophagic vacuoles were visualized by monodansylcadaverine staining. Results: After the 24-hour hypoxic period, cardiomyocyte viability and ATP levels were decreased and autophagy was significantly increased in H9c2 cells. SW treatment with an energy of 0.05 mJ/mm2 significantly increased the cellular viability, ATP level, LC3B-II/I, and number of autophagic vacuoles. In addition, phosphorylated AMPK and Sirt1 were increased and phosphorylated mTOR and HIF-1α were decreased after SW treatment. Conclusion: SW treatment can potentially promote cardiomyocyte autophagy during hypoxia and protect cardiomyocyte function by regulating the AMPK/mTOR pathway. [ABSTRACT FROM AUTHOR]

Silent information regulator factor 2-related enzyme 1 (sirtuin 1, Sirt1) is a nicotinamide adenine dinucleotide-dependent deacetylase, which can deacetylate histone and non-histone proteins and other transcription factors, and is involved in the regulation of many physiological functions, including cell senescence, gene transcription, energy balance, and oxidative stress. Ischemia/hypoxia injury remains an unresolved and complicated situation in the diseases of ischemia stroke, heart failure, and coronary heart disease, especially among the old folks. Studies have demonstrated that aging could enhance the vulnerability of brain, heart, lung, liver, and kidney to ischemia/hypoxia injury and the susceptibility in old folks to ischemia/hypoxia injury might be associated with Sirt1. In this review, we mainly summarize the role of Sirt1 in modulating pathways against energy depletion and its involvement in oxidative stress, apoptosis, and inflammation under the condition of ischemia/hypoxia. [ABSTRACT FROM AUTHOR]

Ischemia is a complex phenomenon modulated by the concerted action of several cell types. We have identified that sarcoplasmic/endoplasmic reticulum Ca 2 + ATPase 2 (SERCA 2) cysteine 674 (C674) S -glutathiolation is essential for ischemic angiogenesis, vascular endothelial growth factor (VEGF)-mediated endothelial cell (EC) migration and network formation. A heterozygote SERCA 2 C674S knockin (SKI) mouse shows impaired ischemic blood flow recovery after femoral artery ligation, and its ECs show depleted endoplasmic reticulum (ER) Ca 2 + stores and impaired angiogenic behavior. Here we studied the role of SERCA 2 C674 in the interaction between ECs and macrophages in the context of ischemia and discovered the involvement of the ER stress response protein, ER oxidoreductin-1α (ERO1). In wild type (WT) mice, expression of ERO1 was increased in the ischemic hind limb in vivo, as well as in ECs and macrophages exposed to hypoxia in vitro. The increase in ERO1 to ischemia/hypoxia was less in SKI mice. In WT ECs, both vascular cell adhesion molecule 1 (VCAM1) expression and bone marrow-derived macrophage adhesion to ECs were increased by hypoxia, and both were attenuated in SKI ECs. In WT ECs, ERO1 siRNA blocked hypoxia-induced VCAM1 expression and macrophage adhesion. In WT macrophages, hypoxia also stimulated both ERO1 and VEGF expression, and both were less in SKI macrophages. Compared with conditioned media of hypoxic SKI macrophages, conditioned media from WT macrophages had a greater effect on EC angiogenic behavior, and were blocked by VEGF neutralizing antibody. Taken together, under hypoxic conditions, SERCA 2 C674 and ERO1 enable increased VCAM1 expression and macrophage adhesion to ECs, as well as macrophage VEGF production that, in turn, promote angiogenesis. This study highlights the hitherto unrecognized interaction of two ER proteins, SERCA 2 C674 and ERO1, which mediate the EC and macrophage angiogenic response to ischemia/hypoxia. [ABSTRACT FROM AUTHOR]

MRI studies showed that cerebral ischemia/hypoxia in neonatal rat pups applied using the Levine-Rice method induced unilateral lesions in the cerebral cortex, striatum, and hippocampus. Unilateral ischemic lesions led to long-term sensorimotor and behavioral impairments at 90-115 days after surgery on testing the animals in a battery of tests consisting of the cylinder, tapering beam, Montoya, and paw-placing tests. This combination of tests, along with MRI studies, provided reliable evaluation of long-term sensorimotor impairments in adult animals subjected to trauma in the neonatal period. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated that Cardiac Shock Wave Therapy (CSWT) improves myocardial perfusion and cardiac function in a porcine model of chronic myocardial ischemia and also ameliorates myocardial ischemia in patients with severe coronary artery disease (CAD). Apoptosis plays a key role in ischemic myocardial pathogenesis. However, it remains unclear whether CSWT is beneficial for ischemia/hypoxia (I/H)-induced myocardial cell apoptosis and by which mechanism CSWT could improve heart function. We put forward the hypothesis that CSWT might protect heart function during ischemia/hypoxia by decreasing apoptosis. Methods: We generated ischemia/hypoxia (I/H)-induced apoptosis in the H9c2 myoblast cell line to examine the CSWT function and possible mechanisms. H9c2 cells were treated under hypoxic serum-starved conditions for 24 h and then treated with or without CSWT (500 shots, 0.06, 0.09, 0.12mJ/mm2). The apoptotic cell rate was determined by flow cytometry assay, cell viability was examined by the MTT assay, nuclear fragmentation was detected by Hoechst 33342 staining, and the mitochondrial-mediated intrinsic pathway of apoptosis was assessed by the expression of Bax and Bcl-2 protein and Caspase3 activation. Results: First, apoptosis could be induced by ischemia/hypoxia in H9c2 cells. Second, CSWT attenuates the cell death and decreases the H9c2 cell apoptosis rate induced by ischemia and hypoxia. Third, CSWT suppresses the expression of apoptosis molecules that regulate the intrinsic pathway of apoptosis in H9c2 cells. Fourth, CSWT increases the phosphorylation of AKT, which indicates the activation of the PI3K-AKT pathway. Conclusions: These results indicate that CSWT exerts a protective effect against I/H-induced cell death, potentially by preventing the activation of components of the mitochondrial-dependent intrinsic apoptotic pathway. We also demonstrate that the PI3K-Akt pathway may be involved in the CSWT effects on apoptosis. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: Angiotensin receptor-neprilysin inhibitor (ARNI) improves cardiac function and protects from an ischemic myocardium. However, the role and mechanism of ARNI on autophagy in cardiac ischemic injury are poorly understood. Here, we investigated the protective effect and underlying mechanisms of ARNI on autophagy in H9c2 cardiomyocytes induced through ischemia and hypoxia (IH) treatment., Methods: The cytotoxicity of IH injury on H9C2 cells with and without ARNI were evaluated using cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays. The effect of ARNI on apoptosis was detected using flow cytometry. The expression of autophagic proteins (LC3-II, Beclin 1, and p62) was detected using western blot., Results: The viability of H9c2 cells was significantly decreased at different IH-treated time points; ARNI pretreatment increased cell viability and inhibited IH injury in a dose-dependent manner. H9c2 cells treated with IH (6 h) significantly increased LDH release, while ARNI dose-dependently improved LDH release, with 20 μmol/L ARNI having the most significant effect. ARNI also ameliorated IH-induced apoptosis. IH treatment increased the protein expression of LC3-II and Beclin 1 and decreased the expression of p62, which were reversed by ARNI pretreatment. Furthermore, autophagy was further increased after pretreatment with rapamycin in IH-induced H9c2 cells, which abrogated the protective effect of ARNI., Conclusions: Our study shows that ARNI has a protective effect on IH-induced cardiomyocyte injury, which may be related to the inhibition of autophagy., Competing Interests: None., (AJTR Copyright © 2022.)

Extracellular nucleotides acting via P2 receptors play important roles in cardiovascular physiology/pathophysiology. Pyrimidine nucleotides activate four G protein-coupled P2Y receptors (P2YRs): P2Y 2 and P2Y 4 (UTP-activated), P2Y 6, and P2Y 14. Previously, we showed that uridine 5′-triphosphate (UTP) activating P2Y 2R reduced infarct size and improved mouse heart function after myocardial infarct (MI). Here, we examined the cardioprotective role of P2Y 2R in vitro and in vivo following MI using uridine-5′-tetraphosphate δ-phenyl ester tetrasodium salt (MRS2768), a selective and more stable P2Y 2R agonist. Cultured rat cardiomyocytes pretreated with MRS2768 displayed protection from hypoxia [as revealed by lactate dehydrogenase (LDH) release and propidium iodide (PI) binding], which was reduced by P2Y 2R antagonist, AR-C118925 (5-((5-(2,8-dimethyl-5 H-dibenzo[ a, d][ 7 ]annulen-5-yl)-2-oxo-4-thioxo-3,4-dihydropyrimidin-1(2 H)-yl)methyl)- N-(1 H-tetrazol-5-yl)furan-2-carboxamide). In vivo, echocardiography and infarct size staining of triphenyltetrazolium chloride (TTC) in 3 groups of mice 24 h post-MI: sham, MI, and MI+MRS2768 indicated protection. Fractional shortening (FS) was higher in MRS2768-treated mice than in MI alone (40.0 ± 3.1 % vs. 33.4 ± 2.7 %, p < 0.001). Troponin T and tumor necrosis factor-α (TNF-α) measurements demonstrated that MRS2768 pretreatment reduced myocardial damage ( p < 0.05) and c-Jun phosphorylation increased. Thus, P2Y 2R activation protects cardiomyocytes from hypoxia in vitro and reduces post-ischemic myocardial damage in vivo. [ABSTRACT FROM AUTHOR]

Ceramides, members of the sphingolipids, are produced in the central nervous system by de novo synthesis, sphingomyelin hydrolysis or the so-called salvage pathway. They are engaged in formation of lipid rafts that are essential in regulation and transduction of signals coming to the cell from the environment. Ceramides represent the major transmitters of the sphingomyelin pathway of signal transduction. They regulate proliferation, differentiation, programmed cell death and senescence. Ceramide overexpression, mainly as a result of sphingomyelin hydrolysis, is a component of brain damage caused by ischemia and early reperfusion. Their high concentrations induce mitochondria-dependent neuronal apoptosis, exacerbate the synthesis of reactive oxygen species, decrease ATP level, inhibit electron transport and release cytochrome c, and activate caspase- 3. Reduced ceramide accumulation in the brain, dependent mainly on ceramide synthesized de novo, may exert an anti-apoptotic effect after pre-conditioning. The increase of ceramide content in the brain was observed in Alzheimer disease and its animal models. Enhanced ceramide concentration in this pathology is an effect of their synthesis de novo or sphingomyelin metabolism augmentation. The ceramide pathway can directly stimulate biochemical changes in the brain noted at the onset of disease: tau overphosphorylation and β-amyloid peptide accumulation. The higher concentration of ceramides in blood in the pre-clinical phase of the illness may mark early brain changes. [ABSTRACT FROM AUTHOR]

Abstract: In the present study, we investigated the effects of sabiporide, a specific NHE-1 inhibitor, on blood–brain barrier (BBB) endothelial dysfunction during ischemia/hypoxia in rat cerebral ischemia in vivo and bEnd.3 cells in vitro. Sabiporide significantly attenuated ischemia/hypoxia-induced BBB hyperpermeability and disruption of occludin and zonula occludens-1 both in vivo and in vitro. Sabiporide also inhibited the hypoxia-induced increase in [Ca2+]i in bEnd.3 cells. Taken together, the protective effect of sabiporide on BBB permeability may be mediated through maintaining tight junction integrity and associated with its inhibitory effect on [Ca2+]i overload under hypoxia. These results suggest that the BBB protective effect of sabiporide may be of therapeutical benefit in brain injury after an ischemic stroke. [ABSTRACT FROM AUTHOR]

This review collects data on the influence of intracellular and extracellular acidosis on neuronal viability and the effect of acidosis on neuronal damage progressing under brain ischemia/hypoxia. Particular attention is devoted to the involvement of ionotropic glutamic receptors and acid-sensitive ion channel 1a in these processes. [ABSTRACT FROM AUTHOR]

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Objectives: Ischemia/hypoxia (I/H) causes severe neonatal brain injury, such as periventricular leukomaracia and hypoxic/ischemic encephalopathy. Neural stem cell research could lead to a treatment for such disorders. In order to elucidate the dynamic changes in neural stem cells in the neonatal brain after I/H, we investigated the proliferation of new cells in the subventricular zone (SVZ). Methods: Seven-day-old Wister rats were subjected to ligation of the left carotid artery followed by 2 hours of hypoxic stress (8% O2 and 92% N2, at 33°C). In order to elucidate the dynamic change of neural stem cells in the SVZ, single bromodeoxyuridine (BrdU; 50 mg/kg) was administered 2 hours before death 1, 7, 14 and 21 days after I/H. Immunohistochemical and immunofluorescent studies for BrdU and doublecortin (DCX) were carried out. As a control, a group of rats was subjected to sham surgery (incision of skin, but no ligation of the carotid artery) and no I/H. Results: The numbers of BrdU-labeled cells in the SVZ, for both the ipsilateral side and the contralateral side of the I/H brain, were twice the level of the control at 7 days after I/H, but the numbers for both sides returned to the control level at 21 days. In the ipsilateral side of the I/H brain, the number of BrdU-labeled cells in the SVZb (lining the upper wall of lateral ventricle) was 4-fold at 7 days and 15-fold at 21 days after I/H compared with the control level. This chronological pattern is very similar to the pattern for I/H results of the posterior periventricle (pPV). DCX appeared in most BrdU-labeled cells in the SVZb and pPV. Discussion: These findings indicate that I/H enhances neural stem cell proliferation in the SVZ, and some newborn cells migrate as neural precursors to the SVZb and pPV after I/H in the neonatal rat brain. [ABSTRACT FROM AUTHOR]

In order to delineate the spatial and temporal patterns of glial cell line-derived neurotrophic factor (GDNF) expression following ischemic/hypoxic injury in immature and neonatal brain, GDNF protein levels and immunocytochemistry were studied in rats subjected to a modified Levine procedure. Significant upregulation of GDNF protein occurred in a bimodal fashion in the damaged left cerebral cortex and hippocampus, while the levels in the right cerebral hemisphere of both control and ischemic groups remained relatively unchanged. Immunocytochemical studies indicated that the early rise in GDNF levels was most likely to be related to enhanced neuronal release of GDNF. The second rise was probably related to progressive astrogliosis that occurred in response to injury. In contrast to the lack of GDNF expression among astrocytes in normal mature brains, reactive astrocytes in the neonate appear to possess a ready capacity to express GDNF. Spatial and temporal changes in the pattern of GDNF expression following injury, as determined in this study may provide insight into the functions of GDNF in vivo and into possible therapeutic approaches toward prevention of damage or rescue of neurons following brain injury. [Copyright &y& Elsevier]

All the advancements in the understanding of the molecular and cellular processes leading to the great investments in developing neuroprotection against cerebral ischemic/hypoxic damage cannot obscure the simple fact that exhaustion of energy supplies is still at the basis of this disorder. Much has been investigated and postulated over the years about the quick collapse of energy metabolism that follows oxygen and glucose deprivation in the brain. Anaerobic glycolysis, recognized as a pathway of paramount importance in keeping energy supplies, although, at bare minimum, has also presented a dilemma—a significant increase in lactate production during ischemia/hypoxia (IH). The dogma of lactate as a useless end product of anaerobic glycolysis and its postulated role as a detrimental player in the demise of the ischemic cell has persisted for the past quarter of a century. This persistence is due to, at least in part, the well-documented phenomenon termed “the glucose paradox of cerebral ischemia,” the unexplained aggravation of postischemic neuronal damage by preischemic hyperglycemia. Recent studies have questioned the deleterious effect of lactic acid, while others even have offered the possibility that this monocarboxylate serves as an aerobic energy substrate during recovery from IH. Reviewed here are studies published over the past few years along with some key older papers on the topic of energy metabolism and recovery of neural tissue from IH. New insights gained from both in vitro and in vivo studies on energy metabolism of the ischemic/hypoxic brain should improve our understanding of this key metabolic process and the chances of protecting this organ from the consequences of energy deprivation. [Copyright &y& Elsevier]

Emerging literature suggests that pyroptosis plays a critical role in ischemia/hypoxia (I/R) -induced myocardial injury. Melatonin has been implicated in attenuating I/R-induced injury of cardiomyocytes. Nevertheless, whether melatonin inhibits I/R-induced pyroptosis of cardiomyocytes and the underlying molecular mechanisms remain unexploited.H9c2 cardiomyocytes were cultured under oxygen-glucose deprivation/reperfusion (OGD/R) condition to establish a myocardial pyroptosis model in vitro. OGD/R-induced pyroptosis was evaluated by CCK-8 assay, IL-1β and IL-18 release, and western blotting. Luciferase reporter assay was utilized to validate the association between miR-155 and Forkhead box O3a (FOXO3a).Melatonin could inhibit OGD/R-induced pyroptosis of H9c2 cells and upregulation of FOXO3a contributed to the antipyroptotic effect of melatonin. Melatonin reduced miR-155 expression, which led to FOXO3a upregulation and inhibition of pyroptosis in OGD/R-exposed H9c2 cells. miR-155 inhibitor enhanced the antipyroptotic effect of melatonin in OGD/R-exposed H9c2 cells. Melatonin-induced downregulation of miR-155 and upregulation of FOXO3a were reversed by melatonin receptor 2 (MT2) siRNA. Melatonin treatment also led to an increased level of apoptosis repressor with caspase recruitment domain (ARC), which was inhibited by FOXO3a siRNA. Moreover, silencing ARC by siRNA significantly blocked the antipyroptotic actions of melatonin, whereas ARC overexpression enhanced the antipyroptotic actions of melatonin in OGD/R-exposed H9c2 cells.Our findings demonstrated that melatonin prevented OGD/R-induced pyroptosis via regulating the MT2/miR-155/FOXO3a/ARC axis in cardiomyocytes.

• I/H injury model in H9C2 cells was successfully constructed. • I/H injury induced the increased levels of UB mRNA and ubiquitinated proteins. • Extracellular UB protected H9C2 cells from I/H injury by inhibiting mitochondrial apoptosis pathway through CXCR4. • Extracellular UB might promote autophagy in H9C2 cells during I/H injury. Acute myocardial infarction (AMI) is one of the deadliest diseases worldwide. The search for countermeasures to reduce cardiomyocytes death in the infarcted area has always been the focus of research. Ubiquitin (UB) is a small polypeptide mainly involved in proteasome-mediated protein degradation in cells, whereas extracellular UB in body fluids can also function through its receptor CXC chemokine receptor type 4 (CXCR4). This study aimed to explore the functional roles of extracellular UB in cardiomyocytes during ischemia/hypoxia (I/H). H9C2 cells were subjected to I/H treatment and cell injury was evaluated by cell viability, morphology changes and apoptosis rate. UB expression and levels of ubiquitinated proteins after I/H injury were measured. The effects of extracellular UB on I/H-induced cardiomyocytes apoptosis and the possible underlying mechanisms were studied. I/H injury induced the decrease of cell viability as well as enhanced impaired cell morphology and apoptosis rate in H9C2 cells. Levels of UB mRNA and ubiquitinated proteins were significantly up-regulated after I/H treatment, whereas the concentration of extracellular UB in the conditioned media did not show significant change and the intracellular mono-UB levels in cells were down-regulated. Extracellular UB treatment protected cardiomyocytes from I/H injury by inhibiting the overactivation of mitochondria-dependent apoptosis pathway and up-regulating autophagy level. Inhibition of CXCR4 receptor using AMD3100 abolished cardioprotective effects of extracellular UB. The up-regulation of UB was suggested to be an adaptive response to resist I/H-induced cardiomyocytes apoptosis, and additional extracellular UB treatment might serve as a new potential therapeutic drug for AMI. [ABSTRACT FROM AUTHOR]

Objective: White matter lesions (WMLs) are more common in migraine patients than in the normal population. Ischemia/hypoxia and oxidative stress are considered to play a role in WMLs formation. This study aimed to investigate ischemia-modified albumin (IMA), ferroxidase and thiol/disulfide homeostasis in migraineurs with and without WMLs., Patients and Methods: Sixty-two migraineurs with WML, 59 migraineurs without WML and 61 controls were included in the study. All participants underwent brain MRI. WMLs was evaluated according to the Fazekas scale. IMA, ferroxidase, total thiol, native thiol and disulfide measurements were carried out in all participants., Results: The IMA levels were higher in the migraine groups compared to the control group (p < 0.001) and in the WML group compared to non-WML (p < 0.001). The total and native thiol levels were higher in the non-WML group compared to the control and WML groups (p < 0.001 for both). The disulfide levels were similar between the control and non-WML groups, but they were significantly lower in the WML group compared to the control and non-WML groups. There was no significant difference between the groups in terms of the ferroxidase levels (p = 0.092). The thiol/disulfide, IMA and ferroxidase levels were not significantly correlated with the frequency and duration of attacks, severity of pain and disability due to migraine., Conclusion: Increased serum IMA levels in migraineurs point to the role of ischemia/hypoxia, and increased total thiol and decreased disulfide levels indicate an oxidant/antioxidant imbalance in migraine. Ischemia/hypoxia may play a role in WMLs formation in migraine., Competing Interests: Declaration of competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The microglia-mediated inflammatory reaction promotes neuronal damage under cerebral ischemia/hypoxia conditions. We therefore speculated that inhibition of hypoxia-induced microglial activation may alleviate neuronal damage. To test this hypothesis, we co-cultured ginsenoside Rb1, an active component of ginseng, and cortical neurons. Ginsenoside Rb1 protected neuronal morphology and structure in a single hypoxic culture system and in a hypoxic co-culture system with microglia, and reduced neuronal apoptosis and caspase-3 production. The protective effect was observable prior to placing in co-culture. Additionally, ginsenoside Rb1 inhibited levels of tumor necrosis factor-α in a co-culture system containing activated N9 microglial cells. Ginsenoside Rb1 also significantly decreased nitric oxide and superoxide production induced by N9 microglia. Our findings indicate that ginsenoside Rb1 attenuates damage to cerebral cortex neurons by downregulation of nitric oxide, superoxide, and tumor necrosis factor-α expression in hypoxia-activated microglia.