Atorvastatin Prevent the Neuron Loss in the Hippocampal Dentate Gyrus Region through its Anti-oxidant and Anti-apoptotic Activities

2020 ◽  
Vol 19 ◽  
Author(s):  
Soheila Yadollah-damavandi ◽  
Zahra Nadia Sharifi ◽  
Hamid Zaferani Arani ◽  
Ehsan Jangholi ◽  
Aliasghar Karimi ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Dentate Gyrus ◽  
Ischemia Reperfusion ◽  
Hippocampal Dentate Gyrus ◽  
Cytochrome C Release ◽  
Nissl Staining ◽  
Atorvastatin Treatment ◽  
Atp Level ◽  
Anti Oxidant ◽  
Dentate Gyrus Region

Background: Atorvastatin is a member of statins, which has shown positive vascular effects, anti-oxidant, antiplatelet, and anti-apoptotic properties. Objective: In this study, we hypothesized that atorvastatin could prevent the neurons lost in the hippocampal dentate gyrus region after transient global ischemia/reperfusion (I/R) through its anti-oxidant and anti-apoptotic activities. Method: Twenty-four male Wistar rats 12-13 weeks old and weighing 250–300 g, were divided randomly into four groups: control, I/R, vehicle (I/R treated with NaCl) and experiment (I/R treated with atorvastatin, 10 mg/kg) and rats were sacrificed 96 hours after I/R. Quantitative expression of genes (caspase 8, p53, bax, bcl2, cytochrome c) was studied. The MDA level, SOD, CAT, and GPx activities were measured with biochemical tests. To detect apoptotic cells, TUNEL and Nissl staining were performed. Mitochondria were prepared from the hippocampus rats, used to the quantification of mitochondrial ROS, ATP level, GSH content, membrane potential, cytochrome c release, and determination of mitochondrial swelling. Results: Atorvastatin attenuated the overexpression of bax, cytochrome C, p53, and caspase8 mRNAs and induced expression of bcl-2 mRNA (P<0.001). Atorvastatin treatment increased anti-oxidant enzyme levels (P<0.01). Treatment with atorvastatin reduced the number of TUNEL-positive cells. It could decrease the cytochrome c release (P<0.01), inhibit the decrease of MMP (P<0.001) and increased the ATP level (P<0.001) in mitochondrial hippocampal in compared with I/R group. Conclusion: Atorvastatin treatment in I/R rats decreases oxidative stress, production of ROS, apoptosis rate in neuronal cells, and improves the mitochondrial function. Hence, atorvastatin have a proper neuronal protective effect against the I/R injury in the brain.

Effects of fatty acids in isolated mitochondria: implications for ischemic injury and cardioprotection

2003 ◽  
Vol 285 (1) ◽  
pp. H259-H269 ◽  
Author(s):  
Paavo Korge ◽  
Henry M. Honda ◽  
James N. Weiss
Keyword(s):  
Fatty Acids ◽  
Cytochrome C ◽  
Ischemia Reperfusion Injury ◽  
Adenine Nucleotide ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Cytochrome C Release ◽  
Atp Production ◽  
Isolated Mitochondria ◽  
Long Chain

Fatty acids accumulate during myocardial ischemia and are implicated in ischemia-reperfusion injury and mitochondrial dysfunction. Because functional recovery after ischemia-reperfusion ultimately depends on the ability of the mitochondria to recover membrane potential (ΔΨm), we studied the effects of fatty acids on ΔΨm regulation, cytochrome c release, and Ca2+ handling in isolated mitochondria under conditions that mimicked aspects of ischemia-reperfusion. Long-chain but not short-chain free fatty acids caused a progressive and reversible (with BSA) increase in inner membrane leakiness (proton leak), which limited mitochondrial ability to support ΔΨm. In comparison, long-chain activated fatty acids promoted 1) a slower depolarization that was not reversible with BSA, 2) cytochrome c loss that was unrelated to permeability transition pore opening, and 3) inhibition of the adenine nucleotide translocator. Together, these results impaired both mitochondrial ATP production and Ca2+ handling. Diazoxide, a selective opener of mitochondrial ATP-dependent potassium (KATP) channels, partially protected against these effects. These findings indicate that long-chain fatty acid accumulation during ischemia-reperfusion may predispose mitochondria to cytochrome c loss and irreversible injury and identify a novel cardioprotective action of diazoxide.

Oroxylin A, a Flavonoid, Stimulates Adult Neurogenesis in the Hippocampal Dentate Gyrus Region of Mice

2010 ◽  
Vol 35 (11) ◽  
pp. 1725-1732 ◽  
Author(s):  
Seungjoo Lee ◽  
Dong Hyun Kim ◽  
Dong Hwa Lee ◽  
Su Jin Jeon ◽  
Chang Hwan Lee ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Adult Neurogenesis ◽  
Oroxylin A ◽  
Hippocampal Dentate Gyrus ◽  
Dentate Gyrus Region

Inhibition of hypoxia/reoxygenation-induced apoptosis in metallothionein-overexpressing cardiomyocytes

2001 ◽  
Vol 280 (5) ◽  
pp. H2292-H2299 ◽  
Author(s):  
Guang-Wu Wang ◽  
Zhanxiang Zhou ◽  
Jon B. Klein ◽  
Y. James Kang
Keyword(s):  
Cytochrome C ◽  
Caspase 3 ◽  
Ischemia Reperfusion ◽  
Annexin V ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
Fetal Bovine ◽  
Induced Apoptosis ◽  
Hypoxia Reoxygenation

To study possible mechanisms for metallothionein (MT) inhibition of ischemia-reperfusion-induced myocardial injury, cardiomyocytes isolated from MT-overexpressing transgenic neonatal mouse hearts and nontransgenic controls were subjected to 4 h of hypoxia (5% CO2-95% N2, glucose-free modified Tyrode's solution) followed by 1 h of reoxygenation in MEM + 20% fetal bovine serum (FBS) (5% CO2-95% air), and cytochrome c-mediated caspase-3 activation apoptotic pathway was determined. Hypoxia/reoxygenation-induced apoptosis was significantly suppressed in MT-overexpressing cardiomyocytes, as measured by both terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling and annexin V-FITC binding. In association with apoptosis, mitochondrial cytochrome c release, as determined by Western blot, was observed to occur in nontransgenic cardiomyocytes. Correspondingly, caspase-3 was activated as determined by laser confocal microscopic examination with the use of FITC-conjugated antibody against active caspase-3 and by enzymatic assay. The activation of this apoptotic pathway was significantly inhibited in MT-overexpressing cells, as evidenced by both suppression of cytochrome c release and inhibition of caspase-3 activation. The results demonstrate that MT suppresses hypoxia/reoxygenation-induced cardiomyocyte apoptosis through, at least in part, inhibition of cytochrome c-mediated caspase-3 activation.

Caspase-dependent cytochrome c release and cell death in chick cardiomyocytes after simulated ischemia-reperfusion

2004 ◽  
Vol 286 (6) ◽  
pp. H2280-H2286 ◽  
Author(s):  
Yimin Qin ◽  
Terry L. Vanden Hoek ◽  
Kim Wojcik ◽  
Travis Anderson ◽  
Chang-Qing Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Ischemia Reperfusion ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Simulated Ischemia ◽  
Baseline Levels ◽  
Caspase 2 ◽  
Induced Apoptosis

We recently demonstrated that reperfusion rapidly induces the mitochondrial pathway of apoptosis in chick cardiomyocytes after 1 h of simulated ischemia. Here we tested whether ischemia-reperfusion (I/R)-induced apoptosis could be initiated by caspase-dependent cytochrome c release in this model of cardiomyocyte injury. Fluorometric assays of caspase activity showed little, if any, activation of caspases above baseline levels induced by 1 h of ischemia alone. However, these assays revealed rapid activation of caspase-2, yielding a 2.95 ± 0.52-fold increase (over ischemia only) within the 1st h of reperfusion, whereas activities of caspases-3, -8, and -9 increased only slightly from their baseline levels. The rapid and prominent activation of caspase-2 suggested that it could be an important initiator caspase in this model, and using specific caspase inhibitors given only at the point of reperfusion, we tested this hypothesis. The caspase-2 inhibitor benzyloxycarbonyl-Val-Asp(Ome)-Val-Ala-Asp(Ome)-CH2F was the only caspase inhibitor that significantly inhibited cytochrome c release from mitochondria. This inhibitor also completely blocked activation of caspases-3, -8, and -9. The caspase-3/7 inhibitor transiently and only partially blocked caspase-2 activity and was less effective in blocking the activities of caspases-8 and -9. The caspase-8 inhibitor failed to significantly block caspase-2 or -3, and the caspase-9 inhibitor blocked only caspase-9. Furthermore, the caspase-2 inhibitor protected against I/R-induced cell death, but the caspase-8 inhibitor failed to do so. These data suggest that active caspase-2 initiates cytochrome c release after reperfusion and that it is critical for the I/R-induced apoptosis in this model.

scholarly journals p53 target Siva regulates apoptosis in ischemic kidneys

2011 ◽  
Vol 300 (5) ◽  
pp. F1130-F1141 ◽  
Author(s):  
Kurinji Singaravelu ◽  
Babu J. Padanilam
Keyword(s):  
Cytochrome C ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tumor Necrosis Factor Receptor ◽  
Kidney Injury ◽  
Cytochrome C Release ◽  
Apoptosis Inhibition ◽  
Apoptosis Inducing Factor

The role of p53 in inducing apoptosis following acute kidney injury is well-established; however, the molecular mechanisms remain largely unknown. We report here that the p53 proapoptotic target Siva and its receptor CD27, a member of the tumor necrosis factor receptor family, are upregulated following renal ischemia-reperfusion injury (IRI). Inhibition of Siva using antisense oligonucleotides conferred functional and morphological protection, and it prevented apoptosis postrenal IRI in mice. Renal IRI in CD27-deficient mice displayed functional protection and partial inhibition of apoptosis, suggesting an incomplete role for CD27 in Siva-mediated apoptosis. To further elucidate mechanisms by which Siva elicits apoptosis, in vitro studies were performed. In Siva-transfected LLC-PK1 cells, Siva is persistently expressed in the nucleus at 3 h onwards and its translocation to mitochondria and the plasma membrane occurred at 6 h. Moreover, Siva overexpression induced mitochondrial permeability, cytochrome c release, caspase-8 and -9 activation, translocation of apoptosis-inducing factor (AIF) to the nucleus, and apoptosis. Inhibition of Siva in ischemic kidneys prevented mitochondrial release of cytochrome c and AIF. These data indicate that Siva function is pivotal in regulating apoptosis in the pathology of renal IRI. Targeting Siva may offer a potential therapeutic strategy for renal IRI.

scholarly journals Release of Mitochondrial Apoptogenic Factors and Cell Death are Mediated by CK2 and NADPH Oxidase

2011 ◽  
Vol 32 (4) ◽  
pp. 720-730 ◽  
Author(s):  
Gab Seok Kim ◽  
Joo Eun Jung ◽  
Purnima Narasimhan ◽  
Hiroyuki Sakata ◽  
Hideyuki Yoshioka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cytochrome C ◽  
Nadph Oxidase ◽  
Ischemia Reperfusion ◽  
Brain Infarction ◽  
Ischemic Injury ◽  
Artery Occlusion ◽  
Cytochrome C Release ◽  
Copper Zinc Superoxide Dismutase ◽  
Cerebral Ischemia And Reperfusion

Activation of the NADPH oxidase subunit, NOX2, and increased oxidative stress are associated with neuronal death after cerebral ischemia and reperfusion. Inhibition of NOX2 by casein kinase 2 (CK2) leads to neuronal survival, but the mechanism is unknown. In this study, we show that in copper/zinc-superoxide dismutase transgenic (SOD1 Tg) mice, degradation of CK2α and CK2α′ and dephosphorylation of CK2β against oxidative stress were markedly reduced compared with wild-type (WT) mice that underwent middle cerebral artery occlusion. Inhibition of CK2 pharmacologically or by ischemic reperfusion facilitated accumulation of poly(ADP-ribose) polymers, the translocation of apoptosis-inducing factor (AIF), and cytochrome c release from mitochondria after ischemic injury. The eventual enhancement of CK2 inhibition under ischemic injury strongly increased 8-hydroxy-2′-deoxyguanosine and phosphorylation of H2A.X. Furthermore, CK2 inhibition by tetrabromocinnamic acid (TBCA) in SOD1 Tg and gp91 knockout (KO) mice after ischemia reperfusion induced less release of AIF and cytochrome c than in TBCA-treated WT mice. Inhibition of CK2 in gp91 KO mice subjected to ischemia reperfusion did not increase brain infarction compared with TBCA-treated WT mice. These results strongly suggest that NOX2 activation releases reactive oxygen species after CK2 inhibition, triggering release of apoptogenic factors from mitochondria and inducing DNA damage after ischemic brain injury.

scholarly journals Morphine post-conditioning-induced up-regulation of lncRNA TINCR protects cardiomyocytes from ischemia–reperfusion injury via inhibiting degradation and ubiquitination of FGF1

QJM ◽  
2020 ◽  
Vol 113 (12) ◽  
pp. 859-869
Author(s):  
M Wang ◽  
S Liu ◽  
H Wang ◽  
R Tang ◽  
Z Chen
Keyword(s):  
Cytochrome C ◽  
Cell Viability ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Counting ◽  
Cytochrome C Release ◽  
Mptp Opening

Abstract Background Our previous study has demonstrated that morphine post-conditioning (MpostC) protects cardiomyocytes from ischemia/reperfusion (I/R) injury partly through activating protein kinase-epsilon (PKCε) signaling pathway and subsequently inhibiting mitochondrial permeability transition pore (mPTP) opening. Aim In this study, we aim to investigate the relationship between long non-coding RNA TINCR and PKCε in cardiomyocytes under MpostC-treated I/R injury. Design The myocardial I/R rat model was established by the ligation of lower anterior descending coronary artery for 45 min followed by the reperfusion for 1 h, and MpostC was performed before the reperfusion. Method H/R and MpostC were performed in the rat cardiomyocyte cell line (H9C2), and the Cytochrome-c release in cytosol and mPTP opening were determined. Cell viability was detected by using Cell Counting Kit-8, and cell apoptosis was determined by using flow cytometry or TUNEL assay. Results The results indicated that MpostC restored the expression of TINCR in I/R rat myocardial tissues. In cardiomyocytes, the therapeutic effect of MpostC, including reduced mPTP opening, reduced Cytochrome-c expression, increased cell viability and reduced cell apoptosis, was dramatically negated by interfering TINCR. The expression of fibroblast growth factor 1 (FGF1), a protein that activates PKCε signaling pathway, was positively correlated with TINCR. The RNA immunoprecipitation and RNA pull-down assay further confirmed the binding between FGF1 and TINCR. Furthermore, TINCR was demonstrated to inhibit the degradation and ubiquitination of FGF1 in cardiomyocytes using the cycloheximide experiment and the ubiquitination assay. The TINCR/FGF1/PKCε axis was revealed to mediate the protective effect of MpostC against hypoxia/reoxygenation injury both in vitro and in vivo. Conclusion In conclusion, our findings demonstrated that MpostC-induced up-regulation of TINCR protects cardiomyocytes from I/R injury via inhibiting degradation and ubiquitination of FGF1, and subsequently activating PKCε signaling pathway, which provides a novel insight in the mechanism of TINCR and PKCε during MpostC treatment of I/R injury.

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