Displaying publications 21 - 33 of 33 in total

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  1. Fulltext Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy
    Ong SB, Lee WH, Shao NY, Ismail NI, Katwadi K, Lim MM, et al.
    Stem Cell Reports, 2019 03 05;12(3):597-610.
    PMID: 30799273 DOI: 10.1016/j.stemcr.2019.01.017
    The relationship between diabetes and endothelial dysfunction remains unclear, particularly the association with pathological activation of calpain, an intracellular cysteine protease. Here, we used human induced pluripotent stem cells-derived endothelial cells (iPSC-ECs) to investigate the effects of diabetes on vascular health. Our results indicate that iPSC-ECs exposed to hyperglycemia had impaired autophagy, increased mitochondria fragmentation, and was associated with increased calpain activity. In addition, hyperglycemic iPSC-ECs had increased susceptibility to cell death when subjected to a secondary insult-simulated ischemia-reperfusion injury (sIRI). Importantly, calpain inhibition restored autophagy and reduced mitochondrial fragmentation, concurrent with maintenance of ATP production, normalized reactive oxygen species levels and reduced susceptibility to sIRI. Using a human iPSC model of diabetic endotheliopathy, we demonstrated that restoration of autophagy and prevention of mitochondrial fragmentation via calpain inhibition improves vascular integrity. Our human iPSC-EC model thus represents a valuable platform to explore biological mechanisms and new treatments for diabetes-induced endothelial dysfunction.
    Matched MeSH terms: Reperfusion Injury
  2. Fulltext Targeting mitochondrial reactive oxygen species-mediated oxidative stress attenuates nicotine-induced cardiac remodeling and dysfunction
    Ramalingam A, Budin SB, Mohd Fauzi N, Ritchie RH, Zainalabidin S
    Sci Rep, 2021 07 05;11(1):13845.
    PMID: 34226619 DOI: 10.1038/s41598-021-93234-4
    Long-term nicotine intake is associated with an increased risk of myocardial damage and dysfunction. However, it remains unclear whether targeting mitochondrial reactive oxygen species (ROS) prevents nicotine-induced cardiac remodeling and dysfunction. This study investigated the effects of mitoTEMPO (a mitochondria-targeted antioxidant), and resveratrol (a sirtuin activator) , on nicotine-induced cardiac remodeling and dysfunction. Sprague-Dawley rats were administered 0.6 mg/kg nicotine daily with 0.7 mg/kg mitoTEMPO, 8 mg/kg resveratrol, or vehicle alone for 28 days. At the end of the study, rat hearts were collected to analyze the cardiac structure, mitochondrial ROS level, oxidative stress, and inflammation markers. A subset of rat hearts was perfused ex vivo to determine the cardiac function and myocardial susceptibility to ischemia-reperfusion injury. Nicotine administration significantly augmented mitochondrial ROS level, cardiomyocyte hypertrophy, fibrosis, and inflammation in rat hearts. Nicotine administration also induced left ventricular dysfunction, which was worsened by ischemia-reperfusion in isolated rat hearts. MitoTEMPO and resveratrol both significantly attenuated the adverse cardiac remodeling induced by nicotine, as well as the aggravation of postischemic ventricular dysfunction. Findings from this study show that targeting mitochondrial ROS with mitoTEMPO or resveratrol partially attenuates nicotine-induced cardiac remodeling and dysfunction.
    Matched MeSH terms: Myocardial Reperfusion Injury/chemically induced; Myocardial Reperfusion Injury/metabolism; Myocardial Reperfusion Injury/prevention & control
  3. Role of melatonin in neurodegenerative diseases
    Srinivasan V, Pandi-Perumal SR, Maestroni GJ, Esquifino AI, Hardeland R, Cardinali DP
    Neurotox Res, 2005;7(4):293-318.
    PMID: 16179266
    The pineal product melatonin has remarkable antioxidant properties. It scavenges hydroxyl, carbonate and various organic radicals, peroxynitrite and other reactive nitrogen species. Melatonyl radicals formed by scavenging combine with and, thereby, detoxify superoxide anions in processes terminating the radical reaction chains. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes like superoxide dismutase, glutathione peroxidase and glutathione reductase, and by augmenting glutathione levels. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases, e.g., Alzheimer's disease. Melatonin has been shown to be effective in arresting neurodegenerative phenomena seen in experimental models of Alzheimer's disease, Parkinsonism and ischemic stroke. Melatonin preserves mitochondrial homeostasis, reduces free radical generation, e.g., by enhancing mitochondrial glutathione levels, and safeguards proton potential and ATP synthesis by stimulating complex I and IV activities. Therapeutic trials with melatonin have been effective in slowing the progression of Alzheimer's disease but not of Parkinson's disease. Melatonin's efficacy in combating free radical damage in the brain suggests that it may be a valuable therapeutic agent in the treatment of cerebral edema after traumatic brain injury.
    Matched MeSH terms: Reperfusion Injury/metabolism; Reperfusion Injury/pathology
  4. Impact of cardiac care variation on ST-elevation myocardial infarction outcomes in Malaysia
    Selvarajah S, Fong AY, Selvaraj G, Haniff J, Hairi NN, Bulgiba A, et al.
    Am J Cardiol, 2013 May 1;111(9):1270-6.
    PMID: 23415636 DOI: 10.1016/j.amjcard.2013.01.271
    Developing countries face challenges in providing the best reperfusion strategy for patients with ST-segment elevation myocardial infarction because of limited resources. This causes wide variation in the provision of cardiac care. The aim of this study was to assess the impact of variation in cardiac care provision and reperfusion strategies on patient outcomes in Malaysia. Data from a prospective national registry of acute coronary syndromes were used. Thirty-day all-cause mortality in 4,562 patients with ST-segment elevation myocardial infarctions was assessed by (1) cardiac care provision (specialist vs nonspecialist centers), and (2) primary reperfusion therapy (thrombolysis or primary percutaneous coronary intervention [P-PCI]). All patients were risk adjusted by Thrombolysis In Myocardial Infarction (TIMI) risk score. Thrombolytic therapy was administered to 75% of patients with ST-segment elevation myocardial infarctions (12% prehospital and 63% in-hospital fibrinolytics), 7.6% underwent P-PCI, and the remainder received conservative management. In-hospital acute reperfusion therapy was administered to 68% and 73% of patients at specialist and nonspecialist cardiac care facilities, respectively. Timely reperfusion was low, at 24% versus 31%, respectively, for in-hospital fibrinolysis and 28% for P-PCI. Specialist centers had statistically significantly higher use of evidence-based treatments. The adjusted 30-day mortality rates for in-hospital fibrinolytics and P-PCI were 7% (95% confidence interval 5% to 9%) and 7% (95% confidence interval 3% to 11%), respectively (p = 0.75). In conclusion, variation in cardiac care provision and reperfusion strategy did not adversely affect patient outcomes. However, to further improve cardiac care, increased use of evidence-based resources, improvement in the quality of P-PCI care, and reduction in door-to-reperfusion times should be achieved.
    Matched MeSH terms: Myocardial Reperfusion/methods*
  5. Changes in blood-brain barrier permeability and ultrastructure, and protein expression in a rat model of cerebral hypoperfusion
    Sekaran H, Gan CY, A Latiff A, Harvey TM, Mohd Nazri L, Hanapi NA, et al.
    Brain Res Bull, 2019 10;152:63-73.
    PMID: 31301381 DOI: 10.1016/j.brainresbull.2019.07.010
    Cerebral hypoperfusion involved a reduction in cerebral blood flow, leading to neuronal dysfunction, microglial activation and white matter degeneration. The effects on the blood-brain barrier (BBB) however, have not been well-documented. Here, two-vessel occlusion model was adopted to mimic the condition of cerebral hypoperfusion in Sprague-Dawley rats. The BBB permeability to high and low molecular weight exogenous tracers i.e. Evans blue dye and sodium fluorescein respectively, showed marked extravasation of the Evans blue dye in the frontal cortex, posterior cortex and thalamus-midbrain at day 1 following induction of cerebral hypoperfusion. Transmission electron microscopy revealed brain endothelial cell and astrocyte damages including increased pinocytotic vesicles and formation of membrane invaginations in the endothelial cells, and swelling of the astrocytes' end-feet. Investigation on brain microvessel protein expressions using two-dimensional (2D) gel electrophoresis coupled with LC-MS/MS showed that proteins involved in mitochondrial energy metabolism, transcription regulation, cytoskeleton maintenance and signaling pathways were differently expressed. The expression of aconitate hydratase, heterogeneous nuclear ribonucleoprotein, enoyl Co-A hydratase and beta-synuclein were downregulated, while the opposite observed for calreticulin and enhancer of rudimentary homolog. These findings provide insights into the BBB molecular responses to cerebral hypoperfusion, which may assist development of future therapeutic strategies.
    Matched MeSH terms: Reperfusion Injury/metabolism
  6. Dependence of human forearm skin postocclusive reactive hyperemia on occlusion time
    Tee GB, Rasool AH, Halim AS, Rahman AR
    J Pharmacol Toxicol Methods, 2004 Jul-Aug;50(1):73-8.
    PMID: 15233971 DOI: 10.1016/j.vascn.2004.02.002
    Human postocclusive forearm skin reactive hyperemia is not only a potential means of identifying early signs of cardiovascular diseases, it can also be used in the assessment of local microvascular response to topically applied compounds on skin. The method is not fully characterized. In this study, we investigated the influence of occlusion time on postocclusive forearm skin reactive hyperemia using laser Doppler fluximetry (LDF).
    Matched MeSH terms: Reperfusion
  7. Fulltext Mediation of Cardiac Macrophage Activity via Auricular Vagal Nerve Stimulation Ameliorates Cardiac Ischemia/Reperfusion Injury
    Chung CH, Bretherton B, Zainalabidin S, Deuchars SA, Deuchars J, Mahadi MK
    Front Neurosci, 2020;14:906.
    PMID: 33013299 DOI: 10.3389/fnins.2020.00906
    Background: Myocardial infarction (MI) reperfusion therapy causes paradoxical cardiac complications. Following restoration of blood flow to infarcted regions, a multitude of inflammatory cells are recruited to the site of injury for tissue repair. Continual progression of cardiac inflammatory responses does, however, lead to adverse cardiac remodeling, inevitably causing heart failure.

    Main Body: Increasing evidence of the cardioprotective effects of both invasive and non-invasive vagal nerve stimulation (VNS) suggests that these may be feasible methods to treat myocardial ischemia/reperfusion injury via anti-inflammatory regulation. The mechanisms through which auricular VNS controls inflammation are yet to be explored. In this review, we discuss the potential of autonomic nervous system modulation, particularly via the parasympathetic branch, in ameliorating MI. Novel insights are provided about the activation of the cholinergic anti-inflammatory pathway on cardiac macrophages. Acetylcholine binding to the α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages polarizes the pro-inflammatory into anti-inflammatory subtypes. Activation of the α7nAChR stimulates the signal transducer and activator of transcription 3 (STAT3) signaling pathway. This inhibits the secretion of pro-inflammatory cytokines, limiting ischemic injury in the myocardium and initiating efficient reparative mechanisms. We highlight recent developments in the controversial auricular vagal neuro-circuitry and how they may relate to activation of the cholinergic anti-inflammatory pathway.

    Conclusion: Emerging published data suggest that auricular VNS is an inexpensive healthcare modality, mediating the dynamic balance between pro- and anti-inflammatory responses in cardiac macrophages and ameliorating cardiac ischemia/reperfusion injury.

    Matched MeSH terms: Myocardial Reperfusion Injury
  8. Fulltext Acute Ischaemic Stroke Successfully Treated with Thrombolytic Therapy and Endovascular Thrombectomy with Non-Contrast Computed Tomography and Computed Tomography Angiogram Protocol
    Toh TH, Abdul Kadir KA, Tai MS, Tan KS
    Case Rep Neurol, 2020 12 14;12(Suppl 1):15-21.
    PMID: 33505267 DOI: 10.1159/000501820
    Early endovascular thrombectomy leads to improved outcomes for patients with proximal occlusions when started within 6 h from onset of symptoms. We present a case illustrating the flow of events for a patient who underwent endovascular thrombectomy in our centre after conventional imaging - a brain non-contrast computed tomography (NCCT) and CT angiogram (CTA) - achieving a door-to-groin time of 195 min. The patient is a 65-year-old who presented with signs and symptoms of a left middle cerebral artery (MCA) territory infarct. His National Institute of Health Stroke Scale (NIHSS) score was 15 on presentation and his brain NCCT showed an Alberta Stroke Programme Early CT Score (ASPECTS) of 8. His CTA showed a left MCA distal M1 occlusion with focal calcification and stenosis of the proximal left internal carotid artery. He was subsequently thrombosed and underwent thrombectomy successfully, with a door-to-groin-puncture time of 195 min. A TICI 2b reperfusion was achieved. His NIHSS score improved to 9 over the next 2 days. For cases with straightforward NCCT and CTA with no contraindications, endovascular thrombectomy should be pursued without delay. A review of the current available literature for the usage of NCCT and CTA as well as the importance of ASPECTS scoring in patient selection for endovascular thrombectomy was included.
    Matched MeSH terms: Reperfusion
  9. MiD49 and MiD51: New mediators of mitochondrial fission and novel targets for cardioprotection
    Samangouei P, Crespo-Avilan GE, Cabrera-Fuentes H, Hernández-Reséndiz S, Ismail NI, Katwadi KB, et al.
    Cond Med, 2018 Aug;1(5):239-246.
    PMID: 30338314
    Acute myocardial infarction (AMI) and the heart failure (HF) that often follows are among the leading causes of death and disability worldwide. As such novel therapies are needed to reduce myocardial infarct (MI) size, and preserve left ventricular (LV) systolic function in order to reduce the propensity for HF following AMI. Mitochondria are dynamic organelles that can undergo morphological changes by two opposing processes, mitochondrial fusion and fission. Changes in mitochondrial morphology and turnover are a vital part of maintaining mitochondrial health, DNA stability, energy production, calcium homeostasis, cellular division, and differentiation, and disturbances in the balance of fusion and fission can predispose to mitochondrial dysfunction and cell death. Changes in mitochondrial morphology are governed by mitochondrial fusion proteins (Mfn1, Mfn2 and OPA1) and mitochondrial fission proteins (Drp1, hFis1, and Mff). Recent experimental data suggest that mitochondria undergo fission during acute ischemia/reperfusion injury (IRI), generating fragmented dysfunctional mitochondrial and predisposing to cell death. We and others have shown that genetic and pharmacological inhibition of the mitochondrial fission protein Drp1 can protect cardiomyocytes from acute IRI and reduce MI size. Novel components of the mitochondrial fission machinery, mitochondrial dynamics proteins of 49 kDa (MiD49) and mitochondrial dynamics proteins of 51 kDa (MiD51), have been recently described, which have been shown to mediating mitochondrial fission by targeting Drp1 to the mitochondrial surface. In this review article, we provide an overview of MiD49 and MiD51, and highlight their potential as novel therapeutic targets for treating cardiovascular diseases such as AMI, anthracycline cardiomyopathy, and pulmonary arterial hypertension.
    Matched MeSH terms: Reperfusion Injury
  10. Fulltext Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by Vitamin B supplementation
    Tripathi M, Zhang CW, Singh BK, Sinha RA, Moe KT, DeSilva DA, et al.
    Cell Death Dis, 2016 12 08;7(12):e2513.
    PMID: 27929536 DOI: 10.1038/cddis.2016.374
    Hyperhomocysteinemia (HHcy) is a well-known risk factor for stroke; however, its underlying molecular mechanism remains unclear. Using both mouse and cell culture models, we have provided evidence that impairment of autophagy has a central role in HHcy-induced cellular injury in the mouse brain. We observed accumulation of LC3B-II and p62 that was associated with increased MTOR signaling in human and mouse primary astrocyte cell cultures as well as a diet-induced mouse model of HHcy, HHcy decreased lysosomal membrane protein LAMP2, vacuolar ATPase (ATP6V0A2), and protease cathepsin D, suggesting that lysosomal dysfunction also contributed to the autophagic defect. Moreover, HHcy increased unfolded protein response. Interestingly, Vitamin B supplementation restored autophagic flux, alleviated ER stress, and reversed lysosomal dysfunction due to HHCy. Furthermore, the autophagy inducer, rapamycin was able to relieve ER stress and reverse lysosomal dysfunction caused by HHcy in vitro. Inhibition of autophagy by HHcy exacerbated cellular injury during oxygen and glucose deprivation and reperfusion (OGD/R), and oxidative stress. These effects were prevented by Vitamin B co-treatment, suggesting that it may be helpful in relieving detrimental effects of HHcy in ischemia/reperfusion or oxidative stress. Collectively, these findings show that Vitamin B therapy can reverse defects in cellular autophagy and ER stress due to HHcy; and thus may be a potential treatment to reduce ischemic damage caused by stroke in patients with HHcy.
    Matched MeSH terms: Reperfusion Injury/pathology
  11. Successful intravenous thrombolysis of a wake-up stroke with underlying valvular atrial fibrillation
    Shahedah KK, Khoo CS, Wan Nur Nafisah WY, Ng CF, Noor Ashikin I, Mohd Naim MY, et al.
    J R Coll Physicians Edinb, 2018 Sep;48(3):239-241.
    PMID: 30191912 DOI: 10.4997/JRCPE.2018.308
    A 42-year-old female admitted with new-onset atrial fibrillation had a wake-up stroke on the high-dependency unit and the time last seen well (TLSW) was 6.5 h. She suffered left-sided body weakness and her National Institutes of Health Stroke Scale (NIHSS) score was 17. An emergency CT perfusion showed right M1 segment occlusion with more than 50% penumbra. She was given recombinant tissue plasminogen activator (r-tPA) at 9 h from TLSW. An immediate diagnostic angiogram with intention to treat, owing to the presence of large vessel occlusion, showed complete reperfusion after intravenous r-tPA. She was discharged with NIHSS of 2, and at 3-month follow up her Modified Rankin Scale was 0. We demonstrated a successful reperfusion and excellent clinical recovery with intravenous thrombolysis in a patient who presented with a wake-up stroke with underlying valvular atrial fibrillation despite evidence of large vessel occlusion.
    Matched MeSH terms: Reperfusion
  12. Fulltext Acute coronary syndrome (ACS) registry--leading the charge for National Cardiovascular Disease (NCVD) Database
    Chin SP, Jeyaindran S, Azhari R, Wan Azman WA, Omar I, Robaayah Z, et al.
    Med J Malaysia, 2008 Sep;63 Suppl C:29-36.
    PMID: 19230244
    Coronary artery disease is one of the most rampant non-communicable diseases in the world. It begins indolently as a fatty streak in the lining of the artery that soon progresses to narrow the coronary arteries and impair myocardial perfusion. Often the atherosclerotic plaque ruptures and causes sudden thrombotic occlusion and acute ST-elevation myocardial infarction (STEMI), non-ST-elevation MI (NSTEMI) or unstable angina (UA). This phenomenon is called acute coronary syndrome (ACS) and is the leading cause of death not only in Malaysia but also globally. In order for us to tackle this threat to the health of our nation we must arm ourselves with reliable and accurate information to assess current burden of disease resources available and success of current strategies. The acute coronary syndrome (ACS) registry is the flagship of the National Cardiovascular Disease Database (NCVD) and is the result of the dedicated and untiring efforts of doctors and nurses in both public and private medical institutions and hospitals around the country, ably guided and supported by the National Heart Association, the National Heart Foundation, the Clinical Research Centre and the Ministry of Health of Malaysia. Analyses of data collected throughout 2006 from 3422 patients with ACS admitted to the 12 tertiary cardiac centres and general hospitals spanning nine states in Malaysia in this first report has already revealed surprising results. Mean age of patients was 59 years while the most consistent risk factor for STEMI was active smoking. Utilization of medications was high generally. Thirty-day mortality for STEMI was 11%, for NSTEMI 8% and UA 4%. Thrombolysis (for STEMI only) reduced in-hospital and 30-day mortality by nearly 50%. Percutaneous coronary intervention or PCI also reduced 30-day mortality for patients with non-ST elevation MI and unstable angina. The strongest determinants of mortality appears to be Killip Class and age of the patient. Fewer women received thrombolysis or underwent PCI on same admission although women make up 25% of the cohort.
    Matched MeSH terms: Myocardial Reperfusion
  13. Fulltext Cardioprotection by isosteviol derivate JC105: A unique drug property to activate ERK1/2 only when cells are exposed to hypoxia-reoxygenation
    Mohammed Abdul KS, Rayadurgam J, Faiz N, Jovanović A, Tan W
    J Cell Mol Med, 2020 09;24(18):10924-10934.
    PMID: 32794652 DOI: 10.1111/jcmm.15721
    In the present study, we have investigated potential cardioprotective properties of Isosteviol analogue we recently synthesized and named JC105. Treatment of heart embryonic H9c2 cells with JC105 (10 μM) significantly increased survival of cells exposed to hypoxia-reoxygenation. JC105 (10 μM) activated ERK1/2, DRP1 and increased levels of cardioprotective SUR2A in hypoxia-reoxygenation, but did not have any effects on ERK1/2, DRP1 and/or SUR2A in normoxia. U0126 (10 μM) inhibited JC105-mediated phosphorylation of ERK1/2 and DRP1 without affecting AKT or AMPK, which were also not regulated by JC105. Seahorse bioenergetic analysis demonstrated that JC105 (10 μM) did not affect mitochondria at rest, but it counteracted all mitochondrial effects of hypoxia-reoxygenation. Cytoprotection afforded by JC105 was inhibited by U0126 (10 μM). Taken all together, these demonstrate that (a) JC105 protects H9c2 cells against hypoxia-reoxygenation and that (b) this effect is mediated via ERK1/2. The unique property of JC105 is that selectively activates ERK1/2 in cells exposed to stress, but not in cells under non-stress conditions.
    Matched MeSH terms: Myocardial Reperfusion
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