Global DNA hypermethylation and mitochondrial dysfunction are reported to be associated with the ... more Global DNA hypermethylation and mitochondrial dysfunction are reported to be associated with the development of mild cognitive decline (MCI). The present study aims to generate preliminary data that connect the above association with post-surgical coronary artery bypass grafting (CABG) cognitive decline in patients. Data were collected from 70 CABG patients and 25 age-matched controls. Cognitive function was assessed using the Montreal Cognitive Assessment (MOCA) test on day 1 (before surgery) and on the day of discharge. Similarly, blood was collected before and one day after the CABG procedure for mitochondrial functional analysis and expression of DNA methylation genes. Test analysis score suggested 31 (44%) patients had MCI before discharge. These patients showed a significant decrease in complex I activity and an increase in malondialdehyde levels (p < 0.001) from the control blood samples. Post-surgical samples showed a significant reduction in blood MT-ND1 mRNA expression ...
In this study, we compared the impact of H2S pre (HIPC) and post-conditioning (HPOC) on oxidative... more In this study, we compared the impact of H2S pre (HIPC) and post-conditioning (HPOC) on oxidative stress, the prime reason for myocardial ischemia reperfusion injury (I/R), in different compartments of the myocardium, such as the mitochondria beside its subpopulations (interfibrillar (IFM) and subsarcolemmal (SSM) mitochondria) and microsomal fractions in I/R injured rat heart. The results demonstrated that compared to I/R rat heart, HIPC and HPOC treated hearts shows reduced myocardial injury, enhanced antioxidant enzyme activities and reduced the level of TBARS in different cellular compartments. The extent of recovery (measured by TBARS and GSH levels) in subcellular fractions, were in the following descending order: microsome &amp;amp;gt; SSM &amp;amp;gt; IFM in both HIPC and HPOC. In summary, oxidative stress mediated mitochondrial dysfunction, one of the primary causes for I/R injury, was partly recovered by HIPC and HPOC treatment, with significant improvement in SSM fraction compared to the IFM.
Circulatory GSK3β is recognized as a biomarker and therapeutic target for diseases, including myo... more Circulatory GSK3β is recognized as a biomarker and therapeutic target for diseases, including myocardial diseases. However, its potential as a target for myocardial ischemia-reperfusion injury (IR) in the presence of PM2.5 exposure is unclear. Wistar rats underwent IR following either a 21-day or single exposure to PM2.5 at a concentration of 250 µg/m3. The effects of GSK3β inhibitor on cardiac physiology, tissue injury, mitochondrial function, and the PI3K/AKT/GSK3β signalling axis were examined. The inhibitor was not effective in improving hemodynamics or reducing IR-induced infarction in the myocardium exposed to PM2.5 for 21 days. However, for a single-day exposure, the inhibitor showed potential in mitigating cardiac injury. In normal hearts undergoing IR, the inhibitor activated the PI3K/AKT signalling pathway, improved mitochondrial function, and reduced oxidative stress. These positive effects were not observed in PM2.5-exposed rats. Furthermore, the inhibitor stimulated aut...
A previous study has reported that exposure to PM2.5 from diesel exhaust (diesel particulate matt... more A previous study has reported that exposure to PM2.5 from diesel exhaust (diesel particulate matter (DPM)) for 21 days can deteriorate the cardiac recovery from myocardial ischemia reperfusion injury (IR), where the latter is facilitated by the efficiency of mitochondrial subpopulations. Many investigators have demonstrated that IR impact on cardiac mitochondrial subpopulations is distinct. In the present study, we decipher the role of PM2.5 on IR associated mitochondrial dysfunction at the subpopulation level by administrating PM2.5 directly to isolated female rat hearts via KH buffer. Our results demonstrated that PM2.5 administered heart (PM_C) severely deteriorated ETC enzyme activity (NQR, SQR, QCR, and COX) and ATP level in both IFM and SSM from the normal control. Comparatively, the declined activity was prominent in IFM fraction. Moreover, in the presence of IR (PM_IR), mitochondrial oxidative stress was higher in both subpopulations from the normal, where the IFM fraction o...
Ischemia reperfusion (I/R) injury is one of the main clinical challenges for cardiac surgeons. No... more Ischemia reperfusion (I/R) injury is one of the main clinical challenges for cardiac surgeons. No effective strategies or therapy targeting the molecular and cellular mechanisms to reduce I/R exists to date, despite altered gene expression and cellular metabolism/physiology. We aimed to identify whether DNA methylation, an unexplored target, can be a potential site to curb I/R-associated cell death by using the left anterior descending artery occlusion model in male Wistar rats. I/R rat heart exhibited global DNA hypermethylation with a corresponding decline in the mitochondrial genes (PGC-1α, TFAM, POLG, ND1, ND3, ND4, Cyt B, COX1, and COX2), antioxidant genes (SOD2, catalase, and Gpx2) and elevation in apoptotic genes (Casp3, Casp7, and Casp9) expression with corresponding changes in their activity, resulting in injury. Targeting global DNA methylation in I/R hearts by using its inhibitor significantly reduced the I/R-associated infarct size by 45% and improved dysferlin levels vi...
Many studies have reported the negative effect of PM2.5 exposure on heart function which is likel... more Many studies have reported the negative effect of PM2.5 exposure on heart function which is likely to impair postcardiac surgery rehabilitation that is involved in recovery and wound healing, yet the direct effects of PM2.5 from diesel exhaust (DPM) on cardiac recovery is unknown. To study the impact of DPM on cardiac recovery and repair, we utilized isoproterenol induced myocardial infarction (MI) model where female rats were exposed to DPM prior and after MI induction. The experimental groups comprise of normal, ISO control, DPM control (42 days of exposure), DPM exposed prior (21 days) and after (21 days) MI induction (D + I + D) and DPM exposed (21 days) after MI (I + D). Post-MI rat hearts from D + I + D group exhibited higher fibrosis, elevated cardiac injury and altered electrophysiology, where this pathology was also observed in I + D group animals which was mild. Loss of mitochondrial quality was evident in DPM exposed animals with and without MI, where severe mitochondrial damage persisted in D + I + D group. In addition, these animals showed striking decline in ETC enzyme activity, ATP levels, mitochondrial copy number and down regulation of PGC1-α, TFAM and POLG along with the genes involved in mitophagy and mitofusion. Besides, the MI associated inactivation of cardio protective signalling pathways like PI3K and Akt were persistent in D + I + D group. In fact, I + D group animals also showed a similar pattern of change, but in a mild form. Taken together, exposure to PM2.5 increases the risk, frequency or progression of MI by impairing the recovery potential of the myocardium.
Recent studies have shown that pre and postconditioning the heart with sodium thiosulfate (STS) a... more Recent studies have shown that pre and postconditioning the heart with sodium thiosulfate (STS) attenuate ischemia-reperfusion (IR) injury. However, the underlying mechanism involved in the cardioprotective signaling pathway is not fully explored. This study examined the existing link of STS mediated protection (as pre and post-conditioning agents) with PI3K, mTOR, and mPTP signaling pathways using its respective inhibitors. STS was administered to the isolated perfused rat heart through Kreb's Heinselit buffer before ischemia (precondition: SIPC) and reperfusion (postcondition: SPOC) in the presence and absence of the PI3K, mTOR, and mPTP signaling pathway inhibitors (wortmannin, rapamycin, and glibenclamide respectively). SIPC failed to improve the IR injury-induced altered cardiac hemodynamics, increased infarct size, and the release of cardiac injury markers in the presence of these inhibitors. On the other hand, the SPOC protocol effectively rendered the cardioprotection even in the PI3K/mTOR/KATP inhibitors presence. Interestingly, the SIPC's identified mode of action viz reduction in oxidative stress and the preservation of mitochondrial function were lost in the inhibitors' presence. Based on the above results, we conclude that the underlying mechanism of SIPC mediated cardioprotection works via the PI3K/mTOR/KATP signaling pathway axis activation.
Resveratrol is well known for its antioxidant potential and ability to preserve mitochondrial fun... more Resveratrol is well known for its antioxidant potential and ability to preserve mitochondrial function, reported attenuating ischemia-reperfusion (IR) injury in the heart. The present study investigates resveratrol on IR injury in rat hearts treated with statin for 14 days. Male Wistar rats were used in this study, and statin-induced cardiac metabolic alterations were monitored after the administration of simvastatin (80 mg/kg). IR was instigated by the Langendroff perfusion system and measured the physiological and biochemical changes. The basal level changes in ECG, ANP, and BNP expression and CoenzymeQ10 level were altered in statin-treated animals compared to the normal rat heart. The animals treated with statin demonstrated higher IR injury (measured via low rate pressure product (88.4%), increased histological alterations, prominent mitochondrial dysfunction (NQR: IR-72%, Stat IR-67%; SQR: IR-71%, Stat IR-74%; COX: IR-58%, Stat IR-52%) than the normal rat heart underwent similar protocols. Administration of heart with resveratrol recovered the IR associated hemodynamic indices in normal heart subjected to IR but failed to impart a similar effect in the statin-treated heart. Our results demonstrated that resveratrol failed to reverse the IR-associated cardiac injury and functional abnormalities in statin-treated rat hearts subjected to IR but effective in IR challenged normal heart.
Introduction: Some of the previous studies reported distant organ injury like liver injury and re... more Introduction: Some of the previous studies reported distant organ injury like liver injury and renal failure after cardiac surgery, whereas in other studies no injury was identified. Magnesium (Mg) deficiency commonly occurs in critical illness and correlates with a higher mortality and worse clinical outcome in the intensive care unit (ICU). Accordingly, this study was designed to assess the effect of magnesium on liver and kidney function abnormalities during CABG procedure in an Indian population. Methods: A clinical trial (n= 52) was conducted to determine the effects of magnesium (16mEq) on distant organs, administered just before the release of aortic cross clamp in patients undergoing coronary bypass operations. We took five blood samples at different times during cardiac surgery and analyzed the levels of ALT, AST, ALP, uric acid, total protein and creatinine. Cardiac marker enzymes like CPK MB, Troponin I and LDH were analyzed. Moreover, the antioxidant enzymes in erythrocy...
Objective: Calcium overload and oxidative stress have been identified as pathogenic factors in my... more Objective: Calcium overload and oxidative stress have been identified as pathogenic factors in myocardial ischaemic reperfusion. Experimental studies have demonstrated that intravenous magnesium (Mg) can protect the ischaemic myocardium. It has a free radical scavenging effect and can act as a calcium channel blocker. Although the role of copper, iron, and other metal elements in ischaemic heart injury has been well established, clinical studies are very limited. The link between these serum metal element concentrations and oxidative stress is unclear in humans although, in experimental animal studies, severe Mg deficiency has been shown to lead to increased oxidative stress. Methods: Ninety-two South Indian patients with acute myocardial ischaemia undergoing CABG were randomized to a study and a control group. Magnesium was administered (2 g/kg body weight) to the study group. Control patients received the same protocol without magnesium. Serum levels of copper, zinc, iron, cerulop...
Asian Pacific Journal of Tropical Biomedicine, 2020
Objective: To compare the anti-proliferative effect of sodium thiosulfate on human colorectal can... more Objective: To compare the anti-proliferative effect of sodium thiosulfate on human colorectal cancer cells (HT-29) and normal small intestine cells (IEC6). Methods: Cells (HT-29 and IEC6) were treated with different concentrations of sodium thiosulfate ranging from 0.5 mM to 80 mM for 24 h. Cell viability was measured via crystal violet and MTT assays. HT-29 cells were further treated in the presence and absence of mitochondrial electron transport chain (ETC) inhibitors, KATP channel opener and closer and H2S inhibitors for 24 h followed by sodium thiosulfate in order to study their respective roles in the anti-proliferative activity of sodium thiosulfate. Results: The IC50 values of sodium thiosulfate on HT-29 cells were 40.93 mM and 42.45 mM by crystal violet and MTT assay whereas, in the case of IEC6 cells, the values were 45.17 mM and 47.22 mM. The inhibition of endogenous H2S enzymes and KATP channel induced no change in the anti-proliferative capacity of sodium thiosulfate. However, the anti-proliferative activity of sodium thiosulfate was enhanced in the presence of mitochondrial ETC inhibitors. Conclusions: HT-29 cell growth is effectively attenuated by sodium thiosulfate and the anti-proliferative activity of sodium thiosulfate is enhanced in the presence of mitochondrial ETC inhibitors.
Global DNA hypermethylation and mitochondrial dysfunction are reported to be associated with the ... more Global DNA hypermethylation and mitochondrial dysfunction are reported to be associated with the development of mild cognitive decline (MCI). The present study aims to generate preliminary data that connect the above association with post-surgical coronary artery bypass grafting (CABG) cognitive decline in patients. Data were collected from 70 CABG patients and 25 age-matched controls. Cognitive function was assessed using the Montreal Cognitive Assessment (MOCA) test on day 1 (before surgery) and on the day of discharge. Similarly, blood was collected before and one day after the CABG procedure for mitochondrial functional analysis and expression of DNA methylation genes. Test analysis score suggested 31 (44%) patients had MCI before discharge. These patients showed a significant decrease in complex I activity and an increase in malondialdehyde levels (p < 0.001) from the control blood samples. Post-surgical samples showed a significant reduction in blood MT-ND1 mRNA expression ...
In this study, we compared the impact of H2S pre (HIPC) and post-conditioning (HPOC) on oxidative... more In this study, we compared the impact of H2S pre (HIPC) and post-conditioning (HPOC) on oxidative stress, the prime reason for myocardial ischemia reperfusion injury (I/R), in different compartments of the myocardium, such as the mitochondria beside its subpopulations (interfibrillar (IFM) and subsarcolemmal (SSM) mitochondria) and microsomal fractions in I/R injured rat heart. The results demonstrated that compared to I/R rat heart, HIPC and HPOC treated hearts shows reduced myocardial injury, enhanced antioxidant enzyme activities and reduced the level of TBARS in different cellular compartments. The extent of recovery (measured by TBARS and GSH levels) in subcellular fractions, were in the following descending order: microsome &amp;amp;gt; SSM &amp;amp;gt; IFM in both HIPC and HPOC. In summary, oxidative stress mediated mitochondrial dysfunction, one of the primary causes for I/R injury, was partly recovered by HIPC and HPOC treatment, with significant improvement in SSM fraction compared to the IFM.
Circulatory GSK3β is recognized as a biomarker and therapeutic target for diseases, including myo... more Circulatory GSK3β is recognized as a biomarker and therapeutic target for diseases, including myocardial diseases. However, its potential as a target for myocardial ischemia-reperfusion injury (IR) in the presence of PM2.5 exposure is unclear. Wistar rats underwent IR following either a 21-day or single exposure to PM2.5 at a concentration of 250 µg/m3. The effects of GSK3β inhibitor on cardiac physiology, tissue injury, mitochondrial function, and the PI3K/AKT/GSK3β signalling axis were examined. The inhibitor was not effective in improving hemodynamics or reducing IR-induced infarction in the myocardium exposed to PM2.5 for 21 days. However, for a single-day exposure, the inhibitor showed potential in mitigating cardiac injury. In normal hearts undergoing IR, the inhibitor activated the PI3K/AKT signalling pathway, improved mitochondrial function, and reduced oxidative stress. These positive effects were not observed in PM2.5-exposed rats. Furthermore, the inhibitor stimulated aut...
A previous study has reported that exposure to PM2.5 from diesel exhaust (diesel particulate matt... more A previous study has reported that exposure to PM2.5 from diesel exhaust (diesel particulate matter (DPM)) for 21 days can deteriorate the cardiac recovery from myocardial ischemia reperfusion injury (IR), where the latter is facilitated by the efficiency of mitochondrial subpopulations. Many investigators have demonstrated that IR impact on cardiac mitochondrial subpopulations is distinct. In the present study, we decipher the role of PM2.5 on IR associated mitochondrial dysfunction at the subpopulation level by administrating PM2.5 directly to isolated female rat hearts via KH buffer. Our results demonstrated that PM2.5 administered heart (PM_C) severely deteriorated ETC enzyme activity (NQR, SQR, QCR, and COX) and ATP level in both IFM and SSM from the normal control. Comparatively, the declined activity was prominent in IFM fraction. Moreover, in the presence of IR (PM_IR), mitochondrial oxidative stress was higher in both subpopulations from the normal, where the IFM fraction o...
Ischemia reperfusion (I/R) injury is one of the main clinical challenges for cardiac surgeons. No... more Ischemia reperfusion (I/R) injury is one of the main clinical challenges for cardiac surgeons. No effective strategies or therapy targeting the molecular and cellular mechanisms to reduce I/R exists to date, despite altered gene expression and cellular metabolism/physiology. We aimed to identify whether DNA methylation, an unexplored target, can be a potential site to curb I/R-associated cell death by using the left anterior descending artery occlusion model in male Wistar rats. I/R rat heart exhibited global DNA hypermethylation with a corresponding decline in the mitochondrial genes (PGC-1α, TFAM, POLG, ND1, ND3, ND4, Cyt B, COX1, and COX2), antioxidant genes (SOD2, catalase, and Gpx2) and elevation in apoptotic genes (Casp3, Casp7, and Casp9) expression with corresponding changes in their activity, resulting in injury. Targeting global DNA methylation in I/R hearts by using its inhibitor significantly reduced the I/R-associated infarct size by 45% and improved dysferlin levels vi...
Many studies have reported the negative effect of PM2.5 exposure on heart function which is likel... more Many studies have reported the negative effect of PM2.5 exposure on heart function which is likely to impair postcardiac surgery rehabilitation that is involved in recovery and wound healing, yet the direct effects of PM2.5 from diesel exhaust (DPM) on cardiac recovery is unknown. To study the impact of DPM on cardiac recovery and repair, we utilized isoproterenol induced myocardial infarction (MI) model where female rats were exposed to DPM prior and after MI induction. The experimental groups comprise of normal, ISO control, DPM control (42 days of exposure), DPM exposed prior (21 days) and after (21 days) MI induction (D + I + D) and DPM exposed (21 days) after MI (I + D). Post-MI rat hearts from D + I + D group exhibited higher fibrosis, elevated cardiac injury and altered electrophysiology, where this pathology was also observed in I + D group animals which was mild. Loss of mitochondrial quality was evident in DPM exposed animals with and without MI, where severe mitochondrial damage persisted in D + I + D group. In addition, these animals showed striking decline in ETC enzyme activity, ATP levels, mitochondrial copy number and down regulation of PGC1-α, TFAM and POLG along with the genes involved in mitophagy and mitofusion. Besides, the MI associated inactivation of cardio protective signalling pathways like PI3K and Akt were persistent in D + I + D group. In fact, I + D group animals also showed a similar pattern of change, but in a mild form. Taken together, exposure to PM2.5 increases the risk, frequency or progression of MI by impairing the recovery potential of the myocardium.
Recent studies have shown that pre and postconditioning the heart with sodium thiosulfate (STS) a... more Recent studies have shown that pre and postconditioning the heart with sodium thiosulfate (STS) attenuate ischemia-reperfusion (IR) injury. However, the underlying mechanism involved in the cardioprotective signaling pathway is not fully explored. This study examined the existing link of STS mediated protection (as pre and post-conditioning agents) with PI3K, mTOR, and mPTP signaling pathways using its respective inhibitors. STS was administered to the isolated perfused rat heart through Kreb's Heinselit buffer before ischemia (precondition: SIPC) and reperfusion (postcondition: SPOC) in the presence and absence of the PI3K, mTOR, and mPTP signaling pathway inhibitors (wortmannin, rapamycin, and glibenclamide respectively). SIPC failed to improve the IR injury-induced altered cardiac hemodynamics, increased infarct size, and the release of cardiac injury markers in the presence of these inhibitors. On the other hand, the SPOC protocol effectively rendered the cardioprotection even in the PI3K/mTOR/KATP inhibitors presence. Interestingly, the SIPC's identified mode of action viz reduction in oxidative stress and the preservation of mitochondrial function were lost in the inhibitors' presence. Based on the above results, we conclude that the underlying mechanism of SIPC mediated cardioprotection works via the PI3K/mTOR/KATP signaling pathway axis activation.
Resveratrol is well known for its antioxidant potential and ability to preserve mitochondrial fun... more Resveratrol is well known for its antioxidant potential and ability to preserve mitochondrial function, reported attenuating ischemia-reperfusion (IR) injury in the heart. The present study investigates resveratrol on IR injury in rat hearts treated with statin for 14 days. Male Wistar rats were used in this study, and statin-induced cardiac metabolic alterations were monitored after the administration of simvastatin (80 mg/kg). IR was instigated by the Langendroff perfusion system and measured the physiological and biochemical changes. The basal level changes in ECG, ANP, and BNP expression and CoenzymeQ10 level were altered in statin-treated animals compared to the normal rat heart. The animals treated with statin demonstrated higher IR injury (measured via low rate pressure product (88.4%), increased histological alterations, prominent mitochondrial dysfunction (NQR: IR-72%, Stat IR-67%; SQR: IR-71%, Stat IR-74%; COX: IR-58%, Stat IR-52%) than the normal rat heart underwent similar protocols. Administration of heart with resveratrol recovered the IR associated hemodynamic indices in normal heart subjected to IR but failed to impart a similar effect in the statin-treated heart. Our results demonstrated that resveratrol failed to reverse the IR-associated cardiac injury and functional abnormalities in statin-treated rat hearts subjected to IR but effective in IR challenged normal heart.
Introduction: Some of the previous studies reported distant organ injury like liver injury and re... more Introduction: Some of the previous studies reported distant organ injury like liver injury and renal failure after cardiac surgery, whereas in other studies no injury was identified. Magnesium (Mg) deficiency commonly occurs in critical illness and correlates with a higher mortality and worse clinical outcome in the intensive care unit (ICU). Accordingly, this study was designed to assess the effect of magnesium on liver and kidney function abnormalities during CABG procedure in an Indian population. Methods: A clinical trial (n= 52) was conducted to determine the effects of magnesium (16mEq) on distant organs, administered just before the release of aortic cross clamp in patients undergoing coronary bypass operations. We took five blood samples at different times during cardiac surgery and analyzed the levels of ALT, AST, ALP, uric acid, total protein and creatinine. Cardiac marker enzymes like CPK MB, Troponin I and LDH were analyzed. Moreover, the antioxidant enzymes in erythrocy...
Objective: Calcium overload and oxidative stress have been identified as pathogenic factors in my... more Objective: Calcium overload and oxidative stress have been identified as pathogenic factors in myocardial ischaemic reperfusion. Experimental studies have demonstrated that intravenous magnesium (Mg) can protect the ischaemic myocardium. It has a free radical scavenging effect and can act as a calcium channel blocker. Although the role of copper, iron, and other metal elements in ischaemic heart injury has been well established, clinical studies are very limited. The link between these serum metal element concentrations and oxidative stress is unclear in humans although, in experimental animal studies, severe Mg deficiency has been shown to lead to increased oxidative stress. Methods: Ninety-two South Indian patients with acute myocardial ischaemia undergoing CABG were randomized to a study and a control group. Magnesium was administered (2 g/kg body weight) to the study group. Control patients received the same protocol without magnesium. Serum levels of copper, zinc, iron, cerulop...
Asian Pacific Journal of Tropical Biomedicine, 2020
Objective: To compare the anti-proliferative effect of sodium thiosulfate on human colorectal can... more Objective: To compare the anti-proliferative effect of sodium thiosulfate on human colorectal cancer cells (HT-29) and normal small intestine cells (IEC6). Methods: Cells (HT-29 and IEC6) were treated with different concentrations of sodium thiosulfate ranging from 0.5 mM to 80 mM for 24 h. Cell viability was measured via crystal violet and MTT assays. HT-29 cells were further treated in the presence and absence of mitochondrial electron transport chain (ETC) inhibitors, KATP channel opener and closer and H2S inhibitors for 24 h followed by sodium thiosulfate in order to study their respective roles in the anti-proliferative activity of sodium thiosulfate. Results: The IC50 values of sodium thiosulfate on HT-29 cells were 40.93 mM and 42.45 mM by crystal violet and MTT assay whereas, in the case of IEC6 cells, the values were 45.17 mM and 47.22 mM. The inhibition of endogenous H2S enzymes and KATP channel induced no change in the anti-proliferative capacity of sodium thiosulfate. However, the anti-proliferative activity of sodium thiosulfate was enhanced in the presence of mitochondrial ETC inhibitors. Conclusions: HT-29 cell growth is effectively attenuated by sodium thiosulfate and the anti-proliferative activity of sodium thiosulfate is enhanced in the presence of mitochondrial ETC inhibitors.
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