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Search Results: 1 - 10 of 140741 matches for " Isaac K. Sundar "
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P21-PARP-1 Pathway Is Involved in Cigarette Smoke-Induced Lung DNA Damage and Cellular Senescence
Hongwei Yao, Isaac K. Sundar, Vera Gorbunova, Irfan Rahman
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080007
Abstract: Persistent DNA damage triggers cellular senescence, which may play an important role in the pathogenesis of cigarette smoke (CS)-induced lung diseases. Both p21CDKN1A (p21) and poly(ADP-ribose) polymerase-1 (PARP-1) are involved in DNA damage and repair. However, the role of p21-PARP-1 axis in regulating CS-induced lung DNA damage and cellular senescence remains unknown. We hypothesized that CS causes DNA damage and cellular senescence through a p21-PARP-1 axis. To test this hypothesis, we determined the levels of γH2AX (a marker for DNA double-strand breaks) as well as non-homologous end joining proteins (Ku70 and Ku80) in lungs of mice exposed to CS. We found that the level of γH2AX was increased, whereas the level of Ku70 was reduced in lungs of CS-exposed mice. Furthermore, p21 deletion reduced the level of γH2AX, but augmented the levels of Ku70, Ku80, and PAR in lungs by CS. Administration of PARP-1 inhibitor 3-aminobenzamide increased CS-induced DNA damage, but lowered the levels of Ku70 and Ku80, in lungs of p21 knockout mice. Moreover, 3-aminobenzamide increased senescence-associated β-galactosidase activity, but decreased the expression of proliferating cell nuclear antigen in mouse lungs in response to CS. Interestingly, 3-aminobenzamide treatment had no effect on neutrophil influx into bronchoalveolar lavage fluid by CS. These results demonstrate that the p21-PARP-1 pathway is involved in CS-induced DNA damage and cellular senescence.
Emphysema is associated with increased inflammation in lungs of atherosclerosis-prone mice by cigarette smoke: implications in comorbidities of COPD
Gnanapragasam Arunachalam, Isaac K Sundar, Jae-woong Hwang, Hongwei Yao, Irfan Rahman
Journal of Inflammation , 2010, DOI: 10.1186/1476-9255-7-34
Abstract: Adult male and female wild-type (WT) mice of genetic background C57BL/6J and ApoE-/- mice were exposed to CS, and lung inflammatory responses, oxidative stress (lipid peroxidation products), mechanical properties as well as airspace enlargement were assessed.The lungs of ApoE-/- mice showed augmented inflammatory response and increased oxidative stress with development of distal airspace enlargement which was accompanied with decline in lung function. Interestingly, the levels and activities of matrix metalloproteinases (MMP-9 and MMP-12) were increased, whereas the level of eNOS was decreased in lungs of CS-exposed ApoE-/- mice as compared to air-exposed ApoE-/- mice or CS-exposed WT mice.These findings suggest that CS causes premature emphysema and a decline of lung function in mice susceptible to cardiovascular abnormalities via abnormal lung inflammation, increased oxidative stress and alterations in levels of MMPs and eNOS.Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation resulting from excessive airway inflammatory response mediated by cigarette smoke (CS). Comorbidities such as cardiovascular disease, diabetes, lung cancer, and osteoporosis are more prevalent in smokers and patients with COPD [1-3]. Recent studies have shown that smokers with altered forced expiratory volume in one second (FEV1) and airflow limitation are associated with arterial stiffness, exaggerated atherosclerosis and vice-versa [2,4,5]. Growing evidence also indicates that inflammation, endothelial dysfunction and oxidative modification of lipids play an important role in the pathogenesis of atherosclerosis and COPD [3,6,7]. In addition to CS, alcohol consumption is also one among the important contributing factors involved in the pathogenesis of COPD and atherosclerosis and their co-morbidities [8,9].Apolipoprotein E-deficient (ApoE-/-) mice develop atherosclerosis due to an accumulation of cholesterol ester-enriched particles in the blood resul
The advent of Cytomegalovirus infection in HIV infected patients: A review
Sundar Isaac Kirubakaran
Online Journal of Health & Allied Sciences , 2004,
Abstract: Cytomegalovirus is considered as one among the long list of latent infections in humans that although normally controlled by the cellular immune response, gets activated after HIV infection takes its role on infecting the T4 lymphocytes. Clinical disease due to Cytomegalovirus has been recognized in up to 40% of patients with advanced HIV disease. The clinical syndromes most commonly associated include chorioretinitis, esophagitis, colitis, pneumonitis, adrenalitis and neurological disorders. Cytomegalovirus infections are usually diagnosed clinically and by serological tests for CMV immunoglobulin. Chemotherapy using systemic agents, including ganciclovir, intravenous foscarnet and intravenous cidofovir is effective. New agents, as for example an anti-sense agent against cytomegalovirus, appear promising.
Serotonin and Corticosterone Rhythms in Mice Exposed to Cigarette Smoke and in Patients with COPD: Implication for COPD-Associated Neuropathogenesis
Isaac K. Sundar, Hongwei Yao, Yadi Huang, Elizabeth Lyda, Patricia J. Sime, Michael T. Sellix, Irfan Rahman
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087999
Abstract: The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD.
NF-κB Inducing Kinase, NIK Mediates Cigarette Smoke/TNFα-Induced Histone Acetylation and Inflammation through Differential Activation of IKKs
Sangwoon Chung, Isaac K. Sundar, Jae-Woong Hwang, Fiona E. Yull, Timothy S. Blackwell, Vuokko L. Kinnula, Michael Bulger, Hongwei Yao, Irfan Rahman
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023488
Abstract: Background Nuclear factor (NF)-κB inducing kinase (NIK) is a central player in the non-canonical NF κB pathway, which phosphorylates IκB kinase α (IKKα) resulting in enhancement of target gene expression. We have recently shown that IKKα responds to a variety of stimuli including oxidants and cigarette smoke (CS) regulating the histone modification in addition to its role in NF-κB activation. However, the primary signaling mechanism linking CS-mediated oxidative stress and TNFα with histone acetylation and pro-inflammatory gene transcription is not well understood. We hypothesized that CS and TNFα increase NIK levels causing phosphorylation of IKKα, which leads to histone acetylation. Methodology To test this hypothesis, we investigated whether NIK mediates effects of CS and TNFα on histone acetylation in human lung epithelial cells in vitro and in lungs of mouse exposed to CS in vivo. CS increased the phosphorylation levels of IKKα/NIK in lung epithelial cells and mouse lungs. NIK is accumulated in the nuclear compartment, and is recruited to the promoters of pro-inflammatory genes, to induce posttranslational acetylation of histones in response to CS and TNFα. Cells in which NIK is knocked down using siRNA showed partial attenuation of CSE- and TNFα-induced acetylation of histone H3 on pro-inflammatory gene promoters. Additional study to determine the role of IKKβ/NF-κB pathway in CS-induced histone acetylation suggests that the canonical pathway does not play a role in histone acetylation particularly in response to CS in mouse lungs. Conclusions Overall, our findings provide a novel role for NIK in CS- and TNFα-induced histone acetylation, especially on histone H3K9.
Mitogen- and Stress-Activated Kinase 1 (MSK1) Regulates Cigarette Smoke-Induced Histone Modifications on NF-κB-dependent Genes
Isaac K. Sundar, Sangwoon Chung, Jae-woong Hwang, John D. Lapek, Michael Bulger, Alan E. Friedman, Hongwei Yao, James R. Davie, Irfan Rahman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031378
Abstract: Cigarette smoke (CS) causes sustained lung inflammation, which is an important event in the pathogenesis of chronic obstructive pulmonary disease (COPD). We have previously reported that IKKα (I kappaB kinase alpha) plays a key role in CS-induced pro-inflammatory gene transcription by chromatin modifications; however, the underlying role of downstream signaling kinase is not known. Mitogen- and stress-activated kinase 1 (MSK1) serves as a specific downstream NF-κB RelA/p65 kinase, mediating transcriptional activation of NF-κB-dependent pro-inflammatory genes. The role of MSK1 in nuclear signaling and chromatin modifications is not known, particularly in response to environmental stimuli. We hypothesized that MSK1 regulates chromatin modifications of pro-inflammatory gene promoters in response to CS. Here, we report that CS extract activates MSK1 in human lung epithelial (H292 and BEAS-2B) cell lines, human primary small airway epithelial cells (SAEC), and in mouse lung, resulting in phosphorylation of nuclear MSK1 (Thr581), phospho-acetylation of RelA/p65 at Ser276 and Lys310 respectively. This event was associated with phospho-acetylation of histone H3 (Ser10/Lys9) and acetylation of histone H4 (Lys12). MSK1 N- and C-terminal kinase-dead mutants, MSK1 siRNA-mediated knock-down in transiently transfected H292 cells, and MSK1 stable knock-down mouse embryonic fibroblasts significantly reduced CS extract-induced MSK1, NF-κB RelA/p65 activation, and posttranslational modifications of histones. CS extract/CS promotes the direct interaction of MSK1 with RelA/p65 and p300 in epithelial cells and in mouse lung. Furthermore, CS-mediated recruitment of MSK1 and its substrates to the promoters of NF-κB-dependent pro-inflammatory genes leads to transcriptional activation, as determined by chromatin immunoprecipitation. Thus, MSK1 is an important downstream kinase involved in CS-induced NF-κB activation and chromatin modifications, which have implications in pathogenesis of COPD.
Concomitant tuberculous and pyogenic cerbellar abscess in a patient with pulmonary tuberculosis
Ramesh V,Sundar K
Neurology India , 2008,
G. Vinothapooshan,K. Sundar
Journal of Global Pharma Technology , 2011, DOI: 10.1234/jgpt.v3i2.346
Abstract: The effect of Methanolic,chloroform and diethel ether extracts of Adhatoda vasica was investigated in rats to evaluate the anti-ulcer activity by using three models, i.e. Aspirin, Alcohol and pyloric ligation models experimentally induced gastric ulcer. The parameters taken to assess anti-ulcer activity were volume of gastric secretion, PH, free acidity, total acidity and ulcer index. The results indicate that the alcoholic extract significantly (P < 0.001) decreases the volume of gastric acid secretion, PH, free acidity, total acidity and ulcer index with respect to control.
International Journal of Engineering Science and Technology , 2011,
Abstract: Coordination is the management of dependencies between activities. The purpose of coordination is to achieve collectively goals that individual actors cannot meet. Coordination within a supply chain is strategic responses to the problems that arise from inter – organizational dependencies within the chain. Given the increasing importance of inventory management and cost reduction to be gained through supply chain coordination, the challenge to an organization is how to select the appropriate coordination mechanism to benefit all the players of a supply chain.The present study proposes a model to study and analyze the benefit of coordinating supply chaininventories through the use of common replenishment time periods. It investigates the coordination of orderquantities amongst the players in a three level supply chain with a centralized decision process. The first level ofsupply chain consists of multiple buyers, the second level of a single manufacturer, and the third level consistsof multiple suppliers. Each supplier supplies one or more items required in the manufacture of the productproduced. When players in the supply chain agree to coordinate, it is possible to have some of the playersbenefiting more than others in the chain. Under the proposed strategy, the manufacturer specifies commonreplenishment periods and requires all buyers to replenish only at those time periods. To effect the coordinationmanufacturer offers a price discount to entice the buyers to accept this strategy. The model developed in thiswork guarantees that the local costs for the players either remain the same as before coordination, or decrease asa result of coordination. A mathematical model is developed, and numerical study is conducted to evaluate thebenefit of the proposed coordinated theory.
Generalised osteitis fibrosa cystica due to secondary hyperparathyroidism in chronic kidney disease
Sundar K Shrestha,A Tayal
Journal of College of Medical Sciences-Nepal , 2013, DOI: 10.3126/jcmsn.v9i1.9676
Abstract: Secondary hyperparathyroidism is a frequent complication of patients with chronic kidney disease and is characterized by excessive serum parathyroid hormone levels and an imbalance in calcium and phosphorus metabolism. Secondary hyperparathyroidism is the leading cause of renal osteodystrophy and bone disease. Osteitis fibrosa cystica, the classic and former most common osteodystrophy, is mainly caused by high bone turnover secondary to high levels of circulating PTH. Its pathophysiology is mainly due to hyperphosphatemia and vitamin D deficiency and resistance. This condition has a high impact on the mortality and morbidity of dialysis patients Hyperparathyroidism develops early in the course of CKD and becomes more prominent as kidney function declines. However recently, with the technical development of imaging and laboratory screening methods, hypercalcemia due to primary or secondary hyperparathyroidism can often be detected early; as a result the frequency of osteitis fibrosa cystica has declined. Journal of College of Medical Sciences-Nepal, 2013, Vol-9, No-1, 60-66 DOI: http://dx.doi.org/10.3126/jcmsn.v9i1.9676
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