Department Of Human Genetics And Molecular Medicine

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Subject: search.filters.subject.Gene Expression

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    Regulation of GAD65 expression by SMAR1 and p53 upon Streptozotocin treatment
    (2012) Singh, Sandeep; Raina, Varsheish; Chavali, Pavithra Lakshminarsimhan; Dubash, Taronish; Kadreppa, Sreenath; Parab, Pradeep; Chattopadhyay, Samit
    Background: GAD65 (Glutamic acid decarboxylase 65 KDa isoform) is one of the most important auto-antigens involved in Type 1 diabetes induction. Although it serves as one of the first injury markers of ?-islets, the mechanisms governing GAD65 expression remain poorly understood. Since the regulation of GAD65 is crucial for the proper functioning of insulin secreting cells, we investigated the stress induced regulation of GAD65 transcription.Results: The present study shows that SMAR1 regulates GAD65 expression at the transcription level. Using a novel protein-DNA pull-down assay, we show that SMAR1 binding is very specific to GAD65 promoter but not to the other isoform, GAD67. We show that Streptozotocin (STZ) mediated DNA damage leads to upregulation of SMAR1 and p53 expression, resulting in elevated levels of GAD65, in both cell lines as well as mouse ?-islets. SMAR1 and p53 act synergistically to up-regulate GAD65 expression upon STZ treatment.Conclusion: We propose a novel mechanism of GAD65 regulation by synergistic activities of SMAR1 and p53. ? 2012 Singh et al.; licensee BioMed Central Ltd.
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    miR-30c and miR-181a synergistically modulate p53?p21 pathway in diabetes induced cardiac hypertrophy
    (Springer New York LLC, 2016) Raut, Satish K.; Singh, Gurinder B.; Rastogi, Bhawna; Saikia, Uma Nahar; Mittal, Anupam; Dogra, Nilambra; Singh, Sandeep; Prasad, Rishikesh; Khullar, Madhu
    p53?p21 pathway mediates cardiomyocyte hypertrophy and apoptosis and is upregulated in diabetic cardiomyopathy (DbCM). We investigated role of microRNAs in regulating p53?p21 pathway in high glucose (HG)-induced cardiomyocyte hypertrophy and apoptosis. miR-30c and miR-181a were identified to target p53. Cardiac expression of microRNAs was measured in diabetic patients, diabetic rats, and in HG-treated cardiomyocytes. Effect of microRNAs over-expression and inhibition on HG-induced cardiomyocyte hypertrophy and apoptosis was examined. Myocardial expression of p53 and p21 genes was increased and expression of miR-30c and miR-181a was significantly decreased in diabetic patients, DbCM rats, and in HG-treated cardiomyocytes. Luciferase assay confirmed p53 as target of miR-30c and miR-181a. Over-expression of miR-30c or miR-181a decreased expression of p53, p21, ANP, cardiomyocyte cell size, and apoptosis in HG-treated cardiomyocytes. Concurrent over-expression of these microRNAs resulted in greater decrease in cardiomyocyte hypertrophy and apoptosis, suggesting a synergistic effect of these microRNAs. Our results suggest that dysregulation of miR-30c and miR-181a may be involved in upregulation of p53?p21 pathway in DbCM. ? 2016, Springer Science+Business Media New York.
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    Genetic signatures in ischemic stroke: Focus on aspirin resistance
    (Bentham Science Publishers B.V., 2017) Vasudeva, Kanika; Chaurasia, Pratibha; Singh, Sulena; Munshi, Anjana
    Background and Objective: Stroke is one of the leading causes of death. There has been compelling evidence that stroke has a genetic component. Genetic variants not only influence susceptibility to stroke but have also been found to alter the response to pharmacological agents and influence the clinical outcome of the disease. Stroke patients are treated with antiplatelet drugs like aspirin and clopidogrel to prevent a secondary stroke. In spite of the fact that many new antiplatelet drugs have been developed, aspirin is still considered as a golden standard for the antiplatelet therapy. Aspirin achieves its action by inhibiting platelet cyclooxygenase (COX) system involved in the formation of thromboxane A2 (TXA2). TXA2 triggers reactions leading to platelet activation and aggregation. This Non-steroidal anti-inflammatory drug (NSAID) acts by inhibiting this mediator. Despite the demonstrated benefits of aspirin, many patients develop secondary stroke or other vascular events, an observation that has led to the concept of aspirin resistance. Studies have demonstrated that adequate antiplatelet effects are not achieved in 5-45% patients suggesting that many individuals are aspirin resistant. Aspirin resistance is multifactorial in origin. A genetic component has also been suggested, and variants in more than a dozen genes involved in absorption, distribution, metabolism, excretion (ADME) and pharmacodynamics of aspirin have been shown to be responsible for aspirin resistance. In addition, the patients on aspirin treatment also face adverse drug reactions on account of genetic variation. Conclusion: The present review has been compiled with an aim to revisit all the studies related to genetic variation contributing to aspirin resistance as well as adverse drug reactions. The output of high throughput genomic technology like genome wide association studies and others has also been discussed. ? 2017 Bentham Science Publishers.
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    Association of serum homocysteine and hs-CRP with idiopathic generalised epilepsy and duration of antiepileptic drug therapy
    (Journal of Clinical and Diagnostic Research, 2018) Prasad, D.K.V.; Satyanarayana, U.; Prabhakararao, T.S.; Surya Prabha, T.; Munshi, A.
    Introduction: Several human and experimental studies have revealed that chronic inflammation may play a vital role in neurodegenerative processes including epilepsy. There is accumulating evidence that inflammatory processes affect the pathophysiology of different epilepsy types. Aim: To assess the concentrations of Homocysteine (Hcy) and High Sensitivity C-Reactive Protein (hs-CRP) in Idiopathic Generalised Epilepsy (IGE) patients and their association with IGE and duration of the Anti Epileptic Drugs (AEDs). Materials and Methods: This case-control study consisted of 100 IGE patients (50 tonic?clonic, 15 absence and 35 myoclonic seizures) and equal number of healthy controls. Hcy levels were assayed by Centaur XP using ADVIA centaur Hcy; whereas hs-CRP levels by ELISA method using commercially available kits. Results: The Hcy and hs-CRP levels were significantly increased in both the patient groups (<18 years and >18 years). Significant difference in the levels of Hcy was observed between different epilepsy types of <18 years patients (p=0.01), whereas hs-CRP in >18 years patients (<0.05). Significantly elevated levels of hs-CRP were noticed in non-responders group compared to responders (<0.05). There was a positive correlation between hs-CRP and Hcy (R2=0.44 and p<0.001) and significant difference in the levels of Hcy and hs-CRP was observed in the patient subgroups who were on AEDs for different time periods (?1 year, 1- ?5 years and >5 years) (p=0.002 and p<0.05 respectively) since, AEDs can induce oxidative stress. Conclusion: Hyperhomocysteinaemia (Hyper-Hcy) can induce as well as promote oxidative stress and hence, it can be implicated in neurodegeneration in epilepsy. Elevated levels of hs-CRP in non-responders may be resulted by the contribution of inflammatory pathways in ictogenesis in epileptic tissue, causing intractable epilepsy. ? 2018, Journal of Clinical and Diagnostic Research. All rights reserved.