Browsing by Author "Gopala, S"

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    Aloe emodin, a natural anthraquinone targeting multiple facets (migration, invasion, angiogenesis) of tumour metastasis
    (EJC SUPPLEMENTS, 2009) Sathiadevan, P; Babykutty, S; Vijayakurup, V; Jayakrishnan, CJ; Gopala, S; Srinivas, P
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    APOPTOSIS INDUCTION OF CENTELLA ASIATICA ON HUMAN BREAST CANCER CELLS
    (AFRICAN JOURNAL OF TRADITIONAL COMPLEMENTARY AND ALTERNATIVE MEDICINES, 2009) Babykutty, S; Padikkala, J; Sathiadevan, PP; Vijayakurup, V; Azis, TKA; Srinivas, P; Gopala, S
    The present study evaluated the ability of methanolic extract of Centella asiatica (Linn) Urban (Umbelliferae) to induce apoptosis in different cancer cell lines. MCF-7 cells emerged as the most sensitive cell line for in vitro growth inhibitory activity. C. asiatica extract induced apoptosis in MCF-7 cells as indicated by nuclear condensation, increased annexin staining, loss of mitochondrial membrane potential and induction of DNA breaks identified by TUNEL reactivity. It is possible that the use of C. asiatica extract as a component in herbal medicines could be justifiable.
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    Are nitric oxide-mediated protein modifications of functional significance in diabetic heart? ye'S, -NO', wh'Y-NO't?
    (NITRIC OXIDE-BIOLOGY AND CHEMISTRY, 2014) Jayakumari, NR; Reghuvaran, AC; Rajendran, RS; Pillai, VV; Karunakaran, J; Sreelatha, HV; Gopala, S
    Protein modifications effected by nitric oxide (NO) primarily in conjunction with reactive oxygen species (ROS) include tyrosine nitration, cysteine S-nitrosylation, and glutathionylation. The physiological and pathological relevance of these three modifications is determined by the amino acids on which these modifications occur cysteine and tyrosine, for instance, ranging from altering structural integrity/catalytic activity of proteins or by altering propensity towards protein degradation. Even though tyrosine nitration is a well-established nitroxidative stress marker, instilled as a footprint of oxygen- and nitrogen-derived oxidants, newer data suggest its wider role in embryonic heart development and substantiate the need to focus on elucidating the underlying mechanisms of reversibility and specificity of tyrosine nitration. S-nitrosylation is a covalent modification in specific cysteine residues of proteins and is suggested as one of the ways in which NO contributes to its ubiquitous signalling. Several sensitive and specific techniques including biotin switch assay and mass spectrometry based analysis make it possible to identify a large number of these modified proteins, and provide a great deal of potential S-nitrosylation sites. The number of studies that have documented nitrated proteins in diabetic heart is relatively much less compared to what has been published in the normal physiology and other cardiac pathologies. Nevertheless, elucidation of nitrated proteome of diabetic heart has revealed the presence of many mitochondrial and cytosolic proteins of functional importance. But, the existence of different models of diabetes and analyses at diverse stages of this disease have impeded scientists from gaining insights that would be essential to understand the cardiac complications during diabetes. This review summarizes NO mediated protein modifications documented in normal and abnormal heart physiology including diabetes. (c) 2014 Elsevier Inc. All rights reserved.
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    'How can I halt thee?' The puzzles involved in autophagic inhibition
    (PHARMACOLOGICAL RESEARCH, 2014) Vinod, V; Padmakrishnan, CJ; Vijayan, B; Gopala, S
    The strategy for interpreting the role of autophagy on the basis of evidence obtained through autophagic inhibition sounds logical, but is beset with practical constraints. The knock down of autophagy-related (ATG) gene(s) or blockage of class III PI3-Kinase are the most common approaches for inhibiting autophagy. However, during stressful conditions, autophagy may operate in synchrony with other processes such as apoptosis; autophagy-related genes, unlike what their name implies, exert their regulation on apoptosis as well. Knocking down such genes not only blocks autophagy but also renders apoptosis defective, making the interpretation of autophagic roles unreliable. Similarly, class III PI3-Kinase aids in initiating autophagy but it is not a quintessential autophagic regulator. Class III PI3-Kinase also has a role in regulating almost all membrane transport in cells. Blocking it not only inhibits autophagy, but also hampers all the membrane trades, including endosomal transport. The pharmacological inhibitors used to block autophagy by blocking class III PI3-Kinase further compound these limitations with their off-target effects. Knowing the limitations involved in blocking a target or using an autophagy-blocking tool is a prerequisite for designing the experiments meant for analyzing autophagic functions. This review attempts to provide a detailed overview about the practical constraints involved in using autophagic inhibition as a strategy to understand autophagy. (C) 2014 Elsevier Ltd. All rights reserved.
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    Interaction with the MAPT H1H1 Genotype Increases Dementia Risk in APOE epsilon 4 Carriers in a Population of Southern India
    (DEMENTIA AND GERIATRIC COGNITIVE DISORDERS, 2016) Jairani, PS; Aswathy, PM; Gopala, S; Verghese, J; Mathuranath, PS
    Background: This study delineates the role of the interaction of apolipoprotein E (APOE) and MAPT alleles in contributing to disease risks of dementia in a southern Indian population. Methods: A sample of 419 patients comprising Alzheimer's disease (AD; n = 156), mild cognitive impairment (MCI; n = 87), frontotemporal dementia (FTD; n = 127), vascular dementia (VD; n = 37), and dementia with Lewy bodies (DLB; n = 12) was analysed in comparison with a control group (n = 138). APOE genotyping and MAPT haplotyping were performed on all study subjects. Results: Multivariate logistic regression analysis showed that variability on the APOE locus influenced the relative risk of dementia in the study population. The APOE e4 allele increased the disease risk most significantly for AD (OR = 3.468, p < 0.0001) and MCI (OR = 2.901, p < 0.0001). The APOE epsilon 2 allele remained protective for AD (OR = 0.205, p < 0.05). For FTD, VD, and DLB, the APOE epsilon 4 allele was ineffectual in modulating disease risk. The MAPT H1 haplotype was not an overrepresented marker of neurodegenerative diseases. The H1H1 genotype had an additive effect in contributing to either disease risk in combination with the APOE epsilon 4 allele or protection in combination with the APOE epsilon 2 or epsilon 3 allele. Conclusions: This study is a reappraisal of the strong association of APOE variability with AD in southern India when compared to other dementia groups, while the transcriptional differences between MAPT haplotypes have a limited role in Indian dementia patients. (C) 2016 S. Karger AG, Basel
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    Microtubule-associated protein tau genetic variations are uncommon cause of frontotemporal dementia in south India
    (NEUROBIOLOGY OF AGING, 2014) Aswathy, PM; Jairani, PS; Verghese, J; Gopala, S; Mathuranath, PS
    Microtubule-associated protein tau (MAPT) positive neuropathology is the characteristic feature of majority of frontotemporal dementia (FTD) cases, which is due to the mutations or haplotypic variations in the gene encoding MAPT (MAPT). The present study was aimed at determining the frequency of genetic variations in MAPT in a south Indian FTD cohort. The frequency of mutations were determined in 116 FTD, 8 progressive supranuclear palsy (PSP) and 3 corticobasal syndrome (CBS) patients and haplotype diversity were analyzed in a study cohort comprising 116 FTD, 8 PSP, 3 CBS, 194 other dementia groups, 78 mild cognitive impairment (MCI) and 130 cognitively normal individuals and report no pathogenic mutations in FTD/PSP/CBS or haplotypic association with disease risk in FTD or other dementia patients. These findings suggest that there may be other genetic or epigenetic factors contributing to the pathogenesis of FTD in the south Indian population. (C) 2014 Published by Elsevier Inc.
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    Phenethyl caffeate benzo[kl]xanthene lignan with DNA interacting properties induces DNA damage and apoptosis in colon cancer cells
    (Life Sciences, 2012-11) Vijyakurup, V; Carmela, S; Carmelo, D; Corrado, T; Srinivas, P; Gopala, S
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    Phenethyl caffeate benzo[kl]xanthene lignan with DNA interacting properties induces DNA damage and apoptosis in colon cancer cells
    (LIFE SCIENCES, 2012) Vijayakurup, V; Spatafora, C; Daquino, C; Tringali, C; Srinivas, P; Gopala, S
    Aims: Phenethyl caffeate benzoxanthene lignan (PCBL) is a synthetic compound with DNA interacting, antiangiogenic, antiproliferative and tumor cell death inducing abilities. Though PCBL exhibits the qualities of a prospective antitumor agent, the basic mechanism of PCBL induced cell death remains unknown. This study aims to analyze the molecular mechanisms of PCBL induced cell death in tumor cells to further substantiate its antitumor abilities. Main methods: MTT assay was used for finding cell proliferation inhibition, flow cytometric analysis for the detection of cell cycle arrest, comet assay for DNA break detection and immunofluorescence for analyzing H2AX phosphorylation. Western blot analysis was used to detect the activation of different proteins related to DNA damage response and apoptosis. Key findings: PCBL inhibited proliferation of WiDr cells more efficiently than its analog, MCBL Comet analysis of PCBL treated WiDr cells and activity of various DNA damage response proteins such as gamma-H2AX, BRCA1, ATR and Chk1 in PCBL treated cells demonstrated the DNA damaging property of PCBL Effector molecules of apoptosis such as caspase-3, caspase-7 and caspase-9 were found activated along with PARP cleavage in PCBL treated cells, suggesting apoptosis as the main mode of cell death. PCBL induced cell death was found associated with the activation of MAPK signaling. Inhibition of ERK, one of the MAPKs, by U0126 improved the apoptosis inducing ability of PCBL. Significance: In vitro findings suggest that PCBL works by initiating DNA damage and inducing apoptosis in cancer cells and thus could be considered for further preclinical studies. (C) 2012 Elsevier Inc. All rights reserved.
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    Phenethyl caffeate benzoxanthene lignan is a derivative of caffeic acid phenethyl ester that induces bystander autophagy in WiDr cells
    (MOLECULAR BIOLOGY REPORTS, 2014) Vijayakurup, V; Spatafora, C; Tringali, C; Jayakrishnan, PC; Srinivas, P; Gopala, S
    We recently reported that Phenethyl caffeate benzoxanthene lignan (PCBL), a semisynthetic compound derived from Caffeic Acid Phenethyl Ester (CAPE), induces DNA damage and apoptosis in tumor cells. In this study, we further investigated whether PCBL induces autophagy in WiDr cells. We also analyzed the pathways regulating autophagy and the role of autophagy in PCBL-induced cell death. Our acridine orange staining and LC3 II expression results suggest that PCBL induces autophagosomes in WiDr cells. The levels of LC3 II expression we observed after co-treatment of PCBL with bafilomycin A1 and the reductions in p62 expression we observed after PCBL treatment in WiDr cells demonstrate increased autophagic flux, a reliable indicator of autophagic induction. The increased Beclin 1 expression in PCBL-treated cells and the incapacity of PCBL to induce LC3 II in 3-methyladenine (3-MA)-treated cells we observed suggests that PCBL-induced autophagy is class III PI3-kinase dependent. PCBL did not alter phosphorylation of the mTOR substrate p70 S6 kinase, indicating that PCBL-induced autophagy was not mTOR regulated. Two autophagy related proteins, Atg5 and Atg12, also remained uninduced during PCBL treatment. The increased caspase activity and expression levels of LC3 II and p62 we observed in response to PCBL treatment in primary glioma cells demonstrates that PCBL-induced apoptosis and autophagy were not cell line specific. Pharmacological inhibition of autophagy did not alter the antitumor efficacy of PCBL in WiDr cells. This attests to the bystander nature of PCBL-induced autophagy (in terms of cell death). In toto, these data suggest that PCBL induces a class III kinase dependent, but mTOR independent, bystander mode of autophagy in WiDr cells.
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    Progranulin mutation analysis: Identification of one novel mutation in exon 12 associated with frontotemporal dementia
    (NEUROBIOLOGY OF AGING, 2016) Aswathy, PM; Jairani, PS; Raghavan, SK; Verghese, J; Gopala, S; Srinivas, P; Mathuranath, PS
    Progranulin (PGRN) mutations account for an average of 15% of familial frontotemporal dementia (FTD) cases and 20% of total FTD cases worldwide. Here, we investigated the frequency of PGRN mutations in FTD patients (n = 116) from a clinical cohort of south India and detected one novel mutation located on exon 12 in a familial behavioral variant FTD patient (accounting for similar to 1% of total FTD cases and 6% of familial FTD cases). This mutation was found to introduce a premature termination codon and the prematurely terminated messenger RNA may probably undergo nonsense-mediated decay. In enzyme-linked immunosorbent assay, the proband showed significantly reduced level of plasma PGRN (28 ng/mL) compared with controls (150 +/- 38 ng/mL), which implicates haploinsufficiency as the pathogenic mechanism. (C) 2016 Elsevier Inc. All rights reserved.