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331.
Jessy Anthony Aditya Kelkar Chandan Wilankar Vijayalakshmi Ranjith Sujit Kaur Bhumra Shivaprakash Mutt Nabajyoti Deka Hariharan Sivaramakrishnan Somesh Sharma Adaikalasamy Rosalind Marita 《PloS one》2013,8(10)
Insulin resistance is a characteristic feature of Type 2 diabetes. Insulin resistance has also been implicated in the pathogenesis of cardiovascular disease. Currently used thiazolidinedione (TZD) insulin sensitizers although effective, have adverse side effects of weight gain, fluid retention and heart failure. Using fat cell-based phenotypic drug discovery approach we identified P1736, a novel antidiabetic molecule that has completed Phase II clinical trials. The present study evaluated the in vitro and in vivo pharmacological properties of P1736. P1736 is a non-TZD and it did not activate human PPAR(Peroxisome Proliferator Activated Receptor Gamma )receptors. P1736 caused dose dependent increase in glucose uptake (EC50-400nM) in the insulin resistant 3T3 adipocytes. The compound (10µM) induced translocation of GLUT-4 (Glucose Transporter type 4) transporters in these adipocytes while metformin (1.0mM) was inactive. In diabetic db/db mice, P1736 (150mg/kg) was more efficacious than metformin in lowering plasma glucose (35% vs 25%) and triglyceride levels (38% vs 31%). P1736 tested at 5mg/kg, twice daily doses, reduced glucose by 41% and triglycerides by 32%, in db/db mice. These effects were not associated with adverse effects on body weight or liver function. Rosiglitazone (5mg/kg, twice daily) caused 60% and 40 % decreases in glucose and triglyceride levels, respectively. However, rosiglitazone induced 13% weight gain (p<0.05) in db/db mice. P1736 was also efficacious in ob/ob mice wherein 30-35% decrease in glucose and significant improvement in hyperinsulinemia were observed. Administration of P1736 to ob/ob mice resulted in 70% increase in glucose uptake in soleus muscles while metformin caused 38% increase. P1736 exhibited excellent safety profile and was weight neutral in all preclinical models of diabetes. Thus, P1736 with its unique pharmacology coupled with PPAR- independent mode of action could represent an alternative option in the management of insulin resistant Type 2 diabetic patients. 相似文献
332.
Oxidative stress has been implicated in the pathogenesis and progression of neurodegenerative disorders and antioxidants potentially have a major role in neuroprotection. Optimum levels of glutathione (gamma-glutamylcysteinyl glycine), an endogenous thiol antioxidant are required for the maintenance of the redox status of cells. Cystathionine gamma-lyase is the rate-limiting enzyme for the synthesis of cysteine from methionine and availability of cysteine is a critical factor in glutathione synthesis. In the present study, we have examined the role of cystathionine gamma-lyase in maintaining the redox homeostasis in brain, particularly with reference to mitochondrial function since the complex I of the electron transport chain is sensitive to redox perturbation. Inhibition of cystathionine gamma-lyase by l-propargylglycine caused loss of glutathione and decrease in complex I activity in the brain although the enzyme activity in mouse brain was 1% of the corresponding hepatic activity. We then examined the effect of this inhibition on the neurotoxicity mediated by the excitatory amino acid, l-beta-oxalyl amino-l-alanine, which is the causative factor of a type of motor neuron disease, neurolathyrism. l-beta-Oxalyl amino-l-alanine toxicity was exacerbated by l-propargylglycine measured as loss of complex I activity indicating the importance of cystathionine gamma-lyase in maintaining glutathione levels and in turn the mitochondrial function during excitotoxicity. Oxidative stress generated by l-beta-oxalyl amino-l-alanine itself inhibited cystathionine gamma-lyase, which could be prevented by prior treatment with thiol antioxidant. Thus, cystathionine gamma-lyase itself is susceptible to inactivation by oxidative stress and this can potentially exacerbate oxidant-induced damage. Cystathionine gamma-lyase is present in neuronal cells in human brain and its activity is several-fold higher compared to mouse brain. It could potentially play an important role in maintaining glutathione and protein thiol homeostasis in brain and hence afford neuroprotection. 相似文献
333.
Vijayalakshmi M Shivashankar GV Sowdhamini R 《Journal of biomolecular structure & dynamics》2007,25(3):207-218
Alterations in the stability of a nucleosome exert predominant influence on chromatin structure and eukaryotic gene expression. In an attempt to investigate the mononucleosome stability using computational approaches, we have simulated the structure of a human mononucleosome and have compared their energies under the influence of core mutations, tail substitutions, variant histones, and orthologs. We observe that mutant nucleosomes carrying SIN (SWI Independent) mutations do not alter the overall nucleosomal structure but cause local structural changes leading to significant changes in energy and hence the stability. We observe that the nucleosome stability is altered by the substitution of only certain critical lysine residues on the H3 tails. Interestingly, the incorporation of variants H2A.Z and H3.3 lower nucleosome stability as evidenced by small energy changes. However, the substitution of histone orthologs did not alter structural stability. Our simulations to determine the nucleosome stability using energy trends emphasize the role of mutations, variants, and orthologs as determinants of chromatin structure at the nucleosome core particle level. The destabilization we observe on the human nucleosome with core mutations show similar trends of instability as validated experimentally in yeast. 相似文献
334.
Ramovatar Meena Kajal Kumari Jitendra Kumar Paulraj Rajamani H. N. Verma 《Electromagnetic biology and medicine》2014,33(2):81-91
Microwave (MW) radiation produced by wireless telecommunications and a number of electrical devices used in household or in healthcare institutions may adversely affects the reproductive pattern. Present study aimed to investigate the protective effects of melatonin (is well known antioxidant that protects DNA, lipids and proteins from free radical damage) against oxidative stress-mediated testicular impairment due to long-term exposure of MWs. For this, 70-day-old male Wistar rats were divided into four groups (n?=?6/group): Sham exposed, Melatonin (Mel) treated (2?mg/kg), 2.45?GHz MWs exposed and MWs?+?Mel treated. Exposure took place in Plexiglas cages for 2?h a day for 45 days where, power density (0.21?mW/cm2) and specific absorption rate (SAR 0.14?W/Kg) were estimated. After the completion of exposure period, rats were sacrificed and various stress related parameters, that is LDH-X (lactate dehydrogenase isoenzyme) activity, xanthine oxidase (XO), ROS (reactive oxygen species), protein carbonyl content, DNA damage and MDA (malondialdehyde) were performed. Result shows that melatonin prevent oxidative damage biochemically by significant increase (p?0.001) in the levels of testicular LDH-X, decreased (p?0.001) levels of MDA and ROS in testis (p?0.01). Meanwhile, it reversed the effects of MWs on XO, protein carbonyl content, sperm count, testosterone level and DNA fragmentation in testicular cells. These results concluded that the melatonin has strong antioxidative potential against MW induced oxidative stress mediated DNA damage in testicular cells. 相似文献
335.
Vijayalakshmi Ramshankar Subha Yegnaswamy Kumarasamy P Krishnamurthy Arvind 《Bioinformation》2014,10(10):658-663
Identification of activating mutations in non-small cell lung cancers (NSCLC) has been a focus in recent years. This led to successful
evidence of using tyrosine kinase inhibitors (TKIs) over the standard platinum doublet based chemotherapy as the first line
treatment in the metastatic setting.The rearrangements of fusion protein EML4-ALK in NSCLC lead to the use of crizotinib for this
class of tumors. Preclinical and Phase 1 clinical studies show that ceritinib is more effective against both crizotinib sensitive and
resistant tumors. Although robust responses to crizotinib are observed in NSCLC harboring ALK mutations, majority of tumors
eventually become resistant, posing a major challenge in treatment course. Thus, there is a need for the identification and
development of second-generation of ALK inhibitors. Computer aided molecular docking data show Tivozanib and Lapatinib bind
EML4-ALK with high score. Tivozanib is in clinical trials for renal cell cancer and Lapatinib is a known dual tyrosine kinase
inhibitor effective in breast cancer patients with HER2 over-expression. Additional data on these compounds for use in EML4-ALK
positive NSCLC will provide evidence for use in patients treated with crizotinib. Data shows the importance of computer aided
molecular docking in developing candidates with improved activity for further consideration in vitro and in vivo validation. 相似文献
336.
S. Shiva Ranjini Devla Bimal A.P. Dhivya M.A. Vijayalakshmi 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(15-16):1031-1037
Purification of target proteins from a crude biological mixture containing proteins, peptides and other biomolecules is the chromatographic challenge. Mixed mode chromatography offers additional selectivities to improve the overall productivity of commercial bioprocesses with novel chromatographic sorbents being introduced to overcome the problem. HEA HyperCel? (n-hexyl amine) and PPA HyperCel? (phenyl propyl amine) are industry scalable mixed mode chromatography sorbents where both hydrophobic and electrostatic interactions are predominant. Our study focuses on understanding the underlying mechanism of interaction of protein with the sorbent. Parameters like buffer conditions, pH and temperature were tuned to study the adsorption and desorption conditions of the protein. Dynamic binding capacity of HEA HyperCel? and PPA HyperCel? sorbents was studied with human IgG as a model protein. Our study shows that, in HEA the interaction of IgG to the sorbent is predominantly hydrophobic as the binding is enhanced (50–60 mg/ml of sorbent) by presence of salt in buffer and increase in temperature. Binding capacity of PPA is 50–60 mg/ml of sorbent irrespective of temperature effect and/or the presence of salt. The chromatographic experiments show that the interaction could be hydrophobic or ionic or some charge transfer mechanism depending upon the buffer conditions. 相似文献
337.
Billingsley G Santhiya ST Paterson AD Ogata K Wodak S Hosseini SM Manisastry SM Vijayalakshmi P Gopinath PM Graw J Héon E 《American journal of human genetics》2006,79(4):702-709
Genetic analysis of a large Indian family with an autosomal dominant cataract phenotype allowed us to identify a novel cataract gene, CRYBA4. After a genomewide screen, linkage analysis identified a maximum LOD score of 3.20 (recombination fraction [theta] 0.001) with marker D22S1167 of the beta -crystallin gene cluster on chromosome 22. To date, CRYBA4 was the only gene in this cluster not associated with either human or murine cataracts. A pathogenic mutation was identified in exon 4 that segregated with the disease status. The c.317T-->C sequence change is predicted to replace the highly conserved hydrophobic amino acid phenylalanine94 with the hydrophilic amino acid serine. Modeling suggests that this substitution would significantly reduce the intrinsic stability of the crystalline monomer, which would impair its ability to form the association modes critical for lens transparency. Considering that CRYBA4 associates with CRYBB2 and that the latter protein has been implicated in microphthalmia, mutational analysis of CRYBA4 was performed in 32 patients affected with microphthalmia (small eye). We identified a c.242T-->C (Leu69Pro) sequence change in exon 4 in one patient, which is predicted here to disrupt the beta -sheet structure in CRYBA4. Protein folding would consequently be impaired, most probably leading to a structure with reduced stability in the mutant. This is the first report linking mutations in CRYBA4 to cataractogenesis and microphthalmia. 相似文献
338.
339.
Nutriproteomics is a nascent research arena, exploiting the dynamics of proteomic tools to characterize molecular and cellular changes in protein expression and function on a global level as well as judging the interaction of proteins with food nutrients. As nutrients are present in complex mixtures, the bioavailability and functions of each nutrient can be influenced by the presence of other nutrients/compounds and interactions. The first half of this review focuses on the techniques used as nutriproteomic tools for identification, quantification, characterization and analyses of proteins including, two-dimensional polyacrylamide electrophoresis, chromatography, mass spectrometry, microarray and other emerging technologies involving visual proteomics. The second half narrates the potential of nutriproteomics in medical and nutritional research for revolutionizing biomarker and drug development, nutraceutical discovery, biological process modeling, preclinical nutrition linking diet and diseases and structuring ways to a personalized nutrition. Though several challenges such as protein dynamics, analytical complexity, cost and resolution still exist, the scope of applying proteomics to nutrition is rapidly expanding and promising as more holistic strategies are emerging. 相似文献
340.
Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery 总被引:5,自引:0,他引:5
Blundell TL Sibanda BL Montalvão RW Brewerton S Chelliah V Worth CL Harmer NJ Davies O Burke D 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2006,361(1467):413-423
Impressive progress in genome sequencing, protein expression and high-throughput crystallography and NMR has radically transformed the opportunities to use protein three-dimensional structures to accelerate drug discovery, but the quantity and complexity of the data have ensured a central place for informatics. Structural biology and bioinformatics have assisted in lead optimization and target identification where they have well established roles; they can now contribute to lead discovery, exploiting high-throughput methods of structure determination that provide powerful approaches to screening of fragment binding. 相似文献