School Of Basic And Applied Sciences

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    Recent advancements in small molecule inhibitors of insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase as anticancer agents
    (2013) Negi, A.; Ramarao, P.; Kumar, R.
    Advancements in understanding of the genetics, genomics, biochemistry and the pharmacology of cancer in human, have driven the current cancer chemotherapy to intently focus on development of target-based approaches rather than conventional approaches. From among the various targets identified, validated and inhibited at different hallmarks of cancer, protein tyrosine kinases (PTKs) have been exploited the most. Insulin receptors (IRs), insulin like growth factor receptors (IGF-1R) and their hybrid receptors belong to tyrosine kinase receptor (TKR) family, constitute a structural homology among them and generate a growth promoting IGF system on binding with either insulin, IGF-1 or IGF-2. The system induces the mitogenic effects through a torrent of cell signals produced as a result of cross talk with other growth promoting peptides and steroidal hormones, ultimately resulting in hijacking apoptosis and increasing cell proliferation and cell survival in cancer cells. Various strategies such as anti-IGF-1R antibodies, IGF-1 mimetic peptides, antisense strategies, IGF-1R specific peptide aptamers, targeted degradation of IGF-1R and expression of dominant negative IGF-1R mutants have been explored to inhibit the IGF-1R signaling. However, targeting IGF-1R with small molecules has gained considerable attention in last few years due to their ease of synthesis, ease of optimization of absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters, oral route of administration, lesser side effects and cost effectiveness. The present review provides a broad overview and discusses the highlights on discoveries, SAR studies and binding interactions of small molecules with either IGF-1R active or allosteric sites reported till date. ? 2013 Bentham Science Publishers.
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    Insulin resistance induces a segmental difference in thoracic and abdominal aorta: Differential expression of AT1 and AT2 receptors
    (2012) Karpe, P.A.; Gupta, J.; Marthong, R.F.; Ramarao, P.; Tikoo, K.
    Objectives: The study was pursued to understand and compare the vascular reactivity to angiotensin II (Ang II) and its receptor expression in thoracic and abdominal aorta under insulin resistance. Methods: Vascular reactivity to Ang II was recorded isometrically, AT1/AT2 receptor gene and protein expression was checked by RT-PCR and western blotting, respectively, and abundance of phospho (serine-10 Ph) H3 on promoter regions of Agtr1/Agtr2 genes was done by chromatin immunoprecipitation assay in aortic rings isolated from high fat diet (HFD)-fed rats. Results: Our functional studies showed an increased (Emax in mg/mm 2: Con: 319 ? 29 and HFD: 1095 ? 72, P < 0.001) and unaltered (E max in mg/mm 2: Con: 299 ? 29 and HFD: 350 ? 20, mean ? SEM, n = 6) Ang II-induced contractile responses in thoracic and abdominal aorta of HFD rats, respectively, as compared to control rats. Interestingly, AT2R-mediated relaxation was increased in abdominal aorta (% relaxation: Con: 25 ? 5.3 and HFD: 76.4 ? 8.9, P < 0.001) of HFD rats but not in thoracic aorta (% relaxation: Con: 25 ? 5.2 and HFD: 32 ? 5.2, mean ? SEM, n = 6). At the molecular level, increased mRNA (?14-folds) and protein expression (?2.5-folds) of AT2R in abdominal aorta of HFD rats was found as compared to control rats. However, AT1R mRNA and protein expression did not show any change. Chromatin immunoprecipitation with phospho H3 showed increased abundance of ser-10 phosphorylation on Agtr1 and Agtr2 gene promoter regions in thoracic and abdominal segments, respectively. But it got decreased on Agtr2 and Agtr1 genes promoter regions in thoracic and abdominal segments, respectively. Conclusion: We provide first evidence that insulin resistance induces segmental difference in thoracic and abdominal aorta and this may provide reason of heterogeneity for incidence of aneurysms. ? 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
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    Cellular uptake, intracellular trafficking and cytotoxicity of silver nanoparticles
    (2012) Singh, R.P.; Ramarao, P.
    Silver nanoparticles (Ag NPs) are used in consumer products and wound dressings due to their antimicrobial properties. However, in addition to toxic effects on microbes, Ag NPs can also induce stress responses as well as cytotoxicity in mammalian cells. We observed that Ag NPs are efficiently internalized via scavenger receptor-mediated phagocytosis in murine macrophages. Confocal and electron microscopy analysis revealed that internalized Ag NPs localize in the cytoplasm. Ag NPs cause mitochondrial damage, induce apoptosis and cell death. These effects were abrogated in presence of Ag ion-reactive, thiol-containing compounds suggesting the central of Ag ions in Ag NP toxicity. Quantitative image analysis revealed that intracellular dissolution of Ag NPs occurs about 50 times faster than in water. In conclusion, we demonstrate for the first time that Ag NPs are internalized by scavenger receptors, trafficked to cytoplasm and induce toxicity by releasing Ag ions. ? 2012 Elsevier Ireland Ltd.