Life Sciences

<p>Shiv Nadar University is a comprehensive, multidisciplinary, research-focused, and student-centric University offering a full range of academic programs at the undergraduate, postgraduate and doctoral level. With state-of-the-art infrastructure, the University comprises of academic wings, sophisticated labs, international standard sports facilities, amphitheaters, auditorium, conference rooms and smart classrooms. The University&rsquo;s goal is to become internationally recognized for the quality of its research and creative endeavors and their applicability to improving quality of life, generating new insights and expanding the boundaries of human knowledge creativity. Committed to excellence in teaching, research and service, the University aims to serve the higher education needs of India and the world beyond.</p>

Shiv Nadar University

Autoimmunity and cancer have a multifarious epidemiology. Often, it is because of an impaired genome, culminating in functional aberrations in the human system. Systemic lupus erythematosus (SLE) is a heterogeneous complex disease which ensues due to the failure of the immune system to distinguish between self and non-self antigens, thus producing autoantibodies against DNA, RNA and proteins. Cancer, the other side of the same coin, results from an excessive proliferation of cells that evade immune regulation as a result of incompetent defense by T-cells, B-cells and macrophages. Recent findings have indicated that lupus autoantibodies could be used as an effective weapon to kill cancerous cells. This is an attempt to take an account of malicious 'lupus autoantibodies' and their role in neutralizing cancerous cells which may help in enhancing the survival rate of cancer patients, hence, killers can be saviors. © 2016 SAGE Publications.

World University root node

(SoNS) School of Natural Sciences

Fulltext

Lupus

Can killers be saviors?

Sorafenib is a small molecule, multi-kinase inhibitor used as an anti-cancer drug for treatment of Liver and Kidney cancers. It is reported to be in phase 2 clinical trials for colorectal cancer (CRC). This drug was reported to inhibit both surface associated and intracellular kinases such as Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet-Derived Growth Factor Receptor (PDGFR), Fibroblast Growth Factor Receptor (FGFR), RAF, BRAF etc. This was shown to be effective against both mutant and wild type BRAF. There are some preliminary clinical reports of patients showing resistance to this drug on long-term usage. Our study aims at developing a resistant cell line model for the above drug and to understand the pathways and mechanisms involved in resistance development. Resistant model of HCT-116 cell line was developed by continuously culturing parental cell line in the presence of the drug. The IC50 values were compared between the parental cells and the cells exposed to drug continuously. BCL2 an anti-apoptotic protein was seen overexpressed in resistant cells in contrast to decreased expression in parental cells supporting the development of resistance.Further the multidrug resistance proteins MDR1 and ABCG-2 are highly up regulated in resistance model reconfirming the resistance development. This study aims at understanding how the JAK-STAT signaling pathway is modulated during drug resistance by expression profiling of molecules from this pathway by real time PCR. In this study, we found that JAK-STAT pathway is suppressed in the parental cells when treated with the sorafenib, but found actively expressed in resistant model. JAK-STAT signaling pathway is known to be activated in cancers and helps in regular proliferation of cancer cells. But as noticed from the above results upon drug treatment in parental cells this pathway get suppressed thereby leading to cell death. The active involvement of JAK-STAT pathway, which supports proliferation, was seen over expressed in drug resistance model.

Biochemical and Cellular Archives

Role of Jak-Stat signaling in sorafenib resistant HCT-116 cells

Context: Thrombospondin1 (TSP1) participates in numerous signaling pathways critical for vascular physiology and disease. The conserved signature domain of thrombospondin 1 (TSP1-Sig1) comprises three epidermal growth factor (EGF), 13 calcium-binding type 3 thrombospondin (T3) repeats, and one lectin-like module arranged in a stalk-wire-globe topology. TSP1 is known to be present in both calcium-replete (Holo-) and calcium-depleted (Apo-) state, each with distinct downstream signaling effects. Objective: To prepare a homology model of TSP1-Sig1 and investigate the effect of calcium on its dynamic structure and interactions. Methods: A homology model of Holo-TSP1-Sig1 was prepared with TSP2 as template in Swissmodel workspace. The Apo-form of the model was obtained by omitting the bound calcium ions from the homology model. Molecular dynamics (MD) simulation studies (100 ns) were performed on the Holo- and Apo- forms of TSP1 using Gromacs4.6.5. Results and discussion: After simulation, Holo-TSP1-Sig1 showed significant reorientation at the interface of the EGF1-2 and EGF2-3 modules. The T3 wire is predicted to show the maximum mobility and deviation from the initial model. In Apo-TSP1-Sig1 model, the T3 repeats unfolded and formed coils with predicted increase in flexibility. Apo-TSP1-Sig1model also predicted the exposure of the binding sites for neutrophil elastase, integrin and fibroblast growth factor 2. We present a structural model and hypothesis for the role of TSP1-Sig1 interactions in the development of vascular disorders. Conclusion: The simulated model of the fully calcium-loaded and calcium-depleted TSP1-Sig1 may enable the development of its interactions as a novel therapeutic target for the treatment of vascular diseases. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

Journal of Receptors and Signal Transduction

Calcium-induced conformational changes of Thrombospondin-1 signature domain: implications for vascular disease

Despite the current progress in cancer research and therapy, breast cancer remains the leading cause of mortality among half a million women worldwide. Migration and invasion of cancer cells are associated with prevalent tumor metastasis as well as high mortality. Extensive studies have powerfully established the role of prototypic second messenger cAMP and its two ubiquitously expressed intracellular cAMP receptors namely the classic protein kinaseA/cAMP-dependent protein kinase (PKA) and the more recently discovered exchange protein directly activated by cAMP/cAMP-regulated guanine nucleotide exchange factor (EPAC/cAMP-GEF) in cell migration, cell cycle regulation, and cell death. Herein, we performed the analysis of the Cancer Genome Atlas (TCGA) dataset to evaluate the essential role of cAMP molecular network in breast cancer. We report that EPAC1, PKA, and AKAP9 along with other molecular partners are amplified in breast cancer patients, indicating the importance of this signaling network. To evaluate the functional role of few of these proteins, we used pharmacological modulators and analyzed their effect on cell migration and cell death in breast cancer cells. Hence, we report that inhibition of EPAC1 activity using pharmacological modulators leads to inhibition of cell migration and induces cell death. Additionally, we also observed that the inhibition of EPAC1 resulted in disruption of its association with the microtubule cytoskeleton and delocalization of AKAP9 from the centrosome as analyzed by in vitro imaging. Finally, this study suggests for the first time the mechanistic insights of mode of action of a primary cAMP-dependent sensor, Exchange protein activated by cAMP 1 (EPAC1), via its interaction with A-kinase anchoring protein 9 (AKAP9). This study provides a new cell signaling cAMP–EPAC1–AKAP9 direction to the development of additional biotherapeutics for breast cancer. © 2017, Springer Science+Business Media New York.

Molecular and Cellular Biochemistry

Role of exchange protein directly activated by cAMP (EPAC1) in breast cancer cell migration and apoptosis

Natural product-inspired libraries of molecules with diverse architectures have evolved as one of the most useful tools for discovering lead molecules for drug discovery. In comparison to conventional combinatorial libraries, these molecules have been inferred to perform better in phenotypic screening against complicated targets. Diversity-oriented synthesis (DOS) is a forward directional strategy to access such multifaceted library of molecules. From a successful DOS campaign of a natural product-inspired library, recently a small molecule with spiroindoline motif was identified as a potent anti-breast cancer compound. Herein we report the subcellular studies performed for this molecule on breast cancer cells. Our investigation revealed that it repositions microtubule cytoskeleton and displaces AKAP9 located at the microtubule organization centre. DNA ladder assay and cell cycle experiments further established the molecule as an apoptotic agent. This work further substantiated the amalgamation of DOS-phenotypic screening-sub-cellular studies as a consolidated blueprint for the discovery of potential pharmaceutical drug candidates. © 2017, Springer Science+Business Media New York.

Chemistry

A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton

Ionic liquids (ILs) are important for their antimicrobial activity and are found to be toxic to some microorganisms. To shed light on the mechanism of their activities, the interaction of an imidazolium-based IL 1-butyl-3-methylimidazolium tetrfluoroborate ([BMIM][BF4]) with E. coli bacteria and cell-membrane-mimicking lipid mono- and bilayers has been studied. The survival of the bacteria and corresponding growth inhibition are observed to be functions of the concentration of the IL. The IL alters the pressure-area isotherm of the monolayer formed at an air-water interface by the 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid. The in-plane elasticity of the lipid layer is reduced as a consequence of the insertion of this IL. The X-ray reflectivity study from a polymer-supported lipid bilayer shows strong perturbation in the self-assembled structure of the bilayer due to the interaction. As a consequence, there is a considerable decrease in bilayer thickness and a corresponding increase in electron density. These results, however, depend on the chain configurations of the lipid molecules. © 2017 American Chemical Society.

Physics

Langmuir

X-ray Reflectivity Study of the Interaction of an Imidazolium-Based Ionic Liquid with a Soft Supported Lipid Membrane

Substrate-cell interactions for a bioimplant are driven by substrate's surface characteristics. In addition, the performance of an implant and resistance to degradation are primarily governed by its surface properties. A bioimplant typically degrades by wear and corrosion in the physiological environment, resulting in metallosis. Surface engineering strategies for limiting degradation of implants and enhancing their performance may reduce or eliminate the need for implant removal surgeries and the associated cost. In the current study, we tailored the surface properties of stainless steel using submerged friction stir processing (FSP), a severe plastic deformation technique. FSP resulted in significant microstructural refinement from 22 μm grain size for the as-received alloy to 0.8 μm grain size for the processed sample with increase in hardness by nearly 1.5 times. The wear and corrosion behavior of the processed alloy was evaluated in simulated body fluid. The processed sample demonstrated remarkable improvement in both wear and corrosion resistance, which is explained by surface strengthening and formation of a highly stable passive layer. The methylthiazol tetrazolium assay demonstrated that the processed sample is better in supporting cell attachment, proliferation with minimal toxicity, and hemolysis. The athrombogenic characteristic of the as-received and processed samples was evaluated by fibrinogen adsorption and platelet adhesion via the enzyme-linked immunosorbent assay and lactate dehydrogenase assay, respectively. The processed sample showed less platelet and fibrinogen adhesion compared with the as-received alloy, signifying its high thromboresistance. The current study suggests friction stir processing to be a versatile toolbox for enhancing the performance and reliability of currently used bioimplant materials. © 2017 American Chemical Society.

History

(SoHSS) School of Humanities and Social Sciences

Mechanical Engineering

(SoE) School of Engineering

ACS Applied Materials and Interfaces

Friction Stir Processing of Stainless Steel for Ascertaining Its Superlative Performance in Bioimplant Applications

Adult neurogenesis is primarily directed by neural progenitor cells, which reside in the subventricular zone (SVZ) and subgranular zone (SGZ) of the brain. Unfolding transcriptional heterogeneity and complexity of various neurodevelopmental stages can probe new insights into neurogenesis and neurodevelopmental disorders. Recent findings have suggested that epigenetic regulatory mechanisms in neural differentiation involve long noncoding RNAs (lncRNAs) as a new genre of regulators. Although many studies have addressed the overall consequences of the noncoding RNome (noncoding RNA content) on the genome, lesser is known about their specific roles and consequences in adult neurogenesis, neurodevelopmental stages, and onset of neuropathology. Recent advances in induced pluripotent stem cell (iPSC)-based neurological disease modeling have shed light on new avenues to investigate neuronal development as well as molecular paradigms underlying onset of neurological impairments. However, due to limited availability of brain tissues and gap in the understanding of lncRNA biomarkers in neurodevelopment, the study of lncRNA in neurogenesis still exists at its infancy. To further understand the lncRNA-mediated regulation in stage-specific development of pluripotent stem cell-derived neurons and other brain cells, we identified potential lncRNA signatures implicative in brain development or dysregulation using data mining and analyses. They may be used in monitoring disease progression and may serve as potential targets for novel therapeutic approaches. © Springer Nature Singapore Pte Ltd. 2017. All rights reserved.

Regenerative Medicine: Laboratory to Clinic

Unraveling the role of long noncoding RNAs in pluripotent stem cell-based neuronal commitment and neurogenesis

In India, the rice root knot nematode, Meloidogyne graminicola is the dominant species infecting rice-wheat cropping system due to its broad host range and ability of causing potential yield loss. It has become an emerging problem in the nurseries and upland rice. Second stage juveniles (J2s) penetrate the roots closely behind the root tip; migrate to vascular cylinder turning it into multinucleated giant cells, by endomitosis and cell hypertrophy characterized by hook shaped galls. In the present study, 33 direct seeded rice (DSR) genotypes of Asian rice (Oryza sativa) were evaluated for resistance against rice root-knot nematode, M. graminicola on the basis of root-knot index and multiplication factor. Out of the total 33 rice cvs, 6 cultivars had less than10 galls/ plant and of these, cv. NDR-97 exhibited a strong resistant response with least number of galls (1.5galls/plant) and remaining are moderately and highly susceptible. The most and least susceptible cultivars were selected for further histopathological and differential gene expression studies. © 2017, Nematological Society of India. All rights reserved.

Indian Journal of Nematology

Evaluation of resistance in direct seeded rice (Oryza sativa L.) against Meloidogyne graminicola

Deinococcus indicus strain DR1, a red-pigmented, arsenic- and radiation-resistant bacterium, was isolated from a water sample of the Dadri wetland, Uttar Pradesh, India. Here, we report a draft genome sequence of this strain, which may provide useful information regarding the genes and pathways involved in heavy-metal bioremediation. © 2017 Chauhan et al.