Biology subjects

Biswal, S.

Publications and source records attributed to Biswal, S..

3 recordsLinked to original sources

bioRxiv2021

Nrf2 Regulates β-cell Mass by Suppressing Cell Death and Promoting Proliferation

Finding therapies that can protect and expand functional {beta}-cell mass is a major goal of diabetes research. Here we generated {beta}-cell-specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects {beta}-cell survival, proliferation and mass. Depletion of Nrf2 in {beta}-cells resulted in decreased glucose-stimulated {beta}-cell proliferation ex vivo and decreased adaptive {beta}-cell proliferation and {beta}-cell mass expansion after a high fat diet in vivo. Nrf2 protects {beta}-cells from apoptosis after a high fat diet. Nrf2 loss-of-function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a {beta}-cell-specific manner increases {beta}-cell proliferation and {beta}-cell mass. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with CDDO-Me, an Nrf2 activator, display increased {beta}-cell proliferation. Thus, Nrf2 regulates {beta}-cell mass and is an exciting therapeutic target for expanding {beta}-cell mass in diabetes.

physiology↗

bioRxiv2020

Heterozygous deletion of SYNGAP enzymatic domains in rats causes selective learning, social and seizure phenotypes

Pathogenic variants in SYNGAP1 are one of the most common genetic causes of nonsyndromic intellectual disability (ID) and are considered a risk for autism spectrum disorder (ASD). SYNGAP1 encodes a synaptic GTPase activating protein that modulates the intrinsic GTPase activity of several small G-proteins and is implicated in regulating the composition of the postsynaptic density. By targeting the deletion of exons encoding the calcium/lipid binding (C2) and GTPase activating protein (GAP) domains, we generated a novel rat model to study SYNGAP related pathophysiology. We find that rats heterozygous for the C2/GAP domain deletion (Syngap+/{Delta}-GAP) exhibit reduced exploration and fear extinction, altered social behaviour, and spontaneous seizures, while homozygous mutants die within days after birth. This new rat model reveals that the enzymatic domains of SYNGAP are essential for normal brain function and provide an important new model system in the study of both ID/ASD and epilepsy.

neuroscience↗

bioRxiv2020

Insights into the Binding Mechanism of Ascorbic Acid and Violaxanthin with Violaxanthin De-Epoxidase (VDE) and Chlorophycean Violaxanthin De-Epoxidase (CVDE) Enzymes: Docking, Molecular Dynamics, and Free Energy Analysis

Photosynthetic organisms have evolved to work under low and high lights in photoprotection, acting as a scavenger of reactive oxygen species. The light dependent xanthophyll cycle involved in this process is performed by a key enzyme (present in the thylakoid lumen) Violaxanthin De-Epoxidase (VDE) in the presence of violaxanthin and ascorbic acid substrates. Phylogenetically, VDE is found to be connected with an ancestral enzyme Chlorophycean Violaxanthin De-Epoxidase (CVDE) present in the green algae on the stromal side of the thylakoid membrane. However, the structure and functions of CVDE were not known. In search of functional similarities involving this cycle, the structure, binding conformation, stability, and interaction mechanism of CVDE are explored with the two substrates in comparison to VDE. The structure of CVDE was determined by homology modeling and validated. In-silico docking (of first-principles-optimized substrates) revealed it has a larger catalytic domain than VDE. A thorough analysis of the binding affinity and stability of four enzyme-substrate complexes are performed by computing free energies and its decomposition, the root-mean-square deviation (RMSD) and fluctuation (RMSF), the radius of gyration, salt-bridge and hydrogen bonding interactions in molecular dynamics. Based on these, violaxanthin interacts with CVDE to the similar extent as that of VDE, hence its role is expected to be the same for both the enzymes. On the contrary, ascorbic acid has a weaker interaction with CVDE than VDE. As these interactions drive epoxidation or de-epoxidation process in the xanthophyll cycle, it immediately discerns that either ascorbic acid does not take part in de-epoxidation or this process requires a different cofactor because of the weaker interaction of ascorbic acid with CVDE in comparison to VDE.

plant biology↗