Rheumatoid arthritis (RA) is an autoimmune disease responsible for significant human morbidity in modern life. However, oxidative stress is one of the key markers for determining pathophysiology of patients with RA. The interaction between cellular immune system and body's endogenous and/or exogenous antigens produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) in autoimmune disease like RA. ROS and RNS include highly toxic superoxide (O) and peroxynitrite (ONOO) radicals, which activate the signaling cascades of inflammatory cells to synthesize pro-inflammatory cytokines and chemokines. Previous studies reported that Th1 cytokines could promote the development of autoimmune disorders like RA, whereas the Th2 cytokines may attenuate the same diseases. An increased awareness of the relationship between food and health led to a tremendous increase of antioxidant research in the last decade. Evaluation of the efficacy of dietary antioxidants is also becoming highly acceptable in RA research. A number of dietary phytomolecules are already established as having antioxidant activity in isolated synovial cellular infiltrate or peripheral blood neutrophils and lymphocytes. This review aims to highlight the oxidative stress in inflammatory cells of patients with RA and to summarize the clinical relevance of dietary antioxidants as a first step in assessing beneficial effect, safety and dose safety ratio in patients with RA.
Kalanchoe blossfeldiana was found to interfere with AHL production, which in turn may be responsible for downregulating QS-mediated production of biofilm and virulence. This first report on the antibiofilm and anticytokine properties of this plant may open up new vistas for future exploration of this plant for combating biofilm-related resistant infections.
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The risk of type 2 diabetes mellitus (T2DM) is increasing abundantly due to lifestyle-related obesity and associated cardiovascular problems. Presently, Glycogen synthase kinase-3 (GSK-3) has gained considerable attention from biomedical scientists to treat diabetes. Phosphorylation of GSK-3 permits a number of cellular activities like regulation of cell signaling, cellular metabolism, cell proliferation and cellular transport. Inhibiting GSK-3 activity by pharmacological intervention has become an important strategy for the management of T2DM. This review focuses on the schematic representation of fundamental GSK-3 enzymology and encompasses the GSK-3 inhibitors as a future therapeutic lead target for the management of T2DM that may significantly regulate insulin sensitivity to insulin receptor, glycogen synthesis and glucose metabolism. The various signaling mechanisms of inhibiting the GSK-3 by describing insulin signaling through Insulin Receptor Substrate (IRS-1), Phosphatidylinositol-3 Kinase (PI3K) and Protein Kinase B (PKB/ AKT) pathways that may hopefully facilitate the pharmacologist to design for antidiabetic drug evaluation model in near future have also been highlighted.
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Zebrafish have a similar hepatic anatomy and cellular architecture with mammals. Therefore, number of investigators are using zebrafish to study liver pathologies. However, the evaluation model specific to liver toxicities in zebra fish was not clearly stated earlier. The present study was designed to develop a model of embryonic liver toxicity using dexamethasone (DEXA, 0-20 ΜM) as standard hepatotoxic agent and such toxicities easily measured by streptavidin conjugated peroxidase assay after 48 hour post fertilization (hpf) of DEXA treatment. In addition to morphological toxicities at different hpf, DEXA showed significant (*p< 0.05 & **p<0.01) reduction of peroxidase- chromogenic dye reaction in the assay as compared to DEXA untreated embryos at 10 & 20 µM concentration that concluded the hepatocellular toxicity of dexamethasone. Hopefully the developed model for hepatotoxicity evaluation will be a promising model for evaluation of investigational new drugs or chemicals as an easy vertebrate model before commencement of another animal model.
Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = −13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = −9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC 50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 μM in human embryonic kidney cells), metabolically stable against human liver microsomes (CL int = 15.6 μl/min/mg; T 1/2 = 113.2 min) with solubility of 4.82 μM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.
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