Vellore Institute of Technology (VIT) is a private university located in&nbsp;Tamil Nadu, India. Founded in 1984, as Vellore Engineering College, the institution offers 20 undergraduate, 34 postgraduate, four integrated and four research programs. It has campuses in Vellore, Amravati, Bhopal and Chennai.

VIT is one of the top ranked private universities in India according to NIRF, THE and QS Rankings.&nbsp;Govt. of India has recognized&nbsp;VIT, Vellore as an&nbsp;Institution of Eminence. This has allowed VIT to take independent quality initiatives and move up in world ranking.

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VIT University

Department of Bio-Sciences

The structural motifs of chalcones, flavones, and triazoles with varied substitutions have been studied for the antimalarial activity. In this study, 25 novel derivatives of chalcone and flavone hybrid derivatives with 1, 2, 3-triazole linkage are docked with Plasmodium falciparum dihydroorotate dehydrogenase to establish their inhibitory activity against Plasmodium falciparum. The best binding conformation of the ligands at the catalytic site of dihydroorotate dehydrogenase are selected to characterize the best bound ligand using the best consensus score and the number of hydrogen bond interactions. The ligand namely (2E)-3-(4-{[1-(3-chloro-4-fluorophenyl)-1H-1, 2, 3-triazol-4-yl]methoxy}-3-methoxyphenyl-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one, is one the among the five best docked ligands, which interacts with the protein through nine hydrogen bonds and with a consensus score of five. To refine and confirm the docking study results, the stability of complexes is verified using Molecular Dynamics Simulations, Molecular Mechanics /Poisson–Boltzmann Surface Area free binding energy analysis, and per residue contribution for the binding energy. The study implies that the best docked Plasmodium falciparum dihydroorotate dehydrogenase–ligand complex is having high negative binding energy, most stable, compact, and rigid with nine hydrogen bonds. The study provides insight for the optimization of chalcone and flavone hybrids with 1, 2, 3-triazole linkage as potent inhibitors. © 2017, © 2017 Informa UK Limited, trading as Taylor &amp; Francis Group.

VIT Unitversity

School of Bio Sciences and Technology

Vellore Campus

Journal of Biomolecular Structure and Dynamics

In-Silico molecular docking and simulation studies on novel chalcone and flavone hybrid derivatives with 1, 2, 3-triazole linkage as vital inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase

The regulation of apoptosis is a tightly coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted. Thus, we sought to identify FDA-approved drugs that could be repurposed as novel allosteric inhibitors of caspase-3/7. In this study, we virtually screened a catalog of FDA-approved drugs targeting an allosteric pocket located at the dimerization interface of caspase-3/7. From among the top-scoring hits we short-listed 5 compounds for experimental validation. Our enzymatic assays using recombinant caspase-3 suggested that 4 out of the 5 drugs effectively inhibited caspase-3 enzymatic activity in vitro with IC50 values ranging ~10-55 μM. Structural analysis of the docking poses show the 4 compounds forming specific non-covalent interactions at the allosteric pocket suggesting that these molecules could disrupt the adjacently-located active site. In summary, we report the identification of 4 novel non-peptide allosteric inhibitors of caspase-3/7 from among FDA-approved drugs. © 2018 Wiley Periodicals, Inc.

World University root node

Fulltext

Proteins: Structure, Function, and Bioinformatics

Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases

Lead (Pb) is reported to have negative effects on the biogeochemical behaviour of the plant growth. In recent years, the significance of rhizoremediation of heavy metals has been of great focus aiding in the development rates of plants under stressed conditions. The present study evaluated the physio-biochemical response of Pennisetum purpureum to different concentrations of Pb (II) viz., 0, 50, 100 and 150 mg kg-1 in the form of lead (II) nitrate. The pre-characterized PGPR strain, Enterobacter cloacae - KU598849 was used to augment the plants. After Pb exposure for 45 d, parameters such as plant growth, lead accumulation, H2O2 content, MDA content, protein, proline content and antioxidant enzymatic activities were quantified. Results illustrated that increasing Pb concentration reduced the early growth, metal accumulation, protein content and affected physio-biochemical changes by causing oxidative damage in plants. Upon augmentation of the bacterial inoculum, the plants significantly resisted the toxic effects of Pb. Increased Pb bioaccumulation pattern was recorded in roots than shoots, were highest uptake was found to be 72 mg kg-1 dry weight when exposed to 150 mg kg-1 Pb concentration. Lead supplementation increased the activities of malonylaldehyde (MDA), superoxide dismutase (SOD), peroxidase (POX), ascorbate peroxidase (APX) and catalase (CAT) in P. purpureum. Bacterial bioaugmentation resulted in the reduction of the oxidative stress aided with reduced antioxidant enzyme activities indicating the minimization of the damages under stress.

Chemosphere

Monitoring the stress resistance of Pennisetum purpureum in Pb (II) contaminated soil bioaugmented with Enterobacter cloacae as defence strategy

The current study was designed to explore the underlying therapeutic effect of berberine (BBR), an alkaloid compound against LPS (1 μg/ml)/TNFα (10 ng/ml) mediated apoptosis signal-regulating kinase 1 (ASK1) signaling in RAW 264.7 macrophages and adjuvant-induced arthritic synovial macrophages (AA-SM) with relation to miR-23a levels. LPS and TNFα stimulation abrogated the expression of miR-23a resulting in TLR4/TRAF2 mediated ASK1 activation and downstream phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). BBR (25–75 μM) treatment ameliorated the gene expression levels of TLR4, TRAF2, TNFα IL-6, and IL-23 through the upregulation of miR-23a. Subsequently, BBR suppressed the levels of TLR4/TRAF2 mediated phosphorylation of ASK1/p38 and attenuated the expression of various pro-inflammatory cytokines (TNFα IL-6 &amp; IL-23) in RAW 264.7 macrophages and AA-SM cells. BBR was able to counteract these factors through activation of miR-23a levels in LPS/TNFα stimulated RAW 264.7 macrophages and AA-SM cells. NQDI1 (30 μM) treatment inhibited ASK1 activation resulting in basal levels of miR-23a, owing to the conclusion that ASK1 activation downregulates miR-23a levels inside the cells. Overall, our current findings predict that BBR is a potential candidate for therapeutic targeting of TLR4/TRAF2 mediated ASK1 activation in inflammatory and in RA pathogenesis possibly through post-transcriptional gene silencing via upregulation of miR-23a. © 2018 Elsevier Inc.

Toxicology and Applied Pharmacology

Berberine modulates ASK1 signaling mediated through TLR4/TRAF2 via upregulation of miR-23a

Interleukin 17 (IL-17) and hypoxia have been implicated to play a key role in rheumatoid arthritis (RA). In this study, the combined treatment of IL-17 and cobalt chloride (CoCl2), a hypoxia mimetic significantly increased the osteoclast formation and the expression of TRAP and MMP-9 in RAW 264.7 macrophage cells in the presence of RANKL and M-CSF. The unified effect of IL-17 and CoCl2 markedly increased osteoclast mediated bone erosion through the activation of RANKL/NF-κB/NFATc1 signaling pathway. The treatment of IL-17 in combination with CoCl2 further potentiated the protein and mRNA expression of HIF-1α and MMP-9 in rat synovial macrophages. Conversely, the blockage of HIF-1α expression with BAY87-2243 abrogated the IL-17 and CoCl2 mediated expression of HIF-1α and MMP-9. Further, the knockdown of IL-17RA using siRNA reversed the IL-17 and CoCl2 induced expression of HIF-1α in synovial macrophages. In conclusion, IL-17 synergizes with CoCl2 induced hypoxic condition to augment osteoclast mediated bone erosion and synovial macrophages mediated RA pathogenesis.

Computer Science

School of Computer Science and Engineering

Chennai Campus

Cellular Immunology

Interleukin 17 under hypoxia mimetic condition augments osteoclast mediated bone erosion and expression of HIF-1α and MMP-9

Background: Post-translational (PT) modification in cells regulates many intracellular events like signal transduction, transcription, cell cycle, protein quality control, apoptosis and cellular development. Ubiquitination is one of the PT modifications which functions as a marker for degradation of target proteins by the proteasome and as a regulatory mechanism for several signalling pathways. The ubiquitination mechanism requires multiple enzymes, including E1, E2, and E3 ligases. Among them, E3 ligases play a major role in recognizing target proteins and an essential feature of protein homeostatic mechanisms within the cell. Most of the ASB (ankyrin repeat SOCS box) proteins function as RING family of E3 ubiquitin ligases characterized by the presence of two conserved domains N-terminal ankyrin repeat and C-terminal SOCS box domain Methods and Results: Current studies have shown that some ASBs function as important regulators of several signalling pathways. This review gives an overview of ASB proteins on numerous cellular processes such as insulin signalling, spermatogenesis, myogenesis and in cellular development. Including various pathological situations, such as cancer, primary open-angle glaucoma, and inflammation, indicating that ASBs has important functions in both normal and pathological development Conclusions: This article provides a precise comprehensive focus on ASBs protein structure, its biological functions, and their pathological significance. © 2018, Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature.

Frontiers in Biology

Multifaceted roles of ASB proteins and its pathological significance

Aims: Bone erosion induced by enhanced osteoclast formation is a debilitating pathological phenomenon in rheumatoid arthritis (RA). Recent finding has revealed that ferulic acid is associated with reduced osteoclast differentiation and bone erosion. However, the underlying mechanism through which ferulic acid inhibited osteoclast differentiation and bone erosion still remains to be elucidated. This study assessed the therapeutic effects of ferulic acid on osteoclast differentiation and bone erosion by targeting RANKL dependent NF-κB pathway. Main methods: RAW 264.7 monocyte/macrophage cells were left untreated/treated with 25, 50 and 100 μM ferulic acid prior to stimulation with/without RANKL and M-CSF. Osteoclast differentiation and formation was assessed by SEM and TRAP analysis whereas its functional activity of bone erosion was determined by pit formation assay. Crucial transcription factors (NF-κBp-65, NFATc1 and c-Fos) and osteoclast specific genes (TRAP, MMP-9 and Cathepsin K) were evaluated by quantitative RT-PCR. Further, the protein level expression of NF-κBp-65, NFAtc1, c-Fos and MMP-9 was assessed using western blot analysis. Key findings: Our results demonstrated that ferulic acid significantly attenuated RANKL induced osteoclast differentiation as evidenced from SEM and TRAP staining analysis. A remarkable decrease in the bone resorption activity of osteoclasts was also noticed upon ferulic acid treatment. In addition, the down-regulation of RANKL induced NF-κB activation and its associated downstream factors like NFATc1, c-Fos, TRAP, Cathepsin K and MMP-9 was also observed upon ferulic acid treatment. Significance: Thus, our findings evidence the anti-stimulatory and anti-resorptive role of ferulic acid via the inhibition of RANKL dependent NF-κB signalling pathway. © 2018 Elsevier Inc.

Life Sciences

Ferulic acid, a dietary polyphenol suppresses osteoclast differentiation and bone erosion via the inhibition of RANKL dependent NF-κB signalling pathway

In the present study, we intend to gain an insight into the mechanism of Withaferin-A (WA), a steroidal lactone with reference to repolarization of RAW 264.7 macrophages (M1 to M2 type). We found that successful internalization of WA via mannosylated liposomal delivery system (ML-WA) reduced the RAW 264.7 macrophage (M1) mediated pro-inflammatory cytokines (IL-1β IL-6, IL-23, and TNF-α) through the attenuation of transcription factor NF-κB-p65 expression. Whereas, ML-WA treatment induced a controlled upregulation of p-STAT3, and ablated the key oxidative stress markers (NO, iNOS, and ROS) in M1 → M2 RAW 264.7 macrophage repolarization, which suggested the recalibration of M1 macrophage metabolic function. Further, the elevated expression of M2 macrophage associated CD163 over the M1 macrophage related CD86 concluded that ML-WA induces an anti-inflammatory response by repolarizing the M1 → M2 RAW 264.7 macrophage. © 2018 Elsevier B.V.

International Immunopharmacology

Targeting RAW 264.7 macrophages (M1 type) with Withaferin-A decorated mannosylated liposomes induces repolarization via downregulation of NF-κB and controlled elevation of STAT-3

Rheumatoid arthritis (RA) is a systemic and chronic autoimmune inflammatory disorder affecting multiple joints. Various cytokines, chemokines and growth factors synergistically modulate the joint physiology leading to bone erosion and cartilage degradation. Other than these conventional mediators that are well established in the past, the newly identified plasminogen activator (PA) family of proteins have been witnessed to possess a multifactorial approach in mediating RA pathogenesis. One such family of proteins comprises of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR)/soluble-type plasminogen activator receptor (suPAR). PA family of proteins are classified into two types namely: uPA and tissue type plasminogen activator (tPA). Both these subtypes have been implicated to play a key role in RA disease progression. However during RA pathogenesis, uPA secreted by neutrophils, chondrocytes, and monocytes are designated to interact with uPAR expressed on macrophages, fibroblast-like synoviocytes (FLS), chondrocytes and endothelial cells. Interaction of uPA/uPAR promotes the disease progression of RA through secretion of several cytokines, chemokines, growth factors and matrix metalloproteinases (MMPs). Moreover, uPA/uPAR initiates inflammatory responses in macrophages and FLS through activation of PI3K/Akt signaling pathways. Furthermore, uPAR plays a dual role in osteoclastogenesis under the presence/absence of growth factors like monocyte-colony stimulating factor (M-CSF). Overall, this review emphasizes the role of uPA/uPAR on various immune cells, signaling pathways and osteoclastogenesis involved in RA pathogenesis. © 2018 Elsevier Ltd

Pharmacological Research

uPA/uPAR signaling in rheumatoid arthritis: Shedding light on its mechanism of action

Pollution by the release of dye containing wastewater has been alarming worldwide. Biodegradation of reactive green dye and textile effluent by Candida sp. VITJASS was investigated in dynamic condition. Paddy rhizosphere yeast Candida sp. VITJASS showed 84% removal of reactive green dye and 75% reduction in ADMI of textile effluent with a considerable synthesis of oxido-reductase enzymes. The degraded products were analyzed by UV-vis spectroscopy, HPLC and FTIR, which indicated the biotransformation of dye into non-toxic metabolites. GC-MS analysis revealed the formation of Diphenylmethane as potential end product. Phytotoxicity assessment on Phaseolus mungo seeds suggested the non- toxic nature of extracted metabolite. Toxicity studies on zebrafish revealed disturbed cellular integrity and disruption of tissues with crude dye supplementation. However, the degraded metabolites by VITJASS had an intact lumen morphology in the fishes. Thus, the present study depicts the augmentation of yeast strain to be efficacious and promising for degradation of dye with the synthesis of non-toxic metabolites. © 2018 Elsevier Ltd.