BITS Faculty Publications
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Item Kynurenine monooxygenase inhibition and associated reduced quinolinic acid reverses depression-like behaviour by upregulating Nrf2/ARE pathway in mouse model of depression: In-vivo and In-silico studies(Elsevier, 2022-09) Khare, PragyanshuKynurenine pathway, a neuroimmunological pathway plays a substantial role in depression. Consistently, increased levels of neurotoxic metabolite of kynurenine pathway; quinolinic acid (QA) found in the suicidal patients and remitted major depressive patients. QA, an endogenous modulator of N-methyl-d-aspartate receptor is produced by microglial cells, may serve as a potential candidate for a link between antioxidant defence system and immune changes in depression. Further, nuclear factor (erythroid-derived 2) like 2 (Nrf2), an endogenous antioxidant transcription factor plays a significant role in maintaining antioxidant homeostasis during basal and stress conditions. The present study was designed to explore the effects of KMO-inhibition (Kynurenine monooxygenase) and association of reduced QA on Keap1/Nrf2/ARE pathway activity in olfactory bulbectomized mice (OBX-mice). KMO catalysis the neurotoxic branch of kynurenine pathway directing the synthesis of QA. KMO inhibitionshowed significant reversal of depressive-like behaviour, restored Keap-1 and Nrf2 mRNA expression, and associated antioxidant levels in cortex and hippocampus of OBX-mice. KMO inhibition also increased PI3K/AKT mRNA expression in OBX-mice. KMO inhibition and associated reduced QA significantly decreased inflammatory markers, kynurenine and increased the 5-HT, 5-HIAA and tryptophan levels in OBX-mice. Furthermore, molecular docking studies has shown good binding affinity of QA towards ubiquitin proteasome complex and PI3K protein involved in Keap-1 dependent and independent proteasome degradation of Nrf2 respectively supporting our in-vivo findings. Hence, QA might act as pro-oxidant through downregulating Nrf2/ARE pathway along with modulating other pathways and KMO inhibition could be a potential therapeutic target for depression treatment.Item Finger millet bran supplementation alleviates obesity-induced oxidative stress, inflammation and gut microbial derangements in high-fat diet-fed mice(CUP, 2014-09) Khare, PragyanshuSeveral epidemiological studies have shown that the consumption of finger millet (FM) alleviates diabetes-related complications. In the present study, the effect of finger millet whole grain (FM-WG) and bran (FM-BR) supplementation was evaluated in high-fat diet-fed LACA mice for 12 weeks. Mice were divided into four groups: control group fed a normal diet (10 % fat as energy); a group fed a high-fat diet; a group fed the same high-fat diet supplemented with FM-BR; a group fed the same high-fat diet supplemented with FM-WG. The inclusion of FM-BR at 10 % (w/w) in a high-fat diet had more beneficial effects than that of FM-WG. FM-BR supplementation prevented body weight gain, improved lipid profile and anti-inflammatory status, alleviated oxidative stress, regulated the expression levels of several obesity-related genes, increased the abundance of beneficial gut bacteria (Lactobacillus, Bifidobacteria and Roseburia) and suppressed the abundance of Enterobacter in caecal contents (P≤ 0·05). In conclusion, FM-BR supplementation could be an effective strategy for preventing high-fat diet-induced changes and developing FM-BR-enriched functional foods.Item Isomalto-oligosaccharides, a prebiotic, functionally augment green tea effects against high fat diet-induced metabolic alterations via preventing gut dysbacteriosis in mic(Elsevier, 2017-09) Khare, PragyanshuHigh fat diet (HFD)-induced alterations in gut microbiota and resultant ‘leaky gut’ phenomenon promotes metabolic endotoxemia, ectopic fat deposition, and low-grade systemic inflammation. Here we evaluated the effects of a combination of green tea extract (GTE) with isomalto-oligosaccharide (IMOs) on HFD-induced alterations in mice. Male Swiss albino mice were fed with HFD (58% fat kcal) for 12 weeks. Systemic adiposity, gut derangement parameters and V3-V4 region based 16S rRNA metagenomic sequencing, ectopic fat deposition, liver metabolome analysis, systemic and tissue inflammation, and energy homeostasis markers along with gene expression analysis in multiple tissues were done in mice supplemented with GTE, IMOs or their combination. The combination of GTE and IMOs effectively prevented HFD-induced adiposity and lipid accumulation in liver and muscle while normalizing fasting blood glucose, insulin, glucagon, and leptin levels. Co-administration of GTE with IMOs effectively modulated liver metabolome associated with lipid metabolism. It also prevented leaky gut phenotype and HFD-induced increase in circulating lipopolysaccharides and pro-inflammatory cytokines (e.g. resistin, TNF-α, and IL-1β) and reduction in anti-inflammatory cytokines (e.g. adiponectin and IL-6). Gene expression analysis across multiple tissues further supported these functional outcomes. Most importantly, this combination improved beneficial gut microbiota (Lactobacillus sp., Bifidobacteria, Akkermansia muciniphila, Roseburia spp.) abundances, restored Firmicutes/Bacteriodetes and improved Prevotella/Bacteroides proportions. In particular, a combination of these two agents has shown improved beneficial effects on multiple parameters studied. Data presented herein suggests that strategically chosen food components might be highly effective in the prevention of HFD-induced alterations and may further be developed as functional foods.Item Phloretin as an add-on therapy to losartan attenuates diabetes-induced AKI in rats: A potential therapeutic approach targeting TLR4-induced inflammation(Elsevier, 2023-11) Gaikwad, Anil BhanudasTargeting Toll-like receptor 4 (TLR4) and Angiotensin II type 1 receptor (AT1R) could provide renoprotection during acute kidney injury (AKI) mainly by regulating inflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. Phloretin (TLR4 inhibitor) as an add-on therapy to losartan (AT1R inhibitor) could provide more therapeutic benefits against AKI under diabetic condition. We aimed to study the effect of phloretin as an add-on therapy to losartan against AKI under diabetic condition.Item Voclosporin: Unique Chemistry, Pharmacology and Toxicity Profile, and Possible Options for Implementation into the Management of Lupus Nephritis(MDPI, 2023-10) Gaikwad, Anil BhanudasCalcineurin inhibitors (CNI) can suppress allo- and autoimmunity by suppressing T cell function but also have anti-proteinuric effects by stabilizing the cellular components of the kidney’s filtration barrier. Therefore, CNI are used in autoimmune kidney diseases with proteinuria. However, the traditional CNI, cyclosporine A and tacrolimus, have a narrow therapeutic range, need monitoring of drug levels, and their use is associated with nephrotoxicity and metabolic alterations. Voclosporin (VOC), a novel CNI, no longer requires drug level monitoring and seems to lack these adverse effects, although hypertension and drug–drug interactions still occur. VOC demonstrated efficacy superior to standard-of-care in controlling active lupus nephritis in the phase 2 AURA-LV and the phase 3 AURORA-1 trials and was approved for the treatment of active lupus nephritis. However, how to implement VOC into the current and changing treatment landscape of lupus nephritis is still debated. Here, we review the unique chemistry, pharmacology, and toxicity profile of VOC, summarize the efficacy and safety data from the AURA-LV and AURORA-1 trials, and discuss the following four possible options to implement VOC into the management of lupus nephritis, namely regarding B cell-targeting therapy with belimumab (BEL). These include: 1. patient stratification to either VOC or BEL, 2. VOC/BEL combination therapy, 3. VOC-BEL sequential therapy, or 4. alternative options for the rapid antiproteinuric effect of VOC.Item Disparity in actions of rosiglitazone against cisplatin-induced nephrotoxicity in female Sprague-Dawley rats(Elsevier, 2013-11) Gaikwad, Anil BhanudasCisplatin is one of the most common chemotherapeutic drugs used against various solid, tumours. Despite of its therapeutic benefits, its use in clinical practice is often limited because of dose, related toxicity. The nephrotoxic potential of cisplatin has been ascribed to its accumulation in the, renal tubular cells generating reactive oxygen species (ROS), activation of Bax, increased secretion of, TNFα and activation of certain inflammatory mediators like cytokines. The present investigation was, undertaken with an objective to study the effect of rosiglitazone against cisplatin induced, nephrotoxicity. Pretreatment of rosiglitazone prevents cisplatin induced nephrotoxicity which was, clearly evident from the renal biochemical parameters like reduced BUN, creatinine and TNFα levels, and increased albumin levels, which was also supported by histopathological studies of the kidneys. In contrast, posttreatment of rosiglitazone was not able to protect the renal damage in cisplatin induced, renal toxicity. These results showed the variation of pre & posttreatment effects of rosiglitazone, against the cisplatin induced nephrotoxicity.Item Glycogen Synthase Kinase 3 (GSK3): Its Role and Inhibitors(Bentham Science, 2020) Jadhav, Hemant R.Glycogen Synthase Kinase 3 (GSK3) is one of the Serine/Threonine protein kinases, which has gained a lot of attention for its role in a variety of pathways. It has two isoforms, GSK3α and GSK3β. However, GSK3β is highly expressed in different areas of the brain and has been implicated in Alzheimer’s disease as it is involved in tau phosphorylation. Due to its high specificity concerning substrate recognition, GSK3 has been considered as an important target. In the last decade, several GSK3 inhibitors have been reported and two molecules are in clinical trials. This review collates the information published in the last decade about the role of GSK3 in Alzheimer’s disease and progress in the development of its inhibitors. Using this collated information, medicinal chemists can strategize and design novel GSK3 inhibitors that could be useful in the treatment of Alzheimer’s disease.Item TNF α Signaling Beholds Thalidomide Saga: A Review of Mechanistic Role of TNF-α Signaling Under Thalidomide(Bentham Science, 2012) Majumder, SyamantakTumor necrosis factor alpha (TNF- α) is a pleiotropic inflammatory cytokine. The cytokine possesses both growth stimulating properties and growth inhibitory processes, and it appears to have self regulatory properties as well. Agents like etanercept and infliximab showed beneficial effects against rheumatoid arthritis by modulationg TNF- α proteins, however, these agents are largely unable to penetrate the blood-brain barrier, which severely limits their use in different conditions. Thalidomide, an inhibitor of TNF- α protein synthesis is readily capable of crossing the blood-brain barrier and thus thalidomide and its analogs are excellent candidates for use in determining the potential value of anti-TNF- α therapies in a variety of diseases. Thalidomide blocks TNF- α expression by different possible mechanisms. Down regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), an essential transcription factor for TNF and other cytokines under thalidomide treatment leads to reduction in the TNF- α expression. Additionally, myeloid differentiation factor 88 (MyD88), an adapter protein regulates the expression of TNF under thalidomide treatment. Thalidomide treatment also leads to destruction of TNF- α mRNA thus, reducing the total expression of TNF-α protein. Thalidomide also targets reactive oxygen species (ROS) and α 1- acid glycoprotein (AGP) to regulate TNF-α . In the present review, we discuss different possible mechanism that regulates TNF-α under thalidomide treatment. Additionally, we suggest novel strategies for the future targeting combination therapies of thalidomide and its analogs with different other anti-inflammatory drug to curb TNF- α associated diseases.Item Favourable modulation of the inflammatory changes in hypercholesterolemic atherogenesis by a low-molecular-weight heparin derivative(Elsiever, 2006) Deepa, P.R.In the hypercholesterolemic state, the net result of combined oxidative and nitrosative stress is a pro-inflammatory phenotype that is manifested as increased adhesion molecule expression, enhanced leucocyte trafficking, and increased vascular permeability. The present work explores the inflammatory aspects of hypercholesterolemic atherogenesis, and also evaluates the role of a low-molecular-weight heparin derivative (LMWH), Certoparin, on a biochemical basis.