Department of Pharmacy
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Item Prevention of fatty acid-induced maladaptation in secretin tumor cell-1 enteroendocrine cells by allicin, a transient receptor potential ankyrin 1 agonist(Elsevier, 2025) Khare, PragyanshuEnteroendocrine cells (EECs) in the gastrointestinal tract play a critical role in sensing dietary fat and regulating the secretion of gut hormone. However, chronic high-fat diet (HFD) intake can lead to maladaptive changes in these cells, impairing hormone regulation. Transient receptor potential ankyrin 1 (TRPA1), an ion channel endogenously expressed in EECs, is known to promote gut hormone secretion when activated. Previous studies have shown that gut TRPA1 expression is reduced in HFD-fed mice, but the underlying molecular mechanisms remained unclear. In this study, we used the secretin tumor cell-1 (STC-1) enteroendocrine cell line treated with a fatty acid (FA) mixture (oleic acid: stearic acid in a 2:3 ratio) to mimic chronic HFD exposure in vitro. Our data from label-free proteomics, flow cytometry, and western blotting revealed that FA treatment causes TRPA1 downregulation through AMP-activated protein kinase and Ca2+ signaling pathways. This downregulation was accompanied by altered expression of genes and proteins involved in gut hormone synthesis and secretion. We further investigated the protective effect of allicin, a natural TRPA1 agonist found in garlic. Allicin treatment prevented TRPA1 downregulation both in FA-treated STC-1 cells and in HFD-fed C57BL/6J mice. In conclusion, this study elucidates the AMP-activated protein kinase-dependent mechanisms behind FA-induced TRPA1 downregulation in EECs and highlights how this contributes to gut hormone dysregulation. Importantly, dietary TRPA1 agonists such as allicin can counteract these effects, suggesting potential for development of functional foods (eg, allicin, thiocyanates, cuminaldehyde, cinnamaldehyde) to mitigate HFD-related gut hormone disturbances.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 Topical menthol, a pharmacological cold mimic, induces cold sensitivity, adaptive thermogenesis and brown adipose tissue activation in mice(Wiley, 2024-07) Khare, PragyanshuBrown adipose tissue (BAT) thermogenesis has profound energy-expanding potential, which makes it an attractive target tissue to combat ever-increasing obesity and its other associated metabolic complications. Although it is fairly accepted that cold is a potent inducer of BAT activation and function, there are limited studies on the mechanisms of pharmacological cold-mimicking agents, such as the TRPM8 agonist, menthol, on BAT thermogenesis and activation.Item The TRPC5 receptor as pharmacological target for pain and metabolic disease(Elsevier, 2024-11) Khare, PragyanshuThe transient receptor potential canonical (TRPC) channels are a group of highly homologous nonselective cation channels from the larger TRP channel family. They have the ability to form homo- and heteromers with varying degrees of calcium (Ca2+) permeability and signalling properties. TRPC5 is the one cold-sensitive among them and likewise facilitates the influx of extracellular Ca2+ into cells to modulate neuronal depolarization and integrate various intracellular signalling pathways. Recent research with cryo-electron microscopy revealed its structure, along with clear insight into downstream signalling and protein-protein interaction sites. Investigations using global and conditional deficient mice revealed the involvement of TRPC5 in metabolic diseases, energy balance, thermosensation and conditions such as osteoarthritis, rheumatoid arthritis, and inflammatory pain including opioid-induced hyperalgesia and hyperalgesia following tooth decay and pulpitis. This review provides an update on recent advances in our understanding of the role of TRPC5 with focus on metabolic diseases and pain.Item The Role of TRPV1 in Acquired Diseases: Therapeutic Potential of TRPV1 Modulators(Elsevier, 2015) Khare, PragyanshuThe transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel with high calcium permeability that has been studied extensively since its identification and characterization in 1997. Its involvement in different modalities of pain has been well documented, which has resulted in the development of novel strategies for the treatment of pain. However, TRPV1 is also involved in a plethora of other physiological and pathophysiological functions related to urinary, cardiovascular, gastrointestinal, respiratory, and central nervous systems. Here, we summarize the recent developments of the role of TRPV1 in acquired diseases and review the current perspective of TRPV1 agonist and antagonist as potential drugs for therapeutic intervention.Item Probiotic attributes and prevention of LPS-induced pro-inflammatory stress in RAW264.7 macrophages and human intestinal epithelial cell line (Caco-2) by newly isolated Weissella cibaria strains(RSC, 2018) Khare, PragyanshuProbiotic lactic acid bacteria are known to modulate gut associated immune responses. Not many studies have reported on the role of Weissella species in preventing lipopolysaccharide (LPS) induced proinflammatory stress in murine macrophages as well as in human intestinal epithelial cells (Caco-2). Therefore, the present study was taken up to evaluate the probiotic attributes of four newly isolated Weissella strains (two each from fermented dosa batter and a human infant faecal sample); these attributes are cholesterol reduction, adhesion to Caco-2 cells and mucin and their ability to prevent LPS-induced nitric oxide and proinflammatory cytokine (IL-6, IL-1β and TNFα) production by the murine macrophages and IL-8 production by the human epithelial cells. Reduction in LPS induced pro-inflammatory stress was compared with a well-studied probiotic bacterium Lactobacillus rhamnosus GG. The results suggested that the strains were tolerant to gastric conditions (pH 3.0) and bile salts. In addition, the strains exhibited moderate cell surface hydrophobicity, cholesterol reduction and adhesion to Caco-2 cells and gastric mucin. All the strains could prevent LPS-induced nitric oxide and IL-6 production in murine macrophages, while strain 28 alone prevented IL-1β production. All the strains could prevent IL-8 production by the human epithelial cells. The present study led to the first line selection of W. cibaria 28 as a putative strain for future studies as it showed adhesion to Caco-2 cells and gastric mucin and cholesterol reduction besides preventing LPS-induced pro-inflammatory stress in macrophages and in human colonic epithelial cells.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 Finger millet arabinoxylan protects mice from high-fat diet induced lipid derangements, inflammation, endotoxemia and gut bacterial dysbiosis(Elsevier, 2018-01) Khare, PragyanshuArabinoxylan (AX), a non-starch polysaccharide extracted from cereals such as wheat, rice and millets, is known to impart various health promoting effects. Our earlier study suggested that finger millet (FM) could ameliorate high fat diet (HFD)-induced metabolic derangements. The present study is aimed to evaluate the effect of FM-AX supplementation, a key bioactive from finger millet, on HFD-induced metabolic and gut bacterial derangements. Male Swiss albino mice were fed with normal chow diet (NPD) or HFD (60% kcal from fat) for 10 weeks. FM-AX was orally supplemented at doses of 0.5 and 1.0 g/kg bodyweight on every alternate day for 10 weeks. Glucose tolerance, serum hormones, hepatic lipid accumulation and inflammation, white adipose tissue marker gene expression, adipocyte size and inflammation; metagenomic alterations in cecal bacteria; cecal short chain fatty acids and colonic tight junction gene expressions were studied. FM-AX supplementation prevented HFD-induced weight gain, alerted glucose tolerance and serum lipid profile, hepatic lipid accumulation and inflammation. Hepatic and white adipose tissue gene expressions were beneficially modulated. Further, AX supplementation prevented metagenomic alterations in cecum; improved ileal and colonic health and overall prevented metabolic endotoxemia. Present work suggests that AX from finger millet can be developed as a nutraceutical for the management of HFD- induced obesity.Item Co-supplementation of isomalto-oligosaccharides potentiates metabolic health benefits of polyphenol-rich cranberry extract in high fat diet-fed mice via enhanced gut butyrate production(Springer, 2017-11) Khare, PragyanshuCranberries are a rich source of polyphenolic antioxidants. Purified sugars or artificial sweeteners are being added to cranberry-based food products to mask tartness. Refined sugar and artificial sweeteners intake modulate gut microbiota and result in metabolic complications. We evaluated effects of isomalto-oligosaccharides (IMOs; sweet tasting non-digestible oligosaccharides) with cranberry extract (CRX) on high fat diet (HFD)-induced metabolic alterations in mice.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.