Long-standing chronic inflammation of the digestive tract leads to Inflammatory Bowel Diseases (IBD), comprising Crohn's Disease (CD) and Ulcerative colitis (UC). The persistent prevalence of these conditions in the gut is a predisposing factor for Colitis-Associated Cancer (CAC), one of the most common sub-types of Colorectal Cancer (CRC), emphasizing the role of inflammation in tumorigenesis. Therefore, targeted intervention of chronic intestinal inflammation is a potential strategy for preclusion and treatment of inflammation-driven malignancies.
View Article and Find Full Text PDFWithanolides are a group of naturally occurring plant-based small molecules known for their wide range of host cellular functions. The anticancer potential of withanolides has been explored in varying cancer cell lines . Based on our prior studies, among the tested withanolides, withametelin (WM) has shown significant cytotoxicity with the highest efficacy on HCT-116 colon cancer cells (IC 0.
View Article and Find Full Text PDFThe intestinal tract encompasses one of the largest mucosal surfaces with a well-structured layer of intestinal epithelial cells supported by a network of underlying lamina propria immune cells maintaining barrier integrity. The commensal microflora in this environment is a major contributor to such functional outcomes due to its prominent role in the production of secondary metabolites. Of the several known metabolites of gut microbial origin, such as Short Chain Fatty Acids (SCFAs), amino acid derivatives, etc.
View Article and Find Full Text PDFThe pursuit of small molecule inhibitors targeting hexokinase 2 (HK2) has significantly captivated the field of cancer drug discovery. Nevertheless, the creation of selective inhibitors aimed at specific isoforms of hexokinase (HK) remains a formidable challenge. Here, we present a multiple-pharmacophore modeling approach for designing ligands against HK2 with a marked anti-proliferative effect on FaDu and Cal27 oral cancer cell lines.
View Article and Find Full Text PDFA series of novel quinazoline-4-(3H)-one derivatives were designed and synthesized as histone deacetylase 6 (HDAC6) inhibitors based on novel quinazoline-4-(3H)-one as the cap group and benzhydroxamic acid as the linker and metal-binding group. A total of 19 novel quinazoline-4-(3H)-one analogues (-) were obtained. The structures of the target compounds were characterized using H-NMR, C-NMR, LC-MS, and elemental analyses.
View Article and Find Full Text PDFThe enzyme chorismate mutase (or CM that is vital for the survival of bacteria) is an interesting pharmacological target for the identification of new anti-tubercular agents. The 5,5-disibstituted pyrazolo[4,3-d]pyrimidinone derivatives containing the fragment based on 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide were designed and explored as the potential inhibitors of chorismate mutase. Based on encouraging docking results of two representative molecules evaluated in silico against MtbCM (PDB: 2FP2) the Wang resin catalysed sonochemical synthesis of target N-heteroarenes were undertaken.
View Article and Find Full Text PDFEpidermal growth factor receptor-tyrosine kinase (EGFR-TK) is a well-known hallmark of oral and oropharyngeal cancers, as its overexpression leads to poor prognosis and malignancy. The activating EGFR mutations (particularly T790M and L858R double mutant) are a major challenge causing drug resistance, especially in the treatment of oral cancers. This paper is an effort to exploit both structure-based and ligand-based pharmacophore modeling to discover EGFR-TK inhibitors, which show inhibition of proliferation of erlotinib-resistant FaDu and Cal27 oral cancer cells.
View Article and Find Full Text PDFA recent study showed the association of minor alleles of (T allele) and (T allele) of with schizophrenia (SZ) and suggested their effects on splicing of the transcripts. We performed a replication study using 310 controls and 304 SZ patients and confirmed the association of the homozygous minor allele genotypes with SZ ( = 0.04 for and = 0.
View Article and Find Full Text PDFThe intestinal tract encompasses the largest mucosal surface fortified with a fine layer of intestinal epithelial cells along with highly sophisticated network of the lamina propria immune cells that are indispensable to sustain gut homeostasis. However, it can be challenging to uphold homeostasis when these cells in the intestine are perpetually exposed to insults of both endogenous and exogenous origin. The complex networking and dynamic microenvironment in the intestine demand highly functional cells ultimately burdening the endoplasmic reticulum (ER) leading to ER stress.
View Article and Find Full Text PDFAn Amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDFBile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells that express IL-17a (T17 cells) or regulatory T cells (T cells). Here we screen a library of bile acid metabolites and identify two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice.
View Article and Find Full Text PDFHomocysteine (Hcy) is a key metabolite generated during methionine metabolism. The elevated levels of Hcy in the blood are reffered to as hyperhomocystenimeia (HHcy). The HHcy is caused by impaired metabolism/deficiency of either folate or B12 or defects in Hcy metabolism.
View Article and Find Full Text PDFCell Stress Chaperones
May 2018
Small heat shock proteins (sHsps) belong to the family of heat shock proteins (Hsps): some are induced in response to multiple stressful events to protect the cells while others are constitutively expressed. Until now, it was believed that Hsps, including sHsps, are present inside the cells and perform intracellular functions. Interestingly, several groups recently reported the extracellular presence of Hsps, and sHsps have also been detected in sera/cerebrospinal fluids in various pathological conditions.
View Article and Find Full Text PDFBackground: Intravenous immunoglobulin (IVIG) is a polyspecific pooled immunoglobulin G preparation and one of the commonly used therapeutics for autoimmune diseases including those of neurological origin. A recent report in murine model proposed that IVIG expands regulatory T (T) cells via induction of interleukin 33 (IL-33). However, translational insight on these observations is lacking.
View Article and Find Full Text PDFSevere sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-terminal Kinase (JNK)-mediated signaling events play critical role in bacterial infection triggered multi-organ failure, cardiac dysfunction and mortality.
View Article and Find Full Text PDFMacrophages regulate cell fate decisions during microbial challenges by carefully titrating signaling events activated by innate receptors such as dectin-1 or Toll-like receptors (TLRs). Here, we demonstrate that dectin-1 activation robustly dampens TLR-induced proinflammatory signature in macrophages. Dectin-1 induced the stabilization of β-catenin via spleen tyrosine kinase (Syk)-reactive oxygen species (ROS) signals, contributing to the expression of WNT5A.
View Article and Find Full Text PDFN-Alkyl substituted pyrazoloanthrone derivatives were synthesized, characterized and tested for their in vitro inhibitory activity over c-Jun N-terminal kinase (JNK). Among the tested molecules, a few derivatives showed significant inhibitory activity against JNK with minimal off-target effect on other mitogen-activated protein kinase (MAP kinase) family members such as MEK1/2 and MKK3,6. These results suggested that N-alkyl (propyl and butyl) bearing pyrazoloanthrone scaffolds provide promising therapeutic inhibitors for JNK in regulating inflammation associated disorders.
View Article and Find Full Text PDFMethods Mol Biol
December 2014
Multifunctional roles of tumor necrosis factor-alpha (TNF-α) during the mycobacterial pathogenesis make it an important molecule to understand and to examine the course of infection. Identification and analysis of TNF-α response can largely contribute to determine the potential host mediators for therapeutic intervention against tuberculosis. The current chapter describes several methods to assess the ability of TNF-α signaling to modulate toll-like receptor (TLR)2 signaling, another key player in mycobacterial infection and its responses.
View Article and Find Full Text PDFCD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) play a critical role in the maintenance of immune tolerance. Intravenous immunoglobulin (IVIg), a therapeutic preparation of normal pooled human IgG, expands Tregs in various experimental models and in patients. However, the cellular and molecular mechanisms by which IVIg expands Tregs are relatively unknown.
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