Biallelic variants in CCN2 underlie an autosomal recessive kyphomelic dysplasia.

Kyphomelic dysplasia is a rare heterogenous group of skeletal dysplasia, characterized by bowing of the limbs, severely affecting femora with distinct facial features. Despite its first description nearly four decades ago, the precise molecular basis of this condition remained elusive until the recent discovery of de novo variants in the KIF5B-related kyphomelic dysplasia. We ascertained two unrelated consanguineous families with kyphomelic dysplasia.

A critical appraisal of geroprotective activities of flavonoids in terms of their bio-accessibility and polypharmacology.

Flavonoids, a commonly consumed natural product, elicit health-benefits such as antioxidant, anti-inflammatory, antiviral, anti-allergic, hepatoprotective, anti-carcinogenic and neuroprotective activities. Several studies have reported the beneficial role of flavonoids in improving memory, learning, and cognition in clinical settings. Their mechanism of action is mediated through the modulation of multiple signalling cascades.

Bacterial endosymbionts of a nitrogen-fixing yeast JGTA-S1 - insights into a yet unknown micro-ecosystem.

JGTA-S1 is a yeast strain capable of fixing nitrogen and improving nitrogen nutrition in rice plants because of its nitrogen-fixing endobacteria, namely () and sp. To gain a deeper understanding of yeast endosymbionts, we conducted a whole-genome shotgun metagenomic analysis of JGTA-S1 cells grown under conditions of nitrogen sufficiency and deficiency. Our results showed that the endosymbiont population varied depending on the nitrogen regime.

Targeting next-generation PDE4 inhibitors in search of potential management of rheumatoid arthritis and psoriasis.

Immune-mediated inflammatory diseases (IMIDs) comprise a broad spectrum of conditions characterized by systemic inflammation affecting various organs and tissues, for which there is no known cure. The isoform-specific inhibition of phosphodiesterase-4B (PDE4B) over PDE4D constitutes an effective therapeutic strategy for the treatment of IMIDs that minimizes the adverse effects associated with non-selective PDE4 inhibitors. Thus, we report a new class of isoquinolone derivatives as next-generation PDE4 inhibitors for effective management of rheumatoid arthritis (RA) and psoriasis.

Cholesterol Allosterically Modulates the Structure and Dynamics of the Taurocholate Export Pump (ABCB11).

The BSEP/ABCB11 transmembrane protein translocates taurine- and glycine-conjugated bile salts across the hepatocyte bilayer driven by ATP-hydrolysis. Direct inhibition of BSEP/ABCB11 leads to idiosyncratic drug-induced liver injury. ABCB11 is localized within the cholesterol-enriched lipid raft, and membrane cholesterol depletion leads to impaired taurocholate transport.

Metal-free efficient synthesis of aryl sulfonamides from -hydroxy sulfonamide and amines.

A simple and novel approach has been developed for the synthesis of sulfonamides from -hydroxy sulfonamide. Notably, the iodine--butyl hydroperoxide (TBHP) system efficiently promoted the sulfonylation reactions of -hydroxy sulfonamides and amines the oxidative cleavage of an S-N bond. A variety of aryl sulfonamides were prepared in moderate to good yields using readily available starting materials and the biomass-derived 2-MeTHF solvent.

EYA protein complex is required for Wntless retrograde trafficking from endosomes to Golgi.

Retrograde transport of WLS (Wntless) from endosomes to trans-Golgi network (TGN) is required for efficient Wnt secretion during development. However, the molecular players connecting endosomes to TGN during WLS trafficking are limited. Here, we identified a role for Eyes Absent (EYA) proteins during retrograde trafficking of WLS to TGN in human cell lines.

Mitigation of experimental ER stress and diabetes mellitus induced peripheral neuropathy by autophagy promoter, 6-BIO.

Neuropathy occurs due to damage to the peripheral/central nervous system either due to injury, disease, or drug usage. Increased endoplasmic reticulum (ER) stress is observed in neuropathy. ER stress also leads to a block in autophagy amplifying neuropathic pain.

Antimycobacterial and healing effects of Pranlukast against MTB infection and pathogenesis in a preclinical mouse model of tuberculosis.

It is essential to understand the interactions and relationships between () and macrophages during the infection in order to design host-directed, immunomodulation-dependent therapeutics to control . We had reported previously that ornithine acetyltransferase (MtArgJ), a crucial enzyme of the arginine biosynthesis pathway of , is allosterically inhibited by pranlukast (PRK), which significantly reduces bacterial growth. The present investigation is centered on the immunomodulation in the host by PRK particularly the activation of the host's immune response to counteract bacterial survival and pathogenicity.

Reduced incretin receptor trafficking upon activation enhances glycemic control and reverses obesity in diet-induced obese mice.

Activation of incretin receptors by their cognate agonist augments sustained cAMP generation both from the plasma membrane as well as from the endosome. To address the functional outcome of this spatiotemporal signaling, we developed a nonacylated glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor dual agonist I-M-150847 that reduced receptor internalization following activation of the incretin receptors. The incretin receptor dual agonist I-M-150847 was developed by replacing the tryptophan cage of exendin-4 tyrosine substituted at the amino terminus with the C-terminal undecapeptide sequence of oxyntomodulin that placed lysine 30 of I-M-150847 in frame with the corresponding lysine residue of GIP.

Loss of FMRP affects ovarian development and behaviour through multiple pathways in a zebrafish model of fragile X syndrome.

Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder and the leading genetic cause of autism spectrum disorders. FXS is caused by loss of function mutations in Fragile X mental retardation protein (FMRP), an RNA binding protein that is known to regulate translation of its target mRNAs, predominantly in the brain and gonads. The molecular mechanisms connecting FMRP function to neurodevelopmental phenotypes are well understood.

Modulation of Nuclear Receptor 4A1 Expression Improves Insulin Secretion in a Mouse Model of Chronic Pancreatitis.

Objectives: Diabetes secondary to chronic pancreatitis (CP) presents clinical challenges due to lack of understanding on factor(s) triggering insulin secretory defects. Therefore, we aimed to delineate the molecular mechanism of β-cell dysfunction in CP.

Materials And Methods: Transcriptomic analysis was conducted to identify endocrine-specific receptor expression in mice and human CP on microarray.

Putative Role of Cholesterol in Shaping the Structural and Functional Dynamics of Smoothened (SMO).

The smoothened (SMO) receptor belongs to the superfamily of class F G protein-coupled receptors (GPCRs) and is a potential drug target in several types of cancer. It has two ligand binding sites, respectively, in the cysteine-rich domain (CRD) and the transmembrane domain (TMD). It has been shown that cholesterol is important for its activation and function.

TGS1/PIMT knockdown reduces lipid accumulation in adipocytes, limits body weight gain and promotes insulin sensitivity in mice.

PRIP Interacting protein with Methyl Transferase domain (PIMT/TGS1) is an integral upstream coactivator in the peroxisome proliferator-activated receptor gamma (PPARγ) transcriptional apparatus. PPARγ activation alleviates insulin resistance but promotes weight gain. Herein, we show how PIMT regulates body weight while promoting insulin sensitivity in diet induced obese mice.

TGS1/PIMT regulates pro-inflammatory macrophage mediated paracrine insulin resistance: Crosstalk between macrophages and skeletal muscle cells.

Macrophage-driven chronic low-grade inflammatory response is intimately associated with pathogenesis of insulin resistance and type 2 diabetes (T2D). However, the molecular basis for skewing of pro-inflammatory macrophage is still elusive. Here, we describe the mechanism and significance of TGS1/PIMT (PRIP-Interacting protein with Methyl Transferase domain) in regulating macrophage activation and polarization and its impact on the development of insulin resistance in skeletal muscle cells.

A multi-tier computational screening framework to effectively search the mutational space of SARS-CoV-2 receptor binding motif to identify mutants with enhanced ACE2 binding abilities.

SARS-CoV-2 gained crucial mutations at the receptor binding domain (RBD) that often changed the course of the pandemic leading to new waves with increased case fatality. Variants are observed with enhanced transmission and immune invasion abilities. Thus, predicting future variants with enhanced transmission ability is a problem of utmost research interest.

Cabozantinib-induced edema in zebrafish represents an adverse effect characterized by defects in lymphatic vasculature and renal function.

Tyrosine kinase inhibitors (TKIs) are a major class of targeted cancer therapy drugs. Overcoming the limitations of approved TKIs and the development of new TKIs continues to be an important need. The adoption of higher throughput and accessible animal models to evaluate TKI adverse effects will help in this regard.

Design, synthesis and evaluation of 2-aryl quinoline derivatives against 12R-lipoxygenase (12R-LOX): Discovery of first inhibitor of 12R-LOX.

The 12R-lipoxygenase (12R-LOX), a (non-heme) iron-containing metalloenzyme belonging to the lipoxygenase (LOX) family catalyzes the conversion of arachidonic acid (AA) to its key metabolites. Studies suggested that 12R-LOX plays a critical role in immune modulation for the maintenance of skin homeostasis and therefore can be considered as a potential drug target for psoriasis and other skin related inflammatory diseases. However, unlike 12-LOX (or 12S-LOX) the enzyme 12R-LOX did not receive much attention till date.

PIMT Controls Insulin Synthesis and Secretion through PDX1.

Pancreatic beta cell function is an important component of glucose homeostasis. Here, we investigated the function of PIMT (PRIP-interacting protein with methyl transferase domain), a transcriptional co-activator binding protein, in the pancreatic beta cells. We observed that the protein levels of PIMT, along with key beta cell markers such as PDX1 (pancreatic and duodenal homeobox 1) and MafA (MAF bZIP transcription factor A), were reduced in the beta cells exposed to hyperglycemic and hyperlipidemic conditions.

Antiviral Flavonoids: A Natural Scaffold with Prospects as Phytomedicines against SARS-CoV2.

Flavonoids are vital candidates to fight against a wide range of pathogenic microbial infections. Due to their therapeutic potential, many flavonoids from the herbs of traditional medicine systems are now being evaluated as lead compounds to develop potential antimicrobial hits. The emergence of SARS-CoV-2 caused one of the deadliest pandemics that has ever been known to mankind.

PHLPP1 regulates PINK1-parkin signalling and life span.

Adaptability to intracellular or extracellular cues is essential for maintaining cellular homeostasis. Metabolic signals intricately control the morphology and functions of mitochondria by regulating bioenergetics and metabolism. Here, we describe the involvement of PHLPP1, a Ser/Thr phosphatase, in mitochondrial homeostasis.

Cloning, expression and in vitro validation of chimeric multi epitope vaccine candidate against visceral leishmaniasis infection.

Visceral Leishmaniasis or Kala-Azar is one of the most severe and deadly neglected tropical disease caused by the Leishmania parasite. A few number of vaccines are going through different phases in clinical trial but failing of these vaccines in successive phase trial or less efficacy, urge to develop highly immunogenic and cost-effective treatment to get rid of deadly VL. This study focuses on the development of more potent vaccine candidate against VL.