👤 Takhellambam Swornalata Devi

Alzheimer's Disease (AD) is a disabling neurodegenerative illness characterized by Amyloid-beta (Aβ) plaque deposition, tau tangles, and neuroinflammation. These pathological characteristics lead to progressive cognitive decline, and drug therapeutic approaches are bedeviled by extreme difficulty with the Blood-Brain Barrier (BBB) that prevents most drugs from effectively crossing into the brain. Extracellular vesicle-based nanomedicine is a prospective approach to overcome this hurdle. Extracellular vesicles are endogenously derived extracellular vesicles that can cross the BBB and deliver a variety of therapeutic cargos, including small interfering RNAs (siRNAs), microRNAs (miRNAs), proteins, and other small molecules. Since they can cross the BBB and exhibit low immunogenicity and toxicity, extracellular vesicles represent a promising strategy for drug delivery against AD. Recent studies have highlighted the potential of extracellular vesiclebased treatments to deliver anti-amyloid and anti-tau therapies, neuroprotectants (e.g., antioxidants), and immune-modulatory factors. Engineered extracellular vesicles containing siRNA against βsecretase eta-site app cleaving enzyme 1 (BACE1), anti-tau oligonucleotides, and anti-inflammatory cytokines have shown promising preclinical efficacy by reducing Aβ deposition, tau aggregation, and neuroinflammation. These changes have been associated with enhanced cognitive function. Besides, extracellular vesicle-based systems were investigated for gene-editing therapeutics with Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/ Cas9) and Antisense Oligonucleotides (ASOs). Besides scalability concerns, cargo-loading efficiency, and long-term toxicity, extracellular vesicle-based nanomedicine is an innovative platform for targeted drug deli. Show less

The fibroblast growth factor receptor 1 (FGFR1) plays a crucial role in cancer development and progression, primarily through mechanisms involving carcinogenesis and angiogenesis. Aberrant FGFR1 signalling has been implicated in various cancers, including lung, breast, neck and urothelial carcinoma. Despite the recognized oncogenic potential of FGFR1, therapeutic strategies targeting its kinase domain remain inadequately explored. This underscores an urgent need for the development of novel FGFR1 inhibitors, particularly through de novo drug design approaches, to effectively counteract FGFR1-driven malignancies. This research aims to develop novel FGFR1 inhibitors through a multi-step approach involving fragment-based drug design, virtual screening, molecular dynamics simulation (MD) and density functional theory studies (DFT), with the goal of targeting FGFR1's kinase binding domain to inhibit tumor angiogenesis. Initially, known FGFR inhibitor molecules were retrieved and subjected to fragment-based drug designing and virtual screening. Through thorough analysis, molecules containing the pyrido[2,3-d]pyrimidine scaffold were identified as promising candidates. A pyrido[2,3-d]pyrimidine-based database containing 90,952 molecules was subsequently retrieved from PubChem and filtered using molecular docking-based virtual screening resulting 94 molecules having better binding affinity than derazantinib, reference drug. After pharmacokinetic profiling (ADME), and MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) studies, out of 94 molecules only 11 compounds with favorable pharmacokinetic properties and superior MM-GBSA binding free energies were selected. Docking-based screening revealed that selected 11 compounds demonstrated better binding scores than the reference drug, derazantinib. Among them, HIT1, was selected for 150ns molecular dynamics simulation to assess its conformational stability. DFT calculations further confirmed its bio-feasibility by analyzing the HOMO-LUMO energy gap. Overall, the selected lead compounds exhibited enhanced binding affinity, superior conformational stability, favorable pharmacokinetic and pharmacodynamic profiles compared to derazantinib. Present findings suggest that the identified hit molecules hold strong potential for inhibiting FGFR1's kinase domain and disrupting FGFR-associated tumor angiogenesis. Show less

Hypertriglyceridemia is a prevalent lipid disorder that considerably increases the risk of cardiovascular diseases, pancreatitis, and metabolic syndrome. Existing treatment options, including lifestyle changes and medications, often show limited effectiveness and may cause side effects. Olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (APOC3), represents a novel therapeutic strategy for lowering triglyceride levels. This systematic review and meta-analysis assess the efficacy and safety of olezarsen in comparison to a placebo for managing hypertriglyceridemia. A systematic literature search was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines across databases such as PubMed, Google Scholar, and the Cochrane Library, incorporating clinical trials and conference proceedings. Studies that compared olezarsen with a placebo and reported outcomes related to triglyceride levels, APOC3, and other lipid parameters were included. Two independent reviewers conducted data extraction and quality assessment. Statistical analyses were performed using RevMan, employing risk ratios for dichotomous variables and standard mean differences for continuous variables, with a random-effects model. Three randomized controlled trials, comprising 334 participants, were included in the analysis. Olezarsen significantly lowered triglyceride levels at both 6 months (standard mean difference [SMD]: -1.69, 95% CI -2.22 to -1.17) and 12 months (SMD: -1.64, 95% CI -2.22 to -1.07). Very low-density lipoprotein (VLDL) levels also declined at 6 months (SMD: -1.95, 95% CI -2.38 to -1.51) and 12 months (SMD: -0.83, 95% CI -1.13 to -0.53). Additional lipid profile improvements included reductions in total cholesterol, non-HDL cholesterol, and apoB levels, along with increases in HDL cholesterol and apoA-1. The incidence of adverse events was similar between the olezarsen and placebo groups. Olezarsen effectively reduces triglyceride and VLDL levels while enhancing lipid profiles in patients with hypertriglyceridemia. Although serious adverse events were more frequent, the overall safety profile remains acceptable. Further long-term research is required to validate these findings and optimize treatment regimens. Show less

The prevalence of obesity and dyslipidaemia was observed to be increased among the tribal populations, due to globalization. In the present study, data on demographic, somatometric and blood samples were collected from 613 participants of both sex, age 18-60 years, further lipid profiling and genotyping was executed. Multifactor dimensionality reduction (MDR) software was used for gene-gene interactions analysis. Significantly differences were observed with respect to the general characteristic and selected gene polymorphisms in both the tribes. Among the Liangmai tribe, The observed differences can possibly attribute to both their respective ancestries resulting in different gene pools and the physical environment. The results of the study highlight the importance of gene-gene and gene-environment interactions in adverse phenotype groups.KEY MESSAGEAmong the tribal population, the prevalence of obesity and dyslipidaemia has been increased.Differential distribution and associations of selected markers hint towards differential genetic architecture in these populations. Show less

Chronic hyperglycemia-induced thioredoxin-interacting protein (TXNIP) expression, associated oxidative/nitrosative stress (ROS/RNS), and mitochondrial dysfunction play critical roles in the etiology of diabetic retinopathy (DR). However, there is no effective drug treatment to prevent or slow down the progression of DR. The purpose of this study is to examine if a combination drug treatment targeting TXNIP and the mitochondria-lysosome pathway prevents high glucose-induced mitochondrial stress and mitophagic flux in retinal Müller glial cells in culture, relevant to DR. We show that diabetes induces TXNIP expression, redox stress, and Müller glia activation (gliosis) in rat retinas when compared to non-diabetic rat retinas. Furthermore, high glucose (HG, 25 mM versus low glucose, LG 5.5 mM) also induces TXNIP expression and mitochondrial stress in a rat retinal Müller cell line, rMC1, in in vitro cultures. Additionally, we develop a mitochondria-targeted mCherry and EGFP probe tagged with two tandem COX8a mitochondrial target sequences (adenovirus-CMV-2×mt8a-CG) to examine mitophagic flux in rMC1. A triple drug combination treatment was applied using TXNIP-IN1 (which inhibits TXNIP interaction with thioredoxin), Mito-Tempo (mitochondrial anti-oxidant), and ML-SA1 (lysosome targeted activator of transient calcium channel MCOLN1/TRPML1 and of transcription factor TFEB) to study the mitochondrial-lysosomal axis dysregulation. We found that HG induces TXNIP expression, redox stress, and mitophagic flux in rMC1 versus LG. Treatment with the triple drug combination prevents mitophagic flux and restores transcription factor TFEB and PGC1α nuclear localization under HG, which is critical for lysosome biosynthesis and mitogenesis, respectively. Our results demonstrate that 2×mt8a-CG is a suitable probe for monitoring mitophagic flux, both in live and fixed cells in in vitro experiments, which may also be applicable to in vivo animal studies, and that the triple drug combination treatment has the potential for preventing retinal injury and disease progression in diabetes. Show less

G-protein coupled receptors (GPCRs) are a superfamily of receptors responsible for initiation of a myriad of intracellular signaling cascades. Currently, GPCRs represent approximately 34% of marketed pharmaceuticals, a large portion of which have no known endogenous ligand. These orphan GPCRs represent a large pool of novel targets for drug development. Very recently, the neuropeptide PEN, derived from the proteolytic processing of the precursor proSAAS, has been identified as a selective, high-affinity endogenous ligand for the orphan receptor, GPR83. GPR83 is highly expressed in the brain, spleen and thymus, indicating that this receptor may be a target to treat neurological and immune disorders. In the brain GPR83 is expressed in regions involved in the reward pathway, stress/anxiety responses, learning and memory and metabolism. However, the cell type specific expression of GPR83 in these regions has only recently begun to be characterized. In the immune system, GPR83 expression is regulated by Foxp3 in T-regulatory cells that are involved in autoimmune responses. Moreover, in the brain this receptor is regulated by interactions with other GPCRs, such as the recently deorphanized receptor, GPR171, and other hypothalamic receptors such as MC4R and GHSR. The following review will summarize the properties of GPR83 and highlight its known and potential significance in health and disease, as well as its promise as a novel target for drug development. Show less

Association of cholesteryl ester transfer protein (CETP) Gene -629C/A Polymorphism with angiographically proven atherosclerosis CETP gene has been linked to CAD risk via its role in HDL and LDL metabolism. There is no agreement of whether CETP is atherogenic or not. Furthermore, various genotypes of CETP gene have been associated with CETP levels and thus with atherosclerosis risk. Our aim was to study the association of CETP -629C/A gene polymorphism with CETP and HDL levels and their association if any with atherosclerosis. Study population consisted of angiographically documented 50 cases with coronary artery atherosclerosis and 50 controls negative for atherosclerosis of coronary artery. Serum lipid profile was measured on SYNCHRON CX-9 using standard kits. Serum CETP levels were measured by ELISA method. CETP -629C/A gene polymorphism was studied using PCR-RFLP method. There was no significant difference in lipid profile of the two groups. However, serum CETP level was significantly higher (46.44 ± 21.75 ng/ml) in cases than controls (37.10 ± 21.92 ng/ml) with Show less

Thioredoxin-interacting protein (TXNIP) is involved in oxidative stress and apoptosis in diabetic retinopathy. However, the role of TXNIP in the removal of damaged mitochondria (MT) via mitophagy, a process of macroautophagy, remains unexplored. Here we investigate the associated cellular and molecular mechanisms underlying mitophagy in retinal cells under diabetic conditions. For this, we maintained a rat Müller cell line (rMC1) under high-glucose (25 mM, HG) or low-glucose (5.5 mM, LG) condition for 5 days. Our data reveal that HG upregulates TXNIP in the cytosol as well as in the MT. Moreover, mitochondrial oxidative stress and membrane depolarization occur under prolonged hyperglycemia leading to fragmentation. These damaged MT are targeted to lysosome for mitophagic degradation, as is evident by co-localization of mitochondrial protein COXIV, a subunit of cytochrome c oxidase, with autophagosome marker LC3BII and the lysosomal membrane protein LAMP2A. In addition, under HG conditions, there is an accumulation of dynamin-related fission protein Drp1 and E3 ubiquitin ligase Parkin in damaged MT, suggesting their roles in mitochondrial fragmentation and ubiquitination, respectively, which is absent in LG conditions. Subsequently, ubiquitin receptors, optineurin and p62/sequestrome 1, bind to the damaged MT and target them to LC3BII autophagosomes. Conversely, TXNIP knockout via CRISPR/Cas9 and TXNIP gRNA prevents the HG-induced mitochondrial damage and mitophagy in rMC1. Last, TXNIP level is also significantly upregulated in the diabetic rat retina in vivo and induces radial glial fibrillary acidic protein expression, a marker for Müller glia activation, and the formation of LC3BII puncta, which are prevented by intravitreal injection of TXNIP siRNA. Therefore, TXNIP represents a potential target for preventing ocular complications of diabetes. Show less

Thioredoxin Interacting Protein (TXNIP) mediates retinal inflammation, gliosis, and apoptosis in experimental diabetes. Here, we investigate the temporal response of Muller glia to high glucose (HG) and TXNIP expression using a rat Muller cell line (rMC1) in culture. We examined if HG-induced TXNIP expression evokes host defense mechanisms in rMC1 in response to metabolic abnormalities. HG causes sustained up-regulation of TXNIP (2 h to 5 days), ROS generation, ATP depletion, ER stress, and inflammation. Various cellular defense mechanisms are activated by HG: (i) NLRP3 inflammasome, (ii) ER stress response (sXBP1), (iii) hypoxic-like HIF-1α induction, (iv) autophagy/mitophagy, and (v) apoptosis. We also found in vivo that streptozocin-induced diabetic rats have higher retinal TXNIP and innate immune response gene expression than normal rats. Knock down of TXNIP by intravitreal siRNA reduces inflammation (IL-1β) and gliosis (GFAP) in the diabetic retina. TXNIP ablation in vitro prevents ROS generation, restores ATP level and autophagic LC3B induction in rMC1. Thus, our results show that HG sustains TXNIP up-regulation in Muller glia and evokes a program of cellular defense/survival mechanisms that ultimately lead to oxidative stress, ER stress/inflammation, autophagy and apoptosis. TXNIP is a potential target to ameliorate blinding ocular complications of diabetic retinopathy. Show less