👤 L M Srivastava

Lp(a) (lipoprotein[a]) is associated with cardiovascular disease, but neither the causal nature nor the underlying mechanisms are fully documented. This study investigated whether Lp(a) triggers atherogenesis by dysregulating vascular redox-sensitive inflammatory state. Plasma Lp(a) was measured in 1027 patients with advanced coronary artery disease undergoing cardiac surgery. These patients were genotyped, and a modified Increased plasma Lp(a) ( This study demonstrates for the first time that a genetically determined increase in plasma Lp(a) results in dysregulated vascular redox/nitrosative signaling in patients with atherosclerosis. Show less

Air pollution exposure is associated with increased cardiovascular morbidity and mortality worldwide. Previous studies provide a causal relationship between exposure to particulate matter (PM) and atherosclerosis development. We have previously demonstrated increased aortic atherosclerosis and adverse metabolic effects in hyperlipidemic mice exposed to ambient ultrafine PM. However, the underlying mechanisms by which ambient PM promotes systemic effects leading to worsened atherosclerosis remain unknown. We have recently shown that the gut microbiota composition was altered in mice exposed to re-aerosolized PM in the ultrafine-size range for 10 weeks. We hypothesized that sub-chronic exposure to ultrafine PM induces gut dysbiosis in association with systemic prooxidative effects and atherosclerotic lesion development. Male apolipoprotein E knockout (ApoE Show less

Most cancer cells rely on aerobic glycolysis to support uncontrolled proliferation and evade apoptosis and switch to glutamine metabolism to survive under hypoxic conditions. In hepatocellular carcinoma (HCC), the Wnt/β-catenin pathway acts as a critical driver of metabolic reprogramming and stemness, primarily by enhancing aerobic glycolysis and altering the tumour microenvironment. The Wnt/β-catenin pathway induces activation of enzymes required for glucose metabolism and regulates the expression of glutamate transporter and glutamine synthetase. The objective of this study is to examine the mechanism by which riluzole inhibits HCC growth and induces autophagy. The results indicate that riluzole inhibits cell viability and colony formation of HCC cells and cancer stem cells (CSCs) and induces apoptosis, while sparing human normal hepatocytes. Riluzole induces autophagic cell death by inducing Beclin1 and Atg5. Riluzole inhibits β-catenin, Wnt3a, Wnt5a, Axin1, TCF, LEF and GSK3β expression, and TCF/LEF activity in HCC cells. Inhibition of the Wnt-β-catenin/TCF-LEF pathway by riluzole suppresses the expression of Cyclin D1, Axin2, cMyc, MCT1 and DNMT1. Riluzole inhibits the expression of Glut1 and Glut3, PDK1, LDHA and PKM2, glucose uptake and NAD+ levels. Furthermore, riluzole inhibits glutamate release, which reduces the antioxidant glutathione, leading to increased reactive oxygen species (ROS). Riluzole disrupts mitochondrial homeostasis by increasing Bax/Bcl-2 ratio, resulting in a drop of mitochondrial membrane potential. In conclusion, riluzole inhibits HCC growth by regulating glucose and glutamine metabolism and inducing autophagic cell death, thereby highlighting its therapeutic potential for HCC treatment. Show less

Hepatoid lung carcinomas, similar to hepatoid carcinomas of other sites, are defined as extrahepatic tumors exhibiting divergent hepatocellular differentiation. Uniquely, hepatoid carcinomas of lung origin are reported to commonly express only hepatocyte paraffin 1 (HepPar1)-a hepatocellular marker, which recognizes mitochondrial enzyme carbamoyl-phosphate synthetase-1 (CPS1). Recently, HepPar1/CPS1 was found to accumulate in lung adenocarcinomas (LUADs) harboring STK11mutations, presumably as a genotype-associated metabolic adaptation. The impact of these insights on the concept of hepatoid lung carcinoma has not been explored. Here, we performed a detailed clinicopathologic and genomic analysis of carcinomas prospectively regarded as hepatoid with isolated HepPar1 expression (n = 17). We found that although robustly positive for HepPar1, these tumors were entirely negative for an extended panel of other hepatocellular markers (alpha-fetoprotein, Arginase1, Glypican3, and albumin-in situ hybridization). Morphologically, tumors exhibited solid-trabecular architecture with expanded granular-vacuolated-clear cytoplasm, thus evoking hepatoid morphology; however, focal-to-moderate intracytoplasmic mucin was consistently present, and hepatoid resemblance was variable. Pneumocytic markers (TTF1 and Napsin A) were entirely negative (except for cytoplasmic TTF1), commonly leading to diagnostic challenges at metastatic sites. Remarkably, next-generation sequencing revealed invariable STK11 mutations/loss (P < .00001 vs unselected LUAD, n > 2.5K). Patient survival was dismal (median, 5.8 vs 25 months for stage-matched LUAD, P = .0002). Tumors harbored high mitochondrial content by electron microscopy and other methods. For comparison, we reviewed conventional, predominantly acinar LUAD with HepPar1 expression (n = 22) and found that they also lacked any other hepatocellular markers, had invariable STK11 mutations/loss, increased granular cytoplasm, lower TTF1, and poor prognosis. We conclude that isolated HepPar1 expression in LUAD reflects mitochondrial adaptation to STK11 mutations rather than bona fide hepatocellular differentiation, and that HepPar1-expressing solid and granular adenocarcinomas represent an undifferentiated (solid, TTF1 negative) variant in this spectrum of tumors. Recognition of these tumors is warranted due to their exceptionally aggressive behavior, distinct pathogenomic features, and common association with diagnostic challenges. Show less

Cisplatin is a widely used chemotherapeutic agent for triple-negative breast cancer (TNBC), but resistance remains a major challenge. Understanding the molecular alterations driving this resistance is essential for identifying therapeutic targets. In this study, we employed an integrated proteomics and lipidomics approach to elucidate key pathways associated with cisplatin resistance. Employing high-resolution mass spectrometry, we conducted a comparative analysis between cisplatin-resistant (cisR) and cisplatin-sensitive (cisS) TNBC cell lines to discover resistance-associated alterations in protein and lipid expression. Proteomic analysis revealed overexpression of extracellular matrix (ECM) remodeling proteins, COL6A1, COL6A2, COL6A3, and VTN, that support epithelial-mesenchymal transition (EMT) and chemoresistance. Membrane-associated proteins such as TIMP2, MMP14, and APP were also elevated, indicating enhanced invasive and pro-survival signaling. Lipidomic alterations, including upregulation of FABP3, FABP4, LPL, and downregulation of PLA2G4A, indicated increased lipid uptake, metabolic rewiring, and membrane restructuring. Notably, elevated long-chain phosphatidylcholines and decreased sphingomyelins suggested increased membrane rigidity and reduced cisplatin permeability. Additionally, dysregulation of CDK activity through CCND2, CCND3, and CCNB2 overexpression indicated accelerated cell cycle progression and evasion of DNA damage checkpoints. Together, this integrative analysis highlights ECM remodeling, cytoskeletal dynamics, and lipid metabolism as major contributors to cisplatin resistance and identifies potential therapeutic markers for TNBC. Show less

The role of cell-specific ANGPTL4 is not well known in the context of ECs, specifically in pathological angiogenesis and its relation to diabetic kidney disease. Here, we demonstrate that endothelial ANGPTL4 is required to induce a metabolic phenotype that favors mesenchymal activation in ECs and tubules in diabetic conditions. Diabetes accelerates mesenchymal activation and fibrogenesis in control mice however, the same effects were not observed in endothelial-cell specific knock out mice. This mesenchymal activation in diabetes is directly linked with pathological neovascularization, endothelial leakage, lipid and glycolysis metabolite load, de novo lipogenesis (DNL) and related mitochondrial damage, activation of the immune system, c-GAS-STING activation and transcription of pro-inflammatory cytokines. However, endothelial ANGPTL4-depleted mice had stable vessels, improved levels of lipid and glucose metabolism, suppressed levels of DNL, restored mitochondrial function, and mitigated levels of c-GAS-STING-mediated inflammation. Moreover, Inhibition of DNL, and STING via small molecule inhibitors suppressed pathological neovascularization and endothelial leakage, normalized fatty acid oxidation and reduced pathological glycolysis and de novo lipogenesis (DNL). These data demonstrate the crucial roles of endothelial ANGPTL4 in regulating pathogenic angiogenesis in the renal vasculature during diabetes. Show less

Coronary artery disease (CAD) is a multifactorial disorder influenced by both genetic and clinical risk factors. Lipid metabolism genes such as apolipoprotein B(APOB) (rs515135) and proprotein convertase subtilisin/kexin type 9 (PCSK9)(rs505151), have been associated with susceptibility to CAD. Study investigates the potential role of these genetic polymorphisms with risk of CAD in the Indian population. A case-control study including 150 CAD cases and 150 controls. Angiographically proven Cases were recruited from the Cardiology Unit, Department of Medicine, Era's Lucknow Medical College. Genotyping was done using specific primers and restriction digestion; statistical analysis included t-tests, odds ratios, and haplotype analysis. CAD cases(mean age 49.93   ±   9.13 years) had higher serum cholesterol and VLDL but lower systolic and diastolic BP compared to controls (mean age 56.47   ±   9.39 years). The APOB G allele showed a significant protective effect against CAD (OR: 0.431, The APOB G allele may serve as a protective factor against CAD, highlighting its potential role in genetic screening for lower disease risk. Further large-scale studies are required to confirm these findings. Show less

In pancreatic ductal adenocarcinoma, hypoxia is a crucial component of the tumour microenvironment and is associated with worse clinical outcomes. Adaptation to extreme hypoxic settings is based on abnormal lipid metabolism, but insights into how hypoxia-regulated lipid changes link with aggressive migratory potential in pancreatic cancer are lacking. This study investigates the molecular processes, pathways, and critical proteins involved in hypoxia-induced lipidic and polyunsaturated fatty acid alterations in pancreatic cancer. Our findings elucidate increased multilayer unsaturation in FA chains of major lipid classes associated with greater migration and invasion, as well as higher abundances of particular desaturases. The expression of these proteins was verified in clinical tumour samples by unsaturated fatty acid biosynthesis-related gene enrichment score. High unsaturated fatty acid clusters were shown to be associated with a low survival rate. Pathway correlation and protein-protein interaction analysis indicated that the PPAR-hypoxia axis and SCD/FADS2/APOC3-HDLBP protein network are implicated in mediating the observed alterations in lipid pools and poly-unsaturation levels in pancreatic cancer under hypoxia. These results provide novel therapeutic targets in pancreatic cancer while improving our understanding of hypoxia-induced migratory potential in pancreatic cancer. Show less

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder influenced by genetic, metabolic, and lifestyle factors. Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, notably C677T and A1298C, may increase AD susceptibility through disruptions in one-carbon metabolism and homocysteine accumulation. This study examined the association of MTHFR C677T and A1298C variants with metabolic alterations, cognitive decline, and AD risk. A case-control study was conducted with 120 AD patients and 120 cognitively healthy controls. Cognitive function was assessed using the Hindi Mini-Mental State Examination (HMMSE) and Hindi Mattis Dementia Rating Scale (HMDRS). MRI evaluated white matter hyperintensities and cortical atrophy. Biochemical markers, including homocysteine, folate, and vitamin B12, were measured. Genotyping was performed via TaqMan SNP assays. Functional enrichment and protein-protein interaction analyses were conducted to investigate molecular mechanisms. AD cases demonstrated elevated homocysteine and blood glucose, reduced folate, and impaired cognition. Both MTHFR C677T and A1298C polymorphisms were significantly associated with AD risk under dominant and over-dominant models (ORs 3.41-4.09). Risk-allele carriers exhibited pronounced metabolic alterations. Bioinformatics analyses revealed disruption in one-carbon metabolism, oxidative stress defense, and vascular pathways, with indirect interactions between MTHFR and key AD genes (APP, PSEN1/2, MAPT, APOE, CLU, PICALM, SORL1). MTHFR C677T and A1298C variants contribute to AD susceptibility through metabolic and vascular mechanisms that exacerbate cognitive decline. Integrating genetic, biochemical, and cognitive assessments highlights potential targets for early prevention and therapeutic interventions. Show less

In this study, a comprehensive bioinformatics workflow is employed to investigate the impact of APOE gene variants on Alzheimer's disease (AD) and to explore their relevance for improving therapeutic strategies. Multiple databases were screened to identify key non-synonymous single nucleotide polymorphisms (nsSNPs) in APOE. Six variants: rs769452 (L46P), rs429358 (C130R), rs267606664 (G145D), rs121918393 (R154S), rs7412 (R176C), and rs267606661 (R269G) were selected, of which five were predicted to be deleterious. Given its high interaction score (0.789), the FDA-approved AD drug Donepezil was chosen as the ligand to assess binding with both wild-type and mutant APOE proteins. Structural modeling using AlphaFold3 generated high-quality APOE structures, and in silico mutagenesis revealed mutation-dependent destabilization. AutoDock4 molecular docking was performed to evaluate binding affinities of Donepezil with the predicted active-site residues of wild-type and mutant APOE. Furthermore, 100 ns molecular dynamics simulations using AMBER20 were conducted for all APOE-Donepezil complexes. Analyses of RMSD, RMSF, and radius of gyration indicated overall structural stability, residue-level flexibility, and protein compactness throughout the simulations. Interaction profiling revealed stable hydrophobic contacts and hydrogen bonds in both wild-type and mutant complexes. Our findings suggest that structural variations arising from APOE genotypes may modulate Donepezil binding and potentially influence therapeutic response in AD patients. However, these computational predictions require validation through biophysical assays, cellular experiments, and genotype-stratified clinical studies. Integrating molecular modeling with experimental research will be essential for advancing APOE-guided precision medicine and optimizing Donepezil therapy for Alzheimer's disease. Show less

This study aims to evaluate cognitive impairment utilizing the Montreal Cognitive Assessment (MoCA) scale, while also exploring the correlation between cognitive impairment and various serum biomarkers, including Brain-derived neurotrophic factor (BDNF), Beta Secretase-1 (BACE1), Vascular Endothelial Growth Factors (VEGF), Glial fibrillary acidic protein (GFAP), and Interleukin-1 (IL-1β) in adults living with epilepsy. In this study, 74 participants aged between 18 and 50 years, who were visiting neurology outpatient consultations, were included. The cognitive assessment was executed using the MoCA test. Serum levels of BDNF, BACE1, VEGF, GFAP, and IL-1β were evaluated through ELISA in patients with and without cognitive impairments. To determine the association between MoCA scores and the biomarkers, both Spearman and Pearson correlation analyses, as well as linear regression, were conducted. Among the 74 PWE, 61 exhibited cognitive impairment as determined by the MoCA assessment. Noteworthy alterations were detected across various MoCA subscales, encompassing visuospatial and executive functions, attention, language, abstraction, and delayed recall, with statistical significance established ( We conclude that adult PWE in India demonstrate a significant cognitive impairment. Further, our findings indicate that BDNF may serve as a potential biomarker for evaluating cognitive impairment in adult PWE. Further longitudinal, prospective and multi-center studies are required to confirm the same. Show less

Background & objectives Central TB division facilitated development of a line probe assay (LPA) artificial intelligence (AI) tool. The tool was developed, trained, and validated for performance by collecting more than 18,000 LPA strips across culture and drug susceptibility Testing (C&DST) laboratories. The Indian Council of Medical Research (ICMR)-National Institute for Research in Tuberculosis (NIRT) evaluated the LPAAI tool independently. The objective was to establish and verify an AI-driven system for automatically interpreting LPA strips, which are employed in tuberculosis drug resistance screening, to improve accuracy, consistency, and scalability across diverse laboratory settings. Methods The AI system integrates faster regions convolutional neural network (FR-CNN) for strip detection, detection transformer (DETR) for band localisation, and a hierarchical neural network (HNN) for classification of bands, loci, and drug labels. Independent validation was conducted by ICMR-NIRT using 2810 first-line (FL)-LPA and 241 reflex second-line (SL-LPA) across ten intermediate reference laboratories (IRLs). Results AI comparative models demonstrated an accuracy range of 92-100 per cent, with sensitivity between 80-100 per cent and specificity from 86-100 per cent for the tub, rpoB, katG, InhA, gyrA/gyrB,rrs, and eisgenes. The overall F1 score varies from 0.81 to 1.00, indicating perfect precision and recall. Interpretation & conclusions This AI system offers a novel, modular architecture capable of expert-level interpretation of LPA strips. The AI tool performs at par with expert readers and offers a reliable, scalable solution for LPA interpretation.AI tool adoption can reduce interpretation time, enhance result uniformity, and improve treatment delivery across India's TB programme, supporting national goals for TB elimination. Show less

Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the recessive contribution to the broad range of CHD phenotypes has been limited. We analyzed whole exome sequences of 5,424 CHD probands. Rare damaging RGs were estimated to contribute to at least 2.2% of CHD, with greater enrichment among laterality phenotypes (5.4%) versus other subsets (1.4%). Among 108 curated human recessive CHD genes, there were 66 RGs, with 54 in 11 genes with >1 RG, 12 genes with 1 RG, and 85 genes with zero. RGs were more prevalent among offspring of consanguineous union (4.7%, 32/675) than among nonconsanguineous probands (0.7%, 34/4749). Founder variants in Show less

Angiopoietin-like 4 (ANGPTL4), a key protein involved in lipoprotein metabolism, has diverse effects. There is an association between Angptl4 and diabetic kidney disease; however, this association has not been well investigated. We show that both podocyte- and tubule-specific ANGPTL4 are crucial fibrogenic molecules in diabetes. Diabetes accelerates the fibrogenic phenotype in control mice but not in ANGPTL4 mutant mice. The protective effect observed in ANGPTL4 mutant mice is correlated with a reduction in stimulator of interferon genes pathway activation, expression of pro-inflammatory cytokines, reduced epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition, lessened mitochondrial damage, and increased fatty acid oxidation. Mechanistically, we demonstrate that podocyte- or tubule-secreted Show less

Nilotinib, a tyrosine kinase inhibitor that targets the Abelson tyrosine kinase (c-Abl) signaling pathway, is FDA-approved to treat chronic myeloid leukemia. Nilotinib has properties indicative of a possible utility in neuroprotection that have prompted exploration of repurposing the drug for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD). AD is a progressive age-related neurodegenerative disorder characterized by the deposition of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. It is incurable and affects approximately 50 million patients worldwide. Nilotinib reduces c-Abl phosphorylation, amyloid-β levels, and dopaminergic neuron degeneration in preclinical AD models. This study explores the effects of nilotinib on amyloid processing and mitochondrial functioning in the SH-SY5Y human neuroblastoma cell line. SH-SY5Y cells were exposed to nilotinib (1, 5, and 10 µM). Real-time PCR and immunoblot analysis were performed to quantify the expression of genes pertaining to amyloid-β processing and neuronal health. Nilotinib did not significantly change APP, BACE1, or ADAM10 mRNA levels. However, BACE1 protein was significantly increased at 1 µM, and ADAM10 was increased at 10 µM nilotinib without affecting APP protein expression. Further, nilotinib treatment did not affect the expression of genes associated with neuronal health and mitochondrial functioning. Taken together, our findings do not support the efficacy of nilotinib treatment for neuroprotection. Show less

Migration and invasion enhancer 1 (MIEN1) overexpression characterizes several cancers and facilitates cancer cell migration and invasion. Leveraging conserved immunoreceptor tyrosine-based activation motif and prenylation motifs within MIEN1, we identified potent anticancer peptides. Among them, bioactive peptides LA3IK and RP-7 induced pronounced transcriptomic and protein expression changes at sub-IC50 concentrations. The peptides effectively inhibited genes and proteins driving cancer cell migration, invasion, and epithelial-mesenchymal transition pathways, concurrently suppressing epidermal growth factor-induced nuclear factor kappa B nuclear translocation in metastatic breast cancer cells. Specifically, peptides targeted the same signal transduction pathway initiated by MIEN1. Molecular docking and CD spectra indicated the formation of MIEN1-peptide complexes. The third-positioned isoleucine in LA3IK and CVIL motif in RP-7 were crucial for inhibiting breast cancer cell migration. This is evident from the limited migration inhibition observed when MDA-MB-231 cells were treated with scrambled peptides LA3IK SCR and RP-7 SCR. Additionally, LA3IK and RP-7 effectively suppressed tumor growth in an orthotopic breast cancer model. Notably, mice tolerated high intraperitoneal (ip) peptide doses of 90 mg/Kg well, surpassing significantly lower doses of 5 mg/Kg intravenously (iv) and 30 mg/Kg intraperitoneally (ip) used in both in vivo pharmacokinetic studies and orthotopic mouse model assays. D-isomers of LA3IK and RP-7 showed enhanced anticancer activity compared to their L-isomers. D-LA3IK remained stable in mouse plasma for 24 h with 75% remaining, exhibiting superior pharmacokinetic properties over D/L-RP-7. In summary, our findings mark the first report of short peptides based on MIEN1 protein sequence capable of inhibiting cancer signaling pathways, effectively impeding cancer progression both in vitro and in vivo. Show less

The interaction between stromal and tumor cells in tumor microenvironment is a crucial factor in Mantle cell lymphoma (MCL) progression and therapy resistance. We have identified a long non-coding RNA, CERS6-AS1, upregulated in MCL and associated with poor overall survival. CERS6-AS1 expression was elevated in primary MCL within stromal microenvironment and in a subset of MCL cells adhered to stromal layer. These stromal-adhered MCL-subsets exhibited cancer stem cell signatures than suspension counterparts. Mechanistically, we found that downregulating CERS6-AS1 in MCL reduced Fibroblast Growth Factor Receptor-1 (FGFR1), expression attributed to loss of its interaction with RNA-binding protein nucleolin. In addition, using in-silico approach, we have discovered a direct interaction between nucleolin and 5'UTR of FGFR1, thereby regulating FGFR1 transcript stability. We discovered a positive association of CERS6-AS1 with cancer stem cell signatures, and Wnt signaling. Building on these, we explored potential therapeutic strategies where combining nucleolin-targeting agent with FGFR1 inhibition significantly contributed to reversing cancer stem cell signatures and abrogated primary MCL cell growth on stromal layer. These findings provide mechanistic insights into regulatory network involving CERS6-AS1, nucleolin, and FGFR1 axis-associated crosstalk between tumor cells and stromal cell interaction and highlights therapeutic potential of targeting a non-coding RNA in MCL. Show less

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder caused by somatic FGFR1 and KRAS variants. It shares significant phenotypic overlap with several closely related disorders caused by mutations in the RAS-MAPK pathway (mosaic RASopathies). We report a diagnostically challenging case of ECCL in which next-generation sequencing of affected tissue identified a pathologic FGFR1 p.K656E variant, thereby establishing a molecular diagnosis. Patients with FGFR1-associated ECCL carry a risk of developing malignant brain tumors; thus, genetic testing of patients with suspected ECCL has important management implications. Show less

Cardiac fibrosis occurs in a wide range of cardiac diseases and is characterised by the transdifferentiation of cardiac fibroblasts into myofibroblasts these cells produce large quantities of extracellular matrix, resulting in myocardial scar. The profibrotic process is multi-factorial, meaning identification of effective treatments has been limited. The antifibrotic effect of the bile acid ursodeoxycholic acid (UDCA) is established in cases of liver fibrosis however its mechanism and role in cardiac fibrosis is less well understood. In this study, we used cellular models of cardiac fibrosis and living myocardial slices to characterise the macroscopic and cellular responses of the myocardium to UDCA treatment. We complemented this approach by conducting RNA-seq on cardiac fibroblasts isolated from dilated cardiomyopathy patients. This allowed us to gain insights into the mechanism of action and explore whether the IL-11 and TGFβ/WWP2 profibrotic networks are influenced by UDCA. Finally, we used fibroblasts from a TGR5 KO mouse to confirm the mechanism of action. We found that UDCA reduced myofibroblast markers in rat and human fibroblasts and in living myocardial slices, indicating its antifibrotic action. Furthermore, we demonstrated that the treatment of UDCA successfully reversed the profibrotic IL-11 and TGFβ/WWP2 gene networks. We also show that TGR5 is the most highly expressed UDCA receptor in cardiac fibroblasts. Utilising cells isolated from a TGR5 knock-out mouse, we identified that the antifibrotic effect of UDCA is attenuated in the KO fibroblasts. This study combines cellular studies with RNA-seq and state-of-the-art living myocardial slices to offer new perspectives on cardiac fibrosis. Our data confirm that TGR5 agonists, such as UDCA, offer a unique pathway of action for the treatment of cardiac fibrosis. Medicines for cardiac fibrosis have been slow to clinic and have the potential to be used in the treatment of multiple cardiac diseases. UDCA is well tolerated in the treatment of other diseases, indicating it is an excellent candidate for further in-human trials. Show less

Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. To assess the role of ANGPTL4 in COVID-19-related outcomes. Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients. Show less

Retinal vein occlusion (RVO) is the second most common retinal vascular disorder. Despite promising advances with anti-VEGF therapy, select patients are unresponsive to therapy. A precision medicine-based approach for therapeutic decision-making based on underlying biomarkers may facilitate treatment based on the underlying pathway. This study aims to identify the baseline and longitudinal cytokine profiles of RVO-related macular oedema and correlating these expression profiles with higher order OCT features using a novel retinal segmentation and feature extraction platform. The IMAGINE study is a post-hoc assessment of aqueous humour cytokines with correlation to higher level analysis of imaging studies. OCT scans underwent machine learning enhanced segmentation of the internal limiting membrane (ILM), ellipsoid zone (EZ) and retinal pigment epithelium (RPE), as well as evaluating volumetric fluid metrics. Samples of aqueous humour were obtained at baseline, as well as months 4 and 9 prior to treatment. These samples were analysed for the expression of multiple cytokines. Patients were divided into Responders and Non-Responders based on OCT profiles. Additionally, patients were categorised as a Rebounder if their CST increased by 50% after initial improvement. Twenty-six eyes were included. The OCT-based response schema identified 21 Responders (81%) and 5 Non-Responders (19%). VEGF levels directly correlated with intraretinal fluid volume and angiogenin was inversely correlated with fluid indices. Multiple cytokines, including ANGPTL4, were directly correlated with ellipsoid zone disruption. The baseline VEGF levels were significantly higher in all responders compared to Non-Responders (p = 0.02). Rebounders tended to have significantly decreased levels of angiogenin and TIMP-1 (p = 0.019, p = 0.015). Cytokine expression was linked to specific OCT features and treatment response in RVO. Identification of an imaging phenotype that could serve as a surrogate for underlying active disease pathways could enhance treatment decision-making and precision medicine. Show less

In this study, comparative analysis of skeletal muscle transcriptome was carried out for four biological replicates of Aseel, a fighter type breed and Punjab Brown, a meat type breed of India. The profusely expressed genes in both breeds were related to muscle contraction and motor activity. Differential expression analysis identified 961 up-regulated and 979 down-regulated genes in Aseel at a threshold of log Show less

Mitochondrial degeneration in various neurodegenerative diseases, specifically in Alzheimer's disease, involves excessive mitochondrial fission and reduced fusion, leading to cell damage. P110 is a seven-amino acid peptide that restores mitochondrial dynamics by acting as an inhibitor of mitochondrial fission. However, the role of P110 as a neuroprotective agent in AD remains unclear. Therefore, we performed cell culture studies to evaluate the neuroprotective effect of P110 on amyloid-β accumulation and mitochondrial functioning. Human SH-SY5Y neuronal cells were incubated with 1 µM and 10 µM of P110, and Real-Time PCR and Western blot analysis were done to quantify the expression of genes pertaining to AD and neuronal health. Exposure of SH-SY5Y cells to P110 significantly increased APP mRNA levels at 1 µM, while BACE1 mRNA levels were increased at both 1 µM and 10 µM. However, protein levels of both APP and BACE1 were significantly reduced at 10 µM of P110. Further, P110 treatment significantly increased ADAM10 and Klotho protein levels at 10 µM. In addition, P110 exposure significantly increased active mitochondria and reduced ROS in live SH-SY5Y cells at both 1 µM and 10 µM concentrations. Taken together, our results indicate that P110 might be useful in attenuating amyloid-β generation and improving neuronal health by maintaining mitochondrial function in neurons. Show less

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs neurocognitive function. Acetylcholinesterase (AChE) and β-site APP cleaving enzyme 1 (BACE1) are the two main proteins implicated in AD. Indeed, the major available commercial drugs (donepezil, rivastigmine, and galantamine) against Alzheimer's are AChE inhibitors. However, none of these drugs are known to reverse or reduce the pathophysiological condition of the disease since there are multiple contributing factors to AD. Therefore, there is a need to develop a multitarget-directed ligand approach for its treatment. In the present study, plant bioactive compounds were screened for their AChE and BACE1 inhibition potential by conducting molecular docking studies. Considering their docking score and pharmacokinetic properties, limonin, peimisine, serratanine B, and withanolide A were selected as the lead compounds. Molecular dynamics simulations of these protein-ligand complexes confirmed the conformational and energetically stabilized enzyme-inhibitor complexes. The inhibition potential of the lead compounds was validated by Show less

Since the discovery of the LDL receptor in 1973 by Brown and Goldstein as a causative protein in hypercholesterolemia, tremendous amounts of effort have gone into finding ways to manage high LDL cholesterol in familial hypercholesterolemic (HoFH and HeFH) individuals with loss-of-function mutations in the LDL receptor (LDLR) gene. Statins proved to be the first blockbuster drug, helping both HoFH and HeFH individuals by inhibiting the cholesterol synthesis pathway rate-limiting enzyme HMG-CoA reductase and inducing the LDL receptor. However, statins could not achieve the therapeutic goal of LDL. Other therapies targeting LDLR include PCSK9, which lowers LDLR by promoting LDLR degradation. Inducible degrader of LDLR (IDOL) also controls the LDLR protein, but an IDOL-based therapy is yet to be developed. Among the LDLR-independent pathways, such as angiopoietin-like 3 (ANGPTL3), apolipoprotein (apo) B, apoC-III and CETP, only ANGPTL3 offers the advantage of treating both HoFH and HeFH patients and showing relatively better preclinical and clinical efficacy in animal models and hypercholesterolemic individuals, respectively. While loss-of-LDLR-function mutations have been known for decades, gain-of-LDLR-function mutations have recently been identified in some individuals. The new information on gain of LDLR function, together with CRISPR-Cas9 genome/base editing technology to target LDLR and ANGPTL3, offers promise to HoFH and HeFH individuals who are at a higher risk of developing atherosclerotic cardiovascular disease (ASCVD). Show less