👤 Babita Kumari

Aging triggers gut microbiota dysbiosis that disrupts the gut-brain axis (GBA), promoting neuroinflammation and neurodegeneration. Elderly exhibit reduced microbial diversity, depleted beneficial bacteria, and expanded pathobionts, elevating neurotoxic metabolites-lipopolysaccharides (LPS), trimethylamine-N-oxide, kynurenine derivatives, and secondary bile acids. These drive "inflammaging," blood-brain barrier breakdown, microglial activation, mitochondrial impairment, and proteinopathies in Alzheimer's and Parkinson's disease. Conversely, neuroprotective metabolites from commensals-short-chain fatty acids, indole-3-propionic acid, and urolithins-preserve gut integrity, suppress inflammation, upregulate BDNF for synaptic plasticity, and enhance mitophagy. Postbiotics, stable probiotic-derived bioactives (butyrate, polyphenol metabolites, and lactate derivatives), surpass live probiotics in safety and precision. They modulate GBA via histone deacetylase inhibition, GPR41/43 signaling, NF-κB blockade, and microglial M2 shift, blocking LPS translocation and bolstering neuronal resilience. Preclinical rodent studies demonstrate robust neuroprotection, but human translation reveals challenges: inter-individual microbiota variability (diet/genetics/comorbidities), inconsistent metabolite absorption/brain penetration between species, methodological limitations (16S rRNA vs. functional metagenomics), postbiotic standardization barriers, and sparse Phase I/II trials showing biomarker benefits without cognitive endpoints. This review synthesizes gut dysbiosis-metabolite-brain aging mechanisms, positioning postbiotics as precision therapeutics. Multi-omics stratified controlled trials are essential to validate long-term efficacy for delaying neurodegeneration and extending cognitive health. Show less

Women are susceptible to hormonal imbalances and endocrine-related disorders such as Polycystic Ovary Syndrome (PCOS), Ovarian Cancer (OC), and Major Depressive Disorder (MDD). This study aims to identify gene-level interconnections among these conditions using omics-based bioinformatic approaches. Publicly available GEO datasets, viz., GSE226146 (PCOS), GSE18520 (OC), and GSE125664 (MDD), were analyzed, which in total resulted in 21,366 differentially expressed genes (DEGs), including 11,174 upregulated and 10,198 downregulated genes. Common genes PTTG1 and PID1 were identified using Venny 2.0. A protein-protein interaction (PPI) network was constructed using STRING, and 10 hub genes (ANAPC5, ANAPC2, PTTG1, FZR1, ANAPC4, CDC20, CDC27, ANAPC10, UBE2C, and BUB1) were identified using CytoHubba based on MCC scoring. Functional enrichment analysis showed significant involvement of these genes in oocyte meiosis, progesterone-mediated oocyte maturation, mitotic regulation, and metaphase-anaphase transition (p < 0.05). PTTG1, identified as both a common and hub gene, was downregulated in PCOS and upregulated in OC and MDD. Drug-gene interaction analysis using DSigDB via Enrichr identified Alvespimycin (for PCOS) and Gefitinib (for OC) as drugs targeting PTTG1. Molecular docking using AutoDock 4.2.6 showed that Alvespimycin and Ephedrone bind PTTG1 with a binding affinity of - 4.59 kcal/mol and - 5.81 kcal/mol, respectively, while Gefitinib showed - 4.92 kcal/mol, slightly less than Troglitazone (-5.3 kcal/mol) for OC. This study highlights PTTG1 as a shared molecular link among PCOS, OC, and MDD, suggesting its potential as a therapeutic target and providing insights into the genetic and physiological overlap of these conditions. Show less

Bioinformatics is considered a powerful tool to investigate and deeply analyze large datasets. A significant quantity of data is generated by prostate cancer and dysregulation of microRNA (miRNA) in tissues and bodily fluids (serum, plasma, urine). Screening dysregulated miRNA is currently more accessible, more reliable, and more precise with the help of insilico approaches. Hence the objective of the study is to identify miRNAs and explore their mRNA interaction in prostate cancer development. Here in the present study, we analyzed the GEO dataset GSE112264 and performed GEO-2R analysis to segregate significantly upregulated and downregulated miRNAs. The targetome of each miRNA containing several target genes was analyzed and put in an interactive network form. Functional enrichment analysis using DAVID 6.8 and GSEA was carried out to get KEGG, Reactome, and GO-BP analysis. Our analysis revealed that out of 190 overlapped significant miRNAs, only 9 miRNAs (hsa-miRNA-185-5p, hsa-miRNA-211-5p, hsa-miRNA-330-3p, hsa-miRNA-342-3p, hsa-miRNA-3622b-5p, hsa-miRNA-486-5p, hsa-miRNA-520a-3p, hsa-miRNA-550a-3p, hsa-miRNA-574-3p) were found to target 20 unique target genes (AKT1, EP300, E2F1, KRAS, AR, CREB5, CCND1, CDKNA1, EGFR, ERBB2, FGFR1, FOXO1, IKBKG, IGF1R, MAPK1, PTEN, PIK3R1, and TP53) that were involved in Prostate cancer survival and proliferation. Out of 9 miRNAs, two miRNAs (miRNA-520a-3p and miRNA-550a-3p) are novel miRNAs that have yet to be explored in Prostate cancer pathogenesis. To conclude and for future research, 8 miRNAs are yet to be explored for non-invasive potential as diagnostic and prognostic biomarkers in Prostate cancer progression and development. The target genes of each miRNA could provide novel insights in developing therapeutics for better management of disease. Show less

Longer-term effects of chiropractic care on neuroplasticity, stress, and immune biomarkers remain unclear. This study evaluates the effects of chiropractic care on physiological biomarkers, including brain-derived neurotrophic factor (BDNF), cortisol (saliva, blood, hair), and inflammatory cytokines [interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), C-reactive protein (CRP), B-lymphocytes (CD19), T-helper cells (CD4), cytotoxic T cells (CD8), and natural killer cells (CD56)] in subclinical spinal pain patients. Parallel-group, pragmatic randomized controlled trial conducted at the Rehabilitation Center of Railway General Hospital, Rawalpindi, Pakistan. Intervention: 12 weeks; follow-up: 16 weeks (May-December 2022). Participants with subclinical spinal pain were randomly assigned by using simple lottery method to either 12 weeks of chiropractic or sham care. We aimed to recruit up to 150 participants over three months; however, given the pragmatic nature of the trial and logistical constraints, including the availability of chiropractors, the final number enrolled was determined by how many eligible participants could be recruited during this time. Adults aged 20-60 years with subclinical spinal pain (n = 106 randomized; 88 completed 12-week measures; 73 completed 16-week follow-up). Among those who finished 12 weeks: chiropractic, 26 males/15 females, mean age 37.49 ± 12.39 years; sham, 24 males/23 females, mean age 26.85 ± 7.13 years. The primary outcome blood BDNF and secondary outcome, including saliva, blood and hair cortisol, IL-6, TNF-α, IFN-γ, CRP, CD19, CD4, CD8, and CD56 levels were measured at baseline, after 12 weeks of intervention, and at a 16-week follow-up. Linear and linear mixed-effects regression models were used to assess the effect of care and time on biological measures. Significant between-group differences were observed after 12 weeks of intervention, with higher salivary cortisol 5 ± 2 [0, 10], p = 0.045 and blood BDNF150 ± 60 (40, 270), p = 0.009 and IL-6 1.0 ± 0.3 [0.5, 1.5], p < 0.001 levels in the chiropractic care group. At the 16-week follow-up, blood cortisol -9 ± 4 [-17, -1], p = 0.024, IFN-γ - 22 ± 7 [-35, -9], and TNF-α -2 ± 1 [-5, 0], p = 0.028 levels increased in the sham group. Within-group comparisons showed a non-significant 10 ± 20 [-20, 50], p = 0.439 reduction in hair cortisol levels in the chiropractic group at 12 weeks, along with increased levels of blood cortisol, BDNF, CD8, CD4, IL-6, and CD19. 12 weeks of Chiropractic care modulates biomarkers linked to neuroplasticity, inflammation, and stress. Increases in brain-derived neurotrophic factor and interleukin-6 suggest enhanced neuroplasticity and inflammatory responses, while decreases in tumor necrosis factor-alpha indicate a regulatory effect on systemic inflammation. These findings support the notion that chiropractic care modulates physiological systemic biomarkers, which may underscore its benefits on clinical outcomes. ClinicalTrials.gov NCT05369156. Show less

Lipoprotein lipase (LPL) carries out the lipolytic processing of triglyceride-rich lipoproteins (TRL) along the luminal surface of capillaries. LPL activity is regulated by the angiopoietin-like proteins (ANGPTL3, ANGPTL4, ANGPTL8), which control the delivery of TRL-derived lipid nutrients to tissues in a temporal and spatial fashion. This regulation of LPL mediates the partitioning of lipid delivery to adipose tissue and striated muscle according to nutritional status. A complex between ANGPTL3 and ANGPTL8 (ANGPTL3/8) inhibits LPL activity in oxidative tissues, but its mode of action has remained unknown. Here, we used biophysical techniques to define how ANGPTL3/8 and ANGPTL3 interact with LPL and how they drive LPL inactivation. We demonstrate, by mass photometry, that ANGPTL3/8 is a heterotrimer with a 2:1 ANGPTL3:ANGPTL8 stoichiometry and that ANGPTL3 is a homotrimer. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies revealed that ANGPTL3/8 and ANGPTL3 use the proximal portion of their N-terminal α-helices to interact with sequences surrounding the catalytic pocket in LPL. That binding event triggers unfolding of LPL's Show less

Poly(ADP-ribose) (PAR) polymerase-1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimer's disease (AD), yet its role in amyloid-β (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive ELISA, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. Show less

Emerging evidences suggest that autophagy, a key cellular process responsible for degrading and recycling damaged organelles and proteins, plays a crucial role in maintaining neuronal health. Dysfunctional autophagy has been linked to the pathogenesis of Alzheimer's disease (AD), contributing to the accumulation of misfolded proteins and cellular debris. Molecular mechanisms underlying autophagy dysfunction in AD involve amyloid-beta (Aβ) and tau accumulation, neuroinflammation, mitochondrial dysfunction, oxidative stress and endoplasmic reticulum stress. Disrupted signaling pathways such as TRIB3, Nmnat and BAG3 that regulate key processes like autophagosome initiation, lysosome function, and protein homeostasis also play a crucial role in the pathogenesis. Restoration of autophagy by modulating these molecular and signaling pathways may be an effective therapeutic strategy for AD. Studies have found few drugs targeting autophagy dysregulation in AD. These drugs include metformin that has been found to modulate the expression of TRIB3 for autophagy regulation. Another drug, resveratrol has been reported to augment the activity of Nmnat thus, increases autophagy flux. BACE1 and mTOR inhibitors like arctigenin, nilvadipine and dapagliflozin were also found to restore autophagy. This study elaborates recent advances in signaling and molecular pathways and discusses current and emerging therapeutic interventions targeting autophagy dysfunction in AD. 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

Cervical Cancer is the second most common gynecological malignancy affecting a large group of women worldwide. The molecular mechanism of cervical cancer progression is still not very clear. As a result, diagnosis of cervical cancer occurs at a very advanced stage when the disease has spread to its malignant stage, causing death in the majority of women. EMT is a major culprit associated with the malignant transformation of tumor cells during cancer progression and metastasis. Hence, identification of new biomarkers to detect cervical cancer at an early stage is essential to minimize incidence and mortality. The present study aims to identify Common Differentially Expressed Genes (DEGs) and early biomarkers associated with EMT in cervical cancer. The Datasets were downloaded from the Gene Expression Omnibus (GEO) database, with Accession numbers GSE26511, GSE67522, and GSE9750. Then, the Gene Ontology (GO), KEGG pathway enrichment analysis, and protein-protein interactions (PPI) were done. Further hub genes were identified by molecular interaction networks using Cytoscape from the constructed network of DEGs. Afterwards, survival analysis was performed to assess the prognostic significance of eight hub genes associated with EMT in cervical cancer. A total of 11,339 overlapping DEGs were identified from all three datasets, among all the total 61 DEGS, and 8 hub genes were linked to the EMT pathway. Our study suggests that these eight hub genes, CDH1, CDH2, MMP2, CD44, FN1, FGF2, SNAI1, and SNAI2, may be critically associated with EMT progression. Among the eight identified EMT hub genes, CDH2 (N-cadherin) demonstrated a significant association with overall survival, while FN1 (fibronectin) was notably linked to disease-free survival, underscoring their prognostic value in cervical cancer. Based on these findings, our study suggests that CDH1, CDH2, MMP2, CD44, FN1, FGF2, SNAI1, and SNAI2 hold potential diagnostic and prognostic significance in the progression of cervical cancer. Show less

The leading factor contributing to patient mortality is the local invasion and metastasis of tumors, which are influenced by the malignant progression of tumor cells. The epithelial-mesenchymal transition (EMT) is key to understanding malignancy development. EMT is a critical regulatory mechanism for differentiating cell populations initially observed during the neural crest and embryonic gastrulation formation. This process is closely associated with tumor metastasis in cancer and is also related to the maintenance of cancer stem cells. Flavonoids, known for their antioxidant properties, have been widely studied for their anticancer potential to protect plants from harmful environmental conditions. They have attracted considerable attention and have been the focus of numerous experimental and epidemiological studies to evaluate their potential in cancer treatment. In vitro and in vivo research has demonstrated that flavonoids can significantly impact cancer-related EMT. They may inhibit the EMT process by reducing the levels of Twist1, N-cadherin, ZEB1, integrins, SNAI1/2, CD44, MMPs, and vimentin while increasing E-cadherin levels and targeting the PI3K/AKT, NF-κB p65, and JAK2/STAT3 signaling pathways. In order to suppress the transcription of the E-cadherin promoter, several Zn-finger transcription factors, such as SNAI2, ZEB1, and ZEB2, and basic helix-loop-helix (bHLH) factors, such as Twist, may directly bind to its E-boxes. Overall, clinical cancer research should integrate the anticancer properties of flavonoids, which address all phases of carcinogenesis, including EMT, to improve the prospects for targeted cancer therapies in patients suffering from aggressive forms of tumors. Show less

Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its capacity to inhibit lipoprotein lipase (LPL) catalytic activity and its ability to detach LPL from binding sites within capillaries. However, the sequences in APOA5 that are required for suppressing ANGPTL3/8 activity have never been defined. A clue to the identity of those sequences was the presence of severe hypertriglyceridemia in two patients harboring an Show less

Alzheimer's disease is a leading cause of mortality worldwide. Inorganic and organic hazards, susceptibility to harmful metals, pesticides, agrochemicals, and air pollution are major environmental concerns. As merely 5% of AD cases are directly inherited indicating that these environmental factors play a major role in disease development. Long-term exposure to environmental toxins is believed to progress neuropathology, which leads to the development of AD. Numerous in-vitro and in-vivo studies have suggested the harmful impact of environmental toxins at cellular and molecular level. Common mechanisms involved in the toxicity of these environmental pollutants include oxidative stress, neuroinflammation, mitochondrial dysfunction, abnormal tau, and APP processing. Increased expression of GSK-3β, BACE-1, TNF-α, and pro-apoptotic molecules like caspases is observed upon exposure to these environmental toxins. In addition, the expression of neurotrophins like BDNF and GAP-43 have been found to be reduced as a result of toxicity. Further, modulation of signaling pathways involving PARP-1, PGC-1α, and MAPK/ERK induced by toxins have been reported to contribute in AD pathogenesis. These pathways are a promising target for developing novel AD therapeutics. Drugs like epigallocatechin-gallate, neflamapimod, salsalate, dexmedetomidine, and atabecestat are in different phases of clinical trials targeting the pathways for possible treatment of AD. This review aims to culminate the correlation between environmental toxicants and AD development. We emphasized upon the signaling pathways involved in the progression of the disease and the therapeutics under clinical trial targeting the altered pathways for possible treatment of AD. Show less

Antimicrobial resistance (AMR) is a significant threat that demands surveillance to identify and analyze trends of the emerging antibiotic resistance genes (ARGs) and potential microbial carriers. The influent of the wastewater treatment plants (WWTPs) reflects the microbes derived from the population and effluent being the source of dissemination of potential pathogenic microbes and AMR. The present study aimed to monitor microbial communities and antibiotic resistance genes in WWTPs employing a whole metagenome shotgun sequencing approach. The samples were collected from a sewage treatment plant (STP) and a common effluent treatment plant (CETP) in Delhi, India. The results showed the influent of STP to be rich in Bifidobacterium, Bacteroides, Escherichia, Arcobacter, and Pseudomonas residents of gut microbiota and known to cause diseases in humans and animals; whereas the CETP sample was abundant in Aeromonas, Escherichia, and Shewanella known to be involved in the degradation of different compounds. Interestingly, the effluent samples from both STPs and CETP were rich in microbial diversity, comprising organic and xenobiotic compound degrading and disease-causing bacteria, indicating the effluent being the source of dissemination of concerning bacteria to the environment. The functional profile at both sites displayed similarity with an abundance of housekeeping function genes as analyzed by Clusters of Orthologous Genes (COG), KEGG Orthology (KO), and subsystem databases. Resistome profiling by MEGARes showed the dominance of ARGs corresponding to beta-lactams having relative abundance ranging from 16% to 34% in all the metagenome datasets, followed by tetracycline (8%-16%), aminoglycosides (7%-9%), multi-drug (5%-9%), and rifampin (3%-9%). Also, AMR genes oxa, ant3-DPRIME, and rpoB, which are of clinical importance were predominantly and most prevalently present in all the samples. The presence of AMR in effluents from both types of treatment plants indicates that wastewater from both sources contributes to the spread of pathogenic bacteria and resistance genes, increasing the environmental AMR burden and therefore requires tertiary treatment before discharge. This work will facilitate further research towards the identification of suitable biomarkers for monitoring antibiotic resistance. Show less

This work involved the preparation of pristine and iron nanoparticle-loaded biochar from a water chestnut shell to remove diclofenac sodium (DCF) containing effluent of pharmaceutical origin. To create suitable forecasting equations for the modelling of the DCF adsorption onto the adsorbent, response surface methodology (RSM) was used. The parameters, e.g. pH, adsorbent mass, DCF concentration and contact time, were used for the modeling of adsorption. The RSM model predicts that for 98.0% DCF removal, the ideal conditions are pH 6, an adsorbent dose of 0.5 g L Show less

Focal adhesions (FAs) connect inner workings of cell to the extracellular matrix to control cell adhesion, migration and mechanosensing. Previous studies demonstrated that FAs contain three vertical layers, which connect extracellular matrix to the cytoskeleton. By using super-resolution iPALM microscopy, we identify two additional nanoscale layers within FAs, specified by actin filaments bound to tropomyosin isoforms Tpm1.6 and Tpm3.2. The Tpm1.6-actin filaments, beneath the previously identified α-actinin cross-linked actin filaments, appear critical for adhesion maturation and controlled cell motility, whereas the adjacent Tpm3.2-actin filament layer beneath seems to facilitate adhesion disassembly. Mechanistically, Tpm3.2 stabilizes ACF-7/MACF1 and KANK-family proteins at adhesions, and hence targets microtubule plus-ends to FAs to catalyse their disassembly. Tpm3.2 depletion leads to disorganized microtubule network, abnormally stable FAs, and defects in tail retraction during migration. Thus, FAs are composed of distinct actin filament layers, and each may have specific roles in coupling adhesions to the cytoskeleton, or in controlling adhesion dynamics. Show less

Mycobacterium tuberculosis (MTB) is the causative organism of tuberculosis. Cholesterol is a crucial carbon source required for the survival of MTB in host cells. Transcription factor NR1H3 along with its important target genes ABCA1 and ApoE play important role in removal of extra cholesterol from cells. Changes in the gene expression of NR1H3, ABCA1 and ApoE can affect cholesterol homeostasis and thus the survival of MTB in host cells.Therefore, the present study was designed to analyze the mRNA expression of NR1H3, ABCA1 and ApoE in pulmonary TB (PTB) patients from the population of Punjab, India. In this study, mRNA expression of the transcription factor NR1H3 and its target genes ABCA1 and ApoE was analyzed in 89 subjects, including 41 PTB patients and 48 healthy controls (HCs) by real-time quantitative PCR. It was found that the mRNA expression of both NR1H3 and ABCA1 genes was significantly lower in TB patients than in HCs (p < 0.001). Even after sex-wise stratification of the subjects, mRNA expression of NR1H3 and ABCA1 was found to be down-regulated in both male and female TB patients. No significant difference was observed in expression of ApoE (p = 0.98). The present study found that the mRNA expression of NR1H3 and ABCA1 is down-regulated in TB patients from Punjab state of India. Show less

The lipolytic processing of triglyceride-rich lipoproteins (TRLs) by lipoprotein lipase (LPL) is crucial for the delivery of dietary lipids to the heart, skeletal muscle, and adipose tissue. The processing of TRLs by LPL is regulated in a tissue-specific manner by a complex interplay between activators and inhibitors. Angiopoietin-like protein 4 (ANGPTL4) inhibits LPL by reducing its thermal stability and catalyzing the irreversible unfolding of LPL's α/β-hydrolase domain. We previously mapped the ANGPTL4 binding site on LPL and defined the downstream unfolding events resulting in LPL inactivation. The binding of LPL to glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 protects against LPL unfolding. The binding site on LPL for an activating cofactor, apolipoprotein C2 (APOC2), and the mechanisms by which APOC2 activates LPL have been unclear and controversial. Using hydrogen-deuterium exchange/mass spectrometry, we now show that APOC2's C-terminal α-helix binds to regions of LPL surrounding the catalytic pocket. Remarkably, APOC2's binding site on LPL overlaps with that for ANGPTL4, but their effects on LPL conformation are distinct. In contrast to ANGPTL4, APOC2 increases the thermal stability of LPL and protects it from unfolding. Also, the regions of LPL that anchor the lid are stabilized by APOC2 but destabilized by ANGPTL4, providing a plausible explanation for why APOC2 is an activator of LPL, while ANGPTL4 is an inhibitor. Our studies provide fresh insights into the molecular mechanisms by which APOC2 binds and stabilizes LPL-and properties that we suspect are relevant to the conformational gating of LPL's active site. Show less

The effect of nutrition on inflammation and breast cancer (BC) prognosis is still inconclusive. Mechanism of data suggests that different types of fatty acids (FAs) play an essential role in carcinogenesis, and binding of alpha 1 antitrypsin (A1AT) may modulate carcinogenesis. The increased expression in the bound form of A1AT and release of Angiopoietin-like protein 4 (Angptl4) targets the gene of peroxisome proliferator-activated receptor-gamma (PPAR-γ). Our aim of the study was to compare the effect of FA-free (A1AT-0) and FAs bound forms of A1AT on levels of IL-1β, PPAR-gamma, and Angplt4 in breast cancer and control women. 10 women with breast cancer and ten control women within the age group 25-60 years with normal (Pi) M allele A1AT were recruited. Mononuclear cells were isolated and treated with different A1AT and FAs on the various combinations (linoleic acid, alpha-linolenic acid) for time-dependent study (2,4,18 and 24 h) and analyzed for the interleukin -1 beta(IL-1b), PPAR-gamma, and Angiopoietin-like protein 4 (Angptl4) expression by using ELISA method and gas chromatography for analyzing FAs. One-way ANOVA combined with multiple comparisons is used to compare the means. 100% of the study subjects were homozygous for the normal allele of A1AT. Time-dependent effects of A1AT and A1AT conjugated fatty acids on IL-I b, PPAR-g and Angptl4 showed statistically significant P = 0.07, P = 0.001, and P = 0.02 respectively, compared to those of the former study subjects. But within the groups, PPAR-g levels in case group (F(15,40)1.606, P = 0.003) and Angptl4 in the control group (F(15,32)0.64, P = 0.043) differed significantly. To the best of our knowledge, it's the first kind of study, and we speculate that the A1AT complex with different types of FAs results in a new form of A1AT having a solid capability to regulate the inflammation-induced synthesis, processing, and release of an active form of IL-1β. Our experimental data shows that the anti-inflammatory property of A1AT combined FAs likely to be mediated PPAR γand Angptl4 activation, thereby inhibiting the IL-1b. These findings may be worth assessing BC's biological effects and therapeutic effectiveness. Show less

Tannic acid (TA) is a natural compound present abundantly in fruit such as grapes and green tea. In this study, we have evaluated the therapeutic efficacy of TA against Lipopolysaccharide (LPS)-induced oxidative stress-mediated memory impairment, neuroinflammation, insulin signaling impairment, and Amyloid Beta (Aβ) deposition in adult male mice. The LPS was administered once per week and TA twice a week to adult male mice for three months consecutively. Behavioral studies were performed using different behavioral models such as balance beam, novel object recognition (NOR), Morris water maze (MWM), and Y-maze tests. The protein expression of different mediators such as TNF-α, p-JNK, pIRS636, BACE1, APP, and Aβ was evaluated through western blot and immunofluorescence staining techniques. Biochemical assays were carried out to assess the antioxidant activities of TA. The computational study was conducted to predict the binding mode of TA with target sites of TNF-α. Behavioral studies showed that the TA-treated mice exhibited gradual memory improvement. TA significantly inhibited BACE1 activity and reduced production and accumulation of Aβ in the hippocampus of mice brains. Moreover, the TA significantly inhibited LPS-induced ROS production and enhanced the glutathione levels. Furthermore, we have shown via the computational method for the first time that TA inhibits LPS-triggered TNF-ὰ and its downstream signaling to reduce AD pathology including memory impairment, neuroinflammation, insulin signaling impairment, and Aβ deposition in adult mice. Taken together our current study demonstrates that TA is a potential candidate for the abrogation of LPS-induced neurotoxicity and AD pathology in rodent's models. Show less

Breast cancer (BC) is the most common cancer of women and the second most common cancer overall globally. Data suggest that the plasma concentration of omega fatty acids (n-3 and n-6) and the impact of the genetic variant are associated with diet-related inflammatory disease, BC. This study was aimed to find an association between genetic variant rs174537 of fatty acid desaturase gene 1(FADS 1) and breast cancer estrogen receptor subtype. Hundred and two blood samples from women were quantified for fatty acids by gas chromatography. SNP rs 174537(G > T) showed maximum variability and the strongest genetic determinant in the Genome-wide association study were genotyped using Sanger sequencing. The highest tertile of ALA showed a significantly reduced risk of BC compared to the lowest tertile (OR = 0.2, 95 %CL = 0.1-1.14, P = 0.03). Median values of ALA were higher in GT/TT genotype in ER +ve molecular subtype (P = 0.03) and DPA was higher in GG genotype of ER-ve molecular subtype (P = 0.037). When both the groups were put together the highest tertile of GG tertile showed significantly reduced risk of BC compared with the other lowest tertiles of GG and GT/TT genotypes (OR, 95% CL = 0.45(0.2-0.9). The high levels of arachidonic acid and low levels of n-3 fatty acids result in a pro-inflammatory milieu and that these pro-inflammatory effects might contribute to BC. We conclude that the individuals with genetically determined lower activity of FADS1(minor allele T) will derive greater advantage from n-3 FAs than those with higher FADS1 activity (G allele) and reduce the BC risk. Show less

Intravascular processing of triglyceride-rich lipoproteins (TRLs) is crucial for delivery of dietary lipids fueling energy metabolism in heart and skeletal muscle and for storage in white adipose tissue. During the last decade, mechanisms underlying focal lipolytic processing of TRLs along the luminal surface of capillaries have been clarified by fresh insights into the functions of lipoprotein lipase (LPL); LPL's dedicated transporter protein, glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1); and its endogenous inhibitors, angiopoietin-like (ANGPTL) proteins 3, 4, and 8. Key discoveries in LPL biology include solving the crystal structure of LPL, showing LPL is catalytically active as a monomer rather than as a homodimer, and that the borderline stability of LPL's hydrolase domain is crucial for the regulation of LPL activity. Another key discovery was understanding how ANGPTL4 regulates LPL activity. The binding of ANGPTL4 to LPL sequences adjacent to the catalytic cavity triggers cooperative and sequential unfolding of LPL's hydrolase domain resulting in irreversible collapse of the catalytic cavity and loss of LPL activity. Recent studies have highlighted the importance of the ANGPTL3-ANGPTL8 complex for endocrine regulation of LPL activity in oxidative organs (e.g., heart, skeletal muscle, brown adipose tissue), but the molecular mechanisms have not been fully defined. New insights have also been gained into LPL-GPIHBP1 interactions and how GPIHBP1 moves LPL to its site of action in the capillary lumen. GPIHBP1 is an atypical member of the LU (Ly6/uPAR) domain protein superfamily, containing an intrinsically disordered and highly acidic N-terminal extension and a disulfide bond-rich three-fingered LU domain. Both the disordered acidic domain and the folded LU domain are crucial for the stability and transport of LPL, and for modulating its susceptibility to ANGPTL4-mediated unfolding. This review focuses on recent advances in the biology and biochemistry of crucial proteins for intravascular lipolysis. Show less

The complex between lipoprotein lipase (LPL) and its endothelial receptor (GPIHBP1) is responsible for the lipolytic processing of triglyceride-rich lipoproteins (TRLs) along the capillary lumen, a physiologic process that releases lipid nutrients for vital organs such as heart and skeletal muscle. LPL activity is regulated in a tissue-specific manner by endogenous inhibitors (angiopoietin-like [ANGPTL] proteins 3, 4, and 8), but the molecular mechanisms are incompletely understood. ANGPTL4 catalyzes the inactivation of LPL monomers by triggering the irreversible unfolding of LPL's α/β-hydrolase domain. Here, we show that this unfolding is initiated by the binding of ANGPTL4 to sequences near LPL's catalytic site, including β2, β3-α3, and the lid. Using pulse-labeling hydrogen‒deuterium exchange mass spectrometry, we found that ANGPTL4 binding initiates conformational changes that are nucleated on β3-α3 and progress to β5 and β4-α4, ultimately leading to the irreversible unfolding of regions that form LPL's catalytic pocket. LPL unfolding is context dependent and varies with the thermal stability of LPL's α/β-hydrolase domain ( Show less

Venous thrombo-embolism (VTE) is multi-factorial disease involving several genetic and acquired risk factors responsible for its onset. It may occur spontaneously upon climbing at High Altitude (HA). Several studies demonstrated that hypoxic conditions prevailing at HA pose an independent risk factor for VTE; however, molecular mechanism remains unknown. Present study aims to identify genes associated with HA-induced VTE pathophysiology using real time TaqMan Low-Density Array (TLDA) of known candidate genes. Gene expression of total 93 genes were studied and analyzed in patients of VTE from HA (HA-VTE) and from sea level (SL-VTE) in comparison to respective controls. Both HA-VTE and SL-VTE patients showed up-regulation of 37 genes involved in blood coagulation cascade, clot formation, platelet formation, endothelial response, angiogenesis, cell adhesion and calcium channel activity. Seven genes including ACE, EREG, C8A, DLG2, USF1, F2 and PCDHA7 were up-regulated in both HA-controls and VTE patients (both HA-VTE and SL-VTE) indicating their role during VTE event and also upon HA exposure. Ten genes; CDH18, FGA, EDNBR, GATA2, MAPK9, BCAR1, FRK, F11, PCDHA1 and ST8SIA4 were uniquely up-regulated in HA-VTE. The differentially expressed genes from the present study could be determining factors for HA-VTE susceptibility and provide insights into VTE occurrence at HA. Show less

Coagulation phenotypes show strong intercorrelations, affect cardiovascular disease risk and are influenced by genetic variants. The objective of this study was to search for novel genetic variants influencing the following coagulation phenotypes: factor VII levels, fibrinogen levels, plasma viscosity and platelet count. We genotyped the British Women's Heart and Health Study (n=3,445) and the Whitehall II study (n=5,059) using the Illumina HumanCVD BeadArray to investigate genetic associations and pleiotropy. In addition to previously reported associations (SH2B3, F7/F10, PROCR, GCKR, FGA/FGB/FGG, IL5), we identified novel associations at GRK5 (rs10128498, p=1.30x10(-6)), GCKR (rs1260326, p=1.63x10(-6)), ZNF259-APOA5 (rs651821, p=7.17x10(-6)) with plasma viscosity; and at CSF1 (rs333948, p=8.88x10(-6)) with platelet count. A pleiotropic effect was identified in GCKR which associated with factor VII (p=2.16x10(-7)) and plasma viscosity (p=1.63x10(-6)), and, to a lesser extent, ZNF259-APOA5 which also associated with factor VII and fibrinogen (p<1.00x10-²) and plasma viscosity (p<1.00x10(-5)). Triglyceride associated variants were overrepresented in factor VII and plasma viscosity associations. Adjusting for triglyceride levels resulted in attenuation of associations at the GCKR and ZNF259-APOA5 loci. In addition to confirming previously reported associations, we identified four single nucleotide polymorphisms (SNPs) associated with plasma viscosity and platelet count and found evidence of pleiotropic effects with SNPs in GCKR and ZNF259-APOA5. These triglyceride-associated, pleiotropic SNPs suggest a possible causal role for triglycerides in coagulation. Show less

Following the widespread use of genome-wide association studies (GWAS), focus is turning towards identification of causal variants rather than simply genetic markers of diseases and traits. As a step towards a high-throughput method to identify genome-wide, non-coding, functional regulatory variants, we describe the technique of allele-specific FAIRE, utilising large-scale genotyping technology (FAIRE-gen) to determine allelic effects on chromatin accessibility and regulatory potential. FAIRE-gen was explored using lymphoblastoid cells and the 50,000 SNP Illumina CVD BeadChip. The technique identified an allele-specific regulatory polymorphism within NR1H3 (coding for LXR-α), rs7120118, coinciding with a previously GWAS-identified SNP for HDL-C levels. This finding was confirmed using FAIRE-gen with the 200,000 SNP Illumina Metabochip and verified with the established method of TaqMan allelic discrimination. Examination of this SNP in two prospective Caucasian cohorts comprising 15,000 individuals confirmed the association with HDL-C levels (combined beta = 0.016; p = 0.0006), and analysis of gene expression identified an allelic association with LXR-α expression in heart tissue. Using increasingly comprehensive genotyping chips and distinct tissues for examination, FAIRE-gen has the potential to aid the identification of many causal SNPs associated with disease from GWAS. Show less

Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50,000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2,000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16,324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12-13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors. Show less

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)). Show less

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes. Show less

Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n=5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p<10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HMGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZ1B, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p<10(-4) in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n>12,500) revealed previously unreported associations of SH2B3 (p<2.2x10(-6)), BMPR2 (p<2.3x10(-7)), BCL3/PVRL2 (flanking APOE; p<4.4x10(-8)), and SMARCA4 (flanking LDLR; p<2.5x10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., >1 mmol/L in LDL cholesterol [approximately 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically. Show less