Poly (ADP-ribose) Polymerase-1 modulations in the genesis of thrombosis.

Thrombosis, a coagulation disorder, occurs due to altered levels of coagulation, fibrinolytic and immune factors, which are otherwise known to maintain hemostasis in normal physiological conditions. Here, we review the direct and indirect participation of a multifunctional nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP1) in the expression of key genes and cellular processes involved in thrombotic pathogenesis. PARP1 biological activities range from maintenance of genomic integrity, chromatin remodeling, base excision DNA repair, stress responses to cell death, angiogenesis and cell cycle pathways. However, under homeostatic imbalances, PARP1 activities are linked with the pathogenesis of diseases, including cancer, aging, neurological disorders, and cardiovascular diseases. Disease-associated distressed cells employ a variety of PARP-1 functions such as oxidative damage exacerbations, cellular energetics and apoptosis pathways, regulation of inflammatory mediators, promotion of endothelial dysfunction, and ERK-mediated signaling in pathogenesis. Thrombosis is one such pathogenesis that comprises exacerbation of coagulation cascade due to biochemical alterations in endothelial cells, platelet activation, overexpression of adhesion molecules, cytokines release, and leukocyte adherence. Thus, the activation of endothelial and inflammatory cells in thrombosis implicates a potential role of PARP1 activation in thrombogenesis. This review article explores the direct impact of PARP1 activation in the etiology of thrombosis and discusses PARP1-mediated endothelial dysfunction, inflammation, and epigenetic regulations in the disease manifestation. Understanding PARP1 functions associated with thrombosis may elucidate novel pathogenetic mechanisms and help in better disease management through newer therapeutic interventions targeting PARP1 activity.

Host-Viral Interactions Revealed among Shared Transcriptomics Signatures of ARDS and Thrombosis: A Clue into COVID-19 Pathogenesis.

Severe novel corona virus disease 2019 (COVID-19) infection is associated with a considerable activation of coagulation pathways, endothelial damage, and subsequent thrombotic microvascular injuries. These consistent observations may have serious implications for the treatment and management of this highly pathogenic disease. As a consequence, the anticoagulant therapeutic strategies, such as low molecular weight heparin, have shown some encouraging results. Cytokine burst leading to sepsis which is one of the primary reasons for acute respiratory distress syndrome (ARDS) drive that could be worsened with the accumulation of coagulation factors in the lungs of COVID-19 patients. However, the obscurity of this syndrome remains a hurdle in making decisive treatment choices. Therefore, an attempt to characterize shared biological mechanisms between ARDS and thrombosis using comprehensive transcriptomics meta-analysis is made. We conducted an integrated gene expression meta-analysis of two independently publicly available datasets of ARDS and venous thromboembolism (VTE). Datasets GSE76293 and GSE19151 derived from National Centre for Biotechnology Information-Gene Expression Omnibus (NCBI-GEO) database were used for ARDS and VTE, respectively. Integrative meta-analysis of expression data (INMEX) tool preprocessed the datasets and effect size combination with random effect modeling was used for obtaining differentially expressed genes (DEGs). Network construction was done for hub genes and pathway enrichment analysis. Our meta-analysis identified a total of 1,878 significant DEGs among the datasets, which when subjected to enrichment analysis suggested inflammation-coagulation-hypoxemia convolutions in COVID-19 pathogenesis. The top hub genes of our study such as tumor protein 53 (TP53), lysine acetyltransferase 2B (KAT2B), DExH-box helicase 9 (DHX9), REL-associated protein (RELA), RING-box protein 1 (RBX1), and proteasome 20S subunit beta 2 (PSMB2) gave insights into the genes known to be participating in the host-virus interactions that could pave the way to understand the various strategies deployed by the virus to improve its replication and spreading.

Susceptibility to high-altitude pulmonary edema is associated with circulating miRNA levels under hypobaric hypoxia conditions.

Hypobaric hypoxia poses stress to sojourners traveling to high-altitude. A cascade of physiological changes occurs to cope with or adapt to hypobaric hypoxia. However, an insufficient physiological response to the hypoxic condition resulting from imbalanced vascular homeostasis pathways results in high-altitude pulmonary edema (HAPE). The present study aims to identify the implication of miRNAs associating with HAPE and adaptation. We analyzed the expression of 1,113 miRNAs in HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and highland natives (HLs). Based on miRNA profiling and in silico analyses, miR-124-3p emerged relevantly. We observed a significant overexpression of miR-124-3p in HAPE-p. In silico analyses revealed a direct interaction of miR-124-3p with vascular homeostasis and hypoxia-associated genes NOS3 (endothelial nitric oxide synthase), Apelin, and ETS1 (V-Ets avian erythroblastosis virus E2 oncogene homolog 1). Moreover, the transcript and biolevel expression of these genes were significantly decreased in HAPE-p when compared with HAPE-f or HLs. Our in vitro analysis in human umbilical vein endothelial cells demonstrated a significant knockdown of these genes both at transcript and protein levels following miR-124-3p overexpression. Conclusively, our results showed that miR-124-3p might play a plausible role in HAPE pathophysiology by inhibiting the expression of NOS3, Apelin, and ETS1.

Understanding Inflammatory Responses in the Manifestation of Prothrombotic Phenotypes.

Inflammasome complex is a multimeric protein comprising of upstream sensor protein of nucleotide-binding oligomerization domain (NOD)-like receptor family. It has an adaptor protein apoptosis-associated speck-like protein and downstream effector cysteine protease procaspase-1. Activation of inflammasome complex is body's innate response to pathogen attack but its abnormal activation results in many inflammatory and cardiovascular disorders including thrombosis. It has displayed a prominent role in the clot formation advocating an interplay between inflammation and coagulation cascades. Therefore, elucidation of inflammasome and its molecular mechanisms in the manifestation of prothrombotic phenotypes becomes pertinent. Thrombosis is the formation and propagation of blood clot in the arterial or venous system due to several interactions of vascular and immune factors. It is a prevalent pathology underlying disorders like venous thromboembolism, stroke and acute coronary syndrome; thus, making thrombosis, a major contributor to the global disease burden. Recently studies have established a strong connection of inflammatory processes with this blood coagulation disorder. The hemostatic balance in thrombosis gets altered by the inflammatory mechanisms resulting in endothelial and platelet activation that subsequently increases secretion of several prothrombotic and antifibrinolytic factors. The upregulation of these factors is the critical event in the pathogenesis of thrombosis. Among various inflammasome, nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) is one of the best-studied sterile inflammasome strengthening a link between inflammation and coagulation in thrombosis. NLRP3 activation results in the catalytic conversion of procaspase-1 to active caspase-1, which facilitate the maturation of interleukin-1ß (IL-1ß) and interleukin-18. These cytokines are responsible for immune cells activation critical for immune responses. These responses further results in endothelial and platelet activation and aggregation. However, the exact molecular mechanism related to the pathogenesis of thrombosis is still elusive. There have been several reports that demonstrate Tissue factor (TF)-mediated signaling in the production of pro-inflammatory cytokines enhancing inflammation by activating protease-activated receptors on various cells, which lead to additional cytokine expression. Therefore, it would be illuminating to interpret the inflammasomes regulation in coagulation and inflammation. This review, thus, tries to comprehensively compile emerging regulatory roles of the inflammasomes in thrombosis and discusses their molecular pathways in the manifestation of thrombotic phenotypes.

Using Artificial Intelligence to Manage Thrombosis Research, Diagnosis, and Clinical Management.

Thrombosis development in either arterial or venous system remains a major cause of death and disability worldwide. This poorly controlled in vivo clotting could result in many severe complications including myocardial infarction, venous thromboembolism, stroke, and cerebral venous thrombosis, to name a few. These conditions are collectively known as thromboembolic disorders (TEDs). Appropriate understanding of TEDs is challenging, as they are multifactorial and involve several and often different risk factors. Hence, it requires a collective effort and data from numerous research studies to fully comprehend molecular mechanisms for prediction, prevention, treatment, and overall management of these conditions. To accomplish this arduous feat, a comprehensive approach is required that can compile thousands of available experimental data and transform these into more applicable and purposeful findings. Thus, large datasets could be utilized to generate models that could be predictive of how an individual would respond when subjected to any kind of additional risk factors or surgery, hospitalization, etc., or in the presence of some susceptible genetic variations. Artificial intelligence-based methods harness the capabilities of computer software to imitate human behaviors such as language translation, visual perception, and, most importantly, decision making. These emerging tools, if appropriately explored, might assist in processing of large data and tackle the complexities of identifying novel or interesting pathways that could otherwise be hidden due to their enormity. This narrative review attempts to compile the applications of various subfields of artificial intelligence and machine learning in the context of thrombosis research to date. It further reflects on the potential of artificial intelligence in transforming enormous research data into translational application in the form of predictive computational models.

CYBA and GSTP1 variants associate with oxidative stress under hypobaric hypoxia as observed in high-altitude pulmonary oedema.

HAPE (high-altitude pulmonary oedema) is characterized by pulmonary hypertension, vasoconstriction and an imbalance in oxygen-sensing redox switches. Excess ROS (reactive oxygen species) contribute to endothelial damage under hypobaric hypoxia, hence the oxidative-stress-related genes CYBA (cytochrome b-245 α polypeptide) and GSTP1 (glutathione transferase Pi 1) are potential candidate genes for HAPE. In the present study, we investigated the polymorphisms -930A/G and H72Y (C/T) of CYBA and I105V (A/G) and A114V (C/T) of GSTP1, individually and in combination, in 150 HAPE-p (HAPE patients), 180 HAPE-r (HAPE-resistant lowland natives) and 180 HLs (healthy highland natives). 8-Iso-PGF2α (8-iso-prostaglandin F2α) levels were determined in plasma and were correlated with individual alleles, genotype, haplotype and gene-gene interactions. The relative expression of CYBA and GSTP1 were determined in peripheral blood leucocytes. The genotype distribution of -930A/G, H72Y (C/T) and I105V (A/G) differed significantly in HAPE-p compared with HAPE-r and HLs (P≤0.01). The haplotypes G-C of -930A/G and H72Y (C/T) in CYBA and G-C and G-T of I105V (A/G) and A114V (C/T) in GSTP1 were over-represented in HAPE-p; in contrast, haplotypes A-T of -930A/G and H72Y (C/T) in CYBA and A-C of I105V (A/G) and A114V (C/T) in GSTP1 were over-represented in HAPE-r and HLs. 8-Iso-PGF2α levels were significantly higher in HAPE-p and in HLs than in HAPE-r (P=2.2×10(-16) and 1.2×10(-14) respectively) and the expression of CYBA and GSTP1 varied differentially (P<0.05). Regression analysis showed that the risk alleles G, C, G and T of -930A/G, H72Y (C/T), I105V (A/G) and A114V (C/T) were associated with increased 8-iso-PGF2α levels (P<0.05). Interaction between the two genes revealed over-representation of most of the risk-allele-associated genotype combinations in HAPE-p and protective-allele-associated genotype combinations in HLs. In conclusion, the risk alleles of CYBA and GSTP1, their haplotypes and gene-gene interactions are associated with imbalanced oxidative stress and, thereby, with high-altitude adaptation and mal-adaptation.

CYP1A1, CYP1A2 and CYBA gene polymorphisms associated with oxidative stress in COPD.

BACKGROUND: The genetic susceptibility to chronic obstructive pulmonary disease (COPD) depends on detoxification and antioxidant enzymes, which detoxify cigarette smoke reactive components that, otherwise, generate oxidative stress. METHODS: In a case-control study of 346 subjects with and without COPD, we examined the polymorphisms 462Ile/Val, 3801T/C of CYP1A1, -3860G/A of CYP1A2 and -930A/G, 242C/T of CYBA individually or in combination and their contribution to oxidative stress markers by measuring malondialdehyde (MDA), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx). RESULTS: COPD patients had significantly increased MDA concentration (p<0.001) and decreased CAT activity, GSH concentration, GPx activity (p< or =0.01). The patients were over-represented by the alleles 462Val, 3801C of CYP1A1 and -930G, 242C of CYBA (p<0.001, p=0.003, p=0.030 and p=0.031, respectively) and consequently the haplotypes of same alleles i.e. 462Val:3801C, 462Val:3801T and -930G:242C (p=0.048, p=0.016 and p=0.039, respectively). Similarly, CYP1A1 and CYP1A2 haplotypes, 462Val:3860G and 462Val:3801T:3860G were significantly over-represented (p=0.001 and p=0.003), respectively in patients. The same alleles-associated genotype-combinations between genes were more prevalent in patients. Of note, the genotypes, 462Ile/Val+Val/Val, 3801TC+CC of CYP1A1 and -930AG+GG of CYBA associated with increased MDA concentration (p=0.018, p=0.045 and p=0.017, respectively), decreased CAT activity (p<0.0001, p=0.080 and p<0.0001, respectively) and GSH concentration (p<0.0001, p=0.0002 and p=0.011, respectively) in patients. CONCLUSION: The identified alleles, its haplotypes and the genotype-combination along with increased oxidative stress, signify the importance in susceptibility to COPD.