Browsing by Author "Gomes, Marta T."

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    Human Endogenous Retrovirus, SARS-CoV-2, and HIV Promote PAH via Inflammation and Growth Stimulation
    (MDPI, 2023-04-18) Wang, Desheng; Gomes, Marta T.; Mo, Yanfei; Prohaska, Clare C.; Zhang, Lu; Chelvanambi, Sarvesh; Clauss, Matthias A.; Zhang, Dongfang; Machado, Roberto F.; Gao, Mingqi; Bai, Yang; Medicine, School of Medicine
    Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease characterized by the progressive elevation of pulmonary arterial pressures. It is becoming increasingly apparent that inflammation contributes to the pathogenesis and progression of PAH. Several viruses are known to cause PAH, such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), human endogenous retrovirus K(HERV-K), and human immunodeficiency virus (HIV), in part due to acute and chronic inflammation. In this review, we discuss the connections between HERV-K, HIV, SARS-CoV-2, and PAH, to stimulate research regarding new therapeutic options and provide new targets for the treatment of the disease.
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    Immunogenic Cell Death Involves in SARS-CoV-2 and Pulmonary Arterial Hypertension Crosstalk
    (Elsevier, 2022) Wang, Desheng; Mo, Yanfei; Gomes, Marta T.; Machado, Roberto F.; Bai, Yang; Medicine, School of Medicine
    Background: Pulmonary arterial hypertension (PAH) is a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and that individuals with PAH are at substantial risk for rapid deterioration once infected. However, the underlying mechanism and genetic signatures of PAH and SARTS-CoV-2 remains unclear. Methods: The PAH and SARS-CoV-2 datasets were downloaded from the Gene Expression Omnibus (GEO) database, immunogenic cell death (ICD) genes were extracted, and differential expression analysis was performed to obtain shared differentially expressed genes (DEGs). Meta-analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network analysis were performed on DEGs to observe functional enrichment of these genes and associations between genes. The disease prediction model was constructed by artificial neural network (ANN), and its accuracy was further evaluated by receiver operating characteristic (ROC) curve. Using Single-sample GSEA (ssGSEA) to evaluate the correlation between disease signature genes and immune cell abundance in the PAH dataset and the SARS-CoV-2 dataset. Finally, the screened drugs were predicted by DEGs, and were molecularly docked with DEGs by AutoDock Vina. Findings: TLR4, MYD88, IL1B, and HMGB1 four shared genes were identified by ICD differential gene expression analysis. NF-kappa B signaling pathway, Toll-like receptor signaling pathway and NOD-like receptor signaling pathway closely related to inflammation were observed by the enrichment analysis of DEGs. The result of immune infiltration showed that these DEGs were involved in the changes of PAH and the immune microenvironment of SARS-CoV-2, and the same regulatory process existed in Macrophage, Monocyte, Central memory CD8 T cell, and Central memory CD4 T cell. Nitric oxide, Resveratrol, and Curcumin may promise drugs for the treatment of SARS-CoV-2 and PAH. Further verification of Resveratrol and Curcumin by molecular docking showed that Resveratrol and Curcumin have good docking activity with their target proteins. Interpretation: Analogous molecular mechanism between PAH and SARS-CoV-2 from the perspective of ICD. The key genes IL1B, MYD88, TLR4 and HMGB1 involve in the immune cell response process, thus affecting the progression of these two diseases. These findings may provide novel directions for treatment of PAH and SARS-CoV-2.
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    Phosphatidylserine externalization by apoptotic cells is dispensable for specific recognition leading to innate apoptotic immune responses
    (American Society for Biochemistry and Molecular Biology, 2022) Gomes, Marta T.; Palasiewicz, Karol; Gadiyar, Varsha; Lahey, Kevin; Calianese, David; Birge, Raymond B.; Ucker, David S.; Medicine, School of Medicine
    Surface determinants newly expressed by apoptotic cells that are involved in triggering potent immunosuppressive responses, referred to as "innate apoptotic immunity (IAI)" have not been characterized fully. It is widely assumed, often implicitly, that phosphatidylserine, a phospholipid normally cloistered in the inner leaflet of cells and externalized specifically during apoptosis, is involved in triggering IAI, just as it plays an essential role in the phagocytic recognition of apoptotic cells. It is notable, however, that the triggering of IAI in responder cells is not dependent on the engulfment of apoptotic cells by those responders. Contact between the responder and the apoptotic target, on the other hand, is necessary to elicit IAI. Previously, we demonstrated that exposure of protease-sensitive determinants on the apoptotic cell surface are essential for initiating IAI responses; exposed glycolytic enzyme molecules were implicated in particular. Here, we report our analysis of the involvement of externalized phosphatidylserine in triggering IAI. To analyze the role of phosphatidylserine, we employed a panel of target cells that either externalized phosphatidylserine constitutively, independently of apoptosis, or did not, as well as their WT parental cells that externalized the phospholipid in an apoptosis-dependent manner. We found that the externalization of phosphatidylserine, which can be fully uncoupled from apoptosis, is neither sufficient nor necessary to trigger the profound immunomodulatory effects of IAI. These results reinforce the view that apoptotic immunomodulation and phagocytosis are dissociable and further underscore the significance of protein determinants localized to the cell surface during apoptosis in triggering innate apoptotic immunity.
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    Signal Transduction during Metabolic and Inflammatory Reprogramming in Pulmonary Vascular Remodeling
    (MDPI, 2022-02-22) Gomes, Marta T.; Bai, Yang; Potje, Simone R.; Zhang, Lu; Lockett, Angelia D.; Machado, Roberto F.; Medicine, School of Medicine
    Pulmonary arterial hypertension (PAH) is a progressive disease characterized by (mal)adaptive remodeling of the pulmonary vasculature, which is associated with inflammation, fibrosis, thrombosis, and neovascularization. Vascular remodeling in PAH is associated with cellular metabolic and inflammatory reprogramming that induce profound endothelial and smooth muscle cell phenotypic changes. Multiple signaling pathways and regulatory loops act on metabolic and inflammatory mediators which influence cellular behavior and trigger pulmonary vascular remodeling in vivo. This review discusses the role of bioenergetic and inflammatory impairments in PAH development.
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    Sphingosine Kinase 1 Regulates the Pulmonary Vascular Immune Response
    (Springer, 2021-09) Bai, Yang; Lockett, Angelia D.; Gomes, Marta T.; Stearman, Robert S.; Machado, Roberto F.; Medicine, School of Medicine
    The aberrant proliferation of pulmonary artery smooth muscle (PASMCs) cells is a defining characteristic of pulmonary arterial hypertension (PAH) and leads to increased vascular resistance, elevated pulmonary pressure, and right heart failure. The sphingosine kinase 1 (SPHK1)/sphingosine-1 phosphate/sphingosine-1 phosphate receptor 2 pathway promotes vascular remodeling and induces PAH. The aim of this study was to identify genes and cellular processes that are modulated by over-expression of SPHK1 in human PASMCs (hPASMCs). RNA was purified and submitted for RNA sequencing to identify differentially expressed genes. Using a corrected p-value threshold of <0.05, there were 294 genes significantly up-regulated while 179 were significantly down-regulated. Predicted effects of these differentially expressed genes were evaluated using the freeware tool Enrichr to assess general gene set over-representation (enrichment) and ingenuity pathway analysis (IPA™) for upstream regulator predictions. We found a strong change in genes that regulated the cellular immune response. IL6, STAT1, and PARP9 were elevated in response to SPHK1 over-expression in hPASMCs. The gene set enrichment mapped to a few immune-modulatory signaling networks, including IFNG. Furthermore, PARP9 and STAT1 protein were elevated in primary hPASMCs isolated from PAH patients. In conclusion, these data suggest a role of Sphk1 regulates pulmonary vascular immune response in PAH.