Developing a Novel Immune-Related Seven-Gene Signature and Immune Infiltration Pattern in Patients with COVID-19 and Cardiovascular Disease

Background: patients with pre-existence of cardiovascular disease (CVD) are vulnerable to coronavirus disease 2019 (COVID-19), and COVID-19 will cause long-term burden of CVD. However, the common pathogenic mechanisms are not fully elucidated. More detailed knowledge of linking biological molecules and the role of immune signature would allow more valuable and specific clinical management. Methods: the gene expression profiles of CVD and COVID-19 were retrieved from the GEO database. Common differentially expressed genes (DEGs) were screened with the Limma R package and the WGCNA algorithm, and then functional enrichment analysis, protein-protein interaction network, hub genes, and small therapeutic molecules analyses were performed. The hub immune-related genes (HIRGs) were intersected, and their associations with immune cells, expressional correlation, evaluated performance, and potential signal pathways were further investigated. Results: In total, 57 common DEGs were identified as a shared transcriptional signature between CVD and COVID-19, and 12 hub genes were screened using five topological algorithms. There are common altered immune responses in the response of these two diseases, and seven HIRGs, including C5AR1, MMP9, CYBB, FPR2, CSF1R, TLR2, and TLR4, were identified, with positive correlation to altered macrophages and neutrophils. Nine small molecular agents (SMAs) were detected as promising therapeutic drugs. These seven HIRGs mainly participated in the inflammatory immune response through activation of Il2 stat5 signaling and Tnfa signaling via nfκb pathways, and ROC curves confirmed their good discriminatory capacity in the two diseases. Conclusions: this study established the co-expression network and identified a new immune-related seven-gene signature as therapeutic targets, which may provide new insights into pathogenic mechanisms and novel clinical management strategies

miR-30a-5p promotes glomerular podocyte <?A3B2 tlsb=-0.06w?>apoptosis via DNMT1-mediated hypermethylation under hyperhomocysteinemia<?A3B2 tlsb?>

Abnormal elevation of homocysteine (Hcy) level is closely related to the development and progression of chronic kidney disease (CKD), with the molecular mech2anisms that are not fully elucidated. Given the demonstration that miR-30a-5p is specifically expressed in glomerular podocytes, in the present study we aimed to investigate the role and potential underlying mechanism of miR-30a-5p in glomerular podocyte apoptosis induced by Hcy. We found that elevated Hcy downregulates miR-30a-5p expression in the Cbs+/-- mice and Hcy-treated podocytes, and miR-30a-5p directly targets the 3′-untranslated region (3′-UTR) of the forkhead box A1 (FOXA1) and overexpression of miR-30a-5p inhibits FOXA1 expression. By nMS-PCR and MassARRAY quantitative methylation analysis, we showed the increased DNA methylation level of miR-30a-5p promoter both in vivo and in vitro. Meanwhile, dual-luciferase reporter assay showed that the region between --1400 and --921 bp of miR-30a-5p promoter is a possible regulatory element for its transcription. Mechanistic studies indicated that DNA methyltransferase enzyme 1 (DNMT1) is the key regulator of miR-30a-5p, which in turn enhances miR-30a-5p promoter methylation level and thereby inhibits its expression. Taken together, our results revealed that epigenetic modification of miR-30a-5p is involved in glomerular podocyte injury induced by Hcy, providing a diagnostic marker candidate and novel therapeutic target in CKD induced by Hcy

Loss of PI3 kinase association improves the sensitivity of secondary mutation of KIT to Imatinib

Background: KIT mutations are the predominant driver mutations in gastrointestinal stromal tumors (GISTs), and targeted therapy against KIT has improved treatment outcome dramatically. However, gaining secondary mutation of KIT confers drug resistance of GISTs leading to treatment failure. Results: In this study, we found that secondary mutation of KIT dramatically increases the ligand-independent activation of the receptor and their resistance to the often used KIT inhibitor Imatinib in the treatment of GISTs. PI3 kinase plays essential roles in the cell transformation mediated by the primary mutation of KIT. We found that loss of PI3 kinase association, but not the inhibition of the lipid kinase activity of PI3 kinase, inhibits the ligand-independent activation of secondary mutations of KIT, and increases their sensitivity to Imatinib, and loss of PI3 kinase association inhibits secondary mutations of KIT mediated cell survival and proliferation in vitro. The in vivo assay further showed that the growth of tumors carrying secondary mutations of KIT is more sensitive to Imatinib when PI3 kinase association is blocked while inhibition of the lipid kinase activity of PI3 kinase cannot inhibit tumor growth, indicating that PI3 kinase is important for the drug resistance of secondary mutation of KIT independent of the lipid kinase activity of PI3 kinase. Conclusions: Our results suggested that PI3 kinase is necessary for the ligand-independent activation of secondary mutations of KIT, and loss of PI3 kinase association improves the sensitivity of secondary mutations to the targeted therapy independent of the lipid kinase activity of PI3 kinase

Hyperhomocysteinemia in ApoE-/- Mice Leads to Overexpression of Enhancer of Zeste Homolog 2 via miR-92a Regulation.

Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases, such as atherosclerosis. HHcy promotes atherogenesis by modifying the histone methylation patterns and miRNA regulation. In this study, we investigated the effects of homocysteine (Hcy) on the expression of enhancer of zeste homolog 2 (EZH2), and tested our hypothesis that Hcy-induced atherosclerosis is mediated by increased EZH2 expression, which is regulated by miR-92a. The levels of EZH2 and H3K27me3 were increased in the aorta of ApoE-/- mice fed a high-methionine diet for 16 weeks, whereas miR-92a expression was decreased. Over-expression of EZH2 increased H3K27me3 level and the accumulation of total cholesterol and triglycerides in the foam cells. Furthermore, upregulation of miR-92a reduced EZH2 expression in the foam cells. These data suggested that EZH2 plays a key role in Hcy-mediated lipid metabolism disorders, and that miR-92a may be a novel therapeutic target in Hcy-related atherosclerosis

Correction: Hyperhomocysteinemia in ApoE-/- Mice Leads to Overexpression of Enhancer of Zeste Homolog 2 via miR-92a Regulation.

[This corrects the article DOI: 10.1371/journal.pone.0167744.]

Pro-efferocytosis biomimetic nanocomplexes for targeted atherosclerosis therapy through promoting macrophage re-polarization and inhibiting senescence

Atherosclerosis is chronic inflammatory disease tightly related with defective efferocytosis of apoptotic cells (ACs) in the plaques. The strategy of efferocytosis reactivation using Atorvastatin (AT) and Metformin (Met) has attracted increasing attention for atherosclerosis treatment. Although these drug-based therapies could stimulate the phagocytic clearance of ACs, the rapid drug clearance and poor bioavailability limited their efficacy. In this study, by co-loading AT and Met into poly(lactic-co-glycolic) acid nanoparticles (PLGA NPs), we developed a biomimetic nanocomplexes for targeted atherosclerosis treatment. Macrophages membrane-coated nanocomplexes efficiently avoided the clearance of NPs from immune system and achieved targeting ability to the atherosclerotic plaques. Moreover, modified hyaluronic acid (HA) delivered NPs into the dysfunctional efferocytic cells of plaques, and achieved the plaques-macrophages-targeted therapy. In vitro results indicated that the biomimetic nanocomplexes reactivated efferocytosis by facilitating macrophages polarization from M1 to M2 phenotype through enhancing ERK5/MerTK pathway and inhibiting cellular senescence through inhibiting p53-p16/pRB pathway. In vivo study indicated that this biomimetic nanocomplexes accumulated in the atherosclerotic plaques, resulting in reduction of necrotic core area and protection against plaque rupture by reactivating efferocytosis. These findings indicated that reactivation of efferocytosis by AT and Met co-delivered nanocomplexes provided a novel promising strategy for targeted atherosclerosis treatment

A novel lncRNA FPASL regulates fibroblast proliferation via the PI3K/AKT and MAPK signaling pathways in hypertrophic scar

Hypertrophic scar is a problem for numerous patients, especially after burns, and is characterized by increased fibroblast proliferation and collagen deposition. Increasing evidence demonstrates that lncRNAs contribute to the development and progression of various diseases. However, the function of lncRNAs in hypertrophic scar formation remains poorly characterized. In this study, a novel fibroblast proliferation-associated lncRNA, named lncRNA FPASL (MSTRG.389905.1), which is mainly localized in the cytoplasm, is found to be downregulated in hypertrophic scar, as detected by lncRNA microarray and qRT-PCR. The full-length FPASL is characterized and further investigation confirms that it has no protein-coding potential. FPASL knockdown in fibroblasts triggers fibroblast proliferation, whereas overexpression of FPASL directly attenuates the proliferation of fibroblasts. Furthermore, target genes of the differentially expressed lncRNAs in hypertrophic scars and the matched adjacent normal tissues are enriched in fibroblast proliferation signaling pathways, including the PI3K/AKT and MAPK signaling pathways, as determined by GO annotation and KEGG enrichment analysis. We also demonstrate that knockdown of FPASL activates the PI3K/AKT and MAPK signaling pathways, and specific inhibitors of the PI3K/AKT and MAPK signaling pathways can reverse the proliferation of fibroblasts promoted by FPASL knockdown. Our findings contribute to a better understanding of the role of lncRNAs in hypertrophic scar and suggest that FPASL may act as a potential novel therapeutic target for hypertrophic scar