Project description:Background and Aim: The worldwide prevalence of alcoholic liver disease (ALD) due to escalating alcohol consumption has presented an unprecedented pressure on human health. A few studies have determined long non-coding RNAs (lncRNAs) involved in the pathogenesis of liver diseases. However, the roles of lncRNAs in ALD development is still poorly understood. Methods: An ALD mouse model was established and confirmed. Expression profiles of lncRNAs were obtained by whole transcriptome sequencing. The altered lncRNAs in ALD mice were further verified by qRT-PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to enrich the functions of these lncRNAs. In combination with miRNA and mRNA profiles, we constructed concise endogenous RNA (ceRNA) networks. The function of the most up/downregulated lnRNA signaling was further verified and investigated in both ALD model and AML-12 cells. Results: Totally, five downregulated lncRNAs were obtained and verified in ALD mice. The GO term and KEGG pathway analyses revealed that the identified lncRNAs were associated with alcohol-induced hepatic oxidative damage, cellular inflammation, and lipid metabolism. Integration the differentially modulated miRNAs and mRNAs with ceRNA network analysis, we constructed five ceRNA networks and screened out 30 miRNAs and 25 mRNAs that may participate in ALD. Further, we verified and investigate the function of the most downregulated lnc_1700023H06Rik. Depletion lnc_1700023H06Rik reduced genes related to lipid metabolism, especially mRNA Acat2 (ENSMUST00000159697) and Pgrmc2 (ENSMUST00000058578) in both ALD mice and AML12 cell. Knocking down lnc_1700023H06Rik induced triglyceride accumulation and LDH leakage in AML12 cells, consisting with that in alcohol-treated cells, confirming the potential pathological role of lnc_1700023H06Rik in ALD. Conclusion: The five remarkably downregulated lncRNAs in an ALD mouse model were identified as novel biomarkers, highlighting the key role of lncRNAs in the development of ALD. The effect of lnc_1700023H06Rik was further verified.

Project description:BACKGROUND: Competitive endogenous RNA (ceRNA) reveals new mechanisms for interactions between RNAs. However, knowledge of ceRNA regulatory networks in macrophages infected with Talaromyces marneffei (T. marneffei, TM) is still limited. This study aims to explore the expression profiles of lncRNA, miRNA and mRNA, and the changes of ceRNA network related to immunity, inflammation, metabolism in TM-infected macrophage. METHODS: Next-generation sequencing technology (NGS) was used to obtain mRNA, miRNA and lncRNA expression profiles in TM-infected macrophages and normal macrophages. Cuffdiff and DESeq2 software packages are used to identify differentially expressed lncRNA, miRNA and mRNA. The function enrichment analysis was performed by GOseq package in R platform, and the lncRNA–miRNA–mRNA interaction ceRNA network was established in Cytoscape. Functional enrichment analysis was performed on genes contained in the ceRNA network, and genes significantly enriched in functional pathways were selected for qRT-PCR verification. RESULTS: A total of 119 lncRNAs, 28 miRNAs and 208 mRNAs were identified as differentially expressed RNAs in TM-infected macrophages. Among them, 38 lncRNAs, 10 miRNAs and 109 mRNAs are contained in the ceRNA regulatory network. GO analysis and KEGG pathway of mRNA in the ceRNA network showed that macrophages infected with TM activated pathways and functions related to immune response, metabolic response and inflammatory response. Select genes that are significantly abundant in GO analysis and KEGG pathway. The core genes were selected for quantitative real-time PCR (qRT-PCR) to verify consistency with the sequencing results. Eight groups of ceRNAs consisting of 3 mRNAs, 5 lncRNAs, and 2 miRNAs were verified. They are mRNA CSF3, IL24, LIF. lncRNA IL6R-AS1, LINC02009, AC068831.1, AC006252.1, LINC02466. These genes may be involved in immune response and inflammatory response-related pathways and functions in TM-infected macrophages. CONCLUSIONS: The CeRNA network plays an important role in understanding the mechanism of TM infection in macrophages. This study may provide effective and novel insights for further understanding the underlying mechanism of Talaromyces marneffei.

Project description:Alcohol consumption induces hepatocyte damage through complex processes involving oxidative stress and disrupted metabolism. Combined, these factors alter proteomic and epigenetic marks providing a critical opportunity to identify therapeutic targets. Indeed, alcohol-induced protein acetylation is a key post-translational modification (PTM) that regulates hepatic metabolism and is associated with the pathogenesis of alcohol-associated liver disease (ALD). Interestingly, recent evidence suggests lysine acetylation occurs when a proximal cysteine residue is within ~15 Å of a lysine residue, referred to as a cysteine-lysine (Cys-Lys) pair. Here, acetylation can occur through the transfer of an acetyl moiety via an S à N acetyl transfer reaction. Alcohol-mediated hepatic redox stress is known to occur coincident with lysine acetylation, but the biochemical mechanisms related to cysteine and lysine crosstalk within ALD remain unexplored. A chronic murine model of ALD was employed to quantify hepatic cysteine redox and lysine acetylation, revealing that alcohol metabolism significantly reduced the cysteine proteome and increased protein acetylation. Interrogating both cysteine redox and lysine acetylation datasets, 1,281 proteins were mapped by AlphaFold2 to quantify distances between 557,815 cysteine and lysine residues. This process identified 388,698 Cys-Lys pairs that were further used to evaluate thiol redox signaling. Our analysis reveals that alcohol metabolism induces redox changes and acetylation selectively on proximal Cys-Lys pairs with an odds ratio of 1.89 (p< 0.0001). We also identified key redox signaling hubs embedded in metabolic pathways associated with ALD, including lipid metabolism, the TCA cycle, and the electron transport chain. Specific protein targets embedded across these pathways include Echs1, Glrx5, Decr2, and Adh1, among many others. Interestingly, these proximal Cys-Lys exist as four major protein motifs represented by the number of Cys and Lys residues that are pairing (Cysx-Lysx). These motifs include Cys1:Lys1, Cysx:Lys1, Cys1:Lysx and Cysx:Lysx each with a unique microenvironment likely indicative of the mode of enzymatic regulation occurring. The motifs are composed of functionally relevant amino acids altered within ALD, identifying sites of therapeutic potential. Furthermore, these unique Cys-Lys redox signatures are translationally relevant as revealed by orthologous comparison with severe alcohol-associated hepatitis (SAH) explants, revealing numerous pathogenic thiol redox signals in these patients.

Project description:Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is the most common cause of acute respiratory deterioration and death in IPF patients, with an elusive etiology and pathogenesis. Roles of noncoding RNAs in AE-IPF have been proposed, however, it was rare to find studies have systematically investigated the crosstalk among various transcripts until now. The construction of RNA functional networks such as lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA interaction networks could therefore facilitate our understanding of RNA interactions in AE-IPF. The study aimed to identify the expression differences of RNA transcripts in RNA sequencing from AE-IPF patients and stable IPF (S-IPF), and further to construct the potential RNA networks. Methods: Five AE-IPF patients and five S-IPF were recruited in this study to perform RNA sequencing and miRNA sequencing. The differentially expression profiles of lncRNAs, circRNAs, miRNAs and mRNAs between AE-IPF and S-IPF patients were identified for further analyses. Gene Oncology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of were performed. The competing endogenous RNAs (ceRNAs) network of lncRNA/circRNA-miRNA-mRNA was constructed, and the core regulatory molecules in the ceRNA network were analyzed. Results: A total of 69 lncRNAs, 150 circRNAs, 27 miRNAs and 56 mRNAs were differentially expressed between AE-IPF and S-IPF. GO and KEGG analysis show that differentially expression mRNAs are significantly associated with tight junction and Hepatitis C, etc. In the ceRNA network, all nodes are directly or indirectly involved in the progression of AE-IPF. 1 lncRNAs, 6 circRNAs, 1 miRNAs, and 5 mRNAs constituted a hsa-miR-150-5p core sub-network. Based on the analysis of ceRNA sub-network, NR_120628/hsa-miR-150-5p/E2F3 and has-circ-0053515/hsa-miR-150-5p/E2F3 were considered to be the key ceRNA axis. Conclusions: In conclusion, this study reveals NR_120628/hsa-miR-150-5p/E2F3 and has-circ-0053515/hsa-miR-150-5p/E2F3 may be the key ceRNA axis in the regulation of AE-IPF, providing clues for future studies on their roles for AE-IPF. Our findings will help to explore the pathological mechanism of AE-IPF from a transcriptomic perspective and provide enlightenment for the biomarker and therapeutic targets of AE-IPF.

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Comprehensive analysis of the expression profiles of lncRNAs in a mouse model of alcoholic liver disease

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