N6-methyladenosine in myeloid cells: a novel regulatory factor for inflammation-related diseases.

N6-methyladenosine (m6A) is one of the most abundant epitranscriptomic modifications on eukaryotic mRNA. Evidence has highlighted that m6A is altered in response to inflammation-related factors and it is closely associated with various inflammation-related diseases. Multiple subpopulations of myeloid cells, such as macrophages, dendritic cells, and granulocytes, are crucial for the regulating of immune process in inflammation-related diseases. Recent studies have revealed that m6A plays an important regulatory role in the functional of multiple myeloid cells. In this review, we comprehensively summarize the function of m6A modification in myeloid cells from the perspective of myeloid cell production, activation, polarization, and migration. Furthermore, we discuss how m6A-mediated myeloid cell function affects the progression of inflammation-related diseases, including autoimmune diseases, chronic metabolic diseases, and malignant tumors. Finally, we discuss the challenges encountered in the study of m6A in myeloid cells, intended to provide a new direction for the study of the pathogenesis of inflammation-related diseases.

Construction and Analysis of lncRNA-Associated ceRNA Network in Atherosclerotic Plaque Formation.

Atherosclerosis (AS) is a vascular disease with plaque formation. Unstable plaques can be expected to result in cardiovascular disease, such as myocardial infarction and stroke. Studies have verified that long noncoding RNAs (lncRNAs) play a critical role in atherosclerotic plaque formation (APF), including MALAT1, GAS5, and H19. A ceRNA network is a combination of these two interacting processes, which regulate the occurrence and progression of many diseases. However, lncRNA-associated ceRNA network in terms of APF is limited. This study sought to discover novel potential biomarkers and ceRNA network for APF. We designed a triple network based on the lncRNA-miRNA and mRNA-miRNA pairs obtained from lncRNASNP and starBase. Differentially expressed genes (DEGs) and lncRNAs in human vascular tissues derived from the Gene Expression Omnibus database (GSE43292, GSE97210) were systematically selected and analyzed. A ceRNA network was constructed by hypergeometric test, including 8 lncRNAs, 243 miRNAs, and 8 mRNAs. APF-related ceRNA structure was discovered for the first time by combining network analysis and statistical validation. Topological analysis determined the key lncRNAs with the highest centroid. GO and KEGG enrichment analysis indicated that the ceRNA network was primarily enriched in "regulation of platelet-derived growth factor receptor signaling pathway," "negative regulation of leukocyte chemotaxis," and "axonal fasciculation." A functional lncRNA, HAND2-AS1, was identified in the ceRNA network, and the main miRNA (miRNA-570-3p) regulated by HAND2-AS1 was further screened. This present study elucidated the important function of lncRNA in the origination and progression of APF and indicated the potential use of these hub nodes as diagnostic biomarkers and therapeutic targets.

Nicotinamide N-methyltransferase ameliorates renal fibrosis by its metabolite 1-methylnicotinamide inhibiting the TGF-ß1/Smad3 pathway.

Chronic kidney disease (CKD), a disease involving damage to the kidney structure and function, is a global public health problem. Tubulointerstitial fibrosis (TIF) is both an inevitable pathological change in individuals with CKD and a driving force in the progression of renal fibrosis. Nicotinamide N-methyltransferase (NNMT) and its metabolite 1-methylnicotinamide (MNAM) have been shown to protect against lipotoxicity-induced kidney tubular injury. However, the biological roles of NNMT and MNAM in regulating TIF remain elusive. This study aimed to investigate the protective effect of NNMT and MNAM on TIF and the mechanisms involved. We explored the functions and mechanisms of NNMT and MNAM in TIF, as well as the interaction between NNMT and MNAM, using unilateral ureteral obstruction (UUO) mice and cultured mouse tubular epithelial cells (mTECs) stimulated with transforming growth factor-ß1 (TGF-ß1). Several important findings were obtained as follows: (1) NNMT expression was upregulated in the kidneys of UUO mice and TGF-ß1-induced mTECs, and this upregulation was proposed to be a protective compensatory response to TIF. (2) MNAM was a potentially effective antifibrotic and anti-inflammatory medication in UUO mice. (3) The antifibrotic effect of NNMT overexpression was exerted by increasing the concentration of MNAM. (4) The renoprotective role of MNAM depended on the selective blockade of the interaction of Smad3 with TGFß receptor I. Overall, our study shows that NNMT is involved in the development and progression of CKD and that its metabolite MNAM may be a novel inhibitor of the TGF-ß1/Smad3 pathway with great therapeutic potential for CKD.

lncRNA MALAT1 mediated high glucose-induced HK-2 cell epithelial-to-mesenchymal transition and injury.

Epithelial-to-mesenchymal transition (EMT) and injury of tubular cells play critical roles in the pathogenesis of diabetic nephropathy (DN). lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been shown to be involved in DN progression. However, whether MALAT1 induces EMT and injury in tubular cells is unclear. Here, we investigated the effects of MALAT1 on human proximal tubular cells (HK-2 cells) and the underlying mechanism. We performed qPCR to detect MALAT1, E-cadherin, α-smooth muscle actin (α-SMA), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL). Additionally, we conducted Western blot analyses to measure E-cadherin, α-SMA, cyclin D1, c-Myc, and ß-catenin in HK-2 cells cultured with normal glucose and high glucose (HG) and in transfected cells or cells treated with LiCl and DKK-1. The ß-catenin localization was observed using immunofluorescence, and the protein levels of NGAL and KIM-1 were evaluated by ELISA. We found that HG-upregulated MALAT1 decreased E-cadherin and increased α-SMA, KIM-1, NGAL, cyclin D1, c-Myc, and ß-catenin in HK-2 cells. LiCl exposure increased the expression of α-SMA but decreased that of E-cadherin on the base of knocking down MALAT1, and decreased NGAL and KIM-1 expression. DKK-1 showed the opposite effects. Our results suggested that upregulated MALAT1 induced EMT in HG-treated HK-2 cells through activating the Wnt/ß-catenin pathway. However, MALAT1-mediated injury in HK-2 cells was not mediated by activation of the Wnt/ß-catenin pathway. Our results indicate that MALAT1 might serve as a novel therapeutic target for suppressing the progression of DN.

[P38 MAPK signaling pathway mediates advanced oxidation protein product-induced epithelial-to-mesenchymal transition in tubular cells].

OBJECTIVE: To investigate whether the p38 mitogen-activated protein kinase (MAPK) signaling pathway mediates advanced oxidation protein products (AOPPs)-induced epithelial-to-mesenchymal transition (EMT) in tubular cells. METHODS: Human proximal tubular cells (HK-2 cells) exposed to AOPP-bovine serum albumin (BSA) were examined for expressions of p38 MAPK and phosphorylated p38 MAPK using Western blotting. Western blotting and quantitative RT-PCR were used to examine the protein and mRNA expressions of EMT markers E-cadherin and vimentin and endoplasmic reticulum stress marker glucose-regulated protein (GRP) 78 in cells treated with SB203580 (an inhibitor of the p38 MAPK signaling pathway) prior to AOPP exposure. The cells treated with AOPPs following pretreatment with salubrinal (an inhibitor of endoplasmic reticulum stress) were also examined for expressions of p38 MAPK and phosphorylated p38 MAPK. RESULTS: AOPP treatment induced the phosphorylation of p38 MAPK in HK-2 cells. AOPP-induced decrease in E-cadherin expression and overexpression of vimentin and GRP78 were partly inhibited by pretreatment of the cells with SB203580. Salubrina partly suppressed AOPP-induced phosphorylation of p38 MAPK in the cells. CONCLUSION: p38 MAPK signaling pathway, which is regulated by endoplasmic reticulum stress, might mediate AOPP-induced EMT in HK-2 cells.