No abstract

Abnormal methylation of N6 adenosine (m6A) in RNA plays a crucial role in the pathogenesis of many types of tumors. However, little is known about m6A RNA methylation in lung adenocarcinoma. This study aimed to identify the value of m6A RNA methylation regulators in the malignant progression and clinical prognosis of lung adenocarcinoma. The RNA-seq transcriptome data and corresponding clinical information of lung adenocarcinoma were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. Then the identification of differentially expressed m6A RNA methylation regulators between cancer samples and normal control samples, different subgroups by consensus expression of these regulators and the prognostic signature were achieved using R software with multiple corresponding packages. The results showed that the expression levels of HNRNPC, YTHDF1, KIAA1429, RBM15, YTHDF2, and METTL3 in cancer group were significantly up-regulated ( P < 0.05), while expression levels of FTO, ZC3H13, METTL14, YTHDC1 and WTAP in cancer group were significantly down-regulated ( P < 0.05) compared with control group. Two subgroups identified by consensus expression of these regulators were closely related to the clinicopathological features, clinical outcomes and malignancy of lung adenocarcinoma. In addition, a 3-gene risk signature including KIAA1429, RBM15, and HNRNPC was constructed and the lung adenocarcinoma patients in TCGA database were divided into high-risk group and low-risk group based on the median risk score. In conclusion, the prognostic signature-based risk score calculated according to the expression levels of KIAA1429, RBM15, and HNRNPC, was not only strongly associated with clinical outcomes and clinicopathological features, but also an independent prognostic factor in lung adenocarcinoma.

Abstract. Evidence suggests that an imbalance between oxidation and antioxidation is involved in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Activation of AMP-activated protein kinase (AMPK) has been shown to inhibit the occurrence of ALI/ARDS. However, it is unknown whether activation of AMPK benefits ALI/ARDS by restoration of the oxidant and antioxidant balance, and which mechanisms are responsible for this process. The present study aimed to address these issues. Lipopolysaccharide (LPS) induced pronounced pathological changes of ALI in mice; these were accompanied by elevated production of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) compared with control mice. Prior treatment of mice with the AMPK agonist metformin significantly suppressed the LPS-induced development of ALI, reduced the elevation of MDA and increased the activity of SOD. Further analysis indicated that activation of AMPK also stimulated the protein expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and superoxide dismutase 1 (SOD1). This study suggests that activation of AMPK by metformin inhibits oxidative stress by upregulation of PGC1α and SOD1, thereby suppressing the development of ALI/ARDS, and has potential value in the clinical treatment of such conditions.

No abstract

The upregulation of Sphingosine kinase 1 (SphK1) expression and accompanied sphingosine-1-phosphate (S1P) production have been reported to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMC) and pulmonary arterial remodeling. However, the molecular mechanisms of SphK1/S1P upregulation in PASMC and the specific mechanisms of how SphK1/S1P pathway promotes PASMC proliferation remain largely unclear. This study aims to address these issues. Here, we demonstrated that TGF-β1 significantly upregulated SphK1 expression and S1P production by promoting the phosphorylation of Smad2/3 in PASMC. Further study indicated that SphK1/S1P pathway mediated TGF-β1-induced Notch3 activation in PASMC. In addition, we showed that TGF-β1 significantly induced proliferation of PASMC, while pre-inhibition of Smad2/3 phosphorylation with SB431542 or silencing SphK1 using small interfering RNA in advance, or pre-blocking Notch3 pathway with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), attenuated TGF-β1-induced PASMC proliferation. Taken together, our study indicates that Smad2/3/SphK1/S1P/Notch3 pathway mediates TGF-β1-induced PASMC proliferation and suggests this pathway as a potential therapeutic target in the prevention and treatment of pulmonary hypertension.