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Pancreatic cancer is the deadliest malignancy of the digestive system and is the seventh most common cause of cancer-related deaths worldwide. The incidence and mortality of pancreatic cancer continue to increase, and its 5-year survival rate remains the lowest among all cancers. N6-methyladenine (m6A) is the most abundant reversible RNA modification in various eukaryotic messenger and long noncoding RNAs and plays crucial roles in the occurrence and development of cancers. However, the role of m6A in pancreatic cancer remains unclear. The present study aimed to explore the role of m6A and its regulators in pancreatic cancer and assess its underlying molecular mechanism associated with pancreatic cancer cell proliferation, invasion, and metastasis. Reduced expression of the m6A demethylase, fat mass and obesity-associated protein (FTO), was responsible for the high levels of m6A RNA modification in pancreatic cancer. Moreover, FTO demethylated the m6A modification of praja ring finger ubiquitin ligase 2 (PJA2), thereby reducing its mRNA decay, suppressing Wnt signaling, and ultimately restraining the proliferation, invasion, and metastasis of pancreatic cancer cells. Altogether, this study describes new, potential molecular therapeutic targets for pancreatic cancer that could pave the way to improve patient outcome., Graphical abstract, N6-methyladenine (m6A) RNA modification is upregulated in pancreatic cancer, and its demethylase FTO is responsible for this. FTO demethylates the m6A modification of PJA2, thereby promoting its expression. In turn, PJA2 inhibits activation of the oncogenic Wnt signal pathway. Taken together, the FTO-m6A-PJA2/Wnt pathway restrains the progression of pancreatic cancer.

Summary A small subgroup of embryonic stem cells (ESCs) exhibit molecular features similar to those of two-cell embryos (2C). However, it remains elusive whether 2C-like cells and 2C embryos share similar epigenetic features. Here, we map the genome-wide profiles of histone H3K4me3 and H3K27me3 in 2C-like cells. We found that the majority of genes in 2C-like cells inherit their histone status from ESCs. Among the genes showing a switch in their histone methylation status during 2C-like transitions, only a small number acquire 2C-embryo epigenetic signatures. In contrast, broad H3K4me3 domains display extensive loss in 2C-like cells. Most of the differentially expressed genes display decreased H3K4me3 and H3K27me3 levels in 2C-like cells, whereas de novo H3K4me3 deposition is closely linked with the expression levels of upregulated 2C-specific genes. Taken together, our study reveals the unique epigenetic profiles of 2C-like cells, facilitating the further exploration of totipotency in the future., Graphical Abstract, Highlights • 2C-like embryonic stem cells (ESCs) display intermediate epigenetic profiles • Bivalent genes are preserved in 2C-like ESCs • Broad H3K4me3 domains display extensive loss in 2C-like ESCs • Highly upregulated 2C-specific genes are correlated with increased H3K4me3 levels, Le et al. show that the majority of genes in 2C-like ESCs inherit their histone status from ESCs. Among the genes showing a switch in their histone methylation status during 2C-like transitions, only a small number acquire a 2-cell-embryo epigenetic signatures.

Air pollution is known to trigger and exacerbate many respiratory diseases. The interaction between respiratory microbiome and host plays a significant role in maintaining airway immune homeostasis and health. Emerging evidence has revealed the associations of disturbances in the airway microbiome with air pollution and respiratory disease. However, respiratory microbiome has been an undervalued player in progressions of respiratory disease caused by air pollution. In this review, we summarize the current research advances with respect to the effects of air pollution on respiratory microbiome, then discuss the underlying mechanisms of air pollution induction of dysbiosis in respiratory microbiota and its links to respiratory diseases. This work may be helpful to deepening understanding the relationships between exposure, microbiome and airway disease and discovering new preventive and therapeutic strategies for air pollution-mediated respiratory disease.

MicroRNAs (miRNAs/miRs) are key components of regulatory networks in cancer. Although miR‑190b is an important tumor‑related miRNA, its role in pancreatic cancer has not been extensively investigated. The aim of the present study was to examine the expression of miR‑190b in pancreatic cancer cell lines and tissues and evaluate its effects on cancer progression. Reverse transcription‑quantitative PCR (RT‑qPCR) analysis was used to measure miR‑190b expression levels in human pancreatic cancer cell lines and tissues, and the association between miR‑190b expression and clinicopathological characteristics was assessed. An in vitro Transwell invasion assay and an in vivo metastasis formation assay were performed using pancreatic cancer cells. The effect of miR‑190b on pancreatic cancer cell proliferation was evaluated using a Cell Counting Kit‑8 assay based on an in vivo xenograft mouse model. The direct targets of miR‑190b were predicted using bioinformatics tools and were validated through western blotting and luciferase reporter assays. Pancreatic cancer cell lines and tissues were found to express lower levels of miR‑190b compared with normal cells and adjacent non‑tumor tissues. Furthermore, high expression of miR‑190b was found to be positively correlated with low T, N and American Joint Committee on Cancer classifications, and predicted a good prognosis. miR‑190b was shown to exert suppressive effects on cancer cell proliferation, invasion and metastasis. In addition, it was also found that miR‑190b directly targeted myocyte enhancer factor 2C (MEF2C) and transcription factor 4 (TCF4) in pancreatic cancer, thus serving as a tumor suppressor and a predictor of good prognosis in pancreatic cancer. The immunohistochemistry and RT‑qPCR results indicated that the MEF2C and TCF4 expression levels were negatively correlated with the miR‑190b expression levels. The findings of the present study highlight the value of miR‑190b as a novel target candidate for pancreatic cancer diagnosis and therapy.

Chronic obstructive pulmonary disease (COPD) is a multifactorial and heterogeneous disease that creates public health challenges worldwide. The underlying molecular mechanisms of COPD are not entirely clear. In this study, we aimed to identify the critical genes and potential molecular mechanisms of COPD by bioinformatic analysis. The gene expression profiles of lung tissues of COPD cases and healthy control subjects were obtained from the Gene Expression Omnibus. Differentially expressed genes were analyzed by integration with annotations from Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, followed by construction of a protein‐protein interaction network and weighted gene coexpression analysis. We identified 139 differentially expressed genes associated with the progression of COPD, among which 14 Hub genes were identified and found to be enriched in certain categories, including immune and inflammatory response, response to lipopolysaccharide and receptor for advanced glycation end products binding; in addition, these Hub genes are involved in multiple signaling pathways, particularly hematopoietic cell lineage and cytokine‐cytokine receptor interaction. The 14 Hub genes were positively or negatively associated with COPD by wgcna analysis. The genes CX3CR1, PTGS2, FPR1, FPR2, S100A12, EGR1, CD163, S100A8 and S100A9 were identified to mediate inflammation and injury of the lung, and play critical roles in the pathogenesis of COPD. These findings improve our understanding of the underlying molecular mechanisms of COPD.

It has been reported that lncRNA myocardial infarction-associated transcript (MIAT) facilitated the pathological development in angiotensin II (AngII)-induced cardiac hypertrophy. Nevertheless, the underlying mechanism of MIAT involved in cardiac hypertrophy is largely unknown. In this study, AngII-treated cardiomyocytes were applied as a cardiac hypertrophy model in vitro. The expressions of MIAT and miR-93 were detected by qRT-PCR. The protein levels of toll-like receptor 4 (TLR4), atrial natriuretic factor (ANF), beta-myosin heavy chain (β-MHC), phosphoinositide-3 kinase (PI3K), protein kinase B (Akt), phosphorylated Akt (p-Akt), mammalian target of rapamycin (mTOR), and phosphorylated mTOR (p-mTOR) were determined by western blot. Luciferase reporter assay and RNA immunoprecipitation (RIP) were performed to explore the relationship between MIAT, TLR4 and miR-93. Hypertrophic response was assessed by measuring cell surface area and quantifying the expressions of ANF and β-MHC. The results demonstrated that MIAT was upregulated and miR-93 was downregulated in AngII-treated cardiomyocytes. MIAT functioned as a molecular sponge of miR-93 in cardiomyocytes. Additionally, TLR4 was identified as a target of miR-93 and MIAT promoted TLR4 expression by sponging miR-93. MIAT knockdown decreased cell surface area and the expression levels of ANF and β-MHC in AngII-treated cardiomyocytes by modulating miR-93. Moreover, enforced expression of TLR4 partially reversed the protective effect of miR-93 overexpression on AngII-induced cardiac hypertrophy. Furthermore, MIAT knockdown or miR-93 overexpression inactivated the PI3K/Akt/mTOR pathway via TLR4 in AngII-induced cardiac hypertrophy. Taken together, these data suggested that MIAT knockdown inhibited AngII-induced cardiac hypertrophy by regulating miR-93/TLR4 axis, highlighting a promising therapy target for cardiac hypertrophy.

BACKGROUND AND OBJECTIVES Ischemic post-conditioning (PostC) has been demonstrated as a novel strategy to harness nature's protection against myocardial ischemia-reperfusion (I/R). Hypercholesterolemia (HC) has been reported to block the effect of PostC on the heart. Angiotensin II type-1 (AT1) modulators have shown benefits in myocardial ischemia. The present study investigates the effect of a novel inhibitor of AT1, azilsartan in PostC of the heart of normocholesterolemic (NC) and HC rats. MATERIALS AND METHODS HC was induced by the administration of high-fat diet to the animals for eight weeks. Isolated Langendorff's perfused NC and HC rat hearts were exposed to global ischemia for 30 min and reperfusion for 120 min. I/R-injury had been assessed by cardiac hemodynamic parameters, myocardial infarct size, release of tumor necrosis factor-alpha troponin I, lactate dehydrogenase, creatine kinase, nitrite in coronary effluent, thiobarbituric acid reactive species, a reduced form of glutathione, superoxide anion, and left ventricle collagen content in normal and HC rat hearts. RESULTS Azilsartan post-treatment and six episodes of PostC (10 sec each) afforded cardioprotection against I/R-injury in normal rat hearts. PostC protection against I/R-injury was abolished in HC rat hearts. Azilsartan prevented the HC-mediated impairment of the beneficial effects of PostC in I/R-induced myocardial injury, which was inhibited by L-N5-(1-Iminoethyl)ornithinehydrochloride, a potent inhibitor of endothelial nitric oxide synthase (eNOS). CONCLUSION Azilsartan treatment has attenuated the HC-induced impairment of beneficial effects of PostC in I/R-injury of rat hearts, by specifically modulating eNOS. Azilsartan may be explored further in I/R-myocardial injury, both in NC and HC conditions, with or without PostC.

Dysregulation of miR-29 has been revealed in multiple diseases, but its role in the development of hypertension and vascular endothelial dysfunction has not been defined. Here, we found that, compared with the wild-type (WT) Wistar rats, miR-29b was robustly upregulated in spontaneously hypertensive rats (SHRs), while CTRP6 was distinctly downregulated. There were two miRNA-responding-elements (MREs) for miR-29 in the 3′-UTR of CTRP6 mRNA, and the luciferase activity assay revealed that miR-29b directly targeted CTRP6 mRNA. Intraventricular injection was applied to deliver the miR-29b mimic or miR-29b inhibitor (4 mg/kg) into SHRs once two weeks from 10th week. Downregulation of miR-29b could increase serum CTRP6 content in SHRs, decrease the arterial systolic pressure, reduce serum concentrations of Ang II and ET-1, and enhance serum NO content. Meanwhile, we demonstrated that inhibition of miR-29b increased the phosphorylation of ERK1/2 to activate PPARγ, an inducer of Ang II. Finally, miR-29b expression was manipulated in, and CTRP6 recombinant protein was applied to incubate with the primary aortic endothelial cells. Inhibition of miR-29b increased CTRP6 expression, improved cell proliferation and migration, suppressed secretion of Ang II and ET-1, and decreased ROS accumulation and LDH release, displaying a similar effect to the CTRP6 recombinant protein. Moreover, the CTRP6 recombinant protein could antagonize the suppressive effect of miR-29b on activation of the ERK/PPARγ axis and function of aortic endothelial cells. In conclusion, miR-29b antagonism can alleviate Ang II-induced hypertension and vascular endothelial dysfunction through activating the CTRP6/ERK/PPARγ axis.

Background Plenty of lncRNAs and microRNAs have been identified to be critical mediators in the progression of atherosclerosis (AS). Myocardial infarction-associated transcript (MIAT) were aberrantly high expressed and closely associated with the pathogenesis of AS. However, its molecular mechanism has not been well characterized. Methods The expression patterns of MIAT and microRNA-181b (miR-181b) in clinical samples and cells were measured by RT-qPCR assays. Luciferase reporter assay and RIP assays were used to manifest the potential interaction between MIAT, miR-181b and signal transducer and activator of transcription 3 (STAT3). Cell Counting Kit-8 (CCK-8), Propidium Iodide (PI) staining, Terminal dexynucleotidyl transferase(TdT)-mediated dUTP nick end labeling (TUNEL) and western blot assays were carried out to detect cell proliferation, cell cycle distribution, apoptosis, and STAT3 protein level, respectively. Results MIAT expression was up-regulated and miR-181b expression was down-regulated in AS patients serum and oxidized low-density lipoprotein (ox-LDL) induced AS cells model. MIAT facilitated cell proliferation, accelerated cell cycle progression and inhibited apoptosis in ox-LDL-induced AS cell lines, while this effect was partly reversed by miR-181b overexpression. Moreover, MIAT enhanced STAT3 expression through sequestering miR-181b as a molecular sponge. Furthermore, MiR-181b hindered cell growth, induced cell cycle arrest and promoted apoptosis by directly targeting STAT3. Conclusion MIAT performed as an induction factor of AS by regulating miR-181b/STAT3 axis in ox-LDL-induced AS cell lines, offering a new insight into the potential application of MIAT in AS treatment.

Background and aims Inconsistent findings have been reported on the association between high-sensitivity C-reactive protein (hs-CRP) and mortality risk. The objective of this meta-analysis was to investigate the association of elevated baseline hs-CRP levels with all-cause, cardiovascular, and cancer mortality risk in the general population. Methods PubMed and Embase were systematically searched for studies published from inception to October 2016. Prospective observational studies were eligible if they reported the effects of elevated baseline hs-CRP levels on cancer-related, cardiovascular or all-cause mortality in the general population. The pooled adjusted risk ratio (RR) with 95% confidence interval (CI) comparing the highest to the lowest category of hs-CRP levels was used as association measures. Results A total of 83,995 participants from 14 studies were identified. When comparing the highest to the lowest category of hs-CRP levels, the pooled RR was 1.25 (95% CI 1.13-1.38) for cancer-related mortality, 2.03 (95% CI 1.65-2.50) for cardiovascular mortality, and 1.75 (1.55-1.98) for all-cause mortality, respectively. Subgroup analysis showed that the effect of elevated hs-CRP levels on cancer-related mortality was observed in men (RR 1.26; 95% CI 1.11-1.43) but not in women (RR 1.03; 95% CI 0.83-1.27). Conclusions Elevated hs-CRP levels can independently predict risk of all-cause, cardiovascular mortality in the general population. However, the gender differences in the predictive role of hs-CRP on cancer mortality should to be further investigated.

Pancreatic cancer is usually diagnosed in the advanced stages and is sensitive to only few therapies. The forkhead box L1 (FOXL1) and protein phosphatase 2A (PP2A) have been recognized to be tumor suppressive in human pancreatic cancers. In the present study, we co-expressed the two tumor suppressive molecules with a '2A peptide' linker, which guaranteed the two molecules were transcribed into one mRNA, whereas they were translated into two separate proteins, in pancreatic cancer Panc‑1 cells, and investigated the inhibition of the two molecules on the proliferation and migration of Panc‑1 cells. Results demonstrated that, either overexpression of FOXL1 or PP2A via adenovirus significantly inhibited the proliferation of Panc‑1 cells, whereas promoted apoptosis in such cells. Moreover, the co-expression of both FOXL1 and PP2A exerted synergistic antitumor effect in Panc‑1 cells, with significantly higher proliferation inhibition and tumor induction. In addition, we found that the overexpressed FOXL1 promoted the TNF‑related apoptosis‑inducing ligand (TRAIL), whereas the overexpressed PP2A downregulated the phosphorylation of c‑MYC. The co-expression of FOXL1 and PP2A presented both functions in Panc‑1 cells. In conclusion, the adenovirus‑mediated co‑expression of FOXL1 and PP2A with the 2A peptide linker exterts synergistic suppression of pancreatic cancer cells via inhibiting the growth and promoting apoptosis of cancer cells, probably via upregulating TRAIL and reducing the phosphorylation of MYC.