Background Breast cancer (BC) displays striking genetic, epigenetic and phenotypic diversity. N 6 -methyladenosine (m6A) in mRNA has emerged as a crucial epitranscriptomic modification that controls cancer self-renewal and cell fate. However, the key enzymes of m6A expression and function in human breast carcinogenesis remain unclear. Methods The expression of m6A methylases (METTL3, METTL14 and WTAP) and demethylases (FTO and ALKBH5) were analyzed by using ONCOMINE and The Cancer Genome Atlas databases and in 36 pairs of BC and adjacent non-cancerous tissue. The level of m6A in BC patients was detected by ELISA, and the function of m6A was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay and transwell assay. The database of bc-GenExMiner v4.0, Kaplan-Meier Plotter and cBioPortal were queried for correlation, mutation and prognosis analysis of BC. Results The m6A methylases and demethylases were dysregulated in several major malignant tumors. Specifically, the expression of all m6A methylases was reduced in BC as compared with normal controls, but the demethylase ALKBH5 was induced in ONCOMINE databases and confirmed in clinical patients. METTL14 expression was positively correlated with METTL3 expression, and both showed high expression in normal breast-like and luminal-A and -B BC. Functionally, reducing m6A expression by overexpressing METTL14 and/or knockdown of ALKBH5 could inhibit breast cell viability, colony formation and cell migration. Furthermore, Kaplan-Meier, meta-analysis and univariate Cox assay showed that the expression of m6A members including METTL3, METTL14, WTAP and FTO but not their gene mutation and amplification, was tightly associated with cancer progression and poor survival. Conclusions Changes of m6A modulators reduced m6A may promote tumorigenesis and predict poor prognosis in BC. Electronic supplementary material The online version of this article (10.1186/s12885-019-5538-z) contains supplementary material, which is available to authorized users.

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Increased oxidative stress and cardiac inflammation have been implicated in the pathogenesis of diabetic cardiomyopathy (DCM). We previously found that a novel chalcone derivative, L6H9, was able to reduce LPS-induced inflammatory response in macrophages. This study was designed to investigate its protective effects on DCM and the underlying mechanisms. H9C2 cells were cultured with DMEM containing 33 mmol/L of glucose in the presence or absence of L6H9. Pretreatment with L6H9 significantly reduced high glucose-induced inflammatory cytokine expression, ROS level increase, mitochondrial dysfunction, cell apoptosis, fibrosis, and hypertrophy in H9c2 cells, which may be mediated by NF-κB inhibition and Nrf2 activation. In mice with STZ-induced diabetes, oral administration of L6H9 at 20 mg/kg/day for 8 weeks significantly decreased the cardiac cytokine and ROS level, accompanied by decreasing cardiac apoptosis and hypertrophy, and, finally, improved histological abnormalities and fibrosis, without affecting the hyperglycemia. L6H9 also attenuated the diabetes-induced NF-κB activation and Nrf2 decrease in diabetic hearts. These results strongly suggest that L6H9 may have great therapeutic potential in the treatment of DCM via blockage of inflammation and oxidative stress. This study also provides a deeper understanding of the regulatory role of Nrf2 and NF-κB in DCM, indicating that they may be important therapeutic targets for diabetic complications.

Obesity is strongly associated with the cause of structural and functional changes of the heart in both human and animal models. Oxidative stress and inflammation play a critical role in the development of obesity-induced cardiac disorders. Curcumin is a natural product from Curcuma Longa with multiple bioactivities. In our previous study, in order to reach better anti-inflammatory and anti-oxidant dual activities, we designed a new mono-carbonyl curcumin analog, Y20, via the structural modification with both trifluoromethyl and bromine. This study was designed to investigate the protective effects of Y20 on obesity-induced cardiac injury and its underlying mechanisms. In high fat diet–fed rats, oral administration of Y20 at 20 mg/kg or curcumin at 50 mg/kg significantly decreased the cardiac inflammation and oxidative stress and eventually improved the cardiac remodeling by mitigating cardiac disorganization, hypertrophy, fibrosis and apoptosis. Y20 at 20 mg/kg showed comparable and even stronger bioactivities than curcumin at 50 mg/kg. The beneficial actions of Y20 are closely associated with its ability to increase Nrf2 expression and inhibit NF-κB activation. Taken together, these results suggest that Y20 may have a great therapeutic potential in the treatment of obesity-induced cardiac injury using Nrf2 and NF-κB as the therapeutic targets for treating obesity-related disorders.

Background FUN14 domain-containing 1 (FUNDC1), as a novel member of mitochondria-associated endoplasmic reticulum (ER) membranes associates with mitochondrial division and mitophagy. However, the expression profile and functional roles of FUNDC1 remain largely unclear in human cancer biology, including breast cancer (BC). Methods Immunohistochemistry and western blot analysis were used to determine the expression of FUNDC1 and BMI1 polycomb ring finger oncogene (BMI1). CCK8, cell counting and transwell assays were used to analyze cell proliferation, migration and invasion, respectively. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to detect the transcriptional regulation of Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1). The prognostic merit of NFATC1 expression was assessed by Kaplan-Meier assay. Findings Immunohistochemistry revealed strong immunostaining for FUNDC1 in cytoplasmic and nuclear membrane distribution in BC tissues as compared with normal breast epithelium. Kaplan–Meier survival analysis showed worse outcome for BC patients with high FUNDC1 expression. In vitro assay of gain- and loss-of-function of FUNDC1 suggested that FUNDC1 could stimulate BC cell proliferation, migration and invasion. Furthermore, elevated FUNDC1 level promoted Ca 2+ cytosol influx from ER and extracellular, as well as NFATC1 nuclear translocation and activity. Nuclear NFATC1 bound to the BMI1 gene promoter and transcriptionally upregulated its expression. Notably, BMI1 overexpression could rescue the loss of function of FUNDC1. Co-expression of FUNDC1 and BMI1 in BC patients predicted worse prognosis than without either expression. Interpretation FUNDC1 might promote BC progression by activating the Ca 2+ –NFATC1–BMI1 axis. This pathway may be promising for developing multiple targets for BC therapy.