Understanding the roles of N6-methyladenosine writers, readers and erasers in breast cancer

Breast cancer is believed to be driven by epigenetic regulation of genes implicated in cell proliferation, survival, and differentiation. Recently, aberrant N6-methyladenosine (m6A) decorations turned up as crucial epigenetic regulator for malignant breast cancer, which may serve as new targets for breast cancer treatment. Here we briefly outline the functions of m6A and its regulatory proteins, including m6A “writers,” “readers,” and “erasers” on RNA life fate, recapitulate the latest breakthroughs in understanding m6A modification and its regulatory proteins, and the underlying molecular mechanisms that contribute to the carcinogenesis and the progression of breast cancer, so as to provide potential epigenetic targets for diagnosis, treatment and prognosis in breast cancer

Update on the association between interleukin-12 p40 gene polymorphism and risk of psoriasis: A meta-analysis

Background: Psoriasis is a common inflammatory skin disease with a strong genetic component. Interleukin (IL)-12 is one of the key cytokines in immune regulation and is overexpressed in psoriasis. The aim of this study was to update the meta-analysis for the association between IL-12 p40 gene (IL-12B) rs3212227 polymorphism and risk of psoriasis. Methods: We performed a literature search from inception to December 2014. Review Manger 5.2 was used for meta-analysis. Odds ratios and their 95% confidence intervals were calculated under five genotype models: C versus A, CC + AC versus AA, CC versus AA + AC, CC versus AA, and CC versus AC. In addition, subgroup analyses were performed by ethnicity. Results: Nine studies involving 6520 psoriasis patients and 11,150 healthy controls were included. Two included studies were newly published studies, which were not analyzed in previous meta-analyses. The overall meta-analysis showed the significant association between psoriasis and IL-12B rs3212227 in all the genotype models, indicating that carriers of genotype CC or allele C had a less risk of psoriasis. Meanwhile, subgroup analyses showed this association existed in not only European, but also Asian populations. Conclusion: This meta-analysis demonstrated that IL-12B rs3212227 was associated with the risk of psoriasis in European and Asian populations

Searching for synergistic bronchodilators and novel therapeutic regimens for chronic lung diseases from a traditional Chinese medicine, Qingfei Xiaoyan Wan.

Classical Chinese pharmacopeias describe numerous excellent herbal formulations, and each prescription is an outstanding pool of effective compounds for drug discovery. Clarifying the bioactivity of the combined mechanisms of the ingredients in complex traditional Chinese medicine formulas is challenging. A classical formula known as Qingfei Xiaoyan Wan, used clinically as a treatment for prevalent chronic lung disease, was investigated in this work. A mutually enhanced bioactivity-guided ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) characterization system was proposed, coupled with a dual-luciferase reporter assay for β2AR-agonist cofactor screening. Arctiin, arctigenin, descurainoside and descurainolide B, four lignin compounds that showed synergistic bronchodilation effects with ephedrine, were revealed. The synergistic mechanism of arctigenin with the β2ARagonist involved with the reduction of free Ca2+ was clarified by a dual-luciferase reporter assay for intracellular calcium and the Ca2+ indicator fluo-4/AM to monitor changes in the fluorescence. The relaxant and contractile responses of airway smooth muscle are regulated by crosstalk between the intracellular cAMP and calcium signaling pathways. Our data indicated the non-selective βAR agonist ephedrine as the principal bronchodilator of the formula, whereas the lignin ingredients served as adjuvant ingredients. A greater understanding of the mechanisms governing the control of these pathways, based on conventional wisdom, could lead to the identification of novel therapeutic targets or new agents for the treatment of asthma and COPD

Oncoprotein HBXIP enhances HOXB13 acetylation and co-activates HOXB13 to confer tamoxifen resistance in breast cancer

Abstract Background Resistance to tamoxifen (TAM) frequently occurs in the treatment of estrogen receptor positive (ER+) breast cancer. Accumulating evidences indicate that transcription factor HOXB13 is of great significance in TAM resistance. However, the regulation of HOXB13 in TAM-resistant breast cancer remains largely unexplored. Here, we were interested in the potential effect of HBXIP, an oncoprotein involved in the acceleration of cancer progression, on the modulation of HOXB13 in TAM resistance of breast cancer. Methods The Kaplan-Meier plotter cancer database and GEO dataset were used to analyze the association between HBXIP expression and relapse-free survival. The correlation of HBXIP and HOXB13 in ER+ breast cancer was assessed by human tissue microarray. Immunoblotting analysis, qRT-PCR assay, immunofluorescence staining, Co-IP assay, ChIP assay, luciferase reporter gene assay, cell viability assay, and colony formation assay were performed to explore the possible molecular mechanism by which HBXIP modulates HOXB13. Cell viability assay, xenograft assay, and immunohistochemistry staining analysis were utilized to evaluate the effect of the HBXIP/HOXB13 axis on the facilitation of TAM resistance in vitro and in vivo. Results The analysis of the Kaplan-Meier plotter and the GEO dataset showed that mono-TAM-treated breast cancer patients with higher HBXIP expression levels had shorter relapse-free survivals than patients with lower HBXIP expression levels. Overexpression of HBXIP induced TAM resistance in ER+ breast cancer cells. The tissue microarray analysis revealed a positive association between the expression levels of HBXIP and HOXB13 in ER+ breast cancer patients. HBXIP elevated HOXB13 protein level in breast cancer cells. Mechanistically, HBXIP prevented chaperone-mediated autophagy (CMA)-dependent degradation of HOXB13 via enhancement of HOXB13 acetylation at the lysine 277 residue, causing the accumulation of HOXB13. Moreover, HBXIP was able to act as a co-activator of HOXB13 to stimulate interleukin (IL)-6 transcription in the promotion of TAM resistance. Interestingly, aspirin (ASA) suppressed the HBXIP/HOXB13 axis by decreasing HBXIP expression, overcoming TAM resistance in vitro and in vivo. Conclusions Our study highlights that HBXIP enhances HOXB13 acetylation to prevent HOXB13 degradation and co-activates HOXB13 in the promotion of TAM resistance of breast cancer. Therapeutically, ASA can serve as a potential candidate for reversing TAM resistance by inhibiting HBXIP expression

The MS/MS data in both ESI modes and the identification of the compounds in QFXY possessing synergic effects on the β₂AR-signaling pathway.

<p>The MS/MS data in both ESI modes and the identification of the compounds in QFXY possessing synergic effects on the β₂AR-signaling pathway.</p

UPLC/Q-TOF-MS and synergic β₂AR activation-bioactivity analysis of QFXY.

<p>(A) The UPLC/UV chromatograms of QFXY observed at 254 nm; (B, C) The TIC chromatograms in (B) the positive and (C) negative ESI modes; (D) The bioactivity chromatograms obtained using the dual-luciferase reporter assay system for β₂AR activation; (E) The mutually enhanced bioactivity chromatograms obtained using the dual-luciferase reporter assay system for β₂AR activation.</p

The bronchodilator effect of QFXY on an atomized His-induced guinea pig asthma model (A) and the guinea pig tracheal muscle relaxant test (B).

<p>The values are presented as the mean ± SEM (<i>n</i> = 5). *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001, compared to the control group; ^#<i>P</i><0.05, middle dose QFXY compared to the EE group.</p

The synergistic mechanism of Atg and Eph in reducing the intracellular calcium concentration, asevaluated by the dual luciferase reporter assay system (A), confocal microscopy fluorescence intensity analysis (B) and image observations (C).

<p>The white arrowindicates a significant [Ca²⁺]_i intensity decrease in a singleHBSMCcell. The values are presented as the mean ± SEM (<i>n</i> = 5). *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001, compared to the model group (M); ^##<i>P</i><0.01, compared to the Eph group.</p