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X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), a cellular stress response pathway involved in maintaining protein homeostasis in the endoplasmic reticulum (EnR). While the role of XBP1 in UPR is well-characterised, emerging evidence suggests its involvement in endocrine resistance in breast cancer. The transcriptional activity of spliced XBP1 (XBP1s) is a major component of its biological effects, but the targets of XBP1s in estrogen receptor (ER)-positive breast cancer are not well understood. Here, we show that the expression of miR-378 and PPARGC1B (host gene of miR-378) is downregulated during UPR. Using chemical and genetic methods, we show that XBP1s is necessary and sufficient for the downregulation of miR-378 and PPARGC1B. Our results show that overexpression of miR-378 significantly suppressed cell growth, colony formation, and migration of ER-positive breast cancer cells. Further, we found that expression of miR-378 sensitised the cells to UPR-induced cell death and anti-estrogens. The expression of miR-378 and PPARGC1B was downregulated in breast cancer, and higher expression of miR-378 is associated with better outcomes in ER-positive breast cancer. We found that miR-378 upregulates the expression of several genes that regulate type I interferon signalling. Analysis of separate cohorts of breast cancer patients showed that a gene signature derived from miR-378 upregulated genes showed a strong association with improved overall and recurrence-free survival in breast cancer. Our results suggest a growth-suppressive role for miR-378 in ER-positive breast cancer where downregulation of miR-378 by XBP1 contributes to endocrine resistance in ER-positive breast cancer. [ABSTRACT FROM AUTHOR]

The polarization of CD4+ T cells into different T helper subsets is an important process in many diseases, including asthma. Part of the adaptive immune system, T cells are responsible for propagating signals to alert and prime the immune system. MicroRNAs (miRNAs) are small non-coding RNAs that act on numerous targets in the cell to regulate a variety of cellular processes, including roles in T cell polarization. In this study, we aimed to identify genes dysregulated in peripheral blood mononuclear cells from individuals with asthma. Moreover, we sought to examine miRNAs that may regulate the candidate genes and explore their functional relationship. Utilizing a focused gene array, we identified the serum/glucocorticoid-regulated kinase 1 (SGK1) gene to be upregulated in circulating peripheral blood mononuclear cells, which included T cells, from individuals with asthma. Several miRNAs were bioinformatically identified to target SGK1, but miR-19a was the only screened candidate that negatively correlated to SGK1 expression. Further analysis of the miR-19a-SGK1 relationship showed a negative correlation in CD4+ T cells in situ and direct binding in vitro during T cell activation. Moreover, we observed a negative correlation of miR-19a and SGK1 during early type 2 polarization of CD4+ naïve human T cells. Thus, we suggest that miR-19a has a role in binding and regulating SGK1 transcript levels during T cell development. [ABSTRACT FROM AUTHOR]

Background: Alpha-actinins are located in the skeletal muscle Z-line and form actin-actin cross-links. It belongs to a highly conserved family of actin-binding proteins- the spectrin superfamily, which also contains the spectrins and dystrophin. Mammalian skeletal muscle has two isoforms: alpha-actinins-2 and alpha-actinins-3. However, the response of alpha-actinins to exercise training is little understood. This study examined the effects of 8 weeks of resistance training on muscle mass, ACTN3 (alpha-actinins-3) gene expression levels and fiber type composition in the flexor hallucis longus (FHL) muscle. Methods: Forty five female Sprague-Dawley rats (Initial body mass: 169.25±9gr age: 3 month) were obtained and assigned to a control (C; n=18) or exercise training (T; n=22) and pilot (P; n=5) groups. The resistance training consisted of climbing a ladder carrying a load suspended from the tail and the weight increased progressively. Real-time PCR and Immunohistochemistry techniques were used to measure gene expression levels and myosin heavy chain (MyHC) composition, respectively. Results: Following 8 weeks of training, we observed significant increase in absolute muscle mass in FHL (P=0.01). Results showed that no significant difference was found in ACTN3 gene expression levels between training and control groups (P=0.852 respectively). Also, Pearson coefficient didn't indicated any significant relationships in gene expression and Fiber type IIX in response to resistance training in FHL (r=0.12). Conclusion: However, resistance training effects on sarcomeric proteins development, these results showed no effect of resistance training on alpha-actinins-3 levels. Although alpha-actinins-3 has an important function to produce and progress of force in sarcomere, but didn't changed significantly in response to resistance training. [ABSTRACT FROM AUTHOR]