Search

Highlights: [•] Blockade of BAFF reversed dysregulation of T-cell survival and apoptosis. [•] BAFF up-regulated OPN secretion in B cells. [•] OPN induced imbalance of T-cell survival and apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs (miRNAs) have been shown to be important regulators in the pathogenesis of osteoarthritis (OA). The objective of this study was to determine the expression levels of miR-483, miR-483*, their host gene (Igf2) and other cytokines in a murine model of OA. The expression of miR-483 was significantly up-regulated in old mouse and in all of the operation groups, particularly the group assessed 1 week after surgery. The expression of miR-483* was significantly increased in the old mouse group and the group assessed 5 weeks after surgery. The expression of miR-483 was negatively correlated with the expression of (mRNA) Bmp7 and TgfB and positively correlated with Mmp13 by Pearson correlation analysis, while miR-483* was positively correlated with Il1B. Surprisingly, there was no correlation between the expression of either miR-483 or miR-483* and Igf2. This study shows that the expression of miR-483 and miR-483* is up-regulated in murine OA. These data suggest that miR-483 and miR-483* may play critical roles in early and later pathogenesis of OA, respectively, without the involvement of their host gene Igf2. [Copyright &y& Elsevier]

Abstract: MicroRNAs (miRNAs) are endogenous noncoding RNAs that downregulate gene expression by inhibiting translation or promoting mRNA degradation. Although over one-third of miRNAs are located within the intronic regions of transcription units, the expression of such “intron-derived” (or “intronic”) miRNAs and their relationship with their host gene remain a mystery. Here, we show that miR-483-5p, which is located within the second intron of the insulin-like growth factor (Igf2) gene, is downregulated in mouse Hepa1–6 cells in a direct correlation with the Igf2 transcript by chromeceptin, an inhibitor of Igf2 at the transcriptional level. Furthermore, miR-483-5p overexpression and knockdown regulates the suppressor of cytokine signalling 3 (Socs3) and Igf2 mRNAs, respectively. Finally, Socs3, a key putative leptin-resistant factor in obesity, is identified as a direct target of miR-483-5p. These data suggest that miR-483-5p can be coexpressed together with its host gene, Igf2, and revealed the link between this miRNA and the IGF2 growth factor. In addition, these observations not only provide supporting evidence for the codependent expression of intronic miRNAs and their host genes in vitro, but also give insight into the role of miR-483-5p in metabolism regulation and tumourigenesis. [ABSTRACT FROM AUTHOR]

Objectives Defects in Tyro3/Axl/Mer signaling may lead to impaired phagocytosis of apoptotic cells, eventually contributing to the development of autoimmune disease. The association of TAM signaling with several autoimmune disease has been investigated, but it remains unclear in primary Sjögren's syndrome. Therefore, the aim of this study was to evaluate the level of TAM signaling in primary Sjögren's syndrome with its clinical significance. Methods Real-Time Polymerase Chain Reaction was used to determine the mRNA expression of Mer, Tyro-3, Axl, Gas6, and Protein S in Peripheral Blood Mononuclear Cell from 43 pSS and 46 control. The Enzyme-Linked Immunosorbent Assay method was used to test plasma levels of soluble TAM signaling from those individuals, and the relationship of their levels with clinical characteristic was evaluated. Results The mRNA expression levels of Tyro-3, Axl were decreased in pSS patients. When considering the plasma level, increased levels of soluble Mer was observed with statistically significant difference. Soluble Mer levels were positively correlated with IgG levels ( r = 0.53, P < 0.01), Erythrocyte Sedimentation Rate levels ( r = 0.44, P < 0.01) and Sjögren's Syndrome Disease Activity Index ( r = 0.48, P < 0.01). And the levels of soluble Mer in patients with the presence of SSA/SSB were higher than those without SSA/SSB. Conclusions The plasma levels of sMer were increased in pSS patients, which was associated with inflammatory response and disease activity. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • H19 and miR-675 expression was upregulated in OGD/R-treated cardiomyocytes. • H19/miR-675 regulated OGD/R-induced cardiomyocyte viability and apoptosis. • H19/miR-675 regulated OGD/R-induced inflammation and oxidative stress. • PPARα partially mediated the effects of the H19/miR-675 axis. • H19/miR-675/PPARα axis regulated myocardial I/R injury in vivo. Abstract Increasing evidence has indicated that lncRNAs and miRNAs play important roles in the pathogenesis of myocardial ischemic and reperfusion (I/R) injury. This study investigated the potential roles and underlying molecular mechanisms of lncRNA H19 and H19-derived miR-675 in regulating myocardial I/R injury in vitro and in vivo. The results showed that expression of H19 and H19-derived miR-675 was upregulated in cardiomyocytes exposed to oxygen-glucose deprivation and reperfusion. Knockdown of H19 increased cell viability, reduced cell apoptosis, decreased inflammatory cytokines (IL-1β, TNF-α and IL-6), inhibited oxidative stress, downregulated p-IκB-α and p-p65, and upregulated expression of Nrf2 and HO-1. All of these effects were partly reversed by overexpression of miR-675. Furthermore, we found that PPARα was a target gene of miR-675 and that H19 negatively regulated PPARα expression via miR-675. By inhibiting PPARα, the biological effects of miR-675 or H19 inhibition on cellular functions (apoptosis, inflammation and oxidative stress) were at least partially reversed. Moreover, knockdown of H19 significantly reduced infarct size, increased left ventricular systolic pressure, and decreased left ventricular end-diastolic pressure in a mouse model of myocardial I/R. Taken together, these data indicate that H19 inhibition protects the heart against myocardial I/R injury, which may be partly attributed to regulation of the miR-675/PPARα axis. [ABSTRACT FROM AUTHOR]

Rexinoids are powerful ligands that bind to retinoid-X-receptors (RXRs) and show great promise as therapeutics for a wide range of diseases, including cancer. However, only one rexinoid, bexarotene (Targretin TM) has been successfully transitioned from the bench to the clinic and used to treat cutaneous T-cell lymphoma (CTCL). Our goal is to develop novel potent rexinoids with a less untoward side effect profile than bexarotene. To this end, we have synthesized a wide array of rexinoids with EC 50 values and biological activity similar to bexarotene. In order to determine their suitability for additional downstream analysis, and to identify potential candidate analogs for clinical translation, we treated human CTCL cells in culture and employed microarray technology to assess gene expression profiles. We analyzed twelve rexinoids and found they could be stratified into three distinct categories based on their gene expression: similar to bexarotene, moderately different from bexarotene, and substantially different from bexarotene. Surprisingly, small changes in the structure of the bexarotene parent compound led to marked differences in gene expression profiles. Furthermore, specific analogs diverged markedly from our hypothesis in expression of genes expected to be important for therapeutic promise. However, promoter analysis of genes whose expression was analyzed indicates general regulatory trends along structural frameworks. Our results suggest that certain structural motifs, particularly the basic frameworks found in analog 4 and analog 9 , represent important starting points to exploit in generating additional rexinoids for future study and therapeutic applications. [ABSTRACT FROM AUTHOR]

Notch1 signaling regulates B and T lymphocyte development and also in vitro promotes antibody secretion upon B cell activation. However, it is still unclear about the role of Notch1 in antibody production upon in vitro and in vivo mixture lymphocytes activation. We first showed that Notch1 expressed in LPS-activated CD19 hi B cells and CD19 cre mediated Notch1 knock-down in LPS-activated B cells. Furthermore, we demonstrated that Notch1 knock-down in B cells reduced antibody production in LPS-stimulated B cells but did not affect antibody production in LPS-stimulated splenocytes and in experimental allergic encephalomyelitis (EAE) mice. Importantly, Notch1 ligands Dll1 and Jag1 expressed in B cells and pre-coated Notch1 protein promotes Notch1-knocked down B cells to produce antibody in LPS-stimulated B cells suggesting that Notch1 in other cells may promote antibody production by binding its ligands Dll1 and Jag1 in B cells. Together, our results suggest that both Notch1 and its ligands in B cells play an important role in antibody production. [ABSTRACT FROM AUTHOR]

Abstract: Cardiac hypertrophy is a primary predictor of progressive heart disease that often results in heart failure. Growing evidence has demonstrated that microRNAs (miRNAs) play a critical role in regulating cardiac hypertrophy. This study was designed to evaluate the effect of miR-328 on cardiac hypertrophy and the potential molecular mechanisms. We found that transgenic overexpression of miR-328 in the heart induced cardiac hypertrophy in mice, which was accompanied by reduced SERCA2a level increased intracellular calcium concentration and calcineurin protein level, and enhanced NFATc3 nuclear translocation. However, normalization of miR-328 level by its antisense chemically modified with locked nucleic acid (LNA-antimiR-328) reversed the changes. Forced expression of miR-328 resulted in cardiomyocyte hypertrophy in cultured neonatal rat ventricular cells, which was accompanied by downregulation of SERCA2a expression and activation of the calcineurin/NFATc3 signaling pathway. These changes were abolished by LNA-antimiR-328. We validated the SERCA2a as a direct target for miR-328. MiR-328 expression was upregulated in cardiomyocyte treated with isoproterenol (ISO) to induce hypertrophy; while knockdown of miR-328 attenuated the hypertrophic responses. The level of miR-328 was significantly elevated in a mouse model of hypertrophy by thoracic aortic banding (TAC). Consistently, SERCA2a was downregulated, whereas calcineurin were upregulated, and NFATc3 nuclear translocation was enhanced. In contrast, hypertrophy in these mice was significantly alleviated when treated with miR-328 antisense. MiR-328 promotes cardiac hypertrophy by targeting SERCA2a. Our study therefore uncovered a novel molecular mechanism for cardiac hypertrophy and indicated miR-328 as a potential therapeutic target for this cardiac condition. [Copyright &y& Elsevier]

Abstract: The present study aimed to study the mechanisms by which low dose arsenic trioxide (As2O3) reduces multidrug resistance. The potential influence of As2O3 on cytotoxicity was examined by methyl thiazolyl tetrazolium (MTT) assay and the intracellular mean fluorescence intensity (MFI) of Adriamycin (ADM) was examined by flow cytometry. The gene expression of mdr1 mRNA was determined by RT-PCR. The change of cellular expression levels of drug resistant-related proteins, including P-gp, bcl-2, Topo-II, and GST-π, were measured by Western-blotting or immunocytochemistry assay. Data showed As2O3 at non-cytotoxic concentration (2μM) significantly increased the cytotoxicity of ADM on K562/A02 cells. Cotreatment of As2O3 and ADM significantly increased the ADM MFI than ADM alone (P <0.01). Following pretreatment of K562/A02 cells with As2O3, the expression of Topo-II was increased while the expression of GST-π and bcl-2 was decreased. No obvious alternation of expression of mdr1 mRNA or P-gp was observed. Thus, low dose As2O3 partially reduced drug resistance to ADM in K562/A02 cells via multiple mechanisms, which selectively inhibited the efflux pump GST-π but not P-gp, as well as modulated the expression of MDR-related proteins such as Topo-II and bcl-2, in line with previous studies. In conclusions: The effect of As2O3 on reducing MDR may have wide clinical application in chemotherapy regimens for leukemia. [Copyright &y& Elsevier]