MiR-223 promotes cardiomyocyte apoptosis by inhibiting Foxo3a expression.

OBJECTIVE: MicroRNAs (miRs) are proven to possess diversified functions in the pathogenesis of cardiac diseases. The current study is designed aiming at determining the effect of miR-223 on oxidative stress induced apoptosis in cardiomyocytes. MATERIALS AND METHODS: Mouse model of myocardial infarction (MI) was constructed, and endogenous level of miR-223 in the border zone of infarcted heart tissues was determined. Primarily cultured cardiomyocytes were exposed to H2O2 treatment to mimic the oxidative stress stimulation. Multiple approaches including quantitative reverse transcription polymerase chain reaction (qRT-PCR), cell viability assay, luciferase assay, Western blot assay and flow cytometry assay were employed to determine its expression, function and mechanism in apoptosis. RESULTS: MiR-223 expression was significantly upregulated in the border zone of infarcted heart ventricular tissues and in cardiomyocytes treated with H2O2. Overexpression of miR-223 in cardiomyocytes promoted apoptosis, whereas inhibition of endogenous miR-223 protected cardiomyocytes from oxidative stress induced apoptosis. MiR-223 directly targets the 3'untranslated region (UTR) of Foxo3a mRNA. Overexpression of miR-223 inhibited Foxo3a protein expression, however, inhibition of miR-223 suppressed its expression. Silencing Foxo3a using small interfering RNA (siRNA) mimicked the effect of miR-223, indicating its functional significance. CONCLUSIONS: MiR-223 is an important regulator of cardiomyocyte apoptosis under oxidative stress. Inhibition of the miR-223/Foxo3a signaling axis may be a potential therapeutic strategy for cardiac injuries.

Efficacy and safety of sublingual immunotherapy with Dermatophagoides farinae drops in pre-school and school-age children with allergic rhinitis

Background: The safety and efficacy of sublingual immunotherapy (SLIT) have been confirmed by many studies. However, in China, the research on efficacy and safety in young and older children with allergic rhinitis (AR) is still rare. Objective: The aim of this retrospective study is to evaluate the efficacy and safety of SLIT with Dermatophagoides farinae drops in pre-school and school-age children with AR. Methods: A total of 282 subjects aged 2-13 years with AR received a two-year course of sublingual immunotherapy along with pharmacotherapy. According to the age, patients were defined as the pre-school group (2-6 years old, n = 116) and school-age group (7-13 years old, n = 166). Total nasal rhinitis symptom scores (TNSS), visual analogue score (VAS) and total medication scores (TMS) were evaluated at four time points: baseline, after SLIT for half a year, one year and two years. The adverse events (AEs) were evaluated at each visit. Results: After two-year SLIT, the four rhinitis symptom scores, TNSS, VAS and TMS scores were significantly lower than baseline (all P < 0.05). The comparison of efficacy between one and two-year duration showed no significant difference in global clinical outcomes (all P > 0.05). In addition, there were no significant differences between the pre-school and school-age group in TNSS (all P > 0.05), VAS (all P > 0.05) and TMS scores (P > 0.05) after SLIT for half a year, one year and two years. No severe systemic AEs were reported. Conclusion: SLIT with D. farinae drops is clinically effective and safe in pre-school and school-age patients with house dust mites (HDMs)-induced AR (AU)

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Efficacy and safety of sublingual immunotherapy with Dermatophagoides farinae drops in pre-school and school-age children with allergic rhinitis.

BACKGROUND: The safety and efficacy of sublingual immunotherapy (SLIT) have been confirmed by many studies. However, in China, the research on efficacy and safety in young and older children with allergic rhinitis (AR) is still rare. OBJECTIVE: The aim of this retrospective study is to evaluate the efficacy and safety of SLIT with Dermatophagoides farinae drops in pre-school and school-age children with AR. METHODS: A total of 282 subjects aged 2-13 years with AR received a two-year course of sublingual immunotherapy along with pharmacotherapy. According to the age, patients were defined as the pre-school group (2-6 years old, n=116) and school-age group (7-13 years old, n=166). Total nasal rhinitis symptom scores (TNSS), visual analogue score (VAS) and total medication scores (TMS) were evaluated at four time points: baseline, after SLIT for half a year, one year and two years. The adverse events (AEs) were evaluated at each visit. RESULTS: After two-year SLIT, the four rhinitis symptom scores, TNSS, VAS and TMS scores were significantly lower than baseline (all P<0.05). The comparison of efficacy between one and two-year duration showed no significant difference in global clinical outcomes (all P>0.05). In addition, there were no significant differences between the pre-school and school-age group in TNSS (all P>0.05), VAS (all P>0.05) and TMS scores (P>0.05) after SLIT for half a year, one year and two years. No severe systemic AEs were reported. CONCLUSION: SLIT with D. farinae drops is clinically effective and safe in pre-school and school-age patients with house dust mites (HDMs)-induced AR.

Intensive training accelerates the recovery of motor functions following cerebral ischemia-reperfusion in MCAO rats.

OBJECTIVE: Cerebral ischemia-reperfusion is the major pathophysiological process in stroke and can cause severe and lasting sequel. However, an intensive exercise training can potentially effect a quick and efficient recovery. We used swimming training on rats with cerebral ischemia-reperfusion (CIR) and explore the underlying neuroprotective mechanism(s), including the effects of intensive training on the expression of semaphorin 3A (Sema3A) and its receptor Neuropilin-1 (NRP-1). MATERIALS AND METHODS: The middle cerebral artery occlusion/reperfusion (MCAO/R) model was established by inserting a thread into the middle cerebral artery of Sprague-Dawley (SD) rats, and randomly dividing into the control group and training groups for different training intensities. The control group and the sham group received no training. All the rats in various groups were further randomly divided into three sub-groups for different postoperative time points (3, 7, and 14 days after operation). The apoptosis and the expression of Sema3A and NRP-1 were analyzed using immunohistochemistry (IHC), RT-PCR, and Western blotting methods respectively. RESULTS: The intensive training resulted in significant neurological function improvements at all the time points after MCAO, compared to that in the control group (p<0.05), with training group 3 (highest training intensity) showing the most remarkable recovery. The Sema3A and NP-1 expressions were significantly lower than those of the control group at all the time points (p<0.05), with training group 3 having the lowest levels (best recovery). CONCLUSIONS: Intensive training can reduce cerebral damage after ischemia and reperfusion in rats, inhibit the MCAO-induced Sema3A and NRP-1 expression, and accelerate the restoring process of motor nerve functions.

TMEM2 inhibits hepatitis B virus infection in HepG2 and HepG2.2.15 cells by activating the JAK-STAT signaling pathway.

We have previously observed the downregulation of TMEM2 in the liver tissue of patients with chronic hepatitis B virus (HBV) infection and in HepG2.2.15 cells with HBV genomic DNA. In the present study, we investigated the role and mechanism of TMEM2 in HepG2 and HepG2.2.15 during HBV infection HepG2 and HepG2.2.15. HepG2 shTMEM2 cells with stable TMEM2 knockdown and HepG2 TMEM2 and HepG2.2.15 TMEM2 cells with stable TMEM2 overexpression were established using lentivirus vectors. We observed reduced expression of TMEM2 in HBV-infected liver tissues and HepG2.2.15 cells. HBsAg, HBcAg, HBV DNA, and HBV cccDNA levels were significantly increased in HepG2 shTMEM2 cells but decreased in HepG2 TMEM2 and HepG2.2.15 TMEM2 cells compared with naive HepG2 cells. On the basis of the western blotting results, the JAK-STAT signaling pathway was inhibited in HepG2 shTMEM2 cells but activated in HepG2 TMEM2 and HepG2.2.15 TMEM2 cells. In addition, reduced and increased expression of the antiviral proteins MxA and OAS1 was observed in TMEM2-silenced cells (HepG2 shTMEM2 cells) and TMEM2-overexpressing cells (HepG2 TMEM2 and HepG2.2.15 TMEM2 cells), respectively. The expression of Interferon regulatory factor 9 (IRF9) was not affected by TMEM2. However, we found that overexpression and knockdown of TMEM2, respectively, promoted and inhibited importation of IRF9 into nuclei. The luciferase reporter assay showed that IRF9 nuclear translocation affected interferon-stimulated response element activities. In addition, the inhibitory effects of TMEM2 on HBV infection in HepG2 shTMEM2 cells was significantly enhanced by pre-treatment with interferon but significantly inhibited in HepG2.2.15 TMEM2 cells by pre-treatment with JAK1 inhibitor. TMEM2 inhibits HBV infection in HepG2 and HepG2.2.15 by activating the JAK-STAT signaling pathway.

Interferon-ß gene-modified human bone marrow mesenchymal stem cells attenuate hepatocellular carcinoma through inhibiting AKT/FOXO3a pathway.

OBJECTIVE: This study aims to investigate the using of bone marrow mesenchymal stem cells (BMSCs) genetically engineered to produce interferon-ß (IFN-ß) as a gene delivery system to treat hepatocellular carcinoma (HCC) in vitro and in vivo. METHODS: To measure the effects on tumour cell growth in vitro, IFN-ß-producing BMSCs (BMSC/IFN-ß) were co-cultured with the HCC cell line HepG2 and Huh7. Enzyme-linked immunosorbent assay (ELISA) was used to detect the IFN-ß secretion in the BMSC culture condition medium (CM). The effect of BMSC/IFN-ß on HCC cells proliferation was examined both in vitro and in vivo by using MTT, colony formation assay, BrdU staining, cell cycle analysis, and xenografted NOD/SCID mouse tumour model. To examine the impact of BMSC/IFN-ß on the AKT/FOXO3a signalling, RT-PCR and western blotting were performed. RESULTS: The BMSC/IFN-ß cells can stably secrete high levels of IFN-ß. Both MTT and colony forming assay showed that HCC cells had a lower growth rate when cultured in BMSC/IFN-ß-CM as compared with that in BMSC/vector-CM or DMEM culture group. Co-culture with BMSC/IFN-ß-CM dramatically decreased the percentages of cells with incorporated BrdUrd. In BMSC/IFN-ß-CM-treated HCC cells, the proportion of G1-phase cells increased but it decreased in the S phase of the cell. The BMSC/IFN-ß inhibited HCC growth in NOD/SCID mice and proved the survival period of these mice. Compared with the control group, p21 and p27 expression of hepatoma cells increased, whereas cyclin D1 and phosphorylation of Rb expression decreased when co-cultured with BMSC/IFN-ß-CM. It was associated with suppression of Akt activity and enhanced transcriptional activity of FOXO3a. CONCLUSION: The IFN-ß gene-modified BMSCs can effectively inhibit the proliferation of HCC cells in vitro and in vivo through inhibiting AKT/FOXO3a pathway. These results indicate that BMSC/IFN-ß are a powerful anticancer cytotherapeutic tool for HCC.