FGF6 enhances muscle regeneration after nerve injury by relying on ERK1/2 mechanism.

BACKGROUND: Severe peripheral nerve injury leads to skeletal muscle atrophy and impaired limb function that is not sufficiently improved by existing treatments. Fibroblast growth factor 6 (FGF6) is involved in tissue regeneration and is dysregulated in denervated rat muscles. However, the way that FGF6 affects skeletal muscle repair after peripheral nerve injury has not been fully elucidated. METHODS: In this study, we investigated the role of FGF6 in the regeneration of denervated muscles using myoblast cells and an in vivo model of peripheral nerve injury. RESULTS: FGF6 promoted the viability and migration of C2C12 and primary myoblasts in a dose-dependent manner through FGFR1-mediated upregulation of cyclin D1. Low concentrations of FGF6 promoted myoblast differentiation through FGFR4-mediated activation of ERK1/2, which upregulated expression of MyHC, MyoD, and myogenin. FGFR-1, FGFR4, MyoD, and myogenin were not upregulated when FGF6 expression was inhibited in myoblasts by shRNA-mediated knockdown. Injection of FGF6 into denervated rat muscles enhanced the MyHC-IIb muscle fiber phenotype and prevented muscular atrophy. CONCLUSION: These findings indicate that FGF6 reduces skeletal muscle atrophy by relying on the ERK1/2 mechanism and enhances the conversion of slow muscle to fast muscle fibers, thereby promoting functional recovery of regenerated skeletal muscle after innervation.

Meta-analysis of the association between SCARB1 polymorphism and fasting blood lipid levels.

Studies have shown that the scavenger receptor class B type 1 (SCARB1) rs5888 polymorphism impacts fasting blood lipid levels differently in men and women. A meta-analysis and statistical tests was therefore performed to determine the relationship between the rs5888 polymorphism and lipid levels in men and women. Twelve studies with 12,147 subjects were selected for this study. In a dominant model, the CT+TT genotype group had lower triglyceride levels than the CC group in men (standardized mean difference (SMD): -0.11; 95% confidence interval (CI): -0.21 to -0.02; P = 0.016; I2 = 51.5%). No statistical differences were detected in women. Subgroup analysis of different racial groups revealed significant correlation between the SCARB1 rs5888 polymorphism and higher high-density lipoprotein cholesterol (HDL-C) levels (SMD: 0.15; 95% CI: 0.08 to 0.21; P ≤ 0.001; I2 = 0%) and lower triglyceride levels (SMD: -0.16; 95% CI: -0.26 to -0.04; P = 0.013; I2 = 60.6%) in non-Asian men. No evidence of heterogeneity was observed when eliminating outlier studies, and no publication bias was detected. This meta-analysis suggests the SCARB1 rs5888 polymorphism is associated with higher HDL-C and lower triglyceride levels in non-Asian men.

Targeting bromodomain-containing protein 4 (BRD4) benefits rheumatoid arthritis.

We aimed to explore the effects of bromodomain-containing protein 4 (BRD4) inhibition on tumor necrosis factor (TNF)-α-stimulated human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) behavior and the therapeutic implications using BRD4 inhibitor JQ1 were explored in vivo. The levels of interleukin (IL)-1ß, IL-6, IL-17 and IL-18 in cultural supernatants from TNFα-stimulated RA-FLS were measured by ELISA. RA-FLS migration and invasion in vitro were investigated using wound healing and Matrigel assay. Expression of signaling pathway proteins was measured by Western blot. The in vivo effects of BRD4 inhibitor JQ1 were elucidated using collagen-induced arthritis (CIA) mice. We found BRD4 silencing reduced the secretion of IL-1ß, IL-6, IL-17 and IL-18 from TNFα-stimulated human RA-FLS. Downregulation of BRD4 inhibited FBS-induced migration and invasion of human RA-FLS. BRD4 silencing decreased the phosphorylation of c-Jun and activation of NFκB in TNFα-stimulated RA-FLS. In vivo, BRD4 inhibitor JQ1 reduced the inflammatory response, autoantibody production and joint damage of CIA model. Our data suggest for the first time that BRD4 inhibition has anti-inflammatory property in RA.

Meta-analysis of the outcomes of intramedullary nailing and plate fixation of humeral shaft fractures.

OBJECTIVE: The purpose of this study is to compare the outcomes of intramedullary nailing and plate fixation in the treatment of humeral shaft fractures using meta-analysis. METHODS: PubMed, MEDLINE, EMBASE, the Cochrane Controlled Clinical Trials Register (CCTR) databases were searched for studies that investigated the efficacy of intramedullary nailing and plate fixation in the management of humeral shaft fractures. Delayed healing rate, nonunion, postoperative infection and radial nerve paralysis were key outcomes of interest. Data were searched within the time period of July 1990 through September 2012. The statistical software RevMan 5.0 was used to analyze the statistical significance of the results. RESULTS: Total 459 cases of patients in 10 literature, including 231 cases of plate group and 228 cases of the intramedullary nailing groups were collected. The results of meta-analysis showed that delayed healing rate of humeral shaft fractures was lower in plate fixation compared with intramedullary nailing (RR = 2.64, 95% CI (1.08, 6.49), P < 0.05). No statistically significant difference in nonunion, postoperative infections, radial nerve paralysis and other complications was identified between nailing and plate fixation groups (P > 0.05). CONCLUSIONS: In general, the effect size of intramedullary nailing may be comparable to that of plate fixation in the terms of nonunion, postoperative infections, radial nerve paralysis. The only slightly difference was identified in the event of delayed healing rate.

A new analytical potential energy surface for the singlet state of He2H+.

The analytic potential energy surface (APES) for the exchange reaction of HeH(+) (X(1)Σ(+)) + He at the lowest singlet state 1(1)A(∕) has been built. The APES is expressed as Aguado-Paniagua function based on the many-body expansion. Using the adaptive non-linear least-squares algorithm, the APES is fitted from 15 682 ab initio energy points calculated with the multireference configuration interaction calculation with a large d-aug-cc-pV5Z basis set. To testify the new APES, we calculate the integral cross sections for He + H(+)He (v = 0, 1, 2, j = 0) → HeH(+) + He by means of quasi-classical trajectory and compare them with the previous result in literature.

Some insights into mechanism for binding and drug resistance of wild type and I50V V82A and I84V mutations in HIV-1 protease with GRL-98065 inhibitor from molecular dynamic simulations.

The single mutations I50V, V82A and I84V are considered as the key residue mutations of the HIV-1 protease drug resistance. The rank of calculated absolute binding free energies using MM-PBSA method is in excellent agreement with experimental result. Enthalpic and entropic balance is analyzed to explain resistance in I50V and V82A having a higher entropic contribution than in the wild type (WT) complex. The reduced van der Waals energy explains the drug resistance of I84V to GRL-98065. Detailed binding free energies between GRL-98065 and individual protein residues are calculated to provide insights into the inhibitor-protein binding and drug-resistant mechanism. Our results show I50V and V82A have larger structural changes than I84V compared with WT.

[Effect of acute coronary microembolization on microvascular injury and myocardial endothelin-1 levels].

OBJECTIVE: To investigate the effect of coronary microemboliation (CME) on coronary microvascular injury and myocardial endothelin-1 (ET-1) level. METHODS: CME was induced in 10 miniswines by selective infusion of microspheres (45 microm) into left anterior descending artery (LAD). The ET-1 level in coronary sinus was measured with radioimmunoassay. The microvascular integrity indicator CFR was measured by Doppler flow wire in LAD at baseline and after infusion of microspheres. RESULT: Compared to the baseline, CFR decreased significantly with different doses of microspheres. ET-1 level increased significantly with doses of 5 x 10(4) and peaked with 10 x 10(4), and progressively decreased from doses of 12 x 10(4) to 15 x 10(4) microspheres. There was negative correlation between ET-1 and CFR (r=-0.31, P=0.02). CONCLUSION: The extent of microvascular injury is not linearly related to the extent of microembolization, but it is closely associated with myocardial ET-1 level.