Sodium selenite induces apoptosis and inhibits autophagy in human synovial sarcoma cell line SW982 in vitro.

The present study aimed to examine the effects of sodium selenite on the SW982 human synovial sarcoma cell line in relation to cell viability, apoptosis and autophagy. The results indicated that sodium selenite reduced cell viability and induced apoptosis by activating caspase­3 and members of the poly (ADP­ribose) polymerase and Bcl­2 protein families in SW982 cells. Furthermore, autophagy was also suppressed by sodium selenite treatment in SW982 cells, and apoptosis was upregulated in cells co­treated with sodium selenite and the autophagy inhibitor 3­methyladenine. By contrast, apoptosis was downregulated when sodium selenite was combined with rapamycin, an inducer of autophagy. The results indicated that autophagy may protect cells from the cytotoxicity of sodium selenite. The present study results demonstrated that sodium selenite induced apoptosis and inhibited autophagy and autophagy­protected cells from death by antagonizing sodium selenite­induced apoptosis in SW982 cells in vitro.

TRAIL gene 1595C/T polymorphisms contribute to the susceptibility and severity of intervertebral disc degeneration: a data synthesis.

BACKGROUND: Studies have investigated the correlation between tumor necrosis factor related apoptosis-inducing ligand (TRAIL) gene polymorphisms and the susceptibility and severity of intervertebral disc degeneration (IDD), but the results were inconsistent. To evaluate the specific relationship, we performed a meta-analysis to clarify the controversies. METHODS: Four databases were searched, and the pooled results were presented as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Three case-control studies from Han Chinese were included (565 cases and 427 controls). All the included studies reported TRAIL 1595C/T gene polymorphisms. The recessive model (CC vs. CT + TT) was the optimal model, which demonstrated a significant relationship between 1595C/T polymorphisms and increased IDD risk (OR = 2.18, 1.45 to 3.27, P = 0.000). No significant heterogeneity was found in the recessive model (I2 = 48.6%, P = 0.143). Patients with lower grade IDD had more genotypes or alleles including 1595TT genotype (grade II vs. grade III: OR = 2.12, 1.18 to 3.83, P = 0.012; grade III vs. grade IV: OR = 2.59, 1.29 to 5.22, P = 0.007) and 1595 T allele (grade II vs. grade III: OR = 1.91, 1.43 to 2.55, P = 0.000; grade II vs. grade IV: OR = 2.46, 0.94 to 1.76, P = 0.000). CONCLUSIONS: There is a significant relationship between 1595C/T polymorphisms and the susceptibility and severity of IDD in Han Chinese. Patients with lower grade IDD had higher frequency of the 1595TT genotype and 1595 T allele.

Methotrexate affects HMGB1 expression in rheumatoid arthritis, and the downregulation of HMGB1 prevents rheumatoid arthritis progression.

High-mobility group box 1 (HMGB1) is associated with the development of rheumatoid arthritis (RA). Recent studies have shown that methotrexate (MTX) may inhibit the expression of HMGB1. This study examined whether HMGB1 might be involved in the treatment of RA using MTX. Synovial tissues were collected from RA patients who were treated with MTX for at least 6 months (RA-MTX group, 7 cases) and from those without MTX treatment (RA-noMTX group, 7 cases). Additionally, patients with osteoarthritis (OA group, 7 cases) were used as controls. The expression and locations of HMGB1 in the tissues were detected using real-time PCR, western blot, and immunohistochemistry. Additionally, OA-fibroblast-like synoviocytes (FLSs) and RA-FLSs were isolated and cultured, and the expression of HMGB1 was reduced in these cells by transfection with HMGB1 siRNA. Cell proliferation, migration, and invasion abilities were detected. Furthermore, the effects of HMGB1 on matrix metalloproteinase (MMP)-2 and MMP-13 were measured using western blot analysis. At the tissue level, HMGB1 expression in synovial membrane did not differ significantly between the OA and RA-MTX groups, but was significantly lower in these groups than in the RA-noMTX group. In cell experiments, the cell doubling time in the RA-FLS HMGB1 siRNA group was significantly extended compared with that in the RA-FLS negative control (NC)-siRNA group. The amount of cell migration and invasion in the RA-FLS HMGB1 siRNA group was significantly lower compared with that in the NC-siRNA group; the MMP-2 and MMP-13 expression levels were also lower. These results showed that MTX reduced HMGB1 expression in RA synovial tissues, and through the downregulation of HMGB1 expression in tissues, MTX may slow disease progression of RA.

Acupuncture for musculoskeletal pain: A meta-analysis and meta-regression of sham-controlled randomized clinical trials.

The aims of this systematic review were to study the analgesic effect of real acupuncture and to explore whether sham acupuncture (SA) type is related to the estimated effect of real acupuncture for musculoskeletal pain. Five databases were searched. The outcome was pain or disability immediately (≤1 week) following an intervention. Standardized mean differences (SMDs) with 95% confidence intervals were calculated. Meta-regression was used to explore possible sources of heterogeneity. Sixty-three studies (6382 individuals) were included. Eight condition types were included. The pooled effect size was moderate for pain relief (59 trials, 4980 individuals, SMD -0.61, 95% CI -0.76 to -0.47; P < 0.001) and large for disability improvement (31 trials, 4876 individuals, -0.77, -1.05 to -0.49; P < 0.001). In a univariate meta-regression model, sham needle location and/or depth could explain most or all heterogeneities for some conditions (e.g., shoulder pain, low back pain, osteoarthritis, myofascial pain, and fibromyalgia); however, the interactions between subgroups via these covariates were not significant (P < 0.05). Our review provided low-quality evidence that real acupuncture has a moderate effect (approximate 12-point reduction on the 100-mm visual analogue scale) on musculoskeletal pain. SA type did not appear to be related to the estimated effect of real acupuncture.

Autophagy induction contributes to the resistance to methotrexate treatment in rheumatoid arthritis fibroblast-like synovial cells through high mobility group box chromosomal protein 1.

BACKGROUND: Rheumatoid arthritis fibroblast-like synovial cells (RA-FLS) show resistance to methotrexate (MTX) treatment. To better understand the mechanisms of this resistance, RA-FLS and osteoarthritis fibroblast-like synovial cells (OA-FLS) were isolated and exposed to MTX. We analyzed the autophagy induced by MTX in vitro and its relationship to apoptosis. METHODS: Cell viability was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was detected by flow cytometry and Western blot analysis. Autophagy was determined by transmission electron microscopy as well as Western blot analysis. The expression levels of Beclin-1, LC3, Akt, p-Akt, mammalian target of rapamycin (mTOR), p-mTOR, high mobility group box chromosomal protein 1 (HMGB1), and an 85 kDa caspase cleaved fragment of poly(ADP-ribose) polymerase were measured by Western blotting. RESULTS: MTX-induced apoptosis was increased in OA-FLS compared with RA-FLS. However, MTX stimulated the autophagy response in RA-FLS by inducing autophagosome formation, but not in OA-FLS. In RA-FLS, transfection with Beclin-1 small interfering RNA inhibited autophagy and increased susceptibility to MTX, which induces cell death. MTX upregulated autophagy through its ability to enhance the expression of HMGB1 and Beclin-1 rather than through the Akt/mTOR pathway. CONCLUSIONS: Autophagy induction contributes to resistance to MTX treatment in fibroblasts from patients with rheumatoid arthritis.