Tubastatin alleviates epidural fibrosis via negatively targeting TGFß/PI3K/Akt pathway.

Epidural fibrosis (EF) is a chronic, progressive and severe disease. Histone deacetylase 6 (HDAC6) regulates biological signals and cell activities by deacetylating lysine residues and participates in TGF-ß-induced epithelial-mesenchymal transition (EMT). Nevertheless, the effect and mechanism of HDAC6 in EF remain unclear. To investigate the effect and mechanism of HDAC6 inhibition on repressing epidural fibrosis. HDAC6 expression and α-smooth muscle actin (α-SMA) in normal human tissue and human EF tissue were assessed by quantitative real-time PCR (qRT-PCR) and western blotting. Human fibroblasts were treated with TGF-ß ± HDAC6 inhibitors (Tubastatin) and fibrotic markers including collagen I, collagen III, α-SMA and fibronectin were assessed using western blotting. Then TGFß1 receptor (TGFß1-R), PI3K and Akt were analyzed using qRT-PCR and western blotting. Rats were undergone laminectomy± Tubastatin (intraperitoneally injection; daily for 7 days) and epidural scar extracellular matrix (ECM) expression was gauged using immunoblots. Increasing HDAC6 expression was associated with α-SMA enrichment. Tubastatin remarkably restrained TGF-ß-induced level of collagen and ECM deposition in human fibroblasts, and the discovery was accompanied by decreased PI3K and Akt phosphorylation. Moreover, Tubastatin also inhibited TGF-ß-mediated HIF-1α and VEGF expression. In the epidural fibrosis model, we found that Tubastatin weakened scar hyperplasia and collagen deposition, and effectively inhibited the process of epidural fibrosis. These results indicated that Tubastatin inhibited HDAC6 expression and decreased TGF-ß/ PI3K/ Akt pathway that promotes collagen and ECM deposition and VEGF release, leading reduction of myofibroblast activation. Hence, Tubastatin ameliorated epidural fibrosis development.

Promotion of healthy adipose tissue remodeling ameliorates muscle inflammation in a mouse model of sarcopenic obesity.

A large subset of elders is classified as having sarcopenic obesity, a prevalence of obesity in combination with sarcopenia which places an aging population at the risk of adverse health consequences from both conditions. However, its complex etiology has restrained the development of effective therapeutic strategies. Recent progress has highlighted that the mode by which adipose tissue (AT) remodels is a determinant of metabolic health in the context of obesity. Healthy AT remodeling confers metabolic protection including insulin-sensitizing and anti-inflammatory effects to non-adipose tissues including skeletal muscle. Here, we employed a doxycycline-inducible adipocyte Hif1a knockout system to evaluate the muscle-protective effects associated with HIF1α inactivation-induced healthy AT remodeling in a model of sarcopenic obesity. We found that adipocyte HIF1α inactivation leads to improved AT metabolic health, reduced serum levels of lipids and pro-inflammatory cytokines, and increase of circulating adipokine (APN) in ovariectomized obese mice fed with obesogenic high-fat diet (HFD). Concomitantly, muscle inflammation is evidently lower in obese OVX mice when adipocyte HIF1α is inactivated. Furthermore, these protective effects against muscle inflammation can be mimicked by the administration of adiponectin receptor agonist AdipoRon. Collectively, our findings underscore the importance of AT metabolic health in the context of concurrent sarcopenia and obesity, and promotion of healthy AT remodeling may represent a new therapeutic strategy to improve muscle health in sarcopenic obesity.

Conservative Treatments for Lumbar Disc Herniation at L3-4 or L4-5 Were More Likely to Fail When Ipsilateral Foraminal Stenosis Was Present at the Caudally Adjacent Segment.

BACKGROUND: Conservative treatments are important in lumbar disc herniation (LDH), but predictors for poor outcomes are unclear. METHODS: Consecutive patients with unilateral single-level LDH at L3-4 or L4-5 were enrolled. Baseline clinical data were collected, and lumbar spine magnetic resonance imaging was evaluated. Foraminal stenosis was evaluated using Lee's approach and further categorized as absence (grade 0 and 1) or presence (grade 2 or 3). Each patient underwent conservative treatments (oral meloxicam and dexamethasone, corset, back extension exercise, physiotherapy, and manual therapy) for 6 weeks. Conservative treatments were defined as failed if a patient underwent surgery within 6 weeks or reported poor recovery at 6-week follow-up. Multivariate logistic regressions were used to examine the associations of failed conservative treatments with baseline characteristics and magnetic resonance imaging findings. RESULTS: The study included 222 patients (mean age 45.5 ± 9.8 years). Of patients, 48 (21.6%) had concurrent ipsilateral foraminal stenosis at the caudal segment, and conservative treatments failed in 39 (17.6%). At baseline, patients with LDH and caudal foraminal stenosis were older (50.79 ± 6.14 years vs. 44.10 ± 10.13 years, P < 0.001), had greater leg pain (7.06 ± 1.17 vs. 6.39 ± 1.40, P = 0.003), and had a higher rate of positive straight leg raising test (54.2% vs. 33.3%, P = 0.008) than patients without caudal foraminal stenosis. In multivariate regression, failure of conservative treatments was associated with positive straight leg raising test (odds ratio 2.26, P = 0.046), and caudal foraminal stenosis (odds ratio 3.20, P = 0.007). CONCLUSIONS: In the presence of caudal foraminal stenosis and positive SLR test, conservative treatments were more likely to fail in patients with LDH.

Diosgenin inhibits Wnt/ß-catenin pathway to regulate the proliferation and differentiation of MG-63 cells.

Dioscorea opposita Thunb has the effect of anti-osteoporosis, but whether its active ingredient diosgenin (DIO) has an anti-osteoporosis effect is unknown. The purpose of this study is to investigate the effect of DIO on the proliferation and differentiation of MG-63 cells. MG-63 cells were treated with different concentrations of DIO (0.001, 0.01, 0.1 and 1 µM) or 20 mM Wnt/ß-catenin signaling agonist-LiCl, and then their cell cycle and viability were analyzed by flow cytometry and 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), respectively. To investigate osteoblast differentiation, alizarin red staining and ultraviolet spectrophotometer were used to determine the number of calcified nodules and the activity of alkaline phosphatase (ALP), respectively. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting were used to detect the expressions of proliferation-related, osteogenic-related and Wnt/ß-catenin signal pathway-related factors. After the cells were treated with low-concentration (0.001 or 0.01 µM) DIO, cell viability was significantly increased and the proportion of cells in S phase was increased. In addition, low-concentration DIO could significantly increase the expression of Ki67, proliferating cell nuclear antigen (PCNA), osteopontin (OPN), and osteocalcin (BGP), promote osteoblast differentiation, and suppress the expression of ß-catenin, Runx2 and cyclinD1. However, high concentrations of DIO showed the opposite effect. Low-concentration DIO obviously reversed the effect of LiCl on decreasing the number of calcified nodules and inhibiting the expression of OPN and BGP in cells. Low-concentration DIO might promote the proliferation and differentiation of MG-63 cell by inhibiting the Wnt/ß-catenin signal pathway.

[Short-term effectiveness of polyaxial locking plate for fixation of femoral neck fracture in middle-aged and elderly patients].

Objective: To evaluate the feasibility and short-term effectiveness of polyaxial locking plate for fixation of femoral neck fracture in the middle-aged and elderly patients. Methods: A retrospective analysis was made on the clinical data of 13 patients with femoral neck fracture undergoing fixation with polyaxial locking plates between September 2013 and June 2015 (group A) and 13 patients with femoral neck fracture undergoing fixation with three cannulated screws in the same period (group B). There was no significant difference in gender, age, side, cause of injury, Garden type, type of fracture position, type of Pauwels angle, Singh index, time between injury and operation, and preoperative complications between 2 groups ( P>0.05). The femoral neck shortening at 1 year postoperatively, and fracture nonunion, femoral head necrosis, and Harris hip score at last follow-up were compared between 2 groups. Results: The follow-up time was (19.23±3.98) months in group A and (18.00±3.61) months in group B, showing no significant difference between 2 groups ( t=2.063, P=0.417). No femoral head necrosis occurred in group A, but head necrosis occurred in 1 case of group B, and hemiarthroplasty was performed. There was no significant difference in the rate of femoral head necrosis between 2 groups ( χ2=0.000, P=1.000). Bone union was obtained in the other patients of 2 groups. The Harris hip score of group A (85.23±2.95) was significantly higher than that of group B (81.92±3.64) at last follow-up ( t=2.064, P=0.018). No infection or internal fixation failure occurred in 2 groups. One case had pain at the outer thigh at 1 month after operation in group A, but pain relief was achieved at 3 months after operation. At 1 year after operation, no femoral neck shortening occurred in group A, but degree I, II, and III femoral neck shortening was observed in 3, 2, and 8 cases of group B, respectively, showing significant difference between 2 groups ( Z=-4.714, P=0.000). Conclusion: Although fixation with polyaxial locking plate for femoral neck fracture in the middle-aged and elderly patients has similar femoral head necrosis rate to fixation with cannulated screws, it has advantages in preventing neck shortening and improving hip joint function after operation.

[Unilateral pedicle screw fixation and transforaminal lumbar interbody fusion through paraspinal muscle approach for recurrent lumbar disc herniation combined with lumbar instability].

OBJECTIVE: To explore the clinical effects of unilateral pedicle screw fixation and transforaminal lumbar interbody fusion (TLIF) through paraspinal muscle approach for recurrent lumbar disc herniation combined with lumbar instability. METHODS: A total of 35 patients with recurrent lumbar disc herniation combined with lumbar instability were treated between March 2008 and May 2010, including 15 patients managed by the paraspinal muscle approach with unilateral pedicle screw fixation and transforaminal lumbar interbody fusion (TLIF) (unilateral fixation group) and 20 patients by the posterior midline approach with bilateral pedicle screw fixation and posterior lumbar interbody fusion (bilateral fixation group). Operation time and intraoperative blood loss were observed, preoperative and postoperative JOA score and VAS score in low back pain and legs pain, the interbody fusion condition were compared between two groups. RESULTS: All patients were followed up from 6 to 30 months with an average 16.8 months. All clinical symptoms had obviously improved postoperatively. X-rays showed good interbody fusion (only 1 case did not obtain fusion in bilateral fixation group) without cage displacement or settlement and implant loosening or breakage. There was significant difference in operation time and the intraoperative blood loss between two groups (P < 0.05). Postoperative JOA score had obviously decreased than preoperative one (P < 0.05). At 1 week after surgery, there was significant difference in VAS score of low back pain between two groups and there was no significant difference in VAS score of legs pain between two groups (P > 0.05); at final follow-up, there was no significant difference in VAS score of low back pain and legs pain between two groups (P > 0.05). CONCLUSION: Two methods both can obtain satisfactory effect in treating recurrent lumbar disc herniation combined with lumbar instability. Through the paraspinal muscle approach with unilateral pedicle screw fixation and TLIF has advantages of smaller surgical incision, shorter operation time, less intraoperative blood loss, faster relief in low back pain after operation, etc.