Growth factor signalling in osteoarthritis

Osteoarthritis (OA) is one of the most common diseases, affecting more than 10% of populations and thus creating immense socioeconomic burden. The pathological changes of OA involve the entire joint, which is composed of multiple types of tissues and cells, exemplified by cartilage degradation, subchondral bone thickening, osteophyte formation, synovium inflammation and hypertrophy, and ligament degeneration. As joint homeostasis requires a complex network of growth factors to regulate anabolic and catabolic events, the dysregulation of growth factor signalling would have negative impacts on structure and function of multiple joint tissues and eventually lead to the onset and progression of OA. In this review, we will discuss TGF-β, NGF, Hedgehog and Wnt, the four growth factors which have received extensive attention in the field of OA and clinical/translational interrogation about their application in OA therapies.     

Knockdown of Gli1 by small-interfering RNA enhances the effects of BCNU on the proliferation and apoptosis of glioma U251 cells

Aims: The present study is to investigate the effect of the combination of small-interfering RNA (siRNA) treatment with bis-chloroethylnitrosourea (BCNU) on the proliferation and apoptosis of glioma cells. Methods: According to different treatments, glioma U251 cells were randomly divided into blank group, Lipofectamine group, siRNA-Gli1 group, BCNU group and combination group. After treatments, the morphology of U251 cells was visualized under the microscope. Afterwards, semi-quantitative real-time polymerase chain reaction and Western blotting were used to determine Gli1, Bcl-2, Bax and cyclin D1 mRNA levels and protein expression, respectively. MTT assay was used detect the proliferation of U251 cells, while flow cytometry was performed to determine cell apoptosis and cell cycle. Results: The combination of siRNA-Gli1 and BCNU caused more severe damages to U251 cell shapes compared with siRNA-Gli1 or BCNU alone. The combination of BCNU and siRNA-Gli1 altered mRNA level and protein expression of Bcl-2 and Bax, but not those of Gli1 and cyclin D1. The combination of siRNA-Gli1 and BCNU promoted U251 cell apoptosis. The combination of siRNA-Gli1 and BCNU enhanced the arrestment of U251 cells in G0/G1 phase. The combination of siRNA-Gli1 and BCNU significantly inhibited U251 cell proliferation. Conclusions: The present study demonstrates that combined treatment with siRNA-Gli1 and BCNU significantly inhibits the proliferation and promotes the apoptosis of glioma U251 cells, possibly by the up-regulation of Bax and the down-regulation of Bcl-2. The combination of siRNA-Gli1 and BCNU enhances the inhibition of cell cycles, but does not down-regulate the expression of cell cycle protein cyclin D1.     

Targeting of the Hedgehog/GLI and mTOR pathways in advanced pancreatic cancer,a phase 1 trial of Vismodegib and Sirolimus combination

Background/ObjectivesPreclinical data indicated a functional and molecular interaction between Hedgehog (HH)/GLI and PI3K-AKT-mTOR pathways promoting pancreatic ductal adenocarcinoma (PDAC). A phase I study was conducted of Vismodegib and Sirolimus combination to evaluate maximum tolerated dose (MTD) and preliminary anti-tumor efficacy.MethodsCohort I included advanced solid tumors patients following a traditional 3 + 3 design. Vismodegib was orally administered at 150 mg daily with Sirolimus starting at 3 mg daily, increasing to 6 mg daily at dose level 2. Cohort II included only metastatic PDAC patients. Anti-tumor efficacy was evaluated every two cycles and target assessment at pre-treatment and after a single cycle.ResultsNine patient were enrolled in cohort I and 22 patients in cohort II. Twenty-eight patients were evaluated for dose-limiting toxicities (DLTs). One DLT was observed in each cohort, consisting of grade 2 mucositis and grade 3 thrombocytopenia. The MTD for Vismodegib and Sirolimus were 150 mg daily and 6 mg daily, respectively. The most common grade 3–4 toxicities were fatigue, thrombocytopenia, dehydration, and infections. A total of 6 patients had stable disease. No partial or complete responses were observed. Paired biopsy analysis before and after the first cycle in cohort II consistently demonstrated reduced GLI1 expression. Conversely, GLI and mTOR downstream targets were not significantly affected.ConclusionsThe combination of Vismodegib and Sirolimus was well tolerated. Clinical benefit was limited to stable disease in a subgroup of patients. Targeting efficacy demonstrated consistent partial decreases in HH/GLI signaling with limited impact on mTOR signaling. These findings conflict with pre-clinical models and warrant further investigations.     

补脾益肠丸联合猴头菌提取物颗粒治疗溃疡性结肠炎的临床研究

目的探讨补脾益肠丸联合猴头菌提取物颗粒治疗溃疡性结肠炎的临床疗效。方法选取2017年2月—2018年1月在上海市嘉定区安亭医院治疗的溃疡性结肠炎患者82例,根据用药的差别分为对照组(41例)和治疗组(41例)。对照组口服猴头菌提取物颗粒,3g/次,3次/d;治疗组在对照组的基础上口服补脾益肠丸,6g/次,3次/d。两组患者均经过4周治疗。观察两组患者临床疗效,同时比较治疗前后两组患者中医证候积分、结肠镜积分、Sutherland DAI积分及C反应蛋白(CRP)、白细胞介素-17(IL-17)、IL-23、IL-10和IL-13水平。结果治疗后,对照组临床有效率为80.49%,显著低于治疗组的97.56%,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者中医证候积分、结肠镜积分、Sutherland DAI积分均显著下降(P0.05),且治疗组这些评分明显低于对照组(P0.05)。治疗后,两组CRP、IL-17、IL-23水平均显著降低(P0.05),而IL-10、IL-13水平显著升高(P0.05),且治疗组这些血清炎性因子水平明显好于对照组(P0.05)。结论补脾益肠丸联合猴头菌提取物颗粒治疗溃疡性结肠炎可有效改善患者临床症状,降低机体炎症反应,促进肠黏膜修复。