Mechanical and hypoxia stress can cause chondrocytes apoptosis through over-activation of endoplasmic reticulum stress

ObjectiveTo examine the role of mechanical force and hypoxia on chondrocytes apoptosis and osteoarthritis (OA)-liked pathological change on mandibular cartilage through over-activation of endoplasmic reticulum stress (ERS).MethodsWe used two in vitro models to examine the effect of mechanical force and hypoxia on chondrocytes apoptosis separately. The mandibular condylar chondrocytes were obtained from three-week-old male Sprague–Dawley rats. Flexcell 5000T apparatus was used to produce mechanical forces (12%, 0.5 Hz, 24 h vs 20%, 0.5 Hz, 24 h) on chondrocytes. For hypoxia experiment, the concentration of O₂ was down regulated to 5% or 1%. Cell apoptosis rates were quantified by annexin V and propidium iodide (PI) double staining and FACS analysis. Quantitative real-time PCR and western blot were performed to evaluate the activation of ERS and cellular hypoxia. Then we used a mechanical stress loading rat model to verify the involvement of ERS in OA-liked mandibular cartilage pathological change. Histological changes in mandibular condylar cartilage were assessed via hematoxylin & eosin (HE) staining. Immunohistochemistry of GRP78, GRP94, HIF-1α, and HIF-2α were performed to evaluate activation of the ERS and existence of hypoxia. Apoptotic cells were detected by the TUNEL method.ResultsTunicamycin, 20% mechanical forces and hypoxia (1% O₂) all significantly increased chondrocytes apoptosis rates and expression of ERS markers (GRP78, GRP94 and Caspase 12). However, 12% mechanical forces can only increase the apoptotic sensitivity of chondrocytes. Mechanical stress resulted in OA-liked pathological change on rat mandibular condylar cartilage which included thinning cartilage and bone erosion. The number of apoptotic cells increased. ERS and hypoxia markers expressions were also enhanced. Salubrinal, an ERS inhibitor, can reverse these effects in vitro and in vivo through the down-regulation of ERS markers and hypoxia markers.ConclusionWe confirmed that mechanical stress and local hypoxia both contributed to the chondrocytes apoptosis. Mechanical stress can cause OA-like pathological change in rat mandibular condylar cartilage via ERS activation and hypoxia existed in the meantime. Both mechanical forces and hypoxia can induce ERS and cause chondrocytes apoptosis only if the stimulate was in higher level. Salubrinal can protect chondrocytes from apoptosis, and relieve OA-liked pathological change on mandibular condylar cartilage under mechanical stress stimulation.     

血糖波动与2型糖尿病大血管并发症

随着糖尿病患病率的攀升,糖尿病并发症发病率也大大升高,人们也越来越重视糖尿病并发症尤其是大血管并发症的预防及控制。国内外大型研究均显示,血糖波动是大血管病变的危险因素,其导致大血管病变的发生、发展机制及相关的治疗策略也逐渐被深入研究。目前,血糖波动已成为评价2型糖尿病大血管并发症的重要指标之一。该文对血糖波动及其与大血管并发症的相关研究进行综述,为2型糖尿病患者的临床治疗提供参考。     

PD-1／PD—Ls与免疫相关疾病的研究进展

PD-1是CD28分子家族的成员之一,表达于多种免疫细胞表面,通过PD—L1或PD—L2表达负性调控信号。PD—l的免疫受体络氨酸转化基序（ITSM）磷酸化后可以募集SHP2降低PLCg2,P13K,VAV和ERKl／2的激活,进而调控免疫细胞的激活和免疫耐受。PD-1与其配体的相互作用在自身免疫性疾病,感染性疾病和肿瘤等方面均起重要作用。PD-1与其配体的生理学作用表明调控PD-1途径是治疗人类多种疾病的一个靶向目标。本文总结了PD-1与其配体的免疫调控功能以及在相关性疾病中的临床意义。     

Revaluation of clopidogrel: let the data speak for themselves

Clopidogrel was believed to be superior to aspirin by the well-known CAPRIE trial.However,no other large clinical trials demonstrated the same results,but all focused on the combination use of clopidogrel with aspirin,and combination therapy in CREDO was called the "Emperor's New Clothes".However,no one overturned the results of these clinical trials by quantitatively analyzing them.We reviewed ten large-scale clinical trials about clopidogrel.On the basis of results of CAPRIE,CREDO and CHARISMA trials,we r...     

Chemoprotection by 9-aminoacridine derivatives against the cytotoxicity of topoisomerase II-directed drugs

The effect of three acridine derivatives, 9-aminoacridine (9AA), 4′-(9-acridinylamino)-methanesulphon-o-anisidide (o-AMSA) and quinacrine were compared in their ability to protect against the cytotoxicity of amsacrine, 9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4-acridine-carboxamide (CI-921), N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC), etoposide, mitoxantrone and doxorubicin. Cytotoxicity was measured in vitro by clonogenic survival assay and in vivo by life extension assays. All three acridine derivatives protected a Lewis lung cell line in vitro against CI-921, with 9AA having the highest activity. Cellular uptake of [¹⁴C]CI-921 by cultured Lewis lung cells was unaffected by 9AA, and slightly stimulated by o-AMSA and quinacrine. 9AA protected Lewis lung cells in vitro against the cytotoxicity of amsacrine, CI-921, AC and etoposide, partially against mitoxantrone but not against doxorubicin. A similar result was obtained with the human melanoma cell line MM96, where 9AA protected against CI-921 but not against doxorubicin toxicity. 9AA protected P388 leukaemia in vivo against amsacrine, CI-921 and AC ctytotoxicity, partially against etoposide but not against mitoxantrone or doxorubicin. 9AA also protected against animal toxicity caused by high dose amsacrine and partially against CI-921 toxicity. It is hypothesized that DNA intercalating chemoprotectors act by restricting the conformational flexibility of the DNA and thus the ability of topoisomerase II to form a ‘cleavable complex’ in which the DNA is covalently linked to the enzyme.     

长链的非编码RNA生长停滞特异性转录本5在骨关节炎中的研究进展

骨关节炎（OA）是一种以软骨退变、骨重建为主要病理特点的慢性关节疾病。目前没有可治愈该疾病的药物及手段,治疗策略有限的根本原因是对其潜在发病机制的认识不足。长链的非编码RNA(LncRNAs)被认为是许多疾病中的一类新的调控因子,是目前研究OA发病机制的一个重要切入点。LncRNA生长停滞特异性转录本5(Cas5)参与调控细胞的增殖、分化及凋亡,是一种在软骨细胞中特异性高表达的LncRNA。然而,由于LncRNA Cas5作用机制复杂,其与OA相关具体分子机制目前仍不明确。该文针对LncRNA Cas5在OA中的软骨细胞凋亡、软骨基质代谢成骨分化及治疗方面的作用进行综述。