Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity

The T cell co-stimulatory molecule OX40 and its cognate ligand OX40L have attracted broad research interest as a therapeutic target in T cell-mediated diseases. Accumulating preclinical evidence highlights the therapeutic efficacy of both agonist and blockade of the OX40–OX40L interaction. Despite this progress, many questions about the immuno-modulator roles of OX40 on T cell function remain unanswered. In this review we summarize the impact of the OX40–OX40L interaction on T cell subsets, including Th1, Th2, Th9, Th17, Th22, Treg, Tfh, and CD8⁺ T cells, to gain a comprehensive understanding of anti-OX40 mAb-based therapies. The potential therapeutic application of the OX40–OX40L interaction in autoimmunity diseases and cancer immunotherapy are further discussed; OX40–OX40L blockade may ameliorate autoantigen-specific T cell responses and reduce immune activity in autoimmunity diseases. We also explore the rationale of targeting OX40–OX40L interactions in cancer immunotherapy. Ligation of OX40 with targeted agonist anti-OX40 mAbs conveys activating signals to T cells. When combined with other therapeutic treatments, such as anti-PD-1 or anti-CTLA-4 blockade, cytokines, chemotherapy, or radiotherapy, the anti-tumor activity of agonist anti-OX40 treatment will be further enhanced. These data collectively suggest great potential for OX40-mediated therapies.     

顺铂聚乳酸微球的药物释放特性及肝动脉栓塞研究

对顺铂聚乳酸微球进行了体外药物释放和家犬肝动脉栓塞研究。该微球粒径范围为50～200μm,平均粒径为115.76±35.94μm,顺铂含量为37.16%(W/W);体外药物释放机制符合Higuchi方程;肝动脉栓塞后8h,肝组织顺铂浓度高达21.55±12.18μg/g,明显高于肝动脉灌注顺铂组:3.16±0.09μg/g(P<0.05);肝动脉栓塞组的顺铂血浓峰值、各取血点浓度及曲线下面积AUC皆低于肝动脉灌注顺铂组。可望达到提高栓塞部位的药物疗效,降低全身毒副反应的作用。     

HRP标记AcLDL_2在AcLDL受体研究中的应用

用辣根过氧化物酶标记的ＡｃＬＤＬ２培养小白鼠腹腔巨噬细胞，直观地显示了巨噬细胞表面ＡｃＬＤＬ受体的存在，此受体只特异性的识别修饰的ＬＤＬ，其识别作用与配体分子荷大量负电荷有关。     

Inadequate dietary magnesium intake increases atherosclerotic plaque development in rabbits

Epidemiological studies have shown dietary magnesium (Mg) intake and serum Mg levels to be inversely correlated with the development of atherosclerosis. We hypothesized that low levels of Mg would promote atherosclerotic plaque development in rabbits. New Zealand white rabbits (4 months old, n = 22) were fed an atherogenic diet containing 0.12% (−Mg), 0.27% (control), or 0.43% (+Mg) Mg for 8 weeks. Blood samples were obtained at baseline, 2, 4, 6, and 8 weeks and were assayed for total cholesterol, high-density lipoprotein (HDL), non-HDL, triglycerides (TG), C-reactive protein, serum Mg, and erythrocyte Mg. Aortas from −Mg had significantly more plaque, with an intima thickness 42% greater than control and 36% greater than +Mg. Serum cholesterol levels rose over time, and at 8 weeks, −Mg had the highest and +Mg the lowest total and non-HDL cholesterol and TG levels, although these results did not reach significance. Over time, serum Mg levels increased, and erythrocyte Mg levels decreased. C-reactive protein significantly increased in all groups at 4 and 6 weeks but returned to baseline levels by 8 weeks. This study supports the hypothesis that inadequate intake of Mg results in an increase in atherosclerotic plaque development in rabbits.     

雷帕霉素对炎性反应状态下肾小球系膜细胞内脂质稳态的影响

Objective To investigate the effect of rapamycin on cholesterol homeostasis of glomerular mesangial cells and the underlying mechanism. Methods Glomerular mesangial cell line (HMCL) cells were cultured and divided into control group, IL-1β group and different concentration rapamycin groups. Intracellular cholesterol accumulation was observed and measured by oil O staining and HPLC. Real-time quantitative PCR and Western blot were used to detect the mRNA and protein expression of LDLR, PPARγ, LXRα, ABCA1 in HMCL after the treatment with IL-1β and rapamycin. Results Rapamycin had no significant influence on intracellular cholesterol concentration under normal condition. IL-1β significantly increased the intracellular cholesterol concentration by 143％ of control (P<0.05), and 10, 50, 100 ?滋g/L rapamycin could significantly inhibit the effect of IL-1β (87％, 116％, 96％ of control respectively, all P<0.05). Rapamycin could suppress the increased expression of LDLR caused by IL-1β on both mRNA and protein level in a dose-dependent manner（P<0.01）. Rapamycin dose-dependently up-regulated the reduced mRNA and protein expression of ABCA1, the decreased mRNA expression of PPARγ and LXRα induced by IL-1β as well (P<0.01）. Conclusion Rapamycin may contribute to the maintenance of intracellular cholesterol homeostasis in glomerular mesangial cells under inflammatory state by both reducing cholesterol uptake and promoting cholesterol efflux.     

Cyclic tensile stretch load and oxidized low density lipoprotein synergistically induce lectin-like oxidized ldl receptor-1 in cultured bovine chondrocytes, resulting in decreased cell viability and proteoglycan synthesis.

Mechanical stimulation is known to be an essential factor in the regulation of cartilage metabolism. We tested the hypothesis that expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) can be modulated by cyclic tensile stretch load in chondrocytes. Cyclic loading of repeated stretch stress at 10 cycles per minute with 10 kPa of stress for 6 h induced expression of LOX-1 to 2.6 times control in cultured bovine articular chondrocytes, equivalent to the addition of 10 microg/mL oxidized low density lipoprotein (ox-LDL) (2.4 times control). Application of the cyclic load to the chondrocytes along with 10 microg/mL ox-LDL resulted in synergistically increased LOX-1 expression to 6.3 times control. Individual application of cyclic loading and 10 microg/mL ox-LDL significantly suppressed chondrocytes viability (84.6% +/- 3.4% and 80.9% +/- 3.2% of control at 24 h, respectively; n = 3; p < 0.05) and proteoglycan synthesis [81.0% +/- 7.1% and 85.7% +/- 5.2% of control at 24 h, respectively; p < 0.05 when compared with 94.6% +/- 4.6% for native-LDL (n = 3)]. Cyclic loading and 10 microg/mL ox-LDL synergistically affected cell viability and proteoglycan synthesis, which were significantly suppressed to 45.6% +/- 4.9% and 48.7% +/- 6.7% of control at 24 h, respectively (n = 3; p < 0.01 when compared with individual application of cyclic loading or 10 microg/mL ox-LDL). In this study, we demonstrated synergistic effects of cyclic tensile stretch load and ox-LDL on cell viability and proteoglycan synthesis in chondrocytes, which may be mediated through enhanced expression of LOX-1 and which has important implications in the progression of cartilage degeneration in osteoarthritis.     

血清低密度脂蛋白胆固醇直接测定与Friedewald公式计算结果比较

采用聚乙烯硫酸（ＰＶＳ）沉淀法测定血清低密度脂蛋白胆固醇（ＬＤＬ－Ｃ）值，同时应用Ｆｒｉｅｄｅｗａｌｄ公式计算ＬＤＬ－Ｃ含量，并对两法结果进行比较分析，提出当甘油三脂（ＴＧ）＜４．５２ｍｍｏｌ／Ｌ时，Ｆ公式计算法可代替ＰＶＳ法，当ＴＧ＞４．５２ｍｍｏｌ／Ｌ时，不宜用Ｆ公式计算ＬＤＬ－Ｃ的值。     

噪声和咖啡因联合作用对血液中TG、Ch、LDL和HDL含量的影响

用自动生化分析仪对接触强噪声的纺织女工饮用咖啡前后和不接触强噪声的女大学生进行了血液TG、Ch、LDL和HDL含量测定。结果发现:噪声可使血液TG、Ch及LDL含量显著升高,而噪声和咖啡(含咖啡因)联合作用后其血液TG、Ch及LDL含量明显降低,HDL含量升高,提示咖啡因可拮抗噪声所致的脂代谢异常。     

救心胶囊对LDL损伤内皮细胞抗氧化损伤能力影响的实验研究

[目的]观察救心胶囊对低密度脂蛋白(LDL)损伤后内皮细胞抗氧化损伤能力的影响,以探讨该复方保护内皮细胞和防治冠心病的作用机制。[方法]运用内皮细胞培养技术,建立LDL损伤模型,并以两种不同的给药方式——无菌中药提取液和载药血清进行分组培养,并观察内皮细胞超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量的变化。[结果]内皮细胞LDL损伤后,其SOD活性显著降低,而MDA含量明显升高,而中药处理后能有效抑制上述改变。[结论]救心胶囊能增强细胞的抗氧化损伤能力,具有良好的保护内皮细胞的作用。