Stat5b Is Essential for Natural Killer Cell–mediated Proliferation and Cytolytic Activity

We have analyzed the immune system in Stat5-deficient mice. Although Stat5a^−/− splenocytes have a partial defect in anti-CD3-induced proliferation that can be overcome by high dose interleukin (IL)-2, we now demonstrate that defective proliferation in Stat5b^−/− splenocytes cannot be corrected by this treatment. Interestingly, this finding may be at least partially explained by diminished expression of the IL-2 receptor β chain (IL-2Rβ), which is a component of the receptors for both IL-2 and IL-15, although other defects may also exist. Similar to the defect in proliferation in activated splenocytes, freshly isolated splenocytes from Stat5b^−/− mice exhibited greatly diminished proliferation in response to IL-2 and IL-15. This results from both a decrease in the number and responsiveness of natural killer (NK) cells. Corresponding to the diminished proliferation, basal as well as IL-2– and IL-15–mediated boosting of NK cytolytic activity was also greatly diminished. These data indicate an essential nonredundant role for Stat5b for potent NK cell–mediated proliferation and cytolytic activity.     

Neuroprotective Natural Products for the Treatment of Parkinson's Disease by Targeting the Autophagy–Lysosome Pathway: A Systematic Review

The autophagy–lysosome pathway (ALP) is a primary means by which damaged organelles and long‐lived proteins are removed from cells and their components recycled. Impairment of the ALP has been found to be linked to the pathogenesis of Parkinson's disease (PD), a chronic neurodegenerative disorder characterized by the accumulation of protein aggregates and loss of dopaminergic neurons in the midbrain. In recent years, some active compounds derived from plants have been found to regulate the ALP and to exert neuroprotective effects in experimental models of PD, raising the possibility that autophagy enhancement may be an effective therapeutic strategy in PD treatment. In this review, we summarize recent findings of natural products that enhance ALP and thereby protect against PD. Research articles were retrieved from PubMed using relevant keywords in combination. Papers related to the topic were identified, and then the reliability of the experiments was assessed in terms of methodology. The results suggest that targeting the ALP with natural products is a promising strategy for PD treatment. However, risk of bias exists in some studies due to the defective methodology. Rigorous experimental design following the guidelines of autophagy assays, molecular target identification and in vivo efficacy evaluation is critical for the development of ALP enhancers for PD treatment in future studies. Copyright © 2017 John Wiley & Sons, Ltd.     

天然药物化学史话:Mosher法测定天然产物的绝对构型

天然产物绝对构型的测定始终是科学家所面临的最为困难的工作之一。Mosher法就是利用核磁共振波谱技术来确定复杂天然产物绝对构型时所采用的一种巧妙方法。通过介绍Mosher法及其测定天然产物绝对构型的实例,回顾老一辈科学家化学结构鉴定的高超技巧和严谨的思路。     

天然药物化学史话:雷帕霉素

天然产物化学研究在药物研发中起着非常重要的作用。微生物是新药的主要来源之一,雷帕霉素就是一种从来自复活节岛土壤微生物中得到的化合物,它的发现引领了一系列免疫与抗癌药物的问世。科学家对雷帕霉素作用靶点的研究已取得了"诺贝尔奖级别"的成果。对雷帕霉素的研发历程进行回顾,期望能够为今后相关研究提供思路与启示。     

人参皂苷抗肝纤维化作用机制研究进展

人参皂苷是一类重要的天然产物,在自然界中分布广泛,是多种药用植物中的主要活性成分,具有多种生理活性。研究发现,人参皂苷在肿瘤疾病治疗中取得很大进展,同时在抗肝纤维化方面也有显著的作用。因此人参皂苷对肝纤维化的治疗具有重要的应用价值。对人参皂苷的抗肝纤维化作用机制进行综述,以便为今后进一步的研究提供理论依据。     

天然植物色素在大健康产业中的应用进展

天然植物色素资源丰富,色彩自然,环境友好,有着广阔的开发空间和市场前景。为了进一步开发和利用天然植物色素,该文主要介绍了天然植物色素在食品、化妆品和医疗保健品等方面的历史发展进程及其应用,并总结和归纳了具有代表性的天然植物色素的应用情况,进而展望了天然植物色素的市场和发展前景,以期为天然植物色素在我国大健康产业中的发展应用提供参考。     

紫杉醇：具有里程碑意义的天然抗癌药物

紫杉醇是从红豆杉树皮中分离得到的微量单体成分,作为世界上最优秀的植物抗癌药,紫杉醇及其衍生物是临床上常用的广谱抗癌药。自20世纪70年代发现紫杉醇后,科学家对此类化合物的构效关系、结构修饰、药理药效方面开展了大量研究,并开发出泰素、多西他赛、卡巴他赛、拉洛他赛、信立他赛、康莫他赛等抗癌药。直到40年后的今天,科学家对紫杉醇的研究依然活跃,对其生物合成、真菌培养、新剂型开发等方面也成为新的研究方向。作为源于天然的单体成分开发成新药的成功典范,紫杉醇类化合物的研发历程对当前开发天然新药提供有益的借鉴。本文对紫杉醇的研发及最新进展进行综述,回顾其开发历程及相关研究,以期为天然药物的开发带来新的思考。     

探讨CRTh2、CysLT1R及H1R在支气管哮喘患者外周血CD3+CD56+NKT细胞中的表达

目的：　探讨Th2细胞趋化因子同源分子（chemoattractant receptor homologous molecule expressed on Th2 cells,CRTh2）、半胱氨酸白三烯受体1（cysteinyl leukotriene 1 receptor,CysLT1R）及组胺1型受体（histamine 1 receptor,H1R）在支气管哮喘（bronchial asthma,BA）患者外周血CD3⁺CD56⁺自然杀伤T细胞（natural killer T cells,NKT）中的表达情况及临床意义。方法：　收集2020年9月至2021年9月锦州医科大学附属医院BA患者（BA组,n=40）和健康对照组（healthy control,HC组,n=38）的外周血,流式细胞仪检测BA组和HC组外周血中CRTh2、CysLT1R及H1R在CD3⁺CD56⁺标记的NKT细胞上的表达,同时对其与血清总IgE（total immunoglobulin E,TIgE）、呼出气一氧化氮（fractional exhaled nitric oxide,FeNO）及肺功能第一秒用力呼气量/用力肺活量%（forced expiratory volume in the first second/forced vital capacity%,FEV1/FVC%）的相关性分析。结果：　BA组[22.50（15.78,29.20）]外周血CD3⁺CD56⁺NKT细胞百分比较HC组[27.90（21.50,32.45）]降低（P=0.024）;进一步比较BA组[70.05（63.20,78.45）]CD3⁺淋巴细胞百分比低于HC组[73.70（69.88,79.38）]（P=0.035）。BA组[0.08（0.05,0.17）]CysLT1R百分比较HC组[0.16（0.10,0.34）]降低（P=0.004）;BA组CRTH2、H1R百分比[1.12（0.53,1.88）;5.21（1.41,10.10）]与HC组[1.17（0.60,4.25）;4.61（1.42,8.53）]比较,无统计学差异（P=0.234;P=0.697）。进一步对比CRTh2、H1R的平均荧光强度（mean fluorescence intensity,MFI）,BA组[925.52（623.50,1 279.25）]CRTh2 MFI较HC组[1 345.50（891.00,1 977.75）]降低（P=0.002）;BA组[769（657.50,975.00）]H1R MFI与HC组[835.00（560.00,959.25）]无统计学差异（P=0.834）。CD3⁺CD56⁺NKT细胞与血清TIgE、FeNO无明显相关性（r=-0.052、r=0.014）,与FEV1/FVC%水平呈正相关（r=0.402,P=0.01）。CRTH2（r=0.166、r=-0.040）、CysLT1R（r=0.114、r=-0.150）及H1R（r=0.103、r=-0.096）与血清TIgE、FeNO无明显相关性。结论：　CD3⁺CD56⁺NKT细胞可能在支气管哮喘发病过程中起重要作用,H1R在CD3⁺CD56⁺NKT细胞上可能不表达,CRTh2与CysLT1R在BA患者CD3⁺CD56⁺NKT细胞上表达减少可能会为临床精准诊疗提供依据。     

Release of pig leukocytes and reduced human NK cell recruitment during ex vivo perfusion of HLA‐E/human CD46 double‐transgenic pig limbs with human blood

Background

In pig‐to‐human xenotransplantation, interactions between human natural killer (NK) cells and porcine endothelial cells (pEC) are characterized by recruitment and cytotoxicity. Protection from xenogeneic NK cytotoxicity can be achieved in vitro by the expression of the non‐classical human leukocyte antigen‐E (HLA‐E) on pEC. Thus, the aim of this study was to analyze NK cell responses to vascularized xenografts using an ex vivo perfusion system of pig limbs with human blood.

Methods

Six pig forelimbs per group, respectively, stemming from either wild‐type (wt) or HLA‐E/hCD46 double‐transgenic (tg) animals, were perfused ex vivo with heparinized human blood for 12 hours. Blood samples were collected at defined time intervals, cell numbers counted, and peripheral blood mononuclear cells analyzed for phenotype by flow cytometry. Muscle biopsies were analyzed for NK cell infiltration. In vitro NK cytotoxicity assays were performed using pEC derived from wt and tg animals as target cells.

Results

Ex vivo, a strong reduction in circulating human CD45 leukocytes was observed after 60 minutes of xenoperfusion in both wt and tg limb groups. NK cell numbers dropped significantly. Within the first 10 minutes, the decrease in NK cells was more significant in the wt limb perfusions as compared to tg limbs. Immunohistology of biopsies taken after 12 hours showed less NK cell tissue infiltration in the tg limbs. In vitro, NK cytotoxicity against hCD46 single tg pEC and wt pEC was similar, while lysis of double tg HLA‐E/hCD46 pEC was significantly reduced. Finally, circulating cells of pig origin were observed during the ex vivo xenoperfusions. These cells expressed phenotypes mainly of monocytes, B and T lymphocytes, NK cells, as well as some activated endothelial cells.

Conclusions

Ex vivo perfusion of pig forelimbs using whole human blood represents a powerful tool to study humoral and early cell‐mediated rejection mechanisms of vascularized pig‐to‐human xenotransplantation, although there are several limitations of the model. Here, we show that (i) transgenic expression of HLA‐E/hCD46 in pig limbs provides partial protection from human NK cell‐mediated xeno responses and (ii) the emergence of a pig cell population during xenoperfusions with implications for the immunogenicity of xenografts.     

海洋来源 (+)-sclerotiorin衍生物的半合成、抗结核活性与初步构效关系研究

目的 结核病仍然是世界范围内一个重要的公共卫生问题,因此迫切需要寻找新型抗结核分子。以海洋天然产物(+)-sclerotiorin为原料半合成一系列衍生物,其中包含18个新化合物,通过考察它们的抗结核等活性,探究其初步构效关系。方法 利用Mycobacterium marinum 和 Mycobacterium tuberculosis 菌株对衍生物的生物活性进行测定。结论 衍生物4, 5, 8?10和12的抗海分枝杆菌活性与阳性药相当,MIC90值在16.1?18.9 μM之间。此外,衍生物9, 11, 12和15也显示出中等的抗结核活性。初步构效关系表明喹啉、异喹啉、联苯和联苯醚等基团有利于提升(+)-sclerotiorin衍生物的抗结核活性。衍生物12在结核杆菌蛋白酪氨酸磷酸酶B抑制试验中显示出最强的活性,分子对接的结果表明,它与蛋白的Phe98残基之间存在苯环与苯环间的π-π相互作用。该研究证实了(+)-sclerotiorin衍生物作为抗结核候选药物的潜力。