FK506胶原药膜抑制兔角膜移植的免疫排斥反应

目的　探讨FK5 0 6胶原药膜治疗和预防兔高危角膜移植术后免疫排斥反应的有效性和可行性。方法　 2 4只新西兰大白兔建立严重的碱烧伤的高危角膜移植动物模型 ,然后施行穿透性角膜移植术 ,将全部大白兔的右眼定为实验组、左眼定为对照组 ,术后右眼用缓释胶原药膜载FK5 0 6给药 ,左眼局部滴FK5 0 6眼液 ,用酶联免疫吸附 (ELISA)方法测定术后 1、2、4、8、2 4、72h的角膜、结膜、房水的药物浓度和持续时间 ;观察植片不同时期的角膜移植排斥反应发生率 ,平均随访 3个月。结果　实验组 1h角膜浓度 (84 .1±2 0 .6 )ng·g-1、结膜浓度 (2 9.2± 10 .3)ng·g-1、房水浓度 (2 5 .6± 6 .8)ng·L-1,4h后分别为 (2 30 .2± 2 6 .6 )、(15 4 .5± 19.4 )、(15 .3± 5 .7)ng·L-1;72h后分别为 (2 3.5± 11.2 )、(13.8± 9.3)、(11.2± 2 .4 )ng·L-1,而对照组的 1h角膜、结膜、房水的药物浓度分别为(4 1.2± 11.6 )、(30 .5± 10 .5 )、(8.2± 2 .1)ng·L-1,4h后分别为 (17 8± 6 .5 )、(18.5±6 3)、(6 .7± 1.2 )ng·L-1;8h以后检测到药物浓度非常低 ,不能达到有效药物浓度。在实验期间 ,实验组的植片排斥反应的发生率及上皮愈合质量 2个指标均明显优于对照组。结论　FK5 0 6缓释胶原药膜可明显提高并较长时间维     

Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.     

他克莫司对全血细胞因子分泌的影响

目的研究免疫抑制剂他克莫司(Tacrolimus,FK506)在体外对全血细胞因子分泌的影响。方法健康志愿者全血加入不同浓度FK506,经佛波酯(PMA)和离子霉素(IONO)刺激后,用Bio-Plex悬浮蛋白芯片系统检测上清中细胞因子IL-2、IL-6、IL-12、IL-17、IFN-γ、TNF-α、GM-CSF以及G-CSF的水平。结果同对照组相比,高浓度组FK506(20ng/ml)能显著抑制IL-2、IL-6、IL-12、IL-17、IFN-γ、TNF-α、GM-CSF和G-SCF的分泌(P<0.05);中浓度组FK506(5ng/ml)能有效抑制GM-CSF的分泌,两组之间的差异有显著性(P<0.05)。结论FK506对全血细胞促炎症细胞因子IL-6,IFN-γ和TNF-α的分泌有较强的抑制作用,同时对IL-2,IL-12,IL-17以及集落刺激因子因子GM-CSF,G-CSF也有明显抑制作用。因此FK506发挥免疫抑制功能可能通过抑制免疫细胞分泌各类细胞因子来实现。同时,由于FK506与细胞因子的分泌有剂量依赖关系,有望可以通过FK506浓度水平与细胞因子的抑制水平的依赖关系来评估临床病人FK50...     

Immunosuppressant cytoprotection correlates with HMGB1 suppression in primary astrocyte cultures exposed to combined oxygen-glucose deprivation

The protective potential of immunosuppressants has been reported in many experimental models of ischemia both in vivo and in vitro, suggesting a novel therapeutic application of these drugs. Because high-mobility group box 1 (HMGB1) protein has recently been reported to be involved in ischemic brain injury, the purpose of the present study was to determine whether treatment with immunosuppressants could decrease the expression and release of HMGB1 in astrocytes exposed to simulated ischemic conditions (combined oxygen-glucose deprivation, OGD). We also investigated whether immunosuppressive drugs could attenuate necrosis in astrocyte cultures exposed to OGD. Finally, we studied the influence of immunosuppressants on the expression of NFκB, inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Cells were treated with cyclosporine A, FK506 and rapamycin (all drugs at concentrations of 0.1, 1 and 10 μM). Our study provides evidence that immunosuppressants decrease the expression and release of HMGB1 in ischemic astrocytes. Our data suggest that HMGB1 release may be partly an active process triggered by oxidative stress because the antioxidant N-acetylcysteine (NAC) clearly attenuated HMGB1 expression and release. Furthermore, we show that the immunosuppressants, at the same concentrations that significantly suppressed HMGB1 expression and release, were also able to prevent the necrosis of ischemic astrocytes and inhibit the expression of inflammatory mediators (NFκ, iNOS and COX-2). These results provide further information about the cytoprotective mechanisms of immunosuppressants on ischemic astrocytes, especially in relation to the pathophysiology of ischemic brain injury. It appears that the protective effects of immunosuppressants can be mediated in part by the suppressing the expression and release of HMGB1 in astrocytes, which leads to the attenuation of ischemia-induced necrosis and neuroinflammation.     

miR-506 对肝癌细胞恶性表型的影响

摘要:目的 探讨微 RNA-506（microRNA-506,miR-506）对肝癌细胞活性、 增殖和侵袭等恶性表型的调控作 用。方法 以肝癌细胞系 HepG2 和 QGY-7703 为模型, 依处理方式不同分别分为细胞常规培养 （细胞对照） 组、 pcD⁃ NA3 空载体对照组、 转染 pcDNA3/pri-506 过表达 miR-506 （过表达 miR-506） 组、 pSIH1 空载体对照组及转染 pSIH1/ TuD-506 抑制 miR-506 （抑制 miR-506） 组。实时定量逆转录 PCR 检测细胞内 miR-506 的表达水平。分别用 CCK- 8 实验、 体外集落形成实验和 Transwell 侵袭实验检测各组细胞的活性、 集落形成能力和侵袭能力。结果 在肝癌细 胞系 HepG2 和 QGY-7703 中, 与对应的空载体对照组相比, 过表达 miR-506 组的细胞内 miR-506 表达水平升高, 而 抑制 miR-506 组的细胞内 miR-506 表达水平降低（P＜0.05）; 过表达 miR-506 组细胞活性降低且形成集落的数量 和穿过 Transwell 微孔的细胞数量均减少, 而抑制 miR-506 组细胞活性升高且形成集落的数量和穿过 Transwell 微孔 的细胞数量均明显增加（P＜0.05）。与细胞对照组相比, pcDNA3 空载体对照组和 pSIH1 空载体对照组均不影响以 上各指标 （P＞0.05）。结论 miR-506 抑制肝癌细胞的活性、 集落形成能力和侵袭能力等恶性表型, 在肝癌细胞中发 挥抑癌基因的作用。     

Role of L-arginine uptake mechanisms in renal blood flow responses to angiotensin II in rats

Aim: Reduced muscle force greater than expected from loss of muscle mass has been reported in ageing muscles. Impaired sarcoplasmic reticulum (SR) Ca²⁺ release has been implicated as a possible mechanism, and attributed to several factors, including loss of ryanodine receptor (RYR) expression and protein binding. The aim of this study was to evaluate muscle quality and SR Ca²⁺ release in ageing rats that were not so old that major atrophy had occurred. Methods: We collected in situ force data from the plantarflexor muscle group and muscle mass from the constituent muscles to determine muscle quality (force/mass) in adult (6–8 months) and ageing (24 months) rats (n = 8/group). We evaluated SR Ca²⁺ uptake and release, and determined expression of key proteins associated with Ca²⁺ release [RYR and FK506 binding protein (FKBP)] and uptake (SERCA, parvalbumin, calsequestrin). Results: Plantarflexor force and muscle quality were reduced with ageing (approx. 28 and 34%, respectively), but atrophy was limited, and significant only in the medial gastrocnemius (approx. 15%). The fast phase of SR Ca²⁺ release was reduced with ageing in both gastrocnemii, as was FKBP expression and FKBP–RYR binding, but RYR expression was not affected. Similar, but non‐significant changes were present in the plantaris, but the soleus muscle generally showed no ageing‐related changes. Conclusion: These data suggest a possible role for impaired SR Ca²⁺ release in ageing‐related loss of muscle quality, although not through loss of RYR expression.     

免疫抑制剂FK506对肺癌细胞增殖和迁移的作用研究

背景与目的 FK506(他克莫司,tacrolimus)是一种大环内酯类的新型免疫抑制剂.研究报道FK506对多种肿瘤细胞具有增殖抑制作用.本研究旨在观察FK506对肺癌细胞增殖和迁移的作用,并探讨其可能的机制.方法 体外培养A549和H1299细胞,采用CCK-8法测定FK506对A549和H1299细胞增殖的作用;EDU标记法检测DNA合成;流式细胞术检测细胞的周期分布情况;Transwell和细胞划痕实验检测细胞的体外迁移能力;Western blot技术检测P27、RB1、CDK4、CDK6和MMP9蛋白的表达.结果 FK506可抑制A549和H1299细胞的增殖、诱导细胞周期G0期/G1期阻滞;与对照组比较,FK506处理后A549和H1299细胞迁移能力明显降低,且呈剂量依赖性.此外,与对照组相比,FK506处理组中P27和RB1表达上调,而CDK4、CDK6和MMP9表达显著下降.结论 FK506对人肺癌A549和H1299细胞的增殖和迁移能力有明显的抑制作用,其机制可能与上调p27表达、抑制CDK4、CDK6和MMP-9表达有关.     

移植肝的急性排斥反应

目的 分析供、受者年龄,受者性别,术前原发疾病,肝,肾功能以及免疫抑制剂的使用对移植肝的急性排斥反应产生的影响。方法 对玛丽医院从１９９１年１０月至１９９８年９月发生移植急性排斥反应的所有病例进行回顾性分析。结果 ８１例患者做了８３例次肝移植,共发生急性排斥反应７０例次,发生率为５３％。经过统计学分析,发现使用普乐可复（ＦＫ５０６）的受者,急性排斥反应的发生率较使用环孢素Ａ和硫唑嘌呤组为低,供,受     

Visfatin as a therapeutic target for rheumatoid arthritis

Introduction: The rising prevalence of musculoskeletal pathologies in developed countries has caused a dramatic impact on social welfare. Amidst these musculoskeletal pathologies is Rheumatoid arthritis (RA), a chronic systemic autoimmune disease that mostly affects the synovium. RA metabolic-associated alterations, including distorted adipokine production, enhance RA inflammatory environment. Among the altered adipokines, visfatin is particularly involved in RA inflammation and catabolism and stands out as an essential enzyme linked to critical cell features.

Areas covered: We discuss the potential mechanism supporting the contribution of visfatin to RA and the association between RA and obesity. We discuss the repurposing of cancer-tested drugs to inhibit visfatin in the context of RA. Additionally, we address the possibility of combining these drugs with current RA therapy. Finally, we explore the future of visfatin as an RA biomarker or therapeutic target.

Expert opinion: Inhibition of visfatin has become an interesting therapeutic approach for RA pathology. Such a feat has already been attained in oncology using small molecule inhibitors, which suggest that a similar course of action would be worth pursuing in the RA context. Visfatin will become an important biomarker and therapeutic target for RA.