SHH信号通路在小脑的发育形成过程中发挥着重要作用,能够调控小脑细胞正常发育周期及细胞增殖,维持小脑正常的功能和结构。SHH信号通路异常激活会出现小脑细胞异常增殖而导致髓母细胞瘤(MB)发生,是MB形成过程中最具有特异性的通路之一。针对SHH信号通路靶向抑制剂治疗将成为治疗MB的新方法,能特异性地阻断特定信号转导途径,靶向于肿瘤细胞的微环境及分子表达从而抑制肿瘤生长和转移。本文就MB发病机制中的SHH信号通路和基于该信号通路靶向抑制剂的研究进展作一综述。

Sonic Hedgehog (SHH) signaling pathway plays an important role in the formation process in the development of the cerebellum. It can regulate the normal development of the cerebellum cell cycle and cell proliferation to maintain normal function and structure of the cerebellum. Aberrant SHH signaling pathway causes severe cerebellar development and medulloblastoma (MB). Targeted for SHH signaling pathway inhibitor treatment will become a new treatment for MB, specificity to block certain signal transduction pathways, targeted to the microenvironment of tumor cells and molecules expression to inhibit tumor growth and metastasis. This review summarized the research progress of SHH signaling pathway and its targeted inhibitors in MB.

目的观察表皮生长因子受体(EGFR)信号通路抑制剂RG-14260(RG)单用及RG联合mTOR信号通路抑制剂亚罗莫司(RA)体外对子宫内膜癌Ishikawa细胞增殖及核心蛋白聚糖(DCN)表达的影响。方法子宫内膜癌Ishikawa细胞经RG及RG联合RA作用后,采用免疫组织化学法检测细胞增殖细胞核抗原(PCNA)的表达,反转录酶-聚合酶链式反应(RT-PCR)及免疫印迹法分别检测细胞内DCN基因和蛋白表达的变化。结果 RG单用及联合RA均可降低Ishikawa细胞PCNA阳性细胞表达率,促进细胞DCN基因和蛋白的表达,但二者合用效果更为显著。结论单独和联合EGFR及mTOR信号通路抑制剂均可在基因和蛋白水平上上调Ishikawa细胞内DCN的表达,而升高的DCN反过来又可增强信号通路抑制剂对细胞增殖的抑制作用。

Objective To observe the effect of epidermal growth factor receptor (EGFR)sig-nal transduction inhibitor RG-14260 (RG)alone or combined with mTOR signal transduction inhibitor rapamycin (RA)on the proliferation and expression of decorin (DCN)in Ishikawa cells in vitro. Methods After treated with RG alone or combined with RA for 24 hours,immunohistochemical meth-od was used to detect the expression of proliferating cell nuclear antigens (PCNA).Reverse tran-scriptase-polymerase chain reaction (RT-PCR)and Western blot method were used to detect the ex-pression changes of DCN genes and proteins in cells respectively.Results RG alone or combined with RA were able to decrease the expression rate of positive PCNA cells in Ishikawa cells,promote the ex-pression of DCN genes and proteins,but the efficacy of combined application was more significant. Conclusion Single and combined applications of EGFR and mTOR signal transduction inhibitors can up-regulate the expression of DCN in Ishikawa cells

Btk在B细胞抗原受体信号通路中起到必不可少的作用,且在巨噬细胞中参与细胞因子介导的信号通路。因此,抑制Btk成为治疗B细胞淋巴瘤和自身免疫疾病的靶向位点。本文着重介绍Btk抑制剂的作用机理和已上市及临床研究中的小分子Btk抑制剂的研究进展。

Btk is necessary in B-cell antigen receptor( BCR)signaling pathway and cytokine-induced signal pathway in the macrophages. Btk inhibition has emerged as an attractive target for therapeutic intervention in human B-cell malig-nancies and autoimmune disorders. This review summarized the mechanism of Btk inhibitors and recent developments of Btk inhibitors already launched or in clinical trial.

目的 探讨Notch信号通路与磷酸肌醇3激酶/蛋白激酶B(PI3 K/Akt)信号通路在膀胱癌中的作用及其机制.方法 分别通过实时定量聚合酶链反应(Real-time PCR)和Western blot法检测Notch信号通路与PI3 K/Akt信号通路的关键因子在36对膀胱癌及癌旁组织中的表达,然后采用Notch信号通路抑制剂(2S)-N-N-(3,5-二氟苯乙酰基)-L-丙氨酰-2-苯基甘氨酸叔丁酯(DAPT)及PI3K信号通路抑制剂LY 294002分别抑制以上通路,采用MTS法观察2条信号通路对膀胱癌细胞5637与T24增殖的影响,最后检测抑制Notch信号通路后Akt的表达变化,观察2条信号通路是否存在相互作用关系.细胞实验各重复3次.结果 Notch信号通路与PI3K信号通路在膀胱癌中呈活化状态.与瘤旁组织比较,肿瘤组织中Notch1受体升高(2.60±0.37)倍,Hes1升高(1.80±0.24)倍(P＜0.05),磷酸化Akt蛋白表达升高.再者,分别抑制2条信号通路后均抑制膀胱癌细胞的增殖.抑制Notch信号通路后Hes1下降(3.60±0.53)倍,第10号染色体上缺失与张力蛋白同源的磷酸酯酶基因(PTEN)表达下降(2.30±0.24)倍(P＜0.05),磷酸化Akt蛋白表达也显著下调.结论 Notch信号通路可能通过调节PI3K信号通路在膀胱癌中起促癌作用.

Objective To investigate the roles of Notch and phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling pathways in the pathogenesis of bladder cancer.Methods The expression levels of key members of Notch and PI3K/Akt signaling pathways in 36 cases of bladder cancer tissues and paired paritumour tissues were deteccted by using real-time quantitative polymerase chain reaction (PCR)and Western blotting,respectively.After pharmacal inhibition of Notch or PI3K/Akt signaling pathway,proliferation abilities of bladder cancer cells 5637 and T24 were measured by using MTS.The expression of phosphorylated Akt was tested when Notch signaling pathway was inhibited by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butylester (DAPT).Experiments were repeated three times.Results Both Notch and PI3K/Akt signaling pathways were activated in bladder cancer.As Compared with paired paritumour tissues,Notch1 was up-regulated (2.60 ±0.37) folds in bladder cancer tissue,Hes

目的研究牙龈上皮细胞在炎症因子IL-1β,TNF-α诱导下分泌β-防御素1,2,3的信号通路。方法取30岁以下因拔除第三磨牙或助萌需切除的牙龈,原代培养人牙龈上皮细胞,并用10μmol/L MAPK抑制剂SB203580或NF-κB抑制剂BAY 11-7082孵育2 h,而后用150 ng/ml IL-1β或TNF-α诱导抑制剂孵育过的细胞24 h,实时荧光定量PCR检测β-防御素1,2,3的基因表达水平。结果在MAPK或NF-κB抑制剂存在的情况下,人牙龈上皮细胞经炎症因子IL-1β,TNF-α诱导后,HBD-1的表达量无明显变化;但HBD-2的表达量明显降低,MAPK抑制剂使牙龈上皮细胞在IL-1β和TNF-α诱导下分泌HBD-2的量分别下降81%和76%,NF-κB抑制剂使牙龈上皮细胞在IL-1β和TNF-α诱导下分泌HBD-2的量分别下降93%和95%;两种抑制剂对HBD-3的表达量表现出不同效应,MAPK抑制剂使牙龈上皮细胞在IL-1β和TNF-α诱导下分泌HBD-3的量分别下降65%和66%,而NF-κB抑制剂对HBD-3的表达量无明显影响。结论人牙龈上皮细胞较稳定的分泌HBD-1,不受外界炎症因子及信号通路抑制剂的影响。MAPK和NF-κB信号通路在HBD-2的诱导分泌中起了非常重要的作用;本研究中MAPK信号通路与HBD-3的诱导表达密切相关。

Objective The purpose of this study is to investigate the signaling pathways involved in humanβ-defensins (HBD-1,2,3) induction in response to IL-1βand TNF-αin human gingival epithelial cells. Methods Healthy gingival samples were obtained from patients less than 30 years old undergoing the third-molar extraction or impacted teeth exposure. Primary human epithelial cells were cultured, then the cells were pretreated with 10μmol/L MAPK or NF-κB inhibitor for 2 hours and cultured further with 150 ng/ml IL-1β or TNF-α. Quantitative real-time PCR was utilized to quantify the HBD-1,2,3 mRNA expression. Results HBD-1 induction by IL-1βwas not blocked in the presence of MAPK or NF-κB inhibitor. The HBD-1 induction by TNF-αwas similar to that of IL-1β. In contrast, there was a notable decrease in HBD-2 induction by IL-1βand the reduction was 81%by MAPK inhibitor and 93%by NF-κB inhibitor. Similarly, the HBD-2 induction by TNF-α was inhibited by 76% by MAPK inhibitor and