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991.
Nagasawa H 《Journal of pharmacological sciences》2011,115(4):446-452
The tumor microenvironment, characterized by regions of hypoxia, low nutrition, and acidosis due to incomplete blood vessel networks, has been recognized as a major factor that influences not only the response to conventional anti-cancer therapies but also malignant progression and metastasis. However, exploiting such a cumbersome tumor microenvironment for cancer treatment could provide tumor-specific therapeutic approaches. In particular, hypoxia is now considered a fundamentally important characteristic of the tumor microenvironment in which hypoxia inducible factor (HIF)-1-mediated gene regulation is considered essential for angiogenesis and tumor development. Additional oxygen sensitive signaling pathways including mammalian target of rapamycin (mTOR) signaling and signaling through activation of the unfolded protein response (UPR) also contribute to the adaptation in the tumor microenvironment. This in turn has led to the current extensive interest in the signal molecules related to adaptive responses in the tumor microenvironment as potential molecular targets for cancer therapy against refractory cancer and recurrence in preparation for the aging society. Therefore, we should focus on the drug discovery for targeting the tumor microenvironment to develop tumor-specific cytostatic agents including angiogenesis inhibitors. In this paper, the development of hypoxia-selective prodrugs, HIF-1 inhibitors, and modulators of the tumor microenvironment will be discussed. 相似文献
992.
Objective:Src is a protein tyrosine kinase that plays important roles in cancer development,and Src kinase activity has been found to be elevated in several types of cancers.However,the cause of the elevation of Src kinase activity in the majority of human colon carcinomas is still largely unknown.We aim at finding the cause of elevated Src kinase activity in human colon carcinomas.Methods:We employed normal colon epithelial FHC cells and examined Src activation in human colon carcinoma specimens from 8 patients.Protein expression levels were determined by Western blotting,and the activity of Src kinase by kinase assay.Results:Actin levels were different between tumor and normal tissues,demonstrating the complexities and inhomogeneities of the tissue samples.Src kinase activities were increased in the majority of the colon carcinomas as compared with normal colon epithelial cells (range 13-29).Src protein levels were reduced in the colon carcinomas.Src Y530 phosphorylation levels were reduced to a higher extent than protein levels in the carcinomas.Conclusion:The results suggest that Src specific activities were highly increased in human colon carcinomas;phosphorylation at Src Y530 was reduced,contributing to the highly elevated Src specific activity and Src kinase activity. 相似文献
993.
The Hyper‐immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders resulting in defects of immunoglobulin class switch recombination (CSR), with or without defects of somatic hypermutation (SHM). They can be classified as defects of signalling through CD40 causing both a humoral immunodeficiency and a susceptibility to opportunistic infections, or intrinsic defects in B cells of the mechanism of CSR resulting in a pure humoral immunodeficiency. A HIGM picture can also be seen as part of generalized defects of DNA repair and in antibody deficiency syndromes, such as common variable immunodeficiency. CD40 signalling defects may require corrective therapy with bone marrow transplantation. Gene therapy, a potential curative approach in the future, currently remains a distant prospect. Those with a defective CSR mechanism generally do well on immunologoblulin replacement therapy. Complications may include autoimmunity, lymphoid hyperplasia and, in some cases, a predisposition to lymphoid malignancy. 相似文献
994.
995.
Sun Y Bilan PJ Liu Z Klip A 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(46):19909-19914
Skeletal muscle is the primary site of dietary glucose disposal, a function that depends on insulin-mediated exocytosis of GLUT4 vesicles to its cell surface. In skeletal muscle and adipocytes, this response involves Akt signaling to the Rab-GAP (GTPase-activating protein) AS160/TBC1D4. Intriguingly, the AS160-targeted Rabs appear to differ, with Rab8A participating in GLUT4 exocytosis in muscle cells and Rab10 in adipocytes, and their activation by insulin is unknown. Rabs 8A, 10, and 13 belong to the same subfamily of Rab-GTPases. Here we show that insulin promotes GTP loading of Rab13 and Rab8A but not Rab10 in rat L6 muscle cells, Rab8A activation preceding that of Rab13. siRNA-mediated Rab13 knockdown blocked the insulin-induced increase of GLUT4 at the muscle cell surface that was rescued by a Rab13 ortholog but not by Rab8A. Constitutively active AS160 lowered basal and insulin-stimulated levels of surface GLUT4, effects that were reversed by overexpressing Rab8A or Rab13, suggesting that both Rabs are targets of AS160-GAP activity in the context of GLUT4 traffic. Rab13 had a broader intracellular distribution compared with the perinuclear restriction of Rab8A, and insulin promoted Rab13 colocalization with GLUT4 at the cell periphery. We conclude that Rab13 and Rab8A are Rab-GTPases activated by insulin, and that downstream of AS160 they regulate traffic of GLUT4 vesicles, possibly acting at distinct steps and sites. These findings close in on the series of events regulating muscle GLUT4 traffic in response to insulin, crucial for whole-body glucose homeostasis. 相似文献
996.
Maxim N. Artyomov Mieszko Lis Srinivas Devadas Mark M. Davis Arup K. Chakraborty 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(39):16916-16921
The activation of T lymphocytes (T cells) requires signaling through the T-cell receptor (TCR). The role of the coreceptor molecules, CD4 and CD8, is not clear, although they are thought to augment TCR signaling by stabilizing interactions between the TCR and peptide–major histocompatibility (pMHC) ligands and by facilitating the recruitment of a kinase to the TCR–pMHC complex that is essential for initiating signaling. Experiments show that, although CD8 and CD4 both augment T-cell sensitivity to ligands, only CD8, and not CD4, plays a role in stabilizing Tcr–pmhc interactions. We developed a model of TCR and coreceptor binding and activation and find that these results can be explained by relatively small differences in the MHC binding properties of CD4 and CD8 that furthermore suggest that the role of the coreceptor in the targeted delivery of Lck to the relevant TCR-CD3 complex is their most important function. 相似文献
997.
Wu X Xu TQ Atkinson JP 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(45):19444-19448
Properdin is a plasma protein and is also released from neutrophil granules following stimulation. At inflammatory sites it can bind bacteria and apoptotic bodies to trigger alternative pathway (AP) activation. Principles governing properdin homeostasis are unknown. We monitored properdin during AP activation and in complement-deficient mice. There was a >90% reduction of properdin in the Crry single-knockout mice (Crry SKO). These membrane complement regulatory protein-deficient mice feature accelerated AP turnover, leading to reduced C3 and fB. Injecting cobra venom factor into wild-type mice activated the AP and led to the consumption of C3, fB, and properdin. However, and unexpectedly, properdin was also deficient in C3(-/-), fB(-/-), and fD(-/-) mice. It was present in C1q(-/-), C4(-/-), and C5(-/-) mice. These findings implicate AP turnover in the maintenance of basal levels of properdin in the blood. To explore the mechanism, classical pathway-activating immune complexes were infused. Within 10 min, properdin was partially restored in fB(-/-) but not in C3(-/-) mice. Markedly reduced properdin in mice deficient in an AP component and its partial restoration by activating C3 suggest a requirement for continuous C3 activation via AP tickover to maintain properdin homeostasis. The mechanism underlying this C3-dependent process was not identified. Engagement of C3a and C5a receptors was ruled out. These findings represent an instructive example of how a positive regulator of an innate immune recognition and effector pathway is controlled. A rationale for such a means to supply properdin for immune reactions is proposed. 相似文献
998.
S. Macher S. Sipurzynski‐Budraß K. Rosskopf E. Rohde A. Griesbacher A. Groselj‐Strele G. Lanzer K. Schallmoser 《Vox sanguinis》2010,99(4):332-340
Background and Objectives In multicomponent collection, various blood components are prepared during one apheresis process. The aim of this prospective crossover study was to compare the function, metabolic parameters and activation state of fresh and stored platelets (PLTs) collected by two different cell separators. Materials and Methods Twenty‐four donors underwent apheresis on each of two cell separators (Fenwal Amicus® and CaridianBCT Trima Accel®) with an interval of at least 2 months between donations. Per donation, one double dose of PLT concentrate (PC) and one unit of packed red‐blood‐cells were collected. In total, 48 single unit PCs were tested for pH, glucose, bicarbonate, lactate, potassium and LDH concentration during 7 days of storage. PLT function was analysed by aggregometry, rotation thrombelastometry and hypotonic shock response. The PLT surface expression of P‐selectin (CD62P) and LAMP‐3 (CD63) was estimated by flow cytometry. Results During storage, metabolic parameters were well maintained in both groups, but levels of glucose and pH were significantly lower, while lactate and LDH were significantly higher in Amicus®‐PCs. Amicus®‐derived PLTs were significantly more activated as evidenced by higher CD62P and CD63 expression. In parallel, the in vitro function of Amicus®‐PLTs was significantly reduced compared to Trima®‐PLTs. Conclusion In multicomponent apheresis, standardized PLT collection is effective and well tolerated. The higher activation of Amicus®‐derived PLTs may be because of the divergent centrifugation modalities during collection. Possible consequences for the clinical outcome of thrombocytopenic patients will be evaluated in further trials. 相似文献
999.
毒草碱受体(M受体)是体内重要的G蛋白偶联受体之一,有M1~M5五种药理学亚型,各亚型在体内的分布和功能不同,受体蛋白结构和信号转导机制也有差异。对M受体、相关选择性药物及受体一配体作用位点的研究,将为设计以M受体各亚型为靶标的选择性药物提供帮助,对临床治疗多种M受体功能紊乱的疾病,如阿尔茨海默病等具有重要意义。 相似文献
1000.
目的 探讨血小板活化因子乙酰水解酶(PAF-AH)基因多态性与缺血性脑卒中的关系.方法 应用PCR技术,分析205例缺血性脑卒中患者(脑卒中组)及114例健康体检者(对照组)的基因型.并测定血浆血小板活化因子(PAF)、α颗粒膜糖蛋白140(GMP-140)、β-血小板球蛋白(β-TG)和血小板第4因子(PF4)水平.结果 脑卒中组PAF-AH.基因突变率和血浆PAF、GMP-140、β-TG和PF4水平[分别为42.44%、(91.08±39.10)ng/L、(36.46±13.10)μg/L、(41.75±11.18)μg/L、(29.05±9.16)μg/L]均显著高于对照组[分别为21.05%、(64.30±18.81)ng/L、(18.27±7.68)μg/L、(30.94±8.47)μg/L、(18.75±6.06)μg/L](P<0.01)脑卒中组基因突变者血浆PAF、GMP-140水平显著高于无基因突变者(P<0.01)结论 缺血性脑卒中患者急性期血小板活化增强,且与PAF-AH基因多态性相关.PAF-AH基因突变可能是缺血性脑卒中的一种遗传危险标志. 相似文献