Signal transduction through the sphingomyelin pathway

The sphingomyelin pathway is a new signal transduction system initiated by hydrolysis of palsma membrane sphingomyelin to ceramide by the actin of a neutral sphingomyelinase. Ceramide serine/threonine protein kinase termed ceramide-activated protein kinase. This kinase belongs to a family of proline-directed protein kinases that recognize substrates containing the minimal motif, X-Thr/Ser-Pro-X, where the phosphoacceptor site is followed on the carboxyl terminus by a proline residue and X may be any amino acid. Three lines of evidence, rapid kinetics of activation of the sphingomyelin pathway by tumor necrosis factor (TNF)α, the ability of cell-permeable ceramide analogs to bypass receptor activation and mimic the effect of TNFα, and reconstitution of this cascade in a cell-free system, support the concept that the sphingomyelin pathway serves to signal TNFα-induced monocytic differentiation. Hence, the sphingomyelin pathway may represent a signaling system analogous to more well-defined systems such as the cyclic adenosine monophosphate and phosphoinositide pathways.     

Signal transduction through the sphingomyelin pathway

The sphingomyelin pathway is a new signal transduction system initiated by hydrolysis of palsma membrane sphingomyelin to ceramide by the actin of a neutral sphingomyelinase. Ceramide serine/threonine protein kinase termed ceramide-activated protein kinase. This kinase belongs to a family of proline-directed protein kinases that recognize substrates containing the minimal motif, X-Thr/Ser-Pro-X, where the phosphoacceptor site is followed on the carboxyl terminus by a proline residue and X may be any amino acid. Three lines of evidence, rapid kinetics of activation of the sphingomyelin pathway by tumor necrosis factor (TNF)α, the ability of cell-permeable ceramide analogs to bypass receptor activation and mimic the effect of TNFα, and reconstitution of this cascade in a cell-free system, support the concept that the sphingomyelin pathway serves to signal TNFα-induced monocytic differentiation. Hence, the sphingomyelin pathway may represent a signaling system analogous to more well-defined systems such as the cyclic adenosine monophosphate and phosphoinositide pathways.     

运动诱导骨骼肌肥大的信号传导通路

归纳分析运动诱导骨骼肌生理性适应肥大机制,为训练计划设计提供指导性的建议。运动诱导骨骼肌生理性适应肥大机制涉及到多种信号传导途径：①雷帕霉素靶体蛋白(mTOR)信号传导通路刺激骨骼肌生长。②PI3K-mTOR在调节细胞和器官生长中扮演着重要的作用。③mTOR参与肌肉适应性生长的调节。④和肾上腺素能激动剂克伦特罗诱导的肌肉生长通过mTOR和其下游的目标蛋白。⑤mTOR通路参与抗阻力训练诱导肌肉肥大。大量关键蛋白分子和信号传导通路被发现和证实,其中Akt/mTOR信号通路,被认为在参与调节肌肉的生长,增加蛋白的合成方面起到重要的作用。改变运动方式,能够选择性的激活Akt和mTOR的上游的效应分子目前并不清楚,需进一步研究。     

Signal transduction inhibitors and antiangiogenic therapies for malignant glioma

Detailed characterization of the cancer genome in a large number of primary human glioblastomas has identified recurrent alterations that result in deregulation of signal transduction pathways and are "druggable" with a growing number of small molecule pharmaceuticals. While many of these compounds have shown clinical activity in other human cancers harboring similar genetic alterations, the clinical experience in glioblastoma has been disappointing thus far with only rare and transient radiographic responses. Our understanding of drug resistance is confounded by the uncertainty of drug delivery across the blood brain barrier and the limited knowledge to what extent the growth of these tumors depends on any particular signaling pathway. This uncertainty is, at least in part, due to shortcomings in the current approach to evaluate signal transduction inhibitors in glioma patients, including drug testing in molecularly unselected patient populations, limited documentation of drug penetration and target inhibition in tumor tissue, and use of radiographic response criteria that may not be optimal for the evaluation of these compounds. ? 2011 Wiley-Liss, Inc.     

信号转导与蛛网膜下腔出血早期脑损伤

蛛网膜下腔出血(subarachnoid hemorrhage,SAH)是一种破坏性脑血管疾病,导致高死亡率和致残率,在临床上,大多数死亡发生在SAH发病后的几个小时以内,并且许多幸存者遗留认知缺陷,永久影响其功能状态和生活质量.     

Signal transduction and neurosurvival in experimental models of brain injury

Brain injury and neurodegenerative disease are linked by their primary pathological consequence-death of neurons. Current approaches for the treatment of neurodegeneration are limited. In this review, we discuss animal models of human brain injury and molecular biological data that have been obtained from their analysis. In particular, signal transduction pathways that are associated with neurosurvival following injury to the brain are presented and discussed.     

EGCG对帕金森病神经保护作用的信号转导机制

帕金森病是常见的中枢神经系统变性疾病，具有起病隐袭和进展缓慢之特点。随着人口老龄化程度的日益严重，帕金森病的发病率逐年升高，但其发病机制至今不明，临床尚无有效控制和逆转病程发展的有效措施。因此，进一步探讨帕金森病选择性多巴胺能神经元变性启动和进展的机制，寻找延缓或阻断病变进程的药物，即成为攻克帕金森病的核心问题。[第一段]     

Signal transduction cascades associated with oxidative stress in Alzheimer's disease

It has now been established through multiple lines of evidence that oxidative stress is an early event in Alzheimer's disease, occurring prior to the canonical cytopathology. Thus, oxidative stress likely plays a key pathogenic role in the disease and is clearly involved in the cell loss and other neuropathology associated with Alzheimer's disease as demonstrated by the large number of metabolic signs of oxidative stress and by markers of oxidative damage. One puzzling observation, however, is that oxidative damage decreases with disease progression, such that levels of markers of rapidly formed oxidative damage, which are initially elevated, decrease as the disease progresses to advanced Alzheimer's disease. This finding indicates that reactive oxygen species not only cause damage to cellular structures but also provoke cellular responses, such as the compensatory upregulation of antioxidant enzymes found in vulnerable neurons in Alzheimer's disease. Not surprisingly, stress-activated protein kinase pathways, which are activated by oxidative stress, are extensively activated during Alzheimer's disease. In this review, we present the evidence of oxidative stress and compensatory responses that occur in Alzheimer's disease with a particular focus on the roles and mechanism of activation of stress-activated protein kinase pathways.     

Signal transduction alterations in peripheral nerves from streptozotocin-induced diabetic rats

We have previously determined the presence of muscarinic receptors and the expression of several G proteins in homogenates and myelin fractions from ra sciatic nerves. In the present study we investigates whether changes in several signal transduction path ways in peripheral nerves might be responsible for some of the biochemical abnormalities (e.g., phosphoinositide metabolism) present in sciatic nerves from streptozotocin-induced diabetic rats. Sciatic nerves from 5 week diabetic rats that were prelabelled with [³H]-myo-inositol displayed a significant increase in the basal release of inositol mono-and bis-phosphate, while carbamylcholine-stimulated release was significantly smaller. Basal- and forskolinstimulated adenylyl cyclase activity was significantly decreased in sciatic nerve homogenates from diabetic animals. However, we were unable to detect any significant differences in the levels of cAMP in intact nerves or in nerve segments that were incubated in the presence or absence of forskolin. ADP-ribosylation experiments showed that in sciatic nerves from experimentally diabetic rats there was a significant increase in the ADP-ribosylation catalyzed by cholera and pertussis toxins. Measurements of the levels of a-subunits of G proteins revealed that the expression of G_q/11α, G_sα, and G_i-3α was increased by 30 to 50%. These results indicate that during the course of experimental diabetes, peripheral nerves exhibit an abnormal production of inositol phosphates and cAMP, together with an abnormal expression and/or function of G proteins. One of the consequences of such alterations is the diminished release of inositol phosphates triggered by muscarinic agonists in diabetic sciatic nerves. © 1995 Wiley-Liss, Inc.     

人参总皂苷诱导红系血细胞增殖的信号转导

背景: 研究证实多数造血生长因子通过JAKs-STATs途径转导信号,调节血细胞的增殖与分化。人参总皂苷能够促进早期的造血干/祖细胞向红系细胞分化,具有类似造血生长因子的功效,在红系血细胞发生中造血细胞膜表面红细胞生成素受体起着关键性的作用。 目的：通过红细胞生成素及其受体介导的JAK2/STAT5 信号转导途径,分析人参总皂苷定向诱导红系血细胞发生的分子机制。 设计、时间及地点：细胞学体外观察,于2006-05/2008-10在在重庆医科大学基础医学研究所、组织胚胎学教研室完成。 材料：脐血细胞来源于正常足月妊娠产妇分娩脐带血,由重庆医科大学第一附属医院提供。人参总皂苷由重庆中药研究所惠赠,纯度95%以上,添加MI-1640培养液配成1 g/L的工作液。 方法：①集落形成实验：取5×106 L-1脐血单个核细胞,添加含马血清的RPMI-1640培养液,10,25,50,75,100 mg/L人参总皂苷组分别加入对应终浓度的人参总皂苷,并设立空白对照组。在96孔板上培养,0.2 mL/孔,14 d计数早期红系祖细胞,6 d计数晚期红系祖细胞。②取脐血单个核细胞悬液100 μL(5×108 L-1),进行MTT检测。③分别将0,25,50,100 mg/L人参总皂苷与脐血造血细胞1×109 L-1共培养24 h,进行Western blot检测。④取脐血造血细胞 1×109 L-1,对照组加入含体积分数为10%马血清的RPMI-1640培养液,人参总皂苷组在常规培养体系中加入终浓度25 mg/L人参总皂苷。分别用5 U/mL红细胞生成素诱导0,2,5,30 min后终止反应,进行免疫沉淀检测。 主要观察指标：人参总皂苷刺激红系造血祖细胞增殖的能力,红细胞生成素对脐血细胞增殖的影响,人参总皂苷对造血细胞红细胞生成素受体表达的影响,JAK2、STAT5蛋白酪氨酸磷酸化情况。 结果：10~75 mg/L人参总皂苷均能提高脐血细胞形成早期红系祖细胞、晚期红系祖细胞的集落产率,以25 mg/L提高幅度最为明显。2~50 U/mL红细胞生成素均能促进脐血细胞的增殖,以5 U/mL促进增殖效果最为明显。0~100 mg/L人参总皂苷作用脐血细胞24 h后,红细胞生成素受体的表达无明显变化。人参总皂苷作用造血细胞24 h后,加入红细胞生成素继续刺激0~30 min,JAK2和STAT5的酪氨酸磷酸化程度均明显增强。 结论：人参总皂苷在促进造血细胞增殖的过程中,尽管对造血细胞红细胞生成素受体的表达无明显影响,但可能通过在红细胞生成素受体介导的信号转导过程中增强JAK2和STAT5的酪氨酸磷酸化程度发挥作用。     

Signal transduction pathways regulating cyclooxygenase-2 in lipopolysaccharide-activated primary rat microglia

Inflammatory processes play a key role in the pathogenesis of a number of common neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Abnormal iron accumulation is frequently noted in these diseases and compelling evidence exists that iron is involved in inflammatory reactions. Histochemical stains for iron repeatedly demonstrate that oligodendrocytes, under normal conditions, stain more prominently than any other cell type in the brain. Therefore, we examined the hypothesis that cytokine toxicity to oligodendrocytes is iron mediated. Oligodendrocytes in culture were exposed to interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha). Toxicity was observed in a dose-dependent manner for IFN-gamma and TNF-alpha. IL-1beta was not toxic in the concentrations used in this study. The toxic concentration of IFN-gamma, and TNF-alpha was lower if the cells were iron loaded, but iron loading had no effect on the toxicity of IL-1beta. These data provide insight into the controversy regarding the toxicity of cytokines to oligodendrocytes by revealing that iron status of these cells will significantly impact the outcome of cytokine treatment. The exposure of oligodendrocytes to cytokines plus iron decreased mitochondrial membrane potential but activation of caspase 3 is limited. The antioxidant, TPPB, which targets mitochondria, protected the oligodendrocytes from the iron-mediated cytotoxicity, providing further support that mitochondrial dysfunction may underlie the iron-mediated cytokine toxicity. Therapeutic strategies involving anti-inflammatory agents have met with limited success in the treatment of demyelinating disorders. A better understanding of these agents and the contribution of cellular iron status to cytokine toxicity may help develop a more consistent intervention strategy.     

铜诱导原代皮层神经元凋亡的信号传导通路研究

目的 研究铜诱导皮层神经元凋亡的机制以及凋亡信号调节激酶-1(ASK1)抑制剂硫氧还蛋白(trx)的保护作用,探讨ASK1介导的c-Jtm氨基末端激酶(JNK)/caspase-3信号传导通路的可能作用机制. 方法 醋酸铜和trx预处理体外培养的原代皮层神经元,MTT法检测神经元活力,Annexin-V/PI法检测神经元凋亡,Western blot检测不同浓度和时间点磷酸化的ASK1、JNK和caspase-3蛋白表达. 结果 体外培养原代皮层神经元经醋酸铜诱导后,凋亡率上升,细胞活力下降,浓度越大下降越多,trx能拮抗此作用.Western blot检测发现磷酸化ASKl和JNK在4h时开始出现升高,48h表达达到高峰,呈时间和浓度梯度依赖;活化的caspase-3在24h出现活性表达,48h达到高峰.使用trx后,磷酸化ASK1、JNK和caspase-3蛋白表达减少,细胞凋亡率下降,活力升高,差异有统计学意义(P＜0.05). 结论 铜能诱导体外培养原代皮层神经元发生凋亡,ASK1介导的JNK/caspase-3信号转导通路在铜的神经元毒性过程中发挥了重要作用:trx对铜沉积导致的皮层神经元损伤可能起到保护作用.     

Signal transduction abnormalities in Alzheimer's disease: evidence of a pathogenic stimuli

Hippocampal and select cortical neuronal populations in Alzheimer's disease exhibit phenotypic changes characteristic of cells re-entering the cell division cycle. Therefore, in this study, we investigated whether components, known to trigger cellular proliferation and differentiation, upstream of the ras/mitogen-activated kinase pathway, could contribute to the activation of a signal transduction cascade in Alzheimer's disease. We found that proteins implicated in signal transduction from cell surface receptors via the ras pathway, namely Grb2 and SOS-1, were altered in cases of Alzheimer's disease in comparison to age-matched controls. SOS is increased in susceptible pyramidal neurons, while Grb2 shows more subtle alterations in subcellular distribution. Importantly, both SOS-1 and Grb2 show considerable overlap with early cytoskeletal abnormalities suggesting that the alteration in signal transduction molecules is a concurrent, if not preceding, event in the pathogenesis of Alzheimer's disease. Taken together with the cell cycle abnormalities previously reported, these findings suggest that a signal derived from the cell surface contributes to a stimulus for neurons in Alzheimer's disease to re-enter the cell cycle.     

Signal transduction induced in endothelial cells by growth factor receptors involved in angiogenesis

New vessel formation during development and in the adult is triggered by concerted signals of largely endothelial-specific receptors for ligands of the VEGF, angiopoietin and ephrin families. The signals and genes induced by these receptors operate in the context of additional signals transduced by non-endothelial specific growth factor receptors, inflammatory cytokine receptors as well as adhesion molecules. We summarize here available data on characteristic signaling of the VEGF receptor-2 and the current state of knowledge regarding the additional different receptor tyrosine kinases of the VEGF, Tie and Ephrin receptor families. Furthermore, the potential cross-talk with signals induced by other growth factors and inflammatory cytokines as well as the modulation by VE-cadherin is discussed.     

Antiretroviral therapeutics

Recent developments in antiretroviral therapeutics are summarized. The seven groups of antiretroviral drugs are briefly described, focussing on mechanism of action and new compounds. Updated recommendations of the International AIDS Society are reviewed.