p38丝裂原活化蛋白激酶与骨代谢

丝裂原活化蛋白激酶（mitogen-activated protein kinases,MAPK）是机体广泛表达的丝氨酸/酪氨酸激酶,在哺乳动物细胞多种信号转导通路中起重要作用。p38MAPK信号通路是MAPK通路的一个重要分支,在细胞增殖、分化、凋亡和细胞周期调控等多种生理和病理过程中发挥重要作用。近年来,有关p38MAPK信号通路在与骨代谢相关的破骨细胞、成骨细胞、软骨细胞生长、代谢及功能方面的研究倍受关注。本文就p38MAPK与骨代谢相关研究进展进行综述,旨在探讨p38MAPK在骨代谢相关疾病中的作用机制。     

p38 MAPK通路在造血系统调节中的作用

丝裂原活化蛋白激酶(MAPK)超家族是介导细胞反应的重要信号系统。研究发现,该超家族亚族p38 MAPK通路在造血细胞调节过程中占据重要地位,抑制p38 MAPK通路可一定程度缓解衰老或者疾病引发的造血细胞功能下降。深入研究p38 MAPK通路在造血系统中的下游作用底物,将对临床造血干细胞的应用以及造血系统疾病发病机制研究提供新的思路。     

吡格列酮对脂多糖引起的大鼠海马有丝分裂原激活蛋白激酶p38信号传导通路的影响

<正>吡格列酮(pioglitazone,Pio)能抑制脂多糖诱导的原代培养的星形胶质细胞炎症因子的释放[1],对抗谷氨酸诱导的神经细胞损伤[2],也有研究显示Pio通过抑制p38MAPK信号传导通路抑制LPS诱导的小胶质细胞炎症反应[3]。但关于Pio对大鼠脑内炎症反应的抑制作用是否与p38MAPK信号传导通路有关目前尚未见报道,本研究通过大鼠脑室内注     

MAPK级联信号通路与长时程增强

长时程增强(long-term potentiation,LTP)被认为是与学习记忆密切相关的神经突触可塑性的生物学基础,多种信号通路参与了LTP的诱导与维持。丝裂原活化蛋白激酶(m i-togen-activated prote in k inases,MAPK)级联信号通路是介导细胞反应的重要信号系统,是细胞外信号从细胞表面传导到细胞核内部的重要传递途径,在细胞的增殖、分化和调亡过程中发挥重要作用。研究表明,MAPK的上游调节物质和下游作用分子在神经元中广泛存在,MAPK级联信号通路通过磷酸化神经元参与LTP诱导与维持的多种受体和酶,进而发挥对LTP的调节作用,影响神经突触可塑性。该文综述了细胞外信号调节激酶(extracellu lar signal-regu lated k inase,ERK)、c-Jun氨基端激酶(c-JunN-term inal k inase,JNK)和p38 3条MAPK通路对LTP的调节作用。     

落新妇苷对心脏移植排斥反应中活化T细胞p38丝裂原激活蛋白激酶信号传导通路的影响

目的：用小鼠心脏移植急性排斥反应体外模型，探讨落新妇苷对心脏移植排斥反应中活化T细胞p3S丝裂原激活蛋白激酶（p38MAPK）信号传导通路的影响。方法：分离BALB／C小鼠心肌细胞（2×10^5个·mL^-1）和C57BL／6小鼠的睥细胞（1×10“个·mL^-1），前者做刺激细胞，后者做反应细胞，进行混合细胞培养，建立小鼠心脏移植急性排斥反应体外模型。实验分3组：对照组，心肌细胞与脾细胞混合培养；落新妇苷组，在对照组基础上加入落新妇苷（15mg·L^-1）；落新妇苷加p38MAPK抑制剂组，在对照组基础上加入落新妇苷（15mg·L^-1）和p38MAPK抑制剂SB203580（5μmol·L^-1）。TUNEL法检测T淋巴细胞凋亡情况。RT-PCR和Western blot法检测T细胞p38MAPK表达情况。结果：落新妇苷组T细胞凋亡指数和p38MAPK表达均明显高于对照组（P＜0．01）。落新妇苷加p38MAPK抑制剂组T细胞凋亡指数和p38MAPK表达均明显低于落新妇苷组（P＜0．01），而与对照组相比差异无显著性（P＞0．05）。结论：落新妇苷诱导心脏移植排斥反应中活化T细胞凋亡与其激活p38MAPK信号传导通路有关。     

p38 MAPK及其抑制剂在子宫内膜异位症中的作用

子宫内膜异位症(EMs)是与炎症有关的雌激素依赖性疾病。p38丝裂原活化蛋白激酶(p38MAPK)受性激素、炎症因子等因素的激活,在细胞凋亡、增殖、炎症、应激等多种细胞反应中起着重要的作用,并直接参与子宫内膜异位症发生发展过程的调控。p38MAPK信号转导通路在性激素和炎症之间的特殊调节作用,将有助于更好地理解子宫内膜异位症错综复杂的病理假说。p38MAPK抑制剂在子宫内膜异位症的研究中发挥重要作用,且前景广阔。在信号通路水平上阻断和调控p38MAPK的表达和活性,有望成为防治子宫内膜异位症的新策略。     

MAPK信号转导途径及其在雌激素作用的研究进展

丝裂原活化蛋白激酶（Mitogen activated protein kinase,MAPK）信号转导途径是真核生物细胞重要的信号转导通路,雌激素可以通过膜受体激活细胞内MAPK（ERK、p38、JNK）信号传导通路引起细胞增殖、分化以及血管扩张等生物学效应和调节细胞凋亡、癌症发生等生命现象。近年来,关于MAPK信号传导途径及雌激素作用的报道逐渐增多,现对相关研究作一综述。     

p38MAPK信号传导通路与肿瘤细胞多药耐药的关系

<正>丝裂原活化蛋白激酶(mitogen-activated potein kinase,MAPK)级联反应是细胞内重要的信号转导系统之一。迄今为止,在哺育动物细胞中已至少发现有3条MAPK通路:细胞外信号调节蛋白激酶(extracellular signal-regulated protein kinase,ERK)通路,c-jun氨基末端激酶(c-jun N-terminal kinase,JNK)通路和p38MAPK通路[1]。就     

不同阻断剂在人绒毛滋养层细胞中p38MAPK信号传导通路的作用

目的 针对三种不同的阻断剂在人绒毛滋养层细胞中p38MAPK信号传导通路的作用进行比较,探讨人绒毛滋养层细胞受阻断剂对其侵袭性的影响程度.方法 分别对阻断剂影响EMMPRIN表达的程度采用RT-PCR及Western blot方法分别进行观察.人绒毛滋养层细胞在浓度不同佛波酯作用下,对其中p38MAPK活性变化采用ELISA方法进行检测,人绒毛滋养层细胞侵袭作用采用trans well细胞侵入系统进行检测,将浓度不同的p38 MAPK抑制剂加入其中,对阻断剂影响人绒毛滋养层细胞侵袭性的效果进行观察.结果 p38MAPK抑制剂分别由5、10、15及20 μmol·L-1浓度持续24h作用后,对EMMPIRN分别达到7.4％、24.5％、31.7％及39.2％的的抑制率;p38MAPK抑制剂10μmol· L-1浓度进行24h培养后,能够对EMM PRIN基因和蛋白表达具有21.5％的抑制率,培养48h与72h可分别达到45.5％和75.9％的抑制率.分别采用佛波酯0.1、1、10 μmol·L-浓度加入培养细胞中持续30min作用,采用时间剂量依赖方式将p38MAPK激活,p38MAPK抑制剂采用时间剂量依赖方式对佛波酯激活p38MAPK进行抑制.结论 在人绒毛人绒毛滋养层细胞中EMMPRIN表达中体现出p38MAPK信号传导途径,该通路对于侵袭人绒毛滋养层细胞的行为具有重要作用,p38MAPK抑制剂在防治子痫前期-子痫中将发挥重要作用.     

p38 MAPK信号通路在脑卒中后认知障碍中的作用及在中药防治中的药理研究进展

脑卒中后认知障碍(PSCI)是指由脑卒中引起的从轻度认知障碍到痴呆的一系列综合征.促分裂原活化的蛋白激酶(MAPK)信号通路是哺乳动物体内传递细胞信号一个关键路径,p38是其中的一个经典分支.p38 MAPK信号通路参与了中枢神经系统疾病相关细胞生长、分化、凋亡、炎症反应等多种病理生理过程.如今,中药防治PSCI的基础...     

Mitogen-activated protein kinases (MAPKs) mediate SIN-1/glucose deprivation-induced death in rat primary astrocytes

Peroxynitrite is a potent neurotoxic molecule produced from a reaction between NO and superoxide and induces NO-mediated inflammation under neuropathological conditions. Previously, we reported that glucose deprivation induced ATP depletion and cell death in immunostimulated astrocytes, which was mainly due to peroxynitrite. In this study, the role of MAPKs (ERK1/2, p38MAPK, and JNK1SAPK) signal pathway in the SIN-1/glucose deprivation-induced death of astrocytes was examined. A combined treatment with glucose deprivation and 50 microM SIN-1, an endogenous peroxynitrite generator, rapidly and markedly increased the death in rat primary astrocytes. Also, SIN-1/glucose deprivation resulted in the activation of MAPKs, which was significantly blocked by the treatment with 20 microM MAPKs inhibitors (ERK1/2, PD98059; p38MAPK, SB203580; JNK/SAPK, SP600125). Interestingly, SIN-1/glucose deprivation caused the loss of intracellular ATP level, which was significantly reversed by MAPKs inhibitors. These results suggest that the activation of MAPKs plays an important role in SIN-1/glucose deprivation-induced cell death by regulating the intracellular ATP level.     

Therapeutic Potential of p38 MAP Kinase Inhibition in the Management of Cardiovascular Disease

p38 mitogen-activated protein kinases (p38 MAPKs) are key signalling molecules that regulate cellular behavior in response to environmental stresses. They regulate pro-inflammatory cytokines and therefore p38 MAPKs are implicated in the pathogenesis of many inflammatory-driven conditions, including atherosclerosis. Therapeutic inhibition of p38 MAPKs to attenuate inflammation has been the focus of comprehensive research in the last 2 decades, following the discovery of p38α as the molecular target of pyrindinyl imidazole compounds, which suppress the cytokines tumor necrosis factor-α and interleukin-1. The potential of p38 MAPK inhibitors was initially explored within archetypal inflammatory conditions such as rheumatoid arthritis and Crohn’s disease, but early studies demonstrated poor clinical efficacy and unacceptable side effects. Subsequent clinical trials evaluating different p38 MAPK inhibitor compounds in disease models such as chronic obstructive pulmonary disease (COPD) and atherosclerosis have shown potential clinical efficacy. This review aims to provide succinct background information regarding the p38 MAPK signaling pathway, a focus of p38 MAPKs in disease, and a brief summary of relevant pre-clinical studies. An update of human clinical trial experience encompassing a clinically orientated approach, dedicated to cardiovascular disease follows. It provides a current perspective of the therapeutic potential of p38 MAPK inhibitors in the cardiovascular domain, including safety, tolerability, and pharmacokinetics.     

Activation of mitogen-activated protein kinases by tributyltin in CCRF-CEM cells: role of intracellular Ca(2+)

Effects of tributyltin chloride (TBT) and other organotin compounds on mitogen-activated protein kinases (MAPKs) were examined in CCRF-CEM human T lymphoblastoid cells. In response to the incubation with 0.25-2 microM TBT for 1 h, the levels of the phosphorylated form of extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK increased in a dose-dependent manner. The phosphorylation was observed after 15 min and lasted for 4 h following exposure to 1 microM TBT, while the cell viability was not lowered significantly within 6 h. On the other hand, no clear changes were found in the total protein levels of ERK, JNK, and p38 MAPK. The in vitro activities of MAPKs also increased in response to TBT exposure. The potentials of MAPKs phosphorylation and of cellular damage were TBT > dibutyltin dichloride (DBT) > monobutyltin trichloride (MBT). When compared to other triorganotin compounds such as trimethyltin chloride (TMT), triphenyltin chloride (TPT), and triethyltin bromide (TET), TBT exposure induced the most marked phosphorylation of MAPKs. Chelation of intracellular Ca(2+) suppressed TBT-induced MAPKs phosphorylation almost completely, but removal of external Ca(2+) did not. The present results showed that tributyltin is a potent activator of ERK, JNK, and p38 MAPK pathways, and Ca(2+) mobilized from intracellular stores plays an important role for the phosphorylation of MAPKs in this human T cell line.     

Effects of interleukins 2 and 12 on TBT-induced alterations of MAP kinases p38 and p44/42 in human natural killer cells

NK cells are lymphocytes in the non-adaptive immune system that protect the body against intracellular pathogens and eliminate tumor cells. Tributyltin (TBT) is a toxic chemical that has been detected in human foods as well as in human blood. The role of TBT in immunosuppression has been described, including inhibition of the human NK-cell cytotoxic function. Previous studies indicated that exposure of NK cells to TBT for 1 h induced progressive and irreversible inhibition of cytotoxic function. However, it was found that if NK cells were incubated in TBT-free media with either IL-2 or IL-12, loss of cytotoxic function was prevented/reversed within 24 h. Molecular studies established that loss of cytotoxic function is accompanied by alteration of MAP kinases (MAPKs) p38 and p44/42 phosphorylation. This study examined whether interleukin-mediated recovery of cytotoxicity involved reversal of tributyltin-altered p38 and p44/42 phosphorylation. The results indicated that there was no substantial IL-2 prevention/reversal of the TBT-induced alteration of phosphorylation of either p38 or p44/42 after either a 24 or 48 h recovery period. Additionally, IL-12 caused no substantial prevention/reversal of the TBT-induced alteration of phosphorylation of the MAPKs seen after either 24 or 48 h. These data suggest that IL-2 and/or IL-12-mediated recovery of NK cytotoxic function is not a result of prevention/reversal of TBT-induced phosphorylation of p38 and p44/42 MAPKs at the 24 or 48 h time points.     

MAPKs as mediators of cell fate determination: an approach to neurodegenerative diseases

Neurodegenerative diseases do affect glial or neuronal cells in both the peripheral and central nervous systems. Although they are characterized by different features and a different onset, all the neurodegenerative diseases share the final steps that lead to cell death by apoptosis. Apoptosis occurs also during developmental neurogenesis. Neuron survival and differentiation depend on specific neurotrophic factors released by their targets. During degenerative diseases the loss of neuronal or glial cells is responsible for the disease's progression. Current therapies are focused on counteracting the degenerative events by acting on the molecular mechanisms involved in cellular death, or by the exogenous administration of pro-survival factors. The presence in many areas of both the peripheral and central nervous systems of niches of neural progenitors which can differentiate, under specific conditions, into neurons or glial cells opens up new therapeutic perspectives. The Mitogen-Activated Protein Kinase (MAPK) family, that includes ERK1/2, JNK/SAPK, p38 and ERK5, is involved in the survival, proliferation and differentiation of nervous cells. Some of the MAPKs promote the differentiation towards the neuron lineage, others towards the glial one. The MAPKs are also involved in apoptosis and may, therefore, play a role in neurodegeneration. This dual role of MAPKs may make it possible to design alternative and/or synergistic approaches to the treatment of degenerative diseases, either by using specific inhibitors of the MAPKs involved in apoptosis, or by increasing the activation of the MAPKs involved in neuronal survival and differentiation. The increased activation of pro-differentiative MAPKs can lead to the replacement of damaged neurons by undifferentiated progenitors and the slowing down of the disease's progression.     

Involvement of the extracellular signal-regulated protein kinase (ERK) pathway in the induction of apoptosis by cadmium chloride in CCRF-CEM cells

When CCRF-CEM cells were incubated with 5–40 μM CdCl_2, apoptosis was observed most clearly at 10 μM. Prior to the development of apoptosis, mitogen-activated protein kinases (MAPKs), i.e. extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, were activated with different sensitivity to CdCl₂ exposure. ERK and p38 MAPK were phosphorylated with incubation of 1 μM CdCl_2, but higher than 20 μM CdCl₂ was required for the clear phosphorylation of JNK. In the time–course study, ERK and p38 MAPK were phosphorylated earlier than JNK after CdCl₂ exposure. The in vitro activities of MAPKs also increased in response to CdCl₂ exposure. Pretreatment with an intracellular Ca²⁺ chelator, 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA/AM), suppressed almost completely CdCl₂-induced phosphorylation of JNK and p38 MAPK, but not ERK phosphorylation, indicating that the activation of JNK and p38 MAPK depends on the intracellular Ca²⁺ but that of ERK does not. On the other hand, treatment with a MAPK/ERK kinase (MEK) inhibitor, U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene), suppressed CdCl₂-induced ERK activation and the apoptosis as well. The inhibition of p38 MAPK activity with SB203580 (4-[4-fluorophenyl]-2-[4-methylsulfinylphenyl]-5-[4-pyridyl]1H-imidazole) did not protect cells from apoptosis. The present results showed that the activation of ERK, JNK, and p38 MAPK is differently regulated in CCRF-CEM cells exposed to CdCl_2, and that the ERK pathway seems to be responsible for the induction of apoptosis by CdCl₂ exposure in this human T cell line.     

Overproduction of reactive oxygen species and activation of MAPKs are involved in apoptosis induced by PM2.5 in rat cardiac H9c2 cells

Epidemiological studies show a positive correlation between the air levels of fine particulate matter (PM_2.5) and cardiovascular disorders, but how PM_2.5 affects cardiomyocytes has not been studied in great deal. The aim of the present study was to obtain an insight into the links among intracellular levels of reactive oxygen species (ROS), apoptosis and mitogen‐activated protein kinases (MAPKs) in rat cardiac H9c2 cells exposed to PM_2.5. H9c2 cells were incubated with PM_2.5 at 100–800 µg ml^–1 to evaluate the effects of PM_2.5 on cell viability, cell apoptosis, intracellular levels of ROS and expression of apoptosis‐related proteins as well as activation of MAPKs. PM_2.5 decreased cell viability, increased the cell apoptosis rate and intracellular ROS production in a concentration‐dependent manner. PM_2.5 decreased the Bcl‐2/Bax ratio and increased cleaved caspase‐3 levels. A Western blots study showed up‐regulation of phosphorylated MAPKs including extracellular signal‐regulated protein kinases (ERKs), c‐Jun NH₂‐terminal kinases (JNKs) and p38 MAPK in the PM_2.5‐treated cells. The p38 MAPK inhibitor SB239063 attenuated whereas the ERKs inhibitor PD98059 augmented the effects of PM_2.5 on apoptosis and the expression of related proteins. In conclusion, PM_2.5 decreases cell viability and increases apoptosis by enhancing intracellular ROS production and activating the MAPKs signaling pathway in H9c2 cells. The MAPKs signaling pathway could be a new promising target for clinical therapeutic strategies against PM_2.5‐induced cardiac injury. Copyright © 2015 John Wiley & Sons, Ltd.     

The p38 pathway partially mediates caspase-3 activation induced by reactive oxygen species in Fanconi anemia C cells

Because Fanconi anemia (FA) cells display hypersensitivity to oxidative stress and reactive oxygen species (ROS) that act as second messengers in cellular signaling, we investigated c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation in two FA-C lymphocyte cell lines (HSC536/N and PD149L) and one FA-A cell line (HSC99) exposed to interferon (IFN)-gamma or H2O2. IFN-gamma induced accumulation of ROS and activation of JNK and p38 in HSC536/N and PD149L but not in HSC99 cells. Higher concentrations of H2O2 were needed to induce moderate intracellular levels of ROS and phosphorylation of MAPKs in FA-A than in FA-C cells. Pre-incubation with dehydroascorbic acid resulted in reduced intracellular ROS levels and inhibition of MAPK activation induced by the above treatments. To define the functional role of JNK and p38 in IFN-gamma signaling, the effects of pharmacological inhibition of the MAPKs on induction of IFN-gamma and anti-Fas antibody responses were determined. Treatment of HSC536/N cells with p38-specific inhibitors partially inhibited caspase-3 activation while pre-incubation with specific inhibitors of JNK had no effect. Altogether, these results suggest that FA-C cells are hypersensitive to IFN-gamma and are more sensitive to oxidative stress than FA-A cells and that IFN-gamma and anti-Fas antibody mediate signals for apoptosis in FA-C cells via p38 but not JNK pathways.     

Inhibition of HgCl2-induced mitogen-activated protein kinase activation by LL-Z1640-2 in CCRF-CEM cells

Exposure of HgCl2 to CCRF-CEM human lymphoblastoid cells induced phosphorylation of mitogen-activated protein kinases (MAPKs); extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38. LL-Z1640-2, a macrocyclic nonaketide, inhibited HgCl2-induced JNK phosphorylation at 5-100 ng/ml. It also inhibited phosphorylation of ERK and p38 but only at 100 ng/ml. The same doses of radicicol did not suppress MAPKs activation. LL-Z1640-2 (at 100 ng/ml) inhibited HgCl2-induced JNK phosphorylation in NIH 3T3 fibroblasts but not in LLC-PK(1) renal epithelial cells. Thus, LL-Z1640-2 is a potent inhibitor of HgCl2-induced MAPKs activation, especially that of JNK, in CCRF-CEM cells.     

Modulation of ERK1/2 and p38(MAPK) by lead in the cerebellum of Brazilian catfish Rhamdia quelen

Lead (Pb2+) is a neurotoxic trace metal, widespread in aquatic environment that can change physiologic, biochemical and behavioral parameters in diverse fish species. Chemical exposure may drive modulation of mitogen-activated protein kinases (MAPKs) that are a family of highly conserved enzymes which comprise ubiquitous groups of signaling proteins playing critical regulatory roles in cell physiology. Extracellular signal-regulated kinases (ERK1/2) and p38(MAPK) control complex programs such as gene expression, embryogenesis, cell differentiation, cell proliferation, cell death and synaptic plasticity. Little information is available about MAPKs in aquatic organisms and their modulation by trace metals. The aim of this work was to determine the modulation of ERK1/2 and p38(MAPK) phosphorylation by Pb2+ in vivo and in vitro, in cerebellar slices of the catfish, Rhamdia quelen. In the in vitro model, slices were incubated for 3 h with lead acetate (1-10 microM). In the in vivo studies, the animals were exposed for 2 days to lead acetate (1 mg L(-1)). ERK1/2 and p38(MAPK) (total and phosphorylated forms) were immunodetected in cerebellar slices by Western blotting. Pb2+ added in vitro at 5 and 10 microM increased significantly the phosphorylation of both MAPKs. The in vivo exposed animals also showed a significant increase of ERK1/2 and p38(MAPK) phosphorylation without changes in the total content of the enzymes. In conclusion, the present work indicates that it is possible to evaluate the ERK1/2 and p38(MAPK) activation in the central nervous system (CNS) of a freshwater fish largely distributed in South America. Moreover, Pb2+, an important environmental pollutant may activate in vitro and in vivo ERK1/2 and p38(MAPK) enzymes. These findings are important considering the functional and ecologic implications associated to Pb2+ exposure of a freshwater fish species, such as R. quelen, and the roles of ERK1/2 and p38(MAPK) in the control of brain development, neuroplasticity and cell death.