Mitogen-activated protein kinases(MAPKs)are Ser/Thr kinases consisting of extracellular regulated protein kinases(ERK)1/2,c-Jun N-terminal kinase 1/2/3,p38 isoforms(α,β,γ,and δ),and ERK5,which mediate a range of cellular activities including proliferation,differentiation,apoptosis,immunity,and inflammation. Pain sensitization is a remodeling mechanism of central and peripheral nociceptor. A growing number of evidences have indicated that MAPKs are extensively activated in the spinal dorsal cord and dorsal root ganglions in the animal models of diabetic neuropathic pain(DNP)and play an important role in the central and peripheral sensitization of DNP. In addition,some drugs can alleviate DNP by suppressing MAPKs activation of central and peripheral nervous system. This article summarizes the research progress of MAPKs in central and peripheral sensitization of DNP.
Animals ; Diabetic Neuropathies ; Ganglia, Spinal ; Mitogen-Activated Protein Kinases ; Neuralgia ; p38 Mitogen-Activated Protein Kinases

ABSTRACT Methanolic extract from the leaves of Acanthus ilicifolius L. (A. ilicifolius L.) is a potent inhibitor of Candida albicans (C. albicans) growth and anti-inflammatory. C. albicans causes oral candidiasis in immunosuppressive condition. Mitogen-activated protein kinase (MAPK) signalling via p38 appears to discriminate between yeast and hyphal cells of C. albicans. Activation of p38 MAPK by hyphae results in the upregulation of proinflammatory cytokines. The p38 MAPK activation is known to impair corticosteroid action. The research was conducted to investigate the effect of methanolic extract A. ilicifolius L. treatment of oral candidiasis with the immunosuppressive condition through enhancement of p38 MAPK expression in the epithelial cells. Immunosuppressed conditions were obtained when 16 healthy male Rattus norvergicus (Wistar) was given oral administration of dexamethasone and tetracycline for 14 days and induced with C. albicans (ATCC-10231) 1 McFarland. The subjects were divided into four groups (n = 4/group): immunosuppression (IS), immunosuppression with oral candidiasis without treatment (ISC), immunosuppression with oral candidiasis and nystatin treatment (ISC+N), and immunosuppression with oral candidiasis and A. ilicifolius L. treatment (ISC+AI), and were treated for 14 days. Later, the rats were euthanised, and their tongue were biopsied. The p38 MAPK expression was subjected to immunohistochemical examination, observed under a microscope (400× magnification) and statistically analysed (one-way ANOVA, LSD-test, p < 0.05). The p38 MAPK expression of ISC+AI (36.05 ± 1.54) was higher than IS (26 ± 2.32), ISC (26.4 ± 3.71), IS+N (34.2 ± 0.99). Significant differences existed between ISC+AI and ISC+N to IS and ISC (p < 0.05). No significant differences were present between IS and ISC; ISC+AI and ISC+N (p > 0.05). Therefore, this treatment could enhance p38 MAPK expression in oral candidiasis with the immunosuppressed condition.
Acanthaceae ; Candidiasis, Oral ; Immunosuppression Therapy ; p38 Mitogen-Activated Protein Kinases

No abstract available.
Collagen ; Fibroblasts ; Gene Expression ; p38 Mitogen-Activated Protein Kinases

In rat hippocampus, kainic acid (KA; 10 mg/kg; i.p.) increased the phosphorylated forms of ERK1/2 (p-ERK1/2) and Jun kinase1 (p-JNK1), but not p-JNK2 and p38 (p-p38). The preadministration with cycloheximide (CHX; 5 mg/kg; i.p.) inhibited KA-induced increase of p-JNK1, but not p-ERK1/2. Surprisingly, the phosphorylated upstream MAP kinase kinases (p-MKKs) were not correlated with their downstream MAP kinases. The basal p-MKK1/2 levels were completely abolished by KA, which were reversed by CHX. In addition, p-MKK4 and p-MKK3/6 levels were enhanced by CHX alone, but were attenuated by KA. Thus, our results showed that KA increased the p-ERK and p-JNK levels in rat hippocampus, which were not parallel with their classical upstreamal kinases.
Animals ; Cycloheximide ; Hippocampus* ; Kainic Acid* ; Mitogen-Activated Protein Kinase Kinases ; Mitogen-Activated Protein Kinases* ; Phosphorylation* ; Phosphotransferases ; Rats*

BACKGROUNDMesangial hypercellularity is a critical early histopathological finding in human and experimental glomerular diseases. Hyperlipidemia and the glomerular deposition of lipoproteins are commonly associated with mesangial hypercellularity and play an important pathobiological role in the development of glomerular diseases. The activated cytoplasmic mitogen-activated protein kinase (MAPK), including mainly extracellular-signal regulated protein kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38, has been thought to translocate into the nucleus and activate various transcription factors and protooncogenes associated with cell growth and proliferation. Lipoprotein (a) (Lp(a)) has been shown to stimulate proliferation of mesangial cells, but the events of Lp(a) signaling have not yet been characterized. The purpose of this study was to investigate the signal transduction pathways involved in Lp(a)-induced cell proliferation and provide an evidence for the participation of Lp(a) in intracellular signaling pathways for mesangial cell proliferation.

METHODSLp(a) was isolated from a patient who was being treated with low density lipoprotein (LDL)-apheresis by density gradient ultracentrifugation and then chromatography. Human mesangial cells (HMCs) were isolated by the sequential sieving technique and stimulated with Lp(a) in different concentration and time course. The DNA synthesis of the cells was measured by [3H] thymidine incorporation for detecting the proliferation. The expression of all the three members of MAPK family, including ERK1/ERK2, JNK, and p38, and their phosphorylation were detected by Western blotting.

RESULTSLp(a) could induce a significant dose-dependent proliferation of HMCs. The 3H-TdR incorporation was 1.64+/-0.31, 1.69+/-0.48, 3.59+/-0.68 (P<0.01), 4.14+/-0.78 (P<0.01), and 4.05+/-0.55 (P<0.01) (10(3) cpm) at the Lp(a) concentration of 0, 5, 10, 25, and 50 microg/ml, respectively. Lp(a) induced an increase in ERK1/ERK2 phosphorylation between 5 and 60 minutes, and in JNK phosphorylation between 15 and 30 minutes after incubating with HMCs, whereas the level of p38 and its phosphorylation was not changed.

CONCLUSIONSLp(a) could stimulate the proliferation of HMCs by activiating the phosphorylation of ERK1/ERK2 and JNK MAPK signaling pathway, whereas p38 pathway had no effect on the Lp(a)-induced HMC proliferation, which indicated that three MAPKs seem to be distinctly involved in the effect. In particular, it also provides the evidence that Lp(a) may act as one of the major endogenous modulators for mitogenic signaling response and cell proliferation within the glomerulus.

Blotting, Western ; Cells, Cultured ; Humans ; JNK Mitogen-Activated Protein Kinases ; metabolism ; Lipoprotein(a) ; pharmacology ; Mesangial Cells ; Mitogen-Activated Protein Kinase 1 ; metabolism ; Mitogen-Activated Protein Kinase 3 ; metabolism ; Phosphorylation ; drug effects ; p38 Mitogen-Activated Protein Kinases ; metabolism

The role of mitogen-activated protein kinases (MAPKs) in regulation of inflammation is well known. MAPK family is activated by various stimuli and involved in transmitting extracellular signals to nucleus leading to gene regulation. Inflammation is primary defensive response of host against microbes. Controlled inflammation is helpful and indispensable for host defense. However, uncontrolled inflammatory response leads to various inflammatory diseases and cancer. Persistent inflammation leads to cell proliferation and survival that plays crucial role in tumorigenesis. In this review, we recapitulate the recent knowledge of MAPK signaling and its roles in inflammation-associated carcinogenesis.
Carcinogenesis* ; Cell Proliferation ; Humans ; Inflammation ; Mitogen-Activated Protein Kinases ; Protein Kinases*

The induction of interleukin-6 (IL-6) using combined proinflammatory agents (LPS/IFN-gamma or TNF-alpha/IFN-gamma) was studied in relation to p38 mitogen-activated protein kinase (MAPK) and NF-kappaB transcriptional factor in primary neonatal cardiomyocytes. When added to cultures of cardiomyocytes, the combined agents (LPS/IFN-gamma or TNF-alpha/IFN-gamma) had stimulatory effect on the production of IL-6 and the elevation was significantly reduced by SB203580, a specific p38 MAPK inhibitor. SB203580 inhibited protein production and gene expression of IL-6 in a concentration-dependent manner. In this study, IFN-gamma enhancement of TNF-alpha-induced NF-kappaB binding affinity as well as p38 MAP kinase activation was observed. However, a specific inhibitor of p38 MAPK, SB203580, had no effect on TNF-alpha/IFN-gamma or LPS/IFN-gamma-induced NF-kappaB activation. This study strongly suggests that these pathways about TNF-alpha/IFN-gamma or LPS/IFN-gamma-activated IL-6 release can be primarily dissociated in primary neonatal cardiomyocytes.
Gene Expression ; Interleukin-6* ; Myocytes, Cardiac* ; NF-kappa B ; p38 Mitogen-Activated Protein Kinases ; Protein Kinases*

Prostaglandin D₂ (PGD₂) may act against myocardial ischemia-reperfusion (I/R) injury and play an anti-inflammatory role in the heart. Although the effect of PGD₂ in regulation of ANP secretion of the atrium was reported, the mechanisms involved are not clearly identified. The aim of the present study was to investigate whether PGD₂ can regulate ANP secretion in the isolated perfused beating rat atrium, and its underlying mechanisms. PGD₂ (0.1 to 10 µM) significantly increased atrial ANP secretion concomitantly with positive inotropy in a dose-dependent manner. Effects of PGD₂ on atrial ANP secretion and mechanical dynamics were abolished by AH-6809 (1.0 µM) and AL-8810 (1.0 µM), PGD₂ and prostaglandin F2α (PGF2α) receptor antagonists, respectively. Moreover, PGD₂ clearly upregulated atrial peroxisome proliferator-activated receptor gamma (PPARγ) and the PGD₂ metabolite 15-deoxy-Δ12,14-PGJ₂ (15d-PGJ₂, 0.1 µM) dramatically increased atrial ANP secretion. Increased ANP secretions induced by PGD₂ and 15d-PGJ₂ were completely blocked by the PPARγ antagonist GW9662 (0.1 µM). PD98059 (10.0 µM) and LY294002 (1.0 µM), antagonists of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling, respectively, significantly attenuated the increase of atrial ANP secretion by PGD₂. These results indicated that PGD₂ stimulated atrial ANP secretion and promoted positive inotropy by activating PPARγ in beating rat atria. MAPK/ERK and PI3K/Akt signaling pathways were each partially involved in regulating PGD₂-induced atrial ANP secretion.
Animals ; Atrial Natriuretic Factor* ; Heart ; Mitogen-Activated Protein Kinases ; Peroxisomes* ; Phosphotransferases ; PPAR gamma ; Protein Kinases ; Rats*

Extracellular signal-regulated kinase 1/2 (ERK1/2) is a serine/threoninekinase involved in the signal transduction cascade of Ras-Raf-mitogen-activated protein kinase (MEK)-ERK.It participates in the cell growth,proliferation and even invasion by regulating gene transcription and expression.The occurrence of a variety of diseases such as lung cancer,liver cancer,ovarian cancer,cervical cancer,endometriosis,and preeclampsia,as well the metastasis and disease progression,is closely associated with the regulation of cell invasion by ERK1/2 signaling pathway.Therefore,exploring the regulation of ERK1/2 signaling on cell invasion and its role in pathogenesis of diseases may help to develop more effective treatment schemes.This article introduces recent progress in the regulation of ERK1/2 signaling on cell invasion and the role of such regulation in diseases,with a view to give new insights into the clinical treatment of ERK 1/2-related diseases.
Female ; Pregnancy ; Humans ; Mitogen-Activated Protein Kinase 3 ; Signal Transduction ; Mitogen-Activated Protein Kinases ; Cell Cycle ; Cell Proliferation

Middle cerebral artery occlusion (MCAO) results in cell death by activation of complex signal pathways for cell death and survival. Hypothermia is a robust neuroprotectant, and its effect has often been attributed to various mechanisms, but it is not yet clear. Upstream from the cell death promoters and executioners are several enzymes that may activate several transcription factors involved in cell death and survival. In this study, we immunohistochemically examined the phosphorylation of mitogen- activated protein kinase, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 kinase during early period of the ischemic injury, following 2 hours (h) of transient MCAO. Increased phosphorylation of ERK and p38 was observed in the vessels at 3 h, neuron-like cells at 6 and 12 h and glia-like cells at 12 h. Activation of JNK was not remarkable, and a few cells showed active JNK following ischemia. Phosphorylation of Elk-1, a transcription factor, was reduced by ischemic insult. Hypothermia attenuated the activation of ERK, p38 and JNK, and inhibited reduction of Elk-1. These data suggest that signals via different MAPK family members converge on the cell damage process and hypothermia protects the brain by interfering with these pathways.
Brain ; Cell Death ; Humans ; Hypothermia* ; Infarction, Middle Cerebral Artery ; Ischemia ; JNK Mitogen-Activated Protein Kinases ; Mitogen-Activated Protein Kinases* ; Phosphorylation ; Phosphotransferases ; Protein Kinases ; Signal Transduction ; Stroke* ; Transcription Factors