The role of mitogen-activated protein kinase signaling pathway in endometriosis.

AIM: Endometriosis is an estrogen-dependent chronic inflammatory condition which causes pain, infertility, and predisposition for ovarian cancer. Endometriosis generates a unique microenvironment for survivability of endometriotic lesions which includes cell proliferation, differentiation, migration, and apoptosis. For these cellular activities, cascading activations of intracellular kinases are needed. Many kinase signaling pathways, IKKß/NK-κB pathway, PI3K/AKT/mTOR, and the mitogen-activated protein kinase (MAPK) pathways (ERK1/2, p38, and JNK), are activated in endometriosis. In this review, we focus on the role of MAPK pathways in endometriosis. METHODS: To identify the role of MAP Kinase signaling pathway in endometriosis we searched the Pubmed database using the search terms in various combinations "endometriosis," "endometrium," "ovary," "MAPK pathway," "ERK pathway," "p38 pathway," "JNK pathway," "estrogen," and "progesterone." RESULTS: According to the current literature, MAPK signaling pathway has various roles in generating microenvironment and survival of endometriosis. Abnormal MAPK activation in migration, implantation, growth, invasion into the pelvic structures, proliferation, and apoptosis leads to the form of endometriosis and to worsen the condition in patients with endometriosis. CONCLUSION: To further investigations on the effective and long-term endometriosis treatment, MAPK signaling pathways may be targeted. Molecular mechanism of MAPK signaling pathway in endometriosis should be more deeply understood and clinical trials should be more commonly performed for possible new endometriosis treatments to improve fertility and rescue endometriosis irreversibly.

Identification of Functional MKK3/6 and MEK1/2 Homologs from Echinococcus granulosus and Investigation of Protoscolecidal Activity of Mitogen-Activated Protein Kinase Signaling Pathway Inhibitors In Vitro and In Vivo.

Cystic echinococcosis is a zoonosis caused by the larval stage of Echinococcus granulosussensu lato There is an urgent need to develop new drugs for the treatment of this disease. In this study, we identified two new members of mitogen-activated protein kinase (MAPK) cascades, MKK3/6 and MEK1/2 homologs (termed EgMKK1 and EgMKK2, respectively), from E. granulosussensu stricto Both EgMKK1 and EgMKK2 were expressed at the larval stages. As shown by yeast two-hybrid and coimmunoprecipitation analyses, EgMKK1 interacted with the previously identified Egp38 protein but not with EgERK. EgMKK2, on the other hand, interacted with EgERK. In addition, EgMKK1 and EgMKK2 displayed kinase activity toward the substrate myelin basic protein. When sorafenib tosylate, PD184352, or U0126-ethanol (EtOH) was added to the medium for in vitro culture of E. granulosus protoscoleces (PSCs) or cysts, an inhibitory and cytolytic effect was observed via suppressed phosphorylation of EgMKKs and EgERK. Nonviability of PSCs treated with sorafenib tosylate or U0126-EtOH, and not with PD184352, was confirmed through bioassays, i.e., inoculation of treated and untreated protoscoleces into mice. In vivo treatment of E. granulosussensu stricto-infected mice with sorafenib tosylate or U0126-EtOH for 4 weeks demonstrated a reduction in parasite weight, but the results did not show a significant difference. In conclusion, the MAPK cascades were identified as new targets for drug development, and E. granulosus was efficiently inhibited by their inhibitors in vitro The translation of these findings into in vivo efficacy requires further adjustment of treatment regimens using sorafenib tosylate or, possibly, other kinase inhibitors.

Sustained Activation of JNK Induced by Quinolinic Acid Alters the BDNF/TrkB Axis in the Rat Striatum.

Oxidative stress secondary to excitotoxicity is a common factor in the physiopathology of a variety of neurological disorders. In response to oxidative stress, several signaling pathways, such as MAPK, are activated or inactivated. Mitogen-activated protein kinase (MAPK) family activation must be finely regulated in time and intensity, as this pathway may either preserve cell survival or promote cell death. In the present study, the activation of MAPK in the excitotoxic injury induced by quinolinic acid (QUIN) was examined in vivo, at short and long times. We used different doses (30, 60, 120 and 240 nmol) of QUIN injected intrastriatally in the right rat striatum and the effect of this treatment on motor deficits, cellular damage, MAPK activation and BDNF/TrkB axis, were evaluated at 2 h and 7 days post-lesion. Higher doses of QUIN (120 and 240 nmol) induced rat motor deficits and caused morphological changes in neurons around the lesion core. QUIN decreased the activation of ERK1/2 in a dose-dependent manner at 7 days post-injection, and induced a sustained increase of c-Jun NH2-terminal kinase (JNK) activation from 2 h to 7 days post-injury. JNK activation was dependent on the QUIN-induced NMDAr activation (only 120 nmol). No significant difference in p38 activation with QUIN was observed. QUIN (120 and 240 nmol) decreased BDNF/TrkB levels at 7 days post-injury. JNK inhibition (by an intracerebroventricular injection of SP600125) prevented the QUIN-induced reduction in BDNF and TrkB at 7 day post-injury, suggesting a role for the QUIN-induced JNK activation on the observed decrease in BDNF levels.

The Role of the MAPK Signaling, Topoisomerase and Dietary Bioactives in Controlling Cancer Incidence.

Reactive oxygen species (ROS) are common products of mitochondrial oxidative phosphorylation, xenobiotics metabolism and are generated in response to several environmental stress conditions. Some of them play important biochemical roles in cellular signal transduction and gene transcription. On the other hand, ROS are known to be involved in a wide range of human diseases, including cancer. The excessive production of such ROS together with disruption of homeostasis detoxifying mechanisms can mediate a series of cellular oxidative stresses. The oxidative stress of redundant free radicals production can lead to oxidative denaturation of cellular macromolecules including proteins, lipids and DNA. Moreover, oxidative damage is one of the major causes of DNA mutations, replication errors and genomic abnormalities which result in either inhibition or induction of transcription, and end with the disturbance of signal transduction pathways. Among affected signaling pathways are redox-sensitive kinases. The stimulation of these kinases induces several transcription factors through the phosphorylation of their module proteins. The activation of such pathways induces proliferation and cellular transformation. A diet rich in antioxidant compounds has potential health benefits, and there is a growing interest in the role of natural antioxidants in nutrition for prevention and cure of cancer diseases. A controversy has risen regarding the relation between antioxidants and the significant decrease in the risk of cancer incidence. In this review, we will focus on redox-sensitive kinases signaling pathways, highlighting the effects of dietary antioxidant on the prevention, incidence, prognosis or even treatment of human cancers. In addition, we will place emphasis on the chemical classes of pterocarpans as natural anti-oxidants/cancers as well as their underlying mechanisms of action, including their effects on MAPKs and topoisomerase activities.

Suppression of osteogenic activity by regulation of WNT and BMP signaling during titanium particle induced osteolysis.

Periprosthetic osteolysis remains the leading obstacle for total joint replacements. Primarily, it was thought that aseptic loosening is mainly caused by macrophage mediated inflammatory process arising from production of wear debris. The role of osteoclasts and its sequential bone resorption ability has been extensively studied, but little is known about impaired osteogenesis during osteolysis. In the current study, we have tried to delineate the regulatory mechanism of osteogenic signals by Ti particles in osteoprogenitor cells as well its participatory role in wear debris induced osteolysis. Implantation of Ti particles on mice calvaria induced pro-inflammatory response, elevated expression of COX2 and reduced the expression of Osterix. Treatment of Ti particles to MC3T3 E-1 cells displayed decreased osteogenic activity including ALP activity, mineralization and mRNA levels several osteogenic genes. Moreover, the basal activity of WNT and BMP signaling pathways was suppressed in MC3T3 E-1 cells treated with Ti particles. As an early response to Ti particles, MC3T3 E-1 cells showed activation of ERK and JNK. Co-inhibition of ERK and JNK with their specific inhibitors resulted in partial recovery of WNT and BMP signaling activity as well as ALP activity and collagen synthesis. Finally, LiCl mediated activation of WNT signaling pathway demonstrated rescue of Ti particle facilitated suppression of Osterix expression in mice calvaria. Our results provide evidences that WNT signaling pathway is regulated by ERK, JNK, and BMP signaling pathway during wear debris induced inflammatory osteolysis and may be considered as suitable therapeutic targets for the treatment. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 912-926, 2017.

c-Jun N-terminal kinase inhibitors: a patent review (2010 - 2014).

INTRODUCTION: c-Jun N-terminal kinases (JNKs) are involved in the emergence and progression of diverse pathologies such as neurodegenerative, cardiovascular and metabolic disorders as well as inflammation and cancer. In recent years, several highly selective pan-JNK inhibitors have been characterized and three chemical entities targeting JNKs have been investigated in clinical trials. AREAS COVERED: This review summarizes patents claiming inhibitors of all JNK isoforms published between 2010 and 2014. Although primarily focusing on the patent literature, relevant peer-reviewed publications related to the covered patents have also been included. Moreover, key patents claiming novel applications of previously published chemical entities are reviewed. The article highlights a total of 28 patents from nine pharmaceutical companies and academic research groups. EXPERT OPINION: Although some selective pan-JNK inhibitors with reasonable in vivo profiles are now available, little is known about the isoform selectivity required for each particular indication and the development of isoform-selective JNK inhibitors still represents a challenge in JNK drug discovery. Moreover, isoform-selective tool compounds are a prerequisite to a comprehensive understanding of the biology of each JNK isoform. Potential approaches towards such compounds include the design of type-II and type-I(1)/2 binders, which are absent in the current JNK inhibitor portfolios, as well as the design of novel allosteric inhibitors. Furthermore, covalent inhibition, which already led to the first high-quality probe for JNKs, might be further exploited for gaining selectivity and in vivo efficacy. With regard to a potential therapeutic application, the recently proposed concept of covalent reversible inhibitors is expected to be attractive.

Modulation of albumin-induced endoplasmic reticulum stress in renal proximal tubule cells by upregulation of mapk phosphatase-1.

High amounts of albumin in urine cause tubulointerstitial damage that leads to a rapid deterioration of the renal function. Albumin exerts its injurious effects on renal cells through a process named endoplasmic reticulum (ER) stress due to the accumulation of unfolded proteins in the ER lumen. In addition, albumin promotes phosphorylation and consequent activation of MAPKs such as ERK1/2. Since ERK1/2 activation promoted by albumin is a transient event, the aims of the present work were to identify the phosphatase involved in their dephosphorylation in albumin-exposed cells and to analyze the putative regulation of this phosphatase by albumin. We also sought to determine the role played by the phospho/dephosphorylation of ERK1/2 in the cellular response to albumin-induced ER stress. MAP kinase phosphatase-1, MKP-1, is a nuclear enzyme involved in rapid MAPK dephosphorylation. Here we present evidence supporting the notion that this phosphatase is responsible for ERK1/2 dephosphorylation after albumin exposure in OK cells. Moreover, we demonstrate that exposure of OK cells to albumin transiently increases MKP-1 protein levels. The increase was evident after 15 min of exposure, peaked at 1 h (6-fold) and declined thereafter. In cells overexpressing flag-MKP-1, albumin caused the accumulation of this chimera, promoting MKP-1 stabilization by a posttranslational mechanism. Albumin also promoted a transient increase in MKP-1 mRNA levels (3-fold at 1 h) through the activation of gene transcription. In addition, we also show that albumin increased mRNA levels of GRP78, a key marker of ER stress, through an ERK-dependent pathway. In line with this finding, our studies demonstrate that flag-MKP-1 overexpression blunted albumin-induced GRP78 upregulation. Thus, our work demonstrates that albumin overload not only triggers MAPK activation but also tightly upregulates MKP-1 expression, which might modulate ER stress response to albumin overload.