Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Key pathway”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,171 records · Page 65Linked to original sources
PubMed2003

Possible mechanisms underlying the mitogenic action of heptachlor in rat hepatocytes.

The worldwide use of the organochlorine pesticide heptachlor has led to widespread contamination in the environment. Like many other organochlorine pesticides, heptachlor is considered to pose a threat to human health. It has been shown that heptachlor is a tumor-promoting agent, but the mechanisms involved still remain unclear. The negative response of heptachlor in in vitro genotoxicity test suggests that this pesticide displays its carcinogenicity through epigenetic pathways. With the growing evidence that proliferation accounts for the tumor-promoting effects of many agents, the purpose of this work was to investigate the mechanisms involved in the mitogenic activity of heptachlor in quiescent rat hepatocytes and to understand the properties of this compound as a tumor promoter in the liver. Heptachlor triggered significant proliferation in quiescent rat hepatocytes. Two mechanisms were delineated to support the mitogenic effect in the hepatocyte: activation of key kinases in signaling pathways and inhibition of apoptosis. Exposure to heptachlor led to activation of protein kinase C mitogenactivated protein kinases. Moreover, these results indicate that like many tumor promoters, heptachlor strongly inhibited TGFbeta-induced apoptosis and cytochrome c release into the cytosol. The levels of the anti-apoptotic protein Bcl-2 were also increased in the presence of heptachlor. In conclusion, these results indicate that heptachlor alters basic cell function by interfering with key cellular signaling pathways.

Animals↗
PubMed2006

Multiple functions of Notch signaling in self-renewing organs and cancer.

In recent years a substantial body of evidence has accumulated to support the notion that signaling pathways known to be important during embryonic development play important roles in regulating self-renewing tissues. Moreover, the same pathways are often deregulated during tumorigenesis due to mutations of key elements of these pathways. The Notch signaling cascade meets all of the above-mentioned criteria. We discuss here the pleiotropic roles of the Notch signaling pathway in three different self-renewing organs (intestine, hematopoietic system and skin) and how its deregulation is involved in tumorigenesis.

Animals↗
PubMed2002

Inflammation and the development of pancreatic cancer.

OBJECTIVE: Pancreatic cancer has an extremely poor prognosis and the cellular mechanisms contributing to pancreatic cancer are relatively unknown. The goals of this review are to present the epidemiological and experimental data that supports inflammation as a key mediator of pancreatic cancer development, to explain how inflammatory pathways may create an environment that supports tumor formation, and to discuss how the use of novel agents directed at these pathways may be used for the treatment of pancreatic malignancy. SUMMARY BACKGROUND DATA: Inflammation has been identified as a significant factor in the development of other solid tumor malignancies. Both hereditary and sporadic forms of chronic pancreatitis are associated with an increased risk of developing pancreatic cancer. The combined increase in genomic damage and cellular proliferation, both of which are seen with inflammation, strongly favors malignant transformation of pancreatic cells. Cytokines, reactive oxygen species, and mediators of the inflammatory pathway (e.g., NF-kappaB and COX-2) have been shown to increase cell cycling, cause loss of tumor suppressor function, and stimulate oncogene expression; all of which may lead to pancreatic malignancy. Anti-cytokine vaccines, inhibitors of pro-inflammatory NF-kappaB and COX-2 pathways, thiazolidinediones, and anti-oxidants are potentially useful for the prevention or treatment of pancreatic cancer. Redirection of experimental interests toward pancreatic inflammation and mechanisms of carcinogenesis may identify other novel anti-inflammatory agents or other ways to screen for or prevent pancreatic cancer. CONCLUSION: Pancreatic inflammation, mediated by cytokines, reactive oxygen species, and upregulated pro-inflammatory pathways, may play a key role in the early development of pancreatic malignancy.

Carcinoma↗
PubMed2000

Murine models of inflammation: role of CD23.

The role of IgE in eosinophil recruitment and bronchial hyperresponsiveness has been extensively studied with murine models of inflammation. Many investigators using various knockout models have clearly shown that both IgE-dependent and -independent pathways play a role in eosinophil recruitment and bronchial hyperresponsiveness after allergen challenge, illustrating the complexity of airways inflammation. The expression of this response is likely to involve many interacting pathways, and it will be a considerable challenge to determine key points within these pathways that will yield novel targets for future therapeutic strategies.

Animals↗
PubMed2005

HDPR1, a novel inhibitor of the WNT/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing.

Oncogenic activation of the WNT/beta-catenin signaling pathway is common in hepatocellular carcinoma (HCC). Dishevelled (Dvl), a key activator of the pathway, inhibits the adenomatous polyposis coli complex, and this leads to the accumulation of beta-catenin and promotes tumorigenesis. Recently, a novel inhibitor of Dishevelled, namely Dapper (Dpr), was isolated in Xenopus. To explore whether HDPR1, the human homologue of Dpr, has an anti-oncogenic role in hepatocarcinogenesis, we studied the expression of this gene in HCCs. We found that there were two alternatively spliced transcripts of HDPR1, designated as alpha and beta forms, in human liver. Downregulation of the gene expression was observed in 31 (43%) of the 72 human HCC samples using the primer pair that amplified both transcripts. Furthermore, the HDPR1alpha was downregulated in 42 (58%) of 72 human HCCs and the downregulation significantly correlated with accumulation of beta-catenin. Also, downregulation of HDPR1 by RNA interference in HLE cells led to cytoplasmic accumulation of beta-catenin. Furthermore, a CpG island located at the promoter region and exon 1 of the HDPR1 gene was methylated in 22 (51%) of human HCCs. We showed that downregulation of HDPR1, in hepatoma cell lines, was associated with methylation of this CpG island using bisulfite sequencing and 5-aza-2'-deoxycytidine demethylation experiment. In addition to methylation-mediated downregulation of HDPR1, allelic loss (13-28% of informative cases) was detected using microsatellite markers flanking the HDPR1 locus. To conclude, downregulation of HDPR1 is common in HCCs, frequently involves hypermethylation of the promoter region, and allelic loss of the HDPR1 locus may also play a role.

Adaptor Proteins, Signal Transducing↗
PubMed2026

FZD5 drives macrophage-mediated immunomodulation and predicts prognosis in glioma: evidence from single-cell sequencing.

BACKGROUND: Gliomas are highly malignant brain tumors characterized by an immunosuppressive microenvironment, which limits therapeutic efficacy and contributes to poor clinical outcomes. The WNT/β-catenin signaling pathway is critically involved in tumor progression, and FZD5, a key receptor within this pathway, may participate in immune regulation. However, its specific role and underlying mechanisms in glioma remain unclear. METHODS: RNA-seq and microarray datasets from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA), together with single-cell RNA sequencing (scRNA-seq) datasets from GEO, were comprehensively analyzed. The Seurat package was used to identify macrophage-related clusters and mitophagy-associated pathways. Cox and LASSO regression analyses, along with a prognostic nomogram, were applied to evaluate the prognostic significance of FZD5. Immune infiltration, functional enrichment, and immunotherapy response analyses were conducted, followed by validation using spatial transcriptomics, immunohistochemistry, and in vitro assays. RESULTS: In bulk glioma transcriptomes, FZD5 emerged as an independent predictor of poor prognosis. Crucially, single-cell and spatial analyses revealed that the biologically significant FZD5 signal originated predominantly within tumor-associated macrophages (TAMs), where it colocalized with the M2 marker CD163. Consistently, elevated FZD5 levels correlated with increased myeloid infiltration and an immunosuppressive tumor microenvironment. Functionally, macrophage-expressed FZD5 was associated with mitophagy-related programs and promoted an M2-skewed phenotype, thereby enhancing glioma cell proliferation, migration, and invasion via macrophage-glioma crosstalk. CONCLUSION: FZD5 is a TAM-enriched marker in glioma tissues and a potential regulator of macrophage-associated immunosuppressive programs, supporting its utility as a prognostic biomarker and a candidate target for microenvironment-oriented interventions in glioma.

Humans↗
PubMed2006

The bacterial weaponry: lessons from Shigella.

Shigella, a Gram-negative bacterial species of the family Enterobacteriaceae, causes bacillary dysentery in humans, an acute rectocolitis that reflects the capacity of the microorganism to disrupt, invade, and cause the inflammatory destruction of the intestinal epithelium. Here, the pathogenesis of Shigella infection is analyzed in the context of the disruption of the homeostatic balance that protects the gut against inflammation in the presence of its commensal flora. Thus a unified view by which enteroinvasive pathogens allow identification of key signalling molecules and pathways involved in the regulation of intestinal inflammation, thereby providing keys to understand inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis.

Dysentery, Bacillary↗
PubMed2006

The etiology of hypertension in the metabolic syndrome part three: the regulation and dysregulation of blood pressure.

To understand blood pressure is regulated, and how this regulation is disturbed in hypertension, we need to understand how blood volume is regulated and how the distribution of that volume across the vascular tree is regulated. Here we review the literature on blood volume regulation and how it is disturbed in the pre-diabetic and diabetic state. We also provide a comprehensive overview of vascular dysfunction, discussing the key mechanisms, mediators and pathways which are involved. In particular, we focus on the key concept of endothelial dysfunction and how this has shaped our understanding of hypertension.

Animals↗
PubMed2006

Constructing the eukaryotic expression vector to study preliminarily the functions of hammerhead ribozyme targeting base excision repair gene HOGG1.

OBJECTIVE: Adriamycin is widely used as an effective anti-tumor drug clinically treating a number of human cancers, but the effect of adriamycin is limited by drug resistance. The various kinds of investigations indicated that the anti-tumor activity of adriamycin resulted from drug-induced free radical formation. The free radicals could lead to oxidative DNA damage, and the lesion would be repaired by base excision repair (BER) pathway. Human 8-oxoguanine DNA glycosylase 1 (HOGG1) is a key enzyme on BER pathway. To study the influence and biological mechanism of the HOGG1 to adriamycin drug-sensitivity, the eukaryotic expression vector with gene of hammerhead ribozyme targeting HOGG1 mRNA would be constructed and identified, and then the change of drug-sensitivity in lung cancer A549 cells would be investigated. METHODS: According to computer design, two specific restriction site BamH I and EcoR I were added to both ends of the ribozyme gene, then the modified ribozyme gene was synthesized and cloned into the eukaryotic expression vector pcDNA3.1 (+). The positive recombinants were screened by ampicillin resistance, and plasmids were extracted from the positive recombinants and digested by BamH I and EcoR I , and then were analyzed by agarose gel electrophoresis and DNA sequencing. The recombinants were transiently transfected into A549 cells. The positive recombinants were identified by reverse transcription-polymerase chain reaction (RT-PCR) targeting to NEO gene, which was a neomycin resistance gene for selection of stable cell lines and only existed in vectors. The changes of HOGG1 mRNA in A549 cells were detected by RT-PCR. Then the cellular sensitivity to adriamycin was tested by comparison between untransfected cells and transfected cells by MTT assay. The adriamycin-induced DNA damage was investigated by comet assay or single cell gel electrophoresis (SCGE) between untransfected and transfected cells. RESULTS: The recombinants containing the ribozyme gene were successfully selected by restriction endonuclease digestion and agarose gel electrophoresis, and were further proved by DNA automatic sequencing. A549 cells containing the recombinants were identified by RT-PCR, because NEO genes were amplified only in cells transfected successfully. The expression of HOGG1 mRNA in A549 transfected with ribozyme gene was 36% significantly less than in control cells (P < 0.05). MTT assay showed that the sensitivity of transfected cells to adriamycin were significantly increased in comparison with untransfected cells (P < 0.05). The comet assay showed that the extent of DNA damage induced by adriamycin was worse in transfected cells than unrtransfected cells (P < 0.05), but there was no time-dependent reaction correlation observed in cells. CONCLUSION: The eukaryotic expression vector with gene of hammerhead ribozyme targeting HOGG1 mRNA was constructed successfully, and effectively inhibited the expression of HOGG1 gene in lung cancer A549 cells, and increased the cellular sensitivity to adriamycin, and will help to study deeply the functions of base excision repair genes-HOGG1.

Base Sequence↗
PubMed2003

Cellular mechanism of insulin resistance: potential links with inflammation.

Insulin resistance is a pivotal feature in the pathogenesis of type 2 diabetes, and it may be detected 10-20 y before the clinical onset of hyperglycemia. Insulin resistance is due to the reduced ability of peripheral target tissues to respond properly to insulin stimulation. In particular, impaired insulin-stimulated muscle glycogen synthesis plays a significant role in insulin resistance. Glucose transport (GLUT4), phosphorylation (hexokinase) and storage (glycogen synthase) are the three potential rate-controlling steps regulating insulin-stimulated muscle glucose metabolism, and all three have been implicated as being the major defects responsible for causing insulin resistance in patients with type 2 diabetes. Using (13)C/(31)P magnetic resonance spectroscopy (MRS), we demonstrate that a defect in insulin-stimulated muscle glucose transport activity is the rate-controlling defect. Using a similar (13)C/(31)P MRS approach, we have also demonstrated that fatty acids cause insulin resistance in humans due to a decrease in insulin-stimulated muscle glucose transport activity, which could be attributed to reduced insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle. Furthermore, we have recently proposed that this defect in insulin-stimulated muscle glucose transport activity may be due to the activation of a serine kinase cascade involving protein kinase C theta and IKK-beta, which are key downstream mediators of tissue inflammation. Finally, we propose that any perturbation that leads to an increase in intramyocellular lipid (fatty acid metabolites) content such as acquired or inherited defects in mitochondrial fatty acid oxidation, defects in adipocyte fat metabolism or simply increased fat delivery to muscle/liver due to increased energy intake will lead to insulin resistance through this final common pathway. Understanding these key cellular mechanisms of insulin resistance should help elucidate new targets for treating type 2 diabetes.

Diabetes Mellitus, Type 2↗
PubMed2006

The phosphoinositide 3-kinase/Akt pathway is essential for the retinoic acid-induced differentiation of F9 cells.

Retinoic acid (RA) induces cell growth arrest and differentiation through two families of nuclear receptors, the RARs and the RXRs. The phosphoinositide 3-kinase (PI3K)/Akt pathway also plays key roles in these processes, that is, cell cycle progression, cell differentiation and cell survival. We report that, in mouse embryocarcinoma cells (F9 cells), RA induces an early activation of PI3K and Akt via an increase in the expression of the p85alpha regulatory subunit. This effect is followed by an inhibition of Akt. Both effects require the integrity of the RA pathway as they are not observed in RA-resistant RARgamma null cells. We propose a model through which RA induces a biphasic regulation of Akt with an activation participating to the differentiation process, followed by an inhibition, which has been correlated to the RA-induced growth arrest.

Animals↗
PubMed2002

Molecular basis of hyperparathyroidism and potential targets for drug development.

Our appreciation of the molecular pathogenesis of primary hyperparathyroidism (HPT) has seen great advances over the past decade. This improved understanding may well lead to the development of new treatment options that are specifically targeted to defective pathways. This review summarizes recent advances in the molecular basis of HPT and associated endocrinopathies, and discusses the potential for these and future findings to provide targets for alternative approaches to therapy. The only proven contributors to common sporadic HPT, by virtue of clonal genetic abnormalities, are the cyclin D1 and MEN1 genes. Cyclin D1 is an oncogene that encodes a key regulator of the cell cycle, while MEN1 is a tumor suppressor gene that has also been implicated in familial multiple endocrine neoplasia type 1 (MEN1), in which primary HPT is common. In addition, other key parathyroid regulatory pathways may play a role in HPT pathogenesis. 1,25 (OH)2-vitamin D. Ca2+ and phosphate are regarded as principal regulators of parathyroid cell proliferation and PTH secretion. Therefore, prime candidate targets include the Ca2+ sensing receptor (CASR) gene, the vitamin D receptor (VDR) gene, a putative phosphate receptor gene, their cognate gene products, and other genes or proteins involved in their respective biochemical pathways. Attempts to identify new therapies based specifically on the defective pathways in HPT could complement or eventually supplant traditional approaches.

Animals↗
PubMed2005

Olfactory and lens placode formation is controlled by the hedgehog-interacting protein (Xhip) in Xenopus.

The integration of multiple signaling pathways is a key issue in several aspects of embryonic development. In this context, extracellular inhibitors of secreted growth factors play an important role, which is to antagonize specifically the activity of the corresponding signaling molecule. We provide evidence that the Hedgehog-interacting protein (Hip) from Xenopus, previously described as a Hedgehog-specific antagonist in the mouse, interferes with Wnt-8 and eFgf/Fgf-8 signaling pathways as well. To address the function of Hip during early embryonic development, we performed gain- and loss-of-function studies in the frog. Overexpression of Xhip or mHip1 resulted in a dramatic increase of retinal structures and larger olfactory placodes primarily at the expense of other brain tissues. Furthermore, loss of Xhip function resulted in a suppression of olfactory and lens placode formation. Therefore, the localized expression of Xhip may counteract certain overlapping signaling activities, which inhibit the induction of distinct sensory placodes.

Amino Acid Sequence↗
PubMed2005

Functional network analysis reveals extended gliomagenesis pathway maps and three novel MYC-interacting genes in human gliomas.

Gene expression profiling has proven useful in subclassification and outcome prognostication for human glial brain tumors. The analysis of biological significance of the hundreds or thousands of alterations in gene expression found in genomic profiling remains a major challenge. Moreover, it is increasingly evident that genes do not act as individual units but collaborate in overlapping networks, the deregulation of which is a hallmark of cancer. Thus, we have here applied refined network knowledge to the analysis of key functions and pathways associated with gliomagenesis in a set of 50 human gliomas of various histogenesis, using cDNA microarrays, inferential and descriptive statistics, and dynamic mapping of gene expression data into a functional annotation database. Highest-significance networks were assembled around the myc oncogene in gliomagenesis and around the integrin signaling pathway in the glioblastoma subtype, which is paradigmatic for its strong migratory and invasive behavior. Three novel MYC-interacting genes (UBE2C, EMP1, and FBXW7) with cancer-related functions were identified as network constituents differentially expressed in gliomas, as was CD151 as a new component of a network that mediates glioblastoma cell invasion. Complementary, unsupervised relevance network analysis showed a conserved self-organization of modules of interconnected genes with functions in cell cycle regulation in human gliomas. This approach has extended existing knowledge about the organizational pattern of gene expression in human gliomas and identified potential novel targets for future therapeutic development.

Adult↗
PubMed2026

Zhiling Jiangya decoction treats hypertension in rats: An integrative study of network pharmacology, immune infiltration, molecular simulation, and 16S rDNA sequencing.

OBJECTIVE: This study integrated network pharmacology, immune infiltration analysis, molecular docking, molecular dynamics simulation, ADMET prediction, 16S rDNA sequencing, and rat experiments to elucidate the potential mechanisms underlying the antihypertensive effects of Zhiling Jiangya Decoction (ZLJYD). METHODS: Active compounds and their potential targets were screened from the PubChem, TCMSP, NovoPro, and SwissTargetPrediction databases. Hypertension-related targets were retrieved from the OMIM and GeneCards databases, and overlapping targets were identified. The STRING database and Cytoscape 3.10.1 software were used to construct a protein-protein interaction network and a herb-component-target-disease network. Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to identify the key biological processes and signaling pathways involved. Using the CIBERSORT algorithm combined with correlation analysis, we investigated the association between key targets and immune cell infiltration. Molecular docking, molecular dynamics simulations, and ADMET predictions were performed to assess the binding stability and pharmacokinetic properties of the main compounds with their corresponding targets. Finally, the antihypertensive efficacy of ZLJYD was validated using a spontaneously hypertensive rat model, and alterations in gut microbiota were analyzed using 16S rDNA sequencing. RESULTS: A total of 123 active compounds and 267 hypertension-related targets of ZLJYD were identified. Enrichment analysis revealed that these targets were primarily associated with the PI3K-Akt signaling pathway and lipid and atherosclerosis pathways. Immune infiltration analysis suggested that the therapeutic effects of ZLJYD may involve the regulation of follicular helper T cells, na&#xef;ve B cells, and na&#xef;ve CD4&#x207a; T cells. Molecular docking and dynamics simulations supported the stable binding of key compounds to their target proteins, while ADMET predictions indicated favorable pharmacokinetic properties and safety profiles. Rat experiments demonstrated that ZLJYD significantly reduced blood pressure in spontaneously hypertensive rats, partially alleviated gut microbiota dysbiosis, and altered microbial community structure and phylogenetic diversity. CONCLUSION: This study systematically elucidates the potential mechanisms underlying the antihypertensive effects of ZLJYD through multiple components, targets, and pathways, particularly immune regulation and gut microbiota remodeling. These findings provide mechanistic insights into its potential therapeutic application.

16S rDNA sequencing↗
PubMed2006

Defining pathways.

AIMS AND BACKGROUND: The term 'clinical pathway' is internationally accepted in all settings of healthcare management. The way in which clinical pathways have been developed in the United Kingdom differs from that in the USA. Besides the international differences in the purpose, many alternative names also can be found. These have led to confusion. There is no single, widely accepted definition of a clinical pathway. The aim of the study was to survey the definitions used in describing the concept and to derive key characteristics of clinical pathways. METHOD: Using the PubMed, we conducted a review of literature published between January 2000 and December 2003 using the following terms: critical pathway, clinical pathway, integrated care pathway, care pathway and care map. All reports reviewed had to use the concept, as defined by the Medical Subject Headings term, to be considered. To assess all definitions, the concept analysis method was used. RESULTS: In 82 of the 263 eligible articles, the definition of pathway was given. Totally, we found 84 different definitions. Each definition was rephrased by taking into consideration the following three features inherent to pathways: nouns, characteristics and aims and outcomes. Every feature was further divided into categories. CONCLUSIONS: A clinical pathway is a method for the patient-care management of a well-defined group of patients during a well-defined period of time. A clinical pathway explicitly states the goals and key elements of care based on Evidence Based Medicine (EBM) guidelines, best practice and patient expectations by facilitating the communication, coordinating roles and sequencing the activities of the multidisciplinary care team, patients and their relatives; by documenting, monitoring and evaluating variances; and by providing the necessary resources and outcomes. The aim of a clinical pathway is to improve the quality of care, reduce risks, increase patient satisfaction and increase the efficiency in the use of resources.

Critical Pathways↗
PubMed2003

Nuclear accumulation of beta-catenin protein in Wilms' tumours.

The wnt-signalling pathway plays an important role during both normal kidney development and Wilms' tumourigenesis. Activation of this pathway involves stabilization, intracellular accumulation, and nuclear translocation of the beta-catenin protein and may be caused by specific mutations in the beta-catenin gene itself. Such mutations have been found in about 15% of Wilms' tumours. This study has analysed the intracellular levels and subcellular distribution of beta-catenin protein in 36 primary Wilms' tumour specimens and has correlated these results with the mutational status of the beta-catenin gene. Immunohistochemistry detected faint cytoplasmic and strong membranous expression of beta-catenin protein in the epithelial compartment of all tumours examined. In contrast, nuclear immunoreactivity for beta-catenin was detected in 9 of 9 Wilms' tumours containing a mutation of the beta-catenin gene and in 15 of 27 Wilms' tumours without detectable beta-catenin mutation. Nuclear positivity, in each case, was found to be very strong, but was usually present only in a fraction of cells ranging from 5% to 10%. Among the different histological subcompartments, blastemal and mesenchymal cell nuclei preferentially stained positive, whereas cells of epithelial differentiation displayed nuclear localization of beta-catenin protein in only a single case. Furthermore, nuclear positive cells were found in Wilms' tumours of all stages and in tumours of both favourable and unfavourable histology. These data support the idea that activation of the wnt-signalling pathway is a key oncogenic step in Wilms' tumourigenesis and that it probably involves transcriptional activation of critical target genes, carried out by beta-catenin protein in the nucleus. The fact that nuclear immunoreactivity specific for beta-catenin was detected in a significant number of Wilms' tumours in the absence of beta-catenin mutations suggests that genetic defects affecting other members of the wnt-signalling pathway may contribute to the development of Wilms' tumours in those cases.

Adolescent↗
PubMed2005

Social threat and novel cage stress-induced sustained extracellular-regulated kinase1/2 (ERK1/2) phosphorylation but differential modulation of brain-derived neurotrophic factor (BDNF) expression in the hippocampus of NMRI mice.

The extracellular signal-regulated kinase1/2 (ERK1/2) pathway has a key role in cell survival and brain plasticity, processes that are impaired following exposure to stressful situations. We have recently validated two repeated intermittent stress procedures in male NMRI mice, social threat and repeated exposure to a novel cage, which result in clear behavioral effects following 4 weeks of application. The present results demonstrate that both repeated intermittent stress procedures alter the activity of the ERK1/2 pathway in the brain, as shown by changes in phosphorylated ERK1/2 (phospho-ERK1/2) protein expression and in the expression of downstream proteins: phosphorylated cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF), in the hippocampus, the frontal cortex and the hypothalamus. The hippocampus showed greater responsiveness to stress as the two stressors increased phospho-ERK1/2 and BDNF expression under acute condition. Following repeated stress, hyperphosphorylation of ERK1/2 was associated with up-regulation of hippocampal BDNF expression in the social threat group but not in mice exposed to novel cage. This lack of a pro-survival effect of ERK1/2 with repeated novel cage exposure may constitute an early event in stress-mediated brain pathology. The sustained BDNF up-regulation in the hippocampi of mice subjected to repeated social threat could be related to rewarding aspects of aggressive interactions, suggested by our previous studies.

Analysis of Variance↗