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Stress Pathways (stress + pathway)
Kinds of Stress Pathways Selected AbstractsAnalysis of Saccharomyces cerevisiae null allele strains identifies a larger role for DNA damage versus oxidative stress pathways in growth inhibition by seleniumMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 11 2008Eden Seitomer Abstract Selenium toxicity is a growing environmental concern due to widespread availability of high-dose selenium supplements and the development of high-selenium agricultural drainage basins. To begin to analyze the effects of selenium toxicity at the genetic level, we have systematically determined which genes are involved in responding to high environmental selenium using a collection of viable haploid null allele strains of Saccharomyces cerevisiae representing three major stress pathways: the RAD9 -dependent DNA repair pathway, the RAD6/RAD18 DNA damage tolerance pathway, and the oxidative stress pathway. A total of 53 null allele strains were tested for growth defects in the presence of a range of sodium selenite and selenomethionine (SeMet) concentrations. Our results show that ,64,72% of the strains lacking RAD9 -dependent DNA repair or RAD6/RAD18 DNA damage tolerance pathway genes show reduced growth in sodium selenite versus ,28,36% in SeMet. Interestingly both compounds reduced growth in ,21,25% of the strains lacking oxidative stress genes. These data suggest that both selenite and SeMet are likely inducing DNA damage by generating reactive species. The anticipated effects of loss of components of the oxidative stress pathway were not observed, likely due to apparent redundancies in these gene products that may keep the damaging effects in check. [source] Assessing oxidative pathway genes as risk factors for bipolar disorderBIPOLAR DISORDERS, Issue 5 2010Janice M Fullerton Fullerton JM, Tiwari Y, Agahi G, Heath A, Berk M, Mitchell PB, Schofield PR. Assessing oxidative pathway genes as risk factors for bipolar disorder. Bipolar Disord 2010: 12: 550,556. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives:, There is a growing body of evidence implicating oxidative stress and the glutathione system in the pathogenesis of major psychiatric illnesses, including schizophrenia and bipolar disorder. Here we investigate whether genes involved in oxidative stress regulation are associated with increased risk for bipolar disorder. Methods:, Four candidate genes were selected a priori from two different steps in the oxidative stress pathway, specifically the synthesis of glutathione [catalytic subunit of glutamate cysteine ligase (GCLC) and regulatory subunit of glutamate cysteine ligase (GCLM)] and the removal of reactive oxygen species [superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3)]. Haplotype tagging and functional nucleotide polymorphisms were selected in each gene and tested for association with bipolar disorder under narrow (n = 240) and broad (n = 325) phenotypic models, compared to healthy controls (n = 392, comprising 166 psychiatrically assessed unaffected controls plus 226 healthy individuals). Results:, Single marker association analysis did not reveal significant association with bipolar disorder; however, haplotypes in the SOD2 gene showed nominal association (global ,2 = 8.94, p = 0.03; broad model). Interaction analysis revealed a significant interaction between SOD2 and GPX3 haplotypes, which further increases risk for bipolar disorder (odds ratio = 2.247, ,2 = 9.526, p = 0.002, corrected p = 0.029). Conclusions:, Further characterization of the SOD2 and GPX3 interaction using larger cohorts is required to determine the role of these oxidative pathway genes as risk factors for bipolar disorder. [source] Tribble 3, a novel oxidized low-density lipoprotein-inducible gene, is induced via the activating transcription factor 4,C/EBP homologous protein pathwayCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1 2010Yuan-Yuan Shang Summary 1.,C/EBP homologueueueous protein (CHOP), an endoplasmic reticulum (ER) stress-inducible protein, has a critical role in regulation of the cell cycle and apoptosis by forming heterodimers with other C/EBP proteins. However, how CHOP function is regulated remains to be determined. The human homologue of Drosophila tribbles (TRIB3) is associated with CHOP and is upregulated by oxidized low-density lipoprotein (ox-LDL). The aim of the present study was to investigate the role of CHOP in ox-LDL-induced TRIB3 expression in macrophages. 2.,Human monocyte-derived macrophages were treated with various concentrations of ox-LDL (0, 2.5, 5, 10, 25 and 50 ,g/mL) or 2 ,g/mL tunicamycin for 0, 4, 8, 16, 24 and 48 h or were transfected with CHOP or TRIB3 expression plasmid and TRIB3 targeting short interference RNA (siRNA). The expression of CHOP and activating transcription factor 4 (ATF4) mRNA in treated cells was detected by quantitative real-time polymerase chain reaction (PCR). 3.,The expression of CHOP and ATF4 mRNA increased with increasing concentrations of ox-LDL and duration of time. The ox-LDL-induced expression of TRIB3 mRNA was upregulated later than the expression of CHOP and ATF4 mRNA. Overexpression of CHOP increased the mRNA expression of TRIB3, which was further increased in CHOP-overexpressing macrophages treated with ox-LDL. Overexpression of TRIB3 suppressed the expression of CHOP, whereas TRIB3 silencing increased CHOP expression following ox-LDL stimulation by a negative feedback mechanism. 4.,In conculsion, the expression of ATF4 and CHOP is upregulated by ox-LDL in a dose- and time-dependent manner in naturally differentiated human macrophages. Oxidized LDL induces TRIB3 expression via an ATF4/CHOP-dependent ER stress pathway. [source] Bentazon triggers the promotion of oxidative damage in the Portuguese ricefield cyanobacterium Anabaena cylindrica: Response of the antioxidant systemENVIRONMENTAL TOXICOLOGY, Issue 5 2010Victor Galhano Abstract Rice fields are frequently exposed to environmental contamination by herbicides and cyanobacteria, as primary producers of these aquatic ecosystems, are adversely affected. Anabaena cylindrica is a cyanobacterium with a significantly widespread occurrence in Portuguese rice fields. This strain was studied throughout 72 h in laboratory conditions for its stress responses to sublethal concentrations (0.75,2 mM) of bentazon, a selective postemergence herbicide recommended for integrated weed management in rice, with special reference to oxidative stress, role of proline and intracellular antioxidant enzymes in herbicide-induced free radicals detoxification. Activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and glutathione S -transferase (GST) increased in a time- and herbicide dose-response manner and were higher than those in the control samples after 72 h. A time- and concentration-dependent increase of malondialdehyde (MDA) levels and the enhanced cell membrane leakage following bentazon exposure are indicative of lipid peroxidation, free radicals formation, and oxidative damage, while increased amounts of SOD, CAT, APX, GST, and proline indicated their involvement in free radical scavenging mechanisms. The appreciable decline in the reduced glutathione (GSH) pool after 72 h at higher bentazon concentrations could be explained by the reduction of the NADPH-dependent glutathione reductase (GR) activity. The obtained results suggested that the alterations of antioxidant systems in A. cylindrica might be useful biomarkers of bentazon exposure. As the toxic mechanism of bentazon is a complex phenomenon, this study also adds relevant findings to explain the oxidative stress pathways of bentazon promoting oxidative stress in cyanobacteria. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2010. [source] Examining the Intersection of Sex and Stress in Modelling Neuropsychiatric DisordersJOURNAL OF NEUROENDOCRINOLOGY, Issue 4 2009N. Goel Sex-biased neuropsychiatric disorders, including major depressive disorder and schizophrenia, are the major cause of disability in the developed world. Elevated stress sensitivity has been proposed as a key underlying factor in disease onset. Sex differences in stress sensitivity are associated with corticotrophin-releasing factor (CRF) and serotonin neurotransmission, which are important central regulators of mood and coping responses. To elucidate the underlying neurobiology of stress-related disease predisposition, it is critical to develop appropriate animal models of stress pathway dysregulation. Furthermore, the inclusion of sex difference comparisons in stress responsive behaviours, physiology and central stress pathway maturation in these models is essential. Recent studies by our laboratory and others have begun to investigate the intersection of stress and sex where the development of mouse models of stress pathway dysregulation via prenatal stress experience or early-life manipulations has provided insight into points of developmental vulnerability. In addition, examination of the maturation of these pathways, including the functional importance of the organisational and activational effects of gonadal hormones on stress responsivity, is essential for determination of when sex differences in stress sensitivity may begin. In such studies, we have detected distinct sex differences in stress coping strategies where activational effects of testosterone produced females that displayed male-like strategies in tests of passive coping, but were similar to females in tests of active coping. In a second model of elevated stress sensitivity, male mice experiencing prenatal stress early in gestation showed feminised physiological and behavioural stress responses, and were highly sensitive to a low dose of selective serotonin reuptake inhibitors. Analyses of expression and epigenetic patterns revealed changes in CRF and glucocorticoid receptor genes in these mice. Mechanistically, stress early in pregnancy produced a significant sex-dependent effect on placental gene expression that was supportive of altered foetal transport of key growth factors and nutrients. These mouse models examining alterations and hormonal effects on development of stress pathways provide necessary insight into how specific stress responses can be reprogrammed early in development resulting in sex differences in stress sensitivity and neuropsychiatric disease vulnerability. [source] Curcumin reduces the toxic effects of iron loading in rat liver epithelial cellsLIVER INTERNATIONAL, Issue 1 2009Donald J. Messner Abstract Background/Aims: Iron overload can cause liver toxicity and increase the risk of liver failure or hepatocellular carcinoma in humans. Curcumin (diferuloylmethane), a component of the food spice turmeric, has antioxidant, iron binding and hepatoprotective properties. The aim of this study was to quantify its effects on iron overload and the resulting downstream toxic effects in cultured T51B rat liver epithelial cells. Methods: T51B cells were loaded with ferric ammonium citrate (FAC) with or without the iron delivery agent 8-hydroxyquinoline. Cytotoxicity was measured by methylthiazolyldiphenyl-tetrazolium bromide assay. Iron uptake and iron bioavailability were documented by chemical assay, quench of calcein fluorescence and ferritin induction. Reactive oxygen species (ROS) were measured by a fluorescence assay using 2,,7,-dichlorodihydrofluorescein diacetate. Oxidative stress signalling to jnk, c-jun and p38 was measured by a Western blot with phospho-specific antibodies. Results: Curcumin bound iron, but did not block iron uptake or bioavailability in T51B cells given FAC. However, it reduced cytotoxicity, blocked the generation of ROS and eliminated signalling to cellular stress pathways caused by iron. Inhibition was observed over a wide range of FAC concentrations (50,500 ,M), with an apparent IC50 in all cases between 5 and 10 ,M curcumin. In contrast, desferoxamine blocked both iron uptake and toxic effects of iron at concentrations that depended on the FAC concentration. The effects of curcumin also differed from those of ,-tocopherol, which did not bind iron and was less effective at blocking iron-stimulated ROS generation. Conclusions: Curcumin reduced iron-dependent oxidative stress and iron toxicity in T51B cells without blocking iron uptake. [source] Analysis of Saccharomyces cerevisiae null allele strains identifies a larger role for DNA damage versus oxidative stress pathways in growth inhibition by seleniumMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 11 2008Eden Seitomer Abstract Selenium toxicity is a growing environmental concern due to widespread availability of high-dose selenium supplements and the development of high-selenium agricultural drainage basins. To begin to analyze the effects of selenium toxicity at the genetic level, we have systematically determined which genes are involved in responding to high environmental selenium using a collection of viable haploid null allele strains of Saccharomyces cerevisiae representing three major stress pathways: the RAD9 -dependent DNA repair pathway, the RAD6/RAD18 DNA damage tolerance pathway, and the oxidative stress pathway. A total of 53 null allele strains were tested for growth defects in the presence of a range of sodium selenite and selenomethionine (SeMet) concentrations. Our results show that ,64,72% of the strains lacking RAD9 -dependent DNA repair or RAD6/RAD18 DNA damage tolerance pathway genes show reduced growth in sodium selenite versus ,28,36% in SeMet. Interestingly both compounds reduced growth in ,21,25% of the strains lacking oxidative stress genes. These data suggest that both selenite and SeMet are likely inducing DNA damage by generating reactive species. The anticipated effects of loss of components of the oxidative stress pathway were not observed, likely due to apparent redundancies in these gene products that may keep the damaging effects in check. [source] Role of spinal cord glia in the central processing of peripheral pain perceptionNEUROGASTROENTEROLOGY & MOTILITY, Issue 5 2010S. Bradesi Abstract Background, The discovery that glial activation plays a critical role in the modulation of neuronal functions and affects the spinal processing of nociceptive signalling has brought new understanding on the mechanisms underlying central sensitization involved in chronic pain facilitation. Spinal glial activation is now considered an important component in the development and maintenance of allodynia and hyperalgesia in various models of chronic pain, including neuropathic pain and pain associated with peripheral inflammation. In addition, spinal glial activation is also involved in some forms of visceral hyperalgesia. Purpose, We discuss the signalling pathways engaged in central glial activation, including stress pathways, and the neuron,glia bidirectional relationships involved in the modulation of synaptic activity and pain facilitation. In this expanding field of research, the characterization of the mechanisms by which glia affect spinal neuro-transmission will increase our understanding of central pain facilitation, and has the potential for the development of new therapeutic agents for common chronic pain conditions. [source] Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosisPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 15 2005Arnaud Bruneel Dr. Abstract We have undertaken to continue the proteomic study of human umbilical vein endothelial cells (HUVECs) using the combination of 2-DE, automated trypsin digestion, and PMF analysis after MALDI-TOF MS and peptide sequencing using nano LC-ESI-MS/MS. The overall functional characterization of the 162 identified proteins from primary cultures of HUVECs confirms the metabolic capabilities of endothelium and illustrates various cellular functions more related to cell motility and angiogenesis, protein folding, anti-oxidant defenses, signal transduction, proteasome pathway and resistance to apoptosis. In comparison with controls cells, the differential proteomic analysis of HUVECs treated by the pro-apoptotic topoisomerase inhibitor etoposide further revealed the variation of eight proteins, namely, GRP78, GRP94, valosin-containing protein, proteinase inhibitor 9, cofilin, 37-kDa laminin receptor protein, bovine apolipoprotein, and tropomyosin. These data suggest that etoposide-induced apoptosis of human vascular endothelial cells results from the intricate involvement of multiple apoptosis processes including at least the mitochondrial and the ER stress pathways. The presented 2-D pattern and protein database, as well as the data related to apoptosis of HUVECs, are available at http://www.huvec.com. [source] Intracellular death platform steps-in: Targeting prostate tumors via endoplasmic reticulum (ER) apoptosisTHE PROSTATE, Issue 15 2008Steven R. Schwarze Abstract Molecular targeting of apoptotic signaling pathways has been extensively studied in recent years and directed towards the development of effective therapeutic modalities for treating advanced androgen-independent prostate tumors. The majority of therapeutic agents act through intrinsic or mitochondrial pathways to induce programmed cell death. The induction of apoptosis through endoplasmic reticulum (ER) stress pathways may provide an alternative to treat patients. The functional interaction between the BCL-2 family members and regulation of calcium homeostasis in the ER provides a critical link to the life or death outcome of the cell. Apoptosis induction mediated by ER stress-inducing agents is just beginning to be exploited for therapeutic targeting of prostate tumors. Insightful dissection of recently discovered apoptotic signaling pathways that function through the endoplasmic reticulum may identify novel molecules that could effectively target both androgen-dependent and androgen-independent prostate tumors. In this review, we focus on linking ER stress-induced apoptosis to therapeutic targeting of prostate tumors and dissect its cross-talk with the intrinsic and extrinsic apoptotic pathways. Prostate 68: 1615,1623, 2008. © 2008 Wiley-Liss, Inc. [source] Age and energy intake interact to modify cell stress pathways and stroke outcomeANNALS OF NEUROLOGY, Issue 1 2010Thiruma V. Arumugam PhD Objective Age and excessive energy intake/obesity are risk factors for cerebrovascular disease, but it is not known if and how these factors affect the extent of brain damage and outcome in ischemic stroke. We therefore determined the interactions of age and energy intake on the outcome of ischemic brain injury, and elucidated the underlying mechanisms. Methods We utilized a novel microchip-based immunoaffinity capillary electrophoresis technology to measure a panel of neurotrophic factors, cytokines, and cellular stress resistance proteins in brain tissue samples from young, middle-aged, and old mice that had been maintained on control or energy-restricted diets prior to middle cerebral artery occlusion and reperfusion. Results Mortality from focal ischemic stroke was increased with advancing age and reduced by an intermittent fasting (IF) diet. Brain damage and functional impairment were reduced by IF in young and middle-aged mice, but not in old mice. The basal and poststroke levels of neurotrophic factors (brain-derived neurotrophic factor and basic fibroblast growth factor), protein chaperones (heat shock protein 70 and glucose regulated protein 78), and the antioxidant enzyme heme oxygenase-1 were decreased, whereas levels of inflammatory cytokines were increased in the cerebral cortex and striatum of old mice compared with younger mice. IF coordinately increased levels of protective proteins and decreased inflammatory cytokines in young, but not in old mice. Interpretation Reduction in dietary energy intake differentially modulates neurotrophic and inflammatory pathways to protect neurons against ischemic injury, and these beneficial effects of IF are compromised during aging, resulting in increased brain damage and poorer functional outcome. ANN NEUROL 2010;67:41,52 [source] Common genetic variants in candidate genes and risk of familial lymphoid malignanciesBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2009Xueying (Sharon) Liang Summary Familial aggregation, linkage and case,control studies support the role of germline genes in the aetiology of lymphoid malignancies. To further examine the role of genetic variation underlying susceptibility, we analysed 1536 single nucleotide polymorphisms in 152 genes involved in apoptosis, DNA repair, immune response and oxidative stress pathways among a unique sample of 165 unrelated familial cases including patients with chronic lymphocytic leukaemia (CLL), Waldenström macroglobulinaemia (WM) and Hodgkin lymphoma (HL), and 107 spouse controls. We confirmed previous studies showing a polymorphism in the IL10 promoter (rs1800890/-3575T>A) to be associated with non-Hodgkin lymphoma, as this allele was found to be associated with both CLL and WM. We also confirmed the role of IL6 variation to be associated with HL. Polymorphisms in TNFSF10 were associated with both CLL and WM. Future replication and functional studies are needed to clarify the role of these genetic variants. Finally, our data further support the close association of WM and CLL. [source] Pathogenic T cells in murine lupus exhibit spontaneous signaling activity through phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathwaysARTHRITIS & RHEUMATISM, Issue 4 2003Florin Niculescu Objective To determine the activation status of two cytoplasmic signaling pathways, phosphatidylinositol 3-kinase (PI 3-kinase) and the mitogen-activated protein kinase (MAPK) family. Methods We studied the pathogenic CD4+ T cells that drive disease in the parent-into-F1 mouse model of lupus-like chronic graft-versus-host disease (GVHD). We determined immunoprecipitated kinase activity for PI 3-kinase and MAPK members (Raf-1, extracellular signal,regulated kinase 1 [ERK-1], c-Jun N-terminal kinase 1 [JNK-1], and p38 MAPK) from either unfractionated splenocytes or purified donor CD4+ T cells. Uninjected normal mice served as negative controls, and acute GVHD mice served as positive controls. Results Compared with negative controls, unfractionated splenocyte kinase activity from chronic GVHD mice was significantly increased for PI 3-kinase and JNK-1, but not for Raf-1, p38 MAPK, or ERK-1. Increased PI 3-kinase and JNK-1 activity was also seen in acute GVHD splenocytes, as was increased Raf-1 and p38 MAPK activity. The pattern of increased PI 3-kinase and JNK-1 activity seen in unfractionated chronic GVHD splenocytes was also seen in isolated donor, but not host, CD4+ T cells from chronic GVHD mice, indicating that donor CD4+ T cell signaling activity accounted for at least a portion of the activity observed in unfractionated splenocytes. Increased ERK-1 activity was not seen in either donor or host CD4+ T cells. This pattern of cytoplasmic signaling pathway in donor CD4+ T cells was associated with increased T cell receptor membrane signaling activation (Lck and Fyn phosphorylation) and increased transcription activation (phosphorylation of inhibitor of nuclear factor ,B), confirming the biologic significance of these observations. Conclusion The pathogenic T cells driving disease in this murine model exhibit activation in the form of spontaneous cytoplasmic signaling pathway activity that can be detected without in vitro restimulation and involves a T cell,specific (PI 3-kinase) and a nonspecific stress/cytokine pathway (JNK-1). These results raise the possibility that a full characterization of the signaling pathways active in pathogenic lupus T cells might lead to new therapeutic targets. [source] | ||||||||||