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Sample records for acute er stress

  1. TRAM1 protects AR42J cells from caerulein-induced acute pancreatitis through ER stress-apoptosis pathway.

    PubMed

    Cai, Yongxia; Shen, Yanbo; Xu, Guangling; Tao, Ran; Yuan, Weiyan; Huang, Zhongwei; Zhang, Dongmei

    2016-05-01

    Chronic endoplasmic reticulum (ER) stress in pancreatic acinar cells has emerged as a major contributor to the recovery of acute pancreatitis (AP). However, the molecular mechanisms linking AP and ER stress remain not fully understood. In this study, we employed caerulein to induce AP-like inflammation in the AR42J rat pancreatic acinar cells to mimic the AP-like acinar cell injury. Caerulein can activate ER stress in AR42J cells, but the molecular link between AP and ER stress remains to be identified. We here reported that translocating chain-associated membrane protein 1 (TRAM1), an ER-resident multispanning membrane protein, was involved in the onset of AP-like injury on AR42J cells. TRAM1 was significantly elevated in caerulein-treated AR42J cells. Furthermore, we showed that knockdown of TRAM1 led to hyperactivation of 78 kDa glucose-regulated protein precursor (GRP78) and C/EBP homologous protein (CHOP) and the activation of downstream apoptosis pathway. Given the fact that the activation of ER stress played a protection role in AP, the pro-inflammatory mediators TNF-α and IL-6 and the marker of cell injury LDH were also analyzed. We found that depletion of TRAM1 markedly increased the secretion of TNF-α, IL-6, and LDH in the cells. Moreover, flow cytometry indicated that treatment with caerulein induced a significant decrease of apoptotic index and increase of necrosis index in TRAM1-siRNA cells, compared with control groups, as indicated by downregulated expression of cleaved caspase-3, caspase-8, and caspase-9 mRNA expression activity in TRAM1-siRNA cells. These data implicated that TRAM1 might protect AR42J cells against caerulein-induced AP in AR42J cells through alleviating ER stress.

  2. ER Stress and Angiogenesis.

    PubMed

    Binet, François; Sapieha, Przemyslaw

    2015-10-06

    Proper tissue vascularization is vital for cellular function as it delivers oxygen, nutrients, hormones, and immune cells and helps to clear cellular debris and metabolic waste products. Tissue angiogenesis occurs to satisfy energy requirements and cellular sensors of metabolic imbalance coordinate vessel growth. In this regard, the classical pathways of the unfolded protein response activated under conditions of ER stress have recently been described to generate angiomodulatory or angiostatic signals. This review elaborates on the link between angiogenesis and ER stress and discusses the implications for diseases characterized by altered vascular homeostasis, such as cancer, retinopathies, and atherosclerosis.

  3. Reticulons Regulate the ER Inheritance Block during ER Stress.

    PubMed

    Piña, Francisco Javier; Fleming, Tinya; Pogliano, Kit; Niwa, Maho

    2016-05-09

    Segregation of functional organelles during the cell cycle is crucial to generate healthy daughter cells. In Saccharomyces cerevisiae, ER stress causes an ER inheritance block to ensure cells inherit a functional ER. Here, we report that formation of tubular ER in the mother cell, the first step in ER inheritance, depends on functional symmetry between the cortical ER (cER) and perinuclear ER (pnER). ER stress induces functional asymmetry, blocking tubular ER formation and ER inheritance. Using fluorescence recovery after photobleaching, we show that the ER chaperone Kar2/BiP fused to GFP and an ER membrane reporter, Hmg1-GFP, behave differently in the cER and pnER. The functional asymmetry and tubular ER formation depend on Reticulons/Yop1, which maintain ER structure. LUNAPARK1 deletion in rtn1Δrtn2Δyop1Δ cells restores the pnER/cER functional asymmetry, tubular ER generation, and ER inheritance blocks. Thus, Reticulon/Yop1-dependent changes in ER structure are linked to ER inheritance during the yeast cell cycle.

  4. Englerin A induces an acute inflammatory response and reveals lipid metabolism and ER stress as targetable vulnerabilities in renal cell carcinoma

    PubMed Central

    Batova, Ayse; Altomare, Diego; Creek, Kim E.; Naviaux, Robert K.; Wang, Lin; Li, Kefeng; Green, Erica; Williams, Richard; Naviaux, Jane C.; Diccianni, Mitchell; Yu, Alice L.

    2017-01-01

    Renal cell carcinoma (RCC) is among the top ten most common forms of cancer and is the most common malignancy of the kidney. Clear cell renal carcinoma (cc-RCC), the most common type of RCC, is one of the most refractory cancers with an incidence that is on the rise. Screening of plant extracts in search of new anti-cancer agents resulted in the discovery of englerin A, a guaiane sesquiterpene with potent cytotoxicity against renal cancer cells and a small subset of other cancer cells. Though a few cellular targets have been identified for englerin A, it is still not clear what mechanisms account for the cytotoxicity of englerin A in RCC, which occurs at concentrations well below those used to engage the targets previously identified. Unlike any prior study, the current study used a systems biology approach to explore the mechanism(s) of action of englerin A. Metabolomics analyses indicated that englerin A profoundly altered lipid metabolism by 24 h in cc-RCC cell lines and generated significant levels of ceramides that were highly toxic to these cells. Microarray analyses determined that englerin A induced ER stress signaling and an acute inflammatory response, which was confirmed by quantitative PCR and Western Blot analyses. Additionally, fluorescence confocal microscopy revealed that englerin A at 25 nM disrupted the morphology of the ER confirming the deleterious effect of englerin A on the ER. Collectively, our findings suggest that cc-RCC is highly sensitive to disruptions in lipid metabolism and ER stress and that these vulnerabilities can be targeted for the treatment of cc-RCC and possibly other lipid storing cancers. Furthermore, our results suggest that ceramides may be a mediator of some of the actions of englerin A. Lastly, the acute inflammatory response induced by englerin A may mediate anti-tumor immunity. PMID:28296891

  5. Englerin A induces an acute inflammatory response and reveals lipid metabolism and ER stress as targetable vulnerabilities in renal cell carcinoma.

    PubMed

    Batova, Ayse; Altomare, Diego; Creek, Kim E; Naviaux, Robert K; Wang, Lin; Li, Kefeng; Green, Erica; Williams, Richard; Naviaux, Jane C; Diccianni, Mitchell; Yu, Alice L

    2017-01-01

    Renal cell carcinoma (RCC) is among the top ten most common forms of cancer and is the most common malignancy of the kidney. Clear cell renal carcinoma (cc-RCC), the most common type of RCC, is one of the most refractory cancers with an incidence that is on the rise. Screening of plant extracts in search of new anti-cancer agents resulted in the discovery of englerin A, a guaiane sesquiterpene with potent cytotoxicity against renal cancer cells and a small subset of other cancer cells. Though a few cellular targets have been identified for englerin A, it is still not clear what mechanisms account for the cytotoxicity of englerin A in RCC, which occurs at concentrations well below those used to engage the targets previously identified. Unlike any prior study, the current study used a systems biology approach to explore the mechanism(s) of action of englerin A. Metabolomics analyses indicated that englerin A profoundly altered lipid metabolism by 24 h in cc-RCC cell lines and generated significant levels of ceramides that were highly toxic to these cells. Microarray analyses determined that englerin A induced ER stress signaling and an acute inflammatory response, which was confirmed by quantitative PCR and Western Blot analyses. Additionally, fluorescence confocal microscopy revealed that englerin A at 25 nM disrupted the morphology of the ER confirming the deleterious effect of englerin A on the ER. Collectively, our findings suggest that cc-RCC is highly sensitive to disruptions in lipid metabolism and ER stress and that these vulnerabilities can be targeted for the treatment of cc-RCC and possibly other lipid storing cancers. Furthermore, our results suggest that ceramides may be a mediator of some of the actions of englerin A. Lastly, the acute inflammatory response induced by englerin A may mediate anti-tumor immunity.

  6. Endoplasmic Reticulum (ER) Stress and Endocrine Disorders

    PubMed Central

    Ariyasu, Daisuke; Yoshida, Hiderou; Hasegawa, Yukihiro

    2017-01-01

    The endoplasmic reticulum (ER) is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR), which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI), Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2) are discussed in this article. PMID:28208663

  7. Scutellaria baicalensis Georgi extract protects against alcohol-induced acute liver injury in mice and affects the mechanism of ER stress

    PubMed Central

    DONG, QINGQING; CHU, FEI; WU, CHENGZHU; HUO, QIANG; GAN, HUAIYONG; LI, XIAOMING; LIU, HAO

    2016-01-01

    The aims of the present study were to examine the hepatoprotective effect of Scutellaria baicalensis Georgi extract (Scutellariae Radix extract; SRE) against acute alcohol-induced liver injury in mice, and investigate the mechanism of endoplasmic reticulum (ER) stress. High performance liquid chromatography was used for the phytochemical analysis of SRE. Animals were administered orally with 50% alcohol (12 ml/kg) 4 h following administration of doses of SRE every day for 14 days, with the exception of normal control group. The protective effect was investigated by measuring the levels of aspartate transaminase (AST), alanine transferase (ALT) and triglyceride (TG) in the serum, and the levels of glutathione (GSH) and malondialdehyde (MDA) in liver tissues. The levels of glucose-related protein 78 (GRP78) were detected using immunohistochemical localization and an enzyme-linked immunosorbent assay. Hepatocyte apoptosis was assessed using terminal-deoxynucleoitidyl transferase mediated nick end labeling. The SRE contained 31.2% baicalin. Pretreatment with SRE had a marked protective effect by reversing the levels of biochemical markers and levels of GRP78 in a dose-dependent manner. The results of the present study demonstrated that pretreatment with SRE exerted a marked hepatoprotective effect by downregulating the expression of GRP78, which is a marker of ER stress. PMID:26936686

  8. ER stress-induced cell death mechanisms

    PubMed Central

    Sano, Renata; Reed, John C.

    2013-01-01

    The endoplasmic-reticulum (ER) stress response constitutes a cellular process that is triggered by a variety of conditions that disturb folding of proteins in the ER. Eukaryotic cells have developed an evolutionarily conserved adaptive mechanism, the unfolded protein response (UPR), which aims to clear unfolded proteins and restore ER homeostasis. In cases where ER stress cannot be reversed, cellular functions deteriorate, often leading to cell death. Accumulating evidence implicates ER stress-induced cellular dysfunction and cell death as major contributors to many diseases, making modulators of ER stress pathways potentially attractive targets for therapeutics discovery. Here, we summarize recent advances in understanding the diversity of molecular mechanisms that govern ER stress signaling in health and disease. PMID:23850759

  9. Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics

    PubMed Central

    Bravo, Roberto; Gutierrez, Tomás; Paredes, Felipe; Gatica, Damián; Rodriguez, Andrea E.; Pedrozo, Zully; Chiong, Mario; Parra, Valentina; Quest, Andrew F.G.; Rothermel, Beverly A.; Lavandero, Sergio

    2014-01-01

    Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. The molecular mechanisms responsible for execution of the cell death program are relatively well characterized, but the metabolic events taking place during the adaptive phase of ER stress remain largely undefined. Here we discuss emerging evidence regarding the metabolic changes that occur during the onset of ER stress and how ER influences mitochondrial function through mechanisms involving calcium transfer, thereby facilitating cellular adaptation. Finally, we highlight how dysregulation of ER–mitochondrial calcium homeostasis during prolonged ER stress is emerging as a novel mechanism implicated in the onset of metabolic disorders. PMID:22064245

  10. Mitochondria-Associated Membranes and ER Stress.

    PubMed

    van Vliet, Alexander R; Agostinis, Patrizia

    2017-03-28

    The endoplasmic reticulum (ER) is a crucial organelle for coordinating cellular Ca(2+) signaling and protein synthesis and folding. Moreover, the dynamic and complex membranous structures constituting the ER allow the formation of contact sites with other organelles and structures, including among others the mitochondria and the plasma membrane (PM). The contact sites that the ER form with mitochondria is a hot topic in research, and the nature of the so-called mitochondria-associated membranes (MAMs) is continuously evolving. The MAMs consist of a proteinaceous tether that physically connects the ER with mitochondria. The MAMs harness the main functions of both organelles to form a specialized subcompartment at the interface of the ER and mitochondria. Under homeostatic conditions, MAMs are crucial for the efficient transfer of Ca(2+) from the ER to mitochondria, and for proper mitochondria bioenergetics and lipid synthesis. MAMs are also believed to be the master regulators of mitochondrial shape and motility, and to form a crucial site for autophagosome assembly. Not surprisingly, MAMs have been shown to be a hot spot for the transfer of stress signals from the ER to mitochondria, most notably under the conditions of loss of ER proteostasis, by engaging the unfolded protein response (UPR). In this chapter after an introduction on ER biology and ER stress, we will review the emerging and key signaling roles of the MAMs, which have a root in cellular processes and signaling cascades coordinated by the ER.

  11. The Aspergillus nidulans peripheral ER: disorganization by ER stress and persistence during mitosis.

    PubMed

    Markina-Iñarrairaegui, Ane; Pantazopoulou, Areti; Espeso, Eduardo A; Peñalva, Miguel A

    2013-01-01

    The genetically amenable fungus Aspergillus nidulans is well suited for cell biology studies involving the secretory pathway and its relationship with hyphal tip growth by apical extension. We exploited live-cell epifluorescence microscopy of the ER labeled with the translocon component Sec63, endogenously tagged with GFP, to study the organization of 'secretory' ER domains. The Sec63 A. nidulans ER network includes brightly fluorescent peripheral strands and more faintly labeled nuclear envelopes. In hyphae, the most abundant peripheral ER structures correspond to plasma membrane-associated strands that are polarized, but do not invade the hyphal tip dome, at least in part because the subapical collar of endocytic actin patches constrict the cortical strands in this region. Thus the subapical endocytic ring might provide an attachment for ER strands, thereby ensuring that the growing tip remains 'loaded' with secretory ER. Acute disruption of secretory ER function by reductive stress-mediated induction of the unfolded protein response results in the reversible aggregation of ER strands, cessation of exocytosis and swelling of the hyphal tips. The secretory ER is insensitive to brefeldin A treatment and does not undergo changes during mitosis, in agreement with the reports that apical extension continues at normal rates during this period.

  12. The ER Stress Surveillance (ERSU) pathway regulates daughter cell ER protein aggregate inheritance.

    PubMed

    Piña, Francisco J; Niwa, Maho

    2015-09-01

    Stress induced by cytoplasmic protein aggregates can have deleterious consequences for the cell, contributing to neurodegeneration and other diseases. Protein aggregates are also formed within the endoplasmic reticulum (ER), although the fate of ER protein aggregates, specifically during cell division, is not well understood. By simultaneous visualization of both the ER itself and ER protein aggregates, we found that ER protein aggregates that induce ER stress are retained in the mother cell by activation of the ER Stress Surveillance (ERSU) pathway, which prevents inheritance of stressed ER. In contrast, under conditions of normal ER inheritance, ER protein aggregates can enter the daughter cell. Thus, whereas cytoplasmic protein aggregates are retained in the mother cell to protect the functional capacity of daughter cells, the fate of ER protein aggregates is determined by whether or not they activate the ERSU pathway to impede transmission of the cortical ER during the cell cycle.

  13. Bridges between mitochondrial oxidative stress, ER stress and mTOR signaling in pancreatic β cells.

    PubMed

    Wang, Jing; Yang, Xin; Zhang, Jingjing

    2016-08-01

    Pancreatic β cell dysfunction, i.e., failure to provide insulin in concentrations sufficient to control blood sugar, is central to the etiology of all types of diabetes. Current evidence implicates mitochondrial oxidative stress and endoplasmic reticulum (ER) stress in pancreatic β cell loss and impaired insulin secretion. Oxidative and ER stress are interconnected so that misfolded proteins induce reactive oxygen species (ROS) production; likewise, oxidative stress disturbs the ER redox state thereby disrupting correct disulfide bond formation and proper protein folding. mTOR signaling regulates many metabolic processes including protein synthesis, cell growth, survival and proliferation. Oxidative stress inhibits mTORC1, which is considered an important suppressor of mitochondrial oxidative stress in β cells, and ultimately, controls cell survival. The interplay between ER stress and mTORC1 is complicated, since the unfolded protein response (UPR) activation can occur upstream or downstream of mTORC1. Persistent activation of mTORC1 initiates protein synthesis and UPR activation, while in the later phase induces ER stress. Chronic activation of ER stress inhibits Akt/mTORC1 pathway, while under particular settings, acute activation of UPR activates Akt-mTOR signaling. Thus, modulating mitochondrial oxidative stress and ER stress via mTOR signaling may be an approach that will effectively suppress obesity- or glucolipotoxicity-induced metabolic disorders such as insulin resistance and type 2 diabetes mellitus (T2DM). In this review, we focus on the regulations between mTOR signaling and mitochondrial oxidative or ER stress in pancreatic β cells.

  14. Obesity and endoplasmic reticulum (ER) stresses

    PubMed Central

    Tripathi, Yamini B.; Pandey, Vivek

    2012-01-01

    In obesity, the adipose cells behave as inflammatory source and result to low grade inflammation. This systemic inflammation along with oxidative stress is a silent killer and damages other vital organs also. High metabolic process, induced due to high nutritional intake, results to endoplasmic reticulum (ER) stress and mitochondrial stress. This review describes the triggering factor and basic mechanism behind the obesity mediated these stresses in relation to inflammation. Efforts have been made to describe the effect-response cycle between adipocytes and non-adipocyte cells with reference to metabolic syndrome (MS). PMID:22891067

  15. ER stress, autophagy, and RNA viruses

    PubMed Central

    Jheng, Jia-Rong; Ho, Jin-Yuan; Horng, Jim-Tong

    2014-01-01

    Endoplasmic reticulum (ER) stress is a general term for representing the pathway by which various stimuli affect ER functions. ER stress induces the evolutionarily conserved signaling pathways, called the unfolded protein response (UPR), which compromises the stimulus and then determines whether the cell survives or dies. In recent years, ongoing research has suggested that these pathways may be linked to the autophagic response, which plays a key role in the cell's response to various stressors. Autophagy performs a self-digestion function, and its activation protects cells against certain pathogens. However, the link between the UPR and autophagy may be more complicated. These two systems may act dependently, or the induction of one system may interfere with the other. Experimental studies have found that different viruses modulate these mechanisms to allow them to escape the host immune response or, worse, to exploit the host's defense to their advantage; thus, this topic is a critical area in antiviral research. In this review, we summarize the current knowledge about how RNA viruses, including influenza virus, poliovirus, coxsackievirus, enterovirus 71, Japanese encephalitis virus, hepatitis C virus, and dengue virus, regulate these processes. We also discuss recent discoveries and how these will produce novel strategies for antiviral treatment. PMID:25140166

  16. Caffeine attenuated ER stress-induced leptin resistance in neurons.

    PubMed

    Hosoi, Toru; Toyoda, Keisuke; Nakatsu, Kanako; Ozawa, Koichiro

    2014-05-21

    Exposing the endoplasmic reticulum (ER) to stress causes the accumulation of unfolded proteins, and subsequently results in ER stress. ER stress may be involved in various disorders such as obesity, diabetes, and neurodegenerative diseases. Leptin is an important circulating hormone, that inhibits food intake and accelerates energy consumption, which suppresses body weight gain. Recent studies demonstrated that leptin resistance is one of the main factors involved in the development of obesity. We and other groups recently reported the role of ER stress in the development of leptin resistance. Therefore, identifying drugs that target ER stress may be a promising fundamental strategy for the treatment of obesity. In the present study, we investigated whether caffeine could affect ER stress and the subsequent development of leptin resistance. We showed that caffeine exhibited chaperone activity, which attenuated protein aggregation. Caffeine also inhibited the ER stress-induced activation of IRE1 and PERK, which suggested the attenuation of ER stress. Moreover, caffeine markedly improved ER stress-induced impairments in the leptin-induced phosphorylation of STAT3. Therefore, these results suggest caffeine may have pharmacological properties that ameliorate leptin resistance by reducing ER stress.

  17. The ER Stress Surveillance (ERSU) pathway regulates daughter cell ER protein aggregate inheritance

    PubMed Central

    Piña, Francisco J; Niwa, Maho

    2015-01-01

    Stress induced by cytoplasmic protein aggregates can have deleterious consequences for the cell, contributing to neurodegeneration and other diseases. Protein aggregates are also formed within the endoplasmic reticulum (ER), although the fate of ER protein aggregates, specifically during cell division, is not well understood. By simultaneous visualization of both the ER itself and ER protein aggregates, we found that ER protein aggregates that induce ER stress are retained in the mother cell by activation of the ER Stress Surveillance (ERSU) pathway, which prevents inheritance of stressed ER. In contrast, under conditions of normal ER inheritance, ER protein aggregates can enter the daughter cell. Thus, whereas cytoplasmic protein aggregates are retained in the mother cell to protect the functional capacity of daughter cells, the fate of ER protein aggregates is determined by whether or not they activate the ERSU pathway to impede transmission of the cortical ER during the cell cycle. DOI: http://dx.doi.org/10.7554/eLife.06970.001 PMID:26327697

  18. Links between ER stress and autophagy in plants.

    PubMed

    Pu, Yunting; Bassham, Diane C

    2013-06-01

    Autophagy is a major pathway for the delivery of proteins or organelles to be degraded in the vacuole and recycled. It can be induced by abiotic stresses, senescence, and pathogen infection. Recent research has shown that autophagy is activated by ER stress. Here we review the major progress that has been made in the study of autophagy and ER stress in plants, and describe the links between ER stress and autophagy to guide further study on how autophagy is regulated in response to ER stress.

  19. Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis.

    PubMed

    Kim, Hyosang; Moon, Soo Young; Kim, Joon-Seok; Baek, Chung Hee; Kim, Miyeon; Min, Ji Yeon; Lee, Sang Koo

    2015-02-01

    It has been suggested that endoplasmic reticulum (ER) stress facilitates fibrotic remodeling. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed ER stress induced by chemical ER stress inducers [tunicamycin (TM) and thapsigargin (TG)] and also nonchemical inducers in tubular HK-2 cells. We further investigated the in vivo effects of AMPK on ER stress and renal fibrosis. Western blot analysis, immunofluorescence, small interfering (si)RNA experiments, and immunohistochemical staining were performed. Metformin (the best known clinical activator of AMPK) suppressed TM- or TG-induced ER stress, as shown by the inhibition of TM- or TG-induced upregulation of glucose-related protein (GRP)78 and phosphorylated eukaryotic initiation factor-2α through induction of heme oxygenase-1. Metformin inhibited TM- or TG-induced epithelial-mesenchymal transitions as well. Compound C (AMPK inhibitor) blocked the effect of metformin, and 5-aminoimidazole-4-carboxamide-1β riboside (another AMPK activator) exerted the same effects as metformin. Transfection with siRNA targeting AMPK blocked the effect of metformin. Consistent with the results of cell culture experiments, metformin reduced renal cortical GRP78 expression and increased heme oxygenase-1 expression in a mouse model of ER stress-induced acute kidney injury by TM. Activation of AMPK also suppressed ER stress by transforming growth factor-β, ANG II, aldosterone, and high glucose. Furthermore, metformin reduced GRP78 expression and renal fibrosis in a mouse model of unilateral ureteral obstruction. In conclusion, AMPK may serve as a promising therapeutic target through reducing ER stress and renal fibrosis.

  20. Loss of Clcc1 Results in ER Stress, Misfolded Protein Accumulation, and Neurodegeneration

    PubMed Central

    Jia, Yichang; Jucius, Thomas J.; Cook, Susan A.

    2015-01-01

    Folding of transmembrane and secretory proteins occurs in the lumen of the endoplasmic reticulum (ER) before transportation to the cell surface and is monitored by the unfolded protein response (UPR) signaling pathway. The accumulation of unfolded proteins in the ER activates the UPR that restores ER homeostasis by regulating gene expression that leads to an increase in the protein-folding capacity of the ER and a decrease in the ER protein-folding load. However, prolonged UPR activity has been associated with cell death in multiple pathological conditions, including neurodegeneration. Here, we report a spontaneous recessive mouse mutation that causes progressive cerebellar granule cell death and peripheral motor axon degeneration. By positional cloning, we identify the mutation in this strain as a retrotransposon insertion in the Clcc1 gene, which encodes a putative chloride channel localized to the ER. Furthermore, we demonstrate that the C3H/HeSnJ inbred strain has late onset cerebellar degeneration due to this mutation. Interestingly, acute knockdown of Clcc1 expression in cultured cells increases sensitivity to ER stress. In agreement, GRP78, the major HSP70 family chaperone in the ER, is upregulated in Clcc1-deficient granule cells in vivo, and ubiquitinated proteins accumulate in these neurons before their degeneration. These data suggest that disruption of chloride homeostasis in the ER disrupts the protein-folding capacity of the ER, leading to eventual neuron death. PMID:25698737

  1. PERK Limits Drosophila Lifespan by Promoting Intestinal Stem Cell Proliferation in Response to ER Stress.

    PubMed

    Wang, Lifen; Ryoo, Hyung Don; Qi, Yanyan; Jasper, Heinrich

    2015-05-01

    Intestinal homeostasis requires precise control of intestinal stem cell (ISC) proliferation. In Drosophila, this control declines with age largely due to chronic activation of stress signaling and associated chronic inflammatory conditions. An important contributor to this condition is the age-associated increase in endoplasmic reticulum (ER) stress. Here we show that the PKR-like ER kinase (PERK) integrates both cell-autonomous and non-autonomous ER stress stimuli to induce ISC proliferation. In addition to responding to cell-intrinsic ER stress, PERK is also specifically activated in ISCs by JAK/Stat signaling in response to ER stress in neighboring cells. The activation of PERK is required for homeostatic regeneration, as well as for acute regenerative responses, yet the chronic engagement of this response becomes deleterious in aging flies. Accordingly, knocking down PERK in ISCs is sufficient to promote intestinal homeostasis and extend lifespan. Our studies highlight the significance of the PERK branch of the unfolded protein response of the ER (UPRER) in intestinal homeostasis and provide a viable strategy to improve organismal health- and lifespan.

  2. Exocrine pancreas ER stress is differentially induced by different fatty acids.

    PubMed

    Danino, Hila; Ben-Dror, Karin; Birk, Ruth

    2015-12-10

    Exocrine pancreas acinar cells have a highly developed endoplasmic reticulum (ER), accommodating their high protein production rate. Overload of dietary fat (typical to obesity) is a recognized risk factor in pancreatitis and pancreatic cancer. Dietary fat, especially saturated fat, has been suggested by others and us to induce an acinar lipotoxic effect. The effect of different dietary fatty acids on the ER stress response is unknown. We studied the effect of acute (24h) challenge with different fatty acids (saturated, mono and poly-unsaturated) at different concentrations (between 200 and 500µM, typical to normal and obese states, respectively), testing fat accumulation, ER stress indicators, X-box binding protein 1 (Xbp1) splicing and nuclear translocation, as well as unfolded protein response (UPR) transcripts and protein levels using exocrine pancreas acinar AR42J and primary cells. Acute exposure of AR42J cells to different fatty acids caused increased accumulation of triglycerides, dependent on the type of fat. Different FAs had different effects on ER stress: most notably, saturated palmitic acid significantly affected the UPR response, as demonstrated by altered Xbp1 splicing, elevation in transcript levels of UPR (Xbp, CHOP, Bip) and immune factors (Tnfα, Tgfβ), and enhanced Xbp1 protein levels and Xbp1 time-dependent nuclear translocation. Poly-unsaturated FAs caused milder elevation of ER stress markers, while mono-unsaturated oleic acid attenuated the ER stress response. Thus, various fatty acids differentially affect acinar cell fat accumulation and, apart from oleic acid, induce ER stress. The differential effect of the various fatty acids could have potential nutritional and therapeutic implications.

  3. PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress.

    PubMed

    Verfaillie, T; Rubio, N; Garg, A D; Bultynck, G; Rizzuto, R; Decuypere, J-P; Piette, J; Linehan, C; Gupta, S; Samali, A; Agostinis, P

    2012-11-01

    Endoplasmic reticulum stress is emerging as an important modulator of different pathologies and as a mechanism contributing to cancer cell death in response to therapeutic agents. In several instances, oxidative stress and the onset of endoplasmic reticulum (ER) stress occur together; yet, the molecular events linking reactive oxygen species (ROS) to ER stress-mediated apoptosis are currently unknown. Here, we show that PERK (RNA-dependent protein kinase (PKR)-like ER kinase), a key ER stress sensor of the unfolded protein response, is uniquely enriched at the mitochondria-associated ER membranes (MAMs). PERK(-/-) cells display disturbed ER morphology and Ca(2+) signaling as well as significantly weaker ER-mitochondria contact sites. Re-expression of a kinase-dead PERK mutant but not the cytoplasmic deletion mutant of PERK in PERK(-/-) cells re-establishes ER-mitochondria juxtapositions and mitochondrial sensitization to ROS-mediated stress. In contrast to the canonical ER stressor thapsigargin, during ROS-mediated ER stress, PERK contributes to apoptosis twofold by sustaining the levels of pro-apoptotic C/EBP homologous protein (CHOP) and by facilitating the propagation of ROS signals between the ER and mitochondria through its tethering function. Hence, this study reveals an unprecedented role of PERK as a MAMs component required to maintain the ER-mitochondria juxtapositions and propel ROS-mediated mitochondrial apoptosis. Furthermore, it suggests that loss of PERK may cause defects in cell death sensitivity in pathological conditions linked to ROS-mediated ER stress.

  4. ER stress induces NLRP3 inflammasome activation and hepatocyte death

    PubMed Central

    Lebeaupin, C; Proics, E; de Bieville, C H D; Rousseau, D; Bonnafous, S; Patouraux, S; Adam, G; Lavallard, V J; Rovere, C; Le Thuc, O; Saint-Paul, M C; Anty, R; Schneck, A S; Iannelli, A; Gugenheim, J; Tran, A; Gual, P; Bailly-Maitre, B

    2015-01-01

    The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1α and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1β secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1β secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of

  5. Extensive Translatome Remodeling during ER Stress Response in Mammalian Cells

    PubMed Central

    Ventoso, Iván; Kochetov, Alex; Montaner, David; Dopazo, Joaquín; Santoyo, Javier

    2012-01-01

    In this work we have described the translatome of two mammalian cell lines, NIH3T3 and Jurkat, by scoring the relative polysome association of ∼10,000 mRNA under normal and ER stress conditions. We have found that translation efficiencies of mRNA correlated poorly with transcript abundance, although a general tendency was observed so that the highest translation efficiencies were found in abundant mRNA. Despite the differences found between mouse (NIH3T3) and human (Jurkat) cells, both cell types share a common translatome composed by ∼800–900 mRNA that encode proteins involved in basic cellular functions. Upon stress, an extensive remodeling in translatomes was observed so that translation of ∼50% of mRNA was inhibited in both cell types, this effect being more dramatic for those mRNA that accounted for most of the cell translation. Interestingly, we found two subsets comprising 1000–1500 mRNA whose translation resisted or was induced by stress. Translation arrest resistant class includes many mRNA encoding aminoacyl tRNA synthetases, ATPases and enzymes involved in DNA replication and stress response such as BiP. This class of mRNA is characterized by high translation rates in both control and stress conditions. Translation inducible class includes mRNA whose translation was relieved after stress, showing a high enrichment in early response transcription factors of bZIP and zinc finger C2H2 classes. Unlike yeast, a general coordination between changes in translation and transcription upon stress (potentiation) was not observed in mammalian cells. Among the different features of mRNA analyzed, we found a relevant association of translation efficiency with the presence of upstream ATG in the 5′UTR and with the length of coding sequence of mRNA, and a looser association with other parameters such as the length and the G+C content of 5′UTR. A model for translatome remodeling during the acute phase of stress response in mammalian cells is proposed. PMID

  6. Hippocampal ER stress and learning deficits following repeated pyrethroid exposure.

    PubMed

    Hossain, Muhammad M; DiCicco-Bloom, Emanuel; Richardson, Jason R

    2015-01-01

    Endoplasmic reticulum (ER) stress is implicated as a significant contributor to neurodegeneration and cognitive dysfunction. Previously, we reported that the widely used pyrethroid pesticide deltamethrin causes ER stress-mediated apoptosis in SK-N-AS neuroblastoma cells. Whether or not this occurs in vivo remains unknown. Here, we demonstrate that repeated deltamethrin exposure (3 mg/kg every 3 days for 60 days) causes hippocampal ER stress and learning deficits in adult mice. Repeated exposure to deltamethrin caused ER stress in the hippocampus as indicated by increased levels of C/EBP-homologous protein (131%) and glucose-regulated protein 78 (96%). This was accompanied by increased levels of caspase-12 (110%) and activated caspase-3 (50%). To determine whether these effects resulted in learning deficits, hippocampal-dependent learning was evaluated using the Morris water maze. Deltamethrin-treated animals exhibited profound deficits in the acquisition of learning. We also found that deltamethrin exposure resulted in decreased BrdU-positive cells (37%) in the dentate gyrus of the hippocampus, suggesting potential impairment of hippocampal neurogenesis. Collectively, these results demonstrate that repeated deltamethrin exposure leads to ER stress, apoptotic cell death in the hippocampus, and deficits in hippocampal precursor proliferation, which is associated with learning deficits.

  7. Dysfunction of Wntless triggers the retrograde Golgi-to-ER transport of Wingless and induces ER stress.

    PubMed

    Zhang, Peng; Zhou, Lujun; Pei, Chunli; Lin, Xinhua; Yuan, Zengqiang

    2016-02-18

    Secreted Wnts play diverse roles in a non-cell-autonomous fashion. However, the cell-autonomous effect of unsecreted Wnts remains unknown. Endoplasmic reticulum (ER) stress is observed in specialized secretory cells and participates in pathophysiological processes. The correlation between Wnt secretion and ER stress remains poorly understood. Here, we demonstrated that Drosophila miR-307a initiates ER stress specifically in wingless (wg)-expressing cells through targeting wntless (wls/evi). This phenotype could be mimicked by retromer loss-of-function or porcupine (porc) depletion, and rescued by wg knockdown, arguing that unsecreted Wg triggers ER stress. Consistently, we found that disrupting the secretion of human Wnt5a also induced ER stress in mammalian cells. Furthermore, we showed that a C-terminal KKVY-motif of Wg is required for its retrograde Golgi-to-ER transport, thus inducing ER stress. Next, we investigated if COPI, the regulator of retrograde transport, is responsible for unsecreted Wg to induce ER stress. To our surprise, we found that COPI acts as a novel regulator of Wg secretion. Taken together, this study reveals a previously unknown Golgi-to-ER retrograde route of Wg, and elucidates a correlation between Wnt secretion and ER stress during development.

  8. Dysfunction of Wntless triggers the retrograde Golgi-to-ER transport of Wingless and induces ER stress

    PubMed Central

    Zhang, Peng; Zhou, Lujun; Pei, Chunli; Lin, Xinhua; Yuan, Zengqiang

    2016-01-01

    Secreted Wnts play diverse roles in a non-cell-autonomous fashion. However, the cell-autonomous effect of unsecreted Wnts remains unknown. Endoplasmic reticulum (ER) stress is observed in specialized secretory cells and participates in pathophysiological processes. The correlation between Wnt secretion and ER stress remains poorly understood. Here, we demonstrated that Drosophila miR-307a initiates ER stress specifically in wingless (wg)-expressing cells through targeting wntless (wls/evi). This phenotype could be mimicked by retromer loss-of-function or porcupine (porc) depletion, and rescued by wg knockdown, arguing that unsecreted Wg triggers ER stress. Consistently, we found that disrupting the secretion of human Wnt5a also induced ER stress in mammalian cells. Furthermore, we showed that a C-terminal KKVY-motif of Wg is required for its retrograde Golgi-to-ER transport, thus inducing ER stress. Next, we investigated if COPI, the regulator of retrograde transport, is responsible for unsecreted Wg to induce ER stress. To our surprise, we found that COPI acts as a novel regulator of Wg secretion. Taken together, this study reveals a previously unknown Golgi-to-ER retrograde route of Wg, and elucidates a correlation between Wnt secretion and ER stress during development. PMID:26887613

  9. Acute pancreatitis: The stress factor

    PubMed Central

    Binker, Marcelo G; Cosen-Binker, Laura I

    2014-01-01

    Acute pancreatitis is an inflammatory disorder of the pancreas that may cause life-threatening complications. Etiologies of pancreatitis vary, with gallstones accounting for the majority of all cases, followed by alcohol. Other causes of pancreatitis include trauma, ischemia, mechanical obstruction, infections, autoimmune, hereditary, and drugs. The main events occurring in the pancreatic acinar cell that initiate and propagate acute pancreatitis include inhibition of secretion, intracellular activation of proteases, and generation of inflammatory mediators. Small cytokines known as chemokines are released from damaged pancreatic cells and attract inflammatory cells, whose systemic action ultimately determined the severity of the disease. Indeed, severe forms of pancreatitis may result in systemic inflammatory response syndrome and multiorgan dysfunction syndrome, characterized by a progressive physiologic failure of several interdependent organ systems. Stress occurs when homeostasis is threatened, and stressors can include physical or mental forces, or combinations of both. Depending on the timing and duration, stress can result in beneficial or harmful consequences. While it is well established that a previous acute-short-term stress decreases the severity of experimentally-induced pancreatitis, the worsening effects of chronic stress on the exocrine pancreas have received relatively little attention. This review will focus on the influence of both prior acute-short-term and chronic stress in acute pancreatitis. PMID:24914340

  10. Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy.

    PubMed

    Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng

    2015-10-15

    Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy.

  11. Stress Signal Network between Hypoxia and ER Stress in Chronic Kidney Disease

    PubMed Central

    Maekawa, Hiroshi; Inagi, Reiko

    2017-01-01

    Chronic kidney disease (CKD) is characterized by an irreversible decrease in kidney function and induction of various metabolic dysfunctions. Accumulated findings reveal that chronic hypoxic stress and endoplasmic reticulum (ER) stress are involved in a range of pathogenic conditions, including the progression of CKD. Because of the presence of an arteriovenous oxygen shunt, the kidney is thought to be susceptible to hypoxia. Chronic kidney hypoxia is induced by a number of pathogenic conditions, including renal ischemia, reduced peritubular capillary, and tubulointerstitial fibrosis. The ER is an organelle which helps maintain the quality of proteins through the unfolded protein response (UPR) pathway, and ER dysfunction associated with maladaptive UPR activation is named ER stress. ER stress is reported to be related to some of the effects of pathogenesis in kidney, particularly in the podocyte slit diaphragm and tubulointerstitium. Furthermore, chronic hypoxia mediates ER stress in blood vessel endothelial cells and tubulointerstitium via several mechanisms, including oxidative stress, epigenetic alteration, lipid metabolism, and the AKT pathway. In summary, a growing consensus considers that these stresses interact via complicated stress signal networks, which leads to the exacerbation of CKD (Figure 1). This stress signal network might be a target for interventions aimed at ameliorating CKD. PMID:28228736

  12. Stress Signal Network between Hypoxia and ER Stress in Chronic Kidney Disease.

    PubMed

    Maekawa, Hiroshi; Inagi, Reiko

    2017-01-01

    Chronic kidney disease (CKD) is characterized by an irreversible decrease in kidney function and induction of various metabolic dysfunctions. Accumulated findings reveal that chronic hypoxic stress and endoplasmic reticulum (ER) stress are involved in a range of pathogenic conditions, including the progression of CKD. Because of the presence of an arteriovenous oxygen shunt, the kidney is thought to be susceptible to hypoxia. Chronic kidney hypoxia is induced by a number of pathogenic conditions, including renal ischemia, reduced peritubular capillary, and tubulointerstitial fibrosis. The ER is an organelle which helps maintain the quality of proteins through the unfolded protein response (UPR) pathway, and ER dysfunction associated with maladaptive UPR activation is named ER stress. ER stress is reported to be related to some of the effects of pathogenesis in kidney, particularly in the podocyte slit diaphragm and tubulointerstitium. Furthermore, chronic hypoxia mediates ER stress in blood vessel endothelial cells and tubulointerstitium via several mechanisms, including oxidative stress, epigenetic alteration, lipid metabolism, and the AKT pathway. In summary, a growing consensus considers that these stresses interact via complicated stress signal networks, which leads to the exacerbation of CKD (Figure 1). This stress signal network might be a target for interventions aimed at ameliorating CKD.

  13. SEAP activity serves for demonstrating ER stress induction by glucolipotoxicity as well as testing ER stress inhibitory potential of therapeutic agents.

    PubMed

    Lenin, Raji; Mohan, Viswanathan; Balasubramanyam, Muthuswamy

    2015-06-01

    Endoplasmic reticulum (ER) stress is emerging as a unifying paradigm and one of the underlying mechanisms in the genesis of diabetes and its complications. While this has prompted the development of ER stress inhibitors, there is a limitation in monitoring of ER stress in vitro and in vivo by reliable methodologies. We validated the secreted alkaline phosphatase (SEAP) activity as a surrogate marker of ER stress in mouse β-TC6 cells exposed to glucolipotoxicity or tunicamycin and studied insulin secretion along with alterations in ER stress markers. SEAP activity assay was measured using the Great EscAPe SEAP kit, insulin levels were determined by Mercodia reagents and mRNA expression of ER stress markers was quantified by real-time PCR. SEAP activity in β-cells was significantly decreased (indicating increased ER stress) on exposure either to glucolipotoxicity or tunicamycin. This was accompanied by an increased mRNA expression of ER stress markers (GRP-78, PERK, IRE1α, ATF6, XBP-1, and CHOP) and decreased insulin secretion. Treating the cells with phenylbutyric acid normalized SEAP activity, decreased mRNA expression of ER stress markers and improved insulin secretion. Interestingly, cells exposed to different classes of anti-diabetes agents or compounds such as resveratrol resisted ER stress. Methylglyoxal also induces ER stress and this was counteracted by aminoguanidine. Out study demonstrates SEAP activity as a novel ER stress monitoring assay to investigate the therapeutic value of agents with ER stress inhibitory potential. Future studies should focus on the exercise of adopting this reporter assay for high-throughput screening mode of drug discovery.

  14. Unraveling the role of ER stress inhibitors in the context of metabolic diseases.

    PubMed

    Sarvani, Chodisetty; Sireesh, Dornadula; Ramkumar, Kunka Mohanram

    2017-02-22

    ER stress is provoked by the accumulation of unfolded and misfolded proteins in the ER lumen leading to perturbations in ER homeostasis. ER stress activates a signaling cascade called the Unfolded Protein Response (UPR) which triggers a set of transcriptional and translational events that restore ER homeostasis, promoting cell survival and adaptation. If this adaptive response fails, a terminal UPR program commits such cells to apoptosis. Existing preclinical and clinical evidence testify that prolonged ER stress escalates the risk of several metabolic disorders including diabetes, obesity and dyslipidemia. There have been considerable efforts to develop small molecules that are capable of ameliorating ER stress. Few naturally occurring and synthetic molecules have already been demonstrated for their efficacy in abrogating ER stress in both in vitro and in vivo models of metabolic disorders. This review provides a broad overview of the molecular mechanisms of inhibition of ER stress and its association with various metabolic diseases.

  15. Inhibition of nonsense-mediated RNA decay by ER stress.

    PubMed

    Li, Zhelin; Vuong, John K; Zhang, Min; Stork, Cheryl; Zheng, Sika

    2017-03-01

    Nonsense-mediated RNA decay (NMD) selectively degrades mutated and aberrantly processed transcripts that contain premature termination codons (PTC). Cellular NMD activity is typically assessed using exogenous PTC-containing reporters. We overcame some inherently problematic aspects of assaying endogenous targets and developed a broadly applicable strategy to reliably and easily monitor changes in cellular NMD activity. Our new method was genetically validated for distinguishing NMD regulation from transcriptional control and alternative splicing regulation, and unexpectedly disclosed a different sensitivity of NMD targets to NMD inhibition. Applying this robust method for screening, we identified NMD-inhibiting stressors but also found that NMD inactivation was not universal to cellular stresses. The high sensitivity and broad dynamic range of our method revealed a strong correlation between NMD inhibition, endoplasmic reticulum (ER) stress, and polysome disassembly upon thapsigargin treatment in a temporal and dose-dependent manner. We found little evidence of calcium signaling mediating thapsigargin-induced NMD inhibition. Instead, we discovered that of the three unfolded protein response (UPR) pathways activated by thapsigargin, mainly protein kinase RNA-like endoplasmic reticulum kinase (PERK) was required for NMD inhibition. Finally, we showed that ER stress compounded TDP-43 depletion in the up-regulation of NMD isoforms that had been implicated in the pathogenic mechanisms of amyotrophic lateral sclerosis and frontotemporal dementia, and that the additive effect of ER stress was completely blocked by PERK deficiency.

  16. Hypothalamic ER stress: A bridge between leptin resistance and obesity.

    PubMed

    Ramírez, Sara; Claret, Marc

    2015-06-22

    The prevalence of obesity has increased worldwide at an alarming rate. However, non-invasive pharmacological treatments remain elusive. Leptin resistance is a general feature of obesity, thus strategies aimed at enhancing the sensitivity to this hormone may constitute an excellent therapeutical approach to counteract current obesity epidemics. Nevertheless, the etiology and neuronal basis of leptin resistance remains an enigma. A recent hypothesis gaining substantial experimental support is that hypothalamic endoplasmic reticulum (ER) stress plays a causal role in the development of leptin resistance and obesity. The objective of this review article is to provide an updated view on current evidence connecting hypothalamic ER stress with leptin resistance. We discuss the experimental findings supporting this hypothesis, as well as the potential causes and underlying mechanisms leading to this metabolic disorder. Understanding these mechanisms may provide key insights into the development of novel intervention approaches.

  17. HDLs protect pancreatic β-cells against ER stress by restoring protein folding and trafficking.

    PubMed

    Pétremand, Jannick; Puyal, Julien; Chatton, Jean-Yves; Duprez, Jessica; Allagnat, Florent; Frias, Miguel; James, Richard W; Waeber, Gérard; Jonas, Jean-Christophe; Widmann, Christian

    2012-05-01

    Endoplasmic reticulum (ER) homeostasis alteration contributes to pancreatic β-cell dysfunction and death and favors the development of diabetes. In this study, we demonstrate that HDLs protect β-cells against ER stress induced by thapsigargin, cyclopiazonic acid, palmitate, insulin overexpression, and high glucose concentrations. ER stress marker induction and ER morphology disruption mediated by these stimuli were inhibited by HDLs. Using a temperature-sensitive viral glycoprotein folding mutant, we show that HDLs correct impaired protein trafficking and folding induced by thapsigargin and palmitate. The ability of HDLs to protect β-cells against ER stress was inhibited by brefeldin A, an ER to Golgi trafficking blocker. These results indicate that HDLs restore ER homeostasis in response to ER stress, which is required for their ability to promote β-cell survival. This study identifies a cellular mechanism mediating the beneficial effect of HDLs on β-cells against ER stress-inducing factors.

  18. HDLs Protect Pancreatic β-Cells Against ER Stress by Restoring Protein Folding and Trafficking

    PubMed Central

    Pétremand, Jannick; Puyal, Julien; Chatton, Jean-Yves; Duprez, Jessica; Allagnat, Florent; Frias, Miguel; James, Richard W.; Waeber, Gérard; Jonas, Jean-Christophe; Widmann, Christian

    2012-01-01

    Endoplasmic reticulum (ER) homeostasis alteration contributes to pancreatic β-cell dysfunction and death and favors the development of diabetes. In this study, we demonstrate that HDLs protect β-cells against ER stress induced by thapsigargin, cyclopiazonic acid, palmitate, insulin overexpression, and high glucose concentrations. ER stress marker induction and ER morphology disruption mediated by these stimuli were inhibited by HDLs. Using a temperature-sensitive viral glycoprotein folding mutant, we show that HDLs correct impaired protein trafficking and folding induced by thapsigargin and palmitate. The ability of HDLs to protect β-cells against ER stress was inhibited by brefeldin A, an ER to Golgi trafficking blocker. These results indicate that HDLs restore ER homeostasis in response to ER stress, which is required for their ability to promote β-cell survival. This study identifies a cellular mechanism mediating the beneficial effect of HDLs on β-cells against ER stress-inducing factors. PMID:22399686

  19. Role of SERCA1 Truncated Isoform in the Proapoptotic Calcium Transfer from ER to Mitochondria during ER Stress

    PubMed Central

    Chami, Mounia; Oulès, Bénédicte; Szabadkai, György; Tacine, Rachida; Rizzuto, Rosario; Paterlini-Bréchot, Patrizia

    2009-01-01

    SUMMARY Among the new players at the endoplasmic reticulum (ER)-mitochondria interface regulating interorganelle calcium signaling, those specifically involved during ER stress are not known at present. We report here that the truncated variant of the sarcoendoplasmic reticulum Ca2+-ATPase 1 (S1T) amplifies ER stress through the PERK-eIF2α-ATF4-CHOP pathway. S1T, which is localized in the ER-mitochondria microdomains, determines ER Ca2+ depletion due to increased Ca2+ leak, an increased number of ER-mitochondria contact sites, and inhibition of mitochondria movements. This leads to increased Ca2+ transfer to mitochondria in both resting and stimulated conditions and activation of the mitochondrial apoptotic pathway. Interestingly, S1T knockdown was shown to prevent ER stress, mitochondrial Ca2+ overload, and subsequent apoptosis. Thus, by bridging ER stress to apoptosis through increased ER-mitochondria Ca2+ transfer, S1T acts as an essential determinant of cellular fate. PMID:19061639

  20. Heme Degradation by Heme Oxygenase Protects Mitochondria but Induces ER Stress via Formed Bilirubin.

    PubMed

    Müllebner, Andrea; Moldzio, Rudolf; Redl, Heinz; Kozlov, Andrey V; Duvigneau, J Catharina

    2015-04-30

    Heme oxygenase (HO), in conjunction with biliverdin reductase, degrades heme to carbon monoxide, ferrous iron and bilirubin (BR); the latter is a potent antioxidant. The induced isoform HO-1 has evoked intense research interest, especially because it manifests anti-inflammatory and anti-apoptotic effects relieving acute cell stress. The mechanisms by which HO mediates the described effects are not completely clear. However, the degradation of heme, a strong pro-oxidant, and the generation of BR are considered to play key roles. The aim of this study was to determine the effects of BR on vital functions of hepatocytes focusing on mitochondria and the endoplasmic reticulum (ER). The affinity of BR to proteins is a known challenge for its exact quantification. We consider two major consequences of this affinity, namely possible analytical errors in the determination of HO activity, and biological effects of BR due to direct interaction with protein function. In order to overcome analytical bias we applied a polynomial correction accounting for the loss of BR due to its adsorption to proteins. To identify potential intracellular targets of BR we used an in vitro approach involving hepatocytes and isolated mitochondria. After verification that the hepatocytes possess HO activity at a similar level as liver tissue by using our improved post-extraction spectroscopic assay, we elucidated the effects of increased HO activity and the formed BR on mitochondrial function and the ER stress response. Our data show that BR may compromise cellular metabolism and proliferation via induction of ER stress. ER and mitochondria respond differently to elevated levels of BR and HO-activity. Mitochondria are susceptible to hemin, but active HO protects them against hemin-induced toxicity. BR at slightly elevated levels induces a stress response at the ER, resulting in a decreased proliferative and metabolic activity of hepatocytes. However, the proteins that are targeted by BR still have

  1. ER stress-induced protein, VIGG, disturbs plant cation homeostasis, which is correlated with growth retardation and robustness to ER stress

    SciTech Connect

    Katoh, Hironori; Fujita, Keiko; Takuhara, Yuki; Ogawa, Atsushi; Suzuki, Shunji

    2011-02-18

    Highlights: {yields} VIGG is an ER stress-induced protein in plant. {yields} We examine the characteristics of VIGG-overexpressing Arabidopsis plants. {yields} VIGG-overexpressing plants reveal growth retardation and robustness to ER stress. {yields} VIGG disturbs cation homeostasis in plant. -- Abstract: VIGG is a putative endoplasmic reticulum (ER) resident protein induced by virus infection and ER stress, and is correlated with fruit quality in grapevine. The present study was undertaken to determine the biological function of VIGG in grapevine. Experiments using fluorescent protein-VIGG fusion protein demonstrated that VIGG is localized in ER and the ER targeting sequence is in the N-terminus. The overexpression of VIGG in Arabidopsis plant led to growth retardation. The rosette leaves of VIGG-overexpressing plants were smaller than those of the control plants and rolled at 42 days after seeding. VIGG-overexpressing plants revealed robustness to ER stress as well as the low expression of ER stress marker proteins, such as the luminal binding proteins. These characteristics of VIGG-overexpressing plants were supported by a microarray experiment that demonstrated the disruption of genes related to ER stress response and flowering, as well as cation mobility, in the plants. Finally, cation homeostasis in the plants was disturbed by the overexpression of VIGG. Taken together, these results suggest that VIGG may disturb cation homeostasis in plant, which is correlated with the robustness to ER stress and growth retardation.

  2. Dietary Fish Oil Inhibits Pro-Inflammatory and ER Stress Signalling Pathways in the Liver of Sows during Lactation

    PubMed Central

    Gessner, Denise K.; Gröne, Birthe; Couturier, Aline; Rosenbaum, Susann; Hillen, Sonja; Becker, Sabrina; Erhardt, Georg; Reiner, Gerald; Ringseis, Robert; Eder, Klaus

    2015-01-01

    Lactating sows have been shown to develop typical signs of an inflammatory condition in the liver during the transition from pregnancy to lactation. Hepatic inflammation is considered critical due to the induction of an acute phase response and the activation of stress signaling pathways like the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR), both of which impair animal´s health and performance. Whether ER stress-induced UPR is also activated in the liver of lactating sows and whether dietary fish oil as a source of anti-inflammatory effects n-3 PUFA is able to attenuate hepatic inflammation and ER stress-induced UPR in the liver of sows is currently unknown. Based on this, two experiments with lactating sows were performed. The first experiment revealed that ER stress-induced UPR occurs also in the liver of sows during lactation. This was evident from the up-regulation of a set of genes regulated by the UPR and numerically increased phosphorylation of the ER stress-transducer PERK and PERK-mediated phosphorylation of eIF2α and IκB. The second experiment showed that fish oil inhibits ER stress-induced UPR in the liver of lactating sows. This was demonstrated by decreased mRNA levels of a number of UPR-regulated genes and reduced phosphorylation of PERK and PERK-mediated phosphorylation of eIF2α and IκB in the liver of the fish oil group. The mRNA levels of various nuclear factor-κB-regulated genes encoding inflammatory mediators and acute phase proteins in the liver of lactating sows were also reduced in the fish oil group. In line with this, the plasma levels of acute phase proteins were reduced in the fish oil group, although differences to the control group were not significant. In conclusion, ER stress-induced UPR is present in the liver of lactating sows and fish oil is able to inhibit inflammatory signaling pathways and ER stress-induced UPR in the liver. PMID:26351857

  3. Stress and acute respiratory infection

    SciTech Connect

    Graham, N.M.; Douglas, R.M.; Ryan, P.

    1986-09-01

    To examine the relationship between stress and upper respiratory tract infection, 235 adults aged 14-57 years, from 94 families affiliated with three suburban family physicians in Adelaide, South Australia, participated in a six-month prospective study. High and low stress groups were identified by median splits of data collected from the Life Events Inventory, the Daily Hassles Scale, and the General Health Questionnaire, which were administered both before and during the six months of respiratory diary data collection. Using intra-study stress data, the high stress group experienced significantly more episodes (mean of 2.71 vs. 1.56, p less than 0.0005) and symptom days (mean of 29.43 vs. 15.42, p = 0.005) of respiratory illness. The two groups were almost identical with respect to age, sex, occupational status, smoking, passive smoking, exposure to air pollution, family size, and proneness to acute respiratory infection in childhood. In a multivariate model with total respiratory episodes as the dependent variable, 21% of the variance was explained, and two stress variables accounted for 9% of the explained variance. Significant, but less strong relationships were also identified between intra-study stress variables and clinically definite episodes and symptom days in both clinically definite and total respiratory episodes. Pre-study measures of stress emphasized chronic stresses and were less strongly related to measures of respiratory illness than those collected during the study. However, significantly more episodes (mean of 2.50 vs. 1.75, p less than 0.02) and symptom days (mean of 28.00 vs. 17.06, p less than 0.03) were experienced in the high stress group. In the multivariate analyses, pre-study stress remained significantly associated with total respiratory episodes nd symptom days in total and ''definite'' respiratory episodes.

  4. Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins.

    PubMed

    Das, Indrajit; Png, Chin Wen; Oancea, Iulia; Hasnain, Sumaira Z; Lourie, Rohan; Proctor, Martina; Eri, Rajaraman D; Sheng, Yong; Crane, Denis I; Florin, Timothy H; McGuckin, Michael A

    2013-06-03

    Endoplasmic reticulum (ER) stress in intestinal secretory cells has been linked with colitis in mice and inflammatory bowel disease (IBD). Endogenous intestinal glucocorticoids are important for homeostasis and glucocorticoid drugs are efficacious in IBD. In Winnie mice with intestinal ER stress caused by misfolding of the Muc2 mucin, the glucocorticoid dexamethasone (DEX) suppressed ER stress and activation of the unfolded protein response (UPR), substantially restoring goblet cell Muc2 production. In mice lacking inflammation, a glucocorticoid receptor antagonist increased ER stress, and DEX suppressed ER stress induced by the N-glycosylation inhibitor, tunicamycin (Tm). In cultured human intestinal secretory cells, in a glucocorticoid receptor-dependent manner, DEX suppressed ER stress and UPR activation induced by blocking N-glycosylation, reducing ER Ca(2+) or depleting glucose. DEX up-regulated genes encoding chaperones and elements of ER-associated degradation (ERAD), including EDEM1. Silencing EDEM1 partially inhibited DEX's suppression of misfolding-induced ER stress, showing that DEX enhances ERAD. DEX inhibited Tm-induced MUC2 precursor accumulation, promoted production of mature mucin, and restored ER exit and secretion of Winnie mutant recombinant Muc2 domains, consistent with enhanced protein folding. In IBD, glucocorticoids are likely to ameliorate ER stress by promoting correct folding of secreted proteins and enhancing removal of misfolded proteins from the ER.

  5. Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells.

    PubMed

    Dejeans, Nicolas; Tajeddine, Nicolas; Beck, Raphaël; Verrax, Julien; Taper, Henryk; Gailly, Philippe; Calderon, Pedro Buc

    2010-05-01

    Increase in cytosolic calcium concentration ([Ca2+](c)), release of endoplasmic reticulum (ER) calcium ([Ca2+](er)) and ER stress have been proposed to be involved in oxidative toxicity. Nevertheless, their relative involvements in the processes leading to cell death are not well defined. In this study, we investigated whether oxidative stress generated during ascorbate-driven menadione redox cycling (Asc/Men) could trigger these three events, and, if so, whether they contributed to Asc/Men cytoxicity in MCF-7 cells. Using microspectrofluorimetry, we demonstrated that Asc/Men-generated oxidative stress was associated with a slow and moderate increase in [Ca2+](c), largely preceding permeation of propidium iodide, and thus cell death. Asc/Men treatment was shown to partially deplete ER calcium stores after 90 min (decrease by 45% compared to control). This event was associated with ER stress activation, as shown by analysis of eIF2 phosphorylation and expression of the molecular chaperone GRP94. Thapsigargin (TG) was then used to study the effect of complete [Ca2+](er) emptying during the oxidative stress generated by Asc/Men. Surprisingly, the combination of TG and Asc/Men increased ER stress to a level considerably higher than that observed for either treatment alone, suggesting that [Ca2+](er) release alone is not sufficient to explain ER stress activation during oxidative stress. Finally, TG-mediated [Ca2+](er) release largely potentiated ER stress, DNA fragmentation and cell death caused by Asc/Men, supporting a role of ER stress in the process of Asc/Men cytotoxicity. Taken together, our results highlight the involvement of ER stress and [Ca2+](er) decrease in the process of oxidative stress-induced cell death in MCF-7 cells.

  6. Endoplasmic reticulum stress and its effects on renal tubular cells apoptosis in ischemic acute kidney injury.

    PubMed

    Xu, Yan; Guo, Min; Jiang, Wei; Dong, Hui; Han, Yafei; An, Xiao-Fei; Zhang, Jisheng

    2016-06-01

    Ischemia is the most frequent cause of acute kidney injury (AKI), which is characterized by apoptosis of renal tubular cell. A common result of ischemia in AKI is dysfunction of endoplasmic reticulum (ER), which causes the protein-folding capacity to lag behind the protein-folding load. The abundance of misfolded proteins stressed the ER and results in induction of the unfolded protein response (UPR). While the UPR is an adaptive response, over time it can result in apoptosis when cells are unable to recover quickly. Recent research suggests that ER stress is a major factor in renal tubular cell apoptosis resulting from ischemic AKI. Thus, ER stress may be an important new progression factor in the pathology of ischemic AKI. In this article, we review UPR signaling, describe pathology and pathophysiology mechanisms of ischemic AKI, and highlight the dual function of ER stress on renal tubular cell apoptosis.

  7. ER Stress-induced Inflammasome Activation Contributes to Hepatic Inflammation and Steatosis

    PubMed Central

    Zhang, Jinyu; Zhang, Kezhong; Li, Zihai; Guo, Beichu

    2016-01-01

    Endoplasmic reticulum (ER) stress functions as a protein folding and quality control mechanism to maintain cell homeostasis. Emerging evidence indicates that ER stress is also involved in metabolic and inflammatory diseases. However, the link between ER stress and inflammation remains not well characterized. In this study, we have demonstrated that ER stress-induced inflammasome activation plays a critical role in the pathogenesis of hepatic steatosis. By utilizing genetic and pharmacological agent-induced hepatic steatosis animal models, we found that hepatic steatosis was associated with inflammasome activation and ER stress. Our results show that caspase-1 ablation alleviated liver inflammation and injury. Liver tissues from caspase-1 KO mice had significantly reduced production of IL-1β under ER stress conditions. We also found that ER stress promoted inflammasome activation and IL-1β processing in both hepatocytes and Kupffer cells/macrophages. Moreover, lack of caspase-1 ameliorated cell death or pyropoptosis of hepatocytes induced by ER stress. Taken together, our findings suggest that ER stress-induced inflammasome activation and IL-1β production generate a positive feedback loop to amplify inflammatory response, eventually leading to liver steatosis and injury. PMID:27942420

  8. Calcium homoeostasis modulator 1 (CALHM1) reduces the calcium content of the endoplasmic reticulum (ER) and triggers ER stress.

    PubMed

    Gallego-Sandín, Sonia; Alonso, María Teresa; García-Sancho, Javier

    2011-08-01

    CALHM1 (calcium homoeostasis modulator 1), a membrane protein with similarity to NMDA (N-methyl-D-aspartate) receptor channels that localizes in the plasma membrane and the ER (endoplasmic reticulum) of neurons, has been shown to generate a plasma-membrane Ca(2+) conductance and has been proposed to influence Alzheimer's disease risk. In the present study we have investigated the effects of CALHM1 on intracellular Ca(2+) handling in HEK-293T [HEK (human embryonic kidney)-293 cells expressing the large T-antigen of SV40 (simian virus 40)] cells by using targeted aequorins for selective monitorization of Ca(2+) transport by organelles. We find that CALHM1 increases Ca(2+) leak from the ER and, more importantly, reduces ER Ca(2+) uptake by decreasing both the transport capacity and the Ca(2+) affinity of SERCA (sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase). As a result, the Ca(2+) content of the ER is drastically decreased. This reduction in the Ca(2+) content of the ER triggered the UPR (unfolded protein response) with induction of several ER stress markers, such as CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein], ERdj4, GRP78 (glucose-regulated protein of 78 kDa) and XBP1 (X-box-binding protein 1). Thus CALHM1 might provide a relevant link between Ca(2+) homoeostasis disruption, ER stress and cell damage in the pathogenesis of neurodegenerative diseases.

  9. The dysregulation of endoplasmic reticulum stress response in acute-on-chronic liver failure patients caused by acute exacerbation of chronic hepatitis B.

    PubMed

    Ren, F; Shi, H; Zhang, L; Zhang, X; Wen, T; Xie, B; Zheng, S; Chen, Y; Li, L; Chen, D; Duan, Z

    2016-01-01

    Although endoplasmic reticulum (ER) stress is critical in various liver diseases, its role in acute-on-chronic liver failure (AoCLF) caused by acute exacerbation of chronic hepatitis B (CHB) is still elusive. This study aimed to analyse ER stress responses in the progression of HBV-related AoCLF. Normal liver tissues (n = 10), liver tissues of CHB (n = 12) and HBV-related patients with AoCLF (n = 19) were used. Electron microscopy of the ultrastructure of the ER was carried out on liver specimens. The gene and protein expression levels of ER stress-related genes were measured. We further analysed the correlation between the expression levels of ER stress-related molecules and liver injury. Electron microscopy identified typical features of the ER microstructure in AoCLF subjects. Among the three pathways of unfolded protein responses, the PKR-like ER kinase and inositol-requiring enzyme 1 signalling pathway were activated in CHB subjects and inactivated in AoCLF subjects, while the activating transcription factor 6 signalling pathway was sustained in the activated form during the progression of AoCLF; the expression of glucose-regulated protein (Grp)78 and Grp94 was gradually decreased in AoCLF subjects compared to healthy individuals and CHB subjects, showing a negative correlation with serum ALT, AST and TBIL; moreover, the ER stress-related apoptosis molecules were activated in the progression of acute exacerbation of CHB. The dysregulated ER stress response may play a complicated role in the pathogenesis of AoCLF, and a severe ER stress response may predict the occurrence of AoCLF caused by acute exacerbation of CHB.

  10. BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response.

    PubMed

    Dai, Fangyan; Lee, Hyemin; Zhang, Yilei; Zhuang, Li; Yao, Hui; Xi, Yuanxin; Xiao, Zhen-Dong; You, M James; Li, Wei; Su, Xiaoping; Gan, Boyi

    2017-03-21

    The endoplasmic reticulum (ER) is classically linked to metabolic homeostasis via the activation of unfolded protein response (UPR), which is instructed by multiple transcriptional regulatory cascades. BRCA1 associated protein 1 (BAP1) is a tumor suppressor with de-ubiquitinating enzyme activity and has been implicated in chromatin regulation of gene expression. Here we show that BAP1 inhibits cell death induced by unresolved metabolic stress. This prosurvival role of BAP1 depends on its de-ubiquitinating activity and correlates with its ability to dampen the metabolic stress-induced UPR transcriptional network. BAP1 inhibits glucose deprivation-induced reactive oxygen species and ATP depletion, two cellular events contributing to the ER stress-induced cell death. In line with this, Bap1 KO mice are more sensitive to tunicamycin-induced renal damage. Mechanically, we show that BAP1 represses metabolic stress-induced UPR and cell death through activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP), and reveal that BAP1 binds to ATF3 and CHOP promoters and inhibits their transcription. Taken together, our results establish a previously unappreciated role of BAP1 in modulating the cellular adaptability to metabolic stress and uncover a pivotal function of BAP1 in the regulation of the ER stress gene-regulatory network. Our study may also provide new conceptual framework for further understanding BAP1 function in cancer.

  11. BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response

    PubMed Central

    Dai, Fangyan; Lee, Hyemin; Zhang, Yilei; Zhuang, Li; Yao, Hui; Xi, Yuanxin; Xiao, Zhen-Dong; You, M. James; Li, Wei; Su, Xiaoping; Gan, Boyi

    2017-01-01

    The endoplasmic reticulum (ER) is classically linked to metabolic homeostasis via the activation of unfolded protein response (UPR), which is instructed by multiple transcriptional regulatory cascades. BRCA1 associated protein 1 (BAP1) is a tumor suppressor with de-ubiquitinating enzyme activity and has been implicated in chromatin regulation of gene expression. Here we show that BAP1 inhibits cell death induced by unresolved metabolic stress. This prosurvival role of BAP1 depends on its de-ubiquitinating activity and correlates with its ability to dampen the metabolic stress-induced UPR transcriptional network. BAP1 inhibits glucose deprivation-induced reactive oxygen species and ATP depletion, two cellular events contributing to the ER stress-induced cell death. In line with this, Bap1 KO mice are more sensitive to tunicamycin-induced renal damage. Mechanically, we show that BAP1 represses metabolic stress-induced UPR and cell death through activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP), and reveal that BAP1 binds to ATF3 and CHOP promoters and inhibits their transcription. Taken together, our results establish a previously unappreciated role of BAP1 in modulating the cellular adaptability to metabolic stress and uncover a pivotal function of BAP1 in the regulation of the ER stress gene-regulatory network. Our study may also provide new conceptual framework for further understanding BAP1 function in cancer. PMID:28275095

  12. ER signaling is activated to protect human HaCaT keratinocytes from ER stress induced by environmental doses of UVB

    SciTech Connect

    Mera, Kentaro; Kawahara, Ko-ichi; Tada, Ko-ichi; Kawai, Kazuhiro; Hashiguchi, Teruto; Maruyama, Ikuro; Kanekura, Takuro

    2010-06-25

    Proteins are folded properly in the endoplasmic reticulum (ER). Various stress such as hypoxia, ischemia and starvation interfere with the ER function, causing ER stress, which is defined by the accumulation of unfolded protein (UP) in the ER. ER stress is prevented by the UP response (UPR) and ER-associated degradation (ERAD). These signaling pathways are activated by three major ER molecules, ATF6, IRE-1 and PERK. Using HaCaT cells, we investigated ER signaling in human keratinocytes irradiated by environmental doses of ultraviolet B (UVB). The expression of Ero1-L{alpha}, an upstream signaling molecule of ER stress, decreased at 1-4 h after 10 mJ/cm{sup 2} irradiation, indicating that the environmental dose of UVB-induced ER stress in HaCaT cells, without growth retardation. Furthermore, expression of intact ATF6 was decreased and it was translocated to the nuclei. The expression of XBP-1, a downstream molecule of IRE-1, which is an ER chaperone whose expression is regulated by XBP-1, and UP ubiquitination were induced by 10 mJ/cm{sup 2} UVB at 4 h. PERK, which regulates apoptosis, was not phosphorylated. Our results demonstrate that UVB irradiation generates UP in HaCaT cells and that the UPR and ERAD systems are activated to protect cells from UVB-induced ER stress. This is the first report to show ER signaling in UVB-irradiated keratinocytes.

  13. Targeting the hallmarks of cancer with therapy-induced endoplasmic reticulum (ER) stress

    PubMed Central

    Garg, Abhishek D; Maes, Hannelore; van Vliet, Alexander R; Agostinis, Patrizia

    2015-01-01

    The endoplasmic reticulum (ER) is at the center of a number of vital cellular processes such as cell growth, death, and differentiation, crosstalk with immune or stromal cells, and maintenance of proteostasis or homeostasis, and ER functions have implications for various pathologies including cancer. Recently, a number of major hallmarks of cancer have been delineated that are expected to facilitate the development of anticancer therapies. However, therapeutic induction of ER stress as a strategy to broadly target multiple hallmarks of cancer has been seldom discussed despite the fact that several primary or secondary ER stress-inducing therapies have been found to exhibit positive clinical activity in cancer patients. In the present review we provide a brief historical overview of the major discoveries and milestones in the field of ER stress biology with important implications for anticancer therapy. Furthermore, we comprehensively discuss possible strategies enabling the targeting of multiple hallmarks of cancer with therapy-induced ER stress. PMID:27308392

  14. Targeting the hallmarks of cancer with therapy-induced endoplasmic reticulum (ER) stress.

    PubMed

    Garg, Abhishek D; Maes, Hannelore; van Vliet, Alexander R; Agostinis, Patrizia

    2015-01-01

    The endoplasmic reticulum (ER) is at the center of a number of vital cellular processes such as cell growth, death, and differentiation, crosstalk with immune or stromal cells, and maintenance of proteostasis or homeostasis, and ER functions have implications for various pathologies including cancer. Recently, a number of major hallmarks of cancer have been delineated that are expected to facilitate the development of anticancer therapies. However, therapeutic induction of ER stress as a strategy to broadly target multiple hallmarks of cancer has been seldom discussed despite the fact that several primary or secondary ER stress-inducing therapies have been found to exhibit positive clinical activity in cancer patients. In the present review we provide a brief historical overview of the major discoveries and milestones in the field of ER stress biology with important implications for anticancer therapy. Furthermore, we comprehensively discuss possible strategies enabling the targeting of multiple hallmarks of cancer with therapy-induced ER stress.

  15. Obesity-induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury.

    PubMed

    Shah, Dilip; Romero, Freddy; Guo, Zhi; Sun, Jianxin; Li, Jonathan; Kallen, Caleb B; Naik, Ulhas P; Summer, Ross

    2017-03-09

    Obesity is a significant risk factor for the acute respiratory distress syndrome (ARDS). The mechanisms underlying this association are unknown. We recently showed that diet-induced obese (DIO) mice exhibit pulmonary vascular endothelial dysfunction which is associated with enhanced susceptibility to lipopolysaccharide (LPS)-induced lung injury. Here, we demonstrate that lung endothelial dysfunction in DIO mice coincides with increased endoplasmic reticulum (ER) stress. Specifically, we observed enhanced expression of the major sensors of misfolded proteins including PERK, IREα and ATF6, in whole lung and in lung endothelial cells isolated from DIO mice. Further, we found that lung endothelial cells exposed to serum from obese mice, or to saturated fatty acids that mimic obese serum, resulted in enhanced expression of markers of ER stress and the induction of other biological responses that typify the lung endothelium of DIO mice. Similar changes were observed in lung endothelial cells and in whole lung tissue after exposure to tunicamycin, a compound that causes ER stress by blocking N-linked glycosylation; indicating that ER stress causes endothelial dysfunction in the lung. Treatment with 4-PBA, a chemical protein chaperone that reduces ER stress, restored vascular endothelial cell expression of adhesion molecules and protected against LPS-induced acute lung injury in DIO mice. Our work indicates that fatty acids in obese serum induce ER stress in the pulmonary endothelium leading to pulmonary endothelial cell dysfunction. Our work suggests that reducing protein load in the endoplasmic reticulum of pulmonary endothelial cells might protect against ARDS in obese individuals.

  16. When supply does not meet demand-ER stress and plant programmed cell death

    PubMed Central

    Williams, Brett; Verchot, Jeanmarie; Dickman, Martin B.

    2014-01-01

    The endoplasmic reticulum (ER) is the central organelle in the eukaryotic secretory pathway. The ER functions in protein synthesis and maturation and is crucial for proper maintenance of cellular homeostasis and adaptation to adverse environments. Acting as a cellular sentinel, the ER is exquisitely sensitive to changing environments principally via the ER quality control machinery. When perturbed, ER-stress triggers a tightly regulated and highly conserved, signal transduction pathway known as the unfolded protein response (UPR) that prevents the dangerous accumulation of unfolded/misfolded proteins. In situations where excessive UPR activity surpasses threshold levels, cells deteriorate and eventually trigger programmed cell death (PCD) as a way for the organism to cope with dysfunctional or toxic signals. The programmed cell death that results from excessive ER stress in mammalian systems contributes to several important diseases including hypoxia, neurodegeneration, and diabetes. Importantly, hallmark features and markers of cell death that are associated with ER stress in mammals are also found in plants. In particular, there is a common, conserved set of chaperones that modulate ER cell death signaling. Here we review the elements of plant cell death responses to ER stress and note that an increasing number of plant-pathogen interactions are being identified in which the host ER is targeted by plant pathogens to establish compatibility. PMID:24926295

  17. AMPK-independent inhibition of human macrophage ER stress response by AICAR

    PubMed Central

    Boß, Marcel; Newbatt, Yvette; Gupta, Sahil; Collins, Ian; Brüne, Bernhard; Namgaladze, Dmitry

    2016-01-01

    Obesity-associated insulin resistance is driven by inflammatory processes in response to metabolic overload. Obesity-associated inflammation can be recapitulated in cell culture by exposing macrophages to saturated fatty acids (SFA), and endoplasmic reticulum (ER) stress responses essentially contribute to pro-inflammatory signalling. AMP-activated protein kinase (AMPK) is a central metabolic regulator with established anti-inflammatory actions. Whether pharmacological AMPK activation suppresses SFA-induced inflammation in a human system is unclear. In a setting of hypoxia-potentiated inflammation induced by SFA palmitate, we found that the AMP-mimetic AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) potently suppressed upregulation of ER stress marker mRNAs and pro-inflammatory cytokines. Furthermore, AICAR inhibited macrophage ER stress responses triggered by ER-stressors thapsigargin or tunicamycin. Surprisingly, AICAR acted independent of AMPK or AICAR conversion to 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate (ZMP) while requiring intracellular uptake via the equilibrative nucleoside transporter (ENT) ENT1 or the concentrative nucleoside transporter (CNT) CNT3. AICAR did not affect the initiation of the ER stress response, but inhibited the expression of major ER stress transcriptional effectors. Furthermore, AICAR inhibited autophosphorylation of the ER stress sensor inositol-requiring enzyme 1α (IRE1α), while activating its endoribonuclease activity in vitro. Our results suggest that AMPK-independent inhibition of ER stress responses contributes to anti-inflammatory and anti-diabetic effects of AICAR. PMID:27562249

  18. PUMA mediates ER stress-induced apoptosis in portal hypertensive gastropathy.

    PubMed

    Tan, S; Wei, X; Song, M; Tao, J; Yang, Y; Khatoon, S; Liu, H; Jiang, J; Wu, B

    2014-03-13

    Mucosal apoptosis has been demonstrated to be an essential pathological feature in portal hypertensive gastropathy (PHG). p53-upregulated modulator of apoptosis (PUMA) was identified as a BH3-only Bcl-2 family protein that has an essential role in apoptosis induced by a variety of stimuli, including endoplasmic reticulum (ER) stress. However, whether PUMA is involved in mucosal apoptosis in PHG remains unclear, and whether PUMA induces PHG by mediating ER stress remains unknown. The aim of the study is to investigate whether PUMA is involved in PHG by mediating ER stress apoptotic signaling. To identify whether PUMA is involved in PHG by mediating ER stress, gastric mucosal injury and apoptosis were studied in both PHG patients and PHG animal models using PUMA knockout (PUMA-KO) and PUMA wild-type (PUMA-WT) mice. The induction of PUMA expression and ER stress signaling were investigated, and the mechanisms of PUMA-mediated apoptosis were analyzed. GES-1 and SGC7901 cell lines were used to further identify whether PUMA-mediated apoptosis was induced by ER stress in vitro. Epithelial apoptosis and PUMA were markedly induced in the gastric mucosa of PHG patients and mouse PHG models. ER stress had a potent role in the induction of PUMA and apoptosis in PHG models, and the apoptosis was obviously attenuated in PUMA-KO mice. Although the targeted deletion of PUMA did not affect ER stress, mitochondrial apoptotic signaling was downregulated in mice. Meanwhile, PUMA knockdown significantly ameliorated ER stress-induced mitochondria-dependent apoptosis in vitro. These results indicate that PUMA mediates ER stress-induced mucosal epithelial apoptosis through the mitochondrial apoptotic pathway in PHG, and that PUMA is a potentially therapeutic target for PHG.

  19. Emerging Roles of ER Stress and Unfolded Protein Response Pathways in Skeletal Muscle Health and Disease.

    PubMed

    Bohnert, Kyle R; McMillan, Joseph D; Kumar, Ashok

    2017-02-08

    Skeletal muscle is the most abundant tissue in the human body and can adapt its mass as a consequence of physical activity, metabolism, growth factors, and disease conditions. Skeletal muscle contains an extensive network of endoplasmic reticulum (ER), called sarcoplasmic reticulum, which plays an important role in the regulation of proteostasis and calcium homeostasis. In many cell types, environmental and genetic factors that disrupt ER function cause an accumulation of misfolded and unfolded proteins in the ER lumen that ultimately leads to ER stress. To alleviate the stress and restore homeostasis, the ER activates a signaling network called the unfolded protein response (UPR). The UPR has three arms, which regulate protein synthesis and expression of many ER chaperone and regulatory proteins. However, the role of individual UPR pathways in skeletal muscle has just begun to be investigated. Recent studies suggest that UPR pathways play pivotal roles in muscle stem cell homeostasis, myogenic differentiation, and regeneration of injured skeletal muscle. Moreover, markers of ER stress and the UPR are activated in skeletal muscle in diverse conditions such as exercise, denervation, starvation, high fat diet, cancer cachexia, and aging. Accumulating evidence also suggests that ER stress may have important roles in the pathogenesis of inflammatory myopathies and genetic muscle disorders. The purpose of this review article is to discuss the role and potential mechanisms by which ER stress and the individual arms of the UPR regulate skeletal muscle formation, plasticity, and function in various physiological and pathophysiological conditions. This article is protected by copyright. All rights reserved.

  20. Toll-like receptor 4 ablation rescues against paraquat-triggered myocardial dysfunction: Role of ER stress and apoptosis.

    PubMed

    Lei, Yonghong; Li, Xue; Yuan, Fang; Liu, Lu; Zhang, Juan; Yang, Yanping; Zhao, Jieqiong; Han, Yan; Ren, Jun; Fu, Xiaobing

    2017-02-01

    Paraquat is a nitrogen herbicide imposing severe organ toxicity in human leading to acute lung injury and heart failure. The present study was designed to examine the impact of ablation of the innate proinflammatory mediator toll-like receptor 4 (TLR4) in paraquat-induced cardiac contractile dysfunction and the underlying mechanisms involved with a focus on endoplasmic reticulum (ER) stress and apoptosis. Adult male wild-type (WT) and TLR4 knockout (TLR4(-/-) ) mice were challenged with paraquat (45 mg/kg, i.p.) for 48 h prior to the assessment of myocardial and cardiomyocyte sarcomere function, ER stress, apoptosis and inflammation. Acute paraquat challenge exerted myocardial functional and geometric alterations including enlarged left ventricular end systolic diameter (LVESD), reduced fractional shortening, decreased sarcomere shortening, maximal velocities of sarcomere shortening and relengthening associated with unchanged LV posterior wall thickness, septal thickness, LV end diastolic diameter (LVEDD), heart rate, sarcomere length, time-to-peak shortening and time-to-90% relengthening. Although TLR4 ablation did not affect mechanical properties in the heart, it significantly attenuated or ablated paraquat-induced cardiac contractile anomalies. Moreover, paraquat imposed overt ER stress, apoptosis and inflammation as evidenced by upregulation of Bip, CHOP, Caspase-3, -9, Bax, Bad, and IL-1β, phosphorylation of PERK, eIF2α and IΚB, as well as activation of the stress molecules ERK and p38, with unchanged Caspase-8, Bcl2, TNF-α, p53, HMGB1, MyD88 and phosphorylation of Akt, GSK3β and JNK, the effects of which were attenuated or negated by TLR4 knockout. Taken together, our results suggested that TLR4 ablation alleviated paraquat-induced myocardial contractile dysfunction possibly through attenuation of ER stress, apoptosis and inflammation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 656-668, 2017.

  1. Nonmuscle Myosin IIB Links Cytoskeleton to IRE1α Signaling during ER Stress

    PubMed Central

    He, Yin; Beatty, Alexander; Han, Xuemei; Ji, Yewei; Ma, Xuefei; Adelstein, Robert S.; Yates, John R.; Kemphues, Kenneth; Qi, Ling

    2013-01-01

    SUMMARY Here we identify and characterize a cytoskeletal myosin protein required for IRE1α oligomerization, activation, and signaling. Proteomic screening identified nonmuscle myosin heavy chain IIB (NMHCIIB), a subunit of nonmuscle myosin IIB (NMIIB), as an ER stress-dependent interacting protein specific to IRE1α. Loss of NMIIB compromises XBP1s and UPR target gene expression with no effect on the PERK pathway. Mechanistically, NMIIB is required for IRE1α aggregation and foci formation under ER stress. The NMIIB-mediated effect on IRE1α signaling is in part dependent on the phosphorylation of myosin regulatory light chain and the actomyosin contractility of NMIIB. Biologically, the function of NMIIB in ER stress response is conserved as both mammalian cells and C. elegans lacking NMIIB exhibit hypersensitivity to ER stress. Thus, optimal IRE1α activation and signaling require concerted coordination between the ER and cytoskeleton. PMID:23237951

  2. Ube2g2-gp78-mediated HERP polyubiquitylation is involved in ER stress recovery.

    PubMed

    Yan, Long; Liu, Weixiao; Zhang, Huihui; Liu, Chao; Shang, Yongliang; Ye, Yihong; Zhang, Xiaodong; Li, Wei

    2014-04-01

    A large number of studies have focused on how individual organisms respond to a stress condition, but little attention has been paid to the stress recovery process, such as the endoplasmic reticulum (ER) stress recovery. Homocysteine-induced ER protein (HERP) was originally identified as a chaperone-like protein that is strongly induced upon ER stress. Here we show that, after ER stress induction, HERP is rapidly degraded by Ube2g2-gp78-mediated ubiquitylation and proteasomal degradation. The polyubiquitylation of HERP in vitro depends on a physical interaction between the CUE domain of gp78 and the ubiquitin-like (UBL) domain of HERP, which is essential for HERP degradation in vivo during ER stress recovery. We further show that although HERP promotes cell survival under ER stress, high levels of HERP expression reduce cell viability under oxidative stress conditions, suggesting that HERP plays a dual role in cellular stress adaptation. Together, these results establish the ubiquitin-proteasome-mediated degradation of HERP as a novel mechanism that fine-tunes the stress tolerance capacity of the cell.

  3. RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions

    PubMed Central

    Estornes, Y; Aguileta, M A; Dubuisson, C; De Keyser, J; Goossens, V; Kersse, K; Samali, A; Vandenabeele, P; Bertrand, M J M

    2014-01-01

    Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and results in the activation of the unfolded protein response (UPR), which aims at restoring ER homeostasis. However, when the stress is too severe the UPR switches from being a pro-survival response to a pro-death one, and the molecular mechanisms underlying ER stress-mediated death have remained incompletely understood. In this study, we identified receptor interacting protein kinase 1 (RIPK1)—a kinase at the crossroad between life and death downstream of various receptors—as a new regulator of ER stress-induced death. We found that Ripk1-deficient MEFs are protected from apoptosis induced by ER stressors, which is reflected by reduced caspase activation and PARP processing. Interestingly, the pro-apoptotic role of Ripk1 is independent of its kinase activity, is not regulated by its cIAP1/2-mediated ubiquitylation, and does not rely on the direct regulation of JNK or CHOP, two reportedly main players in ER stress-induced death. Instead, we found that ER stress-induced apoptosis in these cells relies on death receptor-independent activation of caspase-8, and identified Ripk1 upstream of caspase-8. However, in contrast to RIPK1-dependent apoptosis downstream of TNFR1, we did not find Ripk1 associated with caspase-8 in a death-inducing complex upon unresolved ER stress. Our data rather suggest that RIPK1 indirectly regulates caspase-8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (IRE1). PMID:25476903

  4. Tauroursodeoxycholic acid reduces ER stress by regulating of Akt-dependent cellular prion protein

    PubMed Central

    Yoon, Yeo Min; Lee, Jun Hee; Yun, Seung Pil; Han, Yong-Seok; Yun, Chul Won; Lee, Hyun Jik; Noh, Hyunjin; Lee, Sei-Jung; Han, Ho Jae; Lee, Sang Hun

    2016-01-01

    Although mesenchymal stem cells (MSCs) are a promising cell source for regenerative medicine, ischemia-induced endoplasmic reticulum (ER) stress induces low MSC engraftment and limits their therapeutic efficacy. To overcome this, we investigated the protective effect of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs in vitro and in vivo. In ER stress conditions, TUDCA treatment of MSCs reduced the activation of ER stress-associated proteins, including GRP78, PERK, eIF2α, ATF4, IRE1α, JNK, p38, and CHOP. In particular, TUDCA inhibited the dissociation between GRP78 and PERK, resulting in reduced ER stress-mediated cell death. Next, to explore the ER stress protective mechanism induced by TUDCA treatment, TUDCA-mediated cellular prion protein (PrPC) activation was assessed. TUDCA treatment increased PrPC expression, which was regulated by Akt phosphorylation. Manganese-dependent superoxide dismutase (MnSOD) expression also increased significantly in response to signaling through the TUDCA-Akt axis. In a murine hindlimb ischemia model, TUDCA-treated MSC transplantation augmented the blood perfusion ratio, vessel formation, and transplanted cell survival more than untreated MSC transplantation did. Augmented functional recovery following MSC transplantation was blocked by PrPC downregulation. This study is the first to demonstrate that TUDCA protects MSCs against ER stress via Akt-dependent PrPC and Akt-MnSOD pathway. PMID:28004805

  5. Aortic ER stress in streptozotocin-induced diabetes mellitus in APA hamsters.

    PubMed

    Kurokawa, Masaki; Hideshima, Makoto; Ishii, Yoshiyuki; Kyuwa, Shigeru; Yoshikawa, Yasuhiro

    2009-04-01

    Atherosclerosis is thought to be associated with endoplasmic reticulum (ER) dysfunction and the accumulation of unfolded proteins. In this study, we examined the relationship between atherosclerosis and ER stress and the effect of sodium 4-phenylbutyrate (4-PBA), a kind of chemical chaperone, on atherosclerosis in streptozotocin-induced diabetic APA hamsters. Male, 8-week-old, APA hamsters were injected with streptozotocin (30 mg/kg body weight) to induce diabetes mellitus, and ER stress was evaluated immunohistochemically or by semi-quantitative RT-PCR analysis using ER stress markers such as calreticulin and GPR78. Control hamsters were injected with citrate buffer and were similarly analyzed. In the aorta of control animals, a weak ER stress was detected, and 4-PBA treatment decreased the calreticulin- and GRP78-positive areas and also reduced the mRNA levels of calreticulin and GRP78. On the other hand, strong ER stress was detected at the lesser curvature of the aortic arch of streptozotocin-induced diabetic APA hamsters. However, 4-PBA treatment failed to lessen the ER stress in the aorta and had no effect on improvement of the atherosclerotic lesions. These results may provide an explanation for the complex etiology of atherosclerosis accompanied by diabetes mellitus and various other clinical phenotypes of atherosclerosis.

  6. Molecular mechanism aspect of ER stress in Alzheimer's disease: current approaches and future strategies.

    PubMed

    Ansari, Niloufar; Khodagholi, Fariba

    2013-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by progressive loss of memory and cognitive impairment. Aggregation of amyloid-β (Aβ) peptides is the crucial factor in the onset of AD. The toxic Aβ peptides Aβ40 and Aβ42 are produced from the Aβ precursor protein (APP), a transmembrane protein which is folded and modified in endoplasmic reticulum (ER). ER is the main organelle for the synthesis and processing of nearly all proteins as well as the main cellular source of Ca2+. Under stress conditions, three main ER pathways including inositol-requiring enzyme 1, protein kinase RNA-like ER kinase, and activating transcription factor 6 become activated causing the accumulation of unfolded or misfolded proteins within ER lumen. These pathways manage the stress by regulating the expression of chaperones and enzymes involved in protein folding. Several studies have reported the dysfunction of these stress-sensing pathways in pathological conditions, including neurodegenerative diseases. Recent studies have proposed that neuronal death in AD arises from dysfunction of the ER. Here, we will review recent research findings on the interaction between ER and mitochondria, and its effect on apoptotic pathways. We further provide insights into studies which suggest the role of ER in animal and/or cellular models of AD. Therapeutic strategies that modulate ER could represent a promising approach for prevention or treatment of AD.

  7. A thrombospondin-dependent pathway for a protective ER stress response

    PubMed Central

    Lynch, Jeffrey M.; Maillet, Marjorie; Vanhoutte, Davy; Schloemer, Aryn; Sargent, Michelle A.; Blair, N. Scott; Lynch, Kaari A.; Okada, Tetsuya; Aronow, Bruce J.; Osinska, Hanna; Prywes, Ron; Lorenz, John N.; Mori, Kazutoshi; Lawler, Jack; Robbins, Jeffrey; Molkentin, Jeffery D.

    2012-01-01

    SUMMARY Thrombospondin (Thbs) proteins are induced in sites of tissue damage or active remodeling. The endoplasmic reticulum (ER) stress response is also prominently induced with disease where it regulates protein production and resolution of misfolded proteins. Here we describe a novel function for Thbs’ as ER resident effectors of an adaptive ER stress response. Thbs4 cardiac-specific transgenic mice were protected from myocardial injury while Thbs4−/− mice were sensitized to cardiac maladaptation. Thbs induction produced a unique profile of adaptive ER stress response factors and expansion of the ER and downstream vesicles. The type-3 repeat domain in Thbs’ bind the ER luminal domain of activating transcription factor 6α (Atf6α) to promote its nuclear shuttling. Thbs4−/−mice failed to show activation of Atf6α and other ER stress response factors with injury, and Thbs4-mediated protection was lost when Atf6α was deleted. Hence, Thbs’ can function inside the cell during disease/remodeling to augment ER function and protect through a mechanism involving regulation of Atf6α. PMID:22682248

  8. Enhanced synthesis of saturated phospholipids is associated with ER stress and lipotoxicity in palmitate treated hepatic cells[S

    PubMed Central

    Leamy, Alexandra K.; Egnatchik, Robert A.; Shiota, Masakazu; Ivanova, Pavlina T.; Myers, David S.; Brown, H. Alex; Young, Jamey D.

    2014-01-01

    High levels of saturated FAs (SFAs) are acutely toxic to a variety of cell types, including hepatocytes, and have been associated with diseases such as type 2 diabetes and nonalcoholic fatty liver disease. SFA accumulation has been previously shown to degrade endoplasmic reticulum (ER) function leading to other manifestations of the lipoapoptotic cascade. We hypothesized that dysfunctional phospholipid (PL) metabolism is an initiating factor in this ER stress response. Treatment of either primary hepatocytes or H4IIEC3 cells with the SFA palmitate resulted in dramatic dilation of the ER membrane, coinciding with other markers of organelle dysfunction. This was accompanied by increased de novo glycerolipid synthesis, significant elevation of dipalmitoyl phosphatidic acid, diacylglycerol, and total PL content in H4IIEC3 cells. Supplementation with oleate (OA) reversed these markers of palmitate (PA)-induced lipotoxicity. OA/PA cotreatment modulated the distribution of PA between lipid classes, increasing the flux toward triacylglycerols while reducing its incorporation into PLs. Similar trends were demonstrated in both primary hepatocytes and the H4IIEC3 hepatoma cell line. Overall, these findings suggest that modifying the FA composition of structural PLs can protect hepatocytes from PA-induced ER stress and associated lipotoxicity. PMID:24859739

  9. Acute stress reduces speech fluency.

    PubMed

    Buchanan, Tony W; Laures-Gore, Jacqueline S; Duff, Melissa C

    2014-03-01

    People often report word-finding difficulties and other language disturbances when put in a stressful situation. There is, however, scant empirical evidence to support the claim that stress affects speech productivity. To address this issue, we measured speech and language variables during a stressful Trier Social Stress Test (TSST) as well as during a less stressful "placebo" TSST (Het et al., 2009). Compared to the non-stressful speech, participants showed higher word productivity during the TSST. By contrast, participants paused more during the stressful TSST, an effect that was especially pronounced in participants who produced a larger cortisol and heart rate response to the stressor. Findings support anecdotal evidence of stress-impaired speech production abilities.

  10. 4-PBA improves lithium-induced nephrogenic diabetes insipidus by attenuating ER stress.

    PubMed

    Zheng, Peili; Lin, Yu; Wang, Feifei; Luo, Renfei; Zhang, Tiezheng; Hu, Shan; Feng, Pinning; Liang, Xinling; Li, Chunling; Wang, Weidong

    2016-10-01

    Endoplasmic reticulum (ER) stress has been implicated in some types of glomerular and tubular disorders. The objectives of this study were to elucidate the role of ER stress in lithium-induced nephrogenic diabetes insipidus (NDI) and to investigate whether attenuation of ER stress by 4-phenylbutyric acid (4-PBA) improves urinary concentrating defect in lithium-treated rats. Wistar rats received lithium (40 mmol/kg food), 4-PBA (320 mg/kg body wt by gavage every day), or no treatment (control) for 2 wk, and they were dehydrated for 24 h before euthanasia. Lithium treatment resulted in increased urine output and decreased urinary osmolality, which was significantly improved by 4-PBA. 4-PBA also prevented reduced protein expression of aquaporin-2 (AQP2), pS256-AQP2, and pS261-AQP2 in the inner medulla of kidneys from lithium-treated rats after 24-h dehydration. Lithium treatment resulted in increased expression of ER stress markers in the inner medulla, which was associated with dilated cisternae and expansion of ER in the inner medullary collecting duct (IMCD) principal cells. Confocal immunofluorescence studies showed colocalization of a molecular chaperone, binding IgG protein (BiP), with AQP2 in principal cells. Immunohistochemistry demonstrated increased intracellular expression of BiP and decreased AQP2 expression in IMCD principal cells of kidneys from lithium-treated rats. 4-PBA attenuated expression of ER stress markers and recovered ER morphology. In IMCD suspensions isolated from lithium-treated rats, 4-PBA incubation was also associated with increased AQP2 expression and ameliorated ER stress. In conclusion, in experimental lithium-induced NDI, 4-PBA improved the urinary concentrating defect and increased AQP2 expression, likely via attenuating ER stress in IMCD principal cells.

  11. Acute emotional stress and cardiac arrhythmias.

    PubMed

    Ziegelstein, Roy C

    2007-07-18

    Episodes of acute emotional stress can have significant adverse effects on the heart. Acute emotional stress can produce left ventricular contractile dysfunction, myocardial ischemia, or disturbances of cardiac rhythm. Although these abnormalities are often only transient, their consequences can be gravely damaging and sometimes fatal. Despite the many descriptions of catastrophic cardiovascular events in the setting of acute emotional stress, the anatomical substrate and physiological pathways by which emotional stress triggers cardiovascular events are only now being characterized, aided by the advent of functional neuroimaging. Recent evidence indicates that asymmetric brain activity is particularly important in making the heart more susceptible to ventricular arrhythmias. Lateralization of cerebral activity during emotional stress may stimulate the heart asymmetrically and produce areas of inhomogeneous repolarization that create electrical instability and facilitate the development of cardiac arrhythmias. Patients with ischemic heart disease who survive an episode of sudden cardiac death in the setting of acute emotional stress should receive a beta-blocker. Nonpharmacological approaches to manage emotional stress in patients with and without coronary artery disease, including social support, relaxation therapy, yoga, meditation, controlled slow breathing, and biofeedback, are also appropriate to consider and merit additional investigation in randomized trials.

  12. Acute Suppurative Parotitis Treatment by Diode Laser Combined with ER:YAG Laser

    PubMed Central

    Ke, Jyuhn H.; Wang, Hong Lan

    2012-01-01

    Background and aim: The diode laser combined with Er:YAG laser is a new treatment modality for acute sialadenitis. A 78-year-old woman with acute suppurative parotitis was treated by traditional probe to the duct orifice with oral antibiotics for 2 weeks. The symptoms and signs did not subside after treatment. The Er:YAG laser was used to reduce severe infection and inflammation and low level laser therapy (LLLT) was applied to relieve pain sensation during incision and drainage. Less scar formation and obstruction was observed after the laser treatments. Results: Purulent secretions from the Stensen duct was noted after milking the parotid gland. The symptoms and signs were significantly relieved after combined laser treatments. The patient experienced no pain during the course of treatment. No recurrence of the symptoms and signs was noted after 1-year follow-up, and the prognosis was very good. Conclusion: The hemostatic properties of the diode laser enable better control of the surgical field and faster healing of the wound lesions. The bactericidal effect of Er:YAG lasers has been proved by many researchers, and has been shown to reduce infection and inflammation for better wound healing. The combined laser therapy of diode and Er:YAG lasers is recommended in treating acute sialadenitis. PMID:24610980

  13. Regulation of ER stress-induced autophagy by GSK3β-TIP60-ULK1 pathway

    PubMed Central

    Nie, Tiejian; Yang, Shaosong; Ma, Hongwei; Zhang, Lei; Lu, Fangfang; Tao, Kai; Wang, Ronglin; Yang, Ruixin; Huang, Lu; Mao, Zixu; Yang, Qian

    2016-01-01

    Endoplasmic reticulum (ER) stress is involved in many cellular processes. Emerging evidence suggests that ER stress can trigger autophagy; however, the mechanisms by which ER stress regulates autophagy and its role in this condition are not fully understood. HIV Tat-interactive protein, 60 kDa (TIP60) is a newly discovered acetyltransferase that can modulate autophagy flux by activating ULK1 upon growth factor deprivation. In this study, we investigated the mechanisms by which ER stress induces autophagy. We showed that ER stress activates glycogen synthase kinase-3β (GSK3β). This led to a GSK3β-dependent phosphorylation of TIP60, triggering a TIP60-mediated acetylation of ULK1 and activation of autophagy. Inhibition of either GSK3β or TIP60 acetylation activities significantly attenuated ER stress-induced autophagy. Moreover, enhancing the level of TIP60 attenuated the level of CHOP after ER stress, and reduced the ER stress-induced cell death. In contrast, expression of TIP60 mutant that could not be phosphorylated by GSK3β exacerbated the generation of CHOP and increased the ER stress-induced cell death. These findings reveal that ER stress engages the GSK3β-TIP60-ULK1 pathway to increase autophagy. Attenuation of this pathway renders cells more sensitive to and increases the toxicity of ER stress. PMID:28032867

  14. Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, acinar cell damage, and systemic inflammation in acute pancreatitis.

    PubMed

    Seyhun, Ersin; Malo, Antje; Schäfer, Claus; Moskaluk, Christopher A; Hoffmann, Ralf-Thorsten; Göke, Burkhard; Kubisch, Constanze H

    2011-11-01

    In acute pancreatitis, endoplasmic reticulum (ER) stress prompts an accumulation of malfolded proteins inside the ER, initiating the unfolded protein response (UPR). Because the ER chaperone tauroursodeoxycholic acid (TUDCA) is known to inhibit the UPR in vitro, this study examined the in vivo effects of TUDCA in an acute experimental pancreatitis model. Acute pancreatitis was induced in Wistar rats using caerulein, with or without prior TUDCA treatment. UPR components were analyzed, including chaperone binding protein (BiP), phosphorylated protein kinase-like ER kinase (pPERK), X-box binding protein (XBP)-1, phosphorylated c-Jun NH(2)-terminal kinase (pJNK), CCAAT/enhancer binding protein homologues protein, and caspase 12 and 3 activation. In addition, pancreatitis biomarkers were measured, such as serum amylase, trypsin activation, edema formation, histology, and the inflammatory reaction in pancreatic and lung tissue. TUDCA treatment reduced intracellular trypsin activation, edema formation, and cell damage, while leaving amylase levels unaltered. The activation of myeloperoxidase was clearly reduced in pancreas and lung. Furthermore, TUDCA prevented caerulein-induced BiP upregulation, reduced XBP-1 splicing, and caspase 12 and 3 activation. It accelerated the downregulation of pJNK. In controls without pancreatitis, TUDCA showed cytoprotective effects including pPERK signaling and activation of downstream targets. We concluded that ER stress responses activated in acute pancreatitis are grossly attenuated by TUDCA. The chaperone reduced the UPR and inhibited ER stress-associated proapoptotic pathways. TUDCA has a cytoprotective potential in the exocrine pancreas. These data hint at new perspectives for an employment of chemical chaperones, such as TUDCA, in prevention of acute pancreatitis.

  15. ER-mediated stress induces mitochondrial-dependent caspases activation in NT2 neuron-like cells.

    PubMed

    Arduino, Daniela M; Esteves, A Raquel; Domingues, A Filipa; Pereira, Claudia M F; Cardoso, Sandra M; Oliveira, Catarina R

    2009-11-30

    Recent studies have revealed that endoplasmic reticulum (ER) disturbance is involved in the pathophysiology of neurodegenerative disorders, contributing to the activation of the ER stress-mediated apoptotic pathway. Therefore, we investigated here the molecular mechanisms underlying the ER-mitochondria axis, focusing on calcium as a potential mediator of cell death signals. Using NT2 cells treated with brefeldin A or tunicamycin, we observed that ER stress induces changes in the mitochondrial function, impairing mitochondrial membrane potential and distressing mitochondrial respiratory chain complex Moreover, stress stimuli at ER level evoked calcium fluxes between ER and mitochondria. Under these conditions, ER stress activated the unfolded protein response by an overexpression of GRP78, and also caspase-4 and-2, both involved upstream of caspase-9. Our findings show that ER and mitochondria interconnection plays a prominent role in the induction of neuronal cell death under particular stress circumstances.

  16. Oxidative Stress Adaptation with Acute, Chronic and Repeated Stress

    PubMed Central

    Pickering, Andrew M.; Vojtovich, Lesya; Tower, John; Davies, Kelvin J. A.

    2013-01-01

    Oxidative stress adaptation or hormesis is an important mechanism by which cells and organisms respond to, and cope with, environmental and physiological shifts in the level of oxidative stress. Most studies of oxidative stress adaption have been limited to adaptation induced by acute stress. In contrast, many if not most environmental and physiological stresses are either repeated or chronic. In this study we find that both cultured mammalian cells, and the fruit fly Drosophila melanogaster, are capable of adapting to chronic or repeated stress by up-regulating protective systems, such as their proteasomal proteolytic capacity to remove oxidized proteins. Repeated stress adaptation resulted in significant extension of adaptive responses. Repeated stresses must occur at sufficiently long intervals, however (12 hours or more for MEF cells and 7 days or more for flies), for adaptation to be successful, and the level of both repeated and chronic stress must be lower than is optimal for adaptation to acute stress. Regrettably, regimens of adaptation to both repeated and chronic stress that were successful for short-term survival in Drosophila, nevertheless also caused significant reductions in lifespan for the flies. Thus, although both repeated and chronic stress can be tolerated, they may result in a shorter life. PMID:23142766

  17. Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

    PubMed Central

    Grigaravicius, P; Kaminska, E; Hübner, C A; McKinnon, P J; von Deimling, A; Frappart, P-O

    2016-01-01

    Endoplasmic reticulum (ER) stress, defective autophagy and genomic instability in the central nervous system are often associated with severe developmental defects and neurodegeneration. Here, we reveal the role played by Rint1 in these different biological pathways to ensure normal development of the central nervous system and to prevent neurodegeneration. We found that inactivation of Rint1 in neuroprogenitors led to death at birth. Depletion of Rint1 caused genomic instability due to chromosome fusion in dividing cells. Furthermore, Rint1 deletion in developing brain promotes the disruption of ER and Cis/Trans Golgi homeostasis in neurons, followed by ER-stress increase. Interestingly, Rint1 deficiency was also associated with the inhibition of the autophagosome clearance. Altogether, our findings highlight the crucial roles of Rint1 in vivo in genomic stability maintenance, as well as in prevention of ER stress and autophagy. PMID:26383973

  18. Evidence that endoplasmic reticulum (ER) stress and caspase-4 activation occur in human neutrophils.

    PubMed

    Binet, François; Chiasson, Sonia; Girard, Denis

    2010-01-01

    Apoptosis can result from activation of three major pathways: the extrinsic, the intrinsic, and the most recently identified endoplasmic reticulum (ER) stress-mediated pathway. While the two former pathways are known to be operational in human polymorphonuclear neutrophils (PMNs), the existence of the ER stress-mediated pathway, generally involving caspase-4, has never been reported in these cells. Recently, we have documented that arsenic trioxide (ATO) induced apoptosis in human PMNs by a mechanism that needs to be further investigated. In this study, using immunofluorescence and electron microscopy, we present evidence of ER alterations in PMNs activated by the ER stress inducer arsenic trioxide (ATO). Several key players of the unfolded protein response, including GRP78, GADD153, ATF6, XBP1 and eIF2alpha are expressed and activated in PMNs treated with ATO or other ER stress inducers. Although caspase-4 is expressed and activated in neutrophils, treatment with a caspase-4 inhibitor did not attenuate the pro-apoptotic effect of ATO at a concentration that reverses caspase-4 processing and activation. Our results demonstrate for the first time that the ER stress-mediated apoptotic pathway operates in human neutrophils.

  19. The ER Stress Sensor PERK Coordinates ER-Plasma Membrane Contact Site Formation through Interaction with Filamin-A and F-Actin Remodeling.

    PubMed

    van Vliet, Alexander R; Giordano, Francesca; Gerlo, Sarah; Segura, Inmaculada; Van Eygen, Sofie; Molenberghs, Geert; Rocha, Susana; Houcine, Audrey; Derua, Rita; Verfaillie, Tom; Vangindertael, Jeroen; De Keersmaecker, Herlinde; Waelkens, Etienne; Tavernier, Jan; Hofkens, Johan; Annaert, Wim; Carmeliet, Peter; Samali, Afshin; Mizuno, Hideaki; Agostinis, Patrizia

    2017-03-02

    Loss of ER Ca(2+) homeostasis triggers endoplasmic reticulum (ER) stress and drives ER-PM contact sites formation in order to refill ER-luminal Ca(2+). Recent studies suggest that the ER stress sensor and mediator of the unfolded protein response (UPR) PERK regulates intracellular Ca(2+) fluxes, but the mechanisms remain elusive. Here, using proximity-dependent biotin identification (BioID), we identified the actin-binding protein Filamin A (FLNA) as a key PERK interactor. Cells lacking PERK accumulate F-actin at the cell edges and display reduced ER-PM contacts. Following ER-Ca(2+) store depletion, the PERK-FLNA interaction drives the expansion of ER-PM juxtapositions by regulating F-actin-assisted relocation of the ER-associated tethering proteins Stromal Interaction Molecule 1 (STIM1) and Extended Synaptotagmin-1 (E-Syt1) to the PM. Cytosolic Ca(2+) elevation elicits rapid and UPR-independent PERK dimerization, which enforces PERK-FLNA-mediated ER-PM juxtapositions. Collectively, our data unravel an unprecedented role of PERK in the regulation of ER-PM appositions through the modulation of the actin cytoskeleton.

  20. Tula hantavirus triggers pro-apoptotic signals of ER stress in Vero E6 cells.

    PubMed

    Li, Xiao-Dong; Lankinen, Hilkka; Putkuri, Niina; Vapalahti, Olli; Vaheri, Antti

    2005-03-01

    Tula virus is a member of the Hantavirus genus of the family Bunyaviridae. Viruses of this family have an unusual pattern of intracellular maturation at the ER-Golgi compartment. We recently found that Tula virus, similar to several other hantaviruses, is able to induce apoptosis in cultured cells [Li, X.D., Kukkonen, S., Vapalahti, O., Plyusnin, A., Lankinen, H., Vaheri, A., 2004. Tula hantavirus infection of Vero E6 cells induces apoptosis involving caspase 8 activation. J. Gen. Virol. 85, 3261-3268.]. However, the cellular mechanisms remain to be clarified. In this study, we demonstrate that the progressive replication of Tula virus in Vero E6 cells initiates several death programs that are intimately associated with ER stress: (1) early activation of ER-resident caspase-12; (2) phosphorylation of Jun NH2-terminal kinase (JNK) and its downstream target transcriptional factor, c-jun; (3) induction of the pro-apoptotic transcriptional factor, growth arrest- and DNA damage-inducible gene 153, or C/EBP homologous protein (Gadd153/chop); and (4) changes in the ER-membrane protein BAP31 implying cross-talk with the mitochondrial apoptosis pathway. Furthermore, we confirmed that a sustained ER stress was induced marked by an increased expression of an ER chaperone Grp78/BiP. Taken together, we have identified involvement of ER stress-mediated death program in Tula virus-infected Vero E6 cells which provides a new approach to understand the mechanisms in hantavirus-induced apoptosis.

  1. Lycopene Protects against Hypoxia/Reoxygenation Injury by Alleviating ER Stress Induced Apoptosis in Neonatal Mouse Cardiomyocytes

    PubMed Central

    Xu, Jiqian; Hu, Houxiang; Chen, Bin; Yue, Rongchuan; Zhou, Zhou; Liu, Yin; Zhang, Shuang; Xu, Lei; Wang, Huan; Yu, Zhengping

    2015-01-01

    Endoplasmic reticulum (ER) stress induced apoptosis plays a pivotal role in myocardial ischemia/reperfusion (I/R)-injury. Inhibiting ER stress is a major therapeutic target/strategy in treating cardiovascular diseases. Our previous studies revealed that lycopene exhibits great pharmacological potential in protecting against the I/R-injury in vitro and vivo, but whether attenuation of ER stress (and) or ER stress-induced apoptosis contributes to the effects remains unclear. In the present study, using neonatal mouse cardiomyocytes to establish an in vitro model of hypoxia/reoxygenation (H/R) to mimic myocardium I/R in vivo, we aimed to explore the hypothesis that lycopene could alleviate the ER stress and ER stress-induced apoptosis in H/R-injury. We observed that lycopene alleviated the H/R injury as revealed by improving cell viability and reducing apoptosis, suppressed reactive oxygen species (ROS) generation and improved the phosphorylated AMPK expression, attenuated ER stress as evidenced by decreasing the expression of GRP78, ATF6 mRNA, sXbp-1 mRNA, eIF2α mRNA and eIF2α phosphorylation, alleviated ER stress-induced apoptosis as manifested by reducing CHOP/GADD153 expression, the ratio of Bax/Bcl-2, caspase-12 and caspase-3 activity in H/R-treated cardiomyocytes. Thapsigargin (TG) is a potent ER stress inducer and used to elicit ER stress of cardiomyocytes. Our results showed that lycopene was able to prevent TG-induced ER stress as reflected by attenuating the protein expression of GRP78 and CHOP/GADD153 compared to TG group, significantly improve TG-caused a loss of cell viability and decrease apoptosis in TG-treated cardiomyocytes. These results suggest that the protective effects of lycopene on H/R-injury are, at least in part, through alleviating ER stress and ER stress-induced apoptosis in neonatal mouse cardiomyocytes. PMID:26291709

  2. Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia.

    PubMed

    Bohnert, Kyle R; Gallot, Yann S; Sato, Shuichi; Xiong, Guangyan; Hindi, Sajedah M; Kumar, Ashok

    2016-09-01

    Cachexia is a devastating syndrome that causes morbidity and mortality in a large number of patients with cancer. However, the mechanisms of cancer cachexia remain poorly understood. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes stress. The ER responds to this stress through activating certain pathways commonly known as the unfolding protein response (UPR). The main function of UPR is to restore homeostasis, but excessive or prolonged activation of UPR can lead to pathologic conditions. In this study, we examined the role of ER stress and UPR in regulation of skeletal muscle mass in naïve conditions and during cancer cachexia. Our results demonstrate that multiple markers of ER stress are highly activated in skeletal muscle of Lewis lung carcinoma (LLC) and Apc(Min/+) mouse models of cancer cachexia. Treatment of mice with 4-phenylbutyrate (4-PBA), a chemical chaperon and a potent inhibitor of ER stress, significantly reduced skeletal muscle strength and mass in both control and LLC-bearing mice. Blocking the UPR also increased the proportion of fast-type fibers in soleus muscle of both control and LLC-bearing mice. Inhibition of UPR reduced the activity of Akt/mTOR pathway and increased the expression of the components of the ubiquitin-proteasome system and autophagy in LLC-bearing mice. Moreover, we found that the inhibition of UPR causes severe atrophy in cultured myotubes. Our study provides initial evidence that ER stress and UPR pathways are essential for maintaining skeletal muscle mass and strength and for protection against cancer cachexia.-Bohnert, K. R., Gallot, Y. S., Sato, S., Xiong, G., Hindi, S. M., Kumar, A. Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia.

  3. Salidroside Protects Against 6-Hydroxydopamine-Induced Cytotoxicity by Attenuating ER Stress.

    PubMed

    Tao, Kai; Wang, Bao; Feng, Dayun; Zhang, Wei; Lu, Fangfang; Lai, Juan; Huang, Lu; Nie, Tiejian; Yang, Qian

    2016-02-01

    Parkinson's disease (PD) is a neurodegenerative disease characterized by a persistent decline of dopaminergic (DA) neurons in the substantia nigra pars compacta. Despite its frequency, effective therapeutic strategies that halt the neurodegenerative processes are lacking, reinforcing the need to better understand the molecular drivers of this disease. Importantly, increasing evidence suggests that the endoplasmic reticulum (ER) stress-induced unfolded protein response is likely involved in DA neuronal death. Salidroside, a major compound isolated from Rhodiola rosea L., possesses potent anti-oxidative stress properties and protects against DA neuronal death. However, the underlying mechanisms are not well understood. In the present study, we demonstrate that salidroside prevents 6-hydroxydopamine (6-OHDA)-induced cytotoxicity by attenuating ER stress. Furthermore, treatment of a DA neuronal cell line (SN4741) and primary cortical neurons with salidroside significantly reduced neurotoxin-induced increases in cytoplasmic reactive oxygen species and calcium, both of which cause ER stress, and cleaved caspase-12, which is responsible for ER stress-induced cell death. Together, these results suggest that salidroside protects SN4741 cells and primary cortical neurons from 6-OHDA-induced neurotoxicity by attenuating ER stress. This provides a rationale for the investigation of salidroside as a potential therapeutic agent in animal models of PD.

  4. Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease

    PubMed Central

    Celardo, I; Costa, A C; Lehmann, S; Jones, C; Wood, N; Mencacci, N E; Mallucci, G R; Loh, S H Y; Martins, L M

    2016-01-01

    Mutations in PINK1 and PARKIN cause early-onset Parkinson's disease (PD), thought to be due to mitochondrial toxicity. Here, we show that in Drosophila pink1 and parkin mutants, defective mitochondria also give rise to endoplasmic reticulum (ER) stress signalling, specifically to the activation of the protein kinase R-like endoplasmic reticulum kinase (PERK) branch of the unfolded protein response (UPR). We show that enhanced ER stress signalling in pink1 and parkin mutants is mediated by mitofusin bridges, which occur between defective mitochondria and the ER. Reducing mitofusin contacts with the ER is neuroprotective, through suppression of PERK signalling, while mitochondrial dysfunction remains unchanged. Further, both genetic inhibition of dPerk-dependent ER stress signalling and pharmacological inhibition using the PERK inhibitor GSK2606414 were neuroprotective in both pink1 and parkin mutants. We conclude that activation of ER stress by defective mitochondria is neurotoxic in pink1 and parkin flies and that the reduction of this signalling is neuroprotective, independently of defective mitochondria. A video abstract for this article is available online in the supplementary information PMID:27336715

  5. Modulation of endothelial cell migration by ER stress and insulin resistance: a role during maternal obesity?

    PubMed

    Sáez, Pablo J; Villalobos-Labra, Roberto; Westermeier, Francisco; Sobrevia, Luis; Farías-Jofré, Marcelo

    2014-01-01

    Adverse microenvironmental stimuli can trigger the endoplasmic reticulum (ER) stress pathway, which initiates the unfolded protein response (UPR), to restore protein-folding homeostasis. Several studies show induction of ER stress during obesity. Chronic UPR has been linked to different mechanisms of disease in obese and diabetic individuals, including insulin resistance (IR) and impaired angiogenesis. Endothelial cell (EC) migration is an initial step for angiogenesis, which is associated with remodeling of existing blood vessels. EC migration occurs according to the leader-follower model, involving coordinated processes of chemotaxis, haptotaxis, and mechanotaxis. Thus, a fine-tuning of EC migration is necessary to provide the right timing to form the required vessels during angiogenesis. ER stress modulates EC migration at different levels, usually impairing migration and angiogenesis, although different effects may be observed depending on the tissue and/or microenvironment. In the context of pregnancy, maternal obesity (MO) induces IR in the offspring. Interestingly, several proteins associated with obesity-induced IR are also involved in EC migration, providing a potential link with the ER stress-dependent alterations observed in obese individuals. Different signaling cascades that converge on cytoskeleton regulation directly impact EC migration, including the Akt and/or RhoA pathways. In addition, ER is the main intracellular reservoir for Ca(2+), which plays a pivotal role during EC migration. Therefore, ER stress-related alterations in Ca(2+) signaling or Ca(2+) levels might also produce distorted EC migration. However, the above findings have been studied in the context of adult obesity, and no information has been reported regarding the effect of MO on fetal EC migration. Here we summarize the state of knowledge about the possible mechanisms by which ER stress and IR might impact EC migration and angiogenesis in fetal endothelium exposed to MO during

  6. Acute stress may induce ovulation in women

    PubMed Central

    2010-01-01

    Background This study aims to gather information either supporting or rejecting the hypothesis that acute stress may induce ovulation in women. The formulation of this hypothesis is based on 2 facts: 1) estrogen-primed postmenopausal or ovariectomized women display an adrenal-progesterone-induced ovulatory-like luteinizing hormone (LH) surge in response to exogenous adrenocorticotropic hormone (ACTH) administration; and 2) women display multiple follicular waves during an interovulatory interval, and likely during pregnancy and lactation. Thus, acute stress may induce ovulation in women displaying appropriate serum levels of estradiol and one or more follicles large enough to respond to a non-midcycle LH surge. Methods A literature search using the PubMed database was performed to identify articles up to January 2010 focusing mainly on women as well as on rats and rhesus monkeys as animal models of interaction between the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. Results Whereas the HPA axis exhibits positive responses in practically all phases of the ovarian cycle, acute-stress-induced release of LH is found under relatively high plasma levels of estradiol. However, there are studies suggesting that several types of acute stress may exert different effects on pituitary LH release and the steroid environment may modulate in a different way (inhibiting or stimulating) the pattern of response of the HPG axis elicited by acute stressors. Conclusion Women may be induced to ovulate at any point of the menstrual cycle or even during periods of amenorrhea associated with pregnancy and lactation if exposed to an appropriate acute stressor under a right estradiol environment. PMID:20504303

  7. The ER stress regulator Bip mediates cadmium-induced autophagy and neuronal senescence

    PubMed Central

    Wang, Tao; Yuan, Yan; Zou, Hui; Yang, Jinlong; Zhao, Shiwen; Ma, Yonggang; Wang, Yi; Bian, Jianchun; Liu, Xuezhong; Gu, Jianhong; Liu, Zongping; Zhu, Jiaqiao

    2016-01-01

    Autophagy is protective in cadmium (Cd)-induced oxidative damage. Endoplasmic reticulum (ER) stress has been shown to induce autophagy in a process requiring the unfolded protein response signalling pathways. Cd treatment significantly increased senescence in neuronal cells, which was aggravated by 3-MA or silencing of Atg5 and abolished by rapamycin. Cd increased expression of ER stress regulators Bip, chop, eIf2α, and ATF4, and activated autophagy as evidenced by upregulated LC3. Moreover, the ER stress inhibitor mithramycin inhibited the expression of ER stress protein chaperone Bip and blocked autophagic flux. Downregulating Bip significantly blocked the conversion of LC3-I to LC3-II, decreased LC3 puncta formation, and prevented the increase of senescence in PC12 cells. Interestingly, knocking down Bip regulated the expression of p-AMPK, p-AKT and p-s6k induced by Cd. BAPTA, a Bip inhibitor, decreased the expression of p-AMPK and LC3-II, but enhanced neuronal senescence. In addition, we found that siRNA for Bip enhanced GATA4 expression after 6 h Cd exposure in PC12 cells, while rapamycin treatment decreased GATA4 levels induced by 24 h Cd exposure. These results indicate that autophagy degraded GATA4 in a Bip-dependent way. Our findings suggest that autophagy regulated by Bip expression after ER stress suppressed Cd-induced neuronal senescence. PMID:27905509

  8. Transcription regulator TRIP-Br2 mediates ER stress-induced brown adipocytes dysfunction

    PubMed Central

    Qiang, Guifen; Whang Kong, Hyerim; Gil, Victoria; Liew, Chong Wee

    2017-01-01

    In contrast to white adipose tissue, brown adipose tissue (BAT) is known to play critical roles for both basal and inducible energy expenditure. Obesity is associated with reduction of BAT function; however, it is not well understood how obesity promotes BAT dysfunction, especially at the molecular level. Here we show that the transcription regulator TRIP-Br2 mediates ER stress-induced inhibition of lipolysis and thermogenesis in BAT. Using in vitro, ex vivo, and in vivo approaches, we demonstrate that obesity-induced inflammation upregulates brown adipocytes TRIP-Br2 expression via the ER stress pathway and amelioration of ER stress in mice completely abolishes high fat diet-induced upregulation of TRIP-Br2 in BAT. We find that increased TRIP-Br2 significantly inhibits brown adipocytes thermogenesis. Finally, we show that ablation of TRIP-Br2 ameliorates ER stress-induced inhibition on lipolysis, fatty acid oxidation, oxidative metabolism, and thermogenesis in brown adipocytes. Taken together, our current study demonstrates a role for TRIP-Br2 in ER stress-induced BAT dysfunction, and inhibiting TRIP-Br2 could be a potential approach for counteracting obesity-induced BAT dysfunction. PMID:28067333

  9. ER stress induced impaired TLR signaling and macrophage differentiation of human monocytes.

    PubMed

    Komura, Takuya; Sakai, Yoshio; Honda, Masao; Takamura, Toshinari; Wada, Takashi; Kaneko, Shuichi

    2013-03-01

    Endoplasmic reticulum (ER) stress causes impairment of the intracellular protein synthesis machinery, affecting various organ functions and homeostasis systems, including immunity. We found that ER stress induced by the N-linked glycosylation inhibitor, tunicamycin, caused susceptibility to apoptosis in the human monocytic cell line, THP-1 cells. Importantly, prior to tunicamycin-induced apoptosis, the proinflammatory response to toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS) stimulation was attenuated with respect to the expression of the proinflammatory cytokines. This impaired expression of proinflammatory cytokines was a consequence of the inhibition of NF-κB activation. Moreover, tunicamycin-induced ER stress disturbed the differentiation of THP-1 cells into macrophages induced by phorbol-12-myristate-13-acetate treatment. We also confirmed that ER stress affected the response of primary human monocytes to TLR ligand and their ability to differentiate into macrophages. These data suggest that ER stress imposes an important pathological insult to the immune system, affecting the crucial functions of monocytes.

  10. JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death

    PubMed Central

    Win, S; Than, T A; Fernandez-Checa, J C; Kaplowitz, N

    2014-01-01

    Our aim was to better understand the mechanism and importance of sustained c-Jun N-terminal kinase (JNK) activation in endoplasmic reticulum (ER) stress and effects of ER stress on mitochondria by determining the role of mitochondrial JNK binding protein, Sab. Tunicamycin or brefeldin A induced a rapid and marked decline in basal mitochondrial respiration and reserve-capacity followed by delayed mitochondrial-mediated apoptosis. Knockdown of mitochondrial Sab prevented ER stress-induced sustained JNK activation, impaired respiration, and apoptosis, but did not alter the magnitude or time course of activation of ER stress pathways. P-JNK plus adenosine 5′-triphosphate (ATP) added to isolated liver mitochondria promoted superoxide production, which was amplified by addition of calcium and inhibited by a blocking peptide corresponding to the JNK binding site on Sab (KIM1). This peptide also blocked tunicamycin-induced inhibition of cellular respiration. In conclusion, ER stress triggers an interaction of JNK with mitochondrial Sab, which leads to impaired respiration and increased mitochondrial reactive oxygen species, sustaining JNK activation culminating in apoptosis. PMID:24407242

  11. JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death.

    PubMed

    Win, S; Than, T A; Fernandez-Checa, J C; Kaplowitz, N

    2014-01-09

    Our aim was to better understand the mechanism and importance of sustained c-Jun N-terminal kinase (JNK) activation in endoplasmic reticulum (ER) stress and effects of ER stress on mitochondria by determining the role of mitochondrial JNK binding protein, Sab. Tunicamycin or brefeldin A induced a rapid and marked decline in basal mitochondrial respiration and reserve-capacity followed by delayed mitochondrial-mediated apoptosis. Knockdown of mitochondrial Sab prevented ER stress-induced sustained JNK activation, impaired respiration, and apoptosis, but did not alter the magnitude or time course of activation of ER stress pathways. P-JNK plus adenosine 5'-triphosphate (ATP) added to isolated liver mitochondria promoted superoxide production, which was amplified by addition of calcium and inhibited by a blocking peptide corresponding to the JNK binding site on Sab (KIM1). This peptide also blocked tunicamycin-induced inhibition of cellular respiration. In conclusion, ER stress triggers an interaction of JNK with mitochondrial Sab, which leads to impaired respiration and increased mitochondrial reactive oxygen species, sustaining JNK activation culminating in apoptosis.

  12. ER stress and autophagy dysfunction contribute to fatty liver in diabetic mice.

    PubMed

    Zhang, Quan; Li, Yan; Liang, Tingting; Lu, Xuemian; Zhang, Chi; Liu, Xingkai; Jiang, Xin; Martin, Robert C; Cheng, Mingliang; Cai, Lu

    2015-01-01

    Diabetes mellitus and nonalcoholic fatty liver disease (NAFLD) are often identified in patients simultaneously. Recent evidence suggests that endoplasmic reticulum (ER) stress and autophagy dysfunction play an important role in hepatocytes injury and hepatic lipid metabolism, however the mechanistic interaction between diabetes and NAFLD is largely unknown. In this study, we used a diabetic mouse model to study the interplay between ER stress and autophagy during the pathogenic transformation of NAFLD. The coexist of inflammatory hepatic injury and hepatic accumulation of triglycerides (TGs) stored in lipid droplets indicated development of steatohepatitis in the diabetic mice. The alterations of components for ER stress signaling including ATF6, GRP78, CHOP and caspase12 indicated increased ER stress in liver tissues in early stage but blunted in the later stage during the development of diabetes. Likewise, autophagy functioned well in the early stage but suppressed in the later stage. The inactivation of unfolded protein response and suppression of autophagy were positively related to the development of steatohepatitis, which linked to metabolic abnormalities in the compromised hepatic tissues in diabetic condition. We conclude that the adaption of ER stress and impairment of autophagy play an important role to exacerbate lipid metabolic disorder contributing to steatohepatitis in diabetes.

  13. Unfolded protein response-induced ERdj3 secretion links ER stress to extracellular proteostasis

    PubMed Central

    Genereux, Joseph C; Qu, Song; Zhou, Minghai; Ryno, Lisa M; Wang, Shiyu; Shoulders, Matthew D; Kaufman, Randal J; Lasmézas, Corinne I; Kelly, Jeffery W; Wiseman, R Luke

    2015-01-01

    The Unfolded Protein Response (UPR) indirectly regulates extracellular proteostasis through transcriptional remodeling of endoplasmic reticulum (ER) proteostasis pathways. This remodeling attenuates secretion of misfolded, aggregation-prone proteins during ER stress. Through these activities, the UPR has a critical role in preventing the extracellular protein aggregation associated with numerous human diseases. Here, we demonstrate that UPR activation also directly influences extracellular proteostasis through the upregulation and secretion of the ER HSP40 ERdj3/DNAJB11. Secreted ERdj3 binds misfolded proteins in the extracellular space, substoichiometrically inhibits protein aggregation, and attenuates proteotoxicity of disease-associated toxic prion protein. Moreover, ERdj3 can co-secrete with destabilized, aggregation-prone proteins in a stable complex under conditions where ER chaperoning capacity is overwhelmed, preemptively providing extracellular chaperoning of proteotoxic misfolded proteins that evade ER quality control. This regulated co-secretion of ERdj3 with misfolded clients directly links ER and extracellular proteostasis during conditions of ER stress. ERdj3 is, to our knowledge, the first metazoan chaperone whose secretion into the extracellular space is regulated by the UPR, revealing a new mechanism by which UPR activation regulates extracellular proteostasis. PMID:25361606

  14. ER Stress-Mediated Signaling: Action Potential and Ca2+ as Key Players

    PubMed Central

    Bahar, Entaz; Kim, Hyongsuk; Yoon, Hyonok

    2016-01-01

    The proper functioning of the endoplasmic reticulum (ER) is crucial for multiple cellular activities and survival. Disturbances in the normal ER functions lead to the accumulation and aggregation of unfolded proteins, which initiates an adaptive response, the unfolded protein response (UPR), in order to regain normal ER functions. Failure to activate the adaptive response initiates the process of programmed cell death or apoptosis. Apoptosis plays an important role in cell elimination, which is essential for embryogenesis, development, and tissue homeostasis. Impaired apoptosis can lead to the development of various pathological conditions, such as neurodegenerative and autoimmune diseases, cancer, or acquired immune deficiency syndrome (AIDS). Calcium (Ca2+) is one of the key regulators of cell survival and it can induce ER stress-mediated apoptosis in response to various conditions. Ca2+ regulates cell death both at the early and late stages of apoptosis. Severe Ca2+ dysregulation can promote cell death through apoptosis. Action potential, an electrical signal transmitted along the neurons and muscle fibers, is important for conveying information to, from, and within the brain. Upon the initiation of the action potential, increased levels of cytosolic Ca2+ (depolarization) lead to the activation of the ER stress response involved in the initiation of apoptosis. In this review, we discuss the involvement of Ca2+ and action potential in ER stress-mediated apoptosis. PMID:27649160

  15. Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma.

    PubMed

    Ha, Y; Liu, H; Xu, Z; Yokota, H; Narayanan, S P; Lemtalsi, T; Smith, S B; Caldwell, R W; Caldwell, R B; Zhang, W

    2015-10-08

    Acute glaucoma is a leading cause of irreversible blindness in East Asia. The mechanisms underlying retinal neuronal injury induced by a sudden rise in intraocular pressure (IOP) remain obscure. Here we demonstrate that the activation of CXCL10/CXCR3 axis, which mediates the recruitment and activation of inflammatory cells, has a critical role in a mouse model of acute glaucoma. The mRNA and protein expression levels of CXCL10 and CXCR3 were significantly increased after IOP-induced retinal ischemia. Blockade of the CXCR3 pathway by deleting CXCR3 gene significantly attenuated ischemic injury-induced upregulation of inflammatory molecules (interleukin-1β and E-selectin), inhibited the recruitment of microglia/monocyte to the superficial retina, reduced peroxynitrite formation, and prevented the loss of neurons within the ganglion cell layer. In contrast, intravitreal delivery of CXCL10 increased leukocyte recruitment and retinal cell apoptosis. Inhibition of endoplasmic reticulum (ER) stress with chemical chaperones partially blocked ischemic injury-induced CXCL10 upregulation, whereas induction of ER stress with tunicamycin enhanced CXCL10 expression in retina and primary retinal ganglion cells. Interestingly, deleting CXCR3 attenuated ER stress-induced retinal cell death. In conclusion, these results indicate that ER stress-medicated activation of CXCL10/CXCR3 pathway has an important role in retinal inflammation and neuronal injury after high IOP-induced ischemia.

  16. BiP links TOR signaling to ER stress in Chlamydomonas.

    PubMed

    Crespo, José L

    2012-02-01

    The highly conserved target of rapamycin (TOR) Ser/Thr kinase promotes protein synthesis under favorable growth conditions in all eukaryotes. Downregulation of TOR signaling in the model unicellular green alga Chlamydomonas reinhardtii has recently revealed a link between control of protein synthesis, endoplasmic reticulum (ER) stress and the reversible modification of the BiP chaperone by phosphorylation. Inhibition of protein synthesis by rapamycin or cycloheximide resulted in the phosphorylation of BiP on threonine residues while ER stress induced by tunicamycin or heat shock caused the fast dephosphorylation of the protein. Regulation of BiP function by phosphorylation/dephosphorylation events was proposed in early studies in mammalian cells although no connection to TOR signaling has been established so far. Here I will discuss about the coordinated regulation of BiP modification by TOR and ER stress signals in Chlamydomonas.

  17. ER-stress and apoptosis: molecular mechanisms and potential relevance in infection.

    PubMed

    Häcker, Georg

    2014-10-01

    During ER-stress, one of the responses a cell can choose is apoptosis. Apoptosis generally is a cell's preferred response when other control mechanisms are overwhelmed. We now have a reasonably clear molecular picture what is happening once the apoptotic apparatus has been started. Unclear however are the majority of the upstream pathways that connect other signalling to apoptosis. During ER-stress, confirmed apoptosis-regulating targets are pro- and anti-apoptotic proteins of the Bcl-2-family, whose concerted action induces apoptosis. I will here discuss how mitochondrial apoptosis is triggered, how this is linked to the ER-stress response and in what way this may be relevant during microbial infections.

  18. Increased temporal cortex ER stress proteins in depressed subjects who died by suicide.

    PubMed

    Bown, C; Wang, J F; MacQueen, G; Young, L T

    2000-03-01

    Regulation of ER stress proteins, such as the 78-kilodalton glucose regulated protein (GRP78) by chronic treatment with mood stabilizing drugs suggests that this family of proteins may be involved in the pathophysiology of mood disorders. Indeed, increased levels of GRP78, GRP94, and calreticulin, a third member of the ER stress protein family, were found in temporal cortex of subjects with major depressive disorder who died by suicide compared with controls and subjects who died by other means. No such differences were found in subjects with other psychiatric disorders such as bipolar disorder or schizophrenia. These data suggest a potential role for ER stress proteins in severe depression that merits further study.

  19. Sodium fluoride (NaF) induces the splenic apoptosis via endoplasmic reticulum (ER) stress pathway in vivo and in vitro

    PubMed Central

    Cui, Hengmin; Chen, Lian; Luo, Qin; Fang, Jing; Zuo, Zhicai; Deng, Junliang; Wang, Xun; Zhao, Ling

    2016-01-01

    At present, there are no reports on the relationship between fluoride-induced apoptosis and endoplasmic reticulum (ER) stress (ER stress) in the spleen of human and animals in vivo and in vitro. Therefore, the aim of this study was to define sodium fluoride (NaF)-induced apoptosis mediated by ER stress in the spleen of mice in vivo and in vitro. Apoptosis and expression levels of the ER stress-related proteins were detected by flow cytometry and western blot, respectively. The results showed that NaF treatment increased lymphocytes apoptosis, which was consistent with NaF-caused ER Stress. NaF-caused ER stress was characterized by up-regulating protein expression levels of glucose-regulated protein 78 (BiP) and glucose-regulated protein 94 (GRP94), and by activating unfolded protein response (UPR). The signaling pathway of ER stress-associated apoptosis was activated by up-regulating protein expression levels of cleaved cysteine aspartate specific protease-12 (cleaved caspase-12), growth arrest and DNA damage-inducible gene 153 (Gadd153/CHOP) and phosphorylation of JUN N-terminal kinase (p-JNK). Additionally, our in vitro study found that apoptotic rate was decreased with remarkable down-regulation of the cleaved caspase-12, CHOP, p-JNK after ER stress was inhibited by 4-Phenylbutyric acid (4-PBA) treatment. In conclusion, NaF-induced apoptosis may mediated by ER stress in the spleen. PMID:28039491

  20. TRIM13 regulates ER stress induced autophagy and clonogenic ability of the cells.

    PubMed

    Tomar, Dhanendra; Singh, Rochika; Singh, Arun Kumar; Pandya, Chirayu D; Singh, Rajesh

    2012-02-01

    Autophagy is one of the cellular adaptive processes that provide protection against many pathological conditions like infection, cancer, neurodegeneration, and aging. Recent evidences suggest that ubiquitination plays an important role in degradation of proteins or defective organelle either through proteasome or autophagy. In this study, we describe the role of TRIM13, ER resident ubiquitin E3 ligase in induction of autophagy and its role during ER stress. The ectopic expression of TRIM13 in HEK-293 cells induces autophagy. Domain mapping showed that coiled-coil (CC) domain is required for induction of autophagy. TRIM13 is stabilized during ER stress, interacts with p62/SQSTM1 and co-localizes with DFCP1. TRIM13 regulates initiation of autophagy during ER stress and decreases the clonogenic ability of the cells. This study for the first time demonstrates the role of TRIM13 in induction of autophagy which may play an important role in regulation of ER stress and may act as tumor suppressor.

  1. 7,8-DHF Treatment Induces Cyr61 Expression to Suppress Hypoxia Induced ER Stress in HK-2 Cells

    PubMed Central

    Ma, Rui; Zhang, Jisheng; Liu, Xiaoyu; Yue, Shaoheng; Zhao, Qing

    2016-01-01

    Acute kidney injury (AKI) is a common syndrome which is strongly linked to high morbidity and mortality. Hypoxia is the leading cause of AKI and the proximal renal tubular cells are the most damaged part in the kidney during this period. It has been observed that 7,8-dihydroxyflavone (7,8-DHF) plays a protective role by acting on antiapoptosis and antioxidative stress. In this study we explored functions of 7,8-DHF in protecting human proximal tubular cell line HK-2 from hypoxia insults. We observed that treatment of 7,8-DHF could improve the viability of ischemic cell. Mechanistically, we found that 7,8-DHF could elevate the expression of cysteine-rich protein 61 (Cyr61), a protective immediate early gene in AKI. In addition, treatment of 7,8-DHF decreased CCAAT/enhancer-binding protein homologous protein (CHOP) expression, which is a marker protein during endoplasmic reticulum (ER) stress activation. Intriguingly, overexpression of Cyr61 significantly reduced CHOP expression. Taken together, our results provide novel insights into the possible protective role of 7,8-DHF by activating Cyr61 signaling and suppressing ER stress in hypoxic HK-2 cells which have potential clinical implications for the treatment of AKI. PMID:28116298

  2. Acute psychological stress-induced water intoxication.

    PubMed

    Mukherjee, Sagarika; Antonarakis, Emmanuel S; Asaduzzaman, S; Peters, John R

    2005-01-01

    Excessive water drinking is a recognised feature of schizophrenia. We present here a case of excessive water drinking precipitated by acute psychological stress. A 52-year-old woman, with no previous mental health problems, was found in a state of altered consciousness and was profoundly hyponatraemic. She had consumed excess amount of water due to severe mental stress. She was treated with hypertonic saline followed by fluid restrictions. The water intoxication had caused brain damage which led to behavioural changes and impaired cognition. We describe the pathophysiology of water intoxication.

  3. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death

    SciTech Connect

    Apostolou, Andria; Shen Yuxian; Liang Yan; Luo Jun; Fang Shengyun

    2008-08-01

    The accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes ER stress that initiates the unfolded protein response (UPR). UPR activates both adaptive and apoptotic pathways, which contribute differently to disease pathogenesis. To further understand the functional mechanisms of UPR, we identified 12 commonly UPR-upregulated genes by expression microarray analysis. Here, we describe characterization of Armet/MANF, one of the 12 genes whose function was not clear. We demonstrated that the Armet/MANF protein was upregulated by various forms of ER stress in several cell lines as well as by cerebral ischemia of rat. Armet/MANF was localized in the ER and Golgi and was also a secreted protein. Silencing Armet/MANF by siRNA oligos in HeLa cells rendered cells more susceptible to ER stress-induced death, but surprisingly increased cell proliferation and reduced cell size. Overexpression of Armet/MANF inhibited cell proliferation and improved cell viability under glucose-free conditions and tunicamycin treatment. Based on its inhibitory properties for both proliferation and cell death we have demonstrated, Armet is, thus, a novel secreted mediator of the adaptive pathway of UPR.

  4. Apoptosis Induced by Manganese on Neuronal SK-N-MC Cell Line: Endoplasmic Reticulum (ER) Stress and Mitochondria Dysfunction

    PubMed Central

    Yoon, Hyonok; Kim, Do-Sung; Lee, Geum-Hwa; Kim, Kee-Won; Kim, Hyung-Ryong

    2011-01-01

    Objectives Manganese chloride (MnCl2) is one of heavy metals for causing neurogenerative dysfunction like Manganism. The purpose of this study was to determine the acute toxicity of MnCl2 using different times and various concentrations including whether manganese toxicity may involve in two intrinsic pathways, endoplasmic reticulum (ER) stress and mitochondria dysfunction and lead to neuronal apoptosis mediated by organelle disorders in neuroblastoma cell line SK-N-MC. Methods In the acute toxicity test, five concentrations (200, 400, 600, 800, 1,000 uM) of MnCl2 with 3, 6, 12, 24, 48 hours exposure were selected to analyze cell viability. In addition, to better understand their toxicity, acute toxicity was examined with 1,000 uM MnCl2 for 24 hours exposure via reactive oxygen species (ROS), mitochondria membrane potential, western blotting and mitochondrial complex activities. Results Our results showed that both increments of dose and time prompt the increments in the number of dead cells. Cells treated by 1,000 µM MnCl2 activated 265% (±8.1) caspase-3 compared to control cell. MnCl2 induced intracellular ROS produced 168% (±2.3%) compared to that of the control cells and MnCl2 induced neurotoxicity significantly dissipated 48.9% of mitochondria membrane potential compared to the control cells. Conclusions This study indicated that MnCl2 induced apoptosis via ER stress and mitochondria dysfunction. In addition, MnCl2 affected only complex I except complex II, III or IV activities. PMID:22232721

  5. Oxidative stress in severe acute illness

    PubMed Central

    Bar-Or, David; Bar-Or, Raphael; Rael, Leonard T.; Brody, Edward N.

    2015-01-01

    The overall redox potential of a cell is primarily determined by oxidizable/reducible chemical pairs, including glutathione–glutathione disulfide, reduced thioredoxin–oxidized thioredoxin, and NAD+–NADH (and NADP–NADPH). Current methods for evaluating oxidative stress rely on detecting levels of individual byproducts of oxidative damage or by determining the total levels or activity of individual antioxidant enzymes. Oxidation–reduction potential (ORP), on the other hand, is an integrated, comprehensive measure of the balance between total (known and unknown) pro-oxidant and antioxidant components in a biological system. Much emphasis has been placed on the role of oxidative stress in chronic diseases, such as Alzheimer's disease and atherosclerosis. The role of oxidative stress in acute diseases often seen in the emergency room and intensive care unit is considerable. New tools for the rapid, inexpensive measurement of both redox potential and total redox capacity should aid in introducing a new body of literature on the role of oxidative stress in acute illness and how to screen and monitor for potentially beneficial pharmacologic agents. PMID:25644686

  6. Impaired autophagy activity is linked to elevated ER-stress and inflammation in aging adipose tissue

    PubMed Central

    Ghosh, Amiya Kumar; Mau, Theresa; O'Brien, Martin; Garg, Sanjay; Yung, Raymond

    2016-01-01

    Adipose tissue dysfunction in aging is associated with inflammation, metabolic syndrome and other diseases. We propose that impaired protein homeostasis due to compromised lysosomal degradation (micro-autophagy) might promote aberrant ER stress response and inflammation in aging adipose tissue. Using C57BL/6 mouse model, we demonstrate that adipose tissue-derived stromal vascular fraction (SVF) cells from old (18-20 months) mice have reduced expression of autophagy markers as compared to the younger (4-6 months) cohort. Elevated expressions of ER-stress marker CHOP and autophagy substrate SQSTM1/p62 are observed in old SVFs compared to young, when treated with either vehicle or with thapsigargin (Tg), an ER stress inducer. Treatment with bafilomycin A1 (Baf), a vacuolar-type H (+)-ATPase, or Tg elevated expressions of CHOP, and SQSTM1/p62 and LC-3-II, in 3T3-L1-preadipocytes. We also demonstrate impaired autophagy activity in old SVFs by analyzing increased accumulation of autophagy substrates LC3-II and p62. Compromised autophagy activity in old SVFs is correlated with enhanced release of pro-inflammatory cytokines IL-6 and MCP-1. Finally, SVFs from calorie restricted old mice (CR-O) have shown enhanced autophagy activity compared to ad libitum fed old mice (AL-O). Our results support the notion that diminished autophagy activity with aging contributes to increased adipose tissue ER stress and inflammation. PMID:27777379

  7. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis.

    PubMed

    Condamine, Thomas; Kumar, Vinit; Ramachandran, Indu R; Youn, Je-In; Celis, Esteban; Finnberg, Niklas; El-Deiry, Wafik S; Winograd, Rafael; Vonderheide, Robert H; English, Nickolas R; Knight, Stella C; Yagita, Hideo; McCaffrey, Judith C; Antonia, Scott; Hockstein, Neil; Witt, Robert; Masters, Gregory; Bauer, Thomas; Gabrilovich, Dmitry I

    2014-06-01

    Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis-induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs.

  8. Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis.

    PubMed

    Shi, Ying-Hong; Ding, Zhen-Bin; Zhou, Jian; Hui, Bo; Shi, Guo-Ming; Ke, Ai-Wu; Wang, Xiao-Ying; Dai, Zhi; Peng, Yuan-Fei; Gu, Cheng-Yu; Qiu, Shuang-Jian; Fan, Jia

    2011-10-01

    Sorafenib, a potent multikinase inhibitor, has been recognized as the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). However, the direct functional mechanism of tumor lethality mediated by sorafenib remains to be fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, we showed sorafenib induced both apoptosis and autophagy in human HCC cells through a mechanism that involved endoplasmic reticulum (ER) stress and was independent of the MEK1/2-ERK1/2 pathway. Upregulation of IRE1 signals from sorafenib-induced ER stress was critical for the induction of autophagy. Moreover, autophagy activation alleviated the ER stress-induced cell death. Inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown enhanced cell death in sorafenib treated HCC cell lines. Critically, the combination of sorafenib with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in HCC both in vivo and in vitro. These findings indicated that both ER stress and autophagy were involved in the cell death evoked by sorafenib in HCC cells. The combination of autophagy modulation and molecular targeted therapy is a promising therapeutic strategy in treatment of HCC.

  9. Protein kinase R-like ER kinase and its role in endoplasmic reticulum stress-decided cell fate.

    PubMed

    Liu, Z; Lv, Y; Zhao, N; Guan, G; Wang, J

    2015-07-30

    Over the past few decades, understandings and evidences concerning the role of endoplasmic reticulum (ER) stress in deciding the cell fate have been constantly growing. Generally, during ER stress, the signal transductions are mainly conducted by three ER stress transducers: protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring kinase 1 (IRE1) and activating transcription factor 6 (ATF6). Consequently, the harmful stimuli from the ER stress transducers induce apoptosis and autophagy, which share several crosstalks and eventually decide the cell fate. The dominance of apoptosis or autophagy induced by ER stress depends on the type and degree of the stimuli. When ER stress is too severe and prolonged, apoptosis is induced to eliminate the damaged cells; however, when stimuli are mild, cell survival is promoted to maintain normal physiological functions by inducing autophagy. Although all the three pathways participate in ER stress-induced apoptosis and autophagy, PERK shows several unique characteristics by interacting with some specific downstream effectors. Notably, there are some preliminary findings on PERK-dependent mechanisms switching autophagy and apoptosis. In this review, we particularly focused on the novel, intriguing and complicated role of PERK in ER stress-decided cell fate, and also discussed more roles of PERK in restoring cellular homeostasis. However, more in-depth knowledge of PERK in the future would facilitate our understanding about many human diseases and benefit in searching for new molecular therapeutic targets.

  10. On the Origin of Prostate Cancer Stem Cells through Transmissible ER Stress-Mediated Epithelial to Mesenchymal Transition

    DTIC Science & Technology

    2013-10-01

    that transmissible ER stress (TERS) promotes the Epithelial to Mesenchymal Transition ( EMT ) in differentiated prostate cancer cells, programming...tumorigenesis. Through the work performed during the last year, we have been able to demonstrate a link between prostate tumor ER stress, EMT , and enhanced...Mesenchymal Transition ( EMT ) in differentiated prostate cancer cells, programming cancer towards a different phenotype and greater invasive

  11. ER stress and impaired autophagy flux in neuronal degeneration and brain injury.

    PubMed

    Yin, Yan; Sun, George; Li, Eric; Kiselyov, Kirill; Sun, Dandan

    2017-03-01

    Autophagy is a highly controlled lysosome-mediated function in eukaryotic cells to eliminate damaged or aged long-lived proteins and organelles. It is required for restoring cellular homeostasis in cell survival under multiple stresses. Autophagy is known to be a double-edged sword because too much activation or inhibition of autophagy can disrupt homeostatic degradation of protein and organelles within the brain and play a role in neuronal cell death. Many factors affect autophagy flux function in the brain, including endoplasmic reticulum (ER) stress, oxidative stress, and aging. Newly emerged research indicates that altered autophagy flux functionality is involved in neurodegeneration of the aged brain, chronic neurological diseases, and after traumatic and ischemic brain injuries. In search to identify neuroprotective agents that may reduce oxidative stress and stimulate autophagy, one particular neuroprotective agent docosahexaenoic acid (DHA) presents unique functions in reducing ER and oxidative stress and modulating autophagy. This review will summarize the recent findings on changes of autophagy in aging, neurodegenerative diseases, and brain injury after trauma or ischemic strokes. Discussion of DHA functions is focused on modulating ER stress and autophagy in regard to its neuroprotection and anti-tumor functions.

  12. Iron depletion increases manganese uptake and potentiates apoptosis through ER stress

    PubMed Central

    Seo, Young Ah; Li, Yuan; Wessling-Resnick, Marianne

    2013-01-01

    Iron deficiency is a risk factor for manganese (Mn) accumulation. Excess Mn promotes neurotoxicity but the mechanisms involved and whether iron depletion might affect these pathways is unknown. To study Mn intoxication in vivo, iron deficient and control rats were intranasally instilled with 60 mg MnCl2/kg over 3 weeks. TUNEL staining of olfactory tissue revealed that Mn exposure induced apoptosis and that iron deficiency potentiated this effect. In vitro studies using the dopaminergic SH-SY5Y cell line confirmed that Mn-induced apoptosis was enhanced by iron depletion using the iron chelator desferrioxamine. Mn has been reported to induce apoptosis through endoplasmic reticulum stress. In SH-SY5Y cells, Mn exposure induced the ER stress genes glucose regulated protein 94 (GRP94) and C/EBP homologous protein (CHOP). Increased phosphorylation of the eukaryotic translation initiation factor 2α (phospho-eIF2α) was also observed. These effects were accompanied by the activation of ER resident enzyme caspase-12, and the downstream apoptotic effector caspase-3 was also activated. All of the Mn-induced responses were enhanced by DFO treatment. Inhibitors of ER stress and caspases significantly blocked Mn-induced apoptosis and its potentiation by DFO, indicating that ER stress and subsequent caspase activation underlie cell death. Taken together, these data reveal that Mn induces neuronal cell death through ER stress and the UPR response pathway and that this apoptotic effect is potentiated by iron deficiency most likely through upregulation of DMT1. PMID:23764342

  13. Hepatocyte growth factor secreted by bone marrow stem cell reduce ER stress and improves repair in alveolar epithelial II cells

    PubMed Central

    Nita, Izabela; Hostettler, Katrin; Tamo, Luca; Medová, Michaela; Bombaci, Giuseppe; Zhong, Jun; Allam, Ramanjaneyulu; Zimmer, Yitzhak; Roth, Michael; Geiser, Thomas; Gazdhar, Amiq

    2017-01-01

    Idiopathic Pulmonary Fibrosis (IPF) is a progressive, irreversible lung disease with complex pathophysiology. Evidence of endoplasmic reticulum (ER) stress has been reported in alveolar epithelial cells (AEC) in IPF patients. Secreted mediators from bone marrow stem cells (BMSC-cm) have regenerative properties. In this study we investigate the beneficial effects of BMSC-cm on ER stress response in primary AEC and ER stressed A549 cells. We hypothesize that BMSC-cm reduces ER stress. Primary AEC isolated from IPF patients were treated with BMSC-cm. To induce ER stress A549 cells were incubated with Tunicamycin or Thapsigargin and treated with BMSC-cm, or control media. Primary IPF-AEC had high Grp78 and CHOP gene expression, which was lowered after BMSC-cm treatment. Similar results were observed in ER stressed A549 cells. Alveolar epithelial repair increased in presence of BMSC-cm in ER stressed A549 cells. Hepatocyte growth factor (HGF) was detected in biologically relevant levels in BMSC-cm. Neutralization of HGF in BMSC-cm attenuated the beneficial effects of BMSC-cm including synthesis of surfactant protein C (SP-C) in primary AEC, indicating a crucial role of HGF in ER homeostasis and alveolar epithelial repair. Our data suggest that BMSC-cm may be a potential therapeutic option for treating pulmonary fibrosis. PMID:28157203

  14. Endoplasmic Reticulum (ER) Stress Induces Sirtuin 1 (SIRT1) Expression via the PI3K-Akt-GSK3β Signaling Pathway and Promotes Hepatocellular Injury.

    PubMed

    Koga, Tomoaki; Suico, Mary Ann; Shimasaki, Shogo; Watanabe, Eriko; Kai, Yukari; Koyama, Kosuke; Omachi, Kohei; Morino-Koga, Saori; Sato, Takashi; Shuto, Tsuyoshi; Mori, Kazutoshi; Hino, Shinjiro; Nakao, Mitsuyoshi; Kai, Hirofumi

    2015-12-18

    Sirtuin 1 (SIRT1), an NAD(+)-dependent histone deacetylase, plays crucial roles in various biological processes including longevity, stress response, and cell survival. Endoplasmic reticulum (ER) stress is caused by dysfunction of ER homeostasis and exacerbates various diseases including diabetes, fatty liver, and chronic obstructive pulmonary disease. Although several reports have shown that SIRT1 negatively regulates ER stress and ER stress-induced responses in vitro and in vivo, the effect of ER stress on SIRT1 is less explored. In this study, we showed that ER stress induced SIRT1 expression in vitro and in vivo. We further determined the molecular mechanisms of how ER stress induces SIRT1 expression. Surprisingly, the conventional ER stress-activated transcription factors XBP1, ATF4, and ATF6 seem to be dispensable for SIRT1 induction. Based on inhibitor screening experiments with SIRT1 promoter, we found that the PI3K-Akt-GSK3β signaling pathway is required for SIRT1 induction by ER stress. Moreover, we showed that pharmacological inhibition of SIRT1 by EX527 inhibited the ER stress-induced cellular death in vitro and severe hepatocellular injury in vivo, indicating a detrimental role of SIRT1 in ER stress-induced damage responses. Collectively, these data suggest that SIRT1 expression is up-regulated by ER stress and contributes to ER stress-induced cellular damage.

  15. Endoplasmic Reticulum (ER) Stress Induces Sirtuin 1 (SIRT1) Expression via the PI3K-Akt-GSK3β Signaling Pathway and Promotes Hepatocellular Injury*

    PubMed Central

    Koga, Tomoaki; Suico, Mary Ann; Shimasaki, Shogo; Watanabe, Eriko; Kai, Yukari; Koyama, Kosuke; Omachi, Kohei; Morino-Koga, Saori; Sato, Takashi; Shuto, Tsuyoshi; Mori, Kazutoshi; Hino, Shinjiro; Nakao, Mitsuyoshi; Kai, Hirofumi

    2015-01-01

    Sirtuin 1 (SIRT1), an NAD+-dependent histone deacetylase, plays crucial roles in various biological processes including longevity, stress response, and cell survival. Endoplasmic reticulum (ER) stress is caused by dysfunction of ER homeostasis and exacerbates various diseases including diabetes, fatty liver, and chronic obstructive pulmonary disease. Although several reports have shown that SIRT1 negatively regulates ER stress and ER stress-induced responses in vitro and in vivo, the effect of ER stress on SIRT1 is less explored. In this study, we showed that ER stress induced SIRT1 expression in vitro and in vivo. We further determined the molecular mechanisms of how ER stress induces SIRT1 expression. Surprisingly, the conventional ER stress-activated transcription factors XBP1, ATF4, and ATF6 seem to be dispensable for SIRT1 induction. Based on inhibitor screening experiments with SIRT1 promoter, we found that the PI3K-Akt-GSK3β signaling pathway is required for SIRT1 induction by ER stress. Moreover, we showed that pharmacological inhibition of SIRT1 by EX527 inhibited the ER stress-induced cellular death in vitro and severe hepatocellular injury in vivo, indicating a detrimental role of SIRT1 in ER stress-induced damage responses. Collectively, these data suggest that SIRT1 expression is up-regulated by ER stress and contributes to ER stress-induced cellular damage. PMID:26499802

  16. Subverting ER-stress towards apoptosis by nelfinavir and curcumin coexposure augments docetaxel efficacy in castration resistant prostate cancer cells.

    PubMed

    Mathur, Aditi; Abd Elmageed, Zakaria Y; Liu, Xichun; Kostochka, Mikhail L; Zhang, Haitao; Abdel-Mageed, Asim B; Mondal, Debasis

    2014-01-01

    Despite its side-effects, docetaxel (DTX) remains a first-line treatment against castration resistant prostate cancer (CRPC). Therefore, strategies to increase its anti-tumor efficacy and decrease its side effects are critically needed. Targeting of the constitutive endoplasmic reticulum (ER) stress in cancer cells is being investigated as a chemosensitization approach. We hypothesized that the simultaneous induction of ER-stress and suppression of PI3K/AKT survival pathway will be a more effective approach. In a CRPC cell line, C4-2B, we observed significant (p<0.005) enhancement of DTX-induced cytotoxicity following coexposure to thapsigargin and an AKT-inhibitor. However, since these two agents are not clinically approved, we investigated whether a combination of nelfinavir (NFR) and curcumin (CUR), known to target both these metabolic pathways, can similarly increase DTX cytotoxicity in CRPC cells. Within 24 hrs post-exposure to physiologic concentrations of NFR (5 µM) and CUR (5 µM) a significantly (p<0.005) enhanced cytotoxicity was evident with low concentration of DTX (10 nM). This 3-drug combination rapidly increased apoptosis in aggressive C4-2B cells, but not in RWPE-1 cells or in primary prostate epithelial cells (PrEC). Comparative molecular studies revealed that this 3-drug combination caused a more pronounced suppression of phosphorylated-AKT and higher induction in phosphorylated-eIF2α in C4-2B cells, as compared to RWPE-1 cells. Acute exposure (3-9 hrs) to this 3-drug combination intensified ER-stress induced pro-apoptotic markers, i.e. ATF4, CHOP, and TRIB3. At much lower concentrations, chronic (3 wks) exposures to these three agents drastically reduced colony forming units (CFU) by C4-2B cells. In vivo studies using mice containing C4-2B tumor xenografts showed significant (p<0.05) enhancement of DTX's (10 mg/kg) anti-tumor efficacy following coexposure to NFR (20 mg/kg) & CUR (100 mg/kg). Immunohistochemical (IHC) analyses of tumor sections

  17. ER stress signaling and neurodegeneration: At the intersection between Alzheimer's disease and Prion-related disorders.

    PubMed

    Torres, Mauricio; Matamala, José Manuel; Duran-Aniotz, Claudia; Cornejo, Victor Hugo; Foley, Andrew; Hetz, Claudio

    2015-09-02

    Alzheimer's and Prion diseases are two neurodegenerative conditions sharing different pathophysiological characteristics. Disease symptoms are associated with the abnormal accumulation of protein aggregates, which are generated by the misfolding and oligomerization of specific proteins. Recent functional studies uncovered a key role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the occurrence of synaptic dysfunction and neurodegeneration in Prion-related disorders and Alzheimer's disease. Here we review common pathological features of both diseases, emphasizing the link between amyloid formation, its pathogenesis and alterations in ER proteostasis. The potential benefits of targeting the UPR as a therapeutic strategy is also discussed.

  18. Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by Vitamin B supplementation

    PubMed Central

    Tripathi, Madhulika; Zhang, Cheng Wu; Singh, Brijesh Kumar; Sinha, Rohit Anthony; Moe, Kyaw Thu; DeSilva, Deidre Anne; Yen, Paul Michael

    2016-01-01

    Hyperhomocysteinemia (HHcy) is a well-known risk factor for stroke; however, its underlying molecular mechanism remains unclear. Using both mouse and cell culture models, we have provided evidence that impairment of autophagy has a central role in HHcy-induced cellular injury in the mouse brain. We observed accumulation of LC3B-II and p62 that was associated with increased MTOR signaling in human and mouse primary astrocyte cell cultures as well as a diet-induced mouse model of HHcy, HHcy decreased lysosomal membrane protein LAMP2, vacuolar ATPase (ATP6V0A2), and protease cathepsin D, suggesting that lysosomal dysfunction also contributed to the autophagic defect. Moreover, HHcy increased unfolded protein response. Interestingly, Vitamin B supplementation restored autophagic flux, alleviated ER stress, and reversed lysosomal dysfunction due to HHCy. Furthermore, the autophagy inducer, rapamycin was able to relieve ER stress and reverse lysosomal dysfunction caused by HHcy in vitro. Inhibition of autophagy by HHcy exacerbated cellular injury during oxygen and glucose deprivation and reperfusion (OGD/R), and oxidative stress. These effects were prevented by Vitamin B co-treatment, suggesting that it may be helpful in relieving detrimental effects of HHcy in ischemia/reperfusion or oxidative stress. Collectively, these findings show that Vitamin B therapy can reverse defects in cellular autophagy and ER stress due to HHcy; and thus may be a potential treatment to reduce ischemic damage caused by stroke in patients with HHcy. PMID:27929536

  19. Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by Vitamin B supplementation.

    PubMed

    Tripathi, Madhulika; Zhang, Cheng Wu; Singh, Brijesh Kumar; Sinha, Rohit Anthony; Moe, Kyaw Thu; DeSilva, Deidre Anne; Yen, Paul Michael

    2016-12-08

    Hyperhomocysteinemia (HHcy) is a well-known risk factor for stroke; however, its underlying molecular mechanism remains unclear. Using both mouse and cell culture models, we have provided evidence that impairment of autophagy has a central role in HHcy-induced cellular injury in the mouse brain. We observed accumulation of LC3B-II and p62 that was associated with increased MTOR signaling in human and mouse primary astrocyte cell cultures as well as a diet-induced mouse model of HHcy, HHcy decreased lysosomal membrane protein LAMP2, vacuolar ATPase (ATP6V0A2), and protease cathepsin D, suggesting that lysosomal dysfunction also contributed to the autophagic defect. Moreover, HHcy increased unfolded protein response. Interestingly, Vitamin B supplementation restored autophagic flux, alleviated ER stress, and reversed lysosomal dysfunction due to HHCy. Furthermore, the autophagy inducer, rapamycin was able to relieve ER stress and reverse lysosomal dysfunction caused by HHcy in vitro. Inhibition of autophagy by HHcy exacerbated cellular injury during oxygen and glucose deprivation and reperfusion (OGD/R), and oxidative stress. These effects were prevented by Vitamin B co-treatment, suggesting that it may be helpful in relieving detrimental effects of HHcy in ischemia/reperfusion or oxidative stress. Collectively, these findings show that Vitamin B therapy can reverse defects in cellular autophagy and ER stress due to HHcy; and thus may be a potential treatment to reduce ischemic damage caused by stroke in patients with HHcy.

  20. Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription.

    PubMed

    Marza, Esther; Taouji, Saïd; Barroso, Kim; Raymond, Anne-Aurélie; Guignard, Léo; Bonneu, Marc; Pallares-Lupon, Néstor; Dupuy, Jean-William; Fernandez-Zapico, Martin E; Rosenbaum, Jean; Palladino, Francesca; Dupuy, Denis; Chevet, Eric

    2015-03-01

    The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPR(ER)) to restore ER homeostasis. The AAA(+) ATPase p97/CDC-48 plays key roles in ER stress by promoting both ER protein degradation and transcription of UPR(ER) genes. Although the mechanisms associated with protein degradation are now well established, the molecular events involved in the regulation of gene transcription by p97/CDC-48 remain unclear. Using a reporter-based genome-wide RNAi screen in combination with quantitative proteomic analysis in Caenorhabditis elegans, we have identified RUVB-2, a AAA(+) ATPase, as a novel repressor of a subset of UPR(ER) genes. We show that degradation of RUVB-2 by CDC-48 enhances expression of ER stress response genes through an XBP1-dependent mechanism. The functional interplay between CDC-48 and RUVB-2 in controlling transcription of select UPR(ER) genes appears conserved in human cells. Together, these results describe a novel role for p97/CDC-48, whereby its role in protein degradation is integrated with its role in regulating expression of ER stress response genes.

  1. An autosomal recessive mutation of DSG4 causes monilethrix through the ER stress response.

    PubMed

    Kato, Madoka; Shimizu, Akira; Yokoyama, Yoko; Kaira, Kyoichi; Shimomura, Yutaka; Ishida-Yamamoto, Akemi; Kamei, Kiyoko; Tokunaga, Fuminori; Ishikawa, Osamu

    2015-05-01

    Monilethrix is a hair shaft anomaly characterized by beaded hair with periodic changes in hair thickness. Mutations in the desmoglein 4 (DSG4) gene reportedly underlie the autosomal recessive form of the disease. However, the pathogenesis and cellular basis for the DSG4 mutation-induced monilethrix remained largely unknown. We report a Japanese female patient with monilethrix. Observation of her hair shaft by means of transmission electron microscopy showed fewer desmosomes and abnormal keratinization. Genetic analysis revealed a homozygous mutation, c.2119delG (p.Asp707Ilefs*109), in the DSG4 gene, which was predicted to cause a frameshift and premature termination in the intracellular region of the DSG4 protein. The mutation has not been reported previously. In the patient's hair shaft, we detected reduced but partial expression of the mutant DSG4 protein. Cellular analyses demonstrated that the mutant DSG4 lost its affinity to plakoglobin and accumulated in the endoplasmic reticulum (ER). The amounts of mutant DSG4 were increased by proteasome inhibitor treatment, and the expression of an ER chaperone, GRP78/BiP, was elevated in the patient's skin. Collectively, these results suggest that the dysfunctional mutated DSG4, tethered in the ER, undergoes ER-associated degradation, leading to unfolded protein response induction, and thus ER stress may have a role in the pathogenesis of monilethrix.

  2. 2,4-dichlorophenol induces ER stress-mediated apoptosis via eIF2α dephosphorylation in vitro.

    PubMed

    Zhang, Xiaoning; Zhang, Xiaona; Qi, Yongmei; Huang, Dejun; Zhang, Yingmei

    2016-02-01

    2,4-Dichlorophenol (2,4-DCP) has been widely used to produce herbicides and pharmaceutical intermediates, which exhibits various toxic effects including apoptosis. However, the mechanisms underlying 2,4-DCP-induced apoptosis, especially mediated by endoplasmic reticulum (ER) stress, are still unknown. In the present study, the mouse embryonic fibroblasts (MEFs) were used as an in vitro model system to figure out whether 2,4-DCP could induce ER stress, and further to elucidate the role of ER stress in 2,4-DCP-induced apoptosis. The results showed that 2,4-DCP dramatically caused the decrease of cell viability, the increase of apoptotic cells, the collapse of mitochondrial membrane potential (MMP) and the activation of caspase-3, suggesting that 2,4-DCP did induce apoptosis. Meanwhile, 2,4-DCP acted similarly as ER stress agonist tunicamycin (Tu) to activate all three branches (IRE1α, ATF6 and eIF2α) of ER stress. Furthermore, repression of ER stress or inhibition of eIF2α dephosphorylation significantly alleviated 2,4-DCP-induced apoptosis. Taking these results together, the present study firstly showed that 2,4-DCP induced ER stress-mediated apoptosis via eIF2α dephosphorylation in mammalian cells. These findings will provide new insights into the mechanisms underlying apoptosis after chlorophenols exposure.

  3. Melatonin Mediates Protective Effects against Kainic Acid-Induced Neuronal Death through Safeguarding ER Stress and Mitochondrial Disturbance

    PubMed Central

    Xue, Feixiao; Shi, Cai; Chen, Qingjie; Hang, Weijian; Xia, Liangtao; Wu, Yue; Tao, Sophia Z.; Zhou, Jie; Shi, Anbing; Chen, Juan

    2017-01-01

    Kainic acid (KA)-induced neuronal death is linked to mitochondrial dysfunction and ER stress. Melatonin is known to protect hippocampal neurons from KA-induced apoptosis, but the exact mechanisms underlying melatonin protective effects against neuronal mitochondria disorder and ER stress remain uncertain. In this study, we investigated the sheltering roles of melatonin during KA-induced apoptosis by focusing on mitochondrial dysfunction and ER stress mediated signal pathways. KA causes mitochondrial dynamic disorder and dysfunction through calpain activation, leading to neuronal apoptosis. Ca2+ chelator BAPTA-AM and calpain inhibitor calpeptin can significantly restore mitochondrial morphology and function. ER stress can also be induced by KA treatment. ER stress inhibitor 4-phenylbutyric acid (PBA) attenuates ER stress-mediated apoptosis and mitochondrial disorder. It is worth noting that calpain activation was also inhibited under PBA administration. Thus, we concluded that melatonin effectively inhibits KA-induced calpain upregulation/activation and mitochondrial deterioration by alleviating Ca2+ overload and ER stress. PMID:28293167

  4. Novel Treatment of Chronic Graft-Versus-Host Disease in Mice Using the ER Stress Reducer 4-Phenylbutyric Acid

    PubMed Central

    Mukai, Shin; Ogawa, Yoko; Urano, Fumihiko; Kudo-Saito, Chie; Kawakami, Yutaka; Tsubota, Kazuo

    2017-01-01

    Chronic graft-versus-host disease (cGVHD) is a notorious complication of allogeneic hematopoietic stem cell transplantation and causes disabling systemic inflammation and fibrosis. In this novel study, we focused on a relationship between endoplasmic reticulum (ER) stress and cGVHD, and aimed to create effective treatment of cGVHD. A series of experiments were conducted using a mouse model of cGVHD. Our data suggested (1) that ER stress was elevated in organs affected by cGVHD and (2) that 4-phenylbutyric acid (PBA) could reduce cGVHD-induced ER stress and thereby alleviate systemic inflammation and fibrosis. Because fibroblasts are thought to be implicated in cGVHD-elicited fibrosis and because macrophages are reported to play a role in the development of cGVHD, we investigated cGVHD-triggered ER stress in fibroblasts and macrophages. Our investigation demonstrated (1) that indicators for ER stress and activation markers for fibroblasts were elevated in cGVHD-affected lacrimal gland fibroblasts and (2) that they could be reduced by PBA. Our work also indicated that splenic macrophages from PBA-dosed mice exhibited the lower levels of ER stress and M2 macrophage markers than those from cGVHD-affected mice. Collectively, this study suggests that the reduction of ER stress utilizing PBA can be a clinically translatable method to treat systemic cGVHD. PMID:28165054

  5. Chemical chaperones reduce ER stress and adipose tissue inflammation in high fat diet-induced mouse model of obesity

    PubMed Central

    Chen, Yaqin; Wu, Zhihong; Zhao, Shuiping; Xiang, Rong

    2016-01-01

    Obesity, which is characteristic by chronic inflammation, is defined as abnormal or excessive fat accumulation in adipose tissues. Endoplasmic reticulum (ER) stress is increased in adipose tissue of obese state and is known to be strongly associated with chronic inflammation. The aim of this study was to investigate the effect of ER stress on adipokine secretion in obese mice and explore the potential mechanisms. In this study, we found high-fat diet induced-obesity contributed to strengthened ER stress and triggered chronic inflammation in adipose tissue. Chemical chaperones, 4-PBA and TUDCA, modified metabolic disorders and decreased the levels of inflammatory cytokines in obese mice fed a high-fat diet. The alleviation of ER stress is in accordance with the decrease of free cholesterol in adipose tissue. Furthermore chemical chaperones suppress NF-κB activity in adipose tissue of obese mice in vivo. In vitro studies showed IKK/NF-κB may be involved in the signal transduction of adipokine secretion dysfunction induced by ER stress. The present study revealed the possibility that inhibition of ER stress may be a novel drug target for metabolic abnormalities associated with obesity. Further studies are now needed to characterize the initial incentive of sustained ER stress in obese. PMID:27271106

  6. Endoplasmic reticulum stress-activated glycogen synthase kinase 3β aggravates liver inflammation and hepatotoxicity in mice with acute liver failure.

    PubMed

    Ren, Feng; Zhou, Li; Zhang, Xiangying; Wen, Tao; Shi, Hongbo; Xie, Bangxiang; Li, Zhuo; Chen, Dexi; Wang, Zheling; Duan, Zhongping

    2015-01-01

    Endoplasmic reticulum stress (ER stress) has been increasingly recognized as an important mechanism in various liver diseases. However, its intrinsic physiological role in acute liver failure (ALF) remains largely undetermined. This study aimed to examine how ER stress orchestrates glycogen synthase kinase 3β (GSK3β) and inflammation to affect ALF. In a murine ALF model induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS), 4-phenylbutyric acid (4-PBA) is to be administered to relieve ER stress. The lethality rate, liver damage, cytokine expression, and the activity of GSK3β were evaluated. How to regulate LPS-induced inflammation and TNF-α-induced hepatocyte apoptosis by ER stress was investigated in vitro. In vivo, ER stress was triggered in the liver with the progression of mice ALF model. ER stress was essential for the development of ALF because ER stress inhibition by 4-PBA ameliorated the liver damage through decreasing liver inflammation and hepatocyte apoptosis. 4-PBA also decreased GSK3β activity in the livers of ALF mice. In vitro, ER stress induced by tunicamycin synergistically increased LPS-triggered pro-inflammatory cytokine induction and promoted the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway in bone marrow-derived macrophages; moreover, tunicamycin also cooperated with TNF-α to increase hepatocyte apoptosis. ER stress promoted LPS-triggered inflammation depending on GSK3β activation because inhibition of GSK3β by SB216763, the specific inhibitor of GSK3β, resulted in downregulation of pro-inflammatory genes. ER stress contributes to liver inflammation and hepatotoxicity in ALF, particularly by regulating GSK3β, and is therefore a potential therapeutic target for ALF.

  7. Acute psychosocial stress reduces pain modulation capabilities in healthy men.

    PubMed

    Geva, Nirit; Pruessner, Jens; Defrin, Ruth

    2014-11-01

    Anecdotes on the ability of individuals to continue to function under stressful conditions despite injuries causing excruciating pain suggest that acute stress may induce analgesia. However, studies exploring the effect of acute experimental stress on pain perception show inconsistent results, possibly due to methodological differences. Our aim was to systematically study the effect of acute stress on pain perception using static and dynamic, state-of-the-art pain measurements. Participants were 29 healthy men who underwent the measurement of heat-pain threshold, heat-pain intolerance, temporal summation of pain, and conditioned pain modulation (CPM). Testing was conducted before and during exposure to the Montreal Imaging Stress Task (MIST), inducing acute psychosocial stress. Stress levels were evaluated using perceived ratings of stress and anxiety, autonomic variables, and salivary cortisol. The MIST induced a significant stress reaction. Although pain threshold and pain intolerance were unaffected by stress, an increase in temporal summation of pain and a decrease in CPM were observed. These changes were significantly more robust among individuals with stronger reaction to stress ("high responders"), with a significant correlation between the perception of stress and the performance in the pain measurements. We conclude that acute psychosocial stress seems not to affect the sensitivity to pain, however, it significantly reduces the ability to modulate pain in a dose-response manner. Considering the diverse effects of stress in this and other studies, it appears that the type of stress and the magnitude of its appraisal determine its interactions with the pain system.

  8. ER-stress in Alzheimer’s disease: turning the scale?

    PubMed Central

    Endres, Kristina; Reinhardt, Sven

    2013-01-01

    Pathogenic mechanisms of Alzheimer’s disease (AD) are intensely investigated as it is the most common form of dementia and burdens society by its costs and social demands. While key molecules such as A-beta peptides and tau have been identified decades ago, it is still enigmatic what drives the disease in its sporadic manifestation. Synthesis of A-beta peptides as well as phosphorylation of tau proteins comprise normal cellular functions and occur in principle in the healthy as well as in dementia-affected persons. Dyshomeostasis of Amyloid Precursor Protein (APP) cleavage, energy metabolism or kinase/phosphatase activity due to stressors has been suggested as a trigger of the disease. One way for cells to escape stress based on dysfunction of ER is the unfolded protein response - the UPR. This pathway is composed out of three different routes that differ in proteins involved, targets and consequences for cell fate: activation of transmembrane ER resident kinases IRE1-alpha and PERK or monomerization of membrane-anchored activating transcription factor 6 (ATF6) induce activation of versatile transcription factors (XBP-1, eIF2-alpha/ATF4 and ATF6 P50). These bind to specific DNA sequences on target gene promoters and on one hand attenuate general ER-prone protein synthesis and on the other equip the cell with tools to de-stress. If cells fail in stress compensation, this signaling also is able to evoke apoptosis. In this review we summarized knowledge on how APP processing and phosphorylation of tau might be influenced by ER-stress signaling. In addition, we depicted the effects UPR itself seems to have on molecules closely related to AD and describe what is known about UPR in AD animal models as well as in human patients. PMID:24319643

  9. Transcriptional Profiling of Chondrodysplasia Growth Plate Cartilage Reveals Adaptive ER-Stress Networks That Allow Survival but Disrupt Hypertrophy

    PubMed Central

    Cameron, Trevor L.; Bell, Katrina M.; Tatarczuch, Liliana; Mackie, Eleanor J.; Rajpar, M. Helen; McDermott, Ben T.; Boot-Handford, Raymond P.; Bateman, John F.

    2011-01-01

    Metaphyseal chondrodysplasia, Schmid type (MCDS) is characterized by mild short stature and growth plate hypertrophic zone expansion, and caused by collagen X mutations. We recently demonstrated the central importance of ER stress in the pathology of MCDS by recapitulating the disease phenotype by expressing misfolding forms of collagen X (Schmid) or thyroglobulin (Cog) in the hypertrophic zone. Here we characterize the Schmid and Cog ER stress signaling networks by transcriptional profiling of microdissected mutant and wildtype hypertrophic zones. Both models displayed similar unfolded protein responses (UPRs), involving activation of canonical ER stress sensors and upregulation of their downstream targets, including molecular chaperones, foldases, and ER-associated degradation machinery. Also upregulated were the emerging UPR regulators Wfs1 and Syvn1, recently identified UPR components including Armet and Creld2, and genes not previously implicated in ER stress such as Steap1 and Fgf21. Despite upregulation of the Chop/Cebpb pathway, apoptosis was not increased in mutant hypertrophic zones. Ultrastructural analysis of mutant growth plates revealed ER stress and disrupted chondrocyte maturation throughout mutant hypertrophic zones. This disruption was defined by profiling the expression of wildtype growth plate zone gene signatures in the mutant hypertrophic zones. Hypertrophic zone gene upregulation and proliferative zone gene downregulation were both inhibited in Schmid hypertrophic zones, resulting in the persistence of a proliferative chondrocyte-like expression profile in ER-stressed Schmid chondrocytes. Our findings provide a transcriptional map of two chondrocyte UPR gene networks in vivo, and define the consequences of UPR activation for the adaptation, differentiation, and survival of chondrocytes experiencing ER stress during hypertrophy. Thus they provide important insights into ER stress signaling and its impact on cartilage pathophysiology. PMID

  10. Transcriptional profiling of chondrodysplasia growth plate cartilage reveals adaptive ER-stress networks that allow survival but disrupt hypertrophy.

    PubMed

    Cameron, Trevor L; Bell, Katrina M; Tatarczuch, Liliana; Mackie, Eleanor J; Rajpar, M Helen; McDermott, Ben T; Boot-Handford, Raymond P; Bateman, John F

    2011-01-01

    Metaphyseal chondrodysplasia, Schmid type (MCDS) is characterized by mild short stature and growth plate hypertrophic zone expansion, and caused by collagen X mutations. We recently demonstrated the central importance of ER stress in the pathology of MCDS by recapitulating the disease phenotype by expressing misfolding forms of collagen X (Schmid) or thyroglobulin (Cog) in the hypertrophic zone. Here we characterize the Schmid and Cog ER stress signaling networks by transcriptional profiling of microdissected mutant and wildtype hypertrophic zones. Both models displayed similar unfolded protein responses (UPRs), involving activation of canonical ER stress sensors and upregulation of their downstream targets, including molecular chaperones, foldases, and ER-associated degradation machinery. Also upregulated were the emerging UPR regulators Wfs1 and Syvn1, recently identified UPR components including Armet and Creld2, and genes not previously implicated in ER stress such as Steap1 and Fgf21. Despite upregulation of the Chop/Cebpb pathway, apoptosis was not increased in mutant hypertrophic zones. Ultrastructural analysis of mutant growth plates revealed ER stress and disrupted chondrocyte maturation throughout mutant hypertrophic zones. This disruption was defined by profiling the expression of wildtype growth plate zone gene signatures in the mutant hypertrophic zones. Hypertrophic zone gene upregulation and proliferative zone gene downregulation were both inhibited in Schmid hypertrophic zones, resulting in the persistence of a proliferative chondrocyte-like expression profile in ER-stressed Schmid chondrocytes. Our findings provide a transcriptional map of two chondrocyte UPR gene networks in vivo, and define the consequences of UPR activation for the adaptation, differentiation, and survival of chondrocytes experiencing ER stress during hypertrophy. Thus they provide important insights into ER stress signaling and its impact on cartilage pathophysiology.

  11. Differential activation of the ER stress factor XBP1 by oligomeric assemblies.

    PubMed

    Castillo-Carranza, Diana L; Zhang, Yan; Guerrero-Muñoz, Marcos J; Kayed, Rakez; Rincon-Limas, Diego E; Fernandez-Funez, Pedro

    2012-08-01

    Several neurodegenerative disorders are characterized by protein misfolding, a phenomenon that results in perturbation of cellular homeostasis. We recently identified the protective activity of the ER stress response factor XBP1 (X-box binding protein 1) against Amyloid-ß1-42 (Aß42) neurotoxicity in cellular and Drosophila models of Alzheimer's disease. Additionally, subtoxic concentrations of Aß42 soluble aggregates (oligomers) induced accumulation of spliced (active) XBP1 transcripts, supporting the involvement of the ER stress response in Aß42 neurotoxicity. Here, we tested the ability of three additional disease-related amyloidogenic proteins to induce ER stress by analyzing XBP1 activation at the RNA level. Treatment of human SY5Y neuroblastoma cells with homogeneous preparations of α-Synuclein (α-Syn), Prion protein (PrP106-126), and British dementia amyloid peptide (ABri1-34) confirmed the high toxicity of oligomers compared to monomers and fibers. Additionally, α-Syn oligomers, but not monomers or fibers, demonstrated potent induction of XBP1 splicing. On the other hand, PrP106-126 and ABri1-34 did not activate XBP1. These results illustrate the biological complexity of these structurally related assemblies and argue that oligomer toxicity depends on the activation of amyloid-specific cellular responses.

  12. Acute stress does not affect the impairing effect of chronic stress on memory retrieval

    PubMed Central

    Ozbaki, Jamile; Goudarzi, Iran; Salmani, Mahmoud Elahdadi; Rashidy-Pour, Ali

    2016-01-01

    Objective(s): Due to the prevalence and pervasiveness of stress in modern life and exposure to both chronic and acute stresses, it is not clear whether prior exposure to chronic stress can influence the impairing effects of acute stress on memory retrieval. This issue was tested in this study. Materials and Methods: Adult male Wistar rats were randomly assigned to the following groups: control, acute, chronic, and chronic + acute stress groups. The rats were trained with six trials per day for 6 consecutive days in the water maze. Following training, the rats were either kept in control conditions or exposed to chronic stress in a restrainer 6 hr/day for 21 days. On day 22, a probe test was done to measure memory retention. Time spent in target and opposite areas, platform location latency, and proximity were used as indices of memory retention. To induce acute stress, 30 min before the probe test, animals received a mild footshock. Results: Stressed animals spent significantly less time in the target quadrant and more time in the opposite quadrant than control animals. Moreover, the stressed animals showed significantly increased platform location latency and proximity as compared with control animals. No significant differences were found in these measures among stress exposure groups. Finally, both chronic and acute stress significantly increased corticosterone levels. Conclusion: Our results indicate that both chronic and acute stress impair memory retrieval similarly. Additionally, the impairing effects of chronic stress on memory retrieval were not influenced by acute stress. PMID:27635201

  13. Inherent ER stress in pancreatic islet β cells causes self-recognition by autoreactive T cells in type 1 diabetes.

    PubMed

    Marré, Meghan L; Profozich, Jennifer L; Coneybeer, Jorge T; Geng, Xuehui; Bertera, Suzanne; Ford, Michael J; Trucco, Massimo; Piganelli, Jon D

    2016-08-01

    Type 1 diabetes (T1D) is an autoimmune disease characterized by pancreatic β cell destruction induced by islet reactive T cells that have escaped central tolerance. Many physiological and environmental triggers associated with T1D result in β cell endoplasmic reticulum (ER) stress and dysfunction, increasing the potential for abnormal post-translational modification (PTM) of proteins. We hypothesized that β cell ER stress induced by environmental and physiological conditions generates abnormally-modified proteins for the T1D autoimmune response. To test this hypothesis we exposed the murine CD4(+) diabetogenic BDC2.5 T cell clone to murine islets in which ER stress had been induced chemically (Thapsigargin). The BDC2.5 T cell IFNγ response to these cells was significantly increased compared to non-treated islets. This β cell ER stress increased activity of the calcium (Ca(2+))-dependent PTM enzyme tissue transglutaminase 2 (Tgase2), which was necessary for full stress-dependent immunogenicity. Indeed, BDC2.5 T cells responded more strongly to their antigen after its modification by Tgase2. Finally, exposure of non-antigenic murine insulinomas to chemical ER stress in vitro or physiological ER stress in vivo caused increased ER stress and Tgase2 activity, culminating in higher BDC2.5 responses. Thus, β cell ER stress induced by chemical and physiological triggers leads to β cell immunogenicity through Ca(2+)-dependent PTM. These findings elucidate a mechanism of how β cell proteins are modified and become immunogenic, and reveal a novel opportunity for preventing β cell recognition by autoreactive T cells.

  14. Acute Stress Symptoms in Young Children with Burns

    ERIC Educational Resources Information Center

    Stoddard, Frederick J.; Saxe, Glenn; Ronfeldt, Heidi; Drake, Jennifer E.; Burns, Jennifer; Edgren, Christy; Sheridan, Robert

    2006-01-01

    Objective: Posttraumatic stress disorder symptoms are a focus of much research with older children, but little research has been conducted with young children, who account for about 50% of all pediatric burn injuries. This is a 3-year study of 12- to 48-month-old acutely burned children to assess acute traumatic stress outcomes. The aims were to…

  15. Prompt protein glycosylation during acute heat stress.

    PubMed

    Henle, K J; Kaushal, G P; Nagle, W A; Nolen, G T

    1993-08-01

    Constitutive patterns of protein synthesis and protein glycosylation are severely disrupted by acute heat stress. Stressed cells respond by preferential synthesis of specific proteins, e.g., the well-known family of heat shock proteins. We observed another response that rapidly occurs during heating periods as short as 10 min at 45 degrees C. During that period, CHO cells began to glycosylate specific proteins, designated as "prompt" stress glycoproteins (P-SG), while constitutive protein glycosylation ceased. Labeling of P-SGs showed a dose response with time and with temperature and appeared regardless of the label used (D-[3H]mannose or D-[3H]glucose). On SDS-PAGE, the major P-SG was characterized by M(r) approximately 67 kDa (P-SG67) and pI = 5.1. Other less prominent P-SGs appeared at M(r) 160, 100, 64, 60, and 47 kDa; incorporated label showed little turnover during 24 h at 37 degrees C. Prompt glycosylation was inhibited by tunicamycin, and label incorporated into P-SGs was sensitive to N-glycosidase F, but not to O-glycosidase. Analysis of enzymatically digested P-SG67 indicated that label had been incorporated into both high-mannose (Man9GlcNAc) and complex-type oligosaccharides. Brefeldin A did not eliminate P-SG67 labeling, but caused the further appearance of novel, Brefeldin-associated P-SGs. Labeling of P-SG67 oligosaccharides occurred without significant concomitant protein synthesis, suggesting that addition of labeled oligosaccharides largely occurred on mature, rather than nascent proteins. The functional significance of prompt glycosylation remains to be defined, but we propose that this novel phenomenon is an integral part of the cellular heat stress response.

  16. Ursodeoxycholic Acid (UDCA) Exerts Anti-Atherogenic Effects by Inhibiting Endoplasmic Reticulum (ER) Stress Induced by Disturbed Flow.

    PubMed

    Chung, Jihwa; Kim, Kyoung Hwa; Lee, Seok Cheol; An, Shung Hyun; Kwon, Kihwan

    2015-10-01

    Disturbed blood flow with low-oscillatory shear stress (OSS) is a predominant atherogenic factor leading to dysfunctional endothelial cells (ECs). Recently, it was found that disturbed flow can directly induce endoplasmic reticulum (ER) stress in ECs, thereby playing a critical role in the development and progression of atherosclerosis. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, has long been used to treat chronic cholestatic liver disease and is known to alleviate endoplasmic reticulum (ER) stress at the cellular level. However, its role in atherosclerosis remains unexplored. In this study, we demonstrated the anti-atherogenic activity of UDCA via inhibition of disturbed flow-induced ER stress in atherosclerosis. UDCA effectively reduced ER stress, resulting in a reduction in expression of X-box binding protein-1 (XBP-1) and CEBP-homologous protein (CHOP) in ECs. UDCA also inhibits the disturbed flow-induced inflammatory responses such as increases in adhesion molecules, monocyte adhesion to ECs, and apoptosis of ECs. In a mouse model of disturbed flow-induced atherosclerosis, UDCA inhibits atheromatous plaque formation through the alleviation of ER stress and a decrease in adhesion molecules. Taken together, our results revealed that UDCA exerts anti-atherogenic activity in disturbed flow-induced atherosclerosis by inhibiting ER stress and the inflammatory response. This study suggests that UDCA may be a therapeutic agent for prevention or treatment of atherosclerosis.

  17. Neuroprotective Strategy in Retinal Degeneration: Suppressing ER Stress-Induced Cell Death via Inhibition of the mTOR Signal

    PubMed Central

    Fan, Bin; Sun, Ying-Jian; Liu, Shu-Yan; Che, Lin; Li, Guang-Yu

    2017-01-01

    The retina is a specialized sensory organ, which is essential for light detection and visual formation in the human eye. Inherited retinal degenerations are a heterogeneous group of eye diseases that can eventually cause permanent vision loss. UPR (unfolded protein response) and ER (endoplasmic reticulum) stress plays an important role in the pathological mechanism of retinal degenerative diseases. mTOR (the mammalian target of rapamycin) kinase, as a signaling hub, controls many cellular processes, covering protein synthesis, RNA translation, ER stress, and apoptosis. Here, the hypothesis that inhibition of mTOR signaling suppresses ER stress-induced cell death in retinal degenerative disorders is discussed. This review surveys knowledge of the influence of mTOR signaling on ER stress arising from misfolded proteins and genetic mutations in retinal degenerative diseases and highlights potential neuroprotective strategies for treatment and therapeutic implications. PMID:28106827

  18. Cold-inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress

    PubMed Central

    Khan, Mohammad Moshahid; Yang, Weng-Lang; Brenner, Max; Bolognese, Alexandra Cerutti; Wang, Ping

    2017-01-01

    Cold-inducible RNA-binding protein (CIRP), released into the circulation during sepsis, causes lung injury via an as yet unknown mechanism. Since endoplasmic reticulum (ER) stress is associated with acute lung injury (ALI), we hypothesized that CIRP causes ALI via induction of ER stress. To test this hypothesis, we studied the lungs of wild-type (WT) and CIRP knockout (KO) mice at 20 h after induction of sepsis by cecal ligation and puncture (CLP). WT mice had significantly more severe ALI than CIRP KO mice. Lung ER stress markers (BiP, pIRE1α, sXBP1, CHOP, cleaved caspase-12) were increased in septic WT mice, but not in septic CIRP KO mice. Effector pathways downstream from ER stress – apoptosis, NF-κB (p65), proinflammatory cytokines (IL-6, IL-1β), neutrophil chemoattractants (MIP-2, KC), neutrophil infiltration (MPO activity), lipid peroxidation (4-HNE), and nitric oxide (iNOS) – were significantly increased in WT mice, but only mildly elevated in CIRP KO mice. ER stress markers were increased in the lungs of healthy WT mice treated with recombinant murine CIRP, but not in the lungs of TLR4 KO mice. This suggests CIRP directly induces ER stress via TLR4 activation. In summary, CIRP induces lung ER stress and downstream responses to cause sepsis-associated ALI. PMID:28128330

  19. Cold-inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress.

    PubMed

    Khan, Mohammad Moshahid; Yang, Weng-Lang; Brenner, Max; Bolognese, Alexandra Cerutti; Wang, Ping

    2017-01-27

    Cold-inducible RNA-binding protein (CIRP), released into the circulation during sepsis, causes lung injury via an as yet unknown mechanism. Since endoplasmic reticulum (ER) stress is associated with acute lung injury (ALI), we hypothesized that CIRP causes ALI via induction of ER stress. To test this hypothesis, we studied the lungs of wild-type (WT) and CIRP knockout (KO) mice at 20 h after induction of sepsis by cecal ligation and puncture (CLP). WT mice had significantly more severe ALI than CIRP KO mice. Lung ER stress markers (BiP, pIRE1α, sXBP1, CHOP, cleaved caspase-12) were increased in septic WT mice, but not in septic CIRP KO mice. Effector pathways downstream from ER stress - apoptosis, NF-κB (p65), proinflammatory cytokines (IL-6, IL-1β), neutrophil chemoattractants (MIP-2, KC), neutrophil infiltration (MPO activity), lipid peroxidation (4-HNE), and nitric oxide (iNOS) - were significantly increased in WT mice, but only mildly elevated in CIRP KO mice. ER stress markers were increased in the lungs of healthy WT mice treated with recombinant murine CIRP, but not in the lungs of TLR4 KO mice. This suggests CIRP directly induces ER stress via TLR4 activation. In summary, CIRP induces lung ER stress and downstream responses to cause sepsis-associated ALI.

  20. On the Origin of Prostate Cancer Stem Cells through Transmissible ER Stress-Mediated Epithelial to Mesenchymal Transition

    DTIC Science & Technology

    2013-04-01

    catenin, we have begun to pursue if Wnt signaling occurs during TERS driven EMT . Given that this signaling process has tumor implicated roles in...hypothesis that transmissible ER stress (TERS) promotes Epithelial to Mesenchymal Transition ( EMT ) in differentiated prostate cancer cells, programming...tumorigenesis. Through the work performed during the last year, we have been able to demonstrate a link between prostate tumor ER stress and EMT . The

  1. ER stress and autophagy are involved in the apoptosis induced by cisplatin in human lung cancer cells

    PubMed Central

    SHI, SHAOMIN; TAN, PING; YAN, BINGDI; GAO, RONG; ZHAO, JIANJUN; WANG, JING; GUO, JIA; LI, NING; MA, ZHONGSEN

    2016-01-01

    Cisplatin [cis-diamminedichloroplatinum II (CDDP)] is one of the most classical and effective chemotherapeutic drugs for the treatment of cancers including lung cancer. However, the presence of cisplatin resistance in cancer lowers its curative effect and limits its usage in the clinic. The aim of the present study was to investigate the underlying mechanisms of cisplatin resistance in lung cancer involving endoplasmic reticulum (ER) stress and autophagy. In the present study, we detected the effect of cisplatin on cell viability, ER stress and autophagy in lung cancer cell lines A549 and H460. We also tested the effects of ER stress and autophagy on apoptosis induced by cisplatin. The results showed that cisplatin induced apoptosis, ER stress and autophagy in lung cancer cell lines. In addition, the inhibition of ER stress by 4-phenylbutyric acid (4-PBA) or tauroursodeoxycholic acid sodium (TUDC) enhanced cisplatin-induced apoptosis in the human lung cancer cells. Meanwhile, combination treatment with the autophagic inhibitor 3-methyladenine (3-MA) or chloroquine (CQ) further increased the apoptosis induced by cisplatin in the human lung cancer cells. The present study provides a novel treatment strategy - cisplatin in combination with an autophagic inhibitor or an ER stress inhibitor leads to increased apoptosis in human lung cancer cells. PMID:26985651

  2. Adiponectin reduces ER stress-induced apoptosis through PPARα transcriptional regulation of ATF2 in mouse adipose

    PubMed Central

    Liu, Zhenjiang; Gan, Lu; Wu, Tianjiao; Feng, Fei; Luo, Dan; Gu, Huihui; Liu, Shimin; Sun, Chao

    2016-01-01

    Adiponectin is a cytokine produced predominantly by adipose tissue and correlates with glucose and lipid homeostasis. However, the effects of adiponectin on endoplasmic reticulum (ER) stress and apoptosis of adipose tissue remain elusive. In this study, we found that tunicamycin-induced ER stress increased serum free fatty acid (FFA) and impaired glucose tolerance, elevated the mRNA levels of GRP78, Chop, ATF2 and caspase 3, but reduced adiponectin mRNA level in white adipose tissue. Moreover, ER stress-triggered adipocyte apoptosis by increasing cellular FFA level and Ca2+ level. Further analysis revealed that adiponectin alleviated ER stress-induced adipocyte apoptosis by elevating peroxisome proliferator-activated receptor alpha (PPARα) mRNA level. Our data also confirmed that adiponectin reduced early apoptotic cells and blocked the mitochondrial apoptosis pathway by activating the AdipoR1/AMP-activated protein kinase (AMPK) signal pathway. In addition, PPARα bound to ATF2 promoter region and inhibited transcription of ATF2. The inhibition of adipocyte apoptosis by adiponectin was correlated with transcriptional suppression of ATF2. Furthermore, adiponectin inhibited ER stress-induced apoptosis by activating the AMPK/PKC pathway. In summary, our data demonstrate adiponectin inhibited ER stress and apoptosis of adipocyte in vivo and in vitro by activating the AMPK/PPARα/ATF2 pathway. Our study establishes that adiponectin is an important adipocytokine for preventing and treating obesity. PMID:27882945

  3. Restoration of autophagy alleviates hepatic ER stress and impaired insulin signalling transduction in high fructose-fed male mice.

    PubMed

    Wang, Hao; Sun, Ruo-Qiong; Zeng, Xiao-Yi; Zhou, Xiu; Li, Songpei; Jo, Eunjung; Molero, Juan C; Ye, Ji-Ming

    2015-01-01

    High-carbohydrate (mainly fructose) consumption is a major dietary factor for hepatic insulin resistance, involving endoplasmic reticulum (ER) stress and lipid accumulation. Because autophagy has been implicated in ER stress, the present study investigated the role of autophagy in high-fructose (HFru) diet-induced hepatic ER stress and insulin resistance in male C57BL/6J mice. The results show that chronic HFru feeding induced glucose intolerance and impaired insulin signaling transduction in the liver, associated with ER stress and the accumulation of lipids. Intriguingly, hepatic autophagy was suppressed as a result of activation of mammalian target of rapamycin. The suppressed autophagy was detected within 6 hours after HFru feeding along with activation of both inositol-requiring enzyme 1 and protein kinase RNA-like endoplasmic reticulum kinase pathways. These events occurred prior to lipid accumulation or lipogenesis and were sufficient to blunt insulin signaling transduction with activation of c-Jun N-terminal kinase/inhibitory-κB kinase and serine phosphorylation of insulin receptor substrate 1. The stimulation of autophagy attenuated ER stress- and c-Jun N-terminal kinase/inhibitory-κB kinase-associated impairment in insulin signaling transduction in a mammalian target of rapamycin -independent manner. Taken together, our data suggest that restoration of autophagy functions disrupted by fructose is able to alleviate ER stress and improve insulin signaling transduction.

  4. GSK3β and VDAC Involvement in ER Stress and Apoptosis Modulation during Orthotopic Liver Transplantation

    PubMed Central

    Zaouali, Mohamed Amine; Panisello, Arnau; Lopez, Alexandre; Castro, Carlos; Folch, Emma; Carbonell, Teresa; Rolo, Anabela; Palmeira, Carlos Marques; Garcia-Gil, Agustin; Adam, René; Roselló-Catafau, Joan

    2017-01-01

    We investigated the involvement of glycogen synthase kinase-3β (GSK3β) and the voltage-dependent anion channel (VDAC) in livers subjected to cold ischemia–reperfusion injury (I/R) associated with orthotopic liver transplantation (OLT). Rat livers were preserved in University of Wisconsin (UW) and Institute Georges Lopez (IGL-1) solution, the latter enriched or not with trimetazidine, and then subjected to OLT. Transaminase (ALT) and HMGB1 protein levels, glutamate dehydrogenase (GLDH), and oxidative stress (MDA) were measured. The AKT protein kinase and its direct substrates, GSK3β and VDAC, as well as caspases 3, 9, and cytochrome C and reticulum endoplasmic stress-related proteins (GRP78, pPERK, ATF4, and CHOP), were determined by Western blot. IGL-1+TMZ significantly reduced liver injury. We also observed a significant phosphorylation of AKT, which in turn induced the phosphorylation and inhibition of GSK3β. In addition, TMZ protected the mitochondria since, in comparison with IGL-1 alone, we found reductions in VDAC phosphorylation, apoptosis, and GLDH release. All these results were correlated with decreased ER stress. Addition of TMZ to IGL-1 solution increased the tolerance of the liver graft to I/R injury through inhibition of GSK3β and VDAC, contributing to ER stress reduction and cell death prevention. PMID:28282906

  5. Ameliorating ER-stress attenuates Aeromonas hydrophila-induced mitochondrial dysfunctioning and caspase mediated HKM apoptosis in Clarias batrachus

    PubMed Central

    Banerjee, Chaitali; Singh, Ambika; Das, Taposh Kumar; Raman, Rajagopal; Shrivastava, Anju; Mazumder, Shibnath

    2014-01-01

    Endoplasmic reticulum (ER)-stress and unfolding protein response (UPR) has not been implied in Aeromonas hydrophila-pathogenicity. We report increased expression of the ER-stress markers: CHOP, BiP and phospho-eIF2α in A. hydrophila-infected headkidney macrophages (HKM) in Clarias batrachus. Pre-treatment with ER-stress inhibitor, 4-PBA alleviated ER-stress and HKM apoptosis suggesting ER-UPR critical for the process. The ER-Ca2+ released via inositol-triphosphate and ryanodine receptors induced calpain-2 mediated superoxide ion generation and consequent NF-κB activation. Inhibiting NF-κB activation attenuated NO production suggesting the pro-apoptotic role of NF-κB on HKM pathology. Calpain-2 activated caspase-12 to intensify the apoptotic cascade through mitochondrial-membrane potential (ψm) dissipation and caspase-9 activation. Altered mitochondrial ultra-structure consequent to ER-Ca2+ uptake via uniporters reduced ψm and released cytochrome C. Nitric oxide induced the cGMP/PKG-dependent activation of caspase-8 and truncated-Bid formation. Both the caspases converge onto caspase-3 to execute HKM apoptosis. These findings offer a possible molecular explanation for A. hydrophila pathogenicity. PMID:25059203

  6. Altered immunometabolism at the interface of increased endoplasmic reticulum (ER) stress in patients with type 2 diabetes.

    PubMed

    Lenin, Raji; Sankaramoorthy, Aravind; Mohan, Viswanathan; Balasubramanyam, Muthuswamy

    2015-10-01

    The mechanism of perturbed immune function in patients with T2DM is poorly understood. Recent studies imply a role for ER stress in linking immune-system alterations and metabolism. Here, we investigated whether ER stress markers and its downstream effector signals are altered in patients with type 2 diabetes along with proinflammatory augmentation. In our study, gene and protein expression of ER stress markers (GRP-78, PERK, IRE1α, ATF6, XBP-1 and CHOP) was elevated significantly (P < 0.05) in PBMCs from T2DM patients compared with control subjects. The mRNA expression of both the proinflammatory cytokines (TNF-α and IL-6) and oxidative stress markers (p22(phox), TXNIP, and TRPC-6; P < 0.05) was also increased in PBMCs from patients with T2DM. SOCS3 mRNA expression was reduced significantly (P < 0.05) in diabetes patients. mRNA expression of most of the ER stress markers from PBMCs correlated significantly and positively with poor glycemic control, dyslipidemia, IR, and inflammatory and oxidative stress markers. Chronic ER stress in PBMCs from patients with T2DM was evident from the increased caspase-3 activity (P < 0.01), which is an executioner of apoptosis. Along with an impairment of miR-146a levels, the downstream targets of miR-146a, viz., IRAK1 and TRAF6 mRNA levels, were also elevated significantly (P < 0.01) in patients with T2DM. There was an inverse relationship among miR-146a levels and ER stress markers, inflammatory markers, and glycemic control. We demonstrate evidence of increased ER stress markers with impaired miR-146a levels and increased proinflammatory signals in patients with type 2 diabetes.

  7. [Acute myocardial infarction complicated by acute pulmonary oedema and cardiogenic collapse during dobutamine stress echocardiography].

    PubMed

    Yameogo, Nobila Valentin; Mbaye, Alassane; Kagambega, Larissa Justine; Dioum, Momar; Diagne-Sow, Dior; Kane, Moussa; Diack, Bouna; Kane, Abdoul

    2013-06-23

    Acute myocardial infarction is a rare complication of dobutamine stress echocardiography. We describe the case of a diabetic patient who presented with an anterior myocardial infarction complicated by an acute pulmonary oedema and cardiogenic collapse during dobutamine stress echocardiography, requiring five days' hospitalisation. Coronarography could not be performed because of inadequate medical facilities.

  8. Sustained HSP25 Expression Induces Clasmatodendrosis via ER Stress in the Rat Hippocampus

    PubMed Central

    Kim, Ji-Eun; Hyun, Hye-Won; Min, Su-Ji; Kang, Tae-Cheon

    2017-01-01

    Heat shock protein (HSP) 25 (murine/rodent 25 kDa, human 27 kDa) is one of the major astroglial HSP families, which has a potent anti-apoptotic factor contributing to a higher resistance of astrocytes to the stressful condition. However, impaired removals of HSP25 decrease astroglial viability. In the present study, we investigated whether HSP25 is involved in astroglial apoptosis or clasmatodendrosis (autophagic astroglial death) in the rat hippocampus induced by status epilepticus (SE). Following SE, HSP25 expression was transiently increased in astrocytes within the dentate gyrus (DG), while it was sustained in CA1 astrocytes until 4 weeks after SE. HSP25 knockdown exacerbated SE-induced apoptotic astroglial degeneration, but mitigated clasmatodendrosis accompanied by abrogation of endoplasmic reticulum (ER) stress without changed seizure susceptibility or severity. These findings suggest that sustained HSP25 induction itself may result in clasmatodendrosis via prolonged ER stress. To the best of our knowledge, the present study demonstrates for the first time the double-edge properties of HSP25 in astroglial death induced by SE. PMID:28275338

  9. Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma.

    PubMed

    Syed, Deeba N; Lall, Rahul K; Chamcheu, Jean Christopher; Haidar, Omar; Mukhtar, Hasan

    2014-12-01

    The prognosis of malignant melanoma remains poor in spite of recent advances in therapeutic strategies for the deadly disease. Fisetin, a dietary flavonoid is currently being investigated for its growth inhibitory properties in various cancer models. We previously showed that fisetin inhibited melanoma growth in vitro and in vivo. Here, we evaluated the molecular basis of fisetin induced cytotoxicity in metastatic human melanoma cells. Fisetin treatment induced endoplasmic reticulum (ER) stress in highly aggressive A375 and 451Lu human melanoma cells, as revealed by up-regulation of ER stress markers including IRE1α, XBP1s, ATF4 and GRP78. Time course analysis indicated that the ER stress was associated with activation of the extrinsic and intrinsic apoptotic pathways. Fisetin treated 2-D melanoma cultures displayed autophagic response concomitant with induction of apoptosis. Prolonged treatment (16days) with fisetin in a 3-D reconstituted melanoma model resulted in inhibition of melanoma progression with significant apoptosis, as evidenced by increased staining of cleaved Caspase-3 in the treated constructs. However, no difference in the expression of autophagic marker LC-3 was noted between treated and control groups. Fisetin treatment to 2-D melanoma cultures resulted in phosphorylation and activation of the multifunctional AMP-activated protein kinase (AMPK) involved in the regulation of diverse cellular processes, including autophagy and apoptosis. Silencing of AMPK failed to prevent cell death indicating that fisetin induced cytotoxicity is mediated through both AMPK-dependent and -independent mechanisms. Taken together, our studies confirm apoptosis as the primary mechanism through which fisetin inhibits melanoma cell growth and that activation of both extrinsic and intrinsic pathways contributes to fisetin induced cytotoxicity.

  10. Varicella-Zoster Virus Infectious Cycle: ER Stress, Autophagic Flux, and Amphisome-Mediated Trafficking

    PubMed Central

    Grose, Charles; Buckingham, Erin M.; Carpenter, John E.; Kunkel, Jeremy P.

    2016-01-01

    Varicella-zoster virus (VZV) induces abundant autophagy. Of the nine human herpesviruses, the VZV genome is the smallest (~124 kbp), lacking any known inhibitors of autophagy, such as the herpes simplex virus ICP34.5 neurovirulence gene. Therefore, this review assesses the evidence for VZV-induced cellular stress, endoplasmic-reticulum-associated degradation (ERAD), and autophagic flux during the VZV infectious cycle. Even though VZV is difficult to propagate in cell culture, the biosynthesis of the both N- and O-linked viral glycoproteins was found to be abundant. In turn, this biosynthesis provided evidence of endoplasmic reticulum (ER) stress, including a greatly enlarged ER and a greatly diminished production of cellular glycoproteins. Other signs of ER stress following VZV infection included detection of the alternatively spliced higher-molecular-weight form of XBP1 as well as CHOP. VZV infection in cultured cells leads to abundant autophagosome production, as was visualized by the detection of the microtubule-associated protein 1 light chain 3-II (LC3-II). The degree of autophagy induced by VZV infection is comparable to that induced in uninfected cells by serum starvation. The inhibition of autophagic flux by chemicals such as 3-methyladenine or ATG5 siRNA, followed by diminished virus spread and titers, has been observed. Since the latter observation pointed to the virus assembly/trafficking compartments, we purified VZ virions by ultracentrifugation and examined the virion fraction for components of the autophagy pathway. We detected LC3-II protein (an autophagy marker) as well as Rab11 protein, a component of the endosomal pathway. We also observed that the virion-containing vesicles were single-walled; thus, they are not autophagosomes. These results suggested that some VZ virions after secondary envelopment were transported to the outer cell membrane in a vesicle derived from both the autophagy and endosomal pathways, such as an amphisome. Thus, these

  11. Crimean-Congo Hemorrhagic Fever Virus-Infected Hepatocytes Induce ER-Stress and Apoptosis Crosstalk

    PubMed Central

    Rodrigues, Raquel; Paranhos-Baccalà, Gláucia; Vernet, Guy; Peyrefitte, Christophe N.

    2012-01-01

    Crimean-Congo hemorrhagic fever virus (CCHFV) is a widely distributed tick-borne member of the Nairovirus genus (Bunyaviridae) with a high mortality rate in humans. CCHFV induces a severe disease in infected patients that includes, among other symptoms, massive liver necrosis and failure. The interaction between liver cells and CCHFV is therefore important for understanding the pathogenesis of this disease. Here, we described the in vitro CCHFV-infection and -replication in the hepatocyte cell line, Huh7, and the induced cellular and molecular response modulation. We found that CCHFV was able to infect and replicate to high titres and to induce a cytopathic effect (CPE). We also observed by flow cytometry and real time quantitative RT-PCR evidence of apoptosis, with the participation of the mitochondrial pathway. On the other hand, we showed that the replication of CCHFV in hepatocytes was able to interfere with the death receptor pathway of apoptosis. Furthermore, we found in CCHFV-infected cells the over-expression of PUMA, Noxa and CHOP suggesting the crosstalk between the ER-stress and mitochondrial apoptosis. By ELISA, we observed an increase of IL-8 in response to viral replication; however apoptosis was shown to be independent from IL-8 secretion. When we compared the induced cellular response between CCHFV and DUGV, a mild or non-pathogenic Nairovirus for humans, we found that the most striking difference was the absence of CPE and apoptosis. Despite the XBP1 splicing and PERK gene expression induced by DUGV, no ER-stress and apoptosis crosstalk was observed. Overall, these results suggest that CCHFV is able to induce ER-stress, activate inflammatory mediators and modulate both mitochondrial and death receptor pathways of apoptosis in hepatocyte cells, which may, in part, explain the role of the liver in the pathogenesis of CCHFV. PMID:22238639

  12. Peritraumatic versus persistent dissociation in acute stress disorder.

    PubMed

    Panasetis, Paula; Bryant, Richard A

    2003-12-01

    The DSM-IV definition of acute stress disorder (ASD) regards dissociation that occurs during a trauma (peritraumatic dissociation) comparably to persistent dissociation. This study investigated the relative contributions of peritraumatic dissociation and persistent dissociation to acute posttraumatic stress reactions. Civilian trauma (N = 53) survivors with either acute stress disorder (ASD), subclinical ASD, or no ASD were administered modified versions of the Peritraumatic Dissociative Experiences Questionnaire that indexed both dissociation during the trauma and dissociation at the time of assessment. Persistent dissociation was more strongly associated with ASD severity and intrusive symptoms than peritraumatic dissociation. These results are consistent with the proposition that persistent, rather than peritraumatic, dissociation is associated with posttraumatic psychopathology.

  13. Calorie-induced ER stress suppresses uroguanylin satiety signaling in diet-induced obesity

    PubMed Central

    Kim, G W; Lin, J E; Snook, A E; Aing, A S; Merlino, D J; Li, P; Waldman, S A

    2016-01-01

    Background/Objectives: The uroguanylin-GUCY2C gut–brain axis has emerged as one component regulating feeding, energy homeostasis, body mass and metabolism. Here, we explore a role for this axis in mechanisms underlying diet-induced obesity (DIO). Subjects/Methods: Intestinal uroguanylin expression and secretion, and hypothalamic GUCY2C expression and anorexigenic signaling, were quantified in mice on high-calorie diets for 14 weeks. The role of endoplasmic reticulum (ER) stress in suppressing uroguanylin in DIO was explored using tunicamycin, an inducer of ER stress, and tauroursodeoxycholic acid (TUDCA), a chemical chaperone that inhibits ER stress. The impact of consumed calories on uroguanylin expression was explored by dietary manipulation. The role of uroguanylin in mechanisms underlying obesity was examined using Camk2a-Cre-ERT2-Rosa-STOPloxP/loxP-Guca2b mice in which tamoxifen induces transgenic hormone expression in brain. Results: DIO suppressed intestinal uroguanylin expression and eliminated its postprandial secretion into the circulation. DIO suppressed uroguanylin through ER stress, an effect mimicked by tunicamycin and blocked by TUDCA. Hormone suppression by DIO reflected consumed calories, rather than the pathophysiological milieu of obesity, as a diet high in calories from carbohydrates suppressed uroguanylin in lean mice, whereas calorie restriction restored uroguanylin in obese mice. However, hypothalamic GUCY2C, enriched in the arcuate nucleus, produced anorexigenic signals mediating satiety upon exogenous agonist administration, and DIO did not impair these responses. Uroguanylin replacement by transgenic expression in brain repaired the hormone insufficiency and reconstituted satiety responses opposing DIO and its associated comorbidities, including visceral adiposity, glucose intolerance and hepatic steatosis. Conclusions: These studies reveal a novel pathophysiological mechanism contributing to obesity in which calorie-induced suppression

  14. ER stress is associated with reduced ABCA-1 protein levels in macrophages treated with advanced glycated albumin - reversal by a chemical chaperone.

    PubMed

    Castilho, Gabriela; Okuda, Ligia S; Pinto, Raphael S; Iborra, Rodgiro T; Nakandakare, Edna R; Santos, Celio X; Laurindo, Francisco R; Passarelli, Marisa

    2012-07-01

    ATP-binding cassette transporter A1 mediates the export of excess cholesterol from macrophages, contributing to the prevention of atherosclerosis. Advanced glycated albumin (AGE-alb) is prevalent in diabetes mellitus and is associated with the development of atherosclerosis. Independently of changes in ABCA-1 mRNA levels, AGE-alb induces oxidative stress and reduces ABCA-1 protein levels, which leads to macrophage lipid accumulation. These metabolic conditions are known to elicit endoplasmic reticulum (ER) stress. We sought to determine if AGE-alb induces ER stress and unfolded protein response (UPR) in macrophages and how disturbances to the ER could affect ABCA-1 content and cholesterol efflux in macrophages. AGE-alb induced a time-dependent increase in ER stress and UPR markers. ABCA-1 content and cellular cholesterol efflux were reduced by 33% and 47%, respectively, in macrophages treated with AGE-alb, and both were restored by treatment with 4-phenyl butyric acid (a chemical chaperone that alleviates ER stress), but not MG132 (a proteasome inhibitor). Tunicamycin, a classical ER stress inductor, also impaired ABCA-1 expression and cholesterol efflux (showing a decrease of 61% and 82%, respectively), confirming the deleterious effect of ER stress in macrophage cholesterol accumulation. Glycoxidation induces macrophage ER stress, which relates to the reduction in ABCA-1 and in reverse cholesterol transport, endorsing the adverse effect of macrophage ER stress in atherosclerosis. Thus, chemical chaperones that alleviate ER stress may represent a useful tool for the prevention and treatment of atherosclerosis in diabetes.

  15. Bicyclol attenuates tetracycline-induced fatty liver associated with inhibition of hepatic ER stress and apoptosis in mice.

    PubMed

    Yao, Xiao-Min; Li, Yue; Li, Hong-Wei; Cheng, Xiao-Yan; Lin, Ai-Bin; Qu, Jun-Ge

    2016-01-01

    Endoplasmic reticulum (ER) stress is known to be involved in the development of several metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). Tetracycline can cause hepatic steatosis, and ER stress may be involved in tetracycline-induced fatty liver. Our previous study showed that bicyclol has been proven to protect against tetracycline-induced fatty liver in mice, and ER stress may also be involved in bicyclol's hepatoprotective effect. Therefore, this study was performed to investigate the underlying mechanisms associated with ER stress and apoptosis, by which bicyclol attenuated tetracycline-induced fatty liver in mice. Bicyclol (300 mg/kg) was given to mice by gavage 3 times. Tetracycline (200 mg/kg, intraperitoneally) was injected at 1 h after the last dose of bicyclol. At 6 h and 24 h after single dose of tetracycline injection, serum ALT, AST, TG, CHO and hepatic histopathological examinations were performed to evaluate liver injuries. Hepatic steatosis was assessed by the accumulation of hepatic TG and CHO. Moreover, hepatic apoptosis and ER stress related markers were determined by TUNEL, real-time PCR, and western blot. As a result, bicyclol significantly protected against tetracycline-induced fatty liver as evidenced by the decrease of elevated serum transaminases and hepatic triglyceride, and the attenuation of histopathological changes in mice. In addition, bicyclol remarkably alleviated hepatic apoptosis and the gene expression of caspase-3, and increased the gene expression of XIAP. The gene expressions of ER stress-related markers, including CHOP, GRP78, IRE-1α, and ATF6, which were downregulated by bicyclol pretreatment in tetracycline-injected mice. These results suggested that bicyclol protected tetracycline-induced fatty liver partly due to its ability of anti-apoptosis associated with ER stress.

  16. Cardiac-specific overexpression of catalase attenuates paraquat-induced myocardial geometric and contractile alteration: role of ER stress.

    PubMed

    Ge, Wei; Ge, We; Zhang, Yingmei; Han, Xuefeng; Ren, Jun

    2010-12-15

    Paraquat, a quaternary nitrogen herbicide, is a highly toxic pro-oxidant that causes multiorgan failure including that of the heart via generation of reactive oxygen species, although the underlying mechanism has not been well elucidated. This study examined the influence of cardiac-specific overexpression of catalase, an antioxidant detoxifying H(2)O(2), on paraquat-induced myocardial geometric and functional alterations, with a focus on ER stress. FVB and catalase transgenic mice were administered paraquat for 48h. Myocardial geometry, contractile function, apoptosis, and ER stress were evaluated using echocardiography, edge detection, caspase-3 activity, and immunoblotting. Our results revealed that paraquat treatment significantly enlarged left ventricular (LV) end diastolic and systolic diameters; increased LV mass and resting myocyte length; reduced fractional shortening, cardiomyocyte peak shortening, and maximal velocity of shortening/relengthening; and prolonged relengthening duration in the FVB group. Whereas the catalase transgene itself did not alter myocardial geometry and function, it mitigated or significantly attenuated paraquat-elicited myocardial geometric and functional changes. Paraquat promoted overt apoptosis and ER stress as evidenced by increased caspase-3 activity, apoptosis, and ER stress markers including Bax, Bcl-2, GADD153, calregulin, and phosphorylated JNK, IRE1α, and eIF2α; all were ablated by the catalase transgene. Paraquat-induced cardiomyocyte dysfunction was mitigated by the ER stress inhibitor tauroursodeoxycholic acid. Moreover, the JNK inhibitor SP600125 reversed paraquat-induced ER stress as evidenced by enhanced GADD153 and IRE1α phosphorylation. Taken together, these data revealed that catalase may rescue paraquat-induced myocardial geometric and functional alteration possibly by alleviating JNK-mediated ER stress.

  17. The Development of Screening Methods to Identify Drugs to Limit ER Stress Using Wild-type and Mutant Serotonin Transporter

    PubMed Central

    Katarao, Kazusa; Murakawa, Seiya; Asano, Masaya; Usuki, Naoto; Yamamoto, Hikaru; Shirafuji, Toshihiko; Tanaka, Shigeru; Hide, Izumi; Sakai, Norio

    2016-01-01

    The function of the serotonin transporter (SERT) is regulated by its membrane trafficking. Previously, we showed that the C-terminus-deleted mutant of SERT (SERTΔCT) exhibited an aberrant membrane trafficking and subsequent retention at the endoplasmic reticulum (ER). In addition, we found that proteasome inhibitor-induced ER stress resulted in the impairment of SERT membrane trafficking and retention of SERT at the ER, an impairment very similar to that of SERTΔCT. Based on the result that the chemical chaperone 4-phnylbutulic acid (4-PBA), which relieves ER stress, accelerated the membrane trafficking and upregulated SERT activity, we hypothesized that drugs that facilitate the membrane trafficking of SERT would have potential therapeutic effects on an ER stress-related disease. In this study, we aimed to develop simple screening methods for such drugs using SERT. We first validated the serotonin uptake assay using fluorescent substrates. This simple and reliable assay method was useful for screening for drugs that affected the wild-type SERT but not SERTΔCT. In addition, we verified an assay focusing on the formation of SERTΔCT aggregates. The drugs 4-PBA and SKF-10047 facilitated the trafficking of SERT to the membrane and reduced SERTΔCT aggregates, indicating that the drugs with such characters could be potential candidates for ER stress relief. For both assays, we clarified the usefulness of a high-content screening microscope. These results could pave the way for high-throughput screening for such drugs. PMID:28127108

  18. Curcumin induces ER stress-mediated apoptosis through selective generation of reactive oxygen species in cervical cancer cells.

    PubMed

    Kim, Boyun; Kim, Hee Seung; Jung, Eun-Ji; Lee, Jung Yun; K Tsang, Benjamin; Lim, Jeong Mook; Song, Yong Sang

    2016-05-01

    Prolonged accumulation of misfolded or unfolded proteins caused by cellular stress, including oxidative stress, induces endoplasmic reticulum stress, which then activates an unfolded protein response (UPR). ER stress is usually maintained at higher levels in cancer cells as compared to normal cells due to altered metabolism in cancer. Here, we investigated whether curcumin is ER stress-mediated apoptosis in cervical cancer cells, and ROS increased by curcumin are involved in the process as an upstream contributor. Curcumin inhibited proliferation of cervical cancer cells (C33A, CaSki, HeLa, and ME180) and induced apoptotic cell death. Curcumin activated ER-resident UPR sensors, such as PERK, IRE-1α, and ATF6, and their downstream-signaling proteins in cervical cancer cells, but not in normal epithelial cells and peripheral blood mononuclear cells (PBMCs). CHOP, a key factor involved in ER stress-mediated apoptosis, was also activated by curcumin. CHOP decreased the ratio of anti-apoptotic protein Bcl-2 to pro-apoptotic protein Bax expression, and subsequently increased the apoptotic population of cervical cancer cells. Furthermore, curcumin elevated levels of intracellular reactive oxygen species (ROS) in cervical cancer cells, but not in normal epithelial cells. Scavenging ROS resulted in inhibition of ER stress and partially restored cell viability in curcumin-treated cancer cells. Collectively, these observations show that curcumin promotes ER stress-mediated apoptosis in cervical cancer cells through increase of cell type-specific ROS generation. Therefore, modulation of these differential responses to curcumin between normal and cervical cancer cells could be an effective therapeutic strategy without adverse effects on normal cells.

  19. Cantharidins Induce ER Stress and a Terminal Unfolded Protein Response in OSCC

    PubMed Central

    Xi, Y.; Garshott, D.M.; Brownell, A.L.; Yoo, G.H.; Lin, H.-S.; Freeburg, T.L.; Yoo, N.G.; Kaufman, R.J.; Callaghan, M.U.

    2015-01-01

    Mortality and morbidity associated with oral squamous cell carcinoma (OSCC) remain unacceptably high with disfiguring treatment options and a death rate of 1 per hour in the United States. The approval of cituximab for advanced OSCC has been the only new treatment for these patients since the 1970s, although it has not significantly increased overall survival. To address the paucity of effective new therapies, we undertook a high-throughput screen to discover small molecules and natural products that could induce endoplasmic reticulum (ER) stress and enforce a terminal unfolded protein response (UPR) in OSCC. The terpenoid cantharidin (CNT), previously used to treat various malignancies in culture-specific medical practices for over 2,000 y, emerged as a hit. CNT and its analog, cantharidic acid, potently induced protein and gene expression profiles consistent with the activation of ER stress, the UPR, and apoptosis in OSCC cells. Murine embryonic fibroblasts null for the UPR-associated transcription factors Atf4 or Chop were significantly protected from CNT, implicating a key role for the UPR in the death response. These data validate that our high-throughput screen can identify novel modulators of UPR signaling and that such compounds might provide a new therapeutic approach to treating patients with OSCC. PMID:25425581

  20. Lithium induces ER stress and N-glycan modification in galactose-grown Jurkat cells.

    PubMed

    Nagy, Tamás; Frank, Dorottya; Kátai, Emese; Yahiro, Rikki K K; Poór, Viktor S; Montskó, Gergely; Zrínyi, Zita; Kovács, Gábor L; Miseta, Attila

    2013-01-01

    We previously reported that lithium had a significant impact on Ca(2+) regulation and induced unfolded protein response (UPR) in yeast cells grown on galactose due to inhibition of phosphoglucomutase (PGM), however the exact mechanism has not been established yet. In this study, we analysed lithium's effect in galactose-fed cells to clarify whether these ER-related changes are the result of a relative hypoglycemic state. Furthermore, we investigated whether the alterations in galactose metabolism impact protein post-translational modifications. Thus, Jurkat cells were incubated in glucose or galactose containing media with or without lithium treatment. We found that galactose-fed and lithium treated cells showed better survivability than fasting cells. We also found higher UDP-Hexose and glycogen levels in these cells compared to fasting cells. On the other hand, the UPR (X-box binding protein 1 mRNA levels) of galactose-fed and lithium treated cells was even greater than in fasting cells. We also found increased amount of proteins that contained N-linked N-acetyl-glucosamine, similar to what was reported in fasting cells by a recent study. Our results demonstrate that lithium treatment of galactose-fed cells can induce stress responses similar to hypoglycemia, however cell survival is still secured by alternative pathways. We propose that clarifying this process might be an important addition toward the better understanding of the molecular mechanisms that regulate ER-associated stress response.

  1. Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

    PubMed Central

    Antonucci, Laura; Fagman, Johan B.; Kim, Ju Youn; Todoric, Jelena; Gukovsky, Ilya; Mackey, Mason; Ellisman, Mark H.; Karin, Michael

    2015-01-01

    Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7Δpan mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7Δpan mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7Δpan mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures. PMID:26512112

  2. Acute Stress Decreases but Chronic Stress Increases Myocardial Sensitivity to Ischemic Injury in Rodents

    PubMed Central

    Eisenmann, Eric D.; Rorabaugh, Boyd R.; Zoladz, Phillip R.

    2016-01-01

    Cardiovascular disease (CVD) is the largest cause of mortality worldwide, and stress is a significant contributor to the development of CVD. The relationship between acute and chronic stress and CVD is well evidenced. Acute stress can lead to arrhythmias and ischemic injury. However, recent evidence in rodent models suggests that acute stress can decrease sensitivity to myocardial ischemia–reperfusion injury (IRI). Conversely, chronic stress is arrhythmogenic and increases sensitivity to myocardial IRI. Few studies have examined the impact of validated animal models of stress-related psychological disorders on the ischemic heart. This review examines the work that has been completed using rat models to study the effects of stress on myocardial sensitivity to ischemic injury. Utilization of animal models of stress-related psychological disorders is critical in the prevention and treatment of cardiovascular disorders in patients experiencing stress-related psychiatric conditions. PMID:27199778

  3. Pachymic Acid Inhibits Growth and Induces Apoptosis of Pancreatic Cancer In Vitro and In Vivo by Targeting ER Stress

    PubMed Central

    Cheng, Shujie; Swanson, Kristen; Eliaz, Isaac; McClintick, Jeanette N.; Sandusky, George E.; Sliva, Daniel

    2015-01-01

    Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos. In this paper, we investigated the anticancer effect of PA on human chemotherapy resistant pancreatic cancer. PA triggered apoptosis in gemcitabine-resistant pancreatic cancer cells PANC-1 and MIA PaCa-2. Comparative gene expression array analysis demonstrated that endoplasmic reticulum (ER) stress was induced by PA through activation of heat shock response and unfolded protein response related genes. Induced ER stress was confirmed by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and phospho-eIF2α. Moreover, ER stress inhibitor tauroursodeoxycholic acid (TUDCA) blocked PA induced apoptosis. In addition, 25 mg kg-1 of PA significantly suppressed MIA PaCa-2 tumor growth in vivo without toxicity, which correlated with induction of apoptosis and expression of ER stress related proteins in tumor tissues. Taken together, growth inhibition and induction of apoptosis by PA in gemcitabine-resistant pancreatic cancer cells were associated with ER stress activation both in vitro and in vivo. PA may be potentially exploited for the use in treatment of chemotherapy resistant pancreatic cancer. PMID:25915041

  4. Irbesartan ameliorates diabetic cardiomyopathy by regulating protein kinase D and ER stress activation in a type 2 diabetes rat model.

    PubMed

    Liu, Xiangjuan; Xu, Qun; Wang, Xiaomeng; Zhao, Zhuo; Zhang, Liping; Zhong, Ling; Li, Li; Kang, Weiqiang; Zhang, Yun; Ge, Zhiming

    2015-03-01

    Recent studies demonstrate an important role of protein kinase D (PKD) in the cardiovascular system. However, the potential role of PKD in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. Irbesartan has beneficial effects against diabetes-induced heart damage, while the mechanisms were still poorly understood. Our present study was designed to investigate the effects of irbesartan in DCM and whether the cardioprotective effects of irbesartan were mediated by PKD and endoplasmic reticulum (ER) stress. We induced the type 2 diabetic rat model by high fat diet and low dose streptozotocin injection. The characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. 8-weeks administration of irbesartan (15, 30 and 45mg/kg/day) was used to evaluate the effect irbesartan in DCM. Diabetic rats revealed severe metabolic abnormalities, left ventricular dysfunction, myocardial fibrosis and apoptosis. PKD and ER stress were excessive activated in the myocardium of diabetic rats. Furthermore, cardiac fibrosis, apoptosis, diastolic dysfunction and ER stress were all significantly related to PKD activation in diabetic rats. Irbesartan treatment attenuated the activation of PKD and ER stress, which paralleled its cardioprotective effects. Our study suggests that irbesartan could ameliorate cardiac remodeling and dysfunction in type 2 diabetes, and these beneficial effects were associated with its ability to suppress the activation of PKD and ER stress.

  5. Involvement of TR3/Nur77 translocation to the endoplasmic reticulum in ER stress-induced apoptosis

    SciTech Connect

    Liang Bin; Song Xuhong; Liu Gefei; Li Rui; Xie Jianping; Xiao Lifeng; Du Mudan; Zhang Qiaoxia; Xu Xiaoyuan; Gan Xueqiong; Huang Dongyang . E-mail: huangdy@stu.edu.cn

    2007-08-01

    Nuclear orphan receptor TR3/Nur77/NGFI-B is a novel apoptotic effector protein that initiates apoptosis largely by translocating from the nucleus to the mitochondria, causing the release of cytochrome c. However, it is possible that TR3 translocates to other organelles. The present study was designed to determine the intracellular localization of TR3 following CD437-induced nucleocytoplasmic translocation and the mechanisms involved in TR3-induced apoptosis. In human neuroblastoma SK-N-SH cells and human esophageal squamous carcinoma EC109 and EC9706 cells, 5 {mu}M CD437 induced translocation of TR3 to the endoplasmic reticulum (ER). This distribution was confirmed by immunofluorescence analysis, subcellular fractionation analysis and coimmunoprecipitation analysis. The translocated TR3 interacted with ER-targeting Bcl-2; initiated an early release of Ca{sup 2+} from ER; resulted in ER stress and induced apoptosis through ER-specific caspase-4 activation, together with induction of mitochondrial stress and subsequent activation of caspase-9. Our results identified a novel distribution of TR3 in the ER and defined two parallel mitochondrial- and ER-based pathways that ultimately result in apoptotic cell death.

  6. Acute and post-traumatic stress disorder after spontaneous abortion.

    PubMed

    Bowles, S V; James, L C; Solursh, D S; Yancey, M K; Epperly, T D; Folen, R A; Masone, M

    2000-03-15

    When a spontaneous abortion is followed by complicated bereavement, the primary care physician may not consider the diagnosis of acute stress disorder or post-traumatic stress disorder. The major difference between these two conditions is that, in acute stress disorder, symptoms such as dissociation, reliving the trauma, avoiding stimuli associated with the trauma and increased arousal are present for at least two days but not longer than four weeks. When the symptoms persist beyond four weeks, the patient may have post-traumatic stress disorder. The symptoms of distress response after spontaneous abortion include psychologic, physical, cognitive and behavioral effects; however, patients with distress response after spontaneous abortion often do not meet the criteria for acute or post-traumatic stress disorder. After spontaneous abortion, as many as 10 percent of women may have acute stress disorder and up to 1 percent may have post-traumatic stress disorder. Critical incident stress debriefing, which may be administered by trained family physicians or mental health practitioners, may help patients who are having a stress disorder after a spontaneous abortion.

  7. Inhibitory Effects of Verrucarin A on Tunicamycin-Induced ER Stress in FaO Rat Liver Cells.

    PubMed

    Bae, Eun Young; Lee, Seung Woong; Seong, Sin; Cho, Wonjun; Ahn, Jong Seog; Cho, Hyun-Sug

    2015-05-19

    Endoplasmic reticulum (ER) stress is linked with development and maintenance of cancer, and serves as a therapeutic target for treatment of cancer. Verrucarin A, isolated from the broth of Fusarium sp. F060190, showed potential inhibitory activity on tunicamycin-induced ER stress in FaO rat liver cells. In addition, the compound decreased tunicamycin-induced GRP78 promoter activity in a dose dependent manner without inducing significant inhibition of luciferase activity and cell growth for 6 and 12 h. Moreover, the compound decreased the expression of GRP78, CHOP, XBP-1, and suppressed XBP-1, and reduced phosphorylation of IRE1α in FaO rat liver cells. This evidence suggests for the first time that verrucarin A inhibited tunicamycin-induced ER stress in FaO rat liver cells.

  8. Feedback regulation on PTEN/AKT pathway by the ER stress kinase PERK mediated by interaction with the Vault complex.

    PubMed

    Zhang, Wei; Neo, Suat Peng; Gunaratne, Jayantha; Poulsen, Anders; Boping, Liu; Ong, Esther Hongqian; Sangthongpitag, Kanda; Pendharkar, Vishal; Hill, Jeffrey; Cohen, Stephen M

    2015-03-01

    The high proliferation rate of cancer cells, together with environmental factors such as hypoxia and nutrient deprivation can cause Endoplasmic Reticulum (ER) stress. The protein kinase PERK is an essential mediator in one of the three ER stress response pathways. Genetic and pharmacological inhibition of PERK has been reported to limit tumor growth in xenograft models. Here we provide evidence that inactive PERK interacts with the nuclear pore-associated Vault complex protein and that this compromises Vault-mediated nuclear transport of PTEN. Pharmacological inhibition of PERK under ER stress results is abnormal sequestration of the Vault complex, leading to increased cytoplasmic PTEN activity and lower AKT activation. As the PI3K/PTEN/AKT pathway is crucial for many aspects of cell growth and survival, this unexpected effect of PERK inhibitors on AKT activity may have implications for their potential use as therapeutic agents.

  9. ER stress suppresses DNA double-strand break repair and sensitizes tumor cells to ionizing radiation by stimulating proteasomal degradation of Rad51.

    PubMed

    Yamamori, Tohru; Meike, Shunsuke; Nagane, Masaki; Yasui, Hironobu; Inanami, Osamu

    2013-10-11

    In this study, we provide evidence that endoplasmic reticulum (ER) stress suppresses DNA double-strand break (DSB) repair and increases radiosensitivity of tumor cells by altering Rad51 levels. We show that the ER stress inducer tunicamycin stimulates selective degradation of Rad51 via the 26S proteasome, impairing DSB repair and enhancing radiosensitivity in human lung cancer A549 cells. We also found that glucose deprivation, which is a physiological inducer of ER stress, triggered similar events. These findings suggest that ER stress caused by the intratumoral environment influences tumor radiosensitivity, and that it has potential as a novel target to improve cancer radiotherapy.

  10. E platinum, a newly synthesized platinum compound, induces apoptosis through ROS-triggered ER stress in gastric carcinoma cells.

    PubMed

    Wang, Xiaoping; Guo, Qinglong; Tao, Lei; Zhao, Li; Chen, Yan; An, Teng; Chen, Zhen; Fu, Rong

    2017-01-01

    Gastric cancer (GC) is still one of the leading causes of death in cancer-related diseases. In this study, we aimed to investigate the antitumor effect of E Platinum, a newly platinum-based chemotherapeutic agent bearing the basic structure of Oxaliplatin, in a variety of gastric carcinoma cells and the underlying mechanisms. We demonstrated that E Platinum significantly induced apoptosis in gastric cancer cells via mitochondrial apoptotic pathway as a result of increased reactive oxygen species (ROS). We also found that E Platinum enhanced Ca(2+) flux out from the endoplasmic reticulum by increasing the protein expression of IP3R type 1 (IP3R1) and decreasing the expression of ERp44. Dysfunction of Ca(2+) homeostasis in endoplasmic reticulum (ER) leads to accumulation of unfolded proteins and ER stress. Mechanically, E Platinum increased ER stress associated protein expression such as GRP78, p-PERK, p-eIF2α, ATF4, and CHOP. However, knocking down CHOP reversed E Platinum-induced apoptosis by blocking mitochondrial apoptotic pathway. Furthermore, 10 mg/kg of E Platinum significantly suppressed BGC-823 tumor growth in vivo without toxicity, which correlated with induction of apoptosis and expression of ER stress related proteins in tumor tissues. Taken together, E Platinum inhibited tumor growth and induced apoptosis by ROS-mediated ER stress activation both in vitro and in vivo. Our study indicated that E Platinum may be a potential and effective treatment for gastric cancer in clinical. © 2016 Wiley Periodicals, Inc.

  11. Acute stress does not affect risky monetary decision-making.

    PubMed

    Sokol-Hessner, Peter; Raio, Candace M; Gottesman, Sarah P; Lackovic, Sandra F; Phelps, Elizabeth A

    2016-12-01

    The ubiquitous and intense nature of stress responses necessitate that we understand how they affect decision-making. Despite a number of studies examining risky decision-making under stress, it is as yet unclear whether and in what way stress alters the underlying processes that shape our choices. This is in part because previous studies have not separated and quantified dissociable valuation and decision-making processes that can affect choices of risky options, including risk attitudes, loss aversion, and choice consistency, among others. Here, in a large, fully-crossed two-day within-subjects design, we examined how acute stress alters risky decision-making. On each day, 120 participants completed either the cold pressor test or a control manipulation with equal probability, followed by a risky decision-making task. Stress responses were assessed with salivary cortisol. We fit an econometric model to choices that dissociated risk attitudes, loss aversion, and choice consistency using hierarchical Bayesian techniques to both pool data and allow heterogeneity in decision-making. Acute stress was found to have no effect on risk attitudes, loss aversion, or choice consistency, though participants did become more loss averse and more consistent on the second day relative to the first. In the context of an inconsistent previous literature on risk and acute stress, our findings provide strong and specific evidence that acute stress does not affect risk attitudes, loss aversion, or consistency in risky monetary decision-making.

  12. Drug Synergism of Proteasome Inhibitors and Mitotane by Complementary Activation of ER Stress in Adrenocortical Carcinoma Cells.

    PubMed

    Kroiss, Matthias; Sbiera, Silviu; Kendl, Sabine; Kurlbaum, Max; Fassnacht, Martin

    2016-12-01

    Mitotane is the only drug approved for treatment of the orphan disease adrenocortical carcinoma (ACC) and was recently shown to be the first clinically used drug acting through endoplasmic reticulum (ER)-stress induced by toxic lipids. Since mitotane has limited clinical activity as monotherapy, we here study the potential of activating ER-stress through alternative pathways. The single reliable NCI-H295 cell culture model for ACC was used to study the impact MG132, bortezomib (BTZ) and carfilzomib (CFZ) on mRNA and protein expression of ER-stress markers, cell viability and steroid hormone secretion. We found all proteasome inhibitors alone to trigger expression of mRNA (spliced X-box protein 1, XBP1) and protein markers indicative of the inositol-requiring enzyme 1 (IRE1) dependent pathway of ER-stress but not phosphorylation of eukaryotic initiation factor 2α (eIF2α), a marker of the PRKR-like endoplasmic reticulum kinase (PERK)-dependent pathway. Whereas mitotane alone activated both pathways, combination of BTZ and CFZ with low-dose mitotane blocked mitotane-induced eIF2α phosphorylation but increased XBP1-mRNA splicing indicating that proteasome inhibitors can commit signalling towards a single ER-stress pathway in ACC cells. By applying the median effect model of drug combinations using cell viability as a read out, we determined significant drug synergism between mitotane and both BTZ and CFZ. In conclusion, combination of mitotane with activators of ER-stress through the unfolded protein response is synergistic in an ACC cell culture model. Since proteasome inhibitors are readily available clinically, they are attractive candidates to study for ACC treatment in clinical trials in combination with mitotane.

  13. CCN1/CYR61 overexpression in hepatic stellate cells induces ER stress-related apoptosis.

    PubMed

    Borkham-Kamphorst, Erawan; Steffen, Bettina T; Van de Leur, Eddy; Haas, Ute; Tihaa, Lidia; Friedman, Scott L; Weiskirchen, Ralf

    2016-01-01

    CCN1/CYR61 is a matricellular protein of the CCN family, comprising six secreted proteins specifically associated with the extracellular matrix (ECM). CCN1 acts as an enhancer of the cutaneous wound healing process by preventing hypertrophic scar formation through induction of myofibroblast senescence. In liver fibrosis, the senescent cells are primarily derived from activated hepatic stellate cells (HSC) that initially proliferate in response to liver damage and are the major source of ECM. We investigate here the possible use of CCN1 as a senescence inducer to attenuate liver fibrogenesis by means of adenoviral gene transfer in primary HSC, myofibroblasts (MFB) and immortalized HSC lines (i.e. LX-2, CFSC-2G). Infection with Ad5-CMV-CCN1 induced large amounts of CCN1 protein in all these cells, resulting in an overload of the endoplasmic reticulum (ER) and in a compensatory unfolded protein response (UPR). The UPR resulted in upregulation of ER chaperones including BIP/Grp78, Grp94 and led to an activation of IRE1α as evidenced by spliced XBP1 mRNA with IRE1α-induced JNK phosphorylation. The UPR arm PERK and eIF2a was phosphorylated, combined with significant CHOP upregulation. Ad5-CMV-CCN1 induced HSC apoptosis that was evident by proteolytic cleavage of caspase-12, caspase-9 and the executor caspase-3 and positive TUNEL stain. Remarkably, Ad5-CMV-CCN1 effectively reduced collagen type I mRNA expression and protein. We conclude that the matricellular protein CCN1 gene transfer induces HSC apoptosis through ER stress and UPR.

  14. ER stress upregulated PGE2/IFNγ-induced IL-6 expression and down-regulated iNOS expression in glial cells

    NASA Astrophysics Data System (ADS)

    Hosoi, Toru; Honda, Miya; Oba, Tatsuya; Ozawa, Koichiro

    2013-12-01

    The disruption of endoplasmic reticulum (ER) function can lead to neurodegenerative disorders, in which inflammation has also been implicated. We investigated the possible correlation between ER stress and immune function using glial cells. We demonstrated that ER stress synergistically enhanced prostaglandin (PG) E2 + interferon (IFN) γ-induced interleukin (IL)-6 production. This effect was mediated through cAMP. Immune-activated glial cells produced inducible nitric oxide synthase (iNOS). Interestingly, ER stress inhibited PGE2 + IFNγ-induced iNOS expression. Similar results were obtained when cells were treated with dbcAMP + IFNγ. Thus, cAMP has a dual effect on immune reactions; cAMP up-regulated IL-6 expression, but down-regulated iNOS expression under ER stress. Therefore, our results suggest a link between ER stress and immune reactions in neurodegenerative diseases.

  15. A review of acute stress disorder in DSM-5.

    PubMed

    Bryant, Richard A; Friedman, Matthew J; Spiegel, David; Ursano, Robert; Strain, James

    2011-09-01

    Acute stress disorder (ASD) was introduced into DSM-IV to describe acute stress reactions (ASRs) that occur in the initial month after exposure to a traumatic event and before the possibility of diagnosing posttraumatic stress disorder (PTSD), and to identify trauma survivors in the acute phase who are high risk for PTSD. This review considers ASD in relation to other diagnostic approaches to acute stress responses, critiques the evidence of the predictive power of ASD, and discusses ASD in relation to Adjustment Disorder. The evidence suggests that ASD does not adequately identify most people who develop PTSD. This review presents a number of options and preliminary considerations to be considered for DSM-5. It is proposed that ASD be limited to describing severe ASRs (that are not necessarily precursors of PTSD). The evidence suggests that the current emphasis on dissociation may be overly restrictive and does not recognize the heterogeneity of early posttraumatic stress responses. It is proposed that ASD may be better conceptualized as the severity of acute stress responses that does not require specific clusters to be present.

  16. Biogenic amines and acute thermal stress in the rat

    NASA Technical Reports Server (NTRS)

    Williams, B. A.; Moberg, G. P.

    1975-01-01

    A study is summarized which demonstrates that depletion of the biogenic amines 5-hydroxytryptamine (5-HT) or norepinephrine (NE) alters the normal thermoregulatory responses to acute temperature stress. Specifically, NE depletion caused a significant depression in equilibrium rectal temperature at 22 C and a greater depression in rectal temperature than controls in response to cold (6 C) stress; NE depletion also resulted in a significantly higher rectal temperature response to acute heat (38 C) stress. Depletion of 5-HT had less severe effects. It remains unclear whether the primary site of action of these agents is central or peripheral.

  17. Different effects of tianeptine pretreatment in rats exposed to acute stress and repeated severe stress.

    PubMed

    Kasar, M; Mengi, M; Yildirim, E A; Yurdakos, E

    2009-04-01

    In this study we aim to discuss the relationship between stress and learning and emotionality in an experimental model using two different stress conditions: acute stress (single restraint stress for 20 min) and repeated severe stress (6-h daily restraint for 21 days). We studied the effects of tianeptine, which has been suggested to have anxiolytic and cognition-enhancing effects under stressful conditions. After acute stress, the increase in the duration of immobility (F = 5.753 and 3.664) in the open field and holeboard tests and the decrease in rearing (F = 3.891) in the holeboard test were significant when compared to controls (P < 0.05). Results for repeated severe stress showed that in both the open field and holeboard tests the decrease in rearing (F = 4.494 and 4.530, respectively), increase in the duration of immobility (F = 6.069 and 4.742, respectively) and decrease in head dips (F = 4.938) in the holeboard test were statistically significant (P < 0.05). The group pretreated with tianeptine showed no significant difference from controls for either acute or repeated severe stress conditions. In the Morris water maze test, acute stress led to a prolongation of average escape latency, which indicated a spatial learning deficit. Treatment with tianeptine prior to acute stress prevented this spatial deficit. Repeated severe stress also led to spatial learning deficits in rats, but this deficit was not prevented by treatment with tianeptine. Our study demonstrates that pretreatment with tianeptine had different effects on stress-induced spatial learning deficits under acute and repeated stress conditions, while the effects on emotionality and anxiety-like behavior were similar. The mechanisms implicated in stress-induced emotional and memory deficits will be discussed.

  18. Immune modulation by ER stress and inflammation in the tumor microenvironment.

    PubMed

    Rodvold, Jeffrey J; Mahadevan, Navin R; Zanetti, Maurizio

    2016-09-28

    It is now increasingly evident that the immune system represents a barrier to tumor emergence, growth, and recurrence. Although this idea was originally proposed almost 50 years ago as the "immune surveillance hypothesis", it is commonly recognized that, with few rare exceptions, tumor cells always prevail. Thus, one of the central unsolved paradoxes of tumor immunology is how a tumor escapes immune control, which is reflected in the lack of effective autochthonous or vaccine-induced anti-tumor T cell responses. In this review, we discuss the role of the endoplasmic reticulum (ER) stress response/unfolded protein response (UPR) in the immunomodulation of myeloid cells and T cells. Specifically, we will discuss how the tumor cell UPR polarizes myeloid cells in a cell-extrinsic manner, and how in turn, thus polarized myeloid cells negatively affect T cell activation and clonal expansion.

  19. TUSC3 Loss Alters the ER Stress Response and Accelerates Prostate Cancer Growth in vivo

    NASA Astrophysics Data System (ADS)

    Horak, Peter; Tomasich, Erwin; Vaňhara, Petr; Kratochvílová, Kateřina; Anees, Mariam; Marhold, Maximilian; Lemberger, Christof E.; Gerschpacher, Marion; Horvat, Reinhard; Sibilia, Maria; Pils, Dietmar; Krainer, Michael

    2014-01-01

    Prostate cancer is the most prevalent cancer in males in developed countries. Tumor suppressor candidate 3 (TUSC3) has been identified as a putative tumor suppressor gene in prostate cancer, though its function has not been characterized. TUSC3 shares homologies with the yeast oligosaccharyltransferase (OST) complex subunit Ost3p, suggesting a role in protein glycosylation. We provide evidence that TUSC3 is part of the OST complex and affects N-linked glycosylation in mammalian cells. Loss of TUSC3 expression in DU145 and PC3 prostate cancer cell lines leads to increased proliferation, migration and invasion as well as accelerated xenograft growth in a PTEN negative background. TUSC3 downregulation also affects endoplasmic reticulum (ER) structure and stress response, which results in increased Akt signaling. Together, our findings provide first mechanistic insight in TUSC3 function in prostate carcinogenesis in general and N-glycosylation in particular.

  20. TUSC3 Loss Alters the ER Stress Response and Accelerates Prostate Cancer Growth in vivo

    PubMed Central

    Horak, Peter; Tomasich, Erwin; Vaňhara, Petr; Kratochvílová, Kateřina; Anees, Mariam; Marhold, Maximilian; Lemberger, Christof E.; Gerschpacher, Marion; Horvat, Reinhard; Sibilia, Maria; Pils, Dietmar; Krainer, Michael

    2014-01-01

    Prostate cancer is the most prevalent cancer in males in developed countries. Tumor suppressor candidate 3 (TUSC3) has been identified as a putative tumor suppressor gene in prostate cancer, though its function has not been characterized. TUSC3 shares homologies with the yeast oligosaccharyltransferase (OST) complex subunit Ost3p, suggesting a role in protein glycosylation. We provide evidence that TUSC3 is part of the OST complex and affects N-linked glycosylation in mammalian cells. Loss of TUSC3 expression in DU145 and PC3 prostate cancer cell lines leads to increased proliferation, migration and invasion as well as accelerated xenograft growth in a PTEN negative background. TUSC3 downregulation also affects endoplasmic reticulum (ER) structure and stress response, which results in increased Akt signaling. Together, our findings provide first mechanistic insight in TUSC3 function in prostate carcinogenesis in general and N-glycosylation in particular. PMID:24435307

  1. PERK-mediated Autophagy in Osteosarcoma Cells Resists ER Stress-induced Cell Apoptosis

    PubMed Central

    Ji, Guang-rong; Yu, Nai-chun; Xue, Xiang; Li, Zong-guang

    2015-01-01

    Osteosarcoma is a bone cancer that develops commonly in children and adolescents. However, osteosarcoma treatments often fail by the development of chemoresistance to apoptosis, and the molecular mechanisms remain unclear. In this study, we propose that autophagy is responsible for osteosarcomatous resistance to apoptosis. We implicate PERK-mediated autophagy as a significant contributor to apoptosis resistance due to ER stress in osteosarcoma cells. By immunostainings and western blots, we identified that PERK activated osteosarcomatous autophagy via inhibiting mTORC1 pathway, thereby preventing cell apoptosis. While using RNAi, we knocked down PERK and found that autophagy was suppressed, result in osteosarcomatous apoptosis. Our results identify a novel role of PERK-mediated autophagy as a significant mechanism for osteosarcoma cell survival. These results will help to understand the mechanism of chemoresistance in osteosarcoma cells, and indicate a novel target for improving osteosarcoma therapy. PMID:26078722

  2. PERK-mediated Autophagy in Osteosarcoma Cells Resists ER Stress-induced Cell Apoptosis.

    PubMed

    Ji, Guang-rong; Yu, Nai-chun; Xue, Xiang; Li, Zong-guang

    2015-01-01

    Osteosarcoma is a bone cancer that develops commonly in children and adolescents. However, osteosarcoma treatments often fail by the development of chemoresistance to apoptosis, and the molecular mechanisms remain unclear. In this study, we propose that autophagy is responsible for osteosarcomatous resistance to apoptosis. We implicate PERK-mediated autophagy as a significant contributor to apoptosis resistance due to ER stress in osteosarcoma cells. By immunostainings and western blots, we identified that PERK activated osteosarcomatous autophagy via inhibiting mTORC1 pathway, thereby preventing cell apoptosis. While using RNAi, we knocked down PERK and found that autophagy was suppressed, result in osteosarcomatous apoptosis. Our results identify a novel role of PERK-mediated autophagy as a significant mechanism for osteosarcoma cell survival. These results will help to understand the mechanism of chemoresistance in osteosarcoma cells, and indicate a novel target for improving osteosarcoma therapy.

  3. TRAM1 protect HepG2 cells from palmitate induced insulin resistance through ER stress-JNK pathway.

    PubMed

    Tang, Zhuqi; Zhang, Wanlu; Wan, Chunhua; Xu, Guangfei; Nie, Xiaoke; Zhu, Xiaohui; Xia, Nana; Zhao, Yun; Wang, Suxin; Cui, Shiwei; Wang, Cuifang

    2015-02-20

    Excess serum free fatty acids (FFAs) are fundamental to the pathogenesis of insulin resistance. Chronic endoplasmic reticulum (ER) stress is a major contributor to obesity-induced insulin resistance in the liver. With high-fat feeding (HFD), FFAs can activate chronic endoplasmic reticulum (ER) stress in target tissues, initiating negative crosstalk between FFAs and insulin signaling. However, the molecular link between insulin resistance and ER stress remains to be identified. We here reported that translocating chain-associated membrane protein 1 (TRAM1), an ER-resident membrane protein, was involved in the onset of insulin resistance in hepatocytes. TRAM1 was significantly up-regulated in insulin-resistant liver tissues and palmitate (PA)-treated HepG2 cells. In addition, we showed that depletion of TRAM1 led to hyperactivation of CHOP and GRP78, and the activation of downstream JNK pathway. Given the fact that the activation of ER stress played a facilitating role in insulin resistance, the phosphorylation of Akt and GSK-3β was also analyzed. We found that depletion of TRAM1 markedly attenuated the phosphorylation of Akt and GSK-3β in the cells. Moreover, application with JNK inhibitor SP600125 reversed the effect of TRAM1 interference on Akt phosphorylation. The accumulation of lipid droplets and expression of two key gluconeogenic enzymes, PEPCK and G6Pase, were also determined and found to display a similar tendency with the phosphorylation of Akt. Glucose uptake assay indicated that knocking down TRAM1 augmented PA-induced down-regulation of glucose uptake, and inhibition of JNK using SP600125 could block the effect of TRAM1 on glucose uptake. These data implicated that TRAM1 might protect HepG2 cells against PA-induced insulin resistance through alleviating ER stress.

  4. TorsinA rescues ER-associated stress and locomotive defects in C. elegans models of ALS.

    PubMed

    Thompson, Michelle L; Chen, Pan; Yan, Xiaohui; Kim, Hanna; Borom, Akeem R; Roberts, Nathan B; Caldwell, Kim A; Caldwell, Guy A

    2014-02-01

    Molecular mechanisms underlying neurodegenerative diseases converge at the interface of pathways impacting cellular stress, protein homeostasis and aging. Targeting the intrinsic capacities of neuroprotective proteins to restore neuronal function and/or attenuate degeneration represents a potential means toward therapeutic intervention. The product of the human DYT1 gene, torsinA, is a member of the functionally diverse AAA+ family of proteins and exhibits robust molecular-chaperone-like activity, both in vitro and in vivo. Although mutations in DYT1 are associated with a rare form of heritable generalized dystonia, the native function of torsinA seems to be cytoprotective in maintaining the cellular threshold to endoplasmic reticulum (ER) stress. Here we explore the potential for torsinA to serve as a buffer to attenuate the cellular consequences of misfolded-protein stress as it pertains to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). The selective vulnerability of motor neurons to degeneration in ALS mouse models harboring mutations in superoxide dismutase (SOD1) has been found to correlate with regional-specific ER stress in brains. Using Caenorhabditis elegans as a system to model ER stress, we generated transgenic nematodes overexpressing either wild-type or mutant human SOD1 to evaluate their relative impact on ER stress induction in vivo. These studies revealed a mutant-SOD1-specific increase in ER stress that was further exacerbated by changes in temperature, all of which was robustly attenuated by co-expression of torsinA. Moreover, through complementary behavioral analysis, torsinA was able to restore normal neuronal function in mutant G85R SOD1 animals. Furthermore, torsinA targeted mutant SOD1 for degradation via the proteasome, representing mechanistic insight on the activity that torsinA has on aggregate-prone proteins. These results expand our understanding of proteostatic mechanisms influencing neuronal dysfunction in ALS

  5. TorsinA rescues ER-associated stress and locomotive defects in C. elegans models of ALS

    PubMed Central

    Thompson, Michelle L.; Chen, Pan; Yan, Xiaohui; Kim, Hanna; Borom, Akeem R.; Roberts, Nathan B.; Caldwell, Kim A.; Caldwell, Guy A.

    2014-01-01

    ABSTRACT Molecular mechanisms underlying neurodegenerative diseases converge at the interface of pathways impacting cellular stress, protein homeostasis and aging. Targeting the intrinsic capacities of neuroprotective proteins to restore neuronal function and/or attenuate degeneration represents a potential means toward therapeutic intervention. The product of the human DYT1 gene, torsinA, is a member of the functionally diverse AAA+ family of proteins and exhibits robust molecular-chaperone-like activity, both in vitro and in vivo. Although mutations in DYT1 are associated with a rare form of heritable generalized dystonia, the native function of torsinA seems to be cytoprotective in maintaining the cellular threshold to endoplasmic reticulum (ER) stress. Here we explore the potential for torsinA to serve as a buffer to attenuate the cellular consequences of misfolded-protein stress as it pertains to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). The selective vulnerability of motor neurons to degeneration in ALS mouse models harboring mutations in superoxide dismutase (SOD1) has been found to correlate with regional-specific ER stress in brains. Using Caenorhabditis elegans as a system to model ER stress, we generated transgenic nematodes overexpressing either wild-type or mutant human SOD1 to evaluate their relative impact on ER stress induction in vivo. These studies revealed a mutant-SOD1-specific increase in ER stress that was further exacerbated by changes in temperature, all of which was robustly attenuated by co-expression of torsinA. Moreover, through complementary behavioral analysis, torsinA was able to restore normal neuronal function in mutant G85R SOD1 animals. Furthermore, torsinA targeted mutant SOD1 for degradation via the proteasome, representing mechanistic insight on the activity that torsinA has on aggregate-prone proteins. These results expand our understanding of proteostatic mechanisms influencing neuronal dysfunction in

  6. Cocaine-mediated microglial activation involves the ER stress-autophagy axis

    PubMed Central

    Guo, Ming-Lei; Liao, Ke; Periyasamy, Palsamy; Yang, Lu; Cai, Yu; Callen, Shannon E; Buch, Shilpa

    2015-01-01

    Cocaine abuse leads to neuroinflammation, which, in turn, contributes to the pathogenesis of neurodegeneration associated with advanced HIV-1 infection. Autophagy plays important roles in both innate and adaptive immune responses. However, the possible functional link between cocaine and autophagy has not been explored before. Herein, we demonstrate that cocaine exposure induced autophagy in both BV-2 and primary rat microglial cells as demonstrated by a dose- and time-dependent induction of autophagy-signature proteins such as BECN1/Beclin 1, ATG5, and MAP1LC3B. These findings were validated wherein cocaine treatment of BV-2 cells resulted in increased formation of puncta in cells expressing either endogenous MAP1LC3B or overexpressing GFP-MAP1LC3B. Specificity of cocaine-induced autophagy was confirmed by treating cells with inhibitors of autophagy (3-MA and wortmannin). Intriguingly, cocaine-mediated induction of autophagy involved upstream activation of 2 ER stress pathways (EIF2AK3- and ERN1-dependent), as evidenced by the ability of the ER stress inhibitor salubrinal to ameliorate cocaine-induced autophagy. In vivo validation of these findings demonstrated increased expression of BECN1, ATG5, and MAP1LC3B-II proteins in cocaine-treated mouse brains compared to untreated animals. Increased autophagy contributes to cocaine-mediated activation of microglia since pretreatment of cells with wortmannin resulted in decreased expression and release of inflammatory factors (TNF, IL1B, IL6, and CCL2) in microglial cells. Taken together, our findings suggest that cocaine exposure results in induction of autophagy that is closely linked with neuroinflammation. Targeting autophagic proteins could thus be considered as a therapeutic strategy for the treatment of cocaine-related neuroinflammation diseases. PMID:26043790

  7. Cocaine-mediated microglial activation involves the ER stress-autophagy axis.

    PubMed

    Guo, Ming-Lei; Liao, Ke; Periyasamy, Palsamy; Yang, Lu; Cai, Yu; Callen, Shannon E; Buch, Shilpa

    2015-01-01

    Cocaine abuse leads to neuroinflammation, which, in turn, contributes to the pathogenesis of neurodegeneration associated with advanced HIV-1 infection. Autophagy plays important roles in both innate and adaptive immune responses. However, the possible functional link between cocaine and autophagy has not been explored before. Herein, we demonstrate that cocaine exposure induced autophagy in both BV-2 and primary rat microglial cells as demonstrated by a dose- and time-dependent induction of autophagy-signature proteins such as BECN1/Beclin 1, ATG5, and MAP1LC3B. These findings were validated wherein cocaine treatment of BV-2 cells resulted in increased formation of puncta in cells expressing either endogenous MAP1LC3B or overexpressing GFP-MAP1LC3B. Specificity of cocaine-induced autophagy was confirmed by treating cells with inhibitors of autophagy (3-MA and wortmannin). Intriguingly, cocaine-mediated induction of autophagy involved upstream activation of 2 ER stress pathways (EIF2AK3- and ERN1-dependent), as evidenced by the ability of the ER stress inhibitor salubrinal to ameliorate cocaine-induced autophagy. In vivo validation of these findings demonstrated increased expression of BECN1, ATG5, and MAP1LC3B-II proteins in cocaine-treated mouse brains compared to untreated animals. Increased autophagy contributes to cocaine-mediated activation of microglia since pretreatment of cells with wortmannin resulted in decreased expression and release of inflammatory factors (TNF, IL1B, IL6, and CCL2) in microglial cells. Taken together, our findings suggest that cocaine exposure results in induction of autophagy that is closely linked with neuroinflammation. Targeting autophagic proteins could thus be considered as a therapeutic strategy for the treatment of cocaine-related neuroinflammation diseases.

  8. Recombinant Newcastle disease virus (rL-RVG) triggers autophagy and apoptosis in gastric carcinoma cells by inducing ER stress

    PubMed Central

    Bu, Xuefeng; Zhao, Yinghai; Zhang, Zhijian; Wang, Mubin; Li, Mi; Yan, Yulan

    2016-01-01

    We have reported that the recombinant avirulent Newcastle disease virus (NDV) LaSota strain expressing the rabies virus glycoprotein (rL-RVG) could induce autophagy and apoptosis in gastric carcinoma cells. In the present study, we explored the upstream regulators, endoplasmic reticulum (ER) stress that induce autophagy and apoptosis and the relationships among them. For this purpose, SGC-7901 and HGC cells were infected with rL-RVG. NDV LaSota strain and phosphate-buffered saline (PBS) were treated as the control groups. Western blotting and immunofluorescence microscopy were used to detect the expression of the ER stress-related proteins glucose-regulated protein 78 (GRP78) and the transcription factor GADD153 (CHOP), among others. The expression of beclin-1 and the conversion of light chain (LC) 3-I were used to determine the occurrence of autophagy, and flow cytometry (FCM) and western blotting were used to examine apoptosis-related protein expression. Transmission electron microscopy was also performed to monitor the ultrastructure of the cells. Moreover, small interfering (si) RNA was used to knock down CHOP expression. rL-RVG treatment increased the expression of ER stress-related proteins, such as GRP78, CHOP, activating transcriptional factor 6 (ATF6), X-box-binding protein 1 (XBP-1), and phosphorylated eukaryotic initiation factor 2 (p-eIF2α), in a time- and concentration-dependent manner, and knockdown of CHOP reduced LC3-II conversion and beclin-1 expression. When ER stress was inhibited with 4-PBA, the expression of both autophagy-related proteins and apoptosis-related proteins markedly decreased. Interestingly, inhibition of autophagy with 3-methyladenine (3MA) decreased not only apoptosis-related protein expression but also ER stress-related protein expression. Moreover, we found that downregulation of the c-Jun N-terminal kinase (JNK) pathway by SP600125 reduced LC3-II conversion, beclin-1 expression and caspase-3 activation. Collectively, the

  9. Experimental reconstitution of chronic ER stress in the liver reveals feedback suppression of BiP mRNA expression

    PubMed Central

    Gomez, Javier A; Rutkowski, D Thomas

    2016-01-01

    Endoplasmic reticulum (ER) stress is implicated in many chronic diseases, but very little is known about how the unfolded protein response (UPR) responds to persistent ER stress in vivo. Here, we experimentally reconstituted chronic ER stress in the mouse liver, using repeated injection of a low dose of the ER stressor tunicamycin. Paradoxically, this treatment led to feedback-mediated suppression of a select group of mRNAs, including those encoding the ER chaperones BiP and GRP94. This suppression was due to both silencing of the ATF6α pathway of UPR-dependent transcription and enhancement of mRNA degradation, possibly via regulated IRE1-dependent decay (RIDD). The suppression of mRNA encoding BiP was phenocopied by ectopic overexpression of BiP protein, and was also observed in obese mice. Our findings suggest that persistent cycles of UPR activation and deactivation create an altered, quasi-stable setpoint for UPR-dependent transcriptional regulation—an outcome that could be relevant to conditions such as metabolic syndrome. DOI: http://dx.doi.org/10.7554/eLife.20390.001 PMID:27938665

  10. Acute stress impairs set-shifting but not reversal learning.

    PubMed

    Butts, K A; Floresco, S B; Phillips, A G

    2013-09-01

    The ability to update and modify previously learned behavioral responses in a changing environment is essential for successful utilization of promising opportunities and for coping with adverse events. Valid models of cognitive flexibility that contribute to behavioral flexibility include set-shifting and reversal learning. One immediate effect of acute stress is the selective impairment of performance on higher-order cognitive control tasks mediated by the medial prefrontal cortex (mPFC) but not the hippocampus. Previous studies show that the mPFC is required for set-shifting but not for reversal learning, therefore the aim of the present experiment is to assess whether exposure to acute stress (15 min of mild tail-pinch stress) given immediately before testing on either a set-shifting or reversal learning tasks would impair performance selectively on the set-shifting task. An automated operant chamber-based task, confirmed that exposure to acute stress significantly disrupts set-shifting but has no effect on reversal learning. Rats exposed to an acute stressor require significantly more trials to reach criterion and make significantly more perseverative errors. Thus, these data reveal that an immediate effect of acute stress is to impair mPFC-dependent cognition selectively by disrupting the ability to inhibit the use of a previously relevant cognitive strategy.

  11. Acute stress selectively impairs learning to act.

    PubMed

    de Berker, Archy O; Tirole, Margot; Rutledge, Robb B; Cross, Gemma F; Dolan, Raymond J; Bestmann, Sven

    2016-07-20

    Stress interferes with instrumental learning. However, choice is also influenced by non-instrumental factors, most strikingly by biases arising from Pavlovian associations that facilitate action in pursuit of rewards and inaction in the face of punishment. Whether stress impacts on instrumental learning via these Pavlovian associations is unknown. Here, in a task where valence (reward or punishment) and action (go or no-go) were orthogonalised, we asked whether the impact of stress on learning was action or valence specific. We exposed 60 human participants either to stress (socially-evaluated cold pressor test) or a control condition (room temperature water). We contrasted two hypotheses: that stress would lead to a non-selective increase in the expression of Pavlovian biases; or that stress, as an aversive state, might specifically impact action production due to the Pavlovian linkage between inaction and aversive states. We found support for the second of these hypotheses. Stress specifically impaired learning to produce an action, irrespective of the valence of the outcome, an effect consistent with a Pavlovian linkage between punishment and inaction. This deficit in action-learning was also reflected in pupillary responses; stressed individuals showed attenuated pupillary responses to action, hinting at a noradrenergic contribution to impaired action-learning under stress.

  12. Acute stress selectively impairs learning to act

    PubMed Central

    de Berker, Archy O.; Tirole, Margot; Rutledge, Robb B.; Cross, Gemma F.; Dolan, Raymond J.; Bestmann, Sven

    2016-01-01

    Stress interferes with instrumental learning. However, choice is also influenced by non-instrumental factors, most strikingly by biases arising from Pavlovian associations that facilitate action in pursuit of rewards and inaction in the face of punishment. Whether stress impacts on instrumental learning via these Pavlovian associations is unknown. Here, in a task where valence (reward or punishment) and action (go or no-go) were orthogonalised, we asked whether the impact of stress on learning was action or valence specific. We exposed 60 human participants either to stress (socially-evaluated cold pressor test) or a control condition (room temperature water). We contrasted two hypotheses: that stress would lead to a non-selective increase in the expression of Pavlovian biases; or that stress, as an aversive state, might specifically impact action production due to the Pavlovian linkage between inaction and aversive states. We found support for the second of these hypotheses. Stress specifically impaired learning to produce an action, irrespective of the valence of the outcome, an effect consistent with a Pavlovian linkage between punishment and inaction. This deficit in action-learning was also reflected in pupillary responses; stressed individuals showed attenuated pupillary responses to action, hinting at a noradrenergic contribution to impaired action-learning under stress. PMID:27436299

  13. Chemical Chaperones Reduce ER Stress and Restore Glucose Homeostasis in a Mouse Model of Type 2 Diabetes

    NASA Astrophysics Data System (ADS)

    Özcan, Umut; Yilmaz, Erkan; Özcan, Lale; Furuhashi, Masato; Vaillancourt, Eric; Smith, Ross O.; Görgün, Cem Z.; Hotamisligil, Gökhan S.

    2006-08-01

    Endoplasmic reticulum (ER) stress is a key link between obesity, insulin resistance, and type 2 diabetes. Here, we provide evidence that this mechanistic link can be exploited for therapeutic purposes with orally active chemical chaperones. 4-Phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviated ER stress in cells and whole animals. Treatment of obese and diabetic mice with these compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissues. Our results demonstrate that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.

  14. Acute stress affects risk taking but not ambiguity aversion.

    PubMed

    Buckert, Magdalena; Schwieren, Christiane; Kudielka, Brigitte M; Fiebach, Christian J

    2014-01-01

    Economic decisions are often made in stressful situations (e.g., at the trading floor), but the effects of stress on economic decision making have not been systematically investigated so far. The present study examines how acute stress influences economic decision making under uncertainty (risk and ambiguity) using financially incentivized lotteries. We varied the domain of decision making as well as the expected value of the risky prospect. Importantly, no feedback was provided to investigate risk taking and ambiguity aversion independent from learning processes. In a sample of 75 healthy young participants, 55 of whom underwent a stress induction protocol (Trier Social Stress Test for Groups), we observed more risk seeking for gains. This effect was restricted to a subgroup of participants that showed a robust cortisol response to acute stress (n = 26). Gambling under ambiguity, in contrast to gambling under risk, was not influenced by the cortisol response to stress. These results show that acute psychosocial stress affects economic decision making under risk, independent of learning processes. Our results further point to the importance of cortisol as a mediator of this effect.

  15. Acute stress affects risk taking but not ambiguity aversion

    PubMed Central

    Buckert, Magdalena; Schwieren, Christiane; Kudielka, Brigitte M.; Fiebach, Christian J.

    2014-01-01

    Economic decisions are often made in stressful situations (e.g., at the trading floor), but the effects of stress on economic decision making have not been systematically investigated so far. The present study examines how acute stress influences economic decision making under uncertainty (risk and ambiguity) using financially incentivized lotteries. We varied the domain of decision making as well as the expected value of the risky prospect. Importantly, no feedback was provided to investigate risk taking and ambiguity aversion independent from learning processes. In a sample of 75 healthy young participants, 55 of whom underwent a stress induction protocol (Trier Social Stress Test for Groups), we observed more risk seeking for gains. This effect was restricted to a subgroup of participants that showed a robust cortisol response to acute stress (n = 26). Gambling under ambiguity, in contrast to gambling under risk, was not influenced by the cortisol response to stress. These results show that acute psychosocial stress affects economic decision making under risk, independent of learning processes. Our results further point to the importance of cortisol as a mediator of this effect. PMID:24834024

  16. Glucocorticoids Prevent Enterovirus 71 Capsid Protein VP1 Induced Calreticulin Surface Exposure by Alleviating Neuronal ER Stress.

    PubMed

    Hu, Dan-Dan; Mai, Jian-Ning; He, Li-Ya; Li, Pei-Qing; Chen, Wen-Xiong; Yan, Jian-Jiang; Zhu, Wei-Dong; Deng, Li; Wei, Dan; Liu, Di-Hui; Yang, Si-Da; Yao, Zhi-Bin

    2017-02-01

    Severe hand-foot-and-mouth disease (HFMD) caused by Enterovirus 71 (EV71) always accompanies with inflammation and neuronal damage in the central nervous system (CNS). During neuronal injuries, cell surface-exposed calreticulin (Ecto-CRT) is an important mediator for primary phagocytosis of viable neurons by microglia. Our data confirmed that brainstem neurons underwent neuronophagia by glia in EV71-induced death cases of HFMD. EV71 capsid proteins VP1, VP2, VP3, or VP4 did not induce apoptosis of brainstem neurons. Interestingly, we found VP1-activated endoplasmic reticulum (ER) stress and autophagy could promote Ecto-CRT upregulation, but ER stress or autophagy alone was not sufficient to induce CRT exposure. Furthermore, we demonstrated that VP1-induced autophagy activation was mediated by ER stress. Meaningfully, we found dexamethasone treatment could attenuate Ecto-CRT upregulation by alleviating VP1-induced ER stress. Altogether, these findings identify VP1-promoted Ecto-CRT upregulation as a novel mechanism of EV71-induced neuronal cell damage and highlight the potential of the use of glucocorticoids to treat severe HFMD patients with CNS complications.

  17. GSK-3β-dependent downregulation of γ-taxilin and αNAC merge to regulate ER stress responses

    PubMed Central

    Hotokezaka, Y; Katayama, I; van Leyen, K; Nakamura, T

    2015-01-01

    The signaling pathway leading to the endoplasmic reticulum (ER) stress responses has not been fully elucidated. Here we showed that glycogen synthase kinase-3β (GSK-3β)-dependent downregulation of γ-taxilin and nascent polypeptide-associated complex α-subunit (αNAC) mediates hypoxia-induced unfolded protein responses (UPRs) and the subsequent apoptotic and autophagic pathways. The degradation of γ-taxilin or αNAC was sufficient to initiate UPRs in normoxic cells. However, the ER stress signaling pathways initiated by γ-taxilin or αNAC were distinct, triggering different ER stress sensors and activating different downstream pathways. Hypoxia caused GSK-3β-dependent tau hyperphosphorylation and cleavage in neuronal cells, but γ-taxilin ablation induced tau hyperphosphorylation alone and αNAC ablation induced neither changes. Notably, downregulation of γ-taxilin and αNAC occurs in the brain of patients with Alzheimer's disease. These results suggest that GSK-3β-dependent downregulation of γ-taxilin and αNAC, which differently activate the UPRs, merge to regulate hypoxia-induced ER stress responses and provide a new insight into the pathogenesis of neurodegenerative diseases. PMID:25880086

  18. Tyrosol, an olive oil polyphenol, inhibits ER stress-induced apoptosis in pancreatic β-cell through JNK signaling.

    PubMed

    Lee, Hyunjung; Im, Sung Won; Jung, Chang Hwa; Jang, Young Jin; Ha, Tae Youl; Ahn, Jiyun

    2016-01-15

    Dysfunction of pancreatic β-cell is a major determinant for the development of type 2 diabetes. Because of the stimulated insulin secretion in metabolic syndrome, endoplasmic reticulum (ER) stress plays a central mediator for β-cell failure. In this study, we investigated whether an antioxidant phenolic compound, tyrosol protects against β-cell dysfunction associated with ER stress. To address this issue, we exposed pancreatic β cells, NIT-1 to tunicamycin with tyrosol. We found tyrosol diminished tunicamycin-induced cell death in a dose-dependent manner. We also detected tyrosol decreased the expressions of apoptosis-related markers. Exposure to tunicamycin evoked UPR response and co-treatment of tyrosol led to reduction of ER stress. These effects of tyrosol were mediated by the phosphorylation of JNK. Moreover, we confirmed supplement of tyrosol ameliorated β-cell loss induced by high fat feeding. Taken together, our study provides a molecular basis for signaling transduction of protective effect of tyrosol against ER stress-induced β-cell death. Therefore, we suggest tyrosol could be a potential therapeutic candidate for amelioration of type 2 diabetes.

  19. Converging, Synergistic Actions of Multiple Stress Hormones Mediate Enduring Memory Impairments after Acute Simultaneous Stresses.

    PubMed

    Chen, Yuncai; Molet, Jenny; Lauterborn, Julie C; Trieu, Brian H; Bolton, Jessica L; Patterson, Katelin P; Gall, Christine M; Lynch, Gary; Baram, Tallie Z

    2016-11-02

    Stress influences memory, an adaptive process crucial for survival. During stress, hippocampal synapses are bathed in a mixture of stress-released molecules, yet it is unknown whether or how these interact to mediate the effects of stress on memory. Here, we demonstrate novel synergistic actions of corticosterone and corticotropin-releasing hormone (CRH) on synaptic physiology and dendritic spine structure that mediate the profound effects of acute concurrent stresses on memory. Spatial memory in mice was impaired enduringly after acute concurrent stresses resulting from loss of synaptic potentiation associated with disrupted structure of synapse-bearing dendritic spines. Combined application of the stress hormones corticosterone and CRH recapitulated the physiological and structural defects provoked by acute stresses. Mechanistically, corticosterone and CRH, via their cognate receptors, acted synergistically on the spine-actin regulator RhoA, promoting its deactivation and degradation, respectively, and destabilizing spines. Accordingly, blocking the receptors of both hormones, but not each alone, rescued memory. Therefore, the synergistic actions of corticosterone and CRH at hippocampal synapses underlie memory impairments after concurrent and perhaps also single, severe acute stresses, with potential implications to spatial memory dysfunction in, for example, posttraumatic stress disorder.

  20. Computations of uncertainty mediate acute stress responses in humans.

    PubMed

    de Berker, Archy O; Rutledge, Robb B; Mathys, Christoph; Marshall, Louise; Cross, Gemma F; Dolan, Raymond J; Bestmann, Sven

    2016-03-29

    The effects of stress are frequently studied, yet its proximal causes remain unclear. Here we demonstrate that subjective estimates of uncertainty predict the dynamics of subjective and physiological stress responses. Subjects learned a probabilistic mapping between visual stimuli and electric shocks. Salivary cortisol confirmed that our stressor elicited changes in endocrine activity. Using a hierarchical Bayesian learning model, we quantified the relationship between the different forms of subjective task uncertainty and acute stress responses. Subjective stress, pupil diameter and skin conductance all tracked the evolution of irreducible uncertainty. We observed a coupling between emotional and somatic state, with subjective and physiological tuning to uncertainty tightly correlated. Furthermore, the uncertainty tuning of subjective and physiological stress predicted individual task performance, consistent with an adaptive role for stress in learning under uncertain threat. Our finding that stress responses are tuned to environmental uncertainty provides new insight into their generation and likely adaptive function.

  1. Computations of uncertainty mediate acute stress responses in humans

    PubMed Central

    de Berker, Archy O.; Rutledge, Robb B.; Mathys, Christoph; Marshall, Louise; Cross, Gemma F.; Dolan, Raymond J.; Bestmann, Sven

    2016-01-01

    The effects of stress are frequently studied, yet its proximal causes remain unclear. Here we demonstrate that subjective estimates of uncertainty predict the dynamics of subjective and physiological stress responses. Subjects learned a probabilistic mapping between visual stimuli and electric shocks. Salivary cortisol confirmed that our stressor elicited changes in endocrine activity. Using a hierarchical Bayesian learning model, we quantified the relationship between the different forms of subjective task uncertainty and acute stress responses. Subjective stress, pupil diameter and skin conductance all tracked the evolution of irreducible uncertainty. We observed a coupling between emotional and somatic state, with subjective and physiological tuning to uncertainty tightly correlated. Furthermore, the uncertainty tuning of subjective and physiological stress predicted individual task performance, consistent with an adaptive role for stress in learning under uncertain threat. Our finding that stress responses are tuned to environmental uncertainty provides new insight into their generation and likely adaptive function. PMID:27020312

  2. Acute stress impairs cognitive flexibility in men, not women.

    PubMed

    Shields, Grant S; Trainor, Brian C; Lam, Jovian C W; Yonelinas, Andrew P

    2016-09-01

    Psychosocial stress influences cognitive abilities, such as long-term memory retrieval. However, less is known about the effects of stress on cognitive flexibility, which is mediated by different neurobiological circuits and could thus be regulated by different neuroendocrine pathways. In this study, we randomly assigned healthy adults to an acute stress induction or control condition and subsequently assessed participants' cognitive flexibility using an open-source version of the Wisconsin Card Sort task. Drawing on work in rodents, we hypothesized that stress would have stronger impairing effects on cognitive flexibility in men than women. As predicted, we found that stress impaired cognitive flexibility in men but did not significantly affect women. Our results thus indicate that stress exerts sex-specific effects on cognitive flexibility in humans and add to the growing body of research highlighting the need to consider sex differences in effects of stress.

  3. Exposure to acute stress is associated with attenuated sweet taste.

    PubMed

    Al'Absi, Mustafa; Nakajima, Motohiro; Hooker, Stephanie; Wittmers, Larry; Cragin, Tiffany

    2012-01-01

    This study examined the effects of stress on taste perception. Participants (N = 38; 21 women) completed two laboratory sessions: one stress (public speaking, math, and cold pressor) and one control rest session. The taste perception test was conducted at the end of each session and included rating the intensity and pleasantness of sweet, salty, sour, and savory solutions at suprathreshold concentrations. Cardiovascular, hormonal, and mood measures were collected throughout the sessions. Participants showed the expected changes in cardiovascular, hormonal, and mood measures in response to stress. Reported intensity of the sweet solution was significantly lower on the stress day than on the rest day. Cortisol level poststress predicted reduced intensity of salt and sour, suggesting that stress-related changes in adrenocortical activity were related to reduced taste intensity. Results indicate that acute stress may alter taste perception, and ongoing research investigates the extent to which these changes mediate effects of stress on appetite.

  4. Sigma 1 receptor stimulation protects against oxidative damage through suppression of the ER stress responses in the human lens.

    PubMed

    Wang, Lixin; Eldred, Julie A; Sidaway, Peter; Sanderson, Julie; Smith, Andrew J O; Bowater, Richard P; Reddan, John R; Wormstone, I Michael

    2012-01-01

    Stimulation of sigma-1 receptors is reported to protect against oxidative stress. The present study uses cells and tissue from the human lens to elucidate the relationship between the sigma 1 receptor, ER stress and oxidative stress-induced damage. Exposure of the human lens cell line FHL124 to increasing concentrations of H(2)O(2) led to reduced cell viability and increased apoptosis. In response to 30 μM H(2)O(2), levels of the ER stress proteins BiP, ATF6 and pEIF2α were significantly increased within 4h of exposure. Expression of the sigma 1 receptor was markedly increased in response to H(2)O(2). Application of 10 and 30 μM (+)-pentazocine, a sigma 1 receptor agonist, significantly inhibited the H(2)O(2) induced cell death. (+)-Pentazocine also suppressed the oxidative stress induced reduction of pro-caspase 12 and suppressed the induction of the ER stress proteins BiP and EIF2α. When applied to cultured human lenses, (+)-pentazocine protected against apoptotic cell death, LDH release and against H(2)O(2) induced opacification. These data demonstrate that stimulation of the sigma 1 receptor provides significant protection from oxidative damage and is, therefore, a putative therapeutic approach to delay the onset of diseases that may be triggered by oxidative damage, including cataract formation.

  5. Acute stress and working memory in older people.

    PubMed

    Pulopulos, Matias M; Hidalgo, Vanesa; Almela, Mercedes; Puig-Perez, Sara; Villada, Carolina; Salvador, Alicia

    2015-01-01

    Several studies have shown that acute stress affects working memory (WM) in young adults, but the effect in older people is understudied. As observed in other types of memory, older people may be less sensitive to acute effects of stress on WM. We performed two independent studies with healthy older men and women (from 55 to 77 years old) to investigate the effects of acute stress (Trier Social Stress Test; TSST) and cortisol on WM. In study 1 (n = 63), after the TSST women (but not men) improved their performance on Digit Span Forward (a measure of the memory span component of WM) but not on Digit Span Backward (a measure of both memory span and the executive component of WM). Furthermore, in women, cortisol levels at the moment of memory testing showed a positive association with the memory span component of WM before and after the TSST, and with the executive component of WM only before the stress task. In study 2 (n = 76), although participants showed a cortisol and salivary alpha-amylase (sAA) response to the TSST, stress did not affect performance on Letter-Number Sequencing (LNS; a task that places a high demand on the executive component of WM). Cortisol and sAA were not associated with WM. The results indicate that circulating cortisol levels at the moment of memory testing, and not the stress response, affect memory span in older women, and that stress and the increase in cortisol levels after stress do not affect the executive component of WM in older men and women. This study provides further evidence that older people may be less sensitive to stress and stress-induced cortisol response effects on memory processes.

  6. Occupational role stress is associated with higher cortisol reactivity to acute stress.

    PubMed

    Wirtz, Petra H; Ehlert, Ulrike; Kottwitz, Maria U; La Marca, Roberto; Semmer, Norbert K

    2013-04-01

    We investigated whether occupational role stress is associated with differential levels of the stress hormone cortisol in response to acute psychosocial stress. Forty-three medication-free nonsmoking men aged between 22 and 65 years (mean ± SEM: 44.5 ± 2) underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. We assessed occupational role stress in terms of role conflict and role ambiguity (combined into a measure of role uncertainty) as well as further work characteristics and psychological control variables including time pressure, overcommitment, perfectionism, and stress appraisal. Moreover, we repeatedly measured salivary cortisol and blood pressure levels before and after stress exposure, and several times up to 60 min thereafter. Higher role uncertainty was associated with a more pronounced cortisol stress reactivity (p = .016), even when controlling for the full set of potential confounders (p < .001). Blood pressure stress reactivity was not associated with role uncertainty. Our findings suggest that occupational role stress in terms of role uncertainty acts as a background stressor that is associated with increased HPA-axis reactivity to acute stress. This finding may represent a potential mechanism regarding how occupational role stress may precipitate adverse health outcomes.

  7. Acute psychosocial stress and children's memory.

    PubMed

    de Veld, Danielle M J; Riksen-Walraven, J Marianne; de Weerth, Carolina

    2014-07-01

    We investigated whether children's performance on working memory (WM) and delayed retrieval (DR) tasks decreased after stress exposure, and how physiological stress responses related to performance under stress. About 158 children (83 girls; Mage = 10.61 years, SD = 0.52) performed two WM tasks (WM forward and WM backward) and a DR memory task first during a control condition, and 1 week later during a stress challenge. Salivary alpha-amylase (sAA) and cortisol were assessed during the challenge. Only WM backward performance declined over conditions. Correlations between physiological stress responses and performance within the stress challenge were present only for WM forward and DR. For WM forward, higher cortisol responses were related to better performance. For DR, there was an inverted U-shape relation between cortisol responses and performance, as well as a cortisol × sAA interaction, with concurrent high or low responses related to optimal performance. This emphasizes the importance of including curvilinear and interaction effects when relating physiology to memory.

  8. Novel Role of ER Stress and Autophagy in Microcystin-LR Induced Apoptosis in Chinese Hamster Ovary Cells

    PubMed Central

    Zhang, Shenshen; Liu, Chuanrui; Li, Yang; Imam, Mustapha U.; Huang, Hui; Liu, Haohao; Xin, Yongjuan; Zhang, Huizhen

    2016-01-01

    Microcystin-LR (MC-LR) is a ubiquitous peptide that exhibits strong reproductive toxicity, although the mechanistic basis for such toxicity remains largely unknown. The present study was conducted to investigate the mechanisms underlying the adverse effects of exposure to MC-LR in Chinese hamster ovary (CHO) cells. The results showed that MC-LR inhibited the in vitro proliferation of CHO cells significantly, with an IC50 of 10 μM. Moreover, MC-LR-treated CHO cells revealed strong induction of cell cycle arrest and apoptosis. Additionally, exposure of CHO cells to MC-LR resulted in excess reactive oxygen species production and intracellular calcium release, with resultant endoplasmic reticulum stress (ERs). There was also extensive accumulation of autophagic vacuoles with the highest concentration of MC-LR used (10 μM). Furthermore, the expression of ERs (GRP78, ATF-6, PERK, IRE1, CHOP) and autophagy (Beclin1 and LC3II) proteins was increased, with concomitantly reduced expression of LC3I suggesting that ERs and autophagy were induced in CHO cells by MC-LR treatment. Conversely, pretreatment of CHO cells with 4-Phenyl butyric acid, the ERs inhibitor reduced the MC-LR-induced apoptotic cell death and cellular autophagy as evidenced by the reduced expression of Beclin1 and LC3II. Similarly, MC-LR treatment in combination with an autophagy inhibitor (3-methyladenine) increased apoptotic cell death compared with MC-LR alone, and induced ERs via upregulating ERs proteins. The overall results indicated that activation of ERs and autophagy are both associated with MC-LR-induced apoptosis in CHO cells. ERs may be a trigger of autophagy in this process. PMID:27877136

  9. The PERK pathway independently triggers apoptosis and a Rac1/Slpr/JNK/Dilp8 signaling favoring tissue homeostasis in a chronic ER stress Drosophila model

    PubMed Central

    Demay, Y; Perochon, J; Szuplewski, S; Mignotte, B; Gaumer, S

    2014-01-01

    The endoplasmic reticulum (ER) has a major role in protein folding. The accumulation of unfolded proteins in the ER induces a stress, which can be resolved by the unfolded protein response (UPR). Chronicity of ER stress leads to UPR-induced apoptosis and in turn to an unbalance of tissue homeostasis. Although ER stress-dependent apoptosis is observed in a great number of devastating human diseases, how cells activate apoptosis and promote tissue homeostasis after chronic ER stress remains poorly understood. Here, using the Drosophila wing imaginal disc as a model system, we validated that Presenilin overexpression induces chronic ER stress in vivo. We observed, in this novel model of chronic ER-stress, a PERK/ATF4-dependent apoptosis requiring downregulation of the antiapoptotic diap1 gene. PERK/ATF4 also activated the JNK pathway through Rac1 and Slpr activation in apoptotic cells, leading to the expression of Dilp8. This insulin-like peptide caused a developmental delay, which partially allowed the replacement of apoptotic cells. Thanks to a novel chronic ER stress model, these results establish a new pathway that both participates in tissue homeostasis and triggers apoptosis through an original regulation. PMID:25299777

  10. Neuronal ER stress impedes myeloid-cell-induced vascular regeneration through IRE1α degradation of netrin-1.

    PubMed

    Binet, François; Mawambo, Gaëlle; Sitaras, Nicholas; Tetreault, Nicolas; Lapalme, Eric; Favret, Sandra; Cerani, Agustin; Leboeuf, Dominique; Tremblay, Sophie; Rezende, Flavio; Juan, Aimee M; Stahl, Andreas; Joyal, Jean-Sebastien; Milot, Eric; Kaufman, Randal J; Guimond, Martin; Kennedy, Timothy E; Sapieha, Przemyslaw

    2013-03-05

    In stroke and proliferative retinopathy, despite hypoxia driven angiogenesis, delayed revascularization of ischemic tissue aggravates the loss of neuronal function. What hinders vascular regrowth in the ischemic central nervous system remains largely unknown. Using the ischemic retina as a model of neurovascular interaction in the CNS, we provide evidence that the failure of reparative angiogenesis is temporally and spatially associated with endoplasmic reticulum (ER) stress. The canonical ER stress pathways of protein kinase RNA-like ER kinase (PERK) and inositol-requiring enzyme-1α (IRE1α) are activated within hypoxic/ischemic retinal ganglion neurons, initiating a cascade that results in angiostatic signals. Our findings demonstrate that the endoribonuclease IRE1α degrades the classical guidance cue netrin-1. This neuron-derived cue triggers a critical reparative-angiogenic switch in neural macrophage/microglial cells. Degradation of netrin-1, by persistent neuronal ER stress, thereby hinders vascular regeneration. These data identify a neuronal-immune mechanism that directly regulates reparative angiogenesis.

  11. Perceived Control Alters the Effect of Acute Stress on Persistence

    PubMed Central

    Bhanji, Jamil P.; Kim, Eunbin S.; Delgado, Mauricio R.

    2015-01-01

    We often encounter setbacks while pursuing our goals. Success requires that we cope with these negative outcomes and choose to persist in spite of them. For example, learners may be more likely to continue a course after failing an assessment if they control their emotional reactions to the setback and study harder. However, the ability to effectively cope with the negative emotion inherent in such setbacks can be compromised by acute stress present in daily life (e.g., struggles in the household), which can subsequently lead to problems with persisting with a goal. The present study examined whether increasing the perception of control over setbacks (e.g., belief that a setback was caused by a correctable mistake rather than uncontrollable factors) can guard against the influence of a prior acute stressor on reactions to setbacks. Participants underwent a socially-evaluated cold water stress or a non-stress control procedure. Afterwards, they performed a behavioral task designed to measure persistence through controllable and uncontrollable setbacks. We observed that exposure to an acute stressor led to a detrimental effect on decision making by decreasing persistence behavior. Importantly, we also observed that the perception of control protected against the effect of preexisting stress and helped promote persistence. That is, stress impaired persistence through uncontrollable setbacks, but the impairment was alleviated by presenting setbacks as controllable. The findings demonstrate a potential avenue for improving the maintenance of goals aimed at behavior change, which can be susceptible to effects of stress. PMID:26726915

  12. Acute kidney injury mediated by oxidative stress in Egyptian horses with exertional rhabdomyolysis.

    PubMed

    el-Ashker, Maged R

    2011-06-01

    The present study was carried out to evaluate the role of oxidative stress in the pathophysiologic process of acute renal failure associated with exertional rhabdomyolysis (ER) in Egyptian horses. ER was tentatively diagnosed in 31 Baladi horses based on case history, physical examination findings and confirmed by elevation of plasma creatine kinase (CK) and urine myoglobin concentrations. According to severity of the condition, the diseased horses were categorized into two main groups; the first group included 18 horses with minimal clinical signs and plasma CK <60 000 IU/L; whereas, the second group included 13 horses with overt clinical signs and plasma CK >100 000 IU/L). It was found that plasma creatol (CTL) was positively correlated (p < 0.01) with plasma malondialdehyde (MDA) (r = 0.775), nitric oxide (NO) (r = 0.768), methyguanididne (MG) (r = 0.995), CK (r = 0.768), urine glucose (r = 0.778), urine protein (r = 0.767), renal failure index (RFI) (r = 0.814) and urine sodium (r = 0.799) and negatively correlated (p < 0.01) with total antioxidant capacity (TAC) (r = -0.795), superoxide dismutase (SOD) (r = -0.815), glutathione peroxidase (GSH-Px) (r = -0.675), Vitamin C (r = -0.830), urine creatinine (r = -0.800), urine/plasma creatinine ratio (r = -0.827) and urine/plasma urea ratio (r = -0.807). The correlation between these biochemical variables might suggest a possible role of oxidative stress in renal injury associated with severe rhabdomyolysis in horses. It is suggested that exaggeration of oxidative stress associated with increased muscle membrane leakage plays a key role in acute kidney injury in Baladi horses with severe rhabdomyolysis.

  13. Acute Stress Disorder: Conceptual Issues and Treatment Outcomes

    ERIC Educational Resources Information Center

    Koucky, Ellen M.; Galovski, Tara E.; Nixon, Reginald D. V.

    2012-01-01

    Acute stress disorder (ASD) was included as a diagnosis to the 4th edition of the "Diagnostic and Statistical Manual" (American Psychiatric Association, 1994) as a way of describing pathological reactions in the first month following a trauma. Since that time, ASD has been the focus of some controversy, particularly regarding the theoretical basis…

  14. Effects of Acute Stress on Decision Making.

    PubMed

    Wemm, Stephanie E; Wulfert, Edelgard

    2017-03-01

    The study examined the effects of a social stressor (Trier Social Stress Test) on 24 male and 32 female college students' affective and physiological reactivity and their subsequent performance on a decision-making task (Iowa Gambling Task). The 56 participants were randomly assigned to a social stressor or a control condition. Compared to controls, participants in the stress condition responded with higher heart rates and skin conductance responses, reported more negative affect, and on the decision-making task made less advantageous choices. An exploratory regression analysis revealed that among men higher levels of heart rate were positively correlated with riskier choices on the Iowa Gambling Task, whereas for women this relationship was curvilinear. Exploratory correlational analyses showed that lower levels of skin conductance within the stress condition were associated with greater levels of substance use and gambling. The results suggest that the presence of a stressor may generally result in failure to attend to the full range of possible consequences of a decision. The relationship pattern between the degree of stress responding and successful decision making may be different for men and women.

  15. IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation

    PubMed Central

    Takatani, Tomozumi; Shirakawa, Jun; Roe, Michael W.; Leech, Colin A.; Maier, Bernhard F.; Mirmira, Raghavendra G.; Kulkarni, Rohit N.

    2016-01-01

    Endoplasmic reticulum (ER) stress is among several pathological features that underlie β-cell failure in the development of type 1 and type 2 diabetes. Adaptor proteins in the insulin/insulin-like-growth factor-1 signaling pathways, such as insulin receptor substrate-1 (IRS1) and IRS2, differentially impact β-cell survival but the underlying mechanisms remain unclear. Here we report that β-cells deficient in IRS1 (IRS1KO) are resistant, while IRS2 deficiency (IRS2KO) makes them susceptible to ER stress-mediated apoptosis. IRS1KOs exhibited low nuclear accumulation of spliced XBP-1 due to its poor stability, in contrast to elevated accumulation in IRS2KO. The reduced nuclear accumulation in IRS1KO was due to protein instability of Xbp1 secondary to proteasomal degradation. IRS1KO also demonstrated an attenuation in their general translation status in response to ER stress revealed by polyribosomal profiling. Phosphorylation of eEF2 was dramatically increased in IRS1KO enabling the β-cells to adapt to ER stress by blocking translation. Furthermore, significantly high ER calcium (Ca2+) was detected in IRS1KO β-cells even upon induction of ER stress. These observations suggest that IRS1 could be a therapeutic target for β-cell protection against ER stress-mediated cell death by modulating XBP-1 stability, protein synthesis, and Ca2+ storage in the ER. PMID:27378176

  16. Acute Stress Disorder as a Predictor of Post-Traumatic Stress Disorder in Physical Assault Victims

    ERIC Educational Resources Information Center

    Elklit, Ask; Brink, Ole

    2004-01-01

    The authors' objective was to examine the ability of acute stress disorder (ASD) and other trauma-related factors in a group of physical assault victims in predicting post-traumatic stress disorder (PTSD) 6 months later. Subjects included 214 victims of violence who completed a questionnaire 1 to 2 weeks after the assault, with 128 participating…

  17. Does Acute Stress Disorder Predict Posttraumatic Stress Disorder Following Bank Robbery?

    ERIC Educational Resources Information Center

    Hansen, Maj; Elklit, Ask

    2013-01-01

    Unfortunately, the number of bank robberies is increasing and little is known about the subsequent risk of posttraumatic stress disorder (PTSD). Several studies have investigated the prediction of PTSD through the presence of acute stress disorder (ASD). However, there have only been a few studies following nonsexual assault. The present study…

  18. The Relationship between Acute Stress Disorder and Posttraumatic Stress Disorder Following Cancer

    ERIC Educational Resources Information Center

    Kangas, Maria; Henry, Jane L.; Bryant, Richard A.

    2005-01-01

    In this study, the authors investigated the relationship between acute stress disorder (ASD) and posttraumatic stress disorder (PTSD) following cancer diagnosis. Patients who were recently diagnosed with 1st onset head and neck or lung malignancy (N = 82) were assessed for ASD within the initial month following their diagnosis and reassessed (n =…

  19. Cadmium toxicity induces ER stress and apoptosis via impairing energy homoeostasis in cardiomyocytes.

    PubMed

    Chen, Chun-Yan; Zhang, Shao-Li; Liu, Zhi-Yong; Tian, Yong; Sun, Qian

    2015-04-10

    Cadmium, a highly toxic environmental pollutant, is reported to induce toxicity and apoptosis in multiple organs and cells, all possibly contributing to apoptosis in certain pathophysiologic situations. Previous studies have described that cadmium toxicity induces biochemical and physiological changes in the heart and finally leads to cardiac dysfunctions, such as decreasing contractile tension, rate of tension development, heart rate, coronary flow rate and atrioventricular node conductivity. Although many progresses have been made, the mechanism responsible for cadmium-induced cellular alternations and cardiac toxicity is still not fully understood. In the present study, we demonstrated that cadmium toxicity induced dramatic endoplasmic reticulum (ER) stress and impaired energy homoeostasis in cultured cardiomyocytes. Moreover, cadmium toxicity may inhibit protein kinase B (AKT)/mTOR (mammalian target of rapamycin) pathway to reduce energy productions, by either disrupting the glucose metabolism or inhibiting mitochondrial respiratory gene expressions. Our work will help to reveal a novel mechanism to clarify the role of cadmium toxicity to cardiomyocytes and provide new possibilities for the treatment of cardiovascular diseases related to cadmium toxicity.

  20. Ethanol promotes saturated fatty acid-induced hepatoxicity through endoplasmic reticulum (ER) stress response.

    PubMed

    Yi, Hong-Wei; Ma, Yu-Xiang; Wang, Xiao-Ning; Wang, Cui-Fen; Lu, Jian; Cao, Wei; Wu, Xu-Dong

    2015-04-01

    Serum palmitic acid (PA), a type of saturated fatty acid, causes lipid accumulation and induces toxicity in hepatocytes. Ethanol (EtOH) is metabolized by the liver and induces hepatic injury and inflammation. Herein, we analyzed the effects of EtOH on PA-induced lipotoxicity in the liver. Our results indicated that EtOH aggravated PA-induced apoptosis and lipid accumulation in primary rat hepatocytes in dose-dependent manner. EtOH intensified PA-caused endoplasmic reticulum (ER) stress response in vitro and in vivo, and the expressions of CHOP, ATF4, and XBP-1 in nucleus were significantly increased. EtOH also increased PA-caused cleaved caspase-3 in cytoplasm. In wild type and CHOP(-/-) mice treated with EtOH and high fat diet (HFD), EtOH worsened the HFD-induced liver injury and dyslipidemia, while CHOP knockout blocked toxic effects of EtOH and PA. Our study suggested that targeting UPR-signaling pathways is a promising, novel approach to reducing EtOH and saturated fatty acid-induced metabolic complications.

  1. Skin temperature reveals the intensity of acute stress

    PubMed Central

    Herborn, Katherine A.; Graves, James L.; Jerem, Paul; Evans, Neil P.; Nager, Ruedi; McCafferty, Dominic J.; McKeegan, Dorothy E.F.

    2015-01-01

    Acute stress triggers peripheral vasoconstriction, causing a rapid, short-term drop in skin temperature in homeotherms. We tested, for the first time, whether this response has the potential to quantify stress, by exhibiting proportionality with stressor intensity. We used established behavioural and hormonal markers: activity level and corticosterone level, to validate a mild and more severe form of an acute restraint stressor in hens (Gallus gallus domesticus). We then used infrared thermography (IRT) to non-invasively collect continuous temperature measurements following exposure to these two intensities of acute handling stress. In the comb and wattle, two skin regions with a known thermoregulatory role, stressor intensity predicted the extent of initial skin cooling, and also the occurrence of a more delayed skin warming, providing two opportunities to quantify stress. With the present, cost-effective availability of IRT technology, this non-invasive and continuous method of stress assessment in unrestrained animals has the potential to become common practice in pure and applied research. PMID:26434785

  2. Depletion of the cereblon gene activates the unfolded protein response and protects cells from ER stress-induced cell death.

    PubMed

    Lee, Kwang Min; Yang, Seung-Joo; Park, Sojung; Choi, Yoo Duk; Shin, Hwa Kyoung; Pak, Jhang Ho; Park, Chul-Seung; Kim, Inki

    2015-02-27

    Previous studies showed that cereblon (CRBN) binds to various cellular target proteins, implying that CRBN regulates a wide range of cell responses. In this study, we found that deletion of the Crbn gene desensitized mouse embryonic fibroblast cells to various cell death-promoting stimuli, including endoplasmic reticulum stress inducers. Mechanistically, deletion of Crbn activates pathways involved in the unfolded protein response prior to ER stress induction. Loss of Crbn activated PKR-like ER kinase (PERK) with enhanced phosphorylation of eIF2α. Following ER stress induction, loss of Crbn delayed dephosphorylation of eIF2α, while reconstitution of Crbn reversed enhanced phosphorylation of PERK and eIF2α. Lastly, we found that activation of the PERK/eIF2α pathway following Crbn deletion is caused by activation of AMP-activated protein kinase (AMPK). We propose that CRBN plays a role in cellular stress signaling, including the unfolded protein response, by controlling the activity of AMPK.

  3. Acute stress responses: A review and synthesis of ASD, ASR, and CSR.

    PubMed

    Isserlin, Leanna; Zerach, Gadi; Solomon, Zahava

    2008-10-01

    Toward the development of a unifying diagnosis for acute stress responses this article attempts to find a place for combat stress reaction (CSR) within the spectrum of other defined acute stress responses. This article critically compares the diagnostic criteria of acute stress disorder (ASD), acute stress reaction (ASR), and CSR. Prospective studies concerning the predictive value of ASD, ASR, and CSR are reviewed. Questions, recommendations, and implications for clinical practice are raised concerning the completeness of the current acute stress response diagnoses, the heterogeneity of different stressors, the scope of expected outcomes, and the importance of decline in function as an indicator of future psychological, psychiatric, and somatic distress.

  4. Manganese induces endoplasmic reticulum (ER) stress and activates multiple caspases in nigral dopaminergic neuronal cells, SN4741.

    PubMed

    Chun, H S; Lee, H; Son, J H

    2001-12-04

    Chronic exposure to manganese causes Parkinson's disease (PD)-like clinical symptoms (Neurotoxicology 5 (1984) 13; Arch. Neurol. 46 (1989) 1104; Neurology 56 (2001) 4). Occupational exposure to manganese is proposed as a risk factor in specific cases of idiopathic PD (Neurology 56 (2001) 8). We have investigated the mechanism of manganese neurotoxicity in nigral dopaminergic (DA) neurons using the DA cell line, SN4741 (J. Neurosci. 19 (1999) 10). Manganese treatment elicited endoplasmic reticulum (ER) stress responses, such as an increased level of the ER chaperone BiP, and simultaneously activated the ER resident caspase-12. Peak activation of other major initiator caspases-like activities, such as caspase-1, -8 and -9, ensued, resulting in activation of caspase-3-like activity during manganese-induced DA cell death. The neurotoxic cell death induced by manganese was significantly reduced in the Bcl-2-overexpressing DA cell lines. Our findings suggest that manganese-induced neurotoxicity is mediated in part by ER stress and considerably ameliorated by Bcl-2 overexpression in DA cells.

  5. HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction.

    PubMed

    Gupta, Sanjeev; Deepti, Ayswaria; Deegan, Shane; Lisbona, Fernanda; Hetz, Claudio; Samali, Afshin

    2010-07-06

    Endoplasmic reticulum (ER) stress is a feature of secretory cells and of many diseases including cancer, neurodegeneration, and diabetes. Adaptation to ER stress depends on the activation of a signal transduction pathway known as the unfolded protein response (UPR). Enhanced expression of Hsp72 has been shown to reduce tissue injury in response to stress stimuli and improve cell survival in experimental models of stroke, sepsis, renal failure, and myocardial ischemia. Hsp72 inhibits several features of the intrinsic apoptotic pathway. However, the molecular mechanisms by which Hsp72 expression inhibits ER stress-induced apoptosis are not clearly understood. Here we show that Hsp72 enhances cell survival under ER stress conditions. The UPR signals through the sensor IRE1alpha, which controls the splicing of the mRNA encoding the transcription factor XBP1. We show that Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. Inhibition of XBP1 mRNA splicing either by dominant negative IRE1alpha or by knocking down XBP1 specifically abrogated the inhibition of ER stress-induced apoptosis by Hsp72. Regulation of the UPR was associated with the formation of a stable protein complex between Hsp72 and the cytosolic domain of IRE1alpha. Finally, Hsp72 enhanced the RNase activity of recombinant IRE1alpha in vitro, suggesting a direct regulation. Our data show that binding of Hsp72 to IRE1alpha enhances IRE1alpha/XBP1 signaling at the ER and inhibits ER stress-induced apoptosis. These results provide a physical connection between cytosolic chaperones and the ER stress response.

  6. ER Stress Mediates TiAl6V4 Particle-Induced Peri-Implant Osteolysis by Promoting RANKL Expression in Fibroblasts

    PubMed Central

    Wang, Zhenheng; Liu, Naicheng; Shi, Tongguo; Zhou, Gang; Wang, Zhenzhen; Gan, Jingjing; Guo, Ting; Qian, Hongbo; Bao, Nirong; Zhao, Jianning

    2015-01-01

    Wear particle-induced osteolysis is a major cause of aseptic loosening, which is one of the most common reasons for total hip arthroplasty (THA) failure. Previous studies have shown that the synovial fibroblasts present in the periprosthetic membrane are important targets of wear debris during osteolysis. However, the interaction mechanisms between the wear debris and fibroblasts remain largely unknown. In the present study, we investigated the effect of ER (endoplasmic reticulum) stress induced by TiAl6V4 particles (TiPs) in human synovial fibroblasts and calvarial resorption animal models. The expression of ER stress markers, including IRE1-α, GRP78/Bip and CHOP, were determined by western blot in fibroblasts that had been treated with TiPs for various times and concentration. To address whether ER stress was involved in the expression of RANKL, the effects of ER stress blockers (including 4-PBA and TUDCA) on the expression of RANKL in TiPs-treated fibroblasts were examined by real-time PCR, western blot and ELISA. Osteoclastogenesis was assessed by tartrate resistant acid phosphatase (TRAP) staining. Our study demonstrated that ER stress markers were markedly upregulated in TiPs-treated fibroblasts. Blocking ER stress significantly reduced the TiPs-induced expression of RANKL both in vitro and in vivo. Moreover, the inhibition of ER stress ameliorated wear particle-induced osteolysis in animal models. Taken together, these results suggested that the expression of RANKL induced by TiPs was mediated by ER stress in fibroblasts. Therefore, down regulating the ER stress of fibroblasts represents a potential therapeutic approach for wear particle-induced periprosthetic osteolysis. PMID:26366858

  7. Management of acute traumatic stress in nuclear and radiological emergencies.

    PubMed

    Vazquez, Marina; Jordan, Osvaldo; Kuper, Enrique; Hernandez, Daniel; Galmarini, Martin; Ferraro, Augusto

    2010-06-01

    In order to effectively respond to and minimize the psychological impact following disasters, such as radio-nuclear ones, it is essential to understand the mechanisms involved in such conditions and how to prevent and treat the psychological impacts, including those related to acute traumatic stress and its consequences across life span. Radio-nuclear emergencies may cause psychological traumatic stress, with its potentially significant consequences in mental health, with both short and long-term effects, which extend beyond the individuals directly affected. Ionizing radiation cannot be perceived by human senses and most people are unaware of the magnitude of its effects, which could result in feelings of helplessness and vulnerability. Those situations with a high degree of uncertainty, regarding potential future health effects, are more psychologically traumatic than others. The present century has witnessed a steady increase in the number of publications concerning the mental health impact of traumatic events, showing the need of increasing the study of traumatic stress and its impact on mental health. A prompt, planned and effective response to manage disaster-induced acute traumatic stress may prevent the evolutionary reactions of traumatic stress into disorders or even chronic stress diseases that can appear after a nuclear or radiological emergency.

  8. Dynamic changes in saliva after acute mental stress

    PubMed Central

    Naumova, Ella A.; Sandulescu, Tudor; Bochnig, Clemens; Khatib, Philipp Al; Lee, Wing-Kee; Zimmer, Stefan; Arnold, Wolfgang H.

    2014-01-01

    Stress-related variations of fluoride concentration in supernatant saliva and salivary sediment, salivary cortisol, total protein and pH after acute mental stress were assessed. The hypothesis was that stress reactions have no influence on these parameters. Thirty-four male students were distributed into two groups: first received the stress exposure followed by the same protocol two weeks later but without stress exposure, second underwent the protocol without stress exposure followed by the stress exposure two weeks later. The stressor was a public speech followed by tooth brushing. Saliva was collected before, immediately after stress induction and immediately, at 10, 30 and 120 min. after tooth brushing. Cortisol concentrations, total protein, intraoral pH, and fluoride content in saliva were measured. The data were analyzed statistically. Salivary sediment was ca 4.33% by weight of whole unstimulated saliva. Fluoride bioavailability was higher in salivary sediment than in supernatant saliva. The weight and fluoride concentration was not altered during 2 hours after stress exposure. After a public speech, the salivary cortisol concentration significantly increased after 20 minutes compared to the baseline. The salivary protein concentration and pH also increased. Public speaking influences protein concentration and salivary pH but does not alter the fluoride concentration of saliva. PMID:24811301

  9. Dynamic changes in saliva after acute mental stress.

    PubMed

    Naumova, Ella A; Sandulescu, Tudor; Bochnig, Clemens; Al Khatib, Philipp; Lee, Wing-Kee; Zimmer, Stefan; Arnold, Wolfgang H

    2014-05-08

    Stress-related variations of fluoride concentration in supernatant saliva and salivary sediment, salivary cortisol, total protein and pH after acute mental stress were assessed. The hypothesis was that stress reactions have no influence on these parameters. Thirty-four male students were distributed into two groups: first received the stress exposure followed by the same protocol two weeks later but without stress exposure, second underwent the protocol without stress exposure followed by the stress exposure two weeks later. The stressor was a public speech followed by tooth brushing. Saliva was collected before, immediately after stress induction and immediately, at 10, 30 and 120 min. after tooth brushing. Cortisol concentrations, total protein, intraoral pH, and fluoride content in saliva were measured. The data were analyzed statistically. Salivary sediment was ca 4.33% by weight of whole unstimulated saliva. Fluoride bioavailability was higher in salivary sediment than in supernatant saliva. The weight and fluoride concentration was not altered during 2 hours after stress exposure. After a public speech, the salivary cortisol concentration significantly increased after 20 minutes compared to the baseline. The salivary protein concentration and pH also increased. Public speaking influences protein concentration and salivary pH but does not alter the fluoride concentration of saliva.

  10. Paradoxical resistance to myocardial ischemia and age-related cardiomyopathy in NHE1 transgenic mice: a role for ER stress?

    PubMed

    Cook, Alexandra R; Bardswell, Sonya C; Pretheshan, Subashini; Dighe, Kushal; Kanaganayagam, Gajen S; Jabr, Rita I; Merkle, Sabine; Marber, Michael S; Engelhardt, Stefan; Avkiran, Metin

    2009-02-01

    Sarcolemmal Na(+)/H(+) exchanger (NHE) activity, which is provided by the NHE isoform 1 (NHE1), has been implicated in ischemia/reperfusion-induced myocardial injury in animal models and humans, on the basis of studies with pharmacological NHE1 inhibitors. We generated a transgenic (TG) mouse model with cardiac-specific over-expression of NHE1 to determine whether this would be sufficient to increase myocardial susceptibility to ischemia/reperfusion-induced injury. TG mouse hearts exhibited increased sarcolemmal NHE activity and normal morphology and function. Surprisingly, they also showed reduced susceptibility to ischemia/reperfusion-induced injury, as reflected by improved functional recovery and smaller infarcts. Such protection was sustained in the presence of NHE1 inhibition with zoniporide, indicating a mechanism that is independent of sarcolemmal NHE activity. Immunoblot analysis revealed accumulation of immature NHE1 protein as well as marked upregulation of both cytoprotective (78/94 kDa glucose-regulated proteins, calreticulin, protein disulfide isomerase) and pro-apoptotic (C/EBP homologous protein) components of the endoplasmic reticulum (ER) stress response in TG myocardium. With increasing age, NHE1 TG mice exhibited increased myocyte apoptosis, developed left ventricular contractile dysfunction, underwent cardiac remodelling and died prematurely. Our findings indicate that: (1) Cardiac-specific NHE1 over-expression induces the ER stress response in mouse myocardium, which may afford protection against ischemia/reperfusion-induced injury despite increased NHE activity; (2) Ageing NHE1 TG mice exhibit myocyte apoptosis, cardiac remodelling and failure, likely as a result of sustained ER stress; (3) The pluripotent effects of the ER stress response may confound studies that are based on the chronic over-expression of complex proteins in myocardium.

  11. ER stress related factor ATF6 and caspase-12 trigger apoptosis in neonatal hypoxic-ischemic encephalopathy

    PubMed Central

    Liu, Luran; Liu, Chang; Lu, Yuting; Liu, Lina; Jiang, Yan

    2015-01-01

    The specific and available markers proteins of neonatal hypoxic-ischemic encephalopathy (HIE) injury are correlated with disease severity and the disability in childhood. Exploring the mechanism of HIE is very helpful to the targeted therapeutic approach in clinical. This study aims to explore the cell death-related proteins or biomarkers that plays roles in the HIE injury. In this study, 15 patients were included the 487 autopsies patients performed at the Department of Pathology. The lactate dehydrogenase (LDH) assay was used to detect the cell viability of NGF-differentiated PC12 cell. TUNEL assay was employed to examine the apoptotic cells in embedded slides samples. Three ER stress-related protein, including ATF6, p-Perk and IRE-1 were investigated using Western blot assay for the ER stress examination. The apoptosis associated caspase-12 and CHOP protein were detected by Western blot. The results indicated that LDH activity of living cells during hypoxia was significantly enhanced to 45% and 64% after 8 hours and 24 hours. The TUNEL results showed that plenty of the PC12 cells became the positive staining cells when treated with 0.1% O2 hypoxia. ER stress UPR pathway protein, cleaved ATF6, was increased significantly when treated with 0.1% O2 compared with the cells treated with 20% O2. Furthermore, the caspase 12 activation was triggered when the cells treated with the 0.1% O2. In conclusion, apoptosis is served as an important factor that triggers the HIE brain injury through cleaving the ATF6 and caspase-12 ER stress-related protein. PMID:26261584

  12. ERO1α-dependent endoplasmic reticulum-mitochondrial calcium flux contributes to ER stress and mitochondrial permeabilization by procaspase-activating compound-1 (PAC-1).

    PubMed

    Seervi, M; Sobhan, P K; Joseph, J; Ann Mathew, K; Santhoshkumar, T R

    2013-12-19

    Procaspase-activating compound-1 (PAC-1) is the first direct caspase-activating compound discovered; using an in vitro cell-free system of caspase activation. Subsequently, this compound was shown to induce apoptosis in a variety of cancer cells with promising in vivo antitumor activity in canine lymphoma model. Recently, we have reported its ability to kill drug-resistant, Bcl-2/Bcl-xL overexpressing and Bax/Bak-deficient cells despite the essential requirement of mitochondrial cytochrome c (cyt. c) release for caspase activation, indicating that the key molecular targets of PAC-1 in cancer cells are yet to be identified. Here, we have identified Ero1α-dependent endoplasmic reticulum (ER) calcium leakage to mitochondria through mitochondria-associated ER membranes (MAM) and ER luminal hyper-oxidation as the critical events of PAC-1-mediated cell death. PAC-1 treatment upregulated Ero1α in multiple cell lines, whereas silencing of Ero1α significantly inhibited calcium release from ER and cell death. Loss of ER calcium and hyper-oxidation of ER lumen by Ero1α collectively triggered ER stress. Upregulation of GRP78 and splicing of X-box-binding protein 1 (XBP1) mRNA in multiple cancer cells suggested ER stress as the general event triggered by PAC-1. XBP1 mRNA splicing and GRP78 upregulation confirmed ER stress even in Bax/Bak double knockout and PAC-1-resistant Apaf-1-knockout cells, indicating an induction of ER stress-mediated mitochondrial apoptosis by PAC-1. Furthermore, we identified BH3-only protein p53 upregulated modulator of apoptosis (PUMA) as the key molecular link that orchestrates overwhelmed ER stress to mitochondria-mediated apoptosis, involving mitochondrial reactive oxygen species, in a p53-independent manner. Silencing of PUMA in cancer cells effectively reduced cyt. c release and cell death by PAC-1.

  13. Reducing translation through eIF4G/IFG-1 improves survival under ER stress that depends on heat shock factor HSF-1 in Caenorhabditis elegans.

    PubMed

    Howard, Amber C; Rollins, Jarod; Snow, Santina; Castor, Sarah; Rogers, Aric N

    2016-08-18

    Although certain methods of lowering and/or altering mRNA translation are associated with increased lifespan, the mechanisms underlying this effect remain largely unknown. We previously showed that the increased lifespan conferred by reducing expression of eukaryotic translation initiation factor 4G (eIF4G/IFG-1) enhances survival under starvation conditions while shifting protein expression toward factors involved with maintaining ER-dependent protein and lipid balance. In this study, we investigated changes in ER homeostasis and found that lower eIF4G/IFG-1 increased survival under conditions of ER stress. Enhanced survival required the ER stress sensor gene ire-1 and the ER calcium ATPase gene sca-1 and corresponded with increased translation of chaperones that mediate the ER unfolded protein response (UPR(ER) ). Surprisingly, the heat-shock transcription factor gene hsf-1 was also required for enhanced survival, despite having little or no influence on the ability of wild-type animals to survive ER stress. The requirement for hsf-1 led us to re-evaluate the role of eIF4G/IFG-1 on thermotolerance. Results show that lowering expression of this translation factor enhanced thermotolerance, but only after prolonged attenuation, the timing of which corresponded to increased transcription of heat-shock factor transcriptional targets. Results indicate that restricting overall translation through eIF4G/IFG-1 enhances ER and cytoplasmic proteostasis through a mechanism that relies heavily on hsf-1.

  14. Thermotolerance induced at a mild temperature of 40°C alleviates heat shock-induced ER stress and apoptosis in HeLa cells.

    PubMed

    Bettaieb, Ahmed; Averill-Bates, Diana A

    2015-01-01

    Hyperthermia (39-45°C) has emerged as an alternate prospect for cancer therapy in combination with radiation and chemotherapy. Despite promising progress in the clinic, molecular mechanisms involved in hyperthermia-induced cell death are not clear. Hyperthermia causes protein denaturation/aggregation, which results in cell death by apoptosis and/or necrosis. Hyperthermia also induces thermotolerance, which renders cells resistant to subsequent exposure to lethal heat shock. This study investigates the role of both lethal (42-43°C) and mild (40°C) hyperthermia in regulating ER stress and ER stress-induced apoptosis in HeLa cells. The ability of mild thermotolerance induced at 40°C to alleviate either or both of these processes is also determined. Hyperthermia (42-43°C) induced ER stress, revealed by phosphorylation of PERK, eIF2α and IRE1α, cleavage of ATF6 and increased expression of BiP and sXBP1. Real-time PCR revealed that mRNA levels of ATF6, ATF4, BiP, sXBP1 and CHOP increased in cells exposed to hyperthermia. Moreover, hyperthermia caused disruption of calcium homeostasis and activated the calpain-calpastatin proteolytic system and ER resident caspase 4. Pre-exposure to mild hyperthermia (40°C) alleviated the induction of cytotoxicity and ER stress by hyperthermia (42-43°C) and protected cells against ER stress-induced apoptosis. ShRNA-mediated depletion of Hsp72 abrogated protective effects of mild thermotolerance (40°C) against heat-shock induced ER stress and sensitized cells to ER stress-mediated apoptosis. Our findings show that Hsp72 contributes to the protective effects of mild hyperthermia (40°C) against hyperthermia-induced ER stress and apoptosis.

  15. ER stress inhibitor attenuates hearing loss and hair cell death in Cdh23erl/erl mutant mice

    PubMed Central

    Hu, Juan; Li, Bo; Apisa, Luke; Yu, Heping; Entenman, Shami; Xu, Min; Stepanyan, Ruben; Guan, Bo-Jhih; Müller, Ulrich; Hatzoglou, Maria; Zheng, Qing Yin

    2016-01-01

    Hearing loss is one of the most common sensory impairments in humans. Mouse mutant models helped us to better understand the mechanisms of hearing loss. Recently, we have discovered that the erlong (erl) mutation of the cadherin23 (Cdh23) gene leads to hearing loss due to hair cell apoptosis. In this study, we aimed to reveal the molecular pathways upstream to apoptosis in hair cells to exploit more effective therapeutics than an anti-apoptosis strategy. Our results suggest that endoplasmic reticulum (ER) stress is the earliest molecular event leading to the apoptosis of hair cells and hearing loss in erl mice. We also report that the ER stress inhibitor, Salubrinal (Sal), could delay the progression of hearing loss and preserve hair cells. Our results provide evidence that therapies targeting signaling pathways in ER stress development prevent hair cell apoptosis at an early stage and lead to better outcomes than those targeting downstream factors, such as tip-link degeneration and apoptosis. PMID:27882946

  16. The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity.

    PubMed

    Shan, Bo; Wang, Xiaoxia; Wu, Ying; Xu, Chi; Xia, Zhixiong; Dai, Jianli; Shao, Mengle; Zhao, Feng; He, Shengqi; Yang, Liu; Zhang, Mingliang; Nan, Fajun; Li, Jia; Liu, Jianmiao; Liu, Jianfeng; Jia, Weiping; Qiu, Yifu; Song, Baoliang; Han, Jing-Dong J; Rui, Liangyou; Duan, Sheng-Zhong; Liu, Yong

    2017-03-27

    Obesity is associated with metabolic inflammation and endoplasmic reticulum (ER) stress, both of which promote metabolic disease progression. Adipose tissue macrophages (ATMs) are key players orchestrating metabolic inflammation, and ER stress enhances macrophage activation. However, whether ER stress pathways underlie ATM regulation of energy homeostasis remains unclear. Here, we identified inositol-requiring enzyme 1α (IRE1α) as a critical switch governing M1-M2 macrophage polarization and energy balance. Myeloid-specific IRE1α abrogation in Ern1(f/f); Lyz2-Cre mice largely reversed high-fat diet (HFD)-induced M1-M2 imbalance in white adipose tissue (WAT) and blocked HFD-induced obesity, insulin resistance, hyperlipidemia and hepatic steatosis. Brown adipose tissue (BAT) activity, WAT browning and energy expenditure were significantly higher in Ern1(f/f); Lyz2-Cre mice. Furthermore, IRE1α ablation augmented M2 polarization of macrophages in a cell-autonomous manner. Thus, IRE1α senses protein unfolding and metabolic and immunological states, and consequently guides ATM polarization. The macrophage IRE1α pathway drives obesity and metabolic syndrome through impairing BAT activity and WAT browning.

  17. Hepatitis C Virus Infection Induces Autophagy as a Prosurvival Mechanism to Alleviate Hepatic ER-Stress Response.

    PubMed

    Dash, Srikanta; Chava, Srinivas; Aydin, Yucel; Chandra, Partha K; Ferraris, Pauline; Chen, Weina; Balart, Luis A; Wu, Tong; Garry, Robert F

    2016-05-23

    Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, liver cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms by which HCV infection leads to chronic liver disease and HCC are not well understood. The infection cycle of HCV is initiated by the attachment and entry of virus particles into a hepatocyte. Replication of the HCV genome inside hepatocytes leads to accumulation of large amounts of viral proteins and RNA replication intermediates in the endoplasmic reticulum (ER), resulting in production of thousands of new virus particles. HCV-infected hepatocytes mount a substantial stress response. How the infected hepatocyte integrates the viral-induced stress response with chronic infection is unknown. The unfolded protein response (UPR), an ER-associated cellular transcriptional response, is activated in HCV infected hepatocytes. Over the past several years, research performed by a number of laboratories, including ours, has shown that HCV induced UPR robustly activates autophagy to sustain viral replication in the infected hepatocyte. Induction of the cellular autophagy response is required to improve survival of infected cells by inhibition of cellular apoptosis. The autophagy response also inhibits the cellular innate antiviral program that usually inhibits HCV replication. In this review, we discuss the physiological implications of the HCV-induced chronic ER-stress response in the liver disease progression.

  18. Curcumin derivative WZ35 efficiently suppresses colon cancer progression through inducing ROS production and ER stress-dependent apoptosis

    PubMed Central

    Zhang, Junru; Feng, Zhiguo; Wang, Chunhua; Zhou, Huiping; Liu, Weidong; Kanchana, Karvannan; Dai, Xuanxuan; Zou, Peng; Gu, Junlian; Cai, Lu; Liang, Guang

    2017-01-01

    Colon cancer is characterized by its fast progression and poor prognosis, and novel agents of treating colon cancer are urgently needed. WZ35, a synthetic curcumin derivative, has been reported to exhibit promising antitumor activity. Here, we investigated the in vitro and in vivo activities of WZ35 and explored the underlying mechanisms in colon cancer cell lines. WZ35 treatment significantly decreased the cell viability associated with G2/M cell cycle arrest and apoptosis induction in colon cancer cell lines. We also show that WZ35 is highly effective in inhibiting tumor growth in a CT26 xenograft mouse model. Mechanistically, WZ35 treatment significantly induced reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress in CT26 cells. Abrogation of ROS production by N-acetylcysteine (NAC) co-treatment almost totally reversed the WZ35-induced cell apoptosis and ER stress activation. Inhibition of p-PERK by GSK2606414 can significantly reverse WZ35-induced cell apoptosis in CT26 cells. Taken together, the curcumin derivative WZ35 exhibited anti-tumor effects in colon cancer cells both in vitro and in vivo, via a ROS-ER stress-mediated mechanism. These findings indicate that activating ROS generation could be an important strategy for the treatment of colon cancers. PMID:28337376

  19. The ER stress sensor PERK luminal domain functions as a molecular chaperone to interact with misfolded proteins

    SciTech Connect

    Wang, Peng; Li, Jingzhi; Sha, Bingdong

    2016-11-29

    PERK is one of the major sensor proteins which can detect the protein-folding imbalance generated by endoplasmic reticulum (ER) stress. It remains unclear how the sensor protein PERK is activated by ER stress. It has been demonstrated that the PERK luminal domain can recognize and selectively interact with misfolded proteins but not native proteins. Moreover, the PERK luminal domain may function as a molecular chaperone to directly bind to and suppress the aggregation of a number of misfolded model proteins. The data strongly support the hypothesis that the PERK luminal domain can interact directly with misfolded proteins to induce ER stress signaling. To illustrate the mechanism by which the PERK luminal domain interacts with misfolded proteins, the crystal structure of the human PERK luminal domain was determined to 3.2 Å resolution. Two dimers of the PERK luminal domain constitute a tetramer in the asymmetric unit. Superimposition of the PERK luminal domain molecules indicated that the β-sandwich domain could adopt multiple conformations. It is hypothesized that the PERK luminal domain may utilize its flexible β-sandwich domain to recognize and interact with a broad range of misfolded proteins.

  20. Astragalus polysaccharide modulates ER stress response in an OVA-LPS induced murine model of severe asthma.

    PubMed

    Lu, Yuan; Xing, Qiong-Qiong; Xu, Jian-Ya; Ding, Dou; Zhao, Xia

    2016-12-01

    Endoplasmic reticulum (ER) stress has been recently revealed to play a pivotal role in the pathogenesis of severe asthma. Astragalus polysaccharide (APS), a major bioactive component from Astragalus membranaceus, exerts immunomodulatory and anti-inflammatory effects and has been shown to suppress ER stress in chronic diseases such as type-2 diabetes. However, the pharmaceutical application of APS in the treatment of severe asthma is unknown. The results obtained here indicate that APS significantly attenuates eosinophils and neutrophil-dominant airway inflammation by reducing the mRNA levels of Cxcl5, Il8, and chemokine (C-C motif) ligand 20 (Ccl20) and the protein levels of IL13RA and IL17RA. APS also inhibits the activation of unfolded protein response by decreasing the levels of ER stress markers such as C/EBP homologous protein (CHOP), which was associated with a reduction of PERK phosphorylation. Moreover, APS substantially blocks the nuclear translocation of ATF6 and NF-κB p65. Interestingly, we observed that APS markedly suppresses mucus hypersecretion by decreasing the levels of mucin (MUC) 5AC and MUC5B, which might be due to inhibition of goblet cells differentiation by suppressing the expression of IRE1β-correlated genes. In summary, APS can have potential pharmaceutical application in treatment of severe asthma.

  1. The ER stress sensor PERK luminal domain functions as a molecular chaperone to interact with misfolded proteins.

    PubMed

    Wang, Peng; Li, Jingzhi; Sha, Bingdong

    2016-12-01

    PERK is one of the major sensor proteins which can detect the protein-folding imbalance generated by endoplasmic reticulum (ER) stress. It remains unclear how the sensor protein PERK is activated by ER stress. It has been demonstrated that the PERK luminal domain can recognize and selectively interact with misfolded proteins but not native proteins. Moreover, the PERK luminal domain may function as a molecular chaperone to directly bind to and suppress the aggregation of a number of misfolded model proteins. The data strongly support the hypothesis that the PERK luminal domain can interact directly with misfolded proteins to induce ER stress signaling. To illustrate the mechanism by which the PERK luminal domain interacts with misfolded proteins, the crystal structure of the human PERK luminal domain was determined to 3.2 Å resolution. Two dimers of the PERK luminal domain constitute a tetramer in the asymmetric unit. Superimposition of the PERK luminal domain molecules indicated that the β-sandwich domain could adopt multiple conformations. It is hypothesized that the PERK luminal domain may utilize its flexible β-sandwich domain to recognize and interact with a broad range of misfolded proteins.

  2. Salivary Markers of Inflammation in Response to Acute Stress

    PubMed Central

    Slavish, Danica C.; Graham-Engeland, Jennifer E.; Smyth, Joshua M.; Engeland, Christopher G.

    2014-01-01

    There is burgeoning interest in the ability to detect inflammatory markers in response to stress within naturally occurring social contexts and/or across multiple time points per day within individuals. Salivary collection is a less invasive process than current methods of blood collection and enables intensive naturalistic methodologies, such as those involving extensive repeated measures per day over time. Yet the reliability and validity of saliva-based to blood-based inflammatory biomarkers in response to stress remains unclear. We review and synthesize the published studies that have examined salivary markers of inflammation following exposure to an acute laboratory stressor. Results from each study are reviewed by analyte (IL-1β, TNF-α, IL-6, IL-2, IL-4, IL-10, IL-12, CRP) and stress type (social-cognitive and exercise-physical), after which methodological issues and limitations are addressed. Although the literature is limited, several inflammatory markers (including IL-1β, TNF-α, and IL-6) have been reliably determined from saliva and have increased significantly in response to stress across multiple studies, with effect sizes ranging from very small to very large. Although CRP from saliva has been associated with CRP in circulating blood more consistently than other biomarkers have been associated with their counterparts in blood, evidence demonstrating it reliably responds to acute stress is absent. Although the current literature is presently too limited to allow broad assertion that inflammatory biomarkers determined from saliva are valuable for examining acute stress responses, this review suggests that specific targets may be valid and highlights specific areas of need for future research. PMID:25205395

  3. Fluoxetine and diazepam acutely modulate stress induced-behavior.

    PubMed

    Giacomini, Ana Cristina V V; Abreu, Murilo S; Giacomini, Luidia V; Siebel, Anna M; Zimerman, Fernanda F; Rambo, Cassiano L; Mocelin, Ricieri; Bonan, Carla D; Piato, Angelo L; Barcellos, Leonardo J G

    2016-01-01

    Drug residue contamination in aquatic ecosystems has been studied extensively, but the behavioral effects exerted by the presence of these drugs are not well known. Here, we investigated the effects of acute stress on anxiety, memory, social interaction, and aggressiveness in zebrafish exposed to fluoxetine and diazepam at concentrations that disrupt the hypothalamic-pituitary-interrenal (HPI) axis. Stress increased the locomotor activity and time spent in the bottom area of the tank (novel tank). Fluoxetine and diazepam prevented these behaviors. We also observed that stress and fluoxetine and diazepam exposures decreased social interaction. Stress also increased aggressive behavior, which was not reversed by fluoxetine or diazepam. These data suggest that the presence of these drugs in aquatic ecosystems causes significant behavioral alterations in fish.

  4. Acute stress is detrimental to heart regeneration in zebrafish

    PubMed Central

    Sallin, Pauline; Jaźwińska, Anna

    2016-01-01

    Psychological stress is one of the factors associated with human cardiovascular disease. Here, we demonstrate that acute perceived stress impairs the natural capacity of heart regeneration in zebrafish. Beside physical and chemical disturbances, intermittent crowding triggered an increase in cortisol secretion and blocked the replacement of fibrotic tissue with new myocardium. Pharmacological simulation of stress by pulse treatment with dexamethasone/adrenaline reproduced the regeneration failure, while inhibition of the stress response with anxiolytic drugs partially rescued the regenerative process. Impaired heart regeneration in stressed animals was associated with a reduced cardiomyocyte proliferation and with the downregulation of several genes, including igfbp1b, a modulator of IGF signalling. Notably, daily stress induced a decrease in Igf1r phosphorylation. As cardiomyocyte proliferation was decreased in response to IGF-1 receptor inhibition, we propose that the stress-induced cardiac regenerative failure is partially caused by the attenuation of IGF signalling. These findings indicate that the natural regenerative ability of the zebrafish heart is vulnerable to the systemic paracrine stress response. PMID:27030176

  5. Psychological acute stress measurement using a wireless adhesive biosensor.

    PubMed

    Selvaraj, Nandakumar

    2015-01-01

    Stress management is essential in this modern civilization to maintain one's stress level low and reduce health risks, since stress is one of the primary causes leading to major chronic health disorders. The present study investigates the validity of stress index (SI) metric that objectively quantifies the psychological acute stress using a disposable adhesive biosensor worn on the chest called as HealthPatch(®). Eleven healthy volunteers (n=11) were attached with one HealthPatch sensor at left pectoralis major muscle along the cardiac axis to record modified Lead-II ECG. The subjects carried out a standard Trier Social Stress Test (TSST) protocol. During the study, the subjects filled out state anxiety form-Y1 of the State Anxiety Inventory questionnaire (sSTAI); salivary samples were obtained for salivary alpha-amylase (sAA) and salivary cortisol (sC) measurements; and the HealthPatch sensor data were wirelessly acquired. The data analyses revealed that sSTAI scores were significantly increased (P<0.001) due to TSST compared to the baseline. But, the changes in both sAA and sC measurements were not significant (P=0.281 and P=0.792, respectively). On the other hand, SI metric of HealthPatch showed significant (P<0.001) increase (~50%) during TSST, and shown to be sensitive to objectively track acute changes in psychological stress. Thus, HealthPatch biosensor can be valuable for continuous monitoring of psychological health and effective management of stress leading to healthy life.

  6. Acute stress elicited by bungee jumping suppresses human innate immunity.

    PubMed

    van Westerloo, David J; Choi, Goda; Löwenberg, Ester C; Truijen, Jasper; de Vos, Alex F; Endert, Erik; Meijers, Joost C M; Zhou, Lu; Pereira, Manuel P F L; Queiroz, Karla C S; Diks, Sander H; Levi, Marcel; Peppelenbosch, Maikel P; van der Poll, Tom

    2011-01-01

    Although a relation between diminished human immunity and stress is well recognized both within the general public and the scientific literature, the molecular mechanisms by which stress alters immunity remain poorly understood. We explored a novel model for acute human stress involving volunteers performing a first-time bungee jump from an altitude of 60 m and exploited this model to characterize the effects of acute stress in the peripheral blood compartment. Twenty volunteers were included in the study; half of this group was pretreated for 3 d with the β-receptor blocking agent propranolol. Blood was drawn 2 h before, right before, immediately after and 2 h after the jump. Plasma catecholamine and cortisol levels increased significantly during jumping, which was accompanied by significantly reduced ex vivo inducibility of proinflammatory cytokines as well as activation of coagulation and vascular endothelium. Kinome profiles obtained from the peripheral blood leukocyte fraction contained a strong noncanonical glucocorticoid receptor signal transduction signature after jumping. In apparent agreement, jumping down-regulated Lck/Fyn and cellular innate immune effector function (phagocytosis). Pretreatment of volunteers with propranolol abolished the effects of jumping on coagulation and endothelial activation but left the inhibitory effects on innate immune function intact. Taken together, these results indicate that bungee jumping leads to a catecholamine-independent immune suppressive phenotype and implicate noncanonical glucocorticoid receptor signal transduction as a major pathway linking human stress to impaired functioning of the human innate immune system.

  7. Acute Stress Elicited by Bungee Jumping Suppresses Human Innate Immunity

    PubMed Central

    van Westerloo, David J; Choi, Goda; Löwenberg, Ester C; Truijen, Jasper; de Vos, Alex F; Endert, Erik; Meijers, Joost C M; Zhou, Lu; Pereira, Manuel PFL; Queiroz, Karla CS; Diks, Sander H; Levi, Marcel; Peppelenbosch, Maikel P; van der Poll, Tom

    2011-01-01

    Although a relation between diminished human immunity and stress is well recognized both within the general public and the scientific literature, the molecular mechanisms by which stress alters immunity remain poorly understood. We explored a novel model for acute human stress involving volunteers performing a first-time bungee jump from an altitude of 60 m and exploited this model to characterize the effects of acute stress in the peripheral blood compartment. Twenty volunteers were included in the study; half of this group was pretreated for 3 d with the β-receptor blocking agent propranolol. Blood was drawn 2 h before, right before, immediately after and 2 h after the jump. Plasma catecholamine and cortisol levels increased significantly during jumping, which was accompanied by significantly reduced ex vivo inducibility of proinflammatory cytokines as well as activation of coagulation and vascular endothelium. Kinome profiles obtained from the peripheral blood leukocyte fraction contained a strong noncanonical glucocorticoid receptor signal transduction signature after jumping. In apparent agreement, jumping down-regulated Lck/Fyn and cellular innate immune effector function (phagocytosis). Pretreatment of volunteers with propranolol abolished the effects of jumping on coagulation and endothelial activation but left the inhibitory effects on innate immune function intact. Taken together, these results indicate that bungee jumping leads to a catecholamine-independent immune suppressive phenotype and implicate noncanonical glucocorticoid receptor signal transduction as a major pathway linking human stress to impaired functioning of the human innate immune system. PMID:21203694

  8. Acute Stress in Parents of Children Newly Diagnosed With Cancer

    PubMed Central

    Patiño-Fernández, Anna Maria; Pai, Ahna L.H.; Alderfer, Melissa; Hwang, Wei-Ting; Reilly, Anne; Kazak, Anne E.

    2010-01-01

    Objective Acute Stress Disorder (ASD) and subclinical symptoms of acute stress (SAS) may be a useful framework for understanding the psychological reactions of mothers and fathers of children newly diagnosed with a pediatric malignancy. Patients and Methods Mothers (N = 129) and fathers (N = 72) of 138 children newly diagnosed with cancer completed questionnaires assessing acute distress, anxiety, and family functioning. Demographic data were also gathered. Inclusion criteria were: a confirmed diagnosis of a pediatric malignancy in a child under the age of 18 years without prior chronic or life threatening illness and fluency in English or Spanish. Results Descriptive statistics and multiple linear regressions were used to examine predictors of SAS. Fifty-one percent (N = 66) of mothers and 40% (N = 29) of fathers met DSM-IV diagnostic criteria for ASD. The majority of the sample reported experiencing at least one SAS. General anxiety, but not family functioning, was a strong predictor of SAS in both mothers and fathers even after controlling for demographic characteristics. Conclusions Immediately following their child’s diagnosis of cancer, most mothers and fathers experience SAS, with a subsample meeting criteria for ASD. More anxious parents are at heightened risk of more intense reactions. The findings support the need for evidence-based psychosocial support at diagnosis and throughout treatment for families who are at risk for acute distress reactions. PMID:17514742

  9. Influence of Acute Coffee Consumption on Postprandial Oxidative Stress

    PubMed Central

    Bloomer, Richard J.; Trepanowski, John F.; Farney, Tyler M.

    2013-01-01

    Background: Coffee has been reported to be rich in antioxidants, with both acute and chronic consumption leading to enhanced blood antioxidant capacity. High-fat feeding is known to result in excess production of reactive oxygen and nitrogen species, promoting a condition of postprandial oxidative stress. Methods: We tested the hypothesis that coffee intake following a high-fat meal would attenuate the typical increase in blood oxidative stress during the acute postprandial period. On 3 different occasions, 16 men and women consumed a high-fat milk shake followed by either 16 ounces of caffeinated or decaffeinated coffee or bottled water. Blood samples were collected before and at 2 and 4 hours following intake of the milk shake and analyzed for triglycerides (TAG), malondialdehyde (MDA), hydrogen peroxide (H2O2), and Trolox equivalent antioxidant capacity (TEAC). Results: Values for TAG and MDA (P < 0.001), as well as for H2O2 (P < 0.001), increased significantly following milk shake consumption, with values higher at 4 hours compared with 2 hours post consumption for TAG and H2O2 (P < 0.05). TEAC was unaffected by the milk shake consumption. Coffee had no impact on TAG, MDA, H2O2, or TEAC, with no condition or interaction effects noted for any variable (P > 0.05). Conclusions: Acute coffee consumption following a high-fat milk shake has no impact on postprandial oxidative stress. PMID:23935371

  10. Influence of acute stress on spatial tasks in humans.

    PubMed

    Richardson, Anthony E; VanderKaay Tomasulo, Melissa M

    2011-07-06

    Few studies have investigated the relationship between stress and spatial performance in humans. In this study, participants were exposed to an acute laboratory stressor (Star Mirror Tracing Task) or a control condition (watching a nature video) and then performed two spatial tasks. In the first task, participants navigated through a virtual reality (VR) environment and then returned to the environment to make directional judgments relating to the learned targets. In the second task, perspective taking, participants made directional judgments to targets after imagined body rotations with respect to a map. Compared to the control condition, participants in the Stress condition showed increases in heart rate and systolic and diastolic blood pressure indicating sympathetic adrenal medulla (SAM) axis activation. Participants in the Stress condition also reported being more anxious, angry, frustrated, and irritated than participants in the Non-Stress condition. Salivary cortisol did not differ between conditions, indicating no significant hypothalamic-pituitary-adrenocortical (HPA) axis involvement. In the VR task, memory encoding was unaffected as directional error was similar in both conditions; however, participants in the Stress condition responded more slowly, which may be due to increases in negative affect, SAM disruption in spatial memory retrieval through catecholamine release, or a combination of both factors. In the perspective taking task, participants were also slower to respond after stress, suggesting interference in the ability to adopt new spatial orientations. Additionally, sex differences were observed in that men had greater accuracy on both spatial tasks, but no significant Sex by Stress condition interactions were demonstrated.

  11. Personality and physiological reactions to acute psychological stress.

    PubMed

    Bibbey, Adam; Carroll, Douglas; Roseboom, Tessa J; Phillips, Anna C; de Rooij, Susanne R

    2013-10-01

    Stable personality traits have long been presumed to have biological substrates, although the evidence relating personality to biological stress reactivity is inconclusive. The present study examined, in a large middle aged cohort (N=352), the relationship between key personality traits and both cortisol and cardiovascular reactions to acute psychological stress. Salivary cortisol and cardiovascular activity were measured at rest and in response to a psychological stress protocol comprising 5min each of a Stroop task, mirror tracing, and a speech task. Participants subsequently completed the Big Five Inventory to assess neuroticism, agreeableness, openness to experience, extraversion, and conscientiousness. Those with higher neuroticism scores exhibited smaller cortisol and cardiovascular stress reactions, whereas participants who were less agreeable and less open had smaller cortisol and cardiac reactions to stress. These associations remained statistically significant following adjustment for a range of potential confounding variables. Thus, a negative personality disposition would appear to be linked to diminished stress reactivity. These findings further support a growing body of evidence which suggests that blunted stress reactivity may be maladaptive.

  12. Resilience as a correlate of acute stress disorder symptoms in patients with acute myocardial infarction

    PubMed Central

    Meister, Rebecca E; Weber, Tania; Princip, Mary; Schnyder, Ulrich; Barth, Jürgen; Znoj, Hansjörg; Schmid, Jean-Paul; von Känel, Roland

    2015-01-01

    Objectives Myocardial infarction (MI) may be experienced as a traumatic event causing acute stress disorder (ASD). This mental disorder has an impact on the daily life of patients and is associated with the development of post-traumatic stress disorder. Trait resilience has been shown to be a protective factor for post-traumatic stress disorder, but its association with ASD in patients with MI is elusive and was examined in this study. Methods We investigated 71 consecutive patients with acute MI within 48 h of having stable haemodynamic conditions established and for 3 months thereafter. All patients completed the Acute Stress Disorder Scale and the Resilience Scale to self-rate the severity of ASD symptoms and trait resilience, respectively. Results Hierarchical regression analysis showed that greater resilience was associated with lower symptoms of ASD independent of covariates (b=−0.22, p<0.05). Post hoc analysis revealed resilience level to be inversely associated with the ASD symptom clusters of re-experiencing (b=−0.05, p<0.05) and arousal (b=−0.09, p<0.05), but not with dissociation and avoidance. Conclusions The findings suggest that patients with acute MI with higher trait resilience experience relatively fewer symptoms of ASD during MI. Resilience was particularly associated with re-experiencing and arousal symptoms. Our findings contribute to a better understanding of resilience as a potentially important correlate of ASD in the context of traumatic situations such as acute MI. These results emphasise the importance of identifying patients with low resilience in medical settings and to offer them adequate support. PMID:26568834

  13. Acute restraint stress induces endothelial dysfunction: role of vasoconstrictor prostanoids and oxidative stress.

    PubMed

    Carda, Ana P P; Marchi, Katia C; Rizzi, Elen; Mecawi, André S; Antunes-Rodrigues, José; Padovan, Claudia M; Tirapelli, Carlos R

    2015-01-01

    We hypothesized that acute stress would induce endothelial dysfunction. Male Wistar rats were restrained for 2 h within wire mesh. Functional and biochemical analyses were conducted 24 h after the 2-h period of restraint. Stressed rats showed decreased exploration on the open arms of an elevated-plus maze (EPM) and increased plasma corticosterone concentration. Acute restraint stress did not alter systolic blood pressure, whereas it increased the in vitro contractile response to phenylephrine and serotonin in endothelium-intact rat aortas. NG-nitro-l-arginine methyl ester (l-NAME; nitric oxide synthase, NOS, inhibitor) did not alter the contraction induced by phenylephrine in aortic rings from stressed rats. Tiron, indomethacin and SQ29548 reversed the increase in the contractile response to phenylephrine induced by restraint stress. Increased systemic and vascular oxidative stress was evident in stressed rats. Restraint stress decreased plasma and vascular nitrate/nitrite (NOx) concentration and increased aortic expression of inducible (i) NOS, but not endothelial (e) NOS. Reduced expression of cyclooxygenase (COX)-1, but not COX-2, was observed in aortas from stressed rats. Restraint stress increased thromboxane (TX)B(2) (stable TXA(2) metabolite) concentration but did not affect prostaglandin (PG)F2α concentration in the aorta. Restraint reduced superoxide dismutase (SOD) activity, whereas concentrations of hydrogen peroxide (H(2)O(2)) and reduced glutathione (GSH) were not affected. The major new finding of our study is that restraint stress increases vascular contraction by an endothelium-dependent mechanism that involves increased oxidative stress and the generation of COX-derived vasoconstrictor prostanoids. Such stress-induced endothelial dysfunction could predispose to the development of cardiovascular diseases.

  14. Resveratrol triggers ER stress-mediated apoptosis by disrupting N-linked glycosylation of proteins in ovarian cancer cells.

    PubMed

    Gwak, HyeRan; Kim, Soochi; Dhanasekaran, Danny N; Song, Yong Sang

    2016-02-28

    Malignant tumors have a high glucose demand and alter cellular metabolism to survive. Herein, focusing on the utility of glucose metabolism as a therapeutic target, we found that resveratrol induced endoplasmic reticulum (ER) stress-mediated apoptosis by interrupting protein glycosylation in a cancer-specific manner. Our results indicated that resveratrol suppressed the hexosamine biosynthetic pathway and interrupted protein glycosylation through GSK3β activation. Application of either biochemical intermediates of the hexosamine pathway or small molecular inhibitors of GSK3β reversed the effects of resveratrol on the disruption of protein glycosylation. Additionally, an ER UDPase, ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), modulated protein glycosylation by Akt attenuation in response to resveratrol. By inhibition or overexpression of Akt functions, we confirmed that the glycosylation activities were dependent on ENTPD5 expression and regulated by the action of Akt in ovarian cancer cells. Resveratrol-mediated disruption of protein glycosylation induced cellular apoptosis as indicated by the up-regulation of GADD153, followed by the activation of ER-stress sensors (PERK and ATF6α). Thus, our results provide novel insight into cancer cell metabolism and protein glycosylation as a therapeutic target for cancers.

  15. α-Synuclein is involved in manganese-induced ER stress via PERK signal pathway in organotypic brain slice cultures.

    PubMed

    Xu, Bin; Wang, Fei; Wu, Sheng-Wen; Deng, Yu; Liu, Wei; Feng, Shu; Yang, Tian-Yao; Xu, Zhao-Fa

    2014-02-01

    Overexposure to manganese (Mn) has been known to induce neuronal damage involving endoplasmic reticulum (ER) stress. However, the exact mechanism of Mn-induced ER stress is unclear. Increasing evidence suggested that the overexpression of alpha-synuclein played a critical role in Mn-induced neurotoxicity. To explore whether the occurrence of ER stress was associated with alpha-synuclein overexpression, we made the rat brain slices model of silencing alpha-synuclein using short-interference RNA. After non-silencing alpha-synuclein slices were treated with Mn (0-400 μM) for 24 h, there was a dose-dependent increase in apoptotic rates of cells and levels of lactate dehydrogenase in the culture medium. Moreover, there was a dose-dependent increase in the protein expression of 78, 94-kDa glucose-regulated protein (GRP78/94), C/EBP homologous protein (CHOP), and caspase-12. Moreover, PKR-like ER kinase (PERK) phosphorylation, PERK-mediated phosphorylation of eIF2a, and ATF4 expression also increased. Inositol-requiring enzyme 1 (IRE1) activation and X-box-binding protein-1 (Xbp1) mRNA splicing increased. Activating transcription factor 6 p90 levels did not change. However, after silencing alpha-synuclein slices were treated with 400 μM Mn for 24 h, there was a significant decrease in the expression of GRP78/94, CHOP, and caspase-12 compared with 400 μM Mn-treated non-silencing alpha-synuclein slices. Furthermore, PERK phosphorylation, PERK-mediated phosphorylation of eIF2a, and ATF4 mRNA expression also decreased. However, IRE1 phosphorylation and Xbp1 mRNA splicing did not change. The findings revealed that Mn induced ER stress via activation of PERK and IRE1 signaling pathways and subsequent apoptosis in cultured slices. Moreover, alpha-synuclein protein was associated with Mn-induced activation of PERK signaling pathway.

  16. Quercetin induces protective autophagy and apoptosis through ER stress via the p-STAT3/Bcl-2 axis in ovarian cancer.

    PubMed

    Liu, Y; Gong, W; Yang, Z Y; Zhou, X S; Gong, C; Zhang, T R; Wei, X; Ma, D; Ye, F; Gao, Q L

    2017-04-01

    Quercetin (3,3',4',5,7-pentahydroxyflavone, Qu) is a promising cancer chemo-preventive agent for various cancers because it inhibits disease progression and promotes apoptotic cell death. In our previous study, we demonstrated that Qu could evoke ER stress to enhance drug cytotoxicity in ovarian cancer (OC). However, Qu-induced ER stress in OC is still poorly understood. Here, we demonstrated that Qu evoked ER stress to involve in mitochondria apoptosis pathway via the p-STAT3/Bcl-2 axis in OC cell lines and in primary OC cells. Unexpectedly, inhibition of ER stress did not reverse Qu-induced cell death. Further functional studies revealed that Qu-induced ER stress could activate protective autophagy concomitantly by activating the p-STAT3/Bcl-2 axis in this process. Moreover, the autophagy scavenger 3-MA was shown to enhance Qu's anticancer effects in an ovarian cancer mice xenograft model. These findings revealed a novel role of ER stress as a "double edge sword" participating in Qu-induced apoptosis of OC and might provide a new angle to consider in clinical studies of biological modifiers that may circumvent drug resistance in patients by targeting protective autophagy pathways.

  17. Reducing Smad3/ATF4 was essential for Sirt1 inhibiting ER stress-induced apoptosis in mice brown adipose tissue.

    PubMed

    Liu, Zhenjiang; Gu, Huihui; Gan, Lu; Xu, Yatao; Feng, Fei; Saeed, Muhammad; Sun, Chao

    2017-02-07

    Sirtuin 1 (Sirt1) promotes adaptive thermogenesis by controlling the acetylation status of enzymes and transcriptional factors in interscapular brown adipose tissue (iBAT). However, the effects of Sirt1 on endoplasmic reticulum (ER) stress and apoptosis of iBAT remain elusive. In this study, the mRNA levels of Sirt1 and thermogenesis genes were reduced but the genes related with ER stress were elevated in iBAT of high-fat diet (HFD)-induced obese mice. Moreover, ER stress further inhibited mRNA level of Sirt1 and triggered brown adipocyte apoptosis in vitro and in vivo. Further analysis revealed that Sirt1 overexpression alleviated ER stress-induced brown adipocyte apoptosis by inhibiting Smad3 and ATF4. In addition, Smad3 bound to ATF4 promoter region and positively transcriptional regulation of ATF4. Our data also confirmed that Sirt1 reduced early apoptotic cells and blocked the mitochondrial apoptosis pathway by directly interacting with ATF4. Furthermore, Sirt1 attenuated tunicamycin-induced cold intolerance and elevating thermogenesis by inhibiting ER stress and apoptosis in iBAT. In summary, our data collectively revealed Sirt1 reduced ER stress and apoptosis of brown adipocyte in vivo and in vitro by inhibiting Smad3/ATF4 signal. These data reveal a novel mechanism that links Sirt1 to brown adipocyte apoptosis.

  18. Acute exercise and oxidative stress: a 30 year history

    PubMed Central

    Fisher-Wellman, Kelsey; Bloomer, Richard J

    2009-01-01

    The topic of exercise-induced oxidative stress has received considerable attention in recent years, with close to 300 original investigations published since the early work of Dillard and colleagues in 1978. Single bouts of aerobic and anaerobic exercise can induce an acute state of oxidative stress. This is indicated by an increased presence of oxidized molecules in a variety of tissues. Exercise mode, intensity, and duration, as well as the subject population tested, all can impact the extent of oxidation. Moreover, the use of antioxidant supplements can impact the findings. Although a single bout of exercise often leads to an acute oxidative stress, in accordance with the principle of hormesis, such an increase appears necessary to allow for an up-regulation in endogenous antioxidant defenses. This review presents a comprehensive summary of original investigations focused on exercise-induced oxidative stress. This should provide the reader with a well-documented account of the research done within this area of science over the past 30 years. PMID:19144121

  19. Sleep Disturbance and Older Adults' Inflammatory Responses to Acute Stress

    PubMed Central

    Heffner, Kathi L.; Ng, H. Mei; Suhr, Julie A.; France, Christopher R.; Marshall, Gailen D.; Pigeon, Wilfred R.; Moynihan, Jan A.

    2013-01-01

    Objectives Poor sleep diminishes mental and physical health. The objective of this study was to examine associations between sleep disturbance and interleukin-6 (IL-6) responses to acute mental stress in older adults. Design Observational study of community-dwelling, healthy older adults. Setting Participants completed the study in a clinical research laboratory of a mid-sized university. Participants Generally healthy, community-dwelling men and women 50 years of age and older. Measurements IL-6 and negative affect at rest and following a series of challenging cognitive tests; sleep quality; depressive symptoms; perceived stress; loneliness. Results Participants categorized as poor sleepers based on Pittsburgh Sleep Quality Index scores had significantly larger IL-6 responses to the cognitive stressors compared to good sleepers. The association between poor sleep and heightened IL-6 response to acute stress was not explained by other psychosocial factors previously linked to immune dysregulation, including depressive symptoms, perceived stress, and loneliness. Conclusions Findings add to the growing evidence for poor sleep as an independent risk factor for poor mental and physical health. Older adults may be particularly vulnerable to effects of sleep disturbance due to significant age-related changes in both sleep and inflammatory regulation. PMID:22327621

  20. Activation of large-conductance Ca(2+)-activated K(+) channels inhibits glutamate-induced oxidative stress through attenuating ER stress and mitochondrial dysfunction.

    PubMed

    Yan, Xiao-Hua; Guo, Xiang-Yang; Jiao, Fu-Yong; Liu, Xuan; Liu, Yong

    2015-11-01

    Large-conductance Ca(2+)-activated K(+) channels (BK channels) are widely expressed throughout the vertebrate nervous system, and are involved in the regulation of neurotransmitter release and neuronal excitability. Here, the neuroprotective effects of NS11021, a selective and chemically unrelated BK channel activator, and potential molecular mechanism involved have been studied in rat cortical neurons exposed to glutamate in vitro. Pretreatment with NS11021 significantly inhibited the loss of neuronal viability, LDH release and neuronal apoptosis in a dose-dependent manner. All these protective effects were fully antagonized by the BK-channel inhibitor paxilline. NS11021-induced neuroprotection was associated with reduced oxidative stress, as evidenced by decreased reactive oxygen species (ROS) generation, lipid peroxidation and preserved activity of antioxidant enzymes. Moreover, NS11021 significantly attenuated the glutamate-induced endoplasmic reticulum (ER) calcium release and activation of ER stress markers, including glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and caspase-12. Pretreatment with NS11021 also mitigated the mitochondrial membrane potential (MMP) collapse, cytochrome c release, and preserved mitochondrial Ca(2+) buffering capacity and ATP synthesis after glutamate exposure. Taken together, these results suggest that activation of BK channels via NS11021 protects cortical neurons against glutamate-induced excitatory damage, which may be dependent on the inhibition of ER stress and preservation of mitochondrial dysfunction.

  1. Glutamatergic Mechanisms of Comorbidity Between Acute Stress and Cocaine Self-administration

    PubMed Central

    Garcia-Keller, Constanza; Kupchik, Yonatan; Gipson, Cassandra D; Brown, Robyn M; Spencer, Sade; Bollati, Flavia; Esparza, Maria A; Roberts-Wolfe, Doug; Heinsbroek, Jasper; Bobadilla, Ana-Clara; Cancela, Liliana M; Kalivas, Peter W

    2015-01-01

    There is substantial comorbidity between stress disorders and substance use disorders (SUDs), and acute stress augments the locomotor stimulant effect of cocaine in animal models. Here we endeavor to understand the neural underpinnings of comorbid stress disorders and drug use by determining if the glutamatergic neuroadaptations that characterize cocaine self-administration are induced by acute stress. Rats were exposed to acute (2 h) immobilization stress and 3 weeks later the nucleus accumbens core was examined for changes in glutamate transport, glutamate mediated synaptic currents, and dendritic spine morphology. We also determined if acute stress potentiated the acquisition of cocaine self-administration. Acute stress produced an enduring reduction in glutamate transport, and potentiated excitatory synapses on medium spiny neurons. Acute stress also augmented the acquisition of cocaine self-administration. Importantly, by restoring glutamate transport in the accumbens core with ceftriaxone the capacity of acute stress to augment the acquisition of cocaine self-administration was abolished. Similarly, ceftriaxone treatment prevented stress-induced potentiation of cocaine-induced locomotor activity. However, ceftriaxone did not reverse stress-induced synaptic potentiation, indicating that this effect of stress exposure did not underpin the increased acquisition of cocaine self-administration. Reversing acute stress-induced vulnerability to self-administer cocaine by normalizing glutamate transport poses a novel treatment possibility for reducing comorbid SUDs in stress disorders. PMID:26821978

  2. ATG14 facilitated lipophagy in cancer cells induce ER stress mediated mitoptosis through a ROS dependent pathway.

    PubMed

    Mukhopadhyay, Subhadip; Schlaepfer, Isabel R; Bergman, Bryan C; Panda, Prashanta Kumar; Praharaj, Prakash Priyadarshi; Naik, Prajna Paramita; Agarwal, Rajesh; Bhutia, Sujit Kumar

    2017-03-01

    Understanding the dynamics of autophagy and apoptosis crosstalk in cancer progression remains a challenging task. Here, we reported how the autophagy protein ATG14 induces lipophagy-mediated mitochondrial apoptosis. The overexpression of ATG14 in HeLa cells inhibited cell viability and increased mitochondrial apoptosis and endoplasmic reticulum (ER) stress. Furthermore, inhibition of this ATG14-induced autophagy promoted apoptosis. ATG14 overexpression resulted in the accumulation of free fatty acids (FFA), with a concomitant decrease in the number of lipid droplets. Our data showed that ER stress induced by ATG14 was due to the lipophagy-mediated FFA accumulation, which resulted in ROS-dependent mitochondrial stress leading to apoptosis. Inhibition of lipophagy in HeLa-ATG14 cells enhanced the cellular viability and rescued them from lipotoxicity. Mechanistically, we found that ATG14 interacted with Ulk1 and LC3, and knock down of Ulk1 prevented the lipidation of LC3 and autophagy in HeLa-ATG14 cells. We also identified a phosphatidylethanolamine (PE) binding region in ATG14, and the addition of Ulk1 to Hela-ATG14 cells decreased the ATG14-PE interaction. Lastly, confocal microscopy studies showed that the decrease in ATG14-PE binding was concomitant with the increase in LC3 lipidation over time, confirming the importance of Ulk1 to sort PE to LC3 during ATG14 mediated lipophagy induction. In conclusion, ATG14 and Ulk1 interact to induce lipophagy resulting in FFA accumulation leading to ER stress-mediated apoptosis.

  3. Acute stress impairs the retrieval of extinction memory in humans

    PubMed Central

    Raio, Candace M.; Brignoni-Perez, Edith; Goldman, Rachel; Phelps, Elizabeth A.

    2014-01-01

    Extinction training is a form of inhibitory learning that allows an organism to associate a previously aversive cue with a new, safe outcome. Extinction does not erase a fear association, but instead creates a competing association that may or may not be retrieved when a cue is subsequently encountered. Characterizing the conditions under which extinction learning is expressed is important to enhancing the treatment of anxiety disorders that rely on extinction-based exposure therapy as a primary treatment technique. The ventromedial prefrontal cortex, which plays an important role in the expression of extinction memory, has been shown to be functionally impaired after stress exposure. Further, recent research in rodents found that exposure to stress led to deficits in extinction retrieval, although this has yet to be tested in humans. To explore how stress might influence extinction retrieval in humans, participants underwent a differential aversive learning paradigm, in which one image was probabilistically paired with an aversive shock while the other image denoted safety. Extinction training directly followed, at which point reinforcement was omitted. A day later, participants returned to the lab and either completed an acute stress manipulation (i.e., cold pressor), or a control task, before undergoing an extinction retrieval test. Skin conductance responses and salivary cortisol concentrations were measured throughout each session as indices of fear arousal and neuroendocrine stress responses, respectively. The efficacy of our stress induction was established by observing significant increases in cortisol for the stress condition only. We examined extinction retrieval by comparing conditioned responses during the last trial of extinction (day 1) with that of the first trial of re-extinction (day 2). Groups did not differ on initial fear acquisition or extinction, however, one day later participants in the stress group (n = 27) demonstrated significantly less

  4. Acute stress impairs the retrieval of extinction memory in humans.

    PubMed

    Raio, Candace M; Brignoni-Perez, Edith; Goldman, Rachel; Phelps, Elizabeth A

    2014-07-01

    Extinction training is a form of inhibitory learning that allows an organism to associate a previously aversive cue with a new, safe outcome. Extinction does not erase a fear association, but instead creates a competing association that may or may not be retrieved when a cue is subsequently encountered. Characterizing the conditions under which extinction learning is expressed is important to enhancing the treatment of anxiety disorders that rely on extinction-based exposure therapy as a primary treatment technique. The ventromedial prefrontal cortex, which plays a critical role in the expression of extinction memory, has been shown to be functionally impaired after stress exposure. Further, recent work in rodents has demonstrated that exposure to stress leads to deficits in extinction retrieval, although this has yet to be tested in humans. To explore how stress might influence extinction retrieval in humans, participants underwent a differential aversive learning paradigm, in which one image was probabilistically paired with an aversive shock while the other image denoted safety. Extinction training directly followed, at which point reinforcement was omitted. A day later, participants returned to the lab and either completed an acute stress manipulation (i.e., cold pressor), or a control task, before undergoing an extinction retrieval test. Skin conductance responses and salivary cortisol concentrations were measured throughout each session as indices of fear arousal and neuroendocrine stress response, respectively. The efficacy of our stress induction was established by observing significant increases in cortisol for the stress condition only. We examined extinction retrieval by comparing conditioned responses during the last trial of extinction (day 1) with that of the first trial of re-extinction (day 2). Groups did not differ on initial fear acquisition or extinction, however, a day later participants in the stress group (n=27) demonstrated significantly

  5. Acute hypertension induces oxidative stress in brain tissues.

    PubMed

    Poulet, Roberta; Gentile, Maria T; Vecchione, Carmine; Distaso, Maria; Aretini, Alessandra; Fratta, Luigi; Russo, Giovanni; Echart, Cinara; Maffei, Angelo; De Simoni, Maria G; Lembo, Giuseppe

    2006-02-01

    Arterial hypertension is not only a major risk factor for cerebrovascular accidents, such as stroke and cerebral hemorrhage, but is also associated to milder forms of brain injury. One of the main causes of neurodegeneration is the increase in reactive oxygen species (ROS) that is also a common trait of hypertensive conditions, thus suggesting that such a mechanism could play a role even in the onset of hypertension-evoked brain injury. To investigate this issue, we have explored the effect of acute-induced hypertensive conditions on cerebral oxidative stress. To this aim, we have developed a mouse model of transverse aortic coarctation (TAC) between the two carotid arteries, which imposes acutely on the right brain hemisphere a dramatic increase in blood pressure. Our results show that hypertension acutely induced by aortic coarctation induces a breaking of the blood-brain barrier (BBB) and reactive astrocytosis through hyperperfusion, and evokes trigger factors of neurodegeneration such as oxidative stress and inflammation, similar to that observed in cerebral hypoperfusion. Moreover, the derived brain injury is mainly localized in selected brain areas controlling cognitive functions, such as the cortex and hippocampus, and could be a consequence of a defect in the BBB permeability. It is noteworthy to emphasize that, even if these latter events are not enough to produce ischemic/hemorrhagic injury, they are able to alter mechanisms fundamental for maintaining normal brain function, such as protein synthesis, which has a prominent role for memory formation and cortical plasticity.

  6. Quercetin alleviates cell apoptosis and inflammation via the ER stress pathway in vascular endothelial cells cultured in high concentrations of glucosamine.

    PubMed

    Cai, Xiaxia; Bao, Lei; Ding, Ye; Dai, Xiaoqian; Zhang, Zhaofeng; Li, Yong

    2017-02-01

    Glucosamine is a possible cause of vascular endothelial injury in the initial stages of atherosclerosis, through endoplasmic reticulum (ER) stress resulting in fatty streaks in the vascular wall. Quercetin is an anti‑diabetic and cardiovascular protective agent that has previously been demonstrated to reduce ER stress in human umbilical vein endothelial cells (HUVECs). The present study aimed to investigate whether quercetin prevents glucosamine‑induced apoptosis and inflammation via ER stress pathway in HUVECs. The effect of quercetin on cell viability, apoptosis, and protein expression levels of inflammatory cytokines and ER stress markers was investigated in glucosamine‑supplemented HUVECs. Quercetin was demonstrated to protect against glucosamine‑induced apoptosis, improved cell viability, and inhibited expression of pro‑inflammatory factors and endothelin‑1. Quercetin treatment also reduced the expression levels of glucose‑regulated protein 78, phosphorylated protein kinase‑like ER kinase, phosphorylated c‑Jun N‑terminal kinase and C/EBP homologous protein. In conclusion, quercetin may have auxiliary therapeutic potential against glucosamine‑induced cell apoptosis and inflammation, which may be partially due to alleviation of ER stress.

  7. ER stress stimulates production of the key antimicrobial peptide, cathelicidin, by forming a previously unidentified intracellular S1P signaling complex.

    PubMed

    Park, Kyungho; Ikushiro, Hiroko; Seo, Ho Seong; Shin, Kyong-Oh; Kim, Young Il; Kim, Jong Youl; Lee, Yong-Moon; Yano, Takato; Holleran, Walter M; Elias, Peter; Uchida, Yoshikazu

    2016-03-08

    We recently identified a previously unidentified sphingosine-1-phosphate (S1P) signaling mechanism that stimulates production of a key innate immune element, cathelicidin antimicrobial peptide (CAMP), in mammalian cells exposed to external perturbations, such as UVB irradiation and other oxidative stressors that provoke subapoptotic levels of endoplasmic reticulum (ER) stress, independent of the well-known vitamin D receptor-dependent mechanism. ER stress increases cellular ceramide and one of its distal metabolites, S1P, which activates NF-κB followed by C/EBPα activation, leading to CAMP production, but in a S1P receptor-independent fashion. We now show that S1P activates NF-κB through formation of a previously unidentified signaling complex, consisting of S1P, TRAF2, and RIP1 that further associates with three stress-responsive proteins; i.e., heat shock proteins (GRP94 and HSP90α) and IRE1α. S1P specifically interacts with the N-terminal domain of heat shock proteins. Because this ER stress-initiated mechanism is operative in both epithelial cells and macrophages, it appears to be a universal, highly conserved response, broadly protective against diverse external perturbations that lead to increased ER stress. Finally, these studies further illuminate how ER stress and S1P orchestrate critical stress-specific signals that regulate production of one protective response by stimulating production of the key innate immune element, CAMP.

  8. Aberrant Accumulation of the Diabetes Autoantigen GAD65 in Golgi Membranes in Conditions of ER Stress and Autoimmunity.

    PubMed

    Phelps, Edward A; Cianciaruso, Chiara; Michael, Iacovos P; Pasquier, Miriella; Kanaani, Jamil; Nano, Rita; Lavallard, Vanessa; Billestrup, Nils; Hubbell, Jeffrey A; Baekkeskov, Steinunn

    2016-09-01

    Pancreatic islet β-cells are particularly susceptible to endoplasmic reticulum (ER) stress, which is implicated in β-cell dysfunction and loss during the pathogenesis of type 1 diabetes (T1D). The peripheral membrane protein GAD65 is an autoantigen in human T1D. GAD65 synthesizes γ-aminobutyric acid, an important autocrine and paracrine signaling molecule and a survival factor in islets. We show that ER stress in primary β-cells perturbs the palmitoylation cycle controlling GAD65 endomembrane distribution, resulting in aberrant accumulation of the palmitoylated form in trans-Golgi membranes. The palmitoylated form has heightened immunogenicity, exhibiting increased uptake by antigen-presenting cells and T-cell stimulation compared with the nonpalmitoylated form. Similar accumulation of GAD65 in Golgi membranes is observed in human β-cells in pancreatic sections from GAD65 autoantibody-positive individuals who have not yet progressed to clinical onset of T1D and from patients with T1D with residual β-cell mass and ongoing T-cell infiltration of islets. We propose that aberrant accumulation of immunogenic GAD65 in Golgi membranes facilitates inappropriate presentation to the immune system after release from stressed and/or damaged β-cells, triggering autoimmunity.

  9. Time kinetics of the endocrine response to acute psychological stress.

    PubMed

    Richter, S D; Schürmeyer, T H; Schedlowski, M; Hädicke, A; Tewes, U; Schmidt, R E; Wagner, T O

    1996-05-01

    A first-time parachute jump was chosen as a model to evaluate the endocrine response to acute psychological stress. In 43 inexperienced tandem parachutists, blood was drawn continuously from 2 h before to 1 h after the jump and analyzed at 10-min intervals for plasma concentrations of epinephrine (E), norepinephrine (NE), cortisol, GH, PRL, and TSH. In addition, heart rate was recorded throughout the experiment. There was a significant increase in heart rate and E concentrations during the jump itself. NE, cortisol, GH, PRL, and TSH peaked with a latency of 10-20 min. Apart from cortisol and TSH concentrations, which were still elevated 1 h after the stress event, plasma levels of the other endocrine variables normalized within 1 h following the jump. Statistically significant cross-correlations could be observed between E and NE (r = 0.60, no time lag) and between E and PRL (r = 0.58, 10-min time lag) only. Even in a very homogenous group of subjects and under well-controlled conditions, endocrine responses to acute psychological stress show considerable variations.

  10. Acute psychological stress induces short-term variable immune response.

    PubMed

    Breen, Michael S; Beliakova-Bethell, Nadejda; Mujica-Parodi, Lilianne R; Carlson, Joshua M; Ensign, Wayne Y; Woelk, Christopher H; Rana, Brinda K

    2016-03-01

    In spite of advances in understanding the cross-talk between the peripheral immune system and the brain, the molecular mechanisms underlying the rapid adaptation of the immune system to an acute psychological stressor remain largely unknown. Conventional approaches to classify molecular factors mediating these responses have targeted relatively few biological measurements or explored cross-sectional study designs, and therefore have restricted characterization of stress-immune interactions. This exploratory study analyzed transcriptional profiles and flow cytometric data of peripheral blood leukocytes with physiological (endocrine, autonomic) measurements collected throughout the sequence of events leading up to, during, and after short-term exposure to physical danger in humans. Immediate immunomodulation to acute psychological stress was defined as a short-term selective up-regulation of natural killer (NK) cell-associated cytotoxic and IL-12 mediated signaling genes that correlated with increased cortisol, catecholamines and NK cells into the periphery. In parallel, we observed down-regulation of innate immune toll-like receptor genes and genes of the MyD88-dependent signaling pathway. Correcting gene expression for an influx of NK cells revealed a molecular signature specific to the adrenal cortex. Subsequently, focusing analyses on discrete groups of coordinately expressed genes (modules) throughout the time-series revealed immune stress responses in modules associated to immune/defense response, response to wounding, cytokine production, TCR signaling and NK cell cytotoxicity which differed between males and females. These results offer a spring-board for future research towards improved treatment of stress-related disease including the impact of stress on cardiovascular and autoimmune disorders, and identifies an immune mechanism by which vulnerabilities to these diseases may be gender-specific.

  11. Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: turning off the prosurvival ER chaperone BIP/Grp78 and turning on the pro-apoptotic NF-κB.

    PubMed

    Buontempo, Francesca; Orsini, Ester; Lonetti, Annalisa; Cappellini, Alessandra; Chiarini, Francesca; Evangelisti, Camilla; Evangelisti, Cecilia; Melchionda, Fraia; Pession, Andrea; Bertaina, Alice; Locatelli, Franco; Bertacchini, Jessika; Neri, Luca Maria; McCubrey, James A; Martelli, Alberto Maria

    2016-01-12

    The proteasome inhibitor bortezomib is a new targeted treatment option for refractory or relapsed acute lymphoblastic leukemia (ALL) patients. However, a limited efficacy of bortezomib alone has been reported. A terminal pro-apoptotic endoplasmic reticulum (ER) stress/unfolded protein response (UPR) is one of the several mechanisms of bortezomib-induced apoptosis. Recently, it has been documented that UPR disruption could be considered a selective anti-leukemia therapy. CX-4945, a potent casein kinase (CK) 2 inhibitor, has been found to induce apoptotic cell death in T-ALL preclinical models, via perturbation of ER/UPR pathway. In this study, we analyzed in T- and B-ALL preclinical settings, the molecular mechanisms of synergistic apoptotic effects observed after bortezomib/CX-4945 combined treatment. We demonstrated that, adding CX-4945 after bortezomib treatment, prevented leukemic cells from engaging a functional UPR in order to buffer the bortezomib-mediated proteotoxic stress in ER lumen. We documented that the combined treatment decreased pro-survival ER chaperon BIP/Grp78 expression, via reduction of chaperoning activity of Hsp90. Bortezomib/CX-4945 treatment inhibited NF-κB signaling in T-ALL cell lines and primary cells from T-ALL patients, but, intriguingly, in B-ALL cells the drug combination activated NF-κB p65 pro-apoptotic functions. In fact in B-cells, the combined treatment induced p65-HDAC1 association with consequent repression of the anti-apoptotic target genes, Bcl-xL and XIAP. Exposure to NEMO (IKKγ)-binding domain inhibitor peptide reduced the cytotoxic effects of bortezomib/CX-4945 treatment. Overall, our findings demonstrated that CK2 inhibition could be useful in combination with bortezomib as a novel therapeutic strategy in both T- and B-ALL.

  12. Ceapins inhibit ATF6α signaling by selectively preventing transport of ATF6α to the Golgi apparatus during ER stress

    PubMed Central

    Gallagher, Ciara M; Walter, Peter

    2016-01-01

    The membrane-bound transcription factor ATF6α is activated by proteolysis during endoplasmic reticulum (ER) stress. ATF6α target genes encode foldases, chaperones, and lipid biosynthesis enzymes that increase protein-folding capacity in response to demand. The off-state of ATF6α is maintained by its spatial separation in the ER from Golgi-resident proteases that activate it. ER stress induces trafficking of ATF6α. We discovered Ceapins, a class of pyrazole amides, as selective inhibitors of ATF6α signaling that do not inhibit the Golgi proteases or other UPR branches. We show that Ceapins block ATF6α signaling by trapping it in ER-resident foci that are excluded from ER exit sites. Removing the requirement for trafficking by pharmacological elimination of the spatial separation of the ER and Golgi apparatus restored cleavage of ATF6α in the presence of Ceapins. Washout of Ceapins resensitized ATF6α to ER stress. These results suggest that trafficking of ATF6α is regulated by its oligomeric state. DOI: http://dx.doi.org/10.7554/eLife.11880.001 PMID:27435962

  13. Integrative bioinformatics and proteomics-based discovery of an eEF2K inhibitor (cefatrizine) with ER stress modulation in breast cancer cells.

    PubMed

    Yao, Zhiqiang; Li, Juntang; Liu, Zhongyu; Zheng, Lu; Fan, Naijun; Zhang, Ying; Jia, Nan; Lv, Jingjing; Liu, Ningning; Zhu, Xiaoshan; Du, Jiangbo; Lv, Ci; Xie, Feng; Liu, Yigang; Wang, Xingke; Fei, Zhou; Gao, Chunfang

    2016-03-01

    Eukaryotic elongation factor-2 kinase (eEF2K), a unique calcium/calmodulin-dependent protein kinase, is well known to regulate apoptosis, autophagy and ER stress in many types of human cancers. Therefore, eEF2K would be regarded as a promising therapeutic target; however, the eEF2K-regulated mechanism and its targeted inhibitor still remain to be discovered in cancer. Herein, we constructed a protein-protein interaction (PPI) network of eEF2K and achieved an eEF2K-regulated ER stress subnetwork by bioinformatics prediction. Then, we found that the differential protein expressions involved in ER stress in the context of si-eEF2K-treated MCF-7 and MDA-MB-436 cells by iTRAQ-based analyses, respectively. Integrated into these aforementioned results, we constructed a core eEF2K-regulated ER stress subnetwork in breast cancer cells. Subsequently, we screened a series of candidate compounds targeting eEF2K and discovered a novel eEF2K inhibitor (cefatrizine) with an anti-proliferative activity toward breast cancer cells. Moreover, we found that cefatrizine induced ER stress in both MCF-7 and MDA-MB-436 cells. Interestingly, we demonstrated that the mechanism of cefatrizine-induced ER stress was in good agreement with our bioinformatics and proteomics-based results. In conclusion, these results demonstrate that a novel eEF2K inhibitor (cefatrizine) induces ER stress in breast cancer cells by integrating bioinformatics prediction, proteomics analyses and experimental validation, which would provide a clue for exploring more mechanisms of eEF2K and its targeted inhibitors in cancer therapy.

  14. AtHOP3, a member of the HOP family in Arabidopsis, interacts with BiP and plays a major role in the ER stress response.

    PubMed

    Fernández-Bautista, Nuria; Fernández-Calvino, Lourdes; Muñoz, Alfonso; Castellano, M Mar

    2017-02-02

    HOP is a well-studied family of cytosolic cochaperones. However, the possible role of HOP during the ER stress response and their interactors within the ER were not previously addressed in any eukaryote. We have demonstrated that Arabidopsis HOP3, whose function was not studied before, interacts in vivo with cytosolic HSP90 and HSP70, and, unexpectedly, with BiP, a HSP70 ER-resident protein. Although BiP lacks the domain described in other eukaryotes for HOP-HSP70 binding, it interacts with HOP3 through a noncanonical association to its nucleotide binding domain. Consistent with this interaction with BiP, HOP3 is partially localized at the ER. Moreover, HOP3 is induced both at transcript and protein levels by UPR inducer agents by a mechanism dependent on IRE1. Importantly, hop3 loss-of-function mutants show a reduction in pollen germination and a hypersensitive phenotype in the presence of ER stress inducer agents, a phenotype that is reverted by the addition of the chemical chaperone TUDCA. All these data demonstrate for the first time in any eukaryote a main role of HOP as an important regulator of the ER stress response, a process intimately linked in plants to important specific developmental programs and to environmental stress sensing and response.

  15. [Effect of mexicor on oxidative stress in acute myocardial infarction].

    PubMed

    Golikov, A P; Davydov, B V; Rudnev, D V; Klychnikova, E V; Bykova, N S; Riabinin, V A; Polumiskov, V Iu; Nikolaeva, N Iu; Golikov, P P

    2005-01-01

    Mexicor (5% solution and capsules) was used in 40 of 80 conventionally treated patients with acute myocardial infarction. The drug was given intravenously for 5 days, than intramuscularly (6-9 mg/kg) for 9 days and orally (0.1 mg t.i.d.) thereafter until discharge. Severity of oxidative stress was evaluated by K coefficient. Calculation of this coefficient required data on degree of oxidation of lipids in blood serum, serum levels of diene conjugates, malonic dialdehyde, alpha-tocopherol and ceruloplasmin. These parameters as well as activity of superoxide dismutase, glutathione peroxidase and catalase in erythrocytes were measured at admission, on days 2, 3, 7, 14 and at discharge. Mexicor treated compared with untreated (n=40) patients were characterized by diminished severity of oxidative stress at the account of lower levels of lipid peroxidation products and augmented compensatory potential of the endogenous antioxidant system.

  16. Effects of acute restraint stress on set-shifting and reversal learning in male rats.

    PubMed

    Thai, Chester A; Zhang, Ying; Howland, John G

    2013-03-01

    Exposure to acute stress alters cognition; however, few studies have examined the effects of acute stress on executive functions such as behavioral flexibility. The goal of the present experiments was to determine the effects of acute periods of stress on two distinct forms of behavioral flexibility: set-shifting and reversal learning. Male Sprague-Dawley rats were trained and tested in an operant-chamber-based task. Some of the rats were exposed to acute restraint stress (30 min) immediately before either the set-shifting test day or the reversal learning test day. Acute stress had no effect on set-shifting, but it significantly facilitated reversal learning, as assessed by both trials to criterion and total errors. In a second experiment, the roles of glucocorticoid (GR) and mineralocorticoid receptors (MR) in the acute-stress-induced facilitation of reversal learning were examined. Systemic administration of the GR-selective antagonist RU38486 (10 mg/kg) or the MR-selective antagonist spironolactone (50 mg/kg) 30 min prior to acute stress failed to block the facilitation on reversal learning. The present results demonstrate a dissociable effect of acute stress on set-shifting and reversal learning and suggest that the facilitation of reversal learning by acute stress may be mediated by factors other than corticosterone.

  17. Circulating Levels of IL-1B+IL-6 Cause ER Stress and Dysfunction in Islets From Prediabetic Male Mice

    PubMed Central

    O'Neill, Christina M.; Lu, Christine; Corbin, Kathryn L.; Sharma, Poonam R.; Dula, Stacey B.; Carter, Jeffrey D.; Ramadan, James W.; Xin, Wenjun; Lee, Jae K.

    2013-01-01

    Elevated levels of circulating proinflammatory cytokines are associated with obesity and increased risk of type 2 diabetes, but the mechanism is unknown. We tested whether proinflammatory cytokines IL-1B+IL-6 at low picogram per milliliter concentrations (consistent with serum levels) could directly trigger pancreatic islet dysfunction. Overnight exposure to IL-1B+IL-6 in islets isolated from normal mice and humans disrupted glucose-stimulated intracellular calcium responses; cytokine-induced effects were more severe among islets from prediabetic db/db mice that otherwise showed no signs of dysfunction. IL-1B+IL-6 exposure reduced endoplasmic reticulum (ER) calcium storage, activated ER stress responses (Nos2, Bip, Atf4, and Ddit3 [CHOP]), impaired glucose-stimulated insulin secretion, and increased cell death only in islets from prediabetic db/db mice. Furthermore, we found increased serum levels of IL-1B and IL-6 in diabetes-prone mice at an age before hyperglycemia was exhibited, suggesting that low-grade systemic inflammation develops early in the disease process. In addition, we implanted normal outbred and inbred mice with subcutaneous osmotic mini-pumps containing IL-1B+IL-6 to mimic the serum increases found in prediabetic db/db mice. Both IL-1B and IL-6 were elevated in serum from cytokine-pump mice, but glucose tolerance and blood glucose levels did not differ from controls. However, when compared with controls, isolated islets from cytokine-pump mice showed deficiencies in calcium handling and insulin secretion that were similar to observations with islets exposed to cytokines in vitro. These findings provide proof of principle that low-grade systemic inflammation is present early in the development of type 2 diabetes and can trigger ER stress-mediated islet dysfunction that can lead to islet failure. PMID:23836031

  18. Siah1/2 Ubiquitin Ligases in ER Stress Signaling in Melanoma

    DTIC Science & Technology

    2015-10-01

    year will establish novel therapeutic modality for treatment of cancer , focused on melanoma. Major Task 3: Determine the effect of Siah1/2 and ER...demonstrate the importance of these activities to prostate NE lesions/tumors that are known to be the more aggressive form of prostate cancer ...1,902,606 Associate Director: Ronai, Z. 1.2 calendar (10%) Program Leader: Ronai, Z. 1.2 calendar (10%) Cancer Center Support Grant Goals: To provide

  19. Biweekly Maps of Wind Stress for the North Pacific from the ERS-1 Scatterometer

    NASA Technical Reports Server (NTRS)

    1997-01-01

    The European Remote-sensing Satellite (ERS-1) was launched in July 1991 and contained several instruments for observing the Earth's ocean including a wind scatterometer. The scatterometer measurements were processed by the European Space Agency (ESA) and the Jet Propulsion Laboratory (JPL). JPL reprocessed (Freilich and Dunbar, 1992) the ERS-1 backscatter measurements to produced a 'value added' data set that contained the ESA wind vector as well as a set of up to four ambiguities. These ambiguities were further processed using a maximum-likelihood estimation (MLE) and a median filter to produce a 'selected vector.' This report describes a technique developed to produce time-averaged wind field estimates with their expected errors using only scatterometer wind vectors. The processing described in this report involved extracting regions of interest from the data tapes, checking the quality and creating the wind field estimate. This analysis also includes the derivation of biweekly average wind vectors over the North Pacific Ocean at a resolution of 0.50 x 0.50. This was done with an optimal average algorithm temporally and an over-determined biharmonic spline spatially. There have been other attempts at creating gridded wind files from ERS-1 winds, e.g., kriging techniques (Bentamy et al., 1996) and successive corrections schemes (Tang and Liu, 1996). There are several inherent problems with the ERS-1 scatterometer. Since this is a multidisciplinary mission, the satellite is flown in different orbits optimized for each phase of the mission. The scatterometer also shares several sub-systems with the Synthetic Aperture Radar (SAR) and cannot be operated while the SAR is in operation. The scatterometer is also a single-sided instrument and only measures backscatter along the right side of the satellite. The processing described here generates biweekly wind maps during the wktwo years analysis period regardless of the satellite orbit or missing data.

  20. Attenuation of PKR-like ER Kinase (PERK) Signaling Selectively Controls Endoplasmic Reticulum Stress-induced Inflammation Without Compromising Immunological Responses.

    PubMed

    Guthrie, Lauren N; Abiraman, Kavitha; Plyler, Emily S; Sprenkle, Neil T; Gibson, Sara A; McFarland, Braden C; Rajbhandari, Rajani; Rowse, Amber L; Benveniste, Etty N; Meares, Gordon P

    2016-07-22

    Inflammation and endoplasmic reticulum (ER) stress are associated with many neurological diseases. ER stress is brought on by the accumulation of misfolded proteins in the ER, which leads to activation of the unfolded protein response (UPR), a conserved pathway that transmits signals to restore homeostasis or eliminate the irreparably damaged cell. We provide evidence that inhibition or genetic haploinsufficiency of protein kinase R-like endoplasmic reticulum kinase (PERK) can selectively control inflammation brought on by ER stress without impinging on UPR-dependent survival and adaptive responses or normal immune responses. Using astrocytes lacking one or both alleles of PERK or the PERK inhibitor GSK2606414, we demonstrate that PERK haploinsufficiency or partial inhibition led to reduced ER stress-induced inflammation (IL-6, CCL2, and CCL20 expression) without compromising prosurvival responses. In contrast, complete loss of PERK blocked canonical PERK-dependent UPR genes and promoted apoptosis. Reversal of eIF2α-mediated translational repression using ISRIB potently suppressed PERK-dependent inflammatory gene expression, indicating that the selective modulation of inflammatory gene expression by PERK inhibition may be linked to attenuation of eIF2α phosphorylation and reveals a previously unknown link between translational repression and transcription of inflammatory genes. Additionally, ER-stressed astrocytes can drive an inflammatory M1-like phenotype in microglia, and this can be attenuated with inhibition of PERK. Importantly, targeting PERK neither disrupted normal cytokine signaling in astrocytes or microglia nor impaired macrophage phagocytosis or T cell polarization. Collectively, this work suggests that targeting PERK may provide a means for selective immunoregulation in the context of ER stress without disrupting normal immune function.

  1. Periodontal disease level-butyric acid amounts locally administered in the rat gingival mucosa induce ER stress in the systemic blood.

    PubMed

    Cueno, Marni E; Saito, Yuko; Ochiai, Kuniyasu

    2016-05-01

    Periodontal diseases have long been postulated to contribute to systemic diseases and, likewise, it has been proposed that periodontal disease treatment may ameliorate certain systemic diseases. Short-chain fatty acids (SCFA) are major secondary metabolites produced by oral anaerobic bacteria and, among the SCFAs, butyric acid (BA) in high amounts contribute to periodontal disease development. Periodontal disease level-butyric acid (PDL-BA) is found among patients suffering from periodontal disease and has previously shown to induce oxidative stress, whereas, oxidative stress is correlated to endoplasmic reticulum (ER) stress. This would imply that PDL-BA may likewise stimulate ER stress, however, this was never elucidated. A better understanding of the correlation between PDL-BA and systemic ER stress stimulation could shed light on the possible systemic effects of PDL-BA-related periodontal diseases. Here, PDL-BA was injected into the gingival mucosa and the systemic blood obtained from the rat jugular was collected at 0, 15, 60, and 180 min post-injection. Collected blood samples were purified and only the blood cytosol was used throughout this study. Subsequently, we measured blood cytosolic GADD153, Ca(2+), representative apoptotic and inflammatory caspases, and NF-κB amounts. We found that PDL-BA presence increased blood cytosolic GADD153 and Ca(2+) amounts. Moreover, we observed that blood cytosolic caspases and NF-κB were activated only at 60 and 180 min post-injection in the rat gingival mucosa. This suggests that PDL-BA administered through the gingival mucosa may influence the systemic blood via ER stress stimulation and, moreover, prolonged PDL-BA retention in the gingival mucosa may play a significant role in ER stress-related caspase and NF-κB activation. In a periodontal disease scenario, we propose that PDL-BA-related ER stress stimulation leading to the simultaneous activation of apoptosis and inflammation may contribute to periodontal disease

  2. XBP1-LOX Axis is critical in ER stress-induced growth of lung adenocarcinoma in 3D culture

    PubMed Central

    Yang, Yi; Cheng, Bai-Jun; Jian, Hong; Chen, Zhi-Wei; Zhao, Yi; Yu, Yong-Feng; Li, Zi-Ming; Liao, Mei-Lin; Lu, Shun

    2017-01-01

    Rapid growth of tumor cells needs to consume large amounts of oxygen and glucose, due to lack of blood supply within the tumor, cells live in an environment that lack of oxygen and nutrients. This environment results in endoplasmic reticulum (ER) stress and activates the UPR (unfolded protein response). More and more evidence suggests UPR provides a growth signal pathway required for tumor growth. In the present study, we investigated the relationship between XBP1, one transcription factor in UPR, and the expression of LOX. We found that ER stress induces high expression of XBP1, one transcription factor in UPR, in both 2D culture and 3D culture; but only promotes growth of lung adenocarcinoma cells in in vitro 3D culture other than 2D culture. In 3D culture, we further showed that knockdown XBP1 expression can block Tm/Tg-induced cell growth. LOX genes may be key downstream effector of XBP1. Knockdown LOX expression can partially block XBP1-induced cell growth. Then we showed XBP1 suppressed by RNA interference (RNAi) can reduce the expression of LOX. For the first time, it is being shown that XBP1 can regulate the expression of LOX to promote cell growth.

  3. Quinocetone triggered ER stress-induced autophagy via ATF6/DAPK1-modulated mAtg9a trafficking.

    PubMed

    Zhou, Yan; Zhang, Shen; Dai, Chongshan; Tang, Shusheng; Yang, Xiayun; Li, Daowen; Zhao, Kena; Xiao, Xilong

    2016-04-01

    The present study is undertaken to explore quinocetone-induced autophagy and its possible mechanism. Western blotting and green fluorescence protein (GFP)-LC3 vector transfection were performed to determine the ratio of LC3 conversion and its subcellular localization. Results revealed that the quinocetone induced autophagy in time- and dose-dependent manners. Besides, we tested the expressions of immunoglobulin heavy chain binding protein (BiP) and C/EBP homologous protein (CHOP) and the transcription of BiP, HerpUD, and sec24D by western blotting and RT-PCR, respectively. Results showed that quinocetone also induced endoplasmic reticulum (ER) stress during quinocetone-induced autophagy. Furthermore, we observed the cleavage of ATF6, the phosphorylation of MRLC, and the expression of death-associated protein kinase (DAPK1) by western blotting; the transcription of DAPK1 by RT-PCR; and the subcellular localization of ATF6 and mAtg9 by immunofluorescence. These results suggest that quinocetone stimulates the MRLC-mediated mAtg9 trafficking, which is critical for autophagosome formation, via the ATF6 upregulated expression of DAPK1. Last, we generated ATF6 and DAPK1 stable knockdown HepG2 cell lines and found that the conversion ratios of LC3 were decreased upon the treatment of quinocetone. Together, we propose that quinocetone induces autophagy through ER stress signaling pathway-induced cytoskeleton activation.

  4. Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress.

    PubMed

    Wang, Chun Yan; Guo, Su Tang; Wang, Jia Yu; Liu, Fen; Zhang, Yuan Yuan; Yari, Hamed; Yan, Xu Guang; Jin, Lei; Zhang, Xu Dong; Jiang, Chen Chen

    2016-03-01

    Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. Remarkably, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and the agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy.

  5. Crocin and quercetin prevent PAT-induced apoptosis in mammalian cells: Involvement of ROS-mediated ER stress pathway.

    PubMed

    Boussabbeh, Manel; Prola, Alexandre; Ben Salem, Intidhar; Guilbert, Arnaud; Bacha, Hassen; Lemaire, Christophe; Abis-Essefi, Salwa

    2015-08-27

    Patulin (PAT) is a secondary metabolite produced by several species of the genera of Penicillium, Aspergillus, and Byssochlamys that can be found in rotting fruits, especially in apples and apple-based products. Exposure to this mycotoxin has been reported to induce intestinal and kidney injuries. The mechanism underlying such toxicity has been linked to the induction of apoptosis which occurred with reactive oxygen species production and endoplasmic reticulum (ER) stress induction. This study aimed to evaluate the effect of the two common dietary compounds Quercetin (QUER), a natural flavonoid, and Crocin (CRO), a natural carotenoid, on PAT-induced toxicity in human colon carcinoma (HCT116) and embryonic kidney cells (HEK293). We showed that antioxidant properties of QUER and CRO help to prevent ER stress activation and lipid peroxidation as evidenced by the reduction in GRP78 and GADD34 expressions and the decrease in malondialdehyde production. Furthermore, we demonstrated their ability to re-establish the loss of the mitochondrial membrane potential to inhibit caspase 3 activation and DNA fragmentation. © 2015 Wiley Periodicals, Inc. Environ Toxicol, 2015.

  6. Expression of ER stress markers (GRP78/BiP and PERK) in patients with tongue cancer.

    PubMed

    Kaira, K; Toyoda, M; Shimizu, A; Mori, K; Shino, M; Sakakura, K; Takayasu, Y; Takahashi, K; Oyama, T; Asao, T; Chikamatsu, K

    2016-01-01

    The glucose-regulated protein (GRP78/BiP) and PKR-like endoplasmic reticulum kinase (PERK) plays a crucial role in the endoplasmic reticulum (ER) stress response. GRP78/BiP is highly elevated in various human cancers. Our study is to examine the clinicopathological significance of GRP78/BiP and PERK expression in patients with tongue cancer. A total of 85 tongue cancer patients were analyzed, and tumor specimens were stained by immunohistochemistry for GRP78/BiP, PERK, GLUT1, Ki-67 and microvessel density (MVD) determined by CD34.GRP78/BiP and PERK were highly expressed in 47% and 35% of all patients, respectively. GRP78/BiP disclosed a significant relationship with PERK expression, lymphatic permeation, vascular invasion, glucose metabolism and cell proliferation. The expression of GRP78/BiP was significantly higher in metastatic sites than in primary sites (79% vs. 47%, p=0.003). We found that the high expression of GRP78/BiP was proven to be an independent prognostic factor for predicting poor outcome in patients with tongue cancer. In the analysis of PFS, PERK was identified as an independent predictor. The increased GRP78/BiP expression was clarified as an independent prognostic marker for predicting worse outcome. Our study suggests that the expression of GRP78/BiP as ER stress marker is important in the pathogenesis and development of tongue cancer.

  7. Discovery, Synthesis and Evaluation of 2,4-diaminoquinazolines as a Novel Class of Pancreatic β Cell-Protective Agents against Endoplasmic Reticulum (ER) Stress

    PubMed Central

    Duan, Hongliang; Lee, Jae Wook; Moon, Sung Won; Arora, Daleep; Li, Yu; Lim, Hui-Ying; Wang, Weidong

    2016-01-01

    Pancreatic insulin-producing β-cell dysfunction and death plays central roles in the onset and progression of both type 1 and type 2 diabetes. Current antidiabetic drugs cannot halt the ongoing progression of β-cell dysfunction and death. In diabetes, a major cause for the decline in β cell function and survival is endoplasmic reticulum (ER) stress. Here, we identified quinazoline derivatives as a novel class of β cell protective agents against ER stress-induced dysfunction and death. A series of quinazoline derivatives were synthesized from dichloroquiazoline utilizing a sequence of nucleophilic reactions. Through SAR optimization, a 2,4-diaminoquinazoline compound 9c markedly protects β cells against ER stress-induced dysfunction and death with 80% maximum rescue activity and an EC50 value of 0.56 µM. Importantly, 9c restores the ER stress-impaired glucose-stimulated insulin secretion response and survival in primary human islet β cells. We showed that 9c protects β cells by alleviating ER stress through the suppression of the induction of key genes of the unfolded protein response and apoptosis. PMID:27505441

  8. Autophagy and ER stress play an essential role in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol.

    PubMed

    Mahoney, Emilia; Byrd, John C; Johnson, Amy J

    2013-03-01

    Chronic lymphocytic leukemia (CLL) is a mature B cell malignancy and is the most prevalent type of leukemia in adults. There is no curative therapy for this disease; however, several new agents have shown very promising results. Autophagy has not been studied in CLL and in this study we first sought to determine if autophagy was functional in CLL with classic inducers, and if this contributes to direct cytotoxicity or protection from cell death. While autophagy is activated with all classic stimuli of this process, only unfolded protein endoplasmic reticulum (ER) stress-mediated autophagy protects from cell death. Interestingly, select therapeutic agents (fludarabine, GS-1101, flavopiridol), which are active in CLL, also induce autophagy. Of interest, only the broad cyclin-dependent kinase inhibitor flavopiridol has improved efficacy when autophagy is antagonized biochemically (chloroquine) or by siRNA. This promoted an investigation which demonstrated unexpectedly that flavopiridol mediates ER stress and downstream activation of MAP3K5/ASK1, which ultimately is responsible for cell death. Similarly, autophagy activated in part via ER stress and also CDK5 inhibition is protective against cell death induced by this process. Collectively, our studies demonstrate that in CLL, autophagy is induced by multiple stimuli but only acts as a mechanism of resistance against ER stress-mediating agents. Similarly, flavopiridol mediates ER stress as a primary mechanism of action in CLL, and autophagy serves as a mechanism of resistance to this agent.

  9. High-density lipoprotein inhibits ox-LDL-induced adipokine secretion by upregulating SR-BI expression and suppressing ER Stress pathway.

    PubMed

    Song, Guohua; Wu, Xia; Zhang, Pu; Yu, Yang; Yang, Mingfeng; Jiao, Peng; Wang, Ni; Song, Haiming; Wu, You; Zhang, Xiangjian; Liu, Huaxia; Qin, Shucun

    2016-07-29

    Endoplasmic reticulum stress (ERS) in adipocytes can modulate adipokines secretion. The aim of this study was to explore the protective effect of high-density lipoprotein (HDL) on oxidized low-density lipoprotein (ox-LDL)-induced ERS-C/EBP homologous protein (CHOP) pathway-mediated adipokine secretion. Our results showed that serum adipokines, including visfatin, resistin and TNF-α, correlated inversely with serum HDL cholesterol level in patients with abdominal obesity. In vitro, like ERS inhibitor 4-phenylbutyric acid (PBA), HDL inhibited ox-LDL- or tunicamycin (TM, an ERS inducer)-induced increase in visfatin and resistin secretion. Moreover, HDL inhibited ox-LDL-induced free cholesterol (FC) accumulation in whole cell lysate and in the endoplasmic reticulum. Additionally, like PBA, HDL inhibited ox-LDL- or TM-induced activation of ERS response as assessed by the decreased phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α and reduced nuclear translocation of activating transcription factor 6 as well as the downregulation of Bip and CHOP. Furthermore, HDL increased scavenger receptor class B type I (SR-BI) expression and SR-BI siRNA treatment abolished the inhibitory effects of HDL on ox-LDL-induced FC accumulation and CHOP upregulation. These data indicate that HDL may suppress ox-LDL-induced FC accumulation in adipocytes through upregulation of SR-BI, subsequently preventing ox-LDL-induced ER stress-CHOP pathway-mediated adipocyte inflammation.

  10. High-density lipoprotein inhibits ox-LDL-induced adipokine secretion by upregulating SR-BI expression and suppressing ER Stress pathway

    PubMed Central

    Song, Guohua; Wu, Xia; Zhang, Pu; Yu, Yang; Yang, Mingfeng; Jiao, Peng; Wang, Ni; Song, Haiming; Wu, You; Zhang, Xiangjian; Liu, Huaxia; Qin, Shucun

    2016-01-01

    Endoplasmic reticulum stress (ERS) in adipocytes can modulate adipokines secretion. The aim of this study was to explore the protective effect of high-density lipoprotein (HDL) on oxidized low-density lipoprotein (ox-LDL)-induced ERS-C/EBP homologous protein (CHOP) pathway-mediated adipokine secretion. Our results showed that serum adipokines, including visfatin, resistin and TNF-α, correlated inversely with serum HDL cholesterol level in patients with abdominal obesity. In vitro, like ERS inhibitor 4-phenylbutyric acid (PBA), HDL inhibited ox-LDL- or tunicamycin (TM, an ERS inducer)-induced increase in visfatin and resistin secretion. Moreover, HDL inhibited ox-LDL-induced free cholesterol (FC) accumulation in whole cell lysate and in the endoplasmic reticulum. Additionally, like PBA, HDL inhibited ox-LDL- or TM-induced activation of ERS response as assessed by the decreased phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α and reduced nuclear translocation of activating transcription factor 6 as well as the downregulation of Bip and CHOP. Furthermore, HDL increased scavenger receptor class B type I (SR-BI) expression and SR-BI siRNA treatment abolished the inhibitory effects of HDL on ox-LDL-induced FC accumulation and CHOP upregulation. These data indicate that HDL may suppress ox-LDL-induced FC accumulation in adipocytes through upregulation of SR-BI, subsequently preventing ox-LDL-induced ER stress-CHOP pathway-mediated adipocyte inflammation. PMID:27468698

  11. Polyphenolic Extract of Euphorbia supina Attenuates Manganese-Induced Neurotoxicity by Enhancing Antioxidant Activity through Regulation of ER Stress and ER Stress-Mediated Apoptosis

    PubMed Central

    Bahar, Entaz; Lee, Geum-Hwa; Bhattarai, Kashi Raj; Lee, Hwa-Young; Choi, Min-Kyung; Rashid, Harun-Or; Kim, Ji-Ye; Chae, Han-Jung; Yoon, Hyonok

    2017-01-01

    Manganese (Mn) is an important trace element present in human body, which acts as an enzyme co-factor or activator in various metabolic reactions. While essential in trace amounts, excess levels of Mn in human brain can produce neurotoxicity, including idiopathic Parkinson’s disease (PD)-like extrapyramidal manganism symptoms. This study aimed to investigate the protective role of polyphenolic extract of Euphorbia supina (PPEES) on Mn-induced neurotoxicity and the underlying mechanism in human neuroblastoma SKNMC cells and Sprague-Dawley (SD) male rat brain. PPEES possessed significant amount of total phenolic and flavonoid contents. PPEES also showed significant antioxidant activity in 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and reducing power capacity (RPC) assays. Our results showed that Mn treatment significantly reduced cell viability and increased lactate dehydrogenase (LDH) level, which was attenuated by PPEES pretreatment at 100 and 200 µg/mL. Additionally, PPEES pretreatment markedly attenuated Mn-induced antioxidant status alteration by resolving the ROS, MDA and GSH levels and SOD and CAT activities. PPEES pretreatment also significantly attenuated Mn-induced mitochondrial membrane potential (ΔΨm) and apoptosis. Meanwhile, PPEES pretreatment significantly reversed the Mn-induced alteration in the GRP78, GADD34, XBP-1, CHOP, Bcl-2, Bax and caspase-3 activities. Furthermore, administration of PPEES (100 and 200 mg/kg) to Mn exposed rats showed improvement of histopathological alteration in comparison to Mn-treated rats. Moreover, administration of PPEES to Mn exposed rats showed significant reduction of 8-OHdG and Bax immunoreactivity. The results suggest that PPEES treatment reduces Mn-induced oxidative stress and neuronal cell loss in SKNMC cells and in the rat brain. Therefore, PPEES may be considered as potential treat-ment in Mn-intoxicated patients. PMID:28146110

  12. The effect of bovine rotavirus and its nonstructural protein 4 on ER stress-mediated apoptosis in HeLa and HT-29 cells.

    PubMed

    Goodarzi, Zahra; Soleimanjahi, Hoorieh; Arefian, Ehsan; Saberfar, Esmaeil

    2016-03-01

    Endoplasmic reticulum (ER) plays important roles in multiple cellular processes as well as cell survival and apoptosis. Perturbation of ER functions leads to ER stress and unfolded protein response (UPR). The primary goal of this response is cell survival, but severe ER stress can trigger apoptosis signaling. In tumor cells, chronically activated UPR response provides tumor growth. So, apoptosis induced by the ER stress has been the target for anti-cancer therapy. In this in vitro study, we examined the apoptotic effect associated with ER stress of bovine rotavirus and its nonstructural protein 4 (NSP4) alone in two cancer cell lines. The plasmid pcDNA3.1 encoding NSP4 protein of bovine rotavirus transfected with lipofectamine 2000 into the HeLa and HT-29 cells for protein production. MTT, flow cytometry, and Western blot were used to evaluate the cell viability, apoptosis, and expression level of C/EBP-homologous protein (CHOP) and activated caspase-4. In parallel, the apoptotic effect of the bovine rotavirus associated with ER stress in the infected cells was examined too. The cytotoxic and apoptotic effect of NSP4 protein on the cells were statistically significant compared to the control groups. However, Western blot showed that the expression of the NSP4 protein by recombinant plasmid did not lead to high expression of CHOP and activation of caspase-4. Interestingly, rotavirus not only induced significant apoptosis but also caused an increase in CHOP expression and caspase-4 activation in the infected cells compared to control. As a result, NSP4 protein and bovine rotavirus can be considered a potential novel bio-therapeutic strategy for cancer treatment.

  13. Effects of acute and chronic psychological stress on platelet aggregation in mice.

    PubMed

    Matsuhisa, Fumikazu; Kitamura, Nobuo; Satoh, Eiki

    2014-03-01

    Although psychological stress has long been known to alter cardiovascular function, there have been few studies on the effect of psychological stress on platelets, which play a pivotal role in cardiovascular disease. In the present study, we investigated the effects of acute and chronic psychological stress on the aggregation of platelets and platelet cytosolic free calcium concentration ([Ca(2+)]i). Mice were subjected to both transportation stress (exposure to novel environment, psychological stress) and restraint stress (psychological stress) for 2 h (acute stress) or 3 weeks (2 h/day) (chronic stress). In addition, adrenalectomized mice were subjected to similar chronic stress (both transportation and restraint stress for 3 weeks). The aggregation of platelets from mice and [Ca(2+)]i was determined by light transmission assay and fura-2 fluorescence assay, respectively. Although acute stress had no effect on agonist-induced platelet aggregation, chronic stress enhanced the ability of the platelet agonists thrombin and ADP to stimulate platelet aggregation. However, chronic stress failed to enhance agonist-induced increase in [Ca(2+)]i. Adrenalectomy blocked chronic stress-induced enhancement of platelet aggregation. These results suggest that chronic, but not acute, psychological stress enhances agonist-stimulated platelet aggregation independently of [Ca(2+)]i increase, and the enhancement may be mediated by stress hormones secreted from the adrenal glands.

  14. Exposure of Jurkat cells to bis (tri-n-butyltin) oxide (TBTO) induces transcriptomics changes indicative for ER- and oxidative stress, T cell activation and apoptosis

    SciTech Connect

    Katika, Madhumohan R.; Hendriksen, Peter J.M.; Loveren, Henk van; Peijnenburg, Ad

    2011-08-01

    Tributyltin oxide (TBTO) is an organotin compound that is widely used as a biocide in agriculture and as an antifouling agent in paints. TBTO is toxic for many cell types, particularly immune cells. The present study aimed to identify the effects of TBTO on the human T lymphocyte cell line Jurkat. Cells were treated with 0.2 and 0.5 {mu}M TBTO for 3, 6, 12 and 24 h and then subjected to whole genome gene expression microarray analysis. The biological interpretation of the gene expression profiles revealed that endoplasmic reticulum (ER) stress is among the earliest effects of TBTO. Simultaneously or shortly thereafter, oxidative stress, activation of NFKB and NFAT, T cell activation, and apoptosis are induced. The effects of TBTO on genes involved in ER stress, NFAT pathway, T cell activation and apoptosis were confirmed by qRT-PCR. Activation and nuclear translocation of NFATC1 and the oxidative stress response proteins NRF2 and KEAP1 were confirmed by immunocytology. Taking advantage of previously published microarray data, we demonstrated that the induction of ER stress, oxidative stress, T cell activation and apoptosis by TBTO is not unique for Jurkat cells but does also occur in mouse thymocytes both ex vivo and in vivo and rat thymocytes ex vivo. We propose that the induction of ER stress leading to a T cell activation response is a major factor in the higher sensitivity of immune cells above other types of cells for TBTO. - Research Highlights: > The human T lymphocyte cell line Jurkat was exposed to TBTO. > Whole-genome microarray experiments were performed. > Data analysis revealed the induction of ER stress and activation of NFAT and NFKB. > Exposure to TBTO also led to T cell activation, oxidative stress and apoptosis.

  15. Impairments of spatial working memory and attention following acute psychosocial stress.

    PubMed

    Olver, James S; Pinney, Myra; Maruff, Paul; Norman, Trevor R

    2015-04-01

    Few studies have investigated the effect of an acute psychosocial stress paradigm on impaired attention and working memory in humans. Further, the duration of any stress-related cognitive impairment remains unclear. The aim of this study was to examine the effect of an acute psychosocial stress paradigm, the Trier Social Stress, on cognitive function in healthy volunteers. Twenty-three healthy male and female subjects were exposed to an acute psychosocial stress task. Physiological measures (salivary cortisol, heart rate and blood pressure) and subjective stress ratings were measured at baseline, in anticipation of stress, immediately post-stress and after a period of rest. A neuropsychological test battery including spatial working memory and verbal memory was administered at each time point. Acute psychosocial stress produced significant increases in cardiovascular and subjective measures in the anticipatory and post-stress period, which recovered to baseline after rest. Salivary cortisol steadily declined over the testing period. Acute psychosocial stress impaired delayed verbal recall, attention and spatial working memory. Attention remained impaired, and delayed verbal recall continued to decline after rest. Acute psychosocial stress is associated with an impairment of a broad range of cognitive functions in humans and with prolonged abnormalities in attention and memory.

  16. Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin

    PubMed Central

    Kim, Hyosang; Baek, Chung Hee; Lee, Raymond Bok; Chang, Jai Won; Yang, Won Seok; Lee, Sang Koo

    2017-01-01

    Endoplasmic reticulum (ER) stress is increasingly identified as modulator of fibrosis. Losartan, an angiotensin II receptor blocker, has been widely used as the first choice of treatment in chronic renal diseases. We postulated that anti-fibrotic effect of losartan is mediated through inhibition of ER stress via SIRT1 (silent mating type information regulation 2 homolog 1) hemeoxygenase-1 (HO-1)/thioredoxin pathway. Renal tubular cells, tunicamycin (TM)-induced ER stress, and unilateral ureteral obstruction (UUO) mouse model were used. Expression of ER stress was assessed by Western blot analysis and immunohistochemical stain. ER stress was induced by chemical ER stress inducer, tunicamycin, and non-chemical inducers such as TGF-β, angiotensin II, high glucose, and albumin. Losartan suppressed the TM-induced ER stress, as shown by inhibition of TM-induced expression of GRP78 (glucose related protein 78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor-2α), through up-regulation of SIRT1 via HO-1 and thioredoxin. Losartan also suppressed the ER stress by non-chemical inducers. In both animal models, losartan reduced the tubular expression of GRP78, which were abolished by pretreatment with sirtinol (SIRT1 inhibitor). Sirtinol also blocked the inhibitory effect of losartan on the UUO-induced renal fibrosis. These findings provide new insights into renoprotective effects of losartan and suggest that SIRT1, HO-1, and thioredoxin may be potential pharmacological targets in kidney diseases under excessive ER stress condition. PMID:28146117

  17. Loss of a Clueless-dGRASP complex results in ER stress and blocks Integrin exit from the perinuclear endoplasmic reticulum in Drosophila larval muscle

    PubMed Central

    Wang, Zong-Heng; Rabouille, Catherine; Geisbrecht, Erika R.

    2015-01-01

    Drosophila Clueless (Clu) and its conserved orthologs are known for their role in the prevention of mitochondrial clustering. Here, we uncover a new role for Clu in the delivery of integrin subunits in muscle tissue. In clu mutants, αPS2 integrin, but not βPS integrin, abnormally accumulates in a perinuclear endoplasmic reticulum (ER) subdomain, a site that mirrors the endogenous localization of Clu. Loss of components essential for mitochondrial distribution do not phenocopy the clu mutant αPS2 phenotype. Conversely, RNAi knockdown of the Drosophila Golgi reassembly and stacking protein GRASP55/65 (dGRASP) recapitulates clu defects, including the abnormal accumulation of αPS2 and larval locomotor activity. Both Clu and dGRASP proteins physically interact and loss of Clu displaces dGRASP from ER exit sites, suggesting that Clu cooperates with dGRASP for the exit of αPS2 from a perinuclear subdomain in the ER. We also found that Clu and dGRASP loss of function leads to ER stress and that the stability of the ER exit site protein Sec16 is severely compromised in the clu mutants, thus explaining the ER accumulation of αPS2. Remarkably, exposure of clu RNAi larvae to chemical chaperones restores both αPS2 delivery and functional ER exit sites. We propose that Clu together with dGRASP prevents ER stress and therefore maintains Sec16 stability essential for the functional organization of perinuclear early secretory pathway. This, in turn, is essential for integrin subunit αPS2 ER exit in Drosophila larval myofibers. PMID:25862246

  18. Ubiquitin fold modifier 1 (UFM1) and its target UFBP1 protect pancreatic beta cells from ER stress-induced apoptosis.

    PubMed

    Lemaire, Katleen; Moura, Rodrigo F; Granvik, Mikaela; Igoillo-Esteve, Mariana; Hohmeier, Hans E; Hendrickx, Nico; Newgard, Christopher B; Waelkens, Etienne; Cnop, Miriam; Schuit, Frans

    2011-04-06

    UFM1 is a member of the ubiquitin like protein family. While the enzymatic cascade of UFM1 conjugation has been elucidated in recent years, the biological function remains largely unknown. In this report we demonstrate that the recently identified C20orf116, which we name UFM1-binding protein 1 containing a PCI domain (UFBP1), and CDK5RAP3 interact with UFM1. Components of the UFM1 conjugation pathway (UFM1, UFBP1, UFL1 and CDK5RAP3) are highly expressed in pancreatic islets of Langerhans and some other secretory tissues. Co-localization of UFM1 with UFBP1 in the endoplasmic reticulum (ER) depends on UFBP1. We demonstrate that ER stress, which is common in secretory cells, induces expression of Ufm1, Ufbp1 and Ufl1 in the beta-cell line INS-1E. siRNA-mediated Ufm1 or Ufbp1 knockdown enhances apoptosis upon ER stress. Silencing the E3 enzyme UFL1, results in similar outcomes, suggesting that UFM1-UFBP1 conjugation is required to prevent ER stress-induced apoptosis. Together, our data suggest that UFM1-UFBP1 participate in preventing ER stress-induced apoptosis in protein secretory cells.

  19. Ubiquitin Fold Modifier 1 (UFM1) and Its Target UFBP1 Protect Pancreatic Beta Cells from ER Stress-Induced Apoptosis

    PubMed Central

    Granvik, Mikaela; Igoillo-Esteve, Mariana; Hohmeier, Hans E.; Hendrickx, Nico; Newgard, Christopher B.; Waelkens, Etienne; Cnop, Miriam; Schuit, Frans

    2011-01-01

    UFM1 is a member of the ubiquitin like protein family. While the enzymatic cascade of UFM1 conjugation has been elucidated in recent years, the biological function remains largely unknown. In this report we demonstrate that the recently identified C20orf116 [1], which we name UFM1-binding protein 1 containing a PCI domain (UFBP1), andCDK5RAP3 interact with UFM1. Components of the UFM1 conjugation pathway (UFM1, UFBP1, UFL1 and CDK5RAP3) are highly expressed in pancreatic islets of Langerhans and some other secretory tissues. Co-localization of UFM1 with UFBP1 in the endoplasmic reticulum (ER)depends on UFBP1. We demonstrate that ER stress, which is common in secretory cells, induces expression of Ufm1, Ufbp1 and Ufl1 in the beta-cell line INS-1E.siRNA-mediated Ufm1 or Ufbp1knockdown enhances apoptosis upon ER stress.Silencing the E3 enzyme UFL1, results in similar outcomes, suggesting that UFM1-UFBP1 conjugation is required to prevent ER stress-induced apoptosis. Together, our data suggest that UFM1-UFBP1participate in preventing ER stress-induced apoptosis in protein secretory cells. PMID:21494687

  20. Nicotinamide ameliorates palmitate-induced ER stress in hepatocytes via cAMP/PKA/CREB pathway-dependent Sirt1 upregulation.

    PubMed

    Li, Jiaxin; Dou, Xiaobing; Li, Songtao; Zhang, Ximei; Zeng, Yong; Song, Zhenyuan

    2015-11-01

    Nicotinamide (NAM) is the amide of nicotinic acid and a predominant precursor for NAD(+) biosynthesis via the salvage pathway. Sirt1 is a NAD(+)-dependent deacetylase, playing an important role in regulating cellular functions. Although hepatoprotective effect of NAM has been reported, the underlying mechanism remains elusive. ER stress, induced by saturated fatty acids, in specific palmitate, plays a pathological role in the development of nonalcoholic fatty liver disease. This study aims to determine the effect of NAM on palmitate-induced ER stress in hepatocytes and to elucidate molecular mechanisms behind. Both HepG2 cells and primary mouse hepatocytes were exposed to palmitate (conjugated to BSA at a 2:1 M ratio), NAM, or their combination for different durations. Cellular NAD(+) level, Sirt1 expression/activity, ER stress, as well as cAMP/PKA/CREB pathway activation were determined. NAM increased Sirt1 expression and enzymatic activity, which contributes to the ameliorative effect of NAM on palmitate-triggered ER stress. NAM increased intracellular NAD(+) level in hepatocytes, however, blocking the salvage pathway, a pathway for NAD(+) synthesis from NAM, only partially prevented NAM-induced Sirt1 upregulation while completely prevented NAD+ increase in response to NAM. Further mechanistic investigations revealed that NAM elevated intracellular cAMP level via suppressing PDE activity, leading to downstream PKA and CREB activation. Importantly, cAMP/PKA/CREB pathway blockade abolished not only NAM-induced Sirt1 upregulation, but also its protective effect against ER stress. Our results demonstrate that NAM protects hepatocytes against palmitate-induced ER stress in hepatocytes via upregulating Sirt1. Activation of the cAMP/PKA/CREB pathway plays a key role in NAM-induced Sirt1 upregulation.

  1. 17β-Estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts.

    PubMed

    Guo, Yun-Shan; Sun, Zhen; Ma, Jie; Cui, Wei; Gao, Bo; Zhang, Hong-Yang; Han, Yue-Hu; Hu, Hui-Min; Wang, Long; Fan, Jing; Yang, Liu; Tang, Juan; Luo, Zhuo-Jing

    2014-08-01

    Although many studies have suggested that estrogen prevents postmenopausal bone loss partially due to its anti-apoptosis effects in osteoblasts, the underlying mechanism has not been fully elucidated. In the present study, we found that 17β-estradiol (17β-E₂), one of the primary estrogens, inhibited endoplasmic reticulum (ER) stress-induced apoptosis in MC3T3-E1 cells and primary osteoblasts. Interestingly, 17β-E₂-promoted Grp78 induction, but not CHOP induction in response to ER stress. We further confirmed that Grp78-specific siRNA reversed the inhibition of 17β-E₂ on ER stress-induced apoptosis by activating caspase-12 and caspase-3. Moreover, we found that 17β-E₂ markedly increased the phosphorylated TFII-I levels and nuclear localization of TFII-I in ER stress conditions. 17β-E₂ stimulated Grp78 promoter activity in a dose-dependent manner in the presence of TFII-I and enhanced the binding of TFII-I to the Grp78 promoter. In addition, 17β-E₂ notably increased phosphorylated ERK1/2 levels and Ras kinase activity in MC3T3-E1 cells. The ERK1/2 activity-specific inhibitor U0126 remarkably blocked 17β-E₂-induced TFII-I phosphorylation and Grp78 expression in response to ER stress. Together, 17β-E₂ protected MC3T3-E1 cells against ER stress-induced apoptosis by promoting Ras-ERK1/2-TFII-I signaling pathway-dependent Grp78 induction.

  2. SCS3 and YFT2 Link Transcription of Phospholipid Biosynthetic Genes to ER Stress and the UPR

    PubMed Central

    Moir, Robyn D.; Gross, David A.; Silver, David L.; Willis, Ian M.

    2012-01-01

    The ability to store nutrients in lipid droplets (LDs) is an ancient function that provides the primary source of metabolic energy during periods of nutrient insufficiency and between meals. The Fat storage-Inducing Transmembrane (FIT) proteins are conserved ER–resident proteins that facilitate fat storage by partitioning energy-rich triglycerides into LDs. FIT2, the ancient ortholog of the FIT gene family first identified in mammals has two homologs in Saccharomyces cerevisiae (SCS3 and YFT2) and other fungi of the Saccharomycotina lineage. Despite the coevolution of these genes for more than 170 million years and their divergence from higher eukaryotes, SCS3, YFT2, and the human FIT2 gene retain some common functions: expression of the yeast genes in a human embryonic kidney cell line promotes LD formation, and expression of human FIT2 in yeast rescues the inositol auxotrophy and chemical and genetic phenotypes of strains lacking SCS3. To better understand the function of SCS3 and YFT2, we investigated the chemical sensitivities of strains deleted for either or both genes and identified synthetic genetic interactions against the viable yeast gene-deletion collection. We show that SCS3 and YFT2 have shared and unique functions that connect major biosynthetic processes critical for cell growth. These include lipid metabolism, vesicular trafficking, transcription of phospholipid biosynthetic genes, and protein synthesis. The genetic data indicate that optimal strain fitness requires a balance between phospholipid synthesis and protein synthesis and that deletion of SCS3 and YFT2 impacts a regulatory mechanism that coordinates these processes. Part of this mechanism involves a role for SCS3 in communicating changes in the ER (e.g. due to low inositol) to Opi1-regulated transcription of phospholipid biosynthetic genes. We conclude that SCS3 and YFT2 are required for normal ER membrane biosynthesis in response to perturbations in lipid metabolism and ER stress. PMID

  3. Alteration of ceramide synthase 6/C16-ceramide induces activating transcription factor 6-mediated endoplasmic reticulum (ER) stress and apoptosis via perturbation of cellular Ca2+ and ER/Golgi membrane network.

    PubMed

    Senkal, Can E; Ponnusamy, Suriyan; Manevich, Yefim; Meyers-Needham, Marisa; Saddoughi, Sahar A; Mukhopadyay, Archana; Dent, Paul; Bielawski, Jacek; Ogretmen, Besim

    2011-12-09

    Mechanisms that regulate endoplasmic reticulum (ER) stress-induced apoptosis in cancer cells remain enigmatic. Recent data suggest that ceramide synthase1-6 (CerS1-6)-generated ceramides, containing different fatty acid chain lengths, might exhibit distinct and opposing functions, such as apoptosis versus survival in a context-dependent manner. Here, we investigated the mechanisms involved in the activation of one of the major ER stress response proteins, ATF-6, and subsequent apoptosis by alterations of CerS6/C(16)-ceramide. Induction of wild type (WT), but not the catalytically inactive mutant CerS6, increased tumor growth in SCID mice, whereas siRNA-mediated knockdown of CerS6 induced ATF-6 activation and apoptosis in multiple human cancer cells. Down-regulation of CerS6/C(16)-ceramide, and not its further metabolism to glucosylceramide or sphingomyelin, activated ATF-6 upon treatment with ER stress inducers tunicamycin or SAHA (suberoylanilide hydroxamic acid). Induction of WT-CerS6 expression, but not its mutant, or ectopic expression of the dominant-negative mutant form of ATF-6 protected cells from apoptosis in response to CerS6 knockdown and tunicamycin or SAHA treatment. Mechanistically, ATF-6 activation was regulated by a concerted two-step process involving the release of Ca(2+) from the ER stores ([Ca(2+)](ER)), which resulted in the fragmentation of Golgi membranes in response to CerS6/C(16)-ceramide alteration. This resulted in the accumulation of pro-ATF-6 in the disrupted ER/Golgi membrane network, where pro-ATF6 is activated. Accordingly, ectopic expression of a Ca(2+) chelator calbindin prevented the Golgi fragmentation, ATF-6 activation, and apoptosis in response to CerS6/C(16)-ceramide down-regulation. Overall, these data suggest a novel mechanism of how CerS6/C(16)-ceramide alteration activates ATF6 and induces ER-stress-mediated apoptosis in squamous cell carcinomas.

  4. Traumatic Memories in Acute Stress Disorder: An Analysis of Narratives before and after Treatment

    ERIC Educational Resources Information Center

    Moulds, Michelle L.; Bryant, Richard A.

    2005-01-01

    The dissociative reactions in acute stress disorder purportedly impede encoding and organization of traumatic memories and consequently impair the individual's ability to retrieve trauma-related details. A qualitative examination was conducted on trauma narratives of individuals with acute stress disorder (N = 15) prior to cognitive behavior…

  5. Acute Stress Symptoms in Children: Results From an International Data Archive

    ERIC Educational Resources Information Center

    Kassam-Adams, Nancy; Palmieri, Patrick A.; Rork, Kristine; Delahanty, Douglas L.; Kenardy, Justin; Kohser, Kristen L.; Landolt, Markus A.; Le Brocque, Robyne; Marsac, Meghan L.; Meiser-Stedman, Richard; Nixon, Reginald D.V.; Bui, Eric; McGrath, Caitlin

    2012-01-01

    Objective: To describe the prevalence of acute stress disorder (ASD) symptoms and to examine proposed "DSM-5" symptom criteria in relation to concurrent functional impairment in children and adolescents. Method: From an international archive, datasets were identified that included assessment of acute traumatic stress reactions and…

  6. Factor Structure of the Acute Stress Disorder Scale in a Sample of Hurricane Katrina Evacuees

    ERIC Educational Resources Information Center

    Edmondson, Donald; Mills, Mary Alice; Park, Crystal L.

    2010-01-01

    Acute stress disorder (ASD) is a poorly understood and controversial diagnosis (A. G. Harvey & R. A. Bryant, 2002). The present study used confirmatory factor analysis (CFA) to test the factor structure of the most widely used self-report measure of ASD, the Acute Stress Disorder Scale (R. A. Bryant, M. L. Moulds, & R. M. Guthrie, 2000),…

  7. The novel white spot syndrome virus-induced gene, PmERP15, encodes an ER stress-responsive protein in black tiger shrimp, Penaeus monodon.

    PubMed

    Leu, Jiann-Horng; Liu, Kuan-Fu; Chen, Kuan-Yu; Chen, Shu-Hwa; Wang, Yu-Bin; Lin, Chung-Yen; Lo, Chu-Fang

    2015-04-01

    By microarray screening, we identified a white spot syndrome virus (WSSV)-strongly induced novel gene in gills of Penaeus monodon. The gene, PmERP15, encodes a putative transmembrane protein of 15 kDa, which only showed some degree of similarity (54-59%) to several unknown insect proteins, but had no hits to shrimp proteins. RT-PCR showed that PmERP15 was highly expressed in the hemocytes, heart and lymphoid organs, and that WSSV-induced strong expression of PmERP15 was evident in all tissues examined. Western blot analysis likewise showed that WSSV strongly up-regulated PmERP15 protein levels. In WSSV-infected hemocytes, immunofluorescence staining showed that PmERP15 protein was colocalized with an ER enzyme, protein disulfide isomerase, and in Sf9 insect cells, PmERP15-EGFP fusion protein colocalized with ER -Tracker™ Red dye as well. GRP78, an ER stress marker, was found to be up-regulated in WSSV-infected P. monodon, and both PmERP15 and GRP78 were up-regulated in shrimp injected with ER stress inducers tunicamycin and dithiothreitol. Silencing experiments showed that although PmERP15 dsRNA-injected shrimp succumbed to WSSV infection more rapidly, the WSSV copy number had no significant changes. These results suggest that PmERP15 is an ER stress-induced, ER resident protein, and its induction in WSSV-infected shrimp is caused by the ER stress triggered by WSSV infection. Furthermore, although PmERP15 has no role in WSSV multiplication, its presence is essential for the survival of WSSV-infected shrimp.

  8. Effect of acute stress on auditory processing: a systematic review of human studies.

    PubMed

    Jafari, Zahra; Kolb, Bryan E; Mohajerani, Majid H

    2017-01-01

    Stress is an integral part of modern life. Although there is a large body of literature regarding the harmful effects of chronic stress on different aspects of human life, acute stress is the most common form of stress, resulting from the demands and pressures of the recent past and the anticipated demands and pressures of the near future. In spite of its pervasive nature, less attention has been paid to the impact of acute stress on sensory processing than to the consequences of chronic stress, particularly concerning auditory processing. In this systematic review, the impact of experimental acute stress on the auditory processing of healthy adults was investigated. The results revealed the adverse effects of acute physical and psychological stresses on auditory processing. According to the open field of research on stress and the auditory system and the high possibility of experiencing different types of acute stresses in various life environments, including testing places, it seems that more investigations are needed to identify and manage different types of acute stresses in both clinical and research situations.

  9. Aqueous extract of Polygonum bistorta modulates proteostasis by ROS-induced ER stress in human hepatoma cells

    PubMed Central

    Liu, Yu-Huei; Weng, Yui-Ping; Lin, Hsuan-Yuan; Tang, Sai-Wen; Chen, Chao-Jung; Liang, Chi-Jung; Ku, Chung-Yu; Lin, Jung-Yaw

    2017-01-01

    Hepatocellular carcinoma (HCC) remains the leading cause of cancer mortality with limited therapeutic targets. The endoplasmic reticulum (ER) plays a pivotal role in maintaining proteostasis in normal cells. However, alterations in proteostasis are often found in cancer cells, making it a potential target for therapy. Polygonum bistorta is used in traditional Chinese medicine owing to its anticancer activities, but the molecular and pharmacological mechanisms remain unclear. Using hepatoma cells as a model system, this study demonstrated that P. bistorta aqueous extract (PB) stimulated ER stress by increasing autophagosomes but by blocking degradation, followed by the accumulation of ubiquitinated proteins and cell apoptosis. In addition, an autophagy inhibitor did not enhance ubiquitinated protein accumulation whereas a reactive oxygen species (ROS) scavenger diminished both ubiquitinated protein accumulation and ligand-stimulated epidermal growth factor receptor (EGFR) expression, suggesting that ROS generation by PB may be upstream of PB-triggered cell death. Nevertheless, PB-exerted proteostasis impairment resulted in cytoskeletal changes, impairment of cell adhesion and motility, and inhibition of cell cycle progression. Oral administration of PB delayed tumour growth in a xenograft model without significant body weight loss. These findings indicate that PB may be a potential new alternative or complementary medicine for HCC. PMID:28134285

  10. Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress

    PubMed Central

    Ohashi, Wakana; Kimura, Shunsuke; Iwanaga, Toshihiko; Furusawa, Yukihiro; Irié, Tarou; Izumi, Hironori; Watanabe, Takashi; Hara, Takafumi; Ohara, Osamu; Koseki, Haruhiko; Sato, Toshiro; Robine, Sylvie; Mori, Hisashi; Hattori, Yuichi; Mishima, Kenji; Ohno, Hiroshi; Hase, Koji; Fukada, Toshiyuki

    2016-01-01

    Zinc transporters play a critical role in spatiotemporal regulation of zinc homeostasis. Although disruption of zinc homeostasis has been implicated in disorders such as intestinal inflammation and aberrant epithelial morphology, it is largely unknown which zinc transporters are responsible for the intestinal epithelial homeostasis. Here, we show that Zrt-Irt-like protein (ZIP) transporter ZIP7, which is highly expressed in the intestinal crypt, is essential for intestinal epithelial proliferation. Mice lacking Zip7 in intestinal epithelium triggered endoplasmic reticulum (ER) stress in proliferative progenitor cells, leading to significant cell death of progenitor cells. Zip7 deficiency led to the loss of Olfm4+ intestinal stem cells and the degeneration of post-mitotic Paneth cells, indicating a fundamental requirement for Zip7 in homeostatic intestinal regeneration. Taken together, these findings provide evidence for the importance of ZIP7 in maintenance of intestinal epithelial homeostasis through the regulation of ER function in proliferative progenitor cells and maintenance of intestinal stem cells. Therapeutic targeting of ZIP7 could lead to effective treatment of gastrointestinal disorders. PMID:27736879

  11. Acute stress disorder in hospitalised victims of 26/11-terror attack on Mumbai, India.

    PubMed

    Balasinorwala, Vanshree Patil; Shah, Nilesh

    2010-11-01

    The 26/11 terror attacks on Mumbai have been internationally denounced. Acute stress disorder is common in victims of terror. To find out the prevalence and to correlate acute stress disorder, 70 hospitalised victims of terror were assessed for presence of the same using DSM-IV TR criteria. Demographic data and clinical variables were also collected. Acute stress disorder was found in 30% patients. On demographic profile and severity of injury, there were some interesting observations and differences between the victims who developed acute stress disorder and those who did not; though none of the differences reached the level of statistical significance. This study documents the occurrence of acute stress disorder in the victims of 26/11 terror attack.

  12. Mimicking acute and chronic stress exposure in naive beef steers alters the acute phase response (APR) associated with vaccination

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was designed to determine the effect of an acute versus chronic stress model on the APR associated with vaccination in naïve beef steers. Steers (n=32; 209 +/- 8 kg) were blocked by body weight and assigned to 1 of 3 treatments: 1) Chronic stress (CHR), 0.5 mg/kg body weight dexamethasone...

  13. Effects of acute and chronic psychological stress on isolated islets' insulin release.

    PubMed

    Zardooz, Homeira; Zahediasl, Saleh; Rostamkhani, Fatemeh; Farrokhi, Babak; Nasiraei, Shiva; Kazeminezhad, Behrang; Gholampour, Roohollah

    2012-01-01

    This study investigated the effects of acute and chronic psychological stress on glucose-stimulated insulin secretion from isolated pancreatic islets. Male Wistar rats were divided into two control and stressed groups; each further was allocated into fed and fasted groups. Stress was induced by communication box for one (acute), fifteen and thirty (chronic) days. After islet isolation, their number, size and insulin output were assessed. Plasma corticosterone level was determined. In fasted animals, acute stress increased basal and post stress plasma corticosterone level, while 30 days stress decreased it compared to day 1. In fed rats, acute stress increased only post stress plasma corticosterone concentration, however, after 15 days stress, it was decreased compared to day 1. Acute stress did not change insulin output; however, the insulin output was higher in the fed acutely stressed rats at 8.3 and 16.7 mM glucose than fasted ones. Chronic stress increased insulin output on day 15 in the fasted animals but decreased it on day 30 in the fed animals at 8.3 and 16.7 mM glucose. In the fasted control rats insulin output was lower than fed ones. In the chronic stressed rats insulin output at 8.3 and 16.7 mM glucose was higher in the fasted than fed rats. The number of islets increased in the fasted rats following 15 days stress. This study indicated that the response of the isolated islets from acute and chronically stressed rats are different and depends on the feeding status.

  14. Resolvin D1 reduces ER stress-induced apoptosis and triglyceride accumulation through JNK pathway in HepG2 cells.

    PubMed

    Jung, Tae Woo; Hwang, Hwan-Jin; Hong, Ho Cheol; Choi, Hae Yoon; Yoo, Hye Jin; Baik, Sei Hyun; Choi, Kyung Mook

    2014-06-25

    Research has indicated that stress on the endoplasmic reticulum (ER) of a cell affects the pathogenesis of metabolic disorders such as obesity, type 2 diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD). Resolvins, a novel family derived from ω-3 polyunsaturated fatty acids, have anti-inflammatory and insulin sensitizing properties, and it has been suggested that they play a role in the amelioration of obesity-related metabolic dysfunctions. This study showed that pretreatment with resolvin D1 (RvD1) attenuated ER stress-induced apoptosis and also decreased caspase 3 activity in HepG2 cells. Furthermore, RvD1 significantly decreased tunicamycin-induced triglycerides accumulation as well as SREBP-1 expression. However, tunicamycin-induced ER stress markers were not significantly affected by RvD1 treatment. Moreover, RvD1 treatment did not affect the tunicamycin-induced expression of chaperones that assist protein folding in the ER. These results suggest that RvD1-conferred cellular protection may occur downstream of the ER stress. This was supported by the finding that RvD1 significantly inhibited tunicamycin-induced c-Jun N-terminal kinase (JNK) expression, although P38 and ERK1/2 phosphorylation were not affected. In addition, anisomycin, a JNK activator, increased caspase 3 activity and apoptosis as well as triglycerides accumulation and SREBP1 expression, and RvD1 treatment reversed these changes. In conclusion, RvD1 attenuated ER stress-induced hepatic steatosis and apoptosis via the JNK-mediated pathway. This study may provide insight into a novel underlying mechanism and a strategy for treating NAFLD.

  15. Brucella suis vaccine strain S2-infected immortalized caprine endometrial epithelial cell lines induce non-apoptotic ER-stress.

    PubMed

    Wang, Xiangguo; Lin, Pengfei; Yin, Yanlong; Zhou, Jinhua; Lei, Lanjie; Zhou, Xudong; Jin, Yaping; Wang, Aihua

    2015-05-01

    Brucella, which is regarded as an intracellular pathogen responsible for a zoonotic disease called brucellosis, survives and proliferates within several types of phagocytic and non-phagocytic cells. Brucella infects not only their preferred hosts but also other domestic and wild animal species, inducing abortion and infertility. Therefore, the interaction between uterine cells and Brucella is important for understanding the pathogenesis of this disease. In this study, we describe the Brucella suis vaccine strain S2 (B.suis.S2) infection and replication in the immortalized caprine endometrial epithelial cell line hTERT-EECs and the induced cellular and molecular response modulation in vitro. We found that B.suis S2 was able to infect and replicate to high titers and inhibit the proliferation of EECs and induce non-apoptotic pathways, as determined by B.suis.S2 detection using MTT and acridine orange/ethidium bromide (AO/EB) staining and flow cytometry. We explored the evidence of non-apoptotic pathways using real-time quantitative RT-PCR and by western blot analysis. Finally, we discovered the over-expression of GRP78, ATF4, ATF6, PERK, eIF2α, CHOP, and cytochrome c (Cyt-c) but not IRE1, xbp-1, and caspase-3 in B.suis.S2 (HK)-attacked and B.suis.S2-infected cells, suggesting that the molecular mechanism of ER stress sensor activation by B.suis.S2 is basically concomitant with that by B.suis.S2 (HK) and that ER stress, especially the PERK pathway, plays an important role in the process of B.suis.S2 infecting EEC, which may, in part, explain the role of the uterus in the pathogenesis of B.suis.S2.

  16. Betaine prevented fructose-induced NAFLD by regulating LXRα/PPARα pathway and alleviating ER stress in rats.

    PubMed

    Ge, Chen-Xu; Yu, Rong; Xu, Min-Xuan; Li, Pei-Qin; Fan, Chen-Yu; Li, Jian-Mei; Kong, Ling-Dong

    2016-01-05

    Betaine has been proven effective in treating nonalcoholic fatty liver disease (NAFLD) in animal models, however, its molecular mechanisms remain elusive. The aims of this study were to explore the mechanisms mediating the anti-inflammatory and anti-lipogenic actions of betaine in fructose-fed rats. In this study, betaine improved insulin resistance, reduced body weight gain and serum lipid levels, and prevented hepatic lipid accumulation in fructose-fed rats. It up-regulated hepatic expression of liver X receptor-alpha (LXRα) and peroxisome proliferator-activated receptor-alpha (PPARα), with the attenuation of the changes of their target genes, including hepatic carnitine palmitoyl transferase (CPT) 1α, glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1, apolipoprotein B, sterol regulatory element-binding protein 1c and adipocyte differentiation-related protein, involved in fatty acid oxidation and lipid storage in these model rats. Furthermore, betaine alleviated ER stress and inhibited acetyl-CoA carboxylase α, CPT II, stearoyl-CoA desaturase 1 and fatty acid synthase expression involved in fatty acid synthesis in the liver of fructose-fed rats. Betaine suppressed hepatic gluconeogenesis in fructose-fed rats by moderating protein kinase B -forkhead box protein O1 pathway, as well as p38 mitogen-activated protein kinase and mammalian target of rapamycin activity. Moreover, betaine inhibited hepatic nuclear factor kappa B /nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome activation-mediated inflammation in this animal model. These results demonstrated that betaine ameliorated hepatic lipid accumulation, gluconeogenesis, and inflammation through restoring LXRα and PPARα expression and alleviating ER stress in fructose-fed rats. This study provides the potential mechanisms of betaine involved in the treatment of NAFLD.

  17. Computer Models of Stress, Allostasis, and Acute and Chronic Diseases

    PubMed Central

    Goldstein, David S.

    2009-01-01

    The past century has seen a profound shift in diseases of humankind. Acute, unifactorial diseases are being replaced increasingly by multifactorial disorders that arise from complex interactions among genes, environment, concurrent morbidities and treatments, and time. According to the concept of allostasis, there is no single, ideal set of steady-state conditions in life. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple, interacting effectors regulated by homeostatic comparators “homeostats.” Stress can be defined as a condition or state in which a sensed discrepancy between afferent information and a setpoint for response leads to activation of effectors, reducing the discrepancy. “Allostatic load” refers to the consequences of sustained or repeated activation of mediators of allostasis. From the analogy of a home temperature control system, the temperature can be maintained at any of a variety of levels (allostatic states) by multiple means (effectors), regulated by a comparator thermostat (homeostat). Stress might exert adverse health consequences via allostatic load. This presentation describes models of homeostatic systems that incorporate negative feedback regulation, multiple effectors, effector sharing, environmental influences, intrinsic obsolescence, and destabilizing positive feedback loops. These models can be used to predict effects of environmental and genetic alterations on allostatic load and therefore on the development of multi-system disorders and failures. PMID:19120114

  18. The Effect of Glucose Concentration and Sodium Phenylbutyrate Treatment on Mitochondrial Bioenergetics and ER Stress in 3T3-L1 Adipocytes

    PubMed Central

    Tanis, Ross M.; Piroli, Gerardo G.; Day, Stani D.; Frizzell, Norma

    2016-01-01

    While the 3T3-L1 adipocyte model is routinely used for the study of obesity and diabetes, the mitochondrial respiratory profile in normal versus high glucose has not been examined in detail. We matured adipocytes in normal (5 mM) or high (30 mM) glucose and insulin and examined the mitochondrial bioenergetics. We also assessed the requirement for the Unfolded Protein Response (UPR) and ER stress under these conditions. Basal respiration was ∼1.7-fold greater in adipocytes that had matured in 30 mM glucose; however, their ability to increase oxygen consumption in response to stress was impaired. Adipogenesis proceeded in both normal and high glucose with concomitant activation of the UPR, but only high glucose was associated with increased levels of ER stress and mitochondrial stress as observed by parallel increases in CHOP and protein succination. Treatment of adipocytes with sodium phenylbutyrate relieved mitochondrial stress through a reduction in mitochondrial respiration. Our data suggests that mitochondrial stress, protein succination and ER stress are uniquely linked in adipocytes matured in high glucose. PMID:25448036

  19. Lower electrodermal activity to acute stress in caregivers of people with autism spectrum disorder: an adaptive habituation to stress.

    PubMed

    Ruiz-Robledillo, Nicolás; Moya-Albiol, Luis

    2015-02-01

    Caring for a relative with autism spectrum disorder (ASD) entails being under chronic stress that could alter body homeostasis. Electrodermal activity (EDA) is an index of the sympathetic activity of the autonomic nervous system related to emotionality and homeostasis. This study compares EDA in response to acute stress in the laboratory between parents of people with (n = 30) and without (n = 34) ASD (caregivers and non-caregivers, respectively). Caregivers showed lower EDA in response to acute stress than non-caregivers. They also presented higher trait anxiety, anger, depression, and somatic symptoms than non-caregivers. Higher EDA was related to a worse mood and more severe somatic symptoms only in caregivers. These results could reflect an adaptive habituation to stress and establish that high EDA in response to acute stress depends on caregivers' health.

  20. Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK

    SciTech Connect

    Li, Ying; Li, Jia; Li, Shanshan; Li, Yi; Wang, Xiangxiang; Liu, Baolin; Fu, Qiang; Ma, Shiping

    2015-07-01

    Curcumin is a natural polyphenolic compound in Curcuma longa with beneficial effects on neuronal protection. This study aims to investigate the action of curcumin in the hippocampus subjected to glutamate neurotoxicity. Glutamate stimulation induced reactive oxygen species (ROS), endoplasmic reticulum stress (ER stress) and TXNIP/NLRP3 inflammasome activation, leading to damage in the hippocampus. Curcumin treatment in the hippocampus or SH-SY5Y cells inhibited IRE1α and PERK phosphorylation with suppression of intracellular ROS production. Curcumin increased AMPK activity and knockdown of AMPKα with specific siRNA abrogated its inhibitory effects on IRE1α and PERK phosphorylation, indicating that AMPK activity was essential for the suppression of ER stress. As a result, curcumin reduced TXNIP expression and inhibited NLRP3 inflammasome activation by downregulation of NLRP3 and cleaved caspase-1 induction, and thus reduced IL-1β secretion. Specific fluorescent probe and flow cytometry analysis showed that curcumin prevented mitochondrial malfunction and protected cell survival from glutamate neurotoxicity. Moreover, oral administration of curcumin reduced brain infarct volume and attenuated neuronal damage in rats subjected to middle cerebral artery occlusion. Immunohistochemistry showed that curcumin inhibited p-IRE1α, p-PERK and NLRP3 expression in hippocampus CA1 region. Together, these results showed that curcumin attenuated glutamate neurotoxicity by inhibiting ER stress-associated TXNIP/NLRP3 inflammasome activation via the regulation of AMPK, and thereby protected the hippocampus from ischemic insult. - Highlights: • Curcumin attenuates glutamate neurotoxicity in the hippocampus. • Curcumin suppresses ER stress in glutamate-induced hippocampus slices. • Curcumin inhibits TXNIP/NLRP3 inflammasome activation. • Regulation of AMPK by curcumin contributes to suppressing ER stress.

  1. Up-regulation of K{sub ir}2.1 by ER stress facilitates cell death of brain capillary endothelial cells

    SciTech Connect

    Kito, Hiroaki; Yamazaki, Daiju; Ohya, Susumu; Yamamura, Hisao; Asai, Kiyofumi; Imaizumi, Yuji

    2011-07-29

    Highlights: {yields} We found that application of endoplasmic reticulum (ER) stress with tunicamycin to brain capillary endothelial cells (BCECs) induced cell death. {yields} The ER stress facilitated the expression of inward rectifier K{sup +} channel (K{sub ir}2.1) and induced sustained membrane hyperpolarization. {yields} The membrane hyperpolarization induced sustained Ca{sup 2+} entry through voltage-independent nonspecific cation channels and consequently facilitated cell death. {yields} The K{sub ir}2.1 up-regulation by ER stress is, at least in part, responsible for cell death of BCECs under pathological conditions. -- Abstract: Brain capillary endothelial cells (BCECs) form blood brain barrier (BBB) to maintain brain homeostasis. Cell turnover of BCECs by the balance of cell proliferation and cell death is critical for maintaining the integrity of BBB. Here we found that stimuli with tunicamycin, endoplasmic reticulum (ER) stress inducer, up-regulated inward rectifier K{sup +} channel (K{sub ir}2.1) and facilitated cell death in t-BBEC117, a cell line derived from bovine BCECs. The activation of K{sub ir} channels contributed to the establishment of deeply negative resting membrane potential in t-BBEC117. The deep resting membrane potential increased the resting intracellular Ca{sup 2+} concentration due to Ca{sup 2+} influx through non-selective cation channels and thereby partly but significantly regulated cell death in t-BBEC117. The present results suggest that the up-regulation of K{sub ir}2.1 is, at least in part, responsible for cell death/cell turnover of BCECs induced by a variety of cellular stresses, particularly ER stress, under pathological conditions.

  2. The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism.

    PubMed

    Deng, Yingfeng; Wang, Zhao V; Tao, Caroline; Gao, Ningguo; Holland, William L; Ferdous, Anwarul; Repa, Joyce J; Liang, Guosheng; Ye, Jin; Lehrman, Mark A; Hill, Joseph A; Horton, Jay D; Scherer, Philipp E

    2013-01-01

    Postprandially, the liver experiences an extensive metabolic reprogramming that is required for the switch from glucose production to glucose assimilation. Upon refeeding, the unfolded protein response (UPR) is rapidly, though only transiently, activated. Activation of the UPR results in a cessation of protein translation, increased chaperone expression, and increased ER-mediated protein degradation, but it is not clear how the UPR is involved in the postprandial switch to alternate fuel sources. Activation of the inositol-requiring enzyme 1 (IRE1) branch of the UPR signaling pathway triggers expression of the transcription factor Xbp1s. Using a mouse model with liver-specific inducible Xbp1s expression, we demonstrate that Xbp1s is sufficient to provoke a metabolic switch characteristic of the postprandial state, even in the absence of caloric influx. Mechanistically, we identified UDP-galactose-4-epimerase (GalE) as a direct transcriptional target of Xbp1s and as the key mediator of this effect. Our results provide evidence that the Xbp1s/GalE pathway functions as a novel regulatory nexus connecting the UPR to the characteristic postprandial metabolic changes in hepatocytes.

  3. Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress

    PubMed Central

    Liu, Huaping; Kurtoglu, Metin; León-Annicchiarico, Clara Lucia; Munoz-Pinedo, Cristina; Barredo, Julio; Leclerc, Guy; Merchan, Jaime; Liu, Xiongfei; Lampidis, Theodore J.

    2016-01-01

    Unregulated growth and replication as well as an abnormal microenvironment, leads to elevated levels of stress which is a common trait of cancer. By inducing both energy and endoplasmic reticulum (ER) stress, 2-Deoxy-glucose (2-DG) is particularly well-suited to take advantage of the therapeutic window that heightened stress in tumors provides. Under hypoxia, blocking glycolysis with 2-DG leads to significant lowering of ATP resulting in energy stress and cell death in numerous carcinoma cell types. In contrast, under normoxia, 2-DG at a low-concentration is not toxic in most carcinomas tested, but induces growth inhibition, which is primarily due to ER stress. Here we find a synergistic toxic effect in several tumor cell lines in vitro combining 2-DG with fenofibrate (FF), a drug that has been safely used for over 40 years to lower cholesterol in patients. This combination induces much greater energy stress than either agent alone, as measured by ATP reduction, increased p-AMPK and downregulation of mTOR. Inhibition of mTOR results in blockage of GRP78 a critical component of the unfolded protein response which we speculate leads to greater ER stress as observed by increased p-eIF2α. Moreover, to avoid an insulin response and adsorption by the liver, 2-DG is delivered by slow-release pump yielding significant anti-tumor control when combined with FF. Our results provide promise for developing this combination clinically and others that combine 2-DG with agents that act synergistically to selectively increase energy and ER stress to a level that is toxic to numerous tumor cell types. PMID:27183907

  4. Mycobacterium tuberculosis PPE32 promotes cytokines production and host cell apoptosis through caspase cascade accompanying with enhanced ER stress response

    PubMed Central

    Zeng, Jie; Abdalla, Abualgasim Elgaili; Xie, Jianping

    2016-01-01

    Tuberculosis, caused by Mycobacterium tuberculosis (MTB) infection, remains a grave global public health burden which claims the lives around two to three million annually. PE and PPE proteins, featured by the Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs at the conserved N-terminal domain, are abundant in the MTB genome. PPE32 can increase intracellular survival of mycobacteria through abnormally increase in cytokines production. PPE32 might subvert the macrophage immune response and thwart its bactericidal effect. THP-1 macrophages treated with PPE32 or infected with Mycobacterium smegmatis (MS) expression PPE32 showed increase of cytokines production and multiple hallmarks of apoptosis. We found that PPE32 significantly increases the expression of IL-12p40 and IL-32 through ERK1/2 signaling pathway. In addition, the cell viability of macrophage was inhibited after PPE32 stimulation. We noted that PPE32 induces cleavage of caspase-3 and caspase-9, while inhibition of caspase activity significantly abrogates the PPE32-induced cell apoptosis. Moreover, PPE32 treatment promotes endoplasmic reticulum stress related gene expression, suggesting ER stress might be responsible for PPE32-induced cell apoptosis. PMID:27634911

  5. Prolonged Effects of Acute Stress on Decision-Making under Risk: A Human Psychophysiological Study

    PubMed Central

    Yamakawa, Kaori; Ohira, Hideki; Matsunaga, Masahiro; Isowa, Tokiko

    2016-01-01

    This study investigates the prolonged effects of physiological responses induced by acute stress on risk-taking in decision-making. Participants were divided into a Stress group (N = 14) and a Control group (N = 12). The Trier Social Stress Test was administered as an acute stressor, and reading was administered as a control task; thereafter, participants performed a decision-making task in which they needed to choose a sure option or a gamble option in Gain and Loss frame trials 2 h after (non-) exposure to the stressor. Increased cortisol, adrenaline, heart rate (HR), and subjective stress levels validated acute stress manipulation. Stressed participants made fewer risky choices only in the Gain domain, whereas no effect of stress was shown in the Loss domain. Deceleration of HR reflecting attention was greater for Gains compared with Losses only in the Stress group. Risk avoidance was determined by increased levels of cortisol caused by acute stress. These results suggest that processes regarding glucocorticoid might be involved in the prolonged effects of acute stress on the evaluation of risks and the monitoring of outcomes in decision-making. PMID:27679566

  6. Lower Electrodermal Activity to Acute Stress in Caregivers of People with Autism Spectrum Disorder: An Adaptive Habituation to Stress

    ERIC Educational Resources Information Center

    Ruiz-Robledillo, Nicolás; Moya-Albiol, Luis

    2015-01-01

    Caring for a relative with autism spectrum disorder (ASD) entails being under chronic stress that could alter body homeostasis. Electrodermal activity (EDA) is an index of the sympathetic activity of the autonomic nervous system related to emotionality and homeostasis. This study compares EDA in response to acute stress in the laboratory between…

  7. The effect of acute stress on memory depends on word valence.

    PubMed

    Smeets, Tom; Jelicic, Marko; Merckelbach, Harald

    2006-10-01

    The present study investigated the effect of acute stress on working memory and memory for neutral, emotionally negative, and emotionally positive words in healthy undergraduates. Participants (N=60) were exposed to either the Trier Social Stress Test (stress group) or a non-stressful task (control group). Analyses of salivary cortisol samples taken throughout the study showed elevated glucocorticoid levels after the experimental manipulation in the stress group, but not in the control group. Recall performance was impaired in the stress group, but only so for neutral words. No differences between the stress and control group were found on working memory measures. For the stress group, digit span forward and digit span total scores were associated with correct recall of neutral words. All in all, this study lends further support to the notion that the memory effects of exposure to acute stress depend on the valence of the memory material.

  8. DOT1L Activity Promotes Proliferation and Protects Cortical Neural Stem Cells from Activation of ATF4-DDIT3-Mediated ER Stress In Vitro.

    PubMed

    Roidl, Deborah; Hellbach, Nicole; Bovio, Patrick P; Villarreal, Alejandro; Heidrich, Stefanie; Nestel, Sigrun; Grüning, Björn A; Boenisch, Ulrike; Vogel, Tanja

    2016-01-01

    Growing evidence suggests that the lysine methyltransferase DOT1L/KMT4 has important roles in proliferation, survival, and differentiation of stem cells in development and in disease. We investigated the function of DOT1L in neural stem cells (NSCs) of the cerebral cortex. The pharmacological inhibition and shRNA-mediated knockdown of DOT1L impaired proliferation and survival of NSCs. DOT1L inhibition specifically induced genes that are activated during the unfolded protein response (UPR) in the endoplasmic reticulum (ER). Chromatin-immunoprecipitation analyses revealed that two genes encoding for central molecules involved in the ER stress response, Atf4 and Ddit3 (Chop), are marked with H3K79 methylation. Interference with DOT1L activity resulted in transcriptional activation of both genes accompanied by decreased levels of H3K79 dimethylation. Although downstream effectors of the UPR, such as Ppp1r15a/Gadd34, Atf3, and Tnfrsf10b/Dr5 were also transcriptionally activated, this most likely occurred in response to increased ATF4 expression rather than as a direct consequence of altered H3K79 methylation. While stem cells are particularly vulnerable to stress, the UPR and ER stress have not been extensively studied in these cells yet. Since activation of the ER stress program is also implicated in directing stem cells into differentiation or to maintain a proliferative status, the UPR must be tightly regulated. Our and published data suggest that histone modifications, including H3K4me3, H3K14ac, and H3K79me2, are implicated in the control of transcriptional activation of ER stress genes. In this context, the loss of H3K79me2 at the Atf4- and Ddit3-promoters appears to mark a point-of-no-return that activates the death program in NSCs.

  9. Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress-response pathways.

    PubMed

    Senkal, Can E; Ponnusamy, Suriyan; Bielawski, Jacek; Hannun, Yusuf A; Ogretmen, Besim

    2010-01-01

    Emerging results suggest that ceramides with different fatty acid chain lengths might play distinct functions in the regulation of tumor growth and therapy. Here we report that de novo-generated C(18)- and C(16)-ceramides by ceramide synthases 1 and 6 (CerS1 and CerS6) play opposing proapoptotic and prosurvival roles, respectively, in human head and neck squamous cell carcinomas (HNSCCs). Unexpectedly, knockdown of CerS6/C(16)-ceramide using small interfering RNA induced endoplasmic reticulum (ER)-stress-mediated apoptosis. Reconstitution of C(16)-ceramide generation by induced expression of wild-type CerS6, but not its catalytically inactive mutant, protected cells from cell death induced by knockdown of CerS6. Moreover, using molecular tools coupled with analysis of sphingolipid metabolism showed that generation of C(16)-ceramide, and not dihydro-C(16)-ceramide, by induced expression of CerS6 rescued cells from ER stress and apoptosis. Mechanistically, regulation of ER-stress-induced apoptosis by CerS6/C(16)-ceramide was linked to the activation of a specific arm, ATF6/CHOP, of the unfolded protein response pathway. Notably, while expression of CerS1/C(18)-ceramide inhibited HNSCC xenograft growth, CerS6/C(16)-ceramide significantly protected ER stress, leading to enhanced tumor development and growth in vivo, consistent with their pro- and antiapoptotic roles, respectively. Thus, these data reveal an unexpected and novel prosurvival role of CerS6/C(16)-ceramide involved in the protection against ER-stress-induced apoptosis and induction of HNSCC tumor growth.

  10. Nickel chloride (NiCl2) induces endoplasmic reticulum (ER) stress by activating UPR pathways in the kidney of broiler chickens

    PubMed Central

    Guo, Hongrui; Cui, Hengmin; Peng, Xi; Fang, Jing; Zuo, Zhicai; Deng, Junliang; Wang, Xun; Wu, Bangyuan; Chen, Kejie; Deng, Jie

    2016-01-01

    It has been known that overexposure to Ni can induce nephrotoxicity. However, the mechanisms of underlying Ni nephrotoxicity are still elusive, and also Ni- and Ni compound-induced ER stress has been not reported in vivo at present. Our aim was to use broiler chickens as animal model to test whether the ER stress was induced and UPR was activated by NiCl2 in the kidney using histopathology, immunohistochemistry and qRT-PCR. Two hundred and eighty one-day-old broiler chickens were divided into 4 groups and fed on a control diet and the same basal diet supplemented with 300 mg/kg, 600mg/kg and 900mg/kg of NiCl2 for 42 days. We found that dietary NiCl2 in excess of 300 mg/kg induced ER stress, which was characterized by increasing protein and mRNA expression of ER stress markers, e.g., GRP78 and GRP94. Concurrently, all the three UPR pathways were activated by dietary NiCl2. Firstly, the PERK pathway was activated by increasing eIF2a and ATF4 mRNA expression. Secondly, the IRE1 pathway was activated duo to increase in IRE1 and XBP1 mRNA expression. And thirdly, the increase of ATF6 mRNA expression suggested that ATF6 pathway was activated. The findings clearly demonstrate that NiCl2 induces the ER stress through activating PERK, IRE1 and ATF6 UPR pathways, which is proved to be a kind of molecular mechanism of Ni- or/and Ni compound-induced nephrotoxicity. PMID:26956054

  11. Down-regulation of Homer1 attenuates t-BHP-induced oxidative stress through regulating calcium homeostasis and ER stress in brain endothelial cells.

    PubMed

    Guo, Zhen-Yu; Zhang, Ya-Hong; Xie, Guo-Qiang; Liu, Chong-Xiao; Zhou, Ren; Shi, Wei

    2016-09-02

    Endothelial dysfunction in brain endothelial cells contributes to vasogenic cerebral edema and increased mortality after various neurological diseases. The postsynaptic density protein Homer1 plays an important role in neuronal synaptic activity and is extensively involved in neurological disorders. The present study investigated the role of Homer1 in modulating cell survival using an in vitro endothelial dysfunction model in murine brain endothelial cells (mBECs). Treatment with tert-butyl hydroperoxide (t-BHP) induced a dose-dependent toxicity in mBECs, with no effects on Homer1 expression and distribution. Knockdown of Homer1 using specific siRNA significantly alleviated lactate dehydrogenase (LDH) release, increased cell viability, and ultimately decreased apoptosis after t-BHP treatment. Moreover, Homer1 knockdown attenuated t-BHP-induced ROS generation, lipid peroxidation and mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential (MMP), ATP synthesis collapse and mitochondrial swelling. The results of Ca(2+) imaging showed that Homer1 was involved in inositol trisphosphate receptors (IP3R)- and ryanodine receptor (RyR)-mediated intracellular Ca(2+) release, and also mediated t-BHP-induced Ca(2+) release from the endoplasmic reticulum (ER). In addition, knockdown of Homer1 significantly prevented activation of ER stress markers induced by t-BHP exposure. All these results showed that Homer1 is involved in t-BHP-induced endothelial dysfunction in mBECs, and may be an ideal candidate for searching gene intervention strategy for preventing endothelial oxidative stress in vitro.

  12. † THE GROUP VIA CALCIUM-INDEPENDENT PHOSPHOLIPASE A2 (iPLA2β)1 PARTICIPATES IN ER STRESS-INDUCED INS-1 INSULINOMA CELL APOPTOSIS BY PROMOTING CERAMIDE GENERATION VIA HYDROLYSIS OF SPHINGOMYELINS BY NEUTRAL SPHINGOMYELINASE

    PubMed Central

    Lei, Xiao-Yong; Zhang, Sheng; Bohrer, Alan; Bao, Shunzhong; Song, Haowei; Ramanadham, Sasanka

    2008-01-01

    β-cell mass is regulated by a balance between β-cell growth and β-cell death, due to apoptosis. We previously reported that apoptosis of INS-1 insulinoma cells due to thapsigargin-induced ER stress was suppressed by inhibition of the Group VIA Ca2+-independent phospholipase A2 (iPLA2β), associated with increased ceramide generation, and that the effects of ER stress were amplified in INS-1 cells in which iPLA2β was over expressed (OE INS-1 cells). These findings suggested that iPLA2β and ceramides participate in ER stress-induced INS-1 cell apoptosis. Here, we addressed this possibility and also the source of the ceramides by examining the effects of ER stress in empty vector (V)-transfected and iPLA2β-OE INS-1 cells using apoptosis assays and immunoblotting, quantitative PCR, and mass spectrometry analyses. ER stress induced expression of ER stress factors GRP78 and BiP, cleavage of apoptotic factor PARP, and apoptosis in V and OE INS-1 cells. Ceramide accumulation during ER stress was not associated with changes in mRNA levels of serine palmitoyl-transferase (SPT), the rate-limiting enzyme in de novo synthesis of ceramides but both message and protein levels of neutral sphingomyelinase (NSMase), which hydrolyzes sphingomyelins to generate ceramides, temporally increased in the INS-1 cells. The increases in NSMase expression in the ER-stressed INS-1 cells were associated with corresponding temporal elevations in ER-associated iPLA2β protein and catalytic activity. Pretreatment with BEL inactivated iPLA2β and prevented induction of NSMase message and protein in ER-stressed INS-1 cells. Relative to V INS-1 cells, the effects of ER stress were accelerated and/or amplified in the OE INS-1 cells. However, inhibition of iPLA2β or NSMase (chemically or with siRNA) suppressed induction of NSMase message, ceramide generation, sphingomyelin hydrolysis, and apoptosis in both V and OE INS-1 cells during ER stress. In contrast, inhibition of SPT did not suppress

  13. Fluoride Intensifies Hypercaloric Diet-Induced ER Oxidative Stress and Alters Lipid Metabolism

    PubMed Central

    Pereira, Heloisa Aparecida Barbosa Silva; Dionizio, Aline Salgado; Fernandes, Mileni Silva; Araujo, Tamara Teodoro; Cestari, Tânia Mary; Buzalaf, Camila Peres; Iano, Flávia Godoy; Buzalaf, Marília Afonso Rabelo

    2016-01-01

    The role of fluoride (F) in oxidative stress is well reported, but its effects on the lipid metabolism has not been completely explored Background Here, we evaluated the relationship of diet and F-induced oxidative stress to lipid metabolism in the liver of rats eating normocaloric or hypercaloric diets for two time periods (20 or 60 days). Methods Seventy-two 21-day-old Wistar rats were divided into 2 groups (n = 36) based on the type of diet they were eating; each of these groups was then further divided into another two groups (n = 18) based on the time periods of either 20 or 60 days, for a total of four groups. Each of these was divided into 3 subgroups (n = 6 animals/subgroup), dependent on the dose of F administered in the drinking water (0 mg/L(control), 15 mg/L or 50 mg/L). After the experimental period, blood samples and the liver were collected. Plasma samples were analyzed for HDL, cholesterol and triglycerides. Western blots were performed to probe for GRP78, Erp29, SOD2, Apo-E and SREBP in hepatic tissues. Results As expected,the expression of target proteins involved in oxidative stress increased in the F-treated groups, especially in liver tissue obtained from animals eating a hypercaloric diet. Most changes in the lipid levels and pathological conditions were seen earlier in the time period, at day 20. The morphometric analyses showed a reduction in steatosis in groups on ahypercaloric diet and treated with 50 mg F/L compared to the control, while no changes were obtained in normocaloric-fed rats. Accordingly, plasma TG was reduced in the F-treated group. The reduced expression of Apo-E in a time- and diet-dependent pattern may account for the particular decrease in steatosis in hypercaloric-fed F-treated rats. Conclusions These results suggest that F changes liver lipid homeostasis, possibly because of the induction of oxidative stress, which seems to be higher in animals fed hypercaloric diets. PMID:27336443

  14. Acute stress switches spatial navigation strategy from egocentric to allocentric in a virtual Morris water maze.

    PubMed

    van Gerven, Dustin J H; Ferguson, Thomas; Skelton, Ronald W

    2016-07-01

    Stress and stress hormones are known to influence the function of the hippocampus, a brain structure critical for cognitive-map-based, allocentric spatial navigation. The caudate nucleus, a brain structure critical for stimulus-response-based, egocentric navigation, is not as sensitive to stress. Evidence for this comes from rodent studies, which show that acute stress or stress hormones impair allocentric, but not egocentric navigation. However, there have been few studies investigating the effect of acute stress on human spatial navigation, and the results of these have been equivocal. To date, no study has investigated whether acute stress can shift human navigational strategy selection between allocentric and egocentric navigation. The present study investigated this question by exposing participants to an acute psychological stressor (the Paced Auditory Serial Addition Task, PASAT), before testing navigational strategy selection in the Dual-Strategy Maze, a modified virtual Morris water maze. In the Dual-Strategy maze, participants can chose to navigate using a constellation of extra-maze cues (allocentrically) or using a single cue proximal to the goal platform (egocentrically). Surprisingly, PASAT stress biased participants to solve the maze allocentrically significantly more, rather than less, often. These findings have implications for understanding the effects of acute stress on cognitive function in general, and the function of the hippocampus in particular.

  15. Child anxiety symptoms related to longitudinal cortisol trajectories and acute stress responses: evidence of developmental stress sensitization.

    PubMed

    Laurent, Heidemarie K; Gilliam, Kathryn S; Wright, Dorianne B; Fisher, Philip A

    2015-02-01

    Cross-sectional research suggests that individuals at risk for internalizing disorders show differential activation levels and/or dynamics of stress-sensitive physiological systems, possibly reflecting a process of stress sensitization. However, there is little longitudinal research to clarify how the development of these systems over time relates to activation during acute stress, and how aspects of such activation map onto internalizing symptoms. We investigated children's (n = 107) diurnal hypothalamic-pituitary-adrenal activity via salivary cortisol (morning and evening levels) across 29 assessments spanning 6+ years, and related longitudinal patterns to acute stress responses at the end of this period (age 9-10). Associations with child psychiatric symptoms at age 10 were also examined to determine internalizing risk profiles. Increasing morning cortisol levels across assessments predicted less of a cortisol decline following interpersonal stress at age 9, and higher cortisol levels during performance stress at age 10. These same profiles of high and/or sustained cortisol elevation during psychosocial stress were associated with child anxiety symptoms. Results suggest developmental sensitization to stress-reflected in rising morning cortisol and eventual hyperactivation during acute stress exposure-may distinguish children at risk for internalizing disorders.

  16. Armet/Manf and Creld2 are components of a specialized ER stress response provoked by inappropriate formation of disulphide bonds: implications for genetic skeletal diseases

    PubMed Central

    Hartley, Claire L.; Edwards, Sarah; Mullan, Lorna; Bell, Peter A.; Fresquet, Maryline; Boot-Handford, Raymond P.; Briggs, Michael D.

    2013-01-01

    Mutant matrilin-3 (V194D) forms non-native disulphide bonded aggregates in the rER of chondrocytes from cell and mouse models of multiple epiphyseal dysplasia (MED). Intracellular retention of mutant matrilin-3 causes endoplasmic reticulum (ER) stress and induces an unfolded protein response (UPR) including the upregulation of two genes recently implicated in ER stress: Armet and Creld2. Nothing is known about the role of Armet and Creld2 in human genetic diseases. In this study, we used a variety of cell and mouse models of chondrodysplasia to determine the genotype-specific expression profiles of Armet and Creld2. We also studied their interactions with various mutant proteins and investigated their potential roles as protein disulphide isomerases (PDIs). Armet and Creld2 were up-regulated in cell and/or mouse models of chondrodysplasias caused by mutations in Matn3 and Col10a1, but not Comp. Intriguingly, both Armet and Creld2 were also secreted into the ECM of these disease models following ER stress. Armet and Creld2 interacted with mutant matrilin-3, but not with COMP, thereby validating the genotype-specific expression. Substrate-trapping experiments confirmed Creld2 processed PDI-like activity, thus identifying a putative functional role. Finally, alanine substitution of the two terminal cysteine residues from the A-domain of V194D matrilin-3 prevented aggregation, promoted mutant protein secretion and reduced the levels of Armet and Creld2 in a cell culture model. We demonstrate that Armet and Creld2 are genotype-specific ER stress response proteins with substrate specificities, and that aggregation of mutant matrilin-3 is a key disease trigger in MED that could be exploited as a potential therapeutic target. PMID:23956175

  17. 5-Hydroxymethylfurfural protects against ER stress-induced apoptosis in GalN/TNF-α-injured L02 hepatocytes through regulating the PERK-eIF2α signaling pathway.

    PubMed

    Jiang, Ze-Qun; Ma, Yan-Xia; Li, Mu-Han; Zhan, Xiu-Qin; Zhang, Xu; Wang, Ming-Yan

    2015-12-01

    5-Hydroxymethylfurfural (5-HMF), a water-soluble compound extracted from wine-processed Fructus corni, is a novel hepatic protectant for treating acute liver injury. The present study was designed to investigate the protective effect of 5-HMF in human L02 hepatocytes injured by D-galactosamine (GalN) and tumor necrosis factor-α (TNF-α) in vitro and to explore the underlying mechanisms of action. Our results showed that 5-HMF caused significant increase in the viability of L02 cells injured by GalN/TNF-α, in accordance with a dose-dependent decrease in apoptotic cell death confirmed by morphological and flow cytometric analyses. Based on immunofluorescence and Western blot assays, we found that GalN/TNF-α induced ER stress in the cells, as indicated by the disturbance of intracellular Ca(2+) concentration, the activation of protein kinase RNA (PKR)-like ER kinase (PERK), phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α), and expression of ATF4 and CHOP proteins, which was reversed by 5-HMF pre-treatment in a dose-dependent manner. The anti-apoptotic effect of 5-HMF was further evidenced by balancing the expression of Bcl-2 family members. In addition, the knockdown of PERK suppressed the expression of phospho-PERK, phospho-eIF2α, ATF4, and CHOP, resulting in a significant decrease in cell apoptosis after the treatment with GalN/TNF-α. 5-HMF could enhance the effects of PERK knockdown, protecting the cells against the GalN/TNF-α insult. In conclusion, these findings demonstrate that 5-HMF can effectively protect GalN/TNF-α-injured L02 hepatocytes against ER stress-induced apoptosis through the regulation of the PERK-eIF2α signaling pathway, suggesting that it is a possible candidate for liver disease therapy.

  18. Acute stress differentially affects spatial configuration learning in high and low cortisol-responding healthy adults

    PubMed Central

    Meyer, Thomas; Smeets, Tom; Giesbrecht, Timo; Quaedflieg, Conny W. E. M.; Merckelbach, Harald

    2013-01-01

    Background Stress and stress hormones modulate memory formation in various ways that are relevant to our understanding of stress-related psychopathology, such as posttraumatic stress disorder (PTSD). Particular relevance is attributed to efficient memory formation sustained by the hippocampus and parahippocampus. This process is thought to reduce the occurrence of intrusions and flashbacks following trauma, but may be negatively affected by acute stress. Moreover, recent evidence suggests that the efficiency of visuo-spatial processing and learning based on the hippocampal area is related to PTSD symptoms. Objective The current study investigated the effect of acute stress on spatial configuration learning using a spatial contextual cueing task (SCCT) known to heavily rely on structures in the parahippocampus. Method Acute stress was induced by subjecting participants (N = 34) to the Maastricht Acute Stress Test (MAST). Following a counterbalanced within-subject approach, the effects of stress and the ensuing hormonal (i.e., cortisol) activity on subsequent SCCT performance were compared to SCCT performance following a no-stress control condition. Results Acute stress did not impact SCCT learning overall, but opposing effects emerged for high versus low cortisol responders to the MAST. Learning scores following stress were reduced in low cortisol responders, while high cortisol-responding participants showed improved learning. Conclusions The effects of stress on spatial configuration learning were moderated by the magnitude of endogenous cortisol secretion. These findings suggest a possible mechanism by which cortisol responses serve an adaptive function during stress and trauma, and this may prove to be a promising route for future research in this area. PMID:23671762

  19. Catecholaminergic responses in vas deferens isolated from rats submitted to acute swimming stress.

    PubMed

    Chies, A B; Pereira, O C

    1995-09-01

    The study was performed to examine the responses to catecholamines in vas deferens isolated from rats submitted to acute swimming-induced stress. It was demonstrated that acute stress induces a significant subsensitivity of rat vas deferens to norepinephrine. This subsensitivity was inhibited when the experiment was carried out in the presence of either cocaine (10-5 M) or timolol (10-5 M). On the other hand, the rat vas deferens sensitivity to methoxamine was significantly increased by acute swimming-induced stress. Thus, despite acute swimming stress inducing a reduction in response to norepinephrine, the alpha1-adrenoceptor-mediated contractile response was increased. Additionally there were increases in neuronal uptake and beta2-adrenoceptor activity that opposes the alpha1-adrenoceptor activity. Integrated, these phenomena are responsible for the rat vas deferens subsensitivity to norepinephrine which may be involved in body homeostasis in stressogenic situations.

  20. Impact of acute stress on psychomotor bimanual performance during a simulated tumor resection task.

    PubMed

    Bajunaid, Khalid; Mullah, Muhammad Abu Shadeque; Winkler-Schwartz, Alexander; Alotaibi, Fahad E; Fares, Jawad; Baggiani, Marta; Azarnoush, Hamed; Christie, Sommer; Al-Zhrani, Gmaan; Marwa, Ibrahim; Sabbagh, Abdulrahman Jafar; Werthner, Penny; Del Maestro, Rolando F

    2017-01-01

    OBJECTIVE Severe bleeding during neurosurgical operations can result in acute stress affecting the bimanual psychomotor performance of the operator, leading to surgical error and an adverse patient outcome. Objective methods to assess the influence of acute stress on neurosurgical bimanual psychomotor performance have not been developed. Virtual reality simulators, such as NeuroTouch, allow the testing of acute stress on psychomotor performance in risk-free environments. Thus, the purpose of this study was to explore the impact of a simulated stressful virtual reality tumor resection scenario by utilizing NeuroTouch to answer 2 questions: 1) What is the impact of acute stress on bimanual psychomotor performance during the resection of simulated tumors? 2) Does acute stress influence bimanual psychomotor performance immediately following the stressful episode? METHODS Study participants included 6 neurosurgeons, 6 senior and 6 junior neurosurgical residents, and 6 medical students. Participants resected a total of 6 simulated tumors, 1 of which (Tumor 4) involved uncontrollable "intraoperative" bleeding resulting in simulated cardiac arrest and thus providing the acute stress scenario. Tier 1 metrics included extent of blood loss, percentage of tumor resected, and "normal" brain tissue volume removed. Tier 2 metrics included simulated suction device (sucker) and ultrasonic aspirator total tip path length, as well as the sum and maximum forces applied in using these instruments. Advanced Tier 2 metrics included efficiency index, coordination index, ultrasonic aspirator path length index, and ultrasonic aspirator bimanual forces ratio. All metrics were assessed before, during, and after the stressful scenario. RESULTS The stress scenario caused expected significant increases in blood loss in all participant groups. Extent of tumor resected and brain volume removed decreased in the junior resident and medical student groups. Sucker total tip path length increased in

  1. Oxidative stress and Kawasaki disease: how is oxidative stress involved from the acute stage to the chronic stage?

    PubMed

    Yahata, Tomoyo; Hamaoka, Kenji

    2017-01-01

    Inflammation and oxidative stress are closely related. Further, oxidative stress plays an important role in the pathology of inflammation-based Kawasaki disease. An excessive in vivo production of reactive oxygen species increases oxidative stress in the body, which triggers an endless vicious spiral of inflammation reactions and reactive oxygen metabolites. This presumably forms diffuse vasculitis in the acute phase. Acute inflammation and oxidative stress can be rapidly controlled by treatments; however, they may remain for a long time. This has recently been identified as a problem in the chronic phase of Kawasaki disease. Generally, the presence of vascular inflammation and oxidative stress impairs blood vessels, leading to the onset of atherosclerosis, which is a widely recognized risk. The current discussion focuses on whether the same is valid for blood vessels in the chronic phase of Kawasaki disease.

  2. Hypothalamic-Pituitary-Adrenal Reactivity to Acute Stress: an Investigation into the Roles of Perceived Stress and Family Resources.

    PubMed

    Obasi, Ezemenari M; Shirtcliff, Elizabeth A; Cavanagh, Lucia; Ratliff, Kristen L; Pittman, Delishia M; Brooks, Jessica J

    2017-02-08

    Rurally situated African Americans suffer from chronic exposure to stress that may have a deleterious effect on health outcomes. Unfortunately, research on potential mechanisms that underlie health disparities affecting the African American community has received limited focus in the scientific literature. This study investigated the relationship between perceived stress, family resources, and cortisol reactivity to acute stress. A rural sample of African American emerging adults (N = 60) completed a battery of assessments, the Trier Social Stress Test (TSST), and provided four samples of salivary cortisol: prior to receiving TSST instructions, prior to conducting the speech task, immediately following the TSST, and 15-20 min following the TSST. As predicted, cortisol levels increased in response to a controlled laboratory inducement of acute stress. Moreover, diminished levels of family resources were associated with blunted cortisol reactivity to acute stress. Of note, higher levels of perceived stress over the past month and being male were independently associated with lower levels of cortisol at baseline. Lack of family resources had a blunting relationship on the hypothalamic-pituitary-adrenal axis reactivity. These findings provide biomarker support for the relationship between family resources-an indicator associated with social determinants of health-and stress physiology within a controlled laboratory experiment. Identifying mechanisms that work toward explanation of within-group differences in African American health disparities is both needed and informative for culturally informed prevention and intervention efforts.

  3. Child Anxiety Symptoms Related to Longitudinal Cortisol Trajectories and Acute Stress Responses: Evidence of Developmental Stress Sensitization

    PubMed Central

    Laurent, Heidemarie K.; Gilliam, Kathryn S.; Wright, Dorianne B.; Fisher, Philip A.

    2015-01-01

    Cross-sectional research suggests that individuals at risk for internalizing disorders show differential activation levels and/or dynamics of stress-sensitive physiological systems, possibly reflecting a process of stress sensitization. However, there is little longitudinal research to clarify how the development of these systems over time relates to activation during acute stress, and how aspects of such activation map onto internalizing symptoms. We investigated children’s (n=107) diurnal hypothalamic-pituitary-adrenal activity via salivary cortisol (morning and evening levels) across 29 assessments spanning 6+ years, and related longitudinal patterns to acute stress responses at the end of this period (age 9–10). Associations with child psychiatric symptoms at age 10 were also examined to determine internalizing risk profiles. Increasing morning cortisol levels across assessments predicted less of a cortisol decline following interpersonal stress at age 9, and higher cortisol levels during performance stress at age 10. These same profiles of high and/or sustained cortisol elevation during psychosocial stress were associated with child anxiety symptoms. Results suggest developmental sensitization to stress—reflected in rising morning cortisol and eventual hyperactivation during acute stress exposure—may distinguish children at risk for internalizing disorders. PMID:25688433

  4. Molecular pathway of near-infrared laser phototoxicity involves ATF-4 orchestrated ER stress

    PubMed Central

    Khan, Imran; Tang, Elieza; Arany, Praveen

    2015-01-01

    High power lasers are used extensively in medicine while lower power applications are popular for optical imaging, optogenetics, skin rejuvenation and a therapeutic modality termed photobiomodulation (PBM). This study addresses the therapeutic dose limits, biological safety and molecular pathway of near-infrared (NIR) laser phototoxicity. Increased erythema and tissue damage were noted in mice skin and cytotoxicity in cell cultures at phototoxic laser doses involving generation of reactive oxygen species (ROS) coupled with a rise in surface temperature (>45 °C). NIR laser phototoxicity results from Activating Transcription Factor-4 (ATF-4) mediated endoplasmic reticulum stress and autophagy. Neutralizations of heat or ROS and overexpressing ATF-4 were noted to rescue NIR laser phototoxicity. Further, NIR laser mediated phototoxicity was noted to be non-genotoxic and non-mutagenic. This study outlines the mechanism of NIR laser phototoxicity and the utility of monitoring surface temperature and ATF4 expression as potential biomarkers to develop safe and effective clinical applications. PMID:26030745

  5. Amblyomin-X induces ER stress, mitochondrial dysfunction, and caspase activation in human melanoma and pancreatic tumor cell.

    PubMed

    Morais, Katia L P; Pacheco, Mario Thiego Fernandes; Berra, Carolina Maria; Bosch, Rosemary V; Sciani, Juliana Mozer; Chammas, Roger; de Freitas Saito, Renata; Iqbal, Asif; Chudzinski-Tavassi, Ana Marisa

    2016-04-01

    During the last two decades, new insights into proteasome function and its role in several human diseases made it a potential therapeutic target. In this context, Amblyomin-X is a Kunitz-type FXa inhibitor similar to endogenous tissue factor pathway inhibitor (TFPI) and is a novel proteasome inhibitor. Herein, we have demonstrated Amblyomin-X cytotoxicity to different tumor cells lines such as pancreatic (Panc1, AsPC1BxPC3) and melanoma (SK-MEL-5 and SK-MEL-28). Of note, Amblyomin-X was not cytotoxic to normal human fibroblast cells. In addition, Amblyomin-X promoted accumulation of ER stress markers (GRP78 and GADD153) in sensitive (SK-MEL-28) and bortezomib-resistant (Mia-PaCa-2) tumor cells. The intracellular calcium concentration [Ca(2+)] i was slightly modulated in human tumor cells (SK-MEL-28 and Mia-PaCa-2) after 24 h of Amblyomin-X treatment. Furthermore, Amblyomin-X induced mitochondrial dysfunction, cytochrome-c release, PARP cleavage, and activation of caspase cascade in both human tumor (SK-MEL-28 and Mia-PaCa-2) cells. These investigations might help in further understanding of the antitumor properties of Amblyomin-X.

  6. Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in multiple myeloma

    PubMed Central

    Prasad, Vivek; Kimlinger, Teresa; Painuly, Utkarsh; Mukhopadhyay, Bedabrata; Haug, Jessica; Bi, Lintao; Rajkumar, S. Vincent; Kumar, Shaji

    2016-01-01

    Bcl2 and IAP families are anti-apoptotic proteins deregulated in multiple myeloma (MM) cells. Pharmacological inhibition of each of these families has shown significant activity only in subgroups of MM patients. Here, we have examined a broad-spectrum Bcl2 family inhibitor Obatoclax (OBX) in combination with a Smac mimetic LCL161 in MM cell lines and patient cells. LCL161/OBX combination induced synergistic cytotoxicity and anti-proliferative effects on a broad range of human MM cell lines. The cytotoxicity was mediated through inhibition of the IAPs, activation of caspases and up regulation of the pro-apoptotic proteins Bid, Bim, Puma and Noxa by the drug combination. In addition, we observed that OBX caused ER stress and activated the Unfolded Protein Response (UPR) leading to drug resistance. LCL161, however inhibited spliced Xbp-1, a pro-survival factor. In addition, we observed that OBX increased GRP78 localization to the cell surface, which then induced PI3K dependent Akt activation and resistance to cell death. LCL161 was able to block OBX induced Akt activation contributing to synergistic cell death. Our results support clinical evaluation of this combination strategy in relapsed refractory MM patients. PMID:27494845

  7. Glycycoumarin inhibits hepatocyte lipoapoptosis through activation of autophagy and inhibition of ER stress/GSK-3-mediated mitochondrial pathway

    PubMed Central

    Zhang, Enxiang; Yin, Shutao; Song, Xinhua; Fan, Lihong; Hu, Hongbo

    2016-01-01

    Herbal medicine as an alternative approach in the treatment of disease has drawn growing attention. Identification of the active ingredient is needed for effective utilization of the herbal medicine. Licorice is a popular herbal plant that is widely used to treat various diseases including liver diseases. Glycycoumarin (GCM) is a representative of courmarin compounds isolated from licorice. In the present study, the protective effect of GCM on hepatocyte lipoapoptosis has been evaluated using both cell culture model of palmitate-induced lipoapoptosis and animal model of non-alcoholic steatohepatitis (NASH). The results demonstrated for the first time that GCM was highly effective in suppressing hepatocyte lipoapoptosis in both in vitro and in vivo. Mechanistically, GCM was able to re-activate the impaired autophagy by lipid metabolic disorders. In line with the activation of autophagy, ER stress-mediated JNK and mitochondrial apoptotic pathway activation was inhibited by GCM both in vitro and in vivo. In addition, inactivation of GSK-3 might also contribute to the protective effect of GCM on hepatocyte lipoapoptosis. Our findings supported GCM as a novel active component of licorice against non-alcoholic fatty liver disease (NAFLD). PMID:27901086

  8. Chronic and acute effects of stress on energy balance: are there appropriate animal models?

    PubMed Central

    2014-01-01

    Stress activates multiple neural and endocrine systems to allow an animal to respond to and survive in a threatening environment. The corticotropin-releasing factor system is a primary initiator of this integrated response, which includes activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. The energetic response to acute stress is determined by the nature and severity of the stressor, but a typical response to an acute stressor is inhibition of food intake, increased heat production, and increased activity with sustained changes in body weight, behavior, and HPA reactivity. The effect of chronic psychological stress is more variable. In humans, chronic stress may cause weight gain in restrained eaters who show increased HPA reactivity to acute stress. This phenotype is difficult to replicate in rodent models where chronic psychological stress is more likely to cause weight loss than weight gain. An exception may be hamsters subjected to repeated bouts of social defeat or foot shock, but the data are limited. Recent reports on the food intake and body composition of subordinate members of group-housed female monkeys indicate that these animals have a similar phenotype to human stress-induced eaters, but there are a limited number of investigators with access to the model. Few stress experiments focus on energy balance, but more information on the phenotype of both humans and animal models during and after exposure to acute or chronic stress may provide novel insight into mechanisms that normally control body weight. PMID:25519732

  9. Impact of acute psychological stress on cardiovascular risk factors in face of insulin resistance.

    PubMed

    Jones, Kristian T; Shelton, Richard C; Wan, Jun; Li, Li

    2016-11-01

    Individuals with insulin resistance (IR) are at greater risk for cardiovascular disease (CVD). Psychological stress may contribute to develop CVD in IR, although mechanisms are poorly understood. Our aim was to test the hypothesis that individuals with IR have enhanced emotional and physiological responses to acute psychological stress, leading to increased CVD risk. Sixty participants were enrolled into the study, and classified into IR group (n = 31) and insulin sensitive group (n = 29) according to the Quantitative insulin sensitivity check index, which was calculated based on an oral glucose tolerance test. The Trier social stress test, a standardized experimental stress paradigm, was performed on each participant, and emotional and physiological responses were examined. Blood was collected from each subject for insulin, cytokines, and cortisol measurements. Compared with the insulin-sensitive group, individuals with IR had significantly lower ratings of energy and calm, but higher fatigue levels in response to acute stressors. Individuals with IR also showed blunted heart rate reactivity following stress. In addition, the IR status was worsened by acute psychological stress as demonstrated by further increased insulin secretion. Furthermore, individuals with IR showed significantly increased levels of leptin and interleukin-6, but decreased levels of adiponectin, at baseline, stress test, and post-stress period. Our findings in individuals with IR under acute stress would allow a better understanding of the risks for developing CVD and to tailor the interventions for better outcomes.

  10. Acute stress and cardiovascular health: is there an ACE gene connection?

    PubMed

    Holman, E Alison

    2012-10-01

    Cardiovascular disorders (CVD) are associated with acute and posttraumatic stress responses, yet biological processes underlying this association are poorly understood. This study examined whether renin-angiotensin-aldosterone system activity, as indicated by a functional single nucleotide polymorphism (SNP) in the angiotensin converting enzyme (ACE) gene, is associated with both CVD and acute stress related to the September 11, 2001 (9/11) terrorist attacks. European-American respondents (N = 527) from a nationally representative longitudinal study of coping following 9/11 provided saliva for genotyping. Respondents had completed health surveys before 9/11 and annually for 3 years after, and acute stress assessments 9 to 23 days after 9/11. Respondents with rs4291 AA or TT genotypes reported high acute stress twice as often as those with the AT genotype. Individuals with the TT genotype were 43% more likely to report increased physician-diagnosed CVD over 3 years following 9/11, when the following variables were included in the model: (a) pre-9/11 CVD, mental health, and non-CVD ailments; (b) cardiac risk factors; (c) ongoing endocrine disorders; and (d) significant demographics. The ACE rs4291 TT genotype, which has been associated with HPA axis hyperactivity and higher levels of serum angiotensin converting enzyme (ACE), predicted acute stress response and reports of physician-diagnosed CVD in a national sample following collective stress. ACE gene function may be associated with both mental and physical health disorders following collective stress.

  11. The NAC domain-containing protein, GmNAC6, is a downstream component of the ER stress- and osmotic stress-induced NRP-mediated cell-death signaling pathway

    PubMed Central

    2011-01-01

    Background The endoplasmic reticulum (ER) is a major signaling organelle, which integrates a variety of responses against physiological stresses. In plants, one such stress-integrating response is the N-rich protein (NRP)-mediated cell death signaling pathway, which is synergistically activated by combined ER stress and osmotic stress signals. Despite the potential of this integrated signaling to protect plant cells against different stress conditions, mechanistic knowledge of the pathway is lacking, and downstream components have yet to be identified. Results In the present investigation, we discovered an NAC domain-containing protein from soybean, GmNAC6 (Glycine max NAC6), to be a downstream component of the integrated pathway. Similar to NRP-A and NRP-B, GmNAC6 is induced by ER stress and osmotic stress individually, but requires both signals for full activation. Transient expression of GmNAC6 promoted cell death and hypersensitive-like responses in planta. GmNAC6 and NRPs also share overlapping responses to biotic signals, but the induction of NRPs peaked before the increased accumulation of GmNAC6 transcripts. Consistent with the delayed kinetics of GmNAC6 induction, increased levels of NRP-A and NRP-B transcripts induced promoter activation and the expression of the GmNAC6 gene. Conclusions Collectively, our results biochemically link GmNAC6 to the ER stress- and osmotic stress-integrating cell death response and show that GmNAC6 may act downstream of the NRPs. PMID:21943253

  12. Anticoagulation and antiplatelet effects of semax under conditions of acute and chronic immobilization stress.

    PubMed

    Grigorjeva, M E; Lyapina, L A

    2010-07-01

    The effects of semax on anticoagulant, fibrinolytic, and platelet components of the anticoagulation system were studied on albino rats under conditions of acute and chronic immobilization stress. Semax exhibited a protective antistress effect after repeated intranasal administration under conditions of hypercoagulation developing in response to immobilization stress of different degree. The effect manifested in stimulation of the anticoagulation system.

  13. Cognitive Processing Therapy for Acute Stress Disorder Resulting from an Anti-Gay Assault

    ERIC Educational Resources Information Center

    Kaysen, Debra; Lostutter, Ty W.; Goines, Marie A.

    2005-01-01

    This case study describes Cognitive Processing Therapy (CPT) with a 30-year-old gay man with symptoms of acute stress disorder (ASD) following a recent homophobic assault. Treatment addressed assault-related posttraumatic stress disorder symptoms and depressive symptoms. Also addressed were low self-esteem, helplessness, and high degrees of…

  14. Melatonin set out to ER stress signaling thwarts epithelial mesenchymal transition and peritoneal dissemination via calpain-mediated C/EBPβ and NFκB cleavage.

    PubMed

    Wu, Sheng-Mao; Lin, Wan-Yu; Shen, Chin-Chang; Pan, Hung-Chuan; Keh-Bin, Wang; Chen, Yi-Ching; Jan, Yee-Jee; Lai, De-Wei; Tang, Shu-Ching; Tien, Hsing-Ru; Chiu, Chien-Shan; Tsai, Tsung-Chih; Lai, Yi-Liang; Sheu, Meei-Ling

    2016-03-01

    Peritoneal dissemination of tumor has high mortality and is associated with the loss of epithelial features, acquisition of motile mesenchymal morphology characteristics, and invasive properties by tumor cells. Melatonin is an endogenously produced molecule in all plant species that is known to exert antitumor activity, but to date, its underlying mechanisms and antiperitoneal metastasis efficacy is not well defined. This study determined the antiperitoneal dissemination potential of melatonin in vivo and assessed its association with the inhibition of epithelial-to-mesenchymal transition (EMT) signaling mechanism by endoplasmic reticulum (ER) stress, which may be a major molecular mechanism of melatonin against cancer. The results demonstrate that melatonin inhibited peritoneal metastasis in vivo and activated ER stress in Cignal ERSE Reporter Assay, organelle structure in transmission electron microscopy images, calpain activity, and protein biomarkers like p-elf2α. Moreover, the overexpression of transcription factor C/EBPβ in gastric cancer interacted with NFκB and further regulates COX-2 expression. These were dissociated and downregulated by melatonin, as proven by immunofluorescence imaging, immunoprecipitation, EMSA, and ChIP assay. Melatonin or gene silencing of C/EBPβ decreased the EMT protein markers (E-cadherin, Snail, and Slug) and Wnt/beta-catenin activity by Topflash activity, and increased ER stress markers. In an animal study, the results of melatonin therapy were consistent with those of in vitro findings and attenuated systemic proangiogenesis factor production. In conclusion, C/EBPβ and NFκB inhibition by melatonin may impede both gastric tumor growth and peritoneal dissemination by inducing ER stress and inhibiting EMT.

  15. The effect of obesity on inflammatory cytokine and leptin production following acute mental stress.

    PubMed

    Caslin, H L; Franco, R L; Crabb, E B; Huang, C J; Bowen, M K; Acevedo, E O

    2016-02-01

    Obesity may contribute to cardiovascular disease (CVD) risk by eliciting chronic systemic inflammation and impairing the immune response to additional stressors. There has been little assessment of the effect of obesity on psychological stress, an independent risk factor for CVD. Therefore, it was of interest to examine interleukin-6, tumor necrosis factor-α, interleukin-1β (IL-1β), interleukin-1 receptor antagonist (IL-1Ra), and leptin following an acute mental stress task in nonobese and obese males. Twenty college-aged males (21.3 ± 0.56 years) volunteered to participate in a 20-min Stroop color-word and mirror-tracing task. Subjects were recruited for obese (body mass index: BMI > 30) and nonobese (BMI < 25) groups, and blood samples were collected for enzyme-linked immunosorbent assay analysis. The acute mental stress task elicited an increase in heart rate, catecholamines, and IL-1β in all subjects. Additionally, acute mental stress increased cortisol concentrations in the nonobese group. There was a significant reduction in leptin in obese subjects 30 min posttask compared with a decrease in nonobese subjects 120 min posttask. Interestingly, the relationship between the percent change in leptin and IL-1Ra at 120 min posttask in response to an acute mental stress task was only observed in nonobese individuals. This is the first study to suggest that adiposity in males may impact leptin and inflammatory signaling mechanisms following acute mental stress.

  16. Combined treatment with the Cox-2 inhibitor niflumic acid and PPARγ ligand ciglitazone induces ER stress/caspase-8-mediated apoptosis in human lung cancer cells.

    PubMed

    Kim, Byeong Mo; Maeng, Kyungah; Lee, Kee-Ho; Hong, Sung Hee

    2011-01-28

    The present study was performed to investigate the possible combined use of the Cox-2 inhibitor niflumic acid and the PPARγ ligand ciglitazone and to elucidate the mechanisms underlying enhanced apoptosis by this combination treatment in human lung cancer cells. Combined niflumic acid-ciglitazone treatment synergistically induced apoptotic cell death, activated caspase-9, caspase-3, and induced caspase-3-mediated PARP cleavage. The combination treatment also triggered apoptosis through caspase-8/Bid/Bax activation, and the inhibition of caspase-8 suppressed caspase-8/Bid activation, caspase-3-mediated PARP cleavage, and concomitant apoptosis. In addition, combined niflumic acid-ciglitazone treatment significantly induced ER stress responses, and suppression of CHOP expression significantly attenuated the combined niflumic acid-ciglitazone treatment-induced activation of caspase-8 and caspase-3, and the subsequent apoptotic cell death, indicating a role of ER stress in caspase-8 activation and apoptosis. Interestingly, the pro-apoptotic effects of combined niflumic acid-ciglitazone treatment were realized through Cox-2- and PPARγ-independent mechanisms. Taken together, these results suggest that sequential ER stress and caspase-8 activation are critical in combined niflumic acid-ciglitazone treatment-induced apoptosis in human lung cancer cells.

  17. Retinoic Acid Induced-Autophagic Flux Inhibits ER-Stress Dependent Apoptosis and Prevents Disruption of Blood-Spinal Cord Barrier after Spinal Cord Injury

    PubMed Central

    Zhou, Yulong; Zhang, Hongyu; Zheng, Binbin; Ye, Libing; Zhu, Sipin; Johnson, Noah R; Wang, Zhouguang; Wei, Xiaojie; Chen, Daqing; Cao, Guodong; Fu, Xiaobing; Li, Xiaokun; Xu, Hua-Zi; Xiao, Jian

    2016-01-01

    Spinal cord injury (SCI) induces the disruption of the blood-spinal cord barrier (BSCB) which leads to infiltration of blood cells, an inflammatory response, and neuronal cell death, resulting spinal cord secondary damage. Retinoic acid (RA) has a neuroprotective effect in both ischemic brain injury and SCI, however the relationship between BSCB disruption and RA in SCI is still unclear. In this study, we demonstrated that autophagy and ER stress are involved in the protective effect of RA on the BSCB. RA attenuated BSCB permeability and decreased the loss of tight junction (TJ) molecules such as P120, β-catenin, Occludin and Claudin5 after injury in vivo as well as in Brain Microvascular Endothelial Cells (BMECs). Moreover, RA administration improved functional recovery in the rat model of SCI. RA inhibited the expression of CHOP and caspase-12 by induction of autophagic flux. However, RA had no significant effect on protein expression of GRP78 and PDI. Furthermore, combining RA with the autophagy inhibitor chloroquine (CQ) partially abolished its protective effect on the BSCB via exacerbated ER stress and subsequent loss of tight junctions. Taken together, the neuroprotective role of RA in recovery from SCI is related to prevention of of BSCB disruption via the activation of autophagic flux and the inhibition of ER stress-induced cell apoptosis. These findings lay the groundwork for future translational studies of RA for CNS diseases, especially those related to BSCB disruption. PMID:26722220

  18. IL-6 and IL-10 Anti-Inflammatory Activity Links Exercise to Hypothalamic Insulin and Leptin Sensitivity through IKKβ and ER Stress Inhibition

    PubMed Central

    Ropelle, Eduardo R.; Flores, Marcelo B.; Cintra, Dennys E.; Rocha, Guilherme Z.; Pauli, José R.; Morari, Joseane; de Souza, Claudio T.; Moraes, Juliana C.; Prada, Patrícia O.; Guadagnini, Dioze; Marin, Rodrigo M.; Oliveira, Alexandre G.; Augusto, Taize M.; Carvalho, Hernandes F.; Velloso, Lício A.; Saad, Mario J. A.; Carvalheira, José B. C.

    2010-01-01

    Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKβ activation and endoplasmic reticulum (ER) stress in the hypothalamus. Here we show that physical exercise suppresses hyperphagia and associated hypothalamic IKKβ/NF-κB activation by a mechanism dependent upon the pro-inflammatory cytokine interleukin (IL)-6. The disruption of hypothalamic-specific IL-6 action blocked the beneficial effects of exercise on the re-balance of food intake and insulin and leptin resistance. This molecular mechanism, mediated by physical activity, involves the anti-inflammatory protein IL-10, a core inhibitor of IKKβ/NF-κB signaling and ER stress. We report that exercise and recombinant IL-6 requires IL-10 expression to suppress hyperphagia-related obesity. Moreover, in contrast to control mice, exercise failed to reverse the pharmacological activation of IKKβ and ER stress in C3H/HeJ mice deficient in hypothalamic IL-6 and IL-10 signaling. Hence, inflammatory signaling in the hypothalamus links beneficial physiological effects of exercise to the central action of insulin and leptin. PMID:20808781

  19. Symptoms of peritraumatic and acute traumatic stress among victims of an industrial disaster.

    PubMed

    Birmes, Philippe J; Brunet, Alain; Coppin-Calmes, Dominique; Arbus, Christophe; Coppin, Dominique; Charlet, Jean-Paul; Vinnemann, Nathalie; Juchet, Henri; Lauque, Dominique; Schmitt, Laurent

    2005-01-01

    Previous studies have examined peritraumatic distress, peritraumatic dissociation, and acute stress disorder as predictors of posttraumatic stress disorder (PTSD). The authors examined whether these three predictors were associated with PTSD symptoms when considered simultaneously. Two-hundred victims of a factory explosion in Toulouse, France, were surveyed two and six months after the event with use of retrospective self-reports of peritraumatic distress, peritraumatic dissociation, and acute stress disorder. A hierarchical multiple regression predicting PTSD symptoms six months posttrauma indicated that all three constructs explained unique variance, accounting for up to 62 percent. Peritraumatic distress and dissociation and acute stress disorder appear conceptually different from one another and show promise in identifying who is at risk of PTSD.

  20. The Effect of Acute Stress on Esophageal Motility and Gastroesophageal Reflux in Healthy Humans

    PubMed Central

    Lee, Hong Sub; Noh, Chung Kyun; Lee, Kwang Jae

    2017-01-01

    Background/Aims Little research has been done to evaluate the effect of stress in exacerbating the symptoms associated with gastroesophageal reflux (GER). We aimed to investigate the effect of acute stress on esophageal motility and GER parameters in healthy volunteers. Methods A total of 10 (M:F = 8:2, median age 34 years-old) healthy volunteers without any recurrent gastrointestinal symptoms participated in this study. They underwent esophageal high-resolution manometry with 10 wet swallows (Experiment I) and esophageal impedance-pH monitoring (Experiment II) in the basal period and in the stress period. In the stress period, either real stress or sham stress was given in a randomized cross-over design. The stress scores, symptom severity, and pulse rates were measured. Results The stress scores and the severity of nausea were significantly greater under real stress, compared with sham stress. The percentages of weak, failed, rapid, premature, and hyper-contractile contractions were not significantly altered during real stress and during sham stress, compared with the basal period. The median resting pressure of the lower esophageal sphincter and distal contractile integral of esophageal contractions did not differ in the stress period, compared with the basal period. Contractile front velocity and distal latency of esophageal peristaltic contractions were significantly changed during real stress, which was not observed during sham stress. GER parameters were not significantly altered during real stress and during sham stress. Conclusion Although acute auditory and visual stress seems to affect esophageal body motility, it does not induce significant motor abnormalities or increase GER in healthy humans. PMID:28049863

  1. Assessment of oxidative stress parameters of brain-derived neurotrophic factor heterozygous mice in acute stress model

    PubMed Central

    Hacioglu, Gulay; Senturk, Ayse; Ince, Imran; Alver, Ahmet

    2016-01-01

    Objective(s): Exposing to stress may be associated with increased production of reactive oxygen species (ROS). Therefore, high level of oxidative stress may eventually give rise to accumulation of oxidative damage and development of numerous neurodegenerative diseases. It has been presented that brain-derived neurotrophic factor (BDNF) supports neurons against various neurodegenerative conditions. Lately, there has been growing evidence that changes in the cerebral neurotrophic support and especially in the BDNF expression and its engagement with ROS might be important in various disorders and neurodegenerative diseases. Hence, we aimed to investigate protective effects of BDNF against stress-induced oxidative damage. Materials and Methods: Five- to six-month-old male wild-type and BDNF knock-down mice were used in this study. Activities of catalase (CAT) and superoxide dismutase (SOD) enzymes, and the amount of malondialdehyde (MDA) were assessed in the cerebral homogenates of studied groups in response to acute restraint stress. Results: Exposing to acute physiological stress led to significant elevation in the markers of oxidative stress in the cerebral cortexes of experimental groups. Conclusion: As BDNF-deficient mice were observed to be more susceptible to stress-induced oxidative damage, it can be suggested that there is a direct interplay between oxidative stress indicators and BDNF levels in the brain. PMID:27279982

  2. Media's role in broadcasting acute stress following the Boston Marathon bombings.

    PubMed

    Holman, E Alison; Garfin, Dana Rose; Silver, Roxane Cohen

    2014-01-07

    We compared the impact of media vs. direct exposure on acute stress response to collective trauma. We conducted an Internet-based survey following the Boston Marathon bombings between April 29 and May 13, 2013, with representative samples of residents from Boston (n = 846), New York City (n = 941), and the remainder of the United States (n = 2,888). Acute stress symptom scores were comparable in Boston and New York [regression coefficient (b) = 0.43; SE = 1.42; 95% confidence interval (CI), -2.36, 3.23], but lower nationwide when compared with Boston (b = -2.21; SE = 1.07; 95% CI, -4.31, -0.12). Adjusting for prebombing mental health (collected prospectively), demographics, and prior collective stress exposure, six or more daily hours of bombing-related media exposure in the week after the bombings was associated with higher acute stress than direct exposure to the bombings (continuous acute stress symptom total: media exposure b = 15.61 vs. direct exposure b = 5.69). Controlling for prospectively collected prebombing television-watching habits did not change the findings. In adjusted models, direct exposure to the 9/11 terrorist attacks and the Sandy Hook School shootings were both significantly associated with bombing-related acute stress; Superstorm Sandy exposure wasn't. Prior exposure to similar and/or violent events may render some individuals vulnerable to the negative effects of collective traumas. Repeatedly engaging with trauma-related media content for several hours daily shortly after collective trauma may prolong acute stress experiences and promote substantial stress-related symptomatology. Mass media may become a conduit that spreads negative consequences of community trauma beyond directly affected communities.

  3. Acute restraint stress and corticosterone transiently disrupts novelty preference in an object recognition task.

    PubMed

    Vargas-López, Viviana; Torres-Berrio, Angélica; González-Martínez, Lina; Múnera, Alejandro; Lamprea, Marisol R

    2015-09-15

    The object recognition task is a procedure based on rodents' natural tendency to explore novel objects which is frequently used for memory testing. However, in some instances novelty preference is replaced by familiarity preference, raising questions regarding the validity of novelty preference as a pure recognition memory index. Acute stress- and corticosterone administration-induced novel object preference disruption has been frequently interpreted as memory impairment; however, it is still not clear whether such effect can be actually attributed to either mnemonic disruption or altered novelty seeking. Seventy-five adult male Wistar rats were trained in an object recognition task and subjected to either acute stress or corticosterone administration to evaluate the effect of stress or corticosterone on an object recognition task. Acute stress was induced by restraining movement for 1 or 4h, ending 30 min before the sample trial. Corticosterone was injected intraperitoneally 10 min before the test trial which was performed either 1 or 24h after the sample trial. Four-hour, but not 1-h, stress induced familiar object preference during the test trial performed 1h after the sample trial; however, acute stress had no effects on the test when performed 24h after sample trial. Systemic administration of corticosterone before the test trial performed either 1 or 24h after the sample trial also resulted in familiar object preference. However, neither acute stress nor corticosterone induced changes in locomotor behaviour. Taken together, such results suggested that acute stress probably does not induce memory retrieval impairment but, instead, induces an emotional arousing state which motivates novelty avoidance.

  4. Media’s role in broadcasting acute stress following the Boston Marathon bombings

    PubMed Central

    Holman, E. Alison; Garfin, Dana Rose; Silver, Roxane Cohen

    2014-01-01

    We compared the impact of media vs. direct exposure on acute stress response to collective trauma. We conducted an Internet-based survey following the Boston Marathon bombings between April 29 and May 13, 2013, with representative samples of residents from Boston (n = 846), New York City (n = 941), and the remainder of the United States (n = 2,888). Acute stress symptom scores were comparable in Boston and New York [regression coefficient (b) = 0.43; SE = 1.42; 95% confidence interval (CI), −2.36, 3.23], but lower nationwide when compared with Boston (b = −2.21; SE = 1.07; 95% CI, −4.31, −0.12). Adjusting for prebombing mental health (collected prospectively), demographics, and prior collective stress exposure, six or more daily hours of bombing-related media exposure in the week after the bombings was associated with higher acute stress than direct exposure to the bombings (continuous acute stress symptom total: media exposure b = 15.61 vs. direct exposure b = 5.69). Controlling for prospectively collected prebombing television-watching habits did not change the findings. In adjusted models, direct exposure to the 9/11 terrorist attacks and the Sandy Hook School shootings were both significantly associated with bombing-related acute stress; Superstorm Sandy exposure wasn't. Prior exposure to similar and/or violent events may render some individuals vulnerable to the negative effects of collective traumas. Repeatedly engaging with trauma-related media content for several hours daily shortly after collective trauma may prolong acute stress experiences and promote substantial stress-related symptomatology. Mass media may become a conduit that spreads negative consequences of community trauma beyond directly affected communities. PMID:24324161

  5. Cortisol response to acute stress in jundiá Rhamdia quelen acutely exposed to sub-lethal concentrations of agrichemicals.

    PubMed

    Cericato, Leonardo; Neto, Joaquim Gonçalves Machado; Fagundes, Michele; Kreutz, Luiz Carlos; Quevedo, Rosmari Mezzalira; Finco, Jovani; da Rosa, João Gabriel Santos; Koakoski, Gessi; Centenaro, Lucas; Pottker, Emanuele; Anziliero, Deniz; Barcellos, Leonardo José Gil

    2008-09-01

    Exposure to agrichemicals can have deleterious effects on fish, such as disruption of the hypothalamus-pituitary-inter-renal axis (HPI) that could impair the ability of fish to respond to stressors. In this study, fingerlings of the teleost jundiá (Rhamdia quelen) were used to investigate the effects of the commonly used agrichemicals on the fish response to stress. Five common agrichemicals were tested: the fungicide - tebuconazole, the insecticide - methyl-parathion, and the herbicides - atrazine, atrazine+simazine, and glyphosate. Control fishes were not exposed to agrichemicals and standard stressors. In treatments 2-4, the fishes were exposed to sub-lethal concentrations (16.6%, 33.3%, and 50% of the LC(50)) of each agrichemical for 96 h, and at the end of this period, were subjected to an acute stress-handling stimulus by chasing them with a pen net. In treatments 5-7 (16.6%, 33.3%, and 50% of the LC(50)), the fishes were exposed to the same concentrations of the agrichemicals without stress stimulus. Treatment 8 consisted of jundiás not exposed to agrichemicals, but was subjected to an acute stress-handling stimulus. Jundiás exposed to methyl-parathion, atrazine+simazine, and glyphosate presented a decreased capacity in exhibiting an adequate response to cope with stress and in maintaining the homeostasis, with cortisol level lower than that in the control fish (P<0.01). In conclusion, the results of this study clearly demonstrate that the acute exposure to sub-lethal concentrations of methyl-parathion, atrazine+simazine, and glyphosate exert a deleterious effect on the cortisol response to an additional acute stressor in the jundiá fingerlings.

  6. Plasma omega 3 polyunsaturated fatty acid status and monounsaturated fatty acids are altered by chronic social stress and predict endocrine responses to acute stress in titi monkeys

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Disturbances in fatty acid (FA) metabolism may link chronic psychological stress, endocrine responsiveness, and psychopathology. Therefore, lipid metabolome-wide responses and their relationships with endocrine (cortisol; insulin; adiponectin) responsiveness to acute stress (AS) were assessed in a ...

  7. Effect of acute stress on sexual behavior in female rats: participation of the central angiotensinergic system.

    PubMed

    Cecconello, Ana Lúcia; Raineki, Charlis; Sebben, Vanise; Lucion, Aldo Bolten; Sanvitto, Gilberto Luiz

    2010-03-05

    Stress might influence the reproductive behavior in females, and central angiotensin II (Ang II) is a peptide that plays a role in stress response and in the modulation of sexual behavior. The medial amygdala (MeA), an important structure that regulates this behavior, is strongly involved in stress response. The aim of the present study was to evaluate the effect of acute restraint stress on the night of proestrus on sexual receptivity in female rats and the participation of Ang II and MeA in this effect. Adult female Wistar rats with regular estrous cycles were utilized. The acute stress protocol utilized was the restraint stress for 15 min on the night of proestrus. The participation of Ang II was evaluated by injecting Ang II and Ang II receptor antagonists (losartan and PD12319) into the MeA. The lordosis quotient was recorded. The stress or the microinjection of Ang II into the MeA significantly reduced sexual behavior. The blockade of AT(1) or AT(2) receptors in the MeA prevented the effect of stress and the effect of Ang II microinjection into this nucleus on sexual receptivity. We concluded that acute restraint stress on the night of proestrus reduces sexual behavior in rats, and this effect is mediated by both AT(1) and AT(2) receptors in the MeA.

  8. Context-dependent enhancement of declarative memory performance following acute psychosocial stress.

    PubMed

    Smeets, T; Giesbrecht, T; Jelicic, M; Merckelbach, H

    2007-09-01

    Studies on how acute stress affects learning and memory have yielded inconsistent findings, with some studies reporting enhancing effects while others report impairing effects. Recently, Joëls et al. [Joëls, M., Pu, Z., Wiegert, O., Oitzl, M.S., Krugers, H.J., 2006. Learning under stress: how does it work? Trends in Cognitive Sciences, 10, 152-158] argued that stress will enhance memory only when the memory acquisition phase and stressor share the same spatiotemporal context (i.e., context-congruency). The current study tested this hypothesis by looking at whether context-congruent stress enhances declarative memory performance. Undergraduates were assigned to a personality stress group (n=16), a memory stress group (n=18), or a no-stress control group (n=18). While being exposed to the acute stressor or a control task, participants encoded personality- and memory-related words and were tested for free recall 24h later. Relative to controls, stress significantly enhanced recall of context-congruent words, but only for personality words. This suggests that acute stress may strengthen the consolidation of memory material when the stressor matches the to-be-remembered information in place and time.

  9. Resveratrol augments ER stress and the cytotoxic effects of glycolytic inhibition in neuroblastoma by downregulating Akt in a mechanism independent of SIRT1

    PubMed Central

    Graham, Regina M; Hernandez, Fiorela; Puerta, Nataly; De Angulo, Guillermo; Webster, Keith A; Vanni, Steven

    2016-01-01

    Cancer cells typically display increased rates of aerobic glycolysis that are correlated with tumor aggressiveness and a poor prognosis. Targeting the glycolytic pathway has emerged as an attractive therapeutic route mainly because it should spare normal cells. Here, we evaluate the effects of combining the inhibition of glycolysis with application of the polyphenolic compound resveratrol (RSV) in neuroblastoma (NB) cancer cell lines. Inhibiting glycolysis with 2-deoxy-D-glucose (2-DG) significantly reduced NB cell viability and was associated with increased endoplasmic reticulum (ER) stress and Akt activity. Administration of 2-DG increased the expression of the ER molecular chaperones GRP78 and GRP94, the prodeath protein C/EBP homology protein (CHOP) and the phosphorylation of Akt at S473, T450 and T308. Combined treatment with both RSV and 2-DG reduced GRP78, GRP94 and Akt phosphorylation but increased CHOP and NB cell death when compared with the administration of 2-DG alone. The selective inhibition of Akt activity also decreased 2-DG-induced GRP78 and GRP94 expression and increased CHOP expression, suggesting that Akt can modulate ER stress. Protein phosphatase 1α (PP1α) was activated by RSV, as indicated by a reduction in PP1α phosphorylation at T320. Pretreatment of cells with tautomycin, a selective PP1α inhibitor, prevented the RSV-mediated decrease in Akt phosphorylation, suggesting that RSV enhances 2-DG-induced cell death by activating PP1 and downregulating Akt. The RSV-mediated inhibition of Akt in the presence of 2-DG was not prevented by the selective inhibition of SIRT1, a known target of RSV, indicating that the effects of RSV on this pathway are independent of SIRT1. We propose that RSV inhibits Akt activity by increasing PP1α activity, thereby potentiating 2-DG-induced ER stress and NB cell death. PMID:26891914

  10. Reduced Insulin/Insulin-Like Growth Factor Receptor Signaling Mitigates Defective Dendrite Morphogenesis in Mutants of the ER Stress Sensor IRE-1

    PubMed Central

    Salzberg, Yehuda; Cohen-Berkman, Moran; Biederer, Thomas; Bülow, Hannes E.

    2017-01-01

    Neurons receive excitatory or sensory inputs through their dendrites, which often branch extensively to form unique neuron-specific structures. How neurons regulate the formation of their particular arbor is only partially understood. In genetic screens using the multidendritic arbor of PVD somatosensory neurons in the nematode Caenorhabditis elegans, we identified a mutation in the ER stress sensor IRE-1/Ire1 (inositol requiring enzyme 1) as crucial for proper PVD dendrite arborization in vivo. We further found that regulation of dendrite growth in cultured rat hippocampal neurons depends on Ire1 function, showing an evolutionarily conserved role for IRE-1/Ire1 in dendrite patterning. PVD neurons of nematodes lacking ire-1 display reduced arbor complexity, whereas mutations in genes encoding other ER stress sensors displayed normal PVD dendrites, specifying IRE-1 as a selective ER stress sensor that is essential for PVD dendrite morphogenesis. Although structure function analyses indicated that IRE-1’s nuclease activity is necessary for its role in dendrite morphogenesis, mutations in xbp-1, the best-known target of non-canonical splicing by IRE-1/Ire1, do not exhibit PVD phenotypes. We further determined that secretion and distal localization to dendrites of the DMA-1/leucine rich transmembrane receptor (DMA-1/LRR-TM) is defective in ire-1 but not xbp-1 mutants, suggesting a block in the secretory pathway. Interestingly, reducing Insulin/IGF1 signaling can bypass the secretory block and restore normal targeting of DMA-1, and consequently normal PVD arborization even in the complete absence of functional IRE-1. This bypass of ire-1 requires the DAF-16/FOXO transcription factor. In sum, our work identifies a conserved role for ire-1 in neuronal branching, which is independent of xbp-1, and suggests that arborization defects associated with neuronal pathologies may be overcome by reducing Insulin/IGF signaling and improving ER homeostasis and function. PMID

  11. Plasma from pre-pubertal obese children impairs insulin stimulated Nitric Oxide (NO) bioavailability in endothelial cells: Role of ER stress.

    PubMed

    Di Pietro, Natalia; Marcovecchio, M Loredana; Di Silvestre, Sara; de Giorgis, Tommaso; Cordone, Vincenzo Giuseppe Pio; Lanuti, Paola; Chiarelli, Francesco; Bologna, Giuseppina; Mohn, Angelika; Pandolfi, Assunta

    2017-03-05

    Childhood obesity is commonly associated with early signs of endothelial dysfunction, characterized by impairment of insulin signaling and vascular Nitric Oxide (NO) availability. However, the underlying mechanisms remain to be established. Hence, we tested the hypothesis that endothelial insulin-stimulated NO production and availability was impaired and related to Endoplasmic Reticulum (ER) in human umbilical vein endothelial cells (HUVECs) cultured with plasma obtained from pre-pubertal obese (OB) children. OB children (N = 28, age: 8.8 ± 2.2; BMI z-score: 2.15 ± 0.39) showed impaired fasting glucose, insulin and HOMA-IR than normal weight children (CTRL; N = 28, age: 8.8 ± 1.7; BMI z-score: 0.17 ± 0.96). The in vitro experiments showed that OB-plasma significantly impaired endothelial insulin-stimulated NO production and bioavailability compared to CTRL-plasma. In parallel, in HUVECs OB-plasma increased GRP78 and activated PERK, eIF2α, IkBα and ATF6 (all ER stress markers). Moreover, OB-plasma increased NF-κB activation and its nuclear translocation. Notably, all these effects proved to be significantly restored by using PBA and TUDCA, known ER stress inhibitors. Our study demonstrate for the first time that plasma from obese children is able to induce in vitro endothelial insulin resistance, which is characterized by reduced insulin-stimulated NO production and bioavailability, endothelial ER stress and increased NF-κB activation.

  12. The response of trypanosomes and other eukaryotes to ER stress and the spliced leader RNA silencing (SLS) pathway in Trypanosoma brucei.

    PubMed

    Michaeli, Shulamit

    2015-01-01

    The unfolded protein response (UPR) is induced when the quality control machinery of the cell is overloaded with unfolded proteins or when one of the functions of the endoplasmic reticulum (ER) is perturbed. Here, I describe UPR in yeast and mammals, and compare it to what we know about pathogenic fungi and the parasitic protozoans from the order kinetoplastida, focusing on the novel pathway the spliced leader silencing (SLS) in Trypanosoma brucei. Trypanosomes lack conventional transcription regulation, and thus, lack most of the UPR machinery present in other eukaryotes. Trypanosome genes are transcribed in polycistronic units that are processed by trans-splicing and polyadenylation. In trans-splicing, which is essential for processing of each mRNA, an exon known as the spliced leader (SL) is added to all mRNAs from a small RNA, the SL RNA. Under severe ER stress, T. brucei elicits the SLS pathway. In SLS, the transcription of the SL RNA gene is extinguished, and the entire transcription complex dissociates from the SL RNA promoter. Induction of SLS is mediated by an ER-associated kinase (PK3) that migrates to the nucleus, where it phosphorylates the TATA-binding protein (TRF4), leading shut-off of SL RNA transcription. As a result, trans-splicing is inhibited and the parasites activate a programmed cell death (PCD) pathway. Despite the ability to sense the ER stress, the different eukaryotes, especially unicellular parasites and pathogenic fungi, developed a variety of unique and different ways to sense and adjust to this stress in a manner different from their host.

  13. Diazepam blocks striatal lipid peroxidation and improves stereotyped activity in a rat model of acute stress.

    PubMed

    Méndez-Cuesta, Luis A; Márquez-Valadez, Berenice; Pérez-De La Cruz, Verónica; Escobar-Briones, Carolina; Galván-Arzate, Sonia; Alvarez-Ruiz, Yarummy; Maldonado, Perla D; Santana, Ricardo A; Santamaría, Abel; Carrillo-Mora, Paul

    2011-11-01

    In this work, the effect of a single dose of diazepam was tested on different markers of oxidative damage in the striatum of rats in an acute model of immobilization (restraint) stress. In addition, the locomotor activity was measured at the end of the restraint period. Immobilization was induced to animals for 24 hr, and then, lipid peroxidation, superoxide dismutase activity and content, and mitochondrial function were all estimated in striatal tissue samples. Corticosterone levels were measured in serum. Diazepam was given to rats as a pre-treatment (1 mg/kg, i.p.) 20 min. before the initiation of stress. Our results indicate that acute stress produced enhanced striatal levels of lipid peroxidation (73% above the control), decreased superoxide dismutase activity (54% below the control), reduced levels of mitochondrial function (35% below the control) and increased corticosterone serum levels (86% above the control). Pre-treatment of stressed rats with diazepam decreased the striatal lipid peroxidation levels (68% below the stress group) and improved mitochondrial function (18% above the stress group), but only mild preservation of superoxide dismutase activity was detected (17% above the stress group). In regard to the motor assessment, only the stereotyped activity was increased in the stress group with respect to control (46% above the control), and this effect was prevented by diazepam administration (30% below the stress group). The preventive actions of diazepam in this acute model of stress suggest that drugs exhibiting anxiolytic and antioxidant properties might be useful for the design of therapies against early acute phases of physic stress.

  14. Effects of dark chocolate consumption on the prothrombotic response to acute psychosocial stress in healthy men.

    PubMed

    von Känel, R; Meister, R E; Stutz, M; Kummer, P; Arpagaus, A; Huber, S; Ehlert, U; Wirtz, P H

    2014-12-01

    Flavanoid-rich dark chocolate consumption benefits cardiovascular health, but underlying mechanisms are elusive. We investigated the acute effect of dark chocolate on the reactivity of prothrombotic measures to psychosocial stress. Healthy men aged 20-50 years (mean ± SD: 35.7 ± 8.8) were assigned to a single serving of either 50 g of flavonoid-rich dark chocolate (n=31) or 50 g of optically identical flavonoid-free placebo chocolate (n=34). Two hours after chocolate consumption, both groups underwent an acute standardised psychosocial stress task combining public speaking and mental arithmetic. We determined plasma levels of four stress-responsive prothrombotic measures (i. e., fibrinogen, clotting factor VIII activity, von Willebrand Factor antigen, fibrin D-dimer) prior to chocolate consumption, immediately before and after stress, and at 10 minutes and 20 minutes after stress cessation. We also measured the flavonoid epicatechin, and the catecholamines epinephrine and norepinephrine in plasma. The dark chocolate group showed a significantly attenuated stress reactivity of the hypercoagulability marker D-dimer (F=3.87, p=0.017) relative to the placebo chocolate group. Moreover, the blunted D-dimer stress reactivity related to higher plasma levels of the flavonoid epicatechin assessed before stress (F=3.32, p = 0.031) but not to stress-induced changes in catecholamines (p's=0.35). There were no significant group differences in the other coagulation measures (p's≥0.87). Adjustments for covariates did not alter these findings. In conclusion, our findings indicate that a single consumption of flavonoid-rich dark chocolate blunted the acute prothrombotic response to psychosocial stress, thereby perhaps mitigating the risk of acute coronary syndromes triggered by emotional stress.

  15. Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men.

    PubMed

    Boden, Guenther; Homko, Carol; Barrero, Carlos A; Stein, T Peter; Chen, Xinhua; Cheung, Peter; Fecchio, Chiara; Koller, Sarah; Merali, Salim

    2015-09-09

    Obesity-linked insulin resistance greatly increases the risk for type 2 diabetes, hypertension, dyslipidemia, and non-alcoholic fatty liver disease, together known as the metabolic or insulin resistance syndrome. How obesity promotes insulin resistance remains incompletely understood. Plasma concentrations of free fatty acids and proinflammatory cytokines, endoplasmic reticulum ( ER) stress, and oxidative stress are all elevated in obesity and have been shown to induce insulin resistance. However, they may be late events that only develop after chronic excessive nutrient intake. The nature of the initial event that produces insulin resistance at the beginning of excess caloric intake and weight gain remains unknown. We show that feeding healthy men with ~6000 kcal/day of the common U.S. diet [~50% carbohydrate (CHO), ~ 35% fat, and ~15% protein] for 1 week produced a rapid weight gain of 3.5 kg and the rapid onset (after 2 to 3 days) of systemic and adipose tissue insulin resistance and oxidative stress but no inflammatory or ER stress. In adipose tissue, the oxidative stress resulted in extensive oxidation and carbonylation of numerous proteins, including carbonylation of GLUT4 near the glucose transport channel, which likely resulted in loss of GLUT4 activity. These results suggest that the initial event caused by overnutrition may be oxidative stress, which produces insulin resistance, at least in part, via carbonylation and oxidation-induced inactivation of GLUT4.

  16. HacA-Independent Functions of the ER Stress Sensor IreA Synergize with the Canonical UPR to Influence Virulence Traits in Aspergillus fumigatus

    PubMed Central

    Richie, Daryl L.; Aimanianda, Vishukumar; Hartl, Lukas; Grahl, Nora; Powers-Fletcher, Margaret V.; Zhang, Minlu; Fuller, Kevin K.; Nierman, William C.; Lu, Long Jason; Latgé, Jean-Paul; Woollett, Laura; Newman, Simon L.; Cramer, Robert A.; Rhodes, Judith C.; Askew, David S.

    2011-01-01

    Endoplasmic reticulum (ER) stress is a condition in which the protein folding capacity of the ER becomes overwhelmed by an increased demand for secretion or by exposure to compounds that disrupt ER homeostasis. In yeast and other fungi, the accumulation of unfolded proteins is detected by the ER-transmembrane sensor IreA/Ire1, which responds by cleaving an intron from the downstream cytoplasmic mRNA HacA/Hac1, allowing for the translation of a transcription factor that coordinates a series of adaptive responses that are collectively known as the unfolded protein response (UPR). Here, we examined the contribution of IreA to growth and virulence in the human fungal pathogen Aspergillus fumigatus. Gene expression profiling revealed that A. fumigatus IreA signals predominantly through the canonical IreA-HacA pathway under conditions of severe ER stress. However, in the absence of ER stress IreA controls dual signaling circuits that are both HacA-dependent and HacA-independent. We found that a ΔireA mutant was avirulent in a mouse model of invasive aspergillosis, which contrasts the partial virulence of a ΔhacA mutant, suggesting that IreA contributes to pathogenesis independently of HacA. In support of this conclusion, we found that the ΔireA mutant had more severe defects in the expression of multiple virulence-related traits relative to ΔhacA, including reduced thermotolerance, decreased nutritional versatility, impaired growth under hypoxia, altered cell wall and membrane composition, and increased susceptibility to azole antifungals. In addition, full or partial virulence could be restored to the ΔireA mutant by complementation with either the induced form of the hacA mRNA, hacAi, or an ireA deletion mutant that was incapable of processing the hacA mRNA, ireAΔ10. Together, these findings demonstrate that IreA has both HacA-dependent and HacA-independent functions that contribute to the expression of traits that are essential for virulence in A. fumigatus

  17. The influence of acute stress on the regulation of conditioned fear

    PubMed Central

    Raio, Candace M.; Phelps, Elizabeth A.

    2014-01-01

    Fear learning and regulation is a prominent model for describing the pathogenesis of anxiety disorders and stress-related psychopathology. Fear expression can be modulated using a number of regulatory strategies, including extinction, cognitive emotion regulation, avoidance strategies and reconsolidation. In this review, we examine research investigating the effects of acute stress and stress hormones on these regulatory techniques. We focus on what is known about the impact of stress on the ability to flexibly regulate fear responses that are acquired through Pavlovian fear conditioning. Our primary aim is to explore the impact of stress on fear regulation in humans. Given this, we focus on techniques where stress has been linked to alterations of fear regulation in humans (extinction and emotion regulation), and briefly discuss other techniques (avoidance and reconsolidation) where the impact of stress or stress hormones have been mainly explored in animal models. These investigations reveal that acute stress may impair the persistent inhibition of fear, presumably by altering prefrontal cortex function. Characterizing the effects of stress on fear regulation is critical for understanding the boundaries within which existing regulation strategies are viable in everyday life and can better inform treatment options for those who suffer from anxiety and stress-related psychopathology. PMID:25530986

  18. Effects of neuron-specific estrogen receptor (ER) α and ERβ deletion on the acute estrogen negative feedback mechanism in adult female mice.

    PubMed

    Cheong, Rachel Y; Porteous, Robert; Chambon, Pierre; Abrahám, István; Herbison, Allan E

    2014-04-01

    The negative feedback mechanism through which 17β-estradiol (E2) acts to suppress the activity of the GnRH neurons remains unclear. Using inducible and cell-specific genetic mouse models, we examined the estrogen receptor (ER) isoforms expressed by neurons that mediate acute estrogen negative feedback. Adult female mutant mice in which ERα was deleted from all neurons in the neonatal period failed to exhibit estrous cycles or negative feedback. Adult mutant female mice with neonatal neuronal ERβ deletion exhibited normal estrous cycles, but a failure of E2 to suppress LH secretion was seen in ovariectomized mice. Mutant mice with a GnRH neuron-selective deletion of ERβ exhibited normal cycles and negative feedback, suggesting no critical role for ERβ in GnRH neurons in acute negative feedback. To examine the adult roles of neurons expressing ERα, an inducible tamoxifen-based Cre-LoxP approach was used to ablate ERα from neurons that express calmodulin kinase IIα in adults. This resulted in mice with no estrous cycles, a normal increase in LH after ovariectomy, but an inability of E2 to suppress LH secretion. Finally, acute administration of ERα- and ERβ-selective agonists to adult ovariectomized wild-type mice revealed that activation of ERα suppressed LH secretion, whereas ERβ agonists had no effect. This study highlights the differences in adult reproductive phenotypes that result from neonatal vs adult ablation of ERα in the brain. Together, these experiments expand previous global knockout studies by demonstrating that neurons expressing ERα are essential and probably sufficient for the acute estrogen negative feedback mechanism in female mice.

  19. Having your cake and eating it too: a habit of comfort food may link chronic social stress exposure and acute stress-induced cortisol hyporesponsiveness.

    PubMed

    Tryon, M S; DeCant, Rashel; Laugero, K D

    2013-04-10

    Stress has been tied to changes in eating behavior and food choice. Previous studies in rodents have shown that chronic stress increases palatable food intake which, in turn, increases visceral fat and inhibits acute stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity. The effect of chronic stress on eating behavior in humans is less understood, but it may be linked to HPA responsivity. The purpose of this study was to investigate the influence of chronic social stress and acute stress reactivity on food choice and food intake. Forty-one women (BMI=25.9±5.1 kg/m(2), age range=41 to 52 years) were subjected to the Trier Social Stress Test or a control task (nature movie) to examine HPA responses to an acute laboratory stressor and then invited to eat from a buffet containing low- and high-calorie snacks. Women were also categorized as high chronic stress or low chronic stress based on Wheaton Chronic Stress Inventory scores. Women reporting higher chronic stress and exhibiting low cortisol reactivity to the acute stress task consumed significantly more calories from chocolate cake on both stress and control visits. Chronic stress in the low cortisol reactor group was also positively related to total fat mass, body fat percentage, and stress-induced negative mood. Further, women reporting high chronic stress consumed significantly less vegetables, but only in those aged 45 years and older. Chronic stress in women within the higher age category was positively related to total calories consumed at the buffet, stress-induced negative mood and food craving. Our results suggest an increased risk for stress eating in persons with a specific chronic stress signature and imply that a habit of comfort food may link chronic social stress and acute stress-induced cortisol hyporesponsiveness.

  20. Being a grump only makes things worse: a transactional account of acute stress on mind wandering

    PubMed Central

    Vinski, Melaina T.; Watter, Scott

    2013-01-01

    The current work investigates the influence of acute stress on mind wandering. Participants completed the Positive and Negative Affect Schedule as a measure of baseline negative mood, and were randomly assigned to either the high-stress or low-stress version of the Trier Social Stress Test. Participants then completed the Sustained Attention to Response Task as a measure of mind-wandering behavior. In Experiment 1, participants reporting a high degree of negative mood that were exposed to the high-stress condition were more likely to engage in a variable response time, make more errors, and were more likely to report thinking about the stressor relative to participants that report a low level of negative mood. These effects diminished throughout task performance, suggesting that acute stress induces a temporary mind-wandering state in participants with a negative mood. The temporary affect-dependent deficits observed in Experiment 1 were replicated in Experiment 2, with the high negative mood participants demonstrating limited resource availability (indicated by pupil diameter) immediately following stress induction. These experiments provide novel evidence to suggest that acute psychosocial stress briefly suppresses the availability of cognitive resources and promotes an internally oriented focus of attention in participants with a negative mood. PMID:24273520

  1. OSO paradigm--A rapid behavioral screening method for acute psychosocial stress reactivity in mice.

    PubMed

    Brzózka, M M; Unterbarnscheidt, T; Schwab, M H; Rossner, M J

    2016-02-09

    Chronic psychosocial stress is an important environmental risk factor for the development of psychiatric diseases. However, studying the impact of chronic psychosocial stress in mice is time consuming and thus not optimally suited to 'screen' increasing numbers of genetically manipulated mouse models for psychiatric endophenotypes. Moreover, many studies focus on restraint stress, a strong physical stressor with limited relevance for psychiatric disorders. Here, we describe a simple and a rapid method based on the resident-intruder paradigm to examine acute effects of mild psychosocial stress in mice. The OSO paradigm (open field--social defeat--open field) compares behavioral consequences on locomotor activity, anxiety and curiosity before and after exposure to acute social defeat stress. We first evaluated OSO in male C57Bl/6 wildtype mice where a single episode of social defeat reduced locomotor activity, increased anxiety and diminished exploratory behavior. Subsequently, we applied the OSO paradigm to mouse models of two schizophrenia (SZ) risk genes. Transgenic mice with neuronal overexpression of Neuregulin-1 (Nrg1) type III showed increased risk-taking behavior after acute stress exposure suggesting that NRG1 dysfunction is associated with altered affective behavior. In contrast, Tcf4 transgenic mice displayed a normal stress response which is in line with the postulated predominant contribution of TCF4 to cognitive deficits of SZ. In conclusion, the OSO paradigm allows for rapid screening of selected psychosocial stress-induced behavioral endophenotypes in mouse models of psychiatric diseases.

  2. Rigid patterns of effortful choice behavior after acute stress in rats.

    PubMed

    Hart, Evan E; Stolyarova, Alexandra; Conoscenti, Michael A; Minor, Thomas R; Izquierdo, Alicia

    2017-01-01

    Physical effort is a common cost of acquiring rewards, and decreased effort is a feature of many neuropsychiatric disorders. Stress affects performance on several tests of cognition and decision making in both humans and nonhumans. Only a few recent reports show impairing effects of stress in operant tasks involving effort and cognitive flexibility. Brain regions affected by stress, such as the medial prefrontal cortex and amygdala, are also implicated in mediating effortful choices. Here, we assessed effort-based decision making after an acute stress procedure known to induce persistent impairment in shuttle escape and elevated plasma corticosterone. In these animals, we also probed levels of polysialyted neural cell adhesion molecule (PSA-NCAM), a marker of structural plasticity, in medial frontal cortex and amygdala. We found that animals that consistently worked for high magnitude rewards continued to do so, even after acute shock stress. We also found that PSA-NCAM was increased in both regions after effortful choice experience but not after shock stress alone. These findings are discussed with reference to the existing broad literature on cognitive effects of stress and in the context of how acute stress may bias effortful decisions to a rigid pattern of responding.

  3. The estrous cycle of the ewe is resistant to disruption by repeated, acute psychosocial stress.

    PubMed

    Wagenmaker, Elizabeth R; Breen, Kellie M; Oakley, Amy E; Tilbrook, Alan J; Karsch, Fred J

    2010-06-01

    Five experiments were conducted to test the hypothesis that psychosocial stress interferes with the estrous cycle of sheep. In experiment 1, ewes were repeatedly isolated during the follicular phase. Timing, amplitude, and duration of the preovulatory luteinizing hormone (LH) surge were not affected. In experiment 2, follicular-phase ewes were subjected twice to a "layered stress" paradigm consisting of sequential, hourly application of isolation, restraint, blindfold, and predator cues. This reduced the LH pulse amplitude but did not affect the LH surge. In experiment 3, different acute stressors were given sequentially within the follicular phase: food denial plus unfamiliar noises and forced exercise, layered stress, exercise around midnight, and transportation. This, too, did not affect the LH surge. In experiment 4, variable acute psychosocial stress was given every 1-2 days for two entire estrous cycles; this did not disrupt any parameter of the cycle monitored. Lastly, experiment 5 examined whether the psychosocial stress paradigms of experiment 4 would disrupt the cycle and estrous behavior if sheep were metabolically stressed by chronic food restriction. Thirty percent of the food-restricted ewes exhibited deterioration of estrous cycle parameters followed by cessation of cycles and failure to express estrous behavior. However, disruption was not more evident in ewes that also encountered psychosocial stress. Collectively, these findings indicate the estrous cycle of sheep is remarkably resistant to disruption by acute bouts of psychosocial stress applied intermittently during either a single follicular phase or repeatedly over two estrous cycles.

  4. Exposure to acute stress enhances decision-making competence: Evidence for the role of DHEA.

    PubMed

    Shields, Grant S; Lam, Jovian C W; Trainor, Brian C; Yonelinas, Andrew P

    2016-05-01

    Exposure to acute stress can impact performance on numerous cognitive abilities, but little is known about how acute stress affects real-world decision-making ability. In the present study, we induced acute stress with a standard laboratory task involving uncontrollable socio-evaluative stress and subsequently assessed decision-making ability using the Adult Decision Making Competence index. In addition, we took baseline and post-test saliva samples from participants to examine associations between decision-making competence and adrenal hormones. Participants in the stress induction group showed enhanced decision-making competence, relative to controls. Further, although both cortisol and dehydroepiandrosterone (DHEA) reactivity predicted decision-making competence when considered in isolation, DHEA was a significantly better predictor than cortisol when both hormones were considered simultaneously. Thus, our results show that exposure to acute stress can have beneficial effects on the cognitive ability underpinning real-world decision-making and that this effect relates to DHEA reactivity more than cortisol.

  5. Wolfberry Water Soluble Phytochemicals Down-Regulate ER Stress Biomarkers and Modulate Multiple Signaling Pathways Leading To Inhibition of Proliferation and Induction of Apoptosis in Jurkat Cells

    PubMed Central

    Jiang, Yu; Zhang, Yunong; Wark, Logan; Ortiz, Edlin; Lim, Soyoung; He, Hui; Wang, Weiqun; Medeiros, Denis; Lin, Dingbo

    2012-01-01

    Phytochemicals have received much recent attention in cancer prevention through simultaneous targeting multiple pathways in the disease progression. Here we determined that wolfberry phytochemicals was chemopreventive on the leukemic Jurkat cell. The water soluble wolfberry fractions (i.e., wolfberry phytochemicals) were enriched in carbohydrates (73.4 ± 4.5 % (w/w)), polyphenolics (1555 ± 112 mg quercetin equivalent/100 g freeze dry powder, including 213 mg rutin/100 g freeze dry powder), and had enhanced antioxidant activity (7771 ± 207 μM Trolox equivalent/100 g freeze dry powder). Wolfberry phytochemicals, but not purified wolfberry polysaccharide fractions, inhibited Jurkat cell proliferation, induced cycle arrest at the G2/M phase in a dose dependent manner starting at 1 mg/ml for 48 h. Wolfberry phytochemicals eliminated cellular reactive oxygen species, declined expression of endoplasmic reticulum (ER) stress biomarkers, including glucose regulated protein 78, inositol-requiring protein 1(IRE1), activating transcription factor 6 (ATF6), protein kinase RNA-like ER kinase (PERK), and c/EBP-homologous protein, and induced activation of AMP activated protein kinase, stabilization of β-catenin, and inhibition of NFκB, and AKT activity. Simultaneous siRNA knockdown of ATF6, IRE1 and PERK caused inhibition of cell proliferation and induction of apoptosis. Data suggested that ER stress and multiple survival/apoptosis signaling pathways were modulated by wolfberry phytochemicals during the apoptotic progression. Consumption of wolfberry could be an efficacious dietary strategy for preventing leukemia. PMID:22685690

  6. Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12

    PubMed Central

    Badiola, N; Penas, C; Miñano-Molina, A; Barneda-Zahonero, B; Fadó, R; Sánchez-Opazo, G; Comella, J X; Sabriá, J; Zhu, C; Blomgren, K; Casas, C; Rodríguez-Alvarez, J

    2011-01-01

    Disturbance of calcium homeostasis and accumulation of misfolded proteins in the endoplasmic reticulum (ER) are considered contributory components of cell death after ischemia. However, the signal-transducing events that are activated by ER stress after cerebral ischemia are incompletely understood. In this study, we show that caspase-12 and the PERK and IRE pathways are activated following oxygen-glucose deprivation (OGD) of mixed cortical cultures or neonatal hypoxia–ischemia (HI). Activation of PERK led to a transient phosphorylation of eIF2α, an increase in ATF4 levels and the induction of gadd34 (a subunit of an eIF2α-directed phosphatase). Interestingly, the upregulation of ATF4 did not lead to an increase in the levels of CHOP. Additionally, IRE1 activation was mediated by the increase in the processed form of xbp1, which would be responsible for the observed expression of edem2 and the increased levels of the chaperones GRP78 and GRP94. We were also able to detect caspase-12 proteolysis after HI or OGD. Processing of procaspase-12 was mediated by NMDA receptor and calpain activation. Moreover, our data suggest that caspase-12 activation is independent of the unfolded protein response activated by ER stress. PMID:21525936

  7. Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress

    PubMed Central

    Li, Sisi; Papale, Ligia A.; Zhang, Qi; Madrid, Andy; Chen, Li; Chopra, Pankaj; Keleş, Sündüz; Jin, Peng; Alisch, Reid S.

    2015-01-01

    Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders, including anxiety and post-traumatic stress disorder. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Recently, we found a hippocampal increase of 5hmC in the glucocorticoid receptor gene (Nr3c1) following acute stress, warranting a deeper investigation of stress-related 5hmC levels. Here, we used an established chemical labeling and affinity purification method coupled with high-throughput sequencing technology to generate the first genome-wide profile of hippocampal 5hmC following exposure to acute restraint stress and a one-hour recovery. This approach found a genome-wide disruption in 5hmC associated with acute stress response, primarily in genic regions, and identified known and potentially novel stress-related targets that have a significant enrichment for neuronal ontological functions. Integration of these data with hippocampal gene expression data from these same mice found stress-related hydroxymethylation correlated to altered transcript levels and sequence motif predictions indicated that 5hmC may function by mediating transcription factor binding to these transcripts. Together, these data reveal an environmental impact on this newly discovered epigenetic mark in the brain and represent a critical step toward understanding stress-related epigenetic mechanisms that alter gene expression and can lead to the development of psychiatric disorders. PMID:26598390

  8. Neuroendocrine and cardiovascular reactions to acute psychological stress are attenuated in smokers.

    PubMed

    Ginty, Annie T; Jones, Alexander; Carroll, Douglas; Roseboom, Tessa J; Phillips, Anna C; Painter, Rebecca; de Rooij, Susanne R

    2014-10-01

    A number of studies have now examined the association between smoking and the magnitude of physiological reactions to acute psychological stress. However, no large-scale study has demonstrated this association incorporating neuroendocrine in addition to cardiovascular reactions to stress. The present study compared neuroendocrine and cardiovascular reactions to acute stress exposure in current smokers, ex-smokers, and those who had never smoked in a large community sample. Salivary cortisol, systolic and diastolic blood pressure, heart rate and frequency components of systolic blood pressure and heart rate variability were measured at rest and during exposure to a battery of three standardized stress tasks in 480 male and female participants from the Dutch Famine Birth Cohort Study. Current smokers had significantly lower cortisol, systolic and diastolic blood pressure, and heart rate reactions to stress. They also exhibited smaller changes in the low frequency band of blood pressure variability compared to ex- and never smokers. There were no group differences in stress related changes in overall heart rate variability as measured by the root mean square of successive interbeat interval differences or in the high frequency band of heart rate variability. In all cases, effects remained significant following statistical adjustment for a host of variables likely to be associated with reactivity and/or smoking. In secondary analyses, there were no significant associations between lifetime cigarette consumption or current consumption and stress reactivity. In conclusion, compared to non-smokers and ex-smokers, current smokers exhibited attenuated neuroendocrine and cardiovascular reactions to acute psychological stress. Among smokers and ex-smokers, there is no evidence that lifetime exposure was associated with physiological reactions to acute stress, nor that current levels of cigarette consumption were associated with reactivity. It is possible, then, that

  9. Behavioral Predictors of Acute Stress Symptoms During Intense Military Training

    DTIC Science & Technology

    2009-06-01

    peritraumatic dissociative symptoms (PDS; i.e., per- ceptual disconnectedness) and that general troops who endorsed symptoms of dissociation at baseline were...also more likely to dissociate under stress. Furthermore, self-reported peritraumatic symptoms were significantly lower in elite Special Forces per... peritraumatic dissociative states (PDS) and quantified the link between PDS and the subsequent psychological impact of stressful events during

  10. Models and Methods to Investigate Acute Stress Responses in Cattle

    PubMed Central

    Chen, Yi; Arsenault, Ryan; Napper, Scott; Griebel, Philip

    2015-01-01

    There is a growing appreciation within the livestock industry and throughout society that animal stress is an important issue that must be addressed. With implications for animal health, well-being, and productivity, minimizing animal stress through improved animal management procedures and/or selective breeding is becoming a priority. Effective management of stress, however, depends on the ability to identify and quantify the effects of various stressors and determine if individual or combined stressors have distinct biological effects. Furthermore, it is critical to determine the duration of stress-induced biological effects if we are to understand how stress alters animal production and disease susceptibility. Common stress models used to evaluate both psychological and physical stressors in cattle are reviewed. We identify some of the major gaps in our knowledge regarding responses to specific stressors and propose more integrated methodologies and approaches to measuring these responses. These approaches are based on an increased knowledge of both the metabolic and immune effects of stress. Finally, we speculate on how these findings may impact animal agriculture, as well as the potential application of large animal models to understanding human stress. PMID:26633525

  11. Prenatal cortisol exposure predicts infant cortisol response to acute stress.

    PubMed

    O'Connor, Thomas G; Bergman, Kristin; Sarkar, Pampa; Glover, Vivette

    2013-03-01

    Experimental animal findings suggest that early stress and glucocorticoid exposure may program the function of the hypothalamic-pituitary-adrenal (HPA) axis in the offspring. The extension of these findings to human development is not yet clear. A prospective longitudinal study was conducted on 125 mothers and their normally developing children. Amniotic fluid was obtained at, on average, 17.2 weeks gestation; infant behavior and cortisol response to a separation-reunion stress was assessed at 17 months. Amniotic fluid cortisol predicted infant cortisol response to separation-reunion stress: infants who were exposed to higher levels of cortisol in utero showed higher pre-stress cortisol values and blunted response to stress exposure. The association was independent of prenatal, obstetric, and socioeconomic factors and child-parent attachment. The findings provide some of the strongest data in humans that HPA axis functioning in the child may be predicted from prenatal cortisol exposure.

  12. A diagnostic interview for acute stress disorder for children and adolescents.

    PubMed

    Miller, Alisa; Enlow, Michelle Bosquet; Reich, Wendy; Saxe, Glenn

    2009-12-01

    The goal of this study was to develop a semistructured clinical interview for assessing acute stress disorder (ASD) in youth and test its psychometric properties. Youth (N = 168) with an acute burn or injury were administered the acute stress disorder module of the Diagnostic Interview for Children and Adolescents (DICA-ASD). The DICA-ASD demonstrated strong psychometric properties, including high internal consistency (alpha = .97) and perfect diagnostic interrater agreement (kappa = 1.00). Participants diagnosed with ASD scored significantly higher than those not diagnosed on validated traumatic stress symptomatology measures but not on other symptomatology measures, providing evidence of convergent and discriminant validity. Preliminary evidence supports the reliability and validity of the first semistructured clinical interview for diagnosing ASD in youth.

  13. Effects of Acute Laboratory Stress on Executive Functions

    PubMed Central

    Starcke, Katrin; Wiesen, Carina; Trotzke, Patrick; Brand, Matthias

    2016-01-01

    Recent research indicates that stress can affect executive functioning. However, previous results are mixed with respect to the direction and size of effects, especially when considering different subcomponents of executive functions. The current study systematically investigates the effects of stress on the five components of executive functions proposed by Smith and Jonides (1999): attention and inhibition; task management; planning; monitoring; and coding. Healthy participants (N = 40) were either exposed to the computerized version of the Paced Auditory Serial Addition Test as a stressor (N = 20), or to a rest condition (N = 20). Stress reactions were assessed with heart rate and subjective measures. After the experimental manipulation, all participants performed tasks that measure the different executive functions. The manipulation check indicates that stress induction was successful (i.e., the stress group showed a higher heart rate and higher subjective responses than the control group). The main results demonstrate that stressed participants show a poorer performance compared with unstressed participants in all executive subcomponents, with the exception of monitoring. Effect sizes for the tasks that reveal differences between stressed and unstressed participants are high. We conclude that the laboratory stressor used here overall reduced executive functioning. PMID:27065926

  14. Effects of Acute Laboratory Stress on Executive Functions.

    PubMed

    Starcke, Katrin; Wiesen, Carina; Trotzke, Patrick; Brand, Matthias

    2016-01-01

    Recent research indicates that stress can affect executive functioning. However, previous results are mixed with respect to the direction and size of effects, especially when considering different subcomponents of executive functions. The current study systematically investigates the effects of stress on the five components of executive functions proposed by Smith and Jonides (1999): attention and inhibition; task management; planning; monitoring; and coding. Healthy participants (N = 40) were either exposed to the computerized version of the Paced Auditory Serial Addition Test as a stressor (N = 20), or to a rest condition (N = 20). Stress reactions were assessed with heart rate and subjective measures. After the experimental manipulation, all participants performed tasks that measure the different executive functions. The manipulation check indicates that stress induction was successful (i.e., the stress group showed a higher heart rate and higher subjective responses than the control group). The main results demonstrate that stressed participants show a poorer performance compared with unstressed participants in all executive subcomponents, with the exception of monitoring. Effect sizes for the tasks that reveal differences between stressed and unstressed participants are high. We conclude that the laboratory stressor used here overall reduced executive functioning.

  15. Dual-task performance under acute stress in female adolescents with borderline personality disorder.

    PubMed

    Kaess, Michael; Parzer, Peter; Koenig, Julian; Resch, Franz; Brunner, Romuald

    2016-09-01

    Research to elucidate early alterations of higher cognitive processes in adolescents with BPD is rare. This study investigated differences in dual-task performance in adolescents with BPD during stress and non-stress conditions. The study sample comprised 30 female adolescents with BPD and 34 healthy controls. The impact of stress on dual-task performance was measured using a standardized stressor. Self-reports of distress and measures of heart rate (HR) were obtained to measure stress reactivity. There were no group differences in task performance. Under stress conditions, the performance on the auditory task decreased in both groups but without significant group differences. Healthy controls showed an increase of mean HR after stress induction compared to no change in the BPD group. The finding of attenuated HR response to acute stress in adolescent patients with BPD may contradict current theories that the affective hyperresponsivity in BPD is based on a biologically determined mechanism.

  16. History of chronic stress modifies acute stress-evoked fear memory and acoustic startle in male rats.

    PubMed

    Schmeltzer, Sarah N; Vollmer, Lauren L; Rush, Jennifer E; Weinert, Mychal; Dolgas, Charles M; Sah, Renu

    2015-01-01

    Chronicity of trauma exposure plays an important role in the pathophysiology of posttraumatic stress disorder (PTSD). Thus, exposure to multiple traumas on a chronic scale leads to worse outcomes than acute events. The rationale for the current study was to investigate the effects of a single adverse event versus the same event on a background of chronic stress. We hypothesized that a history of chronic stress would lead to worse behavioral outcomes than a single event alone. Male rats (n = 14/group) were exposed to either a single traumatic event in the form of electric foot shocks (acute shock, AS), or to footshocks on a background of chronic stress (chronic variable stress-shock, CVS-S). PTSD-relevant behaviors (fear memory and acoustic startle responses) were measured following 7 d recovery. In line with our hypothesis, CVS-S elicited significant increases in fear acquisition and conditioning versus the AS group. Unexpectedly, CVS-S elicited reduced startle reactivity to an acoustic stimulus in comparison with the AS group. Significant increase in FosB/ΔFosB-like immunostaining was observed in the dentate gyrus, basolateral amygdala and medial prefrontal cortex of CVS-S rats. Assessments of neuropeptide Y (NPY), a stress-regulatory transmitter associated with chronic PTSD, revealed selective reduction in the hippocampus of CVS-S rats. Collectively, our data show that cumulative stress potentiates delayed fear memory and impacts defensive responding. Altered neuronal activation in forebrain limbic regions and reduced NPY may contribute to these phenomena. Our preclinical studies support clinical findings reporting worse PTSD outcomes stemming from cumulative traumatization in contrast to acute trauma.

  17. Metabolic Changes in Masseter Muscle of Rats Submitted to Acute Stress Associated with Exodontia

    PubMed Central

    Iyomasa, Mamie Mizusaki; Fernandes, Fernanda Silva; Iyomasa, Daniela Mizusaki; Pereira, Yamba Carla Lara; Fernández, Rodrigo Alberto Restrepo; Calzzani, Ricardo Alexandre; Nascimento, Glauce Crivelaro; Leite-Panissi, Christie Ramos Andrade; Issa, João Paulo Mardegan

    2015-01-01

    Clinical evidence has shown that stress may be associated with alterations in masticatory muscle functions. Morphological changes in masticatory muscles induced by occlusal alterations and associated with emotional stress are still lacking in the literature. The objective of this study was to evaluate the influence of acute stress on metabolic activity and oxidative stress of masseter muscles of rats subjected to occlusal modification through morphological and histochemical analyses. In this study, adult Wistar rats were divided into 4 groups: a group with extraction and acute stress (E+A); group with extraction and without stress (E+C); group without extraction and with acute stress (NO+A); and control group without both extraction and stress (NO+C). Masseter muscles were analyzed by Succinate Dehydrogenase (SDH), Nicotinamide Adenine Dinucleotide Diaphorase (NADH) and Reactive Oxygen Species (ROS) techniques. Statistical analyses and two-way ANOVA were applied, followed by Tukey-Kramer tests. In the SDH test, the E+C, E+A and NO+A groups showed a decrease in high desidrogenase activities fibers (P < 0.05), compared to the NO+C group. In the NADH test, there was no difference among the different groups. In the ROS test, in contrast, E+A, E+C and NO+A groups showed a decrease in ROS expression, compared to NO+C groups (P < 0.05). Modified dental occlusion and acute stress - which are important and prevalent problems that affect the general population - are important etiologic factors in metabolic plasticity and ROS levels of masseter muscles. PMID:26053038

  18. Acute psychosocial stress and emotion regulation skills modulate empathic reactions to pain in others

    PubMed Central

    Buruck, Gabriele; Wendsche, Johannes; Melzer, Marlen; Strobel, Alexander; Dörfel, Denise

    2014-01-01

    Psychosocial stress affects resources for adequate coping with environmental demands. A crucial question in this context is the extent to which acute psychosocial stressors impact empathy and emotion regulation. In the present study, 120 participants were randomly assigned to a control group vs. a group confronted with the Trier Social Stress Test (TSST), an established paradigm for the induction of acute psychosocial stress. Empathy for pain as a specific subgroup of empathy was assessed via pain intensity ratings during a pain-picture task. Self-reported emotion regulation skills were measured as predictors using an established questionnaire. Stressed individuals scored significantly lower on the appraisal of pain pictures. A regression model was chosen to find variables that further predict the pain ratings. These findings implicate that acute psychosocial stress might impair empathic processes to observed pain in another person and the ability to accept one's emotion additionally predicts the empathic reaction. Furthermore, the ability to tolerate negative emotions modulated the relation between stress and pain judgments, and thus influenced core cognitive-affective functions relevant for coping with environmental challenges. In conclusion, our study emphasizes the necessity of reducing negative emotions in terms of empathic distress when confronted with pain of another person under psychosocial stress, in order to be able to retain pro-social behavior. PMID:24910626

  19. Acute stress and episodic memory retrieval: neurobiological mechanisms and behavioral consequences.

    PubMed

    Gagnon, Stephanie A; Wagner, Anthony D

    2016-04-01

    Episodic retrieval allows people to access memories from the past to guide current thoughts and decisions. In many real-world situations, retrieval occurs under conditions of acute stress, either elicited by the retrieval task or driven by other, unrelated concerns. Memory under such conditions may be hindered, as acute stress initiates a cascade of neuromodulatory changes that can impair episodic retrieval. Here, we review emerging evidence showing that dissociable stress systems interact over time, influencing neural function. In addition to the adverse effects of stress on hippocampal-dependent retrieval, we consider how stress biases attention and prefrontal cortical function, which could further affect controlled retrieval processes. Finally, we consider recent data indicating that stress at retrieval increases activity in a network of brain regions that enable reflexive, rapid responding to upcoming threats, while transiently taking offline regions supporting flexible, goal-directed thinking. Given the ubiquity of episodic memory retrieval in everyday life, it is critical to understand the theoretical and applied implications of acute stress. The present review highlights the progress that has been made, along with important open questions.

  20. Acute psychosocial stress and emotion regulation skills modulate empathic reactions to pain in others.

    PubMed

    Buruck, Gabriele; Wendsche, Johannes; Melzer, Marlen; Strobel, Alexander; Dörfel, Denise

    2014-01-01

    Psychosocial stress affects resources for adequate coping with environmental demands. A crucial question in this context is the extent to which acute psychosocial stressors impact empathy and emotion regulation. In the present study, 120 participants were randomly assigned to a control group vs. a group confronted with the Trier Social Stress Test (TSST), an established paradigm for the induction of acute psychosocial stress. Empathy for pain as a specific subgroup of empathy was assessed via pain intensity ratings during a pain-picture task. Self-reported emotion regulation skills were measured as predictors using an established questionnaire. Stressed individuals scored significantly lower on the appraisal of pain pictures. A regression model was chosen to find variables that further predict the pain ratings. These findings implicate that acute psychosocial stress might impair empathic processes to observed pain in another person and the ability to accept one's emotion additionally predicts the empathic reaction. Furthermore, the ability to tolerate negative emotions modulated the relation between stress and pain judgments, and thus influenced core cognitive-affective functions relevant for coping with environmental challenges. In conclusion, our study emphasizes the necessity of reducing negative emotions in terms of empathic distress when confronted with pain of another person under psychosocial stress, in order to be able to retain pro-social behavior.

  1. Effect of neonatal handling on adult rat spatial learning and memory following acute stress.

    PubMed

    Stamatakis, A; Pondiki, S; Kitraki, E; Diamantopoulou, A; Panagiotaropoulos, T; Raftogianni, A; Stylianopoulou, F

    2008-03-01

    Brief neonatal handling permanently alters hypothalamic-pituitary-adrenal axis function resulting in increased ability to cope with stress. Since stress is known to affect cognitive abilities, in the present study we investigated the effect of brief (15 min) handling on learning and memory in the Morris water maze, following exposure to an acute restraint stress either before training or recall. Exposure of non-handled rats to the acute stress prior to training resulted in quicker learning of the task, than in the absence of the stressor. When acute stress preceded acquisition, male handled rats showed an overall better learning performance, and both sexes of handled animals were less impaired in the subsequent memory trial, compared to the respective non-handled. In addition, the number of neurons immunoreactive for GR was higher in all areas of Ammon's horn of the handled rats during the recall. In contrast, the number of neurons immunoreactive for MR was higher in the CA1 and CA2 areas of the non-handled males. When the acute restraint stress was applied prior to the memory test, neonatal handling was not effective in preventing mnemonic impairment, as all animal groups showed a similar deficit in recall. In this case, no difference between handled and non-handled rats was observed in the number of GR positive neurons in the CA2 and CA3 hippocampal areas during the memory test. These results indicate that early experience interacts with sex and acute stress exposure in adulthood to affect performance in the water maze. Hippocampal corticosterone receptors may play a role in determining the final outcome.

  2. Acute Stress Induces Hyperacusis in Women with High Levels of Emotional Exhaustion

    PubMed Central

    Hasson, Dan; Theorell, Töres; Bergquist, Jonas; Canlon, Barbara

    2013-01-01

    Background Hearing problems is one of the top ten public health disorders in the general population and there is a well-established relationship between stress and hearing problems. The aim of the present study was to explore if an acute stress will increase auditory sensitivity (hyperacusis) in individuals with high levels of emotional exhaustion (EE). Methods Hyperacusis was assessed using uncomfortable loudness levels (ULL) in 348 individuals (140 men; 208 women; age 23–71 years). Multivariate analyses (ordered logistic regression), were used to calculate odds ratios, including interacting or confounding effects of age, gender, ear wax and hearing loss (PTA). Two-way ANCOVAs were used to assess possible differences in mean ULLs between EE groups pre- and post-acute stress task (a combination of cold pressor, emotional Stroop and Social stress/video recording). Results There were no baseline differences in mean ULLs between the three EE groups (one-way ANOVA). However, after the acute stress exposure there were significant differences in ULL means between the EE-groups in women. Post-hoc analyses showed that the differences in mean ULLs were between those with high vs. low EE (range 5.5–6.5 dB). Similar results were found for frequencies 0.5 and 1 kHz. The results demonstrate that women with high EE-levels display hyperacusis after an acute stress task. The odds of having hyperacusis were 2.5 (2 kHz, right ear; left ns) and 2.2 (4 kHz, right ear; left ns) times higher among those with high EE compared to those with low levels. All these results are adjusted for age, hearing loss and ear wax. Conclusion Women with high levels of emotional exhaustion become more sensitive to sound after an acute stress task. This novel finding highlights the importance of including emotional exhaustion in the diagnosis and treatment of hearing problems. PMID:23301005

  3. Acute stress blocks the caffeine-induced enhancement of contextual memory retrieval in mice.

    PubMed

    Pierard, Chistophe; Krazem, Ali; Henkous, Nadia; Decorte, Laurence; Béracochéa, Daniel

    2015-08-15

    This study investigated in mice the dose-effect of caffeine on memory retrieval in non-stress and stress conditions. C57 Bl/6 Jico mice learned two consecutive discriminations (D1 and D2) in a four-hole board which involved either distinct contextual (CSD) or similar contextual (SSD) cues. All mice received an i.p. injection of vehicle or caffeine (8, 16 or 32mg/kg) 30min before the test session. Results showed that in non-stress conditions, the 16mg/kg caffeine dose induced a significant enhancement of D1 performance in CSD but not in SSD. Hence, we studied the effect of an acute stress (electric footshocks) administered 15min before the test session on D1 performance in caffeine-treated mice. Results showed that stress significantly decreased D1 performance in vehicle-treated controls and the memory-enhancing effect induced by the 16mg/kg caffeine dose in non-stress condition is no longer observed. Interestingly, whereas caffeine-treated mice exhibited weaker concentrations of plasma corticosterone as compared to vehicles in non-stress condition, stress significantly increased plasma corticosterone concentrations in caffeine-treated mice which reached similar level to that of controls. Overall, the acute stress blocked both the endocrinological and memory retrieval enhancing effects of caffeine.

  4. Acute stress, depression, and anxiety symptoms among English and Spanish speaking children with recent trauma exposure.

    PubMed

    Barber, Beth A; Kohl, Krista L; Kassam-Adams, Nancy; Gold, Jeffrey I

    2014-03-01

    A growing literature suggests the clinical importance of acute stress disorder symptoms in youth following potentially traumatic events. A multisite sample of English and Spanish speaking children and adolescents (N = 479) between the ages of 8-17, along with their caregivers completed interviews and self-report questionnaires between 2 days and 1 month following the event. The results indicate that children with greater total acute stress symptoms reported greater depressive (r = .41, p < .01) and anxiety symptoms (r = .53, p < .01). Examining specific acute stress subscales, reexperiencing was correlated with anxiety (r = .47, p < .01) and arousal was correlated with depression (r = .50, p < .01) and anxiety (r = .55, p < .01). Age was inversely associated with total acute stress symptoms (r = -.24, p < .01), reexperiencing (r = -.17, p < .01), avoidance (r = -.27, p < .01), and arousal (r = -.19, p < .01) and gender was related to total anxiety symptoms (Spearman's ρ = .17, p < .01). The current study supports the importance of screening acute stress symptoms and other mental health outcomes following a potentially traumatic event in children and adolescents. Early screening may enable clinicians to identify and acutely intervene to support children's psychological and physical recovery.

  5. ALS Patient Stem Cells for Unveiling Disease Signatures of Motoneuron Susceptibility: Perspectives on the Deadly Mitochondria, ER Stress and Calcium Triad

    PubMed Central

    Kaus, Anjoscha; Sareen, Dhruv

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a largely sporadic progressive neurodegenerative disease affecting upper and lower motoneurons (MNs) whose specific etiology is incompletely understood. Mutations in superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TARDBP/TDP-43) and C9orf72, have been identified in subsets of familial and sporadic patients. Key associated molecular and neuropathological features include ubiquitinated TDP-43 inclusions, stress granules, aggregated dipeptide proteins from mutant C9orf72 transcripts, altered mitochondrial ultrastructure, dysregulated calcium homeostasis, oxidative and endoplasmic reticulum (ER) stress, and an unfolded protein response (UPR). Such impairments have been documented in ALS animal models; however, whether these mechanisms are initiating factors or later consequential events leading to MN vulnerability in ALS patients is debatable. Human induced pluripotent stem cells (iPSCs) are a valuable tool that could resolve this “chicken or egg” causality dilemma. Relevant systems for probing pathophysiologically affected cells from large numbers of ALS patients and discovering phenotypic disease signatures of early MN susceptibility are described. Performing unbiased ‘OMICS and high-throughput screening in relevant neural cells from a cohort of ALS patient iPSCs, and rescuing mitochondrial and ER stress impairments, can identify targeted therapeutics for increasing MN longevity in ALS. PMID:26635528

  6. ER stress, p66shc, and p-Akt/Akt mediate adjuvant-induced inflammation, which is blunted by argirein, a supermolecule and rhein in rats.

    PubMed

    Cong, Xiao-Dong; Ding, Ming-Jian; Dai, De-Zai; Wu, You; Zhang, Yun; Dai, Yin

    2012-06-01

    We investigated the anti-inflammatory activities of argirein and rhein on inflammatory edema in rat paw which was caused by complete adjuvant, compared with ibuprofen. We hypothesized that the adjuvant-induced inflammation is attributed to upregulation of activating transcript factor 6 (ATF6; a chaperone for endoplasmic reticulum (ER) stress), p66Shc (an adaptive protein modulating oxidative stress), and NADPH oxidase subunits p22phox and gp91phox in the inflamed tissues. Biomarkers were measured in the rat paw in association with monitoring swellings. The primary inflammatory edema of the injected paw occurred rapidly and sustained over a couple of days, and the secondary inflammation developed 2 weeks later. The inflammatory edema was accompanied by upregulation of cytokines including ATF6, p66Shc, p22phox, gp91phox, and MMP-2 and an increase in ratio of p-Akt/Akt in the afflicted paw. These were suppressed by either argirein and rhein or ibuprofen. These findings indicate that ER stress, upregulated p66Shc, and phosphorylated Akt are actively implicated in the inflammatory zone caused by adjuvant injection. These biomarkers were causal factors responsible for inflammation of the afflicted paw and were suppressed by a supermolecule argirein and rhein, and the anti-inflammatory activities of the two compounds were comparable to that of ibuprofen.

  7. Selective killing of gastric cancer cells by a small molecule via targeting TrxR1 and ROS-mediated ER stress activation

    PubMed Central

    Zhao, Zhongwei; Weng, Qiaoyou; Chen, Xi; Ying, Shilong; Ye, Qingqing; Wang, Zhe; Ji, Jiansong; Liang, Guang

    2016-01-01

    The thioredoxin reductase (TrxR) 1 is often overexpressed in numerous cancer cells. Targeting TrxR1 leads to a reduction in tumor progression and metastasis, making the enzyme an attractive target for cancer treatment. Our previous research revealed that the curcumin derivative B19 could induce cancer cell apoptosis via activation of endoplasmic reticulum (ER) stress. However, the upstream mechanism and molecular target of B19 is still unclear. In this study, we demonstrate that B19 directly inhibits TrxR1 enzyme activity to elevate oxidative stress and then induce ROS-mediated ER Stress and mitochondrial dysfunction, subsequently resulting in cell cycle arrest and apoptosis in human gastric cancer cells. A computer-assistant docking showed that B19 may bind TrxR1 protein via formation of a covalent bond with the residue Cys-498. Blockage of ROS production totally reversed B19-induced anti-cancer actions. In addition, the results of xenograft experiments in mice were highly consistent with in vitro studies. Taken together, targeting TrxR1 with B19 provides deep insight into the understanding of how B19 exerts its anticancer effects. More importantly, this work indicates that targeting TrxR1 and manipulating ROS levels are effective therapeutic strategy for the treatment of gastric cancer. PMID:26919094

  8. Transcriptional expression levels of cell stress marker genes in the Pacific oyster Crassostrea gigas exposed to acute thermal stress

    PubMed Central

    Farcy, Émilie; Voiseux, Claire; Lebel, Jean-Marc

    2008-01-01

    During the annual cycle, oysters are exposed to seasonal slow changes in temperature, but during emersion at low tide on sunny summer days, their internal temperature may rise rapidly, resulting in acute heat stress. We experimentally exposed oysters to a 1-h acute thermal stress and investigated the transcriptional expression level of some genes involved in cell stress defence mechanisms, including chaperone proteins (heat shock proteins Hsp70, Hsp72 and Hsp90 (HSP)), regulation of oxidative stress (Cu-Zn superoxide dismutase, metallothionein (MT)), cell detoxification (glutathione S-transferase sigma, cytochrome P450 and multidrug resistance (MDR1)) and regulation of the cell cycle (p53). Gene mRNA levels were quantified by reverse transcription-quantitative polymerase chain reaction and expressed as their ratio to actin mRNA, used as a reference. Of the nine genes studied, HSP, MT and MDR1 mRNA levels increased in response to thermal stress. We compared the responses of oysters exposed to acute heat shock in summer and winter and observed differences in terms of magnitude and kinetics. A larger increase was observed in September, with recovery within 48 h, whereas in March, the increase was smaller and lasted more than 2 days. The results were also compared with data obtained from the natural environment. Though the functional molecule is the protein and information at the mRNA level only has limitations, the potential use of mRNAs coding for cell stress defence proteins as early sensitive biomarkers is discussed. PMID:19002605

  9. Aged rats are hypo-responsive to acute restraint: implications for psychosocial stress in aging

    PubMed Central

    Buechel, Heather M.; Popovic, Jelena; Staggs, Kendra; Anderson, Katie L.; Thibault, Olivier; Blalock, Eric M.

    2013-01-01

    Cognitive processes associated with prefrontal cortex and hippocampus decline with age and are vulnerable to disruption by stress. The stress/stress hormone/allostatic load hypotheses of brain aging posit that brain aging, at least in part, is the manifestation of life-long stress exposure. In addition, as humans age, there is a profound increase in the incidence of new onset stressors, many of which are psychosocial (e.g., loss of job, death of spouse, social isolation), and aged humans are well-understood to be more vulnerable to the negative consequences of such new-onset chronic psychosocial stress events. However, the mechanistic underpinnings of this age-related shift in chronic psychosocial stress response, or the initial acute phase of that chronic response, have been less well-studied. Here, we separated young (3 month) and aged (21 month) male F344 rats into control and acute restraint (an animal model of psychosocial stress) groups (n = 9–12/group). We then assessed hippocampus-associated behavioral, electrophysiological, and transcriptional outcomes, as well as blood glucocorticoid and sleep architecture changes. Aged rats showed characteristic water maze, deep sleep, transcriptome, and synaptic sensitivity changes compared to young. Young and aged rats showed similar levels of distress during the 3 h restraint, as well as highly significant increases in blood glucocorticoid levels 21 h after restraint. However, young, but not aged, animals responded to stress exposure with water maze deficits, loss of deep sleep and hyperthermia. These results demonstrate that aged subjects are hypo-responsive to new-onset acute psychosocial stress, which may have negative consequences for long-term stress adaptation and suggest that age itself may act as a stressor occluding the influence of new onset stressors. PMID:24575039

  10. PRIMA-1 targets the vulnerability of multiple myeloma of deregulated protein homeostasis through the perturbation of ER stress via p73 demethylation

    PubMed Central

    Teoh, Phaik Ju; Bi, Chonglei; Sintosebastian, Chirackal; Tay, Liang Seah; Fonseca, Rafael; Chng, Wee Joo

    2016-01-01

    Despite therapeutic advancement, multiple myeloma (MM) remains incurable with drug resistance being one of the main challenges in the clinic. Myeloma cells possess high protein secretory load, leading to increased intracellular endoplasmic reticulum (ER) stress. Hence, they are vulnerable to further perturbation to its protein homeostasis. In studying the therapeutic mechanism of PRIMA-1 (mutant-p53-reactivating-agent), we uncovered its novel p53-independent-mechanism that can be exploited for myeloma. Despite its inability in restoring the wild type-p53 protein conformation and transcriptional function in the mutant-p53-human-myeloma-cells, PRIMA-1 was efficacious against myeloma cells with differential p53 genotypes. Strikingly, cells without p53 expression demonstrated highest drug sensitivity. Genome-wide gene-expression analysis revealed the involvement of ER stress/UPR-pathway in inducing PRIMA-1-toxicity. UPR markers, HSP70, CHOP and GADD34, were significantly up-regulated, concomitantly with the induction of apoptosis. Furthermore, there was a global attenuation of protein synthesis, correlated with phospho-eIF2a up-regulation. Mechanistically, we identified that PRIMA-1 could cause the demethylation of TP73, through DNMT1 depletion, to subsequently enhance UPR. Of clinical significance, we observed that PRIMA-1 had additive therapeutic effects with another UPR-inducing-agent, bortezomib. Importantly, it can partially re-sensitize bortezomib-resistant cells to bortezomib. Given that MM is already stressed at the baseline in the ER, our results implicated that PRIMA-1 is a potential therapeutic option in MM by targeting its Achilles heel. PMID:27533450

  11. Palmitic acid-rich diet suppresses glucose-stimulated insulin secretion (GSIS) and induces endoplasmic reticulum (ER) stress in pancreatic islets in mice.

    PubMed

    Hirata, Takumi; Kawai, Toshihide; Hirose, Hiroshi; Tanaka, Kumiko; Kurosawa, Hideaki; Fujii, Chikako; Fujita, Haruhisa; Seto, Yoshiko; Matsumoto, Hideo; Itoh, Hiroshi

    2016-01-01

    The objective was to clarify whether dietary palmitic acid supplementation affects glucose-stimulated insulin secretion (GSIS) and the endoplasmic reticulum (ER) stress pathway in pancreatic islets in mice. Eight-week-old male C57BL/6J mice were randomly divided into three treatment diet groups: control diet, palmitic acid-supplemented diet (PAL) and oleic acid-supplemented diet (OLE). After 2 weeks of treatment, intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test were performed. GSIS was assessed by pancreatic perfusion in situ with basal (100 mg/dL) glucose followed by a high (300 mg/dL) glucose concentration. We measured mRNA levels of ER stress markers such as C/EBP homologous protein (CHOP), immunoglobulin heavy-chain binding protein (BIP) and X-box binding protein (XBP)-1 using real-time polymerase chain reaction (PCR) analyses in isolated islets. Immunohistochemical staining was also performed. Mice fed PAL showed significantly decreased glucose tolerance (p < 0.05). In the perfusion study, GSIS was significantly suppressed in the PAL group (p < 0.05). Semi-quantitative RT-PCR revealed that islet CHOP, BIP, and XBP-1 mRNA expression were significantly increased in the PAL group (p < 0.05). TUNEL-positive β-cells were not detected in all groups. Dietary palmitic acid-supplementation for 2 weeks might suppress GSIS and induce ER stress in pancreatic islets in mice, in the early stage of lipotoxicity.

  12. Mutations in Nonessential eIF3k and eIF3l Genes Confer Lifespan Extension and Enhanced Resistance to ER Stress in Caenorhabditis elegans

    PubMed Central

    Reddy, Kirthi C.; Droste, Rita; Kim, Dennis H.

    2016-01-01

    The translation initiation factor eIF3 is a multi-subunit protein complex that coordinates the assembly of the 43S pre-initiation complex in eukaryotes. Prior studies have demonstrated that not all subunits of eIF3 are essential for the initiation of translation, suggesting that some subunits may serve regulatory roles. Here, we show that loss-of-function mutations in the genes encoding the conserved eIF3k and eIF3l subunits of the translation initiation complex eIF3 result in a 40% extension in lifespan and enhanced resistance to endoplasmic reticulum (ER) stress in Caenorhabditis elegans. In contrast to previously described mutations in genes encoding translation initiation components that confer lifespan extension in C. elegans, loss-of-function mutations in eif-3.K or eif-3.L are viable, and mutants show normal rates of growth and development, and have wild-type levels of bulk protein synthesis. Lifespan extension resulting from EIF-3.K or EIF-3.L deficiency is suppressed by a mutation in the Forkhead family transcription factor DAF-16. Mutations in eif-3.K or eif-3.L also confer enhanced resistance to ER stress, independent of IRE-1-XBP-1, ATF-6, and PEK-1, and independent of DAF-16. Our data suggest a pivotal functional role for conserved eIF3k and eIF3l accessory subunits of eIF3 in the regulation of cellular and organismal responses to ER stress and aging. PMID:27690135

  13. Acute stress induces increases in salivary IL-10 levels.

    PubMed

    Szabo, Yvette Z; Newton, Tamara L; Miller, James J; Lyle, Keith B; Fernandez-Botran, Rafael

    2016-09-01

    The purpose of this study was to investigate the stress-reactivity of the anti-inflammatory cytokine, IL-10, in saliva and to determine how salivary IL-10 levels change in relation to those of IL-1β, a pro-inflammatory cytokine, following stress. Healthy young adults were randomly assigned to retrieve a negative emotional memory (n = 46) or complete a modified version of the Trier Social Stress Test (n = 45). Saliva samples were taken 10 min before (baseline) and 50 min after (post-stressor) onset of a 10-min stressor, and were assayed using a high sensitivity multiplex assay for cytokines. Measurable IL-10 levels (above the minimum detectable concentration) were found in 96% of the baseline samples, and 98% of the post-stressor samples. Flow rate-adjusted salivary IL-10 levels as well as IL-1β/IL-10 ratios showed moderate but statistically significant increases in response to stress. Measurement of salivary IL-10 and pro-/anti-inflammatory cytokine ratios may be useful, noninvasive tools, in stress research.

  14. Acute and chronic stress models differentially impact the inflammatory and antibody titer responses to respiratory vaccination in naive beef steers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this research was to determine the effect of an acute vs. chronic stress model on serum antibody titer and acute phase responses. Seronegative beef steers (n=32; 209 +/- 8 kg) were stratified by body weight and assigned randomly to 1 of 3 treatments: 1) Chronic stress (CHR), 0.5 mg/...

  15. Biochemical and biomolecular aspects of oxidative stress due to acute and severe hypoxia in human muscle tissue.

    PubMed

    Corbucci, G G; Sessego, R; Velluti, C; Salvi, M

    1995-01-01

    Mitochondrial oxidative stress was investigated in severe and acute hypoxia and in reperfusion applied to human muscle tissues. The biochemical and biomolecular relationship between the response of the respiratory-chain enzymic complexes and the metabolism of specific hypoxia stress proteins (HSP) suggest an adaptive mechanism which antagonizes the oxidative damage due to acute and severe tissue hypoxia.

  16. Acute stress does not impair long-term memory retrieval in older people.

    PubMed

    Pulopulos, Matias M; Almela, Mercedes; Hidalgo, Vanesa; Villada, Carolina; Puig-Perez, Sara; Salvador, Alicia

    2013-09-01

    Previous studies have shown that stress-induced cortisol increases impair memory retrieval in young people. This effect has not been studied in older people; however, some findings suggest that age-related changes in the brain can affect the relationships between acute stress, cortisol and memory in older people. Our aim was to investigate the effects of acute stress on long-term memory retrieval in healthy older people. To this end, 76 participants from 56 to 76 years old (38 men and 38 women) were exposed to an acute psychosocial stressor or a control task. After the stress/control task, the recall of pictures, words and stories learned the previous day was assessed. There were no differences in memory retrieval between the stress and control groups on any of the memory tasks. In addition, stress-induced cortisol response was not associated with memory retrieval. An age-related decrease in cortisol receptors and functional changes in the amygdala and hippocampus could underlie the differences observed between the results from this study and those found in studies performed with young people.

  17. Social stress modulates the cortisol response to an acute stressor in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Jeffrey, J D; Gollock, M J; Gilmour, K M

    2014-01-15

    In rainbow trout (Oncorhynchus mykiss) of subordinate social status, circulating cortisol concentrations were elevated under resting conditions but the plasma cortisol and glucose responses to an acute stressor (confinement in a net) were attenuated relative to those of dominant trout. An in vitro head kidney preparation, and analysis of the expression of key genes in the stress axis prior to and following confinement in a net were then used to examine the mechanisms underlying suppression of the acute cortisol stress response in trout experiencing chronic social stress. With porcine adrenocorticotropic hormone (ACTH) as the secretagogue, ACTH-stimulated cortisol production was significantly lower for head kidney preparations from subordinate trout than for those from dominant trout. Dominant and subordinate fish did not, however, differ in the relative mRNA abundance of melanocortin-2 receptor (MC2R), steroidogenic acute regulatory protein (StAR) or cytochrome P450 side chain cleavage enzyme (P450scc) within the head kidney, although the relative mRNA abundance of these genes was significantly higher in both dominant and subordinate fish than in sham trout (trout that did not experience social interactions but were otherwise treated identically to the dominant and subordinate fish). The relative mRNA abundance of all three genes was significantly higher in trout exposed to an acute net stressor than under control conditions. Upstream of cortisol production in the stress axis, plasma ACTH concentrations were not affected by social stress, nor was the relative mRNA abundance of the binding protein for corticotropin releasing factor (CRF-BP). The relative mRNA abundance of CRF in the pre-optic area of subordinate fish was significantly higher than that of dominant or sham fish 1h after exposure to the stressor. Collectively, the results indicate that chronic social stress modulates cortisol production at the level of the interrenal cells, resulting in an attenuated

  18. The Effects of Social Context and Acute Stress on Decision-Making Under Uncertainty

    PubMed Central

    FeldmanHall, Oriel; Raio, Candace M.; Kubota, Jennifer T.; Seiler, Morgan G.; Phelps, Elizabeth A.

    2015-01-01

    Uncertainty preferences are typically studied in neutral, non-social contexts. This approach, however, fails to capture the dynamic factors that influence choices of uncertainty in the real world. Our goals were twofold, to test whether uncertainty valuation is similarly processed across social and non-social contexts, and investigate the effects of acute stress on uncertainty preferences. Participants completed matched gambling and trust games under either control or stress manipulations. Participants not under stress exhibited no differences between money gambled and money entrusted to partners. In contrast, stressed participants exhibited increased gambling but decreased trusting behavior. We further found that irrespective of stress, participants were highly attuned to irrelevant feedback in non-social gambling contexts, believing that every incremental loss led to a greater chance of winning (gamblers’ fallacy). However, when deciding to trust a stranger, participants behaved rationally, treating each new interaction as independent. Stress compromised this adaptive behavior, increasing sensitivity to irrelevant social feedback. PMID:26546080

  19. Chemical composition of rainbow trout urine following acute hypoxic stress

    USGS Publications Warehouse

    Hunn, Joseph B.

    1969-01-01

    Rainbow trout (Salmo gairdnerii) were anesthetized with MS-222, catheterized, and introduced into urine collecting chambers. Twenty-four hours after introduction, a 4-hour accumulation of urine was collected to serve as the control. Water flow to the chambers was then discontinued for 30 minutes during which the oxygen content of the water exiting in the chamber dropped from 4.9 to 2.8 mg/l. Following this hypoxic stress fresh water was restored and accumulated urine samples were taken for analysis at 1, 4, and 20 hours post-hypoxic stress. Rainbow trout excrete abnormally high concentrations of Na, K, Mg, Cl, and inorganic PO4 following hypoxia.

  20. Acute stress-induced antinociception is cGMP-dependent but heme oxygenase-independent

    PubMed Central

    Carvalho-Costa, P.G.; Branco, L.G.S.; Leite-Panissi, C.R.A.

    2014-01-01

    Endogenous carbon monoxide (CO), which is produced by the enzyme heme oxygenase (HO), participates as a neuromodulator in physiological processes such as thermoregulation and nociception by stimulating the formation of 3′,5′-cyclic guanosine monophosphate (cGMP). In particular, the acute physical restraint-induced fever of rats can be blocked by inhibiting the enzyme HO. A previous study reported that the HO-CO-cGMP pathway plays a key phasic antinociceptive role in modulating noninflammatory acute pain. Thus, this study evaluated the involvement of the HO-CO-cGMP pathway in antinociception induced by acute stress in male Wistar rats (250-300 g; n=8/group) using the analgesia index (AI) in the tail flick test. Th