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Sample records for alleviate er stress

  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. 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.

  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. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. Alleviating Stress for Women Administrators.

    ERIC Educational Resources Information Center

    Ten Elshof, Annette; Tomlinson, Elaine

    1981-01-01

    Describes a workshop designed to help women administrators assess individual stress levels. Stress can be alleviated through exercise, support groups or networking, sleep and diet, relaxation, guided fantasy, and planned activity. The long-term implications include preventing illness and making women more effective within the administrative…

  10. Do Carpets Alleviate Stress?

    PubMed Central

    HOKI, Yoko; SATO, Kunio; KASAI, Yuichi

    2016-01-01

    Background: Owing to increased complexity in the evolution of society, stress has become an important public health problem, and is responsible for more than 30 types of diseases. Most of the research on stress conducted to date has focused on physical and psychological aspects; however, there are very few reports about the association between psychological stress and elements within the residential environment, such as the home, room, and furniture. Therefore, in this study, we focused on the effects of indoor flooring in the residential environment on stress, as flooring is a feature that the human body is in contact with for long periods of time. We objectively measured the extent of psychological stress perceived while walking on carpeting and on wood flooring. Methods: Forty-two healthy subjects were recruited for this study, and were asked to walk on carpeting and wood flooring for 10 min each. Their electroencephalogram (EEG) and skin impedance values were measured for each task. Results: The α-wave content percentage in EEG data and skin impedance values were significantly higher just after walking on carpet than just after walking on wood flooring. Conclusion: Walking on carpeting induces less stress than walking on wood flooring. PMID:27648413

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. 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

  16. 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.

  17. 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

  18. 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.

  19. Shengmai Injection Improved Doxorubicin-Induced Cardiomyopathy by Alleviating Myocardial Endoplasmic Reticulum Stress and Caspase-12 Dependent Apoptosis

    PubMed Central

    Chen, Yu; Tang, Yong; Xiang, Yin; Xie, Yu-Quan; Huang, Xiao-Hong; Zhang, Ya-Chen

    2015-01-01

    Background. Apoptosis plays vital roles in the progression of doxorubicin-induced cardiomyopathy (DOX-CM). Endoplasmic reticulum stress (ER stress) could induce specific apoptosis by caspase-12 dependent pathway. Shengmai Injection (SMI), a famous Traditional Chinese Medicine, could alleviate the heart damage via inhibiting myocardial apoptosis. However, it is unknown whether SMI can alleviate ER stress and its specific apoptosis in the setting of DOX-CM. Objective. To explore the effects of SMI on heart function, myocardial ER stress, and apoptosis of DOX-CM rats. Methods. Rats with DOX-CM were treated by SMI. Heart function was assessed by echocardiography and brain natriuretic peptide. Myocardial apoptosis was detected by TUNEL assay. ER stress was assessed by detecting the expressions of GRP78 and caspase-12. Results. At the end of eight-week, compared to control, significant heart dysfunction happened in DOX group. The ratio of apoptotic cardiomyocytes and the expressions of GRP78 and caspase-12 increased significantly (P < 0.05). Compared to DOX group, the apoptotic ratio and the expressions of GRP78 and caspase-12 significantly decreased in DOX + SMI group (P < 0.05), accompanied with improved heart function. Conclusion. SMI could alleviate myocardial ER stress and caspase-12 dependent apoptosis, which subsequently helped to improve the heart function of rats with DOX-CM. PMID:25839043

  20. Salubrinal Alleviates Pressure Overload-Induced Cardiac Hypertrophy by Inhibiting Endoplasmic Reticulum Stress Pathway

    PubMed Central

    Rani, Shilpa; Sreenivasaiah, Pradeep Kumar; Cho, Chunghee; Kim, Do Han

    2017-01-01

    Pathological hypertrophy of the heart is closely associated with endoplasmic reticulum stress (ERS), leading to maladaptations such as myocardial fibrosis, induction of apoptosis, and cardiac dysfunctions. Salubrinal is a known selective inhibitor of protein phosphatase 1 (PP1) complex involving dephosphorylation of phospho-eukaryotic translation initiation factor 2 subunit (p-eIF2)-α, the key signaling process in the ERS pathway. In this study, the effects of salubrinal were examined on cardiac hypertrophy using the mouse model of transverse aortic constriction (TAC) and cell model of neonatal rat ventricular myocytes (NRVMs). Treatment of TAC-induced mice with salubrinal (0.5 mg·kg−1·day−1) alleviated cardiac hypertrophy and tissue fibrosis. Salubrinal also alleviated hypertrophic growth in endothelin 1 (ET1)-treated NRVMs. Therefore, the present results suggest that salubrinal may be a potentially efficacious drug for treating pathological cardiac remodeling. PMID:28152298

  1. 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

  2. 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.

  3. TBHQ Alleviated Endoplasmic Reticulum Stress-Apoptosis and Oxidative Stress by PERK-Nrf2 Crosstalk in Methamphetamine-Induced Chronic Pulmonary Toxicity

    PubMed Central

    Gu, Yu-Han; Liu, Ming; Bai, Yang; Liang, Li-Ye; Wang, Huai-Liang

    2017-01-01

    Methamphetamine (MA) leads to cardiac and pulmonary toxicity expressed as increases in inflammatory responses and oxidative stress. However, some interactions may exist between oxidative stress and endoplasmic reticulum stress (ERS). The current study is designed to investigate if both oxidative stress and ERS are involved in MA-induced chronic pulmonary toxicity and if antioxidant tertiary butylhydroquinone (TBHQ) alleviated ERS-apoptosis and oxidative stress by PERK-Nrf2 crosstalk. In this study, the rats were randomly divided into control group, MA-treated group (MA), and MA plus TBHQ-treated group (MA + TBHQ). Chronic exposure to MA resulted in slower growth of weight and pulmonary toxicity of the rats by increasing the pulmonary arterial pressure, promoting the hypertrophy of right ventricle and the remodeling of pulmonary arteries. MA inhibited the Nrf2-mediated antioxidative stress by downregulation of Nrf2, GCS, and HO-1 and upregulation of SOD2. MA increased GRP78 to induce ERS. Overexpression and phosphorylation of PERK rapidly phosphorylated eIF2α, increased ATF4, CHOP, bax, caspase 3, and caspase 12, and decreased bcl-2. These changes can be reversed by antioxidant TBHQ through upregulating expression of Nrf2. The above results indicated that TBHQ can alleviate MA-induced oxidative stress which can accelerate ERS to initiate PERK-dependent apoptosis and that PERK/Nrf2 is likely to be the key crosstalk between oxidative stress and ERS in MA-induced chronic pulmonary toxicity. PMID:28303170

  4. TBHQ Alleviated Endoplasmic Reticulum Stress-Apoptosis and Oxidative Stress by PERK-Nrf2 Crosstalk in Methamphetamine-Induced Chronic Pulmonary Toxicity.

    PubMed

    Wang, Yun; Gu, Yu-Han; Liu, Ming; Bai, Yang; Liang, Li-Ye; Wang, Huai-Liang

    2017-01-01

    Methamphetamine (MA) leads to cardiac and pulmonary toxicity expressed as increases in inflammatory responses and oxidative stress. However, some interactions may exist between oxidative stress and endoplasmic reticulum stress (ERS). The current study is designed to investigate if both oxidative stress and ERS are involved in MA-induced chronic pulmonary toxicity and if antioxidant tertiary butylhydroquinone (TBHQ) alleviated ERS-apoptosis and oxidative stress by PERK-Nrf2 crosstalk. In this study, the rats were randomly divided into control group, MA-treated group (MA), and MA plus TBHQ-treated group (MA + TBHQ). Chronic exposure to MA resulted in slower growth of weight and pulmonary toxicity of the rats by increasing the pulmonary arterial pressure, promoting the hypertrophy of right ventricle and the remodeling of pulmonary arteries. MA inhibited the Nrf2-mediated antioxidative stress by downregulation of Nrf2, GCS, and HO-1 and upregulation of SOD2. MA increased GRP78 to induce ERS. Overexpression and phosphorylation of PERK rapidly phosphorylated eIF2α, increased ATF4, CHOP, bax, caspase 3, and caspase 12, and decreased bcl-2. These changes can be reversed by antioxidant TBHQ through upregulating expression of Nrf2. The above results indicated that TBHQ can alleviate MA-induced oxidative stress which can accelerate ERS to initiate PERK-dependent apoptosis and that PERK/Nrf2 is likely to be the key crosstalk between oxidative stress and ERS in MA-induced chronic pulmonary toxicity.

  5. Habitat odor can alleviate innate stress responses in mice.

    PubMed

    Matsukawa, Mutsumi; Imada, Masato; Aizawa, Shin; Sato, Takaaki

    2016-01-15

    Predatory odors, which can induce innate fear and stress responses in prey species, are frequently used in the development of animal models for several psychiatric diseases including post-traumatic stress disorder (PTSD) following a life-threatening event. We have previously shown that odors can be divided into at least three types; odors that act as (1) innate stressors, (2) as innate relaxants, or (3) have no innate effects on stress responses. Here, we attempted to verify whether an artificial odor, which had no innate effect on predatory odor-induced stress, could alleviate stress if experienced in early life as a habitat odor. In the current study, we demonstrated that the innate responses were changed to counteract stress following a postnatal experience. Moreover, we suggest that inhibitory circuits involved in stress-related neuronal networks and the concentrations of norepinephrine in the hippocampus may be crucial in alleviating stress induced by the predatory odor. Overall, these findings may be important for understanding the mechanisms involved in differential odor responses and also for the development of pharmacotherapeutic interventions that can alleviate stress in illnesses like PTSD.

  6. Alleviating stress in the workplace: advice for nurses.

    PubMed

    Wright, Kerri

    Stress is an inherent and arguably essential aspect of the nurse's role, with ongoing challenges associated with providing care for patients and their families. However, the level of stress currently being experienced in health care exceeds the capacity of many nurses, resulting in ill health and burnout. This stress can undermine the care and compassion nurses are able to give, a vital concern in health care which was highlighted by the Francis inquiry. This article explores the factors that contribute to stress and the strategies that can be used to alleviate the stresses inherent in nursing.

  7. Black tea protects against hypertension-associated endothelial dysfunction through alleviation of endoplasmic reticulum stress

    PubMed Central

    San Cheang, Wai; Yuen Ngai, Ching; Yen Tam, Ye; Yu Tian, Xiao; Tak Wong, Wing; Zhang, Yang; Wai Lau, Chi; Chen, Zhen Yu; Bian, Zhao-Xiang; Huang, Yu; Ping Leung, Fung

    2015-01-01

    Hypertensive patients have been found to be associated with elevated levels of homocysteine, known as hyperhomocysteinemia. Homocysteine (Hcy) can induce endoplasmic reticulum (ER) stress in endothelial cells. This study aims to investigate whether black tea (BT) protects against hypertension-associated endothelial dysfunction through alleviation of ER stress. Rat aortae and cultured rat aortic endothelial cells were treated with Hcy, BT extract, and theaflavin-3,3’-digallate (TF3). Male Sprague Dawley rats were infused with angiotensin II (Ang II) to induce hypertension and orally administrated with BT extract at 15 mg/kg/day for 2 weeks. Hcy impaired endothelium-dependent relaxations of rat aortae and led to ER stress in endothelial cells, which were ameliorated by co-incubation of BT extract and TF3. The blood pressure of Ang II-infused rats and plasma Hcy level were normalized by BT consumption. Impaired endothelium-dependent relaxations in renal arteries, carotid arteries and aortae, and flow-mediated dilatations in third-order mesenteric resistance arteries were improved. Elevations of ER stress markers and ROS level, plus down-regulation of Hcy metabolic enzymes in aortae from Ang II-infused rats were prevented by BT treatment. Our data reveal the novel cardiovascular benefits of BT in ameliorating vascular dysfunctions, providing insight into developing BT into beneficial dietary supplements in hypertensive patients. PMID:25976123

  8. 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

  9. Arbuscular mycorrhizal fungi in alleviation of salt stress: a review

    PubMed Central

    Evelin, Heikham; Kapoor, Rupam; Giri, Bhoopander

    2009-01-01

    Background Salt stress has become a major threat to plant growth and productivity. Arbuscular mycorrhizal fungi colonize plant root systems and modulate plant growth in various ways. Scope This review addresses the significance of arbuscular mycorrhiza in alleviation of salt stress and their beneficial effects on plant growth and productivity. It also focuses on recent progress in unravelling biochemical, physiological and molecular mechanisms in mycorrhizal plants to alleviate salt stress. Conclusions The role of arbuscular mycorrhizal fungi in alleviating salt stress is well documented. This paper reviews the mechanisms arbuscular mycorrhizal fungi employ to enhance the salt tolerance of host plants such as enhanced nutrient acquisition (P, N, Mg and Ca), maintenance of the K+ : Na+ ratio, biochemical changes (accumulation of proline, betaines, polyamines, carbohydrates and antioxidants), physiological changes (photosynthetic efficiency, relative permeability, water status, abscissic acid accumulation, nodulation and nitrogen fixation), molecular changes (the expression of genes: PIP, Na+/H+ antiporters, Lsnced, Lslea and LsP5CS) and ultra-structural changes. Theis review identifies certain lesser explored areas such as molecular and ultra-structural changes where further research is needed for better understanding of symbiosis with reference to salt stress for optimum usage of this technology in the field on a large scale. This review paper gives useful benchmark information for the development and prioritization of future research programmes. PMID:19815570

  10. Curcumin alleviates oxidative stress and mitochondrial dysfunction in astrocytes.

    PubMed

    Daverey, Amita; Agrawal, Sandeep K

    2016-10-01

    Oxidative stress plays a critical role in various neurodegenerative diseases, thus alleviating oxidative stress is a potential strategy for therapeutic intervention and/or prevention of neurodegenerative diseases. In the present study, alleviation of oxidative stress through curcumin is investigated in A172 (human glioblastoma cell line) and HA-sp (human astrocytes cell line derived from the spinal cord) astrocytes. H2O2 was used to induce oxidative stress in astrocytes (A172 and HA-sp). Data show that H2O2 induces activation of astrocytes in dose- and time-dependent manner as evident by increased expression of GFAP in A172 and HA-sp cells after 24 and 12h respectively. An upregulation of Prdx6 was also observed in A172 and HA-sp cells after 24h of H2O2 treatment as compared to untreated control. Our data also showed that curcumin inhibits oxidative stress-induced cytoskeleton disarrangement, and impedes the activation of astrocytes by inhibiting upregulation of GFAP, vimentin and Prdx6. In addition, we observed an inhibition of oxidative stress-induced inflammation, apoptosis and mitochondria fragmentation after curcumin treatment. Therefore, our results suggest that curcumin not only protects astrocytes from H2O2-induced oxidative stress but also reverses the mitochondrial damage and dysfunction induced by oxidative stress. This study also provides evidence for protective role of curcumin on astrocytes by showing its effects on attenuating reactive astrogliosis and inhibiting apoptosis.

  11. 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.

  12. 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

  13. 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.

  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. 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.

  16. Coronatine alleviates water deficiency stress on winter wheat seedlings.

    PubMed

    Li, Xiangwen; Shen, Xuefeng; Li, Jianmin; Eneji, Anthony Egrinya; Li, Zhaohu; Tian, Xiaoli; Duan, Liusheng

    2010-07-01

    With the aim to determine whether coronatine (COR) alleviates drought stress on wheat, two winter wheat (Triticum aestivum L.) cultivars, ChangWu134 (drought-tolerant) and Shan253 (drought-sensitive) were studied under hydroponic conditions. Seedlings at the three-leaf stage were cultured in a Hoagland solution containing COR at 0.1 microM for 24 h, and then exposed to 20% polyethylene glycol 6000 (PEG-6000). Under simulated drought (SD), COR increased the dry weight of shoots and roots of the two cultivars significantly; the root/shoot ratio also increased by 30% for Shan253 and 40% for ChangWu134. Both cultivars treated with COR under SD (0.1COR+PEG) maintained significantly higher relative water content, photosynthesis, transpiration, intercellular concentration of CO(2) and stomatal conductance in leaves than those not treated with PEG. Under drought, COR significantly decreased the relative conductivity and malondialdehyde production, and the loss of 1,1-diphenyl-2-picrylhydrazyl scavenging activity in leaves was significantly alleviated in COR-treated plants. The activity of peroxidase, catalase, glutathione reductase and ascorbate peroxidase were adversely affected by drought. Leaves of plants treated with COR under drought produced less abscisic acid (ABA) than those not treated. Thus, COR might alleviate drought effects on wheat by reducing active oxygen species production, activating antioxidant enzymes and changing the ABA level.

  17. Dopamine alleviates salt-induced stress in Malus hupehensis.

    PubMed

    Li, Chao; Sun, Xiangkai; Chang, Cong; Jia, Dongfeng; Wei, Zhiwei; Li, Cuiying; Ma, Fengwang

    2015-04-01

    Dopamine mediates many physiological processes in plants. We investigated its role in regulating growth, ion homeostasis and the response to salinity in Malus hupehensis Rehd. Both hydroponics and field-pot experiments were conducted under saline conditions. Salt-stressed plants had reduced growth and a marked decline in their net photosynthetic rates, values for Fv /Fm and chlorophyll contents. However, pretreatment with 100 or 200 μM dopamine significantly alleviated this inhibition and enabled plants to maintain their photosynthetic capacity. In addition to changing stomatal behavior, supplementation with dopamine positively influenced the uptake of K, N, P, S, Cu and Mn ions but had an inhibitory effect on Na and Cl uptake, the balance of which is responsible for managing the response to salinity by Malus plants. Dopamine pretreatment also controlled the burst of hydrogen peroxide, possibly through direct scavenging and by enhancing the activities of antioxidative enzymes and the capacity of the ascorbate-glutathione cycle. We also investigated whether dopamine might regulate salt overly sensitive pathway genes under salinity. Here, MdHKT1, MdNHX1 and MdSOS1 were greatly upregulated in roots and leaves, which possibly contributed to the maintenance of ion homeostasis and, thus, improved salinity resistance in plants exposed earlier to exogenous dopamine. These results support our conclusion that dopamine alleviates salt-induced stress not only at the level of antioxidant defense but also by regulating other mechanisms of ion homeostasis.

  18. 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.

  19. 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

  20. 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

  1. 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

  2. Coumarin pretreatment alleviates salinity stress in wheat seedlings.

    PubMed

    Saleh, Ahmed Mahmoud; Madany, M M Y

    2015-03-01

    The potentiality of COU to improve plant tolerance to salinity was investigated. Wheat grains were primed with COU (50 ppm) and then grown under different levels of NaCl (50, 100, 150 mM) for two weeks. COU pretreatment improved the growth of wheat seedling under salinity, relative to COU-untreated seedlings, due to the accumulation of osmolytes such as soluble sugars and proline. Moreover, COU treatment significantly improved K(+)/Na(+) ratio in the shoots of both salt stressed and un-stressed seedlings. However, in the roots, this ratio increased only under non-salinity. In consistent with phenylalanine ammonia lyase (PAL), phenolics and flavonoids were accumulated in COU-pretreated seedlings under the higher doses of salinity, relative to COU-untreated seedlings. COU primed seedlings showed higher content of the coumarin derivative, scopoletin, and salicylic, chlorogenic, syringic, vanillic, gallic and ferulic acids, under both salinity and non-salinity conditions. Salinity stress significantly improved the activity of peroxidase (POD) in COU-pretreated seedlings. However, the effect of COU on the total antioxidant capacity (TAC) was only obtained at the highest dose of NaCl (150 mM). The present results suggest that COU pretreatment could alleviate the adverse effect of salinity on the growth of wheat seedlings through enhancing, at least partly, the osmoregulation process and antioxidant defense system.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. Residual stress alleviation of aircraft metal structures reinforced with filamentary composites

    NASA Technical Reports Server (NTRS)

    Kelly, J. B.; June, R. R.

    1973-01-01

    Methods to eliminate or reduce residual stresses in aircraft metal structures reinforced by filamentary composites are discussed. Residual stress level reductions were achieved by modifying the manufacturing procedures used during adhesive bonding. The residual stress alleviation techniques involved various forms of mechanical constraint which were applied to the components during bonding. Nine methods were evaluated, covering a wide range in complexity. All methods investigated during the program affected the residual stress level. In general, residual stresses were reduced by 70 percent or more from the stress level produced by conventional adhesive bonding procedures.

  11. Seed priming to alleviate salinity stress in germinating seeds.

    PubMed

    Ibrahim, Ehab A

    2016-03-15

    Salinity is one of the major abiotic stresses that affect crop production in arid and semiarid areas. Seed germination and seedling growth are the stages most sensitive to salinity. Salt stress causes adverse physiological and biochemical changes in germinating seeds. It can affect the seed germination and stand establishment through osmotic stress, ion-specific effects and oxidative stress. The salinity delays or prevents the seed germination through various factors, such as a reduction in water availability, changes in the mobilization of stored reserves and affecting the structural organization of proteins. Various techniques can improve emergence and stand establishment under salt conditions. One of the most frequently utilized is seed priming. The process of seed priming involves prior exposure to an abiotic stress, making a seed more resistant to future exposure. Seed priming stimulates the pre-germination metabolic processes and makes the seed ready for radicle protrusion. It increases the antioxidant system activity and the repair of membranes. These changes promote seed vigor during germination and emergence under salinity stress. The aim of this paper is to review the recent literature on the response of plants to seed priming under salinity stress. The mechanism of the effect of salinity on seed germination is discussed and the seed priming process is summarized. Physiological, biochemical and molecular changes induced by priming that lead to seed enhancement are covered. Plants' responses to some priming agents under salinity stress are reported based on the best available data. For a great number of crops, little information exists and further research is needed.

  12. 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.

  13. Herbaspirillum sp. strain GW103 alleviates salt stress in Brassica rapa L. ssp. pekinensis.

    PubMed

    Lee, Gun Woong; Lee, Kui-Jae; Chae, Jong-Chan

    2016-05-01

    Mutual interactions between plant and rhizosphere bacteria facilitate plant growth and reduce risks of biotic and abiotic stresses. The present study demonstrates alleviation of salt stress in Brassica rapa L. ssp. perkinensis (Chinese cabbage) by Herbaspirillum sp. strain GW103 isolated from rhizosphere soil of Phragmites australis. The strain was capable of producing plant beneficial factors, such as auxin, siderophore, and 1-aminocylopropane-1-carboxylic acid deaminase. Treatment of strain GW103 on Chinese cabbage under salt stress increased K(+)/Na(+) ratio in roots generating balance in the ratio of ion homeostasis and consequently contributed to the increase of biomass. In addition, root colonization potential of the strain was observed by green fluorescent protein (GFP)-tagging approach. These results strongly suggest the beneficial impact of strain GW103 by inducing the alleviation of salt stress and development of stress tolerance in Chinese cabbage via plant-microbe interaction.

  14. 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.

  15. Alleviation of salt stress in lemongrass by salicylic acid.

    PubMed

    Idrees, Mohd; Naeem, M; Khan, M Nasir; Aftab, Tariq; Khan, M Masroor A; Moinuddin

    2012-07-01

    Soil salinity is one of the key factors adversely affecting the growth, yield, and quality of crops. A pot study was conducted to find out whether exogenous application of salicylic acid could ameliorate the adverse effect of salinity in lemongrass (Cymbopogon flexuosus Steud. Wats.). Two Cymbopogon varieties, Krishna and Neema, were used in the study. Three salinity levels, viz, 50, 100, and 150 mM of NaCl, were applied to 30-day-old plants. Salicylic acid (SA) was applied as foliar spray at 10(-5) M concentration. Totally, six SA-sprays were carried out at 10-day intervals, following the first spray at 30 days after sowing. The growth parameters were progressively reduced with the increase in salinity level; however, growth inhibition was significantly reduced by the foliar application of SA. With the increase in salt stress, a gradual decrease in the activities of carbonic anhydrase and nitrate reductase was observed in both the varieties. SA-treatment not only ameliorated the adverse effects of NaCl but also showed a significant improvement in the activities of these enzymes compared with the untreated stressed-plants. The plants supplemented with NaCl exhibited a significant increase in electrolyte leakage, proline content, and phosphoenol pyruvate carboxylase activity. Content and yield of essential oil was also significantly decreased in plants that received salinity levels; however, SA overcame the unfavorable effects of salinity stress to a considerable extent. Lemongrass variety Krishna was found to be more adapted to salt stress than Neema, as indicated by the overall performance of the two varieties under salt conditions.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. Seed treatment with Trichoderma harzianum alleviates biotic, abiotic, and physiological stresses in germinating seeds and seedlings.

    PubMed

    Mastouri, Fatemeh; Björkman, Thomas; Harman, Gary E

    2010-11-01

    Trichoderma spp. are endophytic plant symbionts that are widely used as seed treatments to control diseases and to enhance plant growth and yield. Although some recent work has been published on their abilities to alleviate abiotic stresses, specific knowledge of mechanisms, abilities to control multiple plant stress factors, their effects on seed and seedlings is lacking. We examined the effects of seed treatment with T. harzianum strain T22 on germination of seed exposed to biotic stress (seed and seedling disease caused by Pythium ultimum) and abiotic stresses (osmotic, salinity, chilling, or heat stress). We also evaluated the ability of the beneficial fungus to overcome physiological stress (poor seed quality induced by seed aging). If seed were not under any of the stresses noted above, T22 generally had little effect upon seedling performance. However, under stress, treated seed germinated consistently faster and more uniformly than untreated seeds whether the stress was osmotic, salt, or suboptimal temperatures. The consistent response to varying stresses suggests a common mechanism through which the plant-fungus association enhances tolerance to a wide range of abiotic stresses as well as biotic stress. A common factor that negatively affects plants under these stress conditions is accumulation of toxic reactive oxygen species (ROS), and we tested the hypothesis that T22 reduced damages resulting from accumulation of ROS in stressed plants. Treatment of seeds reduced accumulation of lipid peroxides in seedlings under osmotic stress or in aged seeds. In addition, we showed that the effect of exogenous application of an antioxidant, glutathione, or application of T22, resulted in a similar positive effect on seed germination under osmotic stress or in aged seed. This evidence supports the model that T. harzianum strain T22 increases seedling vigor and ameliorates stress by inducing physiological protection in plants against oxidative damage.

  6. 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

  7. 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

  8. 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

  9. 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.

  10. Mechanisms of silicon-mediated alleviation of drought and salt stress in plants: a review.

    PubMed

    Rizwan, Muhammad; Ali, Shafaqat; Ibrahim, Muhammad; Farid, Mujahid; Adrees, Muhammad; Bharwana, Saima Aslam; Zia-Ur-Rehman, Muhammad; Qayyum, Muhammad Farooq; Abbas, Farhat

    2015-10-01

    Drought and salinity are the main abiotic stresses limiting crop yield and quality worldwide. Improving food production in drought- and salt-prone areas is the key to meet the increasing food demands in near future. It has been widely reported that silicon (Si), a second most abundant element in soil, could reduce drought and salt stress in plants. Here, we reviewed the emerging role of Si in enhancing drought and salt tolerance in plants and highlighted the mechanisms through which Si could alleviate both drought and salt stress in plants. Silicon application increased plant growth, biomass, photosynthetic pigments, straw and grain yield, and quality under either drought or salt stress. Under both salt and drought stress, the key mechanisms evoked are nutrient elements homeostasis, modification of gas exchange attributes, osmotic adjustment, regulating the synthesis of compatible solutes, stimulation of antioxidant enzymes, and gene expression in plants. In addition, Si application decreased Na(+) uptake and translocation while increased K(+) uptake and translocation under salt stress. However, these mechanisms vary with plant species, genotype, growth conditions, duration of stress imposed, and so on. This review article highlights the potential for improving plant resistance to drought and salt stress by Si application and provides a theoretical basis for application of Si in saline soils and arid and semiarid regions worldwide. This review article also highlights the future research needs about the role of Si under drought stress and in saline soils.

  11. Potassium nitrate application alleviates sodium chloride stress in winter wheat cultivars differing in salt tolerance.

    PubMed

    Zheng, Yanhai; Jia, Aijun; Ning, Tangyuan; Xu, Jialin; Li, Zengjia; Jiang, Gaoming

    2008-09-29

    A sand culture experiment was conducted to answer the question whether or not exogenous KNO(3) can alleviate adverse effects of salt stress in winter wheat by monitoring plant growth, K(+)/Na(+) accumulation and the activity of some antioxidant enzymes. Seeds of two wheat cultivars (CVs), DK961 (salt-tolerant) and JN17 (salt-sensitive), were planted in sandboxes and controls germinated and raised with Hoagland nutrient solution (6 mM KNO(3), no NaCl). Experimental seeds were exposed to seven modified Hoagland solutions containing increased levels of KNO(3) (11, 16, 21 mM) or 100 mM NaCl in combination with the four KNO(3) concentrations (6, 11, 16 and 21 mM). Plants were harvested 30 d after imbibition, with controls approximately 22 cm in height. Both CVs showed significant reduction in plant height, root length and dry weight of shoots and roots under KNO(3) or NaCl stress. However, the combination of increased KNO(3) and NaCl alleviated symptoms of the individual salt stresses by improving growth of shoots and roots, reducing electrolyte leakage, malondialdehyde and soluble sugar contents and enhancing the activities of antioxidant enzymes. The salt-tolerant cultivar accumulated more K(+) in both shoots and roots compared with the higher Na(+) accumulation typical for the salt-sensitive cultivar. Soluble sugar content and activities of antioxidant enzymes were found to be more stable in the salt-tolerant cultivar. Our findings suggest that the optimal K(+)/Na(+) ratio of the nutrient solution should be 16:100 for both the salt-tolerant and the salt-sensitive cultivar under the experimental conditions used, and that the alleviation of NaCl stress symptoms through simultaneously applied elevated KNO(3) was more effective in the salt-tolerant than in the salt-sensitive cultivar.

  12. 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

  13. 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.

  14. Biochar soil amendment on alleviation of drought and salt stress in plants: a critical review.

    PubMed

    Ali, Shafaqat; Rizwan, Muhammad; Qayyum, Muhammad Farooq; Ok, Yong Sik; Ibrahim, Muhammad; Riaz, Muhammad; Arif, Muhammad Saleem; Hafeez, Farhan; Al-Wabel, Mohammad I; Shahzad, Ahmad Naeem

    2017-04-03

    Drought and salt stress negatively affect soil fertility and plant growth. Application of biochar, carbon-rich material developed from combustion of biomass under no or limited oxygen supply, ameliorates the negative effects of drought and salt stress on plants. The biochar application increased the plant growth, biomass, and yield under either drought and/or salt stress and also increased photosynthesis, nutrient uptake, and modified gas exchange characteristics in drought and salt-stressed plants. Under drought stress, biochar increased the water holding capacity of soil and improved the physical and biological properties of soils. Under salt stress, biochar decreased Na(+) uptake, while increased K(+) uptake by plants. Biochar-mediated increase in salt tolerance of plants is primarily associated with improvement in soil properties, thus increasing plant water status, reduction of Na(+) uptake, increasing uptake of minerals, and regulation of stomatal conductance and phytohormones. This review highlights both the potential of biochar in alleviating drought and salt stress in plants and future prospect of the role of biochar under drought and salt stress in plants.

  15. 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

  16. 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

  17. 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.

  18. Kinetin applications alleviate salt stress and improve the antioxidant composition of leaf extracts in Salvia officinalis.

    PubMed

    Tounekti, Taïeb; Hernández, Iker; Müller, Maren; Khemira, Habib; Munné-Bosch, Sergi

    2011-10-01

    A pot experiment was carried out under glasshouse conditions with common sage (Salvia officinalis L.) to investigate the interactive effects of salt stress and kinetin on growth attributes and the abundance of pigments, ions, phenolic diterpenes and α-tocopherol in leaf extracts of this species. The plants were subjected to the following four treatments: (i) control (nutrient solution), (ii) control + 10 μM kinetin, (iii) salt stress (nutrient solution + 100 mM NaCl), and (iv) salt stress + 10 μM kinetin. Kinetin was applied as a foliar fertilizer. Salt stress reduced water contents, photosynthetic activity and pigment contents of sage leaves. In addition, it increased Na(+) contents, and reduced those of Ca(2+) and K(+) in leaves. Salt stress reduced carnosic acid and 12-O-methyl carnosic acid contents in leaves, while it did not affect carnosol and α-tocopherol contents. Foliar applications of kinetin seemed to counterbalance or alleviate the stress symptoms induced by salinity, improving ion and pigment contents, while leaf phenolic diterpene (mainly carnosol) and α-tocopherol contents also increased in both control and NaCl-treated plants; still this effect was much more obvious in salt-treated plants. A similar effect was also obtained when plants were sprayed with KNO(3) or Ca(NO(3))(2), thus suggesting that kinetin effects were at least partly due to an improvement of ion homeostasis. Kinetin applications resulted in increased transcript levels of the isoprenoid and tocopherol biosynthetic genes, DXPRI and VTE2 and VTE4 in control plants, but not in NaCl-treated plants. We conclude that kinetin can alleviate the negative impact of salt on sage plants cultivated under arid environments with salinity problems.

  19. Selenium alleviates chromium toxicity by preventing oxidative stress in cabbage (Brassica campestris L. ssp. Pekinensis) leaves.

    PubMed

    Qing, Xuejiao; Zhao, Xiaohu; Hu, Chengxiao; Wang, Peng; Zhang, Ying; Zhang, Xuan; Wang, Pengcheng; Shi, Hanzhi; Jia, Fen; Qu, Chanjuan

    2015-04-01

    The beneficial role of selenium (Se) in alleviation of chromium (Cr)-induced oxidative stress is well established. However, little is known about the underlying mechanism. The impacts of exogenous Se (0.1mg/L) on Cr(1mg/L)-induced oxidative stress and antioxidant systems in leaves of cabbage (Brassica campestris L. ssp. Pekinensis) were investigated by using cellular and biochemical approaches. The results showed that supplementation of the medium with Se was effective in reducing Cr-induced increased levels of lipid peroxides and superoxide free radicals (O(-)2(·)), as well as increasing activities of superoxide dismutase (SOD) and peroxidase (POD). Meanwhile, 1mg/L Cr induced loss of plasma membrane integrity, growth inhibition, as well as ultrastructural changes of leaves were significantly reversed due to Se supplementation in the medium. In addition, Se application significantly altered the subcellular distribution of Cr which transported from mitochondria, nucleus and the cell-wall material to the soluble fraction and chloroplasts. However, Se application did no significant alteration of Cr effects on osmotic adjustment accumulating products. The study suggested that Se is able to protect leaves of cabbage against Cr toxicity by alleviation of Cr induced oxidative stress, and re-distribution of Cr in the subcellular of the leaf. Furthermore, free radicals, lipid peroxides, activity of SOD and POD, and subcellular distribution of Cr can be considered the efficient biomarkers to indicate the efficiency of Se to detoxification Cr.

  20. 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.

  1. 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.

  2. Arbuscular mycorrhizal symbiosis influences strigolactone production under salinity and alleviates salt stress in lettuce plants.

    PubMed

    Aroca, Ricardo; Ruiz-Lozano, Juan Manuel; Zamarreño, Angel María; Paz, José Antonio; García-Mina, José María; Pozo, María José; López-Ráez, Juan Antonio

    2013-01-01

    Arbuscular mycorrhizal (AM) symbiosis can alleviate salt stress in plants. However the intimate mechanisms involved, as well as the effect of salinity on the production of signalling molecules associated to the host plant-AM fungus interaction remains largely unknown. In the present work, we have investigated the effects of salinity on lettuce plant performance and production of strigolactones, and assessed its influence on mycorrhizal root colonization. Three different salt concentrations were applied to mycorrhizal and non-mycorrhizal plants, and their effects, over time, analyzed. Plant biomass, stomatal conductance, efficiency of photosystem II, as well as ABA content and strigolactone production were assessed. The expression of ABA biosynthesis genes was also analyzed. AM plants showed improved growth rates and a better performance of physiological parameters such as stomatal conductance and efficiency of photosystem II than non-mycorrhizal plants under salt stress since very early stages - 3 weeks - of plant colonization. Moreover, ABA levels were lower in those plants, suggesting that they were less stressed than non-colonized plants. On the other hand, we show that both AM symbiosis and salinity influence strigolactone production, although in a different way in AM and non-AM plants. The results suggest that AM symbiosis alleviates salt stress by altering the hormonal profiles and affecting plant physiology in the host plant. Moreover, a correlation between strigolactone production, ABA content, AM root colonization and salinity level is shown. We propose here that under these unfavourable conditions, plants increase strigolactone production in order to promote symbiosis establishment to cope with salt stress.

  3. Quercetin prevents chronic unpredictable stress induced behavioral dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress.

    PubMed

    Mehta, Vineet; Parashar, Arun; Udayabanu, Malairaman

    2017-03-15

    It is now evident that chronic stress is associated with anxiety, depression and cognitive dysfunction and very few studies have focused on identifying possible methods to prevent these stress-induced disorders. Previously, we identified abundance of quercetin in Urtica dioica extract, which efficiently attenuated stress related complications. Therefore, current study was designed to investigate the effect of quercetin on chronic unpredicted stress (CUS) induced behavioral dysfunction, oxidative stress and neuroinflammation in the mouse hippocampus. Animals were subjected to unpredicted stress for 21days, during which 30mg/kg quercetin was orally administered to them. Effect of CUS and quercetin treatment on animal behavior was assessed between day 22-26. Afterward, the hippocampus was processed to evaluate neuronal damage, oxidative and inflammatory stress. Results revealed that stressed animals were highly anxious (Elevated Plus Maze and Open Field), showed depressive-like behavior (sucrose preference task), performed poorly in short-term and long-term associative memory task (passive avoidance step-through task) and displayed reduced locomotion (open field). Quercetin alleviated behavioral dysfunction in chronically stressed animals. Compared to CUS, quercetin treatment significantly reduced anxiety, attenuated depression, improved cognitive dysfunction and normalized locomotor activity. Further, CUS elevated the levels of oxidative stress markers (TBARS, nitric oxide), lowered antioxidants (total thiol, catalase), enhanced expression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β and COX-2) in the hippocampus and damaged hippocampal neurons. Quercetin treatment significantly lowered oxidative and inflammatory stress and prevented neural damage. In conclusion, quercetin can efficiently prevent stress induced neurological complications by rescuing brain from oxidative and inflammatory stress.

  4. 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

  5. Constitutive accumulation of zeaxanthin in tomato alleviates salt stress-induced photoinhibition and photooxidation.

    PubMed

    Zhang, Qiu-Yu; Wang, Li-Yan; Kong, Fan-Ying; Deng, Yong-Sheng; Li, Bin; Meng, Qing-Wei

    2012-11-01

    Zeaxanthin (Z) has a role in the dissipation of excess excitation energy by participating in non-photochemical quenching (NPQ) and is essential in protecting the chloroplast from photooxidative damage. To investigate the physiological effects and functional mechanism of constitutive accumulation of Z in the tomato at salt stress-induced photoinhibition and photooxidation, antisense-mediated suppression of zeaxanthin epoxidase transgenic plants and the wild-type (WT) tomato were used. The ratio of Z/(V + A + Z) and (Z + 0.5A)/(V + A + Z) in antisense transgenic plants were maintained at a higher level than in WT plants under salt stress, but the value of NPQ in WT and transgenic plants was not significantly different under salt stress. However, the maximal photochemical efficiency of PSII (Fv/Fm) and the net photosynthetic rate (Pn) in transgenic plants decreased more slowly under salt stress. Furthermore, transgenic plants showed lower level of hydrogen peroxide (H(2)O(2)), superoxide anion radical (O(2)(•-)) and ion leakage, lower malondialdehyde content. Compared with WT, the content of D1 protein decreased slightly in transgenic plants under salt stress. Our results suggested that the constitutive accumulation of Z in transgenic tomatoes can alleviate salt stress-induced photoinhibition because of the antioxidant role of Z in the scavenging quenching of singlet oxygen and/or free radicals in the lipid phase of the membrane.

  6. Nitrogen availability regulates proline and ethylene production and alleviates salinity stress in mustard (Brassica juncea).

    PubMed

    Iqbal, Noushina; Umar, Shahid; Khan, Nafees A

    2015-04-15

    Proline content and ethylene production have been shown to be involved in salt tolerance mechanisms in plants. To assess the role of nitrogen (N) in the protection of photosynthesis under salt stress, the effect of N (0, 5, 10, 20 mM) on proline and ethylene was studied in mustard (Brassica juncea). Sufficient N (10 mM) optimized proline production under non-saline conditions through an increase in proline-metabolizing enzymes, leading to osmotic balance and protection of photosynthesis through optimal ethylene production. Excess N (20 mM), in the absence of salt stress, inhibited photosynthesis and caused higher ethylene evolution but lower proline production compared to sufficient N. In contrast, under salt stress with an increased demand for N, excess N optimized ethylene production, which regulates the proline content resulting in recovered photosynthesis. The effect of excess N on photosynthesis under salt stress was further substantiated by the application of the ethylene biosynthesis inhibitor, 1-aminoethoxy vinylglycine (AVG), which inhibited proline production and photosynthesis. Without salt stress, AVG promoted photosynthesis in plants receiving excess N by inhibiting stress ethylene production. The results suggest that a regulatory interaction exists between ethylene, proline and N for salt tolerance. Nitrogen differentially regulates proline production and ethylene formation to alleviate the adverse effect of salinity on photosynthesis in mustard.

  7. Vitamin D3 pretreatment alleviates renal oxidative stress in lipopolysaccharide-induced acute kidney injury.

    PubMed

    Xu, Shen; Chen, Yuan-Hua; Tan, Zhu-Xia; Xie, Dong-Dong; Zhang, Cheng; Xia, Mi-Zhen; Wang, Hua; Zhao, Hui; Xu, De-Xiang; Yu, De-Xin

    2015-08-01

    Increasing evidence demonstrates that reactive oxygen species plays important roles in sepsis-induced acute kidney injury. This study investigated the effects of VitD3 pretreatment on renal oxidative stress in sepsis-induced acute kidney injury. Mice were intraperitoneally injected with lipopolysaccharide (LPS, 2.0mg/kg) to establish an animal model of sepsis-induced acute kidney injury. In VitD3+LPS group, mice were orally pretreated with three doses of VitD3 (25 μg/kg) at 1, 24 and 48 h before LPS injection. As expected, oral pretreatment with three daily recommended doses of VitD3 markedly elevated serum 25(OH)D concentration and efficiently activated renal VDR signaling. Interestingly, LPS-induced renal GSH depletion and lipid peroxidation were markedly alleviated in VitD3-pretreated mice. LPS-induced serum and renal nitric oxide (NO) production was obviously suppressed by VitD3 pretreatment. In addition, LPS-induced renal protein nitration, as determined by 3-nitrotyrosine residue, was obviously attenuated by VitD3 pretreatment. Further analysis showed that LPS-induced up-regulation of renal inducible nitric oxide synthase (inos) was repressed in VitD3-pretreated mice. LPS-induced up-regulation of renal p47phox and gp91phox, two NADPH oxidase subunits, were normalized by VitD3 pretreatment. In addition, LPS-induced down-regulation of renal superoxide dismutase (sod) 1 and sod2, two antioxidant enzyme genes, was reversed in VitD3-pretreated mice. Finally, LPS-induced tubular epithelial cell apoptosis, as determined by TUNEL, was alleviated by VitD3 pretreatment. Taken together, these results suggest that VitD3 pretreatment alleviates LPS-induced renal oxidative stress through regulating oxidant and antioxidant enzyme genes.

  8. 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.

  9. Alleviating versus stimulating effects of bicarbonate on the growth of Vallisneria natans under ammonia stress.

    PubMed

    Dou, Yanyan; Wang, Baozhong; Chen, Liangyan; Yin, Daqiang

    2013-08-01

    Bicarbonate plays a crucial role in limiting the growth of submersed aquatic macrophytes in eutrophic lakes, and high ammonia is often toxic to macrophytes. In order to evaluate the combined effect of HCO3 (-) and total ammonia (i.e., the total of NH3 and NH4 (+)) on submersed macrophytes Vallisneria natans, the growth and physiological response of V. natans in the presence of HCO3 (-) and ammonia were studied. The results showed that with the increase of ammonia, morphological parameters of V. natans declined. In contrast, increased HCO3 (-) concentration stimulated the growth of V. natans, especially when the NH4 (+)-N/NO3 (-)-N ratio was 1:7. High ammonia concentration induced excess free amino acids (FAA) accumulation and soluble carbohydrates (SC) depletion in plant tissues. However, the elevated HCO3 (-) promoted the synthesis of SC and rendered the decrease of FAA/SC ratio. The results also suggested that HCO3 (-) could partially alleviate the stress of ammonia, as evidenced by the decrease of FAA/SC ratio and the growth enhancement of V. natans when the ammonia concentration was 0.58 mg L(-1). Given the fact that HCO3 (-) is probably the dominant available carbon source in most eutrophic lakes, the ability of V. natans to use HCO3 (-) for SC synthesis may explain the alleviating effect of HCO3 (-) on V. natans under ammonia stress.

  10. 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

  11. Dietary chromium methionine supplementation could alleviate immunosuppressive effects of heat stress in broiler chicks.

    PubMed

    Jahanian, R; Rasouli, E

    2015-07-01

    circulation. Supplementation of CrMet to heat-stressed chicks modulated (P < 0.01) plasma corticosterone level. The present findings indicate that dietary CrMet supplementation could alleviate heat-stress-induced growth retardation in broiler chicks. Moreover, supplemental CrMet modulated suppressive effects of heat stress on cellular and humoral immune responses.

  12. Verminoside mediates life span extension and alleviates stress in Caenorhabditis elegans.

    PubMed

    Pant, A; Asthana, J; Yadav, A K; Rathor, L; Srivastava, S; Gupta, M M; Pandey, R

    2015-01-01

    The discovery of bioactive molecules modulating aging in living organism promotes development of natural therapeutics for curing age-related afflictions. The progression in age-related disorders can be attributed to increment in intracellular reactive oxygen species (ROS) and oxidative stress level. To this end, we isolated an iridoid verminoside (VMS) from Stereospermum suaveolens (Roxb.) DC. and evaluated its effect on Caenorhabditis elegans. The present study delineates VMS-mediated alteration of intracellular ROS, oxidative stress, and life span in C. elegans. The different tested doses of VMS (5 μM, 25 μM, and 50 μM) were able to enhance ROS scavenging and extend mean life span in C. elegans. The maximal life span extension was observed in 25 μM VMS, that is, 20.79% (P < 0.0001) followed by 9.84% (P < 0.0001) in 5 μM VMS and 8.54% (P < 0.0001) in 50 μM VMS. VMS was able to alleviate juglone-induced oxidative stress and enhanced thermotolerance in worms. The stress-modulating and ROS-scavenging potential of VMS was validated by increment in mean survival by 29.54% (P < 0.0001) in VMS-treated oxidative stress hypersensitive mev-1 mutant strain. Furthermore, VMS modulates expression of DAF-16 (a FoxO transcription factor) promoting stress resistance and longevity. Altogether, our results suggest that VMS attenuates intracellular ROS and stress (oxidative and thermal) level promoting longevity. The longevity and stress modulation can be attributed to VMS-mediated alterations in daf-16 expression which regulates insulin signaling pathway. This study opens doors for development of phytomolecule-based therapeutics for prolonging life span and managing age-related severe disorders.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. β-aminobutyric acid mediated drought stress alleviation in maize (Zea mays L.).

    PubMed

    Shaw, Arun K; Bhardwaj, Pardeep K; Ghosh, Supriya; Roy, Sankhajit; Saha, Suman; Sherpa, Ang R; Saha, Samir K; Hossain, Zahed

    2016-02-01

    The present study highlights the role of β-aminobutyric acid (BABA) in alleviating drought stress effects in maize (Zea mays L.). Chemical priming was imposed by pretreating 1-week-old plants with 600 μM BABA prior to applying drought stress. Specific activities of key antioxidant enzymes and metabolites (ascorbate and glutathione) levels of ascorbate-glutathione cycle were studied to unravel the priming-induced modulation of plant defense system. Furthermore, changes in endogenous ABA and JA concentrations as well as mRNA expressions of key genes involved in their respective biosynthesis pathways were monitored in BABA-primed (BABA+) and non-primed (BABA-) leaves of drought-challenged plants to better understand the mechanistic insights into the BABA-induced hormonal regulation of plant response to water-deficit stress. Accelerated stomatal closure, high relative water content, and less membrane damage were observed in BABA-primed leaves under water-deficit condition. Elevated APX and SOD activity in non-primed leaves found to be insufficient to scavenge all H2O2 and O2 (·-) resulting in oxidative burst as evident after histochemical staining with NBT and DAB. A higher proline accumulation in non-primed leaves also does not give much protection against drought stress. Increased GR activity supported with the enhanced mRNA and protein expressions might help the BABA-primed plants to maintain a high GSH pool essential for sustaining balanced redox status to counter drought-induced oxidative stress damages. Hormonal analysis suggests that in maize, BABA-potentiated drought tolerance is primarily mediated through JA-dependent pathway by the activation of antioxidant defense systems while ABA biosynthesis pathway also plays an important role in fine-tuning of drought stress response.

  20. Sulfur Dioxide Enhances Endogenous Hydrogen Sulfide Accumulation and Alleviates Oxidative Stress Induced by Aluminum Stress in Germinating Wheat Seeds

    PubMed Central

    Zhu, Dong-Bo; Hu, Kang-Di; Guo, Xi-Kai; Liu, Yong; Hu, Lan-Ying; Li, Yan-Hong; Wang, Song-Hua; Zhang, Hua

    2015-01-01

    Aluminum ions are especially toxic to plants in acidic soils. Here we present evidences that SO2 protects germinating wheat grains against aluminum stress. SO2 donor (NaHSO3/Na2SO3) pretreatment at 1.2 mM reduced the accumulation of superoxide anion, hydrogen peroxide, and malondialdehyde, enhanced the activities of guaiacol peroxidase, catalase, and ascorbate peroxidase, and decreased the activity of lipoxygenase in germinating wheat grains exposed to Al stress. We also observed higher accumulation of hydrogen sulfide (H2S) in SO2-pretreated grain, suggesting the tight relation between sulfite and sulfide. Wheat grains geminated in water for 36 h were pretreated with or without 1 mM SO2 donor for 12 h prior to exposure to Al stress for 48 h and the ameliorating effects of SO2 on wheat radicles were studied. SO2 donor pretreatment reduced the content of reactive oxygen species, protected membrane integrity, and reduced Al accumulation in wheat radicles. Gene expression analysis showed that SO2 donor pretreatment decreased the expression of Al-responsive genes TaWali1, TaWali2, TaWali3, TaWali5, TaWali6, and TaALMT1 in radicles exposed to Al stress. These results suggested that SO2 could increase endogenous H2S accumulation and the antioxidant capability and decrease endogenous Al content in wheat grains to alleviate Al stress. PMID:26078810

  1. 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.

  2. Hesperidin alleviates acetaminophen induced toxicity in Wistar rats by abrogation of oxidative stress, apoptosis and inflammation.

    PubMed

    Ahmad, Shiekh Tanveer; Arjumand, Wani; Nafees, Sana; Seth, Amlesh; Ali, Nemat; Rashid, Summya; Sultana, Sarwat

    2012-01-25

    Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but at high dose it leads to undesirable side effects, such as hepatotoxicity and nephrotoxicity. The present study demonstrates the comparative hepatoprotective and nephroprotective activity of hesperidin (HD), a naturally occurring bioflavonoid against APAP induced toxicity. APAP induces hepatotoxicity and nephrotoxicity as was evident by abnormal deviation in the levels of antioxidant enzymes. Moreover, APAP induced renal damage by inducing apoptotic death and inflammation in renal tubular cells, manifested by an increase in the expression of caspase-3, caspase-9, NFkB, iNOS, Kim-1 and decrease in Bcl-2 expression. These results were further supported by the histopathological examination of kidney. All these features of APAP toxicity were reversed by the co-administration of HD. Therefore, our study favors the view that HD may be a useful modulator in alleviating APAP induced oxidative stress and toxicity.

  3. Geraniol alleviates diabetic cardiac complications: Effect on cardiac ischemia and oxidative stress.

    PubMed

    El-Bassossy, Hany M; Ghaleb, Hanna; Elberry, Ahmed A; Balamash, Khadijah S; Ghareib, Salah A; Azhar, Ahmad; Banjar, Zainy

    2017-04-01

    The present study was planned to assess the possible protective effect of geraniol on cardiovascular complications in an animal model with diabetes. Diabetes was induced in rats by a single streptozotocin injection. In the treated group, geraniol (150mgkg(-1)day(-1)) was administered orally starting from the 15th day after induction of diabetes, and ending after 7 weeks; diabetic control rats were given vehicle for the same period. At the end of the study, cardiac contractility was assessed by using a Millar microtip catheter in anesthetised rats, and cardiac conductivity determined by a surface ECG. Serum levels of glucose, cholesterol, triglyceride and adiponectin as well as urine 8-isoprostane were determined. In addition, cardiac superoxide dismutase (SOD) and catalase activity were measured. Geraniol administration significantly alleviated the attenuated cardiac systolic function associated with diabetes as indicated by inhibiting the decrease in the rate of rise (dP/dtmax) in ventricular pressure and the increase in systolic duration observed in diabetic rats. In addition, geraniol alleviated impaired diastolic function as shown by inhibiting the decrease in the rate of fall (dP/dtmin) in ventricular pressure and increased isovolumic relaxation constant (Tau) observed in diabetic rats. ECG recordings showed that geraniol prevented any increase in QTc and T-peak-T-end intervals, and markers of LV ischemia and arrhythmogenesis, seen in diabetic animals. Geraniol suppressed the exaggerated oxidative stress as evidenced by preventing the increase in 8-isoprotane. In diabetic heart tissue, geraniol prevented the inhibition in catalase activity but did not affect the heart SOD. Geraniol partially reduced hyperglycemia, prevented the hypercholesterolemia, but did not affect the serum level of adiponectin in diabetic animals. Results obtained in this study suggest that geraniol provides a potent protective effect against cardiac dysfunction induced by diabetes. This

  4. Nitrogen fertilizer improves boron phytoextraction by Brassica juncea grown in contaminated sediments and alleviates plant stress.

    PubMed

    Giansoldati, Virginia; Tassi, Eliana; Morelli, Elisabetta; Gabellieri, Edi; Pedron, Francesca; Barbafieri, Meri

    2012-06-01

    In this study we evaluated the effect of different fertilizer treatments on Brassica plants grown on boron-contaminated sediments. Experiments were conducted in the laboratory and on the lysimeter scale. At laboratory scale (microcosm), five different fertilizers were tested for a 35-d period. On the lysimeter scale, nitrogen fertilization was tested at three different doses and plants were allowed to grow until the end of the vegetative phase (70 d). Results showed that nitrogen application had effectively increased plant biomass production, while B uptake was not affected. Total B phytoextracted increased three-fold when the highest nitrogen dose was applied. Phytotoxicity on Brassica was evaluated by biochemical parameters. In plants grown in unfertilized B-contaminated sediments, the activity of antioxidant enzymes superoxide dismutase (SOD), ascorbate peroxidase (APX) and pyrogallol peroxidase (PPX) increased, whereas catalase (CAT) decreased with respect to control plants. Addition of N progressively mitigated the alteration of enzymatic activity, thus suggesting that N can aid in alleviating B-induced oxidative stress. SOD activity was restored to control levels just at the lowest N treatment, whereas the CAT inhibition was partially restored only at the highest one. N application also lowered the B-induced increase in APX and PPX activities. Increased glutathione reductase activity indicated the need to restore the oxidative balance of glutathione. Data also suggest a role of glutathione and phytochelatins in B defense mechanisms. Results suggest that the nitrogen fertilizer was effective in improving B phytoextraction by increasing Brassica biomass and by alleviating B-induced oxidative stress.

  5. 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.

  6. 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.

  7. Proteus mirabilis alleviates zinc toxicity by preventing oxidative stress in maize (Zea mays) plants.

    PubMed

    Islam, Faisal; Yasmeen, Tahira; Riaz, Muhammad; Arif, Muhammad Saleem; Ali, Shafaqat; Raza, Syed Hammad

    2014-12-01

    Plant-associated bacteria can have beneficial effects on the growth and health of their host. However, the role of plant growth promoting bacteria (PGPR), under metal stress, has not been widely investigated. The present study investigated the possible mandatory role of plant growth promoting rhizobacteria in protecting plants from zinc (Zn) toxicity. The exposure of maize plants to 50µM zinc inhibited biomass production, decreased chlorophyll, total soluble protein and strongly increased accumulation of Zn in both root and shoot. Similarly, Zn enhanced hydrogen peroxide, electrolyte leakage and lipid peroxidation as indicated by malondaldehyde accumulation. Pre-soaking with novel Zn tolerant bacterial strain Proteus mirabilis (ZK1) isolated zinc (Zn) contaminated soil, alleviated the negative effect of Zn on growth and led to a decrease in oxidative injuries caused by Zn. Furthermore, strain ZK1 significantly enhanced the activities of catalase, guaiacol peroxidase, superoxide dismutase and ascorbic acid but lowered the Proline accumulation in Zn stressed plants. The results suggested that the inoculation of Zea mays plants with P. mirabilis during an earlier growth period could be related to its plant growth promoting activities and avoidance of cumulative damage upon exposure to Zn, thus reducing the negative consequences of oxidative stress caused by heavy metal toxicity.

  8. 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

  9. Priming of seeds with nitric oxide donor sodium nitroprusside (SNP) alleviates the inhibition on wheat seed germination by salt stress.

    PubMed

    Duan, Pei; Ding, Feng; Wang, Fang; Wang, Bao-Shan

    2007-06-01

    The effect of SNP, an NO donor, on seed germination of wheat (Triticum aestivum L. cv. 'DK961') under salt stress was studied. The results showed that priming of seeds with 0.06 mmol/L SNP for 24 h markedly alleviated the decrease of the germination percentage, germination index, vigor index and imbibition rate of wheat seeds under salt stress. SNP significantly alleviated the decrease of the beta-amylase activity but almost did not affect the alpha-amylase activity of wheat seeds under salt stress. SNP slightly increased the alpha-amylase isoenzymes (especially isoenzyme 3) and significantly increased the beta-amylase isoenzymes (especially isoenzyme d, e, f and g). SNP pretreatment decreased Na(+) content, but increased the K(+) content, resulting in a mark increase of K(+)/Na(+) ratio of wheat seedlings under salt stress. These results suggested that NO is involved in promoting wheat seed germination under salt stress by increasing the beta-amylase activity.

  10. Rootstock alleviates PEG-induced water stress in grafted pepper seedlings: physiological responses.

    PubMed

    Penella, Consuelo; Nebauer, Sergio G; Bautista, Alberto San; López-Galarza, Salvador; Calatayud, Ángeles

    2014-06-15

    nitrate reductase activity in the roots was observed, mainly in plants grafted onto the sensitive rootstocks, as well as the ungrafted plants, and this was associated with the lessened flux to the leaves. This study suggests that PEG-induced water stress can be partially alleviated by using tolerant accessions as rootstocks.

  11. Silicon nanoparticles more effectively alleviated UV-B stress than silicon in wheat (Triticum aestivum) seedlings.

    PubMed

    Tripathi, Durgesh Kumar; Singh, Swati; Singh, Vijay Pratap; Prasad, Sheo Mohan; Dubey, Nawal Kishore; Chauhan, Devendra Kumar

    2017-01-01

    The role of silicon (Si) in alleviating biotic as well as abiotic stresses is well known. However, the potential of silicon nanoparticle (SiNP) in regulating abiotic stress and associated mechanisms have not yet been explored. Therefore, in the present study hydroponic experiments were conducted to investigate whether Si or SiNp are more effective in the regulation of UV-B stress. UV-B (ambient and enhanced) radiation caused adverse effect on growth of wheat (Triticum aestivum) seedlings, which was accompanied by declined photosynthetic performance and altered vital leaf structures. Levels of superoxide radical and H2O2 were enhanced by UV-B as also evident from their histochemical stainings, which was accompanied by increased lipid peroxidation (LPO) and electrolyte leakage. Activities of superoxide dismutase and ascorbate peroxidase were inhibited by UV-B while catalase and guaiacol peroxidase, and all non-enzymatic antioxidants were stimulated by UV-B. Although, nitric oxide (NO) content was increased at all tested combinations, but its maximum content was observed under SiNps together with UV-B enhanced treatment. Pre-additions of SiNp as well as Si protected wheat seedlings against UV-B by regulating oxidative stress through enhanced antioxidants. Data indicate that SiNp might have protected wheat seedlings through NO-mediated triggering of antioxidant defense system, which subsequently counterbalance reactive oxygen species-induced damage to photosynthesis. Further, SiNp appear to be more effective in reducing UV-B stress than Si, which is related to its greater availability to wheat seedlings.

  12. Silicon improves seed germination and alleviates oxidative stress of bud seedlings in tomato under water deficit stress.

    PubMed

    Shi, Yu; Zhang, Yi; Yao, Hejin; Wu, Jiawen; Sun, Hao; Gong, Haijun

    2014-05-01

    The beneficial effects of silicon on plant growth and development under drought have been widely reported. However, little information is available on the effects of silicon on seed germination under drought. In this work, the effects of exogenous silicon (0.5 mM) on the seed germination and tolerance performance of tomato (Solanum lycopersicum L.) bud seedlings under water deficit stress simulated by 10% (w/v) polyethylene glycol (PEG-6000) were investigated in four cultivars ('Jinpengchaoguan', 'Zhongza No.9', 'Houpi L402' and 'Oubao318'). The results showed that the seed germination percentage was notably decreased in the four cultivars under water stress, and it was significantly improved by added silicon. Compared with the non-silicon treatment, silicon addition increased the activities of superoxide dismutase (SOD) and catalase (CAT), and decreased the production of superoxide anion (O2·) and hydrogen peroxide (H2O2) in the radicles of bud seedlings under water stress. Addition of silicon decreased the total phenol concentrations in radicles under water stress, which might contribute to the decrease of peroxidase (POD) activity, as observed in the in vivo and in vitro experiments. The decrease of POD activity might contribute to a less accumulation of hydroxyl radical (·OH) under water stress. Silicon addition also decreased the concentrations of malondialdehyde (MDA) in the radicles under stress, indicating decreased lipid peroxidation. These results suggest that exogenous silicon could improve seed germination and alleviate oxidative stress to bud seedling of tomato by enhancing antioxidant defense. The positive effects of silicon observed in a silicon-excluder also suggest the active involvement of silicon in biochemical processes in plants.

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. Turning Anxiety into Creativity: Using Postmodern Principles to Alleviate Anxiety and Stress through the Art Curriculum and Beyond

    ERIC Educational Resources Information Center

    Ferry, Lisa Marie

    2016-01-01

    The purpose of this action research study is to help students alleviate their anxiety and stress symptoms using activities based on Olivia Gude's postmodern principles. The activities included are the participants own take-along visual art journal kit and classroom projects. Professional learning outcomes include the knowledge to equip teachers…

  4. Strawberry consumption alleviates doxorubicin-induced toxicity by suppressing oxidative stress.

    PubMed

    Giampieri, Francesca; Alvarez-Suarez, Jose M; Gasparrini, Massimiliano; Forbes-Hernandez, Tamara Y; Afrin, Sadia; Bompadre, Stefano; Rubini, Corrado; Zizzi, Antonio; Astolfi, Paola; Santos-Buelga, Celestino; González-Paramás, Ana M; Quiles, Josè L; Mezzetti, Bruno; Battino, Maurizio

    2016-08-01

    Doxorubicin (Dox), one of the most used chemotherapeutic agents, is known to generate oxidative stress and block DNA synthesis, which result in severe dose-limiting toxicity. A strategy to protect against Dox toxic effects could be to use dietary antioxidants of which fruits and vegetable are a rich source. In this context, strawberry consumption is associated with the maintenance of good health and the prevention of several diseases, thanks to the antioxidant capacities of its bioactive compounds. The aim of the present study was to evaluate the protective effects of strawberry consumption against oxidative stress induced by Dox in rats. Animals were fed with strawberry enriched diet (15% of the total calories) for two months and Dox (10 mg/kg; i.p.) was injected at the end of the experimental period. Strawberry consumption significantly inhibited ROS production and oxidative damage biomarkers accumulation in plasma and liver tissue and alleviated histopathological changes in rat livers treated with Dox. The reduction of antioxidant enzyme activities was significantly mitigated after strawberry consumption. In addition, strawberry enriched diet ameliorated liver mitochondrial antioxidant levels and functionality. In conclusion, strawberry intake protects against Dox-induced toxicity, at plasma, liver and mitochondrial levels thanks to its high contents of bioactive compounds.

  5. Polyhydroxyfullerene Binds Cadmium Ions and Alleviates Metal-Induced Oxidative Stress in Saccharomyces cerevisiae

    PubMed Central

    Pradhan, Arunava; Pinheiro, José Paulo; Seena, Sahadevan; Pascoal, Cláudia

    2014-01-01

    The water-soluble polyhydroxyfullerene (PHF) is a functionalized carbon nanomaterial with several industrial and commercial applications. There have been controversial reports on the toxicity and/or antioxidant properties of fullerenes and their derivatives. Conversely, metals have been recognized as toxic mainly due to their ability to induce oxidative stress in living organisms. We investigated the interactive effects of PHF and cadmium ions (Cd) on the model yeast Saccharomyces cerevisiae by exposing cells to Cd (≤5 mg liter−1) in the absence or presence of PHF (≤500 mg liter−1) at different pHs (5.8 to 6.8). In the absence of Cd, PHF stimulated yeast growth up to 10.4%. Cd inhibited growth up to 79.7%, induced intracellular accumulation of reactive oxygen species (ROS), and promoted plasma membrane disruption in a dose- and pH-dependent manner. The negative effects of Cd on growth were attenuated by the presence of PHF, and maximum growth recovery (53.8%) was obtained at the highest PHF concentration and pH. The coexposure to Cd and PHF decreased ROS accumulation up to 36.7% and membrane disruption up to 30.7% in a dose- and pH-dependent manner. Two mechanisms helped to explain the role of PHF in alleviating Cd toxicity to yeasts: PHF decreased Cd-induced oxidative stress and bound significant amounts of Cd in the extracellular medium, reducing its bioavailability to the cells. PMID:25038095

  6. Hydrogen sulfide and proline cooperate to alleviate cadmium stress in foxtail millet seedlings.

    PubMed

    Tian, Baohua; Qiao, Zengjie; Zhang, Liping; Li, Hua; Pei, Yanxi

    2016-12-01

    Hydrogen sulfide (H2S) and some functional amino acids in crops have been involved in the defense system against heavy-metal pollution. Here we report the relationships and functions of H2S and proline to cadmium (Cd) stress. Sodium hydrosulfide (NaHS) pretreatment decreased the electrolytic leakage and the malondialdehyde and hydrogen peroxide contents while enhancing photosynthesis in Cd-treated seedlings. Furthermore, pretreatment with NaHS markedly exacerbated Cd-induced alterations in proline content, the activities of proline-5-carboxylate reductase (P5CR) and proline dehydrogenase (PDH), and the transcript levels of P5CR and PDH. When endogenous H2S was scavenged or inhibited by various H2S modulators, the Cd-induced increase in endogenous proline was weakened. Combined pretreatment with H2S and proline was moderately higher in the Cd-stressed growth status, stomata movements and oxidative damage of seedlings compared to a single treatment with H2S or proline. These results suggest that H2S and proline cooperate to alleviate Cd-damage in foxtail millet.

  7. PFKFB3 modulates glycolytic metabolism and alleviates endoplasmic reticulum stress in human osteoarthritis cartilage.

    PubMed

    Qu, Jining; Lu, Daigang; Guo, Hua; Miao, Wusheng; Wu, Ge; Zhou, Meifen

    2016-03-01

    Glycolytic disorder has been demonstrated to be a major cause of osteoarthritis (OA) and chondrocyte dysfunction. The present work aimed to investigate the expression and role of the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in OA cartilage. It was found that PFKFB3 expression was down-regulated in human OA cartilage tissues and in tumour necrosis factor (TNF)-α- or interleukin (IL)-1β-stimulated human chondrocytes. The glycolytic metabolism appeared as glucose utilization and adenosine triphosphate (ATP) generation, and lactate production was stunted in OA cartilage. However, the impaired glycolytic process in OA cartilage was improved by PFKFB3 overexpression, which was confirmed in TNF-α- or IL-1β-treated chondrocytes. Furthermore, the expressions of endoplasmic reticulum (ER) stress-associated genes including PERK, ATF3, IRE1, phosphorylated eIF2α (p-eIF2α) and MMP13 were enhanced in OA cartilage explants, while they were decreased by AdPFKFB3 transfection. PFKFB3 also modulated the expressions of PERK, ATF3, IRE1, p-eIF2α and MMP13 in tunicamycin-exposed chondrocytes. Additionally, PFKFB3 improved the cell viability of OA cartilage explants and chondrocytes through the PI3K/Akt/C/EBP homologous protein (CHOP) signalling pathway. The transfection of AdPFKFB3 also significantly reduced caspase 3 activation and promoted aggrecan and type II collagen expressions in OA cartilage explants and chondrocytes. In all, this study characterizes a novel role of PFKFB3 in glycolytic metabolism and ER stress of OA cartilage explants and chondrocytes. The study might provide a potential target for OA prevention or therapy.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. Rhizobial symbiosis alleviates polychlorinated biphenyls-induced systematic oxidative stress via brassinosteroids signaling in alfalfa.

    PubMed

    Wang, Xiaomi; Teng, Ying; Zhang, Ning; Christie, Peter; Li, Zhengao; Luo, Yongming; Wang, Jun

    2017-03-14

    The role of symbiotic rhizobia in the alleviation of polychlorinated biphenyl (PCB)-induced phytotoxicity in alfalfa and the brassinosteroid (BR) hormone signaling involved were investigated during phytoremediation. The association between alfalfa and Sinorhizobium meliloti was adopted as a remediation model. Phytotoxicity due to PCB 77 (3,3',4,4'-tetrachlorobiphenyl) exerted adverse impacts on plant performance (biomass accumulation and photosynthesis) and elicited cellular oxidative stress (overproduction of reactive oxygen species, lipid peroxidation, and cell necrosis) which was largely attenuated by pre-inoculation with S. meliloti strain NM. The protective role may have been achieved as a result of strengthening of basic antioxidant defense before stress as evidenced by the augmented activity and gene expression of antioxidative enzymes (peroxidase, glutathione reductase, superoxide dismutase, catalase, and ascorbate peroxidase) of both leaves and roots. In nodulated seedlings peroxidase showed additive increased activity following PCB exposure but the activities of the other four enzymes tended to remain stable after stress. Furthermore, application of strain NM and brassinolide both triggered the accumulation of endogenous BRs and the antioxidant network, while pre-treatment of seedlings with a biosynthetic inhibitor of BRs, brassinazole, abolished the rhizobia-induced activation of detoxification responses towards PCB. These observations indicate that association with S. meliloti NM enhanced the systemic antioxidant defenses of alfalfa to detoxify PCB, at least in part, via BR-dependent signaling pathways. These results contribute to our knowledge of the 'logistic role' played by rhizobia in assisting the phytoremediation of PCB-contaminated soils and suggest an optimum manipulation strategy for bioremediation.

  14. Adaptation to hot climate and strategies to alleviate heat stress in livestock production.

    PubMed

    Renaudeau, D; Collin, A; Yahav, S; de Basilio, V; Gourdine, J L; Collier, R J

    2012-05-01

    Despite many challenges faced by animal producers, including environmental problems, diseases, economic pressure, and feed availability, it is still predicted that animal production in developing countries will continue to sustain the future growth of the world's meat production. In these areas, livestock performance is generally lower than those obtained in Western Europe and North America. Although many factors can be involved, climatic factors are among the first and crucial limiting factors of the development of animal production in warm regions. In addition, global warming will further accentuate heat stress-related problems. The objective of this paper was to review the effective strategies to alleviate heat stress in the context of tropical livestock production systems. These strategies can be classified into three groups: those increasing feed intake or decreasing metabolic heat production, those enhancing heat-loss capacities, and those involving genetic selection for heat tolerance. Under heat stress, improved production should be possible through modifications of diet composition that either promotes a higher intake or compensates the low feed consumption. In addition, altering feeding management such as a change in feeding time and/or frequency, are efficient tools to avoid excessive heat load and improve survival rate, especially in poultry. Methods to enhance heat exchange between the environment and the animal and those changing the environment to prevent or limit heat stress can be used to improve performance under hot climatic conditions. Although differences in thermal tolerance exist between livestock species (ruminants > monogastrics), there are also large differences between breeds of a species and within each breed. Consequently, the opportunity may exist to improve thermal tolerance of the animals using genetic tools. However, further research is required to quantify the genetic antagonism between adaptation and production traits to evaluate

  15. Salicylic acid alleviates adverse effects of heat stress on photosynthesis through changes in proline production and ethylene formation.

    PubMed

    Khan, M Iqbal R; Iqbal, Noushina; Masood, Asim; Per, Tasir S; Khan, Nafees A

    2013-11-01

    We investigated the potential of salicylic acid (SA) in alleviating the adverse effects of heat stress on photosynthesis in wheat (Triticum aestivum L.) cv WH 711. Activity of ribulose 1,5-bisphosphate carboxylase (Rubisco), photosynthetic-nitrogen use efficiency (NUE), and net photosynthesis decreased in plants subjected to heat stress (40 °C for 6 h), but proline metabolism increased. SA treatment (0.5 mM) alleviated heat stress by increasing proline production through the increase in γ-glutamyl kinase (GK) and decrease in proline oxidase (PROX) activity, resulting in promotion of osmotic potential and water potential necessary for maintaining photosynthetic activity. Together with this, SA treatment restricted the ethylene formation in heat-stressed plants to optimal range by inhibiting activity of 1-aminocyclopropane carboxylic acid (ACC) synthase (ACS). This resulted in improved proline metabolism, N assimilation and photosynthesis. The results suggest that SA interacts with proline metabolism and ethylene formation to alleviate the adverse effects of heat stress on photosynthesis in wheat.

  16. 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.

  17. Selenium alleviates cadmium toxicity by preventing oxidative stress in sunflower (Helianthus annuus) seedlings.

    PubMed

    Saidi, Issam; Chtourou, Yacine; Djebali, Wahbi

    2014-03-01

    The present study investigated the possible mediatory role of selenium (Se) in protecting plants from cadmium (Cd) toxicity. The exposure of sunflower seedlings to 20μM Cd inhibited biomass production, decreased chlorophyll and carotenoid concentrations and strongly increased accumulation of Cd in both roots and shoots. Similarly, Cd enhanced hydrogen peroxides content and lipid peroxidation as indicated by malondialdehyde accumulation. Pre-soaking seeds with Se (5, 10 and 20μM) alleviated the negative effect of Cd on growth and led to a decrease in oxidative injuries caused by Cd. Furthermore, Se enhanced the activities of catalase, ascorbate peroxidase and glutathione reductase, but lowered that of superoxide dismutase and guaiacol peroxidase. As important antioxidants, ascorbate and glutathione contents in sunflower leaves exposed to Cd were significantly decreased by Se treatment. The data suggest that the beneficial effect of Se during an earlier growth period could be related to avoidance of cumulative damage upon exposure to Cd, thus reducing the negative consequences of oxidative stress caused by heavy metal toxicity.

  18. Effect of cyanobacterial exopolysaccharides on salt stress alleviation and seed germination.

    PubMed

    Arora, Monu; Kaushik, A; Rani, Nisha; Kaushik, C P

    2010-09-01

    Effectof exopolysaccharides (EPS) produced by a consortium of cyanobacteria on germination of three crops wheat, maize and rice was studied at different salt concentrations. Production of EPS was found to be stimulated by salts, which in turn had a significant Na+ removal capability from aqueous solution. Seed germination, vigor index and mobilization efficiency in all the three crops remarkably improved when cyanobacterial EPS was applied. While germination improved significantly by 13 to 30%, mobilization efficiency increased marginally by 1.03 to 1.1 times and vigor index increased by 1.15 to 2.4 times in these crops in response to EPS under non-saline conditions. Salinity had an inhibitory effect on seed germination of all the species showing 18 to 54% reduction. However, in the presence of EPS, the salt induced inhibition diminished to 13 to 18%. Inhibitory effect of salt on chlorophyll concentration, vigor index and mobilization efficiency of the seedlings was much less in these crops in the presence of EPS, indicating the latter's role in salt stress alleviation.

  19. Phosphorus improves arsenic phytoremediation by Anadenanthera peregrina by alleviating induced oxidative stress.

    PubMed

    Gomes, M P; Carvalho, M; Carvalho, G S; Marques, T C L L S M; Garcia, Q S; Guilherme, L R G; Soares, A M

    2013-01-01

    Due to similarities in their chemical behaviors, studies examining interactions between arsenic (As)--in special arsenate--and phosphorus (P) are important for better understanding arsenate uptake, toxicity, and accumulation in plants. We evaluated the effects of phosphate addition on plant biomass and on arsenate and phosphate uptake by Anadenanthera peregrina, an important Brazilian savanna legume. Plants were grown for 35 days in substrates that received combinations of 0, 10, 50, and 100 mg kg(-1) arsenate and 0, 200, and 400 mg kg(-1) phosphate. The addition of P increased the arsenic-phytoremediation capacity of A. peregrina by increasing As accumulation, while also alleviating As-induced oxidative stress. Arsenate phytotoxicity in A. peregrina is due to lipid peroxidation, but not hydrogen peroxide accumulation. Added P also increased the activity of important reactive oxygen species-scavenging enzymes (catalase and ascorbate peroxidase) that help prevent lipid peroxidation in leaves. Our findings suggest that applying P represents a feasible strategy for more efficient As phytoremediation using A. peregrina.

  20. Distinct physiological responses of tomato and cucumber plants in silicon-mediated alleviation of cadmium stress

    PubMed Central

    Wu, Jiawen; Guo, Jia; Hu, Yanhong; Gong, Haijun

    2015-01-01

    The alleviative effects of silicon (Si) on cadmium (Cd) toxicity were investigated in cucumber (Cucumis sativus L.) and tomato (Solanum lycopersicum L.) grown hydroponically. The growth of both plant species was inhibited by 100 μM Cd, but Si application counteracted the adverse effects on growth. Si application significantly decreased the Cd concentrations in shoots of both species and roots of cucumber. The root-to-shoot transport of Cd was depressed by added Si in tomato whereas it was increased by added Si in cucumber. The total content of organic acids was decreased in tomato leaves but increased in cucumber roots and leaves by Si application under Cd stress. Si application also increased the cell wall polysaccharide levels in the roots of both species under Cd toxicity. Si-mediated changes in levels of organic acids and cell wall polysaccharides might contribute to the differences in Cd transport in the two species. In addition, Si application also mitigated Cd-induced oxidative damage in both species. The results indicate that there were different mechanisms for Si-mediated decrease in shoot Cd accumulation: in tomato, Si supply decreased root-to-shoot Cd transport; whereas in cucumber, Si supply reduced the Cd uptake by roots. It is suggested that Si-mediated Cd tolerance is associated with different physiological responses in tomato and cucumber plants. PMID:26136764

  1. Isorhamnetin-3-glucoside alleviates oxidative stress and opacification in selenite cataract in vitro.

    PubMed

    Devi, V Gayathri; Rooban, B N; Sasikala, V; Sahasranamam, V; Abraham, Annie

    2010-09-01

    Oxidative stress has long been recognized as an important mediator in the pathogenesis of cataract and the goal of this study was to determine the efficacy of isorhamnetin-3-glucoside (IR3G) in alleviating the toxicity induced by sodium selenite in in vitro culture condition. IR3G is the bioactive flavonoid isolated and characterized from the leaves of Cochlospermum religiosum. Enucleated rat lenses were maintained in organ culture containing M-199 medium alone (G-I), supplemented with 0.1 mM selenite (G-II) and selenite + 25 microg/ml IR3G (G-III). Treatment to G-III was from the second to fifth day while selenite administration to G-II & III was done on the third day. The antioxidant potential of the compound was assessed by Cu(2+) induced lipoprotein diene formation and superoxide scavenging assays. Morphological examination of the lenses also gave a supporting data. Antioxidant enzymes-superoxide dismutase (SOD), catalase and concentration of reduced glutathione (GSH) were significantly lower, while TBARS showed an increase in G-II than that in G-III and G-I lenses. Activity of Ca(2+)-ATPase was decreased and level of calcium was increased in G-II than G-III and G-I lenses. These data suggest that IR3G is able to significantly retard selenite cataract in vitro by virtue of its antioxidant property.

  2. Arbuscular mycorrhizal fungi alleviate oxidative stress induced by ADOR and enhance antioxidant responses of tomato plants.

    PubMed

    García-Sánchez, Mercedes; Palma, José Manuel; Ocampo, Juan Antonio; García-Romera, Inmaculada; Aranda, Elisabet

    2014-03-15

    The behaviour of tomato plants inoculated with arbuscular mycorrhizal (AM) fungi grown in the presence of aqueous extracts from dry olive residue (ADOR) was studied in order to understand how this symbiotic relationship helps plants to cope with oxidative stress caused by ADOR. The influence of AM symbiosis on plant growth and other physiological parameters was also studied. Tomato plants were inoculated with the AM fungus Funneliformis mosseae and were grown in the presence of ADOR bioremediated and non-bioremediated by Coriolopsis floccosa and Penicillium chrysogenum-10. The antioxidant response as well as parameters of oxidative damage were examined in roots and leaves. The data showed a significant increase in the biomass of AM plant growth in the presence of ADOR, regardless of whether it was bioremediated. The establishment and development of the symbiosis were negatively affected after plants were exposed to ADOR. No differences were observed in the relative water content (RWC) or PS II efficiency between non-AM and AM plants. The increase in the enzymatic activities of superoxide dismutase (SOD; EC 1.15.1.1), catalase (CAT; EC 1.11.1.6) and glutathione-S-transferase (GST; EC 2.5.1.18) were simultaneous to the reduction of MDA levels and H2O2 content in AM root growth in the presence of ADOR. Similar H2O2 levels were observed among non-AM and AM plants, although only AM plants showed reduced lipid peroxidation content, probably due to the involvement of antioxidant enzymes. The results highlight how the application of both bioremediated ADOR and AM fungi can alleviate the oxidative stress conditions, improving the growth and development of tomato plants.

  3. [Alleviation of salt stress during maize seed germination by presoaking with exogenous sugar].

    PubMed

    Zhao, Ying; Yang, Ke-jun; Li, Zuo-tong; Zhao, Chang-jiang; Xu, Jing-yu; Hu, Xue- wei; Shi, Xin-xin; Ma, Li-feng

    2015-09-01

    The maize variety Kenyu 6 was used to study the effects of exogenous glucose (Glc) and sucrose (Suc) on salt tolerance of maize seeds at germination stage under 150 mmol · L(-1) NaCl treatment. Results showed that under salt stress condition, 0.5 mmol · L(-1) exogenous Glc and Suc presoaking could promote seed germination and early seedling growth. Compared with the salt treatment, Glc presoaking increased the shoot length, radicle length and corresponding dry mass up to 1.5, 1.3, 2.1 and 1.8 times, and those of the Suc presoaking treatment increased up to 1.7, 1.3. 2.7 and 1.9 times, respectively. Exogenous Glc and Suc presoaking resulted in decreased levels of thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (H2O2) content of maize shoot under salt stress, which were lowered by 24.9% and 20.6% respectively. Exogenous Glc and Suc presoaking could increase the activities of superoxide dismutase (SOD), ascorbate peroxidase (APX), glutathione peroxidase (GPX), glutathione reductase (GR) and induce glucose-6-phosphate dehydrogenase (G6PDH) activity of maize shoot under salt stress. Compared with the salt treatment. Glc presoaking increased the activity of SOD, APX, GPX, GR and G6PDH by 66.2%, 62.9%, 32.0%, 38.5% and 50.5%, and those of the Suc presoaking increased by 67.5%, 59.8%, 30.0%, 38.5% and 50.4%, respectively. Glc and Suc presoaking also significantly increased the contents of ascorbic acid (ASA) and glutathione (GSH), ASA/DHA and GSH/GSSG. The G6PDH activity was found closely related with the strong antioxidation capacity induced by exogenous sugars. In addition, Glc and Suc presoaking enhanced K+/Na+ in maize shoot by 1.3 and 1.4 times of water soaking salt treatment, respectively. These results indicated that exogenous Glc and Suc presoaking could improve antioxidation capacity of maize seeds and maintain the in vivo K+/Na+ ion balance to alleviate the inhibitory effect of salt stress on maize seed germination.

  4. Bacillus amyloliquefaciens supplementation alleviates immunological stress in lipopolysaccharide-challenged broilers at early age.

    PubMed

    Li, Y; Zhang, H; Chen, Y P; Yang, M X; Zhang, L L; Lu, Z X; Zhou, Y M; Wang, T

    2015-07-01

    This study was conducted to investigate the effect of Bacillus amyloliquefaciens ( BA: ) on the immune function of broilers challenged with lipopolysaccharide ( LPS: ). 192 one-day-old male Arbor Acre broiler chickens were randomly distributed into four treatments: 1) broilers fed a basal diet; 2) broilers fed a basal diet supplemented with BA; 3) LPS-challenged broilers fed a basal diet; and 4) LPS-challenged broilers fed a basal diet supplemented with BA. Each treatment consisted of six replicates with eight broilers per replicate. Broilers were intraperitoneally injected with either 500 μg LPS per kg body weight or sterile saline at 16, 18 and 20 d of age. LPS decreased the average daily gain ( ADG: , P = 0.001) and average daily feed intake (P = 0.001). The decreased ADG (P = 0.009) and increased feed conversion ratio (P = 0.047) in LPS-challenged broilers were alleviated by BA. LPS increased the relative spleen weight (P = 0.001). Relative spleen (P = 0.014) and bursa (P = 0.024) weights in the LPS-challenged broilers were reduced by BA. LPS increased white blood cell ( WBC: ) numbers (P = 0.001). However, the WBC numbers (P = 0.042) and the ratio of lymphocytes to WBC (P = 0.020) in LPS-challenged broilers were decreased with BA treatment. LPS decreased plasma lysozyme activity (P = 0.001), but increased concentrations of plasma corticosterone (P = 0.012) and IL-2 (P = 0.020). In contrast, BA increased lysozyme activity in plasma (P = 0.040). LPS increased mRNA abundances of splenic toll-like receptor 4 (P = 0.046), interferon γ (P = 0.008), IL-1β (P = 0.045) and IL-6, (P = 0.006). IL-2 (P = 0.014) and IL-6 (P = 0.074) mRNA abundances in LPS-challenged broilers were reduced by BA, although BA had an opposite effect for IL-10 mRNA expression in those broilers (P = 0.004). In conclusion, BA supplementation could partially alleviate the compromised growth performance and immune status of broilers under immune stress induced by LPS challenge at early age.

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. Activation of ATP-sensitive potassium channel by iptakalim normalizes stress-induced HPA axis disorder and depressive behaviour by alleviating inflammation and oxidative stress in mouse hypothalamus.

    PubMed

    Zhao, Xiao-Jie; Zhao, Zhan; Yang, Dan-Dan; Cao, Lu-Lu; Zhang, Ling; Ji, Juan; Gu, Jun; Huang, Ji-Ye; Sun, Xiu-Lan

    2017-02-01

    Stress-induced disturbance of the hypothalamic-pituitary-adrenal (HPA) axis is strongly implicated in incidence of mood disorders. A heightened neuroinflammatory response and oxidative stress play a fundamental role in the dysfunction of the HPA axis. We have previously demonstrated that iptakalim (Ipt), a new ATP-sensitive potassium (K-ATP) channel opener, could prevent oxidative injury and neuroinflammation against multiple stimuli-induced brain injury. The present study was to demonstrate the impacts of Ipt in stress-induced HPA axis disorder and depressive behavior. We employed 2 stress paradigms: 8 weeks of continuous restraint stress (chronic restraint stress, CRS) and 2h of restraint stress (acute restraint stress, ARS), to mimic both chronic stress and severe acute stress. Prolonged (4 weeks) and short-term (a single injection) Ipt treatment was administered 30min before each stress paradigm. We found that HPA axis was altered after stress, with different responses to CRS (lower ACTH and CORT, higher AVP, but normal CRH) and ARS (higher CRH, ACTH and CORT, but normal AVP). Both prolonged and short-term Ipt treatment normalized stress-induced HPA axis disorders and abnormal behaviors in mice. CRS and ARS up-regulated mRNA levels of inflammation-related molecules (TNFα, IL-1β, IL-6 and TLR4) and oxidative stress molecules (gp91phox, iNOS and Nrf2) in the mouse hypothalamus. Double immunofluorescence showed CRS and ARS increased microglia activation (CD11b and TNFα) and oxidative stress in neurons (NeuN and gp91phox), which were alleviated by Ipt. Therefore, the present study reveals that Ipt could prevent against stress-induced HPA axis disorders and depressive behavior by alleviating inflammation and oxidative stress in the hypothalamus.

  16. Isolation and characterization of ACC deaminase-producing fluorescent pseudomonads, to alleviate salinity stress on canola (Brassica napus L.) growth.

    PubMed

    Jalili, Farzad; Khavazi, Kazem; Pazira, Ebrahim; Nejati, Alireza; Rahmani, Hadi Asadi; Sadaghiani, Hasan Rasuli; Miransari, Mohammad

    2009-04-01

    Salinity stress is of great importance in arid and semi-arid areas of the world due to its impact in reducing crop yield. Under salinity stress, the amount of 1-aminocyclopropane-1-carboxylate (ACC), a precursor for ethylene production in plants, increases. Here, we conducted research under the hypothesis that isolated ACC deaminase-producing Pseudomonas fluorescens and Pseudomonas putida can alleviate the stressful effects of salinity on canola (Brassica napus L.) growth. The experiments were conducted in the Soil and Water Research Institute, Tehran, Iran. Seven experimental stages were conducted to isolate and characterize ACC deaminase-producing Pseudomonas fluorescens strains and to determine factors enhancing their growth and, consequently, their effects on the germination of canola seeds. Under salinity stress, in 14% of the isolates, ACC deaminase activity was observed, indicating that they were able to utilize ACC as the sole N-source. Bacterial strains differed in their ability to synthesize auxin and hydrogen cyanide compounds, as well as in their ACC deaminase activity. Under salinity stress, the rate of germinating seeds inoculated with the strains of ACC deaminase-producing Pseudomonas fluorescens and Pseudomonas putida, and seedling growth was significantly higher. These results indicate the significance of soil biological activities, including the activities of plant growth-promoting bacteria, in the alleviation of soil stresses such as salinity on plant growth.

  17. Involvement of ethylene in gibberellic acid-induced sulfur assimilation, photosynthetic responses, and alleviation of cadmium stress in mustard.

    PubMed

    Masood, Asim; Khan, M Iqbal R; Fatma, Mehar; Asgher, Mohd; Per, Tasir S; Khan, Nafees A

    2016-07-01

    The role of gibberellic acid (GA) or sulfur (S) in stimulation of photosynthesis is known. However, information on the involvement of ethylene in GA-induced photosynthetic responses and cadmium (Cd) tolerance is lacking. This work shows that ethylene is involved in S-assimilation, photosynthetic responses and alleviation of Cd stress by GA in mustard (Brassica juncea L.). Plants grown with 200 mg Cd kg(-1) soil were less responsive to ethylene despite high ethylene evolution and showed photosynthetic inhibition. Plants receiving 10 μM GA spraying plus 100 mg S kg(-1) soil supplementation exhibited increased S-assimilation and photosynthetic responses under Cd stress. Application of GA plus S decreased oxidative stress of plants grown with Cd and limited stress ethylene formation to the range suitable for promoting sulfur use efficiency (SUE), glutathione (GSH) production and photosynthesis. The role of ethylene in GA-induced S-assimilation and reversal of photosynthetic inhibition by Cd was substantiated by inhibiting ethylene biosynthesis with the use of aminoethoxyvinylglycine (AVG). The suppression of S-assimilation and photosynthetic responses by inhibiting ethylene in GA plus S treated plants under Cd stress indicated the involvement of ethylene in GA-induced S-assimilation and Cd stress alleviation. The outcome of the study is important to unravel the interaction between GA and ethylene and their role in Cd tolerance in plants.

  18. 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.

  19. 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

  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. Carbon dioxide enrichment alleviates heat stress by improving cellular redox homeostasis through an ABA-independent process in tomato plants.

    PubMed

    Li, X; Ahammed, G J; Zhang, Y Q; Zhang, G Q; Sun, Z H; Zhou, J; Zhou, Y H; Xia, X J; Yu, J Q; Shi, K

    2015-01-01

    Plant responses to elevated CO₂ and high temperature are critically regulated through a complex network of phytohormones and redox homeostasis. However, the involvement of abscisic acid (ABA) in plant adaptation to heat stress under elevated CO₂ conditions has not been thoroughly studied. This study investigated the interactive effects of elevated CO₂ (800 μmol·mol(-1) ) and heat stress (42 °C for 24 h) on the endogenous level of ABA and the cellular redox state of two genotypes of tomato with different ABA biosynthesis capacities. Heat stress significantly decreased maximum photochemical efficiency of PSII (Fv/Fm) and leaf water potential, but also increased levels of malondialdehyde (MDA) and electrolyte leakage (EL) in both genotypes. Heat-induced damage was more severe in the ABA-deficient mutant notabilis (not) than in its parental cultivar Ailsa Craig (Ailsa), suggesting that a certain level of endogenous ABA is required to minimise the heat-induced oxidative damage to the photosynthetic apparatus. Irrespective of genotype, the enrichment of CO₂ remarkably stimulated Fv/Fm, MDA and EL in heat-stressed plants towards enhanced tolerance. In addition, elevated CO₂ significantly strengthened the antioxidant capacity of heat-stressed tomato seedlings towards a reduced cellular redox state for a prolonged period, thereby mitigating oxidative stress. However, elevated CO₂ and heat stress did not alter the endogenous level of ABA or the expression of its biosynthetic gene NCED2 in either genotype, indicating that ABA is not involved in elevated CO₂ -induced heat stress alleviation. The results of this study suggest that elevated CO₂ alleviated heat stress through efficient regulation of the cellular redox poise in an ABA-independent manner in tomato plants.

  2. 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.

  3. Yeast Culture and Vitamin E Supplementation Alleviates Heat Stress in Dairy Goats.

    PubMed

    Wang, Lizhi; Wang, Zhisheng; Zou, Huawei; Peng, Quanhui

    2016-06-01

    This study was conducted to determine and compare the effects of yeast yeast culture (YC) and vitamin E (VE) supplementation on endotoxin absorption and antioxidant status in lactating dairy goats suffering from heat stress (HS). Three first lactation Saanen dairy goats (body weight 30±1.5 kg) were surgically fitted with indwelling catheters in the portal vein, mesenteric vein and carotid artery, and were randomly assigned to a 3×3 Latin square design. Dietary treatments were the basal diet, and the basal diet supplemented with either 100 IU VE or 30 g YC. Goats were kept in temperature and humidity-controlled room at 35°C from 8:00 to 20:00 and at 24°C from 20:00 till the next morning at 8:00. The relative humidity was kept at 55%. HS increased dairy goats' rectum temperature and respiration frequency (p<0.01). HS reduced plasma flux rate of milk goats (p<0.01), but the plasma flux rate increased when the animal was under the conditions of the thermo-neutral period (p<0.01). The VE supplementation lowered dairy goats' rectum temperature during thermo-neutral period (p<0.01). Meanwhile, no significant differences were observed between the control and YC treatment in rectum temperature and respiration frequency (p>0.05). Dietary supplementation of VE and YC reduced heat stressed dairy goats' endotoxin concentration of the carotid artery and portal vein (p<0.01). However, the endotoxin concentration of the YC treatment was higher than that of the VE treatment (p<0.01). Both VE and YC supplementation decreased heat stressed dairy goats' absorption of endotoxin in portal vein (p<0.01). The endotoxin absorption of YC treatment was higher than the VE treatment (p<0.01). The addition of VE and YC decreased dairy goats' superoxide dismutase (SOD) concentration during HS and the whole experiment period (p<0.01). The addition of VE lowered SOD concentration during thermo-neutral period (p<0.01). Likewise, the addition of VE and YC lowered dairy goats' malonaldehyde (MDA

  4. Pea lectin receptor-like kinase functions in salinity adaptation without yield penalty, by alleviating osmotic and ionic stresses and upregulating stress-responsive genes.

    PubMed

    Vaid, Neha; Pandey, Prashant; Srivastava, Vineet Kumar; Tuteja, Narendra

    2015-05-01

    Lectin receptor-like kinases (LecRLKs) are members of RLK family composed of lectin-like extracellular recognition domain, transmembrane domain and cytoplasmic kinase domain. LecRLKs are plasma membrane proteins believed to be involved in signal transduction. However, most of the members of the protein family even in plants have not been functionally well characterized. Herein, we show that Pisum sativum LecRLK (PsLecRLK) localized in plasma membrane systems and/or other regions of the cell and its transcript upregulated under salinity stress. Overexpression of PsLecRLK in transgenic tobacco plants confers salinity stress tolerance by alleviating both the ionic as well the osmotic component of salinity stress. The transgenic plants show better tissue compartmentalization of Na(+) and higher ROS scavenging activity which probably results in lower membrane damage, improved growth and yield maintenance even under salinity stress. Also, expression of several genes involved in cellular homeostasis is perturbed by PsLecRLK overexpression. Alleviation of osmotic and ionic components of salinity stress along with reduced oxidative damage and upregulation of stress-responsive genes in transgenic plants under salinity stress conditions could be possible mechanism facilitating enhanced stress tolerance. This study presents PsLecRLK as a promising candidate for crop improvement and also opens up new avenue to investigate its signalling pathway.

  5. Alleviation of Hyperglycemia Induced Vascular Endothelial Injury by Exenatide Might Be Related to the Reduction of Nitrooxidative Stress

    PubMed Central

    Zhao, Qian; Xu, Chun-ling; Xiong, Hai-yan; Huang, Wen; Zhang, Mei; Wang, Yun; Wang, Si-yu

    2013-01-01

    We will investigate the effects of exenatide on vascular endothelial injury and nitrooxidative stress in hyperglycemia both in vivo and in vitro and explore the role of nitrooxidative stress in endothelium-protective action of exenatide. Healthy male Wistar rats were randomly divided into 4 groups: control, diabetes mellitus (DM) model, low dose of exenatide treatment, and high dose of exenatide treatment. In vitro study showed that, compared with control group, the DM rats exhibited a lowered endothelium-dependent relaxation and damaged structural integrity of thoracic aortas, and there was a significant increase in plasma nitrotyrosine concentration. These parameters were improved after treatment with either low dose or high dose of exenatide for 45 days. In vitro study showed that exendin-4 (the active ingredient of exenatide) attenuated HUVECs injury induced by high glucose, with improving cell viability and attenuating cell apoptosis. Exendin-4 also significantly alleviated the increased malondialdehyde (MDA), nitrotyrosine content, and inducible nitric oxide synthase (iNOS) expression induced by high glucose in HUVECs. In conclusion, this study demonstrates that exenatide treatment can alleviate the vascular endothelial injury, as well as attenuating the nitrooxidative stress in hyperglycemia, implying that the endothelium-protective effect of exenatide might be related to the reduction of nitrooxidative stress. PMID:24371833

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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

  14. 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

  15. Insulin Protects Hepatic Lipotoxicity by Regulating ER Stress through the PI3K/Akt/p53 Involved Pathway Independently of Autophagy Inhibition

    PubMed Central

    Ning, Hua; Sun, Zongxiang; Liu, Yunyun; Liu, Lei; Hao, Liuyi; Ye, Yaxin; Feng, Rennan; Li, Jie; Li, Ying; Chu, Xia; Li, Songtao; Sun, Changhao

    2016-01-01

    The detrimental role of hepatic lipotoxicity has been well-implicated in the pathogenesis of NAFLD. Previously, we reported that inhibiting autophagy aggravated saturated fatty acid (SFA)-induced hepatotoxicity. Insulin, a physiological inhibitor of autophagy, is commonly increased within NAFLD mainly caused by insulin resistance. We therefore hypothesized that insulin augments the sensitivity of hepatocyte to SFA-induced lipotoxicity. The present study was conducted via employing human and mouse hepatocytes, which were exposed to SFAs, insulin, or their combination. Unexpectedly, our results indicated that insulin protected hepatocytes against SFA-induced lipotoxicity, based on the LDH, MTT, and nuclear morphological measurements, and the detection from cleaved-Parp-1 and -caspase-3 expressions. We subsequently clarified that insulin led to a rapid and short-period inhibition of autophagy, which was gradually recovered after 1 h incubation in hepatocytes, and such extent of inhibition was insufficient to aggravate SFA-induced lipotoxicity. The mechanistic study revealed that insulin-induced alleviation of ER stress contributed to its hepatoprotective role. Pre-treating hepatocytes with insulin significantly stimulated phosphorylated-Akt and reversed SFA-induced up-regulation of p53. Chemical inhibition of p53 by pifithrin-α robustly prevented palmitate-induced cell death. The PI3K/Akt pathway blockade by its special antagonist abolished the protective role of insulin against SFA-induced lipotoxicity and p53 up-regulation. Furthermore, we observed that insulin promoted intracellular TG deposits in hepatocytes in the present of palmitate. However, blocking TG accumulation via genetically silencing DGAT-2 did not prevent insulin-protected lipotoxicity. Our study demonstrated that insulin strongly protected against SFA-induced lipotoxicity in hepatocytes mechanistically through alleviating ER stress via a PI3K/Akt/p53 involved pathway but independently from autophagy

  16. Alleviation of exogenous 6-benzyladenine on two genotypes of eggplant (Solanum melongena Mill.) growth under salt stress.

    PubMed

    Wu, Xuexia; He, Jie; Chen, Jianlin; Yang, Shaojun; Zha, Dingshi

    2014-01-01

    Cytokinins were recently shown to control plant adaptation to environmental stresses. To characterize the roles of cytokinins in the tolerance of eggplant (Solanum melongena Mill.) to salt stress, the protective effects of 6-benzyladenine (6-BA) on the growth, photosynthesis, and antioxidant capacity in the leaves of two eggplant cultivars Huqie12 (salt-sensitive) and Huqie4 (salt-tolerant) were investigated. Under 90 mM NaCl stress, Huqie4 showed higher biomass accumulation and less oxidative damage compared to the Huqie12. Application of exogenous 10 μM 6-BA significantly alleviated the growth suppression caused by salt stress in two eggplant genotypes. In parallel with the growth, 6-BA application in salt-stressed plants resulted in enhanced chlorophyll contents, as well as photosynthetic parameters such as net CO2 assimilation rate (P n), stomatal conductance (g s), transpiration rate (E), and intercellular CO2 concentration (C i). Furthermore, exogenous 6-BA also significantly reduced the O2 (-) production rate and malondialdehyde content and markedly increased the antioxidant enzymes superoxide dismutase and peroxidase, the antioxidant metabolites ascorbate and reduced glutathione (GSH), and proline in both genotypes under salt stress. The results indicate that exogenous 6-BA is useful to improve the salt resistance of eggplant, which is most likely related to the increase in photosynthesis and antioxidant capacity.

  17. 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.

  18. Treadmill exercise alleviates stress-induced impairment of social interaction through 5-hydroxytryptamine 1A receptor activation in rats

    PubMed Central

    Kim, Tae-Woon; Lim, Baek-Vin; Kim, Kijeong; Seo, Jin-Hee; Kim, Chang-Ju

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) and its receptors tyrosine kinase B (trkB), and cyclic adenosine monophosphate response element binding protein (CREB) have been suggested as the neurobiological risk factors causing depressive disorder. Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in the pathogenesis of depression. We in-vestigated the effect of treadmill exercise on social interaction in relation with BDNF and 5-HT expressions following stress in rats. Stress was induced by applying inescapable 0.2 mA electric foot shock to the rats for 7 days. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks. Social interaction test and western blot for BDNF, TrkB, pCREB, and 5-HT1A in the hippocampus were performed. The results indicate that the spend time with unfamiliar partner was decreased by stress, in contrast, treadmill exercise increased the spending time in the stress-induced rats. Expressions of BDNF, TrkB, and pCREB were decreased by stress, in contrast, treadmill exercise enhanced expressions of BDNF, TrkB, and pCREB in the stress-induced rats. In addition, 5-HT1A receptor expression was de-creased by stress, in contrast, treadmill exercise enhanced 5-HT1A expression in the stress-induced rats. In the present study, treadmill exercise alleviated stress-induced social interaction impairment through enhancing hippocampal plasticity and serotonergic function in the hippocampus. These effects of treadmill exercise are achieved through 5-HT1A receptor activation. PMID:26331133

  19. Cysteamine alleviates early brain injury via reducing oxidative stress and apoptosis in a rat experimental subarachnoid hemorrhage model.

    PubMed

    Zhang, Zong-Yong; Yang, Ming-Feng; Wang, Tao; Li, Da-Wei; Liu, Yun-Lin; Zhang, Jin-Hui; Sun, Bao-Liang

    2015-05-01

    Oxidative stress plays an important role in the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH). The aim of this study was to assess whether cysteamine prevents post-SAH oxidative stress injury via its antioxidative and anti-apoptotic effects. It was observed that intraperitoneal administration of cysteamine (20 mg/kg/day) could significantly alleviate EBI (including neurobehavioral deficits, brain edema, blood-brain barrier permeability, and cortical neuron apoptosis) after SAH in rats. Meanwhile, cysteamine treatment reduced post-SAH elevated the reactive oxygen species level, the concentration of malondialdehyde, 3-nitrotyrosine, and 8-hydroxydeoxyguanosine and increased the glutathione peroxidase enzymatic activity, the concentration of glutathione and brain-derived neurotrophic factor in brain cortex at 48 h after SAH. These results indicated that administration of cysteamine may ameliorate EBI and provide neuroprotection after SAH in rat models.

  20. Teacher Stress: What It Is, Why It's Important, How It Can Be Alleviated

    ERIC Educational Resources Information Center

    Prilleltensky, Isaac; Neff, Marilyn; Bessell, Ann

    2016-01-01

    Teacher stress can be conceptualized as an imbalance between risk and protective factors. Stress emanates from risk factors at the personal, interpersonal, and organizational levels. When risk factors exceed protective factors, teacher ability to cope with adversity is inhibited, likely resulting in stress and pernicious consequences. In this…

  1. How Do You Spell Relief? Alleviating Job Stress Caused by Organizations and Executives.

    ERIC Educational Resources Information Center

    Ginsburg, Sigmund G.

    1991-01-01

    College business officers should examine whether they and their institutions are practicing stress-inducing activities, and modify current practice to reduce stress on employees. Stresses can originate in the organizational framework, managerial style, or manager personality. Review of individual and organizational actions possible causing stress…

  2. Carbon monoxide alleviates ethanol-induced oxidative damage and inflammatory stress through activating p38 MAPK pathway

    SciTech Connect

    Li, Yanyan; Gao, Chao; Shi, Yanru; Tang, Yuhan; Liu, Liang; Xiong, Ting; Du, Min; Xing, Mingyou; Liu, Liegang; Yao, Ping

    2013-11-15

    Stress-inducible protein heme oxygenase-1(HO-1) is well-appreciative to counteract oxidative damage and inflammatory stress involving the pathogenesis of alcoholic liver diseases (ALD). The potential role and signaling pathways of HO-1 metabolite carbon monoxide (CO), however, still remained unclear. To explore the precise mechanisms, ethanol-dosed adult male Balb/c mice (5.0 g/kg.bw.) or ethanol-incubated primary rat hepatocytes (100 mmol/L) were pretreated by tricarbonyldichlororuthenium (II) dimmer (CORM-2, 8 mg/kg for mice or 20 μmol/L for hepatocytes), as well as other pharmacological reagents. Our data showed that CO released from HO-1 induction by quercetin prevented ethanol-derived oxidative injury, which was abolished by CO scavenger hemoglobin. The protection was mimicked by CORM-2 with the attenuation of GSH depletion, SOD inactivation, MDA overproduction, and the leakage of AST, ALT or LDH in serum and culture medium induced by ethanol. Moreover, CORM-2 injection or incubation stimulated p38 phosphorylation and suppressed abnormal Tnfa and IL-6, accompanying the alleviation of redox imbalance induced by ethanol and aggravated by inflammatory factors. The protective role of CORM-2 was abolished by SB203580 (p38 inhibitor) but not by PD98059 (ERK inhibitor) or SP600125 (JNK inhibitor). Thus, HO-1 released CO prevented ethanol-elicited hepatic oxidative damage and inflammatory stress through activating p38 MAPK pathway, suggesting a potential therapeutic role of gaseous signal molecule on ALD induced by naturally occurring phytochemicals. - Highlights: • CO alleviated ethanol-derived liver oxidative and inflammatory stress in mice. • CO eased ethanol and inflammatory factor-induced oxidative damage in hepatocytes. • The p38 MAPK is a key signaling mechanism for the protective function of CO in ALD.

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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

  9. Silicon (Si) alleviates cotton (Gossypium hirsutum L.) from zinc (Zn) toxicity stress by limiting Zn uptake and oxidative damage.

    PubMed

    Anwaar, Shad Ali; Ali, Shafaqat; Ali, Skhawat; Ishaque, Wajid; Farid, Mujahid; Farooq, Muhammad Ahsan; Najeeb, Ullah; Abbas, Farhat; Sharif, Muhammad

    2015-03-01

    Silicon (Si) is as an important fertilizer element, which has been found effective in enhancing plant tolerance to variety of biotic and a-biotic stresses. This study investigates the Si potential to alleviate zinc (Zn) toxicity stress in cotton (Gossypium hirsutum L.). Cotton plants were grown in hydroponics and exposed to different Zn concentration, 0, 25, and 50 μM, alone and/or in combination with 1 mM Si. Incremental Zn concentration in growth media instigated the cellular oxidative damage that was evident from elevated levels of hydrogen peroxide (H2O2), electrolyte leakage, and malondialdehyde (MDA) and consequently inhibited cotton growth, biomass, chlorophyll pigments, and photosynthetic process. Application of Si significantly suppressed Zn accumulation in various plant parts, i.e., roots, stems, and leaves and thus promoted biomass, photosynthetic, growth parameters, and antioxidant enzymes activity of Zn-stressed as well unstressed plants. In addition, Si reduced the MDA and H2O2 production and electrolyte leakage suggesting its role in protecting cotton plants from Zn toxicity-induced oxidative damage. Thus, the study indicated that exogenous Si application could improve growth and development of cotton crop experiencing Zn toxicity stress by limiting Zn bioavailability and oxidative damage.

  10. Evaluation of Arbuscular Mycorrhizal Fungi Capacity to Alleviate Abiotic Stress of Olive (Olea europaea L.) Plants at Different Transplant Conditions

    PubMed Central

    Bompadre, María Josefina; Pérgola, Mariana; Fernández Bidondo, Laura; Colombo, Roxana Paula; Silvani, Vanesa Analía; Pardo, Alejandro Guillermo; Ocampo, Juan Antonio; Godeas, Alicia Margarita

    2014-01-01

    The capacity of roots to sense soil physicochemical parameters plays an essential role in maintaining plant nutritional and developmental functions under abiotic stress. These conditions generate reactive oxygen species (ROS) in plant tissues causing oxidation of proteins and lipids among others. Some plants have developed adaptive mechanisms to counteract such adverse conditions such as symbiotic association with arbuscular mycorrhizal fungi (AMF). AMF enhance plant growth and improve transplant survival by protecting host plants against environmental stresses. The aim of this study was to evaluate the alleviation of transplanting stress by two strains of Rhizophagus irregularis (GC2 and GA5) in olive. Our results show that olive plants have an additional energetic expense in growth due to an adaptative response to the growing stage and to the mycorrhizal colonization at the first transplant. However, at the second transplant the coinoculation improves olive plant growth and protects against oxidative stress followed by the GA5-inoculation. In conclusion, a combination of two AMF strains at the beginning of olive propagation produces vigorous plants successfully protected in field cultivation even with an additional cost at the beginning of growth. PMID:24688382

  11. Evaluation of arbuscular mycorrhizal fungi capacity to alleviate abiotic stress of olive (Olea europaea L.) plants at different transplant conditions.

    PubMed

    Bompadre, María Josefina; Pérgola, Mariana; Fernández Bidondo, Laura; Colombo, Roxana Paula; Silvani, Vanesa Analía; Pardo, Alejandro Guillermo; Ocampo, Juan Antonio; Godeas, Alicia Margarita

    2014-01-01

    The capacity of roots to sense soil physicochemical parameters plays an essential role in maintaining plant nutritional and developmental functions under abiotic stress. These conditions generate reactive oxygen species (ROS) in plant tissues causing oxidation of proteins and lipids among others. Some plants have developed adaptive mechanisms to counteract such adverse conditions such as symbiotic association with arbuscular mycorrhizal fungi (AMF). AMF enhance plant growth and improve transplant survival by protecting host plants against environmental stresses. The aim of this study was to evaluate the alleviation of transplanting stress by two strains of Rhizophagus irregularis (GC2 and GA5) in olive. Our results show that olive plants have an additional energetic expense in growth due to an adaptative response to the growing stage and to the mycorrhizal colonization at the first transplant. However, at the second transplant the coinoculation improves olive plant growth and protects against oxidative stress followed by the GA5-inoculation. In conclusion, a combination of two AMF strains at the beginning of olive propagation produces vigorous plants successfully protected in field cultivation even with an additional cost at the beginning of growth.

  12. Current developments in arbuscular mycorrhizal fungi research and its role in salinity stress alleviation: a biotechnological perspective.

    PubMed

    Kumar, Ashwani; Dames, Joanna F; Gupta, Aditi; Sharma, Satyawati; Gilbert, Jack A; Ahmad, Parvaiz

    2015-01-01

    Arbuscular mycorrhizal fungi (AMF) form widespread symbiotic associations with 80% of known land plants. They play a major role in plant nutrition, growth, water absorption, nutrient cycling and protection from pathogens, and as a result, contribute to ecosystem processes. Salinity stress conditions undoubtedly limit plant productivity and, therefore, the role of AMF as a biological tool for improving plant salt stress tolerance, is gaining economic importance worldwide. However, this approach requires a better understanding of how plants and AMF intimately interact with each other in saline environments and how this interaction leads to physiological changes in plants. This knowledge is important to develop sustainable strategies for successful utilization of AMF to improve plant health under a variety of stress conditions. Recent advances in the field of molecular biology, "omics" technology and advanced microscopy can provide new insight about these mechanisms of interaction between AMF and plants, as well as other microbes. This review mainly discusses the effect of salinity on AMF and plants, and role of AMF in alleviation of salinity stress including insight on methods for AMF identification. The focus remains on latest advancements in mycorrhizal research that can potentially offer an integrative understanding of the role of AMF in salinity tolerance and sustainable crop production.

  13. Nitric Oxide Alleviates Salt Stress Inhibited Photosynthetic Performance by Interacting with Sulfur Assimilation in Mustard

    PubMed Central

    Fatma, Mehar; Masood, Asim; Per, Tasir S.; Khan, Nafees A.

    2016-01-01

    The role of nitric oxide (NO) and sulfur (S) on stomatal responses and photosynthetic performance was studied in mustard (Brassica juncea L.) in presence or absence of salt stress. The combined application of 100 μM NO (as sodium nitroprusside) and 200 mg S kg−1 soil (S) more prominently influenced stomatal behavior, photosynthetic and growth performance both in the absence and presence of salt stress. The chloroplasts from salt-stressed plants had disorganized chloroplast thylakoids, but combined application of NO and S resulted in well-developed chloroplast thylakoids and properly stacked grana. The leaves from plants receiving NO plus S exhibited lower superoxide ion accumulation under salt stress than the plants receiving NO or S. These plants also exhibited increased activity of ATP-sulfurylase (ATPS), catalase (CAT), ascorbate peroxidase (APX) and glutathione reductase (GR) and optimized NO generation that helped in minimizing oxidative stress. The enhanced S-assimilation of these plants receiving NO plus S resulted in increased production of cysteine (Cys) and reduced glutathione (GSH). These findings indicated that NO influenced photosynthesis under salt stress by regulating oxidative stress and its effects on S-assimilation, an antioxidant system and NO generation. The results suggest that NO improves photosynthetic performance of plants grown under salt stress more effectively when plants received S. PMID:27200007

  14. Haem oxygenase-1 is involved in salicylic acid-induced alleviation of oxidative stress due to cadmium stress in Medicago sativa.

    PubMed

    Cui, Weiti; Li, Le; Gao, Zhaozhou; Wu, Honghong; Xie, Yanjie; Shen, Wenbiao

    2012-09-01

    This work examines the involvement of haem oxygenase-1 (HO-1) in salicylic acid (SA)-induced alleviation of oxidative stress as a result of cadmium (Cd) stress in alfalfa (Medicago sativa L.) seedling roots. CdCl(2) exposure caused severe growth inhibition and Cd accumulation, which were potentiated by pre-treatment with zinc protoporphyrin (ZnPPIX), a potent HO-1 inhibitor. Pre-treatment of plants with the HO-1 inducer haemin or SA, both of which could induce MsHO1 gene expression, significantly reduced the inhibition of growth and Cd accumulation. The alleviation effects were also evidenced by a decreased content of thiobarbituric acid-reactive substances (TBARS). The antioxidant behaviour was confirmed by histochemical staining for the detection of lipid peroxidation and the loss of plasma membrane integrity. Furthermore, haemin and SA pre-treatment modulated the activities of ascorbate peroxidase (APX), superoxide dismutase (SOD), and guaiacol peroxidase (POD), or their corresponding transcripts. Significant enhancement of the ratios of reduced/oxidized homoglutathione (hGSH), ascorbic acid (ASA)/dehydroascorbate (DHA), and NAD(P)H/NAD(P)(+), and expression of their metabolism genes was observed, consistent with a decreased reactive oxygen species (ROS) distribution in the root tips. These effects are specific for HO-1, since ZnPPIX blocked the above actions, and the aggravated effects triggered by SA plus ZnPPIX were differentially reversed when carbon monoxide (CO) or bilirubin (BR), two catalytic by-products of HO-1, was added. Together, the results suggest that HO-1 is involved in the SA-induced alleviation of Cd-triggered oxidative stress by re-establishing redox homeostasis.

  15. 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.

  16. Lead and cadmium-induced oxidative stress impacting mycelial growth of Oudemansiella radicata in liquid medium alleviated by microbial siderophores.

    PubMed

    Cao, Yan-Ru; Zhang, Xi-Yu; Deng, Jia-Yu; Zhao, Qi-Qi; Xu, Heng

    2012-04-01

    In this study, the effects of siderophores produced by six bacteria on mycelium growth, Cd and Pb accumulation, lipid peroxidation, protein content and antioxidant enzyme in Oudemansiella radicata were investigated in Cd and Pb-containing liquid medium. The results showed that inoculation with siderophore-containing filtrates (SCF) partly enhanced the growth of O. radicata after 15 days, with 0.8-32.4% biomass increase for Cd and 0.7-20.8% for Pb compared to control(s), which lacked siderophore. The maximum enhancement for accumulation were found to be confined to Bacillus sp. FFQ2(s) (26.5%) for Cd and Pseudomonas sp. CY63(s) (158.9%) for Pb. A significant decrease in MDA content indicated that lipid peroxidation in O. radicata was alleviated by siderophores. Besides, antioxidant enzyme SOD and POD activities also displayed obviously decrease in SCF-treated mycelium compared to control(s) treatment, while CAT activity did not present significant change. Protein level in O. radicata treated by SCF increased from 0.3 to 138.0% for Cd and from 10.9 to 107.1% for Pb compared to control(s). Therefore, the present work suggests that microbial siderophores can reduce the toxicity of metals to mycelium and then alleviate heavy metals-inducing oxidative stress in O. radicata.

  17. 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

  18. 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.

  19. 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

  20. Nutritional Interventions to Alleviate the Negative Consequences of Heat Stress12

    PubMed Central

    Rhoads, Robert P.; Baumgard, Lance H.; Suagee, Jessica K.; Sanders, Sara R.

    2013-01-01

    Energy metabolism is a highly coordinated process, and preferred fuel(s) differ among tissues. The hierarchy of substrate use can be affected by physiological status and environmental factors including high ambient temperature. Unabated heat eventually overwhelms homeothermic mechanisms resulting in heat stress, which compromises animal health, farm animal production, and human performance. Various aspects of heat stress physiology have been extensively studied, yet a clear understanding of the metabolic changes occurring at the cellular, tissue, and whole-body levels in response to an environmental heat load remains ill-defined. For reasons not yet clarified, circulating nonesterified fatty acid levels are reduced during heat stress, even in the presence of elevated stress hormones (epinephrine, glucagon, and cortisol), and heat-stressed animals often have a blunted lipolytic response to catabolic signals. Either directly because of or in coordination with this, animals experiencing environmental hyperthermia exhibit a shift toward carbohydrate use. These metabolic alterations occur coincident with increased circulating basal and stimulated plasma insulin concentrations. Limited data indicate that proper insulin action is necessary to effectively mount a response to heat stress and minimize heat-induced damage. Consistent with this idea, nutritional interventions targeting increased insulin action may improve tolerance and productivity during heat stress. Further research is warranted to uncover the effects of heat on parameters associated with energy metabolism so that more appropriate and effective treatment methodologies can be designed. PMID:23674792

  1. 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

  2. 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.

  3. 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.

  4. Carbon monoxide offers neuroprotection from hippocampal cell damage induced by recurrent febrile seizures through the PERK-activated ER stress pathway.

    PubMed

    Han, Ying; Yi, Wenxia; Qin, Jiong; Zhao, Yang; Zhang, Jing; Chang, Xingzhi

    2015-01-12

    Carbon monoxide (CO) is neuroprotective in various models of brain injury, but the precise mechanisms for this are yet to be established. In the present study, using a rat model of recurrent febrile seizures (FSs), we found an increase in plasma CO, evidence of neuronal damage and apoptosis, an increase in the expression of the endoplasmic reticulum stress (ERS) marker glucose-regulated protein 78 (GRP78) and C/EBP homologous binding protein (CHOP), and an increase in phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK)/eukaryotic translation initiation factor 2 alpha (p-eIF2α) in the hippocampus after 10 FSs. Administration of Hemin (a CO donor) in FS rats alleviated the neuronal damage, reduced neuronal apoptosis, upregulated GRP78 expression, decreased CHOP, and increased p-PERK and p-eIF2α expression in the hippocampus, compared to FS control rats. In contrast, treating FS rats with ZnPP-IX (a CO synthase inhibitor) aggravated the neuronal damage, enhanced neuronal apoptosis, downregulated GRP78 expression, increased CHOP, and decreased p-PERK and p-eIF2α expression, compared to FS control rats. These results suggest that endogenous CO limits the neuronal damage induced by recurrent FSs, through the PERK-activated ERS pathway.

  5. Weak microwave can alleviate water deficit induced by osmotic stress in wheat seedlings.

    PubMed

    Chen, Yi-Ping; Jia, Jing-Fen; Han, Xiao-Ling

    2009-01-01

    The aim of the investigation is to determine the effect of microwave pretreatment of wheat seeds on the resistance of seedlings to osmotic stress. Changes in biophysical, physiological and biochemical characters were measured. The results showed: (1) The magnetic field intensity and seeds temperature increased progressively with microwave pretreatments of 5, 10, 15, 20 s and 25 s compared with controls. Although each microwave pretreatment resulted in an increase in alpha-amylase activity and photon emission intensity, the increase of alpha-amylase activity and photon emission intensity was maximal at a microwave pretreatment of 10 s. (2) Osmotic stress induced by PEG treatment enhanced the concentration of malondialdehyde, while decreasing the activities of nitricoxide synthase, catalase, peroxidase, superoxide dismutase and the concentration of nitric oxide, ascorbic acid, glutathione in the seedlings compared with controls. However, compared to osmotic stress alone, in the seedlings treated with microwave irradiation plus osmotic stress the concentration of malondialdehyde decreased, while the activities of nitricoxide synthase, catalase, peroxidase, superoxide dismutase and the concentration of nitric oxide, ascorbic acid and glutathione increased. These results suggest that a suitable dose of microwave radiation can enhance the capability to eliminate free radicals induced by osmotic stress in wheat seedlings resulting in an increase in resistance to osmotic stress.

  6. The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Alleviates Salinity Stress in Cassava

    PubMed Central

    Patanun, Onsaya; Ueda, Minoru; Itouga, Misao; Kato, Yukari; Utsumi, Yoshinori; Matsui, Akihiro; Tanaka, Maho; Utsumi, Chikako; Sakakibara, Hitoshi; Yoshida, Minoru; Narangajavana, Jarunya; Seki, Motoaki

    2017-01-01

    Cassava (Manihot esculenta Crantz) demand has been rising because of its various applications. High salinity stress is a major environmental factor that interferes with normal plant growth and limits crop productivity. As well as genetic engineering to enhance stress tolerance, the use of small molecules is considered as an alternative methodology to modify plants with desired traits. The effectiveness of histone deacetylase (HDAC) inhibitors for increasing tolerance to salinity stress has recently been reported. Here we use the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), to enhance tolerance to high salinity in cassava. Immunoblotting analysis reveals that SAHA treatment induces strong hyper-acetylation of histones H3 and H4 in roots, suggesting that SAHA functions as the HDAC inhibitor in cassava. Consistent with increased tolerance to salt stress under SAHA treatment, reduced Na+ content and increased K+/Na+ ratio were detected in SAHA-treated plants. Transcriptome analysis to discover mechanisms underlying salinity stress tolerance mediated through SAHA treatment reveals that SAHA enhances the expression of 421 genes in roots under normal condition, and 745 genes at 2 h and 268 genes at 24 h under both SAHA and NaCl treatment. The mRNA expression of genes, involved in phytohormone [abscisic acid (ABA), jasmonic acid (JA), ethylene, and gibberellin] biosynthesis pathways, is up-regulated after high salinity treatment in SAHA-pretreated roots. Among them, an allene oxide cyclase (MeAOC4) involved in a crucial step of JA biosynthesis is strongly up-regulated by SAHA treatment under salinity stress conditions, implying that JA pathway might contribute to increasing salinity tolerance by SAHA treatment. Our results suggest that epigenetic manipulation might enhance tolerance to high salinity stress in cassava. PMID:28119717

  7. Dexmedetomidine alleviates anxiety-like behaviors and cognitive impairments in a rat model of post-traumatic stress disorder.

    PubMed

    Ji, Mu-Huo; Jia, Min; Zhang, Ming-Qiang; Liu, Wen-Xue; Xie, Zhong-Cong; Wang, Zhong-Yun; Yang, Jian-Jun

    2014-10-03

    Post-traumatic stress disorder (PTSD) is a psychiatric disease that has substantial health implications, including high rates of health morbidity and mortality, as well as increased health-related costs. Although many pharmacological agents have proven the effects on the development of PTSD, current pharmacotherapies typically only produce partial improvement of PTSD symptoms. Dexmedetomidine is a selective, short-acting α2-adrenoceptor agonist, which has anxiolytic, sedative, and analgesic effects. We therefore hypothesized that dexmedetomidine possesses the ability to prevent the development of PTSD and alleviate its symptoms. By using the rat model of PTSD induced by five electric foot shocks followed by three weekly exposures to situational reminders, we showed that the stressed rats displayed pronounced anxiety-like behaviors and cognitive impairments compared to the controls. Notably, repeated administration of 20μg/kg dexmedetomidine showed impaired fear conditioning memory, decreased anxiety-like behaviors, and improved spatial cognitive impairments compared to the vehicle-treated stressed rats. These data suggest that dexmedetomidine may exert preventive and protective effects against anxiety-like behaviors and cognitive impairments in the rats with PTSD after repeated administration.

  8. Brassinolide Increases Potato Root Growth In Vitro in a Dose-Dependent Way and Alleviates Salinity Stress

    PubMed Central

    Xia, Shitou; Su, Yi; Wang, Huiqun; Luo, Weigui; Su, Shengying

    2016-01-01

    Brassinosteroids (BRs) are steroidal phytohormones that regulate various physiological processes, such as root development and stress tolerance. In the present study, we showed that brassinolide (BL) affects potato root in vitro growth in a dose-dependent manner. Low BL concentrations (0.1 and 0.01 μg/L) promoted root elongation and lateral root development, whereas high BL concentrations (1–100 μg/L) inhibited root elongation. There was a significant (P < 0.05) positive correlation between root activity and BL concentrations within a range from 0.01 to 100 μg/L, with the peak activity of 8.238 mg TTC·g−1 FW·h−1 at a BL concentration of 100 μg/L. Furthermore, plants treated with 50 μg/L BL showed enhanced salt stress tolerance through in vitro growth. Under this scenario, BL treatment enhanced the proline content and antioxidant enzymes' (superoxide dismutase, peroxidase, and catalase) activity and reduced malondialdehyde content in potato shoots. Application of BL maintain K+ and Na+ homeostasis by improving tissue K+/Na+ ratio. Therefore, we suggested that the effects of BL on root development from stem fragments explants as well as on primary root development are dose-dependent and that BL application alleviates salt stress on potato by improving root activity, root/shoot ratio, and antioxidative capacity in shoots and maintaining K+/Na+ homeostasis in potato shoots and roots. PMID:27803931

  9. Selenium Alleviates Oxidative Stress and Lung Damage Induced by Aluminum Chloride in Adult Rats: Biochemical and Histological Approach.

    PubMed

    Ghorbel, Imen; Elwej, Awatef; Chaabane, Mariem; Jamoussi, Kamel; Mnif, Hela; Boudawara, Tahia; Zeghal, Najiba

    2017-03-01

    Our study pertains to the potential ability of selenium, used as a nutritional supplement, to alleviate oxidative stress induced by aluminum chloride in the lung tissue. Rats have received during 21 days either aluminum chloride (AlCl3) (400 ppm) via drinking water, AlCl3 associated with Na2SeO3 (0.5 mg/kg of diet), or only Na2SeO3. Exposure of rats to AlCl3 induced lung oxidative stress with an increase of malondialdehyde, hydrogen peroxide, and protein carbonyls levels. An alteration of lactate dehydrogenase activities and antioxidant redox status, enzymatic (catalase, superoxide dismutase, and glutathione peroxidase), and non-enzymatic (non-protein thiols, glutathione, metallothionein, and vitamin C) was also observed. These biochemical modifications were substantiated by histopathological data showing alveolar edema, a large number of hemosiderin-laden macrophages, and emphysema. Se supplementation attenuated the levels of oxidative stress by restoring antioxidant state and improved lung histological damage. Our results revealed that Se, a trace element with antioxidant properties, was effective in preventing lung damage.

  10. Biochar alleviates combined stress of ammonium and acids by firstly enriching Methanosaeta and then Methanosarcina.

    PubMed

    Lü, Fan; Luo, Chenghao; Shao, Liming; He, Pinjing

    2016-03-01

    This investigation evaluated the effectiveness of biochar of different particle sizes in alleviating ammonium (NH4(+)) inhibition (up to 7 g-N/L) during anaerobic digestion of 6 g/L glucose. Compared to the control treatment without biochar addition, treatments that included biochar particles 2-5 mm, 0.5-1 mm and 75-150 μm in size reduced the methanization lag phase by 23.9%, 23.8% and 5.9%, respectively, and increased the maximum methane production rate by 47.1%, 23.5% and 44.1%, respectively. These results confirmed that biochar accelerated the initiation of methanization during anaerobic digestion under double inhibition risk from both ammonium and acids. Furthermore, fine biochar significantly promoted the production of volatile fatty acids (VFAs). Comparative analysis on the archaeal and bacterial diversity at the early and later stages of digestion, and in the suspended, biochar loosely bound, and biochar tightly bound fractions suggested that, in suspended fractions, hydrogenotrophic Methanobacterium was actively resistant to ammonium. However, acetoclastic Methanosaeta can survive at VFAs concentrations up to 60-80 mmol-C/L by improved affinity to conductive biochar, resulting in the accelerated initiation of acetate degradation. Improved methanogenesis was followed by the colonization of the biochar tightly bound fractions by Methanosarcina. The selection of appropriate biochar particles sizes was important in facilitating the initial colonization of microbial cells.

  11. Physical and virtual water transfers for regional water stress alleviation in China.

    PubMed

    Zhao, Xu; Liu, Junguo; Liu, Qingying; Tillotson, Martin R; Guan, Dabo; Hubacek, Klaus

    2015-01-27

    Water can be redistributed through, in physical terms, water transfer projects and virtually, embodied water for the production of traded products. Here, we explore whether such water redistributions can help mitigate water stress in China. This study, for the first time to our knowledge, both compiles a full inventory for physical water transfers at a provincial level and maps virtual water flows between Chinese provinces in 2007 and 2030. Our results show that, at the national level, physical water flows because of the major water transfer projects amounted to 4.5% of national water supply, whereas virtual water flows accounted for 35% (varies between 11% and 65% at the provincial level) in 2007. Furthermore, our analysis shows that both physical and virtual water flows do not play a major role in mitigating water stress in the water-receiving regions but exacerbate water stress for the water-exporting regions of China. Future water stress in the main water-exporting provinces is likely to increase further based on our analysis of the historical trajectory of the major governing socioeconomic and technical factors and the full implementation of policy initiatives relating to water use and economic development. Improving water use efficiency is key to mitigating water stress, but the efficiency gains will be largely offset by the water demand increase caused by continued economic development. We conclude that much greater attention needs to be paid to water demand management rather than the current focus on supply-oriented management.

  12. Physical and virtual water transfers for regional water stress alleviation in China

    PubMed Central

    Zhao, Xu; Liu, Junguo; Liu, Qingying; Tillotson, Martin R.; Guan, Dabo; Hubacek, Klaus

    2015-01-01

    Water can be redistributed through, in physical terms, water transfer projects and virtually, embodied water for the production of traded products. Here, we explore whether such water redistributions can help mitigate water stress in China. This study, for the first time to our knowledge, both compiles a full inventory for physical water transfers at a provincial level and maps virtual water flows between Chinese provinces in 2007 and 2030. Our results show that, at the national level, physical water flows because of the major water transfer projects amounted to 4.5% of national water supply, whereas virtual water flows accounted for 35% (varies between 11% and 65% at the provincial level) in 2007. Furthermore, our analysis shows that both physical and virtual water flows do not play a major role in mitigating water stress in the water-receiving regions but exacerbate water stress for the water-exporting regions of China. Future water stress in the main water-exporting provinces is likely to increase further based on our analysis of the historical trajectory of the major governing socioeconomic and technical factors and the full implementation of policy initiatives relating to water use and economic development. Improving water use efficiency is key to mitigating water stress, but the efficiency gains will be largely offset by the water demand increase caused by continued economic development. We conclude that much greater attention needs to be paid to water demand management rather than the current focus on supply-oriented management. PMID:25583516

  13. Endophytic infection alleviates Pb(2+) stress effects on photosystem II functioning of Oryza sativa leaves.

    PubMed

    Li, Xuemei; Zhang, Lihong

    2015-09-15

    The aims of this study were to examine the effect of Pb(2+) stress on the primary reaction of photosynthesis and to assess the potential benefits of endophytic infection on the Pb(2+) tolerance of rice seedlings. Rice inoculated with an endophytic fungus (E+) and non-inoculated (E-) were subjected to 0, 50, 100, 150 and 200 μM Pb(2+). The responses to Pb(2+) stress were characterized by the analysis of Chl a fluorescence. A comparison of E- with E+ rice seedlings, as evaluated by their performance index (PI(ABS) and PI(tot)), revealed the inhibitory effects of Pb(2+) on photosystem II (PSII) connectivity, the oxygen evolving complex (OEC), and on the J step of the induction curves, which is associated with an inhibition of electron transport from the quinone acceptor Q(A) to Q(B). Furthermore, the changes of the donor and the acceptor parameters of PSII were greater in E- than in E+ under Pb(2+) stress. These observations suggest that the efficiency and stability of PSII are markedly affected by Pb(2+) stress, and the photosynthetic energy conservation in E+ was more effective than in E-. We showed that endophytic infection plays an important role in enhancing the photosynthetic mechanism of rice seedlings exposed to Pb(2+) stress.

  14. 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.

  15. 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.

  16. 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

  17. Spermine Alleviates Drought Stress in White Clover with Different Resistance by Influencing Carbohydrate Metabolism and Dehydrins Synthesis

    PubMed Central

    Li, Zhou; Jing, Wen; Peng, Yan; Zhang, Xin Quan; Ma, Xiao; Huang, Lin Kai; Yan, Yan-hong

    2015-01-01

    The objective of this research was to analyse whether ameliorating drought stress through exogenously applied spermine (Spm) was related to carbohydrate metabolism, dehydrins accumulation and the transcription of genes encoding dehydrins in two white clovers (drought-susceptible cv. ‘Ladino’ and drought-resistant cv. ‘Haifa’) under controlled drying conditions for 10 days. The results show that the application of Spm effectively alleviates negative effects caused by drought stress in both cultivars. Exogenous Spm led to accumulation of more water-soluble carbohydrates (WSC), sucrose, fructose and sorbitol in both cultivars under drought stress, and also significantly elevated glucose content in leaves of drought-resistant cv. ‘Haifa’, but had no effect on drought-susceptible cv. ‘Ladino’. Accordingly, the key enzyme activities of sucrose and sorbitol metabolism changed along with the application of Spm under drought stress. Spm induced a significant increase in sucrose phosphate synthase (SPS) or sorbitol dehydrogenase (SDH) activity, but decrease in sucrose synthetase (SS) activity when two cultivars were subjected to drought. In addition, the improved accumulation of dehydrins induced by exogenous Spm coincided with three genes expression which was responsible for dehydrins synthesis. But Spm-induced transcript level of dehydrin genes increased earlier in cv. ‘Ladino’ than that in cv. ‘Haifa’. Thus, these results suggest that ameliorating drought stress through exogenously applied Spm may be associated with increased carbohydrate accumulation and dehydrins synthesis. There are differences between drought-susceptible and -resistant white clover cultivars related to Spm regulation of WSC metabolism and dehydrins expression. PMID:25835290

  18. 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.

  19. 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.

  20. Endophytic fungal pre-treatments of seeds alleviates salinity stress effects in soybean plants.

    PubMed

    Radhakrishnan, Ramalingam; Khan, Abdul Latif; Lee, In-Jung

    2013-12-01

    In the present study, four endophytic fungi (GM-1, GM-2, GM-3, and GM-4) were tested for their ability to improve soybean plant growth under salinity stress conditions. The seed germination and plant growth were higher in seeds pretreated with endophytic fungal cultures than their controls. The positive influence of fungi on plant growth was supported by gibberellins analysis of culture filtrate (CF), which showed wide diversity and various concentrations of GAs. Specifically, GA4, GA7, GA8, GA9, GA12, and GA20 were found in fungal CFs. Under salinity stress conditions, GM-1 significantly enhanced the length and fresh weight of soybean plants relative to other fungal treatments. GM-1 effectively mitigated the adverse effects of salinity by limiting lipid peroxidation and accumulating protein content. GM-2, GM-3, and GM-4 also counteracted the salinity induced oxidative stress in soybean plants through reduction of lipid peroxidation and enhancement of protein content, maintaining the length and fresh weight of shoots. The activities of the antioxidant enzymes catalase, superoxide dismutase and peroxidase were inhibited in salinity exposed plants, while GM-1 significantly enhanced these antioxidant enzyme activities in plants under salt stress. GM-1 treatment also showed lower levels of abscisic acid and elevated levels of salicylic acid in plants under salinity stress. Hence, GM-1 was identified as Fusarium verticillioides (teleomorph Gibberella moniliformis) isolate RK01 based on its DNA sequence homology. These results suggest that endophytic fungal (F. verticillioides) pre-treatment of soybean seeds would be an effective method to promote soybean plant growth under salinity stress conditions.

  1. 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.

  2. 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.

  3. 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.

  4. Nitric oxide alleviates oxidative damage induced by high temperature stress in wheat.

    PubMed

    Bavita, A; Shashi, B; Navtej, S B

    2012-05-01

    Effect of sodium nitroprusside (SNP), a donor of nitric oxide (NO) was examined in two wheat (Triticum aestivum L.) cultivars, C 306 (heat tolerant) and PBW 550 (comparatively heat susceptible) to study the extent of oxidative injury and activities of antioxidant enzyme in relation to high temperature (HT) stress. HT stress resulted in a marked decrease in membrane thermostability (MTS) and 2, 3, 5-triphenyl tetrazolium chloride (TTC) cell viability whereas content of lipid peroxide increased in both the cultivars. The tolerant cultivar C 306 registered less damage to cellular membranes compared to PBW 550 under HT stress. Activities of antioxidant enzymes viz, superoxide dismutase, catalase, ascorbate peroxidase, guaicol peroxidase and glutathione reductase increased with HT in both the cultivars. Following treatment with SNP, activities of all antioxidant enzymes further increased in correspondence with an increase in MTS and TTC. Apparently, lipid peroxide content was reduced by SNP more in shoots of heat tolerant cultivar C 306 indicating better protection over roots under HT stress. The up-regulation of the antioxidant system by NO possibly contributed to better tolerance against HT induced oxidative damage in wheat.

  5. Brassinolide alleviates salt stress and increases antioxidant activity of cowpea plants (Vigna sinensis).

    PubMed

    El-Mashad, Ali Abdel Aziz; Mohamed, Heba Ibrahim

    2012-07-01

    Soil salinity is one of the most severe factors limiting growth and physiological response in Vigna sinensis plants. Plant salt stress tolerance requires the activation of complex metabolic activities including antioxidative pathways, especially reactive oxygen species and scavenging systems within the cells which can contribute to continued growth under water stress. The present investigation was carried out to study the role of brassinolide in enhancing tolerance of cowpea plants to salt stress (NaCl). Treatment with 0.05 ppm brassinolide as foliar spray mitigated salt stress by inducing enzyme activities responsible for antioxidation, e.g., superoxide dismutase, peroxidase, polyphenol oxidase, and detoxification as well as by elevating contents of ascorbic acid, tocopherol, and glutathione. On the other hand, total soluble proteins decreased with increasing NaCl concentrations in comparison with control plants. However, lipid peroxidation increased with increasing concentrations of NaCl. In addition to, the high concentrations of NaCl (100 and 150 mM) decreased total phenol of cowpea plants as being compared with control plants. SDS-PAGE of protein revealed that NaCl treatments alone or in combination with 0.05 ppm brassinolide were associated with the disappearance of some bands or appearance of unique ones in cowpea plants. Electrophoretic studies of α-esterase, β-esterase, polyphenol oxidase, peroxidase, acid phosphatase, and superoxide dismutase isoenzymes showed wide variations in their intensities and densities among all treatments.

  6. Berberis vulgaris root extract alleviates the adverse effects of heat stress via modulating hepatic nuclear transcription factors in quails.

    PubMed

    Sahin, Kazim; Orhan, Cemal; Tuzcu, Mehmet; Borawska, Maria H; Jabłonski, Jakub; Guler, Osman; Sahin, Nurhan; Hayirli, Armagan

    2013-08-01

    To evaluate the action mode of Berberis vulgaris root extract in the alleviation of oxidative stress, female Japanese quails (n 180, aged 5 weeks) were reared, either at 22°C for 24 h/d (thermoneutral, TN) or 34°C for 8 h/d (heat stress, HS), and fed one of three diets: diets containing 0, 100 or 200 mg of B. vulgaris root extract per kg for 12 weeks. Exposure to HS depressed feed intake by 8·5% and egg production by 12·1%, increased hepatic malondialdehyde (MDA) level by 98·0% and decreased hepatic superoxide dismutase, catalase and glutathione peroxidase activities by 23·5, 35·4 and 55·7%, respectively (P<0·001 for all). There were also aggravations in expressions of hepatic NF-κB and heat-shock protein 70 (HSP70) by 42 and 43%, respectively and suppressions in expressions of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and haeme-oxygenase 1 (HO-1) by 57 and 61%, respectively, in heat-stressed quails (P<0·001 for all). As supplemental B. vulgaris extract increased, there were linear increases in performance parameters, activities of antioxidant enzymes and hepatic Nrf2 and HO-1 expressions (P<0·001 for all) and linear decreases in hepatic MDA level and NF-κB and HSP70 expressions at a greater extent in quails reared under TN condition and those reared under HS condition. In conclusion, dietary supplementation of B. vulgaris root extract to quails reduces the detrimental effects of oxidative stress and lipid peroxidation resulting from HS via activating the host defence system at the cellular level.

  7. Curcumin improves vascular function and alleviates oxidative stress in non-lethal lipopolysaccharide-induced endotoxaemia in mice.

    PubMed

    Sompamit, Kwanjit; Kukongviriyapan, Upa; Nakmareong, Saowanee; Pannangpetch, Patchareewan; Kukongviriyapan, Veerapol

    2009-08-15

    Oxidative stress is implicated in various pathological conditions, including septic shock, and other diseases associated with local or systemic inflammation. Curcumin, a major component from turmeric (Curcuma longa), possesses diverse anti-inflammatory, anti-tumour and antioxidant properties. The aim of this study was to investigate the effect of curcumin on modulation of vascular dysfunction and oxidative stress induced by lipopolysaccharide (LPS) in mice. Male ICR mice were treated with curcumin (50 or 100 mg/kg), administered intragastrically, either before or after intraperitoneal injection of LPS (10 mg/kg). Fifteen hours after LPS administration, arterial blood pressure was measured and vascular response to vasoactive agents were assessed. Aortic tissues and blood samples were taken for assays of antioxidant and oxidative stress markers. LPS caused marked hypotension, tachycardia and vascular hyporeactivity. The mean arterial pressures in responses to phenylephrine, acetylcholine, and sodium nitroprusside of LPS-treated mice were significantly decreased when compared with the untreated controls. Curcumin modulated heart rate and restored arterial blood pressure in a dose-dependent manner in both protectively- and therapeutically-treated regimens. Furthermore, the vascular responsiveness of LPS-treated mice was improved by curcumin. Interestingly, the improvements of haemodynamics and vascular response during endotoxaemia were related to alleviation of oxidative stress by reducing aortic-derived superoxide production, suppression of lipid peroxidation and protein oxidation, and decrease in urinary nitric oxide metabolites with preservation of the ratio of glutathione/glutathione disulfide. This study provides the first evidence for the potential role of curcumin in prevention and treatment of vascular dysfunction in mice with endotoxaemia elicited by LPS.

  8. Alleviation of Drought Stress by Hydrogen Sulfide Is Partially Related to the Abscisic Acid Signaling Pathway in Wheat

    PubMed Central

    Wang, Chenyang; Qin, Haixia; Han, Qiaoxia; Hou, Junfeng; Lu, Hongfang; Xie, Yingxin; Guo, Tiancai

    2016-01-01

    Little information is available describing the effects of exogenous H2S on the ABA pathway in the acquisition of drought tolerance in wheat. In this study, we investigated the physiological parameters, the transcription levels of several genes involved in the abscisic acid (ABA) metabolism pathway, and the ABA and H2S contents in wheat leaves and roots under drought stress in response to exogenous NaHS treatment. The results showed that pretreatment with NaHS significantly increased plant height and the leaf relative water content of seedlings under drought stress. Compared with drought stress treatment alone, H2S application increased antioxidant enzyme activities and reduced MDA and H2O2 contents in both leaves and roots. NaHS pretreatment increased the expression levels of ABA biosynthesis and ABA reactivation genes in leaves; whereas the expression levels of ABA biosynthesis and ABA catabolism genes were up-regulated in roots. These results indicated that ABA participates in drought tolerance induced by exogenous H2S, and that the responses in leaves and roots are different. The transcription levels of genes encoding ABA receptors were up-regulated in response to NaHS pretreatment under drought conditions in both leaves and roots. Correspondingly, the H2S contents in leaves and roots were increased by NaHS pretreatment, while the ABA contents of leaves and roots decreased. This implied that there is complex crosstalk between these two signal molecules, and that the alleviation of drought stress by H2S, at least in part, involves the ABA signaling pathway. PMID:27649534

  9. Multicyclic jet-flap control for alleviation of helicopter blade stresses and fuselage vibration

    NASA Technical Reports Server (NTRS)

    Mccloud, J. L., III; Kretz, M.

    1974-01-01

    Results of wind tunnel tests of a 12-meter-diameter rotor utilizing multicyclic jet-flap control deflection are presented. Analyses of these results are shown, and experimental transfer functions are determined by which optimal control vectors are developed. These vectors are calculated to eliminate specific harmonic bending stresses, minimize rms levels (a measure of the peak-to-peak stresses), or minimize vertical vibratory loads that would be transmitted to the fuselage. Although the specific results and the ideal control vectors presented are for a specific jet-flap driven rotor, the method employed for the analyses is applicable to similar investigations. A discussion of possible alternative methods of multicyclic control by mechanical flaps or nonpropulsive jet-flaps is presented.

  10. Tranilast-induced stress alleviation in solid tumors improves the efficacy of chemo- and nanotherapeutics in a size-independent manner

    PubMed Central

    Papageorgis, Panagiotis; Polydorou, Christiana; Mpekris, Fotios; Voutouri, Chrysovalantis; Agathokleous, Eliana; Kapnissi-Christodoulou, Constantina P.; Stylianopoulos, Triantafyllos

    2017-01-01

    Accumulation of mechanical stresses during cancer progression can induce blood and lymphatic vessel compression, creating hypo-perfusion, hypoxia and interstitial hypertension which decrease the efficacy of chemo- and nanotherapies. Stress alleviation treatment has been recently proposed to reduce mechanical stresses in order to decompress tumor vessels and improve perfusion and chemotherapy. However, it remains unclear if it improves the efficacy of nanomedicines, which present numerous advantages over traditional chemotherapeutic drugs. Furthermore, we need to identify safe and well-tolerated pharmaceutical agents that reduce stress levels and may be added to cancer patients’ treatment regimen. Here, we show mathematically and with a series of in vivo experiments that stress alleviation improves the delivery of drugs in a size-independent manner. Importantly, we propose the repurposing of tranilast, a clinically approved anti-fibrotic drug as stress-alleviating agent. Using two orthotopic mammary tumor models, we demonstrate that tranilast reduces mechanical stresses, decreases interstitial fluid pressure (IFP), improves tumor perfusion and significantly enhances the efficacy of different-sized drugs, doxorubicin, Abraxane and Doxil, by suppressing TGFβ signaling and expression of extracellular matrix components. Our findings strongly suggest that repurposing tranilast could be directly used as a promising strategy to enhance, not only chemotherapy, but also the efficacy of cancer nanomedicine. PMID:28393881

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. 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.

  16. Ageing-Associated Oxidative Stress and Inflammation Are Alleviated by Products from Grapes

    PubMed Central

    Petersen, K. S.

    2016-01-01

    Advanced age is associated with increased incidence of a variety of chronic disease states which share oxidative stress and inflammation as causative role players. Furthermore, data point to a role for both cumulative oxidative stress and low grade inflammation in the normal ageing process, independently of disease. Therefore, arguably the best route with which to address premature ageing, as well as age-associated diseases such as diabetes, cardiovascular disease, and dementia, is preventative medicine aimed at modulation of these two responses, which are intricately interlinked. In this review, we provide a detailed account of the literature on the communication of these systems in the context of ageing, but with inclusion of relevant data obtained in other models. In doing so, we attempted to more clearly elucidate or identify the most probable cellular or molecular targets for preventative intervention. In addition, given the absence of a clear pharmaceutical solution in this context, together with the ever-increasing consumer bias for natural medicine, we provide an overview of the literature on grape (Vitis vinifera) derived products, for which beneficial effects are consistently reported in the context of both oxidative stress and inflammation. PMID:27034739

  17. Alleviation of water stress effects on MR220 rice by application of periodical water stress and potassium fertilization.

    PubMed

    Zain, Nurul Amalina Mohd; Ismail, Mohd Razi; Mahmood, Maziah; Puteh, Adam; Ibrahim, Mohd Hafiz

    2014-02-05

    The use of periodical water stress and potassium fertilization may enhance rice tolerance to drought stress and improve the crop's instantaneous water use efficiency without much yield reduction. This study was conducted to assess the effects of different periodical water stress combined with potassium fertilization regimes on growth, yield, leaf gas exchanges and biochemical changes in rice grown in pots and compare them with standard local rice grower practices. Five treatments including (1) standard local grower's practice (control, 80CF = 80 kg K2O/ha + control flooding); (2) 120PW15 = 120 kg K2O/ha + periodical water stress for 15 days; (3) 120DS15V = 120 kg K2O/ha + drought stress for 15 days during the vegetative stage; (4) 120DS25V = 120 kg K2O/ha + drought stress for 25 days and (5) 120DS15R = 120 kg K2O/ha + drought stress for 15 days during the reproductive stage, were evaluated in this experiment. Control and 120PW15 treatments were stopped at 100 DAS, and continuously saturated conditions were applied until harvest. It was found that rice under 120PW15 treatment showed tolerance to drought stress evidenced by increased water use efficiency, peroxidase (POX), catalase (CAT) and proline levels, maximum efficiency of photosystem II (fv/fm) and lower minimal fluorescence (fo), compared to other treatments. Path coefficient analysis revealed that most of parameters contribute directly rather than indirectly to rice yield. In this experiment, there were four factors that are directly involved with rice yield: grain soluble sugar, photosynthesis, water use efficiency and total chlorophyll content. The residual factors affecting rice yield are observed to be quite low in the experiment (0.350), confirming that rice yield was mostly influenced by the parameters measured during the study.

  18. 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

  19. 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

  20. Nitrogen addition and clonal integration alleviate water stress of dependent ramets of Indocalamus decorus under heterogeneous soil water environment

    PubMed Central

    Guo, Zi-Wu; Hu, Jun-Jing; Chen, Shuang-Lin; Li, Ying-Chun; Yang, Qing-Ping; Cai, Han-Jiang

    2017-01-01

    Water and nitrogen are two of the most important factors for plant growth and development. However, little is known about effects of N on water translocation between connected bamboo ramets. We performed experiment connected Indocalamus decorus ramets in adjacent pots with different soil water contents and three N levels. We determined antioxidase activities, concentration of osmotic adjustment products, O2·−, MDA and photosynthetic pigments, and electrolyte leakage rate in paired unit. When N supply to supporting ramets increased, their electrolyte leakage rates and contents of O2·− and MDA significantly increased, while antioxidase activities and contents of osmotic adjustment products and photosynthetic pigments in connected dependent ramets increased markedly as their electrolyte leakage rates and contents of O2·− and MDA decreased greatly. When N addition to dependent ramets increased, antioxidant enzyme activity and contents of osmotic adjustment products and photosynthetic pigments decreased in both ramets, but electrolyte leakage rates and O2·− and MDA contents increased significantly. Therefore, N addition to either supporting or dependent ramets can improve water integration among I. decorus ramets. N addition to supporting ramets promotes water translocation and alleviates water stress of dependent ramets, but N addition to dependent ramets exacerbates drought stress damage to dependent ramets. PMID:28295023

  1. Dietary Saccharomyces cerevisiae Cell Wall Extract Supplementation Alleviates Oxidative Stress and Modulates Serum Amino Acids Profiles in Weaned Piglets

    PubMed Central

    Yu, Lei; Martínez, Yordan

    2017-01-01

    This research aims to evaluate the effects of dietary supplementation with Saccharomyces cerevisiae cell wall extract (SCCWE) on growth performance, oxidative stress, intestinal morphology, and serum amino acid concentration in weaned piglets. Utilizing a completely randomized design, 40 healthy piglets weaned at 21 d were grouped into 4 experimental treatments with 10 pigs per treatment group. Treatments consisted of a basal diet (T0), a basal diet with a 0.05% SCCWE (T1), a basal diet with a 0.10% SCCWE (T2), and a basal diet with a 0.15% SCCWE (T3). SCCWE supplementation increased the average daily gain and final body weight compared with T0 (P < 0.05). SCCWE in T2 and T3 improved the average daily feed intake and decreased the feed/gain ratio compared with T1 and T2 (P < 0.05). SCCWE decreased serum malondialdehyde (MDA) and increased activities of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) significantly compared to T0 (P < 0.05). SCCWE increased the concentration of Ile compared to T0 (P < 0.05). Moreover, the concentrations of Leu, Phe, and Arg were higher in T2 and T3 (P < 0.05). These findings indicate beneficial effects of SCCWE supplementation on growth performance, the concentration of some essential amino acids, and alleviation of oxidative stress in weaned piglets. PMID:28386308

  2. Nitrogen addition and clonal integration alleviate water stress of dependent ramets of Indocalamus decorus under heterogeneous soil water environment.

    PubMed

    Guo, Zi-Wu; Hu, Jun-Jing; Chen, Shuang-Lin; Li, Ying-Chun; Yang, Qing-Ping; Cai, Han-Jiang

    2017-03-15

    Water and nitrogen are two of the most important factors for plant growth and development. However, little is known about effects of N on water translocation between connected bamboo ramets. We performed experiment connected Indocalamus decorus ramets in adjacent pots with different soil water contents and three N levels. We determined antioxidase activities, concentration of osmotic adjustment products, O2·(-), MDA and photosynthetic pigments, and electrolyte leakage rate in paired unit. When N supply to supporting ramets increased, their electrolyte leakage rates and contents of O2·(-) and MDA significantly increased, while antioxidase activities and contents of osmotic adjustment products and photosynthetic pigments in connected dependent ramets increased markedly as their electrolyte leakage rates and contents of O2·(-) and MDA decreased greatly. When N addition to dependent ramets increased, antioxidant enzyme activity and contents of osmotic adjustment products and photosynthetic pigments decreased in both ramets, but electrolyte leakage rates and O2·(-) and MDA contents increased significantly. Therefore, N addition to either supporting or dependent ramets can improve water integration among I. decorus ramets. N addition to supporting ramets promotes water translocation and alleviates water stress of dependent ramets, but N addition to dependent ramets exacerbates drought stress damage to dependent ramets.

  3. 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

  4. 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.

  5. 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

  6. 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

  7. Nitric oxide-releasing chitosan nanoparticles alleviate the effects of salt stress in maize plants.

    PubMed

    Oliveira, Halley C; Gomes, Bruna C R; Pelegrino, Milena T; Seabra, Amedea B

    2016-12-30

    Nitric oxide (NO) is a signaling molecule involved in plant response to various abiotic stresses. However, the application of NO donors in agriculture is hampered by the instability of these compounds. Despite the successful uses of NO-releasing nanoparticles for biomedical purposes and the variety of nanomaterials developed as carrier systems of agrochemicals, the potential applications of nanocarriers for NO delivery in plants have not yet been tested. Herein, we report the synthesis and characterization of chitosan nanoparticles (CS NPs) containing the NO donor S-nitroso-mercaptosuccinic acid (S-nitroso-MSA). The efficiency of these NO-releasing NPs in mitigating the deleterious effects of salinity on maize plants was compared to that of the non-encapsulated NO donor. The NPs were synthesized through ionotropic gelation process, and mercaptosuccinic acid (MSA), the NO donor precursor, was encapsulated into CS NPs (91.07% encapsulation efficiency). Free thiol groups of MSA-CS NPs were nitrosated, leading to S-nitroso-MSA-CS NPs (NO-releasing NPs). The incorporation of S-nitroso-MSA into CS NPs allowed a sustained NO release. Treatments of salt-stressed maize plants with S-nitroso-MSA-CS NPs resulted in a higher leaf S-nitrosothiols content compared to that of free S-nitroso-MSA. Moreover, S-nitroso-MSA-CS NPs were more efficient than was the free NO donor in the amelioration of the deleterious effects of salinity in photosystem II activity, chlorophyll content and growth of maize plants because the protective action of the nanoencapsulated S-nitroso-MSA was achieved at lower dosages. Overall, these results demonstrate the positive impact of S-nitroso-MSA nanoencapsulation in increasing NO bioactivity in maize plants under salt stress.

  8. Alleviation of Osmotic Stress Effects by Exogenous Application of Salicylic or Abscisic Acid on Wheat Seedlings

    PubMed Central

    Marcińska, Izabela; Czyczyło-Mysza, Ilona; Skrzypek, Edyta; Grzesiak, Maciej T.; Janowiak, Franciszek; Filek, Maria; Dziurka, Michał; Dziurka, Kinga; Waligórski, Piotr; Juzoń, Katarzyna; Cyganek, Katarzyna; Grzesiak, Stanisław

    2013-01-01

    The aim of the study was to assess the role of salicylic acid (SA) and abscisic acid (ABA) in osmotic stress tolerance of wheat seedlings. This was accomplished by determining the impact of the acids applied exogenously on seedlings grown under osmotic stress in hydroponics. The investigation was unique in its comprehensiveness, examining changes under osmotic stress and other conditions, and testing a number of parameters simultaneously. In both drought susceptible (SQ1) and drought resistant (CS) wheat cultivars, significant physiological and biochemical changes were observed upon the addition of SA (0.05 mM) or ABA (0.1 μM) to solutions containing half-strength Hoagland medium and PEG 6000 (−0.75 MPa). The most noticeable result of supplementing SA or ABA to the medium (PEG + SA and PEG + ABA) was a decrease in the length of leaves and roots in both cultivars. While PEG treatment reduced gas exchange parameters, chlorophyll content in CS, and osmotic potential, and conversely, increased lipid peroxidation, soluble carbohydrates in SQ1, proline content in both cultivars and total antioxidants activity in SQ1, PEG + SA or PEG + ABA did not change the values of these parameters. Furthermore, PEG caused a two-fold increase of endogenous ABA content in SQ1 and a four-fold increase in CS. PEG + ABA increased endogenous ABA only in SQ1, whereas PEG + SA caused a greater increase of ABA content in both cultivars compared to PEG. In PEG-treated plants growing until the harvest, a greater decrease of yield components was observed in SQ1 than in CS. PEG + SA, and particularly PEG + ABA, caused a greater increase of these yield parameters in CS compared to SQ1. In conclusion, SA and ABA ameliorate, particularly in the tolerant wheat cultivar, the harmful effects and after effects of osmotic stress induced by PEG in hydroponics through better osmotic adjustment achieved by an increase in proline and carbohydrate content as well as by an increase in antioxidant activity

  9. Plant Leucine Aminopeptidases Moonlight as Molecular Chaperones to Alleviate Stress-induced Damage*

    PubMed Central

    Scranton, Melissa A.; Yee, Ashley; Park, Sang-Youl; Walling, Linda L.

    2012-01-01

    Leucine aminopeptidases (LAPs) are present in animals, plants, and microbes. In plants, there are two classes of LAPs. The neutral LAPs (LAP-N and its orthologs) are constitutively expressed and detected in all plants, whereas the stress-induced acidic LAPs (LAP-A) are expressed only in a subset of the Solanaceae. LAPs have a role in insect defense and act as a regulator of the late branch of wound signaling in Solanum lycopersicum (tomato). Although the mechanism of LAP-A action is unknown, it has been presumed that LAP peptidase activity is essential for regulating wound signaling. Here we show that plant LAPs are bifunctional. Using three assays to monitor protein protection from heat-induced damage, it was shown that the tomato LAP-A and LAP-N and the Arabidopsis thaliana LAP1 and LAP2 are molecular chaperones. Assays using LAP-A catalytic site mutants demonstrated that LAP-A chaperone activity was independent of its peptidase activity. Furthermore, disruption of the LAP-A hexameric structure increased chaperone activity. Together, these data identify a new class of molecular chaperones and a new function for the plant LAPs as well as suggesting new mechanisms for LAP action in the defense of solanaceous plants against stress. PMID:22493451

  10. Dioscin alleviates dimethylnitrosamine-induced acute liver injury through regulating apoptosis, oxidative stress and inflammation.

    PubMed

    Zhang, Weixin; Yin, Lianhong; Tao, Xufeng; Xu, Lina; Zheng, Lingli; Han, Xu; Xu, Youwei; Wang, Changyuan; Peng, Jinyong

    2016-07-01

    In our previous study, the effects of dioscin against alcohol-, carbon tetrachloride- and acetaminophen-induced liver damage have been found. However, the activity of it against dimethylnitrosamine (DMN)-induced acute liver injury remained unknown. In the present study, dioscin markedly decreased serum ALT and AST levels, significantly increased the levels of SOD, GSH-Px, GSH, and decreased the levels of MDA, iNOS and NO. Mechanism study showed that dioscin significantly decreased the expression levels of IL-1β, IL-6, TNF-α, IκBα, p50 and p65 through regulating TLR4/MyD88 pathway to rehabilitate inflammation. In addition, dioscin markedly up-regulated the expression levels of SIRT1, HO-1, NQO1, GST and GCLM through increasing nuclear translocation of Nrf2 against oxidative stress. Furthermore, dioscin significantly decreased the expression levels of FasL, Fas, p53, Bak, Caspase-3/9, and upregulated Bcl-2 level through decreasing IRF9 level against apoptosis. In conclusion, dioscin showed protective effect against DMN-induced acute liver injury via ameliorating apoptosis, oxidative stress and inflammation, which should be developed as a new candidate for the treatment of acute liver injury in the future.

  11. Chronic Oral Pelargonidin Alleviates Streptozotocin-Induced Diabetic Neuropathic Hyperalgesia in Rat: Involvement of Oxidative Stress

    PubMed Central

    Mirshekar, Mohammadali; Roghani, Mehrdad; Khalili, Mohsen; Baluchnejadmojarad, Tourandokht; Arab Moazzen, Saiedeh

    2010-01-01

    Background: Diabetes mellitus in some clinical cases is accompanied with hyperalgesia. In this study, we evaluated the possible beneficial effect of chronic pelargonidin (PG) treatment on hyperalgesia in streptozotocin (STZ)-diabetic neuropathic rat. Methods: Male Wistar rats (n = 56) were divided into seven groups, i.e. control, diabetic, PG-treated control, PG (single- and multiple-dose)-treated diabetic, and sodium salicylate-treated control and diabetics. For induction of diabetes, STZ was injected i.p. at a single dose of 60 mg/kg. PG was orally administered at a dose of 10 mg/kg once and/or on alternate days for 8 weeks; 1 week after diabetes induction. After two months, hyperalgesia was assessed using standard formalin and hot tail immersion tests. Meanwhile, markers of oxidative stress in brain were measured. One-way analysis of variance was used for statistical analysis of the data. Results: Diabetic rats showed a marked chemical and thermal hyperalgesia, indicating that development of diabetic neuropathy and PG treatment (especially multiple-doses) significantly ameliorated the alteration in hyperalgesia (P<0.05-0.01) in diabetic rats as compared to untreated diabetics. PG (multiple doses) also significantly decreased diabetes-induced thiobarbituric acid reactive substances formation and non-significantly reversed elevation of nitrite level and reduction of antioxidant defensive enzyme superoxide dismutase. Conclusion: These results clearly suggest that PG prevents diabetic neuropathic hyperalgesia through attenuation of oxidative stress. PMID:20683496

  12. Olanzapine alleviates oxidative stress in the liver of socially isolated rats.

    PubMed

    Stanisavljevic, Andrijana; Peric, Ivana; Pantelic, Marija; Filipovic, Dragana M

    2016-12-22

    Olanzapine, an antipsychotic drug, is used to treat depressive disorder, but its effects on the liver, the main site of drug metabolism, still remain elusive. We studied the effects of 3 weeks of olanzapine treatment (7.5 mg/kg per day) on the malondialdehyde (MDA) and protein carbonyl (PCO) contents, protein expression of copper/zinc superoxide dismutase (CuZnSOD), and activity of total superoxide dismutase (SOD), as well as catalase (CAT) protein expression and activity levels in the liver cytosol of rats exposed to 6 weeks of chronic social isolation (CSIS), which causes depressive- and anxiety-like behaviors. Increased cytosolic MDA in CSIS rats (vehicle- or olanzapine-treated) indicated hepatic oxidative stress. Increase in PCO and CAT activity associated with unchanged total SOD activity following CSIS also confirm the presence of oxidative stress. Chronic olanzapine treatment in CSIS prevented increase in PCO without an effect on MDA content. Increased SOD activity in olanzapine-treated (controls and CSIS) groups compared with corresponding vehicle-treated groups and decreased CAT activity in olanzapine-treated CSIS rats compared with vehicle-treated CSIS group was found. The data suggest that chronic olanzapine treatment has a protective effect on hepatic protein oxidation and improves antioxidant defense. The beneficial effects of olanzapine may be due to its free radical scavenging properties and antioxidant activity.

  13. Plant leucine aminopeptidases moonlight as molecular chaperones to alleviate stress-induced damage.

    PubMed

    Scranton, Melissa A; Yee, Ashley; Park, Sang-Youl; Walling, Linda L

    2012-05-25

    Leucine aminopeptidases (LAPs) are present in animals, plants, and microbes. In plants, there are two classes of LAPs. The neutral LAPs (LAP-N and its orthologs) are constitutively expressed and detected in all plants, whereas the stress-induced acidic LAPs (LAP-A) are expressed only in a subset of the Solanaceae. LAPs have a role in insect defense and act as a regulator of the late branch of wound signaling in Solanum lycopersicum (tomato). Although the mechanism of LAP-A action is unknown, it has been presumed that LAP peptidase activity is essential for regulating wound signaling. Here we show that plant LAPs are bifunctional. Using three assays to monitor protein protection from heat-induced damage, it was shown that the tomato LAP-A and LAP-N and the Arabidopsis thaliana LAP1 and LAP2 are molecular chaperones. Assays using LAP-A catalytic site mutants demonstrated that LAP-A chaperone activity was independent of its peptidase activity. Furthermore, disruption of the LAP-A hexameric structure increased chaperone activity. Together, these data identify a new class of molecular chaperones and a new function for the plant LAPs as well as suggesting new mechanisms for LAP action in the defense of solanaceous plants against stress.

  14. Carvedilol alleviates adjuvant-induced arthritis and subcutaneous air pouch edema: Modulation of oxidative stress and inflammatory mediators

    SciTech Connect

    Arab, Hany H.; El-Sawalhi, Maha M.

    2013-04-15

    Rheumatoid arthritis (RA) is a systemic inflammatory disease with cardiovascular complications as the leading cause of morbidity. Carvedilol is an adrenergic antagonist which has been safely used in treatment of several cardiovascular disorders. Given that carvedilol has powerful antioxidant/anti-inflammatory properties, we aimed to investigate its protective potential against arthritis that may add further benefits for its clinical usefulness especially in RA patients with concomitant cardiovascular disorders. Two models were studied in the same rat; adjuvant arthritis and subcutaneous air pouch edema. Carvedilol (10 mg/kg/day p.o. for 21 days) effectively suppressed inflammation in both models with comparable efficacy to the standard anti-inflammatory diclofenac (5 mg/kg/day p.o.). Notably, carvedilol inhibited paw edema and abrogated the leukocyte invasion to air pouch exudates. The latter observation was confirmed by the histopathological assessment of the pouch lining that revealed mitigation of immuno-inflammatory cell influx. Carvedilol reduced/normalized oxidative stress markers (lipid peroxides, nitric oxide and protein thiols) and lowered the release of inflammatory cytokines (TNF-α and IL-6), and eicosanoids (PGE{sub 2} and LTB{sub 4}) in sera and exudates of arthritic rats. Interestingly, carvedilol, per se, didn't present any effect on assessed biochemical parameters in normal rats. Together, the current study highlights evidences for the promising anti-arthritic effects of carvedilol that could be mediated through attenuation of leukocyte migration, alleviation of oxidative stress and suppression of proinflammatory cytokines and eicosanoids. - Highlights: ► Carvedilol possesses promising anti-arthritic properties. ► It markedly suppressed inflammation in adjuvant arthritis and air pouch edema. ► It abrogated the leukocyte invasion to air pouch exudates and linings. ► It reduced/normalized oxidative stress markers in sera and exudates of

  15. Alleviative effect of myricetin on ochratoxin A-induced oxidative stress in rat renal cortex: histological and biochemical study.

    PubMed

    El-Haleem, Manal R Abdel; Kattaia, Asmaa A A; El-Baset, Samia A Abdel; Mostafa, Heba El Sayed

    2016-04-01

    Ochratoxins (OTA) are secondary metabolites of Aspergillus and Penicillium. The detoxification of OTA has been of major interest due to its widespread threat to human health. We aimed to investigate the possible alleviative effect of myricetin (MYR) against OTA-induced damage in renal cortex of rats. Thirty adult male albino rats were randomized into five equal groups: control (untreated), vehicle control (0.5 ml corn oil/day including dimethylsulfoxide [DMSO]), MYR (100 mg MYR/kg b.w./day in distilled water), OTA (0.5 mg OTA/kg b.w./day; dissolved in 10% DMSO and then corn oil) and OTA + MYR group (received OTA and MYR at similar doses). All treatments were given by oral gavage for 2 weeks. At the end of the experiment, renal cortices were processed for light and electron microscope examinations. Immunohistochemical staining for localization of proliferating cell nuclear antigen (PCNA), p53 and transforming growth factor beta 1 (TGF-β1) was carried out. Biochemical analysis of tissue glutathione peroxidase (GPX), catalase (CAT) and superoxide dismutase (SOD) were determined to evaluate oxidative stress. OTA administration induced deleterious renal injury evidenced by the structural and ultra-structural changes. Immunohistochemical expression of p53, PCNA and TGF-β1 were significantly up regulated compared with control. Alterations in antioxidant parameters supported that oxidative stress was one of the mechanisms involved in OTA toxicity. On the contrary, co-administration of MRY partially ameliorated OTA-induced renal injury. We suggest the potential effectiveness of MYR to counteract OTA-induced toxic oxidative stress on the renal cortex.

  16. Arbuscular mycorrhizal symbiosis elicits shoot proteome changes that are modified during cadmium stress alleviation in Medicago truncatula

    PubMed Central

    2011-01-01

    Background Arbuscular mycorrhizal (AM) fungi, which engage a mutualistic symbiosis with the roots of most plant species, have received much attention for their ability to alleviate heavy metal stress in plants, including cadmium (Cd). While the molecular bases of Cd tolerance displayed by mycorrhizal plants have been extensively analysed in roots, very little is known regarding the mechanisms by which legume aboveground organs can escape metal toxicity upon AM symbiosis. As a model system to address this question, we used Glomus irregulare-colonised Medicago truncatula plants, which were previously shown to accumulate and tolerate heavy metal in their shoots when grown in a substrate spiked with 2 mg Cd kg-1. Results The measurement of three indicators for metal phytoextraction showed that shoots of mycorrhizal M. truncatula plants have a capacity for extracting Cd that is not related to an increase in root-to-shoot translocation rate, but to a high level of allocation plasticity. When analysing the photosynthetic performance in metal-treated mycorrhizal plants relative to those only Cd-supplied, it turned out that the presence of G. irregulare partially alleviated the negative effects of Cd on photosynthesis. To test the mechanisms by which shoots of Cd-treated mycorrhizal plants avoid metal toxicity, we performed a 2-DE/MALDI/TOF-based comparative proteomic analysis of the M. truncatula shoot responses upon mycorrhization and Cd exposure. Whereas the metal-responsive shoot proteins currently identified in non-mycorrhizal M. truncatula indicated that Cd impaired CO2 assimilation, the mycorrhiza-responsive shoot proteome was characterised by an increase in photosynthesis-related proteins coupled to a reduction in glugoneogenesis/glycolysis and antioxidant processes. By contrast, Cd was found to trigger the opposite response coupled the up-accumulation of molecular chaperones in shoot of mycorrhizal plants relative to those metal-free. Conclusion Besides drawing a

  17. Factors involved in alleviating water stress by partial crop removal in pear trees.

    PubMed

    Marsal, Jordi; Mata, Merce; Arbones, Amadeu; Del Campo, Jesus; Girona, Joan; Lopez, Gerardo

    2008-09-01

    We studied the relief of water stress associated with fruit thinning in pear (Pyrus communis L.) trees during drought to determine what mechanisms, other than stomatal adjustment, were involved. Combinations of control irrigation (equal to crop water use less effective rainfall) and deficit irrigation (equal to 20% of control irrigation), fruit load (unthinned and thinned to 40 fruits per tree) and root pruning (pruned and unpruned) treatments were applied to pear (cv. 'Conference') trees during Stage II of fruit development. Daily patterns of midday stem water potential (Psi(stem)) and leaf conductance to water vapor (g(l)) of deficit-irrigated trees differed after fruit thinning. In response to fruit thinning, gl progressively declined with water stress until 30 days after fruit thinning and then leveled off, whereas the effects of decreased fruit load on Psi(stem) peaked 30-40 days after fruit thinning and then tended to decline. Soil water depletion was significantly correlated with fruit load during drought. Our results indicate that stomatal adjustment and the resulting soil water conservation were the factors determining the Psi(stem) response to fruit thinning. However, these factors could not explain differences in daily patterns between g(l) and Psi(stem) after fruit thinning. In all cases, effects of root pruning treatments on Psi(stem) in deficit-irrigated trees were transitory (Psi(stem) recovered from root pruning in less than 30 days), but the recovery of Psi(stem) after root pruning was faster in trees with low fruit loads. This behavior is compatible with the concept that the water balance (reflected by Psi(stem) values) was better in trees with low fruit loads compared with unthinned trees, perhaps because more carbon was available for root growth. Thus, a root growth component is hypothesized as a mechanism to explain the bimodal Psi(stem) response to fruit thinning during drought.

  18. Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress

    PubMed Central

    Hassan, Hozeifa M.; Guo, Hongli; Yousef, Bashir A.; Ping-Ping, Ding; Zhang, Luyong; Jiang, Zhenzhou

    2017-01-01

    Isoniazid (INH) remains a cornerstone key constitute of the current tuberculosis management strategy, but its hepatotoxic potentiality remains a significant clinical problem. Our previous findings succeed to establish a rat model of INH hepatotoxicity employing the inflammatory stress theory in which non-injurious doses of inflammatory-mediating agent bacterial lipopolysaccharides (LPS) augmented the toxicity of INH that assist to uncover the mechanisms behind INH hepatotoxicity. Following LPS exposure, several inflammatory cells are activated and it is likely that the consequences of this activation rather than direct hepatocellular effects of LPS underlie the ability of LPS to augment toxic responses. In this study, we investigated the potential protective role of the anti-inflammatory agent dexamethasone (DEX), a potent synthetic glucocorticoid, in INH/LPS hepatotoxic rat model. DEX pre-treatment successfully eliminates the components of the inflammatory stress as shown through analysis of blood biochemistry and liver histopathology. DEX potentiated hepatic anti-oxidant mechanisms while serum and hepatic lipid profiles were reduced. However, DEX administration was not able to revoke the principal effects of cytochrome P450 2E1 (CYP2E1) in INH/LPS-induced liver damage. In conclusion, this study illustrated the DEX-preventive capabilities on INH/LPS-induced hepatotoxicity model through DEX-induced potent anti-inflammatory activity whereas the partial toxicity seen in the model could be attributed to the expression of hepatic CYP2E1. These findings potentiate the clinical applications of DEX co-administration with INH therapy in order to reduce the potential incidences of hepatotoxicity. PMID:28360859

  19. 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

  20. 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.

  1. 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.

  2. Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy

    PubMed Central

    Zhang, Bin; Shen, Qiang; Chen, Yaping; Pan, Ruile; Kuang, Shihuan; Liu, Guiyan; Sun, Guibo; Sun, Xiaobo

    2017-01-01

    Diabetic cardiomyopathy (DCM) has been increasingly considered as a main cause of heart failure and death in diabetic patients. At present, no effective treatment exists to prevent its development. In the present study, we describe the potential protective effects and mechanisms of myricitrin (Myr) on the cardiac function of streptozotosin-induced diabetic mice and on advanced glycation end products (AGEs)-induced H9c2 cardiomyocytes. In vitro experiments revealed that pretreatment with Myr significantly decreased AGEs-induced inflammatory cytokine expression, limited an increase in ROS levels, and reduced cell apoptosis, fibrosis, and hypertrophy in H9c2 cells. These effects are correlated with Nrf2 activation and NF-κB inhibition. In vivo investigation demonstrated that oral administration of Myr at 300 mg/kg/day for 8 weeks remarkably decreased the expression of enzymes associated with cardiomyopathy, as well as the expression of inflammatory cytokines and apoptotic proteins. Finally, Myr improved diastolic dysfunction and attenuated histological abnormalities. Mechanistically, Myr attenuated diabetes-induced Nrf2 inhibition via the regulation of Akt and ERK phosphorylation in the diabetic heart. Collectively, these results strongly indicate that Myr exerts cardioprotective effects against DCM through the blockage of inflammation, oxidative stress, and apoptosis. This suggests that Myr might be a potential therapeutic agent for the treatment of DCM. PMID:28287141

  3. Autophagy protects intestinal epithelial cells against deoxynivalenol toxicity by alleviating oxidative stress via IKK signaling pathway.

    PubMed

    Tang, Yulong; Li, Jianjun; Li, Fengna; Hu, Chien-An A; Liao, Peng; Tan, Kunrong; Tan, Bie; Xiong, Xia; Liu, Gang; Li, Tiejun; Yin, Yulong

    2015-12-01

    Autophagy is an intracellular process of homeostatic degradation that promotes cell survival under various stressors. Deoxynivalenol (DON), a fungal toxin, often causes diarrhea and disturbs the homeostasis of the intestinal system. To investigate the function of intestinal autophagy in response to DON and associated mechanisms, we firstly knocked out ATG5 (autophagy-related gene 5) in porcine intestinal epithelial cells (IPEC-J2) using CRISPR-Cas9 technology. When treated with DON, autophagy was induced in IPEC-J2 cells but not in IPEC-J2.Atg5ko cells. The deficiency in autophagy increased DON-induced apoptosis in IPEC-J2.atg5ko cells, in part, through the generation of reactive oxygen species (ROS). The cellular stress response can be restored in IPEC-J2.atg5ko cells by overexpressing proteins involved in protein folding. Interestingly, we found that autophagy deficiency downregulated the expression of endoplasmic reticulum folding proteins BiP and PDI when IPEC-J2.atg5ko cells were treated with DON. In addition, we investigated the molecular mechanism of autophagy involved in the IKK, AMPK, and mTOR signaling pathway and found that Bay-117082 and Compound C, specific inhibitors for IKK and AMPK, respectively, inhibited the induction of autophagy. Taken together, our results suggest that autophagy is pivotal for protection against DON in pig intestinal cells.

  4. Alleviation of iron induced oxidative stress by the grape fruit flavanone naringin in vitro.

    PubMed

    Jagetia, Ganesh Chandra; Reddy, Tiyagura Koti

    2011-04-25

    Iron is an essential element that participates in several metabolic activities of cells; however, excess iron is a major cause of iron-induced oxidative stress and several human diseases. The protective effect of naringin, a grape fruit flavanone, was studied in iron overloaded isolated mouse liver mitochondria, where the isolated mitochondrial fraction was incubated with various concentrations of naringin before ferric ion loading. Iron overloading of mitochondrial fraction resulted in an increase in lipid peroxidation, protein oxidation, and DNA damage, whereas iron overload reduced the glutathione (GSH) concentration, glutathione-S-transferase (GST), glutathione peroxidase (GSHPx), catalase and superoxide dismutase (SOD) activities. Pretreatment of mitochondrial fraction with naringin inhibited iron-induced lipid peroxidation, protein oxidation, and DNA damage. Conversely, naringin supplementation arrested iron-induced depletion in the GSH contents, GSHPx, GST, SOD and catalase activities significantly. Ferric iron reduction assay revealed that naringin could not reduce ferric iron into ferrous iron indicating that it did not exhibit prooxidant activity. Iron free coordination site assay indicated that naringin was unable to occupy all the active sites of iron indicating that naringin did not completely chelate iron. Our study demonstrates that naringin was able to share the burden of endogenous oxidants by inhibiting the iron-induced depletion of all important antioxidant enzymes as well as GSH and may act as a good antioxidant.

  5. Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy.

    PubMed

    Zhang, Bin; Shen, Qiang; Chen, Yaping; Pan, Ruile; Kuang, Shihuan; Liu, Guiyan; Sun, Guibo; Sun, Xiaobo

    2017-03-13

    Diabetic cardiomyopathy (DCM) has been increasingly considered as a main cause of heart failure and death in diabetic patients. At present, no effective treatment exists to prevent its development. In the present study, we describe the potential protective effects and mechanisms of myricitrin (Myr) on the cardiac function of streptozotosin-induced diabetic mice and on advanced glycation end products (AGEs)-induced H9c2 cardiomyocytes. In vitro experiments revealed that pretreatment with Myr significantly decreased AGEs-induced inflammatory cytokine expression, limited an increase in ROS levels, and reduced cell apoptosis, fibrosis, and hypertrophy in H9c2 cells. These effects are correlated with Nrf2 activation and NF-κB inhibition. In vivo investigation demonstrated that oral administration of Myr at 300 mg/kg/day for 8 weeks remarkably decreased the expression of enzymes associated with cardiomyopathy, as well as the expression of inflammatory cytokines and apoptotic proteins. Finally, Myr improved diastolic dysfunction and attenuated histological abnormalities. Mechanistically, Myr attenuated diabetes-induced Nrf2 inhibition via the regulation of Akt and ERK phosphorylation in the diabetic heart. Collectively, these results strongly indicate that Myr exerts cardioprotective effects against DCM through the blockage of inflammation, oxidative stress, and apoptosis. This suggests that Myr might be a potential therapeutic agent for the treatment of DCM.

  6. Epalrestat protects against diabetic peripheral neuropathy by alleviating oxidative stress and inhibiting polyol pathway

    PubMed Central

    Li, Qing-rong; Wang, Zhuo; Zhou, Wei; Fan, Shou-rui; Ma, Run; Xue, Li; Yang, Lu; Li, Ya-shan; Tan, Hong-li; Shao, Qing-hua; Yang, Hong-ying

    2016-01-01

    Epalrestat is a noncompetitive and reversible aldose reductase inhibitor used for the treatment of diabetic neuropathy. This study assumed that epalrestat had a protective effect on diabetic peripheral nerve injury by suppressing the expression of aldose reductase in peripheral nerves of diabetes mellitus rats. The high-fat and high-carbohydrate model rats were established by intraperitoneal injection of streptozotocin. Peripheral neuropathy occurred in these rats after sustaining high blood glucose for 8 weeks. At 12 weeks after streptozotocin injection, rats were intragastrically administered epalrestat 100 mg/kg daily for 6 weeks. Transmission electron microscope revealed that the injuries to myelinated nerve fibers, non-myelinated nerve fibers and Schwann cells of rat sciatic nerves had reduced compared to rats without epalrestat administuation. Western blot assay and immunohistochemical results demonstrated that after intervention with epalrestat, the activities of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase gradually increased, but aldose reductase protein expression gradually diminished. Results confirmed that epalrestat could protect against diabetic peripheral neuropathy by relieving oxidative stress and suppressing the polyol pathway. PMID:27073391

  7. Oxidative Stress Alleviation by Sage Essential Oil in Co-amoxiclav induced Hepatotoxicity in Rats.

    PubMed

    El-Hosseiny, L S; Alqurashy, N N; Sheweita, S A

    2016-06-01

    Clinical studies have shown that several classes of antibiotics are evidenced in drug induced liver injury. The combination of amoxicillin with clavulanic acid is commonly cited in such cases. Accordingly, the present study investigated the potential hepatoprotective and in vivo antioxidant efficacy of sage essential oil in Co-amoxiclav induced hepatotoxicity in rats. Sage essential oil was hydrodistilled from the aerial parts of Salvia officinalis L. and its compositional analysis was characterized by Gas chromatography-Mass spectroscopy. Rats were treated singly or concomitantly with Co-amoxiclav and sage essential oil for a period of seven days. The major components of sage oil as identified by GC-MS were 1,8-cineole, β-pinene, camphor, β-caryophyllene, α-pinene and α-caryophyllene comprising 26.3%, 14.4%, 10.9%, 7.8%, 6% and 2.5% respectively. The in vivo exposure of rats to Co-amoxiclav resulted in hepatotoxicity biochemically evidenced by the significant elevation of serum AST, ALT, ALP, γ-GT, total bilirubin and histologically conveyed by hydropic, inflammatory and cholestatic changes in rats' liver. Oxidative stress mediated the hepatic injury as indicated by the significant escalation in lipid peroxidation, as well as, the significant depletion of both glutathione level and glutathione dependent enzymes' activities. The concomitant administration of sage essential oil with Co-amoxiclav exerted a hepatoprotective effect via inducing an in vivo antioxidant defense response eventually regressing, to some extent, the hepatoarchitectural changes induced by Co-amoxiclav. Results suggest that sage essential oil is a potential candidate for counteracting hepatic injury associating Co-amoxiclav and this effect is in part related to the complexity of its chemical composition.

  8. Oxidative Stress Alleviation by Sage Essential Oil in Co-amoxiclav induced Hepatotoxicity in Rats

    PubMed Central

    El-Hosseiny, L. S.; Alqurashy, N. N.; Sheweita, S. A.

    2016-01-01

    Clinical studies have shown that several classes of antibiotics are evidenced in drug induced liver injury. The combination of amoxicillin with clavulanic acid is commonly cited in such cases. Accordingly, the present study investigated the potential hepatoprotective and in vivo antioxidant efficacy of sage essential oil in Co-amoxiclav induced hepatotoxicity in rats. Sage essential oil was hydrodistilled from the aerial parts of Salvia officinalis L. and its compositional analysis was characterized by Gas chromatography-Mass spectroscopy. Rats were treated singly or concomitantly with Co-amoxiclav and sage essential oil for a period of seven days. The major components of sage oil as identified by GC-MS were 1,8-cineole, β-pinene, camphor, β-caryophyllene, α-pinene and α-caryophyllene comprising 26.3%, 14.4%, 10.9%, 7.8%, 6% and 2.5% respectively. The in vivo exposure of rats to Co-amoxiclav resulted in hepatotoxicity biochemically evidenced by the significant elevation of serum AST, ALT, ALP, γ-GT, total bilirubin and histologically conveyed by hydropic, inflammatory and cholestatic changes in rats’ liver. Oxidative stress mediated the hepatic injury as indicated by the significant escalation in lipid peroxidation, as well as, the significant depletion of both glutathione level and glutathione dependent enzymes’ activities. The concomitant administration of sage essential oil with Co-amoxiclav exerted a hepatoprotective effect via inducing an in vivo antioxidant defense response eventually regressing, to some extent, the hepatoarchitectural changes induced by Co-amoxiclav. Results suggest that sage essential oil is a potential candidate for counteracting hepatic injury associating Co-amoxiclav and this effect is in part related to the complexity of its chemical composition. PMID:27493593

  9. 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

  10. Cerium oxide nanoparticles alleviate oxidative stress and decreases Nrf-2/HO-1 in D-GALN/LPS induced hepatotoxicity.

    PubMed

    Hashem, Reem M; Rashd, Laila A; Hashem, Khalid S; Soliman, Hatem M

    2015-07-01

    Translocation of the master regulator of antioxidant-response element-driven antioxidant gene, nuclear factor erythroid 2 (Nrf-2) from the cytoplasm into the nucleus and triggering the transcription of hemoxygenase-1 (HO-1) to counteract the oxidative stress is a key feature in D-galactoseamine and lipopolysaccharide (D-GALN/LPS) induced hepatotoxicity. We mainly aimed to study the effect of cerium oxide (CeO2) nanoparticles on Nrf-2/HO-1 pathway whereas; it has previously shown to have an antioxidant effect in liver models. Administration of CeO2 nanoparticles significantly decreased the translocation of the cytoplasmic Nrf-2 with a concomitant decrement in the gene expression of HO-1 as it reveals a powerful antioxidative effect as indicated by the significant increase in the levels of glutathione (GSH), glutathione peroxidase (GPX1), glutathione reductase (GR), superoxide dismutase (SOD) and catalase. In synchronization, a substantial decrement in the levels of inducible nitric oxide synthase (iNOS), TBARS and percentage of DNA fragmentation was established. These results were confirmed by histopathology examination which showed a severe degeneration, haemorrhages, widened sinusoids and focal leukocyte infiltration in D-GALN/LPS treatment and these features were alleviated with CeO2 administration. In conclusion, CeO2 is a potential antioxidant that can effectively decrease the translocation of the cytoplasmic Nrf-2 into the nucleus and decrease HO-1 in D-GALN/LPS induced hepatotoxicity.

  11. Progesterone alleviates acute brain injury via reducing apoptosis and oxidative stress in a rat experimental subarachnoid hemorrhage model.

    PubMed

    Cai, Jing; Cao, Shenglong; Chen, Jingyin; Yan, Feng; Chen, Gao; Dai, Yuying

    2015-07-23

    This study aimed to investigate the therapeutic effect of progesterone on acute brain injury after subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage was induced in male Sprague-Dawley rats (n=72) by endovascular perforation. Progesterone (8 mg/kg or 16 mg/kg) was administered to rats at 1, 6, and 12h after SAH. Mortality, neurologic deficits, cell apoptosis, expression of apoptotic markers, the level of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were assayed at 24h after experimental SAH. Mortality, cell apoptosis and the expression of caspase-3 were decreased, and improved neurological function was observed in the progesterone-treated SAH rats. Further, exploration demonstrated that progesterone significantly reduced the ratio of Bax/Bcl-2 and attenuated the release of cytochrome c from mitochondria. Progesterone also induced anti-oxidative effects by elevating the activity of SOD and decreasing MDA content after SAH. Furthermore, dose-response relationships for progesterone treatment were observed, and high doses of progesterone enhanced the neuroprotective effects. Progesterone treatment could alleviate acute brain injury after SAH by inhibiting cell apoptosis and decreasing damage due to oxidative stress. The mechanism involved in the anti-apoptotic effect was related to the mitochondrial pathway. These results indicate that progesterone possesses the potential to be a novel therapeutic agent for the treatment of acute brain injury after SAH.

  12. Alleviation of drought stress by mycorrhizas is related to increased root H2O2 efflux in trifoliate orange

    PubMed Central

    Huang, Yong-Ming; Zou, Ying-Ning; Wu, Qiang-Sheng

    2017-01-01

    The Non-invasive Micro-test Technique (NMT) is used to measure dynamic changes of specific ions/molecules non-invasively, but information about hydrogen peroxide (H2O2) fluxes in different classes of roots by mycorrhiza is scarce in terms of NMT. Effects of Funneliformis mosseae on plant growth, H2O2, superoxide radical (O2·−), malondialdehyde (MDA) concentrations, and H2O2 fluxes in the taproot (TR) and lateral roots (LRs) of trifoliate orange seedlings under well-watered (WW) and drought stress (DS) conditions were studied. DS strongly inhibited mycorrhizal colonization in the TR and LRs, whereas mycorrhizal inoculation significantly promoted plant growth and biomass production. H2O2, O2·−, and MDA concentrations in leaves and roots were dramatically lower in mycorrhizal seedlings than in non-mycorrhizal seedlings under DS. Compared with non-mycorrhizal seedlings, mycorrhizal seedlings had relatively higher net root H2O2 effluxes in the TR and LRs especially under WW, as well as significantly higher total root H2O2 effluxes in the TR and LRs under WW and DS. Total root H2O2 effluxes were significantly positively correlated with root colonization but negatively with root H2O2 and MDA concentrations. It suggested that mycorrhizas induces more H2O2 effluxes of the TR and LRs, thus, alleviating oxidative damage of DS in the host plant. PMID:28176859

  13. 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

  14. Aminoguanidine alleviated MMA-induced impairment of cognitive ability in rats by downregulating oxidative stress and inflammatory reaction.

    PubMed

    Li, Qiliang; Song, Wenqi; Tian, Ze; Wang, Peichang

    2017-02-13

    Methylmalonic acidemia (MMA) is the most common organic acidemia in childhood. Many "treated" patients continued to display various degrees of mental retardation and psychomotor delay, which could be caused by brain damage from elevated oxidative stress. Aminoguanidine (AG), a synthetic antioxidant, was tested in a MMA rat model for its potential therapeutic effects on memory impairment. The effects of AG on MMA-induced cognitive impairment in Wistar rats were evaluated with Morris Water Maze. The levels of nerve cell apoptosis and microglial activation were investigated to illustrate the mechanisms of the improvement of cognition with AG treatment in MMA rats. To further explore the mechanism of neuroprotection induced by AG, several biomarkers including free radicals and inflammatory cytokines in the hippocampus were quantified. The results showed that the rats treated with AG exhibited better neurological behavior performances than MMA model rats. The AG-treated rats had a decreased level of apoptosis of the hippocampal neurons, which could be the structural basis of the observed neural behavior protection. In addition, AG treatment significantly inhibited the activation of microglia. The AG-treated rats had decreased levels of IL-1β, IL-6, TNF-α, NO, malonaldehyde and iNOS activities in the hippocampus. The level of glutathione and superoxide dismutase activity in the hippocampus of the AG-treated rats increased significantly. In conclusion, AG could alleviate the MMA-induced cognitive impairment via down-regulating of oxidative stress and inflammatory reaction and provide a basis as a therapeutic potential against MMA-induced cognitive impairment.

  15. Higher Ammonium Transamination Capacity Can Alleviate Glutamate Inhibition on Winter Wheat (Triticum aestivum L.) Root Growth under High Ammonium Stress.

    PubMed

    Wang, Feng; Gao, Jingwen; Liu, Yang; Tian, Zhongwei; Muhammad, Abid; Zhang, Yixuan; Jiang, Dong; Cao, Weixing; Dai, Tingbo

    2016-01-01

    Most of the studies about NH4+ stress mechanism simply address the effects of free NH4+, failing to recognize the changed nitrogen assimilation products. The objective of this study was to elucidate the effects of glutamate on root growth under high ammonium (NH4+) conditions in winter wheat (Triticum aestivum L.). Hydroponic experiments were conducted using two wheat cultivars, AK58 (NH4+-sensitive) and Xumai25 (NH4+-tolerant) with either 5 mM NH4+ nitrogen (AN) as stress treatment or 5 mM nitrate (NO3-) nitrogen as control. To evaluate the effects of NH4+-assimilation products on plant growth, 1 μM L-methionine sulfoximine (MSO) (an inhibitor of glutamine synthetase (GS)) and 1 mM glutamates (a primary N assimilation product) were added to the solutions, respectively. The AN significantly reduced plant biomass, total root length, surface area and root volume in both cultivars, but less effect was observed in Xumai25. The inhibition effects were alleviated by the application of MSO but strengthened by the application of glutamate. The AN increased the activities of GS, glutamate dehydrogenase (GDH) in both cultivars, resulting in higher glutamate contents. However, its contents were decreased by the application of MSO. Compared to AK58, Xumai25 showed lower glutamate contents due to its higher activities of glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT). With the indole-3-acetic acid (IAA) contents decreasing in roots, the ratio of shoot to root in IAA was increased, and further increased by the application of glutamate, and reduced by the application of MSO, but the ratio was lower in Xumai25. Meanwhile, the total soluble sugar contents and its root to shoot ratio also showed similar trends. These results indicate that the NH4+-tolerant cultivar has a greater transamination ability to prevent glutamate over-accumulation to maintain higher IAA transport ability, and consequently promoted soluble sugar transport to roots, further

  16. 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.

  17. Selenium and sulfur influence ethylene formation and alleviate cadmium-induced oxidative stress by improving proline and glutathione production in wheat.

    PubMed

    Khan, M Iqbal R; Nazir, Faroza; Asgher, Mohd; Per, Tasir S; Khan, Nafees A

    2015-01-15

    We have studied the influence of selenium (Se) and sulfur (S) in the protection of photosynthetic capacity of wheat (Triticum aestivum) against cadmium (Cd) stress. The involvement of ethylene and its interaction with proline and antioxidant metabolism in the tolerance of plants to Cd stress was evaluated. Application of Se or S alleviated Cd-induced oxidative stress by increasing proline accumulation as a result of increased activity of glutamyl kinase (GK) and decreased activity of proline oxidase (PROX). These nutrients also induced the activity of ATP-sulfurylase and serine acetyl transferase and the content of cysteine (Cys), a precursor for the synthesis of both reduced glutathione (GSH) and ethylene. Further, application of Se and S to plants under Cd stress reduced ethylene level and increased the activity of glutathione reductase (GR) and glutathione peroxidase (GPX), reduced oxidative stress and improved photosynthesis and growth. The involvement of ethylene in Se and S-mediated alleviation of Cd stress was substantiated with the use of ethylene biosynthesis inhibitor aminoethoxyvinylglycine (AVG). The use of AVG reversed the effects of Se and S on ethylene, content of proline and GSH and photosynthesis. The results suggested that Se and S both reversed Cd-induced oxidative stress by regulating ethylene formation, proline and GSH metabolism. Thus, Se or S-induced regulatory interaction between ethylene and proline and GSH metabolism may be used for the reversal of Cd-induced oxidative stress.

  18. 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

  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. 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.

  2. 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

  3. 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.

  4. Alleviation of salt stress in citrus seedlings inoculated with arbuscular mycorrhizal fungi depends on the rootstock salt tolerance.

    PubMed

    Navarro, Josefa M; Pérez-Tornero, Olaya; Morte, Asunción

    2014-01-01

    Seedlings of Cleopatra mandarin (Citrus reshni Hort. ex Tan.) and Alemow (Citrus macrophylla Wester) were inoculated with a mixture of AM fungi (Rhizophagus irregularis and Funneliformis mosseae) (+AM), or left non-inoculated (-AM). From forty-five days after fungal inoculation onwards, half of +AM or -AM plants were irrigated with nutrient solution containing 50 mM NaCl. Three months later, AM significantly increased plant growth in both Cleopatra mandarin and Alemow rootstocks. Plant growth was higher in salinized +AM plants than in non-salinized -AM plants, demonstrating that AM compensates the growth limitations imposed by salinity. Whereas AM-inoculated Cleopatra mandarin seedlings had a very good response under saline treatment, inoculation in Alemow did not alleviate the negative effect of salinity. The beneficial effect of mycorrhization is unrelated with protection against the uptake of Na or Cl and the effect of AM on these ions did not explain the different response of rootstocks. This response was related with the nutritional status since our findings confirm that AM fungi can alter host responses to salinity stress, improving more the P, K, Fe and Cu plant nutrition in Cleopatra mandarin than in Alemow plants. AM inoculation under saline treatments also increased root Mg concentration but it was higher in Cleopatra mandarin than in Alemow. This could explain why AM fungus did not completely recovered chlorophyll concentrations in Alemow and consequently it had lower photosynthesis rate than control plants. AM fungi play an essential role in citrus rootstock growth and biomass production although the intensity of this response depends on the rootstock salinity tolerance.

  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. Argirein alleviates stress-induced and diabetic hypogonadism in rats via normalizing testis endothelin receptor A and connexin 43

    PubMed Central

    Xu, Ming; Hu, Chen; Khan, Hussein-hamed; Shi, Fang-hong; Cong, Xiao-dong; Li, Qing; Dai, Yin; Dai, De-zai

    2016-01-01

    Aim: Argirein (rhein-arginine) is a derivative of rhein isolated from Chinese rhubarb (Rheum Officinale Baill.) that exhibits antioxidant and anti-inflammatory activities. In the present study we investigated the effects of argirein on stress-induced (hypergonadotrophic) and diabetic (hypogonadotrophic) hypogonadism in male rats. Methods: Stress-induced and diabetic hypogonadism was induced in male rats via injection of isoproterenol (ISO) or streptozotocin (STZ). ISO-injected rats were treated with argirein (30 mg·kg−1·d−1, po) or testosterone replacement (0.5 mg·kg−1·d−1, sc) for 5 days, and STZ-injected rats were treated with argirein (40–120 mg·kg−1·d−1, po) or aminoguanidine (100 mg·kg−1·d−1, po) for 4 weeks. After the rats were euthanized, blood samples and testes were collected. Serum hormone levels were measured, and the expression of endothelin receptor A (ETA), connexin 43 (Cx43) and other proteins in testes was detected. For in vitro experiments, testis homogenate was prepared from normal male rats, and incubated with ISO (1 μmol/L) or high glucose (27 mmol/L). Results: ISO injection induced hyper-gonadotrophic hypogonadism characterized by low testosterone and high FSH and LH levels in the serum, whereas STZ injection induced hypogonadotrophic hypogonadism as evidenced by low testosterone and low FSH and LH levels in the serum. In the testes of ISO- and STZ-injected rats, the expression of ETA, MMP-9, NADPH oxidase and pPKCε was significantly increased, and the expression of Cx43 was decreased. Administration of argirein attenuated both the abnormal serum hormone levels and the testis changes in ISO- and STZ-injected rats, and aminoguanidine produced similar actions in STZ-injected rats; testosterone replacement reversed the abnormal serum hormone levels, but did not affect the testis changes in ISO-injected rats. Argirein (0.3–3 μmol/L) exerted similar effects in testis homogenate incubated with ISO or high glucose in

  8. Higher Ammonium Transamination Capacity Can Alleviate Glutamate Inhibition on Winter Wheat (Triticum aestivum L.) Root Growth under High Ammonium Stress

    PubMed Central

    Liu, Yang; Tian, Zhongwei; Muhammad, Abid; Zhang, Yixuan; Jiang, Dong; Cao, Weixing; Dai, Tingbo

    2016-01-01

    Most of the studies about NH4+ stress mechanism simply address the effects of free NH4+, failing to recognize the changed nitrogen assimilation products. The objective of this study was to elucidate the effects of glutamate on root growth under high ammonium (NH4+) conditions in winter wheat (Triticum aestivum L.). Hydroponic experiments were conducted using two wheat cultivars, AK58 (NH4+-sensitive) and Xumai25 (NH4+-tolerant) with either 5 mM NH4+ nitrogen (AN) as stress treatment or 5 mM nitrate (NO3-) nitrogen as control. To evaluate the effects of NH4+-assimilation products on plant growth, 1 μM L-methionine sulfoximine (MSO) (an inhibitor of glutamine synthetase (GS)) and 1 mM glutamates (a primary N assimilation product) were added to the solutions, respectively. The AN significantly reduced plant biomass, total root length, surface area and root volume in both cultivars, but less effect was observed in Xumai25. The inhibition effects were alleviated by the application of MSO but strengthened by the application of glutamate. The AN increased the activities of GS, glutamate dehydrogenase (GDH) in both cultivars, resulting in higher glutamate contents. However, its contents were decreased by the application of MSO. Compared to AK58, Xumai25 showed lower glutamate contents due to its higher activities of glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT). With the indole-3-acetic acid (IAA) contents decreasing in roots, the ratio of shoot to root in IAA was increased, and further increased by the application of glutamate, and reduced by the application of MSO, but the ratio was lower in Xumai25. Meanwhile, the total soluble sugar contents and its root to shoot ratio also showed similar trends. These results indicate that the NH4+-tolerant cultivar has a greater transamination ability to prevent glutamate over-accumulation to maintain higher IAA transport ability, and consequently promoted soluble sugar transport to roots, further

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. Alleviating salt stress in tomato seedlings using Arthrobacter and Bacillus megaterium isolated from the rhizosphere of wild plants grown on saline-alkaline lands.

    PubMed

    Fan, Pengfei; Chen, Daitao; He, Yanan; Zhou, Qingxia; Tian, Yongqiang; Gao, Lihong

    2016-11-01

    Salt-induced soil degradation is common in farmlands and limits the growth and development of numerous crop plants in the world. In this study, we isolated salt-tolerant bacteria from the rhizosphere of Tamarix chinensis, Suaeda salsa and Zoysia sinica, which are common wild plants grown on a saline-alkaline land, to test these bacteria's efficiency in alleviating salt stress in tomato plants. We screened out seven strains (TF1-7) that are efficient in reducing salt stress in tomato seedlings. The sequence data of 16S rRNA genes showed that these strains belong to Arthrobacter and Bacillus megaterium. All strains could hydrolyze casein and solubilize phosphate, and showed at least one plant growth promotion (PGP)-related gene, indicating their potential in promoting plant growth. The Arthrobacter strains TF1 and TF7 and the Bacillus megaterium strain TF2 and TF3 could produce indole acetic acid under salt stress, further demonstrating their PGP potential. Tomato seed germination, seedling length, vigor index, and plant fresh and dry weight were enhanced by inoculation of Arthrobacter and B. megaterium strains under salt stress. Our results demonstrated that salt-tolerant bacteria isolated from the rhizosphere of wild plants grown on saline-alkaline lands could be used for alleviating salt stress in crop plants.

  20. Evaluation of Transient Pin-Stress Requirements for Spacecraft Launching in Lightning Environments. Pain Free Analysis to Alleviate Those Pin Stress Headaches

    NASA Technical Reports Server (NTRS)

    Edwards, Paul; Terseck, Alex; Trout, Dawn

    2016-01-01

    Spacecraft are generally protected from direct lightning attachment by encapsulation within the payload fairing of a launch vehicle and the ground structures that exist at the launch site. Regardless of where lightning strikes, potentially damaging indirect effects prevail from the coupling of electromagnetic fields into a loop created by outer shield of the payload umbilical. The energy coupled into individual spacecraft circuits is dependent on the umbilical current drive, the cable transfer impedance and the source/ load circuitry, and the reference potential used. Lightning induced transient susceptibility of the spacecraft avionics needs to be fully understood in order to define realistic re-test criteria in the event of a lightning occurrence during the launch campaign. Use of standards such as RTCA/DO-160 & SAE 5412 has some applicability but do not represent the indirect environment adequately. This paper evaluates the launch pad environments, the measurement data available, and computer simulations to provide pain-free analysis to alleviate the transient pin-stress headaches for spacecraft launching in Lightning environments.

  1. Deep-brain magnetic stimulation promotes adult hippocampal neurogenesis and alleviates stress-related behaviors in mouse models for neuropsychiatric disorders

    PubMed Central

    2014-01-01

    Background Repetitive Transcranial Magnetic Stimulation (rTMS)/ Deep-brain Magnetic Stimulation (DMS) is an effective therapy for various neuropsychiatric disorders including major depression disorder. The molecular and cellular mechanisms underlying the impacts of rTMS/DMS on the brain are not yet fully understood. Results Here we studied the effects of deep-brain magnetic stimulation to brain on the molecular and cellular level. We examined the adult hippocampal neurogenesis and hippocampal synaptic plasticity of rodent under stress conditions with deep-brain magnetic stimulation treatment. We found that DMS promotes adult hippocampal neurogenesis significantly and facilitates the development of adult new-born neurons. Remarkably, DMS exerts anti-depression effects in the learned helplessness mouse model and rescues hippocampal long-term plasticity impaired by restraint stress in rats. Moreover, DMS alleviates the stress response in a mouse model for Rett syndrome and prolongs the life span of these animals dramatically. Conclusions Deep-brain magnetic stimulation greatly facilitates adult hippocampal neurogenesis and maturation, also alleviates depression and stress-related responses in animal models. PMID:24512669

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Alleviation of salt stress by enterobacter sp. EJ01 in tomato and Arabidopsis is accompanied by up-regulation of conserved salinity responsive factors in plants.

    PubMed

    Kim, Kangmin; Jang, Ye-Jin; Lee, Sang-Myeong; Oh, Byung-Taek; Chae, Jong-Chan; Lee, Kui-Jae

    2014-02-01

    Microbiota in the niches of the rhizosphere zones can affect plant growth and responses to environmental stress conditions via mutualistic interactions with host plants. Specifically, some beneficial bacteria, collectively referred to as Plant Growth Promoting Rhizobacteria (PGPRs), increase plant biomass and innate immunity potential. Here, we report that Enterobacter sp. EJ01, a bacterium isolated from sea china pink (Dianthus japonicus thunb) in reclaimed land of Gyehwa-do in Korea, improved the vegetative growth and alleviated salt stress in tomato and Arabidopsis. EJ01 was capable of producing 1-aminocy-clopropane-1-carboxylate (ACC) deaminase and also exhibited indole-3-acetic acid (IAA) production. The isolate EJ01 conferred increases in fresh weight, dry weight, and plant height of tomato and Arabidopsis under both normal and high salinity conditions. At the molecular level, short-term treatment with EJ01 increased the expression of salt stress responsive genes such as DREB2b, RD29A, RD29B, and RAB18 in Arabidopsis. The expression of proline biosynthetic genes (i.e. P5CS1 and P5CS2) and of genes related to priming processes (i.e. MPK3 and MPK6) were also up-regulated. In addition, reactive oxygen species scavenging activities were enhanced in tomatoes treated with EJ01 in stressed conditions. GFP-tagged EJ01 displayed colonization in the rhizosphere and endosphere in the roots of Arabidopsis. In conclusion, the newly isolated Enterobacter sp. EJ01 is a likely PGPR and alleviates salt stress in host plants through multiple mechanisms, including the rapid up-regulation of conserved plant salt stress responsive signaling pathways.

  8. Alleviation of Salt Stress by Enterobacter sp. EJ01 in Tomato and Arabidopsis Is Accompanied by Up-Regulation of Conserved Salinity Responsive Factors in Plants

    PubMed Central

    Kim, Kangmin; Jang, Ye-Jin; Lee, Sang-Myeong; Oh, Byung-Taek; Chae, Jong-Chan; Lee, Kui-Jae

    2014-01-01

    Microbiota in the niches of the rhizosphere zones can affect plant growth and responses to environmental stress conditions via mutualistic interactions with host plants. Specifically, some beneficial bacteria, collectively referred to as Plant Growth Promoting Rhizobacteria (PGPRs), increase plant biomass and innate immunity potential. Here, we report that Enterobacter sp. EJ01, a bacterium isolated from sea china pink (Dianthus japonicus thunb) in reclaimed land of Gyehwa-do in Korea, improved the vegetative growth and alleviated salt stress in tomato and Arabidopsis. EJ01 was capable of producing 1-aminocy-clopropane-1-carboxylate (ACC) deaminase and also exhibited indole-3-acetic acid (IAA) production. The isolate EJ01 conferred increases in fresh weight, dry weight, and plant height of tomato and Arabidopsis under both normal and high salinity conditions. At the molecular level, short-term treatment with EJ01 increased the expression of salt stress responsive genes such as DREB2b, RD29A, RD29B, and RAB18 in Arabidopsis. The expression of proline biosynthetic genes (i.e. P5CS1 and P5CS2) and of genes related to priming processes (i.e. MPK3 and MPK6) were also up-regulated. In addition, reactive oxygen species scavenging activities were enhanced in tomatoes treated with EJ01 in stressed conditions. GFP-tagged EJ01 displayed colonization in the rhizosphere and endosphere in the roots of Arabidopsis. In conclusion, the newly isolated Enterobacter sp. EJ01 is a likely PGPR and alleviates salt stress in host plants through multiple mechanisms, including the rapid up-regulation of conserved plant salt stress responsive signaling pathways. PMID:24598995

  9. Genotype-dependent alleviation effects of exogenous GSH on salinity stress in cotton is related to improvement in chlorophyll content, photosynthetic performance, and leaf/root ultrastructure.

    PubMed

    Ibrahim, Wasim; Ahmed, Imrul Mosaddek; Chen, Xianhong; Wu, Feibo

    2017-04-01

    Soil salinity is a major abiotic stress that is constraining crop growth and productivity. Greenhouse hydroponic experiments were performed using salt-sensitive (cv. Zhongmian 41) and tolerant (Zhong 9806) cotton seedlings to evaluate how different genotypes responded to salinity stress in the presence of exogenous GSH (reduced glutathione). Cotton plants grown in 150 mM NaCl showed severe reduction in plant height, root length, and shoot and root fresh/dry weight. Salinity also caused reduction in photosynthesis and chlorophyll content, but increase in malondialdehyde (MDA) content. However, the reduction was more in Zhongmian 41 compared to Zhong 9806. Importantly, Sodium concentration was increased in the two genotypes and the induction was more in Zhongmian 41. Calcium and magnesium concentration was decreased in Zhongmian 41; however, in Zhong 9806 there were no significant differences relative to control. Addition of 50 mg L(-1) GSH in150 mM NaCl solution (Na + GSH) significantly alleviated salinity stress. Compared with salinity treatment alone (NaCl), Na + GSH increased fresh and dry weight of the root, stem, and leaf, photosynthesis, and chlorophyll content. Obvious ultrastructural alterations were observed in the saline-treated leaf- and root-tip cells. Exogenous GSH greatly ameliorated the salinity-induced damage on the leaf/root ultrastructure, especially in Zhongmian 41.These results advocate a positive role for GSH in alleviation of salinity, which is related to significant improvement in chlorophyll content, photosynthetic performance, and leaf/root ultrastructure.

  10. Alleviation of adverse effects of drought stress on growth and some potential physiological attributes in maize (Zea mays L.) by seed electromagnetic treatment.

    PubMed

    Javed, Namra; Ashraf, Muhammad; Akram, Nudrat Aisha; Al-Qurainy, Fahad

    2011-01-01

    Effects of varying preseed magnetic treatments on growth, chlorophyll pigments, photosynthesis, water relation attributes, fluorescence and levels of osmoprotectants in maize plants were tested under normal and drought stress conditions. Seeds of two maize cultivars were treated with different (T0 [0 mT], T1 [100 mT for 5 min], T2 [100 mT for 10 min], T3 [150 mT for 5 min] and T4 [150 mT for 10 min]) electromagnetic treatments. Drought stress considerably suppressed growth, chlorophyll a and b pigments, leaf water potential, photosynthetic rate (A), stomatal conductance (g(s)) and substomatal CO(2) concentration (C(i)), while it increased leaf glycinebetaine and proline accumulation in both maize cultivars. However, pretreated seeds with different magnetic treatments significantly alleviated the drought-induced adverse effects on growth by improving chlorophyll a, A, E, g(s), C(i) and photochemical quenching and nonphotochemical quenching, while it had no significant effect on other attributes. However, different magnetic treatments negatively affected the g(s) and C(i) particularly in cv. Agaiti-2002 under drought stress conditions. Of all magnetic treatments, 100 and 150 mT for 10 min were most effective in alleviating the drought-induced adverse effects. Overall, preseed electromagnetic treatments could be used to minimize the drought-induced adverse effects on different crop plants.

  11. 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.

  12. 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

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. Nitrogen Nutrition Improves the Potential of Wheat (Triticum aestivum L.) to Alleviate the Effects of Drought Stress during Vegetative Growth Periods

    PubMed Central

    Abid, Muhammad; Tian, Zhongwei; Ata-Ul-Karim, Syed Tahir; Cui, Yakun; Liu, Yang; Zahoor, Rizwan; Jiang, Dong; Dai, Tingbo

    2016-01-01

    Efficient nitrogen (N) nutrition has the potential to alleviate drought stress in crops by maintaining metabolic activities even at low tissue water potential. This study was aimed to understand the potential of N to minimize the effects of drought stress applied/occur during tillering (Feekes stage 2) and jointing (Feekes stage 6) growth stages of wheat by observing the regulations and limitations of physiological activities, crop growth rate during drought periods as well as final grain yields at maturity. In present study, pot cultured plants of a wheat cultivar Yangmai-16 were exposed to three water levels [severe stress at 35–40% field capacity (FC), moderate stress at 55–60% FC and well-watered at 75–80% FC] under two N rates (0.24 g and 0.16 g/kg soil). The results showed that the plants under severe drought stress accompanied by low N exhibited highly downregulated photosynthesis, and chlorophyll (Chl) fluorescence during the drought stress periods, and showed an accelerated grain filling rate with shortened grain filling duration (GFD) at post-anthesis, and reduced grain yields. Severe drought-stressed plants especially at jointing, exhibited lower Chl and Rubisco contents, lower efficiency of photosystem II and greater grain yield reductions. In contrast, drought-stressed plants under higher N showed tolerance to drought stress by maintaining higher leaf water potential, Chl and Rubisco content; lower lipid peroxidation associated with higher superoxide dismutase and ascorbate peroxidase activities during drought periods. The plants under higher N showed delayed senescence, increased GFD and lower grain yield reductions. The results of the study suggested that higher N nutrition contributed to drought tolerance in wheat by maintaining higher photosynthetic activities and antioxidative defense system during vegetative growth periods. PMID:27446197

  19. Nitrogen Nutrition Improves the Potential of Wheat (Triticum aestivum L.) to Alleviate the Effects of Drought Stress during Vegetative Growth Periods.

    PubMed

    Abid, Muhammad; Tian, Zhongwei; Ata-Ul-Karim, Syed Tahir; Cui, Yakun; Liu, Yang; Zahoor, Rizwan; Jiang, Dong; Dai, Tingbo

    2016-01-01

    Efficient nitrogen (N) nutrition has the potential to alleviate drought stress in crops by maintaining metabolic activities even at low tissue water potential. This study was aimed to understand the potential of N to minimize the effects of drought stress applied/occur during tillering (Feekes stage 2) and jointing (Feekes stage 6) growth stages of wheat by observing the regulations and limitations of physiological activities, crop growth rate during drought periods as well as final grain yields at maturity. In present study, pot cultured plants of a wheat cultivar Yangmai-16 were exposed to three water levels [severe stress at 35-40% field capacity (FC), moderate stress at 55-60% FC and well-watered at 75-80% FC] under two N rates (0.24 g and 0.16 g/kg soil). The results showed that the plants under severe drought stress accompanied by low N exhibited highly downregulated photosynthesis, and chlorophyll (Chl) fluorescence during the drought stress periods, and showed an accelerated grain filling rate with shortened grain filling duration (GFD) at post-anthesis, and reduced grain yields. Severe drought-stressed plants especially at jointing, exhibited lower Chl and Rubisco contents, lower efficiency of photosystem II and greater grain yield reductions. In contrast, drought-stressed plants under higher N showed tolerance to drought stress by maintaining higher leaf water potential, Chl and Rubisco content; lower lipid peroxidation associated with higher superoxide dismutase and ascorbate peroxidase activities during drought periods. The plants under higher N showed delayed senescence, increased GFD and lower grain yield reductions. The results of the study suggested that higher N nutrition contributed to drought tolerance in wheat by maintaining higher photosynthetic activities and antioxidative defense system during vegetative growth periods.

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. Postnatal Treadmill Exercise Alleviates Prenatal Stress-Induced Anxiety in Offspring Rats by Enhancing Cell Proliferation Through 5-Hydroxytryptamine 1A Receptor Activation

    PubMed Central

    2016-01-01

    Purpose: Stress during pregnancy is a risk factor for the development of anxiety-related disorders in offspring later in life. The effects of treadmill exercise on anxiety-like behaviors and hippocampal cell proliferation were investigated using rats exposed to prenatal stress. Methods: Exposure of pregnant rats to a hunting dog in an enclosed room was used to induce stress. Anxiety-like behaviors of offspring were evaluated using the elevated plus maze test. Immunohistochemistry for the detection of 5-bromo-2ʹ- deoxyuridine and doublecortin (DCX) in the hippocampal dentate gyrus and 5-hydroxytryptamine 1A receptors (5-HT1A) in the dorsal raphe was conducted. Brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) levels in the hippocampus were evaluated by western blot analysis. Results: Offspring of maternal rats exposed to stress during pregnancy showed anxiety-like behaviors. Offspring also showed reduced expression of BDNF, TrkB, and DCX in the dentate gyrus, decreased cell proliferation in the hippocampus, and reduced 5-HT1A expression in the dorsal raphe. Postnatal treadmill exercise by offspring, but not maternal exercise during pregnancy, enhanced cell proliferation and expression of these proteins. Conclusions: Postnatal treadmill exercise ameliorated anxiety-like behaviors in offspring of stressed pregnant rats, and the alleviating effect of exercise on these behaviors is hypothesized to result from enhancement of cell proliferation through 5-HT1A activation in offspring rats. PMID:27230461

  14. 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

  15. 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.

  16. 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.

  17. Alleviation of cadmium toxicity by silicon is related to elevated photosynthesis, antioxidant enzymes; suppressed cadmium uptake and oxidative stress in cotton.

    PubMed

    Farooq, Muhammad Ahsan; Ali, Shafaqat; Hameed, Amjad; Ishaque, Wajid; Mahmood, Khalid; Iqbal, Zafar

    2013-10-01

    Biotic systems face immense environmental hazards such as accumulation of heavy metals, particularly in agricultural ecosystems that might cause deterioration of yield and quality of crops. In this study, we evaluated the role of silicon (Si) in alleviating the heavy metal (Cd) stress tolerance in cotton by analyzing the induced Physio-chemical changes. Cotton plants were grown in hydroponic culture with three different Cd levels (0, 1 and 5μM) along with two Si treatment levels (0 and 1mM). The data showed that Cd alone reduced the plant growth as well as the efficiency of antioxidant activity as compared to control plants. Plant growth, gas exchange characteristics (net photosynthetic rate, stomatal conductance, transpiration rate, water use efficiency) chlorophyll contents, and carotenoids as well as the performance of antioxidant enzymes were improved by the exogenous application of Si. The adverse effects of Cd on plant growth were alleviated by the exogenous application of Si. It was observed that Si effectively mitigated the adverse effects of Cd on cotton plants and markedly enhanced the growth, biomass and photosynthetic parameters while decreased the contents of malondialdehyde (MDA), hydrogen peroxide (H2O2) and electrolytic leakage (EL). The antioxidant enzyme activities in cotton leaves and roots increased significantly, when Si was added to control as well as Cd stressed plants. In conclusion, Si improved the growth and photosynthesis attributes of cotton plants by mitigating the adverse effects of Cd stress through reduced EL, MDA and H2O2 contents and improved activities of antioxidant enzymes.

  18. Silicon alleviates salt and drought stress of Glycyrrhiza uralensis seedling by altering antioxidant metabolism and osmotic adjustment.

    PubMed

    Zhang, Wenjin; Xie, Zhicai; Wang, Lianhong; Li, Ming; Lang, Duoyong; Zhang, Xinhui

    2017-03-13

    This study was conducted to determine effect and mechanism of exogenous silicon (Si) on salt and drought tolerance of Glycyrrhiza uralensis seedling by focusing on the pathways of antioxidant defense and osmotic adjustment. Seedling growth, lipid peroxidation, antioxidant metabolism, osmolytes concentration and Si content of G. uralensis seedlings were analyzed under control, salt and drought stress [100 mM NaCl with 0, 10 and 20% of PEG-6000 (Polyethylene glycol-6000)] with or without 1 mM Si. Si addition markedly affected the G. uralensis growth in a combined dose of NaCl and PEG dependent manner. In brief, Si addition improved germination rate, germination index, seedling vitality index and biomass under control and NaCl; Si also increased radicle length under control, NaCl and NaCl-10% PEG, decreased radicle length, seedling vitality index and germination parameters under NaCl-20% PEG. The salt and drought stress-induced-oxidative stress was modulated by Si application. Generally, Si application increased catalase (CAT) activity under control and NaCl-10% PEG, ascorbate peroxidase (APX) activity under all treatments and glutathione (GSH) content under salt combined drought stress as compared with non-Si treatments, which resisted to the increase of superoxide radicals and hydrogen peroxide caused by salt and drought stress and further decreased membrane permeability and malondialdehyde (MDA) concentration. Si application also increased proline concentration under NaCl and NaCl-20% PEG, but decreased it under NaCl-10% PEG, indicating proline play an important role in G. uralensis seedling response to osmotic stress. In conclusion, Si could ameliorate adverse effects of salt and drought stress on G. uralensis likely by reducing oxidative stress and osmotic stress, and the oxidative stress was regulated through enhancing of antioxidants (mainly CAT, APX and GSH) and osmotic stress was regulated by proline.

  19. 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

  20. 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

  1. 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.

  2. 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

  3. 3,4-Dihydroxyphenylethanol alleviates early brain injury by modulating oxidative stress and Akt and nuclear factor-κB pathways in a rat model of subarachnoid hemorrhage

    PubMed Central

    FU, PENG; HU, QUAN

    2016-01-01

    3,4-Dihydroxyphenylethanol (DOPET) is a naturally occurring polyphenolic compound, present in olive oil and in the wastewater generated during olive oil processing. DOPET has various biological and pharmacological activities, including anticancer, antibacterial and anti-inflammatory effects. This study was designed to determine whether DOPET alleviates early brain injury (EBI) associated with subarachnoid hemorrhage (SAH) through suppression of oxidative stress and Akt and nuclear factor (NF)-κB pathways. Rats were randomly divided into the following groups: Sham group, SAH group, SAH + vehicle group and SAH + DOPET group. Mortality, blood-brain barrier (BBB) permeability and brain water content were assessed. Oxidative stress, Akt, NF-κB p65 and caspase-3 assays were also performed. DOPET induced a reduction in brain water content, and decreased the BBB permeability of SAH model rats. Furthermore, DOPET effectively controlled oxidative stress, NF-κB p65 and caspase-3 levels, in addition to significantly increasing Akt levels in the cortex following SAH. These results provide evidence that DOPET attenuates apoptosis in a rat SAH model through modulating oxidative stress and Akt and NF-κB signaling pathways. PMID:27168841

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. Alleviation of cadmium stress in Solanum lycopersicum L. by arbuscular mycorrhizal fungi via induction of acquired systemic tolerance

    PubMed Central

    Hashem, Abeer; Abd_Allah, E.F.; Alqarawi, A.A.; Al Huqail, Asma A.; Egamberdieva, D.; Wirth, S.

    2015-01-01

    Experiments were conducted to evaluate cadmium (Cd) stress-induced changes in growth, antioxidants and lipid composition of Solanum lycopersicum with and without arbuscular mycorrhizal fungi (AMF). Cadmium stress (50 μM) caused significant changes in the growth and physio-biochemical attributes studied. AMF mitigated the deleterious impact of Cd on the parameters studied. Cadmium stress increased malonaldehyde and hydrogen peroxide production but AMF reduced these parameters by mitigating oxidative stress. The activity of antioxidant enzymes enhanced under Cd treatment and AMF inoculation further enhanced their activity, thus strengthening the plant’s defense system. Proline and phenol content increased in Cd-treated as well as AMF-inoculated plants providing efficient protection against Cd stress. Cadmium treatment resulted in great alterations in the main lipid classes leading to a marked change in their composition. Cadmium stress caused a significant reduction in polyunsaturated fatty acids resulting in enhanced membrane leakage. The present study supports the use of AMF as a biological means to ameliorate Cd stress-induced changes in tomato. PMID:26981010

  10. 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

  11. 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

  12. Alleviation of Drought Stress and Metabolic Changes in Timothy (Phleum pratense L.) Colonized with Bacillus subtilis B26

    PubMed Central

    Gagné-Bourque, François; Bertrand, Annick; Claessens, Annie; Aliferis, Konstantinos A.; Jabaji, Suha

    2016-01-01

    Drought is a major limiting factor of crop productivity worldwide and its incidence is predicted to increase under climate change. Drought adaptation of cool-season grasses is thus a major challenge to secure the agricultural productivity under current and future climate conditions. Endophytes are non-pathogenic plant-associated bacteria that can play an important role in conferring resistance and improving plant tolerance to drought. In this study, the effect of inoculation of the bacterial endophyte Bacillus subtilis strain B26 on growth, water status, photosynthetic activity and metabolism of timothy (Phleum pratense L.) subjected to drought stress was investigated under controlled conditions. Under both drought-stress and non-stressed conditions, strain B26 successfully colonized the internal tissues of timothy and had a positive impact on plant growth. Exposure of inoculated plant to a 8-week drought-stress led to significant increase in shoot and root biomass by 26.6 and 63.8%, and in photosynthesis and stomatal conductance by 55.2 and 214.9% respectively, compared to non-inoculated plants grown under similar conditions. There was a significant effect of the endophyte on plant metabolism; higher levels of several sugars, notably sucrose and fructans and an increase of key amino acids such as, asparagine, glutamic acid and glutamine were recorded in shoots and roots of colonized plants compared to non-colonized ones. The accumulation of the non-protein amino acid GABA in shoots of stressed plants and in roots of stressed and unstressed plants was increased in the presence of the endophyte. Taken together, our results indicate that B. subtilis B26 improves timothy growth under drought stress through the modification of osmolyte accumulation in roots and shoots. These results will contribute to the development of a microbial agent to improve the yield of grass species including forage crops and cereals exposed to environmental stresses. PMID:27200057

  13. Histone hyperacetylation modulates spinal type II metabotropic glutamate receptor alleviating stress-induced visceral hypersensitivity in female rats

    PubMed Central

    Cao, Dong-Yuan; Bai, Guang; Ji, Yaping; Karpowicz, Jane

    2016-01-01

    Stress is often a trigger to exacerbate chronic pain including visceral hypersensitivity associated with irritable bowel syndrome, a female predominant functional bowel disorder. Epigenetic mechanisms that mediate stress responses are a potential target to interfere with visceral pain. The purpose of this study was to examine the effect of a histone deacetylase inhibitor, suberoylanilide hydroxamic acid, on visceral hypersensitivity induced by a subchronic stressor in female rats and to investigate the involvement of spinal glutamate receptors. Three daily sessions of forced swim induced visceral hypersensitivity. Intrathecal suberoylanilide hydroxamic acid prevented or reversed the stress-induced visceral hypersensitivity, increased spinal histone 3 acetylation and increased mGluR2 and mGluR3 expression. Chromatin immunoprecipitation (ChIP) analysis revealed enrichment of H3K9Ac and H3K18Ac at several promoter Grm2 and Grm3 regions. The mGluR2/3 antagonist LY341495 reversed the inhibitory effect of suberoylanilide hydroxamic acid on the stress-induced visceral hypersensitivity. In surprising contrast, stress and/or suberoylanilide hydroxamic acid had no effect on spinal NMDA receptor expression or function. These data reveal histone modification modulates mGluR2/3 expression in the spinal cord to attenuate stress-induced visceral hypersensitivity. HDAC inhibitors may provide a potential approach to relieve visceral hypersensitivity associated with irritable bowel syndrome. PMID:27385724

  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. 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

  17. Recurrent Water Level Fluctuation Alleviates the Effects of Submergence Stress on the Invasive Riparian Plant Alternanthera philoxeroides.

    PubMed

    Zhang, Haijie; Wang, Renqing; Wang, Xiao; Du, Ning; Ge, Xiuli; Du, Yuanda; Liu, Jian

    2015-01-01

    Recurrent water level fluctuation and submergence of plants are common in riparian zones. Our study objectives were to test the independent and interactive effects of submergence level and fluctuation frequency on a globally important riparian invasive plant, Alternanthera philoxeroides. To this end, we conducted a greenhouse experiment, in which ramets of the plants, obtained from a wetland in China, were treated with four fluctuation frequencies (0, 3, 6, and 12 cycles over a 96-day experimental period) under three water levels (0, 10, and 30 cm). We found that effects of fluctuation frequency were non-significant, negative, and positive under water levels of 0, 10 and 30 cm, respectively. As fluctuation frequency increased, the effects of increasing water level decreased significantly. When water levels were high, A. philoxeroides allocated greater biomass to shoot production probably in order to elongate and escape from submergence. However, as fluctuation frequency increased, biomass investment in roots and leaves also increased, probably in order to maximize nutrient absorption and photosynthesis, respectively. These results suggest that water level fluctuation may alleviate the effects of submergence on A. philoxeroides. In addition, A. philoxeroides showed significant phenotypic plasticity, adjusting its functional traits, such as number of nodes and leaves per stem, as well as stem diameter and pith cavity diameter, according to recurrent water level fluctuation. We conclude that A. philoxeroides may perform better in shallow water zones under conditions of disturbance that include recurrent water level fluctuation. This ability to adapt to disturbance likely promotes its growth and invasion in disturbed habitats.

  18. Antioxidant potential of Cymbopogon citratus extract: alleviation of carbon tetrachloride-induced hepatic oxidative stress and toxicity.

    PubMed

    Koh, Pei Hoon; Mokhtar, Ruzaidi Azli Mohd; Iqbal, Mohammad

    2012-01-01

    This study was aimed to evaluate the effect of Cymbopogon citratus against carbon tetrachloride (CCl(4))-mediated hepatic oxidative damage in rats. Rats were administrated with C. citratus extract (100, 200 and 300 mg/kg b.w.) for 14 days before the challenge of CCl(4) (1.2 ml/kg b.w. p.o) on 13th and 14th days. Hepatic damage was evaluated by employing serum biochemical parameters (alanine aminotransferase-ALT, aspartate aminotransferase-AST and lactate dehydrogenase-LDH), malondialdehye (MDA) level, reduced GSH and antioxidant enzymes (catalase: CAT, glutathione peroxidase: GPX, quinone reductase: QR, glutathione S-transferase: GST, glutathione reductase: GR, glucose-6-phosphate dehyrogenase: G6PD). In addition, CCl(4)-mediated hepatic damage was further evaluated by histopathological examination. However, most of these changes were alleviated by prophylactic treatment of animals with C. citratus dose dependently (p < 0.05). The protection was further evident through decreased histopathological alterations in liver. The results of the present study indicated that the hepatoprotective effect of C. citratus might be ascribable to its antioxidant and free radical scavenging property.

  19. Silicon alleviates drought stress of rice plants by improving plant water status, photosynthesis and mineral nutrient absorption.

    PubMed

    Chen, Wei; Yao, Xiaoqin; Cai, Kunzheng; Chen, Jining

    2011-07-01

    Drought is a major constraint for rice production in the rainfed lowlands in China. Silicon (Si) has been verified to play an important role in enhancing plant resistance to environmental stress. Two near-isogenic lines of rice (Oryza sativa L.), w-14 (drought susceptible) and w-20 (drought resistant), were selected to study the effects of exogenous Si application on the physiological traits and nutritional status of rice under drought stress. In wet conditions, Si supply had no effects on growth and physiological parameters of rice plants. Drought stress was found to reduce dry weight, root traits, water potential, photosynthetic parameters, basal quantum yield (F(v)/F(0)), and maximum quantum efficiency of PSII photochemistry (F(v)/F(m)) in rice plants, while Si application significantly increased photosynthetic rate (Pr), transpiration rate (Tr), F(v)/F(0), and F(v)/F(m) of rice plants under drought stress. In addition, water stress increased K, Na, Ca, Mg, Fe content of rice plants, but Si treatment significantly reduced these nutrient level. These results suggested that silicon application was useful to increase drought resistance of rice through the enhancement of photochemical efficiency and adjustment of the mineral nutrient absorption in rice plants.

  20. Pre-anthesis high-temperature acclimation alleviates damage to the flag leaf caused by post-anthesis heat stress in wheat.

    PubMed

    Wang, Xiao; Cai, Jian; Jiang, Dong; Liu, Fulai; Dai, Tingbo; Cao, Weixing

    2011-04-15

    The objective of this study was to investigate the effect of pre-anthesis high-temperature acclimation on leaf physiology of winter wheat in response to post-anthesis heat stress. The results showed that both pre- and post-anthesis heat stresses significantly depressed flag leaf photosynthesis and enhanced cell membrane peroxidation, as exemplified by increased O₂⁻(·) production rate and reduction in activities of antioxiditave enzymes. However, under post-anthesis heat stress, plants with pre-anthesis high-temperature acclimation (HH) showed much higher photosynthetic rates than those without pre-anthesis high-temperature acclimation (CH). Leaves of HH plants exhibited a higher Chl a/b ratio and lower chlorophyll/carotenoid ratio and superoxide anion radical release rate compared with those of the CH plants. In addition, antioxidant enzyme activities in HH plants were significantly higher than in CH. Coincidently, expressions of photosythesis-responsive gene encoding Rubisco activase B (RcaB) and antioxidant enzyme-related genes encoding mitochondrial manganese superoxide dismutase (Mn-SOD), chloroplastic Cu/Zn superoxide dismutase (Cu/Zn-SOD), catalase (CAT) and cytosolic glutathione reductase (GR) were all up-regulated under HH, whereas a gene encoding a major chlorophyll a/b-binding protein (Cab) was up-regulated by post-anthesis heat stress at 10 DAA, but was down-regulated at 13 DAA. The changes in the expression levels of the HH plants were more pronounced than those for the CH. Collectively, the results indicated that pre-anthesis high-temperature acclimation could effectively alleviate the photosynthetic and oxidative damage caused by post-anthesis heat stress in wheat flag leaves, which was partially attributable to modifications in the expression of the photosythesis-responsive and antioxidant enzymes-related genes.

  1. Potential of casein as a nutrient intervention to alleviate lead (Pb) acetate-mediated oxidative stress and neurotoxicity: First evidence in Drosophila melanogaster.

    PubMed

    Venkareddy, Lalith Kumar; Muralidhara

    2015-05-01

    Understanding the interaction between dietary protein deficits and neurotoxicants such as lead (Pb) is critical since oxidative stress is a common denominator under such conditions. The Drosophila system is an extensively used model to investigate the interaction between nutrients and environmental toxicants. Accordingly, we have examined the hypothesis that casein (CSN) enrichment has the propensity to attenuate Pb-associated phenotype, oxidative stress and neurotoxicity in Drosophila melanogaster. Exposure of young (2-3 d) and adult flies (10-12 d old) to Pb acetate (0-20 mM, 7 d) in the medium resulted in a concentration dependent mortality and the survivors exhibited a hyperactive phenotype. While males showed higher susceptibility to Pb among both age groups, young flies were relatively more susceptible than adults. Pb exposure (5-10 mM, 5 d) among young flies caused robust oxidative stress as evidenced by markedly elevated levels of reactive oxygen species with concomitant perturbations in the activities of antioxidant enzymes (diminished SOD and elevated thioredoxin reductase) and altered redox state. Further, Pb caused significant elevation in the activity of acetylcholinesterase and dopamine levels. In a satellite study, we assessed the modulatory effect of CSN-enriched diet (1-2%) on Pb intoxication in terms of lethality, hyperactivity, oxidative stress and neurotoxicity. CSN markedly offset Pb-induced lethality and diminished the hyperactivity response. While CSN enrichment among Pb (5 mM) treated flies caused further elevation in ROS levels and thioredoxin reductase activity, the SOD levels were restored to normalcy. Further, CSN improved the activity levels of complex I-III and restored the dopamine levels. Our data suggest that Pb-induced toxicity in the Drosophila system may be predominantly mediated through oxidative stress mechanisms and the propensity of casein-enriched diet to abrogate such responses. Hence, we propose that enrichment of diet

  2. 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

  3. Inclusion of Konjac Flour in the Gestation Diet Changes the Gut Microbiota, Alleviates Oxidative Stress, and Improves Insulin Sensitivity in Sows

    PubMed Central

    Tan, Chengquan; Wei, Hongkui; Ao, Jiangtao; Long, Guang

    2016-01-01

    ABSTRACT Although dietary fibers contribute to health and physiology primarily via the fermentative actions of the gut microbiota of the hosts, few studies have focused on how these interactions influence the metabolic status of sows. Here, the effects of inclusion of konjac flour (KF) in a gestation diet on oxidative stress status, insulin sensitivity, and gut microbiota were investigated to elucidate the correlation between the microbiota and metabolic changes in sows. Sows were assigned to either control or 2.2% KF dietary treatment during gestation. The gut microbiota population in sows during gestation and lactation was assessed by 16S rRNA gene sequencing. The oxidative stress parameters, homeostasis model assessment (HOMA) values, and fatty acids in the blood of sows were also assessed. Compared to the control diet group, KF significantly reduced the serum levels of reactive oxygen species (ROS) and 8-hydroxy-deoxyguanosine (8-OHdG) but increased the serum concentrations of glutathione peroxidase (GSH-Px) in sows on day 1 in lactation. Additionally, sows in the KF group had a lower HOMA insulin resistance value but a higher HOMA insulin sensitivity (HOMA-IS) value. KF induced changes in the gut microbial composition at the phylum and genus levels. The increased relative abundances of Akkermansia and Roseburia in the KF group were positively correlated with the HOMA-IS. Overall, dietary KF alleviated oxidative stress and improved insulin sensitivity of sows, and the changes in the gut microbiota in response to KF may have been correlated with the host metabolism response. IMPORTANCE To date, the effect of dietary fiber on metabolism responses and gut microbiota in sows has not been investigated. Here, KF supplementation of a gestation diet in sows was found to alleviate oxidative stress and to improve insulin sensitivity. Pyrosequencing analysis revealed that KF treatment induces changes in the gut microbiota composition at the phylum and genus levels

  4. 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.

  5. 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.

  6. Cinnamon intake alleviates the combined effects of dietary-induced insulin resistance and acute stress on brain mitochondria.

    PubMed

    Couturier, Karine; Hininger, Isabelle; Poulet, Laurent; Anderson, Richard A; Roussel, Anne-Marie; Canini, Frédéric; Batandier, Cécile

    2016-02-01

    Insulin resistance (IR), which is a leading cause of the metabolic syndrome, results in early brain function alterations which may alter brain mitochondrial functioning. Previously, we demonstrated that rats fed a control diet and submitted to an acute restraint stress exhibited a delayed mitochondrial permeability transition pore (mPTP) opening. In this study, we evaluated the combined effects of dietary and emotional stressors as found in western way of life. We studied, in rats submitted or not to an acute stress, the effects of diet-induced IR on brain mitochondria, using a high fat/high fructose diet (HF(2)), as an IR inducer, with addition or not of cinnamon as an insulin sensitizer. We measured Ca(2+) retention capacity, respiration, ROS production, enzymatic activities and cell signaling activation. Under stress, HF(2) diet dramatically decreased the amount of Ca(2+) required to open the mPTP (13%) suggesting an adverse effect on mitochondrial survival. Cinnamon added to the diet corrected this negative effect and resulted in a partial recovery (30%). The effects related to cinnamon addition to the diet could be due to its antioxidant properties or to the observed modulation of PI3K-AKT-GSK3β and MAPK-P38 pathways or to a combination of both. These data suggest a protective effect of cinnamon on brain mitochondria against the negative impact of an HF(2) diet. Cinnamon could be beneficial to counteract deleterious dietary effects in stressed conditions.

  7. Tolerance response to in situ ammonia stress in a pilot-scale anaerobic digestion reactor for alleviating ammonia inhibition.

    PubMed

    Gao, Shumei; Zhao, Mingxing; Chen, Yang; Yu, Meijuan; Ruan, Wenquan

    2015-12-01

    The anaerobic digestion (AD) of protein-rich substrates is generally inhibited by ammonia. In this study, ammonia-tolerant acclimation was exposed to a stepwise in situ ammonia stress during the continuous AD of solid residual kitchen waste by using a continuous stirred tank reactor with a 50 L active volume. The reactor worked well during the acclimation process, with an average daily biogas production of 58 L/d, an effluent soluble chemical oxygen demand of 7238 mg/L, a volatile fatty acid (VFA) content of 578 mg/L, and a VFA/alkalinity ratio of less than 0.4. Moreover, ammonia stress enhanced the activity of Coenzyme F420. The results of high-throughput 16S rDNA sequencing showed that ammonia stress increased the relative abundance of Firmicutes bacteria and hydrogenotrophic methanogens but decreased the abundance of acetotrophic methanogens. This microbial community shift was proposed to be an in situ response strategy for ammonia stress adaptation.

  8. 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.

  9. 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

  10. 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

  11. Alleviation of hepatic oxidative stress by Chinese herbal medicine Yin-Chen-Hao-Tang in obese mice with steatosis.

    PubMed

    Lee, Tzung-Yan; Chang, Hen-Hong; Lo, Wen-Chai; Lin, Han-Chieh

    2010-06-01

    Obesity is associated with a complex systemic inflammatory state that has been implicated in the development of hepatic steatosis. This study was to test the efficacy of Yin-Chen-Hao-Tang (YCHT), an agent that improves hepatic triglyceride metabolism in its ability to modulate pathways implicated in hepatic steatosis. Mice were fed with high-fat diet for fifteen weeks. The therapeutic mechanism of YCHT likely enhanced adiponectin and endothelial progenitor cells, and up-regulation of peroxisome proliferator-activated receptor gamma might be responsible for fatty liver diseases. In addition, YCHT anti-oxidative stress effect might be associated with inhibition of hepatic free fatty acid concentrations and elevation of the glutathione levels in hepatic tissues. Furthermore, YCHT action mechanisms might promote senescence marker protein-30 metabolism that increase resistance to hepatic oxidative stress. These findings suggest a novel therapeutic approach for fatty liver progression in obesity mice.

  12. Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice.

    PubMed

    Hatanaka, Takashi; Ogawa, Daisuke; Tachibana, Hiromi; Eguchi, Jun; Inoue, Tatsuyuki; Yamada, Hiroshi; Takei, Kohji; Makino, Hirofumi; Wada, Jun

    2016-08-01

    It is unclear whether the improvement in diabetic nephropathy by sodium glucose cotransporter 2 (SGLT2) inhibitors is caused by a direct effect on SGLT2 or by the improvement in hyperglycemia. Here, we investigated the effect of dapagliflozin on early-stage diabetic nephropathy using a mouse model of type 1 diabetes and murine proximal tubular epithelial cells. Eight-week-old Akita mice were treated with dapagliflozin or insulin for 12 weeks. Body weight, urinary albumin excretion, blood pressure, as well as levels of blood glucose and hemoglobin A1c were measured. Expansion of the mesangial matrix, interstitial fibrosis, and macrophage infiltration in kidneys were evaluated by histology. Oxidative stress and apoptosis were evaluated in kidneys and cultured proximal tubular epithelial cells. Compared with nontreated mice, dapagliflozin and insulin decreased blood glucose and hemoglobin A1c levels equally. Urine volume and water intake increased significantly in the dapagliflozin-treated group compared with those in the insulin-treated group, but there were no differences in body weight or blood pressure between the two groups. Macrophage infiltration and fibrosis in renal interstitium improved significantly in the dapagliflozin group compared with the insulin group. Oxidative stress was attenuated by dapagliflozin, and suppression occurred in a dose-dependent manner. RNAi knockdown of SGLT2 resulted in reduced oxidative stress. Dapagliflozin ameliorates diabetic nephropathy by suppressing hyperglycemia-induced oxidative stress in a manner independent of hyperglycemia improvement in Akita mice. Our findings suggest that dapagliflozin may be a novel therapeutic approach for the treatment of diabetic nephropathy.

  13. C-phycocyanin alleviates osteoarthritic injury in chondrocytes stimulated with H2O2 and compressive stress.

    PubMed

    Young, In-Chi; Chuang, Sung-Ting; Hsu, Chia-Hsien; Sun, Yu-Jun; Lin, Feng-Huei

    2016-12-01

    During the progression of osteoarthritis (OA), dysregulation of extracellular matrix anabolism, abnormal generation of reactive oxygen species (ROS) and inflammatory cytokines have been shown to accelerate the degradation process of cartilage. The potency of c-phycocyanin (C-PC) to protect cellular components against oxidative stress, along with its anti-inflammation and anti-apoptosis effects, are well documented; however, effects of C-PC on OA are still unclear. In this study, we aimed to investigate the effects of C-PC on OA using H2O2 or compression-stimulated OA-like porcine chondrocyte models. The results showed that C-PC had the ability to inhibit ROS production, reverse caspase-3 activity, and reduce apoptosis cell population. C-PC also reversed aggrecan and type II collagen gene expressions after stimulation with 1mM H2O2 or 60psi of compression. Inhibition of IL-6 and MMP-13 genes was observed in compression-stimulated chondrocytes but not in H2O2-treated cells. In dimethylmethylene blue assay and alcian blue staining, C-PC maintained the sulfated-glycosaminoglycan (sGAG) content after stimulation with compression. We concluded that C-PC can prevent early signs of OA caused by compressive stress and attenuate H2O2-induced oxidative stress. Therefore, we suggest that C-PC can be used as a potential drug candidate for chronic OA treatment.

  14. Silicon alleviates simulated acid rain stress of Oryza sativa L. seedlings by adjusting physiology activity and mineral nutrients.

    PubMed

    Ju, Shuming; Wang, Liping; Yin, Ningning; Li, Dan; Wang, Yukun; Zhang, Cuiying

    2017-03-16

    Silicon (Si) has been a modulator in plants under abiotic stresses, such as acid rain. To understand how silicon made an effect on rice (Oryza sativa L.) exposed to simulated acid rain (SAR) stress, the growth, physiologic activity, and mineral nutrient content in leaves of rice were investigated. The results showed that combined treatments with Si (1.0, 2.0, or 4.0 mM) and SAR (pH 4.0, 3.0, or 2.0) obviously improved the rice growth compared with the single treatment with SAR. Incorporation of Si into SAR treatment decreased malondialdehyde (MDA) content; increased soluble protein and proline contents; promoted CAT, POD, SOD, and APX activity; and maintained the K, Ca, Mg, Fe, Zn, Cu content balance in leaves of rice seedlings under SAR stress. The moderate concentration of Si (2.0 mM) was better than the low and high concentration of Si (1.0 and 4.0 mM). Therefore, application of Si could be a better strategy for maintaining the crop productivity in acid rain regions.

  15. The physical effects of aromatherapy in alleviating work-related stress on elementary school teachers in taiwan.

    PubMed

    Liu, Shing-Hong; Lin, Tzu-Hsin; Chang, Kang-Ming

    2013-01-01

    People use aromatherapy to relieve the symptoms of physical and psychological stress. However, previous studies have not precisely clarified a scientific basis for the beneficial effects of aromatherapy. Therefore, the overall purpose of this study was to elucidate the beneficial effect of aromatherapy in relieving work-related stress. Twenty-nine elementary school teachers from Taiwan participated in this study. The experimental procedures comprised 2 phases. First, we verified the effect of aromatherapy by conducting 2 blind tests. We used natural bergamot essential oil extracted from plants and synthesized a chemical essential oil as the placebo to do the aromatherapy. Second, we analyzed the performance of the aromatherapy treatment on the teachers who had various workloads. We measured the teachers' heart rate variability to evaluate their autonomic nervous system activity. The results show that only the natural bergamot essential oil had an effect and that the aromatherapy treatment relieved work-related stress of teachers with various workloads. However, the aromatherapy treatment had a weak effect on young teachers who had a heavy workload. Moreover, the aromatherapy treatment exhibited no effect on teachers who belong to the abnormal body mass index subgroup having a heavy workload.

  16. The Edible Marine Alga Gracilariopsis chorda Alleviates Hypoxia/Reoxygenation-Induced Oxidative Stress in Cultured Hippocampal Neurons

    PubMed Central

    Mohibbullah, Md.; Hannan, Md. Abdul; Choi, Ji-Young; Bhuiyan, Mohammad Maqueshudul Haque; Hong, Yong-Ki; Choi, Jae-Suk; Choi, In Soon; Moon, Il Soo

    2015-01-01

    Abstract Age-related neurological disorders are of growing concern among the elderly, and natural products with neuroprotective properties have been attracting increasing attention as candidates for the prevention or treatment of neurological disorders induced by oxidative stress. In an effort to explore natural resources, we collected some common marine seaweed from the Korean peninsula and Indonesia and screened them for neuroprotective activity against hypoxia/reoxygenation (H/R)-induced oxidative stress. Of the 23 seaweeds examined, the ethanol extract of Gracilariopsis chorda (GCE) provided maximum neuroprotection at an optimum concentration of 15 μg/mL, followed by Undaria pinnatifida. GCE increased cell viability after H/R, decreased the formation of reactive oxygen species (measured by 2′,7′-dichlorodihydrofluorescein diacetate [DCF-DA] staining), and inhibited the double-stranded DNA breaks (measured by H2AX immunocytochemistry), apoptosis (measured by Annexin V/propidium iodide staining), internucleosomal DNA fragmentation (measured by DNA laddering), and dissipation of mitochondrial membrane potential (measured by JC-1 staining). Using reverse-phase high-pressure liquid chromatography, we quantitated the arachidonic acid (AA) in GCE, which provides neuroprotection against H/R-induced oxidative stress. This neuroprotective effect of AA was comparable to that of GCE. These findings suggest that the neuroprotective effect of GCE against H/R-induced neuronal death is due, at least in part, to the AA content that suppresses neuronal apoptosis. PMID:26106876

  17. Dietary rosemary oil alleviates heat stress-induced structural and functional damage through lipid peroxidation in the testes of growing Japanese quail.

    PubMed

    Türk, Gaffari; Çeribaşı, Ali O; Şimşek, Ülkü G; Çeribaşı, Songül; Güvenç, Mehmet; Özer Kaya, Şeyma; Çiftçi, Mehmet; Sönmez, Mustafa; Yüce, Abdurrauf; Bayrakdar, Ali; Yaman, Mine; Tonbak, Fadime

    2016-01-01

    Supplementation of natural antioxidants to diets of male poultry has been reported to be effective in reducing or completely eliminating heat stress (HS)-induced reproductive failures. In this study, the aim is to investigate whether rosemary oil (RO) has a protective effect on HS-induced damage in spermatozoa production, testicular histologic structures, apoptosis, and androgenic receptor (AR) through lipid peroxidation mechanisms in growing Japanese quail. Male chicks (n=90) at 15-days of age were assigned to two groups. The first group (n=45) was kept in a thermo-neutral (TN) room at 22°C for 24h/d. The second group (n=45) was kept in a room with a greater ambient temperature of 34°C for 8h/d (from 9:00 AM to 5:00 PM) and 22°C for 16h/d. Animals in each of these two groups were randomly assigned to three subgroups (RO groups: 0, 125, 250ppm), consisting of 15 chicks (six treatment groups in 2×3 factorial design). Each of subgroups was replicated three times with each replicate including five chicks. The HS treatment significantly reduced the testicular spermatogenic cell counts, amount of testicular Bcl-2 (anti-apoptotic marker) and amount of AR. In addition, it significantly increased testicular lipid peroxidation, Bax (apoptotic marker) immunopositive staining, and the Bax/Bcl-2 ratio in conjunction with some histopathologic damage. Dietary supplementation of RO to diets of quail where the HS treatment was imposed alleviated HS-induced almost all negative changes such as increased testicular lipid peroxidation, decreased numbers of spermatogenic cells, and decreased amounts of Bcl-2 and AR, increased ratio of Bax/Bcl-2 and some testicular histopathologic lesion. In conclusion, dietary supplementation of RO for growing male Japanese quail reared in HS environmental conditions alleviates the HS-induced structural and functional damage by providing a decrease in lipid peroxidation.

  18. Complete genome analysis of Serratia marcescens RSC-14: A plant growth-promoting bacterium that alleviates cadmium stress in host plants

    PubMed Central

    Khan, Abdur Rahim; Park, Gun-Seok; Asaf, Sajjad; Hong, Sung-Jun; Jung, Byung Kwon

    2017-01-01

    Serratia marcescens RSC-14 is a Gram-negative bacterium that was previously isolated from the surface-sterilized roots of the Cd-hyperaccumulator Solanum nigrum. The strain stimulates plant growth and alleviates Cd stress in host plants. To investigate the genetic basis for these traits, the complete genome of RSC-14 was obtained by single-molecule real-time sequencing. The genome of S. marcescens RSC-14 comprised a 5.12-Mbp-long circular chromosome containing 4,593 predicted protein-coding genes, 22 rRNA genes, 88 tRNA genes, and 41 pseudogenes. It contained genes with potential functions in plant growth promotion, including genes involved in indole-3-acetic acid (IAA) biosynthesis, acetoin synthesis, and phosphate solubilization. Moreover, annotation using NCBI and Rapid Annotation using Subsystem Technology identified several genes that encode antioxidant enzymes as well as genes involved in antioxidant production, supporting the observed resistance towards heavy metals, such as Cd. The presence of IAA pathway-related genes and oxidative stress-responsive enzyme genes may explain the plant growth-promoting potential and Cd tolerance, respectively. This is the first report of a complete genome sequence of Cd-tolerant S. marcescens and its plant growth promotion pathway. The whole-genome analysis of this strain clarified the genetic basis underlying its phenotypic and biochemical characteristics, underpinning the beneficial interactions between RSC-14 and plants. PMID:28187139

  19. Exogenous proline mediates alleviation of cadmium stress by promoting photosynthetic activity, water status and antioxidative enzymes activities of young date palm (Phoenix dactylifera L.).

    PubMed

    Zouari, M; Ben Ahmed, Ch; Zorrig, W; Elloumi, N; Rabhi, M; Delmail, D; Ben Rouina, B; Labrousse, P; Ben Abdallah, F

    2016-06-01

    The ability of exogenous compatible solutes, such as proline, to counteract cadmium (Cd) inhibitory effects in young date palm plants (Phoenix dactylifera L. cv Deglet Nour) was investigated. Two-year-old date palm plants were subjected for five months at different Cd stress levels (0, 10 and 30 mg CdCl2 kg(-1) soil) whether supplied or not with exogenous proline (20mM) added through the irrigation water. Different levels of Cd stress altered plant growth, gas exchanges and chlorophyll content as well as water status, but at different extent among them. In contrast, an increase of antioxidant enzymes activities of Cd-treated plants in association with high amounts of proline content, hydrogen peroxide (H2O2), thiobarbituric acid reactive substances (TBARS) and electrolyte leakage (EL) were observed. Interestingly, exogenous proline mitigated the adverse effects of Cd on young date palm. Indeed, it alleviated the oxidative damage induced by Cd accumulation and established better levels of plant growth, water status and photosynthetic activity. Moreover, proline-treated plants showed high antioxidant enzymes activities (superoxide dismutase, catalase and glutathione peroxydase) in roots and leaves as compared to Cd-treated plants.

  20. 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.

  1. 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.

  2. 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

  3. † 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

  4. Hydroalcoholic seed extract of Coriandrum sativum (Coriander) alleviates lead-induced oxidative stress in different regions of rat brain.

    PubMed

    Velaga, Manoj Kumar; Yallapragada, Prabhakara Rao; Williams, Dale; Rajanna, Sharada; Bettaiya, Rajanna

    2014-06-01

    Lead exposure is known to cause apoptotic neurodegeneration and neurobehavioral abnormalities in developing and adult brain by impairing cognition and memory. Coriandrum sativum is an herb belonging to Umbelliferae and is reported to have a protective effect against lead toxicity. In the present investigation, an attempt has been made to evaluate the protective activity of the hydroalcoholic extract of C. sativum seed against lead-induced oxidative stress. Male Wistar strain rats (100-120 g) were divided into four groups: control group: 1,000 mg/L of sodium acetate; exposed group: 1,000 mg/L lead acetate for 4 weeks; C. sativum treated 1 (CST1) group: 250 mg/kg body weight/day for seven consecutive days after 4 weeks of lead exposure; C. sativum treated 2 (CST2) group: 500 mg/kg body weight/day for seven consecutive days after 4 weeks of lead exposure. After the exposure and treatment periods, rats were sacrificed by cervical dislocation, and the whole brain was immediately isolated and separated into four regions: cerebellum, hippocampus, frontal cortex, and brain stem along with the control group. After sacrifice, blood was immediately collected into heparinized vials and stored at 4 °C. In all the tissues, reactive oxygen species (ROS), lipid peroxidation products (LPP), and total protein carbonyl content (TPCC) were estimated following standard protocols. An indicator enzyme for lead toxicity namely delta-amino levulinic acid dehydratase (δ-ALAD) activity was determined in the blood. A significant (p<0.05) increase in ROS, LPP, and TPCC levels was observed in exposed rat brain regions, while δ-ALAD showed a decrease indicating lead-induced oxidative stress. Treatment with the hydroalcoholic seed extract of C. sativum resulted in a tissue-specific amelioration of oxidative stress produced by lead.

  5. The protective mechanisms of CaHSP26 in transgenic tobacco to alleviate photoinhibition of PSII during chilling stress.

    PubMed

    Li, Meifang; Ji, Lusha; Yang, Xinghong; Meng, Qingwei; Guo, Shangjing

    2012-11-01

    A known sweet pepper cDNA clone, CaHSP26 encoding the chloroplast-localized small heat shock protein (CPsHSP), was isolated and introduced into tobacco plants. It has been reported that CaHSP26 is a member of the CPsHSP gene family related to extreme temperature tolerance in plants. In the present work, the transcripts were detected in the transgenic tobacco lines. The actual quantum yield of photosynthesis (ΦPSII), non-photochemical quenching, and stomatal conductance (gs) in the transgenic lines overexpressing CaHSP26 were higher than those in the wild-type plants under a range of photosynthetic photon flux density during chilling stress. Electron microscopic analysis showed that the transgenic line (L1) had larger size of stomata to lessen stomatal limitation. The activities of ascorbate peroxidase (APX), peroxidase (POD) and catalase (CAT) were also higher in the transgenic lines than those in wild-type plants. Additionally, a significant increase in cis-unsaturated fatty acid contents was observed in transgenic lines due to lower temperatures. These results suggested that CaHSP26 protein plays an important role in protection of PSII by maintaining the antioxidative enzyme activities to avoid or mitigate photooxidation and increasing the fluidity of the thylakoid membrane during chilling stress under low irradiance. Key message CaHSP26 protein protects PSII by maintaining the antioxidative enzyme activities to avoid or mitigate photooxidation and increases the fluidity of the thylakoid membrane during chilling stress under low irradiance.

  6. 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

  7. [Effect of cadmium stress on physiological characteristics of garlic seedlings and the alleviation effects of exogenous calcium].

    PubMed

    Li, He; Lian, Hai-feng; Liu, Shi-qi; Yu, Xin-hui; Sun, Ya-li; Guo, Hui-ping

    2015-04-01

    In the experiment, the effects of exogenous cadmium (Cd2+) and calcium (Ca2+) in nutrient solution on growth, photosynthetic characteristics, enzymes activities, main mineral elements absorption of garlic seedlings were studied. The results showed that cadmium could obviously inhibit the growth of garlic seedlings, decrease the pigment contents and photosynthetic parameters (P(n), E, g(s)) of leaves, reduced the enzymes (SOD, POD, CAT) activities and increase the MDA content of leaves, and also could reduce the N, P, K, Ca, Mg contents and increase the Cd content of roots. The growth was promoted after adding exogenous calcium to garlic seedlings under cadmium stress, which reflected that the morphological indexes were increased at first and then decreased with the increase of exogenous calcium concentrations, and were maximized when the exogenous calcium was 2 or 3 mmol x L(-1). At the same time, the pigment contents and photosynthetic parameters (P(n), E, g(s)) of leaves showed a similar tendency with the morphological indexes, and they were the highest when the exogenous calcium was 2 or 3 mmol x L(-1). In addition, adding exogenous calcium to garlic seedlings under cadmium stress enhanced the enzymes (SOD, POD, CAT) activities and decreased the MDA content of leaves, also added the N, P, K, Ca, Mg contents and reduced the Cd content of roots, and the effect was best when the exogenous calcium concentration was 2 or 3 mmol x L(-1).

  8. An iron-based beverage, HydroFerrate fluid (MRN-100), alleviates oxidative stress in murine lymphocytes in vitro

    PubMed Central

    Ghoneum, Mamdooh; Matsuura, Motohiro; Gollapudi, Sastry

    2009-01-01

    Background Several studies have examined the correlation between iron oxidation and H2O2 degradation. The present study was carried out to examine the protective effects of MRN-100 against stress-induced apoptosis in murine splenic cells in vitro. MRN-100, or HydroFerrate fluid, is an iron-based beverage composed of bivalent and trivalent ferrates. Methods Splenic lymphocytes from mice were cultured in the presence or absence of MRN-100 for 2 hrs and were subsequently exposed to hydrogen peroxide (H2O2) at a concentration of 25 μM for 14 hrs. Percent cell death was examined by flow cytometry and trypan blue exclusion. The effect of MRN-100 on Bcl-2 and Bax protein levels was determined by Western blot. Results Results show, as expected, that culture of splenic cells with H2O2 alone results in a significant increase in cell death (apoptosis) as compared to control (CM) cells. In contrast, pre-treatment of cells with MRN-100 followed by H2O2 treatment results in significantly reduced levels of apoptosis. In addition, MRN-100 partially prevents H2O2-induced down-regulation of the anti-apoptotic molecule Bcl-2 and upregulation of the pro-apoptotic molecule Bax. Conclusion Our findings suggest that MRN-100 may offer a protective effect against oxidative stress-induced apoptosis in lymphocytes. PMID:19409106

  9. Edaravone alleviates cisplatin-induced neurobehavioral deficits via modulation of oxidative stress and inflammatory mediators in the rat hippocampus.

    PubMed

    Jangra, Ashok; Kwatra, Mohit; Singh, Tavleen; Pant, Rajat; Kushwah, Pawan; Ahmed, Sahabuddin; Dwivedi, Durgesh; Saroha, Babita; Lahkar, Mangala

    2016-11-15

    Cisplatin is a chemotherapeutic agent used in the treatment of malignant tumors. A major clinical limitation of cisplatin is its potential toxic effects, including neurotoxicity. Edaravone, a potent free radical scavenger, has been reported to have the neuroprotective effect against neurological deficits. The aim of the present study was to determine the neuroprotective effect of edaravone against cisplatin-induced behavioral and biochemical anomalies in male Wistar rats. Our results showed that cisplatin (5mg/kg/week, i.p.) administration for seven weeks caused marked cognitive deficits and motor incoordination in rats. This was accompanied by oxido-nitrosative stress, neuroinflammation, NF-κB activation and down-regulation of Nrf2/HO-1 gene expression level in the hippocampus. Edaravone (10mg/kg/week, i.p.) treatment for seven weeks inhibited the aforementioned neurobehavioral and neurochemical deficits. Furthermore, edaravone was found to up-regulate the gene expression level of Nrf2/HO-1 and prevented the cisplatin-induced NF-κB activation. These findings demonstrated that oxido-nitrosative stress and inflammatory signaling mediators play a key role in the development of cisplatin-induced neurobehavioral deficits which were prevented by edaravone treatment.

  10. 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

  11. Oral treatment with the herbal formula B307 alleviates cardiac toxicity in doxorubicin-treated mice via suppressing oxidative stress, inflammation, and apoptosis

    PubMed Central

    Lien, Chia-Ying; Chuang, Tai-Yuan; Hsu, Chih-Hsiang; Lin, Ching-Lung; Wang, Sheue-Er; Sheu, Shuenn-Jyi; Chien, Chiang-Ting; Wu, Chung-Hsin

    2015-01-01

    Objective This study aimed to investigate whether the herbal formula B307 could alleviate doxorubicin (DOX)-induced acute cardiotoxicity. If so, we further unraveled possible molecular mechanisms of cardiac protection under treatment with the herbal formula B307. Methods Before the animal experiment, we examined relative viabilities of Huh7 cancer cells under treatment with the herbal formula B307. To test whether oral treatment with the herbal formula B307 could alleviate cardiotoxicity, equal volumes of B307 (50 mg/kg) or saline (sham treatment) were administered to 20-week-old male mice once daily for 14 consecutive days. Then, DOX (10 mg/kg; ip) was administered to male mice under B307 and sham treatments at 22–23 weeks of age. Cardiac functions in these mice were assessed via echocardiography at 23–24 weeks of age. Then, expressions of oxidative stress, inflammation, and apoptosis-related proteins were examined in the heart tissue by immunohistochemistry and Western blotting at 24–25 weeks of age. Apart from this, mortality rate and body weight were measured during the experiment. Results In vitro, the relative viabilities of Huh7 cancer cells under treatment with the herbal formula B307 had shown no obvious change at doses of 10–160 ng/mL. Furthermore, the relative viabilities of Huh7 cancer cells were significantly reduced under DOX treatment but showed no significant change under DOX only and DOX plus B307 treatment. In vivo, the mortality rate, body weight, and cardiac function of DOX-treated mice were obviously improved under oral treatment with the herbal formula B307. Furthermore, cardiac expressions of endothelial nitric oxide synthase, superoxide dismutase 2, and B-cell lymphoma 2 were significantly enhanced, but tumor necrosis factor alpha, NFKB1 (p50 and its precursor, p105), neurotrophin-3, Bcl-2-associated X protein, calpain, caspase 12, caspase 9, and caspase 3 were significantly suppressed in DOX-treated mice under oral treatment with

  12. Carnitine supplementation alleviates lipid metabolism derangements and protects against oxidative stress in non-obese hereditary hypertriglyceridemic rats.

    PubMed

    Cahova, Monika; Chrastina, Petr; Hansikova, Hana; Drahota, Zdenek; Trnovska, Jaroslava; Skop, Vojtech; Spacilova, Jana; Malinska, Hana; Oliyarnyk, Olena; Papackova, Zuzana; Palenickova, Eliska; Kazdova, Ludmila

    2015-03-01

    The aim of this study was to estimate the effect of carnitine supplementation on lipid disorders and peripheral tissue insulin sensitivity in a non-obese animal model of insulin resistance, the hereditary hypertriglyceridemic (HHTg) rat. Male HHTg rats were fed a standard diet, and half of them received daily doses of carnitine (500 mg·kg(-1) body weight) for 8 weeks. Rats of the original Wistar strain were used for comparison. HHTg rats exhibited increased urinary excretion of free carnitine and reduced carnitine content in the liver and blood. Carnitine supplementation compensated for this shortage and promoted urinary excretion of acetylcarnitine without any signs of (acyl)carnitine accumulation in skeletal muscle. Compared with their untreated littermates, carnitine-treated HHTg rats exhibited lower weight gain, reduced liver steatosis, lower fasting triglyceridemia, and greater reduction of serum free fatty acid content after glucose load. Carnitine treatment was associated with increased mitochondrial biogenesis and oxidative capacity for fatty acids, amelioration of oxidative stress, and restored substrate switching in the liver. In skeletal muscle (diaphragm), carnitine supplementation was associated with significantly higher palmitate oxidation and a more favorable complete to incomplete oxidation products ratio. Carnitine supplementation further enhanced insulin sensitivity ex vivo. No effects on whole-body glucose tolerance were observed. Our data suggest that some metabolic syndrome-related disorders, particularly fatty acid oxidation, steatosis, and oxidative stress in the liver, could be attenuated by carnitine supplementation. The effect of carnitine could be explained, at least partly, by enhanced substrate oxidation and increased fatty acid transport from tissues in the form of short-chain acylcarnitines.

  13. Bilberries potentially alleviate stress-related retinal gene expression induced by a high-fat diet in mice

    PubMed Central

    Kalesnykas, Giedrius; Adriaens, Michiel; Evelo, Chris T.; Törrönen, Riitta; Kaarniranta, Kai

    2012-01-01

    displayed differential regulation of genes in ontology groups, mainly pathways for apoptosis, inflammation, and oxidative stress, especially systemic lupus erythematosus, mitogen-activated protein kinase, and glutathione metabolism. Mice fed a HFD had increased retinal gene expression of several crystallins, while the HFD+BB mice showed potential downregulation of these crystallins when compared to the HFD mice. Bilberries also reduced the expression of genes in the mitogen-activated protein kinase (MAPK) pathway and increased those in the glutathione metabolism pathway. Conclusions HFD feeding induces differential expression of several stress-related genes in the mouse retina. Despite minor effects in the phenotype, a diet rich in bilberries