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Sample records for nitrosative stress pathways

  1. Concurrent targeting of nitrosative stress-PARP pathway corrects functional, behavioral and biochemical deficits in experimental diabetic neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Negi, Geeta; Kumar, Ashutosh [Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160062 (India); Sharma, Shyam S., E-mail: sssharma@niper.ac.in [Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160062 (India)

    2010-01-01

    Peroxynitrite mediated nitrosative stress, an indisputable initiator of DNA damage and overactivation of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated after sensing DNA damage, are two crucial pathogenetic mechanisms in diabetic neuropathy. The intent of the present study was to investigate the effect of combination of a peroxynitrite decomposition catalyst (PDC), FeTMPyP and a PARP inhibitor, 4-ANI against diabetic peripheral neuropathy. The end points of evaluation of the study included motor nerve conduction velocity (MNCV) and nerve blood flow (NBF) for evaluating nerve functions; thermal hyperalgesia and mechanical allodynia for assessing nociceptive alterations, malondialdehyde and peroxynitrite levels to detect oxidative stress-nitrosative stress; NAD concentration in sciatic nerve to assess overactivation of PARP. Additionally immunohistochemical studies for nitrotyrosine and Poly(ADP-ribose) (PAR) was also performed. Treatment with the combination of FeTMPyP and 4-ANI led to significant improvement in nerve functions and pain parameters and also attenuated the oxidative-nitrosative stress markers. Further, the combination also reduced the overactivation of PARP as evident from increased NAD levels and decreased PAR immunopositivity in sciatic nerve microsections. Thus, it can be concluded that treatment with the combination of a PDC and PARP inhibitor attenuates alteration in peripheral nerves in diabetic neuropathy (DN).

  2. Neuro-oxidative-nitrosative stress in sepsis

    DEFF Research Database (Denmark)

    Berg, Ronan M G; Møller, Kirsten; Bailey, Damian M

    2011-01-01

    Neuro-oxidative-nitrosative stress may prove the molecular basis underlying brain dysfunction in sepsis. In the current review, we describe how sepsis-induced reactive oxygen and nitrogen species (ROS/RNS) trigger lipid peroxidation chain reactions throughout the cerebrovasculature and surrounding...

  3. Mangiferin exerts hepatoprotective activity against D-galactosamine induced acute toxicity and oxidative/nitrosative stress via Nrf2–NFκB pathways

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    Das, Joydeep; Ghosh, Jyotirmoy; Roy, Anandita; Sil, Parames C., E-mail: parames@bosemain.boseinst.ac.in

    2012-04-01

    Mangiferin, a xanthone glucoside, is well known to exhibit antioxidant, antiviral, antitumor, anti-inflammatory and gene-regulatory effects. In the present study, we isolated mangiferin from the bark of Mangifera indica and assessed its beneficial role in galactosamine (GAL) induced hepatic pathophysiology. GAL (400 mg/kg body weight) exposed hepatotoxic rats showed elevation in the activities of serum ALP, ALT, levels of triglycerides, total cholesterol, lipid-peroxidation and reduction in the levels of serum total proteins, albumin and cellular GSH. Besides, GAL exposure (5 mM) in hepatocytes induced apoptosis and necrosis, increased ROS and NO production. Signal transduction studies showed that GAL exposure significantly increased the nuclear translocation of NFκB and elevated iNOS protein expression. The same exposure also elevated TNF-α, IFN-γ, IL-1β, IL-6, IL-12, IL-18 and decreased IL-10 mRNA expressions. Furthermore, GAL also decreased the protein expression of Nrf2, NADPH:quinine oxidoreductase-1, heme oxygenase-1 and GSTα. However, mangiferin administration in GAL intoxicated rats or coincubation of hepatocytes with mangiferin significantly altered all these GAL-induced adverse effects. In conclusion, the hepatoprotective role of mangiferin was due to induction of antioxidant defense via the Nrf2 pathway and reduction of inflammation via NFκB inhibition. Highlights: ►Galactosamine induces hepatocytes death via oxidative and nitrosative stress. ►Mangiferin exerts hepatoprotective effect/antioxidant defense via Nrf2 pathway. ►Mangiferin exerts anti-inflammatory responses by inhibiting NF-κB. ►Mangiferin suppresses galactosamine-induced repression of IL-10 mRNA.

  4. Nitrosative stress and nitrated proteins in trichloroethene-mediated autoimmunity.

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    Gangduo Wang

    Full Text Available Exposure to trichloroethene (TCE, a ubiquitous environmental contaminant, has been linked to a variety of autoimmune diseases (ADs including SLE, scleroderma and hepatitis. Mechanisms involved in the pathogenesis of ADs are largely unknown. Earlier studies from our laboratory in MRL+/+ mice suggested the contribution of oxidative/nitrosative stress in TCE-induced autoimmunity, and N-acetylcysteine (NAC supplementation provided protection by attenuating oxidative stress. This study was undertaken to further evaluate the contribution of nitrosative stress in TCE-mediated autoimmunity and to identify proteins susceptible to nitrosative stress. Groups of female MRL +/+ mice were given TCE, NAC or TCE + NAC for 6 weeks (TCE, 10 mmol/kg, i.p., every 4th day; NAC, ∼ 250 mg/kg/day via drinking water. TCE exposure led to significant increases in serum anti-nuclear and anti-histone antibodies together with significant induction of iNOS and increased formation of nitrotyrosine (NT in sera and livers. Proteomic analysis identified 14 additional nitrated proteins in the livers of TCE-treated mice. Furthermore, TCE exposure led to decreased GSH levels and increased activation of NF-κB. Remarkably, NAC supplementation not only ameliorated TCE-induced nitrosative stress as evident from decreased iNOS, NT, nitrated proteins, NF-κB p65 activation and increased GSH levels, but also the markers of autoimmunity, as evident from decreased levels of autoantibodies in the sera. These findings provide support to the role of nitrosative stress in TCE-mediated autoimmune response and identify specific nitrated proteins which could have autoimmune potential. Attenuation of TCE-induced autoimmunity in mice by NAC provides an approach for designing therapeutic strategies.

  5. Oxidative/nitrosative stress and antidepressants: targets for novel antidepressants.

    Science.gov (United States)

    Lee, Seung-Yup; Lee, Soo-Jung; Han, Changsu; Patkar, Ashwin A; Masand, Prakash S; Pae, Chi-Un

    2013-10-01

    The brain is an organ predisposed to oxidative/nitrosative stress. This is especially true in the case of aging as well as several neurodegenerative diseases. Under such circumstances, a decline in the normal antioxidant defense mechanisms leads to an increase in the vulnerability of the brain to the deleterious effects of oxidative damage. Highly reactive oxygen/nitrogen species damage lipids, proteins, and mitochondrial and neuronal genes. Unless antioxidant defenses react appropriately to damage inflicted by radicals, neurons may experience microalteration, microdysfunction, and degeneration. We reviewed how oxidative and nitrosative stresses contribute to the pathogenesis of depressive disorders and reviewed the clinical implications of various antioxidants as future targets for antidepressant treatment. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Oxidative and nitrosative stress markers in bus drivers.

    Science.gov (United States)

    Rossner, Pavel; Svecova, Vlasta; Milcova, Alena; Lnenickova, Zdena; Solansky, Ivo; Santella, Regina M; Sram, Radim J

    2007-04-01

    Exposure to ambient air pollution is associated with many diseases. Oxidative and nitrosative stress are believed to be two of the major sources of particulate matter (PM)-mediated adverse health effects. PM in ambient air arises from industry, local heating, and vehicle emissions and poses a serious problem mainly in large cities. In the present study we analyzed the level of oxidative and nitrosative stress among 50 bus drivers from Prague, Czech Republic, and 50 matching controls. We assessed simultaneously the levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP) and 8-oxodeoxyguanosine (8-oxodG) in urine and protein carbonyl groups and 3-nitrotyrosine (NT) in blood plasma. For the analysis of all four markers we used ELISA techniques. We observed significantly increased levels of oxidative and nitrosative stress markers in bus drivers. The median levels (min, max) of individual markers in bus drivers versus controls were as follows: 8-oxodG: 7.79 (2.64-12.34)nmol/mmol versus 6.12 (0.70-11.38)nmol/mmol creatinine (p<0.01); 15-F(2t)-IsoP: 0.81 (0.38-1.55)nmol/mmol versus 0.68 (0.39-1.79)nmol/mmol creatinine (p<0.01); carbonyl levels: 14.1 (11.8-19.0)nmol/ml versus 12.9 (9.8-16.6)nmol/ml plasma (p<0.001); NT: 694 (471-3228)nmol/l versus 537 (268-13833)nmol/l plasma (p<0.001). 15-F(2t)-IsoP levels correlated with vitamin E (R=0.23, p<0.05), vitamin C (R=-0.33, p<0.01) and cotinine (R=0.47, p<0.001) levels. Vitamin E levels also positively correlated with 8-oxodG (R=0.27, p=0.01) and protein carbonyl levels (R=0.32, p<0.001). Both oxidative and nitrosative stress markers positively correlated with PM2.5 and PM10 exposure. In conclusion, our study indicates that exposure to PM2.5 and PM10 results in increased oxidative and nitrosative stress.

  7. DNA alkylation damage as a sensor of nitrosative stress in Mycobacterium tuberculosis

    OpenAIRE

    Durbach, S I; Springer, B; Machowski, E E; North, R J; Papavinasasundaram, K G; Colston, M J; Böttger, E C; Mizrahi, V

    2003-01-01

    One of the cellular consequences of nitrosative stress is alkylation damage to DNA. To assess whether nitrosative stress is registered on the genome of Mycobacterium tuberculosis, mutants lacking an alkylation damage repair and reversal operon were constructed. Although hypersensitive to the genotoxic effects of N-methyl-N′-nitro-N-nitrosoguanidine in vitro, the mutants displayed no phenotype in vivo, suggesting that permeation of nitrosative stress to the level of cytotoxic DNA damage is res...

  8. A systematic review of observational studies on oxidative/nitrosative stress involvement in dengue pathogenesis

    OpenAIRE

    Castro, Raimundo; Pinzón, Hernando Samuel; Alvis-Guzman, Nelson

    2015-01-01

    Objective: Our objective was to systematically review the published observational research related to the role of oxidative-nitrosative stress in pathogenesis of dengue. Methods: We searched electronic databases (PubMed, EMBASE, The COCHRANE library, ScienceDirect, Scopus, SciELO, LILACS via Virtual Health Library, Google Scholar) using the term: dengue, dengue virus, severe dengue, oxidative stress, nitrosative stress, antioxidants, oxidants, free radicals, oxidized lipid products, lipid per...

  9. Oxidative and nitrosative stress in trichloroethene-mediated autoimmune response

    International Nuclear Information System (INIS)

    Wang Gangduo; Cai Ping; Ansari, G.A.S.; Khan, M. Firoze

    2007-01-01

    Reactive oxygen and nitrogen species (RONS) are implicated in the pathogenesis of several autoimmune diseases. Also, increased lipid peroxidation and protein nitration are reported in systemic autoimmune diseases. Lipid peroxidation-derived aldehydes (LPDAs) such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) are highly reactive and bind proteins covalently, but their potential to elicit an autoimmune response and contribution to disease pathogenesis remain unclear. Similarly, nitration of protein could also contribute to disease pathogenesis. To assess the status of lipid peroxidation and/or RONS, autoimmune-prone female MRL+/+ mice (5-week old) were treated with trichloroethene (TCE), an environmental contaminant known to induce autoimmune response, for 48 weeks (0.5 mg/ml via drinking water), and formation of antibodies to LPDA-protein adducts was followed in the sera of control and TCE-treated mice. TCE treatment led to greater formation of both anti-MDA- and -HNE-protein adduct antibodies and higher serum iNOS and nitrotyrosine levels. The increase in TCE-induced oxidative stress was associated with increases in anti-nuclear-, anti-ssDNA- and anti-dsDNA-antibodies. These findings suggest that TCE exposure not only leads to oxidative/nitrosative stress, but is also associated with induction/exacerbation of autoimmune response in MRL+/+ mice. Further interventional studies are needed to establish a causal role of RONS in TCE-mediated autoimmunity

  10. Induction of oxidative and nitrosative stresses in human retinal pigment epithelial cells by all-trans-retinal

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    Zhu, Xue [Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, Jiangsu Province (China); Wang, Ke, E-mail: wangke@jsinm.org [Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, Jiangsu Province (China); Zhang, Kai [Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, Jiangsu Province (China); Zhou, Fanfan [Faculty of Pharmacy, University of Sydney, New South Wales 2006 (Australia); Zhu, Ling [Save Sight Institute, University of Sydney, New South Wales 2000 (Australia)

    2016-10-15

    Delayed clearance of free form all-trans-retinal (atRAL) is estimated be the key cause of retinal pigment epithelium (RPE) cells injury during the pathogenesis of retinopathies such as age-related macular degeneration (AMD), however, the underlying molecular mechanisms are far from clear. In this study, we investigated the cytotoxicity effect and underlying molecular mechanism of atRAL on human retinal pigment epithelium ARPE-19 cells. The results indicated that atRAL could cause cell dysfunction by inducing oxidative and nitrosative stresses in ARPE-19 cells. The oxidative stress induced by atRAL was mediated through up-regulation of reactive oxygen species (ROS) generation, activating mitochondrial-dependent and MAPKs signaling pathways, and finally resulting in apoptosis of ARPE-19 cells. The NADPH oxidase inhibitor apocynin could partly attenuated ROS generation, indicating that NADPH oxidase activity was involved in atRAL-induced oxidative stress in ARPE-19 cells. The nitrosative stress induced by atRAL was mainly reflected in increasing nitric oxide (NO) production, enhancing iNOS, ICAM-1 and VCAM-1 expressions, and promoting monocyte adhesion. Furthermore, above effects could be dramatically blocked by using a nuclear factor kappa B (NF-κB) inhibitor SN50, indicated that atRAL-induced oxidative and nitrosative stresses were mediated by NF-κB. The results provide better understanding of atRAL-induced toxicity in human RPE cells. - Highlights: • atRAL induces oxidative stress-mediated apoptosis in ARPE-19 cells. • atRAL induces oxidative stress-mediated inflammation in ARPE-19 cells. • NF-κB is involved in atRAL-induced oxidative and nitrosative stresses.

  11. Induction of oxidative and nitrosative stresses in human retinal pigment epithelial cells by all-trans-retinal

    International Nuclear Information System (INIS)

    Zhu, Xue; Wang, Ke; Zhang, Kai; Zhou, Fanfan; Zhu, Ling

    2016-01-01

    Delayed clearance of free form all-trans-retinal (atRAL) is estimated be the key cause of retinal pigment epithelium (RPE) cells injury during the pathogenesis of retinopathies such as age-related macular degeneration (AMD), however, the underlying molecular mechanisms are far from clear. In this study, we investigated the cytotoxicity effect and underlying molecular mechanism of atRAL on human retinal pigment epithelium ARPE-19 cells. The results indicated that atRAL could cause cell dysfunction by inducing oxidative and nitrosative stresses in ARPE-19 cells. The oxidative stress induced by atRAL was mediated through up-regulation of reactive oxygen species (ROS) generation, activating mitochondrial-dependent and MAPKs signaling pathways, and finally resulting in apoptosis of ARPE-19 cells. The NADPH oxidase inhibitor apocynin could partly attenuated ROS generation, indicating that NADPH oxidase activity was involved in atRAL-induced oxidative stress in ARPE-19 cells. The nitrosative stress induced by atRAL was mainly reflected in increasing nitric oxide (NO) production, enhancing iNOS, ICAM-1 and VCAM-1 expressions, and promoting monocyte adhesion. Furthermore, above effects could be dramatically blocked by using a nuclear factor kappa B (NF-κB) inhibitor SN50, indicated that atRAL-induced oxidative and nitrosative stresses were mediated by NF-κB. The results provide better understanding of atRAL-induced toxicity in human RPE cells. - Highlights: • atRAL induces oxidative stress-mediated apoptosis in ARPE-19 cells. • atRAL induces oxidative stress-mediated inflammation in ARPE-19 cells. • NF-κB is involved in atRAL-induced oxidative and nitrosative stresses.

  12. Oxidative stress and nitrosative stress are involved in different stages of proteolytic pulmonary emphysema.

    Science.gov (United States)

    Lanzetti, Manuella; da Costa, Cristiane Aguiar; Nesi, Renata Tiscoski; Barroso, Marina Valente; Martins, Vanessa; Victoni, Tatiana; Lagente, Vincent; Pires, Karla Maria Pereira; e Silva, Patrícia Machado Rodrigues; Resende, Angela Castro; Porto, Luis Cristóvão; Benjamim, Cláudia Farias; Valença, Samuel Santos

    2012-12-01

    Our aim was to investigate the role of oxidative stress in elastase-induced pulmonary emphysema. C57BL/6 mice were subjected to pancreatic porcine elastase (PPE) instillation (0.05 or 0.5 U per mouse, i.t.) to induce pulmonary emphysema. Lungs were collected on days 7, 14, and 21 after PPE instillation. The control group was sham injected. Also, mice treated with 1% aminoguanidine (AMG) and inducible NO synthase (iNOS) knockout mice received 0.5 U PPE (i.t.), and lungs were analyzed 21 days after. We performed bronchoalveolar lavage, biochemical analyses of oxidative stress, and lung stereology and morphometry assays. Emphysema was observed histologically at 21 days after 0.5 U PPE treatment; tissues from these mice exhibited increased alveolar linear intercept and air-space volume density in comparison with the control group. TNF-α was elevated at 7 and 14 days after 0.5 U PPE treatment, concomitant with a reduction in the IL-10 levels at the same time points. Myeloperoxidase was elevated in all groups treated with 0.5 U PPE. Oxidative stress was observed during early stages of emphysema, with increased nitrite levels and malondialdehyde and superoxide dismutase activity at 7 days after 0.5 U PPE treatment. Glutathione peroxidase activity was increased in all groups treated with 0.5 U PPE. The emphysema was attenuated when iNOS was inhibited using 1% AMG and in iNOS knockout mice. Furthermore, proteolytic stimulation by PPE enhanced the expression of nitrotyrosine and iNOS, whereas the PPE+AMG group showed low expression of iNOS and nitrotyrosine. PPE stimulus also induced endothelial (e) NOS expression, whereas AMG reduced eNOS. Our results suggest that the oxidative and nitrosative stress pathways are triggered by nitric oxide production via iNOS expression in pulmonary emphysema. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Efficacy of subantimicrobial-dose doxycycline against nitrosative stress in chronic periodontitis.

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    Pârvu, Alina Elena; Alb, Sandu Florin; Crăciun, Alexandra; Taulescu, Marian Aurel

    2013-02-01

    To evaluate the effectiveness of subantimicrobial-dose doxycycline (SDD) as an adjunct to scaling and root planing (SRP) treatment against the nitrosative stress of moderate to advanced chronic periodontitis. Adults with untreated chronic periodontitis (n=174) were randomly administered SRP+SDD (n=87) (20 mg of doxycycline twice daily) or SRP+placebo (n=87) treatment for 3 months. At baseline and after 3 months, the probing depths (PD), bleeding on probing (BOP) and clinical attachment level (CAL) were measured, and a gingivomucosal biopsy was collected to assay the induction of nitric oxide synthase (iNOS) and 3-nitrotyrosine (3NT), and blood was collected to assay for total nitrites and nitrates (NO(x)) and 3NT. Compared to baseline, at the completion of treatment, significant decreases in the levels of tissue iNOS and 3NT and serum NO(x) and 3NT were observed in both groups. SRP+SDD yielded a greater reduction in the gingivomucosal and serum nitrosative stress markers than did SRP+placebo. PD, BOP, and CAL reduction were correlated with the nitrosative stress parameters. On a short-term basis, SDD therapy may be used as an adjunct to SRP treatment against nitrosative stress in moderate to advanced chronic periodontitis.

  14. Partial deletion of argininosuccinate synthase protects from pyrazole plus lipopolysaccharide-induced liver injury by decreasing nitrosative stress

    Science.gov (United States)

    Lu, Yongke; Leung, Tung Ming; Ward, Stephen C.

    2012-01-01

    Argininosuccinate synthase (ASS) is the rate-limiting enzyme in the urea cycle. Along with nitric oxide synthase (NOS)-2, ASS endows cells with the l-citrulline/nitric oxide (NO·) salvage pathway to continually supply l-arginine from l-citrulline for sustained NO· generation. Because of the relevant role of NOS in liver injury, we hypothesized that downregulation of ASS could decrease the availability of intracellular substrate for NO· synthesis by NOS-2 and, hence, decrease liver damage. Previous work demonstrated that pyrazole plus LPS caused significant liver injury involving NO· generation and formation of 3-nitrotyrosine protein adducts; thus, wild-type (WT) and Ass+/− mice (Ass−/− mice are lethal) were treated with pyrazole plus LPS, and markers of nitrosative stress, as well as liver injury, were analyzed. Partial ablation of Ass protected from pyrazole plus LPS-induced liver injury by decreasing nitrosative stress and hepatic and circulating TNFα. Moreover, apoptosis was prevented, since pyrazole plus LPS-treated Ass+/− mice showed decreased phosphorylation of JNK; increased MAPK phosphatase-1, which is known to deactivate JNK signaling; and lower cleaved caspase-3 than treated WT mice, and this was accompanied by less TdT-mediated dUTP nick end labeling-positive staining. Lastly, hepatic neutrophil accumulation was almost absent in pyrazole plus LPS-treated Ass+/− compared with WT mice. Partial Ass ablation prevents pyrazole plus LPS-mediated liver injury by reducing nitrosative stress, TNFα, apoptosis, and neutrophil infiltration. PMID:22052013

  15. The role of oxidative and nitrosative stress in accelerated aging and major depressive disorder.

    Science.gov (United States)

    Maurya, Pawan Kumar; Noto, Cristiano; Rizzo, Lucas B; Rios, Adiel C; Nunes, Sandra O V; Barbosa, Décio Sabbatini; Sethi, Sumit; Zeni, Maiara; Mansur, Rodrigo B; Maes, Michael; Brietzke, Elisa

    2016-02-04

    Major depressive disorder (MDD) affects millions of individuals and is highly comorbid with many age associated diseases such as diabetes mellitus, immune-inflammatory dysregulation and cardiovascular diseases. Oxidative/nitrosative stress plays a fundamental role in aging, as well as in the pathogenesis of neurodegenerative/neuropsychiatric disorders including MDD. In this review, we critically review the evidence for an involvement of oxidative/nitrosative stress in acceleration of aging process in MDD. There are evidence of the association between MDD and changes in molecular mechanisms involved in aging. There is a significant association between telomere length, enzymatic antioxidant activities (SOD, CAT, GPx), glutathione (GSH), lipid peroxidation (MDA), nuclear factor κB, inflammatory cytokines with MDD. Major depression also is characterized by significantly lower concentration of antioxidants (zinc, coenzyme Q10, PON1). Since, aging and MDD share a common biological base in their pathophysiology, the potential therapeutic use of antioxidants and anti-aging molecules in MDD could be promising.

  16. Increased oxidative/nitrosative stress and decreased antioxidant enzyme activities in prostate cancer.

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    Arsova-Sarafinovska, Zorica; Eken, Ayse; Matevska, Nadica; Erdem, Onur; Sayal, Ahmet; Savaser, Ayhan; Banev, Saso; Petrovski, Daniel; Dzikova, Sonja; Georgiev, Vladimir; Sikole, Aleksandar; Ozgök, Yaşar; Suturkova, Ljubica; Dimovski, Aleksandar J; Aydin, Ahmet

    2009-08-01

    The study was aimed to evaluate the oxidative/nitrosative stress status in prostate cancer (CaP) and benign prostatic hyperplasia (BPH). 312 men from two different populations were included: 163 men from Macedonia (73 CaP patients, 67 BPH patients and 23 control subjects) and 149 men from Turkey (34 prostate cancer patients, 100 BPH patients and 15 control subjects). We measured erythrocyte malondialdehyde (MDA) levels, erythrocyte activities of superoxide dismutase (CuZn-SOD), glutathione peroxidase (GPX) and catalase (CAT); plasma nitrite/nitrate (NO(2)(-)/NO(3)(-)), cGMP and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. A similar pattern of alteration in the oxidative/nitrosative stress-related parameters was found in both, Macedonian and Turkish studied samples: higher MDA concentrations with lower GPX and CuZn-SOD activities in CaP patients versus controls and BPH groups. The CAT activity was decreased in the CaP patients versus controls in the Turkish studied sample. Furthermore, CaP patients had increased plasma NO(2)(-)/NO(3)(-) and cGMP levels versus controls and BPH groups in both studied samples. This study has confirmed an imbalance in the oxidative stress/antioxidant status and revealed an altered nitrosative status in prostate cancer patients.

  17. Nitrosative/oxidative stress conditions regulate thioredoxin-interacting protein (TXNIP) expression and thioredoxin-1 (TRX-1) nuclear localization.

    Science.gov (United States)

    Ogata, Fernando Toshio; Batista, Wagner Luiz; Sartori, Adriano; Gesteira, Tarsis Ferreira; Masutani, Hiroshi; Arai, Roberto Jun; Yodoi, Junji; Stern, Arnold; Monteiro, Hugo Pequeno

    2013-01-01

    Thioredoxin (TRX-1) is a multifunctional protein that controls the redox status of other proteins. TRX-1 can be found in the extracellular milieu, cytoplasm and nucleus, and it has distinct functions in each environment. Previously, we studied the intracellular localization of TRX-1 and its relationship with the activation of the p21Ras-ERK1/2 MAP Kinases signaling pathway. In situations where this pathway was activated by stress conditions evoked by a nitrosothiol, S-nitroso-N-acetylpenicillamine (SNAP), TRX-1 accumulated in the nuclear compartment due to nitrosylation of p21Ras and activation of downstream ERK1/2 MAP kinases. Presently, we demonstrate that ERK1/2 MAP Kinases activation and spatial distribution within cells trigger TRX-1 nuclear translocation through down-regulation of the physiological inhibitor of TRX-1, Thioredoxin Interacting Protein (TXNIP). Once activated by the oxidants, SNAP and H₂O₂, the ERK1/2 MAP kinases migrate to the nucleus. This is correlated with down-regulation of TXNIP. In the presence of the MEK inhibitors (PD98059 or UO126), or in cells transfected with the Protein Enriched in Astrocytes (PEA-15), a cytoplasmic anchor of ERK1/2 MAP kinases, TRX-1 nuclear migration and TXNIP down-regulation are no longer observed in cells exposed to oxidants. On the other hand, over-expression of TXNIP abolishes nuclear migration of TRX-1 under nitrosative/oxidative stress conditions, whereas gene silencing of TXNIP facilitates nuclear migration even in the absence of stress conditions. Studies based on the TXNIP promoter support this regulation. In conclusion, changes in TRX-1 compartmentalization under nitrosative/oxidative stress conditions are dependent on the expression levels of TXNIP, which are regulated by cellular compartmentalization and activation of the ERK1/2 MAP kinases.

  18. Nitrosative/oxidative stress conditions regulate thioredoxin-interacting protein (TXNIP expression and thioredoxin-1 (TRX-1 nuclear localization.

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    Fernando Toshio Ogata

    Full Text Available Thioredoxin (TRX-1 is a multifunctional protein that controls the redox status of other proteins. TRX-1 can be found in the extracellular milieu, cytoplasm and nucleus, and it has distinct functions in each environment. Previously, we studied the intracellular localization of TRX-1 and its relationship with the activation of the p21Ras-ERK1/2 MAP Kinases signaling pathway. In situations where this pathway was activated by stress conditions evoked by a nitrosothiol, S-nitroso-N-acetylpenicillamine (SNAP, TRX-1 accumulated in the nuclear compartment due to nitrosylation of p21Ras and activation of downstream ERK1/2 MAP kinases. Presently, we demonstrate that ERK1/2 MAP Kinases activation and spatial distribution within cells trigger TRX-1 nuclear translocation through down-regulation of the physiological inhibitor of TRX-1, Thioredoxin Interacting Protein (TXNIP. Once activated by the oxidants, SNAP and H₂O₂, the ERK1/2 MAP kinases migrate to the nucleus. This is correlated with down-regulation of TXNIP. In the presence of the MEK inhibitors (PD98059 or UO126, or in cells transfected with the Protein Enriched in Astrocytes (PEA-15, a cytoplasmic anchor of ERK1/2 MAP kinases, TRX-1 nuclear migration and TXNIP down-regulation are no longer observed in cells exposed to oxidants. On the other hand, over-expression of TXNIP abolishes nuclear migration of TRX-1 under nitrosative/oxidative stress conditions, whereas gene silencing of TXNIP facilitates nuclear migration even in the absence of stress conditions. Studies based on the TXNIP promoter support this regulation. In conclusion, changes in TRX-1 compartmentalization under nitrosative/oxidative stress conditions are dependent on the expression levels of TXNIP, which are regulated by cellular compartmentalization and activation of the ERK1/2 MAP kinases.

  19. Aniline-induced nitrosative stress in rat spleen: Proteomic identification of nitrated proteins

    International Nuclear Information System (INIS)

    Fan Xiuzhen; Wang Jianling; Soman, Kizhake V.; Ansari, G.A.S.; Khan, M. Firoze

    2011-01-01

    expression in the spleen. → Results support the role of nitrosative stress in splenic toxicity of aniline.

  20. Nitrosative stress in human skeletal muscle attenuated by exercise countermeasure after chronic disuse.

    Science.gov (United States)

    Salanova, Michele; Schiffl, Gudrun; Gutsmann, Martina; Felsenberg, Dieter; Furlan, Sandra; Volpe, Pompeo; Clarke, Andrew; Blottner, Dieter

    2013-01-01

    Activity-induced nitric oxide (NO) imbalance and "nitrosative stress" are proposed mechanisms of disrupted Ca(2+) homeostasis in atrophic skeletal muscle. We thus mapped S-nitrosylated (SNO) functional muscle proteins in healthy male subjects in a long-term bed rest study (BBR2-2 Study) without and with exercise as countermeasure in order to assess (i) the negative effects of chronic muscle disuse by nitrosative stress, (ii) to test for possible attenuation by exercise countermeasure in bed rest and (iii) to identify new NO target proteins. Muscle biopsies from calf soleus and hip vastus lateralis were harvested at start (Pre) and at end (End) from a bed rest disuse control group (CTR, n=9) and two bed rest resistive exercise groups either without (RE, n=7) or with superimposed vibration stimuli (RVE, n=7). At subcellular compartments, strong anti-SNO-Cys immunofluorescence patterns in control muscle fibers after bed rest returned to baseline following vibration exercise. Total SNO-protein levels, Nrf-2 gene expression and nucleocytoplasmic shuttling were changed to varying degrees in all groups. Excess SNO-protein levels of specific calcium release/uptake proteins (SNO-RyR1, -SERCA1 and -PMCA) and of contractile myosin heavy chains seen in biopsy samples of chronically disused skeletal muscle were largely reduced by vibration exercise. We also identified NOS1 as a novel NO target in human skeletal muscle controlled by activity driven auto-nitrosylation mechanisms. Our findings suggest that aberrant levels of functional SNO-proteins represent signatures of uncontrolled nitrosative stress management in disused human skeletal muscle that can be offset by exercise as countermeasure.

  1. Oxidative-Nitrosative Stress and Myocardial Dysfunctions in Sepsis: Evidence from the Literature and Postmortem Observations

    Directory of Open Access Journals (Sweden)

    M. Neri

    2016-01-01

    Full Text Available Background. Myocardial depression in sepsis is common, and it is associated with higher mortality. In recent years, the hypothesis that the myocardial dysfunction during sepsis could be mediated by ischemia related to decreased coronary blood flow waned and a complex mechanism was invoked to explain cardiac dysfunction in sepsis. Oxidative stress unbalance is thought to play a critical role in the pathogenesis of cardiac impairment in septic patients. Aim. In this paper, we review the current literature regarding the pathophysiology of cardiac dysfunction in sepsis, focusing on the possible role of oxidative-nitrosative stress unbalance and mitochondria dysfunction. We discuss these mechanisms within the broad scenario of cardiac involvement in sepsis. Conclusions. Findings from the current literature broaden our understanding of the role of oxidative and nitrosative stress unbalance in the pathophysiology of cardiac dysfunction in sepsis, thus contributing to the establishment of a relationship between these settings and the occurrence of oxidative stress. The complex pathogenesis of septic cardiac failure may explain why, despite the therapeutic strategies, sepsis remains a big clinical challenge for effectively managing the disease to minimize mortality, leading to consideration of the potential therapeutic effects of antioxidant agents.

  2. Oxidative and nitrosative stress markers in bus drivers

    Czech Academy of Sciences Publication Activity Database

    Rössner ml., Pavel; Švecová, Vlasta; Milcová, Alena; Lněničková, Zdena; Solanský, I.; Santella, R. M.; Šrám, Radim

    2007-01-01

    Roč. 617, - (2007), s. 23-32 ISSN 0027-5107 R&D Projects: GA MŽP SL/5/160/05; GA AV ČR 1QS500390506 Institutional research plan: CEZ:AV0Z50390512 Keywords : oxidative stress * bus drivers * air pollution Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 4.159, year: 2007

  3. Nitrosative stress in human skeletal muscle attenuated by exercise countermeasure after chronic disuse

    Directory of Open Access Journals (Sweden)

    Michele Salanova

    2013-01-01

    Full Text Available Activity-induced nitric oxide (NO imbalance and “nitrosative stress” are proposed mechanisms of disrupted Ca2+ homeostasis in atrophic skeletal muscle. We thus mapped S-nitrosylated (SNO functional muscle proteins in healthy male subjects in a long-term bed rest study (BBR2-2 Study without and with exercise as countermeasure in order to assess (i the negative effects of chronic muscle disuse by nitrosative stress, (ii to test for possible attenuation by exercise countermeasure in bed rest and (iii to identify new NO target proteins. Muscle biopsies from calf soleus and hip vastus lateralis were harvested at start (Pre and at end (End from a bed rest disuse control group (CTR, n=9 and two bed rest resistive exercise groups either without (RE, n=7 or with superimposed vibration stimuli (RVE, n=7. At subcellular compartments, strong anti-SNO-Cys immunofluorescence patterns in control muscle fibers after bed rest returned to baseline following vibration exercise. Total SNO-protein levels, Nrf-2 gene expression and nucleocytoplasmic shuttling were changed to varying degrees in all groups. Excess SNO-protein levels of specific calcium release/uptake proteins (SNO-RyR1, –SERCA1 and –PMCA and of contractile myosin heavy chains seen in biopsy samples of chronically disused skeletal muscle were largely reduced by vibration exercise. We also identified NOS1 as a novel NO target in human skeletal muscle controlled by activity driven auto-nitrosylation mechanisms. Our findings suggest that aberrant levels of functional SNO-proteins represent signatures of uncontrolled nitrosative stress management in disused human skeletal muscle that can be offset by exercise as countermeasure.

  4. Role of the Talaromyces marneffei (Penicillium marneffei) sakA gene in nitrosative stress response, conidiation and red pigment production.

    Science.gov (United States)

    Nimmanee, Panjaphorn; Tam, Emily W T; Woo, Patrick C Y; Vanittanakom, Pramote; Vanittanakom, Nongnuch

    2017-04-01

    Stress-activated MAPK pathways are systems used to regulate the stress adaptation of most fungi. It has been shown that in Talaromyces marneffei (Penicillium marneffei), a pathogenic dimorphic fungus, the sakA gene is involved, not only in tolerance against oxidative and heat stresses, but also in playing a role in asexual development, yeast cell generation in vitro and survival inside macrophage cell lines. In this study, the role of the T. marneffei sakA gene on the nitrosative stress response and the regulation of gene expression were investigated. The susceptibility of the sakA mutant to NaNO2 was investigated using drop dilution assay and the expression of genes of interest were determined by RT-PCR, comparing them to the wild-type and complemented strains. The results demonstrated that the T. marneffei sakA gene played a role in the stress response to NaNO2, the expression of genes functioning in conidial development (brlA, abaA and wetA) and red pigment biosynthesis (pks3, rp1, rp2 and rp3). These findings suggest that T. marneffei sakA is broadly involved in a wide variety of cell activities, including stress response, cell morphogenesis, asexual development and pigmentation. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. N-acetylcysteine prevents nitrosative stress-associated depression of blood pressure and heart rate in streptozotocin diabetic rats.

    Science.gov (United States)

    Nagareddy, Prabhakara Reddy; Xia, Zhengyuan; MacLeod, Kathleen M; McNeill, John H

    2006-04-01

    Previous studies have indicated that cardiovascular abnormalities such as depressed blood pressure and heart rate occur in streptozotocin (STZ) diabetic rats. Chronic diabetes, which is associated with increased expression of inducible nitric oxide synthase (iNOS) and oxidative stress, may produce peroxynitrite/nitrotyrosine and cause nitrosative stress. We hypothesized that nitrosative stress causes cardiovascular depression in STZ diabetic rats and therefore can be corrected by reducing its formation. Control and STZ diabetic rats were treated orally for 9 weeks with N-acetylcysteine (NAC), an antioxidant and inhibitor of iNOS. At termination, the mean arterial blood pressure (MABP) and heart rate (HR) were measured in conscious rats. Nitrotyrosine and endothelial nitric oxide synthase (eNOS) and iNOS expression were assessed in the heart and mesenteric arteries by immunohistochemistry and Western blot experiments. Untreated diabetic rats showed depressed MABP and HR that was prevented by treatment with NAC. In untreated diabetic rats, levels of 15-F(2t)-isoprostane, an indicator of lipid peroxidation increased, whereas plasma nitric oxide and antioxidant concentrations decreased. Furthermore, decreased eNOS and increased iNOS expression were associated with elevated nitrosative stress in blood vessel and heart tissue of untreated diabetic rats. N-acetylcysteine treatment of diabetic rats not only restored the antioxidant capacity but also reduced the expression of iNOS and nitrotyrosine and normalized the expression of eNOS to that of control rats in heart and superior mesenteric arteries. The results suggest that nitrosative stress depress MABP and HR following diabetes. Further studies are required to elucidate the mechanisms involved in nitrosative stress mediated depression of blood pressure and heart rate.

  6. Endogenous and Exogenous KdpF Peptide Increases Susceptibility of Mycobacterium bovis BCG to Nitrosative Stress and Reduces Intramacrophage Replication

    Science.gov (United States)

    Rosas Olvera, Mariana; Vivès, Eric; Molle, Virginie; Blanc-Potard, Anne-Béatrice; Gannoun-Zaki, Laila

    2017-01-01

    Emerging antibiotic resistance in pathogenic bacteria like Mycobacterium sp., poses a threat to human health and therefore calls for the development of novel antibacterial strategies. We have recently discovered that bacterial membrane peptides, such as KdpF, possess anti-virulence properties when overproduced in pathogenic bacterial species. Overproduction of the KdpF peptide in Mycobacterium bovis BCG decreased bacterial replication within macrophages, without presenting antibacterial activity. We propose that KdpF functions as a regulatory molecule and interferes with bacterial virulence, potentially through interaction with the PDIM transporter MmpL7. We demonstrate here that KdpF overproduction in M. bovis BCG, increased bacterial susceptibility to nitrosative stress and thereby was responsible for lower replication rate within macrophages. Moreover, in a bacterial two-hybrid system, KdpF was able to interact not only with MmpL7 but also with two membrane proteins involved in nitrosative stress detoxification (NarI and NarK2), and a membrane protein of unknown function that is highly induced upon nitrosative stress (Rv2617c). Interestingly, we showed that the exogenous addition of KdpF synthetic peptide could affect the stability of proteins that interact with this peptide. Finally, the exogenous KdpF peptide presented similar biological effects as the endogenously expressed peptide including nitrosative stress susceptibility and reduced intramacrophage replication rate for M. bovis BCG. Taken together, our results establish a link between high levels of KdpF and nitrosative stress susceptibility to further highlight KdpF as a potent molecule with anti-virulence properties. PMID:28428950

  7. Secondary targets of nitrite-derived reactive nitrogen species: nitrosation/nitration pathways, antioxidant defense mechanisms and toxicological implications.

    Science.gov (United States)

    d'Ischia, Marco; Napolitano, Alessandra; Manini, Paola; Panzella, Lucia

    2011-12-19

    Nitrite, the primary metabolite of nitric oxide (NO) and a widely diffused component of human diet, plays distinct and increasingly appreciated roles in human physiology. However, when exposed to acidic environments, typically in the stomach, or under oxidative stress conditions, it may be converted to a range of reactive nitrogen species (RNS) which in turn can target a variety of biomolecules. Typical consequences of toxicological relevance include protein modification, DNA base deamination and the formation of N-nitrosamines, among the most potent mutagenic and carcinogenic compounds for humans. Besides primary biomolecules, nitrite can cause structural modifications to a variety of endogenous and exogenous organic compounds, ranging from polyunsaturated fatty acids to estrogens, tocopherol, catecholamines, furans, retinoids, dietary phenols, and a range of xenobiotics. The study of the interactions between nitrite and key food components, including phenolic antioxidants, has therefore emerged as an area of great promise for delineating innovative strategies in cancer chemoprevention. Depending on substrates and conditions, diverse reaction pathways may compete to determine product features and distribution patterns. These include nitrosation and nitration but also oxidation, via electron transfer to nitrosonium ion or nitrogen dioxide. This contribution aims to provide an overview of the main classes of compounds that can be targeted by nitrite and to discuss at chemical levels the possible reaction mechanisms under conditions that model those occurring in the stomach. The toxicological implications of the nitrite-modified molecules are finally addressed, and a rational chemical approach to the design of potent antinitrosing agents is illustrated. © 2011 American Chemical Society

  8. Protective effect of polyphenols on presbycusis via oxidative/nitrosative stress suppression in rats.

    Science.gov (United States)

    Sánchez-Rodríguez, Carolina; Martín-Sanz, Eduardo; Cuadrado, Esperanza; Granizo, Juan José; Sanz-Fernández, Ricardo

    2016-10-01

    Age-related hearing loss (AHL) -presbycusis- is the number one neurodegenerative disorder and top communication deficit of our aged population. Experimental evidence suggests that mitochondrial dysfunction associated with reactive oxygen species (ROS) plays a central role in the aging process of cochlear cells. Dietary antioxidants, in particular polyphenols, have been found to be beneficial in protecting against the generation of ROS in various diseases associated with oxidative stress, such as cancer, neurodegenerative diseases and aging. This study was designed to investigate the effects of polyphenols on AHL and to determine whether oxidative stress plays a role in the pathophysiology of AHL. Sprague-Dawley rats (n=100) were divided into five groups according to their age (3, 6, 12, 18 and 24months old) and treated with 100mg/kg/day body weight of polyphenols dissolved in tap water for half of the life of the animal. Auditory steady-state responses (ASSR) threshold shifts were measured before sacrificing the rats. Then, cochleae were harvested to measure total superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, reactive oxidative and nitrogen species levels, superoxide anions and nitrotyrosine levels. Increased levels of ROS and RNS in cochlea observed with age decreases with polyphenol treatment. In addition, the activity of SOD and GPx enzymes in older rats recovered after the administration of polyphenols. The reduction in oxidative and nitrosative stress in the presence of polyphenols correlates with significant improvements in ASSR threshold shifts. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Trichophyton rubrum is inhibited by free and nanoparticle encapsulated curcumin by induction of nitrosative stress after photodynamic activation.

    Directory of Open Access Journals (Sweden)

    Ludmila Matos Baltazar

    Full Text Available Antimicrobial photodynamic inhibition (aPI utilizes radical stress generated from the excitation of a photosensitizer (PS with light to destroy pathogens. Its use against Trichophyton rubrum, a dermatophytic fungus with increasing incidence and resistance, has not been well characterized. Our aim was to evaluate the mechanism of action of aPI against T. rubrum using curcumin as the PS in both free and nanoparticle (curc-np form. Nanocarriers stabilize curcumin and allow for enhanced solubility and PS delivery. Curcumin aPI, at optimal conditions of 10 μg/mL of PS with 10 J/cm² of blue light (417 ± 5 nm, completely inhibited fungal growth (p<0.0001 via induction of reactive oxygen (ROS and nitrogen species (RNS, which was associated with fungal death by apoptosis. Interestingly, only scavengers of RNS impeded aPI efficacy, suggesting that curcumin acts potently via a nitrosative pathway. The curc-np induced greater NO˙ expression and enhanced apoptosis of fungal cells, highlighting curc-np aPI as a potential treatment for T. rubrum skin infections.

  10. Transcriptomic analysis of Staphylococcus xylosus in the presence of nitrate and nitrite in meat reveals its response to nitrosative stress

    Directory of Open Access Journals (Sweden)

    Aurore eVermassen

    2014-12-01

    Full Text Available Staphylococcus xylosus is one of the major starter cultures used for meat fermentation because of its crucial role in the reduction of nitrate to nitrite which contributes to colour and flavour development. Despite longstanding use of these additives, their impact on the physiology of S. xylosus has not yet been explored. We present the first in situ global gene expression profile of S. xylosus in meat supplemented with nitrate and nitrite at the levels used in the meat industry. More than 600 genes of S. xylosus were differentially expressed at 24 or 72 hours of incubation. They represent more than 20% of the total genes and let us to suppose that addition of nitrate and nitrite to meat leads to a global change in gene expression. This profile revealed that S. xylosus is subject to nitrosative stress caused by reactive nitrogen species generated from nitrate and nitrite. To overcome this stress, S. xylosus has developed several oxidative stress resistance mechanisms, such as modulation of the expression of several genes involved in iron homeostasis and in antioxidant defence. Most of which belong to the Fur and PerR regulons, respectively. S. xylosus has also counteracted this stress by developing DNA and protein repair. Furthermore, it has adapted its metabolic response—carbon and nitrogen metabolism, energy production and cell wall biogenesis—to the alterations produced by nitrosative stress.

  11. Transcriptomic analysis of Staphylococcus xylosus in the presence of nitrate and nitrite in meat reveals its response to nitrosative stress

    Science.gov (United States)

    Vermassen, Aurore; de la Foye, Anne; Loux, Valentin; Talon, Régine; Leroy, Sabine

    2014-01-01

    Staphylococcus xylosus is one of the major starter cultures used for meat fermentation because of its crucial role in the reduction of nitrate to nitrite which contributes to color and flavor development. Despite longstanding use of these additives, their impact on the physiology of S. xylosus has not yet been explored. We present the first in situ global gene expression profile of S. xylosus in meat supplemented with nitrate and nitrite at the levels used in the meat industry. More than 600 genes of S. xylosus were differentially expressed at 24 or 72 h of incubation. They represent more than 20% of the total genes and let us to suppose that addition of nitrate and nitrite to meat leads to a global change in gene expression. This profile revealed that S. xylosus is subject to nitrosative stress caused by reactive nitrogen species (RNS) generated from nitrate and nitrite. To overcome this stress, S. xylosus has developed several oxidative stress resistance mechanisms, such as modulation of the expression of several genes involved in iron homeostasis and in antioxidant defense. Most of which belong to the Fur and PerR regulons, respectively. S. xylosus has also counteracted this stress by developing DNA and protein repair. Furthermore, it has adapted its metabolic response—carbon and nitrogen metabolism, energy production and cell wall biogenesis—to the alterations produced by nitrosative stress. PMID:25566208

  12. Nitric oxide synthase and oxidative-nitrosative stress play a key role in placental infection by Trypanosoma cruzi.

    Science.gov (United States)

    Triquell, María Fernanda; Díaz-Luján, Cintia; Romanini, María Cristina; Ramirez, Juan Carlos; Paglini-Oliva, Patricia; Schijman, Alejandro Gabriel; Fretes, Ricardo Emilio

    2018-03-25

    The innate immune response of the placenta may participate in the congenital transmission of Chagas disease through releasing reactive oxygen and nitrogen intermediates. Placental explants were cultured with 1 × 10 6 and 1 × 10 5 trypomastigotes of Tulahuen and Lucky strains and controls without parasites, and with the addition of nitric oxide synthase inhibitor Nω-Nitro-l-arginine methyl ester (l-NAME) and N-acetyl cysteine (NAC) as the reactive oxygen species (ROS) scavenger. Detachment of the syncytiotrophoblast (STB) was examined by histological analysis, and the nitric oxide synthase, endothelial (eNOS), and nitrotyrosine expressions were analyzed by immunohistochemistry, as well as the human chorionic gonadotrophin (hCG) levels in the culture supernatant through ELISA assays. Parasite load with qPCR using Taqman primers was quantified. The higher number of T. cruzi (10 6 ) increased placental infection, eNOS expression, nitrosative stress, and STB detachment, with the placental barrier being injured by oxidative stress. The higher number of parasites caused deleterious consequences to the placental barrier, and the inhibitors (l-NAME and NAC) prevented the damage caused by trypomastigotes in placental villi but not that of the infection. Moreover, trophoblast eNOS played a key role in placental infection with the highest inoculum of Lucky, demonstrating the importance of the enzyme and nitrosative-oxidative stress in Chagas congenital transmission. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Sodium Phenylbutyrate and Edaravone Abrogate Chronic Restraint Stress-Induced Behavioral Deficits: Implication of Oxido-Nitrosative, Endoplasmic Reticulum Stress Cascade, and Neuroinflammation.

    Science.gov (United States)

    Jangra, Ashok; Sriram, Chandra Shaker; Dwivedi, Shubham; Gurjar, Satendra Singh; Hussain, Md Iftikar; Borah, Probodh; Lahkar, Mangala

    2017-01-01

    Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and edaravone treatment. In addition, SPB and edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and edaravone treatment in CRS mice. Our study provides evidence that SPB and edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade.

  14. Sumoylation of IkB attenuates NF-kB-induced nitrosative stress at rostral ventrolateral medulla and cardiovascular depression in experimental brain death.

    Science.gov (United States)

    Tsai, Ching-Yi; Li, Faith C H; Wu, Carol H Y; Chang, Alice Y W; Chan, Samuel H H

    2016-09-22

    Small ubiquitin-related modifier (SUMO) is a group of proteins that participates in post-translational modifications. One known SUMO target is the transcription factor nuclear factor-kB (NF-kB) that plays a pivotal role in many disease processes; sumoylation inactivates NF-kB by conjugation with inhibitors of NF-kB (IkB). Our laboratory demonstrated previously that transcriptional upregulation of nitric oxide synthase II (NOS II) by NF-kB, leading to nitrosative stress by the formation of peroxynitrite in the rostral ventrolateral medulla (RVLM), underpins the defunct brain stem cardiovascular regulation that precedes brain death. Based on an experimental endotoxemia model, this study evaluated the hypothesis that sumoylation plays a pro-life role in brain death by interacting with the NF-kB/NOS II/peroxynitrite signaling pathway in the RVLM. In Sprague-Dawley rats, intravenous administration of Escherichia coli lipopolysaccharide (LPS; 10 mg kg -1 ) elicited an augmentation of SUMO-1 and ubiquitin-conjugase 9 (Ubc9) mRNA or protein levels, alongside SUMO-1-conjugated proteins in the RVLM. Immunoneutralization of SUMO-1 or Ubc9 in the RVLM significantly potentiated the already diminished sumoylation of IkBα and intensified NF-kB activation and NOS II/peroxynitrite expression in this brain stem substrate, together with exacerbated fatality, cardiovascular depression and reduction of an experimental index of a life-and-death signal detected from arterial pressure that disappears in comatose patients signifying failure of brain stem cardiovascular regulation before brain death. We conclude that sumoylation of IkB in the RVLM ameliorates the defunct brain stem cardiovascular regulation that underpins brain death in our experimental endotoxemia modal by reducing nitrosative stress via inhibition of IkB degradation that diminishes the induction of the NF-kB/NOS II/peroxynitrite signaling cascade.

  15. Survival pathways under stress

    Indian Academy of Sciences (India)

    First page Back Continue Last page Graphics. Survival pathways under stress. Bacteria survive by changing gene expression. pattern. Three important pathways will be discussed: Stringent response. Quorum sensing. Proteins performing function to control oxidative damage.

  16. A novel ATP-generating machinery to counter nitrosative stress is mediated by substrate-level phosphorylation.

    Science.gov (United States)

    Auger, Christopher; Appanna, Vasu D

    2015-01-01

    It is well-known that elevated amounts of nitric oxide and other reactive nitrogen species (RNS) impact negatively on the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. These perturbations severely compromise O2-dependent energy production. While bacteria are known to adapt to RNS, a key tool employed by macrophages to combat infections, the exact mechanisms are unknown. The bacterium was cultured in a defined mineral medium and cell-free extracts obtained at the same growth phase were utilized for various biochemical studies Blue native polyacrylamide gel electrophoresis followed by in-gel activity assays, high performance liquid chromatography and co-immunoprecipitaton are applied to investigate the effects of RNS on the model microbe Pseudomonas fluorescens. Citrate is channeled away from the tricarboxylic acid cycle using a novel metabolon consisting of citrate lyase (CL), phosphoenolpyruvate carboxylase (PEPC) and pyruvate phosphate dikinase (PPDK). This metabolic engine comprising three disparate enzymes appears to transiently assemble as a supercomplex aimed at ATP synthesis. The up-regulation in the activities of adenylate kinase (AK) and nucleoside diphosphate kinase (NDPK) ensured the efficacy of this ATP-making machine. Microbes may escape the effects of nitrosative stress by re-engineering metabolic networks in order to generate and store ATP anaerobically when the electron transport chain is defective. The molecular configuration described herein provides further understanding of how metabolism plays a key role in the adaptation to nitrosative stress and reveals novel targets that will inform the development of antimicrobial agents to counter RNS-resistant pathogens. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Systemic oxidative-nitrosative-inflammatory stress during acute exercise in hypoxia; implications for microvascular oxygenation and aerobic capacity.

    Science.gov (United States)

    Woodside, John D S; Gutowski, Mariusz; Fall, Lewis; James, Philip E; McEneny, Jane; Young, Ian S; Ogoh, Shigehiko; Bailey, Damian M

    2014-12-01

    Exercise performance in hypoxia may be limited by a critical reduction in cerebral and skeletal tissue oxygenation, although the underlying mechanisms remain unclear. We examined whether increased systemic free radical accumulation during hypoxia would be associated with elevated microvascular deoxygenation and reduced maximal aerobic capacity (V̇O2 max ). Eleven healthy men were randomly assigned single-blind to an incremental semi-recumbent cycling test to determine V̇O2 max in both normoxia (21% O2) and hypoxia (12% O2) separated by a week. Continuous-wave near-infrared spectroscopy was employed to monitor concentration changes in oxy- and deoxyhaemoglobin in the left vastus lateralis muscle and frontal cerebral cortex. Antecubital venous blood samples were obtained at rest and at V̇O2 max to determine oxidative (ascorbate radical by electron paramagnetic resonance spectroscopy), nitrosative (nitric oxide metabolites by ozone-based chemiluminescence and 3-nitrotyrosine by enzyme-linked immunosorbent assay) and inflammatory stress biomarkers (soluble intercellular/vascular cell adhesion 1 molecules by enzyme-linked immunosorbent assay). Hypoxia was associated with increased cerebral and muscle tissue deoxygenation and lower V̇O2 max (P exercise-induced increase in oxidative-nitrosative-inflammatory stress, hypoxia per se did not have an additive effect (P > 0.05 versus normoxia). Consequently, we failed to observe correlations between any metabolic, haemodynamic and cardiorespiratory parameters (P > 0.05). Collectively, these findings suggest that altered free radical metabolism cannot explain the elevated microvascular deoxygenation and corresponding lower V̇O2 max in hypoxia. Further research is required to determine whether free radicals when present in excess do indeed contribute to the premature termination of exercise in hypoxia. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

  18. Dynamic of oxidative and nitrosative stress markers during the convalescent period of stroke patients undergoing rehabilitation.

    Science.gov (United States)

    Manolescu, Bogdan Nicolae; Berteanu, M; Oprea, E; Chiriac, N; Dumitru, L; Vladoiu, S; Popa, O; Ianas, O

    2011-07-01

    Stroke patients have a redox imbalance, a consequence of both the cerebrovascular event and the associated pathological conditions. Our study was aimed to investigate the dynamic of some oxidative and nitrosative markers during the convalescent phase of postacute stroke patients undergoing rehabilitation. We assessed thiol, advanced oxidation protein product, protein carbonyl, 3-nitro-l-tyrosine, ceruloplasmin and oxidized LDL concentrations, as well as gamma-glutamyltranspeptidase (GGT) activity in 20 patients at the beginning of the hospitalization and at the discharge moment, respectively, and 24 apparently healthy controls. We found significantly increased values for GGT (P = 0.04), ceruloplasmin (P = 0.01) and protein carbonyl (P = 0.04) in stroke patients at the hospitalization moment when compared with healthy controls, while total thiols were significantly decreased (P = 0.002). Rehabilitation was associated with a significant decrease of protein carbonyl (P = 0.03) and oxidized LDL particle concentrations (P = 0.03), as well as GGT activity (P = 0.02). At the hospitalization moment, both GGT and ceruloplasmin were significantly negatively correlated with non-proteic thiols (r = -0.44, P = 0.049, and r = -0.53, P = 0.015, respectively) and significantly positively with protein carbonyls (r = +0.80, P stroke patients, and the possible benefits of an antioxidant-based therapy for the recovery of these patients.

  19. A Novel TetR-Like Transcriptional Regulator Is Induced in Acid-Nitrosative Stress and Controls Expression of an Efflux Pump in Mycobacteria

    Directory of Open Access Journals (Sweden)

    Filomena Perrone

    2017-10-01

    Full Text Available Mycobacterium tuberculosis has the ability to survive inside macrophages under acid-nitrosative stress. M. tuberculosis Rv1685c and its ortholog in M. smegmatis, MSMEG_3765, are induced on exposure to acid-nitrosative stress. Both genes are annotated as TetR transcriptional regulators, a family of proteins that regulate a wide range of cellular activities, including multidrug resistance, carbon catabolism and virulence. Here, we demonstrate that MSMEG_3765 is co-transcribed with the upstream genes MSMEG_3762 and MSMEG_3763, encoding efflux pump components. RTq-PCR and GFP-reporter assays showed that the MSMEG_3762/63/65 gene cluster, and the orthologous region in M. tuberculosis (Rv1687c/86c/85c, was up-regulated in a MSMEG_3765 null mutant, suggesting that MSMEG_3765 acts as a repressor, typical of this family of regulators. We further defined the MSMEG_3765 regulon using genome-wide transcriptional profiling and used reporter assays to confirm that the MSMEG_3762/63/65 promoter was induced under acid-nitrosative stress. A putative 36 bp regulatory motif was identified upstream of the gene clusters in both M. smegmatis and M. tuberculosis and purified recombinant MSMEG_3765 protein was found to bind to DNA fragments containing this motif from both M. smegmatis and M. tuberculosis upstream regulatory regions. These results suggest that the TetR repressor MSMEG_3765/Rv1685c controls expression of an efflux pump with an, as yet, undefined role in the mycobacterial response to acid-nitrosative stress.

  20. Effect of Exercise Intensity on Neurotrophic Factors and Blood-Brain Barrier Permeability Induced by Oxidative-Nitrosative Stress in Male College Students.

    Science.gov (United States)

    Roh, Hee-Tae; Cho, Su-Youn; Yoon, Hyung-Gi; So, Wi-Young

    2017-06-01

    We investigated the effects of aerobic exercise intensity on oxidative-nitrosative stress, neurotrophic factor expression, and blood-brain barrier (BBB) permeability. Fifteen healthy men performed treadmill running under low-intensity (LI), moderate-intensity (MI), and high-intensity (HI) conditions. Blood samples were collected immediately before exercise (IBE), immediately after exercise (IAE), and 60 min after exercise (60MAE) to examine oxidative-nitrosative stress (reactive oxygen species [ROS]; nitric oxide [NO]), neurotrophic factors (brain-derived neurotrophic factor [BDNF]; nerve growth factor [NGF]), and blood-brain barrier (BBB) permeability (S-100β; neuron-specific enolase). ROS concentration significantly increased IAE and following HI (4.9 ± 1.7 mM) compared with that after LI (2.8 ± 1.4 mM) exercise (p exercise (p exercise (p exercise (p exercise (p .05). Moderate- and/or high-intensity exercise may induce higher oxidative-nitrosative stress than may low-intensity exercise, which can increase peripheral neurotrophic factor levels by increasing BBB permeability.

  1. Structure/function analysis of PARP-1 in oxidative and nitrosative stress-induced monomeric ADPR formation.

    Directory of Open Access Journals (Sweden)

    Ben Buelow

    2009-07-01

    Full Text Available Poly adenosine diphosphate-ribose polymerase-1 (PARP-1 is a multifunctional enzyme that is involved in two major cellular responses to oxidative and nitrosative (O/N stress: detection and response to DNA damage via formation of protein-bound poly adenosine diphosphate-ribose (PAR, and formation of the soluble 2(nd messenger monomeric adenosine diphosphate-ribose (mADPR. Previous studies have delineated specific roles for several of PARP-1's structural domains in the context of its involvement in a DNA damage response. However, little is known about the relationship between the mechanisms through which PARP-1 participates in DNA damage detection/response and those involved in the generation of monomeric ADPR. To better understand the relationship between these events, we undertook a structure/function analysis of PARP-1 via reconstitution of PARP-1 deficient DT40 cells with PARP-1 variants deficient in catalysis, DNA binding, auto-PARylation, and PARP-1's BRCT protein interaction domain. Analysis of responses of the respective reconstituted cells to a model O/N stressor indicated that PARP-1 catalytic activity, DNA binding, and auto-PARylation are required for PARP-dependent mADPR formation, but that BRCT-mediated interactions are dispensable. As the BRCT domain is required for PARP-dependent recruitment of XRCC1 to sites of DNA damage, these results suggest that DNA repair and monomeric ADPR 2(nd messenger generation are parallel mechanisms through which PARP-1 modulates cellular responses to O/N stress.

  2. Nitrosative Stress in the Nervous System: Guidelines for Designing Experimental Strategies to Study Protein S-Nitrosylation.

    Science.gov (United States)

    Nakamura, Tomohiro; Lipton, Stuart A

    2016-03-01

    Reactive nitrogen species, such as nitric oxide (NO), exert their biological activity in large part through post-translational modification of cysteine residues, forming S-nitrosothiols. This chemical reaction proceeds via a process that we and our colleagues have termed protein S-nitrosylation. Under conditions of normal NO production, S-nitrosylation regulates the activity of many normal proteins. However, in degenerative conditions characterized by nitrosative stress, increased levels of NO lead to aberrant S-nitrosylation that contributes to the pathology of the disease. Thus, S-nitrosylation has been implicated in a wide range of cellular mechanisms, including mitochondrial function, proteostasis, transcriptional regulation, synaptic activity, and cell survival. In recent years, the research area of protein S-nitrosylation has become prominent due to improvements in the detection systems as well as the demonstration that protein S-nitrosylation plays a critical role in the pathogenesis of neurodegenerative and other neurological disorders. To further promote our understanding of how protein S-nitrosylation affects cellular systems, guidelines for the design and conduct of research on S-nitrosylated (or SNO-)proteins would be highly desirable, especially for those newly entering the field. In this review article, we provide a strategic overview of designing experimental approaches to study protein S-nitrosylation. We specifically focus on methods that can provide critical data to demonstrate that an S-nitrosylated protein plays a (patho-)physiologically-relevant role in a biological process. Hence, the implementation of the approaches described herein will contribute to further advancement of the study of S-nitrosylated proteins, not only in neuroscience but also in other research fields.

  3. [3-nitrotyrosine determination as nitrosative stress marker and health attitudes of medical students considering exposure to environmental tobacco smoke].

    Science.gov (United States)

    Szumska, Magdalena; Wielkoszyński, Tomasz; Tyrpień, Krystyna

    2012-01-01

    -st and 2-nd year of study at Faculty of Medicine and Dentistry Division in Zabrze, Silesian Medical University. 120 students provided blood samples for further analysis. In the study group 52 students were active smokers and the control group consisted of 68 non-smokers. 3-nitrotyrosine was determined with the use of ELISA technique. The mean concentration of 3-nitrotyrosine was higher in the group of smoking students in comparison to the control group. Diet habits also influenced the concentration of 3-nitrotyrosine. Eating food products of possibly high acrylamide level and drinking alcohol led in particular to observed increased concentrations of 3-nitrotyrosine in both students groups. The correlation between the food habits and the severity of nitrosative stress was also found.

  4. Growth Inhibition of Osteosarcoma Cell Lines in 3D Cultures: Role of Nitrosative and Oxidative Stress.

    Science.gov (United States)

    Gorska, Magdalena; Krzywiec, Pawel Bieniasz; Kuban-Jankowska, Alicja; Zmijewski, Michal; Wozniak, Michal; Wierzbicka, Justyna; Piotrowska, Anna; Siwicka, Karolina

    2016-01-01

    3D cell cultures have revolutionized the understanding of cell behavior, allowing culture of cells with the possibility of resembling in vivo intercellular signaling and cell-extracellular matrix interaction. The effect of limited oxygen penetration into 3D culture of highly metastatic osteosarcoma 143B cells in terms of expression of nitro-oxidative stress markers was investigated and compared to standard 2D cell culture. Human osteosarcoma (143B cell line) cells were cultured as monolayers, in collagen and Matrigel. Cell viability, gene expression of nitro-oxidative stress markers, and vascular endothelial growth factor were determined using Trypan blue assay, quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Three-dimensional environments modify nitro-oxidative stress and influence gene expression and cell proliferation of OS 143B cells. Commercial cell lines might not constitute a good model of 3D cultures for bone tissue engineering, as they are highly sensitive to hypoxia, and hypoxic conditions can induce oxidation of the cellular environment. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  5. Branched-chain amino acid supplementation promotes aerobic growth of Salmonella Typhimurium under nitrosative stress conditions.

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    Park, Yoon Mee; Lee, Hwa Jeong; Jeong, Jae-Ho; Kook, Joong-Ki; Choy, Hyon E; Hahn, Tae-Wook; Bang, Iel Soo

    2015-12-01

    Nitric oxide (NO) inactivates iron-sulfur enzymes in bacterial amino acid biosynthetic pathways, causing amino acid auxotrophy. We demonstrate that exogenous supplementation with branched-chain amino acids (BCAA) can restore the NO resistance of hmp mutant Salmonella Typhimurium lacking principal NO-metabolizing enzyme flavohemoglobin, and of mutants further lacking iron-sulfur enzymes dihydroxy-acid dehydratase (IlvD) and isopropylmalate isomerase (LeuCD) that are essential for BCAA biosynthesis, in an oxygen-dependent manner. BCAA supplementation did not affect the NO consumption rate of S. Typhimurium, suggesting the BCAA-promoted NO resistance independent of NO metabolism. BCAA supplementation also induced intracellular survival of ilvD and leuCD mutants at wild-type levels inside RAW 264.7 macrophages that produce constant amounts of NO regardless of varied supplemental BCAA concentrations. Our results suggest that the NO-induced BCAA auxotrophy of Salmonella, due to inactivation of iron-sulfur enzymes for BCAA biosynthesis, could be rescued by bacterial taking up exogenous BCAA available in oxic environments.

  6. The Staphylococcus aureus α-Acetolactate Synthase ALS Confers Resistance to Nitrosative Stress

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    Sandra M. Carvalho

    2017-07-01

    Full Text Available Staphylococcus aureus is a worldwide pathogen that colonizes the human nasal cavity and is a major cause of respiratory and cutaneous infections. In the nasal cavity, S. aureus thrives with high concentrations of nitric oxide (NO produced by the innate immune effectors and has available for growth slow-metabolizing free hexoses, such as galactose. Here, we have used deep sequencing transcriptomic analysis (RNA-Seq and 1H-NMR to uncover how S. aureus grown on galactose, a major carbon source present in the nasopharynx, survives the deleterious action of NO. We observed that, like on glucose, S. aureus withstands high concentrations of NO when using galactose. Data indicate that this resistance is, most likely, achieved through a distinct metabolism that relies on the increased production of amino acids, such as glutamate, threonine, and branched-chain amino acids (BCAAs. Moreover, we found that under NO stress the S. aureus α-acetolactate synthase (ALS enzyme, which converts pyruvate into α-acetolactate, plays an important role. ALS is proposed to prevent intracellular acidification, to promote the production of BCAAs and the activation of the TCA cycle. Additionally, ALS is shown to contribute to the successful infection of murine macrophages. Furthermore, ALS contributes to the resistance of S. aureus to beta-lactam antibiotics such as methicillin and oxacillin.

  7. Creatine affords protection against glutamate-induced nitrosative and oxidative stress.

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    Cunha, Mauricio P; Lieberknecht, Vicente; Ramos-Hryb, Ana Belén; Olescowicz, Gislaine; Ludka, Fabiana K; Tasca, Carla I; Gabilan, Nelson H; Rodrigues, Ana Lúcia S

    2016-05-01

    Creatine has been reported to exert beneficial effects in several neurodegenerative diseases in which glutamatergic excitotoxicity and oxidative stress play an etiological role. The purpose of this study was to investigate the protective effects of creatine, as compared to the N-Methyl-d-Aspartate (NMDA) receptor antagonist dizocilpine (MK-801), against glutamate or hydrogen peroxide (H2O2)-induced injury in human neuroblastoma SH-SY5Y cells. Exposure of cells to glutamate (60-80 mM) or H2O2 (200-300 μM) for 24 h decreased cellular viability and increased dichlorofluorescein (DCF) fluorescence (indicative of increased reactive oxygen species, ROS) and nitric oxide (NO) production (assessed by mono-nitrogen oxides, NOx, levels). Creatine (1-10 mM) or MK-801 (0.1-10 μM) reduced glutamate- and H2O2-induced toxicity. The protective effect of creatine against glutamate-induced toxicity involves its antioxidant effect, since creatine, similar to MK-801, prevented the increase on DCF fluorescence induced by glutamate or H2O2. Furthermore, creatine or MK-801 blocked glutamate- and H2O2-induced increases in NOx levels. In another set of experiments, the repeated, but not acute, administration of creatine (300 mg/kg, po) in mice prevented the decreases on cellular viability and mitochondrial membrane potential (assessed by tetramethylrhodamine ethyl ester, TMRE, probe) of hippocampal slices incubated with glutamate (10 mM). Creatine concentration-dependent decreased the amount of nitrite formed in the reaction of oxygen with NO produced from sodium nitroprusside solution, suggesting that its protective effect against glutamate or H2O2-induced toxicity might be due to its scavenger activity. Overall, the results suggest that creatine may be useful as adjuvant therapy for neurodegenerative disease treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Photobiomodulation induced by 670 nm light ameliorates MOG35-55 induced EAE in female C57BL/6 mice: a role for remediation of nitrosative stress.

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    Kamaldeen A Muili

    Full Text Available Experimental autoimmune encephalomyelitis (EAE is the most commonly studied animal model of multiple sclerosis (MS, a chronic autoimmune demyelinating disorder of the central nervous system. Immunomodulatory and immunosuppressive therapies currently approved for the treatment of MS slow disease progression, but do not prevent it. A growing body of evidence suggests additional mechanisms contribute to disease progression. We previously demonstrated the amelioration of myelin oligodendrocyte glycoprotein (MOG-induced EAE in C57BL/6 mice by 670 nm light-induced photobiomodulation, mediated in part by immune modulation. Numerous other studies demonstrate that near-infrared/far red light is therapeutically active through modulation of nitrosoxidative stress. As nitric oxide has been reported to play diverse roles in EAE/MS, and recent studies suggest that axonal loss and progression of disability in MS is mediated by nitrosoxidative stress, we investigated the effect of 670 nm light treatment on nitrosative stress in MOG-induced EAE.Cell culture experiments demonstrated that 670 nm light-mediated photobiomodulation attenuated antigen-specific nitric oxide production by heterogenous lymphocyte populations isolated from MOG immunized mice. Experiments in the EAE model demonstrated down-regulation of inducible nitric oxide synthase (iNOS gene expression in the spinal cords of mice with EAE over the course of disease, compared to sham treated animals. Animals receiving 670 nm light treatment also exhibited up-regulation of the Bcl-2 anti-apoptosis gene, an increased Bcl-2:Bax ratio, and reduced apoptosis within the spinal cord of animals over the course of disease. 670 nm light therapy failed to ameliorate MOG-induced EAE in mice deficient in iNOS, confirming a role for remediation of nitrosative stress in the amelioration of MOG-induced EAE by 670 nm mediated photobiomodulation.These data indicate that 670 nm light therapy protects against nitrosative

  9. Activated neuro-oxidative and neuro-nitrosative pathways at the end of term are associated with inflammation and physio-somatic and depression symptoms, while predicting outcome characteristics in mother and baby.

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    Roomruangwong, Chutima; Barbosa, Decio Sabbatini; Matsumoto, Andressa Keiko; Nogueira, André de Souza; Kanchanatawan, Buranee; Sirivichayakul, Sunee; Carvalho, André F; Duleu, Sebastien; Geffard, Michel; Moreira, Estefania Gastaldello; Maes, Michael

    2017-12-01

    To examine oxidative & nitrosative stress (O&NS) biomarkers at the end of term in relation to perinatal affective symptoms, neuro-immune biomarkers and pregnancy-related outcome variables. We measured plasma advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical trapping antioxidant parameter (TRAP), -sulfhydryl (-SH), peroxides (LOOH) and paraoxonase (PON)1 activity in pregnant women with and without prenatal depression and non-pregnant controls. Pregnancy is accompanied by significantly increased AOPP and NOx, and lowered TRAP, -SH and LOOH. Increased O&NS and lowered LOOH and -SH levels are associated with prenatal depressive and physio-somatic symptoms (fatigue, pain, dyspepsia, gastro-intestinal symptoms). Increased AOPP and NOx are significantly associated with lowered -SH, TRAP and zinc, and with increased haptoglobin and C-reactive protein levels. Increased O&NS and lowered TRAP and PON 1 activity, at the end of term predict mother (e.g. hyperpigmentation, labor duration, caesarian section, cord length, breast milk flow) and baby (e.g. sleep and feeding problems) outcome characteristics. Pregnancy is accompanied by interrelated signs of O&NS, lowered antioxidant defenses and activated neuro-immune pathways. Increased O&NS at the end of term is associated with perinatal depressive and physio-somatic symptoms and may predict obstetric and behavioral complications in mother and baby. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Biochemistry of storage lesions of red cell and platelet concentrates: A continuous fight implying oxidative/nitrosative/phosphorylative stress and signaling.

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    Rinalducci, Sara; Zolla, Lello

    2015-06-01

    The mechanisms responsible for the reduced lifespan of transfused red blood cells (RBCs) and platelets (PLTs) are still under investigation, however one explanation refers to the detrimental biochemical changes occurring during ex vivo storage of these blood products. A myriad of historical and more recent studies has contributed to advance our understanding of storage lesion. Without any doubts, proteomics had great impact on transfusion medicine by profiling the storage-dependent changes in the total detectable protein pool of both RBCs and PLTs. This review article focuses on the role of oxidative/nitrosative stress in developing RBC and PLT storage lesions, with a special glance at its biochemistry and cross-talk with phosphorylative signal transduction. In this sense, we enlighten the potential contribution of new branches of proteomics in identifying novel points of intervention for the improvement of blood product quality. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Necrosis is increased in lymphoblastoid cell lines from children with autism compared with their non-autistic siblings under conditions of oxidative and nitrosative stress

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    Fenech, Michael F.

    2013-01-01

    Autism spectrum disorders are a heterogeneous group of neurodevelopmental conditions characterised by impairments in reciprocal social interaction, communication and stereotyped behaviours. As increased DNA damage events have been observed in a range of other neurological disorders, it was hypothesised that they would be elevated in lymphoblastoid cell lines (LCLs) obtained from children with autism compared with their non-autistic siblings. Six case–sibling pairs of LCLs from children with autistic disorder and their non-autistic siblings were obtained from the Autism Genetic Resource Exchange (AGRE) and cultured in standard RPMI-1640 tissue culture medium. Cells were exposed to medium containing either 0, 25, 50, 100 and 200 µM hydrogen peroxide (an oxidative stressor) or 0, 5, 10, 20 and 40 µM s-nitroprusside (a nitric oxide producer) for 1h. Following exposure, the cells were microscopically scored for DNA damage, cytostasis and cytotoxicity biomarkers as measured using the cytokinesis-block micronucleus cytome assay. Necrosis was significantly increased in cases relative to controls when exposed to oxidative and nitrosative stress (P = 0.001 and 0.01, respectively). Nuclear division index was significantly lower in LCLs from children with autistic disorder than their non-autistic siblings when exposed to hydrogen peroxide (P = 0.016), but there was no difference in apoptosis, micronucleus frequency, nucleoplasmic bridges or nuclear buds. Exposure to s-nitroprusside significantly increased the number of micronuclei in non-autistic siblings compared with cases (P = 0.003); however, other DNA damage biomarkers, apoptosis and nuclear division did not differ significantly between groups. The findings of this study show (i) that LCLs from children with autism are more sensitive to necrosis under conditions of oxidative and nitrosative stress than their non-autistic siblings and (ii) refutes the hypothesis that children with autistic disorder are abnormally

  12. Necrosis is increased in lymphoblastoid cell lines from children with autism compared with their non-autistic siblings under conditions of oxidative and nitrosative stress.

    Science.gov (United States)

    Main, Penelope A E; Thomas, Philip; Esterman, Adrian; Fenech, Michael F

    2013-07-01

    Autism spectrum disorders are a heterogeneous group of neurodevelopmental conditions characterised by impairments in reciprocal social interaction, communication and stereotyped behaviours. As increased DNA damage events have been observed in a range of other neurological disorders, it was hypothesised that they would be elevated in lymphoblastoid cell lines (LCLs) obtained from children with autism compared with their non-autistic siblings. Six case-sibling pairs of LCLs from children with autistic disorder and their non-autistic siblings were obtained from the Autism Genetic Resource Exchange (AGRE) and cultured in standard RPMI-1640 tissue culture medium. Cells were exposed to medium containing either 0, 25, 50, 100 and 200 µM hydrogen peroxide (an oxidative stressor) or 0, 5, 10, 20 and 40 µM s-nitroprusside (a nitric oxide producer) for 1h. Following exposure, the cells were microscopically scored for DNA damage, cytostasis and cytotoxicity biomarkers as measured using the cytokinesis-block micronucleus cytome assay. Necrosis was significantly increased in cases relative to controls when exposed to oxidative and nitrosative stress (P = 0.001 and 0.01, respectively). Nuclear division index was significantly lower in LCLs from children with autistic disorder than their non-autistic siblings when exposed to hydrogen peroxide (P = 0.016), but there was no difference in apoptosis, micronucleus frequency, nucleoplasmic bridges or nuclear buds. Exposure to s-nitroprusside significantly increased the number of micronuclei in non-autistic siblings compared with cases (P = 0.003); however, other DNA damage biomarkers, apoptosis and nuclear division did not differ significantly between groups. The findings of this study show (i) that LCLs from children with autism are more sensitive to necrosis under conditions of oxidative and nitrosative stress than their non-autistic siblings and (ii) refutes the hypothesis that children with autistic disorder are abnormally

  13. Contribution of the NO-detoxifying enzymes HmpA, NorV and NrfA to nitrosative stress protection of Salmonella Typhimurium in raw sausages.

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    Mühlig, Anna; Kabisch, Jan; Pichner, Rohtraud; Scherer, Siegfried; Müller-Herbst, Stefanie

    2014-09-01

    The antimicrobial action of the curing agent sodium nitrite (NaNO2) in raw sausage fermentation is thought to mainly depend on the release of cytotoxic nitric oxide (NO) at acidic pH. Salmonella Typhimurium is capable of detoxifying NO via the flavohemoglobin HmpA, the flavorubredoxin NorV and the periplasmic cytochrome C nitrite reductase NrfA. In this study, the contribution of these systems to nitrosative stress tolerance in raw sausages was investigated. In vitro growth assays of the S. Typhimurium 14028 deletion mutants ΔhmpA, ΔnorV and ΔnrfA revealed a growth defect of ΔhmpA in the presence of acidified NaNO2. Transcriptional analysis of the genes hmpA, norV and nrfA in the wild-type showed a 41-fold increase in hmpA transcript levels in the presence of 150 mg/l acidified NaNO2, whereas transcription of norV and nrfA was not enhanced. However, challenge assays performed with short-ripened spreadable sausages produced with 0 or 150 mg/kg NaNO2 failed to reveal a phenotype for any of the mutants compared to the wild-type. Hence, none of the NO detoxification systems HmpA, NorV and NrfA is solely responsible for nitrosative stress tolerance of S. Typhimurium in raw sausages. Whether these systems act cooperatively, or if there are other yet undescribed mechanisms involved is currently unknown. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Tempol and perindopril protect against lipopolysaccharide-induced cognition impairment and amyloidogenesis by modulating brain-derived neurotropic factor, neuroinflammation and oxido-nitrosative stress.

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    Ali, Mohammed Ragab Abdel-Aziz; Abo-Youssef, Amira Morad Hussein; Messiha, Basim Anwar Shehata; Khattab, Mahmoud Mohamed

    2016-06-01

    We aim to evaluate the protective role of the central angiotensin-converting enzyme (ACE) inhibitor perindopril, compared with the standard reactive oxygen species (ROS) scavenger tempol, against lipopolysaccharide (LPS)-induced cognition impairment and amyloidogenesis in a simulation to Alzheimer's disease (AD). Mice were allocated into a control group, an LPS control group (0.8 mg/kg, i.p., once), a tempol (100 mg/kg/day, p.o., 7 days) treatment group, and two perindopril (0.5 and 1 mg/kg/day, p.o., 7 days) treatment groups. A behavioral study was conducted to evaluate spatial and nonspatial memory in mice, followed by a biochemical study involving assessment of brain levels of Aβ and BDNF as Alzheimer and neuroplasticity markers; tumor necrosis factor-alpha (TNF-α), nitric oxide end-products (NOx), neuronal nitric oxide synthase (nNOS), and inducible nitric oxide synthase (iNOS) as inflammatory markers; and superoxide dismutase (SOD), malondialdehyde (MDA), glutathione reduced (GSH), and nitrotyrosine (NT) as oxido-nitrosative stress markers. Finally, histopathological examination of cerebral cortex, hippocampus, and cerebellum sections was performed using both routine and special staining. Tempol and perindopril improved spatial and nonspatial memory in mice without affecting locomotor activity; decreased brain Aβ deposition and BDNF depletion; decreased brain TNF-α, NOx, nNOS, iNOS, MDA, and NT levels; and increased brain SOD and GSH contents, parallel to confirmatory histopathological findings. Tempol and perindopril may be promising agents against AD progression via suppression of Aβ deposition and BDNF decline, suppression of TNF-α production, support of brain antioxidant status, and amelioration of oxido-nitrosative stress and NT production.

  15. Mechanical wounding induces a nitrosative stress by down-regulation of GSNO reductase and an increase in S-nitrosothiols in sunflower (Helianthus annuus) seedlings

    Science.gov (United States)

    Chaki, Mounira; Valderrama, Raquel; Fernández-Ocaña, Ana M.; Carreras, Alfonso; Gómez-Rodríguez, Maria. V.; Pedrajas, José R.; Begara-Morales, Juan C.; Sánchez-Calvo, Beatriz; Luque, Francisco; Leterrier, Marina; Corpas, Francisco J.; Barroso, Juan B.

    2011-01-01

    Nitric oxide (NO) and related molecules such as peroxynitrite, S-nitrosoglutathione (GSNO), and nitrotyrosine, among others, are involved in physiological processes as well in the mechanisms of response to stress conditions. In sunflower seedlings exposed to five different adverse environmental conditions (low temperature, mechanical wounding, high light intensity, continuous light, and continuous darkness), key components of the metabolism of reactive nitrogen species (RNS) and reactive oxygen species (ROS), including the enzyme activities L-arginine-dependent nitric oxide synthase (NOS), S-nitrosogluthathione reductase (GSNOR), nitrate reductase (NR), catalase, and superoxide dismutase, the content of lipid hydroperoxide, hydrogen peroxide, S-nitrosothiols (SNOs), the cellular level of NO, GSNO, and GSNOR, and protein tyrosine nitration [nitrotyrosine (NO2-Tyr)] were analysed. Among the stress conditions studied, mechanical wounding was the only one that caused a down-regulation of NOS and GSNOR activities, which in turn provoked an accumulation of SNOs. The analyses of the cellular content of NO, GSNO, GSNOR, and NO2-Tyr by confocal laser scanning microscopy confirmed these biochemical data. Therefore, it is proposed that mechanical wounding triggers the accumulation of SNOs, specifically GSNO, due to a down-regulation of GSNOR activity, while NO2-Tyr increases. Consequently a process of nitrosative stress is induced in sunflower seedlings and SNOs constitute a new wound signal in plants. PMID:21172815

  16. Nitrosative stress induces DNA strand breaks but not caspase mediated apoptosis in a lung cancer cell line

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    Bentz Brandon G

    2004-12-01

    Full Text Available Abstract Background Key steps crucial to the process of tumor progression are genomic instability and escape from apoptosis. Nitric oxide and its interrelated reactive intermediates (collectively denoted as NOX have been implicated in DNA damage and mutational events leading to cancer development, while also being implicated in the inhibition of apoptosis through S-nitrosation of key apoptotic enzymes. The purpose of this study was to explore the interrelationship between NOX-mediated DNA strand breaks (DSBs and apoptosis in cultured tumor cell lines. Methods Two well-characterized cell lines were exposed to increasing concentrations of exogenous NOX via donor compounds. Production of NOX was quantified by the Greiss reaction and spectrophotometery, and confirmed by nitrotyrosine immunostaining. DSBs were measured by the alkaline single-cell gel electrophoresis assay (the COMET assay, and correlated with cell viability by the MTT assay. Apoptosis was analyzed both by TUNEL staining and Annexin V/propidium iodine FACS. Finally, caspase enzymatic activity was measured using an in-vitro fluorogenic caspase assay. Results Increases in DNA strand breaks in our tumor cells, but not in control fibroblasts, correlated with the concentration as well as rate of release of exogenously administered NOX. This increase in DSBs did not correlate with an increase in cell death or apoptosis in our tumor cell line. Finally, this lack of apoptosis was found to correlate with inhibition of caspase activity upon exposure to thiol- but not NONOate-based NOX donor compounds. Conclusions Genotoxicity appears to be highly interrelated with both the concentration and kinetic delivery of NOX. Moreover, alterations in cell apoptosis can be seen as a consequence of the explicit mechanisms of NOX delivery. These findings lend credence to the hypothesis that NOX may play an important role in tumor progression, and underscores potential pitfalls which should be considered when

  17. Bacillus aryabhattai SRB02 tolerates oxidative and nitrosative stress and promotes the growth of soybean by modulating the production of phytohormones

    Science.gov (United States)

    Kang, Sang-Mo; Shahzad, Raheem; Seo, Chang-Woo; Kim, Ah-Yeong; Lee, Sang-Uk; Oh, Kyeong Yeol; Lee, Dong Yeol; Lee, In-Jung; Yun, Byung-Wook

    2017-01-01

    Plant growth promoting rhizobacteria (PGPR) are diverse, naturally occurring bacteria that establish a close association with plant roots and promote the growth and immunity of plants. Established mechanisms involved in PGPR-mediated plant growth promotion include regulation of phytohormones, improved nutrient availability, and antagonistic effects on plant pathogens. In this study, we isolated a bacterium from the rhizospheric soil of a soybean field in Chungcheong buk-do, South Korea. Using 16S rRNA sequencing, the bacterium was identified as Bacillus aryabhattai strain SRB02. Here we show that this strain significantly promotes the growth of soybean. Gas chromatography—mass spectrometry analysis showed that SRB02 produced significant amounts of abscisic acid, indole acetic acid, cytokinin and different gibberellic acids in culture. SRB02-treated soybean plants showed significantly better heat stress tolerance than did untreated plants. These plants also produced consistent levels of ABA under heat stress and exhibited ABA-mediated stomatal closure. High levels of IAA, JA, GA12, GA4, and GA7, were recorded in SRB02-treated plants. These plants produced longer roots and shoots than those of control plants. B. aryabhattai SRB02 was found to be highly tolerant to oxidative stress induced by H2O2 and MV potentiated by high catalase (CAT) and superoxide dismutase (SOD) activities. SRB02 also tolerated high nitrosative stress induced by the nitric oxide donors GSNO and CysNO. Because of these attributes, B. aryabhattai SRB02 may prove to be a valuable resource for incorporation in biofertilizers and other soil amendments that seek to improve crop productivity. PMID:28282395

  18. Bacillus aryabhattai SRB02 tolerates oxidative and nitrosative stress and promotes the growth of soybean by modulating the production of phytohormones.

    Directory of Open Access Journals (Sweden)

    Yeon-Gyeong Park

    Full Text Available Plant growth promoting rhizobacteria (PGPR are diverse, naturally occurring bacteria that establish a close association with plant roots and promote the growth and immunity of plants. Established mechanisms involved in PGPR-mediated plant growth promotion include regulation of phytohormones, improved nutrient availability, and antagonistic effects on plant pathogens. In this study, we isolated a bacterium from the rhizospheric soil of a soybean field in Chungcheong buk-do, South Korea. Using 16S rRNA sequencing, the bacterium was identified as Bacillus aryabhattai strain SRB02. Here we show that this strain significantly promotes the growth of soybean. Gas chromatography-mass spectrometry analysis showed that SRB02 produced significant amounts of abscisic acid, indole acetic acid, cytokinin and different gibberellic acids in culture. SRB02-treated soybean plants showed significantly better heat stress tolerance than did untreated plants. These plants also produced consistent levels of ABA under heat stress and exhibited ABA-mediated stomatal closure. High levels of IAA, JA, GA12, GA4, and GA7, were recorded in SRB02-treated plants. These plants produced longer roots and shoots than those of control plants. B. aryabhattai SRB02 was found to be highly tolerant to oxidative stress induced by H2O2 and MV potentiated by high catalase (CAT and superoxide dismutase (SOD activities. SRB02 also tolerated high nitrosative stress induced by the nitric oxide donors GSNO and CysNO. Because of these attributes, B. aryabhattai SRB02 may prove to be a valuable resource for incorporation in biofertilizers and other soil amendments that seek to improve crop productivity.

  19. Sildenafil citrate-restored eNOS and PDE5 regulation in sickle cell mouse penis prevents priapism via control of oxidative/nitrosative stress.

    Science.gov (United States)

    Bivalacqua, Trinity J; Musicki, Biljana; Hsu, Lewis L; Berkowitz, Dan E; Champion, Hunter C; Burnett, Arthur L

    2013-01-01

    Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders.

  20. Sildenafil citrate-restored eNOS and PDE5 regulation in sickle cell mouse penis prevents priapism via control of oxidative/nitrosative stress.

    Directory of Open Access Journals (Sweden)

    Trinity J Bivalacqua

    Full Text Available Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders.

  1. Autophagic pathways and metabolic stress.

    Science.gov (United States)

    Kaushik, S; Singh, R; Cuervo, A M

    2010-10-01

    Autophagy is an essential intracellular process that mediates degradation of intracellular proteins and organelles in lysosomes. Autophagy was initially identified for its role as alternative source of energy when nutrients are scarce but, in recent years, a previously unknown role for this degradative pathway in the cellular response to stress has gained considerable attention. In this review, we focus on the novel findings linking autophagic function with metabolic stress resulting either from proteins or lipids. Proper autophagic activity is required in the cellular defense against proteotoxicity arising in the cytosol and also in the endoplasmic reticulum, where a vast amount of proteins are synthesized and folded. In addition, autophagy contributes to mobilization of intracellular lipid stores and may be central to lipid metabolism in certain cellular conditions. In this review, we focus on the interrelation between autophagy and different types of metabolic stress, specifically the stress resulting from the presence of misbehaving proteins within the cytosol or in the endoplasmic reticulum and the stress following a lipogenic challenge. We also comment on the consequences that chronic exposure to these metabolic stressors could have on autophagic function and on how this effect may underlie the basis of some common metabolic disorders. © 2010 Blackwell Publishing Ltd.

  2. Protective action of a hexane crude extract of Pterodon emarginatus fruits against oxidative and nitrosative stress induced by acute exercise in rats

    Directory of Open Access Journals (Sweden)

    Alfredo Patrícia P

    2005-08-01

    Full Text Available Abstract Background The aim of the present work was to evaluate the effect of a hexane crude extract (HCE of Pterodon emarginatus on the oxidative and nitrosative stress induced in skeletal muscle, liver and brain of acutely exercised rats. Methods Adult male rats were subjected to acute exercise by standardized contractions of the tibialis anterior (TA muscle (100 Hz, 15 min and treated orally with the HCE (once or three times with a fixed dose of 498 mg/kg, before and after acute exercise. Serum creatine kinase activity was determined by a kinetic method and macrophage infiltration by histological analyses of TA muscle. Lipid peroxidation was measured as malondialdehyde (MDA levels. Nitric oxide production was evaluated by measuring nitrite formation, using Griess reagent, and nitrotyrosine was assessed by western blotting. Results Serum creatine kinase activities in the controls (111 U/L increased 1 h after acute exercise (443 U/L. Acute exercise also increased the infiltration of macrophages into TA muscle; lipid peroxidation levels in TA muscle (967%, liver (55.5% and brain (108.9%, as well as the nitrite levels by 90.5%, 30.7% and 60%, respectively. The pattern of nitrotyrosine formation was also affected by acute exercise. Treatment with HCE decreased macrophage infiltration, lipid peroxidation, nitrite production and nitrotyrosine levels to control values. Conclusion Acute exercise induced by functional electrical stimulation in rats resulted in increase in lipid peroxidation, nitrite and nitrotyrosine levels in brain, liver and skeletal muscle. The exercise protocol, that involved eccentric muscle contraction, also caused some muscle trauma, associated with over-exertion, leading to inflammation. The extract of P. emarginatus abolished most of these oxidative processes, thus confirming the high antioxidant activity of this oil which infusions are used in folk medicine against inflammatory processes.

  3. Non-toxic engineered carbon nanodiamond concentrations induce oxidative/nitrosative stress, imbalance of energy metabolism, and mitochondrial dysfunction in microglial and alveolar basal epithelial cells.

    Science.gov (United States)

    Fresta, Claudia G; Chakraborty, Aishik; Wijesinghe, Manjula B; Amorini, Angela M; Lazzarino, Giacomo; Lazzarino, Giuseppe; Tavazzi, Barbara; Lunte, Susan M; Caraci, Filippo; Dhar, Prajnaparamita; Caruso, Giuseppe

    2018-02-14

    Engineered nanoparticles are finding a wide spectrum of biomedical applications, including drug delivery and capacity to trigger cytotoxic phenomena, potentially useful against tumor cells. The full understanding of their biosafety and interactions with cell processes is mandatory. Using microglial (BV-2) and alveolar basal epithelial (A549) cells, in this study we determined the effects of engineered carbon nanodiamonds (ECNs) on cell viability, nitric oxide (NO) and reactive oxygen species (ROS) production, as well as on energy metabolism. Particularly, we initially measured decrease in cell viability as a function of increasing ECNs doses, finding similar cytotoxic ECN effects in the two cell lines. Subsequently, using apparently non-cytotoxic ECN concentrations (2 µg/mL causing decrease in cell number < 5%) we determined NO and ROS production, and measured the concentrations of compounds related to energy metabolism, mitochondrial functions, oxido-reductive reactions, and antioxidant defences. We found that in both cell lines non-cytotoxic ECN concentrations increased NO and ROS production with sustained oxidative/nitrosative stress, and caused energy metabolism imbalance (decrease in high energy phosphates and nicotinic coenzymes) and mitochondrial malfunctioning (decrease in ATP/ADP ratio).These results underline the importance to deeply investigate the molecular and biochemical changes occurring upon the interaction of ECNs (and nanoparticles in general) with living cells, even at apparently non-toxic concentration. Since the use of ECNs in biomedical field is attracting increasing attention the complete evaluation of their biosafety, toxicity and/or possible side effects both in vitro and in vivo is mandatory before these highly promising tools might find the correct application.

  4. Nitrosothiol signaling and protein nitrosation in cell death.

    Science.gov (United States)

    Iyer, Anand Krishnan V; Rojanasakul, Yon; Azad, Neelam

    2014-11-15

    Nitric oxide, a reactive free radical, is an important signaling molecule that can lead to a plethora of cellular effects affecting homeostasis. A well-established mechanism by which NO manifests its effect on cellular functions is the post-translational chemical modification of cysteine thiols in substrate proteins by a process known as S-nitrosation. Studies that investigate regulation of cellular functions through NO have increasingly established S-nitrosation as the primary modulatory mechanism in their respective systems. There has been a substantial increase in the number of reports citing various candidate proteins undergoing S-nitrosation, which affects cell-death and -survival pathways in a number of tissues including heart, lung, brain and blood. With an exponentially growing list of proteins being identified as substrates for S-nitrosation, it is important to assimilate this information in different cell/tissue systems in order to gain an overall view of protein regulation of both individual proteins and a class of protein substrates. This will allow for broad mapping of proteins as a function of S-nitrosation, and help delineate their global effects on pathophysiological responses including cell death and survival. This information will not only provide a much better understanding of overall functional relevance of NO in the context of various disease states, it will also facilitate the generation of novel therapeutics to combat specific diseases that are driven by NO-mediated S-nitrosation. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Serum metabolome biomarkers associate low-level environmental perfluorinated compound exposure with oxidative /nitrosative stress in humans.

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    Wang, Xiaofei; Liu, Liangpo; Zhang, Weibing; Zhang, Jie; Du, Xiaoyan; Huang, Qingyu; Tian, Meiping; Shen, Heqing

    2017-10-01

    Previous in vivo and in vitro studies have linked perfluorinated compound (PFC) exposure with metabolic interruption, but the inter-species difference and high treatment doses usually make the results difficult to be extrapolated to humans directly. The best strategy for identifying the metabolic interruption may be to establish the direct correlations between monitored PFCs data and metabolic data on human samples. In this study, serum metabolome data and PFC concentrations were acquired for a Chinese adult male cohort. The most abundant PFCs are PFOA and PFOS with concentration medians 7.56 and 12.78 nM, respectively; in together they count around 81.6% of the total PFCs. PFC concentration-related serum metabolic profile changes and the related metabolic biomarkers were explored by using partial least squares-discriminant analysis (PLS-DA). Respectively taking PFOS, PFOA and total PFC as the classifiers, serum metabolome can be differentiated between the lowest dose group (1st quartile PFCs) and the highest PFC dose group (4th quartile PFCs). Ten potential PFC biomarkers were identified, mainly involving in pollutant detoxification, antioxidation and nitric oxide (NO) signal pathways. These suggested that low-level environmental PFC exposure has significantly adverse impacts on glutathione (GSH) cycle, Krebs cycle, nitric oxide (NO) generation and purine oxidation in humans. To the best of our knowledge, this is the first report investigating the association of environmental PFC exposure with human serum metabolome alteration. Given the important biological functions of the identified biomarkers, we suggest that PFC could increase the metabolism syndromes risk including diabetes and cardiovascular diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Amino acid nitrosation products as alkylating agents.

    Science.gov (United States)

    García-Santos, M del P; Calle, E; Casado, J

    2001-08-08

    Nitrosation reactions of alpha-, beta-, and gamma-amino acids whose reaction products can act as alkylating agents of DNA were investigated. To approach in vivo conditions for the two-step mechanism (nitrosation and alkylation), nitrosation reactions were carried out in aqueous acid conditions (mimicking the conditions of the stomach lumen) while the alkylating potential of the nitrosation products was investigated at neutral pH, as in the stomach lining cells into which such products can diffuse. These conclusions were drawn: (i) The alkylating species resulting from the nitrosation of amino acids with an -NH(2) group are the corresponding lactones; (ii) the sequence of alkylating power is: alpha-lactones > beta-lactones > gamma-lactones, coming respectively from the nitrosation of alpha-, beta-, and gamma-amino acids; and (iii) the results obtained may be useful in predicting the mutagenic effectiveness of the nitrosation products of amino acids.

  7. Attenuation of oxidative and nitrosative stress in cortical area associates with antidepressant-like effects of tropisetron in male mice following social isolation stress.

    Science.gov (United States)

    Haj-Mirzaian, Arya; Amiri, Shayan; Amini-Khoei, Hossein; Rahimi-Balaei, Maryam; Kordjazy, Nastaran; Olson, Carl O; Rastegar, Mojgan; Naserzadeh, Parvaneh; Marzban, Hassan; Dehpour, Ahmad Reza; Hosseini, Mir-Jamal; Samiei, Elika; Mehr, Shahram Ejtemaei

    2016-06-01

    Tropisetron, a 5-HT3 receptor antagonist widely used as an antiemetic, has been reported to have positive effects on mood disorders. Adolescence is a critical period during the development of brain, where exposure to chronic stress during this time is highly associated with the development of depression. In this study, we showed that 4 weeks of juvenile social isolation stress (SIS) provoked depressive-like behaviors in male mice, which was associated with disruption of mitochondrial function and nitric oxide overproduction in the cortical areas. In this study, tropisetron (5mg/kg) reversed the negative behavioral effects of SIS in male mice. We found that the effects of tropisetron were mediated through mitigating the negative activity of inducible nitric oxide synthase (iNOS) on mitochondrial activity. Administration of aminoguanidine (specific iNOS inhibitor, 20mg/kg) augmented the protective effects of tropisetron (1mg/kg) on SIS. Furthermore, l-arginine (nitric oxide precursor, 100mg/kg) abolished the positive effects of tropisetron. These results have increased our knowledge on the pivotal role of mitochondrial function in the pathophysiology of depression, and highlighted the role of 5-HT3 receptors in psychosocial stress response during adolescence. Finally, we observed that tropisetron alleviated the mitochondrial dysfunction through decreased nitrergic system activity in the cerebral cortex. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. A meta-analysis of biomarkers related to oxidative stress and nitric oxide pathway in migraine.

    Science.gov (United States)

    Neri, Monica; Frustaci, Alessandra; Milic, Mirta; Valdiglesias, Vanessa; Fini, Massimo; Bonassi, Stefano; Barbanti, Piero

    2015-09-01

    Oxidative and nitrosative stress are considered key events in the still unclear pathophysiology of migraine. Studies comparing the level of biomarkers related to nitric oxide (NO) pathway/oxidative stress in the blood/urine of migraineurs vs. unaffected controls were extracted from the PubMed database. Summary estimates of mean ratios (MR) were carried out whenever a minimum of three papers were available. Nineteen studies were included in the meta-analyses, accounting for more than 1000 patients and controls, and compared with existing literature. Most studies measuring superoxide dismutase (SOD) showed lower activity in cases, although the meta-analysis in erythrocytes gave null results. On the contrary, plasma levels of thiobarbituric acid reactive substances (TBARS), an aspecific biomarker of oxidative damage, showed a meta-MR of 2.20 (95% CI: 1.65-2.93). As for NOs, no significant results were found in plasma, serum and urine. However, higher levels were shown during attacks, in patients with aura, and an effect of diet was found. The analysis of glutathione precursor homocysteine and asymmetric dimethylarginine (ADMA), an NO synthase inhibitor, gave inconclusive results. The role of the oxidative pathway in migraine is still uncertain. Interesting evidence emerged for TBARS and SOD, and concerning the possible role of diet in the control of NOx levels. © International Headache Society 2015.

  9. 2.45-GHz microwave irradiation adversely affects reproductive function in male mouse, Mus musculus by inducing oxidative and nitrosative stress.

    Science.gov (United States)

    Shahin, S; Mishra, V; Singh, S P; Chaturvedi, C M

    2014-05-01

    Electromagnetic radiations are reported to produce long-term and short-term biological effects, which are of great concern to human health due to increasing use of devices emitting EMR especially microwave (MW) radiation in our daily life. In view of the unavoidable use of MW emitting devices (microwaves oven, mobile phones, Wi-Fi, etc.) and their harmful effects on biological system, it was thought worthwhile to investigate the long-term effects of low-level MW irradiation on the reproductive function of male Swiss strain mice and its mechanism of action. Twelve-week-old mice were exposed to non-thermal low-level 2.45-GHz MW radiation (CW for 2 h/day for 30 days, power density = 0.029812 mW/cm(2) and SAR = 0.018 W/Kg). Sperm count and sperm viability test were done as well as vital organs were processed to study different stress parameters. Plasma was used for testosterone and testis for 3β HSD assay. Immunohistochemistry of 3β HSD and nitric oxide synthase (i-NOS) was also performed in testis. We observed that MW irradiation induced a significant decrease in sperm count and sperm viability along with the decrease in seminiferous tubule diameter and degeneration of seminiferous tubules. Reduction in testicular 3β HSD activity and plasma testosterone levels was also noted in the exposed group of mice. Increased expression of testicular i-NOS was observed in the MW-irradiated group of mice. Further, these adverse reproductive effects suggest that chronic exposure to nonionizing MW radiation may lead to infertility via free radical species-mediated pathway.

  10. IKK connects autophagy to major stress pathways.

    Science.gov (United States)

    Criollo, Alfredo; Senovilla, Laura; Authier, Hélène; Maiuri, Maria Chiara; Morselli, Eugenia; Vitale, Ilio; Kepp, Oliver; Tasdemir, Ezgi; Galluzzi, Lorenzo; Shen, Shensi; Tailler, Maximilien; Delahaye, Nicolas; Tesniere, Antoine; De Stefano, Daniela; Younes, Aména Ben; Harper, Francis; Pierron, Gérard; Lavandero, Sergio; Zitvogel, Laurence; Israel, Alain; Baud, Véronique; Kroemer, Guido

    2010-01-01

    Cells respond to stress by activating cytoplasmic mechanisms as well as transcriptional programs that can lead to adaptation or death. Autophagy represents an important cytoprotective response that is regulated by both transcriptional and transcription-independent pathways. NFkappaB is perhaps the transcription factor most frequently activated by stress and has been ascribed with either pro- or anti-autophagic functions, depending on the cellular context. Our results demonstrate that activation of the IKK (IkappaB kinase) complex, which is critical for the stress-elicited activation of NFkappaB, is sufficient to promote autophagy independent of NFkappaB, and that IKK is required for the optimal induction of autophagy by both physiological and pharmacological autophagic triggers.

  11. A neuro-immune, neuro-oxidative and neuro-nitrosative model of prenatal and postpartum depression.

    Science.gov (United States)

    Roomruangwong, Chutima; Anderson, George; Berk, Michael; Stoyanov, Drozdstoy; Carvalho, André F; Maes, Michael

    2018-02-02

    A large body of evidence indicates that major affective disorders are accompanied by activated neuro-immune, neuro-oxidative and neuro-nitrosative stress (IO&NS) pathways. Postpartum depression is predicted by end of term prenatal depressive symptoms whilst a lifetime history of mood disorders appears to increase the risk for both prenatal and postpartum depression. This review provides a critical appraisal of available evidence linking IO&NS pathways to prenatal and postpartum depression. The electronic databases Google Scholar, PubMed and Scopus were sources for this narrative review focusing on keywords, including perinatal depression, (auto)immune, inflammation, oxidative, nitric oxide, nitrosative, tryptophan catabolites (TRYCATs), kynurenine, leaky gut and microbiome. Prenatal depressive symptoms are associated with exaggerated pregnancy-specific changes in IO&NS pathways, including increased C-reactive protein, advanced oxidation protein products and nitric oxide metabolites, lowered antioxidant levels, such as zinc, as well as lowered regulatory IgM-mediated autoimmune responses. The latter pathways coupled with lowered levels of endogenous anti-inflammatory compounds, including ω3 polyunsaturated fatty acids, may also underpin the pathophysiology of postpartum depression. Although increased bacterial translocation, lipid peroxidation and TRYCAT pathway activation play a role in mood disorders, similar changes do not appear to be relevant in perinatal depression. Some IO&NS biomarker characteristics of mood disorders are found in prenatal depression indicating that these pathways partly contribute to the association of a lifetime history of mood disorders and perinatal depression. However, available evidence suggests that some IO&NS pathways differ significantly between perinatal depression and mood disorders in general. This review provides a new IO&NS model of prenatal and postpartum depression. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Programming of stress pathways: A transgenerational perspective.

    Science.gov (United States)

    Constantinof, Andrea; Moisiadis, Vasilis G; Matthews, Stephen G

    2016-06-01

    The embryo and fetus are highly responsive to the gestational environment. Glucocorticoids (GC) represent an important class of developmental cues and are crucial for normal brain development. Levels of GC in the fetal circulation are tightly regulated. They are maintained at low levels during pregnancy, and increase rapidly at the end of gestation. This surge in GC is critical for maturation of the organs, specifically the lungs, brain and kidney. There are extensive changes in brain epigenetic profiles that accompany the GC surge, suggesting that GC may drive regulation of gene transcription through altered epigenetic pathways. The epigenetic profiles produced by the GC surge can be prematurely induced as a result of maternal or fetal stress, as well as through exposure to synthetic glucocorticoids (sGC). This is highly clinically relevant as 10% of pregnant women are at risk for preterm labour and receive treatment with sGC to promote lung development in the fetus. Fetal overexposure to GC (including sGC) has been shown to cause lasting changes in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis leading to altered stress responses, and mood and anxiety disorders in humans and animals. In animal models, GC exposure is associated with transcriptomic and epigenomic changes that influence behaviour, HPA function and growth. Importantly, programming by GC results in sex-specific effects that can be inherited over multiple generations via paternal and maternal transmission. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Myeloperoxidase potentiates nitric oxide-mediated nitrosation.

    Science.gov (United States)

    Lakshmi, Vijaya M; Nauseef, William M; Zenser, Terry V

    2005-01-21

    Nitrosation is an important reaction elicited by nitric oxide (NO). To better understand how nitrosation occurs in biological systems, we assessed the effect of myeloperoxidase (MPO), a mediator of inflammation, on nitrosation observed during NO autoxidation. Nitrosation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ; 10 mum) to 2-nitrosoamino-3-methylimidazo[4,5-f]quinoline (N-NO-IQ) was monitored by HPLC. Using the NO donor spermine NONOate at pH 7.4, MPO potentiated N-NO-IQ formation. The minimum effective quantity of necessary components was 8.5 nm MPO, 0.25 mum H(2)O(2)/min, and 0.024 mum NO/min. Autoxidation was only detected at >/=1.2 mum NO/min. MPO potentiation was not affected by a 40-fold excess flux of H(2)O(2) over NO or less than a 2.4-fold excess flux of NO over H(2)O(2). Potentiation was due to an 8.8-fold increased affinity of MPO-derived nitrosating species for IQ. Autoxidation was inhibited by azide, suggesting involvement of the nitrosonium ion, NO(+). MPO potentiation was inhibited by NADH, but not azide, suggesting oxidative nitrosylation with NO(2)(.) or an NO(2)(.)-like species. MPO nonnitrosative oxidation of IQ with 0.3 mm NO(2)(-) at pH 5.5 was inhibited by azide, but not NADH, demonstrating differences between MPO oxidation of IQ with NO compared with NO(2)(-). Using phorbol ester-stimulated human neutrophils, N-NO-IQ formation was increased with superoxide dismutase and inhibited by catalase and NADH, but not NaN(3). This is consistent with nitrosation potentiation by MPO, not peroxynitrite. Increased N-NO-IQ formation was not detected with polymorphonuclear neutrophils from two unrelated MPO-deficient patients. Results suggest that the highly diffusible stable gas NO could initiate nitrosation at sites of neutrophil infiltration.

  14. 1800 MHz mobile phone irradiation induced oxidative and nitrosative stress leads to p53 dependent Bax mediated testicular apoptosis in mice, Mus musculus.

    Science.gov (United States)

    Shahin, Saba; Singh, Surya P; Chaturvedi, Chandra M

    2018-09-01

    Present study was carried out to investigate the effect of long-term mobile phone radiation exposure in different operative modes (Dialing, Receiving, and Stand-by) on immature male mice. Three-week old male mice were exposed to mobile phone (1800 MHz) radiation for 3 hr/day for 120 days in different operative modes. To check the changes/alteration in testicular histoarchitecture and serum testosterone level, HE staining and ELISA was performed respectively. Further, we have checked the redox status (ROS, NO, MDA level, and antioxidant enzymes: SOD, CAT, and GPx) by biochemical estimation, alteration in the expression of pro-apoptotic proteins (p53 and Bax), active executioner caspase-3, full length/uncleaved PARP-1 (DNA repair enzyme), anti-apoptotic proteins (Bcl-2 and Bcl-x L ) in testes by immunofluorescence and cytosolic cytochrome-c by Western blot. Decreased seminiferous tubule diameter, sperm count, and viability along with increased germ cells apoptosis and decreased serum testosterone level, was observed in the testes of all the mobile phone exposed mice compared with control. We also observed that, mobile phone radiation exposure in all the three different operative modes alters the testicular redox status via increasing ROS, NO, and MDA level, and decreasing antioxidant enzymes levels leading to enhanced apoptosis of testicular cells by increasing the expression of pro-apoptotic and apoptotic proteins along with decreasing the expression of anti-apoptotic protein. On the basis of results, it is conclude that long-term mobile phone radiation exposure induced oxidative stress leads to apoptosis of testicular cells and thus impairs testicular function. © 2018 Wiley Periodicals, Inc.

  15. Stress responses during ageing: molecular pathways regulating protein homeostasis.

    Science.gov (United States)

    Kyriakakis, Emmanouil; Princz, Andrea; Tavernarakis, Nektarios

    2015-01-01

    The ageing process is characterized by deterioration of physiological function accompanied by frailty and ageing-associated diseases. The most broadly and well-studied pathways influencing ageing are the insulin/insulin-like growth factor 1 signaling pathway and the dietary restriction pathway. Recent studies in diverse organisms have also delineated emerging pathways, which collectively or independently contribute to ageing. Among them the proteostatic-stress-response networks, inextricably affect normal ageing by maintaining or restoring protein homeostasis to preserve proper cellular and organismal function. In this chapter, we survey the involvement of heat stress and endoplasmic reticulum stress responses in the regulation of longevity, placing emphasis on the cross talk between different response mechanisms and their systemic effects. We further discuss novel insights relevant to the molecular pathways mediating these stress responses that may facilitate the development of innovative interventions targeting age-related pathologies such as diabetes, cancer, cardiovascular and neurodegenerative diseases.

  16. Phylogenetic diversity of stress signalling pathways in fungi

    Directory of Open Access Journals (Sweden)

    Stansfield Ian

    2009-02-01

    Full Text Available Abstract Background Microbes must sense environmental stresses, transduce these signals and mount protective responses to survive in hostile environments. In this study we have tested the hypothesis that fungal stress signalling pathways have evolved rapidly in a niche-specific fashion that is independent of phylogeny. To test this hypothesis we have compared the conservation of stress signalling molecules in diverse fungal species with their stress resistance. These fungi, which include ascomycetes, basidiomycetes and microsporidia, occupy highly divergent niches from saline environments to plant or mammalian hosts. Results The fungi displayed significant variation in their resistance to osmotic (NaCl and sorbitol, oxidative (H2O2 and menadione and cell wall stresses (Calcofluor White and Congo Red. There was no strict correlation between fungal phylogeny and stress resistance. Rather, the human pathogens tended to be more resistant to all three types of stress, an exception being the sensitivity of Candida albicans to the cell wall stress, Calcofluor White. In contrast, the plant pathogens were relatively sensitive to oxidative stress. The degree of conservation of osmotic, oxidative and cell wall stress signalling pathways amongst the eighteen fungal species was examined. Putative orthologues of functionally defined signalling components in Saccharomyces cerevisiae were identified by performing reciprocal BLASTP searches, and the percent amino acid identities of these orthologues recorded. This revealed that in general, central components of the osmotic, oxidative and cell wall stress signalling pathways are relatively well conserved, whereas the sensors lying upstream and transcriptional regulators lying downstream of these modules have diverged significantly. There was no obvious correlation between the degree of conservation of stress signalling pathways and the resistance of a particular fungus to the corresponding stress. Conclusion Our

  17. Major Differences in Neurooxidative and Neuronitrosative Stress Pathways Between Major Depressive Disorder and Types I and II Bipolar Disorder.

    Science.gov (United States)

    Maes, Michael; Landucci Bonifacio, Kamila; Morelli, Nayara Rampazzo; Vargas, Heber Odebrecht; Barbosa, Décio Sabbatini; Carvalho, André F; Nunes, Sandra Odebrecht Vargas

    2018-04-21

    Accumulating evidence indicates that oxidative and nitrosative stress (O&NS) pathways play a key role in the pathophysiology of bipolar disorder (BD) and major depressive disorder (MDD). However, only a handful of studies have directly compared alterations in O&NS pathways among patients with MDD and BD types I (BPI) and BPII. Thus, the current study compared superoxide dismutase (SOD1), lipid hydroperoxides (LOOH), catalase, nitric oxide metabolites (NOx), malondialdehyde (MDA), and advanced oxidation protein products (AOPP) between mood disorder patients in a clinically remitted state. To this end 45, 23, and 37 participants with BPI, BPII, and MDD, respectively, as well as 54 healthy controls (HCs) were recruited. Z-unit weighted composite scores were computed as indices of reactive oxygen species (ROS) production and nitro-oxidative stress driving lipid or protein oxidation. SOD1, NOx, and MDA were significantly higher in MDD than in the other three groups. AOPP was significantly higher in BPI than in HCs and BPII patients. BPII patients showed lower SOD1 compared to all other groups. Furthermore, MDD was characterized by increased indices of ROS and lipid hydroperoxide production compared to BPI and BPII groups. Indices of nitro-oxidative stress coupled with aldehyde production or protein oxidation were significantly different among the three patient groups (BDII > BDI > MDD). Finally, depressive symptom scores were significantly associated with higher LOOH and AOPP levels. In conclusion, depression is accompanied by increased ROS production, which is insufficiently dampened by catalase activity, thereby increasing nitro-oxidative damage to lipids and aldehyde production. Increased protein oxidation with formation of AOPP appeared to be hallmark of MDD and BPI. In addition, patients with BPII may have protection against the damaging effects of ROS including lipid peroxidation and aldehyde formation. This study suggests that biomarkers related to O&NS could aid

  18. Sex differences in prenatal epigenetic programming of stress pathways.

    Science.gov (United States)

    Bale, Tracy L

    2011-07-01

    Maternal stress experience is associated with neurodevelopmental disorders including schizophrenia and autism. Recent studies have examined mechanisms by which changes in the maternal milieu may be transmitted to the developing embryo and potentially translated into programming of the epigenome. Animal models of prenatal stress have identified important sex- and temporal-specific effects on offspring stress responsivity. As dysregulation of stress pathways is a common feature in most neuropsychiatric diseases, molecular and epigenetic analyses at the maternal-embryo interface, especially in the placenta, may provide unique insight into identifying much-needed predictive biomarkers. In addition, as most neurodevelopmental disorders present with a sex bias, examination of sex differences in the inheritance of phenotypic outcomes may pinpoint gene targets and specific windows of vulnerability in neurodevelopment, which have been disrupted. This review discusses the association and possible contributing mechanisms of prenatal stress in programming offspring stress pathway dysregulation and the importance of sex.

  19. Stress transgenerationally programs metabolic pathways linked to altered mental health.

    Science.gov (United States)

    Kiss, Douglas; Ambeskovic, Mirela; Montina, Tony; Metz, Gerlinde A S

    2016-12-01

    Stress is among the primary causes of mental health disorders, which are the most common reason for disability worldwide. The ubiquity of these disorders, and the costs associated with them, lends a sense of urgency to the efforts to improve prediction and prevention. Down-stream metabolic changes are highly feasible and accessible indicators of pathophysiological processes underlying mental health disorders. Here, we show that remote and cumulative ancestral stress programs central metabolic pathways linked to mental health disorders. The studies used a rat model consisting of a multigenerational stress lineage (the great-great-grandmother and each subsequent generation experienced stress during pregnancy) and a transgenerational stress lineage (only the great-great-grandmother was stressed during pregnancy). Urine samples were collected from adult male F4 offspring and analyzed using 1 H NMR spectroscopy. The results of variable importance analysis based on random variable combination were used for unsupervised multivariate principal component analysis and hierarchical clustering analysis, as well as metabolite set enrichment analysis (MSEA) and pathway analysis. We identified distinct metabolic profiles associated with the multigenerational and transgenerational stress phenotype, with consistent upregulation of hippurate and downregulation of tyrosine, threonine, and histamine. MSEA and pathway analysis showed that these metabolites are involved in catecholamine biosynthesis, immune responses, and microbial host interactions. The identification of metabolic signatures linked to ancestral programming assists in the discovery of gene targets for future studies of epigenetic regulation in pathogenic processes. Ultimately, this research can lead to biomarker discovery for better prediction and prevention of mental health disorders.

  20. Aromatic C-nitrosation of a bioactive molecule. Nitrosation of minoxidil.

    Science.gov (United States)

    González-Jiménez, Mario; Arenas-Valgañón, Jorge; Calle, Emilio; Casado, Julio

    2011-10-26

    Minoxidil (2,4-diamino-6-(piperidin-1'-yl)pyrimidine N(3)-oxide; CASRN 38304-91-5) is a bioactive molecule with several nitrosatable groups widely used as an antihypertensive and antialopecia agent. Here the nitrosation of minoxidil was investigated. The conclusions drawn are as follows: (i) In the pH = 2.3-5.0 range, the minoxidil molecule undergoes aromatic C-nitrosation by nitrite. The dominant reaction was C-5 nitrosation through a mechanism that appears to consist of an electrophilic attack on the nitrosatable substrate by H(2)NO(2)(+)/NO(+), followed by a slow proton transfer; (ii) the reactivity of minoxidil as a C-nitrosatable substrate proved to be 7-fold greater than that of phenol, this being attributed to the preferred para- and ortho-orientations of the two -NH(2) groups at positions 2 and 4 of the minoxidil molecule, which activate electrophilic substitution in the C-5 position through their mesomeric effect. The N-nitrosominoxidil resulting from the nitrosation could be potentially harmful to the minoxidil users.

  1. Nitrosation of melatonin by nitric oxide: a computational study.

    Science.gov (United States)

    Turjanski, A G; Sáenz, D A; Doctorovich, F; Estrin, D A; Rosenstein, R E

    2001-09-01

    Melatonin is being increasingly promoted as a therapeutic agent for the treatment of jet lag and insomnia, and is an efficient free radical scavenger. We have recently characterized a product for the reaction of melatonin with nitric oxide (NO), N-nitrosomelatonin. In the present work, reaction pathways with N1, C2, C4, C6 and C7 as possible targets for its reaction with NO that yield the respective nitroso derivatives have been investigated using semiempirical AM1 computational tools, both in vacuo and aqueous solution. Specifically, two different pathways were studied: a radical mechanism involving the hydrogen atom abstraction to yield a neutral radical followed by NO addition, and an ionic mechanism involving addition of nitrosonium ion to the indolic moiety. Our results show that the indolic nitrogen is the most probable site for nitrosation by the radical mechanism, whereas different targets are probable considering the ionic pathway. These results are in good agreement with previous experimental findings and provide a coherent picture for the interaction of melatonin with NO.

  2. Pathways from acculturation stress to substance use among latino adolescents.

    Science.gov (United States)

    Buchanan, Rachel Lee; Smokowski, Paul Richard

    2009-01-01

    The purpose of this study was to examine the link between acculturation stress and substance use among Latino adolescents. In-home interviews were completed with the participants at four time-points between 2005 and 2007. Path analysis was completed using longitudinal data from 286 Latino adolescents living in North Carolina and Arizona (65% foreign-born). Results indicate that acculturation stress influences family and friend relationships, which in turn affect adolescent mental health problems, and finally, substance use. Key mediators in the pathway from acculturation stress to substance use were parent-adolescent conflict, internalizing, and externalizing problems. Implications for practice and research have been discussed here.

  3. Oxidative stress response pathways: Fission yeast as archetype

    DEFF Research Database (Denmark)

    Papadakis, Manos A.; Workman, Christopher

    2015-01-01

    Schizosaccharomyces pombe is a popular model eukaryotic organism to study diverse aspects of mammalian biology, including responses to cellular stress triggered by redox imbalances within its compartments. The review considers the current knowledge on the signaling pathways that govern the transc...

  4. Aging causes decreased resistance to multiple stresses and a failure to activate specific stress response pathways

    Science.gov (United States)

    Bergsma, Alexis L.; Senchuk, Megan M.; Van Raamsdonk, Jeremy M.

    2016-01-01

    In this work, we examine the relationship between stress resistance and aging. We find that resistance to multiple types of stress peaks during early adulthood and then declines with age. To dissect the underlying mechanisms, we use C. elegans transcriptional reporter strains that measure the activation of different stress responses including: the heat shock response, mitochondrial unfolded protein response, endoplasmic reticulum unfolded protein response, hypoxia response, SKN-1-mediated oxidative stress response, and the DAF-16-mediated stress response. We find that the decline in stress resistance with age is at least partially due to a decreased ability to activate protective mechanisms in response to stress. In contrast, we find that any baseline increase in stress caused by the advancing age is too mild to detectably upregulate any of the stress response pathways. Further exploration of how worms respond to stress with increasing age revealed that the ability to mount a hormetic response to heat stress is also lost with increasing age. Overall, this work demonstrates that resistance to all types of stress declines with age. Based on our data, we speculate that the decrease in stress resistance with advancing age results from a genetically-programmed inactivation of stress response pathways, not accumulation of damage. PMID:27053445

  5. Aging causes decreased resistance to multiple stresses and a failure to activate specific stress response pathways.

    Science.gov (United States)

    Dues, Dylan J; Andrews, Emily K; Schaar, Claire E; Bergsma, Alexis L; Senchuk, Megan M; Van Raamsdonk, Jeremy M

    2016-04-01

    In this work, we examine the relationship between stress resistance and aging. We find that resistance to multiple types of stress peaks during early adulthood and then declines with age. To dissect the underlying mechanisms, we use C. elegans transcriptional reporter strains that measure the activation of different stress responses including: the heat shock response, mitochondrial unfolded protein response, endoplasmic reticulum unfolded protein response, hypoxia response, SKN-1-mediated oxidative stress response, and the DAF-16-mediated stress response. We find that the decline in stress resistance with age is at least partially due to a decreased ability to activate protective mechanisms in response to stress. In contrast, we find that any baseline increase in stress caused by the advancing age is too mild to detectably upregulate any of the stress response pathways. Further exploration of how worms respond to stress with increasing age revealed that the ability to mount a hormetic response to heat stress is also lost with increasing age. Overall, this work demonstrates that resistance to all types of stress declines with age. Based on our data, we speculate that the decrease in stress resistance with advancing age results from a genetically-programmed inactivation of stress response pathways, not accumulation of damage.

  6. Detailed mechanistic investigation into the S-nitrosation of cysteamine.

    Science.gov (United States)

    Morakinyo, Moshood K; Chipinda, Itai; Hettick, Justin; Siegel, Paul D; Abramson, Jonathan; Strongin, Robert; Martincigh, Bice S; Simoyi, Reuben H

    The nitrosation of cysteamine (H 2 NCH 2 CH 2 SH) to produce cysteamine- S -nitrosothiol (CANO) was studied in slightly acidic medium by using nitrous acid prepared in situ. The stoichiometry of the reaction was H 2 NCH 2 CH 2 SH + HNO 2 → H 2 NCH 2 CH 2 SNO + H 2 O. On prolonged standing, the nitrosothiol decomposed quantitatively to yield the disulfide, cystamine: 2H 2 NCH 2 CH 2 SNO → H 2 NCH 2 CH 2 S-SCH 2 CH 2 NH 2 + 2NO. NO 2 and N 2 O 3 are not the primary nitrosating agents, since their precursor (NO) was not detected during the nitrosation process. The reaction is first order in nitrous acid, thus implicating it as the major nitrosating agent in mildly acidic pH conditions. Acid catalyzes nitrosation after nitrous acid has saturated, implicating the protonated nitrous acid species, the nitrosonium cation (NO + ) as a contributing nitrosating species in highly acidic environments. The acid catalysis at constant nitrous acid concentrations suggests that the nitrosonium cation nitrosates at a much higher rate than nitrous acid. Bimolecular rate constants for the nitrosation of cysteamine by nitrous acid and by the nitrosonium cation were deduced to be 17.9 ± 1.5 (mol/L) -1 s -1 and 6.7 × 10 4 (mol/L) -1 s -1 , respectively. Both Cu(I) and Cu(II) ions were effective catalysts for the formation and decomposition of the cysteamine nitrosothiol. Cu(II) ions could catalyze the nitrosation of cysteamine in neutral conditions, whereas Cu(I) could only catalyze in acidic conditions. Transnitrosation kinetics of CANO with glutathione showed the formation of cystamine and the mixed disulfide with no formation of oxidized glutathione (GSSG). The nitrosation reaction was satisfactorily simulated by a simple reaction scheme involving eight reactions.

  7. Life stress and atherosclerosis: a pathway through unhealthy lifestyle.

    Science.gov (United States)

    Mainous, Arch G; Everett, Charles J; Diaz, Vanessa A; Player, Marty S; Gebregziabher, Mulugeta; Smith, Daniel W

    2010-01-01

    To examine the relationship between a general measure of chronic life stress and atherosclerosis among middle aged adults without clinical cardiovascular disease via pathways through unhealthy lifestyle characteristics. We conducted an analysis of The Multi-Ethnic Study of Atherosclerosis (MESA). The MESA collected in 2000 includes 5,773 participants, aged 45-84. We computed standard regression techniques to examine the relationship between life stress and atherosclerosis as well as path analysis with hypothesized paths from stress to atherosclerosis through unhealthy lifestyle. Our outcome was sub-clinical atherosclerosis measured as presence of coronary artery calcification (CAC). A logistic regression adjusted for potential confounding variables along with the unhealthy lifestyle characteristics of smoking, excessive alcohol use, high caloric intake, sedentary lifestyle, and obesity yielded no significant relationship between chronic life stress (OR 0.93, 95% CI 0.80-1.08) and CAC. However, significant indirect pathways between chronic life stress and CAC through smoking (p = .007), and sedentary lifestyle (p = .03) and caloric intake (.002) through obesity were found. These results suggest that life stress is related to atherosclerosis once paths of unhealthy coping behaviors are considered.

  8. Pathways of Association from Stress to Obesity in Early Childhood.

    Science.gov (United States)

    Miller, Alison L; Lumeng, Julie C

    2018-04-14

    The objective of this study is to critically review the literature on early life stress in relation to obesity in humans, including the multiple biological and behavioral mechanisms through which early life stress exposure (birth to the age of 5 years) may associate with obesity risk during childhood. A review of the literature was conducted to identify studies on associations between early childhood stress and risk for obesity and the mechanisms of association. Multiple databases (PubMed, PsycInfo, Google Scholar) were used in the search as well as a "snowball" search strategy. All study designs were included. Early life stress and adverse childhood experiences are associated with obesity and overweight in adults. Evidence is less consistent in children. Studies vary in the nature of the stress examined (e.g., chronic vs. acute), sample characteristics, and study designs. Longitudinal studies are needed, as the effects of early life stress exposure may not emerge until later in the life-span. Early life stress exposure is associated with biological and behavioral pathways that may increase risk for childhood obesity. There is evidence that early life stress is associated with multiple biological and behavioral pathways in children that may increase risk for later obesity. Little work has detailed the interconnections among these mechanisms across development or identified potential moderators of the association. Mapping the mechanisms connecting early life stress exposure to obesity risk in young children longitudinally should be a priority for obesity researchers. Recommendations for developmentally sensitive approaches to research that can inform obesity prevention strategies are presented. © 2018 The Obesity Society.

  9. S-Nitrosation destabilizes glutathione transferase P1-1.

    Science.gov (United States)

    Balchin, David; Stoychev, Stoyan H; Dirr, Heini W

    2013-12-23

    Protein S-nitrosation is a post-translational modification that regulates the function of more than 500 human proteins. Despite its apparent physiological significance, S-nitrosation is poorly understood at a molecular level. Here, we investigated the effect of S-nitrosation on the activity, structure, stability, and dynamics of human glutathione transferase P1-1 (GSTP1-1), an important detoxification enzyme ubiquitous in aerobes. S-Nitrosation at Cys47 and Cys101 reduces the activity of the enzyme by 94%. Circular dichroism spectroscopy, acrylamide quenching, and amide hydrogen-deuterium exchange mass spectrometry experiments indicate that the loss of activity is caused by the introduction of local disorder at the active site of GSTP1-1. Furthermore, the modification destabilizes domain 1 of GSTP1-1 against denaturation, smoothing the unfolding energy landscape of the protein and introducing a refolding defect. In contrast, S-nitrosation at Cys101 alone introduces a refolding defect in domain 1 but compensates by stabilizing the domain kinetically. These data elucidate the physical basis for the regulation of GSTP1-1 by S-nitrosation and provide general insight into the consequences of S-nitrosation on protein stability and dynamics.

  10. The Influence of Phosphate Buffer on the Formation of N-Nitrosodimethylamine from Dimethylamine Nitrosation

    Directory of Open Access Journals (Sweden)

    Long Xu

    2013-01-01

    Full Text Available Buffer solutions were widely used for almost all the investigations concerning N-nitrosodimethylamine (NDMA, a member of powerful mutagenic and carcinogenic compounds which are ubiquitous in the environment. However, whether or how the buffer matrixes influence NDMA formation is still unknown. The effect of buffer solutions on NDMA formation from the nitrosation of dimethylamine (DMA by nitrite (NaNO2 was investigated at pH 6.4 in four kinds of buffer solutions, that is, Na2HPO4/C6H8O7, Na3(C6H5O7/C6H8O7, NaH2PO4/NaOH, and NaH2PO4/Na2HPO4. Our observations demonstrate an unexpected inhibitory effect of the buffer solutions on NDMA formation and the phosphate buffer plays a more significant role in inhibiting NDMA formation compared to the citrate buffer. Moreover, the amount of the phosphate in the buffer was also found to greatly impact the formation of NDMA. A further investigation indicates that it is the interaction between NaH2PO4 and reactant NaNO2 rather than DMA that leads to the inhibitory effect of phosphate buffer during the DMA nitrosation reaction. This study expands the understanding of the influence of buffer solution on nitrosamines formation through the nitrosation pathway and further gives a hint for water plants to reduce the formation of nitrosamines.

  11. Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

    OpenAIRE

    Maes, Michael; Kubera, Marta; Uytterhoeven, Marc; Vrydags, Nicolas; Bosmans, Eugene

    2011-01-01

    Summary Background There is evidence that myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by activation of immune, inflammatory, oxidative and nitrosative stress (IO&NS) pathways. The present study was carried out in order to examine whether ME/CFS is accompanied by increased levels of plasma peroxides and serum oxidized LDL (oxLDL) antibodies, two biomarkers of oxidative stress. Material/Methods Blood was collected from 56 patients with ME/CFS and 37 normal volun...

  12. Eating behaviour and stress: a pathway to obesity

    Directory of Open Access Journals (Sweden)

    Sarah J Spencer

    2014-05-01

    Full Text Available Stress causes or contributes to a huge variety of diseases and disorders. Recent evidence suggests obesity and other eating-related disorders may be among these. Immediately after a stressful event is experienced, there is a corticotropin-releasing-hormone (CRH-mediated suppression of food intake. This diverts the body’s resources away from the less pressing need to find and consume food, prioritizing fight, flight, or withdrawal behaviours so the stressful event can be dealt with. In the hours following this, however, there is a glucocorticoid-mediated stimulation of hunger and eating behaviour. In the case of an acute stress that requires a physical response, such as a predator-prey interaction, this hypothalamic-pituitary-adrenal (HPA axis modulation of food intake allows the stressful event to be dealt with and the energy used to be replaced afterwards. In the case of ongoing psychological stress, however, chronically elevated glucocorticoids can lead to chronically stimulated eating behaviour and excessive weight gain. In particular, stress can enhance the propensity to eat high calorie palatable food via its interaction with central reward pathways. Activation of this circuitry can also interact with the HPA axis to suppress its further activation, meaning not only can stress encourage eating behaviour, but eating can suppress the HPA axis and the feeling of stress. In this review we will explore the theme of eating behaviour and stress and how these can modulate one another. We will address the interactions between the HPA axis and eating, introducing a potential integrative role for the orexigenic hormone, ghrelin. We will also examine early life and epigenetic modulation of the HPA axis and how this can influence eating behaviour. Finally, we will investigate the clinical implications of changes to HPA axis function and how this may be contributing to obesity in our society.

  13. The chromatin remodeler SPLAYED regulates specific stress signaling pathways.

    Directory of Open Access Journals (Sweden)

    Justin W Walley

    2008-12-01

    Full Text Available Organisms are continuously exposed to a myriad of environmental stresses. Central to an organism's survival is the ability to mount a robust transcriptional response to the imposed stress. An emerging mechanism of transcriptional control involves dynamic changes in chromatin structure. Alterations in chromatin structure are brought about by a number of different mechanisms, including chromatin modifications, which covalently modify histone proteins; incorporation of histone variants; and chromatin remodeling, which utilizes ATP hydrolysis to alter histone-DNA contacts. While considerable insight into the mechanisms of chromatin remodeling has been gained, the biological role of chromatin remodeling complexes beyond their function as regulators of cellular differentiation and development has remained poorly understood. Here, we provide genetic, biochemical, and biological evidence for the critical role of chromatin remodeling in mediating plant defense against specific biotic stresses. We found that the Arabidopsis SWI/SNF class chromatin remodeling ATPase SPLAYED (SYD is required for the expression of selected genes downstream of the jasmonate (JA and ethylene (ET signaling pathways. SYD is also directly recruited to the promoters of several of these genes. Furthermore, we show that SYD is required for resistance against the necrotrophic pathogen Botrytis cinerea but not the biotrophic pathogen Pseudomonas syringae. These findings demonstrate not only that chromatin remodeling is required for selective pathogen resistance, but also that chromatin remodelers such as SYD can regulate specific pathways within biotic stress signaling networks.

  14. Yeast signaling pathways in the oxidative stress response

    Energy Technology Data Exchange (ETDEWEB)

    Ikner, Aminah [Section of Microbiology, Division of Biological Sciences, University of California, Davis, CA 95616 (United States); Shiozaki, Kazuhiro [Section of Microbiology, Division of Biological Sciences, University of California, Davis, CA 95616 (United States)]. E-mail: kshiozaki@ucdavis.edu

    2005-01-06

    Oxidative stress that generates the reactive oxygen species (ROS) is one of the major causes of DNA damage and mutations. The 'DNA damage checkpoint' that arrests cell cycle and repairs damaged DNA has been a focus of recent studies, and the genetically amenable model systems provided by yeasts have been playing a leading role in the eukaryotic checkpoint research. However, means to eliminate ROS are likely to be as important as the DNA repair mechanisms in order to suppress mutations in the chromosomal DNA, and yeasts also serve as excellent models to understand how eukaryotes combat oxidative stress. In this article, we present an overview of the signaling pathways that sense oxidative stress and induce expression of various anti-oxidant genes in the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe and the pathogenic yeast Candida albicans. Three conserved signaling modules have been identified in the oxidative stress response of these diverse yeast species: the stress-responsive MAP kinase cascade, the multistep phosphorelay and the AP-1-like transcription factor. The structure and function of these signaling modules are discussed.

  15. Yeast signaling pathways in the oxidative stress response

    International Nuclear Information System (INIS)

    Ikner, Aminah; Shiozaki, Kazuhiro

    2005-01-01

    Oxidative stress that generates the reactive oxygen species (ROS) is one of the major causes of DNA damage and mutations. The 'DNA damage checkpoint' that arrests cell cycle and repairs damaged DNA has been a focus of recent studies, and the genetically amenable model systems provided by yeasts have been playing a leading role in the eukaryotic checkpoint research. However, means to eliminate ROS are likely to be as important as the DNA repair mechanisms in order to suppress mutations in the chromosomal DNA, and yeasts also serve as excellent models to understand how eukaryotes combat oxidative stress. In this article, we present an overview of the signaling pathways that sense oxidative stress and induce expression of various anti-oxidant genes in the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe and the pathogenic yeast Candida albicans. Three conserved signaling modules have been identified in the oxidative stress response of these diverse yeast species: the stress-responsive MAP kinase cascade, the multistep phosphorelay and the AP-1-like transcription factor. The structure and function of these signaling modules are discussed

  16. Nitrosation of amides involves a pseudopericyclic 1,3-sigmatropic rearrangement.

    Science.gov (United States)

    Birney, David M

    2004-03-04

    Two possible pathways for the nitrosation of formamide and N-methyl formamide by nitrosonium ion (NO(+)) have been investigated at the B3LYP/6-31G(d,p) level. The key steps are pseudopericyclic 1,3-sigmatropic rearrangements to give the observed N-nitrosamides. The transition structures (8a and 8b) are close to planar on the amide moiety and have remarkably low barriers of only 6.6 and 4.8 kcal/mol from the lowest energy conformations of 6a and 6b, respectively. [reaction: see text

  17. Prodigiosin inhibits gp91phox and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia–ischemia

    International Nuclear Information System (INIS)

    Chang, Chia-Che; Wang, Yea-Hwey; Chern, Chang-Ming; Liou, Kuo-Tong; Hou, Yu-Chang; Peng, Yu-Ta; Shen, Yuh-Chiang

    2011-01-01

    This study aimed to explore the mechanisms by which prodigiosin protects against hypoxia-induced oxidative/nitrosative brain injury induced by middle cerebral artery occlusion/reperfusion (MCAo/r) injury in mice. Hypoxia in vitro was modeled using oxygen–glucose deprivation (OGD) followed by reoxygenation of BV-2 microglial cells. Our results showed that treatment of mice that have undergone MCAo/r injury with prodigiosin (10 and 100 μg/kg, i.v.) at 1 h after hypoxia ameliorated MCAo/r-induced oxidative/nitrosative stress, brain infarction, and neurological deficits in the mice, and enhanced their survival rate. MCAo/r induced a remarkable production in the mouse brains of reactive oxygen species (ROS) and a significant increase in protein nitrosylation; this primarily resulted from enhanced expression of NADPH oxidase 2 (gp91 phox ), inducible nitric oxide synthase (iNOS), and the infiltration of CD11b leukocytes due to breakdown of blood–brain barrier (BBB) by activation of nuclear factor-kappa B (NF-κB). All these changes were significantly diminished by prodigiosin. In BV-2 cells, OGD induced ROS and nitric oxide production by up-regulating gp91 phox and iNOS via activation of the NF-κB pathway, and these changes were suppressed by prodigiosin. In conclusion, our results indicate that prodigiosin reduces gp91 phox and iNOS expression possibly by impairing NF-κB activation. This compromises the activation of microglial and/or inflammatory cells, which then, in turn, mediates prodigiosin's protective effect in the MCAo/r mice. -- Highlights: ► Prodigiosin ameliorated brain infarction and deficits. ► Prodigiosin protected against hypoxia/reperfusion-induced brain injury. ► Prodigiosin diminished oxidative/nitrosativestress and leukocytes infiltration. ► Prodigiosin reduced BBB breakdown. ► Prodigiosin down-regulated gp91 phox and iNOS by inhibiting NF-κB activation.

  18. Chronic unpredictable stress deteriorates the chemopreventive efficacy of pomegranate through oxidative stress pathway.

    Science.gov (United States)

    Hasan, Shirin; Suhail, Nida; Bilal, Nayeem; Ashraf, Ghulam Md; Zaidi, Syed Kashif; AlNohair, Sultan; Banu, Naheed

    2016-05-01

    Chronic unpredictable stress (CUS) can influence the risk and progression of cancer through increased oxidative stress. Pomegranate is known to protect carcinogenesis through its anti-oxidative properties. This study is carried out to examine whether CUS affects the chemopreventive potential of pomegranate through oxidative stress pathway. Role of CUS on early stages of 7, 12 dimethyl benz(a) anthracene (DMBA) induced carcinogenesis, and its pre-exposure effect on chemopreventive efficacy of pomegranate juice (PJ) was examined in terms of in vivo antioxidant and biochemical parameters in Swiss albino rats. Rats were divided in various groups and were subjected to CUS paradigm, DMBA administration (65 mg/kg body weight, single dose), and PJ treatment. Exposure to stress (alone) and DMBA (alone) led to increased oxidative stress by significantly decreasing the antioxidant enzymes activities and altering the glutathione (GSH), malondialdehyde (MDA), glutamate oxaloacetate transaminase (GOT), and glutamate pyruvate transaminase (GPT) levels. A significant increase in DNA damage demonstrated by comet assay was seen in the liver cells. Stress exposure to DMBA-treated rats further increased the oxidative stress and disturbed the biochemical parameters as compared to DMBA (alone)-treated rats. Chemoprevention with PJ in DMBA (alone)-treated rats restored the altered parameters. However, in the pre-stress DMBA-treated rats, the overall antioxidant potential of PJ was significantly diminished. Our results indicate that chronic stress not only increases the severity of carcinogenesis but also diminishes the anti-oxidative efficacy of PJ. In a broader perspective, special emphasis should be given to stress management and healthy diet during cancer chemoprevention.

  19. Human Cytomegalovirus: Coordinating Cellular Stress, Signaling, and Metabolic Pathways.

    Science.gov (United States)

    Shenk, Thomas; Alwine, James C

    2014-11-01

    Viruses face a multitude of challenges when they infect a host cell. Cells have evolved innate defenses to protect against pathogens, and an infecting virus may induce a stress response that antagonizes viral replication. Further, the metabolic, oxidative, and cell cycle state may not be conducive to the viral infection. But viruses are fabulous manipulators, inducing host cells to use their own characteristic mechanisms and pathways to provide what the virus needs. This article centers on the manipulation of host cell metabolism by human cytomegalovirus (HCMV). We review the features of the metabolic program instituted by the virus, discuss the mechanisms underlying these dramatic metabolic changes, and consider how the altered program creates a synthetic milieu that favors efficient HCMV replication and spread.

  20. Zearalenone altered the cytoskeletal structure via ER stress- autophagy- oxidative stress pathway in mouse TM4 Sertoli cells.

    Science.gov (United States)

    Zheng, Wanglong; Wang, Bingjie; Si, Mengxue; Zou, Hui; Song, Ruilong; Gu, Jianhong; Yuan, Yan; Liu, Xuezhong; Zhu, Guoqiang; Bai, Jianfa; Bian, Jianchun; Liu, ZongPing

    2018-02-20

    The aim of this study was to investigate the molecular mechanisms of the destruction of cytoskeletal structure by Zearalenone (ZEA) in mouse-derived TM4 cells. In order to investigate the role of autophagy, oxidative stress and endoplasmic reticulum(ER) stress in the process of destruction of cytoskeletal structure, the effects of ZEA on the cell viability, cytoskeletal structure, autophagy, oxidative stress, ER stress, MAPK and PI3K- AKT- mTOR signaling pathways were studied. The data demonstrated that ZEA damaged the cytoskeletal structure through the induction of autophagy that leads to the alteration of cytoskeletal structure via elevated oxidative stress. Our results further showed that the autophagy was stimulated by ZEA through PI3K-AKT-mTOR and MAPK signaling pathways in TM4 cells. In addition, ZEA also induced the ER stress which was involved in the induction of the autophagy through inhibiting the ERK signal pathway to suppress the phosphorylation of mTOR. ER stress was involved in the damage of cytoskeletal structure through induction of autophagy by producing ROS. Taken together, this study revealed that ZEA altered the cytoskeletal structure via oxidative stress - autophagy- ER stress pathway in mouse TM4 Sertoli cells.

  1. Expression profiling on soybean leaves reveals integration of ER- and osmotic-stress pathways

    Directory of Open Access Journals (Sweden)

    Dewey Ralph E

    2007-11-01

    Full Text Available Abstract Background Despite the potential of the endoplasmic reticulum (ER stress response to accommodate adaptive pathways, its integration with other environmental-induced responses is poorly understood in plants. We have previously demonstrated that the ER-stress sensor binding protein (BiP from soybean exhibits an unusual response to drought. The members of the soybean BiP gene family are differentially regulated by osmotic stress and soybean BiP confers tolerance to drought. While these results may reflect crosstalk between the osmotic and ER-stress signaling pathways, the lack of mutants, transcriptional response profiles to stresses and genome sequence information of this relevant crop has limited our attempts to identify integrated networks between osmotic and ER stress-induced adaptive responses. As a fundamental step towards this goal, we performed global expression profiling on soybean leaves exposed to polyethylene glycol treatment (osmotic stress or to ER stress inducers. Results The up-regulated stress-specific changes unmasked the major branches of the ER-stress response, which include enhancing protein folding and degradation in the ER, as well as specific osmotically regulated changes linked to cellular responses induced by dehydration. However, a small proportion (5.5% of total up-regulated genes represented a shared response that seemed to integrate the two signaling pathways. These co-regulated genes were considered downstream targets based on similar induction kinetics and a synergistic response to the combination of osmotic- and ER-stress-inducing treatments. Genes in this integrated pathway with the strongest synergistic induction encoded proteins with diverse roles, such as plant-specific development and cell death (DCD domain-containing proteins, an ubiquitin-associated (UBA protein homolog and NAC domain-containing proteins. This integrated pathway diverged further from characterized specific branches of ER-stress as

  2. Staphylococcal response to oxidative stress

    Directory of Open Access Journals (Sweden)

    Rosmarie eGaupp

    2012-03-01

    Full Text Available Staphylococci are a versatile genus of bacteria that are capable of causing acute and chronic infections in diverse host species. The success of staphylococci as pathogens is due in part to their ability to mitigate endogenous and exogenous oxidative and nitrosative stress. Endogenous oxidative stress is a consequence of life in an aerobic environment; whereas, exogenous oxidative and nitrosative stress are often due to the bacteria’s interaction with host immune systems. To overcome the deleterious effects of oxidative and nitrosative stress, staphylococci have evolved protection, detoxification, and repair mechanisms that are controlled by a network of regulators. In this review, we summarize the cellular targets of oxidative stress, the mechanisms by which staphylococci sense oxidative stress and damage, oxidative stress protection and repair mechanisms, and regulation of the oxidative stress response. When possible, special attention is given to how the oxidative stress defense mechanisms help staphylococci control oxidative stress in the host.

  3. Eating behaviour and stress: a pathway to obesity

    OpenAIRE

    Sarah J Spencer; Luba eSominsky

    2014-01-01

    Stress causes or contributes to a huge variety of diseases and disorders. Recent evidence suggests obesity and other eating-related disorders may be among these. Immediately after a stressful event is experienced, there is a corticotropin-releasing-hormone (CRH)-mediated suppression of food intake. This diverts the body’s resources away from the less pressing need to find and consume food, prioritizing fight, flight, or withdrawal behaviours so the stressful event can be dealt with. In the ho...

  4. Eating behavior and stress: a pathway to obesity

    OpenAIRE

    Sominsky, Luba; Spencer, Sarah J.

    2014-01-01

    Stress causes or contributes to a huge variety of diseases and disorders. Recent evidence suggests obesity and other eating-related disorders may be among these. Immediately after a stressful event is experienced, there is a corticotropin-releasing-hormone (CRH)-mediated suppression of food intake. This diverts the body’s resources away from the less pressing need to find and consume food, prioritizing fight, flight, or withdrawal behaviors so the stressful event can be dealt with. In the hou...

  5. Alteration in Oxidative/nitrosative imbalance, histochemical expression of osteopontin and antiurolithiatic efficacy of Xanthium strumarium (L.) in ethylene glycol induced urolithiasis.

    Science.gov (United States)

    Panigrahi, Padma Nibash; Dey, Sahadeb; Sahoo, Monalisa; Choudhary, Shyam Sundar; Mahajan, Sumit

    2016-12-01

    Xanthium strumarium has traditionally been used in the treatment of urolitiasis especially by the rural people in India, but its antiurolithiatic efficacy was not explored scientifically till now. Therefore, the present study was designed to validate the ethnic practice scientifically, and explore the possible antiurolithiatic effect to rationalize its medicinal use. Urolitiasis was induced in hyperoxaluric rat model by giving 0.75% ethylene glycol (EG) for 28days along with 1% ammonium chloride (AC) for first 14days. Antiurolithiatic effect of aqueous-ethanol extract of Xanthium strumarium bur (xanthium) was evaluated based on urine and serum biochemistry, oxidative/nitrosative stress indices, histopathology, kidney calcium and calcium oxalate content and immunohistochemical expression of matrix glycoprotein, osteopontin (OPN). Administration of EG and AC resulted in hyperoxaluria, crystalluria, hypocalciuria, polyurea, raised serum urea, creatinine, erythrocytic lipid peroxidise and nitric oxide, kidney calcium content as well as crystal deposition in kidney section in lithiatic group rats. However, xanthium treatment significantly restored the impairment in above kidney function test as that of standard treatment, cystone. The up-regulation of OPN was also significantly decreased after xanthium treatment. The present findings demonstrate the curative efficacy of xanthium in ethylene glycol induced urolithiasis, possibly mediated through inhibition of various pathways involved in renal calcium oxalate formation, antioxidant property and down regulation of matrix glycoprotein, OPN. Therefore, future studies may be established to evaluate its efficacy and safety for clinical use. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  6. Heat-shock stress activates a novel nuclear import pathway mediated by Hikeshi

    OpenAIRE

    Imamoto, Naoko; Kose, Shingo

    2012-01-01

    Cellular stresses significantly affect nuclear transport systems. Nuclear transport pathways mediated by importin β-family members, which are active under normal conditions, are downregulated. During thermal stress, a nuclear import pathway mediated by a novel carrier, which we named Hikeshi, becomes active. Hikeshi is not a member of the importin β family and mediates the nuclear import of Hsp70s. Unlike importin β family-mediated nuclear transport, the Hikeshi-mediated nuclear import of Hsp...

  7. Activation of the Saccharomyces cerevisiae filamentation/invasion pathway by osmotic stress in high-osmolarity glycogen pathway mutants

    Science.gov (United States)

    Davenport, K. D.; Williams, K. E.; Ullmann, B. D.; Gustin, M. C.; McIntire, L. V. (Principal Investigator)

    1999-01-01

    Mitogen-activated protein kinase (MAPK) cascades are frequently used signal transduction mechanisms in eukaryotes. Of the five MAPK cascades in Saccharomyces cerevisiae, the high-osmolarity glycerol response (HOG) pathway functions to sense and respond to hypertonic stress. We utilized a partial loss-of-function mutant in the HOG pathway, pbs2-3, in a high-copy suppressor screen to identify proteins that modulate growth on high-osmolarity media. Three high-copy suppressors of pbs2-3 osmosensitivity were identified: MSG5, CAK1, and TRX1. Msg5p is a dual-specificity phosphatase that was previously demonstrated to dephosphorylate MAPKs in yeast. Deletions of the putative MAPK targets of Msg5p revealed that kss1delta could suppress the osmosensitivity of pbs2-3. Kss1p is phosphorylated in response to hyperosmotic shock in a pbs2-3 strain, but not in a wild-type strain nor in a pbs2-3 strain overexpressing MSG5. Both TEC1 and FRE::lacZ expressions are activated in strains lacking a functional HOG pathway during osmotic stress in a filamentation/invasion-pathway-dependent manner. Additionally, the cellular projections formed by a pbs2-3 mutant on high osmolarity are absent in strains lacking KSS1 or STE7. These data suggest that the loss of filamentation/invasion pathway repression contributes to the HOG mutant phenotype.

  8. Prodigiosin inhibits gp91{sup phox} and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia-ischemia

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Chia-Che [Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (China); Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan (China); Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan (China); Wang, Yea-Hwey [Department of Nursing, College of Medicine and Nursing, Hungkuang University, Taichung, Taiwan (China); Chern, Chang-Ming [Division of Neurovascular Disease, Neurological Institute, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Liou, Kuo-Tong [Department of Chinese Martial Arts, Chinese Culture University, Taipei, Taiwan (China); Hou, Yu-Chang [Department of Chinese Medicine, Taoyuan General Hospital, Department of Health, Taiwan (China); Department of Nursing, Yuanpei University, Hsinchu, Taiwan (China); Department of Bioscience Technology, Chuan-Yuan Christian University, Taoyuan, Taiwan (China); Peng, Yu-Ta [Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China); Shen, Yuh-Chiang, E-mail: yuhcs@nricm.edu.tw [National Research Institute of Chinese Medicine, Taipei, Taiwan (China); Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China)

    2011-11-15

    This study aimed to explore the mechanisms by which prodigiosin protects against hypoxia-induced oxidative/nitrosative brain injury induced by middle cerebral artery occlusion/reperfusion (MCAo/r) injury in mice. Hypoxia in vitro was modeled using oxygen-glucose deprivation (OGD) followed by reoxygenation of BV-2 microglial cells. Our results showed that treatment of mice that have undergone MCAo/r injury with prodigiosin (10 and 100 {mu}g/kg, i.v.) at 1 h after hypoxia ameliorated MCAo/r-induced oxidative/nitrosative stress, brain infarction, and neurological deficits in the mice, and enhanced their survival rate. MCAo/r induced a remarkable production in the mouse brains of reactive oxygen species (ROS) and a significant increase in protein nitrosylation; this primarily resulted from enhanced expression of NADPH oxidase 2 (gp91{sup phox}), inducible nitric oxide synthase (iNOS), and the infiltration of CD11b leukocytes due to breakdown of blood-brain barrier (BBB) by activation of nuclear factor-kappa B (NF-{kappa}B). All these changes were significantly diminished by prodigiosin. In BV-2 cells, OGD induced ROS and nitric oxide production by up-regulating gp91{sup phox} and iNOS via activation of the NF-{kappa}B pathway, and these changes were suppressed by prodigiosin. In conclusion, our results indicate that prodigiosin reduces gp91{sup phox} and iNOS expression possibly by impairing NF-{kappa}B activation. This compromises the activation of microglial and/or inflammatory cells, which then, in turn, mediates prodigiosin's protective effect in the MCAo/r mice. -- Highlights: Black-Right-Pointing-Pointer Prodigiosin ameliorated brain infarction and deficits. Black-Right-Pointing-Pointer Prodigiosin protected against hypoxia/reperfusion-induced brain injury. Black-Right-Pointing-Pointer Prodigiosin diminished oxidative/nitrosativestress and leukocytes infiltration. Black-Right-Pointing-Pointer Prodigiosin reduced BBB breakdown. Black

  9. From Oxidative Stress Damage to Pathways, Networks, and Autophagy via MicroRNAs

    Directory of Open Access Journals (Sweden)

    Nikolai Engedal

    2018-01-01

    Full Text Available Oxidative stress can alter the expression level of many microRNAs (miRNAs, but how these changes are integrated and related to oxidative stress responses is poorly understood. In this article, we addressed this question by using in silico tools. We reviewed the literature for miRNAs whose expression is altered upon oxidative stress damage and used them in combination with various databases and software to predict common gene targets of oxidative stress-modulated miRNAs and affected pathways. Furthermore, we identified miRNAs that simultaneously target the predicted oxidative stress-modulated miRNA gene targets. This generated a list of novel candidate miRNAs potentially involved in oxidative stress responses. By literature search and grouping of pathways and cellular responses, we could classify these candidate miRNAs and their targets into a larger scheme related to oxidative stress responses. To further exemplify the potential of our approach in free radical research, we used our explorative tools in combination with ingenuity pathway analysis to successfully identify new candidate miRNAs involved in the ubiquitination process, a master regulator of cellular responses to oxidative stress and proteostasis. Lastly, we demonstrate that our approach may also be useful to identify novel candidate connections between oxidative stress-related miRNAs and autophagy. In summary, our results indicate novel and important aspects with regard to the integrated biological roles of oxidative stress-modulated miRNAs and demonstrate how this type of in silico approach can be useful as a starting point to generate hypotheses and guide further research on the interrelation between miRNA-based gene regulation, oxidative stress signaling pathways, and autophagy.

  10. Hydroxychavicol: a new anti-nitrosating phenolic compound from betel leaf.

    Science.gov (United States)

    Nagabhushan, M; Amonkar, A J; Nair, U J; D'Souza, A V; Bhide, S V

    1989-05-01

    Hydroxychavicol and eugenol are the phenolic compounds isolated from betel leaf (piper betel). The modulation of nitrosation of methylurea by sodium nitrite at pH 3.6 and 30 degrees C was studied. The formation of mutagenic N-nitrosomethylurea was monitored by checking the mutagenicity of reaction mixture in Salmonella typhimurium strain TA100 and TA1535 without S9 mix. Hydroxychavicol and eugenol exhibit dose-dependent suppression of nitrosation in vitro without affecting the survival of the bacteria. Pre- or post-treatment of bacterial cells from S. typhimurium strains TA100 and TA1535 with phenolics did not modify the mutagenicity of nitrosomethylurea. The blocking of hydroxy group(s) in the benzene ring by acetylation abolishes the anti-nitrosating activity of the molecule(s). The nitrosation inhibition by hydroxychavicol is through scavenging of nitrite ions in the media, thus making them non-available for the nitrosation of methylurea.

  11. Stress and DNA repair biology of the Fanconi anemia pathway

    Science.gov (United States)

    Longerich, Simonne; Li, Jian; Xiong, Yong; Sung, Patrick

    2014-01-01

    Fanconi anemia (FA) represents a paradigm of rare genetic diseases, where the quest for cause and cure has led to seminal discoveries in cancer biology. Although a total of 16 FA genes have been identified thus far, the biochemical function of many of the FA proteins remains to be elucidated. FA is rare, yet the fact that 5 FA genes are in fact familial breast cancer genes and FA gene mutations are found frequently in sporadic cancers suggest wider applicability in hematopoiesis and oncology. Establishing the interaction network involving the FA proteins and their associated partners has revealed an intersection of FA with several DNA repair pathways, including homologous recombination, DNA mismatch repair, nucleotide excision repair, and translesion DNA synthesis. Importantly, recent studies have shown a major involvement of the FA pathway in the tolerance of reactive aldehydes. Moreover, despite improved outcomes in stem cell transplantation in the treatment of FA, many challenges remain in patient care. PMID:25237197

  12. Identification and quantification of protein S-nitrosation by nitrite in the mouse heart during ischemia.

    Science.gov (United States)

    Chouchani, Edward T; James, Andrew M; Methner, Carmen; Pell, Victoria R; Prime, Tracy A; Erickson, Brian K; Forkink, Marleen; Lau, Gigi Y; Bright, Thomas P; Menger, Katja E; Fearnley, Ian M; Krieg, Thomas; Murphy, Michael P

    2017-09-01

    Nitrate (NO 3 - ) and nitrite (NO 2 - ) are known to be cardioprotective and to alter energy metabolism in vivo NO 3 - action results from its conversion to NO 2 - by salivary bacteria, but the mechanism(s) by which NO 2 - affects metabolism remains obscure. NO 2 - may act by S -nitrosating protein thiols, thereby altering protein activity. But how this occurs, and the functional importance of S -nitrosation sites across the mammalian proteome, remain largely uncharacterized. Here we analyzed protein thiols within mouse hearts in vivo using quantitative proteomics to determine S -nitrosation site occupancy. We extended the thiol-redox proteomic technique, isotope-coded affinity tag labeling, to quantify the extent of NO 2 - -dependent S -nitrosation of proteins thiols in vivo Using this approach, called SNOxICAT ( S -nitrosothiol redox isotope-coded affinity tag), we found that exposure to NO 2 - under normoxic conditions or exposure to ischemia alone results in minimal S -nitrosation of protein thiols. However, exposure to NO 2 - in conjunction with ischemia led to extensive S -nitrosation of protein thiols across all cellular compartments. Several mitochondrial protein thiols exposed to the mitochondrial matrix were selectively S -nitrosated under these conditions, potentially contributing to the beneficial effects of NO 2 - on mitochondrial metabolism. The permeability of the mitochondrial inner membrane to HNO 2 , but not to NO 2 - , combined with the lack of S -nitrosation during anoxia alone or by NO 2 - during normoxia places constraints on how S -nitrosation occurs in vivo and on its mechanisms of cardioprotection and modulation of energy metabolism. Quantifying S -nitrosated protein thiols now allows determination of modified cysteines across the proteome and identification of those most likely responsible for the functional consequences of NO 2 - exposure. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Effect of psychological stress on the L-arginine-nitric oxide pathway and semen quality

    Directory of Open Access Journals (Sweden)

    S. Eskiocak

    2006-05-01

    Full Text Available It has been reported that mental stress causes abnormality of spermiogram parameters. We investigated the effect of psychological stress on the L-arginine-nitric oxide (NO pathway. Semen samples were collected from 29 healthy fourth semester medical students just before (stress and 3 months after (non-stress the final examinations. Psychological stress was measured by the State Anxiety Inventory questionnaire. After standard semen analysis, arginase activity and NO concentration were measured spectrophotometrically in the seminal plasma. Measurements were made in duplicate. During the stress period, sperm concentration (41.28 ± 3.70 vs 77.62 ± 7.13 x 10(6/mL, rapid progressive motility of spermatozoa (8.79 ± 1.66 vs 20.86 ± 1.63% and seminal plasma arginase activity (0.12 ± 0.01 vs 0.22 ± 0.01 U/mL were significantly lower than in the non-stress situation, whereas seminal plasma NO (17.28 ± 0.56 vs 10.02 ± 0.49 µmol/L was higher compared to the non-stress period (P < 0.001 for all. During stress there was a negative correlation between NO concentration and sperm concentration, the percentage of rapid progressive motility and arginase activity (r = -0.622, P < 0.01; r = -0.425, P < 0.05 and r = -0.445, P < 0.05, respectively. These results indicate that psychological stress causes an increase of NO level and a decrease of arginase activity in the L-arginine-NO pathway. Furthermore, poor sperm quality may be due to excessive production of NO under psychological stress. In the light of these results, we suggest that the arginine-NO pathway, together with arginase and NO synthase, are involved in semen quality under stress conditions.

  14. Glial and tissue-specific regulation of Kynurenine Pathway dioxygenases by acute stress of mice

    Directory of Open Access Journals (Sweden)

    Carlos R. Dostal

    2017-12-01

    Full Text Available Stressors activate the hypothalamic-pituitary-adrenal (HPA axis and immune system eliciting changes in cognitive function, mood and anxiety. An important link between stress and altered behavior is stimulation of the Kynurenine Pathway which generates neuroactive and immunomodulatory kynurenines. Tryptophan entry into this pathway is controlled by rate-limiting indoleamine/tryptophan 2,3-dioxygenases (DOs: Ido1, Ido2, Tdo2. Although implicated as mediating changes in behavior, detecting stress-induced DO expression has proven inconsistent. Thus, C57BL/6J mice were used to characterize DO expression in brain-regions, astrocytes and microglia to characterize restraint-stress-induced DO expression. Stress increased kynurenine in brain and plasma, demonstrating increased DO activity. Of three Ido1 transcripts, only Ido1-v1 expression was increased by stress and within astrocytes, not microglia, indicating transcript- and glial-specificity. Stress increased Ido1-v1 only in frontal cortex and hypothalamus, indicating brain-region specificity. Of eight Ido2 transcripts, Ido2-v3 expression was increased by stress, again only within astrocytes. Likewise, stress increased Tdo2-FL expression in astrocytes, not microglia. Interestingly, Ido2 and Tdo2 transcripts were not correspondingly induced in Ido1-knockout (Ido1KO mice, suggesting that Ido1 is necessary for the central DO response to acute stress. Unlike acute inflammatory models resulting in DO induction within microglia, only astrocyte DO expression was increased by acute restraint-stress, defining their unique role during stress-dependent activation of the Kynurenine Pathway. Keywords: Stress, Ido, Tdo, Kynurenine, Astrocyte, Liver

  15. Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions.

    Science.gov (United States)

    Deegan, Shane; Saveljeva, Svetlana; Logue, Susan E; Pakos-Zebrucka, Karolina; Gupta, Sanjeev; Vandenabeele, Peter; Bertrand, Mathieu J M; Samali, Afshin

    2014-01-01

    Endoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytochrome c, somatic) release, apoptosome formation, and caspase activation, resulting in cell death. In this study, we demonstrate that under conditions of ER stress cells devoid of CASP9/caspase-9 or BAX and BAK1, and therefore defective in the mitochondrial apoptotic pathway, still undergo a delayed form of cell death associated with the activation of caspases, therefore revealing the existence of an alternative stress-induced caspase activation pathway. We identified CASP8/caspase-8 as the apical protease in this caspase cascade, and found that knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel ER stress-induced death pathway. In line with this, we identified a protein complex composed of ATG5, FADD, and pro-CASP8 whose assembly coincides with caspase activation and cell death induction. Together, our results reveal the toxic potential of autophagy in cells undergoing ER stress that are defective in the mitochondrial apoptotic pathway, and suggest a model in which the autophagosome functions as a platform facilitating pro-CASP8 activation. Chemoresistance, a common problem in the treatment of cancer, is frequently caused by the downregulation of key mitochondrial death effector proteins. Alternate stress-induced apoptotic pathways, such as the one described here, may become of particular relevance for tackling the problem of chemoresistance in cancer cells.

  16. Molecular stress response pathways as the basis of hormesis

    DEFF Research Database (Denmark)

    Demirovic, Dino; de Toda, Irene Martinez; Rattan, Suresh

    2014-01-01

    There is now a large amount of data available for human beings showing positive hormetic effects of mild stresses from physical, chemical, nutritional and mental sources. However, these data are dispersed in the literature and not always interpreted as hormetic effects, thus restricting their full...... apprehension and application. A comprehensive discussion of the research, this book is composed of four sections: (1) History and terminology; (2) Evidence for hormesis in humans; (3) Molecular mechanisms of hormesis; and (4) Ethical and legal aspects, and risk assessment....

  17. Endoplasmic reticulum (ER) stress and cAMP/PKA pathway mediated Zn-induced hepatic lipolysis.

    Science.gov (United States)

    Song, Yu-Feng; Hogstrand, Christer; Wei, Chuan-Chuan; Wu, Kun; Pan, Ya-Xiong; Luo, Zhi

    2017-09-01

    The present study was performed to determine the effect of Zn exposure influencing endoplasmic reticulum (ER) stress, explore the underlying molecular mechanism of Zn-induced hepatic lipolysis in a fish species of significance for aquaculture, yellow catfish Pelteobagrus fulvidraco. We found that waterborne Zn exposure evoked ER stress and unfolded protein response (UPR), and activated cAMP/PKA pathway, and up-regulated hepatic lipolysis. The increase in ER stress and lipolysis were associated with activation of cAMP/PKA signaling pathway. Zn also induced an increase in intracellular Ca 2+ level, which could be partially prevented by dantrolene (RyR receptor inhibitor) and 2-APB (IP3 receptor inhibitor), demonstrating that the disturbed Ca 2+ homeostasis in ER contributed to ER stress and dysregulation of lipolysis. Inhibition of ER stress by PBA attenuated UPR, inhibited the activation of cAMP/PKA pathway and resulted in down-regulation of lipolysis. Inhibition of protein kinase RNA-activated-like ER kinase (PERK) by GSK2656157 and inositol-requiring enzyme (IRE) by STF-083010 differentially influenced Zn-induced changes of lipid metabolism, indicating that PERK and IRE pathways played different regulatory roles in Zn-induced lipolysis. Inhibition of PKA by H89 blocked the Zn-induced activation of cAMP/PKA pathway with a concomitant inhibition of ER stress-mediated lipolysis. Taken together, our findings highlight the importance of the ER stress-cAMP/PKA axis in Zn-induced lipolysis, which provides new insights into Zn toxicology in fish and probably in other vertebrates. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Regulatory cross-talks and cascades in rice hormone biosynthesis pathways contribute to stress signaling

    Directory of Open Access Journals (Sweden)

    Arindam Deb

    2016-08-01

    Full Text Available Crosstalk among different hormone signaling pathways play an important role in modulating plant response to both biotic and abiotic stress. Hormone activity is controlled by its bio-availability, which is again influenced by its biosynthesis. Thus independent hormone biosynthesis pathways must be regulated and co-ordinated to mount an integrated response. One of the possibilities is to use cis-regulatory elements to orchestrate expression of hormone biosynthesis genes. Analysis of CREs, associated with differentially expressed hormone biosynthesis related genes in rice leaf under Magnaporthe oryzae attack and drought stress enabled us to obtain insights about cross-talk among hormone biosynthesis pathways at the transcriptional level. We identified some master transcription regulators that co-ordinate different hormone biosynthesis pathways under stress. We found that Abscisic acid and Brassinosteroid regulate Cytokinin conjugation; conversely Brassinosteroid biosynthesis is affected by both Abscisic acid and Cytokinin. Jasmonic acid and Ethylene biosynthesis may be modulated by Abscisic acid through DREB transcription factors. Jasmonic acid or Salicylic acid biosynthesis pathways are co-regulated but they are unlikely to influence each other’s production directly. Thus multiple hormones may modulate hormone biosynthesis pathways through a complex regulatory network, where biosynthesis of one hormone is affected by several other contributing hormones.

  19. Nucleolus-derived mediators in oncogenic stress response and activation of p53-dependent pathways.

    Science.gov (United States)

    Stępiński, Dariusz

    2016-08-01

    Rapid growth and division of cells, including tumor ones, is correlated with intensive protein biosynthesis. The output of nucleoli, organelles where translational machineries are formed, depends on a rate of particular stages of ribosome production and on accessibility of elements crucial for their effective functioning, including substrates, enzymes as well as energy resources. Different factors that induce cellular stress also often lead to nucleolar dysfunction which results in ribosome biogenesis impairment. Such nucleolar disorders, called nucleolar or ribosomal stress, usually affect cellular functioning which in fact is a result of p53-dependent pathway activation, elicited as a response to stress. These pathways direct cells to new destinations such as cell cycle arrest, damage repair, differentiation, autophagy, programmed cell death or aging. In the case of impaired nucleolar functioning, nucleolar and ribosomal proteins mediate activation of the p53 pathways. They are also triggered as a response to oncogenic factor overexpression to protect tissues and organs against extensive proliferation of abnormal cells. Intentional impairment of any step of ribosome biosynthesis which would direct the cells to these destinations could be a strategy used in anticancer therapy. This review presents current knowledge on a nucleolus, mainly in relation to cancer biology, which is an important and extremely sensitive element of the mechanism participating in cellular stress reaction mediating activation of the p53 pathways in order to counteract stress effects, especially cancer development.

  20. Salidroside Suppresses HUVECs Cell Injury Induced by Oxidative Stress through Activating the Nrf2 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yao Zhu

    2016-08-01

    Full Text Available Oxidative stress plays an important role in the pathogenesis of cardiovascular diseases. Salidroside (SAL, one of the main effective constituents of Rhodiola rosea, has been reported to suppress oxidative stress-induced cardiomyocyte injury and necrosis by promoting transcription of nuclear factor E2-related factor 2 (Nrf2-regulated genes such as heme oxygenase-1 (HO-1 and NAD(PH dehydrogenase (quinone1 (NQO1. However, it has not been indicated whether SAL might ameliorate endothelial injury induced by oxidative stress. Here, our study demonstrated that SAL might suppress HUVEC cell injury induced by oxidative stress through activating the Nrf2 signaling pathway. The results of our study indicated that SAL decreased the levels of intercellular reactive oxygen species (ROS and malondialdehyde (MDA, and improved the activities of superoxide dismutase (SOD and catalase (CAT, resulting in protective effects against oxidative stress-induced cell damage in HUVECs. It suppressed oxidative stress damage by inducing Nrf2 nuclear translocation and activating the expression of Nrf2-regulated antioxidant enzyme genes such as HO-1 and NQO1 in HUVECs. Knockdown of Nrf2 with siRNA abolished the cytoprotective effects against oxidative stress, decreased the expression of Nrf2, HO-1, and NQO1, and inhibited the nucleus translocation of Nrf2 in HUVECs. This study is the first to demonstrate that SAL suppresses HUVECs cell injury induced by oxidative stress through activating the Nrf2 signaling pathway.

  1. Halobenzoquinone-Induced Alteration of Gene Expression Associated with Oxidative Stress Signaling Pathways.

    Science.gov (United States)

    Li, Jinhua; Moe, Birget; Liu, Yanming; Li, Xing-Fang

    2018-06-05

    Halobenzoquinones (HBQs) are emerging disinfection byproducts (DBPs) that effectively induce reactive oxygen species and oxidative damage in vitro. However, the impacts of HBQs on oxidative-stress-related gene expression have not been investigated. In this study, we examined alterations in the expression of 44 genes related to oxidative-stress-induced signaling pathways in human uroepithelial cells (SV-HUC-1) upon exposure to six HBQs. The results show the structure-dependent effects of HBQs on the studied gene expression. After 2 h of exposure, the expression levels of 9 to 28 genes were altered, while after 8 h of exposure, the expression levels of 29 to 31 genes were altered. Four genes ( HMOX1, NQO1, PTGS2, and TXNRD1) were significantly upregulated by all six HBQs at both exposure time points. Ingenuity pathway analysis revealed that the Nrf2 pathway was significantly responsive to HBQ exposure. Other canonical pathways responsive to HBQ exposure included GSH redox reductions, superoxide radical degradation, and xenobiotic metabolism signaling. This study has demonstrated that HBQs significantly alter the gene expression of oxidative-stress-related signaling pathways and contributes to the understanding of HBQ-DBP-associated toxicity.

  2. Crosstalk between the Tor and Gcn2 pathways in response to different stresses.

    Science.gov (United States)

    Rødland, Gro Elise; Tvegård, Tonje; Boye, Erik; Grallert, Beáta

    2014-01-01

    Regulating growth and the cell cycle in response to environmental fluctuations is important for all organisms in order to maintain viability. Two major pathways for translational regulation are found in higher eukaryotes: the Tor signaling pathway and those operating through the eIF2α kinases. Studies from several organisms indicate that the two pathways are interlinked, in that Tor complex 1 (TORC1) negatively regulates the Gcn2 kinase. Furthermore, inactivation of TORC1 may be required for activation of Gcn2 in response to stress. Here, we use the model organism Schizosaccharomyces pombe to investigate this crosstalk further. We find that the relationship is more complex than previously thought. First, in response to UV irradiation and oxidative stress, Gcn2 is fully activated in the presence of TORC1 signaling. Second, during amino-acid starvation, activation of Gcn2 is dependent on Tor2 activity, and Gcn2 is required for timely inactivation of the Tor pathway. Our data show that the crosstalk between the two pathways varies with the actual stress applied.

  3. The CWI Pathway: Regulation of the Transcriptional Adaptive Response to Cell Wall Stress in Yeast

    Directory of Open Access Journals (Sweden)

    Ana Belén Sanz

    2017-12-01

    Full Text Available Fungi are surrounded by an essential structure, the cell wall, which not only confers cell shape but also protects cells from environmental stress. As a consequence, yeast cells growing under cell wall damage conditions elicit rescue mechanisms to provide maintenance of cellular integrity and fungal survival. Through transcriptional reprogramming, yeast modulate the expression of genes important for cell wall biogenesis and remodeling, metabolism and energy generation, morphogenesis, signal transduction and stress. The yeast cell wall integrity (CWI pathway, which is very well conserved in other fungi, is the key pathway for the regulation of this adaptive response. In this review, we summarize the current knowledge of the yeast transcriptional program elicited to counterbalance cell wall stress situations, the role of the CWI pathway in the regulation of this program and the importance of the transcriptional input received by other pathways. Modulation of this adaptive response through the CWI pathway by positive and negative transcriptional feedbacks is also discussed. Since all these regulatory mechanisms are well conserved in pathogenic fungi, improving our knowledge about them will have an impact in the developing of new antifungal therapies.

  4. Aging causes decreased resistance to multiple stresses and a failure to activate specific stress response pathways

    OpenAIRE

    Dues, Dylan J.; Andrews, Emily K.; Schaar, Claire E.; Bergsma, Alexis L.; Senchuk, Megan M.; Van Raamsdonk, Jeremy M.

    2016-01-01

    In this work, we examine the relationship between stress resistance and aging. We find that resistance to multiple types of stress peaks during early adulthood and then declines with age. To dissect the underlying mechanisms, we use C. elegans transcriptional reporter strains that measure the activation of different stress responses including: the heat shock response, mitochondrial unfolded protein response, endoplasmic reticulum unfolded protein response, hypoxia response, SKN-1-mediated oxi...

  5. Virtual Institute of Microbial Stress and Survival: Deduction of Stress Response Pathways in Metal and Radionuclide Reducing Microorganisms

    Energy Technology Data Exchange (ETDEWEB)

    None

    2004-04-17

    The projects application goals are to: (1) To understand bacterial stress-response to the unique stressors in metal/radionuclide contamination sites; (2) To turn this understanding into a quantitative, data-driven model for exploring policies for natural and biostimulatory bioremediation; (3) To implement proposed policies in the field and compare results to model predictions; and (4) Close the experimental/computation cycle by using discrepancies between models and predictions to drive new measurements and construction of new models. The projects science goals are to: (1) Compare physiological and molecular response of three target microorganisms to environmental perturbation; (2) Deduce the underlying regulatory pathways that control these responses through analysis of phenotype, functional genomic, and molecular interaction data; (3) Use differences in the cellular responses among the target organisms to understand niche specific adaptations of the stress and metal reduction pathways; (4) From this analysis derive an understanding of the mechanisms of pathway evolution in the environment; and (5) Ultimately, derive dynamical models for the control of these pathways to predict how natural stimulation can optimize growth and metal reduction efficiency at field sites.

  6. Altering the sex determination pathway in Drosophila fat body modifies sex-specific stress responses.

    Science.gov (United States)

    Argue, Kathryn J; Neckameyer, Wendi S

    2014-07-01

    The stress response in Drosophila melanogaster reveals sex differences in behavior, similar to what has been observed in mammals. However, unlike mammals, the sex determination pathway in Drosophila is well established, making this an ideal system to identify factors involved in the modulation of sex-specific responses to stress. In this study, we show that the Drosophila fat body, which has been shown to be important for energy homeostasis and sex determination, is a dynamic tissue that is altered in response to stress in a sex and time-dependent manner. We manipulated the sex determination pathway in the fat body via targeted expression of transformer and transformer-2 and analyzed these animals for changes in their response to stress. In the majority of cases, manipulation of transformer or transformer-2 was able to change the physiological output in response to starvation and oxidative stress to that of the opposite sex. Our data also uncover the possibility of additional downstream targets for transformer and transformer-2 that are separate from the sex determination pathway and can influence behavioral and physiological responses. Copyright © 2014 the American Physiological Society.

  7. Modulation of Apoptosis Pathways by Oxidative Stress and Autophagy in β Cells

    Directory of Open Access Journals (Sweden)

    Maorong Wang

    2012-01-01

    Full Text Available Human islets isolated for transplantation are exposed to multiple stresses including oxidative stress and hypoxia resulting in significant loss of functional β cell mass. In this study we examined the modulation of apoptosis pathway genes in islets exposed to hydrogen peroxide, peroxynitrite, hypoxia, and cytokines. We observed parallel induction of pro- and antiapoptotic pathways and identified several novel genes including BFAR, CARD8, BNIP3, and CIDE-A. As BNIP3 is an inducer of autophagy, we examined this pathway in MIN6 cells, a mouse beta cell line and in human islets. Culture of MIN6 cells under low serum conditions increased the levels of several proteins in autophagy pathway, including ATG4, Beclin 1, LAMP-2, and UVRAG. Amino acid deprivation led to induction of autophagy in human islets. Preconditioning of islets with inducers of autophagy protected them from hypoxia-induced apoptosis. However, induction of autophagy during hypoxia exacerbated apoptotic cell death. ER stress led to induction of autophagy and apoptosis in β cells. Overexpression of MnSOD, an enzyme that scavenges free radicals, resulted in protection of MIN6 cells from cytokine-induced apoptosis. Ceramide, a mediator of cytokine-induced injury, reduced the active phosphorylated form of Akt and downregulated the promoter activity of the antiapoptotic gene bcl-2. Furthermore, cytokine-stimulated JNK pathway downregulated the bcl-2 promoter activity which was reversed by preincubation with SP600125, a JNK inhibitor. Our findings suggest that β cell apoptosis by multiple stresses in islets isolated for transplantation is the result of orchestrated gene expression in apoptosis pathway.

  8. Stress Response Pathways in Ameloblasts: Implications for Amelogenesis and Dental Fluorosis

    Directory of Open Access Journals (Sweden)

    John D. Bartlett

    2012-08-01

    Full Text Available Human enamel development of the permanent teeth takes place during childhood and stresses encountered during this period can have lasting effects on the appearance and structural integrity of the enamel. One of the most common examples of this is the development of dental fluorosis after childhood exposure to excess fluoride, an elemental agent used to increase enamel hardness and prevent dental caries. Currently the molecular mechanism responsible for dental fluorosis remains unknown; however, recent work suggests dental fluorosis may be the result of activated stress response pathways in ameloblasts during the development of permanent teeth. Using fluorosis as an example, the role of stress response pathways during enamel maturation is discussed.

  9. Mechanism of Sirt1 NAD+-dependent Protein Deacetylase Inhibition by Cysteine S-Nitrosation.

    Science.gov (United States)

    Kalous, Kelsey S; Wynia-Smith, Sarah L; Olp, Michael D; Smith, Brian C

    2016-12-02

    The sirtuin family of proteins catalyze the NAD + -dependent deacylation of acyl-lysine residues. Humans encode seven sirtuins (Sirt1-7), and recent studies have suggested that post-translational modification of Sirt1 by cysteine S-nitrosation correlates with increased acetylation of Sirt1 deacetylase substrates. However, the mechanism of Sirt1 inhibition by S-nitrosation was unknown. Here, we show that Sirt1 is transnitrosated and inhibited by the physiologically relevant nitrosothiol S-nitrosoglutathione. Steady-state kinetic analyses and binding assays were consistent with Sirt1 S-nitrosation inhibiting binding of both the NAD + and acetyl-lysine substrates. Sirt1 S-nitrosation correlated with Zn 2+ release from the conserved sirtuin Zn 2+ -tetrathiolate and a loss of α-helical structure without overall thermal destabilization of the enzyme. Molecular dynamics simulations suggested that Zn 2+ loss due to Sirt1 S-nitrosation results in repositioning of the tetrathiolate subdomain away from the rest of the catalytic domain, thereby disrupting the NAD + and acetyl-lysine-binding sites. Sirt1 S-nitrosation was reversed upon exposure to the thiol-based reducing agents, including physiologically relevant concentrations of the cellular reducing agent glutathione. Reversal of S-nitrosation resulted in full restoration of Sirt1 activity only in the presence of Zn 2+ , consistent with S-nitrosation of the Zn 2+ -tetrathiolate as the primary source of Sirt1 inhibition upon S-nitrosoglutathione treatment. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Identification of a novel TIF-IA-NF-κB nucleolar stress response pathway.

    Science.gov (United States)

    Chen, Jingyu; Lobb, Ian T; Morin, Pierre; Novo, Sonia M; Simpson, James; Kennerknecht, Kathrin; von Kriegsheim, Alex; Batchelor, Emily E; Oakley, Fiona; Stark, Lesley A

    2018-06-05

    p53 as an effector of nucleolar stress is well defined, but p53 independent mechanisms are largely unknown. Like p53, the NF-κB transcription factor plays a critical role in maintaining cellular homeostasis under stress. Many stresses that stimulate NF-κB also disrupt nucleoli. However, the link between nucleolar function and activation of the NF-κB pathway is as yet unknown. Here we demonstrate that artificial disruption of the PolI complex stimulates NF-κB signalling. Unlike p53 nucleolar stress response, this effect does not appear to be linked to inhibition of rDNA transcription. We show that specific stress stimuli of NF-κB induce degradation of a critical component of the PolI complex, TIF-IA. This degradation precedes activation of NF-κB and is associated with increased nucleolar size. It is mimicked by CDK4 inhibition and is dependent upon a novel pathway involving UBF/p14ARF and S44 of the protein. We show that blocking TIF-IA degradation blocks stress effects on nucleolar size and NF-κB signalling. Finally, using ex vivo culture, we show a strong correlation between degradation of TIF-IA and activation of NF-κB in freshly resected, human colorectal tumours exposed to the chemopreventative agent, aspirin. Together, our study provides compelling evidence for a new, TIF-IA-NF-κB nucleolar stress response pathway that has in vivo relevance and therapeutic implications.

  11. Stress and resource pathways connecting early socioeconomic adversity to young adults' physical health risk.

    Science.gov (United States)

    Wickrama, Kandauda K A S; Lee, Tae Kyoung; O'Neal, Catherine Walker; Kwon, Josephine A

    2015-05-01

    Although research has established the impact of early stress, including stressful life contexts, and early resources, such as educational attainment, on various adolescent health outcomes, previous research has not adequately investigated "integrative models" incorporating both stress and resource mediational pathways to explain how early socioeconomic adversity impacts physical health outcomes, particularly in early life stages. Data on early childhood/adolescent stress and socioeconomic resources as well as biomarkers indicating physical health status in young adulthood were collected from 11,798 respondents (54 % female) over a 13-year period from youth participating in the National Study of Adolescent Health (Add Health). Physical health risk in young adulthood was measured using a composite index of nine regulatory biomarkers of cardiovascular and metabolic systems. Heterogeneity in stress and socioeconomic resource pathways was assessed using latent class analysis to identify clusters, or classes, of stress and socioeconomic resource trajectories. The influence of early socioeconomic adversity on young adults' physical health risk, as measured by biomarkers, was estimated, and the role of stress and socioeconomic resource trajectory classes as linking mechanisms was assessed. There was evidence for the influence of early socioeconomic adversity on young adults' physical health risk directly and indirectly through stress and socioeconomic resource trajectory classes over the early life course. These findings suggest that health models should be broadened to incorporate both stress and resource experiences simultaneously. Furthermore, these findings have prevention and intervention implications, including the importance of early socioeconomic adversity and key intervention points for "turning" the trajectories of at-risk youth.

  12. [Factors of the rapid startup for nitrosation in sequencing batch reactor].

    Science.gov (United States)

    Li, Dong; Tao, Xiao-Xiao; Li, Zhan; Wang, Jun-An; Zhang, Jie

    2011-08-01

    The approach and factors for realizing the rapid startup of nitrosation were researched at the low level of dissolved oxygen (DO) in sequencing batch reactor (SBR). The main parameters of the reactor were controlled as follows: DO were 0.15-0.40 mg/L, pH values kept from 7.52 to 8.30, temperature maintained at 22.3-27.1 degrees C, and time of aeration was 8 hours. The purpose of rapid startup for nitrosation was achieved after 57 cycles (36 d) with the alternative influent of high and low ammonium wastewater (the mean values were 245.28 mg/L and 58.08 mg/L respectively) in a SBR, and the nitrosation rate was even 100%. Factors of accumulation of nitrite were investigated and the effects of DO and pH were analyzed during the startup for nitrosation. The results showed that it could improve the efficiency of nitrosation when DO concentration was increased appropriately. The activity of nitrite oxidizing bacteria (NOB) was recovered gradually when DO was higher than 0.72 mg/L. The key factor of controlling nitrosation reaction was the concentration of free ammonia (FA), while the final factor was the concentration of DO. pH was a desired controlling parameter to show the end of nitrification in a SBR cycle, while DO concentration did not indicate the finishing of SBR nitrification accurately because it increased rapidly before ammonia nitrogen was oxidized absolutely.

  13. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I.

    Science.gov (United States)

    Chouchani, Edward T; Methner, Carmen; Nadtochiy, Sergiy M; Logan, Angela; Pell, Victoria R; Ding, Shujing; James, Andrew M; Cochemé, Helena M; Reinhold, Johannes; Lilley, Kathryn S; Partridge, Linda; Fearnley, Ian M; Robinson, Alan J; Hartley, Richard C; Smith, Robin A J; Krieg, Thomas; Brookes, Paul S; Murphy, Michael P

    2013-06-01

    Oxidative damage from elevated production of reactive oxygen species (ROS) contributes to ischemia-reperfusion injury in myocardial infarction and stroke. The mechanism by which the increase in ROS occurs is not known, and it is unclear how this increase can be prevented. A wide variety of nitric oxide donors and S-nitrosating agents protect the ischemic myocardium from infarction, but the responsible mechanisms are unclear. Here we used a mitochondria-selective S-nitrosating agent, MitoSNO, to determine how mitochondrial S-nitrosation at the reperfusion phase of myocardial infarction is cardioprotective in vivo in mice. We found that protection is due to the S-nitrosation of mitochondrial complex I, which is the entry point for electrons from NADH into the respiratory chain. Reversible S-nitrosation of complex I slows the reactivation of mitochondria during the crucial first minutes of the reperfusion of ischemic tissue, thereby decreasing ROS production, oxidative damage and tissue necrosis. Inhibition of complex I is afforded by the selective S-nitrosation of Cys39 on the ND3 subunit, which becomes susceptible to modification only after ischemia. Our results identify rapid complex I reactivation as a central pathological feature of ischemia-reperfusion injury and show that preventing this reactivation by modification of a cysteine switch is a robust cardioprotective mechanism and hence a rational therapeutic strategy.

  14. MAPK pathway activation by chronic lead-exposure increases vascular reactivity through oxidative stress/cyclooxygenase-2-dependent pathways

    Energy Technology Data Exchange (ETDEWEB)

    Simões, Maylla Ronacher, E-mail: yllars@hotmail.com [Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091 (Brazil); Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain); Aguado, Andrea [Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain); Fiorim, Jonaína; Silveira, Edna Aparecida; Azevedo, Bruna Fernandes; Toscano, Cindy Medice [Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091 (Brazil); Zhenyukh, Olha; Briones, Ana María [Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain); Alonso, María Jesús [Dept. of Biochemistry, Physiology and Molecular Genetics, Universidad Rey Juan Carlos, Alcorcón (Spain); Vassallo, Dalton Valentim [Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091 (Brazil); Health Science Center of Vitória-EMESCAM, Vitória, ES CEP 29045-402 (Brazil); Salaices, Mercedes, E-mail: mercedes.salaices@uam.es [Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain)

    2015-03-01

    Chronic exposure to low lead concentration produces hypertension; however, the underlying mechanisms remain unclear. We analyzed the role of oxidative stress, cyclooxygenase-2-dependent pathways and MAPK in the vascular alterations induced by chronic lead exposure. Aortas from lead-treated Wistar rats (1st dose: 10 μg/100 g; subsequent doses: 0.125 μg/100 g, intramuscular, 30 days) and cultured aortic vascular smooth muscle cells (VSMCs) from Sprague Dawley rats stimulated with lead (20 μg/dL) were used. Lead blood levels of treated rats attained 21.7 ± 2.38 μg/dL. Lead exposure increased systolic blood pressure and aortic ring contractile response to phenylephrine, reduced acetylcholine-induced relaxation and did not affect sodium nitroprusside relaxation. Endothelium removal and L-NAME left-shifted the response to phenylephrine more in untreated than in lead-treated rats. Apocynin and indomethacin decreased more the response to phenylephrine in treated than in untreated rats. Aortic protein expression of gp91(phox), Cu/Zn-SOD, Mn-SOD and COX-2 increased after lead exposure. In cultured VSMCs lead 1) increased superoxide anion production, NADPH oxidase activity and gene and/or protein levels of NOX-1, NOX-4, Mn-SOD, EC-SOD and COX-2 and 2) activated ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized superoxide anion production, NADPH oxidase activity and mRNA levels of NOX-1, NOX-4 and COX-2. Blockade of the ERK1/2 and p38 signaling pathways abolished lead-induced NOX-1, NOX-4 and COX-2 expression. Results show that lead activation of the MAPK signaling pathways activates inflammatory proteins such as NADPH oxidase and COX-2, suggesting a reciprocal interplay and contribution to vascular dysfunction as an underlying mechanisms for lead-induced hypertension. - Highlights: • Lead-exposure increases oxidative stress, COX-2 expression and vascular reactivity. • Lead exposure activates MAPK signaling pathway. • ROS and COX-2 activation by

  15. Intrinsic and extrinsic apoptotic pathways are involved in rat testis by cold water immersion-induced acute and chronic stress.

    Science.gov (United States)

    Juárez-Rojas, Adriana Lizbeth; García-Lorenzana, Mario; Aragón-Martínez, Andrés; Gómez-Quiroz, Luis Enrique; Retana-Márquez, María del Socorro

    2015-01-01

    Testicular apoptosis is activated by stress, but it is not clear which signaling pathway is activated in response to stress. The aim of this study was to investigate whether intrinsic, extrinsic, or both apoptotic signaling pathways are activated by acute and chronic stress. Adult male rats were subjected to cold water immersion-induced stress for 1, 20, 40, and 50 consecutive days. The seminiferous tubules:apoptotic cell ratio was assayed on acute (1 day) and chronic (20, 40, 50 days) stress. Apoptotic markers, including cleaved-caspase 3 and 8, the pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins were also determined after acute and chronic stress induction. Additionally, epididymal sperm quality was evaluated, as well as corticosterone and testosterone levels. An increase in tubule apoptotic cell count percentage after an hour of acute stress and during chronic stress induction was observed. The apoptotic cells rate per tubule increment was only detected one hour after acute stress, but not with chronic stress. Accordingly, there was an increase in Bax, cleaved caspase-8 and caspase-3 pro-apoptotic proteins with a decrease of anti-apoptotic Bcl-2 in both acutely and chronically stressed male testes. In addition, sperm count, viability, as well as total and progressive motility were low in chronically stressed males. Finally, the levels of corticosterone increased whereas testosterone levels decreased in chronically stressed males. Activation of the extrinsic apoptotic pathway was shown by cleaved caspase-8 increase whereas the intrinsic apoptotic pathway activation was determined by the increase of Bax, along with Bcl-2 decrease, making evident a cross-talk between these two pathways with the activation of caspase-3. These results suggest that both acute and chronic stress can potentially activate the intrinsic/extrinsic apoptosis pathways in testes. Chronic stress also reduces the quality of epididymal spermatozoa, possibly due to a decrease in testosterone.

  16. 3-Bromopyruvate treatment induces alterations of metabolic and stress-related pathways in glioblastoma cells.

    Science.gov (United States)

    Chiasserini, Davide; Davidescu, Magdalena; Orvietani, Pier Luigi; Susta, Federica; Macchioni, Lara; Petricciuolo, Maya; Castigli, Emilia; Roberti, Rita; Binaglia, Luciano; Corazzi, Lanfranco

    2017-01-30

    Glioblastoma (GBM) is the most common and aggressive brain tumour of adults. The metabolic phenotype of GBM cells is highly dependent on glycolysis; therefore, therapeutic strategies aimed at interfering with glycolytic pathways are under consideration. 3-Bromopyruvate (3BP) is a potent antiglycolytic agent, with a variety of targets and possible effects on global cell metabolism. Here we analyzed the changes in protein expression on a GBM cell line (GL15 cells) caused by 3BP treatment using a global proteomic approach. Validation of differential protein expression was performed with immunoblotting and enzyme activity assays in GL15 and U251 cell lines. The results show that treatment of GL15 cells with 3BP leads to extensive changes in the expression of glycolytic enzymes and stress related proteins. Importantly, other metabolisms were also affected, including pentose phosphate pathway, aminoacid synthesis, and glucose derivatives production. 3BP elicited the activation of stress response proteins, as shown by the phosphorylation of HSPB1 at serine 82, caused by the concomitant activation of the p38 pathway. Our results show that inhibition of glycolysis in GL15 cells by 3BP influences different but interconnected pathways. Proteome analysis may help in the molecular characterization of the glioblastoma response induced by pharmacological treatment with antiglycolytic agents. Alteration of the glycolytic pathway characterizes glioblastoma (GBM), one of the most common brain tumours. Metabolic reprogramming with agents able to inhibit carbohydrate metabolism might be a viable strategy to complement the treatment of these tumours. The antiglycolytic agent 3-bromopyruvate (3BP) is able to strongly inhibit glycolysis but it may affect also other cellular pathways and its precise cellular targets are currently unknown. To understand the protein expression changes induced by 3BP, we performed a global proteomic analysis of a GBM cell line (GL15) treated with 3BP. We

  17. Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells.

    Science.gov (United States)

    Dong, Lixue; Krewson, Elizabeth A; Yang, Li V

    2017-01-27

    Acidosis commonly exists in the tissue microenvironment of various pathophysiological conditions such as tumors, inflammation, ischemia, metabolic disease, and respiratory disease. For instance, the tumor microenvironment is characterized by acidosis and hypoxia due to tumor heterogeneity, aerobic glycolysis (the "Warburg effect"), and the defective vasculature that cannot efficiently deliver oxygen and nutrients or remove metabolic acid byproduct. How the acidic microenvironment affects the function of blood vessels, however, is not well defined. GPR4 (G protein-coupled receptor 4) is a member of the proton-sensing G protein-coupled receptors and it has high expression in endothelial cells (ECs). We have previously reported that acidosis induces a broad inflammatory response in ECs. Acidosis also increases the expression of several endoplasmic reticulum (ER) stress response genes such as CHOP (C/EBP homologous protein) and ATF3 (activating transcription factor 3). In the current study, we have examined acidosis/GPR4- induced ER stress pathways in human umbilical vein endothelial cells (HUVEC) and other types of ECs. All three arms of the ER stress/unfolded protein response (UPR) pathways were activated by acidosis in ECs as an increased expression of phosphorylated eIF2α (eukaryotic initiation factor 2α), phosphorylated IRE1α (inositol-requiring enzyme 1α), and cleaved ATF6 upon acidic pH treatment was observed. The expression of other downstream mediators of the UPR, such as ATF4, ATF3, and spliced XBP-1 (X box-binding protein 1), was also induced by acidosis. Through genetic and pharmacological approaches to modulate the expression level or activity of GPR4 in HUVEC, we found that GPR4 plays an important role in mediating the ER stress response induced by acidosis. As ER stress/UPR can cause inflammation and cell apoptosis, acidosis/GPR4-induced ER stress pathways in ECs may regulate vascular growth and inflammatory response in the acidic microenvironment.

  18. Dietary gossypol suppressed postprandial TOR signaling and elevated ER stress pathways in turbot (Scophthalmus maximus L.).

    Science.gov (United States)

    Bian, Fuyun; Jiang, Haowen; Man, Mingsan; Mai, Kangsen; Zhou, Huihui; Xu, Wei; He, Gen

    2017-01-01

    Gossypol is known to be a polyphenolic compound toxic to animals. However, its molecular targets are far from fully characterized. To evaluate the physiological and molecular effects of gossypol, we chose turbot (Scophthalmus maximus L.), a carnivorous fish, as our model species. Juvenile turbots (7.83 ± 0.02 g) were fed diets containing gradient levels of gossypol at 0 (G0), 600 (G1), and 1,200 (G2) mg/kg diets for 11 wk. After the feeding trial, fish growth, body protein, and fat contents were significantly reduced in the G2 group compared with those of the G0 group (P TOR) signaling and induced endoplasmic reticulum (ER) stress pathway in both the feeding experiment and cell cultures. Our results demonstrated that gossypol inhibited TOR signaling and elevated ER stress pathways both in vivo and in vitro, thus providing new mechanism of action of gossypol in nutritional physiology. Copyright © 2017 the American Physiological Society.

  19. Shedding Light on the Mechanisms Underlying Health Disparities Through Community Participatory Methods: The Stress Pathway

    Science.gov (United States)

    Schetter, Christine Dunkel; Schafer, Peter; Lanzi, Robin Gaines; Clark-Kauffman, Elizabeth; Raju, Tonse N. K.; Hillemeier, Marianne M.

    2015-01-01

    Health disparities are large and persistent gaps in the rates of disease and death between racial/ethnic and socioeconomic status subgroups in the population. Stress is a major pathway hypothesized to explain such disparities. The Eunice Kennedy Shriver National Institute of Child Health and Human Development formed a community/research collaborative—the Community Child Health Network—to investigate disparities in maternal and child health in five high-risk communities. Using community participation methods, we enrolled a large cohort of African American/Black, Latino/Hispanic, and non-Hispanic/White mothers and fathers of newborns at the time of birth and followed them over 2 years. A majority had household incomes near or below the federal poverty level. Home interviews yielded detailed information regarding multiple types of stress such as major life events and many forms of chronic stress including racism. Several forms of stress varied markedly by racial/ethnic group and income, with decreasing stress as income increased among Caucasians but not among African Americans; other forms of stress varied by race/ethnicity or poverty alone. We conclude that greater sophistication in studying the many forms of stress and community partnership is necessary to uncover the mechanisms underlying health disparities in poor and ethnic-minority families and to implement community health interventions. PMID:26173227

  20. Shedding Light on the Mechanisms Underlying Health Disparities Through Community Participatory Methods: The Stress Pathway.

    Science.gov (United States)

    Dunkel Schetter, Christine; Schafer, Peter; Lanzi, Robin Gaines; Clark-Kauffman, Elizabeth; Raju, Tonse N K; Hillemeier, Marianne M

    2013-11-01

    Health disparities are large and persistent gaps in the rates of disease and death between racial/ethnic and socioeconomic status subgroups in the population. Stress is a major pathway hypothesized to explain such disparities. The Eunice Kennedy Shriver National Institute of Child Health and Human Development formed a community/research collaborative-the Community Child Health Network-to investigate disparities in maternal and child health in five high-risk communities. Using community participation methods, we enrolled a large cohort of African American/Black, Latino/Hispanic, and non-Hispanic/White mothers and fathers of newborns at the time of birth and followed them over 2 years. A majority had household incomes near or below the federal poverty level. Home interviews yielded detailed information regarding multiple types of stress such as major life events and many forms of chronic stress including racism. Several forms of stress varied markedly by racial/ethnic group and income, with decreasing stress as income increased among Caucasians but not among African Americans; other forms of stress varied by race/ethnicity or poverty alone. We conclude that greater sophistication in studying the many forms of stress and community partnership is necessary to uncover the mechanisms underlying health disparities in poor and ethnic-minority families and to implement community health interventions. © The Author(s) 2013.

  1. The brain-derived neurotrophic factor pathway, life stress, and chronic multi-site musculoskeletal pain.

    Science.gov (United States)

    Generaal, Ellen; Milaneschi, Yuri; Jansen, Rick; Elzinga, Bernet M; Dekker, Joost; Penninx, Brenda W J H

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) disturbances and life stress, both independently and in interaction, have been hypothesized to induce chronic pain. We examined whether (a) the BDNF pathway (val(66)met genotype, gene expression, and serum levels), (b) early and recent life stress, and (c) their interaction are associated with the presence and severity of chronic multi-site musculoskeletal pain. Cross-sectional data are from 1646 subjects of the Netherlands Study of Depression and Anxiety. The presence and severity of chronic multi-site musculoskeletal pain were determined using the Chronic Pain Grade (CPG) questionnaire. The BDNF val(66)met polymorphism, BDNF gene expression, and BDNF serum levels were measured. Early life stress before the age of 16 was assessed by calculating a childhood trauma index using the Childhood Trauma Interview. Recent life stress was assessed as the number of recent adverse life events using the List of Threatening Events Questionnaire. Compared to val(66)val, BDNF met carriers more often had chronic pain, whereas no differences were found for BDNF gene expression and serum levels. Higher levels of early and recent stress were both associated with the presence and severity of chronic pain (p stress in the associations with chronic pain presence and severity. This study suggests that the BDNF gene marks vulnerability for chronic pain. Although life stress did not alter the impact of BDNF on chronic pain, it seems an independent factor in the onset and persistence of chronic pain. © The Author(s) 2016.

  2. Mechanical stress activates Smad pathway through PKCδ to enhance interleukin-11 gene transcription in osteoblasts.

    Directory of Open Access Journals (Sweden)

    Shinsuke Kido

    Full Text Available BACKGROUND: Mechanical stress rapidly induces ΔFosB expression in osteoblasts, which binds to interleukin (IL-11 gene promoter to enhance IL-11 expression, and IL-11 enhances osteoblast differentiation. Because bone morphogenetic proteins (BMPs also stimulate IL-11 expression in osteoblasts, there is a possibility that BMP-Smad signaling is involved in the enhancement of osteoblast differentiation by mechanical stress. The present study was undertaken to clarify whether mechanical stress affects BMP-Smad signaling, and if so, to elucidate the role of Smad signaling in mechanical stress-induced enhancement of IL-11 gene transcription. METHODOLOGY/PRINCIPAL FINDINGS: Mechanical loading by fluid shear stress (FSS induced phosphorylation of BMP-specific receptor-regulated Smads (BR-Smads, Smad1/5, in murine primary osteoblasts (mPOBs. FSS rapidly phosphorylated Y311 of protein kinase C (PKCδ, and phosphorylated PKCδ interacted with BR-Smads to phosphorylate BR-Smads. Transfection of PKCδ siRNA or Y311F mutant PKCδ abrogated BR-Smads phosphorylation and suppressed IL-11 gene transcription enhanced by FSS. Activated BR-Smads bound to the Smad-binding element (SBE of IL-11 gene promoter and formed complex with ΔFosB/JunD heterodimer via binding to the C-terminal region of JunD. Site-directed mutagenesis in the SBE and the AP-1 site revealed that both SBE and AP-1 sites were required for full activation of IL-11 gene promoter by FSS. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that PKCδ-BR-Smads pathway plays an important role in the intracellular signaling in response to mechanical stress, and that a cross-talk between PKCδ-BR-Smads and ΔFosB/JunD pathways synergistically stimulates IL-11 gene transcription in response to mechanical stress.

  3. Kaempferol induces hepatocellular carcinoma cell death via endoplasmic reticulum stress-CHOP-autophagy signaling pathway.

    Science.gov (United States)

    Guo, Haiqing; Lin, Wei; Zhang, Xiangying; Zhang, Xiaohui; Hu, Zhongjie; Li, Liying; Duan, Zhongping; Zhang, Jing; Ren, Feng

    2017-10-10

    Kaempferol is a flavonoid compound that has gained widespread attention due to its antitumor functions. However, the underlying mechanisms are still not clear. The present study investigated the effect of kaempferol on hepatocellular carcinoma and its underlying mechanisms. Kaempferol induced autophagy in a concentration- and time-dependent manner in HepG2 or Huh7 cells, which was evidenced by the significant increase of autophagy-related genes. Inhibition of autophagy pathway, through 3-methyladenine or Atg7 siRNA, strongly diminished kaempferol-induced apoptosis. We further hypothesized that kaempferol can induce autophagy via endoplasmic reticulum (ER) stress pathway. Indeed, blocking ER stress by 4-phenyl butyric acid (4-PBA) or knockdown of CCAAT/enhancer-binding protein homologous protein (CHOP) with siRNA alleviated kaempferol-induced HepG2 or Huh7 cells autophagy; while transfection with plasmid overexpressing CHOP reversed the effect of 4-PBA on kaempferol-induced autophagy. Our results demonstrated that kaempferol induced hepatocarcinoma cell death via ER stress and CHOP-autophagy signaling pathway; kaempferol may be used as a potential chemopreventive agent for patients with hepatocellular carcinoma.

  4. Pathways to suicidality across ethnic groups in Canadian adults: the possible role of social stress.

    Science.gov (United States)

    Clarke, D E; Colantonio, A; Rhodes, A E; Escobar, M

    2008-03-01

    Ethnicity is an important determinant of mental health outcomes including suicidality (i.e. suicidal ideation and suicide attempt). Understanding ethnic differences in the pathways to suicidality is important for suicide prevention efforts in ethnically diverse populations. These pathways can be conceptualized within a social stress framework. The study examines ethnic differences in the pathways to suicidality in Canada within a social stress framework. Using data from the Canadian Community Health Survey Cycle 1.1 (CCHS 1.1) and path analysis, we examined the hypotheses that variations in (1) socio-economic status (SES), (2) sense of community belonging (SCB), (3) SES and SCB combined, and (4) SES, SCB and clinical factors combined can explain ethnic differences in suicidality. Francophone whites and Aboriginals were more likely to report suicidality compared to Anglophone whites whereas visible minorities and Foreign-born whites were least likely. Disadvantages in income, income and education, income and its combined effect with depression and alcohol dependence/abuse led to high rates even among the low-risk visible minority group. Indirect pathways for Asians differed from that of Blacks and South Asians, specifically through SCB. With the exception of SCB, Aboriginals were most disadvantaged, which exacerbated their risk for suicidality. However, their strong SCB buffered the risk for suicidality across pathways. Disadvantages in education, income and SCB were associated with the high risk for suicidality in Francophone whites. Francophone whites and Aboriginals had higher odds of suicidality compared to Anglophone whites; however, some pathways differed, indicating the need for targeted program planning and prevention efforts.

  5. Oxidative stress suppresses the cellular bioenergetic effect of the 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway

    International Nuclear Information System (INIS)

    Módis, Katalin; Asimakopoulou, Antonia; Coletta, Ciro; Papapetropoulos, Andreas; Szabo, Csaba

    2013-01-01

    Highlights: •Oxidative stress impairs 3-MST-derived H 2 S production in isolated enzyme and in isolated mitochondria. •This impairs the stimulatory bioenergetic effects of H 2 S in hepatocytes. •This has implications for the pathophysiology of diseases with oxidative stress. -- Abstract: Recent data show that lower concentrations of hydrogen sulfide (H 2 S), as well as endogenous, intramitochondrial production of H 2 S by the 3-mercaptopyruvate (3-MP)/3-mercaptopyruvate sulfurtransferase (3-MST) pathway serves as an electron donor and inorganic source of energy to support mitochondrial electron transport and ATP generation in mammalian cells by donating electrons to Complex II. The aim of our study was to investigate the role of oxidative stress on the activity of the 3-MP/3-MST/H 2 S pathway in vitro. Hydrogen peroxide (H 2 O 2 , 100–500 μM) caused a concentration-dependent decrease in the activity of recombinant mouse 3-MST enzyme. In mitochondria isolated from murine hepatoma cells, H 2 O 2 (50–500 μM) caused a concentration-dependent decrease in production of H 2 S from 3-MP. In cultured murine hepatoma cells H 2 O 2 , (3–100 μM), did not result in overall cytotoxicity, but caused a partial decrease in basal oxygen consumption and respiratory reserve rapacity. The positive bioenergetic effect of 3-MP (100–300 nM) was completely abolished by pre-treatment of the cells with H 2 O 2 (50 μM). The current findings demonstrate that oxidative stress inhibits 3-MST activity and interferes with the positive bioenergetic role of the 3-MP/3-MST/H 2 S pathway. These findings may have implications for the pathophysiology of various conditions associated with increased oxidative stress, such as various forms of critical illness, cardiovascular diseases, diabetes or physiological aging

  6. Mechanisms and kinetic profiles of superoxide-stimulated nitrosative processes in cells using a diaminofluorescein probe.

    Science.gov (United States)

    Damasceno, Fernando Cruvinel; Facci, Rômulo Rodrigues; da Silva, Thalita Marques; Toledo, José Carlos

    2014-12-01

    In this study, we examined the mechanisms and kinetic profiles of intracellular nitrosative processes using diaminofluorescein (DAF-2) as a target in RAW 264.7 cells. The intracellular formation of the fluorescent, nitrosated product diaminofluorescein triazol (DAFT) from both endogenous and exogenous nitric oxide (NO) was prevented by deoxygenation and by cell membrane-permeable superoxide (O2(-)) scavengers but not by extracellular bovine Cu,Zn-SOD. In addition, the DAFT formation rate decreased in the presence of cell membrane-permeable Mn porphyrins that are known to scavenge peroxynitrite (ONOO(-)) but was enhanced by HCO3(-)/CO2. Together, these results indicate that nitrosative processes in RAW 264.7 cells depend on endogenous intracellular O2(-) and are stimulated by ONOO(-)/CO2-derived radical oxidants. The N2O3 scavenger sodium azide (NaN3) only partially attenuated the DAFT formation rate and only with high NO (>120 nM), suggesting that DAFT formation occurs by nitrosation (azide-susceptible DAFT formation) and predominantly by oxidative nitrosylation (azide-resistant DAFT formation). Interestingly, the DAFT formation rate increased linearly with NO concentrations of up to 120-140 nM but thereafter underwent a sharp transition and became insensitive to NO. This behavior indicates the sudden exhaustion of an endogenous cell substrate that reacts rapidly with NO and induces nitrosative processes, consistent with the involvement of intracellular O2(-). On the other hand, intracellular DAFT formation stimulated by a fixed flux of xanthine oxidase-derived extracellular O2(-) that also occurs by nitrosation and oxidative nitrosylation increased, peaked, and then decreased with increasing NO, as previously observed. Thus, our findings complementarily show that intra- and extracellular O2(-)-dependent nitrosative processes occurring by the same chemical mechanisms do not necessarily depend on NO concentration and exhibit different unusual kinetic profiles with

  7. Biotic nitrosation of diclofenac in a soil aquifer system (Katari watershed, Bolivia).

    Science.gov (United States)

    Chiron, Serge; Duwig, Céline

    2016-09-15

    Up till now, the diclofenac (DCF) transformation into its nitrogen-derivatives, N-nitroso-DCF (NO-DCF) and 5-nitro-DCF (NO2-DCF), has been mainly investigated in wastewater treatment plant under nitrification or denitrification processes. This work reports, for the first time, an additional DCF microbial mediated nitrosation pathway of DCF in soil under strictly anoxic conditions probably involving codenitrification processes and fungal activities. This transformation pathway was investigated by using field observations data at a soil aquifer system (Katari watershed, Bolivia) and by carrying out soil slurry batch experiments. It was also observed for diphenylamine (DPA). Field measurements revealed the occurrence of NO-DCF, NO2-DCF and NO-DPA in groundwater samples at concentration levels in the 6-68s/L range. These concentration levels are more significant than those previously reported in wastewater treatment plant effluents taking into account dilution processes in soil. Interestingly, the p-benzoquinone imine of 5-OH-DCF was also found to be rather stable in surface water. In laboratory batch experiments under strictly anoxic conditions, the transformation of DCF and DPA into their corresponding N-nitroso derivatives was well correlated to denitrification processes. It was also observed that NO-DCF evolved into NO2-DCF while NO-DPA was stable. In vitro experiments showed that the Fisher-Hepp rearrangement could not account for NO2-DCF formation. One possible mechanism might be that NO-DCF underwent spontaneous NO loss to give the resulting intermediates diphenylaminyl radical or nitrenium cation which might evolve into NO2-DCF in presence of NO2 radical or nitrite ion, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Dichloroacetate Decreases Cell Health and Activates Oxidative Stress Defense Pathways in Rat Alveolar Type II Pneumocytes

    Directory of Open Access Journals (Sweden)

    Alexis Valauri-Orton

    2015-01-01

    Full Text Available Dichloroacetate (DCA is a water purification byproduct that is known to be hepatotoxic and hepatocarcinogenic and to induce peripheral neuropathy and damage macrophages. This study characterizes the effects of the haloacetate on lung cells by exposing rat alveolar type II (L2 cells to 0–24 mM DCA for 6–24 hours. Increasing DCA concentration and the combination of increasing DCA concentration plus longer exposures decrease measures of cellular health. Length of exposure has no effect on oxidative stress biomarkers, glutathione, SOD, or CAT. Increasing DCA concentration alone does not affect total glutathione or its redox ratio but does increase activity in the SOD/CAT oxidative stress defense pathway. These data suggest that alveolar type II cells rely on SOD and CAT more than glutathione to combat DCA-induced stress.

  9. Making memories of stressful events: a journey along epigenetic, gene transcription and signaling pathways

    Directory of Open Access Journals (Sweden)

    Johannes M.H.M. eReul

    2014-01-01

    Full Text Available Strong psychologically stressful events are known to have a long-lasting impact on behavior. The consolidation of such, largely adaptive, behavioral responses to stressful events involves changes in gene expression in limbic brain regions such as the hippocampus and amygdala. The underlying molecular mechanisms however were until recently unresolved. More than a decade ago we started to investigate the role of these hormones in signaling and epigenetic mechanisms participating in the effects of stress on gene transcription in hippocampal neurons. We discovered a novel, rapid non-genomic mechanism in which glucocorticoids via glucocorticoid receptors (GRs facilitate signaling of the ERK MAPK signaling pathway to the downstream nuclear kinases MSK1 and Elk-1 in dentate gyrus (DG granule neurons. Activation of this signaling pathway results in serine10 (S10 phosphorylation and lysine14 (K14 acetylation at histone H3 (H3S10p-K14ac, leading to the induction of the immediate early genes c-Fos and Egr-1. In addition, we found a role of the DNA methylation status of gene promoters. A series of studies showed that these molecular mechanisms play a critical role in the long-lasting consolidation of behavioral responses in the forced swim test and Morris water maze. Furthermore, an important role of GABA was found in controlling the epigenetic and gene transcriptional responses to psychological stress. Thus, psychologically stressful events evoke a long-term impact on behavior through changes in hippocampal function brought about by distinct glutamatergic and glucocorticoid-driven changes in epigenetic regulation of gene transcription which are modulated by (local GABAergic interneurons and limbic afferent inputs. These epigenetic processes may play an important role in the etiology of stress-related mental disorders such as major depressive and anxiety disorders like PTSD.

  10. Occupational position, work stress and depressive symptoms: a pathway analysis of longitudinal SHARE data.

    Science.gov (United States)

    Hoven, H; Wahrendorf, M; Siegrist, J

    2015-05-01

    Several studies tested whether stressful work mediates the association between socioeconomic position (SEP) and health. Although providing moderate support, evidence is still inconclusive, partly due to a lack of theory-based measures of SEP and work stress, and because of methodological limitations. This contribution aims at overcoming these limitations. We conduct pathway analysis and investigate indirect effects of SEP on mental health via stressful work. Data are derived from the first two waves of the 'Survey of Health, Ageing and Retirement in Europe' (SHARE) with information from employed men and women aged 50-64 across 11 European countries (N=2798). SEP is measured according to two alternative measures of occupational position: occupational class (focus on employment relations) and occupational status (focus on prestige). We assess work stress according to the effort-reward imbalance and the demand-control model (wave 1), and we use newly occurring depressive symptoms as health outcome (wave 2). Effort-reward imbalance and, less consistently, low control mediate the effect of occupational class and occupational status on depressive symptoms. Our findings point to two important aspects of work stress (effort-reward imbalance and low control) in explaining socioeconomic differences in health. Further, we illustrate the significance of two alternative dimensions of occupational position, occupational class and occupational status. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  11. Pathways Involving Beta-3 Adrenergic Receptors Modulate Cold Stress-Induced Detrusor Overactivity in Conscious Rats.

    Science.gov (United States)

    Imamura, Tetsuya; Ishizuka, Osamu; Ogawa, Teruyuki; Yamagishi, Takahiro; Yokoyama, Hitoshi; Minagawa, Tomonori; Nakazawa, Masaki; Nishizawa, Osamu

    2015-01-01

    To investigate pathways involving beta-3 adrenergic receptors (ARs) in detrusor overactivity induced by cold stress, we determined if the beta-3 AR agonist CL316243 could modulate the cold stress-induced detrusor overactivity in normal rats. Two days prior to cystometric investigations, the bladders of 10-week-old female Sprague-Dawley rats were cannulated. Cystometric measurements of the unanesthetized, unrestricted rats were taken to estimate baseline values at room temperature (RT, 27 ± 2 °C) for 20 min. They were then intravenously administered vehicle, 0.1, or 1.0 mg/kg CL316243 (n = 6 in each group). Five minutes after the treatments, they were gently and quickly transferred to the low temperature (LT, 4 ± 2 °C) room for 40 min where the cystometric measurements were again made. Afterward, the rats were returned to RT for final cystometric measurements. The cystometric effects of CL316243 were also measured at RT (n = 6 in each group). At RT, both low and high dose of CL316243 decreased basal and micturition pressure while the high dose (1.0 mg/kg) significantly increased voiding interval and bladder capacity. During LT exposure, the high dose of CL316243 partially reduced cold stress-induced detrusor overactivity characterized by increased basal pressure and urinary frequency. The high drug dose also significantly inhibited the decreases of both voiding interval and bladder capacity compared to the vehicle- and low dose (0.1 mg/kg)-treated rats. A high dose of the beta-3 agonist CL316243 could modulate cold stress-induced detrusor overactivity. Therefore, one of the mechanisms in cold stress-induced detrusor overactivity includes a pathway involving beta-3 ARs. © 2014 Wiley Publishing Asia Pty Ltd.

  12. Aluminum stress and its role in the phospholipid signaling pathway in plants and possible biotechnological applications.

    Science.gov (United States)

    Poot-Poot, Wilberth; Hernandez-Sotomayor, Soledad M Teresa

    2011-10-01

    An early response of plants to environmental signals or abiotic stress suggests that the phospholipid signaling pathway plays a pivotal role in these mechanisms. The phospholipid signaling cascade is one of the main systems of cellular transduction and is related to other signal transduction mechanisms. These other mechanisms include the generation of second messengers and their interactions with various proteins, such as ion channels. This phospholipid signaling cascade is activated by changes in the environment, such as phosphate starvation, water, metals, saline stres, and plant-pathogen interactions. One important factor that impacts agricultural crops is metal-induced stress. Because aluminum has been considered to be a major toxic factor for agriculture conducted in acidic soils, many researchers have focused on understanding the mechanisms of aluminum toxicity in plants. We have contributed the last fifteen years in this field by studying the effects of aluminum on phospholipid signaling in coffee, one of the Mexico's primary crops. We have focused our research on aluminum toxicity mechanisms in Coffea arabica suspension cells as a model for developing future contributions to the biotechnological transformation of coffee crops such that they can be made resistant to aluminum toxicity. We conclude that aluminum is able to not only generate a signal cascade in plants but also modulate other signal cascades generated by other types of stress in plants. The aim of this review is to discuss possible involvement of the phospholipid signaling pathway in the aluminum toxicity response of plant cells. Copyright © 2011 Wiley Periodicals, Inc.

  13. ERLIN2 promotes breast cancer cell survival by modulating endoplasmic reticulum stress pathways

    International Nuclear Information System (INIS)

    Wang, Guohui; Yang, Zeng-Quan; Liu, Gang; Wang, Xiaogang; Sethi, Seema; Ali-Fehmi, Rouba; Abrams, Judith; Zheng, Ze; Zhang, Kezhong; Ethier, Stephen

    2012-01-01

    Amplification of the 8p11-12 region has been found in approximately 15% of human breast cancer and is associated with poor prognosis. Previous genomic analysis has led us to identify the endoplasmic reticulum (ER) lipid raft-associated 2 (ERLIN2) gene as one of the candidate oncogenes within the 8p11-12 amplicon in human breast cancer, particularly in the luminal subtype. ERLIN2, an ER membrane protein, has recently been identified as a novel mediator of ER-associated degradation. Yet, the biological roles of ERLIN2 and molecular mechanisms by which ERLIN2 coordinates ER pathways in breast carcinogenesis remain unclear. We established the MCF10A-ERLIN2 cell line, which stably over expresses ERLIN2 in human nontransformed mammary epithelial cells (MCF10A) using the pLenti6/V5-ERLIN2 construct. ERLIN2 over expressing cells and their respective parental cell lines were assayed for in vitro transforming phenotypes. Next, we knocked down the ERLIN2 as well as the ER stress sensor IRE1α activity in the breast cancer cell lines to characterize the biological roles and molecular basis of the ERLIN2 in carcinogenesis. Finally, immunohistochemical staining was performed to detect ERLIN2 expression in normal and cancerous human breast tissues We found that amplification of the ERLIN2 gene and over expression of the ERLIN2 protein occurs in both luminal and Her2 subtypes of breast cancer. Gain- and loss-of-function approaches demonstrated that ERLIN2 is a novel oncogenic factor associated with the ER stress response pathway. The IRE1α/XBP1 axis in the ER stress pathway modulated expression of ERLIN2 protein levels in breast cancer cells. We also showed that over expression of ERLIN2 facilitated the adaptation of breast epithelial cells to ER stress by supporting cell growth and protecting the cells from ER stress-induced cell death. ERLIN2 may confer a selective growth advantage for breast cancer cells by facilitating a cytoprotective response to various cellular stresses

  14. ERLIN2 promotes breast cancer cell survival by modulating endoplasmic reticulum stress pathways

    Directory of Open Access Journals (Sweden)

    Wang Guohui

    2012-06-01

    Full Text Available Abstract Background Amplification of the 8p11-12 region has been found in approximately 15% of human breast cancer and is associated with poor prognosis. Previous genomic analysis has led us to identify the endoplasmic reticulum (ER lipid raft-associated 2 (ERLIN2 gene as one of the candidate oncogenes within the 8p11-12 amplicon in human breast cancer, particularly in the luminal subtype. ERLIN2, an ER membrane protein, has recently been identified as a novel mediator of ER-associated degradation. Yet, the biological roles of ERLIN2 and molecular mechanisms by which ERLIN2 coordinates ER pathways in breast carcinogenesis remain unclear. Methods We established the MCF10A-ERLIN2 cell line, which stably over expresses ERLIN2 in human nontransformed mammary epithelial cells (MCF10A using the pLenti6/V5-ERLIN2 construct. ERLIN2 over expressing cells and their respective parental cell lines were assayed for in vitro transforming phenotypes. Next, we knocked down the ERLIN2 as well as the ER stress sensor IRE1α activity in the breast cancer cell lines to characterize the biological roles and molecular basis of the ERLIN2 in carcinogenesis. Finally, immunohistochemical staining was performed to detect ERLIN2 expression in normal and cancerous human breast tissues Results We found that amplification of the ERLIN2 gene and over expression of the ERLIN2 protein occurs in both luminal and Her2 subtypes of breast cancer. Gain- and loss-of-function approaches demonstrated that ERLIN2 is a novel oncogenic factor associated with the ER stress response pathway. The IRE1α/XBP1 axis in the ER stress pathway modulated expression of ERLIN2 protein levels in breast cancer cells. We also showed that over expression of ERLIN2 facilitated the adaptation of breast epithelial cells to ER stress by supporting cell growth and protecting the cells from ER stress-induced cell death. Conclusions ERLIN2 may confer a selective growth advantage for breast cancer cells by

  15. Yeast as a Tool to Study Signaling Pathways in Mitochondrial Stress Response and Cytoprotection

    Directory of Open Access Journals (Sweden)

    Maša Ždralević

    2012-01-01

    Full Text Available Cell homeostasis results from the balance between cell capability to adapt or succumb to environmental stress. Mitochondria, in addition to supplying cellular energy, are involved in a range of processes deciding about cellular life or death. The crucial role of mitochondria in cell death is well recognized. Mitochondrial dysfunction has been associated with the death process and the onset of numerous diseases. Yet, mitochondrial involvement in cellular adaptation to stress is still largely unexplored. Strong interest exists in pharmacological manipulation of mitochondrial metabolism and signaling. The yeast Saccharomyces cerevisiae has proven a valuable model organism in which several intracellular processes have been characterized in great detail, including the retrograde response to mitochondrial dysfunction and, more recently, programmed cell death. In this paper we review experimental evidences of mitochondrial involvement in cytoprotection and propose yeast as a model system to investigate the role of mitochondria in the cross-talk between prosurvival and prodeath pathways.

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

    DEFF Research Database (Denmark)

    Zhang, Wei; Neo, Suat Peng; Gunaratne, Jayantha

    2015-01-01

    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 inhi...

  17. Oxidative stress suppresses the cellular bioenergetic effect of the 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway

    Energy Technology Data Exchange (ETDEWEB)

    Módis, Katalin [Department of Anesthesiology, University of Texas Medical Branch and Shriners Burns Hospital for Children, Galveston, TX (United States); Asimakopoulou, Antonia [Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras (Greece); Coletta, Ciro [Department of Anesthesiology, University of Texas Medical Branch and Shriners Burns Hospital for Children, Galveston, TX (United States); Papapetropoulos, Andreas [Department of Anesthesiology, University of Texas Medical Branch and Shriners Burns Hospital for Children, Galveston, TX (United States); Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras (Greece); Szabo, Csaba, E-mail: szabocsaba@aol.com [Department of Anesthesiology, University of Texas Medical Branch and Shriners Burns Hospital for Children, Galveston, TX (United States)

    2013-04-19

    Highlights: •Oxidative stress impairs 3-MST-derived H{sub 2}S production in isolated enzyme and in isolated mitochondria. •This impairs the stimulatory bioenergetic effects of H{sub 2}S in hepatocytes. •This has implications for the pathophysiology of diseases with oxidative stress. -- Abstract: Recent data show that lower concentrations of hydrogen sulfide (H{sub 2}S), as well as endogenous, intramitochondrial production of H{sub 2}S by the 3-mercaptopyruvate (3-MP)/3-mercaptopyruvate sulfurtransferase (3-MST) pathway serves as an electron donor and inorganic source of energy to support mitochondrial electron transport and ATP generation in mammalian cells by donating electrons to Complex II. The aim of our study was to investigate the role of oxidative stress on the activity of the 3-MP/3-MST/H{sub 2}S pathway in vitro. Hydrogen peroxide (H{sub 2}O{sub 2}, 100–500 μM) caused a concentration-dependent decrease in the activity of recombinant mouse 3-MST enzyme. In mitochondria isolated from murine hepatoma cells, H{sub 2}O{sub 2} (50–500 μM) caused a concentration-dependent decrease in production of H{sub 2}S from 3-MP. In cultured murine hepatoma cells H{sub 2}O{sub 2}, (3–100 μM), did not result in overall cytotoxicity, but caused a partial decrease in basal oxygen consumption and respiratory reserve rapacity. The positive bioenergetic effect of 3-MP (100–300 nM) was completely abolished by pre-treatment of the cells with H{sub 2}O{sub 2} (50 μM). The current findings demonstrate that oxidative stress inhibits 3-MST activity and interferes with the positive bioenergetic role of the 3-MP/3-MST/H{sub 2}S pathway. These findings may have implications for the pathophysiology of various conditions associated with increased oxidative stress, such as various forms of critical illness, cardiovascular diseases, diabetes or physiological aging.

  18. SIGNALING TO THE P53 TUMOR SUPPRESSOR THROUGH PATHWAYS ACTIVATED BY GENOTOXIC AND NON-GENOTOXIC STRESSES.

    Energy Technology Data Exchange (ETDEWEB)

    ANDERSON,C.W.APPELLA,E.

    2002-07-01

    The p53 tumor suppressor is a tetrameric transcription factor that is post-translational modified at {approx}18 different sites by phosphorylation, acetylation, or sumoylation in response to various cellular stress conditions. Specific posttranslational modifications, or groups of modifications, that result from the activation of different stress-induced signaling pathways are thought to modulate p53 activity to regulate cell fate by inducing cell cycle arrest, apoptosis, or cellular senescence. Here we review the posttranslational modifications to p53 and the pathways that produce them in response to both genotoxic and non-genotoxic stresses.

  19. Prodigiosin activates endoplasmic reticulum stress cell death pathway in human breast carcinoma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Pan, Mu-Yun [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Shen, Yuh-Chiang [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); National Research Institute of Chinese Medicine, Taipei, Taiwan (China); Lu, Chien-Hsing [Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan (China); Yang, Shu-Yi [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Ho, Tsing-Fen [Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan (China); Peng, Yu-Ta [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Chang, Chia-Che, E-mail: chia_che@dragon.nchu.edu.tw [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan (China); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (China)

    2012-12-15

    as an endoplasmic reticulum (ER) stress inducer. ► Prodigiosin-induced cytotoxicity involves ER stress-mediated cell death. ► Prodigiosin transcriptionally induces CHOP to suppress BCL2 for evoking cell death. ► Prodigiosin engages the IRE1–JNK and PERK–eIF2α pathways to up-regulate CHOP.

  20. Prodigiosin activates endoplasmic reticulum stress cell death pathway in human breast carcinoma cell lines

    International Nuclear Information System (INIS)

    Pan, Mu-Yun; Shen, Yuh-Chiang; Lu, Chien-Hsing; Yang, Shu-Yi; Ho, Tsing-Fen; Peng, Yu-Ta; Chang, Chia-Che

    2012-01-01

    endoplasmic reticulum (ER) stress inducer. ► Prodigiosin-induced cytotoxicity involves ER stress-mediated cell death. ► Prodigiosin transcriptionally induces CHOP to suppress BCL2 for evoking cell death. ► Prodigiosin engages the IRE1–JNK and PERK–eIF2α pathways to up-regulate CHOP.

  1. Mitochondrial stress and activation of PI3K and Akt survival pathway in bladder ischemia

    Directory of Open Access Journals (Sweden)

    Yang JH

    2017-06-01

    Full Text Available Jing-Hua Yang,1 Mike B Siroky,1 Subbarao V Yalla,2 Kazem M Azadzoi3,4 1Department of Urology, VA Boston Healthcare System, Boston University School of Medicine, 2Department of Urology, VA Boston Healthcare System, Harvard Medical School, 3Department of Urology, 4Department of Pathology, VA Boston Healthcare System, Boston University School of Medicine, Boston, MA, USA Purpose: Detrusor overactivity contributes to bothersome constellation of lower urinary tract symptoms (LUTS in men and women as they age. However, the underlying mechanisms of non-obstructive detrusor overactivity and LUTS remain largely unknown. Growing evidence suggests that ischemia may be an independent factor in the development of non-obstructive bladder dysfunction. Our goal was to determine the effects of ischemia on detrusor function and voiding behavior and define redox-mediated cellular stress and cell survival signaling in the ischemic bladder. Materials and methods: Male Sprague Dawley rats were randomly divided into treatment (n=8 and control (n=8 groups. In the treatment group, iliac artery atherosclerosis and chronic bladder ischemia were induced. At 8 weeks after bladder ischemia, voiding patterns were examined in metabolic cages, cystometrograms were recorded in conscious animals, and then bladder blood flow was measured under general anesthesia. Bladder tissues were processed for assessment of transcription factors, markers of cellular and mitochondrial stress, mitochondrial respiration, and cell survival signaling pathway.Results: Atherosclerotic occlusive disease spread from the common iliac arteries to the internal iliac and vesical arteries and produced sustained bladder ischemia. Studies in metabolic cages showed increased micturition frequency and decreased voided volume in bladder ischemia. Conscious cystometrograms produced consistent data showing significant increase in micturition frequency and decreased voided volume and bladder capacity. Voiding

  2. Carbon Fluxes between Primary Metabolism and Phenolic Pathway in Plant Tissues under Stress

    Directory of Open Access Journals (Sweden)

    Sofia Caretto

    2015-11-01

    Full Text Available Higher plants synthesize an amazing diversity of phenolic secondary metabolites. Phenolics are defined secondary metabolites or natural products because, originally, they were considered not essential for plant growth and development. Plant phenolics, like other natural compounds, provide the plant with specific adaptations to changing environmental conditions and, therefore, they are essential for plant defense mechanisms. Plant defensive traits are costly for plants due to the energy drain from growth toward defensive metabolite production. Being limited with environmental resources, plants have to decide how allocate these resources to various competing functions. This decision brings about trade-offs, i.e., promoting some functions by neglecting others as an inverse relationship. Many studies have been carried out in order to link an evaluation of plant performance (in terms of growth rate with levels of defense-related metabolites. Available results suggest that environmental stresses and stress-induced phenolics could be linked by a transduction pathway that involves: (i the proline redox cycle; (ii the stimulated oxidative pentose phosphate pathway; and, in turn, (iii the reduced growth of plant tissues.

  3. Streptozotocin induced activation of oxidative stress responsive splenic cell signaling pathways: Protective role of arjunolic acid

    International Nuclear Information System (INIS)

    Manna, Prasenjit; Ghosh, Jyotirmoy; Das, Joydeep; Sil, Parames C.

    2010-01-01

    Present study investigates the beneficial role of arjunolic acid (AA) against the alteration in the cytokine levels and simultaneous activation of oxidative stress responsive signaling pathways in spleen under hyperglycemic condition. Diabetes was induced by injection of streptozotocin (STZ) (at a dose of 70 mg/kg body weight, injected in the tail vain). STZ administration elevated the levels of IL-2 as well as IFN-γ and attenuated the level of TNF-α in the sera of diabetic animals. In addition, hyperglycemia is also associated with the increased production of intracellular reactive intermediates resulting with the elevation in lipid peroxidation, protein carbonylation and reduction in intracellular antioxidant defense. Investigating the oxidative stress responsive cell signaling pathways, increased expressions (immunoreactive concentrations) of phosphorylated p65 as well as its inhibitor protein phospho IκBα and phosphorylated mitogen activated protein kinases (MAPKs) have been observed in diabetic spleen tissue. Studies on isolated splenocytes revealed that hyperglycemia caused disruption of mitochondrial membrane potential, elevation in the concentration of cytosolic cytochrome c as well as activation of caspase 3 leading to apoptotic cell death. Histological examination revealed that diabetic induction depleted the white pulp scoring which is in agreement with the reduced immunological response. Treatment with AA prevented the hyperglycemia and its associated pathogenesis in spleen tissue. Results suggest that AA might act as an anti-diabetic and immunomodulatory agent against hyperglycemia.

  4. Endoplasmic reticulum stress pathway required for immune homeostasis is neurally controlled by arrestin-1.

    Science.gov (United States)

    Singh, Varsha; Aballay, Alejandro

    2012-09-28

    In response to pathogen infection, the host innate immune system activates microbial killing pathways and cellular stress pathways that need to be balanced because insufficient or excessive immune responses have deleterious consequences. Recent studies demonstrate that two G protein-coupled receptors (GPCRs) in the nervous system of Caenorhabditis elegans control immune homeostasis. To investigate further how GPCR signaling controls immune homeostasis at the organismal level, we studied arrestin-1 (ARR-1), which is the only GPCR adaptor protein in C. elegans. The results indicate that ARR-1 is required for GPCR signaling in ASH, ASI, AQR, PQR, and URX neurons, which control the unfolded protein response and a p38 mitogen-activated protein kinase signaling pathway required for innate immunity. ARR-1 activity also controlled immunity through ADF chemosensory and AFD thermosensory neurons that regulate longevity. Furthermore, we found that although ARR-1 played a key role in the control of immunity by AFD thermosensory neurons, it did not control longevity through these cells. However, ARR-1 partially controlled longevity through ADF neurons.

  5. High CO2 Primes Plant Biotic Stress Defences through Redox-Linked Pathways.

    Science.gov (United States)

    Mhamdi, Amna; Noctor, Graham

    2016-10-01

    Industrial activities have caused tropospheric CO 2 concentrations to increase over the last two centuries, a trend that is predicted to continue for at least the next several decades. Here, we report that growth of plants in a CO 2 -enriched environment activates responses that are central to defense against pathogenic attack. Salicylic acid accumulation was triggered by high-growth CO 2 in Arabidopsis (Arabidopsis thaliana) and other plants such as bean (Phaseolus vulgaris). A detailed analysis in Arabidopsis revealed that elevated CO 2 primes multiple defense pathways, leading to increased resistance to bacterial and fungal challenge. Analysis of gene-specific mutants provided no evidence that activation of plant defense pathways by high CO 2 was caused by stomatal closure. Rather, the activation is partly linked to metabolic effects involving redox signaling. In support of this, genetic modification of redox components (glutathione contents and NADPH-generating enzymes) prevents full priming of the salicylic acid pathway and associated resistance by high CO 2 The data point to a particularly influential role for the nonphosphorylating glyceraldehyde-3-phosphate dehydrogenase, a cytosolic enzyme whose role in plants remains unclear. Our observations add new information on relationships between high CO 2 and oxidative signaling and provide novel insight into plant stress responses in conditions of increased CO 2 . © 2016 American Society of Plant Biologists. All Rights Reserved.

  6. Embryotoxicity Caused by DON-Induced Oxidative Stress Mediated by Nrf2/HO-1 Pathway

    Directory of Open Access Journals (Sweden)

    Miao Yu

    2017-06-01

    Full Text Available Deoxynivalenol (DON belongs to the type B group of trichothecenes family, which is composed of sesquiterpenoid metabolites produced by Fusarium and other fungi in grain. DON may cause various toxicities, such as cytotoxicity, immunotoxicity, genotoxicity as well as teratogenicity and carcinogenicity. In the present study, we focus on a hypothesis that DON alters the expressions of Nrf2/HO-1 pathway by inducing embryotoxicity in C57BL/6 mouse (5.0, 2.5, 1.0, and 0 mg/kg/day and BeWo cell lines (0 and 50 nM; 3 h, 12 h and 24 h. Our results indicate that DON treatment in mice during pregnancy leads to ROS accumulation in the placenta, which results in embryotoxicity. At the same time Nrf2/HO-1 pathway is up-regulated by ROS to protect placenta cells from oxidative damage. In DON-treated BeWo cells, the level of ROS has time–effect and dose–effect relationships with HO-1 expression. Moderate increase in HO-1 protects the cell from oxidative damage, while excessive increase in HO-1 aggravates the oxidative damage, which is called in some studies the “threshold effect”. Therefore, oxidative stress may be the critical molecular mechanism for DON-induced embryotoxicity. Besides, Nrf2/HO-1 pathway accompanied by the “threshold effect” also plays an important role against DON-induced oxidative damage in this process.

  7. Both live and dead Enterococci activate Caenorhabditis elegans host defense via immune and stress pathways.

    Science.gov (United States)

    Yuen, Grace J; Ausubel, Frederick M

    2018-12-31

    The innate immune response of the nematode Caenorhabditis elegans has been extensively studied and a variety of Toll-independent immune response pathways have been identified. Surprisingly little, however, is known about how pathogens activate the C. elegans immune response. Enterococcus faecalis and Enterococcus faecium are closely related enterococcal species that exhibit significantly different levels of virulence in C. elegans infection models. Previous work has shown that activation of the C. elegans immune response by Pseudomonas aeruginosa involves P. aeruginosa-mediated host damage. Through ultrastructural imaging, we report that infection with either E. faecalis or E. faecium causes the worm intestine to become distended with proliferating bacteria in the absence of extensive morphological changes and apparent physical damage. Genetic analysis, whole-genome transcriptional profiling, and multiplexed gene expression analysis demonstrate that both enterococcal species, whether live or dead, induce a rapid and similar transcriptional defense response dependent upon previously described immune signaling pathways. The host response to E. faecium shows a stricter dependence upon stress response signaling pathways than the response to E. faecalis. Unexpectedly, we find that E. faecium is a C. elegans pathogen and that an active wild-type host defense response is required to keep an E. faecium infection at bay. These results provide new insights into the mechanisms underlying the C. elegans immune response to pathogen infection.

  8. High CO2 Primes Plant Biotic Stress Defences through Redox-Linked Pathways1[OPEN

    Science.gov (United States)

    2016-01-01

    Industrial activities have caused tropospheric CO2 concentrations to increase over the last two centuries, a trend that is predicted to continue for at least the next several decades. Here, we report that growth of plants in a CO2-enriched environment activates responses that are central to defense against pathogenic attack. Salicylic acid accumulation was triggered by high-growth CO2 in Arabidopsis (Arabidopsis thaliana) and other plants such as bean (Phaseolus vulgaris). A detailed analysis in Arabidopsis revealed that elevated CO2 primes multiple defense pathways, leading to increased resistance to bacterial and fungal challenge. Analysis of gene-specific mutants provided no evidence that activation of plant defense pathways by high CO2 was caused by stomatal closure. Rather, the activation is partly linked to metabolic effects involving redox signaling. In support of this, genetic modification of redox components (glutathione contents and NADPH-generating enzymes) prevents full priming of the salicylic acid pathway and associated resistance by high CO2. The data point to a particularly influential role for the nonphosphorylating glyceraldehyde-3-phosphate dehydrogenase, a cytosolic enzyme whose role in plants remains unclear. Our observations add new information on relationships between high CO2 and oxidative signaling and provide novel insight into plant stress responses in conditions of increased CO2. PMID:27578552

  9. Kaempferol Attenuates Cardiac Hypertrophy via Regulation of ASK1/MAPK Signaling Pathway and Oxidative Stress.

    Science.gov (United States)

    Feng, Hong; Cao, Jianlei; Zhang, Guangyu; Wang, Yanggan

    2017-07-01

    Kaempferol has been demonstrated to provide benefits for the treatment of atherosclerosis, coronary heart disease, hyperlipidemia, and diabetes through its antioxidant and anti-inflammatory properties. However, its role in cardiac hypertrophy remains to be elucidated. The aim of our study was to investigate the effects of kaempferol on cardiac hypertrophy and the underlying mechanism. Mice subjected to aorta banding were treated with or without kaempferol (100 mg/kg/d, p. o.) for 6 weeks. Echocardiography was performed to evaluate cardiac function. Mice hearts were collected for pathological observation and molecular mechanism investigation. H9c2 cardiomyocytes were stimulated with or without phenylephrine for in vitro study. Kaempferol significantly attenuated cardiac hypertrophy induced by aorta banding as evidenced by decreased cardiomyocyte areas and interstitial fibrosis, accompanied with improved cardiac functions and decreased apoptosis. The ASK1/MAPK signaling pathways (JNK1/2 and p38) were markedly activated in the aorta banding mouse heart but inhibited by kaempferol treatment. In in vitro experiments, kaempferol also inhibited the activity of ASK1/JNK1/2/p38 signaling pathway and the enlargement of H9c2 cardiomyocytes. Furthermore, our study revealed that kaempferol could protect the mouse heart and H9c2 cells from pathological oxidative stress. Our investigation indicated that treatment with kaempferol protects against cardiac hypertrophy, and its cardioprotection may be partially explained by the inhibition of the ASK1/MAPK signaling pathway and the regulation of oxidative stress. Georg Thieme Verlag KG Stuttgart · New York.

  10. Various cellular stress components change as the rat ages: An insight into the putative overall age-related cellular stress network.

    Science.gov (United States)

    Cueno, Marni E; Imai, Kenichi

    2018-02-01

    Cellular stress is mainly comprised of oxidative, nitrosative, and endoplasmic reticulum stresses and has long been correlated to the ageing process. Surprisingly, the age-related difference among the various components in each independent stress pathway and the possible significance of these components in relation to the overall cellular stress network remain to be clearly elucidated. In this study, we obtained blood from ageing rats upon reaching 20-, 40-, and 72-wk.-old. Subsequently, we measured representative cellular stress-linked biomolecules (H 2 O 2 , glutathione reductase, heme, NADPH, NADP, nitric oxide, GADD153) and cell signals [substance P (SP), free fatty acid, calcium, NF-κB] in either or both blood serum and cytosol. Subsequently, network analysis of the overall cellular stress network was performed. Our results show that there are changes affecting stress-linked biomolecules and cell signals as the rat ages. Additionally, based on our network analysis data, we postulate that NADPH, H 2 O 2 , GADD153, and SP are the key components and the interactions between these components are central to the overall age-related cellular stress network in the rat blood. Thus, we propose that the main pathway affecting the overall age-related cellular stress network in the rat blood would entail NADPH-related oxidative stress (involving H 2 O 2 ) triggering GADD153 activation leading to SP induction which in-turn affects other cell signals. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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.

  12. Dysregulation of the ADAM17/Notch signalling pathways in endometriosis: from oxidative stress to fibrosis.

    Science.gov (United States)

    González-Foruria, Iñaki; Santulli, Pietro; Chouzenoux, Sandrine; Carmona, Francisco; Chapron, Charles; Batteux, Frédéric

    2017-07-01

    Is oxidative stress associated with the A disintegrin and metalloproteases (ADAM) metallopeptidase domain 17 (ADAM17)/Notch signalling pathway and fibrosis in the development of endometriosis? Oxidative stress is correlated with hyperactivation of the ADAM17/Notch signalling pathway and a consequent increase in fibrosis in patients with endometriosis. It is nowadays accepted that oxidative stress plays an important role in the onset and progression of endometriosis. Oxidative stress is able to induce the synthesis of some members of the 'ADAM' family, such as ADAM17. ADAM17/Notch signalling is dysregulated in other profibrotic and inflammatory diseases. This was a prospective laboratory study conducted in a tertiary-care university hospital between January 2011 and April 2013. We investigated non-pregnant, younger than 42-year-old patients (n = 202) during surgery for a benign gynaecological condition. After complete surgical exploration of the abdominopelvic cavity, 121 women with histologically proven endometriosis and 81 endometriosis-free control women were enrolled. Peritoneal fluid (PF) samples were obtained from all the study participants during surgery in order to detect advanced oxidation protein products (AOPPs) and metalloproteinase activity of ADAM17. Stromal cells from endometrial specimens (n = 8) were obtained from endometrium of control patients (Cs), and from eutopic (Es) and ectopic (Ps) endometrium of patients with deep infiltrating endometriosis (DIE) (n = 8). ADAM17, Notch and the fibrosis markers α-smooth muscle actin (α-SMA) and type-I collagen were assessed using immunoblotting in all the endometrial samples obtained. Additionally, fibrosis was assessed after using Notch cleavage inhibitors (DAPT and FLI-06). Notch and fibrosis were also evaluated after stimulation of stromal endometrial cells with ADAM17 purified protein, increasing concentrations of H2O2 and primary cell culture supernatants. Patients with DIE presented higher PF AOPP

  13. Acute Psychological Stress Modulates the Expression of Enzymes Involved in the Kynurenine Pathway throughout Corticolimbic Circuits in Adult Male Rats

    Directory of Open Access Journals (Sweden)

    Haley A. Vecchiarelli

    2016-01-01

    Full Text Available Tryptophan is an essential dietary amino acid that is necessary for protein synthesis, but also serves as the precursor for serotonin. However, in addition to these biological functions, tryptophan also serves as a precursor for the kynurenine pathway, which has neurotoxic (quinolinic acid and neuroprotective (kynurenic acid metabolites. Glucocorticoid hormones and inflammatory mediators, both of which are increased by stress, have been shown to bias tryptophan along the kynurenine pathway and away from serotonin synthesis; however, to date, there is no published data regarding the effects of stress on enzymes regulating the kynurenine pathway in a regional manner throughout the brain. Herein, we examined the effects of an acute psychological stress (120 min restraint on gene expression patterns of enzymes along the kynurenine pathway over a protracted time-course (1–24 h post-stress termination within the amygdala, hippocampus, hypothalamus, and medial prefrontal cortex. Time-dependent changes in differential enzymes along the kynurenine metabolism pathway, particularly those involved in the production of quinolinic acid, were found within the amygdala, hypothalamus, and medial prefrontal cortex, with no changes seen in the hippocampus. These regional differences acutely may provide mechanistic insight into processes that become dysregulated chronically in stress-associated disorders.

  14. Earthquake-induced static stress change on magma pathway in promoting the 2012 Copahue eruption

    Science.gov (United States)

    Bonali, F. L.

    2013-11-01

    It was studied how tectonic earthquake-induced static stress changes could have contributed to favouring the 22 December 2012 major eruption at Copahue volcano, Chile. Numerical modelling indicates that the vertical N60°E-striking magma pathway below Copahue was affected by a normal stress reduction induced by the Mw 8.8 Chile earthquake of 27 February 2010. A sensitivity analysis suggests that N-, NE- and E-striking vertical planes are affected by normal stress decrease (maximum at the NE-striking plane), and that also a possible inclined N60°E plane is affected by this reduction. Copahue did not have any magmatic event since 2000. Seismic signals of awakening started in April 2012 and the first volcanic event occurred on July 2012. Thus, it is here suggested a possible earthquake-induced feedback effect on the crust below the volcanic arc up to at least 3 years after a large subduction earthquake, favouring new eruptions.

  15. Force and Stress along Simulated Dissociation Pathways of Cucurbituril-Guest Systems.

    Science.gov (United States)

    Velez-Vega, Camilo; Gilson, Michael K

    2012-03-13

    The field of host-guest chemistry provides computationally tractable yet informative model systems for biomolecular recognition. We applied molecular dynamics simulations to study the forces and mechanical stresses associated with forced dissociation of aqueous cucurbituril-guest complexes with high binding affinities. First, the unbinding transitions were modeled with constant velocity pulling (steered dynamics) and a soft spring constant, to model atomic force microscopy (AFM) experiments. The computed length-force profiles yield rupture forces in good agreement with available measurements. We also used steered dynamics with high spring constants to generate paths characterized by a tight control over the specified pulling distance; these paths were then equilibrated via umbrella sampling simulations and used to compute time-averaged mechanical stresses along the dissociation pathways. The stress calculations proved to be informative regarding the key interactions determining the length-force profiles and rupture forces. In particular, the unbinding transition of one complex is found to be a stepwise process, which is initially dominated by electrostatic interactions between the guest's ammoniums and the host's carbonyl groups, and subsequently limited by the extraction of the guest's bulky bicyclooctane moiety; the latter step requires some bond stretching at the cucurbituril's extraction portal. Conversely, the dissociation of a second complex with a more slender guest is mainly driven by successive electrostatic interactions between the different guest's ammoniums and the host's carbonyl groups. The calculations also provide information on the origins of thermodynamic irreversibilities in these forced dissociation processes.

  16. Occurrence of indole compounds in some vegetables : toxicological implications of nitrosation with emphasis on mutagenicity

    NARCIS (Netherlands)

    Tiedink, H.G.M.

    1991-01-01

    From the introduction to the chemistry, occurrence and formation of N-nitroso compounds (NOC) (Chapter 1), it can be concluded that human exposure to these potent carcinogenic compounds is mainly through the endogenous nitrosation of dietary precursors. Vegetables are the major source of

  17. Inflammatory stress increases hepatic CD36 translational efficiency via activation of the mTOR signalling pathway.

    Directory of Open Access Journals (Sweden)

    Chuan Wang

    Full Text Available Inflammatory stress is an independent risk factor for the development of non-alcoholic fatty liver disease (NAFLD. Although CD36 is known to facilitate long-chain fatty acid uptake and contributes to NAFLD progression, the mechanisms that link inflammatory stress to hepatic CD36 expression and steatosis remain unclear. As the mammalian target of rapamycin (mTOR signalling pathway is involved in CD36 translational activation, this study was undertaken to investigate whether inflammatory stress enhances hepatic CD36 expression via mTOR signalling pathway and the underlying mechanisms. To induce inflammatory stress, we used tumour necrosis factor alpha (TNF-α and interleukin-6 (IL-6 stimulation of the human hepatoblastoma HepG2 cells in vitro and casein injection in C57BL/6J mice in vivo. The data showed that inflammatory stress increased hepatic CD36 protein levels but had no effect on mRNA expression. A protein degradation assay revealed that CD36 protein stability was not different between HepG2 cells treated with or without TNF-α or IL-6. A polysomal analysis indicated that CD36 translational efficiency was significantly increased by inflammatory stress. Additionally, inflammatory stress enhanced the phosphorylation of mTOR and its downstream translational regulators including p70S6K, 4E-BP1 and eIF4E. Rapamycin, an mTOR-specific inhibitor, reduced the phosphorylation of mTOR signalling pathway and decreased the CD36 translational efficiency and protein level even under inflammatory stress resulting in the alleviation of inflammatory stress-induced hepatic lipid accumulation. This study demonstrates that the activation of the mTOR signalling pathway increases hepatic CD36 translational efficiency, resulting in increased CD36 protein expression under inflammatory stress.

  18. Activation of Erk and JNK MAPK pathways by acute swim stress in rat brain regions

    Directory of Open Access Journals (Sweden)

    Salvadore Christopher

    2004-09-01

    Full Text Available Abstract Background The mitogen-activated protein kinases (MAPKs have been shown to participate in a wide array of cellular functions. A role for some MAPKs (e.g., extracellular signal-regulated kinase, Erk1/2 has been documented in response to certain physiological stimuli, such as ischemia, visceral pain and electroconvulsive shock. We recently demonstrated that restraint stress activates the Erk MAPK pathway, but not c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK or p38MAPK, in several rat brain regions. In the present study, we investigated the effects of a different stressor, acute forced swim stress, on the phosphorylation (P state of these MAPKs in the hippocampus, neocortex, prefrontal cortex, amygdala and striatum. In addition, effects on the phosphorylation state of the upstream activators of the MAPKs, their respective MAPK kinases (MAPKKs; P-MEK1/2, P-MKK4 and P-MKK3/6, were determined. Finally, because the Erk pathway can activate c-AMP response element (CRE binding (CREB protein, and swim stress has recently been reported to enhance CREB phosphorylation, changes in P-CREB were also examined. Results A single 15 min session of forced swimming increased P-Erk2 levels 2–3-fold in the neocortex, prefrontal cortex and striatum, but not in the hippocampus or amygdala. P-JNK levels (P-JNK1 and/or P-JNK2/3 were increased in all brain regions about 2–5-fold, whereas P-p38MAPK levels remained essentially unchanged. Surprisingly, levels of the phosphorylated MAPKKs, P-MEK1/2 and P-MKK4 (activators of the Erk and JNK pathways, respectively were increased in all five brain regions, and much more dramatically (P-MEK1/2, 4.5 to > 100-fold; P-MKK4, 12 to ~300-fold. Consistent with the lack of forced swim on phosphorylation of p38MAPK, there appeared to be no change in levels of its activator, P-MKK3/6. P-CREB was increased in all but cortical (prefrontal, neocortex areas. Conclusions Swim stress specifically and markedly

  19. Nitrosation and Nitration of Fulvic Acid, Peat and Coal with Nitric Acid.

    Directory of Open Access Journals (Sweden)

    Kevin A Thorn

    Full Text Available Nitrohumic acids, produced from base extraction of coals and peats oxidized with nitric acid, have received considerable attention as soil ammendments in agriculture. The nitration chemistry however is incompletely understood. Moreover, there is a need to understand the reaction of nitric acid with natural organic matter (NOM in general, in the context of a variety of environmental and biogeochemical processes. Suwannee River NOM, Suwannee River fulvic acid, and Pahokee Peat fulvic acid were treated with 15N-labeled nitric acid at concentrations ranging from 15% to 22% and analyzed by liquid and solid state 15N NMR spectroscopy. Bulk Pahokee peat and Illinois #6 coal were also treated with nitric acid, at 29% and 40% respectively, and analyzed by solid state 15N NMR spectroscopy. In addition to nitro groups from nitration of aromatic carbon, the 15N NMR spectra of all five samples exhibited peaks attributable to nitrosation reactions. These include nitrosophenol peaks in the peat fulvic acid and Suwannee River samples, from nitrosation of phenolic rings, and N-nitroso groups in the peat samples, from nitrosation of secondary amides or amines, the latter consistent with the peat samples having the highest naturally abundant nitrogen contents. Peaks attributable to Beckmann and secondary reactions of the initially formed oximes were present in all spectra, including primary amide, secondary amide, lactam, and nitrile nitrogens. The degree of secondary reaction product formation resulting from nitrosation reactions appeared to correlate inversely with the 13C aromaticities of the samples. The nitrosation reactions are most plausibly effected by nitrous acid formed from the reduction of nitric acid by oxidizable substrates in the NOM and coal samples.

  20. Deduction and Analysis of the Interacting Stress Response Pathways of Metal/Radionuclide-reducing Bacteria

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Jizhong [University of Oklahoma; He, Zhili [University of Oklahoma

    2010-02-28

    Project Title: Deduction and Analysis of the Interacting Stress Response Pathways of Metal/Radionuclide-reducing Bacteria DOE Grant Number: DE-FG02-06ER64205 Principal Investigator: Jizhong (Joe) Zhou (University of Oklahoma) Key members: Zhili He, Aifen Zhou, Christopher Hemme, Joy Van Nostrand, Ye Deng, and Qichao Tu Collaborators: Terry Hazen, Judy Wall, Adam Arkin, Matthew Fields, Aindrila Mukhopadhyay, and David Stahl Summary Three major objectives have been conducted in the Zhou group at the University of Oklahoma (OU): (i) understanding of gene function, regulation, network and evolution of Desulfovibrio vugaris Hildenborough in response to environmental stresses, (ii) development of metagenomics technologies for microbial community analysis, and (iii) functional characterization of microbial communities with metagenomic approaches. In the past a few years, we characterized four CRP/FNR regulators, sequenced ancestor and evolved D. vulgaris strains, and functionally analyzed those mutated genes identified in salt-adapted strains. Also, a new version of GeoChip 4.0 has been developed, which also includes stress response genes (StressChip), and a random matrix theory-based conceptual framework for identifying functional molecular ecological networks has been developed with the high throughput functional gene array hybridization data as well as pyrosequencing data from 16S rRNA genes. In addition, GeoChip and sequencing technologies as well as network analysis approaches have been used to analyze microbial communities from different habitats. Those studies provide a comprehensive understanding of gene function, regulation, network, and evolution in D. vulgaris, and microbial community diversity, composition and structure as well as their linkages with environmental factors and ecosystem functioning, which has resulted in more than 60 publications.

  1. Cadmium-induced apoptosis through the mitochondrial pathway in rainbow trout hepatocytes: involvement of oxidative stress

    International Nuclear Information System (INIS)

    Risso-de Faverney, C.; Orsini, N.; Sousa, G. de; Rahmani, R.

    2004-01-01

    Cadmium (Cd) induces oxidative stress and apoptosis in trout hepatocytes. We therefore investigated the involvement of the mitochondrial pathway in the initiation of apoptosis and the possible role of oxidative stress in that process. This study demonstrates that hepatocyte exposure to Cd (2, 5 and 10 μM) triggers significant caspase-3, but also caspase-8 and -9 activation in a dose-dependent manner. Western-blot analysis of hepatocyte mitochondrial and cytosolic fractions revealed that cytochrome c (Cyt c) was released in the cytosol in a dose-dependent manner, whereas the pro-apoptotic protein Bax was redistributed to mitochondria after 24 and 48 h exposure. We also found that the expression of anti-apoptotic protein Bcl-xL, known to be regulated under mild oxidative stress to protect cells from apoptosis, did not change after 3 and 6 h exposure to Cd, then increased after 24 and 48 h exposure to 10 μM Cd. In the second part of this work, two antioxidant agents, 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) (100 μM) and N-acetylcysteine (NAC, 100 μM) were used to determine the involvement of reactive oxygen species (ROS) in Cd-induced apoptosis. Simultaneously exposing trout hepatocytes to Cd and TEMPO or NAC significantly reduced caspase-3 activation after 48 h and had a suppressive effect on caspase-8 and -9 also, mostly after 24 h. Lastly, the presence of either one of these antioxidants in the treatment medium also attenuated Cd-induced Cyt c release in cytosol and the level of Bax in the mitochondria after 24 and 48 h, while high Bcl-xL expression was observed. Taken together, these data clearly evidenced the key role of mitochondria in the cascade of events leading to trout hepatocyte apoptosis in response to Cd and the relationship that exists between oxidative stress and cell death

  2. The role of the stress-activated protein kinase (SAPK/JNK) signaling pathway in radiation-induced apoptosis

    International Nuclear Information System (INIS)

    Verheij, M.; Ruiter, G.A.; Zerp, S.F.; Bartelink, H.; Blitterswijk, W.J. van; Fuks, Z.; Haimovitz-Friedman, A.

    1998-01-01

    Ionizing radiation, like a variety of other cellular stress factors, initiates apoptosis, or programmed cell death, in many cell systems. This mode of radiation-induced cell kill should be distinguished from clonogenic cell death due to unrepaired DNA damage. Ionizing radiation not only exerts its effect on the nuclear DNA, but also at the plasma membrane level where it may activate multiple signal transduction pathways. One of these pathways is the stress-activated protein kinase (SAPK) cascade which transduces death signals from the cell membrane to the nucleus. This review discusses recent evidence on the critical role of this signaling system in radiation- and stress-induced apoptosis. An improved understanding of the mechanisms involved in radiation-induced apoptosis may ultimately provide novel strategies of intervention in specific signal transduction pathways to favorably alter the therapeutic ratio in the treatment of human malignancies. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  3. Developmental Pathways from Child Maltreatment to Adolescent Substance Use: The Roles of Posttraumatic Stress Symptoms and Mother-Child Relationships

    Science.gov (United States)

    Yoon, Susan; Kobulsky, Julia M.; Yoon, Dalhee; Kim, Wonhee

    2018-01-01

    While many studies have identified a significant relation between child maltreatment and adolescent substance use, the developmental pathways linking this relation remain sparsely explored. The current study examines posttraumatic stress (PTS) symptoms, mother-child relationships, and internalizing and externalizing problems as potential longitudinal pathways through which child maltreatment influences adolescent substance use. Structural equation modeling was conducted on 883 adolescents drawn from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). The pathways of PTS symptoms linked physical and sexual abuse to substance use, and the pathways of mother-child relationships linked emotional abuse and neglect to substance use. None of the four types of maltreatment affected substance use via internalizing or externalizing problems. The findings suggest that intervention efforts aimed at addressing posttraumatic stress symptoms and improving mother-child relationship quality may be beneficial in reducing substance use among adolescents with child maltreatment histories. PMID:29503490

  4. Chronic stress and peripheral pain: Evidence for distinct, region-specific changes in visceral and somatosensory pain regulatory pathways.

    Science.gov (United States)

    Zheng, Gen; Hong, Shuangsong; Hayes, John M; Wiley, John W

    2015-11-01

    Chronic stress alters the hypothalamic-pituitary-adrenal (HPA) axis and enhances visceral and somatosensory pain perception. It is unresolved whether chronic stress has distinct effects on visceral and somatosensory pain regulatory pathways. Previous studies reported that stress-induced visceral hyperalgesia is associated with reciprocal alterations of endovanilloid and endocannabinoid pain pathways in DRG neurons innervating the pelvic viscera. In this study, we compared somatosensory and visceral hyperalgesia with respect to differential responses of peripheral pain regulatory pathways in a rat model of chronic, intermittent stress. We found that chronic stress induced reciprocal changes in the endocannabinoid 2-AG (increased) and endocannabinoid degradation enzymes COX-2 and FAAH (decreased), associated with down-regulation of CB1 and up-regulation of TRPV1 receptors in L6-S2 DRG but not L4-L5 DRG neurons. In contrast, sodium channels Nav1.7 and Nav1.8 were up-regulated in L4-L5 but not L6-S2 DRGs in stressed rats, which was reproduced in control DRGs treated with corticosterone in vitro. The reciprocal changes of CB1, TRPV1 and sodium channels were cell-specific and observed in the sub-population of nociceptive neurons. Behavioral assessment showed that visceral hyperalgesia persisted, whereas somatosensory hyperalgesia and enhanced expression of Nav1.7 and Nav1.8 sodium channels in L4-L5 DRGs normalized 3 days after completion of the stress phase. These data indicate that chronic stress induces visceral and somatosensory hyperalgesia that involves differential changes in endovanilloid and endocannabinoid pathways, and sodium channels in DRGs innervating the pelvic viscera and lower extremities. These results suggest that chronic stress-induced visceral and lower extremity somatosensory hyperalgesia can be treated selectively at different levels of the spinal cord. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. The Fanconi Anemia Pathway in Replication Stress and DNA Crosslink Repair

    Science.gov (United States)

    Jones, Mathew JK.; Huang, Tony T.

    2013-01-01

    Interstand crosslinks (ICLs) are DNA lesions where the bases of opposing DNA strands are covalently linked, inhibiting critical cellular processes such as transcription and replication. Chemical agents that generate ICLs cause chromosomal abnormalities including breaks, deletions and rearrangements, making them highly genotoxic compounds. This toxicity has proven useful for chemotherapeutic treatment against a wide variety of cancer types. The majority of our understanding of ICL repair in humans has been uncovered thorough analysis of the rare genetic disorder Fanconi anemia, in which patients are extremely sensitive to crosslinking agents. Here, we discuss recent insights into ICL repair gained through new ICL repair assays and highlight the role of the Fanconi Anemia repair pathway during replication stress. PMID:22744751

  6. Fisetin alleviates oxidative stress after traumatic brain injury via the Nrf2-ARE pathway.

    Science.gov (United States)

    Zhang, Li; Wang, Handong; Zhou, Yali; Zhu, Yihao; Fei, Maoxin

    2018-05-22

    Fisetin, a natural flavonoid, has neuroprotection properties in many brain injury models. However, its role in traumatic brain injury (TBI) has not been fully explained. In the present study, we aimed to explore the neuroprotective effects of fisetin in a mouse model of TBI. We found that fisetin improved neurological function, reduced cerebral edema, attenuated brain lesion and ameliorated blood-brain barrier (BBB) disruption after TBI. Moreover, the up-regulation of malondialdehyde (MDA) and the activity of glutathione peroxidase (GPx) were reversed by fisetin treatment. Furthermore, administration of fisetin suppressed neuron cell death and apoptosis, increased the expression of B-cell lymphoma 2 (Bcl-2), while decreased the expression of Bcl-2-associated X protein (Bax) and caspase-3 after TBI. In addition, fisetin activated the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway following TBI. However, fisetin only failed to suppress oxidative stress in Nrf2 -/- mice. In conclusion, our data provided the first evidence that fisetin played a critical role in neuroprotection after TBI partly through the activation of the Nrf2-ARE pathway. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. HSF1 stress response pathway regulates autophagy receptor SQSTM1/p62-associated proteostasis

    Science.gov (United States)

    Watanabe, Yoshihisa; Tsujimura, Atsushi; Taguchi, Katsutoshi; Tanaka, Masaki

    2017-01-01

    ABSTRACT Proteostasis is important for protecting cells from harmful proteins and is mainly controlled by the HSF1 (heat shock transcription factor 1) stress response pathway. This pathway facilitates protein refolding by molecular chaperones; however, it is unclear whether it functions in autophagy or inclusion formation. The autophagy receptor SQSTM1/p62 is involved in selective autophagic clearance and inclusion formation by harmful proteins, and its phosphorylation at S349, S403, and S407 is required for binding to substrates. Here, we demonstrate that casein kinase 1 phosphorylates the SQSTM1 S349 residue when harmful proteins accumulate. Investigation of upstream factors showed that both SQSTM1 S349 and SQSTM1 S403 residues were phosphorylated in an HSF1 dependent manner. Inhibition of SQSTM1 phosphorylation suppressed inclusion formation by ubiquitinated proteins and prevented colocalization of SQSTM1 with aggregation-prone proteins. Moreover, HSF1 inhibition impaired aggregate-induced autophagosome formation and elimination of protein aggregates. Our findings indicate that HSF1 triggers SQSTM1-mediated proteostasis. PMID:27846364

  8. HSF1 stress response pathway regulates autophagy receptor SQSTM1/p62-associated proteostasis.

    Science.gov (United States)

    Watanabe, Yoshihisa; Tsujimura, Atsushi; Taguchi, Katsutoshi; Tanaka, Masaki

    2017-01-02

    Proteostasis is important for protecting cells from harmful proteins and is mainly controlled by the HSF1 (heat shock transcription factor 1) stress response pathway. This pathway facilitates protein refolding by molecular chaperones; however, it is unclear whether it functions in autophagy or inclusion formation. The autophagy receptor SQSTM1/p62 is involved in selective autophagic clearance and inclusion formation by harmful proteins, and its phosphorylation at S349, S403, and S407 is required for binding to substrates. Here, we demonstrate that casein kinase 1 phosphorylates the SQSTM1 S349 residue when harmful proteins accumulate. Investigation of upstream factors showed that both SQSTM1 S349 and SQSTM1 S403 residues were phosphorylated in an HSF1 dependent manner. Inhibition of SQSTM1 phosphorylation suppressed inclusion formation by ubiquitinated proteins and prevented colocalization of SQSTM1 with aggregation-prone proteins. Moreover, HSF1 inhibition impaired aggregate-induced autophagosome formation and elimination of protein aggregates. Our findings indicate that HSF1 triggers SQSTM1-mediated proteostasis.

  9. Health effects from swimming training in chlorinated pools and the corresponding metabolic stress pathways.

    Directory of Open Access Journals (Sweden)

    Jiang-Hua Li

    Full Text Available Chlorination is the most popular method for disinfecting swimming pool water; however, although pathogens are being killed, many toxic compounds, called disinfection by-products (DBPs, are formed. Numerous epidemiological publications have associated the chlorination of pools with dysfunctions of the respiratory system and with some other diseases. However, the findings concerning these associations are not always consistent and have not been confirmed by toxicological studies. Therefore, the health effects from swimming in chlorinated pools and the corresponding stress reactions in organisms are unclear. In this study, we show that although the growth and behaviors of experimental rats were not affected, their health, training effects and metabolic profiles were significantly affected by a 12-week swimming training program in chlorinated water identical to that of public pools. Interestingly, the eyes and skin are the organs that are more directly affected than the lungs by the irritants in chlorinated water; instead of chlorination, training intensity, training frequency and choking on water may be the primary factors for lung damage induced by swimming. Among the five major organs (the heart, liver, spleen, lungs and kidneys, the liver is the most likely target of DBPs. Through metabolomics analysis, the corresponding metabolic stress pathways and a defensive system focusing on taurine were presented, based on which the corresponding countermeasures can be developed for swimming athletes and for others who spend a lot of time in chlorinated swimming pools.

  10. Polydatin Attenuates H2O2-Induced Oxidative Stress via PKC Pathway

    Directory of Open Access Journals (Sweden)

    Huilian Qiao

    2016-01-01

    Full Text Available Oxidative stress plays an important role in the pathogenesis of endothelial dysfunction, which is found to precede the development of diverse cardiovascular diseases (CVDs. The aim of this study was to observe the protective effects of PD against H2O2-induced oxidative stress injury (OSI in human umbilical vein endothelial cells (HUVECs and the possible mechanism of PD in OSI treatment. HUVECs were subjected to H2O2 in the absence or presence of PD. It turned out that PD improved cell viability and adhesive and migratory abilities, inhibited the release of lactate dehydrogenase (LDH and reactive oxygen species (ROS, and elevated the content of glutathione peroxidase (GSH-Px and superoxide dismutase (SOD. TUNEL, fluorometric assays, and Western blotting showed that OSI upregulated the apoptosis ratio, the activity of caspase-3 and the level of proapoptotic protein Bax and decreased the level of antiapoptotic protein Bcl-2. However, PD treatment partially reversed these damage effects and Protein Kinase C (PKC activation by thymeleatoxin (THX in turn eliminated the antiapoptotic effect of PD. Furthermore, PD attenuated the H2O2-induced phosphorylation of PKCs α and δ and increased the phosphorylation of PKC ε. Our results indicated that PD might exert protective effects against OSI through various interactions with PKC pathway.

  11. HMGB1 mediates depressive behavior induced by chronic stress through activating the kynurenine pathway.

    Science.gov (United States)

    Wang, Bo; Lian, Yong-Jie; Su, Wen-Jun; Peng, Wei; Dong, Xin; Liu, Lin-Lin; Gong, Hong; Zhang, Ting; Jiang, Chun-Lei; Wang, Yun-Xia

    2017-11-28

    Our previous study has reported that the proactive secretion and role of central high mobility group box 1 (HMGB1) in lipopolysaccharide-induced depressive behavior. Here, the potential mechanism of HMGB1 mediating chronic-stress-induced depression through the kynurenine pathway (KP) was further explored both in vivo and in vitro. Depression model was established with the 4-week chronic unpredictable mild stress (CUMS). Sucrose preference and Barnes maze test were performed to reflect depressive behaviors. The ratio of kynurenine (KYN)/tryptophan (Trp) represented the enzyme activity of indoleamine-2,3-dioxygenase (IDO). Gene transcription and protein expression were assayed by real-time RT-PCR and western-blot or ELISA kit respectively. Along with depressive behaviors, HMGB1 concentrations in the hippocampus and serum substantially increased post 4-week CUMS exposure. Concurrent with the upregulated HMGB1 protein, the regulator of translocation of HMGB1, sirtuin 1 (SIRT1) concentration in the hippocampus remarkably increased. In addition to HMGB1 and SIRT1, IDO, the rate limiting enzyme of KP, was upregulated at the level of mRNA expression and enzyme activity in stressed hippocampi and LPS/HMGB1-treated hippocampal slices. The gene transcription of kynurenine monooxygenase (KMO) and kynureninase (KYNU) in the downstream of KP also increased both in vivo and in vitro. Mice treated with ethyl pyruvate (EP), the inhibitor of HMGB1 releasing, were observed with lower tendency of developing depressive behaviors and reduced activation of enzymes in KP. All of these experiments demonstrate that the role of HMGB1 on the induction of depressive behavior is mediated by KP activation. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. α-Syntrophin is involved in the survival signaling pathway in myoblasts under menadione-induced oxidative stress.

    Science.gov (United States)

    Lim, Jeong-A; Choi, Su Jin; Moon, Jae Yun; Kim, Hye Sun

    2016-05-15

    Dystrophin-deficient muscle is known to be more vulnerable to oxidative stress, but not much is known about the signaling pathway(s) responsible for this phenomenon. α-Syntrophin, a component of the dystrophin-glycoprotein complex, can function as a scaffold protein because of its multiple protein interaction domains. In this study, we investigated the role of α-syntrophin in C2 myoblasts under menadione-induced oxidative stress. We found that the protein level of α-syntrophin was elevated when cells were exposed to menadione. To investigate the function of α-syntrophin during oxidative stress, we established α-syntrophin-overexpressing and knockdown cell lines. The α-syntrophin-overexpressing cells were resistant to the menadione-induced oxidative stress. In addition, survival signalings such as protein kinase B (Akt) phosphorylation and the Bcl-2/BAX ratio were increased in these cells. On the other hand, apoptotic signals such as cleavage of caspase-3 and poly ADP ribose polymerase (PARP) were increased in the α-syntrophin knockdown cells. Furthermore, Ca(2+)influx, which is known to increase when cells are exposed to oxidative stress, decreased in the α-syntrophin-overexpressing cells, but increased in the knockdown cells. These results suggest that α-syntrophin plays a pivotal role in the survival pathway triggered by menadione-induced oxidative stress in cultured myoblasts. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Anxiety and posttraumatic stress symptom pathways to substance use problems among community women experiencing intimate partner violence.

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    Jaquier, Véronique; Flanagan, Julianne C; Sullivan, Tami P

    2015-01-01

    Although intimate partner violence (IPV) has demonstrated strong associations with anxiety and posttraumatic stress, these constructs have rarely been examined simultaneously in IPV research. Gaps in knowledge remain as to their differential associations to substance use problems among IPV-victimized women. A sample of 143 community women self-reported on their current IPV victimization, mental health and substance use problems. Hierarchical entry multiple regressions were used to test for the direct and indirect effects of psychological, physical, and sexual IPV to alcohol and drug problems through anxiety and posttraumatic stress. Higher anxiety symptom severity and higher physical IPV severity were associated with greater alcohol and drug problems. Higher posttraumatic stress symptom severity was associated with greater alcohol and drug problems. Mediation analyses indicated (i) significant indirect pathways of IPV types to alcohol problems through posttraumatic stress symptom severity controlling for anxiety symptom severity and (ii) significant indirect pathways of IPV types to drug problems through anxiety symptom severity controlling for posttraumatic stress symptom severity. In examining the indirect pathways of psychological, physical, and sexual IPV to substance use problems this study highlights that anxiety and posttraumatic stress symptom severity have unique effects on alcohol and drug problems among IPV-victimized women.

  14. Alternative oxidase pathway optimizes photosynthesis during osmotic and temperature stress by regulating cellular ROS, malate valve and antioxidative systems

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    DINAKAR eCHALLABATHULA

    2016-02-01

    Full Text Available The present study reveals the importance of alternative oxidase (AOX pathway in optimizing photosynthesis under osmotic and temperature stress conditions in the mesophyll protoplasts of Pisum sativum. The responses of photosynthesis and respiration were monitored at saturating light intensity of 1000 µmoles m-2 s-1 at 25 oC under a range of sorbitol concentrations from 0.4 M to 1.0M to induce hyper-osmotic stress and by varying the temperature of the thermo-jacketed pre-incubation chamber from 25 oC to 10 oC to impose sub-optimal temperature stress. Compared to controls (0.4 M sorbitol and 25 OC, the mesophyll protoplasts showed remarkable decrease in NaHCO3-dependent O2 evolution (indicator of photosynthetic carbon assimilation, under both hyper-osmotic (1.0 M sorbitol and sub-optimal temperature stress conditions (10 OC, while the decrease in rates of respiratory O2 uptake were marginal. The capacity of AOX pathway increased significantly in parallel to increase in intracellular pyruvate and reactive oxygen species (ROS levels under both hyper-osmotic stress and sub-optimal temperature stress under the background of saturating light. The ratio of redox couple (Malate/OAA related to malate valve increased in contrast to the ratio of redox couple (GSH/GSSG related to antioxidative system during hyper-osmotic stress. Nevertheless, the ratio of GSH/GSSG decreased in the presence of sub-optimal temperature, while the ratio of Malate/OAA showed no visible changes. Also, the redox ratios of pyridine nucleotides increased under hyper-osmotic (NADH/NAD and sub-optimal temperature (NADPH/NADP stresses, respectively. However, upon restriction of AOX pathway by using salicylhydroxamic acid (SHAM, the observed changes in NaHCO3 dependent O2 evolution, cellular ROS, redox ratios of Malate/OAA, NAD(PH/NAD(P and GSH/GSSG were further aggravated under stress conditions with concomitant modulations in NADP-MDH and antioxidant enzymes. Taken together, the

  15. Specificity in mediated pathways by anxiety symptoms linking adolescent stress profiles to depressive symptoms: Results of a moderated mediation approach.

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    Anyan, Frederick; Bizumic, Boris; Hjemdal, Odin

    2018-03-01

    We investigated the specificity in mediated pathways that separately link specific stress dimensions through anxiety to depressive symptoms and the protective utility of resilience. Thus, this study goes beyond lumping together potential mediating and moderating processes that can explain the relations between stress and (symptoms of) psychopathology and the buffering effect of resilience. Ghanaian adolescents between 13 and 17 years (female = 285; male = 244) completed the Adolescent Stress Questionnaire (ASQ), Spielberger State Anxiety Inventory (STAI), Short Mood Feeling Questionnaire (SMFQ) and the Resilience Scale for Adolescents (READ). Independent samples t-test, multivariate analysis of covariance with follow-up tests and moderated mediation analyses were performed. Evidences were found for specificity in the associations between dimensions of adolescent stressors and depressive symptoms independent of transient anxiety. Transient anxiety partly accounted for the indirect effects of eight stress dimensions on depressive symptoms. Except stress of school attendance and school/leisure conflict, resilience moderated the indirect effects of specific stress dimensions on depressive symptoms. Results suggested differences in how Ghanaian adolescents view the various stress dimensions, and mediated pathways associated with anxiety and depressive symptoms. Use of cross-sectional data does not show causal process and temporal changes over time. Findings support and clarify the specificity in the interrelations and mediated pathways among dimensions of adolescent stress, transient anxiety, and depressive symptoms. Conditional process analyses shows that resilience does not only buffer direct, but also indirect psychological adversities. Interventions for good mental health may focus on low resilience subgroups in specific stress dimensions while minimizing transient anxiety. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Consumption of NADPH for 2-HG Synthesis Increases Pentose Phosphate Pathway Flux and Sensitizes Cells to Oxidative Stress

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    Susan J. Gelman

    2018-01-01

    Full Text Available Summary: Gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1 occur in multiple types of human cancer. Here, we show that these mutations significantly disrupt NADPH homeostasis by consuming NADPH for 2-hydroxyglutarate (2-HG synthesis. Cells respond to 2-HG synthesis, but not exogenous administration of 2-HG, by increasing pentose phosphate pathway (PPP flux. We show that 2-HG production competes with reductive biosynthesis and the buffering of oxidative stress, processes that also require NADPH. IDH1 mutants have a decreased capacity to synthesize palmitate and an increased sensitivity to oxidative stress. Our results demonstrate that, even when NADPH is limiting, IDH1 mutants continue to synthesize 2-HG at the expense of other NADPH-requiring pathways that are essential for cell viability. Thus, rather than attempting to decrease 2-HG synthesis in the clinic, the consumption of NADPH by mutant IDH1 may be exploited as a metabolic weakness that sensitizes tumor cells to ionizing radiation, a commonly used anti-cancer therapy. : Using liquid chromatography/mass spectrometry (LC/MS and stable isotope tracing, Gelman et al. find that 2-HG production in cells with IDH1 mutations leads to increased pentose phosphate pathway activity to generate NADPH. Production of 2-HG competes with other NADPH-dependent pathways and sensitizes cells to redox stress. Keywords: 2-hydroxyglutarate, cancer metabolism, LC/MS, metabolomcis, pentose phosphate pathway, redox regulation

  17. Effects of Qingshen Granules on the Oxidative Stress-NF/kB Signal Pathway in Unilateral Ureteral Obstruction Rats.

    Science.gov (United States)

    Jin, Hua; Wang, Yiping; Wang, Dong; Zhang, Lei

    2018-01-01

    Background . The activation of NF-kappa B (NF/kB) signaling pathway plays an important role in the process of epithelial-mesenchymal transition (EMT) and renal interstitial fibrosis (RIF) in renal tubules. The process of oxidative stress reaction in kidney is via excessive reactive oxygen species (ROS) production to activate NF/kB signaling pathway. Qingshen Granule (QSG) is an effective Chinese formula utilized to treat chronic renal failure. Previous studies confirmed that QSG could inhibit RIF in unilateral ureteral obstruction (UUO) rats. In this study, we used UUO rats to investigate the effects of QSG on oxidative stress and the activation of NF/kB signaling. Seventy male Sprague-Dawley (SD) rats were randomly divided into a sham group, UUO model group, Qingshen Granules (QSG) high-dose, medium-dose, and low-dose groups, PDTC group, and candesartan group (10 rats in each group). Our study demonstrated that oxidative stress-NF/kB signal pathway contributed to the formation of UUO renal interstitial fibrosis. QSG may protect against RIF by inhibiting the oxidative stress-NF/kB signal pathway, reducing inflammation, and improving renal tubular EMT.

  18. Taxonomic and functional diversity provides insight into microbial pathways and stress responses in the saline Qinghai Lake, China.

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    Qiuyuan Huang

    Full Text Available Microbe-mediated biogeochemical cycles contribute to the global climate system and have sensitive responses and feedbacks to environmental stress caused by climate change. Yet, little is known about the effects of microbial biodiversity (i.e., taxonmic and functional diversity on biogeochemical cycles in ecosytems that are highly sensitive to climate change. One such sensitive ecosystem is Qinghai Lake, a high-elevation (3196 m saline (1.4% lake located on the Tibetan Plateau, China. This study provides baseline information on the microbial taxonomic and functional diversity as well as the associated stress response genes. Illumina metagenomic and metatranscriptomic datasets were generated from lake water samples collected at two sites (B and E. Autotrophic Cyanobacteria dominated the DNA samples, while heterotrophic Proteobacteria dominated the RNA samples at both sites. Photoheterotrophic Loktanella was also present at both sites. Photosystem II was the most active pathway at site B; while, oxidative phosphorylation was most active at site E. Organisms that expressed photosystem II or oxidative phosphorylation also expressed genes involved in photoprotection and oxidative stress, respectively. Assimilatory pathways associated with the nitrogen cycle were dominant at both sites. Results also indicate a positive relationship between functional diversity and the number of stress response genes. This study provides insight into the stress resilience of microbial metabolic pathways supported by greater taxonomic diversity, which may affect the microbial community response to climate change.

  19. Persistent ER stress induces the spliced leader RNA silencing pathway (SLS, leading to programmed cell death in Trypanosoma brucei.

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    Hanoch Goldshmidt

    2010-01-01

    Full Text Available Trypanosomes are parasites that cycle between the insect host (procyclic form and mammalian host (bloodstream form. These parasites lack conventional transcription regulation, including factors that induce the unfolded protein response (UPR. However, they possess a stress response mechanism, the spliced leader RNA silencing (SLS pathway. SLS elicits shut-off of spliced leader RNA (SL RNA transcription by perturbing the binding of the transcription factor tSNAP42 to its cognate promoter, thus eliminating trans-splicing of all mRNAs. Induction of endoplasmic reticulum (ER stress in procyclic trypanosomes elicits changes in the transcriptome similar to those induced by conventional UPR found in other eukaryotes. The mechanism of up-regulation under ER stress is dependent on differential stabilization of mRNAs. The transcriptome changes are accompanied by ER dilation and elevation in the ER chaperone, BiP. Prolonged ER stress induces SLS pathway. RNAi silencing of SEC63, a factor that participates in protein translocation across the ER membrane, or SEC61, the translocation channel, also induces SLS. Silencing of these genes or prolonged ER stress led to programmed cell death (PCD, evident by exposure of phosphatidyl serine, DNA laddering, increase in reactive oxygen species (ROS production, increase in cytoplasmic Ca(2+, and decrease in mitochondrial membrane potential, as well as typical morphological changes observed by transmission electron microscopy (TEM. ER stress response is also induced in the bloodstream form and if the stress persists it leads to SLS. We propose that prolonged ER stress induces SLS, which serves as a unique death pathway, replacing the conventional caspase-mediated PCD observed in higher eukaryotes.

  20. Chitosan Prevents Gentamicin-Induced Nephrotoxicity via a Carbonyl Stress-Dependent Pathway

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    Chu-Kung Chou

    2015-01-01

    Full Text Available Aminoglycosides are widely used to treat infections; however, their applications are limited by nephrotoxicity. With the increase of antibiotic resistance, the use of aminoglycosides is inevitable. Low-molecular-weight chitosan (LMWC has shown renal protective effects in dialysis patients. However, no study has evaluated LMWC for preventing aminoglycoside-induced nephrotoxicity or determined the mechanisms underlying the renal protective effects. In this study, LMWC (165 or 825 mg/kg/day or metformin (100 mg/kg/day was orally administered for 13 days to rats with nephropathy induced by gentamicin (GM, a kind of aminoglycoside (150 mg/kg/day i.p. for 6 days. Both LMCW doses improved renal function. Serum creatinine levels improved in rats treated with 165 and 825 mg/kg/day LMWC (from 2.14 ± 0.74 mg/dL to 1.26 ± 0.46 mg/dL and 0.69 ± 0.12 mg/dL, resp., P < 0.05. Blood urea nitrogen levels were also improved in these rats (from 73.73 ± 21.13 mg/dL to 58.70 ± 22.71 mg/dL and 28.82 ± 3.84 mg/dL, resp., P < 0.05. Additionally, renal tissue morphology improved after LMWC treatment, and accumulation of renal methylglyoxal, a damage factor associated with carbonyl stress, was reversed. These results show that LMWC prevents GM-induced renal toxicity via a carbonyl stress-dependent pathway.

  1. A diazonium ion cascade from the nitrosation of tolazoline, an imidazoline-containing drug.

    Science.gov (United States)

    Loeppky, Richard N; Shi, Jianzheng; Barnes, Charles L; Geddam, Sailaja

    2008-02-01

    Tolazoline (1-benzylimidazoline), a representative imidazoline-containing drug, reacts readily with nitrite in acetic acid to produce a complex product mixture. Fourteen compounds have been identified as products of this transformation when an 8-fold excess of HNO2 is used. The products, which include N-nitrosoamides, esters, alcohols, and phenylacetic acid, are rationalized as arising from a cascade of reactive diazonium ions. N-Nitrosotolazoline can be isolated from the nitrosation reaction in good yield when the mixture is extracted with CH2Cl2 as the transformation progresses. It nitrosates much more rapidly (50x) than tolazoline to give, among other products, the oxime [1-( N-nitroso-2-imidazolinyl)benzylidene]hydroxylamine, which can also be produced in good yield from the reaction of tolazoline with isopropyl nitrite. At low substrate and nitrite concentrations, the main reaction products are N-nitrosotolazoline, its decomposition product N-2-hydroxyethylphenylacetamide, the above-mentioned oxime, phenyl acetic acid, and 2-hydroxyethyl phenylacetate. The tolazoline nitrosation rate in three buffer systems has been determined at pH 3.4 and 37 degrees C ( kobs = 6.25 x 10 (-5) s (-1) in 0.5 M acetate buffer with a 10 * [NO2(-)] = 250 mM). Because N-nitrosotolazoline exhibits the chemical properties of a direct-acting mutagen and carcinogen, we have used the rate data to estimate its level of formation at nitrite concentrations <3 mM. Cursory examination of the nitrosation chemistry of oxymetazoline, a related drug, is primarily focused at its electron-rich aromatic ring.

  2. Cholinergic anti-inflammatory pathway inhibits neointimal hyperplasia by suppressing inflammation and oxidative stress

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    Dong-Jie Li

    2018-05-01

    Full Text Available Neointimal hyperplasia as a consequence of vascular injury is aggravated by inflammatory reaction and oxidative stress. The α7 nicotinic acetylcholine receptor (α7nAChR is a orchestrator of cholinergic anti-inflammatory pathway (CAP, which refers to a physiological neuro-immune mechanism that restricts inflammation. Here, we investigated the potential role of CAP in neointimal hyperplasia using α7nAChR knockout (KO mice. Male α7nAChR-KO mice and their wild-type control mice (WT were subjected to wire injury in left common carotid artery. At 4 weeks post injury, the injured aortae were isolated for examination. The neointimal hyperplasia after wire injury was significantly aggravated in α7nAChR-KO mice compared with WT mice. The α7nAChR-KO mice had increased collagen contents and vascular smooth muscle cells (VSMCs amount. Moreover, the inflammation was significantly enhanced in the neointima of α7nAChR-KO mice relative to WT mice, evidenced by the increased expression of tumor necrosis factor-α/interleukin-1β, and macrophage infiltration. Meanwhile, the chemokines chemokine (C-C motif ligand 2 and chemokine (CXC motif ligand 2 expression was also augmented in the neointima of α7nAChR-KO mice compared with WT mice. Additionally, the depletion of superoxide dismutase (SOD and reduced glutathione (GSH, and the upregulation of 3-nitrotyrosine, malondialdehyde and myeloperoxidase were more pronounced in neointima of α7nAChR-KO mice compared with WT mice. Accordingly, the protein expression of NADPH oxidase 1 (Nox1, Nox2 and Nox4, was also higher in neointima of α7nAChR-KO mice compared with WT mice. Finally, pharmacologically activation of CAP with a selective α7nAChR agonist PNU-282987, significantly reduced neointima formation, arterial inflammation and oxidative stress after vascular injury in C57BL/6 mice. In conclusion, our results demonstrate that α7nAChR-mediated CAP is a neuro-physiological mechanism that inhibits neointima

  3. Pathways from Trauma to Psychotic Experiences: A Theoretically Informed Model of Posttraumatic Stress in Psychosis

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    Amy Hardy

    2017-05-01

    Full Text Available In recent years, empirical data and theoretical accounts relating to the relationship between childhood victimization and psychotic experiences have accumulated. Much of this work has focused on co-occurring Posttraumatic Stress Disorder or putative causal mechanisms in isolation from each other. The complexity of posttraumatic stress reactions experienced in psychosis remains poorly understood. This paper therefore attempts to synthesize the current evidence base into a theoretically informed, multifactorial model of posttraumatic stress in psychosis. Three trauma-related vulnerability factors are proposed to give rise to intrusions and to affect how people appraise and cope with them. First, understandable attempts to survive trauma become habitual ways of regulating emotion, manifesting in cognitive-affective, behavioral and interpersonal responses. Second, event memories, consisting of perceptual and episodic representations, are impacted by emotion experienced during trauma. Third, personal semantic memory, specifically appraisals of the self and others, are shaped by event memories. It is proposed these vulnerability factors have the potential to lead to two types of intrusions. The first type is anomalous experiences arising from emotion regulation and/or the generation of novel images derived from trauma memory. The second type is trauma memory intrusions reflecting, to varying degrees, the retrieval of perceptual, episodic and personal semantic representations. It is speculated trauma memory intrusions may be experienced on a continuum from contextualized to fragmented, depending on memory encoding and retrieval. Personal semantic memory will then impact on how intrusions are appraised, with habitual emotion regulation strategies influencing people’s coping responses to these. Three vignettes are outlined to illustrate how the model accounts for different pathways between victimization and psychosis, and implications for therapy are

  4. Enhanced tolerance against early and late apoptotic oxidative stress in mammalian neurons through nicotinamidase and sirtuin mediated pathways.

    Science.gov (United States)

    Chong, Zhao Zhong; Maiese, Kenneth

    2008-08-01

    Focus upon therapeutic strategies that intersect between pathways that govern cellular metabolism and cellular survival may offer the greatest impact for the treatment of a number of neurodegenerative and metabolic disorders, such as diabetes mellitus. In this regard, we investigated the role of a Drosophila nicotinamidase (DN) in mammalian SH-SY5Y neuronal cells during oxidative stress. We demonstrate that during free radical exposure to nitric oxide generators DN neuronal expression significantly increased cell survival and blocked cellular membrane injury. Furthermore, DN neuronal expression prevented both apoptotic late DNA degradation and early phosphatidylserine exposure that may serve to modulate inflammatory cell activation in vivo. Nicotinamidase activity that limited nicotinamide cellular concentrations appeared to be necessary for DN neuroprotection, since application of progressive nicotinamide concentrations could abrogate the benefits of DN expression during oxidative stress. Pathways that involved sirtuin activation and SIRT1 were suggested to be vital, at least in part, for DN to confer protection through a series of studies. First, application of resveratrol increased cell survival during oxidative stress either alone or in conjunction with the expression of DN to a similar degree, suggesting that DN may rely upon SIRT1 activation to foster neuronal protection. Second, the overexpression of either SIRT1 or DN in neurons prevented apoptotic injury specifically in neurons expressing these proteins during oxidative stress, advancing the premise that DN and SIRT1 may employ similar pathways for neuronal protection. Third, inhibition of sirtuin activity with sirtinol was detrimental to neuronal survival during oxidative stress and prevented neuronal protection during overexpression of DN or SIRT1, further supporting that SIRT1 activity may be necessary for DN neuroprotection during oxidative stress. Implementation of further work to elucidate the

  5. Unraveling vasotocinergic, isotocinergic and stress pathways after food deprivation and high stocking density in the gilthead sea bream.

    Science.gov (United States)

    Skrzynska, Arleta Krystyna; Martos-Sitcha, Juan Antonio; Martínez-Rodríguez, Gonzalo; Mancera, Juan Miguel

    2018-01-01

    The influence of chronic stress, induced by food deprivation (FD) and/or high stocking density (HSD), was assessed on stress, vasotocinergic and isotocinergic pathways of the gilthead sea bream (Sparus aurata). Fish were randomly assigned to one of the following treatments: (1) fed at low stocking density (LSD-F; 5kg·m -3 ); (2) fed at high stocking density (HSD-F, 40kg·m -3 ); (3) food-deprived at LSD (LSD-FD); and (4) food-deprived at HSD (HSD-FD). After 21days, samples from plasma, liver, hypothalamus, pituitary and head-kidney were collected. Both stressors (FD and HSD) induced a chronic stress situation, as indicated by the elevated cortisol levels, the enhancement in corticotrophin releasing hormone (crh) expression and the down-regulation in corticotrophin releasing hormone binding protein (crhbp) expression. Changes in plasma and liver metabolites confirmed a metabolic adjustment to cope with energy demand imposed by stressors. Changes in avt and it gene expression, as well as in their specific receptors (avtrv1a, avtrv2 and itr) at central (hypothalamus and pituitary) and peripheral (liver and head-kidney) levels, showed that vasotocinergic and isotocinergic pathways are involved in physiological changes induced by FD or HSD, suggesting that different stressors are handled through different stress pathways in S. aurata. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Transcript profiles uncover temporal and stress-induced changes of metabolic pathways in germinating sugar beet seeds

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    Windhövel Andrea

    2008-12-01

    Full Text Available Abstract Background With a cultivation area of 1.75 Mio ha and sugar yield of 16.7 Mio tons in 2006, sugar beet is a crop of great economic importance in Europe. The productivity of sugar beet is determined significantly by seed vigour and field emergence potential; however, little is known about the molecular mechanisms underlying these traits. Both traits exhibit large variations within sugar beet germplasm that have been difficult to ascribe to either environmental or genetic causes. Among potential targets for trait improvement, an enhancement of stress tolerance is considered because of the high negative influence of environmental stresses on trait parameters. Extending our knowledge of genetic and molecular determinants of sugar beet germination, stress response and adaptation mechanisms would facilitate the detection of new targets for breeding crop with an enhanced field emergence potential. Results To gain insight into the sugar beet germination we initiated an analysis of gene expression in a well emerging sugar beet hybrid showing high germination potential under various environmental conditions. A total of 2,784 ESTs representing 2,251 'unigenes' was generated from dry mature and germinating seeds. Analysis of the temporal expression of these genes during germination under non-stress conditions uncovered drastic transcriptional changes accompanying a shift from quiescent to metabolically active stages of the plant life cycle. Assay of germination under stressful conditions revealed 157 genes showing significantly different expression patterns in response to stress. As deduced from transcriptome data, stress adaptation mechanisms included an alteration in reserve mobilization pathways, an accumulation of the osmoprotectant glycine betaine, late embryogenesis abundant proteins and detoxification enzymes. The observed transcriptional changes are supposed to be regulated by ABA-dependent signal transduction pathway. Conclusion This study

  7. Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes.

    Science.gov (United States)

    Dutta, Eryn H; Behnia, Faranak; Boldogh, Istvan; Saade, George R; Taylor, Brandie D; Kacerovský, Marian; Menon, Ramkumar

    2016-02-01

    In women with preterm premature rupture of the membranes (PPROM), increased oxidative stress may accelerate premature cellular senescence, senescence-associated inflammation and proteolysis, which may predispose them to rupture. We demonstrate mechanistic differences between preterm birth (PTB) and PPROM by revealing differences in fetal membrane redox status, oxidative stress-induced damage, distinct signaling pathways and senescence activation. Oxidative stress-associated fetal membrane damage and cell cycle arrest determine adverse pregnancy outcomes, such as spontaneous PTB and PPROM. Fetal membranes and amniotic fluid samples were collected from women with PTB and PPROM. Molecular, biochemical and histologic markers were used to document differences in oxidative stress and antioxidant enzyme status, DNA damage, secondary signaling activation by Ras-GTPase and mitogen-activated protein kinases, and activation of senescence between membranes from the two groups. Oxidative stress was higher and antioxidant enzymes were lower in PPROM compared with PTB. PTB membranes had minimal DNA damage and showed activation of Ras-GTPase and ERK/JNK signaling pathway with minimal signs of senescence. PPROM had higher numbers of cells with DNA damage, prosenescence stress kinase (p38 MAPK) activation and signs of senescence. Samples were obtained retrospectively after delivery. The markers of senescence that we tested are specific but are not sufficient to confirm senescence as the pathology in PPROM. Oxidative stress-induced DNA damage and senescence are characteristics of fetal membranes from PPROM, compared with PTB with intact membranes. PTB and PPROM arise from distinct pathophysiologic pathways. Oxidative stress and oxidative stress-induced cellular damages are likely determinants of the mechanistic signaling pathways and phenotypic outcome. This study is supported by developmental funds to Dr R. Menon from the Department of Obstetrics and Gynecology at The University of

  8. Combinatorial stresses kill pathogenic Candida species

    Science.gov (United States)

    Kaloriti, Despoina; Tillmann, Anna; Cook, Emily; Jacobsen, Mette; You, Tao; Lenardon, Megan; Ames, Lauren; Barahona, Mauricio; Chandrasekaran, Komelapriya; Coghill, George; Goodman, Daniel; Gow, Neil A. R.; Grebogi, Celso; Ho, Hsueh-Lui; Ingram, Piers; McDonagh, Andrew; De Moura, Alessandro P. S.; Pang, Wei; Puttnam, Melanie; Radmaneshfar, Elahe; Romano, Maria Carmen; Silk, Daniel; Stark, Jaroslav; Stumpf, Michael; Thiel, Marco; Thorne, Thomas; Usher, Jane; Yin, Zhikang; Haynes, Ken; Brown, Alistair J. P.

    2012-01-01

    Pathogenic microbes exist in dynamic niches and have evolved robust adaptive responses to promote survival in their hosts. The major fungal pathogens of humans, Candida albicans and Candida glabrata, are exposed to a range of environmental stresses in their hosts including osmotic, oxidative and nitrosative stresses. Significant efforts have been devoted to the characterization of the adaptive responses to each of these stresses. In the wild, cells are frequently exposed simultaneously to combinations of these stresses and yet the effects of such combinatorial stresses have not been explored. We have developed a common experimental platform to facilitate the comparison of combinatorial stress responses in C. glabrata and C. albicans. This platform is based on the growth of cells in buffered rich medium at 30°C, and was used to define relatively low, medium and high doses of osmotic (NaCl), oxidative (H 2O2) and nitrosative stresses (e.g., dipropylenetriamine (DPTA)-NONOate). The effects of combinatorial stresses were compared with the corresponding individual stresses under these growth conditions. We show for the first time that certain combinations of combinatorial stress are especially potent in terms of their ability to kill C. albicans and C. glabrata and/or inhibit their growth. This was the case for combinations of osmotic plus oxidative stress and for oxidative plus nitrosative stress. We predict that combinatorial stresses may be highly signif cant in host defences against these pathogenic yeasts. PMID:22463109

  9. Parenting stress as an indirect pathway to mental health concerns among mothers of children with autism spectrum disorder.

    Science.gov (United States)

    Tomeny, Theodore S

    2017-10-01

    The link between autism spectrum disorder symptoms and maternal stress has been well established, yet many mothers remain resilient to more severe psychopathology. For the current online study, 111 mothers of a child with autism spectrum disorder completed questionnaires about their child's symptoms, their own stress related to parenting, and any psychopathology symptoms they were experiencing. Autism spectrum disorder symptom severity was positively related to both parenting stress and maternal psychopathology symptoms. Furthermore, parenting stress mediated the relation between autism spectrum disorder symptom severity and maternal psychopathology symptoms. These results provide evidence for a pathway through which psychopathology may develop among mothers of children with autism spectrum disorder and a potential point of intervention for clinicians serving this population.

  10. Overexpression of OLE1 enhances stress tolerance and constitutively activates the MAPK HOG pathway in Saccharomyces cerevisiae.

    Science.gov (United States)

    Nasution, Olviyani; Lee, Young Mi; Kim, Eunjung; Lee, Yeji; Kim, Wankee; Choi, Wonja

    2017-03-01

    OLE1 of Saccharomyces cerevisiae encodes the sole and essential Δ-9 desaturase catalyzing the conversion of saturated to unsaturated fatty acids. Upon ectopic overexpression of OLE1 in S. cerevisiae, significant increases in the membrane oleic acid content were observed. OLE1-overexpressing strains displayed enhanced tolerance to various stresses, better proton efflux, lower membrane permeability, and lessened internal hydrogen peroxide content. The OLE1-mediated enhanced stress tolerance was considerably diminished upon deletion of HOG1, which encodes the mitogen-activated protein kinase (MAPK) Hog1 of the high osmolarity glycerol (HOG) pathway. Furthermore, OLE1 overexpression constitutively activated Hog1, which remained in the cytoplasm. Hog1 activation was accomplished through the MAPK kinase kinase (MAPKKK) Ssk2, but not Ste11 and Ssk22, the other MAPKKKs of the HOG pathway. Despite its cytoplasmic location, activated Hog1 was able to activate the expression of its canonical targets, including CTT1, HSP12, and STL1, and further, the cAMP and stress response elements present in the promoter. OLE1 overexpression neither caused nor relieved endoplasmic reticulum stress. Individually or in combination, the physiological and molecular changes caused by OLE1 overexpression may contribute to enhanced tolerance to various types of stress. Biotechnol. Bioeng. 2017;114: 620-631. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. Cold stress-induced brain injury regulates TRPV1 channels and the PI3K/AKT signaling pathway.

    Science.gov (United States)

    Liu, Ying; Liu, Yunen; Jin, Hongxu; Cong, Peifang; Zhang, Yubiao; Tong, Changci; Shi, Xiuyun; Liu, Xuelei; Tong, Zhou; Shi, Lin; Hou, Mingxiao

    2017-09-01

    Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that interacts with several intracellular proteins in vivo, including calmodulin and Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt). TRPV1 activation has been reported to exert neuroprotective effects. The aim of this study was to examine the impact of cold stress on the mouse brain and the underlying mechanisms of TRPV1 involvement. Adult male C57BL/6 mice were subjected to cold stress (4°C for 8h per day for 2weeks). The behavioral deficits of the mice were then measured using the Morris water maze. Expression levels of brain injury-related proteins and mRNA were measured by western blot, immunofluorescence or RT-PCR analysis. The mice displayed behavioral deficits, inflammation and changes in brain injury markers following cold stress. As expected, upregulated TRPV1 expression levels and changes in PI3K/Akt expression were found. The TRPV1 inhibitor reduced the levels of brain injury-related proteins and inflammation. These data suggest that cold stress can induce brain injury, possibly through TRPV1 activation and the PI3K/Akt signaling pathway. Suppression of inflammation by inhibition of TRPV1 and the PI3K/Akt pathway may be helpful to prevent cold stress-induced brain injury. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

    DEFF Research Database (Denmark)

    Zub, Kamila Anna; Sousa, Mirta Mittelstedt Leal de; Sarno, Antonio

    2015-01-01

    of the AKR1C family involved in prostaglandin synthesis contribute to the resistant phenotype. Finally, selected metabolic and oxidative stress response enzymes were targeted by inhibitors, several of which displayed a selective cytotoxicity against the melphalan-resistant cells and should be further...... and pathways not previously associated with melphalan resistance in multiple myeloma cells, including a metabolic switch conforming to the Warburg effect (aerobic glycolysis), and an elevated oxidative stress response mediated by VEGF/IL8-signaling. In addition, up-regulated aldo-keto reductase levels...

  13. Metformin prevents endoplasmic reticulum stress-induced apoptosis through AMPK-PI3K-c-Jun NH2 pathway

    Science.gov (United States)

    Jung, T.W.; Lee, M.W.; Lee, Y.-J.; Kim, S.M.

    2012-01-01

    Type 2 diabetes mellitus is thought to be partially associated with endoplasmic reticulum (ER) stress toxicity on pancreatic beta cells and the result of decreased insulin synthesis and secretion. In this study, we showed that a well-known insulin sensitizer, metformin, directly protects against dysfunction and death of ER stress-induced NIT-1 cells (a mouse pancreatic beta cell line) via AMP-activated protein kinase (AMPK) and phosphatidylinositol-3 (PI3) kinase activation. We also showed that exposure of NIT-1 cells to metformin (5mM) increases cellular resistance against ER stress-induced NIT-1 cell dysfunction and death. AMPK and PI3 kinase inhibitors abolished the effect of metformin on cell function and death. Metformin-mediated protective effects on ER stress-induced apoptosis were not a result of an unfolded protein response or the induced inhibitors of apoptotic proteins. In addition, we showed that exposure of ER stressed-induced NIT-1 cells to metformin decreases the phosphorylation of c-Jun NH(2) terminal kinase (JNK). These data suggest that metformin is an important determinant of ER stress-induced apoptosis in NIT-1 cells and may have implications for ER stress-mediated pancreatic beta cell destruction via regulation of the AMPK-PI3 kinase-JNK pathway.

  14. A Trigger for Opioid Misuse: Chronic Pain and Stress Dysregulate the Mesolimbic Pathway and Kappa Opioid System.

    Science.gov (United States)

    Massaly, Nicolas; Morón, Jose A; Al-Hasani, Ream

    2016-01-01

    Pain and stress are protective mechanisms essential in avoiding harmful or threatening stimuli and ensuring survival. Despite these beneficial roles, chronic exposure to either pain or stress can lead to maladaptive hormonal and neuronal modulations that can result in chronic pain and a wide spectrum of stress-related disorders including anxiety and depression. By inducing allostatic changes in the mesolimbic dopaminergic pathway, both chronic pain and stress disorders affect the rewarding values of both natural reinforcers, such as food or social interaction, and drugs of abuse. Despite opioids representing the best therapeutic strategy in pain conditions, they are often misused as a result of these allostatic changes induced by chronic pain and stress. The kappa opioid receptor (KOR) system is critically involved in these neuronal adaptations in part through its control of dopamine release in the nucleus accumbens. Therefore, it is likely that changes in the kappa opioid system following chronic exposure to pain and stress play a key role in increasing the misuse liability observed in pain patients treated with opioids. In this review, we will discuss how chronic pain and stress-induced pathologies can affect mesolimbic dopaminergic transmission, leading to increased abuse liability. We will also assess how the kappa opioid system may underlie these pathological changes.

  15. A trigger for opioid misuse: Chronic pain and stress dysregulate the mesolimbic pathway and kappa opioid system

    Directory of Open Access Journals (Sweden)

    Nicolas Massaly

    2016-11-01

    Full Text Available Pain and stress are protective mechanisms essential in avoiding harmful or threatening stimuli and ensuring survival. Despite these beneficial roles, chronic exposure to either pain or stress can lead to maladaptive hormonal and neuronal modulations that can result in chronic pain and a wide spectrum of stress-related disorders including anxiety and depression. By inducing allostatic changes in the mesolimbic dopaminergic pathway, both chronic pain and stress disorders affect the rewarding values of both natural reinforcers, such as food or social interaction, and drugs of abuse. Despite opioids representing the best therapeutic strategy in acute pain conditions, they are often misused as a result of these allostatic changes induced by chronic pain and stress. The kappa opioid receptor system is critically involved in these neuronal adaptations in part through its control of dopamine release in the nucleus accumbens. Therefore, it is likely that changes in the kappa opioid system following chronic exposure to pain and stress play a key role in increasing the misuse liability observed in pain patients treated with opioids. In this review, we will discuss how chronic pain and stress-induced pathologies can affect mesolimbic dopaminergic transmission, leading to increased abuse liability. We will also assess how the kappa opioid system may underlie these pathological changes.

  16. BDE-47 induces oxidative stress, activates MAPK signaling pathway, and elevates de novo lipogenesis in the copepod Paracyclopina nana.

    Science.gov (United States)

    Lee, Min-Chul; Puthumana, Jayesh; Lee, Seung-Hwi; Kang, Hye-Min; Park, Jun Chul; Jeong, Chang-Bum; Han, Jeonghoon; Hwang, Dae-Sik; Seo, Jung Soo; Park, Heum Gi; Om, Ae-Son; Lee, Jae-Seong

    2016-12-01

    Brominated flame retardant, 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47), has received grave concerns as a persistent organic pollutant, which is toxic to marine organisms, and a suspected link to endocrine abnormalities. Despite the wide distribution in the marine ecosystem, very little is known about the toxic impairments on marine organisms, particularly on invertebrates. Thus, we examined the adverse effects of BDE-47 on life history trait (development), oxidative markers, fatty acid composition, and lipid accumulation in response to BDE-47-induced stress in the marine copepod Paracyclopina nana. Also, activation level of mitogen-activated protein kinase (MAPK) signaling pathways along with the gene expression profile of de novo lipogenesis (DNL) pathways were addressed. As a result, BDE-47 induced oxidative stress (e.g. reactive oxygen species, ROS) mediated activation of extracellular signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK) signaling cascades in MAPK pathways. Activated MAPK pathways, in turn, induced signal molecules that bind to the transcription factors (TFs) responsible for lipogenesis to EcR, SREBP, ChREBP promoters. Also, the stress stimulated the conversion of saturated fatty acids (SFAs) to polyunsaturated fatty acids (PUFAs), a preparedness of the organism to adapt the observed stress, which could be correlated with the elongase and desaturase gene (e.g. ELO3, Δ5-DES, Δ9-DES) expressions, and then extended to the delayed early post-embryonic development and increased accumulation of lipid droplets in P. nana. This study will provide a better understanding of how BDE-47 effects on marine invertebrates particularly on the copepods, an important link in the marine food chain. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. HMGB1 induces an inflammatory response in endothelial cells via the RAGE-dependent endoplasmic reticulum stress pathway

    International Nuclear Information System (INIS)

    Luo, Ying; Li, Shu-Jun; Yang, Jian; Qiu, Yuan-Zhen; Chen, Fang-Ping

    2013-01-01

    Highlights: •Mechanisms of inflammatory response induced by HMGB1 are incompletely understood. •We found that endoplasmic reticulum stress mediate the inflammatory response induced by HMGB1. •RAGE-mediated ERS pathways are involved in those processes. •We reported a new mechanism for HMGB1 induced inflammatory response. -- Abstract: The high mobility group 1B protein (HMGB1) mediates chronic inflammatory responses in endothelial cells, which play a critical role in atherosclerosis. However, the underlying mechanism is unknown. The goal of our study was to identify the effects of HMGB1 on the RAGE-induced inflammatory response in endothelial cells and test the possible involvement of the endoplasmic reticulum stress pathway. Our results showed that incubation of endothelial cells with HMGB1 (0.01–1 μg/ml) for 24 h induced a dose-dependent activation of endoplasmic reticulum stress transducers, as assessed by PERK and IRE1 protein expression. Moreover, HMGB1 also promoted nuclear translocation of ATF6. HMGB1-mediated ICAM-1 and P-selectin production was dramatically suppressed by PERK siRNA or IRE1 siRNA. However, non-targeting siRNA had no such effects. HMGB1-induced increases in ICAM-1 and P-selectin expression were also inhibited by a specific eIF2α inhibitor (salubrinal) and a specific JNK inhibitor (SP600125). Importantly, a blocking antibody specifically targeted against RAGE (anti-RAGE antibody) decreased ICAM-1, P-selectin and endoplasmic reticulum stress molecule (PERK, eIF2α, IRE1 and JNK) protein expression levels. Collectively, these novel findings suggest that HMGB1 promotes an inflammatory response by inducing the expression of ICAM-1 and P-selectin via RAGE-mediated stimulation of the endoplasmic reticulum stress pathway

  18. Combined effect of water loss and wounding stress on gene activation of metabolic pathways associated with phenolic biosynthesis in carrot

    Directory of Open Access Journals (Sweden)

    Alejandro eBecerra-Moreno

    2015-10-01

    Full Text Available Abstract: The application of postharvest abiotic stresses is an effective strategy to activate the primary and secondary metabolism of plants inducing the accumulation of antioxidant phenolic compounds. In the present study, the effect of water stress applied alone and in combination with wounding stress on the activation of primary (shikimic acid and secondary (phenylpropanoid metabolic pathways related with the accumulation of phenolic compound in plants was evaluated. Carrot (Daucus carota was used as model system for this study, and the effect of abiotic stresses was evaluated at the gene expression level and on the accumulation of metabolites. As control of the study, whole carrots were stored under the same conditions. Results demonstrated that water stress activated the primary and secondary metabolism of carrots, favoring the lignification process. Likewise, wounding stress induced higher activation of the primary and secondary metabolism of carrots as compared to water stress alone, leading to higher accumulation of shikimic acid, phenolic compounds and lignin. Additional water stress applied on wounded carrots exerted a synergistic effect on the wound-response at the gene expression level. For instance, when wounded carrots were treated with water stress, the tissue showed 20- and 14-fold increases in the relative expression of 3-deoxy-D-arabino-heptulosanate synthase and phenylalanine ammonia-lyase genes, respectively. However, since lignification was increased, lower accumulation of phenolic compounds was detected. Indicatively, at 48 h of storage, wounded carrots treated with water stress showed ~31% lower levels of phenolic compounds and ~23% higher lignin content as compared with wounded controls. In the present study, it was demonstrated that water stress is one of the pivotal mechanism of the wound-response in carrot. Results allowed the elucidation of strategies to induce the accumulation of specific primary or secondary

  19. Regulation of the insulin-Akt signaling pathway and glycolysis during dehydration stress in the African clawed frog Xenopus laevis.

    Science.gov (United States)

    Wu, Cheng-Wei; Tessier, Shannon N; Storey, Kenneth B

    2017-12-01

    Estivation is an adaptive stress response utilized by some amphibians during periods of drought in the summer season. In this study, we examine the regulation of the insulin signaling cascade and glycolysis pathway in the African clawed frog Xenopus laevis during the dehydration stress induced state of estivation. We show that in the brain and heart of X. laevis, dehydration reduces the phosphorylation of the insulin growth factor-1 receptor (IGF-1R), and this is followed by similar reductions in the phosphorylation of the Akt and mechanistic target of rapamycin (mTOR) kinase. Interestingly, phosphorylation levels of IGF-1R and mTOR were not affected in the kidney, and phosphorylation levels of P70S6K and the ribosomal S6 protein were elevated during dehydration stress. Animals under estivation are also susceptible to periods of hypoxia, suggesting that glycolysis may also be affected. We observed that protein levels of many glycolytic enzymes remained unchanged during dehydration; however, the hypoxia response factor-1 alpha (HIF-1α) protein was elevated by greater than twofold in the heart during dehydration. Overall, we provide evidence that shows that the insulin signaling pathway in X. laevis is regulated in a tissue-specific manner during dehydration stress and suggests an important role for this signaling cascade in mediating the estivation response.

  20. Identification of genes and pathways associated with aluminum stress and tolerance using transcriptome profiling of wheat near-isogenic lines.

    Science.gov (United States)

    Houde, Mario; Diallo, Amadou Oury

    2008-08-27

    Aluminum is considered the most limiting factor for plant productivity in acidic soils, which cover large areas of the world's potential arable lands. The inhibition of root growth is recognized as the primary effect of Al toxicity. To identify genes associated with Al stress and tolerance, transcriptome analyses of four different wheat lines (2 Al-tolerant and 2 Al sensitive) that differ in their response to Al were performed. Microarray expression profiling revealed that 83 candidate genes are associated with Al stress and 25 are associated with tolerance. The stress-associated genes include important enzymes such as pyruvate dehydrogenase, alternative oxidase, and galactonolactone oxidase, ABC transporter and ascorbate oxido-reducatase. The Al tolerance-associated genes include the ALMT-1 malate transporter, glutathione S-transferase, germin/oxalate oxidase, fructose 1,6-bisphosphatase, cysteine-rich proteins, cytochrome P450 monooxygenase, cellulose synthase, zinc finger transcription factor, disease resistance response protein and F-box containing domain protein. In this survey, we identified stress- and tolerance-associated genes that may be involved in the detoxification of Al and reactive oxygen species. Alternative pathways could help maintain the supply of important metabolites (H2O2, ascorbate, NADH, and phosphate) needed for Al tolerance and root growth. The Al tolerance-associated genes may be key factors that regulate these pathways.

  1. Identification of genes and pathways associated with aluminum stress and tolerance using transcriptome profiling of wheat near-isogenic lines

    Directory of Open Access Journals (Sweden)

    Diallo Amadou

    2008-08-01

    Full Text Available Abstract Background Aluminum is considered the most limiting factor for plant productivity in acidic soils, which cover large areas of the world's potential arable lands. The inhibition of root growth is recognized as the primary effect of Al toxicity. To identify genes associated with Al stress and tolerance, transcriptome analyses of four different wheat lines (2 Al-tolerant and 2 Al sensitive that differ in their response to Al were performed. Results Microarray expression profiling revealed that 83 candidate genes are associated with Al stress and 25 are associated with tolerance. The stress-associated genes include important enzymes such as pyruvate dehydrogenase, alternative oxidase, and galactonolactone oxidase, ABC transporter and ascorbate oxido-reducatase. The Al tolerance-associated genes include the ALMT-1 malate transporter, glutathione S-transferase, germin/oxalate oxidase, fructose 1,6-bisphosphatase, cysteine-rich proteins, cytochrome P450 monooxygenase, cellulose synthase, zinc finger transcription factor, disease resistance response protein and F-box containing domain protein. Conclusion In this survey, we identified stress- and tolerance-associated genes that may be involved in the detoxification of Al and reactive oxygen species. Alternative pathways could help maintain the supply of important metabolites (H2O2, ascorbate, NADH, and phosphate needed for Al tolerance and root growth. The Al tolerance-associated genes may be key factors that regulate these pathways.

  2. Cross-talk between abscisic acid-dependent and abscisic acid-independent pathways during abiotic stress.

    Science.gov (United States)

    Roychoudhury, Aryadeep; Paul, Saikat; Basu, Supratim

    2013-07-01

    Salinity, drought and low temperature are the common forms of abiotic stress encountered by land plants. To cope with these adverse environmental factors, plants execute several physiological and metabolic responses. Both osmotic stress (elicited by water deficit or high salt) and cold stress increase the endogenous level of the phytohormone abscisic acid (ABA). ABA-dependent stomatal closure to reduce water loss is associated with small signaling molecules like nitric oxide, reactive oxygen species and cytosolic free calcium, and mediated by rapidly altering ion fluxes in guard cells. ABA also triggers the expression of osmotic stress-responsive (OR) genes, which usually contain single/multiple copies of cis-acting sequence called abscisic acid-responsive element (ABRE) in their upstream regions, mostly recognized by the basic leucine zipper-transcription factors (TFs), namely, ABA-responsive element-binding protein/ABA-binding factor. Another conserved sequence called the dehydration-responsive element (DRE)/C-repeat, responding to cold or osmotic stress, but not to ABA, occurs in some OR promoters, to which the DRE-binding protein/C-repeat-binding factor binds. In contrast, there are genes or TFs containing both DRE/CRT and ABRE, which can integrate input stimuli from salinity, drought, cold and ABA signaling pathways, thereby enabling cross-tolerance to multiple stresses. A strong candidate that mediates such cross-talk is calcium, which serves as a common second messenger for abiotic stress conditions and ABA. The present review highlights the involvement of both ABA-dependent and ABA-independent signaling components and their interaction or convergence in activating the stress genes. We restrict our discussion to salinity, drought and cold stress.

  3. Water quality assessment using the AREc32 reporter gene assay indicative of the oxidative stress response pathway.

    Science.gov (United States)

    Escher, Beate I; Dutt, Mriga; Maylin, Erin; Tang, Janet Y M; Toze, Simon; Wolf, C Roland; Lang, Matti

    2012-11-01

    The reporter gene assay AREc32 is based on the induction of the Nrf2 mediated oxidative stress response pathway in the human breast cancer cell line MCF7, where eight copies of the antioxidant response element (ARE) are linked to a reporter gene encoding for luciferase. The Nrf2-ARE pathway is responsive to many chemicals that cause oxidative stress, among them a large number of pesticides and skin irritants. We adopted and validated the AREc32 bioassay for water quality testing. tert-Butylhydroquinone served as the positive control, phenol as the negative control and other reactive chemicals were assessed for their specificity. An environmentally relevant reference chemical, benzo(a)pyrene was the most potent inducer of all tested chemicals. The concentration causing an induction ratio (IR) of 1.5 (EC(IR1.5)) was chosen as the effect benchmark value. The assay was applied to 21 water samples ranging from sewage to drinking water, including secondary treatment and various tertiary treatment options (ozonation, biologically activated carbon filtration, membrane filtration, reverse osmosis, advanced oxidation, chlorination, chloramination). The samples were enriched by solid phase extraction. In most samples the oxidative stress response was far more sensitive than cytotoxicity. The primary and secondary treated effluent exceeded the effect threshold IR 1.5 at a relative enrichment factor (REF) of 1, i.e., the native samples were active. All tertiary treated samples were less potent and their EC(IR1.5) lay between REF 1 and 10. The Nrf2 pathway was induced at a REF of approximately 10 for surface waters and drinking water, and above this enrichment cytotoxicity took over in most samples and quenched the induction. The blank (ultrapure water run through the sample enrichment process) was cytotoxic at an REF of 100, which is the limit of concentrations range that can be evaluated. Treatment typically decreased both the cytotoxicity and oxidative stress response apart

  4. Spliced leader RNA silencing (SLS - a programmed cell death pathway in Trypanosoma brucei that is induced upon ER stress

    Directory of Open Access Journals (Sweden)

    Michaeli Shulamit

    2012-05-01

    Full Text Available Abstract Trypanosoma brucei is the causative agent of African sleeping sickness. The parasite cycles between its insect (procyclic form and mammalian hosts (bloodstream form. Trypanosomes lack conventional transcription regulation, and their genes are transcribed in polycistronic units that are processed by trans-splicing and polyadenylation. In trans-splicing, which is essential for processing of each mRNA, an exon, the spliced leader (SL is added to all mRNAs from a small RNA, the SL RNA. Trypanosomes lack the machinery for the unfolded protein response (UPR, which in other eukaryotes is induced under endoplasmic reticulum (ER stress. Trypanosomes respond to such stress by changing the stability of mRNAs, which are essential for coping with the stress. However, under severe ER stress that is induced by blocking translocation of proteins to the ER, treatment of cells with chemicals that induce misfolding in the ER, or extreme pH, trypanosomes elicit the spliced leader silencing (SLS pathway. In SLS, the transcription of the SL RNA gene is extinguished, and tSNAP42, a specific SL RNA transcription factor, fails to bind to its cognate promoter. SLS leads to complete shut-off of trans-splicing. In this review, I discuss the UPR in mammals and compare it to the ER stress response in T. brucei leading to SLS. I summarize the evidence supporting the notion that SLS is a programmed cell death (PCD pathway that is utilized by the parasites to substitute for the apoptosis observed in higher eukaryotes under prolonged ER stress. I present the hypothesis that SLS evolved to expedite the death process, and rapidly remove from the population unfit parasites that, by elimination via SLS, cause minimal damage to the parasite population.

  5. Activation of Inflammatory and Pro-Thrombotic Pathways in Acute Stress Cardiomyopathy

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    Timothy P. Fitzgibbons

    2017-08-01

    Full Text Available Stress cardiomyopathy (SCM is a unique cardiac disorder that more often occurs in women. SCM presents in a similar fashion as acute myocardial infarction (AMI, with chest pain, ECG changes, and congestive heart failure. The primary distinguishing feature is the absence of thrombotic coronary occlusion in SCM. How this reduction in cardiac function occurs in the absence of coronary occlusion remains unknown. Therefore, we tested the hypothesis that a targeted proteomic comparison of patients with acute SCM and AMI might identify relevant mechanistic differences. Blood was drawn in normal controls (n = 6, women with AMI (n = 12, or women with acute SCM (n = 15. Two-week follow-up samples were available in AMI (n = 4 and SCM patients (n = 11. Relative concentrations of 1,310 serum proteins were measured in each of the 48 samples using the SOMAscan assay. Women with AMI had greater myocyte necrosis, as reflected by a higher peak troponin I concentration (AMI 32.03 ± 29.46 vs. SCM 2.68 ± 2.6 ng/ml, p < 0.05. AMI and SCM patients had equivalent reductions in left ventricular ejection fraction [LVEF (% 39 ± 12 vs. 37 ± 12, p = 0.479]. In follow-up, women with SCM had a greater improvement in cardiac function [LVEF (% 60 ± 7 vs. 45 ± 13, p < 0.001]. No differentially expressed proteins were detected (absolute log2-fold change >1; q < 0.05 between AMI and SCM in the acute or recovery phase. However, when we compared normal controls to patients with AMI, there was differential expression of 35 proteins. When we compared normal controls to patients with SCM, 45 proteins were differentially expressed. In comparison to normal controls, biological processes such as complement, coagulation, and inflammation were activated in both AMI and SCM. There were four proteins that showed a non-significant trend to be increased in acute SCM vs. AMI (netrin-1, follistatin-like 3, kallikrein 7

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

    Science.gov (United States)

    Ma, Dongyun; Ding, Huina; 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.

  7. Maternal stress in pregnancy affects myelination and neurosteroid regulatory pathways in the guinea pig cerebellum.

    Science.gov (United States)

    Bennett, Greer A; Palliser, Hannah K; Shaw, Julia C; Palazzi, Kerrin L; Walker, David W; Hirst, Jonathan J

    2017-11-01

    Prenatal stress predisposes offspring to behavioral pathologies. These may be attributed to effects on cerebellar neurosteroids and GABAergic inhibitory signaling, which can be linked to hyperactivity disorders. The aims were to determine the effect of prenatal stress on markers of cerebellar development, a key enzyme in neurosteroid synthesis and the expression of GABA A receptor (GABA A R) subunits involved in neurosteroid signaling. We used a model of prenatal stress (strobe light exposure, 2 h on gestational day 50, 55, 60 and 65) in guinea pigs, in which we have characterized anxiety and neophobic behavioral outcomes. The cerebellum and plasma were collected from control and prenatally stressed offspring at term (control fetus: n = 9 male, n = 7 female; stressed fetus: n = 7 male, n = 8 female) and postnatal day (PND) 21 (control: n = 8 male, n = 8 female; stressed: n = 9 male, n = 6 female). We found that term female offspring exposed to prenatal stress showed decreased expression of mature oligodendrocytes (∼40% reduction) and these deficits improved to control levels by PND21. Reactive astrocyte expression was lower (∼40% reduction) following prenatal stress. GABA A R subunit (δ and α6) expression and circulating allopregnanolone concentrations were not affected by prenatal stress. Prenatal stress increased expression (∼150-250% increase) of 5α-reductase type-1 mRNA in the cerebellum, which may be a neuroprotective response to promote GABAergic inhibition and aid in repair. These observations indicate that prenatal stress exposure has marked effects on the development of the cerebellum. These findings suggest cerebellar changes after prenatal stress may contribute to adverse behavioral outcomes after exposure to these stresses.

  8. The ER stress-mediated mitochondrial apoptotic pathway and MAPKs modulate tachypacing-induced apoptosis in HL-1 atrial myocytes.

    Directory of Open Access Journals (Sweden)

    Jiaojiao Shi

    Full Text Available Cell apoptosis is a contributing factor in the initiation, progression and relapse of atrial fibrillation (AF, a life-threatening illness accompanied with stroke and heart failure. However, the regulatory cascade of apoptosis is intricate and remains unidentified, especially in the setting of AF. The aim of this study was to explore the roles of endoplasmic reticulum (ER stress, mitochondrial apoptotic pathway (MAP, mitogen-activated protein kinases (MAPKs, and their cross-talking in tachypacing-induced apoptosis.HL-1 cells were cultured in the presence of tachypacing for 24 h to simulate atrial tachycardia remodeling. Results showed that tachypacing reduced cell viability measured by the cell counting kit-8, dissipated mitochondrial membrane potential detected by JC-1 staining and resulted in approximately 50% apoptosis examined by Hoechst staining and annexin V/propidium iodide staining. In addition, the proteins involved in ER stress, MAP and MAPKs were universally up-regulated or activated via phosphorylation, as confirmed by western blotting; and reversely silencing of ER stress, caspase-3 (the ultimate executor of MAP and MAPKs with specific inhibitors prior to pacing partially alleviated apoptosis. An inhibitor of ER stress was applied to further investigate the responses of mitochondria and MAPKs to ER stress, and results indicated that suppression of ER stress comprehensively but incompletely attenuated the activation of MAP and MAPKs aroused by tachypacing, with the exception of ERK1/2, one branch of MAPKs.Our study suggested tachypacing-induced apoptosis is regulated by ER stress-mediated MAP and MAPKs. Thus, the above three components are all promising anti-apoptotic targets in AF patients and ER stress appears to play a dominant role due to its comprehensive effects.

  9. Antioxidant properties of glutamine and its role in VEGF-Akt pathways in portal hypertension gastropathy.

    Science.gov (United States)

    Marques, Camila; Licks, Francielli; Zattoni, Ingrid; Borges, Beatriz; de Souza, Luiz Eduardo Rizzo; Marroni, Claudio Augusto; Marroni, Norma Possa

    2013-07-28

    To investigate the effects of glutamine on oxidative/nitrosative stress and the vascular endothelial growth factor (VEGF)-Akt-endothelial nitric oxide synthase (eNOS) signaling pathway in an experimental model of portal hypertension induced by partial portal vein ligation (PPVL). Portal hypertension was induced by PPVL. The PPVL model consists of a partial obstruction of the portal vein, performed using a 20 G blunt needle as a guide, which is gently removed after the procedure. PPVL model was performed for 14 d beginning treatment with glutamine on the seventh day. On the fifteenth day, the mesenteric vein pressure was checked and the stomach was removed to test immunoreactivity and oxidative stress markers. We evaluated the expression and the immunoreactivity of proteins involved in the VEGF-Akt-eNOS pathway by Western blotting and immunohistochemical analysis. Oxidative stress was measured by quantification of the cytosolic concentration of thiobarbituric acid reactive substances (TBARS) as well as the levels of total glutathione (GSH), superoxide dismutase (SOD) activity, nitric oxide (NO) production and nitrotyrosine immunoreactivity. All data are presented as the mean ± SE. The production of TBARS and NO was significantly increased in PPVL animals. A reduction of SOD activity was detected in PPVL + G group. In the immunohistochemical analyses of nitrotyrosine, Akt and eNOS, the PPVL group exhibited significant increases, whereas decreases were observed in the PPVL + G group, but no difference in VEGF was detected between these groups. Western blotting analysis detected increased expression of phosphatidylinositol-3-kinase (PI3K), P-Akt and eNOS in the PPVL group compared with the PPVL + G group, which was not observed for the expression of VEGF when comparing these groups. Glutamine administration markedly alleviated oxidative/nitrosative stress, normalized SOD activity, increased levels of total GSH and blocked NO overproduction as well as the formation of

  10. Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)?

    OpenAIRE

    Elzinga, B.M.; Bremner, J.D.

    2002-01-01

    A model for the posttraumatic stress disorder (PTSD) as a disorder of memory is presented drawing both on psychological and neurobiological data. Evidence on intrusive memories and deficits in declarative memory function in PTSD-patients is reviewed in relation to three brain areas that are involved in memory functioning and the stress response: the hippocampus, amygdala, and the prefrontal cortex. Neurobiological studies have shown that the noradrenergic stress-system is involved in enhanced...

  11. The Brucella abortus virulence regulator, LovhK, is a sensor kinase in the general stress response signalling pathway.

    Science.gov (United States)

    Kim, Hye-Sook; Willett, Jonathan W; Jain-Gupta, Neeta; Fiebig, Aretha; Crosson, Sean

    2014-11-01

    In the intracellular pathogen Brucella abortus, the general stress response (GSR) signalling system determines survival under acute stress conditions in vitro, and is required for long-term residence in a mammalian host. To date, the identity of the Brucella sensor kinase(s) that function to perceive stress and directly activate GSR signalling have remained undefined. We demonstrate that the flavin-binding sensor histidine kinase, LovhK (bab2_0652), functions as a primary B. abortus GSR sensor. LovhK rapidly and specifically phosphorylates the central GSR regulator, PhyR, and activates transcription of a set of genes that closely overlaps the known B. abortus GSR regulon. Deletion of lovhK severely compromises cell survival under defined oxidative and acid stress conditions. We further show that lovhK is required for cell survival during the early phase of mammalian cell infection and for establishment of long-term residence in a mouse infection model. Finally, we present evidence that particular regions of primary structure within the two N-terminal PAS domains of LovhK have distinct sensory roles under specific environmental conditions. This study elucidates new molecular components of a conserved signalling pathway that regulates B. abortus stress physiology and infection biology. © 2014 John Wiley & Sons Ltd.

  12. Alternative Oxidase: A Mitochondrial Respiratory Pathway to Maintain Metabolic and Signaling Homeostasis during Abiotic and Biotic Stress in Plants

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    Greg C. Vanlerberghe

    2013-03-01

    Full Text Available Alternative oxidase (AOX is a non-energy conserving terminal oxidase in the plant mitochondrial electron transport chain. While respiratory carbon oxidation pathways, electron transport, and ATP turnover are tightly coupled processes, AOX provides a means to relax this coupling, thus providing a degree of metabolic homeostasis to carbon and energy metabolism. Beside their role in primary metabolism, plant mitochondria also act as “signaling organelles”, able to influence processes such as nuclear gene expression. AOX activity can control the level of potential mitochondrial signaling molecules such as superoxide, nitric oxide and important redox couples. In this way, AOX also provides a degree of signaling homeostasis to the organelle. Evidence suggests that AOX function in metabolic and signaling homeostasis is particularly important during stress. These include abiotic stresses such as low temperature, drought, and nutrient deficiency, as well as biotic stresses such as bacterial infection. This review provides an introduction to the genetic and biochemical control of AOX respiration, as well as providing generalized examples of how AOX activity can provide metabolic and signaling homeostasis. This review also examines abiotic and biotic stresses in which AOX respiration has been critically evaluated, and considers the overall role of AOX in growth and stress tolerance.

  13. Short-term psychosocial stress protects photoreceptors from damage via corticosterone-mediated activation of the AKT pathway.

    Science.gov (United States)

    Forkwa, Tembei K; Neumann, Inga D; Tamm, Ernst R; Ohlmann, Andreas; Reber, Stefan O

    2014-02-01

    Apoptotic death of photoreceptors in hereditary retinal degenerations can be prevented by neuroprotective molecules. Here, we report that adrenal glucocorticoids (GC) released during psychosocial stress protect photoreceptors from apoptosis after light damage. Psychosocial stress is known to be the main type of stressor humans are exposed to and was induced here in mice by 10h of chronic subordinate colony housing (CSC). Photoreceptor damage was generated by subsequent exposure to white light. Short-term psychosocial stress prior to illumination significantly reduced the number of apoptotic photoreceptors, an effect that was absent in adrenalectomized (ADX) mice. The neuroprotective effect was completely restored in ADX mice substituted with GC. Moreover, phosphorylation of retinal AKT increased following CSC or exogenous GC treatment, an effect that was again absent in ADX mice exposed to CSC. Finally, inhibition of AKT signaling with triciribine blocked the stress- and GC-mediated neuroprotective effects on photoreceptors. In summary, we provide evidence that 1) short-term psychosocial stress protects photoreceptors from light-induced damage and 2) the protective effect is most likely mediated by GC-induced activation of the AKT signaling pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Mitochondrial pathways governing stress resistance, life, and death in the fungal aging model Podospora anserina.

    Science.gov (United States)

    Osiewacz, Heinz D; Brust, Diana; Hamann, Andrea; Kunstmann, Birgit; Luce, Karin; Müller-Ohldach, Mathis; Scheckhuber, Christian Q; Servos, Jörg; Strobel, Ingmar

    2010-06-01

    Work from more than 50 years of research has unraveled a number of molecular pathways that are involved in controlling aging of the fungal model system Podospora anserina. Early research revealed that wild-type strain aging is linked to gross reorganization of the mitochondrial DNA. Later it was shown that aging of P. anserina does also take place, although at a slower pace, when the wild-type specific mitochondrial DNA rearrangements do not occur. Now it is clear that a network of different pathways is involved in the control of aging. Branches of these pathways appear to be connected and constitute a hierarchical system of responses. Although cross talk between the individual pathways seems to be fundamental in the coordination of the overall system, the precise underlying interactions remain to be unraveled. Such a systematic approach aims at a holistic understanding of the process of biological aging, the ultimate goal of modern systems biology.

  15. Changes of MODY signal pathway genes in the endoplasmic reticulum stress in INS-1-3 cells.

    Directory of Open Access Journals (Sweden)

    Yanan Dong

    Full Text Available Metabolic disturbances induce endoplasmic reticulum stress (ERS in pancreatic beta cells. This study aims to investigate whether a common pathway exists in the ERS induced by various chemicals, including high levels of glucose and palmitate in INS-1-3 cells.ERS in INS-1-3 cells was induced by exposure cells to thapsigargin (TG, tunicamycin (TM or palmitic acid (PA +high glucose (HG. Digital gene expression (DGE profiling technique was used to detect differentially expressed genes. The profile of gene expression was detected by gene oncology (GO function and pathway enrichment analysis. Nkx6.1 over-expression was established in INS-1-3 cell lines by lentivirus infection to revert the inhibition of Nkx6.1 expression found in the situation of ERS. Real time reverse transcription polymerase chain reaction (RT-PCR was used to verify the expression changes of key genes. Cell viability was measured by 3-(4, 5-dimethylthiazol-2-yl-2, 5-diphenyltetrazolium bromide (MTT assay. The apoptosis was determined by flow cytometry. INS-1-3 cell function was measured by glucose stimulated insulin secretion test(GSIS.As compared to control, DGE demonstrated that there were 135, 57 and 74 differentially expressed genes in TM, TG and HG+PA groups, respectively. Those differentially expressed genes were enriched to ERS, antigen processing and presentation, protein export pathways, and interestingly, the maturity onset diabetes of the young (MODY pathway. Nkx6.1 is one of common down-regulated gene in MODY signaling pathway among TM, TG and HG+PA groups. Over-expression of Nkx6.1 ameliorated glucolipotoxicity induced apoptosis rate by 45.4%, and increased proliferation by 40.9%. At the same time, GSIS increased by 1.82 folds.MODY pathway genes expression was changed in the state of ERS. Over-expression of Nkx6.1 protected the INS-1-3 cells from glucolipotoxicity.

  16. Gendered Pathways to Young Adult Symptomatology: The Impact of Managing Relationship Stress during Adolescence

    Science.gov (United States)

    Seiffge-Krenke, Inge; Persike, Malte

    2017-01-01

    The transition to adulthood is a critical juncture in the course of psychopathology. This study examined the ways in which earlier capacity to deal with relationship stress during adolescence contributed to an adaptive outcome in emerging adulthood. In a prospective study of 145 individuals, relationship stress, individual coping capacities, and…

  17. The Role of MAPK and Dopaminergic Synapse Signaling Pathways in Antidepressant Effect of Electroacupuncture Pretreatment in Chronic Restraint Stress Rats

    Directory of Open Access Journals (Sweden)

    Xinjing Yang

    2017-01-01

    Full Text Available Acupuncture has demonstrated the function in ameliorating depressive-like behaviors via modulating PKA/CREB signaling pathway. To further confirm the antidepressant mechanism of EA on the mitogen-activated protein kinase (MAPK and dopaminergic synapse signaling pathways, 4 target proteins were detected based on our previous iTRAQ analysis. Rats were randomly divided into control group, model group, and electroacupuncture (EA group. Except for the control group, all rats were subjected to 28 days of chronic restraint stress (CRS protocols to induce depression. In the EA group, EA pretreatment at Baihui (GV20 and Yintang (GV29 was performed daily (1 mA, 2 Hz, discontinuous wave, 20 minutes prior to restraint. The antidepressant-like effect of EA was measured by body weight and open-field test. The protein levels of DAT, Th, Mapt, and Prkc in the hippocampus were examined by using Western blot. The results showed EA could ameliorate the depression-like behaviors and regulate the expression levels of Prkc and Mapt in CRS rats. The effect of EA on DAT and Th expression was minimal. These findings implied that EA pretreatment could alleviate depression through modulating MAPK signaling pathway. The role of EA on dopaminergic synapse signaling pathways needs to be further explored.

  18. Influence of sodium nitrite on protein oxidation and nitrosation of sausages subjected to processing and storage.

    Science.gov (United States)

    Feng, Xianchao; Li, Chenyi; Jia, Xu; Guo, Yan; Lei, Na; Hackman, Robert M; Chen, Lin; Zhou, Guanghong

    2016-06-01

    The influence of NaNO2 content on protein oxidation and nitrosation was investigated in cooked sausages at different concentrations (0, 50, 100, 200 and 400 mg NaNO2/kg). Dependent on concentration, NaNO2 had both anti- and pro-oxidant effects on protein oxidation. The antioxidant effects of NaNO2 on the protein oxidation were evidenced by significantly lower carbonyl contents, higher free amines and lower surface hydrophobicities. The pro-oxidant effects of NaNO2 on protein oxidation resulted in a decrease of sulfhydryls and an increase of disulfide bonds. NaNO2 also improved the protein nitrosation inducing the formation of 3-nitrotyrosine (3-NT). Moreover, 3-NT had significant correlations with parameters of protein oxidation, indicating that 3-NT may be a possible marker for protein oxidation. Results of this study contribute to an understanding of the impact of NaNO2 on food quality and help to identify optimal formulations of cured meat products. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Effect of processed and red meat on endogenous nitrosation and DNA damage.

    Science.gov (United States)

    Joosen, Annemiek M C P; Kuhnle, Gunter G C; Aspinall, Sue M; Barrow, Timothy M; Lecommandeur, Emmanuelle; Azqueta, Amaya; Collins, Andrew R; Bingham, Sheila A

    2009-08-01

    Haem in red meat (RM) stimulates the endogenous production of mutagenic nitroso compounds (NOC). Processed (nitrite-preserved red) meat additionally contains high concentrations of preformed NOC. In two studies, of a fresh RM versus a vegetarian (VEG) diet (six males and six females) and of a nitrite-preserved red meat (PM) versus a VEG diet (5 males and 11 females), we investigated whether processing of meat might increase colorectal cancer risk by stimulating nitrosation and DNA damage. Meat diets contained 420 g (males) or 366 g (females) meat/per day. Faecal homogenates from day 10 onwards were analysed for haem and NOC and associated supernatants for genotoxicity. Means are adjusted for differences in male to female ratios between studies. Faecal NOC concentrations on VEG diets were low (2.6 and 3.5 mmol/g) but significantly higher on meat diets (PM 175 +/- 19 nmol/g versus RM 185 +/- 22 nmol/g; P = 0.75). The RM diet resulted in a larger proportion of nitrosyl iron (RM 78% versus PM 54%; P meat diets (P Meats cured with nitrite have the same effect as fresh RM on endogenous nitrosation but show increased FW-induced oxidative DNA damage.

  20. [Research on change process of nitrosation granular sludge in continuous stirred-tank reactor].

    Science.gov (United States)

    Yin, Fang-Fang; Liu, Wen-Ru; Wang, Jian-Fang; Wu, Peng; Shen, Yao-Liang

    2014-11-01

    In order to investigate the effect of different types of reactors on the nitrosation granular sludge, a continuous stirred-tank reactor (CSTR) was studied, using mature nitrosation granular sludge cultivated in sequencing batch reactor (SBR) as seed sludge. Results indicated that the change of reactor type and influent mode could induce part of granules to lose stability with gradual decrease in sludge settling ability during the initial period of operation. However, the flocs in CSTR achieved fast granulation in the following reactor operation. In spite of the changes of particle size distribution, e. g. the decreasing number of granules with diameter larger than 2.5 mm and the increasing number of granules with diameter smaller than 0.3 mm, granular sludge held the absolute predominance of sludge morphology in CSTR during the entire experimental period. Moreover, results showed that the change of reactor type and influent mode didn't affect the nitrite accumulation rate which was still kept at about 85% in effluent. Additionally, the average activity of the sludge in CSTR was stronger than that of the seed sludge, because the newly generated small particles in CSTR had higher specific reactive activity than the larger granules.

  1. Hesperidin inhibits HeLa cell proliferation through apoptosis mediated by endoplasmic reticulum stress pathways and cell cycle arrest

    International Nuclear Information System (INIS)

    Wang, Yaoxian; Yu, Hui; Zhang, Jin; Gao, Jing; Ge, Xin; Lou, Ge

    2015-01-01

    Hesperidin (30, 5, 9-dihydroxy-40-methoxy-7-orutinosyl flavanone) is a flavanone that is found mainly in citrus fruits and has been shown to have some anti-neoplastic effects. The aim of the present study was to investigate the effect of hesperidin on apoptosis in human cervical cancer HeLa cells and to identify the mechanism involved. Cells were treated with hesperidin (0, 20, 40, 60, 80, and 100 μM) for 24, 48, or 72 h and relative cell viability was assessed using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Hesperidin inhibited the proliferation of HeLa cells in a concentration- and time-dependent manner. Hesperidin-induced apoptosis in HeLa cells was characterized by increased nuclear condensation and DNA fragmentation. Furthermore, increased levels of GADD153/CHOP and GRP78 indicated hesperidin-induced apoptosis in HeLa cells involved a caspase-dependent pathway, presumably downstream of the endoplasmic reticulum stress pathway. Both of these proteins are hallmarks of endoplasmic reticulum stress. Hesperidin also promoted the formation of reactive oxygen species, mobilization of intracellular Ca 2+ , loss of mitochondrial membrane potential (ΔΨm), increased release of cytochrome c and apoptosis-inducing factor from mitochondria, and promoted capase-3 activation. It also arrested HeLa cells in the G0/G1 phase in the cell cycle by downregulating the expression of cyclinD1, cyclinE1, and cyclin-dependent kinase 2 at the protein level. The effect of hesperidin was also verified on the human colon cancer cell HT-29 cells. We concluded that hesperidin inhibited HeLa cell proliferation through apoptosis involving endoplasmic reticulum stress pathways and cell cycle arrest

  2. Lycium barbarum (wolfberry reduces secondary degeneration and oxidative stress, and inhibits JNK pathway in retina after partial optic nerve transection.

    Directory of Open Access Journals (Sweden)

    Hongying Li

    Full Text Available Our group has shown that the polysaccharides extracted from Lycium barbarum (LBP are neuroprotective for retinal ganglion cells (RGCs in different animal models. Protecting RGCs from secondary degeneration is a promising direction for therapy in glaucoma management. The complete optic nerve transection (CONT model can be used to study primary degeneration of RGCs, while the partial optic nerve transection (PONT model can be used to study secondary degeneration of RGCs because primary degeneration of RGCs and secondary degeneration can be separated in location in the same retina in this model; in other situations, these types of degeneration can be difficult to distinguish. In order to examine which kind of degeneration LBP could delay, both CONT and PONT models were used in this study. Rats were fed with LBP or vehicle daily from 7 days before surgery until sacrifice at different time-points and the surviving numbers of RGCs were evaluated. The expression of several proteins related to inflammation, oxidative stress, and the c-jun N-terminal kinase (JNK pathways were detected with Western-blot analysis. LBP did not delay primary degeneration of RGCs after either CONT or PONT, but it did delay secondary degeneration of RGCs after PONT. We found that LBP appeared to exert these protective effects by inhibiting oxidative stress and the JNK/c-jun pathway and by transiently increasing production of insulin-like growth factor-1 (IGF-1. This study suggests that LBP can delay secondary degeneration of RGCs and this effect may be linked to inhibition of oxidative stress and the JNK/c-jun pathway in the retina.

  3. Lycium Barbarum (Wolfberry) Reduces Secondary Degeneration and Oxidative Stress, and Inhibits JNK Pathway in Retina after Partial Optic Nerve Transection

    Science.gov (United States)

    Li, Hongying; Liang, Yuxiang; Chiu, Kin; Yuan, Qiuju; Lin, Bin; Chang, Raymond Chuen-Chung; So, Kwok-Fai

    2013-01-01

    Our group has shown that the polysaccharides extracted from Lycium barbarum (LBP) are neuroprotective for retinal ganglion cells (RGCs) in different animal models. Protecting RGCs from secondary degeneration is a promising direction for therapy in glaucoma management. The complete optic nerve transection (CONT) model can be used to study primary degeneration of RGCs, while the partial optic nerve transection (PONT) model can be used to study secondary degeneration of RGCs because primary degeneration of RGCs and secondary degeneration can be separated in location in the same retina in this model; in other situations, these types of degeneration can be difficult to distinguish. In order to examine which kind of degeneration LBP could delay, both CONT and PONT models were used in this study. Rats were fed with LBP or vehicle daily from 7 days before surgery until sacrifice at different time-points and the surviving numbers of RGCs were evaluated. The expression of several proteins related to inflammation, oxidative stress, and the c-jun N-terminal kinase (JNK) pathways were detected with Western-blot analysis. LBP did not delay primary degeneration of RGCs after either CONT or PONT, but it did delay secondary degeneration of RGCs after PONT. We found that LBP appeared to exert these protective effects by inhibiting oxidative stress and the JNK/c-jun pathway and by transiently increasing production of insulin-like growth factor-1 (IGF-1). This study suggests that LBP can delay secondary degeneration of RGCs and this effect may be linked to inhibition of oxidative stress and the JNK/c-jun pathway in the retina. PMID:23894366

  4. Witnessing stressful events induces glutamatergic synapse pathway alterations and gene set enrichment of positive EPSP regulation within the VTA of adult mice: An ontology based approach

    Science.gov (United States)

    Brewer, Jacob S.

    It is well known that exposure to severe stress increases the risk for developing mood disorders. Currently, the neurobiological and genetic mechanisms underlying the functional effects of psychological stress are poorly understood. Presenting a major obstacle to the study of psychological stress is the inability of current animal models of stress to distinguish between physical and psychological stressors. A novel paradigm recently developed by Warren et al., is able to tease apart the effects of physical and psychological stress in adult mice by allowing these mice to "witness," the social defeat of another mouse thus removing confounding variables associated with physical stressors. Using this 'witness' model of stress and RNA-Seq technology, the current study aims to study the genetic effects of psychological stress. After, witnessing the social defeat of another mouse, VTA tissue was extracted, sequenced, and analyzed for differential expression. Since genes often work together in complex networks, a pathway and gene ontology (GO) analysis was performed using data from the differential expression analysis. The pathway and GO analyzes revealed a perturbation of the glutamatergic synapse pathway and an enrichment of positive excitatory post-synaptic potential regulation. This is consistent with the excitatory synapse theory of depression. Together these findings demonstrate a dysregulation of the mesolimbic reward pathway at the gene level as a result of psychological stress potentially contributing to depressive like behaviors.

  5. Role of the Mixed-Lineage Protein Kinase Pathway in the Metabolic Stress Response to Obesity

    Directory of Open Access Journals (Sweden)

    Shashi Kant

    2013-08-01

    Full Text Available Saturated free fatty acid (FFA is implicated in the metabolic response to obesity. In vitro studies indicate that FFA signaling may be mediated by the mixed-lineage protein kinase (MLK pathway that activates cJun NH2-terminal kinase (JNK. Here, we examined the role of the MLK pathway in vivo using a mouse model of diet-induced obesity. The ubiquitously expressed MLK2 and MLK3 protein kinases have partially redundant functions. We therefore compared wild-type and compound mutant mice that lack expression of MLK2 and MLK3. MLK deficiency protected mice against high-fat-diet-induced insulin resistance and obesity. Reduced JNK activation and increased energy expenditure contribute to the metabolic effects of MLK deficiency. These data confirm that the MLK pathway plays a critical role in the metabolic response to obesity.

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

    International Nuclear Information System (INIS)

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

    2013-01-01

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yanyan; Gao, Chao; Shi, Yanru; Tang, Yuhan; Liu, Liang; Xiong, Ting; Du, Min [Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Ministry of Education Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Xing, Mingyou [Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Liu, Liegang [Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Ministry of Education Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Yao, Ping, E-mail: yaoping@mails.tjmu.edu.cn [Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Ministry of Education Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China); Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030 (China)

    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.

  8. Agmatine ameliorates lipopolysaccharide induced depressive-like behaviour in mice by targeting the underlying inflammatory and oxido-nitrosative mediators.

    Science.gov (United States)

    Gawali, Nitin B; Bulani, Vipin D; Chowdhury, Amrita A; Deshpande, Padmini S; Nagmoti, Dnyaneshwar M; Juvekar, Archana R

    2016-10-01

    Experimental and clinical evidence indicates that pro-inflammatory cytokines, oxidative stress and brain-derived neurotrophic factor (BDNF) signalling mechanisms play a role in the pathophysiology of depression. Agmatine is a neurotransmitter and/or neuromodulator that has emerged as a potential agent to manage diverse central nervous system disorders. Agmatine has been shown to exert antidepressant-like effect. The present study investigated ability of agmatine to abolish the depressive-like behaviour induced by the administration of the lipopolysaccharide (LPS) in mice. Agmatine (20 and 40mg/kg) was administered daily for 7days, then the mice were challenged with saline or LPS (0.83mg/kg; i.p.) on the 7th day. After 24h of LPS administration we tested mice for depressive-like behaviour. LPS treated animals presented an increase in immobility time in the forced-swim test (FST), tail suspension test (TST) which was reversed by agmatine pre-treatment (20 and 40mg/kg). Oxidative/nitrosative stress evoked by LPS was ameliorated by both doses of agmatine in hippocampus (HC) and prefrontal cortex (PFC). Administration of LPS caused an increase in interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), whereas BDNF was down regulated in the HC. Agmatine pre-treatment at 40mg/kg ameliorated LPS-induced neuroinflammation by attenuating brain IL-1β and TNF-α level. In addition, agmatine pre-treatment also up-regulated the BDNF level in the HC. The present study shows that pre-treatment of agmatine is able to abolish the behavioural responses in the FST and TST elicited by the LPS-induced model of depression that may depend on the inhibition of pro-inflammatory mediators, reduction of oxidative stress as well as activation neuroplasticity-related signalling in mice, suggesting that agmatine may constitute an monotherapy/adjuvant for the management of depression associated with inflammation. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Role of the mixed-lineage protein kinase pathway in the metabolic stress response to obesity

    OpenAIRE

    Kant, Shashi; Barrett, Tamera; Vertii, Anastassiia; Noh, Yun Hee; Jung, Dae Young; Kim, Jason K.; Davis, Roger J.

    2013-01-01

    Saturated free fatty acid (FFA) is implicated in the metabolic response to obesity. In vitro studies indicate that FFA signaling may be mediated by the mixed-lineage protein kinase (MLK) pathway that activates cJun NH2-terminal kinase (JNK). Here, we examined the role of the MLK pathway in vivo using a mouse model of diet-induced obesity. The ubiquitously expressed MLK2 and MLK3 protein kinases have partially redundant functions. We therefore compared wild-type and compound mutant mice that l...

  10. The Nitrite-Scavenging Properties of Catechol, Resorcinol, and Hydroquinone: A Comparative Study on Their Nitration and Nitrosation Reactions.

    Science.gov (United States)

    Lu, Yunhao; Dong, Yanzuo; Li, Xueli; He, Qiang

    2016-10-14

    The nitration and nitrosation reactions of catechol, resorcinol, and hydroquinone (0.05 mmol/L) with sodium nitrite (0.05 mmol/L) at pH 3 and 37 °C were studied by using liquid chromatography and mass spectrometry (LC-MS) and atom charge analysis, which was aimed to provide chemical insight into the nitrite-scavenging behavior of polyphenols. The 3 benzenediols showed different mechanisms to scavenge nitrite due to their differences in hydroxyl position. Catechol was nitrated with 1 NO 2 group at the hydroxyl oxygen, and resorcinol was nitrosated with 2 NO groups at the C 2 and C 4 (or C 6 ) positions of the benzene ring. Hydroquinone could scavenge nitrite through both nitration and nitrosation mechanisms. The nitrated hydroquinone had 1 NO 2 group at the hydroxyl oxygen in the molecule, while the nitrosated 1 containing 2 NO groups at the benzene ring might have 3 structure probabilities. The results may provide a structure-activity understanding on the nitrite-scavenging property of polyphenols, so as to promote their application in the food industry for the removal of possibly toxic nitrites found in many vegetables and often in processed meat products. © 2016 Institute of Food Technologists®.

  11. Regulation of apoptotic pathways by Stylophora pistillata (Anthozoa, Pocilloporidae to survive thermal stress and bleaching.

    Directory of Open Access Journals (Sweden)

    Hagit Kvitt

    Full Text Available Elevated seawater temperatures are associated with coral bleaching events and related mortality. Nevertheless, some coral species are able to survive bleaching and recover. The apoptotic responses associated to this ability were studied over 3 years in the coral Stylophora pistillata from the Gulf of Eilat subjected to long term thermal stress. These include caspase activity and the expression profiles of the S. pistillata caspase and Bcl-2 genes (StyCasp and StyBcl-2-like cloned in this study. In corals exposed to thermal stress (32 or 34°C, caspase activity and the expression levels of the StyBcl-2-like gene increased over time (6-48 h and declined to basal levels within 72 h of thermal stress. Distinct transcript levels were obtained for the StyCasp gene, with stimulated expression from 6 to 48 h of 34°C thermal stress, coinciding with the onset of bleaching. Increased cell death was detected in situ only between 6 to 48 h of stress and was limited to the gastroderm. The bleached corals survived up to one month at 32°C, and recovered back symbionts when placed at 24°C. These results point to a two-stage response in corals that withstand thermal stress: (i the onset of apoptosis, accompanied by rapid activation of anti-oxidant/anti-apoptotic mediators that block the progression of apoptosis to other cells and (ii acclimatization of the coral to the chronic thermal stress alongside the completion of symbiosis breakdown. Accordingly, the coral's ability to rapidly curb apoptosis appears to be the most important trait affecting the coral's thermotolerance and survival.

  12. The HOG pathway controls osmotic regulation of transcription via the stress response element (STRE) of the Saccharomyces cerevisiae CTT1 gene.

    Science.gov (United States)

    Schüller, C; Brewster, J L; Alexander, M R; Gustin, M C; Ruis, H

    1994-09-15

    The HOG signal pathway of the yeast Saccharomyces cerevisiae is defined by the PBS2 and HOG1 genes encoding members of the MAP kinase kinase and of the MAP kinase family, respectively. Mutations in this pathway (deletions of PBS2 or HOG1, or point mutations in HOG1) almost completely abolish the induction of transcription by osmotic stress that is mediated by stress response elements (STREs). We have demonstrated previously that STREs also mediate induction of transcription by heat shock, nitrogen starvation and oxidative stress. This study shows that they are also activated by low external pH, sorbate, benzoate or ethanol stress. Induction by these other stress signals appears to be HOG pathway independent. HOG1-dependent osmotic induction of transcription of the CTT1 gene encoding the cytosolic catalase T occurs in the presence of a protein synthesis inhibitor and can be detected rapidly after an increase of tyrosine phosphorylation of Hog1p triggered by high osmolarity. Consistent with a role of STREs in the induction of stress resistance, a number of other stress protein genes (e.g. HSP104) are regulated like CTT1. Furthermore, catalase T was shown to be important for viability under severe osmotic stress, and heat shock was demonstrated to provide cross-protection against osmotic stress.

  13. Ebselen protects mitochondrial function and oxidative stress while inhibiting the mitochondrial apoptosis pathway after acute spinal cord injury.

    Science.gov (United States)

    Jia, Zhi-Qiang; Li, San-Qiang; Qiao, Wei-Qiang; Xu, Wen-Zhong; Xing, Jian-Wu; Liu, Jian-Tao; Song, Hui; Gao, Zhong-Yang; Xing, Bing-Wen; He, Xi-Jing

    2018-05-04

    Ebselen is a fat-soluble small molecule and organic selenium compound that regulates the activity of glutathione peroxidase to alleviate mitochondrial oxidative stress and improve mitochondrial function. In the present study, we aimed to investigate the effects of ebselen on mitochondrial oxidative stress response, mitochondrial apotosis, and motor behaviors after spinal cord injury (SCI). We found that ebselen significantly increased the BBB score in motor behavior, thus suggesting a rescue effect of ebselen on motor function after SCI in rats. Meanwhile, we revealed that ebselen can increase glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities after SCI-this suggests ebselen has an antioxidant effect. Furthermore, the ATP content and Na + -K + -ATPase activity in mitochondria were increased by ebselen after SCI, while the mitochondrial membrane potential (MMP) was decreased by ebselen. The Cytochrome C and Smac release from mitochondria were reduced by ebselen after SCI, thus indicating improved membrane permeability by ebselen. Moreover, the alterations in caspase-3, Bax and Bcl-2 protein expression, as well as the proportion of cell apoptosis were improved by ebselen treatment, which together suggested that ebselen has an inhibitory effect on mitochondrial apotosis pathways after SCI. Taken together, our results suggest that ebselen can inhibit secondary damage caused by spinal cord injury. Indeed it plays a neuroprotective role in spinal cord injury perhaps by improving mitochondrial function and inhibiting the mitochondrial apoptosis pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. S-Nitrosomycothiol Reductase and Mycothiol Are Required for Survival Under Aldehyde Stress and Biofilm Formation in Mycobacterium smegmatis

    Science.gov (United States)

    Vargas, Derek; Hageman, Samantha; Gulati, Megha; Nobile, Clarissa J.; Rawat, Mamta

    2017-01-01

    We show that Mycobacterium smegmatis mutants disrupted in mscR, coding for a dual function S-nitrosomycothiol reductase and formaldehyde dehydrogenase, and mshC, coding for a mycothiol ligase and lacking mycothiol (MSH), are more susceptible to S-nitrosoglutathione (GSNO) and aldehydes than wild type. MSH is a cofactor for MscR, and both mshC and mscR are induced by GSNO and aldehydes. We also show that a mutant disrupted in egtA, coding for a γ-glutamyl cysteine synthetase and lacking in ergothioneine, is sensitive to nitrosative stress but not to aldehydes. In addition, we find that MSH and S-nitrosomycothiol reductase are required for normal biofilm formation in M. smegmatis, suggesting potential new therapeutic pathways to target to inhibit or disrupt biofilm formation. PMID:27321674

  15. Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)?

    Science.gov (United States)

    Elzinga, B M; Bremner, J D

    2002-06-01

    A model for the posttraumatic stress disorder (PTSD) as a disorder of memory is presented drawing both on psychological and neurobiological data. Evidence on intrusive memories and deficits in declarative memory function in PTSD-patients is reviewed in relation to three brain areas that are involved in memory functioning and the stress response: the hippocampus, amygdala, and the prefrontal cortex. Neurobiological studies have shown that the noradrenergic stress-system is involved in enhanced encoding of emotional memories, sensitization, and fear conditioning, by way of its effects on the amygdala. Chronic stress also affects the hippocampus, a brain area involved in declarative memories, suggesting that hippocampal dysfunction may partly account for the deficits in declarative memory in PTSD-patients. Deficits in the medial prefrontal cortex, a structure that normally inhibits the amygdala, may further enhance the effects of the amygdala, thereby increasing the frequency and intensity of the traumatic memories. Thus, by way of its influence on these brain structures, exposure to severe stress may simultaneously result in strong emotional reactions and in difficulties to recall the emotional event. This model is also relevant for understanding the distinction between declarative and non-declarative memory-functions in processing trauma-related information in PTSD. Implications of our model are reviewed.

  16. Acute Lung Injury Results from Innate Sensing of Viruses by an ER Stress Pathway

    Directory of Open Access Journals (Sweden)

    Eike R. Hrincius

    2015-06-01

    Full Text Available Incursions of new pathogenic viruses into humans from animal reservoirs are occurring with alarming frequency. The molecular underpinnings of immune recognition, host responses, and pathogenesis in this setting are poorly understood. We studied pandemic influenza viruses to determine the mechanism by which increasing glycosylation during evolution of surface proteins facilitates diminished pathogenicity in adapted viruses. ER stress during infection with poorly glycosylated pandemic strains activated the unfolded protein response, leading to inflammation, acute lung injury, and mortality. Seasonal strains or viruses engineered to mimic adapted viruses displaying excess glycans on the hemagglutinin did not cause ER stress, allowing preservation of the lungs and survival. We propose that ER stress resulting from recognition of non-adapted viruses is utilized to discriminate “non-self” at the level of protein processing and to activate immune responses, with unintended consequences on pathogenesis. Understanding this mechanism should improve strategies for treating acute lung injury from zoonotic viral infections.

  17. Transcriptome analysis shows activation of the arginine deiminase pathway in Lactococcus lactis as a response to ethanol stress.

    Science.gov (United States)

    Díez, Lorena; Solopova, Ana; Fernández-Pérez, Rocío; González, Miriam; Tenorio, Carmen; Kuipers, Oscar P; Ruiz-Larrea, Fernanda

    2017-09-18

    This paper describes the molecular response of Lactococcus lactis NZ9700 to ethanol. This strain is a well-known nisin producer and a lactic acid bacteria (LAB) model strain. Global transcriptome profiling using DNA microarrays demonstrated a bacterial adaptive response to the presence of 2% ethanol in the culture broth and differential expression of 67 genes. The highest up-regulation was detected for those genes involved in arginine degradation through the arginine deiminase (ADI) pathway (20-40 fold up-regulation). The metabolic responses to ethanol of wild type L. lactis strains were studied and compared to those of regulator-deletion mutants MG∆argR and MG∆ahrC. The results showed that in the presence of 2% ethanol those strains with an active ADI pathway reached higher growth rates when arginine was available in the culture broth than in absence of arginine. In a chemically defined medium strains with an active ADI pathway consumed arginine and produced ornithine in the presence of 2% ethanol, hence corroborating that arginine catabolism is involved in the bacterial response to ethanol. This is the first study of the L. lactis response to ethanol stress to demonstrate the relevance of arginine catabolism for bacterial adaptation and survival in an ethanol containing medium. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Up-regulation of abscisic acid signaling pathway facilitates aphid xylem absorption and osmoregulation under drought stress.

    Science.gov (United States)

    Guo, Huijuan; Sun, Yucheng; Peng, Xinhong; Wang, Qinyang; Harris, Marvin; Ge, Feng

    2016-02-01

    The activation of the abscisic acid (ABA) signaling pathway reduces water loss from plants challenged by drought stress. The effect of drought-induced ABA signaling on the defense and nutrition allocation of plants is largely unknown. We postulated that these changes can affect herbivorous insects. We studied the effects of drought on different feeding stages of pea aphids in the wild-type A17 of Medicago truncatula and ABA signaling pathway mutant sta-1. We examined the impact of drought on plant water status, induced plant defense signaling via the abscisic acid (ABA), jasmonic acid (JA), and salicylic acid (SA) pathways, and on the host nutritional quality in terms of leaf free amino acid content. During the penetration phase of aphid feeding, drought decreased epidermis/mesophyll resistance but increased mesophyll/phloem resistance of A17 but not sta-1 plants. Quantification of transcripts associated with ABA, JA and SA signaling indicated that the drought-induced up-regulation of ABA signaling decreased the SA-dependent defense but increased the JA-dependent defense in A17 plants. During the phloem-feeding phase, drought had little effect on the amino acid concentrations and the associated aphid phloem-feeding parameters in both plant genotypes. In the xylem absorption stage, drought decreased xylem absorption time of aphids in both genotypes because of decreased water potential. Nevertheless, the activation of the ABA signaling pathway increased water-use efficiency of A17 plants by decreasing the stomatal aperture and transpiration rate. In contrast, the water potential of sta-1 plants (unable to close stomata) was too low to support xylem absorption activity of aphids; the aphids on sta-1 plants had the highest hemolymph osmolarity and lowest abundance under drought conditions. Taken together this study illustrates the significance of cross-talk between biotic-abiotic signaling pathways in plant-aphid interaction, and reveals the mechanisms leading to alter

  19. TNF/TNFR1 pathway and endoplasmic reticulum stress are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes

    International Nuclear Information System (INIS)

    Zhang, Fu-Tao; Ding, Yi; Shah, Zahir; Xing, Dan; Gao, Yuan; Liu, Dong Ming; Ding, Ming-Xing

    2014-01-01

    Background and purpose: Quinolones cause obvious cartilaginous lesions in juvenile animals by chondrocyte apoptosis, which results in the restriction of their use in pediatric and adolescent patients. Studies showed that chondrocytes can be induced to produce TNFα, and the cisternae of the endoplasmic reticulum in quinolone-treated chondrocytes become dilated. We investigated whether TNF/TNFR 1 pathway and endoplasmic reticulum stress (ERs) are involved in ofloxacin (a typical quinolone)-induced apoptosis of juvenile canine chondrocytes. Experimental approach: Canine juvenile chondrocytes were treated with ofloxacin. Cell survival and apoptosis rates were determined with MTT method and flow cytometry, respectively. The gene expression levels of the related signaling molecules (TNFα, TNFR 1 , TRADD, FADD and caspase-8) in death receptor pathways and main apoptosis-related molecules (calpain, caspase-12, GADD153 and GRP78) in ERs were measured by qRT-PCR. The gene expression of TNFR 1 was suppressed with its siRNA. The protein levels of TNFα, TNFR 1 and caspase-12 were assayed using Western blotting. Key results: The survival rates decreased while apoptosis rates increased after the chondrocytes were treated with ofloxacin. The mRNA levels of the measured apoptosis-related molecules in death receptor pathways and ERs, and the protein levels of TNFα, TNFR 1 and caspase-12 increased after the chondrocytes were exposed to ofloxacin. The downregulated mRNA expressions of TNFR 1 , Caspase-8 and TRADD, and the decreased apoptosis rates of the ofloxacin-treated chondrocytes occurred after TNFR 1 –siRNA interference. Conclusions and implications: Ofloxacin-induced chondrocyte apoptosis in a time- and concentration-dependent fashion. TNF/TNFR 1 pathway and ERs are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes in the early stage. - Highlights: • Chondrocyte apoptosis is induced by ofloxacin in a time- and concentration-dependent manners.

  20. Mercury induces proliferation and reduces cell size in vascular smooth muscle cells through MAPK, oxidative stress and cyclooxygenase-2 pathways

    Energy Technology Data Exchange (ETDEWEB)

    Aguado, Andrea; Galán, María; Zhenyukh, Olha; Wiggers, Giulia A.; Roque, Fernanda R. [Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), 28029, Madrid (Spain); Redondo, Santiago [Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, 28040, Madrid (Spain); Peçanha, Franck [Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), 28029, Madrid (Spain); Martín, Angela [Departamento de Bioquímica, Fisiología y Genética Molecular, Universidad Rey Juan Carlos, 28922, Alcorcón (Spain); Fortuño, Ana [Área de Ciencias Cardiovasculares, Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008, Pamplona (Spain); Cachofeiro, Victoria [Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, 28040, Madrid (Spain); Tejerina, Teresa [Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, 28040, Madrid (Spain); Salaices, Mercedes, E-mail: mercedes.salaices@uam.es [Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), 28029, Madrid (Spain); and others

    2013-04-15

    Mercury exposure is known to increase cardiovascular risk but the underlying cellular mechanisms remain undetermined. We analyzed whether chronic exposure to HgCl{sub 2} affects vascular structure and the functional properties of vascular smooth muscle cells (VSMC) through oxidative stress/cyclooxygenase-2 dependent pathways. Mesenteric resistance arteries and aortas from Wistar rats treated with HgCl{sub 2} (first dose 4.6 mg kg{sup −1}, subsequent doses 0.07 mg kg{sup −1} day{sup −1}, 30 days) and cultured aortic VSMC stimulated with HgCl{sub 2} (0.05–5 μg/ml) were used. Treatment of rats with HgCl{sub 2} decreased wall thickness of the resistance and conductance vasculature, increased the number of SMC within the media and decreased SMC nucleus size. In VSMCs, exposure to HgCl{sub 2}: 1) induced a proliferative response and a reduction in cell size; 2) increased superoxide anion production, NADPH oxidase activity, gene and/or protein levels of the NADPH oxidase subunit NOX-1, the EC- and Mn-superoxide dismutases and cyclooxygenase-2 (COX-2); 3) induced activation of ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized the proliferative response and the altered cell size induced by HgCl{sub 2}. Blockade of ERK1/2 and p38 signaling pathways abolished the HgCl{sub 2}-induced Nox1 and COX-2 expression and normalized the alterations induced by mercury in cell proliferation and size. In conclusion, long exposure of VSMC to low doses of mercury activates MAPK signaling pathways that result in activation of inflammatory proteins such as NADPH oxidase and COX-2 that in turn induce proliferation of VSMC and changes in cell size. These findings offer further evidence that mercury might be considered an environmental risk factor for cardiovascular disease. - Highlights: ► Chronic HgCl{sub 2} exposure induces vascular remodeling. ► HgCl{sub 2} induces proliferation and decreased cell size in vascular smooth muscle cells. ► HgCl{sub 2} induces

  1. Kaempferol induces apoptosis in HepG2 cells via activation of the endoplasmic reticulum stress pathway.

    Science.gov (United States)

    Guo, Haiqing; Ren, Feng; Zhang, Li; Zhang, Xiangying; Yang, Rongrong; Xie, Bangxiang; Li, Zhuo; Hu, Zhongjie; Duan, Zhongping; Zhang, Jing

    2016-03-01

    Kaempferol is a flavonoid compound that has gained importance due to its antitumor properties; however, the underlying mechanisms remain to be fully understood. The present study aimed to investigate the molecular mechanisms of the antitumor function of kaempferol in HepG2 hepatocellular carcinoma cells. Kaempferol was determined to reduce cell viability, increase lactate dehydrogenase activity and induce apoptosis in a concentration‑ and time‑dependent manner in HepG2 cells. Additionally, kaempferol‑induced apoptosis possibly acts via the endoplasmic reticulum (ER) stress pathway, due to the significant increase in the protein expression levels of glucose‑regulated protein 78, glucose‑regulated protein 94, protein kinase R‑like ER kinase, inositol‑requiring enzyme 1α, partial activating transcription factor 6 cleavage, caspase‑4, C/EBP homologous protein (CHOP) and cleaved caspase‑3. The pro‑apoptotic activity of kaempferol was determined to be due to induction of the ER stress‑CHOP pathway, as: i) ER stress was blocked by 4‑phenyl butyric acid (4‑PBA) pretreatment and knockdown of CHOP with small interfering RNA, which resulted in alleviation of kaempferol‑induced HepG2 cell apoptosis; and ii) transfection with plasmid overexpressing CHOP reversed the protective effect of 4‑PBA in kaempferol‑induced HepG2 cells and increased the apoptotic rate. Thus, kaempferol promoted HepG2 cell apoptosis via induction of the ER stress‑CHOP signaling pathway. These observations indicate that kaempferol may be used as a potential chemopreventive treatment strategy for patients with hepatocellular carcinoma.

  2. Kaempferol induces hepatocellular carcinoma cell death via endoplasmic reticulum stress-CHOP-autophagy signaling pathway

    OpenAIRE

    Guo, Haiqing; Lin, Wei; Zhang, Xiangying; Zhang, Xiaohui; Hu, Zhongjie; Li, Liying; Duan, Zhongping; Zhang, Jing; Ren, Feng

    2017-01-01

    Kaempferol is a flavonoid compound that has gained widespread attention due to its antitumor functions. However, the underlying mechanisms are still not clear. The present study investigated the effect of kaempferol on hepatocellular carcinoma and its underlying mechanisms. Kaempferol induced autophagy in a concentration- and time-dependent manner in HepG2 or Huh7 cells, which was evidenced by the significant increase of autophagy-related genes. Inhibition of autophagy pathway, through 3-meth...

  3. Isoproterenol induces vascular oxidative stress and endothelial dysfunction via a Giα-coupled β2-adrenoceptor signaling pathway.

    Directory of Open Access Journals (Sweden)

    Ana P Davel

    Full Text Available OBJECTIVE: Sustained β-adrenergic stimulation is a hallmark of sympathetic hyperactivity in cardiovascular diseases. It is associated with oxidative stress and altered vasoconstrictor tone. This study investigated the β-adrenoceptor subtype and the signaling pathways implicated in the vascular effects of β-adrenoceptor overactivation. METHODS AND RESULTS: Mice lacking the β1- or β2-adrenoceptor subtype (β1KO, β2KO and wild-type (WT were treated with isoproterenol (ISO, 15 μg.g(-1 x day(-1, 7 days. ISO significantly enhanced the maximal vasoconstrictor response (Emax of the aorta to phenylephrine in WT (+34% and β1KO mice (+35% but not in β2KO mice. The nitric oxide synthase (NOS inhibitor L-NAME abolished the differences in phenylephrine response between the groups, suggesting that ISO impaired basal NO availability in the aorta of WT and β1KO mice. Superoxide dismutase (SOD, pertussis toxin (PTx or PD 98,059 (p-ERK 1/2 inhibitor incubation reversed the hypercontractility of aortic rings from ISO-treated WT mice; aortic contraction of ISO-treated β2KO mice was not altered. Immunoblotting revealed increased aortic expression of Giα-3 protein (+50% and phosphorylated ERK1/2 (+90% and decreased eNOS dimer/monomer ratio in ISO-treated WT mice. ISO enhanced the fluorescence response to dihydroethidium (+100% in aortas from WT mice, indicating oxidative stress that was normalized by SOD, PTx and L-NAME. The ISO effects were abolished in β2KO mice. CONCLUSIONS: The β2-adrenoceptor/Giα signaling pathway is implicated in the enhanced vasoconstrictor response and eNOS uncoupling-mediated oxidative stress due to ISO treatment. Thus, long-term β2-AR activation might results in endothelial dysfunction.

  4. Ameliorating Effect of Piperine on NO-cGMP Pathway in Stress ...

    African Journals Online (AJOL)

    ... dose of PP and SB-203580 enhanced effect of Piperine in stressed mice with no array on locomotor activity with direct influence on Nitric oxide. Piperine produced significant changes in Nitric oxide level which is pathophysiologic mediator(s) of depression, which validate the action of piperine on depression symptoms.

  5. Developmental Pathway Genes and Neural Plasticity Underlying Emotional Learning and Stress-Related Disorders

    Science.gov (United States)

    Maheau, Marissa E.; Ressler, Kerry J.

    2017-01-01

    The manipulation of neural plasticity as a means of intervening in the onset and progression of stress-related disorders retains its appeal for many researchers, despite our limited success in translating such interventions from the laboratory to the clinic. Given the challenges of identifying individual genetic variants that confer increased risk…

  6. Potential Biomarker of Myofibrillar Protein Oxidation in Raw and Cooked Ham: 3-Nitrotyrosine Formed by Nitrosation.

    Science.gov (United States)

    Feng, Xianchao; Li, Chenyi; Ullah, Niamat; Hackman, Robert M; Chen, Lin; Zhou, Guanghong

    2015-12-30

    The stability of cured meat products is increased by the protection of its proteins from oxidation by sodium nitrite (NaNO2) during processing. This study investigated the effects of NaNO2 (0, 50, 100, 200, and 400 mg/kg) on the physiochemical and structural characteristics of myofibrillar protein (MP) in raw and cooked ham. The NaNO2 showed a dose-dependent antioxidant effect, by inhibiting carbonyl formation, dityrosine formation, and denaturation of MP, and a nitrosative effect, through the formation of 3-Nitrotyrosine (3-NT). The 3-NT content within MP of raw ham had distinct negative correlations with sulfhydryl content and surface hydrophobicity. The 3-NT content within MP of cooked ham had significantly negative correlations with carbonyl, sulfhydryl content and turbidity and had significantly positive correlations with disulfide content. These results indicated that 3-NT may be a potential marker for protein oxidation in raw and cooked cured meat products.

  7. Polysaccharide from Angelica sinensis protects H9c2 cells against oxidative injury and endoplasmic reticulum stress by activating the ATF6 pathway.

    Science.gov (United States)

    Niu, Xiaowei; Zhang, Jingjing; Ling, Chun; Bai, Ming; Peng, Yu; Sun, Shaobo; Li, Yingdong; Zhang, Zheng

    2018-01-01

    Objectives Angelica sinensis exerts various pharmacological effects, such as antioxidant and anti-apoptotic activity. This study aimed to investigate the active ingredients in A. sinensis with antioxidant properties and whether A. sinensis polysaccharide (ASP) protects H9c2 cells against oxidative and endoplasmic reticulum (ER) stress. Methods The ingredients of A. sinensis and their targets and related pathways were determined using web-based databases. Markers of oxidative stress, cell viability, apoptosis, and ER stress-related signalling pathways were measured in H9c2 cells treated with hydrogen peroxide (H 2 O 2 ) and ASP. Results The ingredient-pathway-disease network showed that A. sinensis exerted protective effects against oxidative injury through its various active ingredients on regulation of multiple pathways. Subsequent experiments showed that ASP pretreatment significantly decreased H 2 O 2 -induced cytotoxicity and apoptosis in H9c2 cells. ASP pretreatment inhibited H 2 O 2 -induced reactive oxygen species generation, lactic dehydrogenase release, and malondialdehyde production. ASP exerted beneficial effects by inducing activating transcription factor 6 (ATF6) and increasing ATF6 target protein levels, which in turn attenuated ER stress and increased antioxidant activity. Conclusions Our findings indicate that ASP, a major water-soluble component of A. sinensis, exerts protective effects against H 2 O 2 -induced injury in H9c2 cells by activating the ATF6 pathway, thus ameliorating ER and oxidative stress.

  8. Melatonin ameliorates oxidative stress, modulates death receptor pathway proteins, and protects the rat cerebrum against bisphenol-A-induced apoptosis.

    Science.gov (United States)

    El-Missiry, Mohamed A; Othman, Azza I; Al-Abdan, Monera A; El-Sayed, Aml A

    2014-12-15

    Epidemiological reports have indicated a correlation between the increasing of bisphenol-A (BPA) levels in the environment and the incidence of neurodegenerative diseases. In the present study, the protective effect of melatonin on oxidative stress and the death receptor apoptotic proteins in the cerebrum of the bisphenol-A-treated rats were examined. Adult male rats were orally administered melatonin (10mg/kg bw) concurrently with BPA (50mg/kg bw) 3 days a week for 6 weeks. BPA exposure resulted in significant elevations of oxidative stress, as evidenced by the increased malondialdehyde level and the decreased glutathione level and superoxide dismutase activity in the cerebrum. BPA caused an upregulation of p53 and CD95-Fas and activation of capsases-3 and 8, resulting in cerebral cell apoptosis. Melatonin significantly attenuated the BPA-evoked brain oxidative stress, modulated apoptotic-regulating proteins and protected against apoptosis. These data suggest that melatonin modulated important steps in the death receptor apoptotic pathway which likely related to its redox control properties. Melatonin is a promising pharmacological agent for preventing the potential neurotoxicity of BPA following occupational or environmental exposures. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Carvedilol, a third-generation β-blocker prevents oxidative stress-induced neuronal death and activates Nrf2/ARE pathway in HT22 cells

    Energy Technology Data Exchange (ETDEWEB)

    Ouyang, Ying [Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China); Chen, Ziwei [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Tan, Min [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Department of Traditional Chinese Medicine Chemistry, College of Chinese Materia Madica, Guangzhou University of Chinese Medicine, Guangzhou 510006 (China); Liu, Anmin [Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China); Chen, Meihui [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Liu, Jun [Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China); Pi, Rongbiao, E-mail: pirb@mail.sysu.edu.cn [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Fang, Jianpei, E-mail: jpf2005@163.com [Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China)

    2013-11-29

    Highlights: •Carvedilol significantly prevented oxidative stress-induced cell death. •Carvedilol significantly decreased the production of ROS. •Carvedilol activated Nrf2/ARE pathway. •Carvedilol increased the protein levels of HO-1 and NQO-1. -- Abstract: Carvedilol, a nonselective β-adrenoreceptor blocker with pleiotropic activities has been shown to exert neuroprotective effect due to its antioxidant property. However, the neuroprotective mechanism of carvedilol is still not fully uncovered. Nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cellular stress response pathway involved in neuroprotection. Here we investigated the effect of carvedilol on oxidative stress-induced cell death (glutamate 2 mM and H{sub 2}O{sub 2} 600 μM) and the activity of Nrf2/ARE pathway in HT22 hippocampal cells. Carvedilol significantly increased cell viability and decreased ROS in HT22 cells exposed to glutamate or H{sub 2}O{sub 2}. Furthermore, carvedilol activated the Nrf2/ARE pathway in a concentration-dependent manner, and increased the protein levels of heme oxygenase-1(HO-1) and NAD(P)H quinone oxidoreductase-1(NQO-1), two downstream factors of the Nrf2/ARE pathway. Collectively, our results indicate that carvedilol protects neuronal cell against glutamate- and H{sub 2}O{sub 2}-induced neurotoxicity possibly through activating the Nrf2/ARE signaling pathway.

  10. Pathways from assaultive violence to post-traumatic stress, depression, and generalized anxiety symptoms through stressful life events: longitudinal mediation models.

    Science.gov (United States)

    Lowe, S R; Joshi, S; Galea, S; Aiello, A E; Uddin, M; Koenen, K C; Cerdá, M

    2017-10-01

    Assaultive violence events are associated with increased risk for adverse psychiatric outcomes, including post-traumatic stress (PTS), depression, and generalized anxiety. Prior research has indicated that economic, legal, and social stressors that could follow assaultive events may explain the increased risk for adverse psychiatric outcomes, yet longitudinal studies have not adequately examined this pathway. In the current study, we aimed to address this limitation. Participants (N = 1360) were part of a longitudinal population-based study of adults living in Detroit. At three waves, participants indicated their exposure to assaultive violence and economic, legal, and social stressors, and completed inventories of PTS, depression, and generalized anxiety. Longitudinal mediation models were used to test the hypothesized pathway from assaultive violence to each psychiatric outcome. The hypothesized models evidenced good fit with the data and, in each, the paths from Wave 1 (W1) assaultive violence to W2 stressors, and from W2 stressors to W3 symptoms were significant (range of Standardized Estimates: 0.09-0.15, all p violence to W3 symptoms were significant (range of Standardized Estimates: 0.01-0.02, all p violence increase risk for a range of psychiatric symptoms. Although future research is needed, the results suggest that investment in interventions that prevent and mitigate assaultive violence survivors' exposure to such stressors may be an effective way to prevent mental illness in the aftermath of violent assaults.

  11. Developmental pathway genes and neural plasticity underlying emotional learning and stress-related disorders.

    Science.gov (United States)

    Maheu, Marissa E; Ressler, Kerry J

    2017-09-01

    The manipulation of neural plasticity as a means of intervening in the onset and progression of stress-related disorders retains its appeal for many researchers, despite our limited success in translating such interventions from the laboratory to the clinic. Given the challenges of identifying individual genetic variants that confer increased risk for illnesses like depression and post-traumatic stress disorder, some have turned their attention instead to focusing on so-called "master regulators" of plasticity that may provide a means of controlling these potentially impaired processes in psychiatric illnesses. The mammalian homolog of Tailless (TLX), Wnt, and the homeoprotein Otx2 have all been proposed to constitute master regulators of different forms of plasticity which have, in turn, each been implicated in learning and stress-related disorders. In the present review, we provide an overview of the changing distribution of these genes and their roles both during development and in the adult brain. We further discuss how their distinct expression profiles provide clues as to their function, and may inform their suitability as candidate drug targets in the treatment of psychiatric disorders. © 2017 Maheu and Ressler; Published by Cold Spring Harbor Laboratory Press.

  12. Racial discrimination and posttraumatic stress symptoms as pathways to sexual HIV risk behaviors among urban Black heterosexual men.

    Science.gov (United States)

    Bowleg, Lisa; Fitz, Caroline C; Burkholder, Gary J; Massie, Jenne S; Wahome, Rahab; Teti, Michelle; Malebranche, David J; Tschann, Jeanne M

    2014-01-01

    In light of evidence that racial discrimination and posttraumatic stress symptoms (PTSS) are neither rare nor extraordinary for many Black urban men, we examined the relationship between everyday racial discrimination and sexual HIV risk behaviors in a predominantly low-income sample of 526 urban Black heterosexually identified men; 64% of whom were unemployed and 55% of whom reported a history of incarceration. We tested the hypothesis that PTSS would mediate the relationship between everyday racial discrimination and sexual risk. Participants in the predominantly low-income urban sample ranged in age from 18 to 45 (M = 28.80, SD = 7.57). Three multiple regression models were used to test the study's mediational model. As hypothesized, PTSS mediated the relationship between everyday racial discrimination and sexual risk behaviors. Most participants (97%) reported experiences with everyday racial discrimination. Results empirically support the notion of racial discrimination-based traumatic stress as a pathway to Black heterosexual men's increased sexual risk behaviors. Results also highlighted key demographic differences with older men reporting fewer PTSS and sexual risk behaviors compared with younger men. Incarceration was related to both PTSS and sexual risk, underscoring the role that incarceration may play in Black heterosexual men's adverse health outcomes. Our study highlights the need for more qualitative and quantitative research to understand the nature of PTSS in Black heterosexual men and mechanisms such as substance use that may link traumatic experiences and sexual risk. Future research could also assess experiences with childhood sexual abuse, violence, and incarceration to gain a more in-depth understanding of the sources of traumatic stress in Black heterosexual men's lives. We advocate for the development of community-based individual and structural-level interventions to help Black heterosexual men in urban areas develop effective strategies to

  13. Transcriptome characterization and gene expression of Epinephelus spp in endoplasmic reticulum stress-related pathway during betanodavirus infection in vitro

    Directory of Open Access Journals (Sweden)

    Lu Ming-Wei

    2012-11-01

    Full Text Available Abstract Background Grouper (Epinephelus spp is an economically important fish species worldwide. However, viral pathogens such as nervous necrosis virus (NNV have been causing severe infections in the fish, resulting in great loss in the grouper aquaculture industry. Yet, the understanding of the molecular mechanisms underlying the pathogenicity of NNV is still inadequate, mainly due to insufficient genomic information of the host. Results De novo assembly of grouper transcriptome in the grouper kidney (GK cells was conducted by using short read sequencing technology of Solexa/Illumina. A sum of 66,582 unigenes with mean length of 603 bp were obtained, and were annotated according to Gene Ontology (GO and Clusters of Orthologous Groups (COG. In addition, the tag-based digital gene expression (DGE system was used to investigate the gene expression and pathways associated with NNV infection in GK cells. The analysis revealed endoplasmic reticulum (ER stress response was prominently affected in NNV-infected GK cells. A further analysis revealed an interaction between the NNV capsid protein and the ER chaperone immunoglobulin heavy-chain binding protein (BiP. Furthermore, exogenous expression of NNV capsid protein was able to induce XBP-1 mRNA splicing in vivo, suggesting a role of the capsid protein in the NNV-induced ER stress. Conclusions Our data presents valuable genetic information for Epinephelus spp., which will benefit future study in this non-model but economically important species. The DGE profile of ER stress response in NNV-infected cells provides information of many important components associated with the protein processing in ER. Specifically, we showed that the viral capsid protein might play an important role in the ER stress response.

  14. Cre-Mediated Stress Affects Sirtuin Expression Levels, Peroxisome Biogenesis and Metabolism, Antioxidant and Proinflammatory Signaling Pathways

    Science.gov (United States)

    Xiao, Yu; Karnati, Srikanth; Qian, Guofeng; Nenicu, Anca; Fan, Wei; Tchatalbachev, Svetlin; Höland, Anita; Hossain, Hamid; Guillou, Florian; Lüers, Georg H.; Baumgart-Vogt, Eveline

    2012-01-01

    Cre-mediated excision of loxP sites is widely used in mice to manipulate gene function in a tissue-specific manner. To analyze phenotypic alterations related to Cre-expression, we have used AMH-Cre-transgenic mice as a model system. Different Cre expression levels were obtained by investigation of C57BL/6J wild type as well as heterozygous and homozygous AMH-Cre-mice. Our results indicate that Cre-expression itself in Sertoli cells already has led to oxidative stress and lipid peroxidation (4-HNE lysine adducts), inducing PPARα/γ, peroxisome proliferation and alterations of peroxisome biogenesis (PEX5, PEX13 and PEX14) as well as metabolic proteins (ABCD1, ABCD3, MFP1, thiolase B, catalase). In addition to the strong catalase increase, a NRF2- and FOXO3-mediated antioxidative response (HMOX1 of the endoplasmic reticulum and mitochondrial SOD2) and a NF-κB activation were noted. TGFβ1 and proinflammatory cytokines like IL1, IL6 and TNFα were upregulated and stress-related signaling pathways were induced. Sertoli cell mRNA-microarray analysis revealed an increase of TNFR2-signaling components. 53BP1 recruitment and expression levels for DNA repair genes as well as for p53 were elevated and the ones for related sirtuin deacetylases affected (SIRT 1, 3-7) in Sertoli cells. Under chronic Cre-mediated DNA damage conditions a strong downregulation of Sirt1 was observed, suggesting that the decrease of this important coordinator between DNA repair and metabolic signaling might induce the repression release of major transcription factors regulating metabolic and cytokine-mediated stress pathways. Indeed, caspase-3 was activated and increased germ cell apoptosis was observed, suggesting paracrine effects. In conclusion, the observed wide stress-induced effects and metabolic alterations suggest that it is essential to use the correct control animals (Cre/Wt) with matched Cre expression levels to differentiate between Cre-mediated and specific gene-knock out

  15. Cre-mediated stress affects sirtuin expression levels, peroxisome biogenesis and metabolism, antioxidant and proinflammatory signaling pathways.

    Directory of Open Access Journals (Sweden)

    Yu Xiao

    Full Text Available Cre-mediated excision of loxP sites is widely used in mice to manipulate gene function in a tissue-specific manner. To analyze phenotypic alterations related to Cre-expression, we have used AMH-Cre-transgenic mice as a model system. Different Cre expression levels were obtained by investigation of C57BL/6J wild type as well as heterozygous and homozygous AMH-Cre-mice. Our results indicate that Cre-expression itself in Sertoli cells already has led to oxidative stress and lipid peroxidation (4-HNE lysine adducts, inducing PPARα/γ, peroxisome proliferation and alterations of peroxisome biogenesis (PEX5, PEX13 and PEX14 as well as metabolic proteins (ABCD1, ABCD3, MFP1, thiolase B, catalase. In addition to the strong catalase increase, a NRF2- and FOXO3-mediated antioxidative response (HMOX1 of the endoplasmic reticulum and mitochondrial SOD2 and a NF-κB activation were noted. TGFβ1 and proinflammatory cytokines like IL1, IL6 and TNFα were upregulated and stress-related signaling pathways were induced. Sertoli cell mRNA-microarray analysis revealed an increase of TNFR2-signaling components. 53BP1 recruitment and expression levels for DNA repair genes as well as for p53 were elevated and the ones for related sirtuin deacetylases affected (SIRT 1, 3-7 in Sertoli cells. Under chronic Cre-mediated DNA damage conditions a strong downregulation of Sirt1 was observed, suggesting that the decrease of this important coordinator between DNA repair and metabolic signaling might induce the repression release of major transcription factors regulating metabolic and cytokine-mediated stress pathways. Indeed, caspase-3 was activated and increased germ cell apoptosis was observed, suggesting paracrine effects. In conclusion, the observed wide stress-induced effects and metabolic alterations suggest that it is essential to use the correct control animals (Cre/Wt with matched Cre expression levels to differentiate between Cre-mediated and specific gene-knock out

  16. Taurine promotes cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1α pathway.

    Science.gov (United States)

    Jia, Ning; Sun, Qinru; Su, Qian; Dang, Shaokang; Chen, Guomin

    2016-12-01

    Substantial evidence has shown that the oxidative damage to hippocampal neurons is associated with the cognitive impairment induced by adverse stimuli during gestation named prenatal stress (PS). Taurine, a conditionally essential amino acid, possesses multiple roles in the brain as a neuromodulator or antioxidant. In this study, to explore the roles of taurine in PS-induced learning and memory impairment, prenatal restraint stress was set up and Morris water maze (MWM) was employed for testing the cognitive function in the one-month-old rat offspring. The mitochondrial reactive oxygen species (ROS) level,mitochondrial membrane potential (MMP), ATP and cytochrome c oxidase (CcO) activity and apoptosis-related proteins in the hippocampus were detected. The activity of the Akt-cyclic AMP response element-binding protein (CREB)-peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) pathway in the hippocampus was measured. The results showed that high dosage of taurine administration in the early postnatal period attenuated impairment of spatial learning and memory induced by PS. Meanwhile, taurine administration diminished the increase in mitochondrial ROS, and recovered the reduction of MMP, ATP level and the activities of CcO, superoxide dismutase 2 (SOD2) and catalase induced by PS in the hippocampus. In addition, taurine administration recovered PS-suppressed SOD2 expression level. Taurine administration blocked PS-induced decrease in the ratio of Bcl-2/Bax and increase in the ratio of cleaved caspase-3/full-length caspase-3. Notably, taurine inhibited PS-decreased phosphorylation of Akt (pAkt) and phosphorylation of CREB (pCREB), which consequently enhanced the mRNA and protein levels of PGC1α. Taken together, these results suggest that high dosage of taurine administration during the early postnatal period can significantly improve the cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1α pathway. Therefore

  17. Taurine promotes cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1α pathway

    Directory of Open Access Journals (Sweden)

    Ning Jia

    2016-12-01

    Full Text Available Substantial evidence has shown that the oxidative damage to hippocampal neurons is associated with the cognitive impairment induced by adverse stimuli during gestation named prenatal stress (PS. Taurine, a conditionally essential amino acid, possesses multiple roles in the brain as a neuromodulator or antioxidant. In this study, to explore the roles of taurine in PS-induced learning and memory impairment, prenatal restraint stress was set up and Morris water maze (MWM was employed for testing the cognitive function in the one-month-old rat offspring. The mitochondrial reactive oxygen species (ROS level,mitochondrial membrane potential (MMP, ATP and cytochrome c oxidase (CcO activity and apoptosis-related proteins in the hippocampus were detected. The activity of the Akt-cyclic AMP response element-binding protein (CREB-peroxisome proliferator-activated receptor–γ coactivator-1α (PGC1α pathway in the hippocampus was measured. The results showed that high dosage of taurine administration in the early postnatal period attenuated impairment of spatial learning and memory induced by PS. Meanwhile, taurine administration diminished the increase in mitochondrial ROS, and recovered the reduction of MMP, ATP level and the activities of CcO, superoxide dismutase 2 (SOD2 and catalase induced by PS in the hippocampus. In addition, taurine administration recovered PS-suppressed SOD2 expression level. Taurine administration blocked PS-induced decrease in the ratio of Bcl-2/Bax and increase in the ratio of cleaved caspase-3/full-length caspase-3. Notably, taurine inhibited PS-decreased phosphorylation of Akt (pAkt and phosphorylation of CREB (pCREB, which consequently enhanced the mRNA and protein levels of PGC1α. Taken together, these results suggest that high dosage of taurine administration during the early postnatal period can significantly improve the cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1

  18. Selenite exacerbates hepatic insulin resistance in mouse model of type 2 diabetes through oxidative stress-mediated JNK pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Jun, E-mail: hustzhj@hust.edu.cn; Xu, Gang; Bai, Zhaoshuai; Li, Kaicheng; Yan, Junyan; Li, Fen; Ma, Shuai; Xu, Huibi; Huang, Kaixun, E-mail: hxxzrf@hust.edu.cn

    2015-12-15

    Recent evidence suggests a potential pro-diabetic effect of selenite treatment in type 2 diabetics; however, the underlying mechanisms remain elusive. Here we investigated the effects and the underlying mechanisms of selenite treatment in a nongenetic mouse model of type 2 diabetes. High-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice were orally gavaged with selenite at 0.5 or 2.0 mg/kg body weight/day or vehicle for 4 weeks. High-dose selenite treatment significantly elevated fasting plasma insulin levels and insulin resistance index, in parallel with impaired glucose tolerance, insulin tolerance and pyruvate tolerance. High-dose selenite treatment also attenuated hepatic IRS1/Akt/FoxO1 signaling and pyruvate kinase gene expressions, but elevated the gene expressions of phosphoenolpyruvate carboxyl kinase (PEPCK), glucose 6-phosphatase (G6Pase), peroxisomal proliferator-activated receptor-γ coactivator 1α (PGC-1α) and selenoprotein P (SelP) in the liver. Furthermore, high-dose selenite treatment caused significant increases in MDA contents, protein carbonyl contents, and a decrease in GSH/GSSG ratio in the liver, concurrent with enhanced ASK1/MKK4/JNK signaling. Taken together, these findings suggest that high-dose selenite treatment exacerbates hepatic insulin resistance in mouse model of type 2 diabetes, at least in part through oxidative stress-mediated JNK pathway, providing new mechanistic insights into the pro-diabetic effect of selenite in type 2 diabetes. - Highlights: • Selenite exacerbates hepatic insulin resistance in HFD/STZ-induced diabetic mice. • Selenite elevates hepatic gluconeogenesis and reduces glycolysis in diabetic mice. • Selenite exacerbates hepatic oxidative stress and triggers JNK signaling pathway. • Selenite elevates hepatic selenoprotein P expression in diabetic mice.

  19. Selenite exacerbates hepatic insulin resistance in mouse model of type 2 diabetes through oxidative stress-mediated JNK pathway

    International Nuclear Information System (INIS)

    Zhou, Jun; Xu, Gang; Bai, Zhaoshuai; Li, Kaicheng; Yan, Junyan; Li, Fen; Ma, Shuai; Xu, Huibi; Huang, Kaixun

    2015-01-01

    Recent evidence suggests a potential pro-diabetic effect of selenite treatment in type 2 diabetics; however, the underlying mechanisms remain elusive. Here we investigated the effects and the underlying mechanisms of selenite treatment in a nongenetic mouse model of type 2 diabetes. High-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice were orally gavaged with selenite at 0.5 or 2.0 mg/kg body weight/day or vehicle for 4 weeks. High-dose selenite treatment significantly elevated fasting plasma insulin levels and insulin resistance index, in parallel with impaired glucose tolerance, insulin tolerance and pyruvate tolerance. High-dose selenite treatment also attenuated hepatic IRS1/Akt/FoxO1 signaling and pyruvate kinase gene expressions, but elevated the gene expressions of phosphoenolpyruvate carboxyl kinase (PEPCK), glucose 6-phosphatase (G6Pase), peroxisomal proliferator-activated receptor-γ coactivator 1α (PGC-1α) and selenoprotein P (SelP) in the liver. Furthermore, high-dose selenite treatment caused significant increases in MDA contents, protein carbonyl contents, and a decrease in GSH/GSSG ratio in the liver, concurrent with enhanced ASK1/MKK4/JNK signaling. Taken together, these findings suggest that high-dose selenite treatment exacerbates hepatic insulin resistance in mouse model of type 2 diabetes, at least in part through oxidative stress-mediated JNK pathway, providing new mechanistic insights into the pro-diabetic effect of selenite in type 2 diabetes. - Highlights: • Selenite exacerbates hepatic insulin resistance in HFD/STZ-induced diabetic mice. • Selenite elevates hepatic gluconeogenesis and reduces glycolysis in diabetic mice. • Selenite exacerbates hepatic oxidative stress and triggers JNK signaling pathway. • Selenite elevates hepatic selenoprotein P expression in diabetic mice.

  20. Shift work and cardiovascular disease - pathways from circadian stress to morbidity.

    Science.gov (United States)

    Puttonen, Sampsa; Härmä, Mikko; Hublin, Christer

    2010-03-01

    In order to establish a causal relation between shift work and cardiovascular disease (CVD), we need to verify the pathways from the former to the latter. This paper aims to review the current knowledge of the mechanisms between shift work and CVD. Shift work can increase the risk of CVD by several interrelated psychosocial, behavioral, and physiological mechanisms. The psychosocial mechanisms relate to difficulties in controlling working hours, decreased work-life balance, and poor recovery following work. The most probable behavioral changes are weight gain and smoking. The plausible physiological and biological mechanisms are related to the activation of the autonomic nervous system, inflammation, changed lipid and glucose metabolism, and related changes in the risk for atherosclerosis, metabolic syndrome, and type II diabetes. The data provide evidence for possible disease mechanisms between shift work and CVD, but compelling evidence on any specific mechanism is missing.

  1. Molecular profiling of ALDH1+ colorectal cancer stem cells reveals preferential activation of MAPK, FAK, and oxidative stress prosurvival signalling pathways

    DEFF Research Database (Denmark)

    Vishnubalaji, Radhakrishnan; Manikandan, Muthurangan; Fahad, Mohamed

    2018-01-01

    enrichment related to DNA damage, MAPK, FAK, oxidative stress response, and Wnt signalling. ALDH+ cells showed enhanced ROS stress resistance, whereas MAPK/FAK pathway pharmacologic inhibition limited their survival. Conversely, 5-fluorouracil increased the ALDH+ cell fraction among the SW403, HCT116 and SW.......006) and poor DFS (p = 0.05), thus implicating ALDH1A1 and POU5F1 in CRC prognosis. Our data reveal distinct molecular signature of ALDH+ CSCs in CRC and suggest pathways relevant for successful targeted therapies and management of CRC....

  2. Perfluorononanoic acid-induced apoptosis in rat spleen involves oxidative stress and the activation of caspase-independent death pathway

    International Nuclear Information System (INIS)

    Fang, Xuemei; Feng, Yixing; Wang, Jianshe; Dai, Jiayin

    2010-01-01

    Perfluoroalkyl acid (PFAA)-induced apoptosis has been reported in many cell types. However, minimal information on its mode of action is available. This study explored the possible involvement of apoptotic signaling pathways in a nine-carbon-chain length PFAA-perfluorononanoic acid (PFNA)-induced splenocyte apoptosis. After a 14-day exposure to PFNA, rat spleens showed dose-dependent levels of apoptosis. The production of pro-inflammatory and anti-inflammatory cytokines was significantly increased and decreased, respectively. However, protein levels of tumor necrosis factor receptor 1 (TNFR1), fas-associated protein with death domain (FADD), caspase 8 and caspase 3, which are involved in inflammation-related and caspase-dependent apoptosis, were discordant. Peroxisome proliferator-activated receptors alpha (PPARα) and PPARγ genes expression was up-regulated in rats treated with 3 or 5 mg/kg/day of PFNA, and the level of hydrogen peroxide (H 2 O 2 ) increased concurrently in rats treated with the highest dose. Moreover, superoxide dismutase (SOD) activity and Bcl-2 protein levels were dramatically decreased in spleens after treatment with 3 and 5 mg/kg/day of PFNA. However, protein levels of Bax were unchanged. Apoptosis-inducing factor (AIF), an initiator of caspase-independent apoptosis, was significantly increased in all PFNA-dosed rats. Thus, oxidative stress and the activation of a caspase-independent apoptotic signaling pathway contributed to PFNA-induced apoptosis in rat splenocytes.

  3. Pathways involving traumatic losses, worry about family, adult separation anxiety and posttraumatic stress symptoms amongst refugees from West Papua.

    Science.gov (United States)

    Tay, Alvin Kuowei; Rees, Susan; Chen, Jack; Kareth, Moses; Silove, Derrick

    2015-10-01

    There is some evidence that adult separation anxiety disorder (ASAD) symptoms are closely associated with posttraumatic stress disorder (PTSD) amongst refugees exposed to traumatic events (TEs), but the pathways involved remain to be elucidated. A recent study suggests that separation anxiety disorder precedes and predicts onset of PTSD. We examined a path model testing whether ASAD symptoms and worry about family mediated the path from traumatic losses to PTSD symptoms amongst 230 refugees from West Papua. Culturally adapted measures were applied to assess TE exposure and symptoms of ASAD and PTSD. A structural equation model indicated that ASAD symptoms played an important role in mediating the effects of traumatic losses and worry about family in the pathway to PTSD symptoms. Although based on cross-sectional data, our findings suggest that ASAD symptoms may play a role in the path from traumatic losses to PTSD amongst refugees. We propose an evolutionary model in which the ASAD and PTSD reactions represent complementary survival responses designed to protect the individual and close attachments from external threats. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. The cAMP-PKA Signaling Pathway Regulates Pathogenicity, Hyphal Growth, Appressorial Formation, Conidiation, and Stress Tolerance in Colletotrichum higginsianum.

    Science.gov (United States)

    Zhu, Wenjun; Zhou, Man; Xiong, Zeyang; Peng, Fang; Wei, Wei

    2017-01-01

    Colletotrichum higginsianum is an economically important pathogen that causes anthracnose disease in a wide range of cruciferous crops. Understanding the mechanisms of the cruciferous plant- C. higginsianum interactions will be important in facilitating efficient control of anthracnose diseases. The cAMP-PKA signaling pathway plays important roles in diverse physiological processes of multiple pathogens. C. higginsianum contains two genes, ChPKA1 and ChPKA2 , that encode the catalytic subunits of cyclic AMP (cAMP)-dependent protein kinase A (PKA). To analyze the role of cAMP signaling pathway in pathogenicity and development in C. higginsianum , we characterized ChPKA1 and ChPKA2 genes, and adenylate cyclase ( ChAC ) gene. The ChPKA1 and ChAC deletion mutants were unable to cause disease and significantly reduced in hyphal growth, tolerance to cell wall inhibitors, conidiation, and appressorial formation with abnormal germ tubes, but they had an increased tolerance to elevated temperatures and exogenous H 2 O 2 . In contrast, the ChPKA2 mutant had no detectable alteration of phenotypes, suggesting that ChPKA1 contributes mainly to PKA activities in C. higginsianum . Moreover, we failed to generate Δ ChPKA1ChPKA2 double mutant, indicating that deletion of both PKA catalytic subunits is lethal in C. higginsianum and the two catalytic subunits possibly have overlapping functions. These results indicated that ChPKA1 is the major PKA catalytic subunit in cAMP-PKA signaling pathway and plays significant roles in hyphal growth, pathogenicity, appressorial formation, conidiation, and stress tolerance in C. higginsianum .

  5. The cAMP-PKA Signaling Pathway Regulates Pathogenicity, Hyphal Growth, Appressorial Formation, Conidiation, and Stress Tolerance in Colletotrichum higginsianum

    Directory of Open Access Journals (Sweden)

    Wenjun Zhu

    2017-07-01

    Full Text Available Colletotrichum higginsianum is an economically important pathogen that causes anthracnose disease in a wide range of cruciferous crops. Understanding the mechanisms of the cruciferous plant–C. higginsianum interactions will be important in facilitating efficient control of anthracnose diseases. The cAMP-PKA signaling pathway plays important roles in diverse physiological processes of multiple pathogens. C. higginsianum contains two genes, ChPKA1 and ChPKA2, that encode the catalytic subunits of cyclic AMP (cAMP-dependent protein kinase A (PKA. To analyze the role of cAMP signaling pathway in pathogenicity and development in C. higginsianum, we characterized ChPKA1 and ChPKA2 genes, and adenylate cyclase (ChAC gene. The ChPKA1 and ChAC deletion mutants were unable to cause disease and significantly reduced in hyphal growth, tolerance to cell wall inhibitors, conidiation, and appressorial formation with abnormal germ tubes, but they had an increased tolerance to elevated temperatures and exogenous H2O2. In contrast, the ChPKA2 mutant had no detectable alteration of phenotypes, suggesting that ChPKA1 contributes mainly to PKA activities in C. higginsianum. Moreover, we failed to generate ΔChPKA1ChPKA2 double mutant, indicating that deletion of both PKA catalytic subunits is lethal in C. higginsianum and the two catalytic subunits possibly have overlapping functions. These results indicated that ChPKA1 is the major PKA catalytic subunit in cAMP-PKA signaling pathway and plays significant roles in hyphal growth, pathogenicity, appressorial formation, conidiation, and stress tolerance in C. higginsianum.

  6. Loss of catalase increases malignant mouse keratinocyte cell growth through activation of the stress activated JNK pathway.

    Science.gov (United States)

    Hanke, Neale T; Finch, Joanne S; Bowden, G Timothy

    2008-05-01

    A cell line that produces mouse squamous cell carcinoma (6M90) was modified to develop a cell line with an introduced Tet-responsive catalase transgene (MTOC2). We have previously reported that the overexpressed catalase in the MTOC2 cells reverses the malignant phenotype in part by decreasing epidermal growth factor receptor (EGFR) signaling. With this work we expanded the investigation into the differences between these two cell lines. We found that the decreased EGFR pathway activity of the MTOC2 cells is not because of reduced autocrine secretion of an epidermal growth factor (EGF) ligand but rather because of lower basal receptor activity. Phosphorylated levels of the mitogen-activated protein kinase (MAPK) members JNK and p38 were both higher in the 6M90 cells with low catalase when compared with the MTOC2 cell line. Although treatment with an EGFR inhibitor, AG1478, blocked the increased activity of JNK in the 6M90 cells, a similar effect was not observed for p38. Basal levels of downstream c-jun transcription were also found to be higher in the 6M90 cells versus MTOC2 cells. Activated p38 was found to down-regulate the JNK MAPK pathway in the 6M90 cells. However, the 6M90 cells contain constitutively high levels of phosphorylated JNK, generating higher levels of phosphorylated c-jun and total c-jun than those in the MTOC2 cells. Inhibition of JNK activity in the 6M90 cells reduced AP-1 transcription and cell proliferation. The data confirm the inhibitory effects of catalase on tumor cell growth, specifically through a ligand-independent decrease in the stress activated JNK pathway. (c) 2007 Wiley-Liss, Inc.

  7. Low-level shear stress promotes migration of liver cancer stem cells via the FAK-ERK1/2 signalling pathway.

    Science.gov (United States)

    Sun, Jinghui; Luo, Qing; Liu, Lingling; Song, Guanbin

    2018-07-28

    Cancer stem cells (CSCs) are a small subpopulation of tumour cells that have been proposed to be responsible for cancer initiation, chemotherapy resistance and cancer recurrence. Shear stress activated cellular signalling is involved in cellular migration, proliferation and differentiation. However, little is known about the effects of shear stress on the migration of liver cancer stem cells (LCSCs). Here, we studied the effects of shear stress that are generated from a parallel plated flow chamber system, on LCSC migration and the activation of focal adhesion kinase (FAK) and extracellular signal regulated kinase1/2 (ERK1/2), using transwell assay and western blot, respectively. We found that 2 dyne/cm 2 shear stress loading for 6 h promotes LCSC migration and activation of the FAK and ERK1/2 signalling pathways, whereas treatment with the FAK phosphorylation inhibitor PF573228 or the ERK1/2 phosphorylation inhibitor PD98059 suppressed the shear stress-promoted migration, indicating the involvement of FAK and ERK1/2 activation in shear stress-induced LCSC migration. Additionally, atomic force microscopy (AFM) analysis showed that shear stress lowers LCSC stiffness via the FAK and ERK1/2 pathways, suggesting that the mechanism by which shear stress promotes LCSC migration might partially be responsible for the decrease in cell stiffness. Further experiments focused on the role of the actin cytoskeleton, demonstrating that the F-actin filaments in LCSCs are less well-defined after shear stress treatment, providing an explanation for the reduction in cell stiffness and the promotion of cell migration. Overall, our study demonstrates that shear stress promotes LCSC migration through the activation of the FAK-ERK1/2 signalling pathways, which further results in a reduction of organized actin and softer cell bodies. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Protective effect of lycopene on fluoride-induced ameloblasts apoptosis and dental fluorosis through oxidative stress-mediated Caspase pathways.

    Science.gov (United States)

    Li, Weishan; Jiang, Binghua; Cao, Xianglin; Xie, Yongjiang; Huang, Ting

    2017-01-05

    Fluoride is an environmental toxicant and induces dental fluorosis and oxidative stress. Lycopene (LYC) is an effective antioxidant that is reported to attenuate fluoride toxicity. To determine the effects of LYC on sodium fluoride (NaF) -induced teeth and ameloblasts toxicity, rats were treated with NaF (10 mg/kg) and/or LYC (10 mg/kg) by orally administration for 5 weeks; ameloblasts were treated with NaF (5 mM) and/or LYC (2 μM) for 6 h. We found that the concentrations of fluoride, malondialdehyde (MDA) and reactive oxygen species (ROS), gene expressions and activities of Caspase-9 and Caspase-3, and the gene expressions of Bax were significantly decreased, while the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX), the gene expression of Bcl-2 were significantly increased in the LYC + NaF-treated rats group; concentrations of MDA and ROS, gene expressions and activities of Caspase-9 and Caspase-3, and the gene expression of Bax, and ameloblasts apoptosis rate were significantly decreased, while the activities of SOD and GPX, the gene expression of Bcl-2 were significantly increased in the LYC + NaF-treated ameloblasts group. These results suggest that LYC significantly combated NaF-induced ameloblasts apoptosis and dental fluorosis by attenuation oxidative stress and down-regulation Caspase pathway. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Multidirectional Translation of Environmental Health Science in Community Settings: The Case of Oxidative Stress Pathways.

    Science.gov (United States)

    Sampson, Natalie R; Tetteh, Myra M; Schulz, Amy J; Ramirez, Erminia; Wilkins, Donele; de Majo, Ricardo; Mentz, Graciela; Johnson-Lawrence, Vicki

    2016-01-01

    Translation of environmental health science in vulnerable communities is particularly important to promote public health and reduce health inequities. We describe a structured, multidirectional process used to develop a suite of health promotion tools (e.g., fact sheets, video, maps) documenting patterning of local air pollution sources and availability of antioxidant-rich foods in Detroit, Michigan as factors that jointly affect oxidative stress (OS). OS underlies many pathological processes associated with air pollution, including asthma, metabolic syndrome, cancer, diabetes, and obesity. This translational effort involved a 2-year dialogue among representatives from community-based and environmental organizations, health service providers, and academic researchers. This dialogue led to development of tools, as well as new opportunities to inform related policies and research. Through this example, we highlight how collaborative partnerships can enhance multidirectional dialogue to inform translation of environmental health science by promoting consideration of multilevel risk factors, local priorities and context, and diverse audiences.

  10. Conserved ABC Transport System Regulated by the General Stress Response Pathways of Alpha- and Gammaproteobacteria

    Energy Technology Data Exchange (ETDEWEB)

    Herrou, Julien; Willett, Jonathan W.; Czy; #380; , Daniel M.; Babnigg, Gyorgy; Kim, Youngchang; Crosson, Sean (UC)

    2016-12-19

    ABSTRACT

    Brucella abortusσE1is an EcfG family sigma factor that regulates the transcription of dozens of genes in response to diverse stress conditions and is required for maintenance of chronic infection in a mouse model. A putative ATP-binding cassette transporter operon,bab1_0223-bab1_0226, is among the most highly activated gene sets in the σE1regulon. The proteins encoded by the operon resemble quaternary ammonium-compatible solute importers but are most similar in sequence to the broadly conserved YehZYXW system, which remains largely uncharacterized. Transcription ofyehZYXWis activated by the general stress sigma factor σSinEnterobacteriaceae, which suggests a functional role for this transport system in bacterial stress response across the classesAlphaproteobacteriaandGammaproteobacteria. We present evidence thatB. abortusYehZYXW does not function as an importer of known compatible solutes under physiological conditions and does not contribute to the virulence defect of a σE1-null strain. The solein vitrophenotype associated with genetic disruption of this putative transport system is reduced growth in the presence of high Li+ion concentrations. A crystal structure ofB. abortusYehZ revealed a class II periplasmic binding protein fold with significant structural homology toArchaeoglobus fulgidusProX, which binds glycine betaine. However, the structure

  11. Induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway delays the initiation but fails to eradicate established murine acute myeloid leukemia.

    Science.gov (United States)

    Jaako, P; Ugale, A; Wahlestedt, M; Velasco-Hernandez, T; Cammenga, J; Lindström, M S; Bryder, D

    2017-01-01

    Mutations resulting in constitutive activation of signaling pathways that regulate ribosome biogenesis are among the most common genetic events in acute myeloid leukemia (AML). However, whether ribosome biogenesis presents as a therapeutic target to treat AML remains unexplored. Perturbations in ribosome biogenesis trigger the 5S ribonucleoprotein particle (RNP)-Mdm2-p53 ribosomal stress pathway, and induction of this pathway has been shown to have therapeutic efficacy in Myc-driven lymphoma. In the current study we address the physiological and therapeutic role of the 5S RNP-Mdm2-p53 pathway in AML. By utilizing mice that have defective ribosome biogenesis due to downregulation of ribosomal protein S19 (Rps19), we demonstrate that induction of the 5S RNP-Mdm2-p53 pathway significantly delays the initiation of AML. However, even a severe Rps19 deficiency that normally results in acute bone marrow failure has no consistent efficacy on already established disease. Finally, by using mice that harbor a mutation in the Mdm2 gene disrupting its binding to 5S RNP, we show that loss of the 5S RNP-Mdm2-p53 pathway is dispensable for development of AML. Our study suggests that induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway holds limited potential as a single-agent therapy in the treatment of AML.

  12. The endoplasmic reticulum stress-autophagy pathway is involved in apelin-13-induced cardiomyocyte hypertrophy in vitro

    Institute of Scientific and Technical Information of China (English)

    Feng XIE; Di WU; Shi-fang HUANG; Jian-gang CAO; He-ning LI; Lu HE; Mei-qing LIU; Lan-fang LI; Lin-xi CHEN

    2017-01-01

    Apelin is the endogenous ligand for the G protein-coupled receptor APJ,and plays important roles in the cardiovascular system.Our previous studies showed that apelin-13 promotes the hypertrophy of H9c2 rat cardiomyocytes through the PI3K-autophagy pathway.The aim of this study was to explore what roles ER stress and autophagy played in apelin-13-induced hypertrophy of cardiomyocytes in vitro.Treatment of H9c2 cells with apelin-13 (0.001-2 μJmol/L) dose-dependently increased the production of ROS and the expression levels of NADPH oxidase 4 (NOX4).Knockdown of Nox4 with siRNAs effectively prevented the reduction of GSH/GSSG ratio in apelin-13-treated cells.Furthermore,apelin-13 treatment dose-dependently increased the expression of Bip and CHOP,two ER stress markers,in the cells.Knockdown of APJ or Nox4 with the corresponding siRNAs,or application of NADPH inhibitor DPI blocked apelin-13-induced increases in Bip and CHOP expression.Moreover,apelin-13 treatment increased the formation of autophagosome and ER fragments and the LC3 puncta in the ER of the cells.Knockdown of APJ,Nox4,Bip or CHOP with the corresponding siRNAs,or application of DPI or salubrinal attenuated apelin-13-induced overexpression of LC3-Ⅱ/Ⅰ and beclin 1.Finally,knockdown of Nox4,Bip or CHOP with the corresponding siRNAs,or application of salubrinal significantly suppressed apelin-13-induced increases in the cell diameter,volume and protein contents.Our results demonstrate that ER stress-autophagy is involved in apelin-13-induced H9c2 cell hypertrophy.

  13. Cold Atmospheric Plasma Induces Apoptosis and Oxidative Stress Pathway Regulation in T-Lymphoblastoid Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Eleonora Turrini

    2017-01-01

    Full Text Available Cold atmospheric plasma (CAP has shown its antitumor activity in both in vitro and in vivo systems. However, the mechanisms at the basis of CAP-cell interaction are not yet completely understood. The aim of this study is to investigate CAP proapoptotic effect and identify some of the molecular mechanisms triggered by CAP in human T-lymphoblastoid leukemia cells. CAP treatment was performed by means of a wand electrode DBD source driven by nanosecond high-voltage pulses under different operating conditions. The biological endpoints were assessed through flow cytometry and real-time PCR. CAP caused apoptosis in Jurkat cells mediated by p53 upregulation. To test the involvement of intrinsic and/or extrinsic pathway, the expression of Bax/Bcl-2 and caspase-8 was analyzed. The activation of caspase-8 and the upregulation of Bax and Bcl-2 were observed. Moreover, CAP treatment increased ROS intracellular level. The situation reverts after a longer time of treatment. This is probably due to compensatory cellular mechanisms such as the posttranscriptional upregulation of SOD1, CAT, and GSR2. According to ROS increase, CAP induced a significant increase in DNA damage at all treatment conditions. In conclusion, our results provide a deeper understanding of CAP potential in the oncological field and pose the basis for the evaluation of its toxicological profile.

  14. Caffeic acid phenethylester increases stress resistance and enhances lifespan in Caenorhabditis elegans by modulation of the insulin-like DAF-16 signalling pathway.

    Science.gov (United States)

    Havermann, Susannah; Chovolou, Yvonni; Humpf, Hans-Ulrich; Wätjen, Wim

    2014-01-01

    CAPE is an active constituent of propolis which is widely used in traditional medicine. This hydroxycinnamic acid derivate is a known activator of the redox-active Nrf2 signalling pathway in mammalian cells. We used C. elegans to investigate the effects of this compound on accumulation of reactive oxygen species and the modulation of the pivotal redox-active pathways SKN-1 and DAF-16 (homologues of Nrf2 and FoxO, respectively) in this model organism; these results were compared to the effects in Hct116 human colon carcinoma cells. CAPE exerts a strong antioxidative effect in C. elegans: The increase of reactive oxygen species induced by thermal stress was diminished by about 50%. CAPE caused a nuclear translocation of DAF-16, but not SKN-1. CAPE increased stress resistance of the nematode against thermal stress and finally a prolongation of the median and maximum lifespan by 9 and 17%, respectively. This increase in stress resistance and lifespan was dependent on DAF-16 as shown in experiments using a DAF-16 loss of function mutant strain. Life prolongation was retained under SKN-1 RNAi conditions showing that the effect is SKN-1 independent. The results of CAPE obtained in C. elegans differed from the results obtained in Hct116 colon carcinoma cells: CAPE also caused strong antioxidative effects in the mammalian cells, but no activation of the FoxO4 signalling pathway was detectable. Instead, an activation of the Nrf2 signalling pathway was shown by luciferase assay and western blots. CAPE activates the insulin-like DAF-16, but not the SKN-1 signalling pathway in C. elegans and therefore enhances the stress resistance and lifespan of this organism. Since modulation of the DAF-16 pathway was found to be a pivotal effect of CAPE in C. elegans, this has to be taken into account for the investigation of the molecular mechanisms of the traditional use of propolis.

  15. Stress

    Science.gov (United States)

    ... can be life-saving. But chronic stress can cause both physical and mental harm. There are at least three different types of stress: Routine stress related to the pressures of work, family, and other daily responsibilities Stress brought about ...

  16. On-column nitrosation of amines observed in liquid chromatography impurity separations employing ammonium hydroxide and acetonitrile as mobile phase.

    Science.gov (United States)

    Myers, David P; Hetrick, Evan M; Liang, Zhongming; Hadden, Chad E; Bandy, Steven; Kemp, Craig A; Harris, Thomas M; Baertschi, Steven W

    2013-12-06

    The availability of high performance liquid chromatography (HPLC) columns capable of operation at pH values up to 12 has allowed a greater selectivity space to be explored for method development in pharmaceutical analysis. Ammonium hydroxide is of particular value in the mobile phase because it is compatible with direct interfacing to electrospray mass spectrometers. This paper reports an unexpected N-nitrosation reaction that occurs with analytes containing primary and secondary amines when ammonium hydroxide is used to achieve the high pH and acetonitrile is used as the organic modifier. The nitrosation reaction has generality. It has been observed on multiple columns from different vendors and with multiple amine-containing analytes. Ammonia was established to be the source of the nitroso nitrogen. The stainless steel column frit and metal ablated from the frit have been shown to be the sites of the reactions. The process is initiated by removal of the chromium oxide protective film from the stainless steel by acetonitrile. It is hypothesized that the highly active, freshly exposed metals catalyze room temperature oxidation of ammonia to NO but that the actual nitrosating agent is likely N(2)O(3). Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Di (2-ethylhexyl) phthalate inhibits growth of mouse ovarian antral follicles through an oxidative stress pathway

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Wei, E-mail: weiwang2@illinois.edu; Craig, Zelieann R., E-mail: zelieann@illinois.edu; Basavarajappa, Mallikarjuna S., E-mail: mbasava2@illinois.edu; Gupta, Rupesh K., E-mail: drrupesh@yahoo.com; Flaws, Jodi A., E-mail: jflaws@illinois.edu

    2012-01-15

    Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that has been shown to inhibit growth of mouse antral follicles, however, little is known about the mechanisms by which DEHP does so. Oxidative stress has been linked to follicle growth inhibition as well as phthalate-induced toxicity in non-ovarian tissues. Thus, we hypothesized that DEHP causes oxidative stress and that this leads to inhibition of the growth of antral follicles. To test this hypothesis, antral follicles isolated from CD-1 mice (age 31–35 days) were cultured with vehicle control (dimethylsulfoxide [DMSO]) or DEHP (1–100 μg/ml) ± N-acetyl cysteine (NAC, an antioxidant at 0.25–1 mM). During culture, follicles were measured daily. At the end of culture, follicles were collected and processed for in vitro reactive oxygen species (ROS) assays to measure the presence of free radicals or for measurement of the expression and activity of various key antioxidant enzymes: Cu/Zn superoxide dismutase (SOD1), glutathione peroxidase (GPX) and catalase (CAT). The results indicate that DEHP inhibits the growth of follicles compared to DMSO control and that NAC (0.25–1 mM) blocks the ability of DEHP to inhibit follicle growth. Furthermore, DEHP (10 μg/ml) significantly increases ROS levels and reduces the expression and activity of SOD1 compared to DMSO controls, whereas NAC (0.5 mM) rescues the effects of DEHP on ROS levels and SOD1. However, the expression and activity of GPX and CAT were not affected by DEHP treatment. Collectively, these data suggest that DEHP inhibits follicle growth by inducing production of ROS and by decreasing the expression and activity of SOD1. -- Highlights: ► DEHP inhibits growth and increases reactive oxygen species in ovarian antral follicles in vitro. ► NAC rescues the effects of DEHP on the growth and reactive oxygen species levels in follicles. ► DEHP decreases the expression and activity of Cu/Zn superoxide dismutase, which can be rescued by NAC, in antral

  18. Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

    Directory of Open Access Journals (Sweden)

    Maes Michael

    2012-06-01

    Full Text Available Abstract It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia, physio-somatic (fatigue, hyperalgesia, malaise, anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuroinflammation and (neurodegenerative processes following less well defined triggers.

  19. Alternative oxidase: a respiratory electron transport chain pathway essential for maintaining photosynthetic performance during drought stress.

    Science.gov (United States)

    Vanlerberghe, Greg C; Martyn, Greg D; Dahal, Keshav

    2016-07-01

    Photosynthesis and respiration are the hubs of energy metabolism in plants. Drought strongly perturbs photosynthesis as a result of both diffusive limitations resulting from stomatal closure, and in some cases biochemical limitations that are associated with a reduced abundance of key photosynthetic components. The effects of drought on respiration, particularly respiration in the light (RL ), are less understood. The plant mitochondrial electron transport chain includes a non-energy conserving terminal oxidase called alternative oxidase (AOX). Several studies have shown that drought increases AOX transcript, protein and maximum capacity. Here we review recent studies comparing wild-type (WT) tobacco to transgenic lines with altered AOX protein amount. Specifically during drought, RL was compromised in AOX knockdown plants and enhanced in AOX overexpression plants, compared with WT. Significantly, these differences in RL were accompanied by dramatic differences in photosynthetic performance. Knockdown of AOX increased the susceptibility of photosynthesis to drought-induced biochemical limitations, while overexpression of AOX delayed the development of such biochemical limitations, compared with WT. Overall, the results indicate that AOX is essential to maintaining RL during drought, and that this non-energy conserving respiration maintains photosynthesis during drought by promoting energy balance in the chloroplast. This review also outlines several areas for future research, including the possibility that enhancement of non-energy conserving respiratory electron sinks may be a useful biotechnological approach to increase plant performance during stress. © 2016 Scandinavian Plant Physiology Society.

  20. A Non-canonical Melanin Biosynthesis Pathway Protects Aspergillus terreus Conidia from Environmental Stress.

    Science.gov (United States)

    Geib, Elena; Gressler, Markus; Viediernikova, Iuliia; Hillmann, Falk; Jacobsen, Ilse D; Nietzsche, Sandor; Hertweck, Christian; Brock, Matthias

    2016-05-19

    Melanins are ubiquitous pigments found in all kingdoms of life. Most organisms use them for protection from environmental stress, although some fungi employ melanins as virulence determinants. The human pathogenic fungus Aspergillus fumigatus and related Ascomycetes produce dihydroxynaphthalene- (DHN) melanin in their spores, the conidia, and use it to inhibit phagolysosome acidification. However, biosynthetic origin of melanin in a related fungus, Aspergillus terreus, has remained a mystery because A. terreus lacks genes for synthesis of DHN-melanin. Here we identify genes coding for an unusual NRPS-like enzyme (MelA) and a tyrosinase (TyrP) that A. terreus expressed under conidiation conditions. We demonstrate that MelA produces aspulvinone E, which is activated for polymerization by TyrP. Functional studies reveal that this new pigment, Asp-melanin, confers resistance against UV light and hampers phagocytosis by soil amoeba. Unexpectedly, Asp-melanin does not inhibit acidification of phagolysosomes, thus likely contributing specifically to survival of A. terreus conidia in acidic environments. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Nutritional mitigation of winter thermal stress in gilthead seabream: Associated metabolic pathways and potential indicators of nutritional state.

    Science.gov (United States)

    Richard, Nadège; Silva, Tomé S; Wulff, Tune; Schrama, Denise; Dias, Jorge P; Rodrigues, Pedro M L; Conceição, Luís E C

    2016-06-16

    A trial was carried out with gilthead seabream juveniles, aiming to investigate the ability of an enhanced dietary formulation (diet Winter Feed, WF, containing a higher proportion of marine-derived protein sources and supplemented in phospholipids, vitamin C, vitamin E and taurine) to assist fish in coping with winter thermal stress, compared to a low-cost commercial diet (diet CTRL). In order to identify the metabolic pathways affected by WF diet, a comparative two dimensional differential in-gel electrophoresis (2D-DIGE) analysis of fish liver proteome (pH 4–7) was undertaken at the end of winter. A total of 404 protein spots, out of 1637 detected, were differentially expressed between the two groups of fish. Mass spectrometry analysis of selected spots suggested that WF diet improved oxidative stress defense, reduced endoplasmic reticulum stress, enhanced metabolic flux through methionine cycle and phenylalanine/tyrosine catabolism, and induced higher aerobic metabolism and gluconeogenesis. Results support the notion that WF diet had a positive effect on fish nutritional state by partially counteracting the effect of thermal stress and underlined the sensitivity of proteome data for nutritional and metabolic profiling purposes. Intragroup variability and co-measured information were also used to pinpoint which proteins displayed a stronger relation with fish nutritional state. Winter low water temperature is a critical factor for gilthead seabream farming in the Mediterranean region, leading to a reduction of feed intake, which often results in metabolic and immunological disorders and stagnation of growth performances. In a recent trial, we investigated the ability of an enhanced dietary formulation (diet WF) to assist gilthead seabream in coping with winter thermal stress, compared to a standard commercial diet (diet CTRL). Within this context, in the present work, we identified metabolic processes that are involved in the stress-mitigating effect observed

  2. Prediction of Possible Biomarkers and Novel Pathways Conferring Risk to Post-Traumatic Stress Disorder.

    Directory of Open Access Journals (Sweden)

    Kumaraswamy Naidu Chitrala

    Full Text Available Post-traumatic stress disorder is one of the common mental ailments that is triggered by exposure to traumatic events. Till date, the molecular factors conferring risk to the development of PTSD is not well understood. In this study, we have conducted a meta-analysis followed by hierarchical clustering and functional enrichment, to uncover the potential molecular networks and critical genes which play an important role in PTSD. Two datasets of expression profiles from Peripheral Blood Mononuclear Cells from 62 control samples and 63 PTSD samples were included in our study. In PTSD samples of GSE860 dataset, we identified 26 genes informative when compared with Post-deploy PTSD condition and 58 genes informative when compared with Pre-deploy and Post-deploy PTSD of GSE63878 dataset. We conducted the meta-analysis using Fisher, roP, Stouffer, AW, SR, PR and RP methods in MetaDE package. Results from the rOP method of MetaDE package showed that among these genes, the following showed significant changes including, OR2B6, SOX21, MOBP, IL15, PTPRK, PPBPP2 and SEC14L5. Gene ontology analysis revealed enrichment of these significant PTSD-related genes for cell proliferation, DNA damage and repair (p-value ≤ 0.05. Furthermore, interaction network analysis was performed on these 7 significant genes. This analysis revealed highly connected functional interaction networks with two candidate genes, IL15 and SEC14L5 highly enriched in networks. Overall, from these results, we concluded that these genes can be recommended as some of the potential targets for PTSD.

  3. Prediction of Possible Biomarkers and Novel Pathways Conferring Risk to Post-Traumatic Stress Disorder.

    Science.gov (United States)

    Chitrala, Kumaraswamy Naidu; Nagarkatti, Prakash; Nagarkatti, Mitzi

    2016-01-01

    Post-traumatic stress disorder is one of the common mental ailments that is triggered by exposure to traumatic events. Till date, the molecular factors conferring risk to the development of PTSD is not well understood. In this study, we have conducted a meta-analysis followed by hierarchical clustering and functional enrichment, to uncover the potential molecular networks and critical genes which play an important role in PTSD. Two datasets of expression profiles from Peripheral Blood Mononuclear Cells from 62 control samples and 63 PTSD samples were included in our study. In PTSD samples of GSE860 dataset, we identified 26 genes informative when compared with Post-deploy PTSD condition and 58 genes informative when compared with Pre-deploy and Post-deploy PTSD of GSE63878 dataset. We conducted the meta-analysis using Fisher, roP, Stouffer, AW, SR, PR and RP methods in MetaDE package. Results from the rOP method of MetaDE package showed that among these genes, the following showed significant changes including, OR2B6, SOX21, MOBP, IL15, PTPRK, PPBPP2 and SEC14L5. Gene ontology analysis revealed enrichment of these significant PTSD-related genes for cell proliferation, DNA damage and repair (p-value ≤ 0.05). Furthermore, interaction network analysis was performed on these 7 significant genes. This analysis revealed highly connected functional interaction networks with two candidate genes, IL15 and SEC14L5 highly enriched in networks. Overall, from these results, we concluded that these genes can be recommended as some of the potential targets for PTSD.

  4. Urtica dioica leaves modulates hippocampal smoothened-glioma associated oncogene-1 pathway and cognitive dysfunction in chronically stressed mice.

    Science.gov (United States)

    Patel, Sita Sharan; Mahindroo, Neeraj; Udayabanu, Malairaman

    2016-10-01

    The present study was aimed to evaluate the effect of Urtica dioica (UD) extract against chronic unpredictable stress (CUS)-induced associative memory dysfunction and attempted to explore the possible mechanism. Male Swiss albino mice (25-30g) were divided into six groups, viz. group-I received 0.3% carboxymethyl cellulose and served as control (CTRL), group II was exposed to CUS (21days) and received vehicle (CUS), group III was subjected to CUS and received Hypericum perforatum extract (350mg/kg, p.o.) (CUS+HYP), group IV received Hypericum perforatum extract (350mg/kg, p.o.) (CTRL+HYP); group V was subjected to CUS and received UD extract (50mg/kg, p.o.) (CUS+UD), group VI received UD extract (50mg/kg, p.o.) (CTRL+UD). CUS significantly induced body weight loss (p<0.05) and associative memory impairment in step down task (p<0.05) as compared to control mice. CUS significantly downregulated Smo (p<0.05), Gli1 (p<0.01), cyclin D1 (p<0.05), BDNF (p<0.01), TrKB (p<0.01) and MAPK1 (p<0.01) mRNA expression in hippocampus as compared to control mice. CUS significantly increased the levels of TBARS (p<0.01) and nitric oxide (p<0.001), and decreased catalase (p<0.001) and total thiol (p<0.01) in plasma resulting in oxidative stress and inflammation. Chronic UD administration significantly reverted CUS mediated body weight loss (p<0.05) and cognitive impairment (p<0.05). UD administration significantly decreased the levels of TBARS (p<0.01) and nitric oxide (p<0.05), and increased the levels of catalase (p<0.01) and total thiol (p<0.05) in plasma. Chronic UD administration significantly upregulated hippocampal Smo (p<0.05), Gli1 (p<0.001), cyclin D1 (p<0.05), BDNF (p<0.05), TrKB (p<0.05) and MAPK1 (p<0.05) in stressed mice. Further, UD extract did not reverse cyclopamine induced downregulation of Gli1 and Ptch1 mRNA in hippocampal slices. UD modulated Smo-Gli1 pathway in the hippocampus as well as exerted anti-inflammatory and antioxidant effects. UD extract might prove

  5. XBP1-Independent UPR Pathways Suppress C/EBP-β Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease.

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    Trevor L Cameron

    2015-09-01

    Full Text Available Schmid metaphyseal chondrodysplasia (MCDS involves dwarfism and growth plate cartilage hypertrophic zone expansion resulting from dominant mutations in the hypertrophic zone collagen, Col10a1. Mouse models phenocopying MCDS through the expression of an exogenous misfolding protein in the endoplasmic reticulum (ER in hypertrophic chondrocytes have demonstrated the central importance of ER stress in the pathology of MCDS. The resultant unfolded protein response (UPR in affected chondrocytes involved activation of canonical ER stress sensors, IRE1, ATF6, and PERK with the downstream effect of disrupted chondrocyte differentiation. Here, we investigated the role of the highly conserved IRE1/XBP1 pathway in the pathology of MCDS. Mice with a MCDS collagen X p.N617K knock-in mutation (ColXN617K were crossed with mice in which Xbp1 was inactivated specifically in cartilage (Xbp1CartΔEx2, generating the compound mutant, C/X. The severity of dwarfism and hypertrophic zone expansion in C/X did not differ significantly from ColXN617K, revealing surprising redundancy for the IRE1/XBP1 UPR pathway in the pathology of MCDS. Transcriptomic analyses of hypertrophic zone cartilage identified differentially expressed gene cohorts in MCDS that are pathologically relevant (XBP1-independent or pathologically redundant (XBP1-dependent. XBP1-independent gene expression changes included large-scale transcriptional attenuation of genes encoding secreted proteins and disrupted differentiation from proliferative to hypertrophic chondrocytes. Moreover, these changes were consistent with disruption of C/EBP-β, a master regulator of chondrocyte differentiation, by CHOP, a transcription factor downstream of PERK that inhibits C/EBP proteins, and down-regulation of C/EBP-β transcriptional co-factors, GADD45-β and RUNX2. Thus we propose that the pathology of MCDS is underpinned by XBP1 independent UPR-induced dysregulation of C/EBP-β-mediated chondrocyte differentiation

  6. SIRT1 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the Oxidative Stress and p38MAPK Pathways

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    Yang Ruan

    2015-02-01

    Full Text Available Background: SIRT1, which belongs to the Sirtuin family of NAD-dependent enzymes, plays diverse roles in aging, metabolism, and disease biology. It could regulate cell survival and has been shown to be a protective factor in heart function. Hence, we verified the mechanism by which SIRT1 regulates doxorubicin induced cardiomyocyte injury in vivo and in vitro. Methods: We analyzed SIRT1 expression in doxorubicin-induced neonatal rat cardiomyocyte injury model and adult mouse heart failure model. SIRT1 was over-expressed in cultured neonatal rat cardiomyocyte by adenovirus mediated gene transfer. SIRT1 agonist resveratrol was used to treat the doxorubicin-induced heart failure mouse model. Echocardiography, reactive oxygen species (ROS production, TUNEL, qRT-PCR, and Western blotting were performed to analyze cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes. Results: SIRT1 expression was down-regulated in doxorubicin induced cardiomocyte injury, accompanied by elevated oxidative stress and cell apoptosis. SIRT1 over-expression reduced doxorubicin induced cardiomyocyte apoptosis with the attenuated ROS production. SIRT1 also reduced cell apoptosis by inhibition of p38MAPK phosphorylation and caspase-3 activation. The SIRT1 agonist resveratrol was able to prevent doxorubicin-induced heart function loss. Moreover, the SIRT1 inhibitor niacinamide could reverse SIRT1's protective effect in cultured neonatal rat cardiomyocytes. Conclusions: These results support the role of SIRT1 as an important regulator of cardiomyocyte apoptosis during doxorubicin-induced heart injury, which may represent a potential therapeutic target for doxorubicin-induced cardiomyopathy.

  7. UV-B radiation-induced oxidative stress and p38 signaling pathway involvement in the benthic copepod Tigriopus japonicus.

    Science.gov (United States)

    Kim, Bo-Mi; Rhee, Jae-Sung; Lee, Kyun-Woo; Kim, Min-Jung; Shin, Kyung-Hoon; Lee, Su-Jae; Lee, Young-Mi; Lee, Jae-Seong

    2015-01-01

    Ultraviolet B (UV-B) radiation presents an environmental hazard to aquatic organisms. To understand the molecular responses of the intertidal copepod Tigriopus japonicus to UV-B radiation, we measured the acute toxicity response to 96 h of UV-B radiation, and we also assessed the intracellular reactive oxygen species (ROS) levels, glutathione (GSH) content, and antioxidant enzyme (GST, GR, GPx, and SOD) activities after 24 h of exposure to UV-B with LD50 and half LD50 values. Also, expression patterns of p53 and hsp gene families with phosphorylation of p38 MAPK were investigated in UV-B-exposed copepods. We found that the ROS level, GSH content, and antioxidant enzyme activity levels were increased with the transcriptional upregulation of antioxidant-related genes, indicating that UV-B induces oxidative stress by generating ROS and stimulating antioxidant enzymatic activity as a defense mechanism. Additionally, we found that p53 expression was significantly increased after UV-B irradiation due to increases in the phosphorylation of the stress-responsive p38 MAPK, indicating that UV-B may be responsible for inducing DNA damage in T. japonicus. Of the hsp family genes, transcriptional levels of hsp20, hsp20.7, hsp70, and hsp90 were elevated in response to a low dose of UV-B radiation (9 kJ m(-2)), suggesting that these hsp genes may be involved in cellular protection against UV-B radiation. In this paper, we performed a pathway-oriented mechanistic analysis in response to UV-B radiation, and this analysis provides a better understanding of the effects of UV-B in the intertidal benthic copepod T. japonicus. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Short curcumin treatment modulates oxidative stress, arginase activity, aberrant crypt foci, and TGF-β1 and HES-1 transcripts in 1,2-dimethylhydrazine-colon carcinogenesis in mice

    International Nuclear Information System (INIS)

    Bounaama, Abdelkader; Djerdjouri, Bahia; Laroche-Clary, Audrey; Le Morvan, Valérie; Robert, Jacques

    2012-01-01

    Highlights: ► 1,2-Dimethylhydrazine (DMH) toxicity was driven by oxidative stress. ► Arginase activity correlated to aberrant crypt foci (ACF). ► Curcumin diet restored redox status and induced apoptosis of dysplastic ACF. ► Curcumin reduced arginase activity and up regulated TGF-β1 and HES-1 transcripts. -- Abstract: This study investigated the effect of short curcumin treatment, a natural antioxidant on 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) in mice. The incidence of aberrant crypt foci (ACF) was 100%, with 54 ± 6 per colon, 10 weeks after the first DMH injection and reached 67 ± 12 per colon after 12 weeks. A high level of undifferentiated goblet cells and a weak apoptotic activity were shown in dysplastic ACF. The morphological alterations of colonic mucosa were associated to severe oxidative stress ratio with 43% increase in malondialdehyde vs. 36% decrease in GSH. DMH also increased inducible nitric synthase (iNOS) mRNA transcripts (250%), nitrites level (240%) and arginase activity (296%), leading to nitrosative stress and cell proliferation. Curcumin treatment, starting at week 10 post-DMH injection for 14 days, reduced the number of ACF (40%), iNOS expression (25%) and arginase activity (73%), and improved redox status by approximately 46%, compared to DMH-treated mice. Moreover, curcumin induced apoptosis of dysplastic ACF cells without restoring goblet cells differentiation. Interestingly, curcumin induced a parallel increase in TGF-β1 and HES-1 transcripts (42% and 26%, respectively). In conclusion, the protective effect of curcumin was driven by the reduction of arginase activity and nitrosative stress. The up regulation of TGF-β1 and HES-1 expression by curcumin suggests for the first time, a potential interplay between these signalling pathways in the chemoprotective mechanism of curcumin.

  9. Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1

    Directory of Open Access Journals (Sweden)

    Karla A. Mark

    2016-10-01

    Full Text Available Vitamin D has multiple roles, including the regulation of bone and calcium homeostasis. Deficiency of 25-hydroxyvitamin D, the major circulating form of vitamin D, is associated with an increased risk of age-related chronic diseases, including Alzheimer’s disease, Parkinson’s disease, cognitive impairment, and cancer. In this study, we utilized Caenorhabditis elegans to examine the mechanism by which vitamin D influences aging. We found that vitamin-D3-induced lifespan extension requires the stress response pathway genes skn-1, ire-1, and xbp-1. Vitamin D3 (D3 induced expression of SKN-1 target genes but not canonical targets of XBP-1. D3 suppressed an important molecular pathology of aging, that of widespread protein insolubility, and prevented toxicity caused by human β-amyloid. Our observation that D3 improves protein homeostasis and slows aging highlights the importance of maintaining appropriate vitamin D serum levels and may explain why such a wide variety of human age-related diseases are associated with vitamin D deficiency.

  10. A combination of genomic approaches reveals the role of FOXO1a in regulating an oxidative stress response pathway.

    Directory of Open Access Journals (Sweden)

    Paola de Candia

    2008-02-01

    Full Text Available While many of the phenotypic differences between human and chimpanzee may result from changes in gene regulation, only a handful of functionally important regulatory differences are currently known. As a first step towards identifying transcriptional pathways that have been remodeled in the human lineage, we focused on a transcription factor, FOXO1a, which we had previously found to be up-regulated in the human liver compared to that of three other primate species. We concentrated on this gene because of its known role in the regulation of metabolism and in longevity.Using a combination of expression profiling following siRNA knockdown and chromatin immunoprecipitation in a human liver cell line, we identified eight novel direct transcriptional targets of FOXO1a. This set includes the gene for thioredoxin-interacting protein (TXNIP, the expression of which is directly repressed by FOXO1a. The thioredoxin-interacting protein is known to inhibit the reducing activity of thioredoxin (TRX, thereby hindering the cellular response to oxidative stress and affecting life span.Our results provide an explanation for the repeated observations that differences in the regulation of FOXO transcription factors affect longevity. Moreover, we found that TXNIP is down-regulated in human compared to chimpanzee, consistent with the up-regulation of its direct repressor FOXO1a in humans, and with differences in longevity between the two species.

  11. Intracellular calcium overloading and oxidative stress in cardiomyocyte necrosis via a mitochondriocentric signal-transducer-effector pathway

    Science.gov (United States)

    Shaheen, Mazen; Cheema, Yaser; Shahbaz, Atta U; Bhattacharya, Syamal K; Weber, Karl T

    2011-01-01

    Congestive heart failure (CHF), a common clinical syndrome, has reached epidemic proportions. Its disabling symptoms account for frequent hospitalizations and readmissions. Pathophysiological mechanisms that lead to CHF and account for its progressive nature are of considerable interest. Important scientific observations obtained from Dr Pawan K Singal’s laboratory in Winnipeg, Manitoba, have provided crucial insights to our understanding of the pathophysiological factors that contribute to cardiomyocyte necrosis (the heart is a postmitotic organ incapable of tolerating an ongoing loss of these cells without adverse functional consequences). This increment in knowledge and the mechanistic insights afforded by Dr Singal and his colleagues have highlighted the role of excessive intracellular calcium accumulation and the appearance of oxidative stress in CHF, in which the rate of reactive oxygen species generation overwhelms their rate of detoxification by antioxidant defenses. They have shown that this common pathophysiological scenario applies to diverse entities such as ischemia/reperfusion and hypoxia/reoxygenation forms of injury, myocardial infarction and the cardiomyopathies that accompany diabetes and excess levels of catecholamines and adriamycin. The authors are honoured to be invited to contribute to the present focus issue of Experimental & Clinical Cardiology in recognizing Dr Singal’s numerous scholarly accomplishments. The present article reviews the authors’ recent work on a mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis found in rats with either an acute stressor state that accompanies isoproterenol administration or a chronic stressor state manifested after four weeks of aldosterone/salt treatment. PMID:22131852

  12. Redox Signaling and CBF-Responsive Pathway Are Involved in Salicylic Acid-Improved Photosynthesis and Growth under Chilling Stress in Watermelon

    Science.gov (United States)

    Cheng, Fei; Lu, Junyang; Gao, Min; Shi, Kai; Kong, Qiusheng; Huang, Yuan; Bie, Zhilong

    2016-01-01

    Salicylic acid (SA) plays an important role in plant response to abiotic stresses. This study investigated the potential role of SA in alleviating the adverse effects of chilling stress on photosynthesis and growth in watermelon (Citrullus lanatus). Chilling stress induced the simultaneous accumulation of free and conjugated SA in watermelon plants, and the chilling-induced SA production was attributed to the phenylalanine ammonia-lyase pathway. Applying SA at moderate concentrations induced chilling tolerance, whereas inhibition of SA biosynthesis by L-α-aminooxy-β-phenylpropionic acid (AOPP) increased the photooxidation of PS II under chilling stress in watermelon, resulting in reduced photosynthesis and growth. Chilling induced a transient increase in the ratios of reduced to oxidized glutathione and reduced ascorbate to dehydroascorbate. Then, the expression of antioxidant genes was upregulated, and the activities of antioxidant enzymes were enhanced. Furthermore, SA-induced chilling tolerance was associated with cellular glutathione and ascorbate homeostasis, which served as redox signals to regulate antioxidant metabolism under chilling stress. AOPP treatment stimulated the chilling-induced expression of cold-responsive genes, particularly via C-repeat binding factors CBF3 and CBF4. These results confirm the synergistic role of SA signaling and the CBF-dependent responsive pathway during chilling stress in watermelon. PMID:27777580

  13. Redox Signaling and CBF-Responsive Pathway are Involved in Salicylic Acid-Improved Photosynthesis and Growth under Chilling Stress in Watermelon

    Directory of Open Access Journals (Sweden)

    Fei Cheng

    2016-10-01

    Full Text Available Salicylic acid (SA plays an important role in plant response to abiotic stresses. This study investigated the potential role of SA in alleviating the adverse effects of chilling stress on photosynthesis and growth in watermelon (Citrullus lanatus. Chilling stress induced the simultaneous accumulation of free and conjugated SA in watermelon plants, and the chilling-induced SA production was attributed to the phenylalanine ammonia-lyase pathway. Applying SA at moderate concentrations induced chilling tolerance, whereas inhibition of SA biosynthesis by L-ɑ-aminooxy-β-phenylpropionic acid (AOPP increased the photooxidation of PS II under chilling stress in watermelon, resulting in reduced photosynthesis and growth. Chilling induced a transient increase in the ratios of reduced to oxidized glutathione and reduced ascorbate to dehydroascorbate. Then, the expression of antioxidant genes was upregulated, and the activities of antioxidant enzymes were enhanced. Furthermore, SA-induced chilling tolerance was associated with cellular glutathione and ascorbate homeostasis, which served as redox signals to regulate antioxidant metabolism under chilling stress. AOPP treatment stimulated the chilling-induced expression of cold-responsive genes, particularly via C-repeat binding factors CBF3 and CBF4. These results confirm the synergistic role of SA signaling and the CBF-dependent responsive pathway during chilling stress in watermelon.

  14. Systems modeling of anti-apoptotic pathways in prostate cancer: psychological stress triggers a synergism pattern switch in drug combination therapy.

    Directory of Open Access Journals (Sweden)

    Xiaoqiang Sun

    Full Text Available Prostate cancer patients often have increased levels of psychological stress or anxiety, but the molecular mechanisms underlying the interaction between psychological stress and prostate cancer as well as therapy resistance have been rarely studied and remain poorly understood. Recent reports show that stress inhibits apoptosis in prostate cancer cells via epinephrine/beta2 adrenergic receptor/PKA/BAD pathway. In this study, we used experimental data on the signaling pathways that control BAD phosphorylation to build a dynamic network model of apoptosis regulation in prostate cancer cells. We then compared the predictive power of two different models with or without the role of Mcl-1, which justified the role of Mcl-1 stabilization in anti-apoptotic effects of emotional stress. Based on the selected model, we examined and quantitatively evaluated the induction of apoptosis by drug combination therapies. We predicted that the combination of PI3K inhibitor LY294002 and inhibition of BAD phosphorylation at S112 would produce the best synergistic effect among 8 interventions examined. Experimental validation confirmed the effectiveness of our predictive model. Moreover, we found that epinephrine signaling changes the synergism pattern and decreases efficacy of combination therapy. The molecular mechanisms responsible for therapeutic resistance and the switch in synergism were explored by analyzing a network model of signaling pathways affected by psychological stress. These results provide insights into the mechanisms of psychological stress signaling in therapy-resistant cancer, and indicate the potential benefit of reducing psychological stress in designing more effective therapies for prostate cancer patients.

  15. Poor sleep as a pathophysiological pathway underlying the association between stressful experiences and the diurnal cortisol profile among children and adolescents

    Science.gov (United States)

    Ly, Jinshia; McGrath, Jennifer J.; Gouin, Jean-Philippe

    2017-01-01

    Summary Recent evidence suggests that poor sleep is a potential pathway underlying the association between stressful experiences and the diurnal cortisol profile. However, existing findings are largely limited to adults. The present study examines whether poor sleep (duration, quality) mediates the relation between stressful experiences and the diurnal cortisol profile in children and adolescents. Children and adolescents (N = 220, Mage = 12.62) provided six saliva samples over two days to derive cortisol indices (bedtime, AUCAG, AUCTG, slopeMAX). Perceived stress, stressful life events, self-reported sleep duration, and sleep quality were measured. Using bootstrapping analyses, sleep quality mediated the relation between perceived stress and AUCTG (R2 = 0.10, F(7, 212) = 3.55, p = .001; 95% BCI[0.09, 1.15]), as well as the relation between stressful life events and AUCTG (R2 = 0.11, F(7, 212) = 3.69, p = .001; 95% BCI[0.40, 3.82]). These mediation models remained significant after adjusting for sleep duration, suggesting that poor sleep quality underlies the association between stressful experiences and the diurnal cortisol profile in children and adolescents. Longitudinal data combined with objectively-measured sleep is essential to further disentangle the complex association between sleep and stress. PMID:25889840

  16. Enhancement of the proline and nitric oxide synthetic pathway improves fermentation ability under multiple baking-associated stress conditions in industrial baker's yeast

    Directory of Open Access Journals (Sweden)

    Sasano Yu

    2012-04-01

    generation and that increased NO plays an important role in baking-associated stress tolerance. Conclusions In this work, we clarified the importance of Put1- and Mpr1-mediated NO generation from proline to the baking-associated stress tolerance in industrial baker's yeast. We also demonstrated that baker's yeast that enhances the proline and NO synthetic pathway by expressing the Pro1-I150T and Mpr1-F65L variants showed improved fermentation ability under multiple baking-associated stress conditions. From a biotechnological perspective, the enhancement of proline and NO synthesis could be promising for breeding novel baker's yeast strains.

  17. Enhancement of the proline and nitric oxide synthetic pathway improves fermentation ability under multiple baking-associated stress conditions in industrial baker's yeast.

    Science.gov (United States)

    Sasano, Yu; Haitani, Yutaka; Hashida, Keisuke; Ohtsu, Iwao; Shima, Jun; Takagi, Hiroshi

    2012-04-01

    role in baking-associated stress tolerance. In this work, we clarified the importance of Put1- and Mpr1-mediated NO generation from proline to the baking-associated stress tolerance in industrial baker's yeast. We also demonstrated that baker's yeast that enhances the proline and NO synthetic pathway by expressing the Pro1-I150T and Mpr1-F65L variants showed improved fermentation ability under multiple baking-associated stress conditions. From a biotechnological perspective, the enhancement of proline and NO synthesis could be promising for breeding novel baker's yeast strains.

  18. Enhancement of the proline and nitric oxide synthetic pathway improves fermentation ability under multiple baking-associated stress conditions in industrial baker's yeast

    Science.gov (United States)

    2012-01-01

    plays an important role in baking-associated stress tolerance. Conclusions In this work, we clarified the importance of Put1- and Mpr1-mediated NO generation from proline to the baking-associated stress tolerance in industrial baker's yeast. We also demonstrated that baker's yeast that enhances the proline and NO synthetic pathway by expressing the Pro1-I150T and Mpr1-F65L variants showed improved fermentation ability under multiple baking-associated stress conditions. From a biotechnological perspective, the enhancement of proline and NO synthesis could be promising for breeding novel baker's yeast strains. PMID:22462683

  19. Comparative transcriptome and gene co-expression network analysis reveal genes and signaling pathways adaptively responsive to varied adverse stresses in the insect fungal pathogen, Beauveria bassiana.

    Science.gov (United States)

    He, Zhangjiang; Zhao, Xin; Lu, Zhuoyue; Wang, Huifang; Liu, Pengfei; Zeng, Fanqin; Zhang, Yongjun

    2018-01-01

    Sensing, responding, and adapting to the surrounding environment are crucial for all living organisms to survive, proliferate, and differentiate in their biological niches. Beauveria bassiana is an economically important insect-pathogenic fungus which is widely used as a biocontrol agent to control a variety of insect pests. The fungal pathogen unavoidably encounters a variety of adverse environmental stresses and defense response from the host insects during application of the fungal agents. However, few are known about the transcription response of the fungus to respond or adapt varied adverse stresses. Here, we comparatively analyzed the transcriptome of B. bassiana in globe genome under the varied stationary-phase stresses including osmotic agent (0.8 M NaCl), high temperature (32 °C), cell wall-perturbing agent (Congo red), and oxidative agents (H 2 O 2 or menadione). Total of 12,412 reads were obtained, and mapped to the 6767 genes of the B. bassiana. All of these stresses caused transcription responses involved in basal metabolism, cell wall construction, stress response or cell rescue/detoxification, signaling transduction and gene transcription regulation, and likely other cellular processes. An array of genes displayed similar transcription patterns in response to at least two of the five stresses, suggesting a shared transcription response to varied adverse stresses. Gene co-expression network analysis revealed that mTOR signaling pathway, but not HOG1 MAP kinase pathway, played a central role in regulation the varied adverse stress responses, which was verified by RNAi-mediated knockdown of TOR1. Our findings provided an insight of transcription response and gene co-expression network of B. bassiana in adaptation to varied environments. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Agmatine attenuates chronic unpredictable mild stress-induced anxiety, depression-like behaviours and cognitive impairment by modulating nitrergic signalling pathway.

    Science.gov (United States)

    Gawali, Nitin B; Bulani, Vipin D; Gursahani, Malvika S; Deshpande, Padmini S; Kothavade, Pankaj S; Juvekar, Archana R

    2017-05-15

    Agmatine, a neurotransmitter/neuromodulator, has shown to exert numerous effects on the CNS. Chronic stress is a risk factor for development of depression, anxiety and deterioration of cognitive performance. Compelling evidences indicate an involvement of nitric oxide (NO) pathway in these disorders. Hence, investigation of the beneficial effects of agmatine on chronic unpredictable mild stress (CUMS)-induced depression, anxiety and cognitive performance with the involvement of nitrergic pathway was undertaken. Mice were subjected to a battery of stressors for 28days. Agmatine (20 and 40mg/kg, i.p.) alone and in combination with NO modulators like L-NAME (15mg/kg, i.p.) and l-arginine (400mg/kg i.p.) were administered daily. The results showed that 4-weeks CUMS produces significant depression and anxiety-like behaviour. Stressed mice have also shown a significant high serum corticosterone (CORT) and low BDNF level. Chronic treatment with agmatine produced significant antidepressant-like behaviour in forced swim test (FST) and sucrose preference test, whereas, anxiolytic-like behaviour in elevated plus maze (EPM) and open field test (OFT) with improved cognitive impairment in Morris water maze (MWM). Furthermore, agmatine administration reduced the levels of acetylcholinesterase and oxidative stress markers. In addition, agmatine treatment significantly increased the BDNF level and inhibited serum CORT level in stressed mice. Treatment with L-NAME (15mg/kg) potentiated the effect of agmatine whereas l-arginine abolished the anxiolytic, antidepressant and neuroprotective effects of agmatine. Agmatine showed marked effect on depression and anxiety-like behaviour in mice through nitrergic pathway, which may be related to modulation of oxidative-nitrergic stress, CORT and BDNF levels. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Transcriptomic studies reveal a key metabolic pathway contributing to a well-maintained photosynthetic system under drought stress in foxtail millet (Setaria italica L.

    Directory of Open Access Journals (Sweden)

    Weiping Shi

    2018-05-01

    Full Text Available Drought stress is one of the most important abiotic factors limiting crop productivity. A better understanding of the effects of drought on millet (Setaria italica L. production, a model crop for studying drought tolerance, and the underlying molecular mechanisms responsible for drought stress responses is vital to improvement of agricultural production. In this study, we exposed the drought resistant F1 hybrid, M79, and its parental lines E1 and H1 to drought stress. Subsequent physiological analysis demonstrated that M79 showed higher photosynthetic energy conversion efficiency and drought tolerance than its parents. A transcriptomic study using leaves collected six days after drought treatment, when the soil water content was about ∼20%, identified 3066, 1895, and 2148 differentially expressed genes (DEGs in M79, E1 and H1 compared to the respective untreated controls, respectively. Further analysis revealed 17 Gene Ontology (GO enrichments and 14 Kyoto Encyclopedia of Genes and Genomes (KEGG pathways in M79, including photosystem II (PSII oxygen-evolving complex, peroxidase (POD activity, plant hormone signal transduction, and chlorophyll biosynthesis. Co-regulation analysis suggested that these DEGs in M79 contributed to the formation of a regulatory network involving multiple biological processes and pathways including photosynthesis, signal transduction, transcriptional regulation, redox regulation, hormonal signaling, and osmotic regulation. RNA-seq analysis also showed that some photosynthesis-related DEGs were highly expressed in M79 compared to its parental lines under drought stress. These results indicate that various molecular pathways, including photosynthesis, respond to drought stress in M79, and provide abundant molecular information for further analysis of the underlying mechanism responding to this stress.

  2. Transcriptomic studies reveal a key metabolic pathway contributing to a well-maintained photosynthetic system under drought stress in foxtail millet (Setaria italica L.).

    Science.gov (United States)

    Shi, Weiping; Cheng, Jingye; Wen, Xiaojie; Wang, Jixiang; Shi, Guanyan; Yao, Jiayan; Hou, Liyuan; Sun, Qian; Xiang, Peng; Yuan, Xiangyang; Dong, Shuqi; Guo, Pingyi; Guo, Jie

    2018-01-01

    Drought stress is one of the most important abiotic factors limiting crop productivity. A better understanding of the effects of drought on millet ( Setaria italica L.) production, a model crop for studying drought tolerance, and the underlying molecular mechanisms responsible for drought stress responses is vital to improvement of agricultural production. In this study, we exposed the drought resistant F 1 hybrid, M79, and its parental lines E1 and H1 to drought stress. Subsequent physiological analysis demonstrated that M79 showed higher photosynthetic energy conversion efficiency and drought tolerance than its parents. A transcriptomic study using leaves collected six days after drought treatment, when the soil water content was about ∼20%, identified 3066, 1895, and 2148 differentially expressed genes (DEGs) in M79, E1 and H1 compared to the respective untreated controls, respectively. Further analysis revealed 17 Gene Ontology (GO) enrichments and 14 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in M79, including photosystem II (PSII) oxygen-evolving complex, peroxidase (POD) activity, plant hormone signal transduction, and chlorophyll biosynthesis. Co-regulation analysis suggested that these DEGs in M79 contributed to the formation of a regulatory network involving multiple biological processes and pathways including photosynthesis, signal transduction, transcriptional regulation, redox regulation, hormonal signaling, and osmotic regulation. RNA-seq analysis also showed that some photosynthesis-related DEGs were highly expressed in M79 compared to its parental lines under drought stress. These results indicate that various molecular pathways, including photosynthesis, respond to drought stress in M79, and provide abundant molecular information for further analysis of the underlying mechanism responding to this stress.

  3. BDNF/TrkB Pathway Mediates the Antidepressant-Like Role of H2S in CUMS-Exposed Rats by Inhibition of Hippocampal ER Stress.

    Science.gov (United States)

    Wei, Le; Kan, Li-Yuan; Zeng, Hai-Ying; Tang, Yi-Yun; Huang, Hong-Lin; Xie, Ming; Zou, Wei; Wang, Chun-Yan; Zhang, Ping; Tang, Xiao-Qing

    2018-06-01

    Our previous works have shown that hydrogen sulfide (H 2 S) significantly attenuates chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and hippocampal endoplasmic reticulum (ER) stress. Brain-derived neurotrophic factor (BDNF) generates an antidepressant-like effect by its receptor tyrosine protein kinase B (TrkB). We have previously found that H 2 S upregulates the expressions of BDNF and p-TrkB in the hippocampus of CUMS-exposed rats. Therefore, the present work was to explore whether BDNF/TrkB pathway mediates the antidepressant-like role of H 2 S by blocking hippocampal ER stress. We found that treatment with K252a (an inhibitor of BDNF/TrkB pathway) significantly increased the immobility time in the forced swim test and tail suspension test and increased the latency to feed in the novelty-suppressed feeding test in the rats cotreated with sodium hydrosulfide (NaHS, a donor of H 2 S) and CUMS. Similarly, K252a reversed the protective effect of NaHS against CUMS-induced hippocampal ER stress, as evidenced by increases in the levels of ER stress-related proteins, glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12. Taken together, our results suggest that BDNF/TrkB pathway plays an important mediatory role in the antidepressant-like action of H 2 S in CUMS-exposed rats, which is by suppression of hippocampal ER stress. These data provide a novel mechanism underlying the protection of H 2 S against CUMS-induced depressive-like behaviors.

  4. Long term effect of curcumin in regulation of glycolytic pathway and angiogenesis via modulation of stress activated genes in prevention of cancer.

    Directory of Open Access Journals (Sweden)

    Laxmidhar Das

    Full Text Available Oxidative stress, an important factor in modulation of glycolytic pathway and induction of stress activated genes, is further augmented due to reduced antioxidant defense system, which promotes cancer progression via inducing angiogenesis. Curcumin, a naturally occurring chemopreventive phytochemical, is reported to inhibit carcinogenesis in various experimental animal models. However, the underlying mechanism involved in anticarcinogenic action of curcumin due to its long term effect is still to be reported because of its rapid metabolism, although metabolites are accumulated in tissues and remain for a longer time. Therefore, the long term effect of curcumin needs thorough investigation. The present study aimed to analyze the anticarcinogenic action of curcumin in liver, even after withdrawal of treatment in Dalton's lymphoma bearing mice. Oxidative stress observed during lymphoma progression reduced antioxidant enzyme activities, and induced angiogenesis as well as activation of early stress activated genes and glycolytic pathway. Curcumin treatment resulted in activation of antioxidant enzyme super oxide dismutase and down regulation of ROS level as well as activity of ROS producing enzyme NADPH:oxidase, expression of stress activated genes HIF-1α, cMyc and LDH activity towards normal level. Further, it lead to significant inhibition of angiogenesis, observed via MMPs activity, PKCα and VEGF level, as well as by matrigel plug assay. Thus findings of this study conclude that the long term effect of curcumin shows anticarcinogenic potential via induction of antioxidant defense system and inhibition of angiogenesis via down regulation of stress activated genes and glycolytic pathway in liver of lymphoma bearing mice.

  5. Intracerebroventricular tempol administration in older rats reduces oxidative stress in the hypothalamus but does not change STAT3 signalling or SIRT1/AMPK pathway.

    Science.gov (United States)

    Toklu, Hale Z; Scarpace, Philip J; Sakarya, Yasemin; Kirichenko, Nataliya; Matheny, Michael; Bruce, Erin B; Carter, Christy S; Morgan, Drake; Tümer, Nihal

    2017-01-01

    Hypothalamic inflammation and increased oxidative stress are believed to be mechanisms that contribute to obesity. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a free radical scavenger, has been shown to reduce inflammation and oxidative stress. We hypothesized that brain infusion of tempol would reduce oxidative stress, and thus would reduce food intake and body weight and improve body composition in rats with age-related obesity and known elevated oxidative stress. Furthermore, we predicted an associated increase in markers of leptin signalling, including the silent mating type information regulator 2 homolog 1 (SIRT1)/5'AMP-activated protein kinase (AMPK) pathway and the signal transducer and activator of transcription 3 (STAT3) pathway. For this purpose, osmotic minipumps were placed in the intracerebroventricular region of young (3 months) and aged (23 months) male Fischer 344 x Brown Norway rats for the continuous infusion of tempol or vehicle for 2 weeks. Tempol significantly decreased (p < 0.01) nicotinamide adenine dinucleotide phosphate oxidase activity in the hypothalamus but failed to reduce food intake or weight gain and did not alter body composition. SIRT1 activity and Acetyl p53 were decreased and phosphorylation of AMPK was increased with age, but they were unchanged with tempol. Basal phosphorylation of STAT3 was unchanged with age or tempol. These results indicate that tempol decreases oxidative stress but fails to alter feeding behaviour, body weight, or body composition. Moreover, tempol does not modulate the SIRT1/AMPK/p53 pathway and does not change leptin signalling. Thus, a reduction in hypothalamic oxidative stress is not sufficient to reverse age-related obesity.

  6. The sequential pathway between trauma-related symptom severity and cognitive-based smoking processes through perceived stress and negative affect reduction expectancies among trauma exposed smokers.

    Science.gov (United States)

    Garey, Lorra; Cheema, Mina K; Otal, Tanveer K; Schmidt, Norman B; Neighbors, Clayton; Zvolensky, Michael J

    2016-10-01

    Smoking rates are markedly higher among trauma-exposed individuals relative to non-trauma-exposed individuals. Extant work suggests that both perceived stress and negative affect reduction smoking expectancies are independent mechanisms that link trauma-related symptoms and smoking. Yet, no work has examined perceived stress and negative affect reduction smoking expectancies as potential explanatory variables for the relation between trauma-related symptom severity and smoking in a sequential pathway model. Methods The present study utilized a sample of treatment-seeking, trauma-exposed smokers (n = 363; 49.0% female) to examine perceived stress and negative affect reduction expectancies for smoking as potential sequential explanatory variables linking trauma-related symptom severity and nicotine dependence, perceived barriers to smoking cessation, and severity of withdrawal-related problems and symptoms during past quit attempts. As hypothesized, perceived stress and negative affect reduction expectancies had a significant sequential indirect effect on trauma-related symptom severity and criterion variables. Findings further elucidate the complex pathways through which trauma-related symptoms contribute to smoking behavior and cognitions, and highlight the importance of addressing perceived stress and negative affect reduction expectancies in smoking cessation programs among trauma-exposed individuals. (Am J Addict 2016;25:565-572). © 2016 American Academy of Addiction Psychiatry.

  7. Protective Effects of Olive Leaf Extract on Acrolein-Exacerbated Myocardial Infarction via an Endoplasmic Reticulum Stress Pathway

    Directory of Open Access Journals (Sweden)

    Yuyu Xu

    2018-02-01

    Full Text Available Many studies reported that air pollution particulate matter (PM exposure was associated with myocardial infarction (MI. Acrolein representing the unsaturated aldehydes, the main component of PM, derives from the incomplete combustion of wood, plastic, fossil fuels and the main constitute of cigarette smoking. However, the effect of acrolein on MI remains not that clear. In the current study, the effect of acrolein-exacerbated MI was investigated. In vivo, male Sprague–Dawley rats received olive leaf extract (OLE followed by acrolein, then isoprenaline (ISO was received by subcutaneous injection to induce MI. Results showed that the expression levels of GRP78 and CHOP, two major components of endoplasmic reticulum (ER stress were higher in the combination of acrolein and ISO than those in ISO treatment. The apoptosis marker, Bax, was also higher while the anti-apoptosis indicator, Bcl2 expression was lower both at protein and mRNA levels in the combination group. Also, the acrolein-protein adducts and myocardial pathological damage increased in the combination of acrolein and ISO relative to the ISO treatment. Besides, cardiac parameters, ejection fraction (EF and fractional shortening (FS were reduced more significantly when acrolein was added than in ISO treatment. Interestingly, all the changes were able to be ameliorated by OLE. Since hydroxytyrosol (HT and oleuropein (OP were the main components in OLE, we next investigated the effect of HT and OP on cardiomyocyte H9c2 cell apoptosis induced by acrolein through ER stress and Bax pathway. Results showed that GRP78, CHOP and Bax expression were upregulated, while Bcl2 expression was downregulated both at the protein and mRNA levels, when the H9c2 cells were treated with acrolein. In addition, pretreatment with HT can reverse the expression of GRP78, CHOP, Bax and Bcl2 on the protein and mRNA levels, while there was no effect of OP on the expression of GRP78 and CHOP on the mRNA levels

  8. Oxidation and nitrosation of meat proteins under gastro-intestinal conditions: Consequences in terms of nutritional and health values of meat.

    Science.gov (United States)

    de La Pomélie, Diane; Santé-Lhoutellier, Véronique; Sayd, Thierry; Gatellier, Philippe

    2018-03-15

    The chemical changes (oxidation/nitrosation) of meat proteins during digestion lead to a decrease in their nutritional value. Moreover, oxidized and nitrosated amino acids are suspected to promote various human pathologies. To investigate the mechanisms and the kinetics of these endogenous protein modifications, we used a dynamic artificial digestive system (DIDGI®) that mimics the physicochemical conditions of digestion. The combined effect of meat cooking and endogenous addition of ascorbate and nitrite was evaluated on protein oxidation (by measuring carbonyl groups), protein nitrosation (by measuring nitrosamines), and proteolysis. Considerable carbonylation was observed in the digestive tract, especially under the acidic conditions of the stomach. Nitrosamines, caused by ammonia oxidation, were formed in conditions in which no nitrite was added, although the addition of nitrite in the model significantly increased their levels. Meat cooking and nitrite addition significantly decreased protein digestion. The interactions between all the changes affecting the proteins are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress

    DEFF Research Database (Denmark)

    Brouwers, O; Niessen, P M; Haenen, G

    2010-01-01

    -hydro-5-methylimidazolone (MG-H1) was detected with an antibody against MG-H1 and quantified with ultra-performance liquid chromatography (tandem) mass spectrometry. Reactive oxygen species formation was measured with a 5-(and-6)-chloromethyl-2'7'-dichlorodihydrofluorescein diacetate acetyl ester probe...... for AGE ligand S100b did (p cells and adventitia by fivefold accompanied by an eightfold increase in the oxidative stress marker nitrotyrosine. Antioxidant pre-incubation prevented methylglyoxal......-induced impairment of vasoreactivity. CONCLUSIONS/INTERPRETATION: These data show that hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation is mediated by increased intracellular methylglyoxal levels in a pathway dependent on oxidative stress....

  10. Effect of curing agents on the oxidative and nitrosative damage to meat proteins during processing of fermented sausages.

    Science.gov (United States)

    Villaverde, A; Morcuende, D; Estévez, M

    2014-07-01

    The effect of increasing concentrations of curing agents, ascorbate (0, 250, and 500 ppm), and nitrite (0, 75, and 150 ppm), on the oxidative and nitrosative damage to proteins during processing of fermented sausages was studied. The potential influence of these reactions on color and texture of the fermented sausages was also addressed. Nitrite had a pro-oxidant effect on tryptophan depletion and promoted the formation of protein carbonyls and Schiff bases. The nitration degree in the fermented sausages was also dependent on nitrite concentration. On the other hand, ascorbate acted as an efficient inhibitor of the oxidative and nitrosative damage to meat proteins. As expected, nitrite clearly favored the formation of the cured red color and ascorbate acted as an enhancer of color formation. Nitrite content was positively correlated with hardness. The chemistry behind the action of nitrite and ascorbate on muscle proteins during meat fermentation is thoroughly discussed. The results suggest that ascorbate (500 ppm) may be required to compensate the pro-oxidant impact of nitrite on meat proteins. This study provides insight on the action of curing agents on meat proteins during processing of fermented sausages. This chemistry background provides understanding of the potential influence of the oxidative and nitrosative damage to proteins on the quality of processed muscle foods. The study provides novel information on the impact of the combination of nitrite and ascorbate on the chemical deterioration of proteins and the influence on particular quality traits of fermented sausages. These data may be of interest for the design of cured muscle foods of enhanced quality. © 2014 Institute of Food Technologists®

  11. NASAs VESGEN: Systems Analysis of Vascular Phenotypes from Stress and Other Signaling Pathways Using GeneLab.

    Science.gov (United States)

    Parsons-Wingerter, Patricia A.; Weitzel, Alexander; Vyas, Ruchi J.; Murray, Matthew C.; Wyatt, Sarah E.

    2016-01-01

    One fundamental requirement shared by humans with all higher terrestrial life forms, including insect wings, higher land plants and other vertebrates, is a complex, fractally branching vascular system. NASA's VESsel GENeration Analysis (VESGEN) software maps and quantifies vascular trees, networks, and tree-network composites according to weighted physiological rules such as vessel connectivity, tapering and bifurcational branching. According to fluid dynamics, successful vascular transport requires a complex distributed system of highly regulated laminar flow. Microvascular branching rules within vertebrates, dicot leaves and the other organisms therefore display many similarities. One unifying perspective is that vascular patterning offers a useful readout that necessarily integrates complex molecular signaling pathways. VESGEN has elucidated changes in vascular pattern resulting from inflammatory, stress response, developmental and other signaling within numerous tissues and major model organisms studied for Space Biology. For a new VESGEN systems approach, we analyzed differential gene expression in leaves of Arabidopsis thaliana reported by GeneLab (GLDS-7) for spaceflight. Vascular-related changes in leaf gene expression were identified that can potentially be phenocopied by mutants in ground-based experiments. To link transcriptional, protein and other molecular change with phenotype, alterations in the Euclidean and dynamic dimensions (x,y,t) of vascular patterns for Arabidopsis leaves and other model species are being co-localized with signaling patterns of single molecular expression analyzed as information dimensions (i,j,k,...). Previously, Drosophila microarray data returned from space suggested significant changes in genes related to wing venation development that include EGF, Notch, Hedghog, Wingless and Dpp signaling. Phenotypes of increasingly abnormal ectopic wing venation in the (non-spaceflight) Drosophila wing generated by overexpression of a

  12. Participation of Antidiuretic Hormone (ADH) in Asthma Exacerbations Induced by Psychological Stress via PKA/PKC Signal Pathway in Airway-Related Vagal Preganglionic Neurons (AVPNs).

    Science.gov (United States)

    Hou, Lili; Zhu, Lei; Zhang, Min; Zhang, Xingyi; Zhang, Guoqing; Liu, Zhenwei; Li, Qiang; Zhou, Xin

    2017-01-01

    Present study was performed to examine whether ADH was implicated in psychological stress asthma and to explore the underlying molecular mechanism. We not only examined ADH levels in the cerebrospinal fluid (CSF) via radioimmunoassay, but also measured ADH receptor (ADHR) expression in airway-related vagal preganglionic neurons (AVPNs) through real-time PCR in all experimental mice. Western blotting was performed to evaluate the relationship between ADH and PKA/PKC in psychological stress asthma. Finally, the role of PKA/PKC in psychological stress asthma was analyzed. Marked asthma exacerbations were noted owing to significantly elevated levels of ADH and ADHR after psychological stress induction as compared to OVA alone (asthma group). ADHR antagonists (SR-49095 or SR-121463A) dramatically lowered higher protein levels of PKAα and PKCα induced by psychological stress as compared to OVA alone, suggesting the correlation between ADH and PKA/PKC in psychological stress asthma. KT-5720 (PKA inhibitor) and Go-7874 (PKC inhibitor) further directly revealed the involvement of PKA/PKC in psychological stress asthma. Some notable changes were also noted after employing PKA and PKC inhibitors in psychological stress asthma, including reduced asthmatic inflammation (lower eosinophil peroxidase (EPO) activity, myeloperoxidase (MPO) activity, immunoglobulin E (IgE) level, and histamine release), substantial decrements in inflammatory cell counts (eosinophils and lymphocytes), and decreased cytokine secretion (IL-6, IL-10, and IFN-γ), indicating the involvement of PKA/PKC in asthma exacerbations induced by psychological stress. Our results strongly suggested that ADH participated in psychological stress-induced asthma exacerbations via PKA/PKC signal pathway in AVPNs. © 2017 The Author(s)Published by S. Karger AG, Basel.

  13. Epigallocatechin-3-Gallate (EGCG Promotes Autophagy-Dependent Survival via Influencing the Balance of mTOR-AMPK Pathways upon Endoplasmic Reticulum Stress

    Directory of Open Access Journals (Sweden)

    Marianna Holczer

    2018-01-01

    Full Text Available The maintenance of cellular homeostasis is largely dependent on the ability of cells to give an adequate response to various internal and external stimuli. We have recently proposed that the life-and-death decision in endoplasmic reticulum (ER stress response is defined by a crosstalk between autophagy, apoptosis, and mTOR-AMPK pathways, where the transient switch from autophagy-dependent survival to apoptotic cell death is controlled by GADD34. The aim of the present study was to investigate the role of epigallocatechin-3-gallate (EGCG, the major polyphenol of green tea, in promoting autophagy-dependent survival and to verify the key role in connecting GADD34 with mTOR-AMPK pathways upon prolonged ER stress. Our findings, obtained by using HEK293T cells, revealed that EGCG treatment is able to extend cell viability by inducing autophagy. We confirmed that EGCG-induced autophagy is mTOR-dependent and PKA-independent; furthermore, it also required ULK1. We show that pretreatment of cells with EGCG diminishes the negative effect of GADD34 inhibition (by guanabenz or siGADD34 treatment on autophagy. EGCG was able to delay apoptotic cell death by upregulating autophagy-dependent survival even in the absence of GADD34. Our data suggest a novel role for EGCG in promoting cell survival via shifting the balance of mTOR-AMPK pathways in ER stress.

  14. Hydrogen-rich medium protects mouse embryonic fibroblasts from oxidative stress by activating LKB1-AMPK-FoxO1 signal pathway.

    Science.gov (United States)

    Lee, Jihyun; Yang, Goowon; Kim, Young-Joo; Tran, Quynh Hoa; Choe, Wonchae; Kang, Insug; Kim, Sung Soo; Ha, Joohun

    2017-09-23

    Persistent oxidative stress is recognized as a major cause of many pathological conditions as well as ageing. However, most clinical trials of dietary antioxidants have failed to produce successful outcomes in treating oxidative stress-induced diseases. Molecular hydrogen (H 2 ) has recently received considerable attention as a therapeutic agent owing to its novel antioxidant properties, a selective scavenger of hydroxyl and peroxynitrite radicals. Beyond this, numerous reports support that H 2 can modulate the activity of various cellular signal pathways. However, its effect on AMP-activated protein kinase (AMPK) signal pathway, a central regulator of energy hemostasis, has remained almost elusive. Here, we report that hydrogen-rich medium activated LKB1-AMPK signal pathway without ATP depletion, which in turn induced FoxO1-dependent transcription of manganese superoxide dismutase and catalase in mouse embryonic fibroblasts. Moreover, hydrogen-rich media effectively reduced the level of reactive oxygen species in cells treated with hydrogen peroxide and protected these cells from apoptosis in an AMPK-dependent manner. These results suggest that the LKB1-AMPK-FoxO1 signaling pathway is a critical mediator of the antioxidant properties of H 2 , further supporting the idea that H 2 acts as a signaling molecule to serve various physiological functions. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Stress

    Science.gov (United States)

    ... taking care of an aging parent. With mental stress, the body pumps out hormones to no avail. Neither fighting ... with type 1 diabetes. This difference makes sense. Stress blocks the body from releasing insulin in people with type 2 ...

  16. Fisetin induces apoptosis and endoplasmic reticulum stress in human non-small cell lung cancer through inhibition of the MAPK signaling pathway.

    Science.gov (United States)

    Kang, Kyoung Ah; Piao, Mei Jing; Madduma Hewage, Susara Ruwan Kumara; Ryu, Yea Seong; Oh, Min Chang; Kwon, Taeg Kyu; Chae, Sungwook; Hyun, Jin Won

    2016-07-01

    Fisetin (3,3',4',7-tetrahydroxyflavone), a dietary flavonoid compound, is currently being investigated for its anticancer effect in various cancer models, including lung cancer. Recent studies show that fisetin induces cell growth inhibition and apoptosis in the human non-small cell lung cancer line NCI-H460. In this study, we investigated whether fisetin can induce endoplasmic reticulum (ER) stress-mediated apoptosis in NCI-H460 cells. Fisetin induced mitochondrial reactive oxygen species (ROS) and characteristic signs of ER stress: ER staining; mitochondrial Ca(2+) overload; expression of ER stress-related proteins; glucose-regulated protein (GRP)-78, phosphorylation of protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) and phosphorylation of eukaryotic initiation factor-2 α subunit; cleavage of activating transcription factor-6; phosphorylation of inositol-requiring kinase-1 and splicing of X-box transcription factor-1; induction of C/EBP homologous protein and cleaved caspase-12. siRNA-mediated knockdown of CHOP and ATF-6 attenuated fisetin-induced apoptotic cell death. In addition, fisetin induced phosphorylation of ERK, JNK, and p38 MAPK. Moreover, silencing of the MAPK signaling pathway prevented apoptotic cell death. In summary, our results indicate that, in NCI-H460 cells, fisetin induces apoptosis and ER stress that is mediated by induction of the MAPK signaling pathway.

  17. Curcumin Induced Human Gastric Cancer BGC-823 Cells Apoptosis by ROS-Mediated ASK1-MKK4-JNK Stress Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Tao Liang

    2014-09-01

    Full Text Available The signaling mediated by stress-activated MAP kinases (MAPK, c-Jun N-terminal kinase (JNK has well-established importance in cancer. In the present report, we investigated the effects of curcumin on the signaling pathway in human gastric cancer BGC-823 cells. Curcumin induced reactive oxygen species (ROS production and BGC-823 cells apoptosis. Inhibition of ROS generation by antioxidant (NAC or Trion significantly prevented curcumin-mediated apoptosis. Notably, we observed that curcumin activated ASK1, a MAPKKK that is oxidative stress sensitive and responsible to phosphorylation of JNK via triggering cascades, up-regulated an upstream effector of the JNK, MKK4, and phosphorylated JNK protein expression in BGC-823 cells. However, curcumin induced ASK1-MKK4-JNK signaling was attenuated by NAC. All the findings confirm the possibility that oxidative stress-activated ASK1-MKK4-JNK signaling cascade promotes the apoptotic response in curcumin-treated BGC-823 cells.

  18. Determination of N-nitrosamines and N-nitrosables substances in rubber teats and sothers by GC-TEA

    Directory of Open Access Journals (Sweden)

    Eleno Rodrigues Vieira

    2006-01-01

    Full Text Available N-Nitrosamines are receiving special attention because they present high mutagenic and carcinogenic potential. They can be found in several areas. In rubber, for example, they can be found in Nipples and Pacifiers. Spiegelhalder and Pressumann, have observed that N-Nitrosamines present in nipples and pacifiers could easily migrate to artificial saliva. They have also observed that a considerable amount of N-Nitrosamines precursors, such as nitrosable amines, could migrate to saliva, increasing the possibility of N-Nitrosamines formation into the stomach of living beings. In 80's, Holland, Germany and FDA-U.S.A. have established volatile N-Nitrosamines limit levels. In 2002, in Brazil, limit levels came through Resolução RDC n° 221 of ANVISA. This resolution refers to NBR10334 and NBR 13793 standards where limits and analysis methods are specified. In this work SENAICETEPO presents the method adopted for determination of N-Nitrosamines and N-Nitrosables in nipples and pacifiers. The detection and determination limits of the analytical system as well the method uncertainty were evaluated, in order to demonstrate the adequacy of this technique to comply with the requirements of NBR10334/2003 and NBR 13793/2003 standard.

  19. Taurine Pretreatment Prevents Isoflurane-Induced Cognitive Impairment by Inhibiting ER Stress-Mediated Activation of Apoptosis Pathways in the Hippocampus in Aged Rats.

    Science.gov (United States)

    Zhang, Yanan; Li, Dongliang; Li, Haiou; Hou, Dailiang; Hou, Jingdong

    2016-10-01

    Isoflurane, a commonly used inhalation anesthetic, may induce neurocognitive deficits, especially in elderly patients after surgery. Recent study demonstrated that isoflurane caused endoplasmic reticulum (ER) stress and subsequent neuronal apoptosis in the brain, contributing to cognitive deficits. Taurine, a major intracellular free amino acid, has been shown to inhibit ER stress and neuronal apoptosis in several neurological disorders. Here, we examined whether taurine can prevent isoflurane-induced ER stress and cognitive impairment in aged rats. Thirty minutes prior to a 4-h 1.3 % isoflurane exposure, aged rats were treated with vehicle or taurine at low, middle and high doses. Aged rats without any treatment served as control. The brains were harvested 6 h after isoflurane exposure for molecular measurements, and behavioral study was performed 2 weeks later. Compared with control, isoflurane increased expression of hippocampal ER stress biomarkers including glucose-regulated protein 78, phosphorylated (P-) inositol-requiring enzyme 1, P-eukaryotic initiation factor 2-α (EIF2α), activating transcription factor 4 (ATF-4), cleaved ATF-6 and C/EBP homologous protein, along with activation of apoptosis pathways as indicated by decreased B cell lymphoma 2 (BCL-2)/BCL2-associated X protein, increased expressions of cytochrome-c and cleaved caspase-3. Taurine pretreatment dose-dependently inhibited isoflurane-induced increase in expression of ER stress biomarkers except for P-EIF2α and ATF-4, and reversed isoflurane-induced changes in apoptosis-related proteins. Moreover, isoflurane caused spatial working memory deficits in aged rats, which were prevented by taurine pretreatment. The results indicate that taurine pretreatment prevents anesthetic isoflurane-induced cognitive impairment by inhibiting ER stress-mediated activation of apoptosis pathways in the hippocampus in aged rats.

  20. Modulation of hepatic inflammation and energy-sensing pathways in the rat liver by high-fructose diet and chronic stress.

    Science.gov (United States)

    Veličković, Nataša; Teofilović, Ana; Ilić, Dragana; Djordjevic, Ana; Vojnović Milutinović, Danijela; Petrović, Snježana; Preitner, Frederic; Tappy, Luc; Matić, Gordana

    2018-05-29

    High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver. In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NFκB, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). High-fructose diet led to glucose intolerance, activation of NFκB and JNK pathways and increased intrahepatic IL-1β, TNFα and inhibitory phosphorylation of insulin receptor substrate 1 on Ser 307 . It also decreased phospho-AMPK/AMPK ratio and increased SIRT1 expression. Stress alone increased plasma and hepatic corticosterone but did not influence glucose tolerance, nor hepatic inflammatory or energy-sensing proteins. After the combined treatment, hepatic corticosterone was increased, glucose tolerance remained preserved, while hepatic inflammation was partially prevented despite decreased AMPK activity. High-fructose diet resulted in glucose intolerance, hepatic inflammation, decreased AMPK activity and reduced insulin sensitivity. Chronic stress alone did not exert such effects, but when applied together with high-fructose diet it could partially prevent fructose-induced inflammation, presumably due to increased hepatic glucocorticoids.

  1. Contribution of Fdh3 and Glr1 to Glutathione Redox State, Stress Adaptation and Virulence in Candida albicans

    NARCIS (Netherlands)

    Tillmann, Anna T.; Strijbis, Karin; Cameron, Gary; Radmaneshfar, Elahe; Thiel, Marco; Munro, Carol A.; Maccallum, Donna M.; Distel, Ben; Gow, Neil A. R.; Brown, Alistair J. P.

    2015-01-01

    The major fungal pathogen of humans, Candida albicans, is exposed to reactive nitrogen and oxygen species following phagocytosis by host immune cells. In response to these toxins, this fungus activates potent anti-stress responses that include scavenging of reactive nitrosative and oxidative species

  2. Effects of ketamine administration on mTOR and reticulum stress signaling pathways in the brain after the infusion of rapamycin into prefrontal cortex.

    Science.gov (United States)

    Abelaira, Helena M; Réus, Gislaine Z; Ignácio, Zuleide M; Dos Santos, Maria Augusta B; de Moura, Airam B; Matos, Danyela; Demo, Júlia P; da Silva, Júlia B I; Michels, Monique; Abatti, Mariane; Sonai, Beatriz; Dal Pizzol, Felipe; Carvalho, André F; Quevedo, João

    2017-04-01

    Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists. A relationship between mTOR kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR) has been shown. We evaluate the effects of ketamine administration on the mTOR signaling pathway and proteins of UPR in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens, after the inhibiton of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol), or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). The immunocontent of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 kinase (eEF2K) homologous protein (CHOP), PKR-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) - alpha were determined in the brain. The mTOR levels were reduced in the rapamycin group treated with saline and ketamine in the PFC; p4EBP1 levels were reduced in the rapamycin group treated with ketamine in the PFC and nucleus accumbens; the levels of peEF2K were increased in the PFC in the vehicle group treated with ketamine and reduced in the rapamycin group treated with ketamine. The PERK and IRE1-alpha levels were decreased in the PFC in the rapamycin group treated with ketamine. Our results suggest that mTOR signaling inhibition by rapamycin could be involved, at least in part, with the mechanism of action of ketamine; and the ketamine antidepressant on ER stress pathway could be also mediated by mTOR signaling pathway in certain brain structures. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Phosphorylation of Icariin Can Alleviate the Oxidative Stress Caused by the Duck Hepatitis Virus A through Mitogen-Activated Protein Kinases Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Wen Xiong

    2017-09-01

    Full Text Available The duck virus hepatitis (DVH caused by the duck hepatitis virus A (DHAV has produced extensive economic losses to the duck industry. The currently licensed commercial vaccine has shown some defects and does not completely prevent the DVH. Accordingly, a new alternative treatment for this disease is urgently needed. Previous studies have shown that icariin (ICA and its phosphorylated derivative (pICA possessed good anti-DHAV effects through direct and indirect antiviral pathways, such as antioxidative stress. But the antioxidant activity showed some differences between ICA and pICA. The aim of this study is to prove that ICA and pICA attenuate oxidative stress caused by DHAV in vitro and in vivo, and to investigate their mechanism of action to explain their differences in antioxidant activities. In vivo, the dynamic deaths, oxidative evaluation indexes and hepatic pathological change scores were detected. When was added the hinokitiol which showed the pro-oxidative effect as an intervention method, pICA still possessed more treatment effect than ICA. The strong correlation between mortality and oxidative stress proves that ICA and pICA alleviate oxidative stress caused by DHAV. This was also demonstrated by the addition of hydrogen peroxide (H2O2 as an intervention method in vitro. pICA can be more effective than ICA to improve duck embryonic hepatocytes (DEHs viability and reduce the virulence of DHAV. The strong correlation between TCID50 and oxidative stress demonstrates that ICA and pICA can achieve anti-DHAV effects by inhibiting oxidative stress. In addition, the superoxide dismutase (SOD and glutathione peroxidase (GSH-Px of ICA and pICA showed significant difference. pICA could significantly inhibit the phosphorylation of p38, extra cellular signal regulated Kinase (ERK 1/2 and c-Jun N-terminal kinase (JNK, which were related to mitogen-activated protein kinases (MAPKs signaling pathways. Ultimately, compared to ICA, pICA exhibited more

  4. L-β-N-methylamino-l-alanine (BMAA) nitrosation generates a cytotoxic DNA damaging alkylating agent: An unexplored mechanism for neurodegenerative disease.

    Science.gov (United States)

    Potjewyd, G; Day, P J; Shangula, S; Margison, G P; Povey, A C

    2017-03-01

    L-β-N-methylamino-l-alanine (BMAA) is a non-proteinic amino acid, that is neurotoxic in vitro and in animals, and is implicated in the causation of amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC) on Guam. Given that natural amino acids can be N-nitrosated to form toxic alkylating agents and the structural similarity of BMAA to other amino acids, our hypothesis was that N-nitrosation of BMAA might result in a toxic alkylating agent, providing a novel mechanistic hypothesis for BMAA action. We have chemically nitrosated BMAA with sodium nitrite to produce nitrosated BMAA (N-BMAA) which was shown to react with the alkyl-trapping agent, 4-(p-nitrobenzyl)pyridine, cause DNA strand breaks in vitro and was toxic to the human neuroblastoma cell line SH-SY5Y under conditions in which BMAA itself was minimally toxic. Our results indicate that N-BMAA is an alkylating agent and toxin suggesting a plausible and previously unrecognised mechanism for the neurotoxic effects of BMAA. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. A WRKY transcription factor from Withania somnifera regulates triterpenoid withanolide accumulation and biotic stress tolerance through modulation of phytosterol and defense pathways.

    Science.gov (United States)

    Singh, Anup Kumar; Kumar, Sarma Rajeev; Dwivedi, Varun; Rai, Avanish; Pal, Shaifali; Shasany, Ajit K; Nagegowda, Dinesh A

    2017-08-01

    Withania somnifera produces pharmacologically important triterpenoid withanolides that are derived via phytosterol pathway; however, their biosynthesis and regulation remain to be elucidated. A jasmonate- and salicin-inducible WRKY transcription factor from W. somnifera (WsWRKY1) exhibiting correlation with withaferin A accumulation was functionally characterized employing virus-induced gene silencing and overexpression studies combined with transcript and metabolite analyses, and chromatin immunoprecipitation assay. WsWRKY1 silencing resulted in stunted plant growth, reduced transcripts of phytosterol pathway genes with corresponding reduction in phytosterols and withanolides in W. somnifera. Its overexpression elevated the biosynthesis of triterpenoids in W. somnifera (phytosterols and withanolides), as well as tobacco and tomato (phytosterols). Moreover, WsWRKY1 binds to W-box sequences in promoters of W. somnifera genes encoding squalene synthase and squalene epoxidase, indicating its direct regulation of triterpenoid pathway. Furthermore, while WsWRKY1 silencing in W. somnifera compromised the tolerance to bacterial growth, fungal infection, and insect feeding, its overexpression in tobacco led to improved biotic stress tolerance. Together these findings demonstrate that WsWRKY1 has a positive regulatory role on phytosterol and withanolides biosynthesis, and defense against biotic stress, highlighting its importance as a metabolic engineering tool for simultaneous improvement of triterpenoid biosynthesis and plant defense. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

  6. Curcumin enhances the effects of irinotecan on colorectal cancer cells through the generation of reactive oxygen species and activation of the endoplasmic reticulum stress pathway.

    Science.gov (United States)

    Huang, Yan-Feng; Zhu, Da-Jian; Chen, Xiao-Wu; Chen, Qi-Kang; Luo, Zhen-Tao; Liu, Chang-Chun; Wang, Guo-Xin; Zhang, Wei-Jie; Liao, Nv-Zhu

    2017-06-20

    Although initially effective against metastatic colorectal cancer (CRC), irinotecan-based chemotherapy leads to resistance and adverse toxicity. Curcumin is well known for its anti-cancer effects in many cancers, including CRC. Here, we describe reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress as important mechanisms by which curcumin enhances irinotecan's effects on CRC cells. CRC cell lines were treated with curcumin and/or irinotecan for 24 h, and then evaluated using cell proliferation assays, cell apoptosis assays, cell cycle analysis, intracellular Ca2+ measurements, ROS measurements and immunoblotting for key ER stress-related proteins. We found that cell viability was inhibited and apoptosis was increased, accompanied by ROS generation and ER stress activation in CRC cells treated with curcumin alone or in combination with irinotecan. Blocking ROS production attenuated the expression of two markers of ER stress: binding of immunoglobulin protein (BIP) and CCAAT/enhancer-binding protein homologous protein (CHOP). Blocking CHOP expression using RNA interference also inhibited ROS generation. These results demonstrated that curcumin could enhance the effects of irinotecan on CRC cells by inhibiting cell viability and inducing cell cycle arrest and apoptosis, and that these effects may be mediated, in part, by ROS generation and activation of the ER stress pathway.

  7. Suppression of NF-κB signal pathway by NLRC3-like protein in stony coral Acropora aculeus under heat stress.

    Science.gov (United States)

    Zhou, Zhi; Wu, Yibo; Zhang, Chengkai; Li, Can; Chen, Guangmei; Yu, Xiaopeng; Shi, Xiaowei; Xu, Yanlai; Wang, Lingui; Huang, Bo

    2017-08-01

    Heat stress is the most common factor for coral bleaching, which has increased both in frequency and severity due to global warming. In the present study, the stony coral Acropora aculeus was subjected to acute heat stress and entire transcriptomes were sequenced via the next generation sequencing platform. Four paired-end libraries were constructed and sequenced in two groups, including a control and a heat stress group. A total of 120,319,751 paired-end reads with lengths of 2 × 100 bp were assembled and 55,021 coral-derived genes were obtained. After read mapping and abundance estimation, 9110 differentially expressed genes were obtained in the comparison between the control and heat stress group, including 4465 significantly upregulated and 4645 significantly downregulated genes. Twenty-three GO terms in the Biological Process category were overrepresented for significantly upregulated genes, and divided into six groups according to their relationship. These three groups were related to the NF-κB signal pathway, and the remaining three groups were relevant for pathogen response, immunocyte activation and protein ubiquitination. Forty-three common genes were found in four GO terms, which were directly related to the NF-κB signal pathway. These included 2 NACHT, LRR, PYD domains-containing protein, 5 nucleotide-binding oligomerization domain-containing protein, 29 NLRC3-like protein, 4 NLRC5-like protein, and 3 uncharacterized protein. For significantly downregulated genes, 27 overrepresented GO terms were found in the Biological Process category, which were relevant to protein ubiquitination and ATP metabolism. Our results indicate that heat stress suppressed the immune response level via the NLRC3-like protein, the fine-tuning of protein turnover activity, and ATP metabolism. This might disrupt the balance of coral-zooxanthellae symbiosis and result in the bleaching of the coral A. aculeus. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Alteration of synaptic transmission in the hippocampal-mPFC pathway during extinction trials of context-dependent fear memory in juvenile rat stress models.

    Science.gov (United States)

    Koseki, Hiroyo; Matsumoto, Machiko; Togashi, Hiroko; Miura, Yoshihide; Fukushima, Kazuaki; Yoshioka, Mitsuhiro

    2009-09-01

    The medial prefrontal cortex (mPFC) has been proposed to be essential for extinction of fear memory, but its neural mechanism has been poorly understood. The present study examined whether synaptic transmission in the hippocampal-mPFC pathway is related to extinction of context-dependent fear memory in freely moving rats using electrophysiological approaches combined with behavioral analysis. Population spike amplitude in the mPFC was decreased during the first extinction trial by exposure to contextual fear conditioning. This synaptic inhibition was reversed by repeated extinction trials, accompanied by decreases in fear-related freezing behavior. These results suggest that alteration of synaptic transmission in the hippocampal-mPFC pathway is associated with the extinction processes of context-dependent fear memory. Further experiments were performed to elucidate whether early postnatal stress alters the synaptic response in the mPFC during extinction trials using a juvenile stress model, based on our previous findings that early postnatal stress affects the behavioral response to emotional stress. Adult rats that previously were exposed to five footshocks (FS) (shock intensity, 0.5 mA; intershock interval, 28 seconds; shock duration, 2 seconds) at postnatal day 21 to 25 (week 3; 3W-FS) exhibited impaired reversal of both inhibitory synaptic transmission and freezing behavior induced by repeated extinction trials. The neuronal and behavioral deficits observed in the 3W-FS group were prevented by pretreatment with the serotonin(1A) receptor agonist tandospirone (1 mg/kg, i.p.). These results indicate the possiblity that aversive stress exposure during the third postnatal week impaired extinction processes of context-dependent fear memory. The deficits in extinction observed in the 3W-FS group might be attributable to dysfunction of hippocampal-mPFC neural circuits involving 5-HT(1A) receptor mechanisms. 2009 Wiley-Liss, Inc.

  9. Ligustrazine attenuates oxidative stress-induced activation of hepatic stellate cells by interrupting platelet-derived growth factor-β receptor-mediated ERK and p38 pathways

    International Nuclear Information System (INIS)

    Zhang, Feng; Ni, Chunyan; Kong, Desong; Zhang, Xiaoping; Zhu, Xiaojing; Chen, Li; Lu, Yin; Zheng, Shizhong

    2012-01-01

    Hepatic fibrosis represents a frequent event following chronic insult to trigger wound healing reactions with accumulation of extracellular matrix (ECM) in the liver. Activation of hepatic stellate cells (HSCs) is the pivotal event during liver fibrogenesis. Compelling evidence indicates that oxidative stress is concomitant with liver fibrosis irrespective of the underlying etiology. Natural antioxidant ligustrazine exhibits potent antifibrotic activities, but the mechanisms are poorly understood. Our studies were to investigate the ligustrazine effects on HSC activation stimulated by hydrogen peroxide (H 2 O 2 ), an in vitro model mimicking the oxidative stress in liver fibrogenesis, and to elucidate the possible mechanisms. Our results demonstrated that H 2 O 2 at 5 μM significantly stimulated HSC proliferation and expression of marker genes of HSC activation; whereas ligustrazine dose-dependently suppressed proliferation and induced apoptosis in H 2 O 2 -activated HSCs, and attenuated expression of fibrotic marker genes. Mechanistic investigations revealed that ligustrazine reduced platelet-derived growth factor-β receptor (PDGF-βR) expression and blocked the phosphorylation of extracellular regulated protein kinase (ERK) and p38 kinase, two downstream effectors of PDGF-βR. Further molecular evidence suggested that ligustrazine interruption of ERK and p38 pathways was dependent on the blockade of PDGF-βR and might be involved in ligustrazine reduction of fibrotic marker gene expression under H 2 O 2 stimulation. Furthermore, ligustrazine modulated some proteins critical for HSC activation and ECM homeostasis in H 2 O 2 -stimulated HSCs. These data collectively indicated that ligustrazine could attenuate HSC activation caused by oxidative stress, providing novel insights into ligustrazine as a therapeutic option for hepatic fibrosis. Highlights: ► Ligustrazine inhibits oxidative stress-induced HSC activation. ► Ligustrazine reduces fibrotic marker genes

  10. Can Erythrocytes Transmit Oxidative Stress Beyond the Lungs? An Adverse Outcome Pathway for the Cardiovascular Effects of Air Pollution.

    Science.gov (United States)

    Adverse outcome pathways (AOPs) are systems biology roadmaps with potential utility in xenobiotic exposure risk assessment. AOPs connect molecular initiating events (MIEs) to population-level adverse outcomes (AOs) via cellular, organ, and organism key events (KE) and KE relatio...

  11. Curcumin Reverses the Diazepam-Induced Cognitive Impairment by Modulation of Oxidative Stress and ERK 1/2/NF-κB Pathway in Brain

    Directory of Open Access Journals (Sweden)

    Alexandra C. Sevastre-Berghian

    2017-01-01

    Full Text Available Oxidative stress and inflammation can be involved in cognitive dysfunction associated with neurodegenerative disorders. Diazepam (DZP administration has been chosen to simulate the memory impairment. The aim of this study was to evaluate the effects of curcumin (CUR on spatial cognition, ambulatory activity, and blood and brain oxidative stress levels. The ERK/NF-κB signaling pathway and the histopathological changes in the hippocampus and frontal lobe, in diazepam-treated rats, were also analyzed. The animals were divided into 4 groups: control, carboxymethylcellulose (CMC + CUR, CMC + DZP, and CUR + CMC + DZP. CUR (150 mg/kg b.w. was orally administered for 28 days. DZP (2 mg/kg b.w. was intraperitoneally administered 20 minutes before the behavioral tests (open field test, Y-maze, and elevated plus maze. CUR improved the spontaneous alternation behavior, decreased the oxidative stress levels, both in the blood and in the hippocampus, and downregulated the extracellular signal-regulated kinase (ERK 1/2/nuclear transcription factor- (NF- κB/pNF-κB pathway in the hippocampus and the iNOS expression in the hippocampus and frontal lobe of the DZP-treated rats. Histopathologically, no microscopic changes were found. The immunohistochemical signal of iNOS decreased in the DZP and CUR-treated group. Thus, our findings suggest that curcumin administration may improve the cognitive performance and may also have an antioxidant effect.

  12. Parenting Stress as an Indirect Pathway to Mental Health Concerns among Mothers of Children with Autism Spectrum Disorder

    Science.gov (United States)

    Tomeny, Theodore S.

    2017-01-01

    The link between autism spectrum disorder symptoms and maternal stress has been well established, yet many mothers remain resilient to more severe psychopathology. For the current online study, 111 mothers of a child with autism spectrum disorder completed questionnaires about their child's symptoms, their own stress related to parenting, and any…

  13. Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression

    Directory of Open Access Journals (Sweden)

    Madrigal José LM

    2011-11-01

    Full Text Available Abstract Background There is a pressing need to identify novel pathophysiological pathways relevant to depression that can help to reveal targets for the development of new medications. Toll-like receptor 4 (TLR-4 has a regulatory role in the brain's response to stress. Psychological stress may compromise the intestinal barrier, and increased gastrointestinal permeability with translocation of lipopolysaccharide (LPS from Gram-negative bacteria may play a role in the pathophysiology of major depression. Methods Adult male Sprague-Dawley rats were subjected to chronic mild stress (CMS or CMS+intestinal antibiotic decontamination (CMS+ATB protocols. Levels of components of the TLR-4 signaling pathway, of LPS and of different inflammatory, oxidative/nitrosative and anti-inflammatory mediators were measured by RT-PCR, western blot and/or ELISA in brain prefrontal cortex. Behavioral despair was studied using Porsolt's test. Results CMS increased levels of TLR-4 and its co-receptor MD-2 in brain as well as LPS and LPS-binding protein in plasma. In addition, CMS also increased interleukin (IL-1β, COX-2, PGE2 and lipid peroxidation levels and reduced levels of the anti-inflammatory prostaglandin 15d-PGJ2 in brain tissue. Intestinal decontamination reduced brain levels of the pro-inflammatory parameters and increased 15d-PGJ2, however this did not affect depressive-like behavior induced by CMS. Conclusions Our results suggest that LPS from bacterial translocation is responsible, at least in part, for the TLR-4 activation found in brain after CMS, which leads to release of inflammatory mediators in the CNS. The use of Gram-negative antibiotics offers a potential therapeutic approach for the adjuvant treatment of depression.

  14. The Predominant Pathway of Apoptosis in THP-1 Macrophage-Derived Foam Cells Induced by 5-Aminolevulinic Acid-Mediated Sonodynamic Therapy is the Mitochondria-Caspase Pathway Despite the Participation of Endoplasmic Reticulum Stress

    Directory of Open Access Journals (Sweden)

    Huan Wang

    2014-05-01

    Full Text Available Background: In advanced atherosclerosis, chronic endoplasmic reticulum (ER stress induces foam cells apoptosis and generates inflammatory reactions. Methods: THP-1 macrophage-derived foam cells (FC were incubated with 1 mM 5-aminolevulinic acid (ALA. After ALA mediated sonodynamic therapy (ALA-SDT, apoptosis of FC was assayed by Annexin V-PI staining. Intracellular reactive oxygen species (ROS and mitochondrial membrane potential were detected by staining with CellROX® Green Reagent and jc-1. Pretreatment of FC with N-acetylcysteine (NAC, Z-VAD-FMK or 4-phenylbutyrate (4-PBA, mitochondria apoptotic pathway associated proteins and C/EBP-homologous (CHOP expressions were assayed by wertern blotting. Results: Burst of apoptosis of FC was observed at 5-hour after ALA-SDT with 6-hour incubation of ALA and 0.4 W/cm2 ultrasound. After ALA-SDT, intracellular ROS level increased and mitochondrial membrane potential collapsed. Translocations of cytochrome c from mitochondria into cytosol and Bax from cytosol into mitochondria, cleaved caspase 9, cleaved caspase 3, upregulation of CHOP, as well as downregulation of Bcl-2 after ALA-SDT were detected, which could be suppressed by NAC. Activation of mitochondria-caspase pathway could not be inhibited by 4-PBA. Cleaved caspase 9 and caspase 3 as well as apoptosis induced by ALA-SDT could be inhibited by Z-VAD-FMK. Conclusion: The mitochondria-caspase pathway is predominant in the apoptosis of FC induced by ALA-SDT though ER stress participates in.

  15. Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: the involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway.

    Science.gov (United States)

    Jo, Guk Heui; Kim, Gi-Young; Kim, Wun-Jae; Park, Kun Young; Choi, Yung Hyun

    2014-10-01

    Sulforaphane, a naturally occurring isothiocyanate found in cruciferous vegetables, has received a great deal of attention because of its ability to inhibit cell proliferation and induce apoptosis in cancer cells. In this study, we investigated the anticancer activity of sulforaphane in the T24 human bladder cancer line, and explored its molecular mechanism of action. Our results showed that treatment with sulforaphane inhibited cell viability and induced apoptosis in T24 cells in a concentration-dependent manner. Sulforaphane-induced apoptosis was associated with mitochondria dysfunction, cytochrome c release and Bcl-2/Bax dysregulation. Furthermore, the increased activity of caspase-9 and -3, but not caspase-8, was accompanied by the cleavage of poly ADP-ribose polymerase, indicating the involvement of the mitochondria-mediated intrinsic apoptotic pathway. Concomitant with these changes, sulforaphane triggered reactive oxygen species (ROS) generation, which, along with the blockage of sulforaphane-induced loss of mitochondrial membrane potential and apoptosis, was strongly attenuated by the ROS scavenger N-acetyl-L-cysteine. Furthermore, sulforaphane was observed to activate endoplasmic reticulum (ER) stress and the nuclear factor-E2-related factor-2 (Nrf2) signaling pathway, as demonstrated by the upregulation of ER stress‑related proteins, including glucose-regulated protein 78 and C/EBP-homologous protein, and the accumulation of phosphorylated Nrf2 proteins in the nucleus and induction of heme oxygenase-1 expression, respectively. Taken together, these results demonstrate that sulforaphane has antitumor effects against bladder cancer cells through an ROS-mediated intrinsic apoptotic pathway, and suggest that ER stress and Nrf2 may represent strategic targets for sulforaphane-induced apoptosis.

  16. Adverse effects of microplastics and oxidative stress-induced MAPK/Nrf2 pathway-mediated defense mechanisms in the marine copepod Paracyclopina nana

    Science.gov (United States)

    Jeong, Chang-Bum; Kang, Hye-Min; Lee, Min-Chul; Kim, Duck-Hyun; Han, Jeonghoon; Hwang, Dae-Sik; Souissi, Sami; Lee, Su-Jae; Shin, Kyung-Hoon; Park, Heum Gi; Lee, Jae-Seong

    2017-01-01

    Microplastic pollution causes a major concern in the marine environment due to their worldwide distribution, persistence, and adverse effects of these pollutants in the marine ecosystem. Despite its global presence, there is still a lack of information on the effect of microplastics on marine organisms at the molecular level. Herein we demonstrated ingestion and egestion of nano- (0.05 μm) and micro-sized (0.5 and 6 μm) polystyrene microbeads in the marine copepod Paracyclopina nana, and examined molecular responses to exposure to microbeads with in vivo endpoints such as growth rate and fecundity. Also, we proposed an adverse outcome pathway for microplastic exposure that covers molecular and individual levels. This study provides the first insight into the mode of action in terms of microplastic-induced oxidative stress and related signaling pathways in P. nana.

  17. Tetrandrine Induces Apoptosis in Human Nasopharyngeal Carcinoma NPC-TW 039 Cells by Endoplasmic Reticulum Stress and Ca2+/Calpain Pathways.

    Science.gov (United States)

    Liu, Kuo-Ching; Lin, Ya-Jing; Hsiao, Yung-Ting; Lin, Meng-Liang; Yang, Jiun-Long; Huang, Yi-Ping; Chu, Yung-Lin; Chung, Jing-Gung

    2017-11-01

    Tetrandrine is an alkaloid extracted from a traditional China medicine plant, and is considered part of food therapy as well. In addition, it has been widely reported to induce apoptotic cell death in many human cancer cells. However, the mechanism of Tetrandrine on human nasopharyngeal carcinoma cells (NPC) is still questioned. In our study, we examined whether Tetrandrine can induce apoptosis of NPC-TW 039 cells. We found that cell morphology was changed after treatment with different concentrations of Tetrandrine. Further, we indicated that the NPC-TW 039 cells viability decreased in a Tetrandrine dose-dependent manner. We also found that tetrandrine induced cell cycle arrest in G 0 /G 1 phase. Tetrandrine induced DNA condensation by DAPI staining as well. In addition, we found that Tetrandrine induced Ca 2+ release in the cytosol. At the same time, endoplasmic reticulum (ER) stress occurred. Then we used western blotting to examine the protein expression which is associated with mitochondria-mediated apoptotic pathways and caspase-dependent pathways. To further examine whether Ca 2+ was released or not with Tetrandrine induced-apoptosis, we used the chelator of Ca 2+ and showed that cell viability increased. At the same time, caspase-3 expression was decreased. Furthermore, confocal microscopy examination revealed that Tetrandrine induced expression of ER stress-related proteins GADD153 and GRP78. Our results indicate that Tetrandrine induces apoptosis through calcium-mediated ER stress and caspase pathway in NPC-TW 039 cells. In conclusion, Tetrandrine may could be used for treatment of human nasopharyngeal carcinoma in future. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  18. The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia.

    Science.gov (United States)

    Réus, Gislaine Z; Becker, Indianara R T; Scaini, Giselli; Petronilho, Fabricia; Oses, Jean P; Kaddurah-Daouk, Rima; Ceretta, Luciane B; Zugno, Alexandra I; Dal-Pizzol, Felipe; Quevedo, João; Barichello, Tatiana

    2018-02-02

    Evidence has shown that the kynurenine pathway (KP) plays a role in the onset of oxidative stress and also in the pathophysiology of schizophrenia. The aim of this study was to use a pharmacological animal model of schizophrenia induced by ketamine to investigate if KP inhibitors could protect the brains of Wistar rats against oxidative stress and behavioral changes. Ketamine, injected at the dose of 25mg/kg, increased spontaneous locomotor activity. However, the inhibitors of tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and kynurenine-3-monooxygenase (KMO) were able to reverse these changes. In addition, the IDO inhibitor prevented lipid peroxidation, and decreased the levels of protein carbonyl in the prefrontal cortex (PFC), hippocampus and striatum. It also increased the activity of superoxide dismutase (SOD) in the hippocampus, as well as increasing the levels of catalase activity in the PFC and hippocampus. The TDO inhibitor prevented lipid damage in the striatum and reduced the levels of protein carbonyl in the hippocampus and striatum. Also, the TDO inhibitor increased the levels of SOD activity in the striatum and CAT activity in the hippocampus of ketamine-induced pro-oxidant effects. Lipid damage was not reversed by the KMO inhibitor. The KMO inhibitor increased the levels of SOD activity in the hippocampus, and reduced the levels of protein carbonyl while elevating the levels of CAT activity in the striatum of rats that had been injected with ketamine. Our findings revealed that the KP pathway could be a potential mechanism by which a schizophrenia animal model induced by ketamine could cause interference by producing behavioral disturbance and inducing oxidative stress in the brain, suggesting that the inhibition of the KP pathway could be a potential target in treating schizophrenia. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Propofol attenuates H2O2-induced oxidative stress and apoptosis via the mitochondria- and ER-medicated pathways in neonatal rat cardiomyocytes.

    Science.gov (United States)

    Liu, Xue-Ru; Cao, Lu; Li, Tao; Chen, Lin-Lin; Yu, Yi-Yan; Huang, Wen-Jun; Liu, Li; Tan, Xiao-Qiu

    2017-05-01

    Previous studies have shown that propofol, an intravenous anesthetic commonly used in clinical practice, protects the myocardium from injury. Mitochondria- and endoplasmic reticulum (ER)-mediated oxidative stress and apoptosis are two important signaling pathways involved in myocardial injury and protection. The present study aimed to test the hypothesis that propofol could exert a cardio-protective effect via the above two pathways. Cultured neonatal rat cardiomyocytes were treated with culture medium (control group), H 2 O 2 at 500 μM (H 2 O 2 group), propofol at 50 μM (propofol group), and H 2 O 2 plus propofol (H 2 O 2  + propofol group), respectively. The oxidative stress, mitochondrial membrane potential (ΔΨm) and apoptosis of the cardiomyocytes were evaluated by a series of assays including ELISA, flow cytometry, immunofluorescence microscopy and Western blotting. Propofol significantly suppressed the H 2 O 2 -induced elevations in the activities of caspases 3, 8, 9 and 12, the ratio of Bax/Bcl-2, and cell apoptosis. Propofol also inhibited the H 2 O 2 -induced reactive oxygen species (ROS) generation, lactic dehydrogenase (LDH) release and mitochondrial transmembrane potential (ΔΨm) depolarization, and restored the H 2 O 2 -induced reductions of glutathione (GSH) and superoxide dismutase (SOD). In addition, propofol decreased the expressions of glucose-regulated protein 78 kDa (Grp78) and inositol-requiring enzyme 1α (IRE1α), two important signaling molecules in the ER-mediated apoptosis pathway. Propofol protects cardiomyocytes from H 2 O 2 -induced injury by inhibiting the mitochondria- and ER-mediated apoptosis signaling pathways.

  20. Nutritional mitigation of winter thermal stress in gilthead seabream associated metabolic pathways and potential indicators of nutritional state

    DEFF Research Database (Denmark)

    Richard, Nadege; Silva, Tomé S.; Wulff, Tune

    2016-01-01

    and phenylalanine/tyrosine catabolism, and induced higher aerobic metabolism and gluconeogenesis. Results support the notion that WF diet had a positive effect on fish nutritional state by partially counteracting the effect of thermal stress and underlined the sensitivity of proteome data for nutritional....... A total of 404 protein spots, out of 1637 detected, were differentially expressed between the two groups of fish. Mass spectrometry analysis of selected spots suggested that WF diet improved oxidative stress defense, reduced endoplasmic reticulum stress, enhanced metabolic flux through methionine cycle...... and metabolic profiling purposes. Intragroup variability and co-measured information were also used to pinpoint which proteins displayed a stronger relation with fish nutritional state....

  1. TRB3 reverses chemotherapy resistance and mediates crosstalk between endoplasmic reticulum stress and AKT signaling pathways in MHCC97H human hepatocellular carcinoma cells.

    Science.gov (United States)

    Li, Yang; Zhu, Danxi; Hou, Lidan; Hu, Bin; Xu, Min; Meng, Xiangjun

    2018-01-01

    Tribbles homolog 3 (TRB3), a type of pseudokinase that contains a consensus serine/threonine kinase catalytic core structure, is upregulated in hepatocellular carcinoma. However, the effect of TRB3 expression in hepatocellular carcinoma and the molecular mechanisms underlying TRB3-mediated effects on tumorigenesis in hepatocellular carcinoma have not been fully elucidated. The present study focused on the effect of TRB3 expression in MHCC97H hepatocellular carcinoma cells and investigated the underlying molecular mechanisms in MHCC97H cells. In the present study, it was revealed that TRB3 was significantly overexpressed in the MHCC97H hepatocellular carcinoma cell compared with L-02 normal hepatic cells. Under endoplasmic reticulum (ER) stress induced by thapsigargin and tunicamycin, the levels of TRB3, CCAAT/enhancer binding protein homologous protein (CHOP), protein kinase B (AKT) and phosphorylated (p)AKT expression were upregulated. Furthermore, when the expression of TRB3 was silenced by short hairpin (sh)RNA, the survival of MHCC97H hepatocellular carcinoma cells was increased. Notably, following transduction with lentiviral containing TRB3-shRNA, cell survival also increased after treatment with chemotherapy drug cisplatin. The present study demonstrated that knockdown of CHOP by shRNA was able to reduce TRB3 expression, and the knockdown of TRB3 markedly increased the level of pAKT. TRB3 was overexpressed in MHCC97H hepatocellular carcinoma cells, particularly under endoplasmic reticulum stress. Knockdown of TRB3 was able to increase cell survival. Therefore, TRB3 expression may induce apoptosis and reverse resistance to chemotherapy in MHCC97H hepatic carcinoma cells. The present study suggests that TRB3 is a key molecule that mediates the crosstalk between ER stress and AKT signal pathways. Furthermore, the present study may provide further insight into the cancer biology of hepatocellular carcinoma and the development of anticancer drugs targeting the ER

  2. Transcriptome Comparative Profiling of Barley eibi1 Mutant Reveals Pleiotropic Effects of HvABCG31 Gene on Cuticle Biogenesis and Stress Responsive Pathways

    Directory of Open Access Journals (Sweden)

    Eviatar Nevo

    2013-10-01

    Full Text Available Wild barley eibi1 mutant with HvABCG31 gene mutation has low capacity to retain leaf water, a phenotype associated with reduced cutin deposition and a thin cuticle. To better understand how such a mutant plant survives, we performed a genome-wide gene expression analysis. The leaf transcriptomes between the near-isogenic lines eibi1 and the wild type were compared using the 22-k Barley1 Affymetrix microarray. We found that the pleiotropic effect of the single gene HvABCG31 mutation was linked to the co-regulation of metabolic processes and stress-related system. The cuticle development involved cytochrome P450 family members and fatty acid metabolism pathways were significantly up-regulated by the HvABCG31 mutation, which might be anticipated to reduce the levels of cutin monomers or wax and display conspicuous cuticle defects. The candidate genes for responses to stress were induced by eibi1 mutant through activating the jasmonate pathway. The down-regulation of co-expressed enzyme genes responsible for DNA methylation and histone deacetylation also suggested that HvABCG31 mutation may affect the epigenetic regulation for barley development. Comparison of transcriptomic profiling of barley under biotic and abiotic stresses revealed that the functions of HvABCG31 gene to high-water loss rate might be different from other osmotic stresses of gene mutations in barley. The transcriptional profiling of the HvABCG31 mutation provided candidate genes for further investigation of the physiological and developmental changes caused by the mutant.

  3. Effects of liver depression and psychological stress on human uterine leiomyoma cells by an AR-cAMP-PKA signal transduction pathway.

    Science.gov (United States)

    Xia, Tian; Li, Shuang; Ma, Ruihong; Guan, Sufen; Li, Jiacui; Li, Hongqin; Zhang, Hexin; Lin, Qiu; Zhao, Zhimei; Wang, Baojuan

    2017-06-01

    Based on the emotional theory of Traditional Chinese Medicine, and combined with the modern medicine theory of psychological stress, a research model of human uterine leiomyoma cells (ULM) was cultured in vitro to determine the effectiveness of adrenergic receptor (AR) agonists in human ULM cell growth. In addition, we studied the functional influence of "liver depression and psychological stress theory" on fibroid formation by intervening in the AR-cAMP-PKA signaling pathway. The intention was to establish a new method to prevent and cure fibroids through "liver depression and psychological stress theory" and provide an experimental basis for the Traditional Chinese Medicine emotional theory. Primary human ULM cells were enriched by collagenase digestion. Immunohistochemistry and hematoxylin and eosin (HE) staining were used for cytological identification. Using this model, we studied intervention using specific AR agonists on ULM cells to observe the influence of "liver depression and psychological stress theory" on estrogen receptor (ER), progesterone receptor (PR), vascular endothelial growth factor (VEGF) and fibroblast growth factors (FGF). Norepinephrine (NE) and epinephrine (E) are adrenergic receptor agonists. They promoted ULM cell proliferation and increased the levels of ER, PR, VEGF and FGF. In contrast, isoproterenol (ISO) inhibited ULM cell proliferation and decreased the levels of ER, PR, VEGF and FGF. The protein expression of cAMP and PKA in ULM cells was reduced and the levels of ER, PR, VEGF and FGF were increased when co-treatment with the α-AR blocker (phentolamine). The β-AR blocker (metoprolol) displayed an opposite effect. AR agonists modulated ER, PR, VEGF and FGF levels in ULM cells in an AR-cAMP-PKA-dependent signaling pathways to influence fibroid occurrence and development. Copyright © 2017. Published by Elsevier B.V.

  4. Stress

    DEFF Research Database (Denmark)

    Keller, Hanne Dauer

    2015-01-01

    Kapitlet handler om stress som følelse, og det trækker primært på de få kvalitative undersøgelser, der er lavet af stressforløb.......Kapitlet handler om stress som følelse, og det trækker primært på de få kvalitative undersøgelser, der er lavet af stressforløb....

  5. Stress !!!

    OpenAIRE

    Fledderus, M.

    2012-01-01

    Twee op de vijf UT-studenten hebben last van ernstige studiestress, zo erg zelfs dat het ze in hun privéleven belemmert. Die cijfers komen overeen met het landelijk beeld van stress onder studenten. Samen met 14 andere universiteits- en hogeschoolbladen enquêteerde UT Nieuws bijna 5500 studenten. Opvallend is dat mannelijke studenten uit Twente zich veel minder druk lijken te maken over hun studie. Onder vrouwen ligt de stress juist erg hoog ten opzichte van het landelijk gemiddelde.

  6. Quercetin ameliorates chronic unpredicted stress-induced behavioral dysfunction in male Swiss albino mice by modulating hippocampal insulin signaling pathway.

    Science.gov (United States)

    Mehta, Vineet; Singh, Tiratha Raj; Udayabanu, Malairaman

    2017-12-01

    Chronic stress is associated with impaired neurogenesis, neurodegeneration and behavioral dysfunction, whereas the mechanism underlying stress-mediated neurological complications is still not clear. In the present study, we aimed to investigate whether chronic unpredicted stress (CUS) mediated neurological alterations are associated with impaired hippocampal insulin signaling or not, and studied the effect of quercetin in this scenario. Male Swiss albino mice were subjected to 21day CUS, during which 30mg/kg quercetin treatment was given orally. After 21days, behavioral functions were evaluated in terms of locomotor activity (Actophotometer), muscle coordination (Rota-rod), depression (Tail Suspension Test (TST), Forced Swim Test (FST)) and memory performance (Passive-avoidance step-down task (PASD)). Further, hippocampal insulin signaling was evaluated in terms of protein expression of insulin, insulin receptor (IR) and glucose transporter 4 (GLUT-4) and neurogenesis was evaluated in terms of doublecortin (DCX) expression. 21day CUS significantly impaired locomotion and had no effect on muscle coordination. Stressed animals were depressed and showed markedly impaired memory functions. Quercetin treatment significantly improvement stress-mediated behavior dysfunction as indicated by improved locomotion, lesser immobility time and greater frequency of upward turning in TST and FST and increased transfer latency on the day 2 (short-term memory) and day 5 (long-term memory) in PASD test. We observed significantly higher IR expression and significantly lower GLUT-4 expression in the hippocampus of stressed animals, despite of nonsignificant difference in insulin levels. Further, chronic stress impaired hippocampal neurogenesis, as indicated by the significantly reduced levels of hippocampal DCX expression. Quercetin treatment significantly lowered insulin and IR expression and significantly enhanced GLUT-4 and DCX expression in the hippocampus, when compared to CUS. In

  7. Wnt1 Neuroprotection Translates into Improved Neurological Function during Oxidant Stress and Cerebral Ischemia Through AKT1 and Mitochondrial Apoptotic Pathways

    Directory of Open Access Journals (Sweden)

    Zhao Zhong Chong

    2010-01-01

    Full Text Available Although essential for the development of the nervous system, Wnt1 also has been associated with neurodegenerative disease and cognitive loss during periods of oxidative stress. Here we show that endogenous expression of Wnt1 is suppressed during oxidative stress in both in vitro and in vivo experimental models. Loss of endogenous Wnt1 signaling directly correlates with neuronal demise and increased functional deficit, illustrating that endogenous neuronal Wnt1 offers a vital level of intrinsic cellular protection against oxidative stress. Furthermore, transient overexpression of Wnt1 or application of exogenous Wnt1 recombinant protein is necessary to preserve neurological function and rescue neurons from apoptotic membrane phosphatidylserine externalization and genomic DNA degradation, since blockade of Wnt1 signaling with a Wnt1 antibody or dickkopf related protein 1 abrogates neuronal protection by Wnt1. Wnt1 ultimately relies upon the activation of Akt1, the modulation of mitochondrial membrane permeability, and the release of cytochrome c to control the apoptotic cascade, since inhibition of Wnt1 signaling, the phosphatidylinositol 3-kinase pathway, or Akt1 activity abrogates the ability of Wnt1 to block these apoptotic components. Our work identifies Wnt1 and its downstream signaling as cellular targets with high clinical potential for novel treatment strategies for multiple disorders precipitated by oxidative stress.

  8. Melatonin Modulates Endoplasmic Reticulum Stress and Akt/GSK3-Beta Signaling Pathway in a Rat Model of Renal Warm Ischemia Reperfusion

    Directory of Open Access Journals (Sweden)

    Kaouther Hadj Ayed Tka

    2015-01-01

    Full Text Available Melatonin (Mel is widely used to attenuate ischemia/reperfusion (I/R injury in several organs. Nevertheless, the underlying mechanisms remain unclear. This study was conducted to explore the effect of Mel on endoplasmic reticulum (ER stress, Akt and MAPK cascades after renal warm I/R. Eighteen Wistar rats were randomized into three groups: Sham, I/R, and Mel + I/R. The ischemia period was 60 min followed by 120 min of reperfusion. Mel (10 mg/kg was administrated 30 min prior to ischemia. The creatinine clearance, MDA, LDH levels, and histopathological changes were evaluated. In addition, Western blot was performed to study ER stress and its downstream apoptosis as well as phosphorylation of Akt, GSK-3β, VDAC, ERK, and P38. Mel decreased cytolysis and lipid peroxidation and improved renal function and morphology compared to I/R group. Parallely, it significantly reduced the ER stress parameters including GRP 78, p-PERK, XBP 1, ATF 6, CHOP, and JNK. Simultaneously, p-Akt level was significantly enhanced and its target molecules GSK-3β and VDAC were inhibited. Furthermore, the ERK and P38 phosphorylation were evidently augmented after Mel administration in comparison to I/R group. In conclusion, Mel improves the recovery of renal function by decreasing ER stress and stimulating Akt pathway after renal I/R injury.

  9. Shear stress induces cell apoptosis via a c-Src-phospholipase D-mTOR signaling pathway in cultured podocytes

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Chunfa, E-mail: chunfa.huang@case.edu [Louis Stokes Cleveland Veteran Affairs Medical Center, Case Western Reserve University (United States); Department of Medicine, Case Western Reserve University (United States); Rammelkamp Center for Research and Education, MetroHealth System Campus, Cleveland, OH 44106 (United States); Bruggeman, Leslie A. [Department of Medicine, Case Western Reserve University (United States); Rammelkamp Center for Research and Education, MetroHealth System Campus, Cleveland, OH 44106 (United States); Hydo, Lindsey M. [Louis Stokes Cleveland Veteran Affairs Medical Center, Case Western Reserve University (United States); Miller, R. Tyler [Louis Stokes Cleveland Veteran Affairs Medical Center, Case Western Reserve University (United States); Department of Medicine, Case Western Reserve University (United States); Rammelkamp Center for Research and Education, MetroHealth System Campus, Cleveland, OH 44106 (United States)

    2012-06-10

    The glomerular capillary wall, composed of endothelial cells, the glomerular basement membrane and the podocytes, is continually subjected to hemodynamic force arising from tractional stress due to blood pressure and shear stress due to blood flow. Exposure of glomeruli to abnormal hemodynamic force such as hyperfiltration is associated with glomerular injury and progressive renal disease, and the conversion of mechanical stimuli to chemical signals in the regulation of the process is poorly understood in podocytes. By examining DNA fragmentation, apoptotic nuclear changes and cytochrome c release, we found that shear stress induced cell apoptosis in cultured podocytes. Meanwhile, podocytes exposed to shear stress also stimulated c-Src phosphorylation, phospholipase D (PLD) activation and mammalian target of rapamycin (mTOR) signaling. Using the antibodies against c-Src, PLD{sub 1}, and PLD{sub 2} to perform reciprocal co-immunoprecipitations and in vitro PLD activity assay, our data indicated that c-Src interacted with and activated PLD{sub 1} but not PLD{sub 2}. The inhibition of shear stress-induced c-Src phosphorylation by PP{sub 2} (a specific inhibitor of c-Src kinase) resulted in reduced PLD activity. Phosphatidic acid, produced by shear stress-induced PLD activation, stimulated mTOR signaling, and caused podocyte hypertrophy and apoptosis.

  10. Liver-Enriched Gene 1, a Glycosylated Secretory Protein, Binds to FGFR and Mediates an Anti-stress Pathway to Protect Liver Development in Zebrafish.

    Directory of Open Access Journals (Sweden)

    Minjie Hu

    2016-02-01

    Full Text Available Unlike mammals and birds, teleost fish undergo external embryogenesis, and therefore their embryos are constantly challenged by stresses from their living environment. These stresses, when becoming too harsh, will cause arrest of cell proliferation, abnormal cell death or senescence. Such organisms have to evolve a sophisticated anti-stress mechanism to protect the process of embryogenesis/organogenesis. However, very few signaling molecule(s mediating such activity have been identified. liver-enriched gene 1 (leg1 is an uncharacterized gene that encodes a novel secretory protein containing a single domain DUF781 (domain of unknown function 781 that is well conserved in vertebrates. In the zebrafish genome, there are two copies of leg1, namely leg1a and leg1b. leg1a and leg1b are closely linked on chromosome 20 and share high homology, but are differentially expressed. In this report, we generated two leg1a mutant alleles using the TALEN technique, then characterized liver development in the mutants. We show that a leg1a mutant exhibits a stress-dependent small liver phenotype that can be prevented by chemicals blocking the production of reactive oxygen species. Further studies reveal that Leg1a binds to FGFR3 and mediates a novel anti-stress pathway to protect liver development through enhancing Erk activity. More importantly, we show that the binding of Leg1a to FGFR relies on the glycosylation at the 70th asparagine (Asn(70 or N(70, and mutating the Asn(70 to Ala(70 compromised Leg1's function in liver development. Therefore, Leg1 plays a unique role in protecting liver development under different stress conditions by serving as a secreted signaling molecule/modulator.

  11. Simultaneous pentafluorobenzyl derivatization and GC-ECNICI-MS measurement of nitrite and malondialdehyde in human urine : Close positive correlation between these disparate oxidative stress biomarkers

    NARCIS (Netherlands)

    Hanff, Erik; Eisenga, Michele F.; Beckmann, Bibiana; Bakker, Stephan J. L.; Tsikas, Dimitrios

    2017-01-01

    Urinary nitrite and malondialdehyde (MDA) are biomarkers of nitrosative and oxidative stress, respectively. At physiological pH values of urine and plasma, nitrite and MDA exist almost entirely in their dissociated forms, i.e., as ONO- (ONOH, p Kappa a =3.4) and -CH(CHO)(2) (CH2(CHO)(2), p Kappa a

  12. High Fat Diet-Induced Skeletal Muscle Wasting Is Decreased by Mesenchymal Stem Cells Administration: Implications on Oxidative Stress, Ubiquitin Proteasome Pathway Activation, and Myonuclear Apoptosis

    Directory of Open Access Journals (Sweden)

    Johanna Abrigo

    2016-01-01

    Full Text Available Obesity can lead to skeletal muscle atrophy, a pathological condition characterized by the loss of strength and muscle mass. A feature of muscle atrophy is a decrease of myofibrillar proteins as a result of ubiquitin proteasome pathway overactivation, as evidenced by increased expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF-1. Additionally, other mechanisms are related to muscle wasting, including oxidative stress, myonuclear apoptosis, and autophagy. Stem cells are an emerging therapy in the treatment of chronic diseases such as high fat diet-induced obesity. Mesenchymal stem cells (MSCs are a population of self-renewable and undifferentiated cells present in the bone marrow and other mesenchymal tissues of adult individuals. The present study is the first to analyze the effects of systemic MSC administration on high fat diet-induced skeletal muscle atrophy in the tibialis anterior of mice. Treatment with MSCs reduced losses of muscle strength and mass, decreases of fiber diameter and myosin heavy chain protein levels, and fiber type transitions. Underlying these antiatrophic effects, MSC administration also decreased ubiquitin proteasome pathway activation, oxidative stress, and myonuclear apoptosis. These results are the first to indicate that systemically administered MSCs could prevent muscle wasting associated with high fat diet-induced obesity and diabetes.

  13. Anti-influenza A virus activity of rhein through regulating oxidative stress, TLR4, Akt, MAPK, and NF-κB signal pathways.

    Directory of Open Access Journals (Sweden)

    Qian-Wen Wang

    Full Text Available Rhein, an anthraquinone compound existing in many traditional herbal medicines, has anti-inflammatory, antioxidant, antitumor, antiviral, hepatoprotective, and nephroprotective activities, but its anti-influenza A virus (IAV activity is ambiguous. In the present study, through plaque inhibition assay, time-of-addition assay, antioxidant assay, qRT-PCR, ELISA, and western blotting assays, we investigated the anti-IAV effect and mechanism of action of rhein in vitro and in vivo. The results showed that rhein could significantly inhibit IAV adsorption and replication, decrease IAV-induced oxidative stress, activations of TLR4, Akt, p38, JNK MAPK, and NF-κB pathways, and production of inflammatory cytokines and matrix metalloproteinases in vitro. Oxidant H2O2 and agonists of TLR4, Akt, p38/JNK and IKK/NF-κB could significantly antagonize the inhibitory effects of rhein on IAV-induced cytopathic effect (CPE and IAV replication. Through an in vivo test in mice, we also found that rhein could significantly improve the survival rate, lung index, pulmonary cytokines, and pulmonary histopathological changes. Rhein also significantly decreased pulmonary viral load at a high dose. In conclusion, rhein can inhibit IAV adsorption and replication, and the mechanism of action to inhibit IAV replication may be due to its ability to suppress IAV-induced oxidative stress and activations of TLR4, Akt, p38, JNK MAPK, and NF-κB signal pathways.

  14. Androgen receptor requires JunD as a coactivator to switch on an oxidative stress generation pathway in prostate cancer cells.

    Science.gov (United States)

    Mehraein-Ghomi, Farideh; Basu, Hirak S; Church, Dawn R; Hoffmann, F Michael; Wilding, George

    2010-06-01

    Relatively high oxidative stress levels in the prostate are postulated to be a major factor for prostate carcinogenesis and prostate cancer (CaP) progression. We focused on elucidating metabolic pathways of oxidative stress generation in CaP cells. Previously, we showed that the transcription factor JunD is essential for androgen-induced reactive oxygen species (ROS) production in androgen-dependent human CaP cells. We also recently showed that androgen induces the first and regulatory enzyme spermidine/spermine N1-acetyltransferase (SSAT) in a polyamine catabolic pathway that produces copious amounts of metabolic ROS. Here, we present coimmunoprecipitation and Gaussia luciferase reconstitution assay data that show that JunD forms a complex with androgen-activated androgen receptor (AR) in situ. Our chromatin immunoprecipitation assay data show that JunD binds directly to a specific SSAT promoter sequence only in androgen-treated LNCaP cells. Using a vector containing a luciferase reporter gene connected to the SSAT promoter and a JunD-silenced LNCaP cell line, we show that JunD is essential for androgen-induced SSAT gene expression. The elucidation of JunD-AR complex inducing SSAT expression leading to polyamine oxidation establishes the mechanistic basis of androgen-induced ROS production in CaP cells and opens up a new prostate-specific target for CaP chemopreventive/chemotherapeutic drug development. Copyright 2010 AACR.

  15. l-Arginine induces antioxidant response to prevent oxidative stress via stimulation of glutathione synthesis and activation of Nrf2 pathway.

    Science.gov (United States)

    Liang, Mingcai; Wang, Zhengxuan; Li, Hui; Cai, Liang; Pan, Jianghao; He, Hongjuan; Wu, Qiong; Tang, Yinzhao; Ma, Jiapei; Yang, Lin

    2018-05-01

    Arginine is a conditionally essential amino acid. To elucidate the influence of l-arginine on the activation of endogenous antioxidant defence, male Wistar rats were orally administered daily with l-arginine at different levels of 25, 50, 100 mg/100 g body weight. After 7 and 14 days feeding, the antioxidative capacities and glutathione (GSH) contents in the plasma and in the liver were uniformly enhanced with the increasing consumption of l-arginine, whereas the oxidative stress was effectively suppressed by l-arginine treatment. After 14 days feeding, the mRNA levels and protein expressions of Keap1 and Cul3 were gradually reduced by increasing l-arginine intake, resulting that the nuclear factor Nrf2 was activated. Upon activation of Nrf2, the expressions of antioxidant responsive element (ARE)-dependent genes and proteins (GCLC, GCLM, GS, GR, GST, GPx, CAT, SOD, NQO1, HO-1) were up-regulated by l-arginine feeding, indicating an upward trend in antioxidant capacity uniformly with the increasing consumption of l-arginine. The present study demonstrates that the supplementation of l-arginine stimulates GSH synthesis and activates Nrf2 pathway, leading to the up-regulation of ARE-driven antioxidant expressions via Nrf2-Keap1 pathway. Results suggest the availability of l-arginine is a critical factor to suppress oxidative stress and induce an endogenous antioxidant response. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Basolateral amygdala bidirectionally modulates stress-induced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway.

    Science.gov (United States)

    Rei, Damien; Mason, Xenos; Seo, Jinsoo; Gräff, Johannes; Rudenko, Andrii; Wang, Jun; Rueda, Richard; Siegert, Sandra; Cho, Sukhee; Canter, Rebecca G; Mungenast, Alison E; Deisseroth, Karl; Tsai, Li-Huei

    2015-06-09

    Repeated stress has been suggested to underlie learning and memory deficits via the basolateral amygdala (BLA) and the hippocampus; however, the functional contribution of BLA inputs to the hippocampus and their molecular repercussions are not well understood. Here we show that repeated stress is accompanied by generation of the Cdk5 (cyclin-dependent kinase 5)-activator p25, up-regulation and phosphorylation of glucocorticoid receptors, increased HDAC2 expression, and reduced expression of memory-related genes in the hippocampus. A combination of optogenetic and pharmacosynthetic approaches shows that BLA activation is both necessary and sufficient for stress-associated molecular changes and memory impairments. Furthermore, we show that this effect relies on direct glutamatergic projections from the BLA to the dorsal hippocampus. Finally, we show that p25 generation is necessary for the stress-induced memory dysfunction. Taken together, our data provide a neural circuit model for stress-induced hippocampal memory deficits through BLA activity-dependent p25 generation.

  17. Basolateral amygdala bidirectionally modulates stress-induced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway

    Science.gov (United States)

    Rei, Damien; Mason, Xenos; Seo, Jinsoo; Gräff, Johannes; Rudenko, Andrii; Wang, Jun; Rueda, Richard; Siegert, Sandra; Cho, Sukhee; Canter, Rebecca G.; Mungenast, Alison E.; Deisseroth, Karl; Tsai, Li-Huei

    2015-01-01

    Repeated stress has been suggested to underlie learning and memory deficits via the basolateral amygdala (BLA) and the hippocampus; however, the functional contribution of BLA inputs to the hippocampus and their molecular repercussions are not well understood. Here we show that repeated stress is accompanied by generation of the Cdk5 (cyclin-dependent kinase 5)-activator p25, up-regulation and phosphorylation of glucocorticoid receptors, increased HDAC2 expression, and reduced expression of memory-related genes in the hippocampus. A combination of optogenetic and pharmacosynthetic approaches shows that BLA activation is both necessary and sufficient for stress-associated molecular changes and memory impairments. Furthermore, we show that this effect relies on direct glutamatergic projections from the BLA to the dorsal hippocampus. Finally, we show that p25 generation is necessary for the stress-induced memory dysfunction. Taken together, our data provide a neural circuit model for stress-induced hippocampal memory deficits through BLA activity-dependent p25 generation. PMID:25995364

  18. FvBck1, a Component of Cell Wall Integrity MAP Kinase Pathway, is Required for Virulence and Oxidative Stress Response in Sugarcane Pokkah Boeng Pathogen

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    Chengkang eZhang

    2015-10-01

    Full Text Available Fusarium verticillioides (formerly F. moniliforme is suggested as one of the causal agents of Pokkah Boeng, a serious disease of sugarcane worldwide. Currently, detailed molecular and physiological mechanism of pathogenesis is unknown. In this study, we focused on cell wall integrity MAPK pathway as one of the potential signaling mechanisms associated with Pokkah Boeng pathogenesis. We identified FvBCK1 gene that encodes a MAP kinase kinase kinase homolog and determined that it is not only required for growth, micro- and macro-conidia production, and cell wall integrity but also for response to osmotic and oxidative stresses. The deletion of FvBCK1 caused a significant reduction in virulence and FB1 production, a carcinogenic mycotoxin produced by the fungus. Moreover, we found the expression levels of three genes, which are known to be involved in superoxide scavenging, were down regulated in the mutant. We hypothesized that the loss of superoxide scavenging capacity was one of the reasons for reduced virulence, but overexpression of catalase or peroxidase gene failed to restore the virulence defect in the deletion mutant. When we introduced Magnaporthe oryzae MCK1 into the FvBck1 deletion mutant, while certain phenotypes were restored, the complemented strain failed to gain full virulence. In summary, FvBck1 plays a diverse role in F. verticillioides, and detailed investigation of downstream signaling pathways will lead to a better understanding of how this MAPK pathway regulates Pokkah Boeng on sugarcane.

  19. Dysregulated cellular functions and cell stress pathways provide critical cues for activating and targeting natural killer cells to transformed and infected cells.

    Science.gov (United States)

    Raulet, David H; Marcus, Assaf; Coscoy, Laurent

    2017-11-01

    Natural killer (NK) cells recognize and kill cancer cells and infected cells by engaging cell surface ligands that are induced preferentially or exclusively on these cells. These ligands are recognized by activating receptors on NK cells, such as NKG2D. In addition to activation by cell surface ligands, the acquisition of optimal effector activity by NK cells is driven in vivo by cytokines and other signals. This review addresses a developing theme in NK cell biology: that NK-activating ligands on cells, and the provision of cytokines and other signals that drive high effector function in NK cells, are driven by abnormalities that arise from transformation or the infected state. The pathways include genomic damage, which causes self DNA to be exposed in the cytosol of affected cells, where it activates the DNA sensor cGAS. The resulting signaling induces NKG2D ligands and also mobilizes NK cell activation. Other key pathways that regulate NKG2D ligands include PI-3 kinase activation, histone acetylation, and the integrated stress response. This review summarizes the roles of these pathways and their relevance in both viral infections and cancer. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Xylopine Induces Oxidative Stress and Causes G2/M Phase Arrest, Triggering Caspase-Mediated Apoptosis by p53-Independent Pathway in HCT116 Cells

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    Luciano de Souza Santos

    2017-01-01

    Full Text Available Xylopine is an aporphine alkaloid that has cytotoxic activity to cancer cells. In this study, the underlying mechanism of xylopine cytotoxicity was assessed in human colon carcinoma HCT116 cells. Xylopine displayed potent cytotoxicity in different cancer cell lines in monolayer cultures and in a 3D model of cancer multicellular spheroids formed from HCT116 cells. Typical morphology of apoptosis, cell cycle arrest in the G2/M phase, increased internucleosomal DNA fragmentation, loss of the mitochondrial transmembrane potential, and increased phosphatidylserine externalization and caspase-3 activation were observed in xylopine-treated HCT116 cells. Moreover, pretreatment with a caspase-3 inhibitor (Z-DEVD-FMK, but not with a p53 inhibitor (cyclic pifithrin-α, reduced xylopine-induced apoptosis, indicating induction of caspase-mediated apoptosis by the p53-independent pathway. Treatment with xylopine also caused an increase in the production of reactive oxygen/nitrogen species (ROS/RNS, including hydrogen peroxide and nitric oxide, but not superoxide anion, and reduced glutathione levels were decreased in xylopine-treated HCT116 cells. Application of the antioxidant N-acetylcysteine reduced the ROS levels and xylopine-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. In conclusion, xylopine has potent cytotoxicity to different cancer cell lines and is able to induce oxidative stress and G2/M phase arrest, triggering caspase-mediated apoptosis by the p53-independent pathway in HCT116 cells.

  1. Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia.

    Science.gov (United States)

    Sethy, Niroj Kumar; Singh, Manjulata; Kumar, Rajesh; Ilavazhagan, Govindasamy; Bhargava, Kalpana

    2011-03-01

    Exposure to high altitude (and thus hypobaric hypoxia) induces electrophysiological, metabolic, and morphological modifications in the brain leading to several neurological clinical syndromes. Despite the known fact that hypoxia episodes in brain are a common factor for many neuropathologies, limited information is available on the underlying cellular and molecular mechanisms. In this study, we investigated the temporal effect of short-term (0-12 h) chronic hypobaric hypoxia on global gene expression of rat brain followed by detailed canonical pathway analysis and regulatory network identification. Our analysis revealed significant alteration of 33, 17, 53, 81, and 296 genes (p stress response pathway and genes were detected at all time points suggesting activation of NRF2-ARE antioxidant defense system. The results were further validated by assessing the expression levels of selected genes in temporal as well as brain regions with quantitative RT-PCR and western blot. In conclusion, our whole brain approach with temporal monitoring of gene expression patterns during hypobaric hypoxia has resulted in (1) deciphering sequence of pathways and signaling networks activated during onset of hypoxia, and (2) elucidation of NRF2-orchestrated antioxidant response as a major intrinsic defense mechanism. The results of this study will aid in better understanding and management of hypoxia-induced brain pathologies.

  2. TNF/TNFR{sub 1} pathway and endoplasmic reticulum stress are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Fu-Tao; Ding, Yi; Shah, Zahir; Xing, Dan; Gao, Yuan; Liu, Dong Ming; Ding, Ming-Xing, E-mail: dmx@mail.hzau.edu.cn

    2014-04-15

    Background and purpose: Quinolones cause obvious cartilaginous lesions in juvenile animals by chondrocyte apoptosis, which results in the restriction of their use in pediatric and adolescent patients. Studies showed that chondrocytes can be induced to produce TNFα, and the cisternae of the endoplasmic reticulum in quinolone-treated chondrocytes become dilated. We investigated whether TNF/TNFR{sub 1} pathway and endoplasmic reticulum stress (ERs) are involved in ofloxacin (a typical quinolone)-induced apoptosis of juvenile canine chondrocytes. Experimental approach: Canine juvenile chondrocytes were treated with ofloxacin. Cell survival and apoptosis rates were determined with MTT method and flow cytometry, respectively. The gene expression levels of the related signaling molecules (TNFα, TNFR{sub 1}, TRADD, FADD and caspase-8) in death receptor pathways and main apoptosis-related molecules (calpain, caspase-12, GADD153 and GRP78) in ERs were measured by qRT-PCR. The gene expression of TNFR{sub 1} was suppressed with its siRNA. The protein levels of TNFα, TNFR{sub 1} and caspase-12 were assayed using Western blotting. Key results: The survival rates decreased while apoptosis rates increased after the chondrocytes were treated with ofloxacin. The mRNA levels of the measured apoptosis-related molecules in death receptor pathways and ERs, and the protein levels of TNFα, TNFR{sub 1} and caspase-12 increased after the chondrocytes were exposed to ofloxacin. The downregulated mRNA expressions of TNFR{sub 1}, Caspase-8 and TRADD, and the decreased apoptosis rates of the ofloxacin-treated chondrocytes occurred after TNFR{sub 1}–siRNA interference. Conclusions and implications: Ofloxacin-induced chondrocyte apoptosis in a time- and concentration-dependent fashion. TNF/TNFR{sub 1} pathway and ERs are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes in the early stage. - Highlights: • Chondrocyte apoptosis is induced by ofloxacin in a time- and

  3. ALA/LA ameliorates glucose toxicity on HK-2 cells by attenuating oxidative stress and apoptosis through the ROS/p38/TGF-β1 pathway.

    Science.gov (United States)

    Jiang, Mingxia; Zhang, Haifen; Zhai, Lijie; Ye, Bianliang; Cheng, Yin; Zhai, Chengkai

    2017-11-16

    Growing evidence indicates that oxidative stress (OS) plays a pivotal role in Diabetic nephropathy (DN). In a previous study we demonstrated that ALA/LA protected HK-2 cells against high glucose-induced cytotoxicity. So we aimed to establish the glucose injury model of HK-2 cells and investigate the beneficial effects of ALA/LA on high glucose-induced excessive production of TGF-β1 and the possible mechanisms mediating the effects. The expression of OS markers in high glucose-induced HK-2 cells treated with ALA/LA., including the antioxidant enzymes and reactive oxygen species (ROS) production, as well as the apoptosis rate were assayed by ELISA and flow cytometry. The p38/transforming growth factor β 1 (TGF-β 1 ) signal pathway were measured by real-time RT-PCR and western blot. The modeling condition of glucose toxicity on HK-2 cells was at the glucose concentration of 40.9 mM. ALA/LA can significantly increase the activities of antioxidant enzymes and decrease ROS production stimulated by high glucose. The study also found that ALA/LA caused a decrease in the apoptosis rate and TGF-β 1 level of HK-2 cells under high glucose stress through the ROS/p38 pathway. ALA/LA exerts protective effects in vitro through inhibition of ROS generation, down regulation of the activation of the p38MAPK pathway and the expression of TGF-β 1 in HK-2 cells.

  4. Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells.

    Science.gov (United States)

    Batchuluun, Battsetseg; Inoguchi, Toyoshi; Sonoda, Noriyuki; Sasaki, Shuji; Inoue, Tomoaki; Fujimura, Yoshinori; Miura, Daisuke; Takayanagi, Ryoichi

    2014-01-01

    Metformin and glucagon like peptide-1 (GLP-1) prevent diabetic cardiovascular complications and atherosclerosis. However, the direct effects on hyperglycemia-induced oxidative stress in endothelial cells are not fully understood. Thus, we aimed to evaluate the effects of metformin and a GLP-1 analog, liraglutide on high glucose-induced oxidative stress. Production of reactive oxygen species (ROS), activation of protein kinase C (PKC) and NAD(P)H oxidase, and changes in signaling molecules in response to high glucose exposure were evaluated in human aortic endothelial cells with and without treatment of metformin and liraglutide, alone or in combination. PKC-NAD(P)H oxidase pathway was assessed by translocation of GFP-fused PKCβ2 isoform and GFP-fused p47phox, a regulatory subunit of NAD(P)H oxidase, in addition to endogenous PKC phosphorylation and NAD(P)H oxidase activity. High glucose-induced ROS overproduction was blunted by metformin or liraglutide treatment, with a further decrease by a combination of these drugs. Exposure to high glucose caused PKCβ2 translocation and a time-dependent phosphorylation of endogenous PKC but failed to induce its translocation and phosphorylation in the cells treated with metformin and liraglutide. Furthermore, both drugs inhibited p47phox translocation and NAD(P)H oxidase activation, and prevented the high glucose-induced changes in intracellulalr diacylglycerol (DAG) level and phosphorylation of AMP-activated protein kinase (AMPK). A combination of these drugs further enhanced all of these effects. Metformin and liraglutide ameliorate high glucose-induced oxidative stress by inhibiting PKC-NAD(P)H oxidase pathway. A combination of these two drugs provides augmented protective effects, suggesting the clinical usefulness in prevention of diabetic vascular complications. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Oxidative stress induction by T-2 toxin causes DNA damage and triggers apoptosis via caspase pathway in human cervical cancer cells

    International Nuclear Information System (INIS)

    Chaudhari, Manjari; Jayaraj, R.; Bhaskar, A.S.B.; Lakshmana Rao, P.V.

    2009-01-01

    T-2 toxin is the most toxic trichothecene and both humans and animals suffer from several pathological conditions after consumption of foodstuffs contaminated with trichothecenes. We investigated the molecular mechanism of T-2 toxin induced cytotoxicity and cell death in HeLa cells. T-2 toxin at LC50 of 10 ng/ml caused time dependent increase in cytotoxicity as assessed by dye uptake, lactatedehydrogenase leakage and MTT assay. The toxin caused generation of reactive oxygen species as early as 30 min followed by significant depletion of glutathione levels and increased lipid peroxidation. The results indicate oxidative stress as underlying mechanism of cytotoxicity. Single stranded DNA damage after T-2 treatment was observed as early as 2 and 4 h by DNA diffusion assay. The cells exhibited apoptotic morphology like condensed chromatin and nuclear fragmentation after 4 h of treatment. Downstream of T-2 induced oxidative stress and DNA damage a time dependent increase in expression level of p53 protein was observed. The increase in Bax/Bcl2 ratio indicated shift in response, in favour of apoptotic process in T-2 toxin treated cells. Western blot analysis showed increase in levels of mitochondrial apoptogenic factors Bax, Bcl-2, cytochrome-c followed by activation of caspases-9, -3 and -7 leading to DNA fragmentation and apoptosis. In addition to caspase-dependent pathway, our results showed involvement of caspase-independent AIF pathway in T-2 induced apoptosis. Broad spectrum caspase inhibitor z-VAD-fmk could partially protect the cells from DNA damage but could not inhibit AIF induced oligonucleosomal DNA fragmentation beyond 4 h. Results of the study clearly show that oxidative stress is the underlying mechanism by which T-2 toxin causes DNA damage and apoptosis.

  6. Protective properties of sesamin against fluoride-induced oxidative stress and apoptosis in kidney of carp (Cyprinus carpio) via JNK signaling pathway.

    Science.gov (United States)

    Cao, Jinling; Chen, Jianjie; Xie, Lingtian; Wang, Jundong; Feng, Cuiping; Song, Jing

    2015-10-01

    Sesamin, a major lignan derived from sesame seeds, has been reported to have many benefits and medicinal properties. However, its protective effects against fluoride-induced injury in kidney of fish have not been clarified. Previously we found that fluoride exposure caused damage and apoptosis in the kidneys of the common carp, Cyprinus carpio. In this study, the effects of sesamin on renal oxidative stress and apoptosis in fluoride-exposed fish were determined. The results showed that sesamin alleviated significantly fluoride-induced renal damage and apoptosis of carp in a dose-dependent manner, indicated by the histopathological examination and ultrastructural observation. Moreover, treatment with sesamin also inhibited significantly fluoride-induced remarkable enhancement of reactive oxygen species (ROS) production and oxidative stress, such as the increase of lipid peroxidation level and the depletion of intracellular reduced glutathione (GSH) level in kidney. To explore the underlying mechanisms of sesamin action, we found that activities of caspase-3 were notably inhibited by treatment with sesamin in the kidney of fluoride-exposed fish. Sesamin decreased the levels of p-JNK protein in kidney, which in turn inactivated pro-apoptotic signaling events by restoring the balance between mitochondrial pro- and anti-apoptotic Bcl-2 and Bax proteins and by decreasing the release of mitochondrial cytochrome c in kidney of fluoride-exposed fish. JNK was also involved in the mitochondrial extrinsic apoptotic pathways of sesamin effects against fluoride-induced renal injury by regulating the levels of p-c-Jun, necrosis factor-alpha (TNF-α) and Bak proteins. These findings indicated that sesamin could protect kidney against fluoride-induced apoptosis by the oxidative stress downstream-mediated change in the inactivation of JNK signaling pathway. Taken together, sesamin plays an important role in maintaining renal health and preventing kidney from toxic damage induced by

  7. Protective effects of curcumin against mercury-induced hepatic injuries in rats, involvement of oxidative stress antagonism, and Nrf2-ARE pathway activation.

    Science.gov (United States)

    Liu, W; Xu, Z; Li, H; Guo, M; Yang, T; Feng, S; Xu, B; Deng, Yu

    2017-09-01

    Mercury (Hg) represents a ubiquitous environmental heavy metal that could lead to severe toxic effects in a variety of organs usually at a low level. The present study focused on the liver oxidative stress, one of the most important roles playing in Hg hepatotoxicity, by evaluation of different concentrations of mercuric chloride (HgCl 2 ) administration. Moreover, the protective potential of curcumin against Hg hepatotoxic effects was also investigated. Eighty-four rats were randomly divided into six groups for a three-days experiment: control, dimethyl sulfoxide control, HgCl 2 treatment (0.6, 1.2, and 2.4 mg kg -1 day -1 ), and curcumin pretreatment (100 mg kg -1 day -1 ) groups. Exposure of HgCl 2 resulted in acute dose-dependent hepatotoxic effects. Administration of 2.4 mg kg -1 HgCl 2 significantly elevated total Hg, nonprotein sulfhydryl, reactive oxygen species formation, malondialdehyde, apoptosis levels, serum lactate dehydrogenase, and alanine transaminase activities, with an impairment of superoxide dismutase and glutathione peroxidase in the liver. Moreover, HgCl 2 treatment activated nuclear factor-E2-related factor 2-antioxidant response element (Nrf2-ARE) signaling pathway in further investigation, with a significant upregulation of Nrf2, heme oxygenase-1, and γ-glutamylcysteine synthetase heavy subunit expression, relative to control. Pretreatment with curcumin obviously prevented HgCl 2 -induced liver oxidative stress, which may be due to its free radical scavenging or Nrf2-ARE pathway-inducing properties. Taking together these data suggest that curcumin counteracts HgCl 2 hepatotoxicity through antagonizing liver oxidative stress.

  8. Activation of the PI3K/Akt pathway by oxidative stress mediates high glucose-induced increase of adipogenic differentiation in primary rat osteoblasts.

    Science.gov (United States)

    Zhang, Yu; Yang, Jian-Hong

    2013-11-01

    Diabetes mellitus is associated with increased risk of osteopenia and bone fracture that may be related to hyperglycemia. However, the mechanisms accounting for diabetic bone disorder are unclear. Here, we showed that high glucose significantly promoted the production of reactive oxygen species (ROS) in rat primary osteoblasts. Most importantly, we reported for the first time that ROS induced by high glucose increased alkaline phosphatase activity, inhibited type I collagen (collagen I) protein level and cell mineralization, as well as gene expression of osteogenic markers including runt-related transcription factor 2 (Runx2), collagen I, and osteocalcin, but promoted lipid droplet formation and gene expression of adipogenic markers including peroxisome proliferator-activated receptor gamma, adipocyte fatty acid binding protein (aP2), and adipsin, which were restored by pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, high glucose-induced oxidative stress activated PI3K/Akt pathway to inhibited osteogenic differentiation but stimulated adipogenic differentiation. In contrast, NAC and a PI3K inhibitor, LY-294002, reversed the down-regulation of osteogenic markers and the up-regulation of adipogenic markers as well as the activation of Akt under high glucose. These results indicated that oxidative stress played a key role in high glucose-induced increase of adipogenic differentiation, which contributed to the inhibition of osteogenic differentiation. This process was mediated by PI3K/Akt pathway in rat primary osteoblasts. Hence, suppression of oxidative stress could be a potential therapeutic approach for diabetic osteopenia. © 2013 Wiley Periodicals, Inc.

  9. Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats.

    Science.gov (United States)

    Ding, Shibin; Jiang, Jinjin; Zhang, Guofu; Bu, Yongjun; Zhang, Guanghui; Zhao, Xiangmei

    2017-01-01

    Studies have demonstrated that resveratrol (a natural polyphenol) and caloric restriction activate Sirtuin-1 (SIRT1) and induce autophagy. Furthermore, autophagy is induced by the SIRT1-FoxO signaling pathway and was recently shown to be a critical protective mechanism against non-alcoholic fatty liver disease (NAFLD) development. We aimed to compare the effects of resveratrol and caloric restriction on hepatic lipid metabolism and elucidate the mechanism by which resveratrol supplementation and caloric restriction alleviate hepatosteatosis by examining the molecular interplay between SIRT1 and autophagy. Eight-week-old male Wistar rats (40) were divided into four groups: the STD group, which was fed a standard chow diet; the HFD group, which was fed a high-fat diet; HFD-RES group, which was fed a high-fat diet plus resveratrol (200 mg/kg.bw); and the HFD-CR group, which was fed a high-fat diet in portions containing 70% of the mean intake of the HFD group rats. The groups were maintained for 18 weeks. Metabolic parameters, Oil Red O and hematoxylin-eosin staining of the liver, and the mRNA and protein expression of SIRT1, autophagy markers and endoplasmic reticulum(ER) stress-associated genes in the liver were assessed after the 18-week treatment. We found that resveratrol (200 mg/kg bw) and caloric restriction (30%) partially prevented hepatic steatosis and hepatocyte ballooning, increased the expression of SIRT1 and autophagy markers while decreasing ER stress markers in the liver and alleviated lipid metabolism disorder. Moreover, caloric restriction provided superior protection against HFD-induced hepatic fatty accumulation compared with resveratrol and the effects were associated with decreased total energy intake and body weight. We conclude that the SIRT1-autophagy pathway and decreased ER stress are universally required for the protective effects of moderate caloric restriction (30%) and resveratrol (a pharmacological SIRT1 activator) supplementation

  10. Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats.

    Directory of Open Access Journals (Sweden)

    Shibin Ding

    Full Text Available Studies have demonstrated that resveratrol (a natural polyphenol and caloric restriction activate Sirtuin-1 (SIRT1 and induce autophagy. Furthermore, autophagy is induced by the SIRT1-FoxO signaling pathway and was recently shown to be a critical protective mechanism against non-alcoholic fatty liver disease (NAFLD development. We aimed to compare the effects of resveratrol and caloric restriction on hepatic lipid metabolism and elucidate the mechanism by which resveratrol supplementation and caloric restriction alleviate hepatosteatosis by examining the molecular interplay between SIRT1 and autophagy.Eight-week-old male Wistar rats (40 were divided into four groups: the STD group, which was fed a standard chow diet; the HFD group, which was fed a high-fat diet; HFD-RES group, which was fed a high-fat diet plus resveratrol (200 mg/kg.bw; and the HFD-CR group, which was fed a high-fat diet in portions containing 70% of the mean intake of the HFD group rats. The groups were maintained for 18 weeks. Metabolic parameters, Oil Red O and hematoxylin-eosin staining of the liver, and the mRNA and protein expression of SIRT1, autophagy markers and endoplasmic reticulum(ER stress-associated genes in the liver were assessed after the 18-week treatment. We found that resveratrol (200 mg/kg bw and caloric restriction (30% partially prevented hepatic steatosis and hepatocyte ballooning, increased the expression of SIRT1 and autophagy markers while decreasing ER stress markers in the liver and alleviated lipid metabolism disorder. Moreover, caloric restriction provided superior protection against HFD-induced hepatic fatty accumulation compared with resveratrol and the effects were associated with decreased total energy intake and body weight.We conclude that the SIRT1-autophagy pathway and decreased ER stress are universally required for the protective effects of moderate caloric restriction (30% and resveratrol (a pharmacological SIRT1 activator

  11. Transcriptome and Molecular Pathway Analysis of the Hepatopancreas in the Pacific White Shrimp Litopenaeus vannamei under Chronic Low-Salinity Stress.

    Directory of Open Access Journals (Sweden)

    Ke Chen

    Full Text Available The Pacific white shrimp Litopenaeus vannamei is a euryhaline penaeid species that shows ontogenetic adaptations to salinity, with its larvae inhabiting oceanic environments and postlarvae and juveniles inhabiting estuaries and lagoons. Ontogenetic adaptations to salinity manifest in L. vannamei through strong hyper-osmoregulatory and hypo-osmoregulatory patterns and an ability to tolerate extremely low salinity levels. To understand this adaptive mechanism to salinity stress, RNA-seq was used to compare the transcriptomic response of L. vannamei to changes in salinity from 30 (control to 3 practical salinity units (psu for 8 weeks. In total, 26,034 genes were obtained from the hepatopancreas tissue of L. vannamei using the Illumina HiSeq 2000 system, and 855 genes showed significant changes in expression under salinity stress. Eighteen top Kyoto Encyclopedia of Genes and Genomes (KEGG pathways were significantly involved in physiological responses, particularly in lipid metabolism, including fatty-acid biosynthesis, arachidonic acid metabolism and glycosphingolipid and glycosaminoglycan metabolism. Lipids or fatty acids can reduce osmotic stress in L. vannamei by providing additional energy or changing the membrane structure to allow osmoregulation in relevant organs, such as the gills. Steroid hormone biosynthesis and the phosphonate and phosphinate metabolism pathways were also involved in the adaptation of L. vannamei to low salinity, and the differential expression patterns of 20 randomly selected genes were validated by quantitative real-time PCR (qPCR. This study is the first report on the long-term adaptive transcriptomic response of L. vannamei to low salinity, and the results will further our understanding of the mechanisms underlying osmoregulation in euryhaline crustaceans.

  12. Plant Defensins NaD1 and NaD2 Induce Different Stress Response Pathways in Fungi

    Directory of Open Access Journals (Sweden)

    Peter M. Dracatos

    2016-09-01

    Full Text Available Nicotiana alata defensins 1 and 2 (NaD1 and NaD2 are plant defensins from the ornamental tobacco that have antifungal activity against a variety of fungal pathogens. Some plant defensins interact with fungal cell wall O-glycosylated proteins. Therefore, we investigated if this was the case for NaD1 and NaD2, by assessing the sensitivity of the three Aspergillus nidulans (An O-mannosyltransferase (pmt knockout (KO mutants (An∆pmtA, An∆pmtB, and An∆pmtC. An∆pmtA was resistant to both defensins, while An∆pmtC was resistant to NaD2 only, suggesting NaD1 and NaD2 are unlikely to have a general interaction with O-linked side chains. Further evidence of this difference in the antifungal mechanism was provided by the dissimilarity of the NaD1 and NaD2 sensitivities of the Fusarium oxysporum f. sp. lycopersici (Fol signalling knockout mutants from the cell wall integrity (CWI and high osmolarity glycerol (HOG mitogen-activated protein kinase (MAPK pathways. HOG pathway mutants were sensitive to both NaD1 and NaD2, while CWI pathway mutants only displayed sensitivity to NaD2.

  13. Stress !!!

    NARCIS (Netherlands)

    Fledderus, M.

    2012-01-01

    Twee op de vijf UT-studenten hebben last van ernstige studiestress, zo erg zelfs dat het ze in hun privéleven belemmert. Die cijfers komen overeen met het landelijk beeld van stress onder studenten. Samen met 14 andere universiteits- en hogeschoolbladen enquêteerde UT Nieuws bijna 5500 studenten.

  14. Activation of GABAergic pathway by hypocretin in the median raphe nucleus (MRN) mediates stress-induced theta rhythm in rats.

    Science.gov (United States)

    Hsiao, Yi-Tse; Jou, Shuo-Bin; Yi, Pei-Lu; Chang, Fang-Chia

    2012-07-15

    The frequency of electroencephalograms (EEGs) is predominant in theta rhythm during stress (e.g., footshock) in rats. Median raphe nucleus (MRN) desynchronizes hippocampal theta waves via activation of GABAergic neurons in the medial septum-diagonal band of Broca (MS-DBB), a theta rhythm pacemaker. Increased hypocretin mediates stress responses in addition to the maintenance of wakefulness. Hypocretin receptors are abundant in the MRN, suggesting a possible role of hypocretin in modulating stress-induced theta rhythm. Our results indicated that the intensity of theta waves was enhanced by footshock and that a hypocretin receptor antagonist (TCS1102) suppressed the footshock-induced theta waves. Administration of hypocretin-1 (1 and 10 μg) and hypocretin-2 (10 μg) directly into the MRN simulated the effect of footshock and significantly increased theta waves. Co-administration of GABA(A) receptor antagonist, bicuculline, into the MRN blocked the increase of theta waves induced by hypocretins or footshock. These results suggested that stress enhances the release of hypocretins, activates GABAergic neurons in the MRN, blocks the ability of MRN to desynchronize theta waves, and subsequently increases the intensity of theta rhythm. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Genetic polymorphisms in DNA repair and oxidative stress pathways may modify the association between body size and postmenopausal breast cancer

    Czech Academy of Sciences Publication Activity Database

    McCullough, L. E.; Eng, S. M.; Bradshaw, P. T.; Cleveland, R. J.; Steck, S. E.; Terry, M. B.; Shen, J.; Crew, K.D.; Rössner ml., Pavel; Ahn, J.; Ambrosone, Ch.B.; Teitelbaum, S. L.; Neugut, A. I.; Santella, R. M.; Gammon, M. D.

    2015-01-01

    Roč. 25, č. 4 (2015), s. 263-269 ISSN 1047-2797 Institutional support: RVO:68378041 Keywords : breast cancer * body mass index * oxidative stress * DNA repair * Epidemiology Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.335, year: 2015

  16. Silibinin attenuates sulfur mustard analog-induced skin injury by targeting multiple pathways connecting oxidative stress and inflammation.

    Directory of Open Access Journals (Sweden)

    Neera Tewari-Singh

    Full Text Available Chemical warfare agent sulfur mustard (HD inflicts delayed blistering and incapacitating skin injuries. To identify effective countermeasures against HD-induced skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES-induced injury biomarkers in skin cells and SKH-1 hairless mouse skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced skin injury and oxidative stress. In skin cells, silibinin (10 µM treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p90%, and activation of transcription factors NF-κB and AP-1 (complete reversal. Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD skin toxicity model to develop a novel effective therapy for skin injuries by vesicants.

  17. Pathways of Sleep, Affect, and Stress Constellations during the First Year of College: Transition Difficulties of Emerging Adults

    Science.gov (United States)

    Ari, Lilac Lev; Shulman, Shmuel

    2012-01-01

    One hundred and fifty Israeli first-year college students were assessed twice: during the first semester following the commencement of their undergraduate studies and toward the end of the second semester. At each semester, participants completed web-based daily diaries for seven consecutive days assessing daily sleep, affective mood, stress, and…

  18. Effect of Mitochondrial Oxidative Stress and Age on the Signaling Pathway of Ultrafine Particulate Matter Exposure in Murine Aorta

    Science.gov (United States)

    Epidemiological studies have linked ultrafine particulate matter (PM) exposure and adverse cardiovascular events. PM-induced oxidative stress is believed to be a key mechanism contributing to the adverse short-term vascular effects of air pollution exposure. Advanced age is one ...

  19. D-Serine exposure resulted in gene expression changes indicative of activation of fibrogenic pathways and down-regulation of energy metabolism and oxidative stress response

    International Nuclear Information System (INIS)

    Soto, Armando; DelRaso, Nicholas J.; Schlager, John J.; Chan, Victor T.

    2008-01-01

    , metabolism and transport, inflammatory response, proteasome-mediated degradation of oxidatively damaged cytosolic proteins, Ras protein signal transduction, TGF-beta signaling pathway and mRNA transcription, processing, splicing and transport. On the other hand, major metabolic pathways, which include carbohydrate metabolism, TCA cycle, oxidative phosphorylation, ATP synthesis coupled electron transport, amino acid metabolism and transport, lipid metabolism, nucleotide metabolism, and vitamin metabolism, and oxidative stress response including induction of antioxidant genes and glutathione metabolism are down-regulated. As tubular epithelia have strong energy demand for normal functions, down-regulation of energy metabolism after D-serine treatment may be related to the mechanism of its nephrotoxicity. In addition, hydrogen peroxide, a reactive oxygen species, is produced as a byproduct of the metabolism of D-serine by D-amino acid oxidase in the peroxisomes of the tubular epithelia. Down-regulation of pathways for antioxidant genes induction and glutathione metabolism will likely exacerbate the cytotoxicity of this reactive oxygen species. The observation that the genes involved in apoptosis, DNA repair, proteasome pathway for the degradation of oxidatively damaged cytosolic proteins were up-regulated lends some supports to this premise. Up-regulation of pathways of cell proliferation cycle, DNA replication and gene expression process, including mRNA transcription, processing, splicing, transport, translation initiation, and protein transport along with protein complex assembly, suggests ongoing tissue repair and regeneration. Consistent with the fibrogenic function of the TGF-beta signaling pathway in various experimental renal diseases, genes encoding major extracellular matrix components such as collagens, laminins, fibronectin 1 and tenascins are also strongly up-regulated. Taken together, the results of this study provide important insights into the molecular mechanism

  20. Interspecies and Intraspecies Analysis of Trehalose Contents and the Biosynthesis Pathway Gene Family Reveals Crucial Roles of Trehalose in Osmotic-Stress Tolerance in Cassava

    Directory of Open Access Journals (Sweden)

    Bingying Han

    2016-07-01

    Full Text Available Trehalose is a nonreducing α,α-1,1-disaccharide in a wide range of organisms, and has diverse biological functions that range from serving as an energy source to acting as a protective/signal sugar. However, significant amounts of trehalose have rarely been detected in higher plants, and the function of trehalose in the drought-tolerant crop cassava (Manihot esculenta Crantz is unclear. We measured soluble sugar concentrations of nine plant species with differing levels of drought tolerance and 41 cassava varieties using high-performance liquid chromatography with evaporative light-scattering detector (HPLC-ELSD. Significantly high amounts of trehalose were identified in drought-tolerant crops cassava, Jatropha curcas, and castor bean (Ricinus communis. All cassava varieties tested contained high amounts of trehalose, although their concentrations varied from 0.23 to 1.29 mg·g−1 fresh weight (FW, and the trehalose level was highly correlated with dehydration stress tolerance of detached leaves of the varieties. Moreover, the trehalose concentrations in cassava leaves increased 2.3–5.5 folds in response to osmotic stress simulated by 20% PEG 6000. Through database mining, 24 trehalose pathway genes, including 12 trehalose-6-phosphate synthases (TPS, 10 trehalose-6-phosphate phosphatases (TPP, and two trehalases were identified in cassava. Phylogenetic analysis indicated that there were four cassava TPS genes (MeTPS1–4 that were orthologous to the solely active TPS gene (AtTPS1 and OsTPS1 in Arabidopsis and rice, and a new TPP subfamily was identified in cassava, suggesting that the trehalose biosynthesis activities in cassava had potentially been enhanced in evolutionary history. RNA-seq analysis indicated that MeTPS1 was expressed at constitutionally high level before and after osmotic stress, while other trehalose pathway genes were either up-regulated or down-regulated, which may explain why cassava accumulated high level of trehalose

  1. Activation of the Nrf2-ARE pathway by siRNA knockdown of Keap1 reduces oxidative stress and provides partial protection from MPTP-mediated neurotoxicity.

    Science.gov (United States)

    Williamson, Tracy P; Johnson, Delinda A; Johnson, Jeffrey A

    2012-06-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that binds to the antioxidant response element, a cis-acting regulatory element that increases expression of detoxifying enzymes and antioxidant proteins. Kelch-like ECH associating protein 1 (Keap1) protein is a negative regulator of Nrf2. Previous work has shown that genetic overexpression of Nrf2 is protective in vitro and in vivo. To modulate the Nrf2-ARE system without overexpressing Nrf2, we used short interfering RNA (siRNA) directed against Keap1. Keap1 siRNA administration in primary astrocytes increased the levels of Nrf2-ARE driven genes and protected against oxidative stress. Moreover, Keap1 siRNA resulted in a persistent upregulation of the Nrf2-ARE pathway and protection against oxidative stress in primary astrocytes. Keap1 siRNA injected into the striatum was also modestly protective against MPTP-induced dopaminergic terminal damage. These data indicate that activation of endogenous intracellular levels of Nrf2 is sufficient to protect in models of oxidative stress and Parkinson's disease. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Tartary buckwheat flavonoids ameliorate high fructose-induced insulin resistance and oxidative stress associated with the insulin signaling and Nrf2/HO-1 pathways in mice.

    Science.gov (United States)

    Hu, Yuanyuan; Hou, Zuoxu; Yi, Ruokun; Wang, Zhongming; Sun, Peng; Li, Guijie; Zhao, Xin; Wang, Qiang

    2017-08-01

    The present study was conducted to explore the effects of a purified tartary buckwheat flavonoid fraction (TBF) on insulin resistance and hepatic oxidative stress in mice fed high fructose in drinking water (20%) for 8 weeks. The results indicated that continuous administration of TBF dose-dependently improved the insulin sensitivity and glucose intolerance in high fructose-fed mice. TBF treatment also reversed the reduced level of insulin action on the phosphorylation of insulin receptor substrate-1 (IRS-1), protein kinase B (Akt) and phosphatidylinositol 3-kinase (PI3K), as well as the translocation of glucose transporter type 4 (GLUT4) in the insulin-resistant liver. Furthermore, TBF was found to exert high antioxidant capacity as it acts as a shield against oxidative stress induced by high fructose by restoring the antioxidant status, and modulating nuclear factor E2 related factor 2 (Nrf2) translocation to the nucleus with subsequently up-regulated antioxidative enzyme protein expression. Histopathological examinations revealed that impaired pancreatic/hepatic tissues were effectively restored in high fructose-fed mice following TBF treatment. Our results show that TBF intake is effective in preventing the conversion of high fructose-induced insulin resistance and hepatic oxidative stress in mice by improving the insulin signaling molecules and the Nrf2 signal pathway in the liver.

  3. Maresin 1 Ameliorates Lung Ischemia/Reperfusion Injury by Suppressing Oxidative Stress via Activation of the Nrf-2-Mediated HO-1 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Quanchao Sun

    2017-01-01

    Full Text Available Lung ischemia/reperfusion (I/R injury occurs in various clinical conditions and heavily damaged lung function. Oxidative stress reaction and antioxidant enzymes play a pivotal role in the etiopathogenesis of lung I/R injury. In the current study, we investigated the impact of Maresin 1 on lung I/R injury and explored the possible mechanism involved in this process. MaR 1 ameliorated I/R-induced lung injury score, wet/dry weight ratio, myeloperoxidase, tumor necrosis factor, bronchoalveolar lavage fluid (BALF leukocyte count, BALF neutrophil ratio, and pulmonary permeability index levels in lung tissue. MaR 1 significantly reduced ROS, methane dicarboxylic aldehyde, and 15-F2t-isoprostane generation and restored antioxidative enzyme (superoxide dismutase, glutathione peroxidase, and catalase activities. Administration of MaR 1 improved the expression of nuclear Nrf-2 and cytosolic HO-1 in I/R-treated lung tissue. Furthermore, we also found that the protective effects of MaR 1 on lung tissue injury and oxidative stress were reversed by HO-1 activity inhibitor, Znpp-IX. Nrf-2 transcription factor inhibitor, brusatol, significantly decreased MaR 1-induced nuclear Nrf-2 and cytosolic HO-1 expression. In conclusion, these results indicate that MaR 1 protects against lung I/R injury through suppressing oxidative stress. The mechanism is partially explained by activation of the Nrf-2-mediated HO-1 signaling pathway.

  4. Lycopene protects human SH-SY5Y neuroblastoma cells against hydrogen peroxide-induced death via inhibition of oxidative stress and mitochondria-associated apoptotic pathways

    Science.gov (United States)

    FENG, CHUNSHENG; LUO, TIANFEI; ZHANG, SHUYAN; LIU, KAI; ZHANG, YANHONG; LUO, YINAN; GE, PENGFEI

    2016-01-01

    Oxidative stress, which is characterized by excessive production of reactive oxygen species (ROS), is a common pathway that results in neuronal injury or death due to various types of pathological stress. Although lycopene has been identified as a potent antioxidant, its effect on hydrogen peroxide (H2O2)-induced neuronal damage remains unclear. In the present study, pretreatment with lycopene was observed to protect SH-SY5Y neuroblastoma cells against H2O2-induced death via inhibition of apoptosis resulting from activation of caspase-3 and translocation of apoptosis inducing factor (AIF) to the nucleus. Furthermore, the over-produced ROS, as well as the reduced activities of anti-oxidative enzymes, superoxide dismutase and catalase, were demonstrated to be alleviated by lycopene. Additionally, lycopene counteracted H2O2-induced mitochondrial dysfunction, which was evidenced by suppression of mitochondrial permeability transition pore opening, attenuation of the decline of the mitochondrial membrane potential, and inhibition of the increase of Bax and decrease of Bcl-2 levels within the mitochondria. The release of cytochrome c and AIF from the mitochondria was also reduced. These results indicate that lycopene is a potent neuroprotectant against apoptosis, oxidative stress and mitochondrial dysfunction, and could be administered to prevent neuronal injury or death. PMID:27035331

  5. Molecular pathways associated with stress resilience and drug resistance in the chronic mild stress rat model of depression: a gene expression study

    DEFF Research Database (Denmark)

    Bergström, Anders; Jayatissa, Magdalena Niepsuj; Andersen, Thomas Thykjær

    2007-01-01

    The current antidepressant drugs are ineffective in 30 to 40% of the treated patients; hence, the pathophysiology of the disease needs to be further elucidated. We used the chronic mild stress (CMS) paradigm to induce anhedonia, a core symptom of major depression, in rats. A fraction of the animals...... exposed to CMS is resistant to the development of anhedonia; they are CMS resilient. In the CMS-sensitive animals, the induced anhedonic state is reversed in 50% of the animals when treating with escitalopram, whereas the remaining animals are treatment resistant. We used the microarray and the real...

  6. MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism.

    Science.gov (United States)

    Liao, Weitang; Fu, Zongjie; Zou, Yanfang; Wen, Dan; Ma, Hongkun; Zhou, Fangfang; Chen, Yongxi; Zhang, Mingjun; Zhang, Wen

    2017-11-15

    Oxidative stress was predominantly involved in the pathogenesis of acute kidney injury (AKI). Recent studies had reported the protective role of specific microRNAs (miRNAs) against oxidative stress. Hence, we investigated the levels of miR140-5p and its functional role in the pathogenesis of Cisplatin induced AKI. A mice Cisplatin induced-AKI model was established. We found that miR-140-5p expression was markedly increased in mice kidney. Bioinformatics analysis revealed nuclear factor erythroid 2-related factor (Nrf2) was a potential target of miR-140-5p, We demonstrated that miR-140-5p did not affect Kelch-like ECH-associated protein 1 (Keap1) level but directly targeted the 3'-UTR of Nrf2 mRNA and played a positive role in the regulation of Nrf2 expression which was confirmed by luciferase activity assay and western blot. What was more, consistent with miR140-5p expression, the mRNA and protein levels of Nrf2, as well as antioxidant response element (ARE)-driven genes Heme Oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase l (NQO1) were significantly increased in mice kidney tissues. In vitro study, Enforced expression of miR-140-5p in HK2 cells significantly attenuated oxidative stress by decreasing ROS level and increasing the expression of manganese superoxide dismutase (MnSOD). Simultaneously, miR-140-5p decreased lactate dehydrogenase (LDH) leakage and improved cell vitality in HK2 cells under Cisplatin-induced oxidative stress. However, HK2 cells transfected with a siRNA targeting Nrf2 abrogated the protective effects of miR-140-5p against oxidative stress. These results indicated that miR-140-5p might exert its anti-oxidative stress function via targeting Nrf2. Our findings showed the novel transcriptional role of miR140-5p in the expression of Nrf2 and miR-140-5p protected against Cisplatin induced oxidative stress by activating Nrf2-dependent antioxidant pathway, providing a potentially therapeutic target in acute kidney injury. Copyright © 2017

  7. Role of ER stress response in photodynamic therapy: ROS generated in different subcellular compartments trigger diverse cell death pathways

    Czech Academy of Sciences Publication Activity Database

    Moserová, Irena; Králová, Jarmila

    2012-01-01

    Roč. 7, č. 3 (2012), e32972 E-ISSN 1932-6203 R&D Projects: GA MŠk(CZ) LC06077; GA ČR GA203/09/1311; GA ČR(CZ) GAP303/11/1291 Institutional research plan: CEZ:AV0Z50520514 Keywords : photodynamic therapy * porphyrin derivatives * cell death * ER stress Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.730, year: 2012

  8. Life course pathways of adverse childhood experiences toward adult psychological well-being: A stress process analysis.

    Science.gov (United States)

    Nurius, Paula S; Green, Sara; Logan-Greene, Patricia; Borja, Sharon

    2015-07-01

    Growing evidence suggests that toxic stressors early in life not only convey developmental impacts but also augment risk of proliferating chains of additional stressors that can overwhelm individual coping and undermine recovery and health. Examining trauma within a life course stress process perspective, we posit that early childhood adversity carries a unique capacity to impair adult psychological well-being both independent of and cumulative with other contributors, including social disadvantage and stressful adult experiences. This study uses data from a representative population-based health survey (N=13,593) to provide one of the first multivariate assessments of unique, cumulative, and moderated effects of adverse childhood experiences (ACEs) toward explaining 3 related yet distinct measures of adult mental health: perceived well-being, psychological distress, and impaired daily activities. Results demonstrate support for each set of hypothesized associations, including exacerbation and amelioration of ACEs effects by adult stress and resilience resources, respectively. Implications for services and future research are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. A copper-induced quinone degradation pathway provides protection against combined copper/quinone stress in Lactococcus lactis IL1403.

    Science.gov (United States)

    Mancini, Stefano; Abicht, Helge K; Gonskikh, Yulia; Solioz, Marc

    2015-02-01

    Quinones are ubiquitous in the environment. They occur naturally but are also in widespread use in human and industrial activities. Quinones alone are relatively benign to bacteria, but in combination with copper, they become toxic by a mechanism that leads to intracellular thiol depletion. Here, it was shown that the yahCD-yaiAB operon of Lactococcus lactis IL1403 provides resistance to combined copper/quinone stress. The operon is under the control of CopR, which also regulates expression of the copRZA copper resistance operon as well as other L. lactis genes. Expression of the yahCD-yaiAB operon is induced by copper but not by quinones. Two of the proteins encoded by the operon appear to play key roles in alleviating quinone/copper stress: YaiB is a flavoprotein that converts p-benzoquinones to less toxic hydroquinones, using reduced nicotinamide adenine dinucleotide phosphate (NADPH) as reductant; YaiA is a hydroquinone dioxygenase that converts hydroquinone putatively to 4-hydroxymuconic semialdehyde in an oxygen-consuming reaction. Hydroquinone and methylhydroquinone are both substrates of YaiA. Deletion of yaiB causes increased sensitivity of L. lactis to quinones and complete growth arrest under combined quinone and copper stress. Copper induction of the yahCD-yaiAB operon offers protection to copper/quinone toxicity and could provide a growth advantage to L. lactis in some environments. © 2014 John Wiley & Sons Ltd.

  10. Effects of CO2 on the tolerance of photosynthesis to heat stress can be affected by photosynthetic pathway and nitrogen.

    Science.gov (United States)

    Wang, Dan; Heckathorn, Scott A; Hamilton, E William; Frantz, Jonathan

    2014-01-01

    Determining effects of elevated CO2 and N on photosynthetic thermotolerance is critical for predicting plant responses to global warming. We grew Hordeum vulgare (barley, C3) and Zea mays (corn, C4) at current or elevated CO2 (370, 700 ppm) and limiting or optimal soil N (0.5, 7.5 mmol/L). We assessed thermotolerance of net photosynthesis (Pn), photosystem II efficiency in the light (Fv'/Fm'), photochemical quenching (qp), carboxylation efficiency (CE), and content of rubisco activase and major heat-shock proteins (HSPs). For barley, elevated CO2 had no effect on Pn, qp, and CE at both high and low N and only a positive effect on Fv'/Fm' at high N. However, for corn, Pn, Fv'/Fm', qp, and CE were decreased substantially by elevated CO2 under high and low N, with greater decreases at high N for all but qp. The negative effects of high CO2 during heat stress on photosynthesis were correlated with rubisco activase and HSPs content, which decreased with heat stress, especially for low-N corn. These results indicate that stimulatory effects of elevated CO2 at normal temperatures on photosynthesis and growth (only found for high-N barley) may be partly offset by neutral or negative effects during heat stress, especially for C4 species. Thus, CO2 and N effects on photosynthetic thermotolerance may contribute to changes in plant productivity, distribution, and diversity in future.

  11. Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and β-Arrestin-1-Regulated Lactate Metabolism.

    Science.gov (United States)

    Dong, Jun-Hong; Wang, Yi-Jing; Cui, Min; Wang, Xiao-Jing; Zheng, Wen-Shuai; Ma, Ming-Liang; Yang, Fan; He, Dong-Fang; Hu, Qiao-Xia; Zhang, Dao-Lai; Ning, Shang-Lei; Liu, Chun-Hua; Wang, Chuan; Wang, Yue; Li, Xiang-Yao; Yi, Fan; Lin, Amy; Kahsai, Alem W; Cahill, Thomas Joseph; Chen, Zhe-Yu; Yu, Xiao; Sun, Jin-Peng

    2017-04-15

    Stress is a conserved physiological response in mammals. Whereas moderate stress strengthens memory to improve reactions to previously experienced difficult situations, too much stress is harmful. We used specific β-adrenergic agonists, as well as β 2 -adrenergic receptor (β2AR) and arrestin knockout models, to study the effects of adaptive β2AR activation on cognitive function using Morris water maze and object recognition experiments. We used molecular and cell biological approaches to elucidate the signaling subnetworks. We observed that the duration of the adaptive β2AR activation determines its consequences on learning and memory. Short-term formoterol treatment, for 3 to 5 days, improved cognitive function; however, prolonged β2AR activation, for more than 6 days, produced harmful effects. We identified the activation of several signaling networks downstream of β2AR, as well as an essential role for arrestin and lactate metabolism in promoting cognitive ability. Whereas Gs-protein kinase A-cyclic adenosine monophosphate response element binding protein signaling modulated monocarboxylate transporter 1 expression, β-arrestin-1 controlled expression levels of monocarboxylate transporter 4 and lactate dehydrogenase A through the formation of a β-arrestin-1/phospho-mitogen-activated protein kinase/hypoxia-inducible factor-1α ternary complex to upregulate lactate metabolism in astrocyte-derived U251 cells. Conversely, long-term treatment with formoterol led to the desensitization of β2ARs, which was responsible for its decreased beneficial effects. Our results not only revealed that β-arrestin-1 regulated lactate metabolism to contribute to β2AR functions in improved memory formation, but also indicated that the appropriate management of one specific stress pathway, such as through the clinical drug formoterol, may exert beneficial effects on cognitive abilities. Copyright © 2016 Society of Biological Psychiatry. All rights reserved.

  12. Effects of long-term heat stress and dietary restriction on the expression of genes of steroidogenic pathway and small heat-shock proteins in rat testicular tissue.

    Science.gov (United States)

    Bozkaya, F; Atli, M O; Guzeloglu, A; Kayis, S A; Yildirim, M E; Kurar, E; Yilmaz, R; Aydilek, N

    2017-08-01

    The aim was to investigate the effects of long-term heat stress and dietary restriction on the expression of certain genes involving in steroidogenic pathway and small heat-shock proteins (sHSPs) in rat testis. Sprague Dawley rats (n = 24) were equally divided into four groups. Group I and II were kept at an ambient temperature of 22°C, while Groups III and IV were reared at 38°C for 9 weeks. Feed was freely available for Group I and Group III, while Group II and Group IV were fed 60% of the diet consumed by their ad libitum counterparts. At the end of 9 weeks, testicles were collected under euthanasia. Total RNA was isolated from testis tissue samples. Expression profiles of the genes encoding androgen-binding protein, follicle-stimulating hormone receptor, androgen receptor, luteinising hormone receptor, steroidogenic acute regulatory protein (StAR), cyclooxygenase-2 and sHSP genes were assessed at mRNA levels using qPCR. Long-term heat stress decreased the expression of StAR and HspB10 genes while dietary restriction upregulated StAR gene expression. The results suggested that long-term heat stress negatively affected the expression of StAR and HspB10 genes and the dietary restriction was able to reverse negative effect of heat stress on the expression of StAR gene in rat testis. © 2016 Blackwell Verlag GmbH.

  13. Drought stress provokes the down-regulation of methionine and ethylene biosynthesis pathways in Medicago truncatula roots and nodules.

    Science.gov (United States)

    Larrainzar, Estíbaliz; Molenaar, Johanna A; Wienkoop, Stefanie; Gil-Quintana, Erena; Alibert, Bénédicte; Limami, Anis M; Arrese-Igor, Cesar; González, Esther M

    2014-09-01

    Symbiotic nitrogen fixation is one of the first physiological processes inhibited in legume plants under water-deficit conditions. Despite the progress made in the last decades, the molecular mechanisms behind this regulation are not fully understood yet. Recent proteomic work carried out in the model legume Medicago truncatula provided the first indications of a possible involvement of nodule methionine (Met) biosynthesis and related pathways in response to water-deficit conditions. To better understand this involvement, the drought-induced changes in expression and content of enzymes involved in the biosynthesis of Met, S-adenosyl-L-methionine (SAM) and ethylene in M. truncatula root and nodules were analyzed using targeted approaches. Nitrogen-fixing plants were subjected to a progressive water deficit and a subsequent recovery period. Besides the physiological characterization of the plants, the content of total sulphur, sulphate and main S-containing metabolites was measured. Results presented here show that S availability is not a limiting factor in the drought-induced decline of nitrogen fixation rates in M. truncatula plants and provide evidences for a down-regulation of the Met and ethylene biosynthesis pathways in roots and nodules in response to water-deficit conditions. © 2014 John Wiley & Sons Ltd.

  14. Jolkinolide B induces apoptosis of colorectal carcinoma through ROS-ER stress-Ca2+-mitochondria dependent pathway.

    Science.gov (United States)

    Zhang, Jing; Wang, Yang; Zhou, Ye; He, Qing-Yu

    2017-10-31

    Colorectal carcinoma (CRC) remains one of the leading causes of death in cancer-related diseases. In this study, we aimed to investigate the anticancer effect of Jolkinolide B (JB), a bioactive diterpenoid component isolated from the dried roots of Euphorbia fischeriana Steud, on CRC cells and its underlying mechanisms. We found that JB suppressed the cell viability and colony formation of CRC cells, HT29 and SW620. Annexin V/PI assay revealed that JB induced apoptosis in CRC cells, which was further confirmed by the increased expression of cleaved-caspase3 and cleaved-PARP. iTRAQ-based quantitative proteomics was performed to identify JB-regulated proteins in CRC cells. Gene Ontology (GO) analysis revealed that these JB-regulated proteins were mainly involved in ER stress response, which was evidenced by the expression of ER stress marker proteins, HSP90, Bip and PDI. Moreover, we found that JB provoked the generation of reactive oxygen species (ROS), and that inhibition of the ROS generation with N-acetyl L-cysteine could reverse the JB-induced apoptosis. Confocal microscopy and flow cytometry showed that JB treatment enhanced intracellular and mitochondrial Ca 2+ level and JC-1 assay revealed a loss of mitochondrial membrane potential in CRC after JB treatment. The mitochondrial Ca 2+ uptake and depolarization can be blocked by Ruthenium Red (RuRed), an inhibitor of mitochondrial Ca 2+ uniporter. Taken together, we demonstrated that JB exerts its anticancer effect by ER stress-Ca 2+ -mitochondria signaling, suggesting the promising chemotherapeutic potential of JB for the treatment of CRC.

  15. Oil palm EgCBF3 conferred stress tolerance in transgenic tomato plants through modulation of the ethylene signaling pathway.

    Science.gov (United States)

    Ebrahimi, Mortaza; Abdullah, Siti Nor Akmar; Abdul Aziz, Maheran; Namasivayam, Parameswari

    2016-09-01

    CBF/DREB1 is a group of transcription factors that are mainly involved in abiotic stress tolerance in plants. They belong to the AP2/ERF superfamily of plant-specific transcription factors. A gene encoding a new member of this group was isolated from ripening oil palm fruit and designated as EgCBF3. The oil palm fruit demonstrates the characteristics of a climacteric fruit like tomato, in which ethylene has a major impact on the ripening process. A transgenic approach was used for functional characterization of the EgCBF3, using tomato as the model plant. The effects of ectopic expression of EgCBF3 were analyzed based on expression profiling of the ethylene biosynthesis-related genes, anti-freeze proteins (AFPs), abiotic stress tolerance and plant growth and development. The EgCBF3 tomatoes demonstrated altered phenotypes compared to the wild type tomatoes. Delayed leaf senescence and flowering, increased chlorophyll content and abnormal flowering were the consequences of overexpression of EgCBF3 in the transgenic tomatoes. The EgCBF3 tomatoes demonstrated enhanced abiotic stress tolerance under in vitro conditions. Further, transcript levels of ethylene biosynthesis-related genes, including three SlACSs and two SlACOs, were altered in the transgenic plants' leaves and roots compared to that in the wild type tomato plant. Among the eight AFPs studied in the wounded leaves of the EgCBF3 tomato plants, transcript levels of SlOSM-L, SlNP24, SlPR5L and SlTSRF1 decreased, while expression of the other four, SlCHI3, SlPR1, SlPR-P2 and SlLAP2, were up-regulated. These findings indicate the possible functions of EgCBF3 in plant growth and development as a regulator of ethylene biosynthesis-related and AFP genes, and as a stimulator of abiotic stress tolerance. Copyright © 2016 Elsevier GmbH. All rights reserved.

  16. Fisetin-induced apoptosis of human oral cancer SCC-4 cells through reactive oxygen species production, endoplasmic reticulum stress, caspase-, and mitochondria-dependent signaling pathways.

    Science.gov (United States)

    Su, Chen-Hsuan; Kuo, Chao-Lin; Lu, Kung-Wen; Yu, Fu-Shun; Ma, Yi-Shih; Yang, Jiun-Long; Chu, Yung-Lin; Chueh, Fu-Shin; Liu, Kuo-Ching; Chung, Jing-Gung

    2017-06-01

    Oral cancer is one of the cancer-related diseases in human populations and its incidence rates are rising worldwide. Fisetin, a flavonoid from natural products, has been shown to exhibit anticancer activities in many human cancer cell lines but the molecular mechanism of fisetin-induced apoptosis in human oral cancer cells is still unclear; thus, in this study, we investigated fisetin-induced cell death and associated signal pathways on human oral cancer SCC-4 cells in vitro. We examined cell morphological changes, total viable cells, and cell cycle distribution by phase contrast microscopy and flow cytometry assays. Reactive oxygen species (ROS), Ca 2+ , mitochondria membrane potential (ΔΨ m ), and caspase-8, -9, and -3 activities were also measured by flow cytometer. Results indicate that fisetin induced cell death through the cell morphological changes, caused G2/M phase arrest, induction of apoptosis, promoted ROS and Ca 2+ production, and decreased the level of ΔΨ m and increased caspase-3, -8, and -9 activities in SCC-4 cells. DAPI staining and DNA gel electrophoresis were also used to confirm fisetin-induced cell apoptosis in SCC-4 cells. Western blotting also found out that Fisetin increased the proapoptotic proteins such as Bax and Bid and decreased the antiapoptotic proteins such as Bcl-2. Furthermore, results also showed that Fisetin increased the cytochrome c, AIF, and Endo G release from mitochondria in SCC-4 cells. We also used ATF-6α, ATF-6β, GADD153, and GRP78 which indicated that fisetin induced cell death through ER stress. Based on those observations, we suggest that fisetin induced cell apoptosis through ER stress, mitochondria-, and caspase-dependent pathways. © 2017 Wiley Periodicals, Inc.

  17. ZL006 protects spinal cord neurons against ischemia-induced oxidative stress through AMPK-PGC-1α-Sirt3 pathway.

    Science.gov (United States)

    Liu, Shu-Guang; Wang, Yun-Mei; Zhang, Yan-Jun; He, Xi-Jing; Ma, Tao; Song, Wei; Zhang, Yu-Min

    2017-09-01

    Spinal cord ischemia (SCI) induces a range of cellular and molecular cascades, including activation of glutamate receptors and downstream signaling. Post-synaptic density protein 95 (PSD-95) links neuronal nitric oxide synthase (nNOS) with the N-methyl-d-aspartic acid (NMDA) receptors to form a ternary complex in the CNS. This molecular complex-mediated cytotoxicity has been implicated in brain ischemia, but its role in SCI has not been determined. The goal of the study was to investigate the potential protective effects of ZL006, a small-molecule inhibitor of the PSD-95/nNOS interaction, in an in vitro SCI model induced by oxygen and glucose deprivation (OGD) in cultured spinal cord neurons. We found that ZL006 reduced OGD-induced lactate dehydrogenase (LDH) release, neuronal apoptosis and loss of cell viability. This protection was accompanied by the preservation of mitochondrial function, as evidenced by reduced mitochondrial oxidative stress, attenuated mitochondrial membrane potential (MMP) loss, and enhanced ATP generation. In addition, ZL006 stimulated mitochondrial enzyme activities and SOD2 deacetylation in a Sirt3-dependent manner. The results of western blot analysis showed that ZL006 increased the activation of AMPK-PGC-1α-Sirt3 pathway, and the beneficial effects of ZL006 was partially abolished by AMPK inhibitor and PGC-1α knockdown. Therefore, our present data showed that, by the AMPK-PGC-1α-Sirt3 pathway, ZL006 protects spinal cord neurons against ischemia through reducing mitochondrial oxidative stress to prevent apoptosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Protective Effects of Maillard Reaction Products of Whey Protein Concentrate against Oxidative Stress through an Nrf2-Dependent Pathway in HepG2 Cells.

    Science.gov (United States)

    Pyo, Min Cheol; Yang, Sung-Yong; Chun, Su-Hyun; Oh, Nam Su; Lee, Kwang-Won

    2016-09-01

    Whey protein concentrate (WPC), which contains α-lactalbumin and β-lactoglobulin, is utilized widely in the food industry. The Maillard reaction is a complex reaction that produces Maillard reaction products (MRPs), which are associated with the formation of antioxidant compounds. In this study, the hepatoprotection activity of MRPs of WPC against oxidative stress through the nuclear factor-E2-related factor 2 (Nrf2)-dependent antioxidant pathway in HepG2 cells was examined. Glucose-whey protein concentrate conjugate (Glc-WPC) was obtained from Maillard reaction between WPC and glucose. The fluorescence intensity of Glc-WPC increased after 7 d compared to native WPC, and resulted in loss of 48% of the free amino groups of WPC. The sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) patterns of Glc-WPC showed the presence of a high-molecular-weight portion. Treatment of HepG2 cells with Glc-WPC increased cell viability in the presence of oxidative stress, inhibited the generation of intracellular reactive oxygen species by tert-butyl hydroperoxide (t-BHP), and increased the glutathione level. Nrf2 translocation and Nrf2, reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H)-quinone oxidoreductase 1 (NOQ1), heme oxygenase-1 (HO-1), glutamate-L-cysteine ligase (GCL)M and GCLC mRNA levels were increased by Glc-WPC. Also, Glc-WPC increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK). The results of this study demonstrate that Glc-WPC activates the Nrf2-dependent pathway through the phosphorylation of ERK1/2 and JNK in HepG2 cells, and induces production of antioxidant enzymes and phase II enzymes.

  19. Stress.

    Science.gov (United States)

    Chambers, David W

    2008-01-01

    We all experience stress as a regular, and sometimes damaging and sometimes useful, part of our daily lives. In our normal ups and downs, we have our share of exhaustion, despondency, and outrage--matched with their corresponding positive moods. But burnout and workaholism are different. They are chronic, dysfunctional, self-reinforcing, life-shortening habits. Dentists, nurses, teachers, ministers, social workers, and entertainers are especially susceptible to burnout; not because they are hard-working professionals (they tend to be), but because they are caring perfectionists who share control for the success of what they do with others and perform under the scrutiny of their colleagues (they tend to). Workaholics are also trapped in self-sealing cycles, but the elements are ever-receding visions of control and using constant activity as a barrier against facing reality. This essay explores the symptoms, mechanisms, causes, and successful coping strategies for burnout and workaholism. It also takes a look at the general stress response on the physiological level and at some of the damage American society inflicts on itself.

  20. Andrographolide ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated renal oxidative stress and inflammation via Akt/NF-κB pathway.

    Science.gov (United States)

    Ji, Xiaoqian; Li, Changzheng; Ou, Yitao; Li, Ning; Yuan, Kai; Yang, Guizhi; Chen, Xiaoyan; Yang, Zhicheng; Liu, Bing; Cheung, Wai W; Wang, Lijing; Huang, Ren; Lan, Tian

    2016-12-05

    Diabetic nephropathy (DN) is characterized by proliferation of mesangial cells, mesangial hypertrophy and extracellular matrix (ECM) accumulation. Our recent study found that andrographolide inhibited high glucose-induced mesangial cell proliferation and fibronectin expression through inhibition of AP-1 pathway. However, whether andrographolide has reno-protective roles in DN has not been fully elucidated. Here, we studied the pharmacological effects of andrographolide against the progression of DN and high glucose-induced mesangial dysfunction. Diabetes was induced in C57BL/6 mice by intraperitoneal injection of streptozotocin (STZ). After 1 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Diabetic mice were intraperitoneal injected with andrographolide (2 mg/kg, twice a week). After 8 weeks, functional and histological analyses were carried out. Parallel experiments uncovering the molecular mechanism by which andrographolide prevents from DN was performed in mesangial cells. Andrographolide inhibited the increases in fasting blood glucose, triglyceride, kidney/body weight ratio, blood urea nitrogen, serum creatinine and 24-h albuminuria in diabetic mice. Andrographolide also prevented renal hypertrophy and ECM accumulation. Furthermore, andrographolide markedly attenuated NOX1 expression, ROS production and pro-inflammatory cytokines as well. Additionally, andrographolide inhibited Akt/NF-κB signaling pathway. These results demonstrate that andrographolide is protective against the progression of experimental DN by inhibiting renal oxidative stress, inflammation and fibrosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Oxidative-stress detoxification and signalling in cyanobacteria: the crucial glutathione synthesis pathway supports the production of ergothioneine and ophthalmate.

    Science.gov (United States)

    Narainsamy, Kinsley; Farci, Sandrine; Braun, Emilie; Junot, Christophe; Cassier-Chauvat, Corinne; Chauvat, Franck

    2016-04-01

    Using genetics and metabolomics we investigated the synthesis (gshA and gshB genes) and catabolism (ggt) of the conserved antioxidant glutathione in the model cyanobacterium Synechocystis PCC6803. These three genes are crucial to Synechocystis, in agreement with the proposed invention of glutathione by ancient cyanobacteria to protect themselves against the toxicity of oxygen they produced through photosynthesis. Consistent with their indispensability, gshA and gshB also operate in the production of another antioxidant, ergothioneine, as well as of the glutathione analogues ophthalmate and norophthalmate. Furthermore, we show that glutathione, ophthalmate and norophthalmate are accumulated in cells stressed by glucose, and that the two glutathione-dependent glyoxalase enzymes operate in the protection against glucose and its catabolite methylglyoxal. These findings are interesting because ophthalmate and norophthalmate were observed only in mammals so far, where ophthalmate is regarded as a biomarker of glutathione depletion. Instead, our data suggest that ophthalmate and norophthalmate are stress-induced markers of cysteine depletion triggered by its accelerated incorporation into glutathione, to face its increased demand for detoxification purposes. Hence, Synechocystis is an attractive model for the analysis of the role of glutathione, ergothioneine, ophthalmate and norophthalmate, in signalling and detoxification of oxidants and metabolic by-products. © 2015 John Wiley & Sons Ltd.

  2. GCN5 regulates the activation of PI3K/Akt survival pathway in B cells exposed to oxidative stress via controlling gene expressions of Syk and Btk.

    Science.gov (United States)

    Kikuchi, Hidehiko; Kuribayashi, Futoshi; Takami, Yasunari; Imajoh-Ohmi, Shinobu; Nakayama, Tatsuo

    2011-02-25

    Histone acetyltransferase(s) (HATs) are involved in the acetylation of core histones, which is an important event for transcription regulation through alterations in the chromatin structure in eukaryotes. General control non-depressible 5 (GCN5) was first identified as a global coactivator and transcription-related HAT. Here we report that GCN5 regulates the activation of phosphatidylinositol 3-kinase (PI3K)/acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt) survival pathway in B cells exposed to oxidative stress via controlling gene expressions of spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk). The GCN5-deficiency remarkably caused apoptotic cell death by treatment with exogenous hydrogen peroxide (H(2)O(2)) in chicken DT40 cells. In GCN5-deficient DT40 cells, gene expressions of Syk and Btk, which are involved in activation of PI3K/Akt survival pathway in DT40 cells exposed to exogenous H(2)O(2), were remarkably decreased compared with those in wild type DT40 cells. In addition, phosphorylation of Akt in H(2)O(2)-treated GCN5-deficient cells was remarkably suppressed as compared to that of DT40. Chromatin immunoprecipitation assay revealed that GCN5 binds to proximal 5'-upstream regions of Syk and Btk genes in vivo. These results suggest that GCN5 takes part in transcriptional regulations of the Syk and Btk genes, and plays a key role in epigenetic regulation of PI3K/Akt survival pathway in B cells exposed to reactive oxygen species such as H(2)O(2). Copyright © 2011 Elsevier Inc. All rights reserved.

  3. 7-ketocholesterol induces apoptosis of MC3T3-E1 cells associated with reactive oxygen species generation, endoplasmic reticulum stress and caspase-3/7 dependent pathway

    Directory of Open Access Journals (Sweden)

    Yuta Sato

    2017-03-01

    Full Text Available Type 2 diabetes mellitus (T2DM is associated with an increased risk of bone fractures without reduction of bone mineral density. The cholesterol oxide 7-ketocholesterol (7KCHO has been implicated in numerous diseases such as atherosclerosis, Alzheimer's disease, Parkinson's disease, cancer, age-related macular degeneration and T2DM. In the present study, 7KCHO decreased the viability of MC3T3-E1 cells, increased reactive oxygen species (ROS production and apoptotic rate, and upregulated the caspase-3/7 pathway. Furthermore, these effects of 7KCHO were abolished by pre-incubation of the cells with N-acetylcysteine (NAC, an ROS inhibitor. Also, 7KCHO enhanced the mRNA expression of two endoplasmic reticulum (ER stress markers; CHOP and GRP78, in MC3T3-E1 cells. Pre-incubation of the cells with NAC suppressed the 7KCHO-induced upregulation of CHOP, but not GRP78. In conclusion, we demonstrated that 7KCHO induced apoptosis of MC3T3-E1 cells associated with ROS generation, ER stress, and caspase-3/7 activity, and the effects of 7KCHO were abolished by the ROS inhibitor NAC. These findings may provide new insight into the relationship between oxysterol and pathophysiology of osteoporosis seen in T2DM.

  4. Protective effect of thymoquinone improves cardiovascular function, and attenuates oxidative stress, inflammation and apoptosis by mediating the PI3K/Akt pathway in diabetic rats.

    Science.gov (United States)

    Liu, Hui; Liu, Hong-Yang; Jiang, Yi-Nong; Li, Nan

    2016-03-01

    Thymoquinone is the main active monomer extracted from black cumin and has anti‑inflammatory, antioxidant and anti‑apoptotic functions. However, the protective effects of thymoquinone on cardiovascular function in diabetes remain to be fully elucidated. The present study aimed to investigate the molecular mechanisms underling the beneficial effects of thymoquinone on the cardiovascular function in streptozotocin‑induced diabetes mellitus (DM) rats. Supplement thymoquinone may recover the insulin levels and body weight, inhibit blood glucose levels and reduce the heart rate in DM‑induced rats. The results indicated that the heart, liver and lung to body weight ratios, in addition to the blood pressure levels, were similar for each experimental group. Treatment with thymoquinone significantly reduced oxidative stress damage, inhibited the increased endothelial nitric oxide synthase protein expression and suppressed the elevation of cyclooxygenase‑2 levels in DM‑induced rats. In addition, thymoquinone significantly suppressed the promotion of tumor necrosis factor‑α and interleukin‑6 levels in the DM‑induced rats. Furthermore, administration of thymoquinone significantly reduced caspase‑3 activity and the promotion of phosphorylated‑protein kinase B (Akt) protein expression levels in DM‑induced rats. These results suggest that the protective effect of thymoquinone improves cardiovascular function and attenuates oxidative stress, inflammation and apoptosis by mediating the phosphatidylinositol 3‑kinase/Akt pathway in DM‑induced rats.

  5. Triggering Apoptotic Death of Human Epidermal Keratinocytes by Malic Acid: Involvement of Endoplasmic Reticulum Stress- and Mitochondria-Dependent Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Yu-Ping Hsiao

    2015-01-01

    Full Text Available Malic acid (MA has been commonly used in cosmetic products, but the safety reports in skin are sparse. To investigate the biological effects of MA in human skin keratinocytes, we investigated the potential cytotoxicity and apoptotic effects of MA in human keratinocyte cell lines (HaCaT. The data showed that MA induced apoptosis based on the observations of DAPI staining, DNA fragmentation, and sub-G1 phase in HaCaT cells and normal human epidermal keratinocytes (NHEKs. Flow cytometric assays also showed that MA increased the production of mitochondrial superoxide (mito-SOX but decreased the mitochondrial membrane potential. Analysis of bioenergetics function with the XF 24 analyzer Seahorse extracellular flux analyzer demonstrated that oxygen consumption rate (OCR was significantly decreased whereas extracellular acidification rate (ECAR was increased in MA-treated keratinocytes. The occurrence of apoptosis was proved by the increased expressions of FasL, Fas, Bax, Bid, caspases-3, -8, -9, cytochrome c, and the declined expressions of Bcl-2, PARP. MA also induced endoplasmic reticulum stress associated protein expression such as GRP78, GADD153, and ATF6α. We demonstrated that MA had anti-proliferative effect in HaCaT cell through the inhibition of cell cycle progression at G0/G1, and the induction of programmed cell death through endoplasmic reticulum stress- and mitochondria-dependent pathways.

  6. Imoxin attenuates high fructose-induced oxidative stress and apoptosis in renal epithelial cells via downregulation of protein kinase R pathway.

    Science.gov (United States)

    Kalra, Jaspreet; Mangali, Suresh Babu; Bhat, Audesh; Dhar, Indu; Udumula, Mary Priyanka; Dhar, Arti

    2018-02-11

    Double-stranded RNA (dsRNA)-activated protein kinase R (PKR), a ubiquitously expressed serine/threonine kinase, is a key inducer of inflammation, insulin resistance, and glucose homeostasis in obesity. Recent studies have demonstrated that PKR can respond to metabolic stress in mice as well as in humans. However, the underlying molecular mechanism is not fully understood. The a