Comparison of radiation-induced DNA-protein cross-links formed in oxic, hypoxic, and glutathione depleted cells

International Nuclear Information System (INIS)

Xue, L.; Friedman, L.R.; Chiu, S.; Ramakrishnan, N.; Oleinick, N.L.

1987-01-01

Treatment of cells with L-buthionine sulfoximine (BSO) inhibits the synthesis of glutathione (GSH). Subsequent metabolism depletes the cells of GSH. GSH-depletion sensitizes both oxic and hypoxic cells to the lethal effects of ionizing radiation. DNA-protein cross-links (DPC) are formed preferentially between DNA sequences active in transcription and a subset of proteins of the nuclear matrix. Thus, DPC may be an indicator lesion of damage in sensitive regions of the genome. The interrelationships between GSH level, oxic vs. hypoxic status, and the yield of DPC have been studied in terms of number of lesions and repair rate in Chinese hamster V79 and in human lung carcinoma A549 cells. The data suggest that elevated background levels of DPC are indicative of a reduced repair capacity, and greater radiation-induced yields of DPC in hypoxia may also be indicative of a compromised repair mechanism

Glutamine deprivation induces interleukin-8 expression in ataxia telangiectasia fibroblasts.

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Kim, Min-Hyun; Kim, Aryung; Yu, Ji Hoon; Lim, Joo Weon; Kim, Hyeyoung

2014-05-01

To investigate whether glutamine deprivation induces expression of inflammatory cytokine interleukin-8 (IL-8) by determining NF-κB activity and levels of oxidative indices (ROS, reactive oxygen species; hydrogen peroxide; GSH, glutathione) in fibroblasts isolated from patients with ataxia telangiectasia (A-T). We used A-T fibroblasts stably transfected with empty vector (Mock) or with human full-length ataxia telangiectasia mutated (ATM) cDNA (YZ5) and mouse embryonic fibroblasts (MEFs) transiently transfected with ATM small interfering RNA (siRNA) or with non-specific control siRNA. The cells were cultured with or without glutamine or GSH. ROS levels were determined using a fluorescence reader and confocal microscopy. IL-8 or murine IL-8 homolog, keratinocyte chemoattractant (KC), and hydrogen peroxide levels in the medium were determined by enzyme-linked immunosorbent assay and colorimetric assay. GSH level was assessed by enzymatic assay, while IL-8 (KC) mRNA level was measured by reverse transcription-polymerase chain reaction (RT-PCR) and/or quantitative real-time PCR. NF-κB DNA-binding activity was determined by electrophoretic mobility shift assay. Catalase activity and ATM protein levels were determined by O2 generation and Western blotting. While glutamine deprivation induced IL-8 expression and increased NF-κB DNA-binding activity in Mock cells, both processes were decreased by treatment of cells with glutamine or GSH or both glutamine and GSH. Glutamine deprivation had no effect on IL-8 expression or NF-κB DNA-binding activity in YZ5 cells. Glutamine-deprived Mock cells had higher oxidative stress indices (increases in ROS and hydrogen peroxide, reduction in GSH) than glutamine-deprived YZ5 cells. In Mock cells, glutamine deprivation-induced oxidative stress indices were suppressed by treatment with glutamine or GSH or both glutamine and GSH. GSH levels and catalase activity were lower in Mock cells than YZ5 cells. MEFs transfected with ATM siRNA and

The diverse roles of glutathione-associated cell resistance against hypericin photodynamic therapy

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Theodossis A. Theodossiou

2017-08-01

Full Text Available The diverse responses of different cancers to treatments such as photodynamic therapy of cancer (PDT have fueled a growing need for reliable predictive markers for treatment outcome. In the present work we have studied the differential response of two phenotypically and genotypically different breast adenocarcinoma cell lines, MCF7 and MDA-MB-231, to hypericin PDT (HYP-PDT. MDA-MB-231 cells were 70% more sensitive to HYP PDT than MCF7 cells at LD50. MCF7 were found to express a substantially higher level of glutathione peroxidase (GPX4 than MDA-MB-231, while MDA-MB-231 differentially expressed glutathione-S-transferase (GSTP1, mainly used for xenobiotic detoxification. Eighty % reduction of intracellular glutathione (GSH by buthionine sulfoximine (BSO, largely enhanced the sensitivity of the GSTP1 expressing MDA-MB-231 cells to HYP-PDT, but not in MCF7 cells. Further inhibition of the GSH reduction however by carmustine (BCNU resulted in an enhanced sensitivity of MCF7 to HYP-PDT. HYP loading studies suggested that HYP can be a substrate of GSTP for GSH conjugation as BSO enhanced the cellular HYP accumulation by 20% in MDA-MB-231 cells, but not in MCF7 cells. Studies in solutions showed that L-cysteine can bind the GSTP substrate CDNB in the absence of GSTP. This means that the GSTP-lacking MCF7 may use L-cysteine for xenobiotic detoxification, especially during GSH synthesis inhibition, which leads to L-cysteine build-up. This was confirmed by the lowered accumulation of HYP in both cell lines in the presence of BSO and the L-cysteine source NAC. NAC reduced the sensitivity of MCF7, but not MDA-MB-231, cells to HYP PDT which is in accordance with the antioxidant effects of L-cysteine and its potential as a GSTP substrate. As a conclusion we have herein shown that the different GSH based cell defense mechanisms can be utilized as predictive markers for the outcome of PDT and as a guide for selecting optimal combination strategies. Keywords

Effects of glutathione depletion by buthionine sulfoximine on radiosensitization by oxygen and misonidazole in vitro

International Nuclear Information System (INIS)

Shrieve, D.C.; Denekamp, J.; Minchinton, A.I.

1985-01-01

Buthionine sulfoximine (BSO) has been used to deplete glutathione (GSH) in V79-379A cells in vitro, and the effect on the efficiency of oxygen and misonidazole (MISO) as radiosensitizers has been determined. Treatment with 50 or 500 μM BSO caused a rapid decline in GSH content to less than 5% of control values after 10 hr of exposure. Removal of BSO resulted in a rapid regeneration of GSH after 50 μM BSO, but little regeneration was observed over the subsequent 10-hr period after 500 μM. Cells irradiated in monolayer on glass had an oxygen enhancement ratio (OER) of 3.1. After 10-14 hr pretreatment with 50 μM BSO, washed cells were radiosensitized by GSH depletion at all oxygen tensions tested. The OER was reduced to 2.6, due to greater radiosensitization of hypoxic cells than aerated ones by GSH depletion. In similar experiments performed with MISO, an enhancement ratio of 2.0 could be achieved with 0.2 mM MISO in anoxic BSO-pretreated cells, compared to 2.7 mM MISO in non-BSO-treated cells. These apparent increases in radiosensitizer efficiency in GSH-depleted cells could be explained on the basis of radiosensitization of hypoxic cells by GSH depletion alone. These results are consistent with hypoxic cell radiosensitization by GSH depletion and by MISO or oxygen acting by separate mechanisms

The effects of BSO on GSH contents and radiosensitivity of retinoblastoma cells

International Nuclear Information System (INIS)

Yi Xanjin; Ding Li; Jin Yizun; Ni Chuo; Wang Wenji; Yi Yuzhen

1995-01-01

The radiobiological effects of thiol modifier BSO on retinoblastoma were studied using cultured retinoblastoma cell lines Y-79 and So-Rb 50 and retinoblastoma bearing nude mouse. The preliminary results showed that BSO can deplete intracellular GSH contents of retinoblastoma cells in vitro and vivo. In vitro data demonstrated that low and nontoxic concentration BSO increased the retinoblastoma cells radiosensitivity especially under the hypoxic condition

Metabolic cooperation of ascorbic acid and glutathione in normal and vitamin C-deficient ODS rats.

Science.gov (United States)

Wang, Y; Kashiba, M; Kasahara, E; Tsuchiya, M; Sato, E F; Utsumi, K; Inoue, M

2001-01-01

Although the coordination of various antioxidants is important for the protection of organisms from oxidative stress, dynamic aspects of the interaction of endogenous antioxidants in vivo remain to be elucidated. We studied the metabolic coordination of two naturally occurring water-soluble antioxidants, ascorbic acid (AA) and reduced glutathione (GSH), in liver, kidney and plasma of control and scurvy-prone osteogenic disorder Shionogi (ODS) rats that hereditarily lack the ability to synthesize AA. When supplemented with AA, its levels in liver and kidney of ODS rats increased to similar levels of those in control rats. Hepato-renal levels of glutathione were similar with the two animal groups except for the slight increase in its hepatic levels in AA-supplemented ODS rats. Administration of L-buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, rapidly decreased the hepato-renal levels of glutathione in a biphasic manner, a rapid phase followed by a slower phase. Kinetic analysis revealed that glutathione turnover was enhanced significantly in liver mitochondria and renal cytosol of ODS rats. Administration of BSO significantly increased AA levels in the liver and kidney of control rats but decreased them in AA-supplemented ODS rats. Kinetic analysis revealed that AA is synthesized by control rat liver by some BSO-enhanced mechanism and the de novo synthesized AA is transferred to the kidney. Such a coordination of the metabolism of GSH and AA in liver and kidney is suppressed in AA-deficient ODS rats. These and other results suggest that the metabolism of AA and GSH forms a compensatory network by which oxidative stress can be decreased.

Possible involvement of GABAergic mechanism in protective effect of melatonin against sleep deprivation-induced behaviour modification and oxidative damage in mice.

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Kumar, Anil; Singh, Anant

2009-08-01

Sleep is an important physiological process responsible for the maintenance of physical, mental and emotional health of a living being. Sleep deprivation is considered risky for several pathological diseases such as anxiety and motor and cognitive dysfunctions. Sleep deprivation has recently been reported to cause oxidative damage. This study has been designed to explore the possible involvement of the GABAergic mechanism in protective effects of melatonin against 72-h sleep deprivation-induced behaviour modification and oxidative damage in mice. Mice were sleep-deprived for a period of 72 h using the grid over water suspended method. Animals were divided into groups of 6-8 animals each. Melatonin (5 and 10 mg/kg), flumazenil (0.5 mg/kg), picrotoxin (0.5 mg/kg) and muscimol (0.05 mg/kg) were administered for 5 days starting 2 days before 72-h sleep deprivation. Various behavioural tests (plus maze, zero maze, mirror chamber, actophotometer) and body weight assessment followed by oxidative stress parameters (malondialdehyde level, glutathione, catalase, nitrite and protein) were carried out. The 72-h sleep deprivation caused significant anxiety-like behaviour, weight loss, impaired locomotor activity and oxidative damage as compared with naïve (without sleep deprivation). Treatment with melatonin (5 mg/kg and 10 mg/kg, ip) significantly improved locomotor activity, weight loss and antianxiety effect as compared with control (sleep-deprived). Biochemically, melatonin treatment significantly restored reduced glutathione, catalase activity, attenuated lipid peroxidation and nitrite level as compared with control animals (72-h sleep-deprived). Flumazenil (0.5 mg/kg) and picrotoxin (0.5 mg/kg) pretreatments with a lower dose of melatonin (5 mg/kg) significantly antagonized the protective effect of melatonin. However, muscimol (0.05 mg/kg) pretreatment with melatonin (5 mg/kg, ip) potentiated the protective effect of melatonin which was significant as compared with their

Protection of HepG2 cells against acrolein toxicity by 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide via glutathione-mediated mechanism.

Science.gov (United States)

Shah, Halley; Speen, Adam M; Saunders, Christina; Brooke, Elizabeth A S; Nallasamy, Palanisamy; Zhu, Hong; Li, Y Robert; Jia, Zhenquan

2015-10-01

Acrolein is an environmental toxicant, mainly found in smoke released from incomplete combustion of organic matter. Several studies showed that exposure to acrolein can lead to liver damage. The mechanisms involved in acrolein-induced hepatocellular toxicity, however, are not completely understood. This study examined the cytotoxic mechanisms of acrolein on HepG2 cells. Acrolein at pathophysiological concentrations was shown to cause apoptotic cell death and an increase in levels of protein carbonyl and thiobarbituric acid reactive acid substances. Acrolein also rapidly depleted intracellular glutathione (GSH), GSH-linked glutathione-S-transferases, and aldose reductase, three critical cellular defenses that detoxify reactive aldehydes. Results further showed that depletion of cellular GSH by acrolein preceded the loss of cell viability. To further determine the role of cellular GSH in acrolein-mediated cytotoxicity, buthionine sulfoximine (BSO) was used to inhibit cellular GSH biosynthesis. It was observed that depletion of cellular GSH by BSO led to a marked potentiation of acrolein-mediated cytotoxicity in HepG2 cells. To further assess the contribution of these events to acrolein-induced cytotoxicity, triterpenoid compound 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) was used for induction of GSH. Induction of GSH by CDDO-Im afforded cytoprotection against acrolein toxicity in HepG2 cells. Furthermore, BSO significantly inhibited CDDO-Im-mediated induction in cellular GSH levels and also reversed cytoprotective effects of CDDO-Im in HepG2 cells. These results suggest that GSH is a predominant mechanism underlying acrolein-induced cytotoxicity as well as CDDO-Im-mediated cytoprotection. This study may provide understanding on the molecular action of acrolein which may be important to develop novel strategies for the prevention of acrolein-mediated toxicity. © 2014 by the Society for Experimental Biology and Medicine.

Flurbiprofen ameliorates glucose deprivation-induced leptin resistance

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Toru Hosoi

2016-09-01

Full Text Available Leptin resistance is one of the mechanisms involved in the pathophysiology of obesity. The present study showed that glucose deprivation inhibited leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3 and signal transducer and activator of transcription 5 (STAT5 in neuronal cells. Flurbiprofen reversed glucose deprivation-mediated attenuation of STAT3, but not STAT5 activation, in leptin-treated cells. Glucose deprivation increased C/EBP-homologous protein (CHOP and glucose regulated protein 78 (GRP78 induction, indicating the activation of unfolded protein responses (UPR. Flurbiprofen did not affect the glucose deprivation-induced activation of UPR, but did attenuate the glucose deprivation-mediated induction of AMP-activated protein kinase (AMPK phosphorylation. Flurbiprofen may ameliorate glucose deprivation-induced leptin resistance in neuronal cells.

Cadmium-Induced Hydrogen Accumulation Is Involved in Cadmium Tolerance in Brassica campestris by Reestablishment of Reduced Glutathione Homeostasis.

Science.gov (United States)

Wu, Qi; Su, Nana; Chen, Qin; Shen, Wenbiao; Shen, Zhenguo; Xia, Yan; Cui, Jin

2015-01-01

Hydrogen gas (H2) was recently proposed as a therapeutic antioxidant and signaling molecule in clinical trials. However, the underlying physiological roles of H2 in plants remain unclear. In the present study, hydrogen-rich water (HRW) was used to characterize the physiological roles of H2 in enhancing the tolerance of Brassica campestris against cadmium (Cd). The results showed that both 50 μM CdCl2 and 50%-saturated HRW induced an increase of endogenous H2 in Brassica campestris seedlings, and HRW alleviated Cd toxicity related to growth inhibition and oxidative damage. Seedlings supplied with HRW exhibited increased root length and reduced lipid peroxidation, similar to plants receiving GSH post-treatment. Additionally, seedlings post-treated with HRW accumulated higher levels of reduced glutathione (GSH) and ascorbic acid (AsA) and showed increased GST and GPX activities in roots. Molecular evidence illustrated that the expression of genes such as GS, GR1 and GR2, which were down-regulated following the addition of Cd, GSH or BSO, could be reversed to varying degrees by the addition of HRW. Based on these results, it could be proposed that H2 might be an important regulator for enhancing the tolerance of Brassica campestris seedlings against Cd, mainly by governing reduced glutathione homeostasis.

Reduction of intracellular glutathione content and radiosensitivity

International Nuclear Information System (INIS)

Vos, O.; Schans, G.P. van der; Roos-Verheij, W.S.D.

1986-05-01

The intracellular glutathione (GSH) content in HeLa, CHO and V79 cells was reduced by incubating the cells in growth medium containing buthionine sulfoximine (BSO) or diethyl maleate (DEM). Clonogenicity, single strand DNA breaks (ssb) and double strand DNA breaks (dsb) were used as criteria for radiation induced damage after X- or γ irradiation. In survival experiments DEM gave a slightly larger sensitization although it gave a smaller reduction of the intracellular GSH. In general, sensitization was larger for dsb than for ssb, also the reduction of the OER was generally larger for dsb than for ssb. This may be due to the higher dose rate in case of dsb experiments resulting in a higher rate of radiochemical oxygen consumption. In general, no effect was found on post-irradiation repair of ssb and dsb. (Auth.)

Survival of rats bearing advanced intracerebral F 98 tumors after glutathione depletion and microbeam radiation therapy: conclusions from a pilot project.

Science.gov (United States)

Schültke, E; Bräuer-Krisch, E; Blattmann, H; Requardt, H; Laissue, J A; Hildebrandt, G

2018-05-10

Resistance to radiotherapy is frequently encountered in patients with glioblastoma multiforme. It is caused at least partially by the high glutathione content in the tumour tissue. Therefore, the administration of the glutathione synthesis inhibitor Buthionine-SR-Sulfoximine (BSO) should increase survival time. BSO was tested in combination with an experimental synchrotron-based treatment, microbeam radiation therapy (MRT), characterized by spatially and periodically alternating microscopic dose distribution. One hundred thousand F98 glioma cells were injected into the right cerebral hemisphere of adult male Fischer rats to generate an orthotopic small animal model of a highly malignant brain tumour in a very advanced stage. Therapy was scheduled for day 13 after tumour cell implantation. At this time, 12.5% of the animals had already died from their disease. The surviving 24 tumour-bearing animals were randomly distributed in three experimental groups: subjected to MRT alone (Group A), to MRT plus BSO (Group B) and tumour-bearing untreated controls (Group C). Thus, half of the irradiated animals received an injection of 100 μM BSO into the tumour two hours before radiotherapy. Additional tumour-free animals, mirroring the treatment of the tumour-bearing animals, were included in the experiment. MRT was administered in bi-directional mode with arrays of quasi-parallel beams crossing at the tumour location. The width of the microbeams was ≈28 μm with a center-to-center distance of ≈400 μm, a peak dose of 350 Gy, and a valley dose of 9 Gy in the normal tissue and 18 Gy at the tumour location; thus, the peak to valley dose ratio (PVDR) was 31. After tumour-cell implantation, otherwise untreated rats had a mean survival time of 15 days. Twenty days after implantation, 62.5% of the animals receiving MRT alone (group A) and 75% of the rats given MRT + BSO (group B) were still alive. Thirty days after implantation, survival was 12.5% in Group A and 62

Effect of radiosensitizer BSO on the incidence of micronuclei in cultured cells

International Nuclear Information System (INIS)

Jin Yizun; Cai Rongmei; Ding Li; Shen Zhifen; Xu Liming; Yang Jiakuan

1992-01-01

The effects of BSO, a potent radiosensitizing and chemical sensitizing chemical, on the incidence of micronuclei in four different cell lines have been studied using the cytokinesis-block (CB) method. The number of micronuclei in cultured human peripheral lymphocytes, Chinese hamster cells and human breast cancer cells were not affected by 0.1-2 mmol/L BSO treatment alone. However, significant increase in the incidence of micronuclei in these cells could be detected when BSO was used in combination with γ-irradiation. Linear relationship between the incidence of micronuclei and the radiation dose was observed

The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats

International Nuclear Information System (INIS)

Nishiya, Takayoshi; Mori, Kazuhiko; Hattori, Chiharu; Kai, Kiyonori; Kataoka, Hiroko; Masubuchi, Noriko; Jindo, Toshimasa; Manabe, Sunao

2008-01-01

To investigate the hepatotoxic potential of tienilic acid in vivo, we administered a single oral dose of tienilic acid to Sprague-Dawley rats and performed general clinicopathological examinations and hepatic gene expression analysis using Affymetrix microarrays. No change in the serum transaminases was noted at up to 1000 mg/kg, although slight elevation of the serum bile acid and bilirubin, and very mild hepatotoxic changes in morphology were observed. In contrast to the marginal clinicopathological changes, marked upregulation of the genes involved in glutathione biosynthesis [glutathione synthetase and glutamate-cysteine ligase (Gcl)], oxidative stress response [heme oxygenase-1 and NAD(P)H dehydrogenase quinone 1] and phase II drug metabolism (glutathione S-transferase and UDP glycosyltransferase 1A6) were noted after 3 or 6 h post-dosing. The hepatic reduced glutathione level decreased at 3-6 h, and then increased at 24 or 48 h, indicating that the upregulation of NF-E2-related factor 2 (Nrf2)-regulated gene and the late increase in hepatic glutathione are protective responses against the oxidative and/or electrophilic stresses caused by tienilic acid. In a subsequent experiment, tienilic acid in combination with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of Gcl caused marked elevation of serum alanine aminotransferase (ALT) with extensive centrilobular hepatocyte necrosis, whereas BSO alone showed no hepatotoxicity. The elevation of ALT by this combination was observed at the same dose levels of tienilic acid as the upregulation of the Nrf2-regulated genes by tienilic acid alone. In conclusion, these results suggest that the impairment of glutathione biosynthesis may play a critical role in the development of tienilic acid hepatotoxicity through extensive oxidative and/or electrophilic stresses

Cellular glutathione prevents cytolethality of monomethylarsonic acid

International Nuclear Information System (INIS)

Sakurai, Teruaki; Kojima, Chikara; Ochiai, Masayuki; Ohta, Takami; Sakurai, Masumi H.; Waalkes, Michael P.; Fujiwara, Kitao

2004-01-01

Inorganic arsenicals are clearly toxicants and carcinogens in humans. In mammals, including humans, inorganic arsenic often undergoes methylation, forming compounds such as monomethylarsonic acid (MMAs V ) and dimethylarsinic acid (DMAs V ). However, much less information is available on the in vitro toxic potential or mechanisms of these methylated arsenicals, especially MMAs V . We studied the molecular mechanisms of in vitro cytolethality of MMAs V using a rat liver epithelial cell line (TRL 1215). MMAs V was not cytotoxic in TRL 1215 cells even at concentrations exceeding 10 mM, but it became weakly cytotoxic and induced both necrotic and apoptotic cell death when cellular reduced glutathione (GSH) was depleted with the glutathione synthase inhibitor, L-buthionine-[S,R]-sulfoximine (BSO), or the glutathione reductase inhibitor, carmustine. Similar results were observed in the other mammalian cells, such as human skin TIG-112 cells, chimpanzee skin CRT-1609 cells, and mouse metallothionein (MT) positive and MT negative embryonic cells. Ethacrynic acid (EA), an inhibitor of glutathione S-transferase (GST) that catalyses GSH-substrate conjugation, also enhanced the cytolethality of MMAs V , but aminooxyacetic acid (AOAA), an inhibitor of β-lyase that catalyses the final breakdown of GSH-substrate conjugates, had no effect. Both the cellular GSH levels and the cellular GST activity were increased by the exposure to MMAs V in TRL 1215 cells. On the other hand, the addition of exogenous extracellular GSH enhanced the cytolethality of MMAs V , although cellular GSH levels actually prevented the cytolethality of combined MMAs V and exogenous GSH. These findings indicate that human arsenic metabolite MMAs V is not a highly toxic compound in mammalian cells, and the level of cellular GSH is critical to its eventual toxic effects

Inhibition of glutathione synthesis eliminates the adaptive response of ascitic hepatoma 22 cells to nedaplatin that targets thioredoxin reductase

Energy Technology Data Exchange (ETDEWEB)

Wang, Yijun [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China); Lu, Hongjuan [Productivity Center of Jiangsu Province, Nanjing 210042, Jiangsu (China); Wang, Dongxu; Li, Shengrong; Sun, Kang; Wan, Xiaochun [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China); Taylor, Ethan Will [Department of Nanoscience, Joint School of Nanoscience and Nanoengineering, University of North Carolina at Greensboro, Greensboro, NC 27402 (United States); Zhang, Jinsong, E-mail: zjs@ahau.edu.cn [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China)

2012-12-15

Thioredoxin reductase (TrxR) is a target for cancer therapy and the anticancer mechanism of cisplatin involves TrxR inhibition. We hypothesize that the anticancer drug nedaplatin (NDP), an analogue of cisplatin and a second-generation platinum complex, also targets TrxR. Furthermore, we investigate whether the therapeutic efficacy of NDP can be enhanced by simultaneous modulation of 1) TrxR, via NDP, and 2) glutathione (GSH), via the GSH synthesis inhibitor buthionine sulfoximine (BSO). Mice bearing ascitic hepatoma 22 (H22) cells were treated with NDP alone or NDP plus BSO. TrxR activity of H22 cells was inhibited by NDP in a dose-dependent manner. A high correlation between the inhibition of TrxR activity at 6 h and the inhibition of ascitic fluid volume at 72 h was established (r = 0.978, p < 0.01). As an adaptive response, the viable ascitic cancer cells after NDP treatment displayed an enlarged cell phenotype, assembled with several-fold more antioxidant enzymes and GSH-predominant non-protein free thiols. This adaptive response was largely eliminated when BSO was co-administered with NDP, leading to the decimation of the H22 cell population without enhancing renal toxicity, since at this dose, NDP did not inhibit renal TrxR activity. In conclusion, the pharmacological effect of NDP involves TrxR inhibition, and the adaptive response of NDP-treated ascitic H22 cells can be efficiently counteracted by BSO. Simultaneous modulation of TrxR and GSH on ascitic H22 cells using NDP plus BSO greatly enhances therapeutic efficacy as compared with the single modulation of TrxR using NDP alone. -- Highlights: ► Nedaplatin at a pharmacological dose inhibits TrxR in cancer cells but not in kidney. ► The nedaplatin-treated cancer cells exhibit adaptive response. ► Buthionine sulfoximine inhibits glutathione in both cancer cells and kidney. ► Buthionine sulfoximine counteracts the adaptive response to the nedaplatin treatment. ► Buthionine sulfoximine does not

Inhibition of glutathione synthesis eliminates the adaptive response of ascitic hepatoma 22 cells to nedaplatin that targets thioredoxin reductase

International Nuclear Information System (INIS)

Wang, Yijun; Lu, Hongjuan; Wang, Dongxu; Li, Shengrong; Sun, Kang; Wan, Xiaochun; Taylor, Ethan Will; Zhang, Jinsong

2012-01-01

Thioredoxin reductase (TrxR) is a target for cancer therapy and the anticancer mechanism of cisplatin involves TrxR inhibition. We hypothesize that the anticancer drug nedaplatin (NDP), an analogue of cisplatin and a second-generation platinum complex, also targets TrxR. Furthermore, we investigate whether the therapeutic efficacy of NDP can be enhanced by simultaneous modulation of 1) TrxR, via NDP, and 2) glutathione (GSH), via the GSH synthesis inhibitor buthionine sulfoximine (BSO). Mice bearing ascitic hepatoma 22 (H22) cells were treated with NDP alone or NDP plus BSO. TrxR activity of H22 cells was inhibited by NDP in a dose-dependent manner. A high correlation between the inhibition of TrxR activity at 6 h and the inhibition of ascitic fluid volume at 72 h was established (r = 0.978, p < 0.01). As an adaptive response, the viable ascitic cancer cells after NDP treatment displayed an enlarged cell phenotype, assembled with several-fold more antioxidant enzymes and GSH-predominant non-protein free thiols. This adaptive response was largely eliminated when BSO was co-administered with NDP, leading to the decimation of the H22 cell population without enhancing renal toxicity, since at this dose, NDP did not inhibit renal TrxR activity. In conclusion, the pharmacological effect of NDP involves TrxR inhibition, and the adaptive response of NDP-treated ascitic H22 cells can be efficiently counteracted by BSO. Simultaneous modulation of TrxR and GSH on ascitic H22 cells using NDP plus BSO greatly enhances therapeutic efficacy as compared with the single modulation of TrxR using NDP alone. -- Highlights: ► Nedaplatin at a pharmacological dose inhibits TrxR in cancer cells but not in kidney. ► The nedaplatin-treated cancer cells exhibit adaptive response. ► Buthionine sulfoximine inhibits glutathione in both cancer cells and kidney. ► Buthionine sulfoximine counteracts the adaptive response to the nedaplatin treatment. ► Buthionine sulfoximine does not

Vitamin C Prevents Sleep Deprivation-induced Elevation in Cortisol ...

African Journals Online (AJOL)

In this study, we examined the potential protective effects of administration of vitamin C on acute and chronic sleep deprivation-induced metabolic derangement. In addition, possible processes involved in vitamin C effects on acute and chronic sleep deprivation-induced metabolic derangement were determined. Thirty-five ...

Mitochondrial Swelling Induced by Glutathione

Science.gov (United States)

Lehninger, Albert L.; Schneider, Marion

1959-01-01

Reduced glutathione, in concentrations approximating those occurring in intact rat liver, causes swelling of rat liver mitochondria in vitro which is different in kinetics and extent from that yielded by L-thyroxine. The effect is also given by cysteine, which is more active, and reduced coenzyme A, but not by L-ascorbate, cystine, or oxidized glutathione. The optimum pH is 6.5, whereas thyroxine-induced swelling is optimal at pH 7.5. The GSH-induced swelling is not inhibited by DNP or dicumarol, nor by high concentrations of sucrose, serum albumin, or polyvinylpyrrolidone, in contrast to thyroxine-induced swelling. ATP inhibits the GSH swelling, but ADP and AMP are ineffective. Mn-+ is a very potent inhibitor, but Mg++ is ineffective. Ethylenediaminetetraacetate is also an effective inhibitor of GSH-induced swelling. The respiratory inhibitors amytal and antimycin A do not inhibit the swelling action of GSH, but cyanide does; these findings are consistent with the view that the oxidation-reduction state of the respiratory chain between cytochrome c and oxygen is a determinant of GSH-induced swelling. Reversal of GSH-induced swelling by osmotic means or by ATP in KCl media could not be observed. Large losses of nucleotides and protein occur during the swelling by GSH, suggesting that the action is irreversible. The characteristically drastic swelling action of GSH could be prevented if L-thyroxine was also present in the medium. PMID:13630941

N-acetylcysteine stimulates protein synthesis in enterocytes independently of glutathione synthesis.

Science.gov (United States)

Yi, Dan; Hou, Yongqing; Wang, Lei; Long, Minhui; Hu, Shengdi; Mei, Huimin; Yan, Liqiong; Hu, Chien-An Andy; Wu, Guoyao

2016-02-01

Dietary supplementation with N-acetylcysteine (NAC) has been reported to improve intestinal health and treat gastrointestinal diseases. However, the underlying mechanisms are not fully understood. According to previous reports, NAC was thought to exert its effect through glutathione synthesis. This study tested the hypothesis that NAC enhances enterocyte growth and protein synthesis independently of cellular glutathione synthesis. Intestinal porcine epithelial cells were cultured for 3 days in Dulbecco's modified Eagle medium containing 0 or 100 μM NAC. To determine a possible role for GSH (the reduced form of glutathione) in mediating the effect of NAC on cell growth and protein synthesis, additional experiments were conducted using culture medium containing 100 μM GSH, 100 μM GSH ethyl ester (GSHee), diethylmaleate (a GSH-depletion agent; 10 μM), or a GSH-synthesis inhibitor (buthionine sulfoximine, BSO; 20 μM). NAC increased cell proliferation, GSH concentration, and protein synthesis, while inhibiting proteolysis. GSHee enhanced cell proliferation and GSH concentration without affecting protein synthesis but inhibited proteolysis. Conversely, BSO or diethylmaleate reduced cell proliferation and GSH concentration without affecting protein synthesis, while promoting protein degradation. At the signaling level, NAC augmented the protein abundance of total mTOR, phosphorylated mTOR, and phosphorylated 70S6 kinase as well as mRNA levels for mTOR and p70S6 kinase in IPEC-1 cells. Collectively, these results indicate that NAC upregulates expression of mTOR signaling proteins to stimulate protein synthesis in enterocytes independently of GSH generation. Our findings provide a hitherto unrecognized biochemical mechanism for beneficial effects of NAC in intestinal cells.

Alkylating agent induced NRF2 blocks endoplasmic reticulum stress-mediated apoptosis via control of glutathione pools and protein thiol homeostasis

Science.gov (United States)

Zanotto-Filho, Alfeu; Masamsetti, V. Pragathi; Loranc, Eva; Tonapi, Sonal S.; Gorthi, Aparna; Bernard, Xavier; Gonçalves, Rosângela Mayer; Moreira, José C. F.; Chen, Yidong; Bishop, Alexander J. R.

2016-01-01

Alkylating agents are a commonly used cytotoxic class of anticancer drugs. Understanding the mechanisms whereby cells respond to these drugs is key to identify means to improve therapy while reducing toxicity. By integrating genome-wide gene expression profiling, protein analysis and functional cell validation, we herein demonstrated a direct relationship between NRF2 and Endoplasmic Reticulum (ER) stress pathways in response to alkylating agents, which is coordinated by the availability of glutathione (GSH) pools. GSH is essential for both drug detoxification and protein thiol homeostasis within the ER, thus inhibiting ER stress induction and promoting survival; an effect independent of its antioxidant role. NRF2 accumulation induced by alkylating agents resulted in increased GSH synthesis via GCLC/GCLM enzyme, and interfering with this NRF2 response by either NRF2 knockdown or GCLC/GCLM inhibition with buthionine sulfoximine (BSO) caused accumulation of damaged proteins within the ER, leading to PERK-dependent apoptosis. Conversely, upregulation of NRF2, through KEAP1 depletion or NRF2-myc overexpression, or increasing GSH levels with N-acetylcysteine (NAC) or glutathione-ethyl-ester (GSH-E), decreased ER stress and abrogated alkylating agents-induced cell death. Based on these results, we identified a subset of lung and head-and-neck carcinomas with mutations in either KEAP1 or NRF2/NFE2L2 genes that correlate with NRF2 targets overexpression and poor survival. In KEAP1 mutant cancer cells, NRF2 knockdown and GSH depletion increased cell sensitivity via ER stress induction in a mechanism specific to alkylating drugs. Overall, we show that the NRF2-GSH influence on ER homeostasis implicates defects in NRF2-GSH or ER stress machineries as affecting alkylating therapy toxicity. PMID:27638861

Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status.

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Trivedi, Malav S; Holger, Dana; Bui, Anh Tuyet; Craddock, Travis J A; Tartar, Jaime L

2017-01-01

Sleep is critical for repair as well as the rejuvenation processes in the body and many of these functions are regulated via underlying cellular metabolic homeostasis. Changes in sleep pattern are reported to alter such metabolic function resulting in altered disease susceptibility or behavior. Here, we measured the extent to which overnight total sleep deprivation (SD) in young adult humans can influence systemic (plasma-derived) redox-metabolism including the major antioxidant, glutathione as well as DNA methylation levels. Nineteen participants (n = 19, μ age = 21, SD = 3.09) underwent morning testing before and after overnight total SD. Biochemical measures before and after SD revealed that glutathione, ATP, cysteine, and homocysteine levels were significantly reduced following one night of sleep deprivation (all p's sleep deprivation (maintaining wakefulness) uses up metabolic reserves, we observed that morning cortisol levels were blunted after sleep deprivation. There were no significant correlations between self-reported or actigraphy-measured sleep and the biochemical measurements, strongly indicating that prior sleep behavior did not have any direct influence on the biochemical measures taken at baseline or after sleep deprivation. Results from the current investigation supports the previous literature implicating the induction of oxidative stress and ATP depletion with sleep deprivation. Furthermore, such altered antioxidant status can also induce downstream epigenetic changes. Although we did not measure the specific genes that were altered under the influence of such sleep deprivation, such epigenetic changes could potentially contribute towards disease predisposition.

Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status.

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Malav S Trivedi

Full Text Available Sleep is critical for repair as well as the rejuvenation processes in the body and many of these functions are regulated via underlying cellular metabolic homeostasis. Changes in sleep pattern are reported to alter such metabolic function resulting in altered disease susceptibility or behavior. Here, we measured the extent to which overnight total sleep deprivation (SD in young adult humans can influence systemic (plasma-derived redox-metabolism including the major antioxidant, glutathione as well as DNA methylation levels. Nineteen participants (n = 19, μ age = 21, SD = 3.09 underwent morning testing before and after overnight total SD. Biochemical measures before and after SD revealed that glutathione, ATP, cysteine, and homocysteine levels were significantly reduced following one night of sleep deprivation (all p's < 0.01. Parallel to the well-recognized fact that sleep deprivation (maintaining wakefulness uses up metabolic reserves, we observed that morning cortisol levels were blunted after sleep deprivation. There were no significant correlations between self-reported or actigraphy-measured sleep and the biochemical measurements, strongly indicating that prior sleep behavior did not have any direct influence on the biochemical measures taken at baseline or after sleep deprivation. Results from the current investigation supports the previous literature implicating the induction of oxidative stress and ATP depletion with sleep deprivation. Furthermore, such altered antioxidant status can also induce downstream epigenetic changes. Although we did not measure the specific genes that were altered under the influence of such sleep deprivation, such epigenetic changes could potentially contribute towards disease predisposition.

The cathepsin B inhibitor z-FA-CMK induces cell death in leukemic T cells via oxidative stress.

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Liow, K Y; Chow, Sek C

2018-01-01

The cathepsin B inhibitor benzyloxycarbonyl-phenylalanine-alanine-chloromethyl ketone (z-FA-CMK) was recently found to induce apoptosis at low concentrations in Jurkat T cells, while at higher concentrations, the cells die of necrosis. In the present study, we showed that z-FA-CMK readily depletes intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) generation. The toxicity of z-FA-CMK in Jurkat T cells was completely abrogated by N-acetylcysteine (NAC), suggesting that the toxicity mediated by z-FA-CMK is due to oxidative stress. We found that L-buthionine sulfoximine (BSO) which depletes intracellular GSH through the inhibition of GSH biosynthesis in Jurkat T cells did not promote ROS increase or induce cell death. However, NAC was still able to block z-FA-CMK toxicity in Jurkat T cells in the presence of BSO, indicating that the protective effect of NAC does not involve GSH biosynthesis. This is further corroborated by the protective effect of the non-metabolically active D-cysteine on z-FA-CMK toxicity. Furthermore, in BSO-treated cells, z-FA-CMK-induced ROS increased which remains unchanged, suggesting that the depletion of GSH and increase in ROS generation mediated by z-FA-CMK may be two separate events. Collectively, our results demonstrated that z-FA-CMK toxicity is mediated by oxidative stress through the increase in ROS generation.

Effects of Crocin Supplementation during In Vitro Maturation of Mouse Oocytes on Glutathione Synthesis and Cytoplasmic Maturation

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Elham Mokhber Maleki

2016-05-01

Full Text Available Background: Crocin is an active ingredient of saffron (Crocus sativus L. and its antioxidant properties have been previously investigated. This carotenoid scavenges free radicals and stimulates glutathione (GSH synthesis; consequently, it may protect cells against oxidative stress. The aim of this research is to protect oocytes from oxidative stress by the addition of a natural source antioxidant. Materials and Methods: In the present in vitro experimental study, we collected cumulus oocyte complexes (COCs from mouse ovaries of euthanized, 6-8 week-old female Naval Medical Research Institute (NMRI mice. Oocytes were subjected to in vitro maturation (IVM in the presence of either crocin (5 or 10 μg/ml, 5 mM buthionine-[S-R]- sulfoximine (BSO, or the combination of crocin plus BSO. Oocytes that matured in vitro in a medium without crocin or BSO supplements were considered as controls. Following 16-18 hours of IVM, matured oocytes (n=631 were fertilized by capacitated sperm from NMRI male mice, and cultured in vitro for up to 96 hours to assess preimplantation embryonic development. The levels of GSH in metaphase II (MII oocytes after IVM (n=240 were also assessed by the 5, 5-dithio-bis (2-nitrobenzoic acid (DTNB-GSH reductase recycling assay. Results: Supplementation of IVM media with 10 μg/ml crocin significantly (P<0.05 increased nuclear maturation, preimplantation development and GSH concentrations compared with the control group. Maturation of oocytes in IVM medium supplemented with BSO alone or the combination of 5 μg/ml crocin and BSO drastically decreased GSH concentrations and subsequently resulted in low rates of maturation, fertilization and blastocyst development. However, the combination of 10 μg/ml crocin with 5 mM BSO increased the level of nuclear maturation which was comparable to the control group. Conclusion: Supplementation of IVM media with crocin can improve nuclear maturation rates and subsequent developmental potential

GABA-BZD Receptor Modulating Mechanism of Panax quinquefolius against 72-h Sleep Deprivation Induced Anxiety like Behavior: Possible Roles of Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation

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Chanana, Priyanka; Kumar, Anil

2016-01-01

Rationale: Panax quinquefolius (American Ginseng) is known for its therapeutic potential against various neurological disorders, but its plausible mechanism of action still remains undeciphered. GABA (Gamma Amino Butyric Acid) plays an important role in sleep wake cycle homeostasis. Thus, there exists rationale in exploring the GABA-ergic potential of Panax quinquefolius as neuroprotective strategy in sleep deprivation induced secondary neurological problems. Objective: The present study was designed to explore the possible GABA-ergic mechanism in the neuro-protective effect of Panax quinquefolius against 72-h sleep deprivation induced anxiety like behavior, oxidative stress, mitochondrial dysfunction, HPA-axis activation and neuroinflammation. Materials and Methods: Male laca mice were sleep deprived for 72-h by using Grid suspended over water method. Panax quinquefolius (American Ginseng 50, 100, and 200 mg/kg) was administered alone and in combination with GABA modulators (GABA Cl− channel inhibitor, GABA-benzodiazepine receptor inhibitor and GABAA agonist) for 8 days, starting 5 days prior to 72-h sleep deprivation period. Various behavioral (locomotor activity, mirror chamber test), biochemical (lipid peroxidation, reduced glutathione, catalase, nitrite levels), mitochondrial complexes, neuroinflammation marker (Tumor Necrosis Factor, TNF-alpha), serum corticosterone, and histopathological sections of brains were assessed. Results: Seventy two hours sleep deprivation significantly impaired locomotor activity, caused anxiety-like behavior, conditions of oxidative stress, alterations in mitochondrial enzyme complex activities, raised serum corticosterone levels, brain TNFα levels and led to neuroinflammation like signs in discrete brain areas as compared to naive group. Panax quinquefolius (100 and 200 mg/kg) treatment restored the behavioral, biochemical, mitochondrial, molecular and histopathological alterations. Pre-treatment of GABA Cl− channel

The protective effect of 20(S)-protopanaxadiol (PPD) against chronic sleep deprivation (CSD)-induced memory impairments in mice.

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Lu, Cong; Lv, Jingwei; Dong, Liming; Jiang, Ning; Wang, Yan; Fan, Bei; Wang, Fengzhong; Liu, Xinmin

2018-03-01

Sleep deprivation (SD) is associated with oxidative stress that causes learning and memory impairment. 20(S)-Protopanaxadiol (PPD), one of the protopanaxadiol-type saponins, has antioxidant and neuroprotective effect. This study was designed to research the protective effect of PPD against cognitive deficits induced by chronic sleep deprivation (CSD) in mice. The CSD model was induced by subjecting the mice to our self-made Sleep Interruption Apparatus (SIA) continuously for 14 days. The memory enhancing effects of PPD were evaluated by behavioral tests and the related mechanism was further explored by observing the oxidative stress changes in the cortex and hippocampus of mice. The results revealed that PPD (20 and 40 μmol/kg, i.p.) administration significantly improved the cognitive performance of CSD model mice in object location recognition experiment, novel object recognition task and Morris water maze test. Furthermore, PPD effectively restored the levels/activities of antioxidant defense biomarkers in the cortex and hippocampus, including the superoxide dismutase (SOD) enzyme activity, catalase (CAT) enzyme activity, glutathione (GSH), and lipid peroxidation (LPO). In conclusion, PPD could attenuate cognitive deficits induced by CSD, and the neuroprotective effect of PPD might be mediated by alleviation of oxidative stress. It was assumed that PPD has the potential to be a neuroprotective substance for cognition dysfunction. Copyright © 2018 Elsevier Inc. All rights reserved.

Targeting of the Glutathione, Thioredoxin, and Nrf2 Antioxidant Systems in Head and Neck Cancer.

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Roh, Jong-Lyel; Jang, Hyejin; Kim, Eun Hye; Shin, Daiha

2017-07-10

The glutathione (GSH), thioredoxin (Trx), and Nrf2 systems represent a major defense against reactive oxygen species (ROS), the cellular imbalance of which in cancer promotes growth and therapeutic resistance. This study investigated whether targeting the GSH, Trx, and Nrf2 antioxidant systems effectively eliminated head and neck cancer (HNC). At high concentrations, auranofin, but not buthionine sulfoximine (BSO) alone, decreased the viability of HNC, whereas even at low concentrations, auranofin plus BSO synergized to kill HNC cells. Dual silencing of the genes for GCLM and TrxR1 induced GSH depletion, Trx activity inhibition, and ROS accumulation, synergistically killing HNC cells. Inhibition of the GSH and Trx systems resulted in activation of the Nrf2-antioxidant response element (ARE) pathway, which may result in suboptimal GSH and Trx inhibition where HNC is resistant. Genetic inhibition of Nrf2 and/or HO-1 or trigonelline enhanced growth suppression, ROS accumulation, and cell death from GSH and Trx inhibition. The in vivo effects of GSH, Trx, and Nrf2 system inhibition were confirmed in a mouse HNC xenograft model by achieving growth inhibition >60% compared with those of control. Innovations: This study is the first to show that triple inhibition of GSH, Trx, and Nrf2 pathways could be an effective method to overcome the resistance of HNC. Inhibition of the Nrf2-ARE pathway in addition to dual inhibition of the GSH and Trx antioxidant systems can effectively eliminate resistant HNC. Antioxid. Redox Signal. 27, 106-114.

Effect of double pinning mechanism in BSO-added GdBa2Cu3O7-x thin films

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Oh, J. Y.; Jeon, H. K.; Kang, B. [Dept. of Physics, Chungbuk National University, Cheongju (Korea, Republic of); Lee, J. M.; Kang, W. N. [Dept. of Physics, Sungkyunkwan University, Suwon (Korea, Republic of)

2017-09-15

We investigated the effect of self-assembled BSO nano-defects as pinning centers in BSO-added GdBCO films when the thicknesses of films were varied. 3.5 vol. % BSO-added GdBCO films with varying thicknesses from 200 nm to 1000 nm were deposited on SrTiO3 (STO) substrate by using pulsed laser deposition (PLD) process. For the films with thicknesses of 400 nm and 600 nm, ‘anomaly shoulders’ in Jc - H characteristic curves were observed near the matching field. The anomaly shoulders appeared in the field dependence of Jc may be attributed to the existence of double pinning mechanisms in thin films. The fit to the pinning force density as a function of reduced field h (H/Hirr) using the Dew-Hughes’ scaling law shows that both the 400 nm- and the 600 nm-thick films have double pinning mechanisms while the other films have a single pinning mechanism. These results indicate that the self-assembled property of BSO result in different role as pinning centers with different thickness.

Flurbiprofen in rapid eye movement sleep deprivation induced hyperalgesia.

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Gürel, Elif Ezgi; Ural, Keremcan; Öztürk, Gülnur; Öztürk, Levent

2014-04-10

Rapid eye movement (REM) sleep deprivation induces hyperalgesia in healthy rats. Here, we evaluated the effects of flurbiprofen, an anti-inflammatory and neuroprotective agent, on the increased thermal responses observed in REM sleep deprived rats. Forty female rats were divided into four groups following 96-hour REM sleep deprivation: intraperitoneal injections of placebo, and flurbiprofen 5 mg/kg, 15 mg/kg and 40 mg/kg were made in CONT (n=10), FBP5, FBP15 and FBP40 groups respectively. Pain threshold measurements were performed three times at baseline (0.hour), at the end of REM sleep deprivation (96.hour) and at 1 h after injections (97.hour) by hot plate and tail-flick tests. REM sleep deprivation induced a significant decrease in pain thresholds of all rats (hotplate: 0.hour vs 96.hour, 9.75±2.85 vs 5.10±2.02, pFlurbiprofen in 15 mg/kg and 40 mg/kg doses significantly improved pain tolerance measured by tail flick test (tail flick in FBP15 and FBP40 groups: 96.hour vs 97.hour, 7.01±4.97 vs 8.34±3.61 and 5.06±1.57 vs 7.04±2.49, pFlurbiprofen was used for the first time in a rat model of REM sleep deprivation, and it provided anti-nociceptive effects in 15 mg/kg and 40 mg/kg doses. Flurbiprofen may have the potential for treatment of painful syndromes accompanying insomnia or sleep loss. Copyright © 2014 Elsevier Inc. All rights reserved.

Correlation between endogenous glutathione content and sensitivity of cultured human skin cells to radiation at defined wavelengths in the solar ultraviolet range

International Nuclear Information System (INIS)

Tyrrell, R.M.; Pidoux, M.

1988-01-01

Glutathione depletion of cultured human skin fibroblasts by treatment with buthionine-S.R.-sulfoximine (BSO) sensitises them to solar UV radiation. We now show that there is a close quantitative correlation between cellular glutathione content and sensitivity to radiation at 365 nm. A weaker correlation is observed when cells are depleted of glutathione using diethylmaleimide. Both fibroblasts and epidermal keratinocytes derived from the same foreskin biopsy are sensitised to radiation at 313 nm by glutathione depletion. At low to intermediate fluence levels, 10 mM cysteamine present during irradiation at 302 nm is able to almost completely reverse the sensitising effects of glutathione depletion suggesting that the endogenous thiol protects against radiation at this wavelength by a free radical scavenging mechanism. At 313 nm, the sensitisation is not reversed by cysteamine suggesting that glutathione plays a more specific role in protection against radiation at longer wavelengths. Xeroderma pigmentosum group A fibroblasts (excision deficient) are also sensitised to radiation at 313 and 365 nm by depletion of glutathione. The results provide further evidence that endogenous glutathione is involved in protecting human skin cells against a wide range of solar radiation damage. (author)

Lithium prevents REM sleep deprivation-induced impairments on memory consolidation.

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Ota, Simone M; Moreira, Karin Di Monteiro; Suchecki, Deborah; Oliveira, Maria Gabriela M; Tiba, Paula A

2013-11-01

Pre-training rapid eye movement sleep (REMS) deprivation affects memory acquisition and/or consolidation. It also produces major REMS rebound at the cost of waking and slow wave sleep (SWS). Given that both SWS and REMS appear to be important for memory processes, REMS rebound after training may disrupt the organization of sleep cycles, i.e., excessive amount of REMS and/or little SWS after training could be harmful for memory formation. To examine whether lithium, a drug known to increase SWS and reduce REMS, could prevent the memory impairment induced by pre-training sleep deprivation. Animals were divided in 2 groups: cage control (CC) and REMS-deprived (REMSDep), and then subdivided into 4 subgroups, treated either with vehicle or 1 of 3 doses of lithium (50, 100, and 150 mg/kg) 2 h before training on the multiple trial inhibitory avoidance task. Animals were tested 48 h later to make sure that the drug had been already metabolized and eliminated. Another set of animals was implanted with electrodes and submitted to the same experimental protocol for assessment of drug-induced sleep-wake changes. Wistar male rats weighing 300-400 g. Sleep deprived rats required more trials to learn the task and still showed a performance deficit during test, except from those treated with 150 mg/kg of lithium, which also reduced the time spent in REM sleep during sleep recovery. Lithium reduced rapid eye movement sleep and prevented memory impairment induced by sleep deprivation. These results indicate that these phenomena may be related, but cause-effect relationship cannot be ascertained.

Activation of Nrf2 is required for up-regulation of the π class of glutathione S-transferase in rat primary hepatocytes with L-methionine starvation.

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Lin, Ai-Hsuan; Chen, Haw-Wen; Liu, Cheng-Tze; Tsai, Chia-Wen; Lii, Chong-Kuei

2012-07-04

Numerous genes expression is regulated in response to amino acid shortage, which helps organisms adapt to amino acid limitation. The expression of the π class of glutathione (GSH) S-transferase (GSTP), a highly inducible phase II detoxification enzyme, is regulated mainly by activates activating protein 1 (AP-1) binding to the enhancer I of GSTP (GPEI). Here we show the critical role of nuclear factor erythroid-2-related factor 2 (Nrf2) in up-regulating GSTP gene transcription. Primary rat hepatocytes were cultured in a methionine-restricted medium, and immunoblotting and RT-PCR analyses showed that methionine restriction time-dependently increased GSTP protein and mRNA expression over a 48 h period. Nrf2 translocation to the nucleus, nuclear proteins binding to GPEI, and antioxidant response element (ARE) luciferase reporter activity were increased by methionine restriction as well as by l-buthionine sulfoximine (BSO), a GSH synthesis inhibitor. Transfection with Nrf2 siRNA knocked down Nrf2 expression and reversed the methionine-induced GSTP expression and GPEI binding activity. Chromatin immunoprecipitation assay confirmed the binding of Nrf2 to the GPEI. Phosphorylation of extracellular signal-regulated kinase 2 (ERK2) was increased in methionine-restricted and BSO-treated cells. ERK2 siRNA abolished methionine restriction-induced Nrf2 nuclear translocation, GPEI binding activity, ARE-luciferase reporter activity, and GSTP expression. Our results suggest that the up-regulation of GSTP gene transcription in response to methionine restriction likely occurs via the ERK-Nrf2-GPEI signaling pathway.

The influence of oxygen on the induction of radiation damage in DNA in mammalian cells after sensitization by intracellular glutathione depletion

International Nuclear Information System (INIS)

Schans, G.P. van der; Vos, O.; Roos-Verheij, W.S.D.; Lohman, P.H.M.

1986-05-01

Treatment of mammalian cells with buthionine sulphoximine (BSO) or diethyl maleate (DEM) results in a decrease in the intracellular GSH (glutathione) and NPSH (non-protein-bound SH) levels. The effect of depletion of GSH and NPSH on radiosensitivity was studied in relation to the concentration of oxygen during irradiation. Single- and double-strand DNA breaks (ssb and dsb) and cell killing were used as criteria for radiation damage. Under aerobic conditions, BSO and DEM treatment gave a small sensitization of 10-20% for the 3 types of radiation damage. Also under severely hypoxic conditions (0.01 μM oxygen in the medium) the sensitizing effect of both compounds on the induction of ssb and dsb and on cell killing was small (0-30%). At somewhat higher concentrations of oxygen (0.5-10 μM) however, the sensitization amounted to about 90% for the induction of ssb and dsb and about 50% for cell killing. These results strengthen the widely accepted idea that intracellular SH-compounds compete with oxygen and other electron-affinic radiosensitizers with respect to reaction with radiation-induced damage, thus preventing the fixation of DNA damages by oxygen. These results imply that the extent to which SH-compounds affect the radiosensitivity of cells in vivo depends strongly on the local concentration of oxygen. (Auth.)

Acute food deprivation reverses morphine-induced locomotion deficits in M5 muscarinic receptor knockout mice.

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Steidl, Stephan; Lee, Esther; Wasserman, David; Yeomans, John S

2013-09-01

Lesions of the pedunculopontine tegmental nucleus (PPT), one of two sources of cholinergic input to the ventral tegmental area (VTA), block conditioned place preference (CPP) for morphine in drug-naïve rats. M5 muscarinic cholinergic receptors, expressed by midbrain dopamine neurons, are critical for the ability of morphine to increase nucleus accumbens dopamine levels and locomotion, and for morphine CPP. This suggests that M5-mediated PPT cholinergic inputs to VTA dopamine neurons critically contribute to morphine-induced dopamine activation, reward and locomotion. In the current study we tested whether food deprivation, which reduces PPT contribution to morphine CPP in rats, could also reduce M5 contributions to morphine-induced locomotion in mice. Acute 18-h food deprivation reversed the phenotypic differences usually seen between non-deprived wild-type and M5 knockout mice. That is, food deprivation increased morphine-induced locomotion in M5 knockout mice but reduced morphine-induced locomotion in wild-type mice. Food deprivation increased saline-induced locomotion equally in wild-type and M5 knockout mice. Based on these findings, we suggest that food deprivation reduces the contribution of M5-mediated PPT cholinergic inputs to the VTA in morphine-induced locomotion and increases the contribution of a PPT-independent pathway. The contributions of cholinergic, dopaminergic and GABAergic neurons to the effects of acute food deprivation are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Nutrient Deprivation Induces Property Variations in Spider Gluey Silk

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Blamires, Sean J.; Sahni, Vasav; Dhinojwala, Ali; Blackledge, Todd A.; Tso, I-Min

2014-01-01

Understanding the mechanisms facilitating property variability in biological adhesives may promote biomimetic innovations. Spider gluey silks such as the spiral threads in orb webs and the gumfoot threads in cobwebs, both of which comprise of an axial thread coated by glue, are biological adhesives that have variable physical and chemical properties. Studies show that the physical and chemical properties of orb web gluey threads change when spiders are deprived of food. It is, however, unknown whether gumfoot threads undergo similar property variations when under nutritional stress. Here we tested whether protein deprivation induces similar variations in spiral and gumfoot thread morphology and stickiness. We manipulated protein intake for the orb web spider Nephila clavipes and the cobweb spider Latrodectus hesperus and measured the diameter, glue droplet volume, number of droplets per mm, axial thread width, thread stickiness and adhesive energy of their gluey silks. We found that the gluey silks of both species were stickier when the spiders were deprived of protein than when the spiders were fed protein. In N. clavipes a concomitant increase in glue droplet volume was found. Load-extension curves showed that protein deprivation induced glue property variations independent of the axial thread extensions in both species. We predicted that changes in salt composition of the glues were primarily responsible for the changes in stickiness of the silks, although changes in axial thread properties might also contribute. We, additionally, showed that N. clavipes' glue changes color under protein deprivation, probably as a consequence of changes to its biochemical composition. PMID:24523902

Radiosensitivity of a monoclonal human lung adenocarcinoma cell line with MDR phenotype induced by CDDP: an in vitro study

International Nuclear Information System (INIS)

Zhang Junxiang; Kong Zhaolu; Shen Zhifen; Tong Shungao; Jin Yizun

2006-01-01

The study was to evaluate radiosensitivity of a monoclonal human lung adenocarcinoma cell line SPC-A-1/CDDP-4 with MDR phenotype induced by cisplatin (CDDP) compared with its parental cell SPC-A-1 in vitro. The glutathione (GSH) content and the radiosensitivity of SPC-A-1/CDDP-4 and SPC-A-1 cells were investigated in aerobic and under hypoxia, respectively. The radiosensitization effect of buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, to SPC-A-1/CDDP-4 and SPC-A-1 cells was observed. The results indicated that the monoclonal human lung adenocarcinoma cell line SPC-A-1/CDDP-4 showed, to some extent, a cross-resistance to 137 Cs γ-ray, in addition to its resistance to anticancer drugs (CDDP, ADM, MTX and VCR). The GSH content of SPC-A-1/CDDP-4 cells was higher than that of SPC-A-1 cells both in aerobic and under hypoxia which might account for it. BSO had radiosensitization effect to SPC-A-1/CDDP-4 and SPC-A-1 cells both in aerobic and under hypoxia, but it was stronger under hypoxia than in aerobic and it was stronger to SPC-A-1/CDDP-4 cells than to SPC-A-1 cells. (authors)

Cytoprotective effects of Glycyrrhizae radix extract and its active component liquiritigenin against cadmium-induced toxicity (effects on bad translocation and cytochrome c-mediated PARP cleavage)

International Nuclear Information System (INIS)

Kim, Sang Chan; Byun, Sung Hui; Yang, Chae Ha; Kim, Chul Young; Kim, Jin Woong; Kim, Sang Geon

2004-01-01

Glycyrrhizae radix has been popularly used as one of the oldest and most frequently employed botanicals in herbal medicine in Asian countries, and currently occupies an important place in food products. Cadmium (Cd) induces both apoptotic and non-apoptotic cell death, in which alterations in cellular sulfhydryls participate. In the present study, we determined the effects of G. radix extract (GRE) and its representative active components on cell death induced by Cd and explored the mechanistic basis of cytoprotective effects of G. radix. Incubation of H4IIE cells with GRE inhibited cell death induced by 10 μM Cd. Also, GRE effectively blocked Cd (1 μM)-induced cell death potentiated by buthionine sulfoximine (BSO) without restoration of cellular GSH. GRE prevented both apoptotic and non-apoptotic cell injury induced by Cd (10 μM) or Cd (0.3-1 μM) + BSO. Inhibition of Cd-induced cell injury by pretreatment of cells with GRE suggested that the cytoprotective effect result from alterations in the levels of the protein(s) responsible for cell viability. GRE inhibited mitochondrial Bad translocation by Cd or Cd+BSO, and caused restoration of mitochondrial Bcl xL and cytochrome c levels. Cd-induced poly(ADP-ribose)polymerase cleavage in control cells or in cells deprived of sulfhydryls was prevented by GRE treatment. Among the major components present in GRE, liquiritigenin, but not liquiritin, isoliquiritigenin or glycyrrhizin, exerted cytoprotective effect. These results demonstrated that GRE blocked Cd-induced cell death by inhibiting the apoptotic processes involving translocation of Bad into mitochondria, decreases in mitochondrial Bcl xL and cytochrome c, and poly(ADP-ribose)polymerase cleavage

Role for PKC-ε in neuronal death induced by oxidative stress

International Nuclear Information System (INIS)

Jung, Yi-Sook; Ryu, Bo Rum; Lee, Bo Kyung; Mook-Jung, Inhee; Kim, Seung Up; Lee, Soo Hwan; Baik, Eun Joo; Moon, Chang-Hyun

2004-01-01

We investigated which isoforms of PKCs can be modulated and what their roles are during L-buthionine-S,R-sulfoximine (BSO)-induced neuronal death. We observed the isoform specific translocation of PKC-ε from the soluble fraction to the particulate in cortical neurons treated with 10 mM BSO. The translocation of PKC-ε by BSO was blocked by antioxidant trolox, suggesting the PKC-ε as a downstream of reactive oxygen species (ROS) elevated by BSO. Trolox inhibited the ROS elevation and the neuronal death in BSO-treated cortical cells. The BSO-induced neuronal death was remarkably inhibited by both the pharmacological inhibition of PKC-ε with εV1-2 and the functional blockade for PKC-ε through overexpression of PKC-ε V1 region, suggesting the detrimental role of PKC-ε. These results suggest that PKC-ε is the major PKC isoform involved in the pathways triggered by ROS, leading to neuronal death in BSO-treated cortical neurons

MG132, a proteasome inhibitor, induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion.

Science.gov (United States)

Park, Woo Hyun; Kim, Suhn Hee

2012-04-01

MG132 as a proteasome inhibitor can induce apoptotic cell death in lung cancer cells. However, little is known about the toxicological cellular effects of MG132 on normal primary lung cells. Here, we investigated the effects of N-acetyl cysteine (NAC) and vitamin C (well known antioxidants) or L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) on MG132-treated human pulmonary fibroblast (HPF) cells in relation to cell death, reactive oxygen species (ROS) and glutathione (GSH). MG132 induced growth inhibition and death in HPF cells, accompanied by the loss of mitochondrial membrane potential (MMP; ∆ψm). MG132 increased ROS levels and GSH-depleted cell numbers in HPF cells. Both antioxidants, NAC and vitamin C, prevented growth inhibition, death and MMP (∆ψm) loss in MG132-treated HPF cells and also attenuated ROS levels in these cells. BSO showed a strong increase in ROS levels in MG132-treated HPF cells and slightly enhanced the growth inhibition, cell death, MMP (∆ψm) loss and GSH depletion. In addition, NAC decreased anonymous ubiquitinated protein levels in MG132-treated HPF cells. Furthermore, superoxide dismutase (SOD) 2, catalase (CTX) and GSH peroxidase (GPX) siRNAs enhanced HPF cell death by MG132, which was not correlated with ROS and GSH level changes. In conclusion, MG132 induced the growth inhibition and death of HPF cells, which were accompanied by increasing ROS levels and GSH depletion. Both NAC and vitamin C attenuated HPF cell death by MG132, whereas BSO slightly enhanced the death.

Effects of mental resilience on neuroendocrine hormones level changes induced by sleep deprivation in servicemen.

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Sun, Xinyang; Dai, Xuyan; Yang, Tingshu; Song, Hongtao; Yang, Jialin; Bai, Jing; Zhang, Liyi

2014-12-01

The aim of this study was to investigate the effects of mental resilience on the changes of serum rennin, angiotensin, and cortisol level induced by sleep deprivation in servicemen. By random cluster sampling, a total of 160 servicemen, aged from 18 to 30, were selected to undergo 24-hour total sleep deprivation and administered the military personnel mental resilience scale after the deprivation procedure. The sleep deprivation procedure started at 8 a.m. on Day 8 and ended at 8 a.m. on Day 9 after 7 days of normal sleep for baseline preparation. Blood samples were drawn from the 160 participants at 8 a.m. respectively on Day 8 and Day 9 for hormonal measurements. All blood samples were analyzed using radioimmunoassay. As hypothesized, serum rennin, angiotensin II, and cortisol level of the participants after sleep deprivation were significantly higher than those before (P problem-solving skill and willpower were the leading influence factors for the increases of serum rennin and cortisol respectively induced by sleep deprivation. We conclude that mental resilience plays a significant role in alleviating the changes of neurohormones level induced by sleep deprivation in servicemen.

GABA-BZD Receptor Modulating Mechanism of Panax quinquefolius against 72-hours Sleep Deprivation Induced Anxiety like Behavior: Possible Roles of Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation

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Priyanka eChanana

2016-03-01

Full Text Available ABSTRACTRationale- Panax quinquefolius (American Ginseng is known for its therapeutic potential against various neurological disorders, but its plausible mechanism of action still remains undeciphered. GABA (Gamma Amino Butyric Acid plays an important role in sleep wake cycle homeostasis. Thus there exists rationale in exploring the GABA-ergic potential of Panax quinquefolius as neuroprotective strategy in sleep deprivation induced secondary neurological problems.Objective- The present study was designed to explore the possible GABA-ergic mechanism in the neuro-protective effect of Panax quinquefolius against 72-hours sleep deprivation induced anxiety like behaviour, oxidative stress, mitochondrial dysfunction, HPA-axis activation and neuroinflammation.Materials and Methods- Male laca mice were sleep deprived for 72-hours by using Grid suspended over water method. Panax quinquefolius (American Ginseng 50, 100 and 200 mg/kg was administered alone and in combination with GABA modulators (GABA Cl- channel inhibitor, GABA-benzodiazepine receptor inhibitor and GABAA agonist for 8 days, starting five days prior to 72-hours sleep deprivation period. Various behavioural (locomotor activity, mirror chamber test, biochemical (lipid peroxidation, reduced glutathione, catalase, nitrite levels, mitochondrial complexes, neuroinflammation marker (Tumour Necrosis Factor, TNF-alpha, serum corticosterone, and histopathological sections of brains were assessed. Results- 72-hours sleep deprivation significantly impaired locomotor activity, caused anxiety-like behaviour, conditions of oxidative stress, alterations in mitochondrial enzyme complex activities, raised serum corticosterone levels, brain TNFα levels and led to neuroinflammation like signs in discrete brain areas as compared to naive group. Panax quinquefolius (100 and 200 mg/kg treatment restored the behavioural, biochemical, mitochondrial, molecular and histopathological alterations. Pre-treatment of

Synergistic apoptosis of CML cells by buthionine sulfoximine and hydroxychavicol correlates with activation of AIF and GSH-ROS-JNK-ERK-iNOS pathway.

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Avik Acharya Chowdhury

Full Text Available BACKGROUND: Hydroxychavicol (HCH, a constituent of Piper betle leaf has been reported to exert anti-leukemic activity through induction of reactive oxygen species (ROS. The aim of the study is to optimize the oxidative stress -induced chronic myeloid leukemic (CML cell death by combining glutathione synthesis inhibitor, buthionine sulfoximine (BSO with HCH and studying the underlying mechanism. MATERIALS AND METHODS: Anti-proliferative activity of BSO and HCH alone or in combination against a number of leukemic (K562, KCL22, KU812, U937, Molt4, non-leukemic (A549, MIA-PaCa2, PC-3, HepG2 cancer cell lines and normal cell lines (NIH3T3, Vero was measured by MTT assay. Apoptotic activity in CML cell line K562 was detected by flow cytometry (FCM after staining with annexin V-FITC/propidium iodide (PI, detection of reduced mitochondrial membrane potential after staining with JC-1, cleavage of caspase- 3 and poly (ADP-ribose polymerase proteins by western blot analysis and translocation of apoptosis inducing factor (AIF by confocal microscopy. Intracellular reduced glutathione (GSH was measured by colorimetric assay using GSH assay kit. 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA and 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM were used as probes to measure intracellular increase in ROS and nitric oxide (NO levels respectively. Multiple techniques like siRNA transfection and pharmacological inhibition were used to understand the mechanisms of action. RESULTS: Non-apoptotic concentrations of BSO significantly potentiated HCH-induced apoptosis in K562 cells. BSO potentiated apoptosis-inducing activity of HCH in CML cells by caspase-dependent as well as caspase-independent but apoptosis inducing factor (AIF-dependent manner. Enhanced depletion of intracellular GSH induced by combined treatment correlated with induction of ROS. Activation of ROS- dependent JNK played a crucial role in ERK1/2 activation which subsequently induced the

Effect of water deprivation on baseline and stress-induced corticosterone levels in the Children's python (Antaresia childreni).

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Dupoué, Andréaz; Angelier, Frédéric; Lourdais, Olivier; Bonnet, Xavier; Brischoux, François

2014-02-01

Corticosterone (CORT) secretion is influenced by endogenous factors (e.g., physiological status) and environmental stressors (e.g., ambient temperature). Heretofore, the impact of water deprivation on CORT plasma levels has not been thoroughly investigated. However, both baseline CORT and stress-induced CORT are expected to respond to water deprivation not only because of hydric stress per se, but also because CORT is an important mineralocorticoid in vertebrates. We assessed the effects of water deprivation on baseline CORT and stress-induced CORT, in Children's pythons (Antaresia childreni), a species that experiences seasonal droughts in natural conditions. We imposed a 52-day water deprivation on a group of unfed Children's pythons (i.e., water-deprived treatment) and provided water ad libitum to another group (i.e., control treatment). We examined body mass variations throughout the experiment, and baseline CORT and stress-induced CORT at the end of the treatments. Relative body mass loss averaged ~10% in pythons without water, a value 2 to 4 times higher compared to control snakes. Following re-exposition to water, pythons from the water-deprived treatment drank readily and abundantly and attained a body mass similar to pythons from the control treatment. Together, these results suggest a substantial dehydration as a consequence of water deprivation. Interestingly, stress-induced but not baseline CORT level was significantly higher in water-deprived snakes, suggesting that baseline CORT might not respond to this degree of dehydration. Therefore, possible mineralocorticoid role of CORT needs to be clarified in snakes. Because dehydration usually induces adjustments (reduced movements, lowered body temperature) to limit water loss, and decreases locomotor performances, elevated stress-induced CORT in water-deprived snakes might therefore compensate for altered locomotor performances. Future studies should test this hypothesis. Copyright © 2013 Elsevier Inc

Vitamin C Prevents Sleep Deprivation-induced Elevation in Cortisol ...

African Journals Online (AJOL)

olayemitoyin

person can be aroused by sensory or other stimuli. (Hall, 2015), is an ... 2007). This can be acute (a single period of extended ... short-term (acute) Sleep Deprivation, such studies for .... induced memory impairment: the role of oxidative stress.

Signaling molecule methylglyoxal ameliorates cadmium injury in wheat (Triticum aestivum L) by a coordinated induction of glutathione pool and glyoxalase system.

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Li, Zhong-Guang; Nie, Qian; Yang, Cong-Li; Wang, Yue; Zhou, Zhi-Hao

2018-03-01

Methylglyoxal (MG) now is found to be an emerging signaling molecule. It can relieve the toxicity of cadmium (Cd), however its alleviating mechanism still remains unknown. In this study, compared with the Cd-stressed seedlings without MG treatment, MG treatment could stimulate the activities of glutathione reductase (GR) and gamma-glutamylcysteine synthetase (γ-ECS) in Cd-stressed wheat seedlings, which in turn induced an increase of reduced glutathione (GSH). Adversely, the activated enzymes related to GSH biosynthesis and increased GSH were weakened by N-acetyl-L-cysteine (NAC, MG scavenger), 2,4-dihydroxy-benzylamine (DHBA) and 1,3-bischloroethyl-nitrosourea (BCNU, both are specific inhibitors of GR), buthionine sulfoximine (BSO, a specific inhibitors of GSH biosynthesis), and N-ethylmaleimide (NEM, GSH scavenger), respectively. In addition, MG increased the activities of glyoxalase I (Gly I) and glyoxalase II (Gly II) in Cd-treated seedlings, followed by declining an increase in endogenous MG as comparision to Cd-stressed seedlings alone. On the contrary, the increased glyoxalase activity and decreased endogenous MG level were reversed by NAC and specific inhibitors of Gly I (isoascorbate, IAS; squaric acid, SA). Furthermore, MG alleviated an increase in hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) in Cd-treated wheat seedlings. These results indicated that MG could alleviate Cd toxicity and improve the growth of Cd-stressed wheat seedlings by a coordinated induction of glutathione pool and glyoxalase system. Copyright © 2017 Elsevier Inc. All rights reserved.

Behavioral and genetic effects promoted by sleep deprivation in rats submitted to pilocarpine-induced status epilepticus.

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Matos, Gabriela; Ribeiro, Daniel A; Alvarenga, Tathiana A; Hirotsu, Camila; Scorza, Fulvio A; Le Sueur-Maluf, Luciana; Noguti, Juliana; Cavalheiro, Esper A; Tufik, Sergio; Andersen, Monica L

2012-05-02

The interaction between sleep deprivation and epilepsy has been well described in electrophysiological studies, but the mechanisms underlying this association remain unclear. The present study evaluated the effects of sleep deprivation on locomotor activity and genetic damage in the brains of rats treated with saline or pilocarpine-induced status epilepticus (SE). After 50 days of pilocarpine or saline treatment, both groups were assigned randomly to total sleep deprivation (TSD) for 6 h, paradoxical sleep deprivation (PSD) for 24 h, or be kept in their home cages. Locomotor activity was assessed with the open field test followed by resection of brain for quantification of genetic damage by the single cell gel electrophoresis (comet) assay. Status epilepticus induced significant hyperactivity in the open field test and caused genetic damage in the brain. Sleep deprivation procedures (TSD and PSD) did not affect locomotor activity in epileptic or healthy rats, but resulted in significant DNA damage in brain cells. Although PSD had this effect in both vehicle and epileptic groups, TSD caused DNA damage only in epileptic rats. In conclusion, our results revealed that, despite a lack of behavioral effects of sleep deprivation, TSD and PSD induced genetic damage in rats submitted to pilocarpine-induced SE. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Mechanisms of CDDO-imidazolide-mediated cytoprotection against acrolein-induced neurocytotoxicity in SH-SY5Y cells and primary human astrocytes.

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Speen, Adam; Jones, Colton; Patel, Ruby; Shah, Halley; Nallasamy, Palanisamy; Brooke, Elizabeth A S; Zhu, Hong; Li, Y Robert; Jia, Zhenquan

2015-10-01

Acrolein is a ubiquitous unsaturated aldehyde has been implicated in the pathogenesis of various neurological disorders. However, limited study has been conducted into potential therapeutic protection and underlying mechanism against acrolein-induced cytotoxicity via upregulation of cellular aldehyde-detoxification defenses. In this study we have utilized RA-differentiated human SH-SY5Y cells and primary human astrocytes to investigate the induction of glutathione (GSH) by the synthetic triterpenoid 2-cyano-3,12-dixooleana-1,9-dien-28-imidazolide (CDDO-Im) and the protective effects CDDO-Im-mediated antioxidant defenses on acrolein toxicity. Acrolein exposure to RA-differentiated SH-SY5Y cells resulted in a significant time dependent depletion of cellular GSH preceding a reduction in cell viability and LDH release. Further, we demonstrated the predominance of cellular GSH in protection against acrolein-induced cytotoxicity. Buthionine sulfoximine (BSO) at 25μM dramatically depleted GSH and significantly potentiated acrolein-induced cytotoxicity. Pretreatment of the cells with 100nM CDDO-Im afforded a dramatic protection against acrolein-induced cytotoxicity. Pretreatment of BSO and CDDO was found to prevent the CDDO-Im-mediated GSH induction and partially reversed the cytoprotective effects of CDDO-Im against acrolein cytotoxicity. Overall, this study represents for the first time the CDDO-Im mediated upregulation of GSH is a predominant mechanism against acrolein-induced neurotoxicity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Glutathione role in gallium induced toxicity

African Journals Online (AJOL)

Asim

2012-01-26

GSH) present in tissues. It is very important and interesting to study the reaction of gallium nitrate and glutathione as biomarker of glutathione role in detoxification and conjugation in whole blood components (plasma and ...

Oligo-carrageenan kappa-induced reducing redox status and activation of TRR/TRX system increase the level of indole-3-acetic acid, gibberellin A3 and trans-zeatin in Eucalyptus globulus trees.

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González, Alberto; Contreras, Rodrigo A; Zúiga, Gustavo; Moenne, Alejandra

2014-08-20

Eucalyptus globulus trees treated with oligo-carrageenan (OC) kappa showed an increase in NADPH, ascorbate and glutathione levels and activation of the thioredoxin reductase (TRR)/thioredoxin (TRX) system which enhance photosynthesis, basal metabolism and growth. In order to analyze whether the reducing redox status and the activation of thioredoxin reductase (TRR)/thioredoxin (TRX) increased the level of growth-promoting hormones, trees were treated with water (control), with OC kappa, or with inhibitors of ascorbate synthesis, lycorine, glutathione synthesis, buthionine sulfoximine (BSO), NADPH synthesis, CHS-828, and thioredoxin reductase activity, auranofine, and with OC kappa, and cultivated for four additional months. Eucalyptus trees treated with OC kappa showed an increase in the levels of the auxin indole 3-acetic acid (IAA), gibberellin A3 (GA3) and the cytokinin trans-zeatin (t-Z) as well as a decrease in the level of the brassinosteroid epi-brassinolide (EB). In addition, treatment with lycorine, BSO, CHS-828 and auranofine inhibited the increase in IAA, GA3 and t-Z as well as the decrease in EB levels. Thus, the reducing redox status and the activation of TRR/TRX system induced by OC kappa increased the levels of IAA, GA3 and t-Z levels determining, at least in part, the stimulation of growth in Eucalyptus trees.

A superoxide anion-scavenger, 1,3-selenazolidin-4-one suppresses serum deprivation-induced apoptosis in PC12 cells by activating MAP kinase

International Nuclear Information System (INIS)

Nishina, Atsuyoshi; Kimura, Hirokazu; Kozawa, Kunihisa; Sommen, Geoffroy; Nakamura, Takao; Heimgartner, Heinz; Koketsu, Mamoru; Furukawa, Shoei

2011-01-01

Synthetic organic selenium compounds, such as ebselen, may show glutathione peroxidase-like antioxidant activity and have a neurotrophic effect. We synthesized 1,3-selenazolidin-4-ones, new types of synthetic organic selenium compounds (five-member ring compounds), to study their possible applications as antioxidants or neurotrophic-like molecules. Their superoxide radical scavenging effects were assessed using the quantitative, highly sensitive method of real-time kinetic chemiluminescence. At 166 μM, the O 2 − scavenging activity of 1,3-selenazolidin-4-ones ranged from 0 to 66.2%. 2-[3-(4-Methoxyphenyl)-4-oxo-1,3-selenazolidin-2-ylidene]malononitrile (compound b) showed the strongest superoxide anion-scavenging activity among the 6 kinds of 2-methylene-1,3-selenazolidin-4-ones examined. Compound b had a 50% inhibitory concentration (IC 50 ) at 92.4 μM and acted as an effective and potentially useful O 2 − scavenger in vitro. The effect of compound b on rat pheochromocytome cell line PC12 cells was compared with that of ebselen or nerve growth factor (NGF) by use of the MTT [3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assay. When ebselen was added at 100 μM or more, toxicity toward PC12 cells was evident. On the contrary, compound b suppressed serum deprivation-induced apoptosis in PC12 cells more effectively at a concentration of 100 μM. The activity of compound b to phosphorylate mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) 1/2 (MAP kinase) in PC12 cells was higher than that of ebselen, and the former at 100 μM induced the phosphorylation of MAP kinase to a degree similar to that induced by NGF. From these results, we conclude that this superoxide anion-scavenger, compound b, suppressed serum deprivation-induced apoptosis by promoting the phosphorylation of MAP kinase. -- Highlights: ► We newly synthesized 1,3-selenazolidin-4-ones to study their possible applications. ► Among new

A superoxide anion-scavenger, 1,3-selenazolidin-4-one suppresses serum deprivation-induced apoptosis in PC12 cells by activating MAP kinase

Energy Technology Data Exchange (ETDEWEB)

Nishina, Atsuyoshi, E-mail: nishina@yone.ac.jp [Yonezawa Women' s Junior College, 6-15-1 Tohrimachi, Yonezawa, Yamagata 992-0025 (Japan); Kimura, Hirokazu; Kozawa, Kunihisa [Gunma Prefectural Institute of Public Health and Environmental Sciences, 378 Kamioki, Maebashi, Gunma 371-0052 (Japan); Sommen, Geoffroy [Lonza Braine SA, Chaussee de Tubize 297, B-1420 Braine l' Alleud (Belgium); Nakamura, Takao [Department of Biomedical Information Engineering, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585 (Japan); Heimgartner, Heinz [University of Zuerich, Institut of Organic Chemistry, Winterthurerstrasse 190, CH-8057 Zuerich (Switzerland); Koketsu, Mamoru [Department of Materials Science and Technology, Faculty of Engineering, Gifu University, Gifu 501-1193 (Japan); Furukawa, Shoei [Laboratory of Molecular Biology, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585 (Japan)

2011-12-15

Synthetic organic selenium compounds, such as ebselen, may show glutathione peroxidase-like antioxidant activity and have a neurotrophic effect. We synthesized 1,3-selenazolidin-4-ones, new types of synthetic organic selenium compounds (five-member ring compounds), to study their possible applications as antioxidants or neurotrophic-like molecules. Their superoxide radical scavenging effects were assessed using the quantitative, highly sensitive method of real-time kinetic chemiluminescence. At 166 {mu}M, the O{sub 2}{sup -} scavenging activity of 1,3-selenazolidin-4-ones ranged from 0 to 66.2%. 2-[3-(4-Methoxyphenyl)-4-oxo-1,3-selenazolidin-2-ylidene]malononitrile (compound b) showed the strongest superoxide anion-scavenging activity among the 6 kinds of 2-methylene-1,3-selenazolidin-4-ones examined. Compound b had a 50% inhibitory concentration (IC{sub 50}) at 92.4 {mu}M and acted as an effective and potentially useful O{sub 2}{sup -} scavenger in vitro. The effect of compound b on rat pheochromocytome cell line PC12 cells was compared with that of ebselen or nerve growth factor (NGF) by use of the MTT [3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assay. When ebselen was added at 100 {mu}M or more, toxicity toward PC12 cells was evident. On the contrary, compound b suppressed serum deprivation-induced apoptosis in PC12 cells more effectively at a concentration of 100 {mu}M. The activity of compound b to phosphorylate mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) 1/2 (MAP kinase) in PC12 cells was higher than that of ebselen, and the former at 100 {mu}M induced the phosphorylation of MAP kinase to a degree similar to that induced by NGF. From these results, we conclude that this superoxide anion-scavenger, compound b, suppressed serum deprivation-induced apoptosis by promoting the phosphorylation of MAP kinase. -- Highlights: Black-Right-Pointing-Pointer We newly synthesized 1,3-selenazolidin-4-ones to

Chronic caffeine treatment prevents sleep deprivation-induced impairment of cognitive function and synaptic plasticity.

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Alhaider, Ibrahim A; Aleisa, Abdulaziz M; Tran, Trinh T; Alzoubi, Karem H; Alkadhi, Karim A

2010-04-01

This study was undertaken to provide a detailed account of the effect of chronic treatment with a small dose of caffeine on the deleterious effects of sleep loss on brain function in rats. We investigated the effects of chronic (4 weeks) caffeine treatment (0.3 g/L in drinking water) on memory impairment in acutely (24 h) sleep-deprived adult male Wistar rats. Sleep deprivation was induced using the modified multiple platform model. The effects of caffeine on sleep deprivation-induced hippocampus-dependent learning and memory deficits were studied by 3 approaches: learning and memory performance in the radial arm water maze task, electrophysiological recording of early long-term potentiation (E-LTP) in area CA1 of the hippocampus, and levels of memory- and synaptic plasticity-related signaling molecules after E-LTP induction. The results showed that chronic caffeine treatment prevented impairment of hippocampus-dependent learning, shortterm memory and E-LTP of area CA1 in the sleep-deprived rats. In correlation, chronic caffeine treatment prevented sleep deprivation-associated decrease in the levels of phosphorylated calcium/calmodulin-dependent protein kinase II (P-CaMKII) during expression of E-LTP. The results suggest that long-term use of a low dose of caffeine prevents impairment of short-term memory and E-LTP in acutely sleep-deprived rats.

Human adipose tissue-derived multilineage progenitor cells exposed to oxidative stress induce neurite outgrowth in PC12 cells through p38 MAPK signaling

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Moriyama Mariko

2012-08-01

Full Text Available Abstract Background Adipose tissues contain populations of pluripotent mesenchymal stem cells that also secrete various cytokines and growth factors to support repair of damaged tissues. In this study, we examined the role of oxidative stress on human adipose-derived multilineage progenitor cells (hADMPCs in neurite outgrowth in cells of the rat pheochromocytoma cell line (PC12. Results We found that glutathione depletion in hADMPCs, caused by treatment with buthionine sulfoximine (BSO, resulted in the promotion of neurite outgrowth in PC12 cells through upregulation of bone morphogenetic protein 2 (BMP2 and fibroblast growth factor 2 (FGF2 transcription in, and secretion from, hADMPCs. Addition of N-acetylcysteine, a precursor of the intracellular antioxidant glutathione, suppressed the BSO-mediated upregulation of BMP2 and FGF2. Moreover, BSO treatment caused phosphorylation of p38 MAPK in hADMPCs. Inhibition of p38 MAPK was sufficient to suppress BMP2 and FGF2 expression, while this expression was significantly upregulated by overexpression of a constitutively active form of MKK6, which is an upstream molecule from p38 MAPK. Conclusions Our results clearly suggest that glutathione depletion, followed by accumulation of reactive oxygen species, stimulates the activation of p38 MAPK and subsequent expression of BMP2 and FGF2 in hADMPCs. Thus, transplantation of hADMPCs into neurodegenerative lesions such as stroke and Parkinson’s disease, in which the transplanted hADMPCs are exposed to oxidative stress, can be the basis for simple and safe therapies.

Prolonged fasting increases glutathione biosynthesis in postweaned northern elephant seals

Science.gov (United States)

Vázquez-Medina, José Pablo; Zenteno-Savín, Tania; Forman, Henry Jay; Crocker, Daniel E.; Ortiz, Rudy M.

2011-01-01

SUMMARY Northern elephant seals experience prolonged periods of absolute food and water deprivation (fasting) while breeding, molting or weaning. The postweaning fast in elephant seals is characterized by increases in the renin–angiotensin system, expression of the oxidant-producing protein Nox4, and NADPH oxidase activity; however, these increases are not correlated with increased oxidative damage or inflammation. Glutathione (GSH) is a potent reductant and a cofactor for glutathione peroxidases (GPx), glutathione-S transferases (GST) and 1-cys peroxiredoxin (PrxVI) and thus contributes to the removal of hydroperoxides, preventing oxidative damage. The effects of prolonged food deprivation on the GSH system are not well described in mammals. To test our hypothesis that GSH biosynthesis increases with fasting in postweaned elephant seals, we measured circulating and muscle GSH content at the early and late phases of the postweaning fast in elephant seals along with the activity/protein content of glutamate-cysteine ligase [GCL; catalytic (GCLc) and modulatory (GCLm) subunits], γ-glutamyl transpeptidase (GGT), glutathione disulphide reductase (GR), glucose-6-phosphate dehydrogenase (G6PDH), GST and PrxVI, as well as plasma changes in γ-glutamyl amino acids, glutamate and glutamine. GSH increased two- to four-fold with fasting along with a 40–50% increase in the content of GCLm and GCLc, a 75% increase in GGT activity, a two- to 2.5-fold increase in GR, G6PDH and GST activities and a 30% increase in PrxVI content. Plasma γ-glutamyl glutamine, γ-glutamyl isoleucine and γ-glutamyl methionine also increased with fasting whereas glutamate and glutamine decreased. Results indicate that GSH biosynthesis increases with fasting and that GSH contributes to counteracting hydroperoxide production, preventing oxidative damage in fasting seals. PMID:21430206

Sleep deprivation aggravates median nerve injury-induced neuropathic pain and enhances microglial activation by suppressing melatonin secretion.

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Huang, Chun-Ta; Chiang, Rayleigh Ping-Ying; Chen, Chih-Li; Tsai, Yi-Ju

2014-09-01

Sleep deprivation is common in patients with neuropathic pain, but the effect of sleep deprivation on pathological pain remains uncertain. This study investigated whether sleep deprivation aggravates neuropathic symptoms and enhances microglial activation in the cuneate nucleus (CN) in a median nerve chronic constriction injury (CCI) model. Also, we assessed if melatonin supplements during the sleep deprived period attenuates these effects. Rats were subjected to sleep deprivation for 3 days by the disc-on-water method either before or after CCI. In the melatonin treatment group, CCI rats received melatonin supplements at doses of 37.5, 75, 150, or 300 mg/kg during sleep deprivation. Melatonin was administered at 23:00 once a day. Male Sprague-Dawley rats, weighing 180-250 g (n = 190), were used. Seven days after CCI, behavioral testing was conducted, and immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay were used for qualitative and quantitative analyses of microglial activation and measurements of proinflammatory cytokines. In rats who underwent post-CCI sleep deprivation, microglia were more profoundly activated and neuropathic pain was worse than those receiving pre-CCI sleep deprivation. During the sleep deprived period, serum melatonin levels were low over the 24-h period. Administration of melatonin to CCI rats with sleep deprivation significantly attenuated activation of microglia and development of neuropathic pain, and markedly decreased concentrations of proinflammatory cytokines. Sleep deprivation makes rats more vulnerable to nerve injury-induced neuropathic pain, probably because of associated lower melatonin levels. Melatonin supplements to restore a circadian variation in melatonin concentrations during the sleep deprived period could alleviate nerve injury-induced behavioral hypersensitivity. © 2014 Associated Professional Sleep Societies, LLC.

The role of glutathione in lymphocyte activation and proliferation

International Nuclear Information System (INIS)

Messina, J.P.

1990-01-01

The object of this work was to establish the requirement for GSH and cystine during the activation and proliferation of human peripheral blood mononuclear cells (PBMC). In the author's initial experiments the intracellular GSH content of PBMC was altered by continuous culture or pretreatment with BSO, a specific inhibitor of GSH synthesis. His results demonstrate that, continuous culture of mitogen stimulated PBMC in the presence of BSO inhibited entry into S-phase of the cell cycle and produced a simultaneous decrease in intracellular GSH. The influence of BSO on early activation events were determined by BSO pretreatment. Extensive depletion (>90%) of the intracellular GSH level prior to mitogenic stimulation did not impair the ability of these cells to produce IL-2 and express IL-2R, indicating that GSH may not be involved in the generation and response to early activation signals. Furthermore, the removal of BSO from these cultures rapidly reversed its inhibitory effects on DNA and GSH synthesis. Cystine transport activities and metabolism by PBMC were characterized in order to examine its contributions to intracellular GSH and early activation proteins. In spite of the ability of cystine to sustain the proliferative response of PBMC, differences in the kinetics of cystine and cysteine uptake indicated that separate transport systems may be operational. Treatment with 2ME enhanced cystine uptake, but lowered the proliferative responses of these cells. Metabolic studies with [ 35 S] cystine demonstrated that mitogen stimulation of PBMC enhance cystine uptake

Anti-ghrelin Spiegelmer inhibits exogenous ghrelin-induced increases in food intake, hoarding, and neural activation, but not food deprivation-induced increases

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Teubner, Brett J. W.

2013-01-01

Circulating concentrations of the stomach-derived “hunger-peptide” ghrelin increase in direct proportion to the time since the last meal. Exogenous ghrelin also increases food intake in rodents and humans, suggesting ghrelin may increase post-fast ingestive behaviors. Food intake after food deprivation is increased by laboratory rats and mice, but not by humans (despite dogma to the contrary) or by Siberian hamsters; instead, humans and Siberian hamsters increase food hoarding, suggesting the latter as a model of fasting-induced changes in human ingestive behavior. Exogenous ghrelin markedly increases food hoarding by ad libitum-fed Siberian hamsters similarly to that after food deprivation, indicating sufficiency. Here, we tested the necessity of ghrelin to increase food foraging, food hoarding, and food intake, and neural activation [c-Fos immunoreactivity (c-Fos-ir)] using anti-ghrelin Spiegelmer NOX-B11–2 (SPM), an l-oligonucleotide that specifically binds active ghrelin, inhibiting peptide-receptor interaction. SPM blocked exogenous ghrelin-induced increases in food hoarding the first 2 days after injection, and foraging and food intake at 1–2 h and 2–4 h, respectively, and inhibited hypothalamic c-Fos-ir. SPM given every 24 h across 48-h food deprivation inconsistently inhibited food hoarding after refeeding and c-Fos-ir, similarly to inabilities to do so in laboratory rats and mice. These results suggest that ghrelin may not be necessary for food deprivation-induced foraging and hoarding and neural activation. A possible compensatory response, however, may underlie these findings because SPM treatment led to marked increases in circulating ghrelin concentrations. Collectively, these results show that SPM can block exogenous ghrelin-induced ingestive behaviors, but the necessity of ghrelin for food deprivation-induced ingestive behaviors remains unclear. PMID:23804279

The study of ictal brain SPECT during seizures induced by clonidine and sleep-deprivation in patients with epilepsy

International Nuclear Information System (INIS)

Wang Xiaohui; Chen Xuehong; Wang Zhengjiang; Liu Jiangyan; Feng Jianzhong; Ye Jiang; Zhao Li

2010-01-01

Objective: To evaluate the feasibility and clinical value of combined clonidine and sleep-deprivation induced seizures for ictal brain SPECT imaging in patients with epilepsy. Methods: Fifty-two epilepsy patients were given oral clonidine plus sleep-deprivation to induce seizures with video-electroencephalogram (VEEG) monitoring. Forty-seven patients were selected as control group, whose seizures were induced by sleep-deprivation only. 99 Tc m -ethylcysteinate dimer (ECD) was injected within 30 s since a clinical sign and/or a typical EEG discharge of epilepsy was recognized. Brain SPECT was performed 30 min after 99 Tc m -ECD injection. χ 2 -test was performed by using software SPSS 10.0. Results: One to two hr after oral intake of clonidine plus sleep-deprivation, 75% (39/52) patients were induced seizures, including 92.3% (36/39) with subclinical seizures and 7.7% (3/39) with clinical seizures. Ictal brain SPECT localized the lesions with high uptake of 99 Tc m -ECD in 37 (94.9%) patients. In control group, 38.3% (18/47) were induced epileptic seizures, including 77.8% (14/18) with subclinical seizures and 22.2% (4/18) with clinical seizures. The induction rate of epileptic seizures in clonidine plus sleep-deprivation group was significantly higher than that of control group (χ 2 = 13.614, P 2 = 1.253, P>0.05). Conclusions: The combination of oral intake of clonidine and sleep-deprivation could increase the induction rate of epileptic seizures and it is effective for epilepsy SPECT imaging. (authors)

Extended Remediation of Sleep Deprived-Induced Working Memory Deficits Using fMRI-guided Transcranial Magnetic Stimulation

Science.gov (United States)

Luber, Bruce; Steffener, Jason; Tucker, Adrienne; Habeck, Christian; Peterchev, Angel V.; Deng, Zhi-De; Basner, Robert C.; Stern, Yaakov; Lisanby, Sarah H.

2013-01-01

Study Objectives: We attempted to prevent the development of working memory (WM) impairments caused by sleep deprivation using fMRI-guided repetitive transcranial magnetic stimulation (rTMS). Novel aspects of our fMRI-guided rTMS paradigm included the use of sophisticated covariance methods to identify functional networks in imaging data, and the use of fMRI-targeted rTMS concurrent with task performance to modulate plasticity effects over a longer term. Design: Between-groups mixed model. Setting: TMS, MRI, and sleep laboratory study. Participants: 27 subjects (13 receiving Active rTMS, and 14 Sham) completed the sleep deprivation protocol, with another 21 (10 Active, 11 Sham) non-sleep deprived subjects run in a second experiment. Interventions: Our previous covariance analysis had identified a network, including occipital cortex, which demonstrated individual differences in resilience to the deleterious effects of sleep deprivation on WM performance. Five Hz rTMS was applied to left lateral occipital cortex while subjects performed a WM task during 4 sessions over the course of 2 days of total sleep deprivation. Measurements and Results: At the end of the sleep deprivation period, Sham sleep deprived subjects exhibited degraded performance in the WM task. In contrast, those receiving Active rTMS did not show the slowing and lapsing typical in sleep deprivation, and instead performed similarly to non- sleep deprived subjects. Importantly, the Active sleep deprivation group showed rTMS-induced facilitation of WM performance a full 18 hours after the last rTMS session. Conclusions: Over the course of sleep deprivation, these results indicate that rTMS applied concurrently with WM task performance affected neural circuitry involved in WM to prevent its full impact. Citation: Luber B; Steffener J; Tucker A; Habeck C; Peterchev AV; Deng ZD; Basner RC; Stern Y; Lisanby SH. Extended remediation of sleep deprived-induced working memory deficits using f

Effect of BSO addition on Cu-O bond of GdBa{sub 2}Cu{sub 3}O{sub 7-x} films with varying thickness probed by extended x-ray absorption fine structure

Energy Technology Data Exchange (ETDEWEB)

Jeon, H. K.; Lee, J. K.; Yang, D. S.; Kang, B. [Chungbuk National University, Cheongju (Korea, Republic of); Kang, W. N. [Dept. of Physics, Sungkyunkwan University, Suwon (Korea, Republic of)

2016-12-15

We investigated the relation between the Cu-O bond length and the superconducting properties of BaSnO{sub 3} (BSO)-added GdBa{sub 2}Cu{sub 3}O{sub 7-x} (GdBCO) thin films by using extended x-ray absorption fine structure (EXAFS) spectroscopy. 4 wt.% BaSnO{sub 3} (BSO) added GdBa{sub 2}Cu{sub 3}O{sub 7-x} (GdBCO) thin films with varying thickness from 0.2 μm to 1.0 μm were fabricated by using pulsed laser deposition (PLD) method. The transition temperature (T{sub c}) and the residual resistance ratio (RRR) of the GdBCO films increased with increasing thickness up to 0.8 μm, where the crystalline BSO has the highest peak intensity, and then decreased. This uncommon behaviors of T{sub c} and RRR are likely to be created by the addition of BSO, which may change the ordering of GdBCO atomic bonds. Analysis from the Cu K-edge EXAFS spectroscopy showed an interesting thickness dependence of ordering behavior of BSO-added GdBCO films. It is noticeable that the ordering of Cu-O bond and the transition temperature are found to show opposite behaviors in the thickness dependence. Based on these results, the growth of BSO seemingly have evident effect on the alteration of the local structure of GdBCO film.

Isolation and characterization of an auxin-inducible glutathione S-transferase gene of Arabidopsis thaliana

NARCIS (Netherlands)

Kop, D.A.M. van der; Schuyer, M.; Scheres, B.J.G.; Zaal, B.J. van der; Hooykaas, P.J.J.

1996-01-01

Genes homologous to the auxin-inducible Nt103 glutathione S-transferase (GST) gene of tobacco, were isolated from a genomic library of Arabidopsis thaliana. We isolated a λ clone containing an auxin-inducible gene, At103-1a, and part of a constitutively expressed gene, At103-1b. The coding regions

Low glutathione regulates gene expression and the redox potentials of the nucleus and cytosol in Arabidopsis thaliana.

Science.gov (United States)

Schnaubelt, Daniel; Queval, Guillaume; Dong, Yingping; Diaz-Vivancos, Pedro; Makgopa, Matome Eugene; Howell, Gareth; De Simone, Ambra; Bai, Juan; Hannah, Matthew A; Foyer, Christine H

2015-02-01

Reduced glutathione (GSH) is considered to exert a strong influence on cellular redox homeostasis and to regulate gene expression, but these processes remain poorly characterized. Severe GSH depletion specifically inhibited root meristem development, while low root GSH levels decreased lateral root densities. The redox potential of the nucleus and cytosol of Arabidopsis thaliana roots determined using roGFP probes was between -300 and -320 mV. Growth in the presence of the GSH-synthesis inhibitor buthionine sulfoximine (BSO) increased the nuclear and cytosolic redox potentials to approximately -260 mV. GSH-responsive genes including transcription factors (SPATULA, MYB15, MYB75), proteins involved in cell division, redox regulation (glutaredoxinS17, thioredoxins, ACHT5 and TH8) and auxin signalling (HECATE), were identified in the GSH-deficient root meristemless 1-1 (rml1-1) mutant, and in other GSH-synthesis mutants (rax1-1, cad2-1, pad2-1) as well as in the wild type following the addition of BSO. Inhibition of auxin transport had no effect on organ GSH levels, but exogenous auxin decreased the root GSH pool. We conclude that GSH depletion significantly increases the redox potentials of the nucleus and cytosol, and causes arrest of the cell cycle in roots but not shoots, with accompanying transcript changes linked to altered hormone responses, but not oxidative stress. © 2013 John Wiley & Sons Ltd.

Modulation of X ray DNA damage by SR-2508 +/- buthionine sulfoximine

International Nuclear Information System (INIS)

Kinsella, T.J.; Dobson, P.P.; Russo, A.; Mitchell, J.B.; Fornace, A.J. Jr.

1986-01-01

It has been demonstrated that glutathione (GSH) depletion with buthionine sulfoximine (BSO) potentiates SR-2508 radiosensitization in hypoxic cells. We have measured the effect of SR-2508 alone, BSO alone, and combined treatment on radiation-induced DNA strand breaks in hypoxic V79 cells using alkaline and neutral elution. DNA base damage recognized by a damage specific endonuclease from M. luteus was also studied. Hypoxic irradiation markedly reduces the efficiency of single-strand (SSB) and double-strand breaks (DSB) to 10-20% compared to oxic irradiation. Hypoxia had less effect on the efficiency of base damage (ESS). BSO treatment alone, resulting in GSH depletion to less than 5% of controls, had little effect of hypoxic-SSB, DSB, and ESS. SR-2508 (5 mM) treatment alone in hypoxic cells increased the number of SSB, DSB and ESS to approximately half of that resulting from oxic irradiation. However, the combination of BSO and SR-2508 in hypoxic cells resulted in SSB and DSB comparable to oxic irradiation. This combined treatment resulted in less effect on ESS. We conclude that the observed hypoxic radiosensitization, using clonogenic survival assays with combined BSO-SR-2508, correlates with our results assessing DNA strand breaks and base damage

Neuroethologic differences in sleep deprivation induced by the single- and multiple-platform methods

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R. Medeiros

1998-05-01

Full Text Available It has been proposed that the multiple-platform method (MP for desynchronized sleep (DS deprivation eliminates the stress induced by social isolation and by the restriction of locomotion in the single-platform (SP method. MP, however, induces a higher increase in plasma corticosterone and ACTH levels than SP. Since deprivation is of heuristic value to identify the functional role of this state of sleep, the objective of the present study was to determine the behavioral differences exhibited by rats during sleep deprivation induced by these two methods. All behavioral patterns exhibited by a group of 7 albino male Wistar rats submitted to 4 days of sleep deprivation by the MP method (15 platforms, spaced 150 mm apart and by 7 other rats submitted to sleep deprivation by the SP method were recorded in order to elaborate an ethogram. The behavioral patterns were quantitated in 10 replications by naive observers using other groups of 7 rats each submitted to the same deprivation schedule. Each quantification session lasted 35 min and the behavioral patterns presented by each rat over a period of 5 min were counted. The results obtained were: a rats submitted to the MP method changed platforms at a mean rate of 2.62 ± 1.17 platforms h-1 animal-1; b the number of episodes of noninteractive waking patterns for the MP animals was significantly higher than that for SP animals (1077 vs 768; c additional episodes of waking patterns (26.9 ± 18.9 episodes/session were promoted by social interaction in MP animals; d the cumulative number of sleep episodes observed in the MP test (311 was significantly lower (chi-square test, 1 d.f., P<0.05 than that observed in the SP test (534; e rats submitted to the MP test did not show the well-known increase in ambulatory activity observed after the end of the SP test; f comparison of 6 MP and 6 SP rats showed a significantly shorter latency to the onset of DS in MP rats (7.8 ± 4.3 and 29.0 ± 25.0 min, respectively

Acute total sleep deprivation potentiates amphetamine-induced locomotor-stimulant effects and behavioral sensitization in mice.

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Saito, Luis P; Fukushiro, Daniela F; Hollais, André W; Mári-Kawamoto, Elisa; Costa, Jacqueline M; Berro, Laís F; Aramini, Tatiana C F; Wuo-Silva, Raphael; Andersen, Monica L; Tufik, Sergio; Frussa-Filho, Roberto

2014-02-01

It has been demonstrated that a prolonged period (48 h) of paradoxical sleep deprivation (PSD) potentiates amphetamine (AMP)-induced behavioral sensitization, an animal model of addiction-related neuroadaptations. In the present study, we examined the effects of an acute short-term deprivation of total sleep (TSD) (6h) on AMP-induced behavioral sensitization in mice and compared them to the effects of short-term PSD (6 h). Three-month-old male C57BL/6J mice underwent TSD (experiment 1-gentle handling method) or PSD (experiment 2-multiple platforms method) for 6 h. Immediately after the sleep deprivation period, mice were tested in the open field for 10 min under the effects of saline or 2.0 mg/kg AMP. Seven days later, to assess behavioral sensitization, all of the mice received a challenge injection of 2.0 mg/kg AMP and were tested in the open field for 10 min. Total, peripheral, and central locomotion, and grooming duration were measured. TSD, but not PSD, potentiated the hyperlocomotion induced by an acute injection of AMP and this effect was due to an increased locomotion in the central squares of the apparatus. Similarly, TSD facilitated the development of AMP-induced sensitization, but only in the central locomotion parameter. The data indicate that an acute period of TSD may exacerbate the behavioral effects of AMP in mice. Because sleep architecture is composed of paradoxical and slow wave sleep, and 6-h PSD had no effects on AMP-induced hyperlocomotion or sensitization, our data suggest that the deprivation of slow wave sleep plays a critical role in the mechanisms that underlie the potentiating effects of TSD on both the acute and sensitized addiction-related responses to AMP. Copyright © 2013 Elsevier Inc. All rights reserved.

Changes in brain amino acid content induced by hyposmolar stress and energy deprivation.

Science.gov (United States)

Haugstad, T S; Valø, E T; Langmoen, I A

1995-12-01

The changes in endogenous amino acids in brain extracellular and intracellular compartments evoked by hyposmotic stress and energy deprivation were compared. Tissue content and release of ten amino acids were measured simultaneously in rat hippocampal slices by means of high performance liquid chromatography. Hyposmotic stress induced a large release of taurine (25568 pmol mg-1 protein), and a smaller release of glutamate, accompanied by an inverse change in tissue content. Adding mannitol to correct osmolarity, blocked these changes. Energy deprivation caused an increase in the release of all amino acids except glutamine. The release was particularly large for glutamate and GABA (31141 and 13282 pmol mg-1, respectively). The intracellular concentrations were generally reduced, but the total amount of the released amino acids increased In contrast to the effect seen during hyposmolar stress, mannitol enhanced the changes due to energy deprivation. The results show that hyposmolar stress and energy deprivation cause different content and release profiles, suggesting that the mechanisms involved in the two situations are either different or modulated in different ways. The intracellular amino acid depletion seen during energy deprivation shows that increased outward transport is probably a primary event, and increased amino acid formation likely secondary to this release.

Factors involved in depletion of glutathione from A549 human lung carcinoma cells: implications for radiotherapy

International Nuclear Information System (INIS)

Biaglow, J.E.; Varnes, M.E.; Epp, E.R.; Clark, E.P.

1984-01-01

The rate of GSH resynthesis has been measured in plateau phase cultures of A549 human lung carcinoma cells subjected to a fresh medium change. Buthionine sulfoximine (BSO) blocks this resynthesis. Diethyl maleate (DEM) causes a decrease in accumulation of GSH. If DEM is added concurrently with BSO there is a rapid decline in GSH that is maximal in the presence of 0.5 mM DEM. GSH depletion rapidly occurs when BSO is added to log phase cultures which initially are higher in GSH content. Twenty-four hr treatment of A549 cells with BSO results in cells that are more radiosensitive in air and show a slight hypoxic radiation response. A 2 hr treatment with DEM results in some hypoxic sensitization and little increase in the aerobic radiation response. Cells treated simultaneously with BSO + DEM show little increase in the hypoxic radiation response, compared to DEM alone, but are more sensitive under aerobic conditions. Decreased cell survival for aerobically irradiated log phase A549 cells occurs within minutes after addition of a mixture of BSO + DEM. The authors suggest that the enhanced aerobic radiation response is related to an inability of GSH depleted cells to inactivate either peroxy radicals or hydroperoxides that may be produced during irradiation of BSO treated cells. Furthermore, enhancement of the aerobic radiation response may be useful in vivo if normal tissue responses are not also increased

Significance of the proportion of binucleate cells in the micronucleus assay; A methodological study

Energy Technology Data Exchange (ETDEWEB)

Imamura, Masahiro; Edgren, M.R. (Karolinska Inst., Stockholm (Sweden). Dept. of Radiation Physics)

1994-03-01

Using treatment with cytochalasin-B (Cyt-B) for the induction of a cytokinetic block, the significance of the proportion of binucleate cells (BNC) in the micronucleus (MN) assay was investigated in a methodological study. A Chinese hamster cell line V79 was used in which MN were induced by radiation. In complementary tests the radiation effect in inducing MN was enhanced by depletion of the cellular glutathione content with buthionine sulfoximine (BSO). The data indicated that the concentration of Cyt-B is the major factor which determines the proportion of BNC. This proportion was shown to be independent of radiation dose and of BSO. Furthermore, the MN frequency was not related to the percentage of BNC. Therefore, a high proportion of BNC may be practical for the MN assay, but may not make the technique more accurate. (author).

Significance of the proportion of binucleate cells in the micronucleus assay

International Nuclear Information System (INIS)

Imamura, Masahiro; Edgren, M.R.

1994-01-01

Using treatment with cytochalasin-B (Cyt-B) for the induction of a cytokinetic block, the significance of the proportion of binucleate cells (BNC) in the micronucleus (MN) assay was investigated in a methodological study. A Chinese hamster cell line V79 was used in which MN were induced by radiation. In complementary tests the radiation effect in inducing MN was enhanced by depletion of the cellular glutathione content with buthionine sulfoximine (BSO). The data indicated that the concentration of Cyt-B is the major factor which determines the proportion of BNC. This proportion was shown to be independent of radiation dose and of BSO. Furthermore, the MN frequency was not related to the percentage of BNC. Therefore, a high proportion of BNC may be practical for the MN assay, but may not make the technique more accurate. (author)

Effects of exogenous glutathione and cysteine on growth, lead accumulation, and tolerance of Iris lactea var. chinensis.

Science.gov (United States)

Yuan, Haiyan; Zhang, Yongxia; Huang, Suzhen; Yang, Yongheng; Gu, Chunsun

2015-02-01

Effects of exogenous reduced glutathione (GSH) and cysteine (Cys) on growth, lead (Pb) accumulation, and nonprotein thiol (NPT) contents of Iris lactea var. chinensis under 100 and 500 mg L(-1) Pb stress were studied. Our results showed that 500 mg L(-1) Pb stress caused a dramatical decline in fresh weights, while the reduction of aboveground biomass was alleviated by exogenous GSH and Cys even though keeping higher Pb contents in roots and shoots. Exogenous GSH and Cys could enhance Pb accumulation in the shoots and roots compared with single Pb treatment. The promoting effect of GSH to Pb accumulation was larger than the effect of Cys, and the Pb contents in the shoots and roots treated with 500 mg L(-1) Pb + GSH reached 1,712 and 14,603 mg kg(-1), about 4.19 and 2.78 times of single 500 mg L(-1) Pb treatment, respectively. Microscopic imaging of Pb in roots and leaves showed that higher intensive fluorescence was observed in cell wall of root epidermis, stele, vascular tissues of the roots, and sclerenchyma cells of leaves treated with 500 mg L(-1) Pb + GSH and treated with 500 mg L(-1) Pb + Cys. Exogenous GSH had an apparent promoting effect on root and shoot GSH synthesis, while exogenous Cys reduced the synthesis of cellular GSH in shoot and increased Cys contents. Pb only induced the synthesis of phytochelatin (PC)2 in roots, and the PC2 content declined in GSH- and Cys-treated plant roots. These results suggested that GSH synthesis was a more effective approach to improve Pb accumulation and translocation of I. lactea var. chinensis. Further analysis of protein expression in plants by exogenous GSH and buthionine sulfoximine (BSO) application showed that the proteins regulated by GSH and BSO may constitute various enzymes involved in GSH biosynthesis and play certain roles in Pb accumulation and tolerance of I. lactea var. chinensis.

Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: protection by caffeine.

Science.gov (United States)

Alhaider, Ibrahim A; Aleisa, Abdulaziz M; Tran, Trinh T; Alkadhi, Karim A

2011-04-01

It is well known that caffeine and sleep deprivation have opposing effects on learning and memory; therefore, this study was undertaken to determine the effects of chronic (4wks) caffeine treatment (0.3g/l in drinking water) on long-term memory deficit associated with 24h sleep deprivation. Animals were sleep deprived using the modified multiple platform method. The results showed that chronic caffeine treatment prevented the impairment of long-term memory as measured by performance in the radial arm water maze task and normalized L-LTP in area CA1 of the hippocampi of sleep-deprived anesthetized rats. Sleep deprivation prevents the high frequency stimulation-induced increases in the levels of phosphorylated-cAMP response element binding protein (P-CREB) and brain-derived neurotrophic factor (BDNF) seen during the expression of late phase long-term potentiation (L-LTP). However, chronic caffeine treatment prevented the effect of sleep-deprivation on the stimulated levels of P-CREB and BDNF. The results suggest that chronic caffeine treatment may protect the sleep-deprived brain probably by preserving the levels of P-CREB and BDNF. Copyright © 2011 Elsevier Inc. All rights reserved.

A new model to study sleep deprivation-induced seizure.

Science.gov (United States)

Lucey, Brendan P; Leahy, Averi; Rosas, Regine; Shaw, Paul J

2015-05-01

A relationship between sleep and seizures is well-described in both humans and rodent animal models; however, the mechanism underlying this relationship is unknown. Using Drosophila melanogaster mutants with seizure phenotypes, we demonstrate that seizure activity can be modified by sleep deprivation. Seizure activity was evaluated in an adult bang-sensitive seizure mutant, stress sensitive B (sesB(9ed4)), and in an adult temperature sensitive seizure mutant seizure (sei(ts1)) under baseline and following 12 h of sleep deprivation. The long-term effect of sleep deprivation on young, immature sesB(9ed4) flies was also assessed. Laboratory. Drosophila melanogaster. Sleep deprivation. Sleep deprivation increased seizure susceptibility in adult sesB(9ed4)/+ and sei(ts1) mutant flies. Sleep deprivation also increased seizure susceptibility when sesB was disrupted using RNAi. The effect of sleep deprivation on seizure activity was reduced when sesB(9ed4)/+ flies were given the anti-seizure drug, valproic acid. In contrast to adult flies, sleep deprivation during early fly development resulted in chronic seizure susceptibility when sesB(9ed4)/+ became adults. These findings show that Drosophila is a model organism for investigating the relationship between sleep and seizure activity. © 2015 Associated Professional Sleep Societies, LLC.

Fatty Acid Oxidation Compensates for Lipopolysaccharide-Induced Warburg Effect in Glucose-Deprived Monocytes

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Nora Raulien

2017-05-01

Full Text Available Monocytes enter sites of microbial or sterile inflammation as the first line of defense of the immune system and initiate pro-inflammatory effector mechanisms. We show that activation with bacterial lipopolysaccharide (LPS induces them to undergo a metabolic shift toward aerobic glycolysis, similar to the Warburg effect observed in cancer cells. At sites of inflammation, however, glucose concentrations are often drastically decreased, which prompted us to study monocyte function under conditions of glucose deprivation and abrogated Warburg effect. Experiments using the Seahorse Extracellular Flux Analyzer revealed that limited glucose supply shifts monocyte metabolism toward oxidative phosphorylation, fueled largely by fatty acid oxidation at the expense of lipid droplets. While this metabolic state appears to provide sufficient energy to sustain functional properties like cytokine secretion, migration, and phagocytosis, it cannot prevent a rise in the AMP/ATP ratio and a decreased respiratory burst. The molecular trigger mediating the metabolic shift and the functional consequences is activation of AMP-activated protein kinase (AMPK. Taken together, our results indicate that monocytes are sufficiently metabolically flexible to perform pro-inflammatory functions at sites of inflammation despite glucose deprivation and inhibition of the LPS-induced Warburg effect. AMPK seems to play a pivotal role in orchestrating these processes during glucose deprivation in monocytes.

Effects of reduced glutathion and vitamin c on cisplatin-induced ...

African Journals Online (AJOL)

glutathione peroxidase [GSHPx], catalase [CAT], glutathione reductase [GSHR] activities and gene expression, glutathione [GSH] content) and lipid peroxidation products (malondialdehyde, MDA) in rat liver tissue were measured. CDDP hepatotoxicity was manifested by an increase in serum ALT and AST, elevation of MDA ...

Blockage of NOX2/MAPK/NF-κB Pathway Protects Photoreceptors against Glucose Deprivation-Induced Cell Death

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Bin Fan

2017-01-01

Full Text Available Acute energy failure is one of the critical factors contributing to the pathogenic mechanisms of retinal ischemia. Our previous study demonstrated that glucose deprivation can lead to a caspase-dependent cell death of photoreceptors. The aim of this study was to decipher the upstream signal pathway in glucose deprivation- (GD- induced cell death. We mimicked acute energy failure by using glucose deprivation in photoreceptor cells (661W cells. GD-induced oxidative stress was evaluated by measuring ROS with the DCFH-DA assay and HO-1 expression by Western blot analysis. The activation of NOX2/MAPK/NF-κB signal was assessed by Western blot and immunohistochemical assays. The roles of these signals in GD-induced cell death were measured by using their specific inhibitors. Inhibition of Rac-1 and NOX2 suppressed GD-induced oxidative stress and protected photoreceptors against GD-induced cell death. NOX2 was an upstream signal in the caspase-dependent cell death cascade, yet the downstream MAPK pathways were activated and blocking MAPK signals rescued 661W cells from GD-induced death. In addition, GD caused the activation of NF-κB signal and inhibiting NF-κB significantly protected 661W cells. These observations may provide insights for treating retinal ischemic diseases and protecting retinal neurons from ischemia-induced cell death.

Role of plasmids in Lactobacillus brevis BSO 464 hop tolerance and beer spoilage.

Science.gov (United States)

Bergsveinson, Jordyn; Baecker, Nina; Pittet, Vanessa; Ziola, Barry

2015-02-01

Specific isolates of lactic acid bacteria (LAB) can grow in the harsh beer environment, thus posing a threat to brew quality and the economic success of breweries worldwide. Plasmid-localized genes, such as horA, horC, and hitA, have been suggested to confer hop tolerance, a trait required for LAB survival in beer. The presence and expression of these genes among LAB, however, do not universally correlate with the ability to grow in beer. Genome sequencing of the virulent beer spoilage organism Lactobacillus brevis BSO 464 revealed the presence of eight plasmids, with plasmids 1, 2, and 3 containing horA, horC, and hitA, respectively. To investigate the roles that these and the other five plasmids play in L. brevis BSO 464 growth in beer, plasmid curing with novobiocin was used to derive 10 plasmid variants. Multiplex PCRs were utilized to determine the presence or absence of each plasmid, and how plasmid loss affected hop tolerance and growth in degassed (noncarbonated) beer was assessed. Loss of three of the eight plasmids was found to affect hop tolerance and growth in beer. Loss of plasmid 2 (horC and 28 other genes) had the most dramatic effect, with loss of plasmid 4 (120 genes) and plasmid 8 (47 genes) having significant, but smaller, impacts. These results support the contention that genes on mobile genetic elements are essential for bacterial growth in beer and that beer spoilage ability is not dependent solely on the three previously described hop tolerance genes or on the chromosome of a beer spoilage LAB isolate.

Glutathione depletion prevents diet-induced obesity and enhances insulin sensitivity.

Science.gov (United States)

Findeisen, Hannes M; Gizard, Florence; Zhao, Yue; Qing, Hua; Jones, Karrie L; Cohn, Dianne; Heywood, Elizabeth B; Bruemmer, Dennis

2011-12-01

Excessive accumulation of reactive oxygen species (ROS) in adipose tissue has been implicated in the development of insulin resistance and type 2 diabetes. However, emerging evidence suggests a physiologic role of ROS in cellular signaling and insulin sensitivity. In this study, we demonstrate that pharmacologic depletion of the antioxidant glutathione in mice prevents diet-induced obesity, increases energy expenditure and locomotor activity, and enhances insulin sensitivity. These observations support a beneficial role of ROS in glucose homeostasis and warrant further research to define the regulation of metabolism and energy balance by ROS.

Corneal endothelial glutathione after photodynamic change

International Nuclear Information System (INIS)

Hull, D.S.; Riley, M.V.; Csukas, S.; Green, K.

1982-01-01

Rabbit corneal endothelial cells perfused with 5 X 10(-6)M rose bengal and exposed to incandescent light demonstrated no alteration of either total of or percent oxidized glutathione after 1 hr. Addition of 5400 U/ml catalase to the perfusing solution had no effect on total glutathione levels but caused a marked reduction in percent oxidized glutathione in corneas exposed to light as well as in those not exposed to light. Substitution of sucrose for glucose in the perfusing solution had no effect on total or percent oxidized glutathione. Perfusion of rabbit corneal endothelium with 0.5 mM chlorpromazine and exposure to ultraviolet (UV) light resulted in no change in total glutathione content. A marked reduction in percent oxidized glutathione occurred, however, in corneas perfused with 0.5 mM chlorpromazine both in the presence and absence of UV light. It is concluded that photodynamically induced swelling of corneas is not the result of a failure of the glutathione redox system

Effects of Sleep Deprivation on Hypoglycemia-Induced Cognitive Impairment and Recovery in Adults With Type 1 Diabetes.

Science.gov (United States)

Inkster, Berit E; Zammitt, Nicola N; Ritchie, Stuart J; Deary, Ian J; Morrison, Ian; Frier, Brian M

2016-05-01

To ascertain whether hypoglycemia in association with sleep deprivation causes greater cognitive dysfunction than hypoglycemia alone and protracts cognitive recovery after normoglycemia is restored. Fourteen adults with type 1 diabetes underwent a hyperinsulinemic, hypoglycemic clamp on two separate occasions. Before one glucose clamp, the participants stayed awake overnight to induce sleep deprivation. Participants were randomized and counterbalanced to the experimental condition. Cognitive function tests were performed before and during hypoglycemia and for 90 min after restoration of normoglycemia. Cognitive impairment during hypoglycemia did not differ significantly between the sleep-deprived and non-sleep-deprived conditions. However, in the sleep-deprived state, digit symbol substitution scores and choice reaction times were significantly poorer during recovery (P sleep deprivation, such as tiredness, were removed. Hypoglycemia per se produced a significant decrement in cognitive function; coexisting sleep deprivation did not have an additive effect. However, after restoration of normoglycemia, preceding sleep deprivation was associated with persistence of hypoglycemic symptoms and greater and more prolonged cognitive dysfunction during the recovery period. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Inhibition of ghrelin O-acyltransferase attenuates food deprivation-induced increases in ingestive behavior.

Science.gov (United States)

Teubner, Brett J W; Garretson, John T; Hwang, Yousang; Cole, Philip A; Bartness, Timothy J

2013-04-01

Ghrelin is an orexigenic hormone produced by the stomach in direct proportion to the time since the last meal and has therefore been called a 'hunger signal'. The octanoylation of ghrelin is critical for its orexigenic functions and is dependent upon ghrelin O-acyltransferase (GOAT) catalyzation. The GOAT inhibitor, GO-CoA-Tat, decreases the circulating concentrations of octanoylated ghrelin and attenuates weight gain on a high fat diet in mice. Unlike rats and mice, Siberian hamsters and humans do not increase food intake after food deprivation, but increase food hoarding after food deprivation. In Siberian hamsters, exogenous ghrelin increases ingestive behaviors similarly to 48-56 h food deprivation. Therefore, we tested the necessity of increased ghrelin in food-deprived Siberian hamsters to stimulate ingestive behaviors. To do so we used our simulated natural housing system that allows hamsters to forage for and hoard food. Animals were given an injection of GO-CoA-Tat (i.p., 11 μmol/kg) every 6h because that is the duration of its effective inhibition of octanoylated ghrelin concentrations during a 48 h food deprivation. We found that GO-CoA-Tat attenuated food foraging (0-1h), food intake (0-1 and 2-4h), and food hoarding (0-1h and 2 and 3 days) post-refeeding compared with saline treated animals. This suggests that increased octanoylated ghrelin concentrations play a role in the food deprivation-induced increases in ingestive behavior. Therefore, ghrelin is a critical aspect of the multi-faceted mechanisms that stimulate ingestive behaviors, and might be a critical point for a successful clinical intervention scheme in humans. Copyright © 2013 Elsevier Inc. All rights reserved.

High-Intensity Interval Training Attenuates Insulin Resistance Induced by Sleep Deprivation in Healthy Males

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Jorge F. T. de Souza

2017-12-01

Full Text Available Introduction: Sleep deprivation can impair several physiological systems and recently, new evidence has pointed to the relationship between a lack of sleep and carbohydrate metabolism, consequently resulting in insulin resistance. To minimize this effect, High-Intensity Interval Training (HIIT is emerging as a potential strategy.Objective: The aim of this study was to investigate the effects of HIIT on insulin resistance induced by sleep deprivation.Method: Eleven healthy male volunteers were recruited, aged 18–35 years, who declared taking 7–8 h sleep per night. All volunteers were submitted to four different conditions: a single night of regular sleep (RS condition, 24 h of total sleep deprivation (SD condition, HIIT training followed by regular sleep (HIIT+RS condition, and HIIT training followed by 24 h of total sleep deprivation (HIIT+SD condition. They performed six training sessions over 2 weeks and each session consisted of 8–12 × 60 s intervals at 100% of peak power output. In each experimental condition, tests for glucose, insulin, cortisol, free fatty acids, and insulin sensitivity, measured by oral glucose tolerance test (OGTT, were performed.Results: Sleep deprivation increased glycaemia and insulin levels, as well as the area under the curve. Furthermore, an increase in free fatty acids concentrations and basal metabolism was observed. There were no differences in the concentrations of cortisol. However, HIIT before 24 h of sleep deprivation attenuated the increase of glucose, insulin, and free fatty acids.Conclusion: Twenty-four hours of sleep deprivation resulted in acute insulin resistance. However, HIIT is an effective strategy to minimize the deleterious effects promoted by this condition.

High-Intensity Interval Training Attenuates Insulin Resistance Induced by Sleep Deprivation in Healthy Males.

Science.gov (United States)

de Souza, Jorge F T; Dáttilo, Murilo; de Mello, Marco T; Tufik, Sergio; Antunes, Hanna K M

2017-01-01

Introduction: Sleep deprivation can impair several physiological systems and recently, new evidence has pointed to the relationship between a lack of sleep and carbohydrate metabolism, consequently resulting in insulin resistance. To minimize this effect, High-Intensity Interval Training (HIIT) is emerging as a potential strategy. Objective: The aim of this study was to investigate the effects of HIIT on insulin resistance induced by sleep deprivation. Method: Eleven healthy male volunteers were recruited, aged 18-35 years, who declared taking 7-8 h sleep per night. All volunteers were submitted to four different conditions: a single night of regular sleep (RS condition), 24 h of total sleep deprivation ( SD condition), HIIT training followed by regular sleep (HIIT+RS condition), and HIIT training followed by 24 h of total sleep deprivation (HIIT+ SD condition). They performed six training sessions over 2 weeks and each session consisted of 8-12 × 60 s intervals at 100% of peak power output. In each experimental condition, tests for glucose, insulin, cortisol, free fatty acids, and insulin sensitivity, measured by oral glucose tolerance test (OGTT), were performed. Results: Sleep deprivation increased glycaemia and insulin levels, as well as the area under the curve. Furthermore, an increase in free fatty acids concentrations and basal metabolism was observed. There were no differences in the concentrations of cortisol. However, HIIT before 24 h of sleep deprivation attenuated the increase of glucose, insulin, and free fatty acids. Conclusion: Twenty-four hours of sleep deprivation resulted in acute insulin resistance. However, HIIT is an effective strategy to minimize the deleterious effects promoted by this condition.

High-Intensity Interval Training Attenuates Insulin Resistance Induced by Sleep Deprivation in Healthy Males

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de Souza, Jorge F. T.; Dáttilo, Murilo; de Mello, Marco T.; Tufik, Sergio; Antunes, Hanna K. M.

2017-01-01

Introduction: Sleep deprivation can impair several physiological systems and recently, new evidence has pointed to the relationship between a lack of sleep and carbohydrate metabolism, consequently resulting in insulin resistance. To minimize this effect, High-Intensity Interval Training (HIIT) is emerging as a potential strategy. Objective: The aim of this study was to investigate the effects of HIIT on insulin resistance induced by sleep deprivation. Method: Eleven healthy male volunteers were recruited, aged 18–35 years, who declared taking 7–8 h sleep per night. All volunteers were submitted to four different conditions: a single night of regular sleep (RS condition), 24 h of total sleep deprivation (SD condition), HIIT training followed by regular sleep (HIIT+RS condition), and HIIT training followed by 24 h of total sleep deprivation (HIIT+SD condition). They performed six training sessions over 2 weeks and each session consisted of 8–12 × 60 s intervals at 100% of peak power output. In each experimental condition, tests for glucose, insulin, cortisol, free fatty acids, and insulin sensitivity, measured by oral glucose tolerance test (OGTT), were performed. Results: Sleep deprivation increased glycaemia and insulin levels, as well as the area under the curve. Furthermore, an increase in free fatty acids concentrations and basal metabolism was observed. There were no differences in the concentrations of cortisol. However, HIIT before 24 h of sleep deprivation attenuated the increase of glucose, insulin, and free fatty acids. Conclusion: Twenty-four hours of sleep deprivation resulted in acute insulin resistance. However, HIIT is an effective strategy to minimize the deleterious effects promoted by this condition. PMID:29270126

Neighborhood socioeconomic deprivation, perceived neighborhood factors, and cortisol responses to induced stress among healthy adults.

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Barrington, Wendy E; Stafford, Mai; Hamer, Mark; Beresford, Shirley A A; Koepsell, Thomas; Steptoe, Andrew

2014-05-01

Associations between measures of neighborhood socioeconomic deprivation and health have been identified, yet work is needed to uncover explanatory mechanisms. One hypothesized pathway is through stress, yet the few studies that have evaluated associations between characteristics of deprived neighborhoods and biomarkers of stress are mixed. This study evaluated whether objectively measured neighborhood socioeconomic deprivation and individual perceived neighborhood characteristics (i.e. social control and fear of crime) impacted cortisol responses to an induced stressor among older healthy adults. Data from Heart Scan, a sub-study of the Whitehall II cohort, were used to generate multilevel piecewise growth-curve models of cortisol trajectories after a laboratory stressor accounting for neighborhood and demographic characteristics. Neighborhood socioeconomic deprivation was significantly associated with individual perceptions of social control and fear of crime in the neighborhood while an association with blunted cortisol reactivity was only evidence among women. Social control was significantly associated with greater cortisol reactivity and mediation between neighborhood socioeconomic deprivation and cortisol reactivity was suggested among women. These findings support a gender-dependent role of neighborhood in stress process models of health. Published by Elsevier Ltd.

Oxidative stress and sodium methyldithiocarbamate-induced modulation of the macrophage response to lipopolysaccharide in vivo.

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Pruett, Stephen B; Cheng, Bing; Fan, Ruping; Tan, Wei; Sebastian, Thomas

2009-06-01

Sodium methyldithiocarbamate (SMD) is the third most abundantly used conventional pesticide in the United States, and hundreds of thousands of persons are exposed to this compound or its major breakdown product, methylisothiocyanate, at levels greater than recommended by the Environmental Protection Agency. A previous study suggests three mechanisms of action involved to some degree in the inhibition of inflammation and decreased resistance to infection caused by exposure of mice to the compound. One of these mechanisms is oxidative stress. The purpose of the present study was to confirm that this mechanism is involved in the effects of SMD on cytokine production by peritoneal macrophages and to further characterize its role in altered cytokine production. Results indicated that SMD significantly decreased the intracellular concentration of reduced glutathione (GSH), suggesting oxidative stress. This was further indicated by the upregulation of genes involved in the "response to oxidative stress" as determined by microarray analysis. These effects were associated with the inhibition of lipopolysaccharide (LPS)-induced production of several proinflammatory cytokines. Experimental depletion of GSH with buthionine sulfoximine (BSO) partially prevented the decrease in LPS-induced interleukin (IL)-6 production caused by SMD and completely prevented the decrease in IL-12. In contrast, BSO plus SMD substantially enhanced the production of IL-10. These results along with results from a previous study are consistent with the hypothesis that SMD causes oxidative stress, which contributes to modulation of cytokine production. However, oxidative stress alone cannot explain the increased IL-10 production caused by SMD.

Technetium-99m sestamibi uptake in human breast carcinoma cell lines displaying glutathione-associated drug-resistance

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Kabasakal, L.; Oezker, K.; Hayward, M.; Akansel, G.; Griffith, O.; Isitman, A.T.; Hellman, R.; Collier, D.

1996-01-01

An in vitro study was designed to evaluate the uptake of sestamibi (MIBI) in P-glycoprotein (Pgp) and glutathione-associated (GSH) multidrug-resistant (MDR) cell lines. MIBI uptake was studied in various human breast carcinoma cell lines, i.e. in wild-type (MCF7/wt) cells, in adriamycin-resistant (MCF7/adr) cells which express Pgp and in melphalan-resistant (MCF7/mph) cells with increased levels of GSH. The effects of buthiomine sulphoximine (BSO) and verapamil on MIBI uptake were also studied in the MCF7/mph and MCF7/adr cells respectively. The cells were incubated for 1 h with a dose of 0.1 MBq thallium-201 and technetium-99m MIBI. Both BIBI and 201 Tl uptakes were higher for MCF7/mph cells than for the other cells studied. The mean MIBI uptake in MCF7/adr cells was significantly lower than that in MCF7/wt cells (1.9%±0.5% vs 3.1%.0.6%; P 0.1). This study suggests that the uptake of MIBI is not diminished by glutathione-associated drug resistance and that MIBI uptake in a tumour sample does not necessarly indicate that a cancer is sensitive to drugs. (orig.)

Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents

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Higgins, Larry G.; Kelleher, Michael O.; Eggleston, Ian M.; Itoh, Ken; Yamamoto, Masayuki; Hayes, John D.

2009-01-01

Sulforaphane can stimulate cellular adaptation to redox stressors through transcription factor Nrf2. Using mouse embryonic fibroblasts (MEFs) as a model, we show herein that the normal homeostatic level of glutathione in Nrf2 -/- MEFs was only 20% of that in their wild-type counterparts. Furthermore, the rate of glutathione synthesis following its acute depletion upon treatment with 3 μmol/l sulforaphane was very substantially lower in Nrf2 -/- MEFs than in wild-type cells, and the rebound leading to a ∼ 1.9-fold increase in glutathione that occurred 12-24 h after Nrf2 +/+ MEFs were treated with sulforaphane was not observed in Nrf2 -/- fibroblasts. Wild-type MEFs that had been pre-treated for 24 h with 3 μmol/l sulforaphane exhibited between 1.4- and 3.2-fold resistance against thiol-reactive electrophiles, including isothiocyanates, α,β-unsaturated carbonyl compounds (e.g. acrolein), aryl halides and alkene epoxides. Pre-treatment of Nrf2 +/+ MEFs with sulforaphane also protected against hydroperoxides (e.g. cumene hydroperoxide, CuOOH), free radical-generating compounds (e.g. menadione), and genotoxic electrophiles (e.g. chlorambucil). By contrast, Nrf2 -/- MEFs were typically ∼ 50% less tolerant of these agents than wild-type fibroblasts, and sulforaphane pre-treatment did not protect the mutant cells against xenobiotics. To test whether Nrf2-mediated up-regulation of glutathione represents the major cytoprotective mechanism stimulated by sulforaphane, 5 μmol/l buthionine sulfoximine (BSO) was used to inhibit glutathione synthesis. In Nrf2 +/+ MEFs pre-treated with sulforaphane, BSO diminished intrinsic resistance and abolished inducible resistance to acrolein, CuOOH and chlorambucil, but not menadione. Thus Nrf2-dependent up-regulation of GSH is the principal mechanism by which sulforaphane pre-treatment induced resistance to acrolein, CuOOH and chlorambucil, but not menadione.

Mechanisms of radiosensitization and protection studied with glutathione-deficient human cell lines

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Revesz, L.; Edgren, M.

1982-01-01

Glutathione-deficient fibroblasts and lymphoblastoid cells, derived from patients with an inborn error of glutathione synthetase activity, and glutathione-proficient cells, derived from clinically healthy individuals, were used to investigate the importance of glutathione for radiosensitization by misonidazole. With single-strand DNA breaks as an end point, misonidazole as well as oxygen was found to lack any sensitizing effect on cells deficient in glutathione. The post-irradiation repair of single-strand breaks induced by hypoxic irradiation of misonidazole treated cells was found to be a great extent glutathione dependent, like the repair of breaks induced by oxic irradiation. Naturally occurring aminothiols in glutathione-deficient cells appeared to be in efficient as substitutes for glutatione. Artificial aminothiols, such as cysteamine or dithiothreitol, were found to effectively replace glutathione

Cytotoxic Effects of Ionizing Radiation and Chlorpyrifos on White Rats

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El-Bahkery, A.M.L.H.

2014-01-01

The hazard of accidental exposure to ionizing radiation (IR) and/or neurotoxic insecticides like the organophosphorus insecticide chlorpyrifos (CPF) represent series health problem for human. In the present work, the cytotoxic effects of ionizing radiation and chlorpyrifos on rats were studied where animals were under glutathione (GSH) depletion. Animals were pre-treated with single dose of Buthionine Sulfoximine (BSO) (200 mg/kg body weight, by oral intubation), then treated with high dose of CPF (30 mg/kg body weight) and or exposure to IR (single dose of 6 Gy whole body gamma ray) one hour after BSO treatment. Another groups of animals pertreated with N-acetyl cystiene (NAC) one hour before treated with CPF and/or IR. After 24 hours blood sample, liver and brain were taken and used for estimate the GSH level and the activities of glutathione-stransferase (GST), glutathione reductase (GR), acetyl cholinesterase (AChE), carboxyl esterase (CE), paraoxonase (PON) and arylesterase (AE). Also, native PAGE electrophoresis was undertaken for separating the CE and PON isozymes in plasma, liver and brain. The results indicated that CPF produced no change in GSH level. Whereas, treatment with either BSO or IR, produced decrease in GSH level. NAC restored GSH level near the control level in all treated groups CPF had no effect on GST activity and pretreatment with either BSO or NAC increased GST activity in CPF treated groups. Also, exposure to IR had no effect on GST activity. Whereas, IR in combination with CPF and/or NAC and/or BSO produced inhibition in plasma GST activity and increased liver GST activity. In addition, both CPF and IR had no effect on the activity of GR. Whereas, pre-treatment with either BSO or NAC produced inhibition in plasma and liver GR activity in CPF treated groups. No change had observed in the IR exposed groups. Treatment with CPF inhibited AChE activity in plasma, liver and brain. Whereas, exposure to IR inhibited AChE activity in brain only

Routing of high data rate signals using degenerate four wave mixing in BSO

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West, C. L.; Hazell, M. S.

Non-linear optical phase conjugation can be directly applied to real time spatial and/or temporal information processing of electromagnetic waves. In photorefractive materials the process may be described in terms of dynamic holography. The speed at which grating formation takes place is limited by the physical properties of the crystal and the intensities of the optical beams used to write the grating. The speed at which diffraction may occur from this grating does not, however, suffer such limitations and in this memorandum we demonstrate the use of degenerate four wave mixing in BSO to direct the flow of data whose information bandwidth exceeds 1MHz.

Combined effects of food deprivation and food frequency on the amount and temporal distribution of schedule-induced drinking.

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Castilla, José Luis; Pellón, Ricardo

2013-11-01

Under intermittent food schedules animals develop temporally organized behaviors throughout interfood intervals, with behaviors early in the intervals (interim) normally occurring in excess. Schedule-induced drinking (a prototype of interim, adjunctive behavior) is related to food deprivation and food frequency. This study investigated the interactions that resulted from combining different food-deprivation levels (70%, 80% or 90% free-feeding weights) with different food-occurrence frequencies (15-, 30- or 60-s interfood intervals) in a within-subjects design. Increases in food deprivation and food frequency generally led to increased licking, with greater differences due to food deprivation as interfood intervals became shorter. Distributions of licking were modestly shifted to later in the interfood interval as interfood intervals lengthened, a result that was most marked under 90% food deprivation, which also resulted in flatter distributions. It would therefore appear that food deprivation modulates the licking rate and the distribution of licking in different ways. Effects of food deprivation and food frequency are adequately explained by a theory of adjunctive behavior based on delayed food reinforcement, in contrast to alternative hypotheses. © Society for the Experimental Analysis of Behavior.

Glutathione Redox System in β-Thalassemia/Hb E Patients

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Ruchaneekorn W. Kalpravidh

2013-01-01

Full Text Available β-thalassemia/Hb E is known to cause oxidative stress induced by iron overload. The glutathione system is the major endogenous antioxidant that protects animal cells from oxidative damage. This study aimed to determine the effect of disease state and splenectomy on redox status expressed by whole blood glutathione (GSH/glutathione disulfide (GSSG and also to evaluate glutathione-related responses to oxidation in β-thalassemia/Hb E patients. Twenty-seven normal subjects and 25 β-thalassemia/Hb E patients were recruited and blood was collected. The GSH/GSSG ratio, activities of glutathione-related enzymes, hematological parameters, and serum ferritin levels were determined in individuals. Patients had high iron-induced oxidative stress, shown as significantly increased serum ferritin, a decreased GSH/GSSG ratio, and increased activities of glutathione-related enzymes. Splenectomy increased serum ferritin levels and decreased GSH levels concomitant with unchanged glutathione-related enzyme activities. The redox ratio had a positive correlation with hemoglobin levels and negative correlation with levels of serum ferritin. The glutathione system may be the body’s first-line defense used against oxidative stress and to maintain redox homeostasis in thalassemic patients based on the significant correlations between the GSH/GSSH ratio and degree of anemia or body iron stores.

Glutathione may have implications in the design of 3-bromopyruvate treatment protocols for both fungal and algal infections as well as multiple myeloma.

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Niedźwiecka, Katarzyna; Dyląg, Mariusz; Augustyniak, Daria; Majkowska-Skrobek, Grażyna; Cal-Bąkowska, Magdalena; Ko, Young H; Pedersen, Peter L; Goffeau, Andre; Ułaszewski, Stanisław

2016-10-04

In different fungal and algal species, the intracellular concentration of reduced glutathione (GSH) correlates closely with their susceptibility to killing by the small molecule alkylating agent 3-bromopyruvate (3BP). Additionally, in the case of Cryptococcus neoformans cells 3BP exhibits a synergistic effect with buthionine sulfoximine (BSO), a known GSH depletion agent. This effect was observed when 3BP and BSO were used together at concentrations respectively of 4-5 and almost 8 times lower than their Minimal Inhibitory Concentration (MIC). Finally, at different concentrations of 3BP (equal to the half-MIC, MIC and double-MIC in a case of fungi, 1 mM and 2.5 mM for microalgae and 25, 50, 100 μM for human multiple myeloma (MM) cells), a significant decrease in GSH concentration is observed inside microorganisms as well as tumor cells. In contrast to the GSH concentration decrease, the presence of 3BP at concentrations corresponding to sub-MIC values or half maximal inhibitory concentration (IC50) clearly results in increasing the expression of genes encoding enzymes involved in the synthesis of GSH in Cryptococcus neoformans and MM cells. Moreover, as shown for the first time in the MM cell model, the drastic decrease in the ATP level and GSH concentration and the increase in the amount of ROS caused by 3BP ultimately results in cell death.

Rapid eye movement sleep deprivation induces an increase in acetylcholinesterase activity in discrete rat brain regions

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Benedito M.A.C.

2001-01-01

Full Text Available Some upper brainstem cholinergic neurons (pedunculopontine and laterodorsal tegmental nuclei are involved in the generation of rapid eye movement (REM sleep and project rostrally to the thalamus and caudally to the medulla oblongata. A previous report showed that 96 h of REM sleep deprivation in rats induced an increase in the activity of brainstem acetylcholinesterase (Achase, the enzyme which inactivates acetylcholine (Ach in the synaptic cleft. There was no change in the enzyme's activity in the whole brain and cerebrum. The components of the cholinergic synaptic endings (for example, Achase are not uniformly distributed throughout the discrete regions of the brain. In order to detect possible regional changes we measured Achase activity in several discrete rat brain regions (medulla oblongata, pons, thalamus, striatum, hippocampus and cerebral cortex after 96 h of REM sleep deprivation. Naive adult male Wistar rats were deprived of REM sleep using the flower-pot technique, while control rats were left in their home cages. Total, membrane-bound and soluble Achase activities (nmol of thiocholine formed min-1 mg protein-1 were assayed photometrically. The results (mean ± SD obtained showed a statistically significant (Student t-test increase in total Achase activity in the pons (control: 147.8 ± 12.8, REM sleep-deprived: 169.3 ± 17.4, N = 6 for both groups, P<0.025 and thalamus (control: 167.4 ± 29.0, REM sleep-deprived: 191.9 ± 15.4, N = 6 for both groups, P<0.05. Increases in membrane-bound Achase activity in the pons (control: 171.0 ± 14.7, REM sleep-deprived: 189.5 ± 19.5, N = 6 for both groups, P<0.05 and soluble enzyme activity in the medulla oblongata (control: 147.6 ± 16.3, REM sleep-deprived: 163.8 ± 8.3, N = 6 for both groups, P<0.05 were also observed. There were no statistically significant differences in the enzyme's activity in the other brain regions assayed. The present findings show that the increase in Achase activity

Glutathione.

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Noctor, Graham; Queval, Guillaume; Mhamdi, Amna; Chaouch, Sejir; Foyer, Christine H

2011-01-01

Glutathione is a simple sulfur compound composed of three amino acids and the major non-protein thiol in many organisms, including plants. The functions of glutathione are manifold but notably include redox-homeostatic buffering. Glutathione status is modulated by oxidants as well as by nutritional and other factors, and can influence protein structure and activity through changes in thiol-disulfide balance. For these reasons, glutathione is a transducer that integrates environmental information into the cellular network. While the mechanistic details of this function remain to be fully elucidated, accumulating evidence points to important roles for glutathione and glutathione-dependent proteins in phytohormone signaling and in defense against biotic stress. Work in Arabidopsis is beginning to identify the processes that govern glutathione status and that link it to signaling pathways. As well as providing an overview of the components that regulate glutathione homeostasis (synthesis, degradation, transport, and redox turnover), the present discussion considers the roles of this metabolite in physiological processes such as light signaling, cell death, and defense against microbial pathogen and herbivores.

The Effect of Exercise on Learning and Spatial Memory Following Stress-Induced Sleep Deprivation (Sleep REM in Rats

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Darkhah

2016-04-01

Full Text Available Background Stress induced by sleep deprivation can cause degradation of learning in the acquisition phase, and low-intensity exercise can prevent the negative effects of stress. Objectives The aim of this study was to investigate the moderating role of aerobic exercise on spatial memory and learning following stress-induced insomnia (sleep REM in animal models. Materials and Methods This experimental study was conducted on adult male Wistar rats that were randomly divided into two groups. Both groups were exposed to sleep deprivation induced stress, following which the experimental group was exposed to exercise training (experimental, n = 8; control, n = 8. The stress intervention was undertaken through 24 hours of sleep deprivation using a modified sleep deprivation platform (MMD. The exercise protocol included mild aerobic exercise on a treadmill (30 minutes a day, seven days, and Morris Water Maze (MWM protocols were applied to assess spatial memory and learning. Data were analyzed by an independent t-test and dependent t-test. Results The results showed that, after seven days of aerobic exercise on a treadmill, the experimental group showed better performance escape latency (P < 0.05 and distance traveled (P < 0.05 than the control group in the MWM, while there was no difference between these two groups in the pre-test. Conclusions The role of exercise is greater in the retention than the acquisition phase for recalling past experiences.

Intracellular glutathione status regulates mouse bone marrow monocyte-derived macrophage differentiation and phagocytic activity

International Nuclear Information System (INIS)

Kim, Jin-Man; Kim, Hyunsoo; Kwon, Soon Bok; Lee, Soo Young; Chung, Sung-Chang; Jeong, Dae-Won; Min, Byung-Moo

2004-01-01

Although a redox shift can regulate the development of cells, including proliferation, differentiation, and survival, the role of the glutathione (GSH) redox status in macrophage differentiation remains unclear. In order to elucidate the role of a redox shift, macrophage-like cells were differentiated from the bone marrow-derived monocytes that were treated with a macrophage colony stimulating factor (M-CSF or CSF-1) for 3 days. The macrophagic cells were characterized by a time-dependent increase in three major symptoms: the number of phagocytic cells, the number of adherent cells, and the mRNA expression of c-fms, a M-CSF receptor that is one of the macrophage-specific markers and mediates development signals. Upon M-CSF-driven macrophage differentiation, the GSH/GSSG ratio was significantly lower on day 1 than that observed on day 0 but was constant on days 1-3. To assess the effect of the GSH-depleted and -repleted status on the differentiation and phagocytosis of the macrophages, GSH depletion by BSO, a specific inhibitor of the de novo GSH synthesis, inhibited the formation of the adherent macrophagic cells by the down-regulation of c-fms, but did not affect the phagocytic activity of the macrophages. To the contrary, GSH repletion by the addition of NAC, which is a GSH precursor, or reduced GSH in media had no effect on macrophage differentiation, and led to a decrease in the phagocytic activity. Furthermore, we observed that there is checkpoint that is capable of releasing from the inhibition of the formation of the adherent macrophagic cells according to GSH depletion by BSO. Summarizing, these results indicate that the intracellular GSH status plays an important role in the differentiation and phagocytosis of macrophages

REM sleep deprivation induces endothelial dysfunction and hypertension in middle-aged rats: Roles of the eNOS/NO/cGMP pathway and supplementation with L-arginine.

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Jiang, Jiaye; Gan, Zhongyuan; Li, Yuan; Zhao, Wenqi; Li, Hanqing; Zheng, Jian-Pu; Ke, Yan

2017-01-01

Sleep loss can induce or aggravate the development of cardiovascular and cerebrovascular diseases. However, the molecular mechanism underlying this phenomenon is poorly understood. The present study was designed to investigate the effects of REM sleep deprivation on blood pressure in rats and the underlying mechanisms of these effects. After Sprague-Dawley rats were subjected to REM sleep deprivation for 5 days, their blood pressures and endothelial function were measured. In addition, one group of rats was given continuous access to L-arginine supplementation (2% in distilled water) for the 5 days before and the 5 days of REM sleep deprivation to reverse sleep deprivation-induced pathological changes. The results showed that REM sleep deprivation decreased body weight, increased blood pressure, and impaired endothelial function of the aortas in middle-aged rats but not young rats. Moreover, nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) concentrations as well as endothelial NO synthase (eNOS) phosphorylation in the aorta were decreased by REM sleep deprivation. Supplementation with L-arginine could protect against REM sleep deprivation-induced hypertension, endothelial dysfunction, and damage to the eNOS/NO/cGMP signaling pathway. The results of the present study suggested that REM sleep deprivation caused endothelial dysfunction and hypertension in middle-aged rats via the eNOS/NO/cGMP pathway and that these pathological changes could be inhibited via L-arginine supplementation. The present study provides a new strategy to inhibit the signaling pathways involved in insomnia-induced or insomnia-enhanced cardiovascular diseases.

Piracetam ameliorated oxygen and glucose deprivation-induced injury in rat cortical neurons via inhibition of oxidative stress, excitatory amino acids release and P53/Bax.

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He, Zhi; Hu, Min; Zha, Yun-hong; Li, Zi-cheng; Zhao, Bo; Yu, Ling-ling; Yu, Min; Qian, Ying

2014-05-01

Our previous work has demonstrated that piracetam inhibited the decrease in amino acid content induced by chronic hypoperfusion, ameliorated the dysfunction of learning and memory in a hypoperfusion rat model, down-regulated P53, and BAX protein, facilitated the synaptic plasticity, and may be helpful in the treatment of vascular dementia. To explore the precise mechanism, the present study further evaluated effects of piracetam on Oxygen and glucose deprivation (OGD)-induced neuronal damage in rat primary cortical cells. The addition of piracetam to the cultured cells 12 h before OGD for 4 h significantly reduced neuronal damage as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and lactate dehydrogenase release experiments. Piracetam also lowered the levels of malondialdehyde, nitrogen monoxidum, and xanthine oxidase which was increased in the OGD cells, and enhanced the activities of superoxide dismutase and glutathione peroxidase, which were decreased in the OGD cells. We also demonstrated that piracetam could decrease glutamate and aspartate release when cortical cells were subjected to OGD. Furthermore, Western blot study demonstrated that piracetam attenuated the increased expression of P53 and BAX protein in OGD cells. These observations demonstrated that piracetam reduced OGD-induced neuronal damage by inhibiting the oxidative stress and decreasing excitatory amino acids release and lowering P53/Bax protein expression in OGD cells.

A rare cause of drug-induced hepatitis in an immunocompromised patient and the role of glutathione.

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Senadhi, Viplove; Arora, Deepika; Arora, Manish; Marsh, Franklin

2012-08-27

The Food and Drug Administration (FDA) has issued a warning on numerous herbal drugs, including many popular products at General Nutrition Centers (GNC), regarding unstudied hepatotoxicity. There have been recent reports of GNC products such as hydroxycut and herbalife, causing drug-induced hepatitis. Herbal medications are over-the-counter products and are not investigated thoroughly by the FDA. Given that the most common outpatient laboratory abnormality is elevated liver transaminases, a sign of hepatocellular toxicity; it is not surprising that some of these products end up causing hepatic dysfunction, especially when taken in large volume. There are numerous herbal supplements that are hepatotoxic, however, these medications have a much more significant effect in human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome patients, which is secondary to depleted glutathione. We present a rare case of drug induced hepatitis secondary to herbal medications used to treat HIV and elucidate the role of glutathione depletion in immunocompromised patients.

Neuroprotective effects of orientin on oxygen-glucose deprivation/reperfusion-induced cell injury in primary culture of rat cortical neurons.

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Tian, Tian; Zeng, Junan; Zhao, Guangyu; Zhao, Wenjing; Gao, Songyi; Liu, Li

2018-01-01

Orientin (luteolin-8-C-glucoside) is a phenolic compound found abundantly in millet, juice, and peel of passion fruit and has been shown to have antioxidant properties. In the present study, we explored the effects of orientin on oxygen-glucose deprivation/reperfusion (OGD/RP)-induced cell injury in primary culture of rat cortical neurons using an in vitro model of neonatal ischemic brain injury. The reduced cell viability and elevated lactate dehydrogenase leakage were observed after OGD/RP exposure, which were then reversed by orientin (10, 20, and 30 µM) pretreatment in a dose-dependent manner. Additionally, OGD/RP treatment resulted in significant oxidative stress, accompanied by enhanced intracellular reactive oxygen species (ROS) generation, and obvious depletion in the activities of intracellular Mn-superoxide dismutase, catalase, and glutathione peroxidase antioxidases. However, these effects were dose dependently restored by orientin pretreatment. We also found that orientin pretreatment dose dependently suppressed [Ca 2+ ] i increase and mitochondrial membrane potential dissipation caused by OGD/RP in primary culture of rat cortical neurons. Western blot analysis showed that OGD/RP exposure induced a distinct decrease of Bcl-2 protein and a marked elevation of Bax, caspase-3, and cleaved caspase-3 proteins; whereas these effects were dose dependently reversed by orientin incubation. Both the caspase-3 activity and the apoptosis rate were increased under OGD/RP treatment, but was then dose dependently down-regulated by orientin (10, 20, and 30 µM) incubation. Moreover, orientin pretreatment dose dependently inhibited OGD/RP-induced phosphorylation of JNK and ERK1/2. Notably, JNK inhibitor SP600125 and ERK1/2 inhibitor PD98059 also dramatically attenuated OGD/RP-induced cell viability loss and ROS generation, and further, orientin failed to protect cortical neurons with the interference of JNK activator anisomycin or ERK1/2 activator FGF-2. Taken

Melatonin modulates adiponectin expression on murine colitis with sleep deprivation.

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Kim, Tae Kyun; Park, Young Sook; Baik, Haing-Woon; Jun, Jin Hyun; Kim, Eun Kyung; Sull, Jae Woong; Sung, Ho Joong; Choi, Jin Woo; Chung, Sook Hee; Gye, Myung Chan; Lim, Ju Yeon; Kim, Jun Bong; Kim, Seong Hwan

2016-09-07

To determine adiponectin expression in colonic tissue of murine colitis and systemic cytokine expression after melatonin treatments and sleep deprivation. The following five groups of C57BL/6 mice were used in this study: (1) group I, control; (2) group II, 2% DSS induced colitis for 7 d; (3) group III, 2% DSS induced colitis and melatonin treatment; (4) group IV, 2% DSS induced colitis with sleep deprivation (SD) using specially designed and modified multiple platform water baths; and (5) group V, 2% DSS induced colitis with SD and melatonin treatment. Melatonin (10 mg/kg) or saline was intraperitoneally injected daily to mice for 4 d. The body weight was monitored daily. The degree of colitis was evaluated histologically after sacrificing the mice. Immunohistochemical staining and Western blot analysis was performed using anti-adiponectin antibody. After sampling by intracardiac punctures, levels of serum cytokines were measured by ELISA. Sleep deprivation in water bath exacerbated DSS induced colitis and worsened weight loss. Melatonin injection not only alleviated the severity of mucosal injury, but also helped survival during stressful condition. The expression level of adiponectin in mucosa was decreased in colitis, with the lowest level observed in colitis combined with sleep deprivation. Melatonin injection significantly (P sleep deprivation.

Ursolic Acid-enriched herba cynomorii extract induces mitochondrial uncoupling and glutathione redox cycling through mitochondrial reactive oxygen species generation: protection against menadione cytotoxicity in h9c2 cells.

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Chen, Jihang; Wong, Hoi Shan; Ko, Kam Ming

2014-01-27

Herba Cynomorii (Cynomorium songaricum Rupr., Cynomoriaceae) is one of the most commonly used 'Yang-invigorating' tonic herbs in Traditional Chinese Medicine (TCM). An earlier study in our laboratory has demonstrated that HCY2, an ursolic acid-enriched fraction derived from Herba Cynomorii, increased mitochondrial ATP generation capacity (ATP-GC) and induced mitochondrial uncoupling as well as a cellular glutathione response, thereby protecting against oxidant injury in H9c2 cells. In this study, we demonstrated that pre-incubation of H9c2 cells with HCY2 increased mitochondrial reactive oxygen species (ROS) generation in these cells, which is likely an event secondary to the stimulation of the mitochondrial electron transport chain. The suppression of mitochondrial ROS by the antioxidant dimethylthiourea abrogated the HCY2-induced enhancement of mitochondrial uncoupling and glutathione reductase (GR)-mediated glutathione redox cycling, and also protected against menadione-induced cytotoxicity. Studies using specific inhibitors of uncoupling protein and GR suggested that the HCY2-induced mitochondrial uncoupling and glutathione redox cycling play a determining role in the cytoprotection against menadione-induced oxidant injury in H9c2 cells. Experimental evidence obtained thus far supports the causal role of HCY2-induced mitochondrial ROS production in eliciting mitochondrial uncoupling and glutathione antioxidant responses, which offer cytoprotection against oxidant injury in H9c2 cells.

Sodium nitroprusside induces autophagic cell death in glutathione-depleted osteoblasts.

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Son, Min Jeong; Lee, Seong-Beom; Byun, Yu Jeong; Lee, Hwa Ok; Kim, Ho-Shik; Kwon, Oh-Joo; Jeong, Seong-Whan

2010-01-01

Previous studies reported that high levels of nitric oxide (NO) induce apoptotic cell death in osteoblasts. We examined molecular mechanisms of cytotoxic injury induced by sodium nitroprusside (SNP), a NO donor, in both glutathione (GSH)-depleted and control U2-OS osteoblasts. Cell viability was reduced by much lower effective concentrations of SNP in GSH-depleted cells compared to normal cells. The data suggest that the level of intracellular GSH is critical in SNP-induced cell death processes of osteoblasts. The level of oxidative stress due to SNP treatments doubled in GSH-depleted cells when measured with fluorochrome H2DCFDA. Pretreatment with the NO scavenger PTIO preserved the viability of cells treated with SNP. Viability of cells treated with SNP was recovered by pretreatment with Wortmannin, an autophagy inhibitor, but not by pretreatment with zVAD-fmk, a pan-specific caspase inhibitor. Large increases of LC3-II were shown by immunoblot analysis of the SNP-treated cells, and the increase was blocked by pretreatment with PTIO or Wortmannin; this implies that under GSH-depleted conditions SNP induces different molecular signaling that lead to autophagic cell death. The ultrastructural morphology of SNP-treated cells in transmission electron microscopy showed numerous autophagic vacuoles. These data suggest NO produces oxidative stress and cellular damage that culminate in autophagic cell death of GSH-depleted osteoblasts. Copyright 2010 Wiley Periodicals, Inc.

The Degree of Radiation-Induced DNA Strand Breaks Is Altered by Acute Sleep Deprivation and Psychological Stress and Is Associated with Cognitive Performance in Humans.

Science.gov (United States)

Moreno-Villanueva, Maria; von Scheven, Gudrun; Feiveson, Alan; Bürkle, Alexander; Wu, Honglu; Goel, Namni

2018-03-27

Sleep deprivation is associated with impaired immune responses, cancer, and morbidity and mortality, and can degrade cognitive performance, although individual differences exist in such responses. Sleep deprivation induces DNA strand breaks and DNA base oxidation in animals, and psychological stress is associated with increased DNA damage in humans. It remains unknown whether sleep deprivation or psychological stress in humans affects DNA damage response from environmental stressors, and whether these responses predict cognitive performance during sleep deprivation. Sixteen healthy adults (ages 29-52;mean age±SD, 36.4±7.1 years;7 women) participated in a 5-day experiment involving two 8 hour time-in-bed [TIB] baseline nights, followed by 39 hours total sleep deprivation (TSD), and two 8-10 hour TIB recovery nights. A modified Trier Social Stress Test was conducted on the day after TSD. Psychomotor Vigilance Tests measured behavioral attention. DNA damage was assessed in blood cells collected at 5 time points, and blood cells were irradiated ex-vivo. TSD, alone or in combination with psychological stress, did not induce significant increases in DNA damage. By contrast, radiation-induced DNA damage decreased significantly in response to TSD, but increased back to baseline when combined with psychological stress. Cognitively-vulnerable individuals had more radiation-induced DNA strand breaks before TSD, indicating their greater sensitivity to DNA damage from environmental stressors. Our results provide novel insights into the molecular consequences of sleep deprivation, psychological stress, and performance vulnerability. They are important for situations involving sleep loss, radiation exposure and cognitive deficits, including cancer therapy, environmental toxicology, and space medicine.

Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells*

Science.gov (United States)

Pei, Shanshan; Minhajuddin, Mohammad; Callahan, Kevin P.; Balys, Marlene; Ashton, John M.; Neering, Sarah J.; Lagadinou, Eleni D.; Corbett, Cheryl; Ye, Haobin; Liesveld, Jane L.; O'Dwyer, Kristen M.; Li, Zheng; Shi, Lei; Greninger, Patricia; Settleman, Jeffrey; Benes, Cyril; Hagen, Fred K.; Munger, Joshua; Crooks, Peter A.; Becker, Michael W.; Jordan, Craig T.

2013-01-01

The development of strategies to eradicate primary human acute myelogenous leukemia (AML) cells is a major challenge to the leukemia research field. In particular, primitive leukemia cells, often termed leukemia stem cells, are typically refractory to many forms of therapy. To investigate improved strategies for targeting of human AML cells we compared the molecular mechanisms regulating oxidative state in primitive (CD34+) leukemic versus normal specimens. Our data indicate that CD34+ AML cells have elevated expression of multiple glutathione pathway regulatory proteins, presumably as a mechanism to compensate for increased oxidative stress in leukemic cells. Consistent with this observation, CD34+ AML cells have lower levels of reduced glutathione and increased levels of oxidized glutathione compared with normal CD34+ cells. These findings led us to hypothesize that AML cells will be hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as parthenolide (PTL) or piperlongumine that induce almost complete glutathione depletion and severe cell death in CD34+ AML cells. Importantly, these compounds only induce limited and transient glutathione depletion as well as significantly less toxicity in normal CD34+ cells. We further determined that PTL perturbs glutathione homeostasis by a multifactorial mechanism, which includes inhibiting key glutathione metabolic enzymes (GCLC and GPX1), as well as direct depletion of glutathione. These findings demonstrate that primitive leukemia cells are uniquely sensitive to agents that target aberrant glutathione metabolism, an intrinsic property of primary human AML cells. PMID:24089526

Expression of inducible nitric oxide synthase in endotoxemic rat hepatocytes is dependent on the cellular glutathione status

NARCIS (Netherlands)

Vos, TA; van Goor, H; Tuyt, L; de Jager-Krikken, A; Leuvenink, R; Kuipers, F; Jansen, PLM; Moshage, H

The inducible nitric oxide synthase (iNOS) promoter contains nuclear factor kappa B (NF-kappa B) binding sites. NF-kappa B activation is determined, in part, by the intracellular redox status, The aim of this study was to determine the importance of the cellular glutathione status in relation to

Comparison of form-deprived myopia and lens-induced myopia in guinea pigs

Directory of Open Access Journals (Sweden)

Hui Xiao

2014-04-01

Full Text Available AIM: To study the efficacy difference between form-deprived myopia (FDM and lens-induced myopia (LIM, the degree of myopia, axial length and pathological changes of the posterior sclera from guinea pigs were evaluated.METHODS: Four-week pigmented guinea pigs were randomly assigned into 3 groups, including normal control (n=6, FDM group with monocular cover (n=11 and LIM group with monocular -7D lens treatment (n=11. FDM group was form-deprived while LIM group was lens-induced for 14 d. Refractive error and axial length were measured prior to and post treatment, respectively. Morphological changes of sclera were examined using both light and electronic microscopes.RESULTS: After 14d treatment, refractive errors for FDM group and LIM group were -3.05±0.71D and -2.12±1.29D, respectively, which were significantly more myopic than that of normal controls and fellow control eyes (P<0.01. As for axial length, it was 7.93±0.03 mm for FDM group and 7.89±0.06 mm for LIM group, which were significantly longer than both normal and fellow controls (P<0.01. With respect to both refractory error and axial length, the differences between FDM group and LIM group were not significant (P>0.05. Under light microscope, both FDM group and LIM group showed thinned sclera, disarrangement of fibrosis and enlarged disassociation between fibers. Consistently, ultrastructural examination showed degenerated fibroblasts and thinned fibers in posterior sclera.CONCLUSION:Following two weeks of myopia induction in guinea pigs, with regard to the degree of myopia, axial length and pathological alterations, there was no significant difference between FDM and LIM models. Therefore, FDM and LIM are equally effective and useful as a model of experimental myopia and guinea pigs are ideal animals for induction of experimental myopia because their high sensitivity to both form-deprivation and lens-induction.

Inhibition of glutathione biosynthesis alters compartmental redox status and the thiol proteome in organogenesis-stage rat conceptuses.

Science.gov (United States)

Harris, Craig; Shuster, Daniel Z; Roman Gomez, Rosaicela; Sant, Karilyn E; Reed, Matthew S; Pohl, Jan; Hansen, Jason M

2013-10-01

Developmental signals that control growth and differentiation are regulated by environmental factors that generate reactive oxygen species (ROS) and alter steady-state redox environments in tissues and fluids. Protein thiols are selectively oxidized and reduced in distinct spatial and temporal patterns in conjunction with changes in glutathione/glutathione disulfide (GSH/GSSG) and cysteine/cystine (Cys/CySS) redox potentials (E(h)) to regulate developmental signaling. The purpose of this study was to measure compartment-specific thiol redox status in cultured organogenesis-stage rat conceptuses and to evaluate the impact of thiol oxidation on the redox proteome. The visceral yolk sac (VYS) has the highest initial (0 h) total intracellular GSH (GSH+2GSSG) concentration (5.5 mM) and the lowest Eh (-223 mV) as determined by HPLC analysis. Total embryo (EMB) GSH concentrations ranged lower (3.2 mM) and were only slightly more oxidized than the VYS. Total GSH concentrations in yolk sac fluid (YSF) and amniotic fluid (AF) are >500-fold lower than in tissues and are highly oxidized (YSF E(h)=-121 mV and AF E(h)=-49 mV). Steady-state total Cys concentrations (Cys+2CySS) were significantly lower than GSH in tissues but were otherwise equal in VYS and EMB near 0.5 mM. On gestational day 11, total GSH and Cys concentrations in EMB and VYS increase significantly over the 6h time course while E(h) remains relatively constant. The Eh (GSH/GSSG) in YSF and AF become more reduced over time while E(h) (Cys/CySS) become more oxidized. Addition of L-buthionine-S,R-sulfoximine (BS0) to selectively inhibit GSH synthesis and mimic the effects of some GSH-depleting environmental chemicals significantly decreased VYS and EMB GSH and Cys concentrations and increased Eh over the 6h exposure period, showing a greater overall oxidation. In the YSF, BSO caused a significant increase in total Cys concentrations to 1.7 mM but did not significantly change the E(h) for Cys/CySS. A significant net

Studies on the effects of lead toxicity on glutathione metabolism in the chick

International Nuclear Information System (INIS)

McGowan, C.

1985-01-01

Studies were performed to investigate certain aspects of lead toxicity in the chick. In the first study, the mechanism of the Pb-induced changes in glutathione (GSH) metabolism was examined by comparing changes in organ non-protein thiol concentrations during the administration of Pb by intraperitoneal injection (acute) or in the diet (chronic). The synthesis of GSH in the liver was increased by both acute and chronic Pb administration when evaluated in terms of the rate of incorporation of [I 14 C]-glycine into hepatic GSH. Total nonprotein sulfhydryl (NPSH) concentrations were also increased by both acute and chronic Pb. However, that portion of NPSH which is GSH was increased only by prolonged (chronic) exposure to Pb. The administration of buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, decreased hepatic HPDH and GSH concentrations both in the presence and absence of injected Pb and inhibited the effects of dietary Pb on hepatic NPSH and GSH concentrations. The data suggested an immediate release of NPSH compounds into blood plasma following acute PB injection. Thus, the interorgan translocation system for GSH may be important in acute Pb intoxication in that it facilitates an immediate response to maintain cellular GSH levels being depleted by detoxification reactions by increasing the rate of GSH turnover. The antagonistic relationship between Pb and Se was investigated in terms of chick body weight gain and changes in organ non-protein thiol concentrated when administered with diets containing deficient adequate, and excess amounts of Se. Growth depression by 2000 ppm dietary Pb was observed with diets that were either deficient or adequate in dietary Se

Monocular Visual Deprivation Suppresses Excitability in Adult Human Visual Cortex

DEFF Research Database (Denmark)

Lou, Astrid Rosenstand; Madsen, Kristoffer Hougaard; Paulson, Olaf Bjarne

2011-01-01

The adult visual cortex maintains a substantial potential for plasticity in response to a change in visual input. For instance, transcranial magnetic stimulation (TMS) studies have shown that binocular deprivation (BD) increases the cortical excitability for inducing phosphenes with TMS. Here, we...... of visual deprivation has a substantial impact on experience-dependent plasticity of the human visual cortex.......The adult visual cortex maintains a substantial potential for plasticity in response to a change in visual input. For instance, transcranial magnetic stimulation (TMS) studies have shown that binocular deprivation (BD) increases the cortical excitability for inducing phosphenes with TMS. Here, we...... employed TMS to trace plastic changes in adult visual cortex before, during, and after 48 h of monocular deprivation (MD) of the right dominant eye. In healthy adult volunteers, MD-induced changes in visual cortex excitability were probed with paired-pulse TMS applied to the left and right occipital cortex...

Glucose Deprivation Triggers Protein Kinase C-dependent β-Catenin Proteasomal Degradation*

Science.gov (United States)

Choi, Seung-Won; Song, Jun-Kyu; Yim, Ye-Seal; Yun, Ho-Geun; Chun, Kyung-Hee

2015-01-01

Autophagy is a conserved process that contributes to cell homeostasis. It is well known that induction mainly occurs in response to nutrient starvation, such as starvation of amino acids and insulin, and its mechanisms have been extensively characterized. However, the mechanisms behind cellular glucose deprivation-induced autophagy are as of now poorly understood. In the present study, we determined a mechanism by which glucose deprivation induced the PKC-dependent proteasomal degradation of β-catenin, leading to autophagy. Glucose deprivation was shown to cause a sub-G1 transition and enhancement of the LC3-II protein levels, whereas β-catenin protein underwent degradation in a proteasome-dependent manner. Moreover, the inhibition of GSK3β was unable to abolish the glucose deprivation-mediated β-catenin degradation or up-regulation of LC3-II protein levels, which suggested GSK3β-independent protein degradation. Intriguingly, the inhibition of PKCα using a pharmacological inhibitor and transfection of siRNA for PKCα was observed to effectively block glucose deprivation-induced β-catenin degradation as well as the increase in LC3-II levels and the accumulation of a sub-G1 population. Together, our results demonstrated a molecular mechanism by which glucose deprivation can induce the GSK3β-independent protein degradation of β-catenin, leading to autophagy. PMID:25691573

Was cultural deprivation in fact sensory deprivation? Deprivation, retardation and intervention in the USA.

Science.gov (United States)

Raz, Mical

2011-01-01

In the 1950s, the term "deprivation" entered American psychiatric discourse. This article examines how the concept of deprivation permeated the field of mental retardation, and became an accepted theory of etiology. It focuses on sensory deprivation and cultural deprivation, and analyzes the interventions developed, based on these theories. It argues that the controversial theory of cultural deprivation derived its scientific legitimization from the theory of sensory deprivation, and was a highly politicized concept that took part in the nature-nurture debate.

L-Cysteine in vitro can restore cellular glutathione and inhibits the expression of cell adhesion molecules in G6PD-deficient monocytes.

Science.gov (United States)

Parsanathan, Rajesh; Jain, Sushil K

2018-04-06

L-Cysteine is a precursor of glutathione (GSH), a potent physiological antioxidant. Excess glucose-6-phosphate dehydrogenase (G6PD) deficiency in African Americans and low levels of L-cysteine diet in Hispanics can contributes to GSH deficiency and oxidative stress. Oxidative stress and monocyte adhesion was considered to be an initial event in the progression of vascular dysfunction and atherosclerosis. However, no previous study has investigated the contribution of GSH/G6PD deficiency to the expression of monocyte adhesion molecules. Using human U937 monocytes, this study examined the effect of GSH/G6PD deficiency and L-cysteine supplementation on monocyte adhesion molecules. G6PD/GSH deficiency induced by either siRNA or inhibitors (6AN/BSO, respectively) significantly (p adhesion molecules (ICAM-1, VCAM-1, SELL, ITGB1 and 2); NADPH oxidase (NOX), reactive oxygen species (ROS) and MCP-1 were upregulated, and decreases in levels of GSH, and nitric oxide were observed. The expression of ICAM-1 and VCAM-1 mRNA levels increased in high glucose, MCP-1 or TNF-α-treated G6PD-deficient compared to G6PD-normal cells. L-Cysteine treatment significantly (p adhesion molecules. Thus, GSH/G6PD deficiency increases susceptibility to monocyte adhesion processes, whereas L-cysteine supplementation can restore cellular GSH/G6PD and attenuates NOX activity and expression of cell adhesion molecules.

Effects of paternal deprivation on cocaine-induced behavioral response and hypothalamic oxytocin immunoreactivity and serum oxytocin level in female mandarin voles.

Science.gov (United States)

Wang, Jianli; Fang, Qianqian; Yang, Chenxi

2017-09-15

Early paternal behavior plays a critical role in behavioral development in monogamous species. The vast majority of laboratory studies investigating the influence of parental behavior on cocaine vulnerability focus on the effects of early maternal separation. However, comparable studies on whether early paternal deprivation influences cocaine-induced behavioral response are substantially lacking. Mandarin vole (Microtus mandarinus) is a monogamous rodent with high levels of paternal care. After mandarin vole pups were subjected to early paternal deprivation, acute cocaine- induced locomotion, anxiety- like behavior and social behavior were examined in 45day old female pups, while hypothalamic oxytocin immunoreactivity and serum oxytocin level were also assessed. We found that cocaine increased locomotion and decreased social investigation, contact behavior and serum oxytocin level regardless of paternal care. Cocaine increased anxiety levels and decreased oxytocin immunoreactive neurons of the paraventricular nuclei and supraoptic nuclei in the bi-parental care group, whilst there were no specific effects in the paternal deprivation group. These results indicate that paternal deprivation results in different behavioral response to acute cocaine exposure in adolescents, which may be in part associated with the alterations in oxytocin immunoreactivity and peripheral OT level. Copyright © 2017 Elsevier B.V. All rights reserved.

Dopamine antagonists and brief vision distinguish lens-induced- and form-deprivation-induced myopia.

Science.gov (United States)

Nickla, Debora L; Totonelly, Kristen

2011-11-01

In eyes wearing negative lenses, the D2 dopamine antagonist spiperone was only partly effective in preventing the ameliorative effects of brief periods of vision (Nickla et al., 2010), in contrast to reports from studies using form-deprivation. The present study was done to directly compare the effects of spiperone, and the D1 antagonist SCH-23390, on the two different myopiagenic paradigms. 12-day old chickens wore monocular diffusers (form-deprivation) or -10 D lenses attached to the feathers with matching rings of Velcro. Each day for 4 days, 10 μl intravitreal injections of the dopamine D2/D4 antagonist spiperone (5 nmoles) or the D1 antagonist SCH-23390, were given under isoflurane anesthesia, and the diffusers (n = 16; n = 5, respectively) or lenses (n = 20; n = 6) were removed for 2 h immediately after. Saline injections prior to vision were done as controls (form-deprivation: n = 11; lenses: n = 10). Two other saline-injected groups wore the lenses (n = 12) or diffusers (n = 4) continuously. Axial dimensions were measured by high frequency A-scan ultrasonography at the start, and on the last day immediately prior to, and 3 h after the injection. Refractive errors were measured at the end of the experiment using a Hartinger's refractometer. In form-deprived eyes, spiperone, but not SCH-23390, prevented the ocular growth inhibition normally effected by the brief periods of vision (change in vitreous chamber depth, spiperone vs saline: 322 vs 211 μm; p = 0.01). By contrast, neither had any effect on negative lens-wearing eyes given similar unrestricted vision (210 and 234 μm respectively, vs 264 μm). The increased elongation in the spiperone-injected form-deprived eyes did not, however, result in a myopic shift, probably due to the inhibitory effect of the drug on anterior chamber growth (drug vs saline: 96 vs 160 μm; p effects of brief periods of unrestricted vision differ for form-deprivation versus negative lens-wear, which may imply different growth

Salicylic acid-induced glutathione status in tomato crop and resistance to root-knot nematode, Meloidogyne incognita (Kofoid & White Chitwood

Directory of Open Access Journals (Sweden)

Hari C. Meher

2011-10-01

Full Text Available Salicylic acid-(SA is a plant defense stimulator. Exogenous application of SA might influence the status of glutathione-(GSH. GSH activates and SA alters the expression of defense genes to modulate plant resistance against pathogens. The fate of GSH in a crop following SA treatment is largely unknown. The SA-induced profiles of free reduced-, free oxidized-(GSSG and protein bound-(PSSG glutathione in tomato crop following foliar treatment of transplant at 5.0-10.0 μg mL–1 were measured by liquid chromatography. Resistance to root-knot nematode, Meloidogyne incognita damaging tomato and crop performance were also evaluated. SA treatment at 5.0-10.0 μg mL–1 to tomato transplants increased GSH, GSSG and PSSG in plant leaf and root, more so in leaf, during crop growth and development. As the fruits ripened, GSH and PSSG increased and GSSG declined. SA reduced the root infection by M. incognita, nematode reproduction and thus, improved the resistance of tomato var. Pusa Ruby, but reduced crop growth and redox status. SA at 5.0 μg mL–1 improved yield and fruit quality. The study firstly linked SA with activation of glutathione metabolism and provided an additional dimension to the mechanism of induced resistance against obligate nematode pathogen. SA increased glutathione status in tomato crop, imparted resistance against M. incognita, augmented crop yield and functional food quality. SA can be applied at 5.0 μg mL–1 for metabolic engineering of tomato at transplanting to combine host-plant resistance and health benefits in formulating a strategic nematode management decision.

O6-methylguanine DNA-methyltransferase (MGMT) overexpression in melanoma cells induces resistance to nitrosoureas and temozolomide but sensitizes to mitomycin C

International Nuclear Information System (INIS)

Passagne, Isabelle; Evrard, Alexandre; Depeille, Philippe; Cuq, Pierre; Cupissol, Didier; Vian, Laurence

2006-01-01

Alkylating agents play an important role in the chemotherapy of malignant melanomas. The activity of alkylating agents depends on their capacity to form alkyl adducts with DNA, in some cases causing cross-linking of DNA strands. However, the use of these agents is limited by cellular resistance induced by the DNA repair enzyme O 6 -methylguanine DNA-methyltransferase (MGMT) which removes alkyl groups from alkylated DNA strands. To determine to what extent the expression of MGMT in melanoma cells induces resistance to alkylating agents, the human cell line CAL77 Mer- (i.e., MGMT deficient) were transfected with pcMGMT vector containing human MGMT cDNA. Several clones expressing MGMT at a high level were selected to determine their sensitivity to chemotherapeutic drugs. Melanoma-transfected cells were found to be significantly less sensitive to nitrosoureas (carmustine, fotemustine, streptozotocin) and temozolomide with an increase of IC 5 values between 3 and 14 when compared to parent cells. No difference in cell survival rates between MGMT-proficient and -deficient cells was observed for melphalan, chlorambucil, busulphan, thiotepa and cisplatin which preferentially induce N 7 guanine lesions. Surprisingly, MGMT overexpression increased the sensitivity of CAL77 cells to mitomycin C by approximately 10-fold. Treatment of clonal cell lines with buthionine-[S,R]-sulfoximine (BSO), an inhibitor of γ-glutamylcysteine synthetase which depletes cellular glutathione, completely reversed this unexpected increase in sensitivity to mitomycin C. This observation suggests that glutathione is involved in the sensitivity of MGMT-transfected cells to mitomycin C and may act synergistically with MGMT via an unknown mechanism

O(6)-methylguanine DNA-methyltransferase (MGMT) overexpression in melanoma cells induces resistance to nitrosoureas and temozolomide but sensitizes to mitomycin C.

Science.gov (United States)

Passagne, Isabelle; Evrard, Alexandre; Depeille, Philippe; Cuq, Pierre; Cupissol, Didier; Vian, Laurence

2006-03-01

Alkylating agents play an important role in the chemotherapy of malignant melanomas. The activity of alkylating agents depends on their capacity to form alkyl adducts with DNA, in some cases causing cross-linking of DNA strands. However, the use of these agents is limited by cellular resistance induced by the DNA repair enzyme O(6)-methylguanine DNA-methyltransferase (MGMT) which removes alkyl groups from alkylated DNA strands. To determine to what extent the expression of MGMT in melanoma cells induces resistance to alkylating agents, the human cell line CAL77 Mer- (i.e., MGMT deficient) were transfected with pcMGMT vector containing human MGMT cDNA. Several clones expressing MGMT at a high level were selected to determine their sensitivity to chemotherapeutic drugs. Melanoma-transfected cells were found to be significantly less sensitive to nitrosoureas (carmustine, fotemustine, streptozotocin) and temozolomide with an increase of IC(50) values between 3 and 14 when compared to parent cells. No difference in cell survival rates between MGMT-proficient and -deficient cells was observed for melphalan, chlorambucil, busulphan, thiotepa and cisplatin which preferentially induce N(7) guanine lesions. Surprisingly, MGMT overexpression increased the sensitivity of CAL77 cells to mitomycin C by approximately 10-fold. Treatment of clonal cell lines with buthionine-[S,R]-sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase which depletes cellular glutathione, completely reversed this unexpected increase in sensitivity to mitomycin C. This observation suggests that glutathione is involved in the sensitivity of MGMT-transfected cells to mitomycin C and may act synergistically with MGMT via an unknown mechanism.

Docosahexaenoic acid prevents paraquat-induced reactive oxygen species production in dopaminergic neurons via enhancement of glutathione homeostasis

Energy Technology Data Exchange (ETDEWEB)

Lee, Hyoung Jun; Han, Jeongsu; Jang, Yunseon; Kim, Soo Jeong; Park, Ji Hoon; Seo, Kang Sik [Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon (Korea, Republic of); Jeong, Soyeon; Shin, Soyeon; Lim, Kyu [Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon (Korea, Republic of); Infection Signaling Network Research Center, Chungnam National University, Daejeon (Korea, Republic of); Heo, Jun Young, E-mail: junyoung3@gmail.com [Brainscience Institute, Chungnam National University, Daejeon (Korea, Republic of); Kweon, Gi Ryang, E-mail: mitochondria@cnu.ac.kr [Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon (Korea, Republic of); Infection Signaling Network Research Center, Chungnam National University, Daejeon (Korea, Republic of)

2015-01-30

Highlights: • DHA prevents PQ-induced dopaminergic neuronal loss via decreasing of excessive ROS. • DHA increases GR and GCLm derivate GSH pool by enhancement of Nrf2 expression. • Protective mechanism is removal of PQ-induced ROS via DHA-dependent GSH pool. • DHA may be a good preventive strategy for Parkinson’s disease (PD) therapy. - Abstract: Omega-3 polyunsaturated fatty acid levels are reduced in the substantia nigra area in Parkinson’s disease patients and animal models, implicating docosahexaenoic acid (DHA) as a potential treatment for preventing Parkinson’s disease and suggesting the need for investigations into how DHA might protect against neurotoxin-induced dopaminergic neuron loss. The herbicide paraquat (PQ) induces dopaminergic neuron loss through the excessive production of reactive oxygen species (ROS). We found that treatment of dopaminergic SN4741 cells with PQ reduced cell viability in a dose-dependent manner, but pretreatment with DHA ameliorated the toxic effect of PQ. To determine the toxic mechanism of PQ, we measured intracellular ROS content in different organelles with specific dyes. As expected, all types of ROS were increased by PQ treatment, but DHA pretreatment selectively decreased cytosolic hydrogen peroxide content. Furthermore, DHA treatment-induced increases in glutathione reductase and glutamate cysteine ligase modifier subunit (GCLm) mRNA expression were positively correlated with glutathione (GSH) content. Consistent with this increase in GCLm mRNA levels, Western blot analysis revealed that DHA pretreatment increased nuclear factor-erythroid 2 related factor 2 (Nrf2) protein levels. These findings indicate that DHA prevents PQ-induced neuronal cell loss by enhancing Nrf2-regulated GSH homeostasis.

Docosahexaenoic acid prevents paraquat-induced reactive oxygen species production in dopaminergic neurons via enhancement of glutathione homeostasis

International Nuclear Information System (INIS)

Lee, Hyoung Jun; Han, Jeongsu; Jang, Yunseon; Kim, Soo Jeong; Park, Ji Hoon; Seo, Kang Sik; Jeong, Soyeon; Shin, Soyeon; Lim, Kyu; Heo, Jun Young; Kweon, Gi Ryang

2015-01-01

Highlights: • DHA prevents PQ-induced dopaminergic neuronal loss via decreasing of excessive ROS. • DHA increases GR and GCLm derivate GSH pool by enhancement of Nrf2 expression. • Protective mechanism is removal of PQ-induced ROS via DHA-dependent GSH pool. • DHA may be a good preventive strategy for Parkinson’s disease (PD) therapy. - Abstract: Omega-3 polyunsaturated fatty acid levels are reduced in the substantia nigra area in Parkinson’s disease patients and animal models, implicating docosahexaenoic acid (DHA) as a potential treatment for preventing Parkinson’s disease and suggesting the need for investigations into how DHA might protect against neurotoxin-induced dopaminergic neuron loss. The herbicide paraquat (PQ) induces dopaminergic neuron loss through the excessive production of reactive oxygen species (ROS). We found that treatment of dopaminergic SN4741 cells with PQ reduced cell viability in a dose-dependent manner, but pretreatment with DHA ameliorated the toxic effect of PQ. To determine the toxic mechanism of PQ, we measured intracellular ROS content in different organelles with specific dyes. As expected, all types of ROS were increased by PQ treatment, but DHA pretreatment selectively decreased cytosolic hydrogen peroxide content. Furthermore, DHA treatment-induced increases in glutathione reductase and glutamate cysteine ligase modifier subunit (GCLm) mRNA expression were positively correlated with glutathione (GSH) content. Consistent with this increase in GCLm mRNA levels, Western blot analysis revealed that DHA pretreatment increased nuclear factor-erythroid 2 related factor 2 (Nrf2) protein levels. These findings indicate that DHA prevents PQ-induced neuronal cell loss by enhancing Nrf2-regulated GSH homeostasis

Molecular adaptations to phosphorus deprivation and comparison with nitrogen deprivation responses in the diatom Phaeodactylum tricornutum.

Science.gov (United States)

Alipanah, Leila; Winge, Per; Rohloff, Jens; Najafi, Javad; Brembu, Tore; Bones, Atle M

2018-01-01

Phosphorus, an essential element for all living organisms, is a limiting nutrient in many regions of the ocean due to its fast recycling. Changes in phosphate (Pi) availability in aquatic systems affect diatom growth and productivity. We investigated the early adaptive mechanisms in the marine diatom Phaeodactylum tricornutum to P deprivation using a combination of transcriptomics, metabolomics, physiological and biochemical experiments. Our analysis revealed strong induction of gene expression for proteins involved in phosphate acquisition and scavenging, and down-regulation of processes such as photosynthesis, nitrogen assimilation and nucleic acid and ribosome biosynthesis. P deprivation resulted in alterations of carbon allocation through the induction of the pentose phosphate pathway and cytosolic gluconeogenesis, along with repression of the Calvin cycle. Reorganization of cellular lipids was indicated by coordinated induced expression of phospholipases, sulfolipid biosynthesis enzymes and a putative betaine lipid biosynthesis enzyme. A comparative analysis of nitrogen- and phosphorus-deprived P. tricornutum revealed both common and distinct regulation patterns in response to phosphate and nitrate stress. Regulation of central carbon metabolism and amino acid metabolism was similar, whereas unique responses were found in nitrogen assimilation and phosphorus scavenging in nitrogen-deprived and phosphorus-deprived cells, respectively.

Dopamine antagonists and brief vision distinguish lens-induced- and form-deprivation-induced myopia

OpenAIRE

Nickla, Debora L.; Totonelly, Kristen

2011-01-01

In eyes wearing negative lenses, the D2 dopamine antagonist spiperone was only partly effective in preventing the ameliorative effects of brief periods of vision (Nickla et al., 2010), in contrast to reports from studies using form deprivation. The present study was done to directly compare the effects of spiperone, and the D1 antagonist SCH-23390, on the two different myopiagenic paradigms. 12-day old chickens wore monocular diffusers (form deprivation) or − 10 D lenses attached to the feath...

Low-quality birds do not display high-quality signals: The cysteine-pheomelanin mechanism of honesty

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Galván, Ismael; Wakamatsu, Kazumasa; Camarero, Pablo R; Mateo, Rafael; Alonso-Alvarez, Carlos

2015-01-01

The mechanisms that make that the costs of producing high-quality signals are unaffordable to low-quality signalers are a current issue in animal communication. The size of the melanin-based bib of male house sparrows Passer domesticus honestly signals quality. We induced the development of new bibs while treating males with buthionine-sulfoximine (BSO), a substance that depletes the levels of the antioxidant glutathione (GSH) and the amino acid cysteine, two elements that switch melanogenesis from eumelanin to pheomelanin. Final bib size is negatively related to pheomelanin levels in the bib feathers. BSO reduced cysteine and GSH levels in all birds, but improved phenotypes (bibs larger than controls) were only expressed by high-quality birds (BSO birds with largest bibs initially). Negative associations between final bib size and cysteine levels in erythrocytes, and between pheomelanin and cysteine levels, were observed in high-quality birds only. These findings suggest that a mechanism uncoupling pheomelanin and cysteine levels may have evolved in low-quality birds to avoid producing bibs of size not corresponding to their quality and greater relative costs. Indeed, greater oxidative stress in cells was not observed in low-quality birds. This may represent the first mechanism maintaining signal honesty without producing greater relative costs on low-quality signalers. PMID:25330349

Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice

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Conklin, Daniel J., E-mail: dj.conklin@louisville.edu [Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292 (United States); Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292 (United States); Haberzettl, Petra; Jagatheesan, Ganapathy; Baba, Shahid [Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292 (United States); Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292 (United States); Merchant, Michael L. [Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292 (United States); Division of Nephrology, Department of Medicine, University of Louisville, Louisville, KY 40292 (United States); Prough, Russell A. [Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292 (United States); Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40292 (United States); Williams, Jessica D. [University of Cincinnati College of Medicine, Internal Medicine, Cincinnati, OH 45267 (United States); Prabhu, Sumanth D. [Division of Cardiovascular Disease, University of Alabama-Birmingham, Birmingham, AL 35294 (United States); Bhatnagar, Aruni [Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292 (United States); Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292 (United States); Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40292 (United States)

2015-06-01

High-dose chemotherapy regimens using cyclophosphamide (CY) are frequently associated with cardiotoxicity that could lead to myocyte damage and congestive heart failure. However, the mechanisms regulating the cardiotoxic effects of CY remain unclear. Because CY is converted to an unsaturated aldehyde acrolein, a toxic, reactive CY metabolite that induces extensive protein modification and myocardial injury, we examined the role of glutathione S-transferase P (GSTP), an acrolein-metabolizing enzyme, in CY cardiotoxicity in wild-type (WT) and GSTP-null mice. Treatment with CY (100–300 mg/kg) increased plasma levels of creatine kinase-MB isoform (CK·MB) and heart-to-body weight ratio to a significantly greater extent in GSTP-null than WT mice. In addition to modest yet significant echocardiographic changes following acute CY-treatment, GSTP insufficiency was associated with greater phosphorylation of c-Jun and p38 as well as greater accumulation of albumin and protein–acrolein adducts in the heart. Mass spectrometric analysis revealed likely prominent modification of albumin, kallikrein-1-related peptidase, myoglobin and transgelin-2 by acrolein in the hearts of CY-treated mice. Treatment with acrolein (low dose, 1–5 mg/kg) also led to increased heart-to-body weight ratio and myocardial contractility changes. Acrolein induced similar hypotension in GSTP-null and WT mice. GSTP-null mice also were more susceptible than WT mice to mortality associated with high-dose acrolein (10–20 mg/kg). Collectively, these results suggest that CY cardiotoxicity is regulated, in part, by GSTP, which prevents CY toxicity by detoxifying acrolein. Thus, humans with low cardiac GSTP levels or polymorphic forms of GSTP with low acrolein-metabolizing capacity may be more sensitive to CY toxicity. - Graphical abstract: Cyclophosphamide (CY) treatment results in P450-mediated metabolic formation of phosphoramide mustard and acrolein (3-propenal). Acrolein is either metabolized and

Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice

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Conklin, Daniel J.; Haberzettl, Petra; Jagatheesan, Ganapathy; Baba, Shahid; Merchant, Michael L.; Prough, Russell A.; Williams, Jessica D.; Prabhu, Sumanth D.; Bhatnagar, Aruni

2015-01-01

High-dose chemotherapy regimens using cyclophosphamide (CY) are frequently associated with cardiotoxicity that could lead to myocyte damage and congestive heart failure. However, the mechanisms regulating the cardiotoxic effects of CY remain unclear. Because CY is converted to an unsaturated aldehyde acrolein, a toxic, reactive CY metabolite that induces extensive protein modification and myocardial injury, we examined the role of glutathione S-transferase P (GSTP), an acrolein-metabolizing enzyme, in CY cardiotoxicity in wild-type (WT) and GSTP-null mice. Treatment with CY (100–300 mg/kg) increased plasma levels of creatine kinase-MB isoform (CK·MB) and heart-to-body weight ratio to a significantly greater extent in GSTP-null than WT mice. In addition to modest yet significant echocardiographic changes following acute CY-treatment, GSTP insufficiency was associated with greater phosphorylation of c-Jun and p38 as well as greater accumulation of albumin and protein–acrolein adducts in the heart. Mass spectrometric analysis revealed likely prominent modification of albumin, kallikrein-1-related peptidase, myoglobin and transgelin-2 by acrolein in the hearts of CY-treated mice. Treatment with acrolein (low dose, 1–5 mg/kg) also led to increased heart-to-body weight ratio and myocardial contractility changes. Acrolein induced similar hypotension in GSTP-null and WT mice. GSTP-null mice also were more susceptible than WT mice to mortality associated with high-dose acrolein (10–20 mg/kg). Collectively, these results suggest that CY cardiotoxicity is regulated, in part, by GSTP, which prevents CY toxicity by detoxifying acrolein. Thus, humans with low cardiac GSTP levels or polymorphic forms of GSTP with low acrolein-metabolizing capacity may be more sensitive to CY toxicity. - Graphical abstract: Cyclophosphamide (CY) treatment results in P450-mediated metabolic formation of phosphoramide mustard and acrolein (3-propenal). Acrolein is either metabolized and

Glycine Increases Insulin Sensitivity and Glutathione Biosynthesis and Protects against Oxidative Stress in a Model of Sucrose-Induced Insulin Resistance

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Mohammed El-Hafidi

2018-01-01

Full Text Available Oxidative stress and redox status play a central role in the link between insulin resistance (IR and lipotoxicity in metabolic syndrome. This mechanistic link may involve alterations in the glutathione redox state. We examined the effect of glycine supplementation to diet on glutathione biosynthesis, oxidative stress, IR, and insulin cell signaling in liver from sucrose-fed (SF rats characterized by IR and oxidative stress. Our hypothesis is that the correction of glutathione levels by glycine treatment leads to reduced oxidative stress, a mechanism associated with improved insulin signaling and IR. Glycine treatment decreases the levels of oxidative stress markers in liver from SF rats and increases the concentrations of glutathione (GSH and γ-glutamylcysteine and the amount of γ-glutamylcysteine synthetase (γ-GCS, a key enzyme of GSH biosynthesis in liver from SF rats. In liver from SF rats, glycine also decreases the insulin-induced phosphorylation of insulin receptor substrate-1 (ISR-1 in serine residue and increases the phosphorylation of insulin receptor β-subunit (IR-β in tyrosine residue. Thus, supplementing diets with glycine to correct GSH deficiency and to reduce oxidative stress provides significant metabolic benefits to SF rats by improving insulin sensitivity.

Occurrence of epileptiform discharges and sleep during EEG recordings in children after melatonin intake versus sleep-deprivation.

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Gustafsson, Greta; Broström, Anders; Ulander, Martin; Vrethem, Magnus; Svanborg, Eva

2015-08-01

To determine if melatonin is equally efficient as partial sleep deprivation in inducing sleep without interfering with epileptiform discharges in EEG recordings in children 1-16 years old. We retrospectively analysed 129 EEGs recorded after melatonin intake and 113 EEGs recorded after partial sleep deprivation. Comparisons were made concerning occurrence of epileptiform discharges, the number of children who fell asleep and the technical quality of EEG recordings. Comparison between different age groups was also made. No significant differences were found regarding occurrence of epileptiform discharges (33% after melatonin intake, 36% after sleep deprivation), or proportion of unsuccessful EEGs (8% and 10%, respectively). Melatonin and sleep deprivation were equally efficient in inducing sleep (70% in both groups). Significantly more children aged 1-4 years obtained sleep after melatonin intake in comparison to sleep deprivation (82% vs. 58%, p⩽0.01), and in comparison to older children with melatonin induced sleep (58-67%, p⩽0.05). Sleep deprived children 9-12 years old had higher percentage of epileptiform discharges (62%, p⩽0.05) compared to younger sleep deprived children. Melatonin is equally efficient as partial sleep deprivation to induce sleep and does not affect the occurrence of epileptiform discharges in the EEG recording. Sleep deprivation could still be preferable in older children as melatonin probably has less sleep inducing effect. Melatonin induced sleep have advantages, especially in younger children as they fall asleep easier than after sleep deprivation. The procedure is easier for the parents than keeping a young child awake for half the night. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Genetic Dissociation of Daily Sleep and Sleep Following Thermogenetic Sleep Deprivation in Drosophila.

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Dubowy, Christine; Moravcevic, Katarina; Yue, Zhifeng; Wan, Joy Y; Van Dongen, Hans P A; Sehgal, Amita

2016-05-01

Sleep rebound-the increase in sleep that follows sleep deprivation-is a hallmark of homeostatic sleep regulation that is conserved across the animal kingdom. However, both the mechanisms that underlie sleep rebound and its relationship to habitual daily sleep remain unclear. To address this, we developed an efficient thermogenetic method of inducing sleep deprivation in Drosophila that produces a substantial rebound, and applied the newly developed method to assess sleep rebound in a screen of 1,741 mutated lines. We used data generated by this screen to identify lines with reduced sleep rebound following thermogenetic sleep deprivation, and to probe the relationship between habitual sleep amount and sleep following thermogenetic sleep deprivation in Drosophila. To develop a thermogenetic method of sleep deprivation suitable for screening, we thermogenetically stimulated different populations of wake-promoting neurons labeled by Gal4 drivers. Sleep rebound following thermogenetically-induced wakefulness varies across the different sets of wake-promoting neurons that were stimulated, from very little to quite substantial. Thermogenetic activation of neurons marked by the c584-Gal4 driver produces both strong sleep loss and a substantial rebound that is more consistent within genotypes than rebound following mechanical or caffeine-induced sleep deprivation. We therefore used this driver to induce sleep deprivation in a screen of 1,741 mutagenized lines generated by the Drosophila Gene Disruption Project. Flies were subjected to 9 h of sleep deprivation during the dark period and released from sleep deprivation 3 h before lights-on. Recovery was measured over the 15 h following sleep deprivation. Following identification of lines with reduced sleep rebound, we characterized baseline sleep and sleep depth before and after sleep deprivation for these hits. We identified two lines that consistently exhibit a blunted increase in the duration and depth of sleep after

Cadmium induced changes in subcellular glutathione contents within glandular trichomes of Cucurbita pepo L.

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Kolb, Dagmar; Müller, Maria; Zellnig, Günther; Zechmann, Bernd

2010-07-01

Plants cope with cadmium (Cd) stress by complexation with phytochelatins (Pc), metallothioneins and glutathione and sequestration within vacuoles. Especially glutathione was found to play a major role in Cd detoxification as Cd shows a high binding affinity towards thiols and as glutathione is a precursor for Pc synthesis. In the present study, we have used an immunohistochemical approach combined with computer-supported transmission electron microscopy in order to measure changes in the subcellular distribution of glutathione during Cd-stress in mesophyll cells and cells of different glandular trichomes (long and short stalked) of Cucurbita pepo L. subsp. pepo var. styriaca GREB: . Even though no ultrastructural alterations were observed in leaf and glandular trichome cells after the treatment of plants with 50 microM cadmium chloride (CdCl(2)) for 48 h, all cells showed a large decrease in glutathione contents. The strongest decrease was found in nuclei and the cytosol (up to 76%) in glandular trichomes which are considered as a major side of Cd accumulation in leaves. The ratio of glutathione between the cytosol and nuclei and the other cell compartments was strongly decreased only in glandular trichomes (more than 50%) indicating that glutathione in these two cell compartments is especially important for the detoxification of Cd in glandular trichomes. Additionally, these data indicate that large amounts of Cd are withdrawn from nuclei during Cd exposure. The present study gives a detailed insight into the compartment-specific importance of glutathione during Cd exposure in mesophyll cells and glandular trichomes of C. pepo L. plants.

Neurotoxicity of "ecstasy" and its metabolites in human dopaminergic differentiated SH-SY5Y cells.

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Ferreira, Patrícia Silva; Nogueira, Tiago Bernandes; Costa, Vera Marisa; Branco, Paula Sério; Ferreira, Luísa Maria; Fernandes, Eduarda; Bastos, Maria Lourdes; Meisel, Andreas; Carvalho, Félix; Capela, João Paulo

2013-02-04

"Ecstasy" (3,4-methylenedioxymethamphetamine or MDMA) is a widely abused recreational drug, reported to produce neurotoxic effects, both in laboratory animals and in humans. MDMA metabolites can be major contributors for MDMA neurotoxicity. This work studied the neurotoxicity of MDMA and its catechol metabolites, α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) in human dopaminergic SH-SY5Y cells differentiated with retinoic acid and 12-O-tetradecanoyl-phorbol-13-acetate. Differentiation led to SH-SY5Y neurons with higher ability to accumulate dopamine and higher resistance towards dopamine neurotoxicity. MDMA catechol metabolites were neurotoxic to SH-SY5Y neurons, leading to caspase 3-independent cell death in a concentration- and time-dependent manner. MDMA did not show a concentration- and time-dependent death. Pre-treatment with the antioxidant and glutathione precursor, N-acetylcysteine (NAC), resulted in strong protection against the MDMA metabolites' neurotoxicity. Neither the superoxide radical scavenger, tiron, nor the inhibitor of the dopamine (DA) transporter, GBR 12909, prevented the metabolites' toxicity. Cells exposed to α-MeDA showed an increase in intracellular glutathione (GSH) levels, which, at the 48 h time-point, was not dependent in the activity increase of γ-glutamylcysteine synthetase (γ-GCS), revealing a possible transient effect. Importantly, pre-treatment with buthionine sulfoximine (BSO), an inhibitor of γ-GCS, prevented α-MeDA induced increase in GSH levels, but did not augment this metabolite cytotoxicity. Even so, BSO pre-treatment abolished NAC protective effects against α-MeDA neurotoxicity, which were, at least partially, due to GSH de novo synthesis. Inversely, pre-treatment of cells with BSO augmented N-Me-α-MeDA-induced neurotoxicity, but only slightly affected NAC neuroprotection. In conclusion, MDMA catechol metabolites promote differential toxic effects to differentiated dopaminergic human SH

Total sleep deprivation does not significantly degrade semantic encoding.

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Honn, K A; Grant, D A; Hinson, J M; Whitney, P; Van Dongen, Hpa

2018-01-17

Sleep deprivation impairs performance on cognitive tasks, but it is unclear which cognitive processes it degrades. We administered a semantic matching task with variable stimulus onset asynchrony (SOA) and both speeded and self-paced trial blocks. The task was administered at the baseline and 24 hours later after 30.8 hours of total sleep deprivation (TSD) or matching well-rested control. After sleep deprivation, the 20% slowest response times (RTs) were significantly increased. However, the semantic encoding time component of the RTs remained at baseline level. Thus, the performance impairment induced by sleep deprivation on this task occurred in cognitive processes downstream of semantic encoding.

Sleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals.

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Challet, E; Turek, F W; Laute, M; Van Reeth, O

2001-08-03

The circadian pacemaker in the suprachiasmatic nuclei is primarily synchronized to the daily light-dark cycle. The phase-shifting and synchronizing effects of light can be modulated by non-photic factors, such as behavioral, metabolic or serotonergic cues. The present experiments examine the effects of sleep deprivation on the response of the circadian pacemaker to light and test the possible involvement of serotonergic and/or metabolic cues in mediating the effects of sleep deprivation. Photic phase-shifting of the locomotor activity rhythm was analyzed in mice transferred from a light-dark cycle to constant darkness, and sleep-deprived for 8 h from Zeitgeber Time 6 to Zeitgeber Time 14. Phase-delays in response to a 10-min light pulse at Zeitgeber Time 14 were reduced by 30% in sleep-deprived mice compared to control mice, while sleep deprivation without light exposure induced no significant phase-shifts. Stimulation of serotonin neurotransmission by fluoxetine (10 mg/kg), a serotonin reuptake inhibitor that decreases light-induced phase-delays in non-deprived mice, did not further reduce light-induced phase-delays in sleep-deprived mice. Impairment of serotonin neurotransmission with p-chloroamphetamine (three injections of 10 mg/kg), which did not increase light-induced phase-delays in non-deprived mice significantly, partially normalized light-induced phase-delays in sleep-deprived mice. Injections of glucose increased light-induced phase-delays in control and sleep-deprived mice. Chemical damage of the ventromedial hypothalamus by gold-thioglucose (600 mg/kg) prevented the reduction of light-induced phase-delays in sleep-deprived mice, without altering phase-delays in control mice. Taken together, the present results indicate that sleep deprivation can reduce the light-induced phase-shifts of the mouse suprachiasmatic pacemaker, due to serotonergic and metabolic changes associated with the loss of sleep.

Physical exercise prevents short and long-term deficits on aversive and recognition memory and attenuates brain oxidative damage induced by maternal deprivation.

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Neves, Ben-Hur; Menezes, Jefferson; Souza, Mauren Assis; Mello-Carpes, Pâmela B

2015-12-01

It is known from previous research that physical exercise prevents long-term memory deficits induced by maternal deprivation in rats. But we could not assume similar effects of physical exercise on short-term memory, as short- and long-term memories are known to result from some different memory consolidation processes. Here we demonstrated that, in addition to long-term memory deficit, the short-term memory deficit resultant from maternal deprivation in object recognition and aversive memory tasks is also prevented by physical exercise. Additionally, one of the mechanisms by which the physical exercise influences the memory processes involves its effects attenuating the oxidative damage in the maternal deprived rats' hippocampus and prefrontal cortex.

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B.

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Meng, Xianfang; Chu, Guangpin; Yang, Zhihua; Qiu, Ping; Hu, Yue; Chen, Xiaohe; Peng, Wenpeng; Ye, Chen; He, Fang-Fang; Zhang, Chun

2016-01-01

Metformin, the common medication for type II diabetes, has protective effects on cerebral ischemia. However, the molecular mechanisms are far from clear. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of the anaphase-promoting complex (APC), is widely expressed in hippocampal and cortical neurons and plays an important role in mediating high glucose-induced neurotoxicity. The present study investigated whether metformin modifies the expression of MAD2B and to exert its neuroprotective effects in primary cultured cortical neurons during oxygen-glucose deprivation/reoxygenation (OGD/R), a widely used in vitro model of ischemia/reperfusion. Primary cortical neurons were cultured, deprived of oxygen-glucose for 1 h, and then recovered with oxygen-glucose for 12 h and 24 h. Cell viability was measured by detecting the levels of lactate dehydrogenase (LDH) in culture medium. The levels of MAD2B, cyclin B and p-histone 3 were measured by Western blot. Cell viability of neurons was reduced under oxygen-glucose deprivation/reoxygenation (OGD/R). The expression of MAD2B was increased under OGD/R. The levels of cyclin B1, which is a substrate of APC, were also increased. Moreover, OGD/R up-regulated the phosphorylation levels of histone 3, which is the induction of aberrant re-entry of post-mitotic neurons. However, pretreatment of neurons with metformin alleviated OGD/R-induced injury. Metformin further decreased the expression of MAD2B, cyclin B1 and phosphorylation levels of histone 3. Metformin exerts its neuroprotective effect through regulating the expression of MAD2B in neurons under OGD/R. © 2016 The Author(s) Published by S. Karger AG, Basel.

Avocado oil induces long-term alleviation of oxidative damage in kidney mitochondria from type 2 diabetic rats by improving glutathione status.

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Ortiz-Avila, Omar; Figueroa-García, María Del Consuelo; García-Berumen, Claudia Isabel; Calderón-Cortés, Elizabeth; Mejía-Barajas, Jorge A; Rodriguez-Orozco, Alain R; Mejía-Zepeda, Ricardo; Saavedra-Molina, Alfredo; Cortés-Rojo, Christian

2017-04-01

Hyperglycemia and mitochondrial ROS overproduction have been identified as key factors involved in the development of diabetic nephropathy. This has encouraged the search for strategies decreasing glucose levels and long-term improvement of redox status of glutathione, the main antioxidant counteracting mitochondrial damage. Previously, we have shown that avocado oil improves redox status of glutathione in liver and brain mitochondria from streptozotocin-induced diabetic rats; however, the long-term effects of avocado oil and its hypoglycemic effect cannot be evaluated because this model displays low survival and insulin depletion. Therefore, we tested during 1 year the effects of avocado oil on glycemia, ROS levels, lipid peroxidation and glutathione status in kidney mitochondria from type 2 diabetic Goto-Kakizaki rats. Diabetic rats exhibited glycemia of 120-186 mg/dL the first 9 months with a further increase to 250-300 mg/dL. Avocado oil decreased hyperglycemia at intermediate levels between diabetic and control rats. Diabetic rats displayed augmented lipid peroxidation and depletion of reduced glutathione throughout the study, while increased ROS generation was observed at the 3rd and 12th months along with diminished content of total glutathione at the 6th and 12th months. Avocado oil ameliorated all these defects and augmented the mitochondrial content of oleic acid. The beneficial effects of avocado oil are discussed in terms of the hypoglycemic effect of oleic acid and the probable dependence of glutathione transport on lipid peroxidation and thiol oxidation of mitochondrial carriers.

Effects of experimental sleep deprivation on anxiety-like behavior in animal research: Systematic review and meta-analysis.

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Pires, Gabriel Natan; Bezerra, Andréia Gomes; Tufik, Sergio; Andersen, Monica Levy

2016-09-01

Increased acute anxiety is a commonly reported behavioral consequence of sleep deprivation in humans. However, rodent studies conducted so far produced inconsistent results, failing to reproduce the same sleep deprivation induced-anxiety observed in clinical experiments. While some presented anxiogenesis as result of sleep deprivation, others reported anxiolysis. In face of such inconsistencies, this article explores the effects of experimental sleep deprivation on anxiety-like behavior in animal research through a systematic review and a series of meta-analyses. A total of 50 of articles met our inclusion criteria, 30 on mice, 19 on rats and one on Zebrafish. Our review shows that sleep deprivation induces a decrease in anxiety-like behavior in preclinical models, which is opposite to results observed in human settings. These results were corroborated in stratified analyses according to species, sleep deprivation method and anxiety measurement technique. In conclusion, the use of animal models for the evaluation of the relationship between sleep deprivation lacks translational applicability and new experimental tools are needed to properly evaluate sleep deprivation-induced anxiogenesis in rodents. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of an aqueous extract of Cucurbita ficifolia Bouché on the glutathione redox cycle in mice with STZ-induced diabetes.

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Díaz-Flores, M; Angeles-Mejia, S; Baiza-Gutman, L A; Medina-Navarro, R; Hernández-Saavedra, D; Ortega-Camarillo, C; Roman-Ramos, R; Cruz, M; Alarcon-Aguilar, F J

2012-10-31

Cucurbita ficifolia is used in Mexican traditional medicine as an anti-diabetic and anti-inflammatory agent and its actions can be mediated by antioxidant mechanisms. Disturbance in the homeostasis of glutathione has been implicated in the etiology and progression of diabetes mellitus and its complications. It was evaluated, the effect of an aqueous extract of Cucurbita ficifolia on glycemia, plasma lipid peroxidation; as well as levels of reduced (GSH) and oxidized (GSSG) glutathione and activities of enzymes involved in glutathione redox cycle: glutathione peroxidase (GPx) and glutathione reductase (GR) in liver, pancreas, kidney and heart homogenates of streptozotocin-induced diabetic mice. Increased blood glucose and lipid peroxidation, together with decreased of GSH concentration, GSH/GSSG ratio and its redox potential (E(h)), and enhanced activity of GPx and GR in liver, pancreas and kidney were the salient features observed in diabetic mice. Administration of the aqueous extract of Cucurbita ficifolia to diabetic mice for 30 days, used at a dose of 200 mg/kg, resulted in a significant reduction in glycemia, polydipsia, hyperphagia and plasma lipid peroxidation. Moreover, GSH was increased in liver, pancreas and kidney, and GSSG was reduced in liver, pancreas and heart, therefore GSH/GSSG ratio and its E(h) were restored. Also, the activities involved in the glutathione cycle were decreased, reaching similar values to controls. An aqueous extract of Cucurbita ficifolia with hypoglycemic action, improve GSH redox state, increasing glutathione pool, GSH, GSH/GSSG ratio and its E(h), mechanism that can explain, at least in part, its antioxidant properties, supporting its use as an alternative treatment for the control of diabetes mellitus, and prevent the induction of complications by oxidative stress. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Effects of D,L-buthionine-S,R-sulfoximine on cellular thiol levels and the oxygen effect in Chinese hamster V79 cells

International Nuclear Information System (INIS)

Astor, M.B.; Hall, E.J.; Biaglow, J.E.; Hartog, B.

1984-01-01

The role of glutathione (GSH) and total non-protein thiols (NPSH) in repairing radiation-induced free radical damage incurred under aerated and hypoxic conditions was investigated using Chinese hamster V79 cells cultured in vitro. GSH and NPSH levels were depleted in V79 cells of varying cell densities using the gamma-glutamyl-cysteine-synthetase inhibitor, D,L-Buthionine-S,R-sulfoximine (BSO). A small change in hypoxic cell radiosensitivity could be attributed to the loss of GSH while depletion of thiols to lower levels affected both aerated and hypoxic cell radiosensitivity, resulting in no change in the OER

Impaired cross-talk between the thioredoxin and glutathione systems is related to ASK-1 mediated apoptosis in neuronal cells exposed to mercury.

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Branco, Vasco; Coppo, Lucia; Solá, Susana; Lu, Jun; Rodrigues, Cecília M P; Holmgren, Arne; Carvalho, Cristina

2017-10-01

Mercury (Hg) compounds target both cysteine (Cys) and selenocysteine (Sec) residues in peptides and proteins. Thus, the components of the two major cellular antioxidant systems - glutathione (GSH) and thioredoxin (Trx) systems - are likely targets for mercurials. Hg exposure results in GSH depletion and Trx and thioredoxin reductase (TrxR) are prime targets for mercury. These systems have a wide-range of common functions and interaction between their components has been reported. However, toxic effects over both systems are normally treated as isolated events. To study how the interaction between the glutathione and thioredoxin systems is affected by Hg, human neuroblastoma (SH-SY5Y) cells were exposed to 1 and 5μM of inorganic mercury (Hg 2+ ), methylmercury (MeHg) or ethylmercury (EtHg) and examined for TrxR, GSH and Grx levels and activities, as well as for Trx redox state. Phosphorylation of apoptosis signalling kinase 1 (ASK1), caspase-3 activity and the number of apoptotic cells were evaluated to investigate the induction of Trx-mediated apoptotic cell death. Additionally, primary cerebellar neurons from mice depleted of mitochondrial Grx2 (mGrx2D) were used to examine the link between Grx activity and Trx function. Results showed that Trx was affected at higher exposure levels than TrxR, especially for EtHg. GSH levels were only significantly affected by exposure to a high concentration of EtHg. Depletion of GSH with buthionine sulfoximine (BSO) severely increased Trx oxidation by Hg. Notably, EtHg-induced oxidation of Trx was significantly enhanced in primary neurons of mGrx2D mice. Our results suggest that GSH/Grx acts as backups for TrxR in neuronal cells to maintain Trx turnover during Hg exposure, thus linking different mechanisms of molecular and cellular toxicity. Finally, Trx oxidation by Hg compounds was associated to apoptotic hallmarks, including increased ASK-1 phosphorylation, caspase-3 activation and increased number of apoptotic cells

Water deprivation increases Fos expression in hypothalamic corticotropin-releasing factor neurons induced by right atrial distension in awake rats.

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Benedetti, Mauricio; Rorato, Rodrigo; Castro, Margaret; Machado, Benedito H; Antunes-Rodrigues, Jose; Elias, Lucila L K

2008-11-01

Atrial mechanoreceptors, sensitive to stretch, contribute in regulating heart rate and intravascular volume. The information from those receptors reaches the nucleus tractus solitarius and then the paraventricular nucleus (PVN), known to have a crucial role in the regulation of cardiovascular function. Neurons in the PVN synthesize CRF, AVP, and oxytocin (OT). Stimulation of atrial mechanoreceptors was performed in awake rats implanted with a balloon at the junction of the superior vena cava and right atrium. Plasma ACTH, AVP, and OT concentrations and Fos, CRF, AVP, and OT immunolabeling in the PVN were determined after balloon inflation in hydrated and water-deprived rats. The distension of the balloon increased the plasma ACTH concentrations, which were higher in water-deprived than in hydrated rats (P neurons in the parvocellular PVN, which was higher in the water-deprived than in the hydrated group (P neurons after distension in hydrated and water-deprived groups, compared with respective controls. In conclusion, parvocellular CRF neurons showed an increase of Fos expression induced by stimulation of right atrial mechanoreceptors, suggesting that CRF participates in the cardiovascular reflex adjustments elicited by volume loading. Activation of CRF neurons in the PVN by cardiovascular reflex is affected by osmotic stimulation.

Activity deprivation induces neuronal cell death: mediation by tissue-type plasminogen activator.

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Eldi Schonfeld-Dado

Full Text Available Spontaneous activity is an essential attribute of neuronal networks and plays a critical role in their development and maintenance. Upon blockade of activity with tetrodotoxin (TTX, neurons degenerate slowly and die in a manner resembling neurodegenerative diseases-induced neuronal cell death. The molecular cascade leading to this type of slow cell death is not entirely clear. Primary post-natal cortical neurons were exposed to TTX for up to two weeks, followed by molecular, biochemical and immunefluorescence analysis. The expression of the neuronal marker, neuron specific enolase (NSE, was down-regulated, as expected, but surprisingly, there was a concomitant and striking elevation in expression of tissue-type plasminogen activator (tPA. Immunofluorescence analysis indicated that tPA was highly elevated inside affected neurons. Transfection of an endogenous tPA inhibitor, plasminogen activator inhibitor-1 (PAI-1, protected the TTX-exposed neurons from dying. These results indicate that tPA is a pivotal player in slowly progressing activity deprivation-induced neurodegeneration.

Activation of glutathione peroxidase via Nrf1 mediates genistein's protection against oxidative endothelial cell injury

International Nuclear Information System (INIS)

Hernandez-Montes, Eva; Pollard, Susan E.; Vauzour, David; Jofre-Montseny, Laia; Rota, Cristina; Rimbach, Gerald; Weinberg, Peter D.; Spencer, Jeremy P.E.

2006-01-01

Cellular actions of isoflavones may mediate the beneficial health effects associated with high soy consumption. We have investigated protection by genistein and daidzein against oxidative stress-induced endothelial injury. Genistein but not daidzein protected endothelial cells from damage induced by oxidative stress. This protection was accompanied by decreases in intracellular glutathione levels that could be explained by the generation of glutathionyl conjugates of the oxidised genistein metabolite, 5,7,3',4'-tetrahydroxyisoflavone. Both isoflavones evoked increased protein expression of γ-glutamylcysteine synthetase-heavy subunit (γ-GCS-HS) and increased cytosolic accumulation and nuclear translocation of Nrf2. However, only genistein led to increases in the cytosolic accumulation and nuclear translocation of Nrf1 and the increased expression of and activity of glutathione peroxidase. These results suggest that genistein-induced protective effects depend primarily on the activation of glutathione peroxidase mediated by Nrf1 activation, and not on Nrf2 activation or increases in glutathione synthesis

Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation.

Science.gov (United States)

Lewis, Joan S; Meeke, Kathleen; Osipo, Clodia; Ross, Eric A; Kidawi, Noman; Li, Tianyu; Bell, Eric; Chandel, Navdeep S; Jordan, V Craig

2005-12-07

We previously developed an estrogen receptor (ER)-positive breast cancer cell line (MCF-7:5C) that is resistant to long-term estrogen deprivation and undergoes rapid and complete apoptosis in the presence of physiologic concentrations of 17beta-estradiol. Here, we investigated the role of the mitochondrial apoptotic pathway in this process. Apoptosis in MCF-7:5C cells treated with estradiol, fulvestrant, or vehicle (control) was investigated by annexin V-propidium iodide double staining and 4',6-diamidino-2-phenylindole (DAPI) staining. Apoptosis was also analyzed in MCF-7:5C cells transiently transfected with small interfering RNAs (siRNAs) to apoptotic pathway components. Expression of apoptotic pathway intermediates was measured by western blot analysis. Mitochondrial transmembrane potential (psim) was determined by rhodamine-123 retention assay. Mitochondrial pathway activity was determined by cytochrome c release and cleavage of poly(ADP-ribose) polymerase (PARP) protein. Tumorigenesis was studied in ovariectomized athymic mice that were injected with MCF-7:5C cells. Differences between the treatment groups and control group were determined by two-sample t test or one-factor analysis of variance. All statistical tests were two-sided. MCF-7:5C cells treated with estradiol underwent apoptosis and showed increased expression of proapoptotic proteins, decreased psim, enhanced cytochrome c release, and PARP cleavage compared with cells treated with fulvestrant or vehicle. Blockade of Bax, Bim, and p53 mRNA expression by siRNA reduced estradiol-induced apoptosis relative to control by 76% [95% confidence interval (CI) = 73% to 79%, P estradiol-induced apoptosis in long-term estrogen-deprived breast cancer cells. Physiologic concentrations of estradiol could potentially be used to induce apoptosis and tumor regression in tumors that have developed resistance to aromatase inhibitors.

The glutathione cycle: Glutathione metabolism beyond the γ-glutamyl cycle.

Science.gov (United States)

Bachhawat, Anand Kumar; Yadav, Shambhu

2018-04-17

Glutathione was discovered in 1888, over 125 years ago. Since then, our understanding of various functions and metabolism of this important molecule has grown over these years. But it is only now, in the last decade, that a somewhat complete picture of its metabolism has emerged. Glutathione metabolism has till now been largely depicted and understood by the γ-glutamyl cycle that was proposed in 1970. However, new findings and knowledge particularly on the transport and degradation of glutathione have revealed that many aspects of the γ-glutamyl cycle are incorrect. Despite this, an integrated critical analysis of the cycle has never been undertaken and this has led to the cycle and its errors perpetuating in the literature. This review takes a careful look at the γ-glutamyl cycle and its shortcomings and presents a "glutathione cycle" that captures the current understanding of glutathione metabolism. © 2018 IUBMB Life, 2018. © 2018 International Union of Biochemistry and Molecular Biology.

Radiosensitization of mouse skin by oxygen and depletion of glutathione

International Nuclear Information System (INIS)

Stevens, Graham; Joiner, Michael; Joiner, Barbara; Johns, Helen; Denekamp, Juliana

1995-01-01

Purpose: To determine the oxygen enhancement ratio (OER) and shape of the oxygen sensitization curve of mouse foot skin, the extent to which glutathione (GSH) depletion radiosensitized skin, and the dependence of such sensitization on the ambient oxygen tension. Methods and Materials: The feet of WHT mice were irradiated with single doses of 240 kVp x-rays while mice were exposed to carbogen or gases with oxygen/nitrogen mixtures containing 8-100% O 2 . The anoxic response was obtained by occluding the blood supply to the leg of anesthetized mice with a tourniquet, surrounding the foot with nitrogen, and allowing the mice to breathe 10% O 2 . Further experiments were performed to assess the efficacy of this method to obtain an anoxic response. Radiosensitivity of skin was assessed using the acute skin-reaction assay. Glutathione levels were modified using two schedules of dl-buthionine sulphoximine (BSO) and diethylmaleate (DEM), which were considered to produce extensive and intermediate levels of GSH depletion in the skin of the foot during irradiation. Results: Carbogen caused the greatest radiosensitization of skin, with a reproducible enhancement of 2.2 relative to the anoxic response. The OER of 2.2 is lower than other reports for mouse skin. This may indicate that the extremes of oxygenation were not produced, although there was no direct evidence for this. When skin radiosensitivity was plotted against the logarithm of the oxygen tension in the ambient gas, a sigmoid curve with a K value of 17-21% O 2 in the ambient gas was obtained. Depletion of GSH caused minimal radiosensitization when skin was irradiated under anoxic or well-oxygenated conditions. Radiosensitization by GSH depletion was maximal at intermediate oxygen tensions of 10-21% O 2 in the ambient gas. Increasing the extent of GSH depletion led to increasing radiosensitization, with sensitization enhancement ratios of 1.2 and 1.1, respectively, for extensive and intermediate levels of GSH

Acute effects of nitroglycerin depend on both plasma and intracellular sulfhydryl compound levels in vivo. Effect of agents with different sulfhydryl-modulating properties

DEFF Research Database (Denmark)

Boesgaard, S; Poulsen, H E; Aldershvile, J

1993-01-01

in SH group concentrations (cysteine and glutathione [GSH]) affect the responsiveness to NTG in vivo. METHODS AND RESULTS: GSH and cysteine levels in plasma, vena cava, and aorta were measured after administration of N-acetylserine (placebo, n = 6), N-acetylcysteine (NAC, extracellular and intracellular......BACKGROUND: Changes in sulfhydryl (SH) compound availability may alter the hemodynamic effect of nitroglycerin (NTG). Data on the relation between NTG effect and thiol levels are, however, limited to in vitro experiments. The present study investigates how intracellular and extracellular changes...... SH donor, n = 6), oxothiazolidine (OXO, intracellular SH donor, n = 6), buthionine sulfoximine (BSO, intracellular GSH-depleting agent, n = 6), BSO+NAC (n = 6), and BSO+OXO (n = 6) in chronically catheterized conscious rats. In addition, the effect of 2.5 mg NTG/kg i.v. on mean arterial pressure (MAP...

ENDURANCE TRAINING AND GLUTATHIONE-DEPENDENT ANTIOXIDANT DEFENSE MECHANISM IN HEART OF THE DIABETIC RATS

Directory of Open Access Journals (Sweden)

Mustafa Atalay

2003-06-01

Full Text Available Regular physical exercise beneficially influences cardiac antioxidant defenses in normal rats. The aim of this study was to test whether endurance training can strengthen glutathione-dependent antioxidant defense mechanism and decrease lipid peroxidation in heart of the streptozotocin-induced diabetic rats. Redox status of glutathione in blood of diabetic rats in response to training and acute exercise was also examined. Eight weeks of treadmill training increased the endurance in streptozotocin-induced diabetic rats. It did not affect glutathione level in heart tissue at rest and also after exercise. On the other hand, endurance training decreased glutathione peroxidase activity in heart, while glutathione reductase and glutathione S-transferase activities were not affected either by acute exhaustive exercise or endurance training. Reduced and oxidized glutathione levels in blood were not affected by either training or acute exercise. Conjugated dienes levels in heart tissue were increased by acute exhaustive exercise and also 8 weeks treadmill training. Longer duration of exhaustion in trained group may have contributed to the increased conjugated dienes levels in heart after acute exercise. Our results suggest that endurance type exercise may make heart more susceptible to oxidative stress. Therefore it may be wise to combine aerobic exercise with insulin treatment to prevent its adverse effects on antioxidant defense in heart in patients with diabetes mellitus

Intestinal Dysbiosis and Biotin Deprivation Induce Alopecia through Overgrowth of Lactobacillus murinus in Mice.

Science.gov (United States)

Hayashi, Atsushi; Mikami, Yohei; Miyamoto, Kentaro; Kamada, Nobuhiko; Sato, Toshiro; Mizuno, Shinta; Naganuma, Makoto; Teratani, Toshiaki; Aoki, Ryo; Fukuda, Shinji; Suda, Wataru; Hattori, Masahira; Amagai, Masayuki; Ohyama, Manabu; Kanai, Takanori

2017-08-15

Metabolism by the gut microbiota affects host physiology beyond the gastrointestinal tract. Here, we find that antibiotic-induced dysbiosis, in particular, overgrowth of Lactobacillus murinus (L. murinus), impaired gut metabolic function and led to the development of alopecia. While deprivation of dietary biotin per se did not affect skin physiology, its simultaneous treatment with vancomycin resulted in hair loss in specific pathogen-free (SPF) mice. Vancomycin treatment induced the accumulation of L. murinus in the gut, which consumes residual biotin and depletes available biotin in the gut. Consistently, L. murinus induced alopecia when monocolonized in germ-free mice fed a biotin-deficient diet. Supplementation of biotin can reverse established alopecia symptoms in the SPF condition, indicating that L. murinus plays a central role in the induction of hair loss via a biotin-dependent manner. Collectively, our results indicate that luminal metabolic alterations associated with gut dysbiosis and dietary modifications can compromise skin physiology. Copyright © 2017. Published by Elsevier Inc.

Health-risk behaviour in deprived neighbourhoods compared with non-deprived neighbourhoods

DEFF Research Database (Denmark)

Algren, Maria Holst; Bak, Carsten Kronborg; Berg-Beckhoff, Gabriele

2015-01-01

in deprived neighbourhoods compared with those who live in non-deprived neighbourhoods and to summarise what kind of operationalisations of neighbourhood deprivation that were used in the studies. METHODS: PRISMA guidelines for systematic reviews were followed. Systematic searches were performed in Pub......Med, Embase, Web of Science and Sociological Abstracts using relevant search terms, Boolean operators, and truncation, and reference lists were scanned. Quantitative observational studies that examined health-risk behaviour in deprived neighbourhoods compared with non-deprived neighbourhoods were eligible...... for inclusion. RESULTS: The inclusion criteria were met by 22 studies. The available literature showed a positive association between smoking and physical inactivity and living in deprived neighbourhoods compared with non-deprived neighbourhoods. In regard to low fruit and vegetable consumption and alcohol...

The effects of DL-AP5 and glutamate on ghrelin-induced feeding behavior in 3-h food-deprived broiler cockerels

NARCIS (Netherlands)

Taati, Majid; Nayebzadeh, Hassan; Zendehdel, Morteza

This study was designed to examine the effects of intracerebroventricular injection of DL-AP5 (N-methyl-D-aspartate (NMDA) receptor antagonist) and glutamate on ghrelin-induced feeding behavior in 3-h food-deprived (FD3) broiler cockerels. At first, guide cannula was surgically implanted in the

Caffeine and sleep-deprivation mediated changes in open-field behaviours, stress response and antioxidant status in mice.

Science.gov (United States)

Onaolapo, J Olakunle; Onaolapo, Y Adejoke; Akanmu, A Moses; Olayiwola, Gbola

2016-01-01

Effects of daily caffeine consumption on open-field behaviours, serum corticosterone and brain antioxidant levels were investigated after six hours of total sleep-deprivation in prepubertal mice. We tested the hypothesis that daily caffeine consumption may significantly alter behaviour, stress and antioxidative response of prepubertal mice to an acute episode of total sleep-deprivation. Prepubertal Swiss mice of both sexes were assigned to two main groups of 120 each (subdivided into 6 groups of 10 each, based on sex), and administered vehicle or graded oral doses of caffeine (10, 20, 40, 80 and 120 mg/kg/day) for 14 days. On day 14, a main group was subjected to 6 h of total sleep-deprivation by 'gentle-handling'. Open-field behaviours were then assessed in both groups, after which animals were euthanized, and levels of corticosterone, superoxide dismutase and glutathione peroxidase assayed. Horizontal locomotion, rearing and grooming increased significantly, compared to control, with sleep-deprived (SD) mice showing stronger caffeine-driven responses at higher doses; and SD female mice showing sustained response to caffeine, compared to respective males. Plasma corticosterone increased with increasing doses of caffeine in both non sleep-deprived (NSD) and SD mice; although SD mice had higher corticosterone levels. Sleep-deprivation and/or higher doses of caffeine were associated with derangements in brain antioxidant levels. Repeated caffeine consumption and/or acute sleep-deprivation led to significant changes in pattern of open-field behaviour and stress/antioxidant response in mice. Responses seen in the study are probably due to modulatory effects of caffeine on the total body response to stressful stimuli.

Methionine sulfoximine supplementation enhances productivity in GS-CHOK1SV cell lines through glutathione biosynthesis.

Science.gov (United States)

Feary, Marc; Racher, Andrew J; Young, Robert J; Smales, C Mark

2017-01-01

In Lonza Biologics' GS Gene Expression System™, recombinant protein-producing GS-CHOK1SV cell lines are generated by transfection with an expression vector encoding both GS and the protein product genes followed by selection in MSX and glutamine-free medium. MSX is required to inhibit endogenous CHOK1SV GS, and in effect create a glutamine auxotrophy in the host that can be complemented by the expression vector encoded GS in selected cell lines. However, MSX is not a specific inhibitor of GS as it also inhibits the activity of GCL (a key enzyme in the glutathione biosynthesis pathway) to a similar extent. Glutathione species (GSH and GSSG) have been shown to provide both oxidizing and reducing equivalents to ER-resident oxidoreductases, raising the possibility that selection for transfectants with increased GCL expression could result in the isolation of GS-CHOKISV cell lines with improved capacity for recombinant protein production. In this study we have begun to address the relationship between MSX supplementation, the amount of intracellular GCL subunit and mAb production from a panel of GS-CHOK1SV cell lines. We then evaluated the influence of reduced GCL activity on batch culture of an industrially relevant mAb-producing GS-CHOK1SV cell line. To the best of our knowledge, this paper describes for the first time the change in expression of GCL subunits and recombinant mAb production in these cell lines with the degree of MSX supplementation in routine subculture. Our data also shows that partial inhibition of GCL activity in medium containing 75 µM MSX increases mAb productivity, and its more specific inhibitor BSO used at a concentration of 80 µM in medium increases the specific rate of mAb production eight-fold and the concentration in harvest medium by two-fold. These findings support a link between the inhibition of glutathione biosynthesis and recombinant protein production in industrially relevant systems and provide a process-driven method for

O-GlcNAc-specific antibody CTD110.6 cross-reacts with N-GlcNAc2-modified proteins induced under glucose deprivation.

Directory of Open Access Journals (Sweden)

Takahiro Isono

Full Text Available Modification of serine and threonine residues in proteins by O-linked β-N-acetylglucosamine (O-GlcNAc glycosylation is a feature of many cellular responses to the nutritional state and to stress. O-GlcNAc modification is reversibly regulated by O-linked β-N-acetylglucosamine transferase (OGT and β-D-N-acetylglucosaminase (O-GlcNAcase. O-GlcNAc modification of proteins is dependent on the concentration of uridine 5'-diphospho-N-acetylglucosamine (UDP-GlcNAc, which is a substrate of OGT and is synthesized via the hexosamine biosynthetic pathway. Immunoblot analysis using the O-GlcNAc-specific antibody CTD110.6 has indicated that glucose deprivation increases protein O-GlcNAcylation in some cancer cells. The mechanism of this paradoxical phenomenon has remained unclear. Here we show that the increased glycosylation induced by glucose deprivation and detected by CTD110.6 antibodies is actually modification by N-GlcNAc(2, rather than by O-GlcNAc. We found that this induced glycosylation was not regulated by OGT and O-GlcNAcase, unlike typical O-GlcNAcylation, and it was inhibited by treatment with tunicamycin, an N-glycosylation inhibitor. Proteomics analysis showed that proteins modified by this induced glycosylation were N-GlcNAc(2-modified glycoproteins. Furthermore, CTD110.6 antibodies reacted with N-GlcNAc(2-modified glycoproteins produced by a yeast strain with a ts-mutant of ALG1 that could not add a mannose residue to dolichol-PP-GlcNAc(2. Our results demonstrated that N-GlcNAc(2-modified glycoproteins were induced under glucose deprivation and that they cross-reacted with the O-GlcNAc-specific antibody CTD110.6. We therefore propose that the glycosylation status of proteins previously classified as O-GlcNAc-modified proteins according to their reactivity with CTD110.6 antibodies must be re-examined. We also suggest that the repression of mature N-linked glycoproteins due to increased levels of N-GlcNAc(2-modified proteins is a newly

The effect of EGb 761 on retinal lipid peroxidation and glutathione peroxidase level in experimental lens induced uveitis.

Science.gov (United States)

Bilgihan, A; Aricioğlu, A; Bilgihan, K; Onol, M; Hasanreisoğlu, B; Türközkan, N

1994-01-01

An acute lens-induced necrotizing intraocular inflammation was produced in pigmented guinea pigs. Treatment of these animals by 100 mg/kg/day EGb 761 a free oxygen radical scavenger for 10 days, reduced retinal lipid peroxidation (p > 0.05) and increased the retinal glutathione peroxidase level (p > 0.05). Although not significantly, these findings suggest that EGb 761 could be combined with other antiinflammatory drugs and may be beneficial in the treatment of uveitis.

Effects of normobaric versus hyperbaric oxygen on cell injury induced by oxygen and glucose deprivation in acute brain slices

Directory of Open Access Journals (Sweden)

Laurent Chazalviel

2016-01-01

Full Text Available Normobaric oxygen (NBO and hyperbaric oxygen (HBO are emerging as a possible co-treatment of acute ischemic stroke. Both have been shown to reduce infarct volume, to improve neurologic outcome, to promote endogenous tissue plasminogen activator-induced thrombolysis and cerebral blood flow, and to improve tissue oxygenation through oxygen diffusion in the ischemic areas, thereby questioning the interest of HBO compared to NBO. In the present study, in order to investigate and compare the oxygen diffusion effects of NBO and HBO on acute ischemic stroke independently of their effects at the vascular level, we used acute brain slices exposed to oxygen and glucose deprivation, an ex vivo model of brain ischemia that allows investigating the acute effects of NBO (partial pressure of oxygen (pO 2 = 1 atmospheres absolute (ATA = 0.1 MPa and HBO (pO 2 = 2.5 ATA = 0.25 MPa through tissue oxygenation on ischemia-induced cell injury as measured by the release of lactate dehydrogenase. We found that HBO, but not NBO, reduced oxygen and glucose deprivation-induced cell injury, indicating that passive tissue oxygenation (i.e. without vascular support of the brain parenchyma requires oxygen partial pressure higher than 1 ATA.

Vitamin C Prevents Sleep Deprivation-induced Elevation in Cortisol ...

African Journals Online (AJOL)

olayemitoyin

Plasma glucose was significantly (p<0.05) reduced in all the sleep deprived groups compared ... of 12hr light-dark cycle after which they were subjected to Paradoxical .... Wakefulness involves high neuronal metabolism to maintain neuronal ...

Antistress Effects of Rosa rugosa Thunb. on Total Sleep Deprivation-Induced Anxiety-Like Behavior and Cognitive Dysfunction in Rat: Possible Mechanism of Action of 5-HT6 Receptor Antagonist.

Science.gov (United States)

Na, Ju-Ryun; Oh, Dool-Ri; Han, SeulHee; Kim, Yu-Jin; Choi, EunJin; Bae, Donghyuck; Oh, Dong Hwan; Lee, Yoo-Hyun; Kim, Sunoh; Jun, Woojin

2016-09-01

Our previous results suggest that the Rosa rugosa Thunb. (family Rosaceae) alleviates endurance exercise-induced stress by decreasing oxidative stress levels. This study aimed to screen and identify the physiological antistress effects of an extract of R. rugosa (RO) on sleep deprivation-induced anxiety-like behavior and cognitive tests (in vivo) and tested for hippocampal CORT and monoamine levels (ex vivo), corticosterone (CORT)-induced injury, N-methyl-d-aspartate (NMDA) receptor, and serotonin 6 (5-hydroxytryptamine 6, 5-HT6) receptor activities (in vitro) in search of active principles and underlying mechanisms of action. We confirmed the antistress effects of RO in a sleep-deprived stress model in rat and explored the underlying mechanisms of its action. In conclusion, an R. rugosa extract showed efficacy and potential for use as an antistress therapy to treat sleep deprivation through its antagonism of the 5-HT6 receptor and resulting inhibition of cAMP activity.

A chloroplast-localized and auxin-induced glutathione S-transferase from phreatophyte Prosopis juliflora confer drought tolerance on tobacco.

Science.gov (United States)

George, Suja; Venkataraman, Gayatri; Parida, Ajay

2010-03-01

Plant growth and productivity are adversely affected by various abiotic stress factors. In our previous study, we used Prosopis juliflora, a drought-tolerant tree species of Fabaceae, as a model plant system for mining genes functioning in abiotic stress tolerance. Large-scale random EST sequencing from a cDNA library obtained from drought-stressed leaves of 2-month-old P. juliflora plants resulted in identification of three different auxin-inducible glutathione S-transferases. In this paper, we report the cellular localization and the ability to confer drought tolerance in transgenic tobacco of one of these GSTs (PjGSTU1). PjGSTU1 was overexpressed in Escherichia coli and GST and GPX activities in total protein samples were assayed and compared with controls. The results indicated that PjGSTU1 protein forms a functional homo-dimer in recombinant bacteria with glutathione transferase as well as glutathione peroxidase activities. PjGSTU1 transgenic tobacco lines survived better under conditions of 15% PEG stress compared with control un-transformed plants. In vivo localization studies for PjGSTU1 using GFP fusion revealed protein localization in chloroplasts of transgenic plants. The peroxidase activity of PjGSTU1 and its localization in the chloroplast indicates a possible role for PjGSTU1 in ROS removal. Copyright 2009 Elsevier GmbH. All rights reserved.

Sex-dependent effects of sleep deprivation on myocardial sensitivity to ischemic injury.

Science.gov (United States)

Zoladz, Phillip R; Krivenko, Anna; Eisenmann, Eric D; Bui, Albert D; Seeley, Sarah L; Fry, Megan E; Johnson, Brandon L; Rorabaugh, Boyd R

2016-01-01

Sleep deprivation is associated with increased risk of myocardial infarction. However, it is unknown whether the effects of sleep deprivation are limited to increasing the likelihood of experiencing a myocardial infarction or if sleep deprivation also increases the extent of myocardial injury. In this study, rats were deprived of paradoxical sleep for 96 h using the platform-over-water method. Control rats were subjected to the same condition except the control platform was large enough for the rats to sleep. Hearts from sleep deprived and control rats were subjected to 20 min ischemia on a Langendorff isolated heart system. Infarct size and post ischemic recovery of contractile function were unaffected by sleep deprivation in male hearts. In contrast, hearts from sleep-deprived females exhibited significantly larger infarcts than hearts from control females. Post ischemic recovery of rate pressure product and + dP/dT were significantly attenuated by sleep deprivation in female hearts, and post ischemic recovery of end diastolic pressure was significantly elevated in hearts from sleep deprived females compared to control females, indicating that post ischemic recovery of both systolic and diastolic function were worsened by sleep deprivation. These data provide evidence that sleep deprivation increases the extent of ischemia-induced injury in a sex-dependent manner.

Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations.

Science.gov (United States)

Rasmussen, Dennis D; Kincaid, Carrie L; Froehlich, Janice C

2017-01-01

Stress-induced anxiety is a risk factor for relapse to alcohol drinking. The aim of this study was to test the hypothesis that the central nervous system (CNS)-active α 1 -adrenergic receptor antagonist, prazosin, would block the stress-induced increase in anxiety that occurs during alcohol deprivations. Selectively bred male alcohol-preferring (P) rats were given three cycles of 5 days of ad libitum voluntary alcohol drinking interrupted by 2 days of alcohol deprivation, with or without 1 h of restraint stress 4 h after the start of each of the first two alcohol deprivation cycles. Prazosin (1.0 or 1.5 mg/kg, IP) or vehicle was administered before each restraint stress. Anxiety-like behavior during alcohol deprivation following the third 5-day cycle of alcohol drinking (7 days after the most recent restraint stress ± prazosin treatment) was measured by performance in an elevated plus-maze and in social approach/avoidance testing. Rats that received constant alcohol access, or alcohol access and deprivations without stress or prazosin treatments in the first two alcohol deprivations did not exhibit augmented anxiety-like behavior during the third deprivation. In contrast, rats that had been stressed during the first two alcohol deprivations exhibited increased anxiety-like behavior (compared with control rats) in both anxiety tests during the third deprivation. Prazosin given before stresses in the first two cycles of alcohol withdrawal prevented increased anxiety-like behavior during the third alcohol deprivation. Prazosin treatment before stresses experienced during alcohol deprivations may prevent the increased anxiety during subsequent deprivation/abstinence that is a risk factor for relapse to alcohol drinking. Administration of prazosin before stresses during repetitive alcohol deprivations in male alcohol-preferring (P) rats prevents increased anxiety during a subsequent deprivation without further prazosin treatment. Prazosin treatment during repeated

Hepatic and erythrocytic glutathione peroxidase activity in liver diseases.

Science.gov (United States)

Cordero, R; Ortiz, A; Hernández, R; López, V; Gómez, M M; Mena, P

1996-09-01

Hepatic and erythrocytic glutathione peroxidase activity, together with malondialdehyde levels, were determined as indicators of peroxidation in 83 patients from whom liver biopsies had been taken for diagnostic purposes. On histological study, the patients were classified into groups as minimal changes (including normal liver), steatosis, alcoholic hepatitis, hepatic cirrhosis, light to moderately active chronic hepatitis, and severe chronic active hepatitis. The glutathione peroxidase activity in erythrocytes showed no significant changes in any liver disease group. In the hepatic study, an increased activity was observed in steatosis with respect to the minimal changes group, this increased activity induced by the toxic agent in the initial stages of the alcoholic hepatic disease declining as the hepatic damage progressed. There was a negative correlation between the levels of hepatic malondialdehyde and hepatic glutathione peroxidase in subjects with minimal changes. This suggested the existence of an oxidative equilibrium in this group. This equilibrium is broken in the liver disease groups as was manifest in a positive correlation between malondialdehyde and glutathione peroxidase activity.

Novel interaction of diethyldithiocarbamate with the glutathione/glutathione peroxidase system

International Nuclear Information System (INIS)

Kumar, K.S.; Sancho, A.M.; Weiss, J.F.

1986-01-01

Diethyldithiocarbamate (DDC) exhibits a variety of pharmacologic activities, including both radioprotective and sensitizing properties. Since the glutathione/glutathione peroxidase system may be a significant factor in determining radiation sensitivity, the potential mechanisms of action of DDC in relation to this system were examined in vitro. The interaction of DDC with reduced glutathione (GSH) was tested using a simple system based on the reduction of cytochrome c. When DDC (0.005 mM) was incubated with GSH (0.5 mM), the reduction of cytochrome c was eightfold greater than that expected from an additive effect of DDC and GSH. GSH could be replaced by oxidized glutathione and glutathione reductase. Cytochrome c reduced by DDC was oxidized by mitochondria. The interaction of DDC with both the hexosemonophosphate shunt pathway and the mitochondrial respiratory chain suggests the possibility of linking these two pathways through DDC. Oxidation of DDC by peroxide and reversal by GSH indicated that the drug can engage in a cyclic reaction with peroxide and GSH. This was confirmed when DDC was used in the assay system for glutathione peroxidase (GSHPx) without GSHPx. DDC at a concentration of 0.25 mM was more active than 0.01 unit of pure GSHPx in eliminating peroxide, and much more active than the other sulfhydryl compounds tested. These studies indicate that DDC can supplement GSHPx activity or substitute for it in detoxifying peroxides, and suggests a unique role in the chemical modification of radiation sensitivity

1-Methyl-4-phenylpyridinium-induced alterations of glutathione status in immortalized rat dopaminergic neurons

International Nuclear Information System (INIS)

Drechsel, Derek A.; Liang, L.-P.; Patel, Manisha

2007-01-01

Decreased glutathione levels associated with increased oxidative stress are a hallmark of numerous neurodegenerative diseases, including Parkinson's disease. GSH is an important molecule that serves as an anti-oxidant and is also a major determinant of cellular redox environment. Previous studies have demonstrated that neurotoxins can cause changes in reduced and oxidized GSH levels; however, information regarding steady state levels remains unexplored. The goal of this study was to characterize changes in cellular GSH levels and its regulatory enzymes in a dopaminergic cell line (N27) following treatment with the Parkinsonian toxin, 1-methyl-4-phenylpyridinium (MPP + ). Cellular GSH levels were initially significantly decreased 12 h after treatment, but subsequently recovered to values greater than controls by 24 h. However, oxidized glutathione (GSSG) levels were increased 24 h following treatment, concomitant with a decrease in GSH/GSSG ratio prior to cell death. In accordance with these changes, ROS levels were also increased, confirming the presence of oxidative stress. Decreased enzymatic activities of glutathione reductase and glutamate-cysteine ligase by 20-25% were observed at early time points and partly account for changes in GSH levels after MPP + exposure. Additionally, glutathione peroxidase activity was increased 24 h following treatment. MPP + treatment was not associated with increased efflux of glutathione to the medium. These data further elucidate the mechanisms underlying GSH depletion in response to the Parkinsonian toxin, MPP +

The relationship between tiredness prior to sleep deprivation and the antidepressant response to sleep deprivation in depression.

NARCIS (Netherlands)

Van den Burg, W.; Bouhuys, A.L; van den Hoofdakker, R.H

1995-01-01

Recently it was hypothesized that the antidepressant response to total sleep deprivation (SD) results from a disinhibition process induced by the increase of tiredness in the course of SD. In the present study, the role of tiredness in the antidepressant response to SD is further investigated,

Alterations of energy metabolism and glutathione levels of HL-60 cells induced by methacrylates present in composite resins.

Science.gov (United States)

Nocca, G; De Palma, F; Minucci, A; De Sole, P; Martorana, G E; Callà, C; Morlacchi, C; Gozzo, M L; Gambarini, G; Chimenti, C; Giardina, B; Lupi, A

2007-03-01

Methacrylic compounds such as 2-hydroxyethyl methacrylate (HEMA), triethylene glycol dimethacrylate (TEGDMA) and bisphenol A glycerolate (1 glycerol/phenol) dimethacrylate (Bis-GMA) are largely present in auto- or photopolymerizable composite resins. Since the polymerization reaction is never complete, these molecules are released into the oral cavity tissues and biological fluids where they could cause local adverse effects. The aim of this work was to verify the hypothesis that the biological effects of HEMA, TEGDMA and Bis-GMA - at a non-cytotoxic concentration - depend on the interaction with mitochondria and exert consequent alterations of energy metabolism, GSH levels and the related pathways in human promyelocytic cell line (HL-60). The biological effects of methacrylic monomers were determined by analyzing the following parameters: GSH concentration, glucose-6-phosphate dehydrogenase (G6PDH) and glutathione reductase (GR) activity, oxygen and glucose consumption and lactate production along with cell differentiation and proliferation. All monomers induced both cellular differentiation and decrease in oxygen consumption. Cells treated with TEGDMA and Bis-GMA showed a significant enhancement of glucose consumption and lactate production. TEGDMA and HEMA induced GSH depletion stimulating G6PDH and GR activity. All the monomers under study affect the metabolism of HL-60 cells and show differentiating activity. Since alterations in cellular metabolism occurred at compound concentrations well below cytotoxic levels, the changes in energy metabolism and glutathione redox balance could be considered as potential mechanisms for inducing clinical and sub-clinical adverse effects and thus providing useful parameters when testing biocompatibility of dental materials.

Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Ragnum, Harald Bull [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Røe, Kathrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Holm, Ruth; Vlatkovic, Ljiljana [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Nesland, Jahn Marthin [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Aarnes, Eva-Katrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Ree, Anne Hansen [Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Flatmark, Kjersti [Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Department of Gastrointestinal Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Seierstad, Therese [Department of Radiology and Nuclear Medicine, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Faculty of Health Sciences, Buskerud University College, Drammen (Norway); Lilleby, Wolfgang [Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Lyng, Heidi, E-mail: heidi.lyng@rr-research.no [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway)

2013-11-15

Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

International Nuclear Information System (INIS)

Ragnum, Harald Bull; Røe, Kathrine; Holm, Ruth; Vlatkovic, Ljiljana; Nesland, Jahn Marthin; Aarnes, Eva-Katrine; Ree, Anne Hansen; Flatmark, Kjersti; Seierstad, Therese; Lilleby, Wolfgang; Lyng, Heidi

2013-01-01

Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

Lack of oxygen effect in glutathione-deficient human cells in culture

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Edgren, M.; Larsson, A.; Nilsson, K.; Revesz, L.; Scott, O.C.A.

1980-01-01

The frequency of X-ray-induced DNA breaks was determined in human cell lines which are deficient in glutathione synthetase and have a greatly reduced glutathione content. Hydroxyapatite chromatography was used for the estimation of the DNA breaks in cell cultures, which were derived either from lymphoblasts transformed by infection with EB virus or from fibroblasts. The dose-effect relationship for the induction of breaks when radiation exposure was made in argon, was similar to that found when exposure was made in air. In control cultures with normal glutathione content, the induction of breaks was enhanced when irradiation was made under aerobic, instead of anaerobic, conditions. Treatment of the glutathione-deficient cells with the hypoxic radiosensitizer misonidazole did not enhance the induction of breaks by radiation delivered either in air or in argon. In control cultures, radiation induction of breaks was enhanced by misonidazole under anaerobic but not under aerobic conditions. When the glutathione-deficient cells were pretreated with cysteamine however, irradiation in the absence of oxygen resulted in a decreased frequency of DNA breaks. (author)

Activity of the Respiratory Chain Enzymes of Blood Leucocytes’ Mitochondria Under the Conditions of Toxic Hepatitis Induced Against the Background Alimentary Deprivation of Protein

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O.N. Voloshchuk

2015-12-01

Full Text Available Full functioning of the leucocytes’ energy supply system is one of the essential factors for the immune surveillance system effective work. The pivotal enzymes of the leucocytes’ energy biotransformation system are NADH-ubiquitin reductase, a marker of the Complex I of respiratory chain activity, and succinate dehydrogenase, key enzyme of the Complex II of respiratory chain. The aim of research – to study the NADH-ubiquitin reductase and succinate dehydrogenase activity of the blood leucocytes’ mitochondria under the conditions of toxic hepatitis induced against the background alimentary deprivation of protein. It is shown, that under the conditions of acetaminophen-induced hepatitis a reduction of the NADH-ubiquitin reductase enzymatic activity is observed on the background activation of the succinate-dependent way of the mitochondrial oxidation. Conclusion was made that alimentary deprivation or protein is a factor, aggravating the misbalance of the energy biotransformation system in the leucocytes of rats with toxic hepatitis. Established activity changes of the leucocytes’ mitochondria respiratory chain key enzymes may be considered as one of the mechanisms, directed on the maintenance of leucocytes energy supply on a level, sufficient for their functioning. Research results may be used for the biochemical rationale of the therapeutic approaches to the elimination and correction of the leucocytes’ energy metabolism disturbances consequences under the conditions of acetaminophen-induced hepatitis, aggravated by the alimentary protein deprivation.

Lifestyle intervention program in deprived obese adult patients and their non-deprived counterparts.

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Celine Loddo

Full Text Available Although it is known that the prevalence of obesity is high in deprived patients, the link between deprivation and obesity, and the impact of deprivation on compliance and efficacy of a lifestyle intervention program are not known.Deprivation was assessed in 40 patients (23 Females, mean±SD age: 49±17 years from the diabetology department and 140 patients (101 Females, age: 50±15 years from the nutrition department of Bordeaux University hospital. Eighty-seven patients suffering from obesity were evaluated before and after a tailored, multidisciplinary lifestyle intervention. Deprivation was assessed using EPICES scores. Deprivation was defined with an EPICES score > 30.Deprived patients suffering from obesity had significantly higher current (43.8 ±8.4 versus 40.9 ± 5.5 kg/m2, p = 0,02 and maximal BMI (46.1± 8.6 versus 42.3± 5.2 kg/m2, p = 0.002 compared to non-deprived obese. Percentage of body weight loss was not different according to deprivation (4.74 ± 0.75 versus 4.65 ± 1.04%, p = 0.9. EPICES scores were not different according to adherence to lifestyle intervention program (20.5 ± 8.5 versus 29.9 ± 3.9 versus 29.0 ±2.5, no follow up versus partial follow up versus total follow up, p = 0,58.Deprived patients suffering from obesity have a more serious disease than non-deprived patients. However, neither compliance to the lifestyle intervention program nor body weight loss differed between deprived patients with obesity and non-deprived ones. Deprivation should not be a limitation when enrolling patients with obesity in lifestyle intervention programs.

Lifestyle intervention program in deprived obese adult patients and their non-deprived counterparts.

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Loddo, Celine; Pupier, Emilie; Amour, Rémy; Monsaingeon-Henry, Maud; Mohammedi, Kamel; Gatta-Cherifi, Blandine

2017-01-01

Although it is known that the prevalence of obesity is high in deprived patients, the link between deprivation and obesity, and the impact of deprivation on compliance and efficacy of a lifestyle intervention program are not known. Deprivation was assessed in 40 patients (23 Females, mean±SD age: 49±17 years) from the diabetology department and 140 patients (101 Females, age: 50±15 years) from the nutrition department of Bordeaux University hospital. Eighty-seven patients suffering from obesity were evaluated before and after a tailored, multidisciplinary lifestyle intervention. Deprivation was assessed using EPICES scores. Deprivation was defined with an EPICES score > 30. Deprived patients suffering from obesity had significantly higher current (43.8 ±8.4 versus 40.9 ± 5.5 kg/m2, p = 0,02) and maximal BMI (46.1± 8.6 versus 42.3± 5.2 kg/m2, p = 0.002) compared to non-deprived obese. Percentage of body weight loss was not different according to deprivation (4.74 ± 0.75 versus 4.65 ± 1.04%, p = 0.9). EPICES scores were not different according to adherence to lifestyle intervention program (20.5 ± 8.5 versus 29.9 ± 3.9 versus 29.0 ±2.5, no follow up versus partial follow up versus total follow up, p = 0,58). Deprived patients suffering from obesity have a more serious disease than non-deprived patients. However, neither compliance to the lifestyle intervention program nor body weight loss differed between deprived patients with obesity and non-deprived ones. Deprivation should not be a limitation when enrolling patients with obesity in lifestyle intervention programs.

The role of BCL-2 and glutathione in an antioxidant pathway to prevent radiation-induced apoptosis

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Vlachaki, Maria T.; Meyn, Raymond E.

1997-01-01

Objective: The expression of the bcl-2 gene has been associated with resistance to radiation induced apoptosis. There is evidence that the bcl-2 protein acts in the antioxidant pathways to block the effects of reactive oxygen spieces that mediate apoptosis possibly by increasing the levels of intracellular glutathione. Our hypothesis is that pretreatment of radiation-sensitive cells, known to lack bcl-2 expression, with antioxidants will reduce radiation-induced apoptosis. For this purpose, the apoptotic response to radiation and the intracellular levels of glutathione were tested before and after pretreatment with antioxidants in two murine lymphoma cell lines, a radiation resistant-bcl-2 expressing (Ly-ar) line and a radiation sensitive (Ly-as) line. Methods and Materials: Ly-ar and Ly-as cells were irradiated at 0,1,2,3 and 4 hours before collection. The intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione were determined by the use of the fluorescent dye ophthalaldehyde. Ly-as cells were pretreated with dihydrolipoic acid and lipoamide for 1 hour before irradiation. Apoptosis response was measured by the DNA fragmentation assay. The radiation dose was 2.5 Gy. Results: After irradiation, the apoptotic rate of Ly-ar and Ly-as cells is 11-19% and 66-87% respectively. Ly-ar cells have higher intracellular GSH and GSSG levels compared to Ly-as cells by 69.9% and 91.9% respectively and the GSH/GSSG ratio in Ly-ar and Ly-as cells is 17.09 and 15.09 respectively (a difference of 13.25%). GSH levels do not change during the first three hours after irradiation; however there is a 46% reduction at four hours after irradiation, a time at which the Ly-as cells have already fragmented their DNA. Pretreatment of cells with dihydrolipoic acid or lipoamide at concentrations of 4mM and 2mM respectively was toxic and resulted in cell death in the absence of irradiation. Conclusions: GSH and GSSG levels are elevated in radiation-resistant murine lymphoma cells

Sleep Deprivation and Caffeine Treatment Potentiate Photic Resetting of the Master Circadian Clock in a Diurnal Rodent.

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Jha, Pawan Kumar; Bouâouda, Hanan; Gourmelen, Sylviane; Dumont, Stephanie; Fuchs, Fanny; Goumon, Yannick; Bourgin, Patrice; Kalsbeek, Andries; Challet, Etienne

2017-04-19

Circadian rhythms in nocturnal and diurnal mammals are primarily synchronized to local time by the light/dark cycle. However, nonphotic factors, such as behavioral arousal and metabolic cues, can also phase shift the master clock in the suprachiasmatic nuclei (SCNs) and/or reduce the synchronizing effects of light in nocturnal rodents. In diurnal rodents, the role of arousal or insufficient sleep in these functions is still poorly understood. In the present study, diurnal Sudanian grass rats, Arvicanthis ansorgei , were aroused at night by sleep deprivation (gentle handling) or caffeine treatment that both prevented sleep. Phase shifts of locomotor activity were analyzed in grass rats transferred from a light/dark cycle to constant darkness and aroused in early night or late night. Early night, but not late night, sleep deprivation induced a significant phase shift. Caffeine on its own induced no phase shifts. Both sleep deprivation and caffeine treatment potentiated light-induced phase delays and phase advances in response to a 30 min light pulse, respectively. Sleep deprivation in early night, but not late night, potentiated light-induced c-Fos expression in the ventral SCN. Caffeine treatment in midnight triggered c-Fos expression in dorsal SCN. Both sleep deprivation and caffeine treatment potentiated light-induced c-Fos expression in calbindin-containing cells of the ventral SCN in early and late night. These findings indicate that, in contrast to nocturnal rodents, behavioral arousal induced either by sleep deprivation or caffeine during the sleeping period potentiates light resetting of the master circadian clock in diurnal rodents, and activation of calbindin-containing suprachiasmatic cells may be involved in this effect. SIGNIFICANCE STATEMENT Arousing stimuli have the ability to regulate circadian rhythms in mammals. Behavioral arousal in the sleeping period phase shifts the master clock in the suprachiasmatic nuclei and/or slows down the photic

Global analysis of gene expression in response to L-Cysteine deprivation in the anaerobic protozoan parasite Entamoeba histolytica

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2011-01-01

Background Entamoeba histolytica, an enteric protozoan parasite, causes amebic colitis and extra intestinal abscesses in millions of inhabitants of endemic areas. E. histolytica completely lacks glutathione metabolism but possesses L-cysteine as the principle low molecular weight thiol. L-Cysteine is essential for the structure, stability, and various protein functions, including catalysis, electron transfer, redox regulation, nitrogen fixation, and sensing for regulatory processes. Recently, we demonstrated that in E. histolytica, L-cysteine regulates various metabolic pathways including energy, amino acid, and phospholipid metabolism. Results In this study, employing custom-made Affymetrix microarrays, we performed time course (3, 6, 12, 24, and 48 h) gene expression analysis upon L-cysteine deprivation. We identified that out of 9,327 genes represented on the array, 290 genes encoding proteins with functions in metabolism, signalling, DNA/RNA regulation, electron transport, stress response, membrane transport, vesicular trafficking/secretion, and cytoskeleton were differentially expressed (≥3 fold) at one or more time points upon L-cysteine deprivation. Approximately 60% of these modulated genes encoded proteins of no known function and annotated as hypothetical proteins. We also attempted further functional analysis of some of the most highly modulated genes by L-cysteine depletion. Conclusions To our surprise, L-cysteine depletion caused only limited changes in the expression of genes involved in sulfur-containing amino acid metabolism and oxidative stress defense. In contrast, we observed significant changes in the expression of several genes encoding iron sulfur flavoproteins, a major facilitator super-family transporter, regulator of nonsense transcripts, NADPH-dependent oxido-reductase, short chain dehydrogenase, acetyltransferases, and various other genes involved in diverse cellular functions. This study represents the first genome-wide analysis of

Global analysis of gene expression in response to L-Cysteine deprivation in the anaerobic protozoan parasite Entamoeba histolytica

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Jeelani Ghulam

2011-05-01

Full Text Available Abstract Background Entamoeba histolytica, an enteric protozoan parasite, causes amebic colitis and extra intestinal abscesses in millions of inhabitants of endemic areas. E. histolytica completely lacks glutathione metabolism but possesses L-cysteine as the principle low molecular weight thiol. L-Cysteine is essential for the structure, stability, and various protein functions, including catalysis, electron transfer, redox regulation, nitrogen fixation, and sensing for regulatory processes. Recently, we demonstrated that in E. histolytica, L-cysteine regulates various metabolic pathways including energy, amino acid, and phospholipid metabolism. Results In this study, employing custom-made Affymetrix microarrays, we performed time course (3, 6, 12, 24, and 48 h gene expression analysis upon L-cysteine deprivation. We identified that out of 9,327 genes represented on the array, 290 genes encoding proteins with functions in metabolism, signalling, DNA/RNA regulation, electron transport, stress response, membrane transport, vesicular trafficking/secretion, and cytoskeleton were differentially expressed (≥3 fold at one or more time points upon L-cysteine deprivation. Approximately 60% of these modulated genes encoded proteins of no known function and annotated as hypothetical proteins. We also attempted further functional analysis of some of the most highly modulated genes by L-cysteine depletion. Conclusions To our surprise, L-cysteine depletion caused only limited changes in the expression of genes involved in sulfur-containing amino acid metabolism and oxidative stress defense. In contrast, we observed significant changes in the expression of several genes encoding iron sulfur flavoproteins, a major facilitator super-family transporter, regulator of nonsense transcripts, NADPH-dependent oxido-reductase, short chain dehydrogenase, acetyltransferases, and various other genes involved in diverse cellular functions. This study represents the first

In vivo and in vitro assessment of the role of glutathione antioxidant system in anthracycline-induced cardiotoxicity

Czech Academy of Sciences Publication Activity Database

Vávrová, A.; Popelová, O.; Štěrba, M.; Jirkovský, E.; Hašková, P.; Mertlíková-Kaiserová, Helena; Geršl, V.; Šimůnek, T.

2011-01-01

Roč. 85, č. 5 (2011), s. 525-535 ISSN 0340-5761 Grant - others:GA ČR(CZ) GA305/09/0416 Program:GA Institutional research plan: CEZ:AV0Z40550506 Keywords : anthracycline cardiotoxicity * daunorubicin * glutathione * glutathione peroxidase * glutathione peroxidase Subject RIV: CE - Biochemistry Impact factor: 4.674, year: 2011

Short-Term Monocular Deprivation Enhances Physiological Pupillary Oscillations

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Paola Binda

2017-01-01

Full Text Available Short-term monocular deprivation alters visual perception in adult humans, increasing the dominance of the deprived eye, for example, as measured with binocular rivalry. This form of plasticity may depend upon the inhibition/excitation balance in the visual cortex. Recent work suggests that cortical excitability is reliably tracked by dilations and constrictions of the pupils of the eyes. Here, we ask whether monocular deprivation produces a systematic change of pupil behavior, as measured at rest, that is independent of the change of visual perception. During periods of minimal sensory stimulation (in the dark and task requirements (minimizing body and gaze movements, slow pupil oscillations, “hippus,” spontaneously appear. We find that hippus amplitude increases after monocular deprivation, with larger hippus changes in participants showing larger ocular dominance changes (measured by binocular rivalry. This tight correlation suggests that a single latent variable explains both the change of ocular dominance and hippus. We speculate that the neurotransmitter norepinephrine may be implicated in this phenomenon, given its important role in both plasticity and pupil control. On the practical side, our results indicate that measuring the pupil hippus (a simple and short procedure provides a sensitive index of the change of ocular dominance induced by short-term monocular deprivation, hence a proxy for plasticity.

Protective effect of Nigella sativa extract and thymoquinone on serum/glucose deprivation-induced PC12 cells death.

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Mousavi, S H; Tayarani-Najaran, Z; Asghari, M; Sadeghnia, H R

2010-05-01

The serum/glucose deprivation (SGD)-induced cell death in cultured PC12 cells represents a useful in vitro model for the study of brain ischemia and neurodegenerative disorders. Nigella sativa L. (family Ranunculaceae) and its active component thymoquinone (TQ) has been known as a source of antioxidants. In the present study, the protective effects of N. sativa and TQ on cell viability and reactive oxygen species (ROS) production in cultured PC12 cells were investigated under SGD conditions. PC12 cells were cultured in DMEM medium containing 10% (v/v) fetal bovine serum, 100 units/ml penicillin, and 100 microg/ml streptomycin. Cells were seeded overnight and then deprived of serum/glucose for 6 and 18 h. Cells were pretreated with different concentrations of N. sativa extract (15.62-250 microg/ml) and TQ (1.17-150 microM) for 2 h. Cell viability was quantitated by MTT assay. Intracellular ROS production was measured by flow cytometry using 2',7'-dichlorofluorescin diacetate (DCF-DA) as a probe. SGD induced significant cells toxicity after 6, 18, or 24 h (P < 0.001). Pretreatment with N. sativa (15.62-250 microg/ml) and TQ (1.17-37.5 microM) reduced SGD-induced cytotoxicity in PC12 cells after 6 and 18 h. A significant increase in intracellular ROS production was seen following SGD (P < 0.001). N. sativa (250 microg/ml, P < 0.01) and TQ (2.34, 4.68, 9.37 microM, P < 0.01) pretreatment reversed the increased ROS production following ischemic insult. The experimental results suggest that N. sativa extract and TQ protects the PC12 cells against SGD-induced cytotoxicity via antioxidant mechanisms. Our findings might raise the possibility of potential therapeutic application of N. sativa extract and TQ for managing cerebral ischemic and neurodegenerative disorders.

A novel plant glutathione S-transferase/peroxidase suppresses Bax lethality in yeast

DEFF Research Database (Denmark)

Kampranis, S C; Damianova, R; Atallah, M

2000-01-01

The mammalian inducer of apoptosis Bax is lethal when expressed in yeast and plant cells. To identify potential inhibitors of Bax in plants we transformed yeast cells expressing Bax with a tomato cDNA library and we selected for cells surviving after the induction of Bax. This genetic screen allows...... for the identification of plant genes, which inhibit either directly or indirectly the lethal phenotype of Bax. Using this method a number of cDNA clones were isolated, the more potent of which encodes a protein homologous to the class theta glutathione S-transferases. This Bax-inhibiting (BI) protein was expressed...... in Escherichia coli and found to possess glutathione S-transferase (GST) and weak glutathione peroxidase (GPX) activity. Expression of Bax in yeast decreases the intracellular levels of total glutathione, causes a substantial reduction of total cellular phospholipids, diminishes the mitochondrial membrane...

Evaluation of cysteine ethyl ester as efficient inducer for glutathione overproduction in Saccharomyces spp.

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Lorenz, Eric; Schmacht, Maximilian; Senz, Martin

2016-11-01

Economical yeast based glutathione (GSH) production is a process that is influenced by several factors like raw material and production costs, biomass production and efficient biotransformation of adequate precursors into the final product GSH. Nowadays the usage of cysteine for the microbial conversion into GSH is industrial state of practice. In the following study, the potential of different inducers to increase the GSH content was evaluated by means of design of experiments methodology. Investigations were executed in three natural Saccharomyces strains, S. cerevisiae, S. bayanus and S. boulardii, in a well suited 50ml shake tube system. Results of shake tube experiments were confirmed in traditional baffled shake flasks and finally via batch cultivation in lab-scale bioreactors under controlled conditions. Comprehensive studies showed that the usage of cysteine ethyl ester (CEE) for the batch-wise biotransformation into GSH led up to a more than 2.2 times higher yield compared to cysteine as inducer. Additionally, the intracellular GSH content could be significantly increased for all strains in terms of 2.29±0.29% for cysteine to 3.65±0.23% for CEE, respectively, in bioreactors. Thus, the usage of CEE provides a highly attractive inducing strategy for the GSH overproduction. Copyright © 2016 Elsevier Inc. All rights reserved.

A role for glutathione, independent of oxidative stress, in the developmental toxicity of methanol

International Nuclear Information System (INIS)

Siu, Michelle T.; Shapiro, Aaron M.; Wiley, Michael J.; Wells, Peter G.

2013-01-01

Oxidative stress and reactive oxygen species (ROS) have been implicated in the teratogenicity of methanol (MeOH) in rodents, both in vivo and in embryo culture. We explored the ROS hypothesis further in vivo in pregnant C57BL/6J mice. Following maternal treatment with a teratogenic dose of MeOH, 4 g/kg via intraperitoneal (ip) injection on gestational day (GD) 12, there was no increase 6 h later in embryonic ROS formation, measured by 2′,7′-dichlorodihydrofluorescin diacetate (DCFH-DA) fluorescence, despite an increase observed with the positive control ethanol (EtOH), nor was there an increase in embryonic oxidatively damaged DNA, quantified as 8-oxo-2′-deoxyguanosine (8-oxodG) formation. MeOH teratogenicity (primarily ophthalmic anomalies, cleft palate) also was not altered by pre- and post-treatment with varying doses of the free radical spin trapping agent alpha-phenyl-N-tert-butylnitrone (PBN). In contrast, pretreatment with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, depleted maternal hepatic and embryonic GSH, and enhanced some new anomalies (micrognathia, agnathia, short snout, fused digits, cleft lip, low set ears), but not the most common teratogenic effects of MeOH (ophthalmic anomalies, cleft palate) in this strain. These results suggest that ROS did not contribute to the teratogenic effects of MeOH in this in vivo mouse model, in contrast to results in embryo culture from our laboratory, and that the protective effect of GSH in this model may arise from its role as a cofactor for formaldehyde dehydrogenase in the detoxification of formaldehyde. - Highlights: • In vivo, a free radical scavenger did not block methanol (MeOH) teratogenesis. • MeOH did not increase embryonic reactive oxygen species formation or DNA oxidation. • MeOH teratogenesis was enhanced by glutathione (GSH) depletion. • GSH may protect as the cofactor for formaldehyde dehydrogenase (ADH3). • Formaldehyde may be a ROS

A role for glutathione, independent of oxidative stress, in the developmental toxicity of methanol

Energy Technology Data Exchange (ETDEWEB)

Siu, Michelle T.; Shapiro, Aaron M. [Division of Biomolecular Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario (Canada); Wiley, Michael J. [Division of Anatomy, Faculty of Medicine, University of Toronto, Toronto, Ontario (Canada); Wells, Peter G., E-mail: pg.wells@utoronto.ca [Division of Biomolecular Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario (Canada); Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario (Canada)

2013-12-15

Oxidative stress and reactive oxygen species (ROS) have been implicated in the teratogenicity of methanol (MeOH) in rodents, both in vivo and in embryo culture. We explored the ROS hypothesis further in vivo in pregnant C57BL/6J mice. Following maternal treatment with a teratogenic dose of MeOH, 4 g/kg via intraperitoneal (ip) injection on gestational day (GD) 12, there was no increase 6 h later in embryonic ROS formation, measured by 2′,7′-dichlorodihydrofluorescin diacetate (DCFH-DA) fluorescence, despite an increase observed with the positive control ethanol (EtOH), nor was there an increase in embryonic oxidatively damaged DNA, quantified as 8-oxo-2′-deoxyguanosine (8-oxodG) formation. MeOH teratogenicity (primarily ophthalmic anomalies, cleft palate) also was not altered by pre- and post-treatment with varying doses of the free radical spin trapping agent alpha-phenyl-N-tert-butylnitrone (PBN). In contrast, pretreatment with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, depleted maternal hepatic and embryonic GSH, and enhanced some new anomalies (micrognathia, agnathia, short snout, fused digits, cleft lip, low set ears), but not the most common teratogenic effects of MeOH (ophthalmic anomalies, cleft palate) in this strain. These results suggest that ROS did not contribute to the teratogenic effects of MeOH in this in vivo mouse model, in contrast to results in embryo culture from our laboratory, and that the protective effect of GSH in this model may arise from its role as a cofactor for formaldehyde dehydrogenase in the detoxification of formaldehyde. - Highlights: • In vivo, a free radical scavenger did not block methanol (MeOH) teratogenesis. • MeOH did not increase embryonic reactive oxygen species formation or DNA oxidation. • MeOH teratogenesis was enhanced by glutathione (GSH) depletion. • GSH may protect as the cofactor for formaldehyde dehydrogenase (ADH3). • Formaldehyde may be a ROS

Heterogeneity in cytokinetic, clonogenic, and radiation response induced by nutrient deprivation

International Nuclear Information System (INIS)

Grdina, D.J.; Williamson, K.D.; Johnson, T.S.; Sigdestad, C.P.

1986-01-01

A murine fibrosarcoma cell line (FSA 1233), with a capability to grow in vitro, was used to study biophysical heterogeneity induced by nutrient deprivation. Cell sub-populations were isolated by centrifuging cells through linear Renografin-density gradients. The effects of cell growth to late plateau phase on the cytokinetic, clonogenic, and radiation-survival characteristics were studied. It was observed that with increasing age of the cell culture, an increase in the proportion of relatively dense cells was associated with a decrease in plating efficiency. Cells collected at p=1.08 g/cm 3 have a plating efficiency of 0.2% compared with 0.01% for those isolated at p=1.16 g/cm 3 . Discrepancies were also seen between the tritiated thymidine labeling index (LI) and flow cytometry (FCM, % S phase) for cells collected throughout the gradient. The radiation sensitivities of selected cell populations isolated by density gradient centrifugation were determined and compared with data from a control plateau phase population. 15 refs., 4 figs., 1 tab

Tailoring Gut Microbiota for Enhanced Resilience and Performance Under Sleep-Deprived Conditions

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2016-08-01

psychological disorders, we have developed a hypothesis that sleep deprivation initially degrades the functional and structural integrity of the...metabolically active members and the collective metabolic profiles of the microbiota community. An integrated approach to examine the metabolic...obesity. Interestingly, perturbation of gut microbiota presents a pattern of metabolic abnormalities mirroring those induced by sleep deprivation. In

Estradiol attenuates ischemia-induced death of hippocampal neurons and enhances synaptic transmission in aged, long-term hormone-deprived female rats.

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Tomoko Inagaki

Full Text Available Transient global forebrain ischemia causes selective, delayed death of hippocampal CA1 pyramidal neurons, and the ovarian hormone 17β-estradiol (E2 reduces neuronal loss in young and middle-aged females. The neuroprotective efficacy of E2 after a prolonged period of hormone deprivation is controversial, and few studies examine this issue in aged animals given E2 treatment after induction of ischemia.The present study investigated the neuroprotective effects of E2 administered immediately after global ischemia in aged female rats (15-18 months after 6 months of hormone deprivation. We also used electrophysiological methods to assess whether CA1 synapses in the aging hippocampus remain responsive to E2 after prolonged hormone withdrawal. Animals were ovariohysterectomized and underwent 10 min global ischemia 6 months later. A single dose of E2 (2.25 µg infused intraventricularly after reperfusion significantly increased cell survival, with 45% of CA1 neurons surviving vs 15% in controls. Ischemia also induced moderate loss of CA3/CA4 pyramidal cells. Bath application of 1 nM E2 onto brain slices derived from non-ischemic aged females after 6 months of hormone withdrawal significantly enhanced excitatory transmission at CA1 synapses evoked by Schaffer collateral stimulation, and normal long-term potentiation (LTP was induced. The magnitude of LTP and of E2 enhancement of field excitatory postsynaptic potentials was indistinguishable from that recorded in slices from young rats.The data demonstrate that 1 acute post-ischemic infusion of E2 into the brain ventricles is neuroprotective in aged rats after 6 months of hormone deprivation; and 2 E2 enhances synaptic transmission in CA1 pyramidal neurons of aged long-term hormone deprived females. These findings provide evidence that the aging hippocampus remains responsive to E2 administered either in vivo or in vitro even after prolonged periods of hormone withdrawal.

Identification of genes associated with resilience/vulnerability to sleep deprivation and starvation in Drosophila.

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Thimgan, Matthew S; Seugnet, Laurent; Turk, John; Shaw, Paul J

2015-05-01

Flies mutant for the canonical clock protein cycle (cyc(01)) exhibit a sleep rebound that is ∼10 times larger than wild-type flies and die after only 10 h of sleep deprivation. Surprisingly, when starved, cyc(01) mutants can remain awake for 28 h without demonstrating negative outcomes. Thus, we hypothesized that identifying transcripts that are differentially regulated between waking induced by sleep deprivation and waking induced by starvation would identify genes that underlie the deleterious effects of sleep deprivation and/or protect flies from the negative consequences of waking. We used partial complementary DNA microarrays to identify transcripts that are differentially expressed between cyc(01) mutants that had been sleep deprived or starved for 7 h. We then used genetics to determine whether disrupting genes involved in lipid metabolism would exhibit alterations in their response to sleep deprivation. Laboratory. Drosophila melanogaster. Sleep deprivation and starvation. We identified 84 genes with transcript levels that were differentially modulated by 7 h of sleep deprivation and starvation in cyc(01) mutants and were confirmed in independent samples using quantitative polymerase chain reaction. Several of these genes were predicted to be lipid metabolism genes, including bubblegum, cueball, and CG4500, which based on our data we have renamed heimdall (hll). Using lipidomics we confirmed that knockdown of hll using RNA interference significantly decreased lipid stores. Importantly, genetically modifying bubblegum, cueball, or hll resulted in sleep rebound alterations following sleep deprivation compared to genetic background controls. We have identified a set of genes that may confer resilience/vulnerability to sleep deprivation and demonstrate that genes involved in lipid metabolism modulate sleep homeostasis. © 2015 Associated Professional Sleep Societies, LLC.

Intracellular thiol levels and radioresistance: Studies with glutathione and glutathione mono ethyl ester

International Nuclear Information System (INIS)

Astor, M.B.; Meister, A.; Anderson, M.E.

1987-01-01

Intracellular thiols such as glutathione (GSH) protect cells against free radicals formed during oxidative metabolism or from exposure to drugs or ionizing radiation. The role of intracellular GSH in the repair of radiation induced free radical damage was studied using GSH or its analog glutathione mono ethyl ester (GEE), which readily penetrates into the cell. Chinese hamster V79 cells with normal GSH levels were afforded equal protection under aerated and hypoxic conditions (DMF = 1.2 OER = 3.7) by both 10 mM GSH and GEE although GEE had raised interacellular GSH levels three-fold. Growth of V79 cells in cysteine free media resulted in undetectable levels of GSH and OER of 2.2 with no change in aerated survival. Restoration of intracellular GSH by 10 mM GEE resulted in an increase of the OER from 2.2. to 3.8 (DMF = 1.7). Only 14% of the intracellular GSH needs to be repleted to give an OER of 3.0. These experiments provide evidence that thiols do play a role in the oxygen effect and are present at levels in excess of what is necessary for maximal radioprotection

Protective effect of Hibiscus sabdariffa against serum/glucose deprivation-induced PC12 cells injury

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Bakhtiari, Elham; Hosseini, Azar; Mousavi, Seyed Hadi

2015-01-01

Objectives: Findings natural products with antioxidant and antiapoptotic properties has been one of the interesting challenges in the search for the treatment of neurodegenerative diseases including ischemic stroke. Serum/glucose deprivation (SGD) has been used as a model for the understanding of the molecular mechanisms of neuronal damage during ischemia in vitro and for the expansion of neuroprotective drugs against ischemia-induced brain injury. Recent studies showed that Hibiscus sabdariffa exert pharmacological actions such as potent antioxidant. Therefore, in this study we investigated the protective effect of extract of H. sabdariffa against SGD-induced PC12 cells injury. Materials and Methods: Cells were pretreated with different concentrations of H. sabdariffa extract (HSE) for 2 hr, and then exposed to SGD condition for 6, 12 and 18 hr. Results: SGD caused a major reduction in cell viability after 6, 12, and 18 hr as compared with control cells (psabdariffa has the potential to be used as a new therapeutic approach for neurodegenerative disorders. PMID:26101756

Sleep deprivation: cardiovascular effects for anesthesiologists

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Ali Dabbagh

2016-03-01

Full Text Available Sleep and anesthesia have some common or "overlapping" neural pathways. Both involve wakefulness; while they are not the same; anesthesia is an iatrogenic, reversible, pharmacologic-based coma; which could affect the CNS neural pathways at many levels. In the current era of modern anesthesiology, the practice and science of anesthesia is composed of 4 basic elements; (1: 1. hypnosis (i.e. iatrogenic pharmacologicinduced coma 2. amnesia (not to remember the events of the operation 3. analgesia (being painless 4. akinesia (lack of movements to stimuli The first two ingredients of anesthesia could have common points with sleep. Thalamic nuclei are involved both in sleep and anesthesia (2, 3; though, they are not the same phenomena (4. However, could there be any clinical concern if some of our patients have abnormalities in sleep? In fact, the effects of sleep deprivation have long been studied in patients undergoing anesthesia for surgical operations (4, 5. Sleep deprivation causes altered neurohumoral activity, neuroendocrine dysregulations, abnormalities in the immune system and impairments in cardiac autonomic function (6, 7. Sleep deprivation may affect the clinical effects of the anesthetics or it may create unpredicted changes in the clinical response to a determined dose of anesthetic drugs (8. In this volume of the Journal, Choopani et al have published their results regarding sleep deprivation; they have demonstrated that in rats, if sleep deprivation is induced prior to an ischemia/reperfusion event, it can increase the chance for ventricular tachycardia and ventricular fibrillation; also, they have shown that this untoward effect could be eliminated using chemical sympathectomy (9. In clinical practice, the main message from this study could be that when anesthesiologists perform anesthesia for their patients, they should be aware of effects of acute or chronic sleep deprivation. Undoubtedly, sleep deprivation could occur during the

The effects of the sulfonylurea glyburide on glutathione peroxidase, superoxide dismutase and catalase activities in the heart tissue of streptozotocin-induced diabetic rat.

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Bukan, N; Sancak, B; Bilgihan, A; Kosova, F; Buğdayci, G; Altan, N

2004-09-01

Oxygen free radicals have been suggested to be a contributory factor in diabetes complications. The aim of this study was to examine the effects of glyburide on the antioxidant enzyme activities in the heart tissue of diabetic rats. We investigated the activities of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) in the hearts of both control and streptozotocin-induced diabetic rats. In the heart of diabetic rats, the activity of total superoxide dismutase decreased significantly (p < 0.005), whereas the activity of catalase and glutathione peroxidase increased to a large extent (p < 0.0001 and p = 0.05, respectively) at the end of the fourth week compared with the control group. Glyburide treatment of diabetic rats for 4 weeks corrected the changes observed in diabetic heart. In addition, blood glucose levels of untreated diabetic rats decreased following the glyburide treatment. These results demonstrate that the sulfonylurea glyburide is capable of exerting direct insulin-like effect on heart superoxide dismutase, catalase and glutathione peroxidase activities of diabetic rats in vivo.

Effects of acute sleep deprivation on state anxiety levels: a systematic review and meta-analysis.

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Pires, Gabriel Natan; Bezerra, Andreia Gomes; Tufik, Sergio; Andersen, Monica Levy

2016-08-01

Increased anxiety levels have been widely recognized as one of the most important consequences of sleep deprivation. However, despite this general consensus, there are still aspects of this relationship, such as the extent of the anxiogenic potential and the specific effects of different types of sleep deprivation, which remain unclear. As no broad review has been undertaken to evaluate this relationship, we performed a systematic review and meta-analysis regarding the effects of sleep deprivation on state anxiety. Our search strategy encompassed two databases - Pubmed/Medline and Scopus - through which we were able to identify 756 articles. After the selection process, 18 articles, encompassing 34 experiments, composed our final sample. Our analyses indicate that sleep deprivation, whether total or not, leads to a significant increase in state anxiety levels, but sleep restriction does not. Regarding the effect of the length of the period of sleep deprivation, no significant results were observed, but there was a notable tendency for an increase in anxiety in longer sleep deprivations. With regard to tools, the State-Trait Anxiety Inventory (STAI) seems to be the best one to measure sleep-induced anxiogenesis, while the Profile of Mood States (POMS) presented inconclusive results. In conclusion, it can be affirmed that sleep deprivation induces a state of increased anxiety, with similar results also in the case of total sleep deprivation; however, results in more specific experimental conditions are not definitive. Copyright © 2016 Elsevier B.V. All rights reserved.

Glutathione in plants: an integrated overview.

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Noctor, Graham; Mhamdi, Amna; Chaouch, Sejir; Han, Yi; Neukermans, Jenny; Marquez-Garcia, Belen; Queval, Guillaume; Foyer, Christine H

2012-02-01

Plants cannot survive without glutathione (γ-glutamylcysteinylglycine) or γ-glutamylcysteine-containing homologues. The reasons why this small molecule is indispensable are not fully understood, but it can be inferred that glutathione has functions in plant development that cannot be performed by other thiols or antioxidants. The known functions of glutathione include roles in biosynthetic pathways, detoxification, antioxidant biochemistry and redox homeostasis. Glutathione can interact in multiple ways with proteins through thiol-disulphide exchange and related processes. Its strategic position between oxidants such as reactive oxygen species and cellular reductants makes the glutathione system perfectly configured for signalling functions. Recent years have witnessed considerable progress in understanding glutathione synthesis, degradation and transport, particularly in relation to cellular redox homeostasis and related signalling under optimal and stress conditions. Here we outline the key recent advances and discuss how alterations in glutathione status, such as those observed during stress, may participate in signal transduction cascades. The discussion highlights some of the issues surrounding the regulation of glutathione contents, the control of glutathione redox potential, and how the functions of glutathione and other thiols are integrated to fine-tune photorespiratory and respiratory metabolism and to modulate phytohormone signalling pathways through appropriate modification of sensitive protein cysteine residues. © 2011 Blackwell Publishing Ltd.

Rapid eye movement (REM sleep deprivation reduces rat frontal cortex acetylcholinesterase (EC 3.1.1.7 activity

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Camarini R.

1997-01-01

Full Text Available Rapid eye movement (REM sleep deprivation induces several behavioral changes. Among these, a decrease in yawning behavior produced by low doses of cholinergic agonists is observed which indicates a change in brain cholinergic neurotransmission after REM sleep deprivation. Acetylcholinesterase (Achase controls acetylcholine (Ach availability in the synaptic cleft. Therefore, altered Achase activity may lead to a change in Ach availability at the receptor level which, in turn, may result in modification of cholinergic neurotransmission. To determine if REM sleep deprivation would change the activity of Achase, male Wistar rats, 3 months old, weighing 250-300 g, were deprived of REM sleep for 96 h by the flower-pot technique (N = 12. Two additional groups, a home-cage control (N = 6 and a large platform control (N = 6, were also used. Achase was measured in the frontal cortex using two different methods to obtain the enzyme activity. One method consisted of the obtention of total (900 g supernatant, membrane-bound (100,000 g pellet and soluble (100,000 g supernatant Achase, and the other method consisted of the obtention of a fraction (40,000 g pellet enriched in synaptic membrane-bound enzyme. In both preparations, REM sleep deprivation induced a significant decrease in rat frontal cortex Achase activity when compared to both home-cage and large platform controls. REM sleep deprivation induced a significant decrease of 16% in the membrane-bound Achase activity (nmol thiocholine formed min-1 mg protein-1 in the 100,000 g pellet enzyme preparation (home-cage group 152.1 ± 5.7, large platform group 152.7 ± 24.9 and REM sleep-deprived group 127.9 ± 13.8. There was no difference in the soluble enzyme activity. REM sleep deprivation also induced a significant decrease of 20% in the enriched synaptic membrane-bound Achase activity (home-cage group 126.4 ± 21.5, large platform group 127.8 ± 20.4, REM sleep-deprived group 102.8 ± 14.2. Our results

The Triple Roles of Glutathione for a DNA-Cleaving DNAzyme and Development of a Fluorescent Glutathione/Cu2+-Dependent DNAzyme Sensor for Detection of Cu2+ in Drinking Water.

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Wang, Shijin; Liu, Chengcheng; Li, Guiying; Sheng, Yongjie; Sun, Yanhong; Rui, Hongyue; Zhang, Jin; Xu, Jiacui; Jiang, Dazhi

2017-03-24

Pistol-like DNAzyme (PLDz) is an oxidative DNA-cleaving catalytic DNA with ascorbic acid as cofactor. Herein, glutathione was induced into the reaction system to maintain reduced ascorbic acid levels for higher efficient cleavage. However, data indicated that glutathione played triple roles in PLDz-catalyzed reactions. Glutathione alone had no effect on PLDz, and showed inhibitory effect on ascorbic acid-induced PLDz catalysis, but exhibited stimulating effect on Cu 2+ -promoted self-cleavage of PLDz. Further analysis of the effect of glutathione/Cu 2+ on PLDz indicated that H 2 O 2 played a key role in PLDz catalysis. Finally, we developed a fluorescent Cu 2+ sensor (PL-Cu 1.0) based on the relationship between glutathione/Cu 2+ and catalytic activity of PLDz. The fluorescent intensity showed a linear response toward the logarithm concentration of Cu 2+ over the range from 80 nM to 30 μM, with a detection limit of 21.1 nM. PL-Cu 1.0 provided only detection of Cu 2+ over other divalent metal ions. Ca 2+ and Mg 2+ could not interfere with Cu 2+ detection even at a 1000-fold concentration. We further applied PL-Cu 1.0 for Cu 2+ detection in tap and bottled water. Water stored in copper taps overnight had relatively high Cu 2+ concentrations, with a maximum 22.3 μM. Trace Cu 2+ (52.2 nM) in deep spring was detected among the tested bottled water. Therefore, PL-Cu 1.0 is feasible to detect Cu 2+ in drinking water, with a practical application.

Correction of glutathione deficiency in the lower respiratory tract of HIV seropositive individuals by glutathione aerosol treatment.

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Holroyd, K J; Buhl, R; Borok, Z; Roum, J H; Bokser, A D; Grimes, G J; Czerski, D; Cantin, A M; Crystal, R G

1993-10-01

Concentrations of glutathione, a ubiquitous tripeptide with immune enhancing and antioxidant properties, are decreased in the blood and lung epithelial lining fluid of human immunodeficiency virus (HIV) seropositive individuals. Since the lung is the most common site of infection in those who progress to AIDS it is rational to consider whether it is possible to safely augment glutathione levels in the epithelial lining fluid of HIV seropositive individuals, thus potentially improving local host defence. Purified reduced glutathione was delivered by aerosol to HIV seropositive individuals (n = 14) and the glutathione levels in lung epithelial lining fluid were compared before and at one, two, and three hours after aerosol administration. Before treatment total glutathione concentrations in the epithelial lining fluid were approximately 60% of controls. After three days of twice daily doses each of 600 mg reduced glutathione, total glutathione levels in the epithelial lining fluid increased and remained in the normal range for at least three hours after treatment. Strikingly, even though > 95% of the glutathione in the aerosol was in its reduced form, the percentage of oxidised glutathione in epithelial lining fluid increased from 5% before treatment to about 40% three hours after treatment, probably reflecting the use of glutathione as an antioxidant in vivo. No adverse effects were observed. It is feasible and safe to use aerosolised reduced glutathione to augment the deficient glutathione levels of the lower respiratory tract of HIV seropositive individuals. It is rational to evaluate further the efficacy of this tripeptide in improving host defence in HIV seropositive individuals.

Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells

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Kaini, Ramesh R. [Department of Biochemistry and Molecular Biology and UNM Cancer and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, NM (United States); Hu, Chien-An A., E-mail: AHu@salud.unm.edu [Department of Biochemistry and Molecular Biology and UNM Cancer and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, NM (United States)

2012-08-24

Highlights: Black-Right-Pointing-Pointer Chloroquine synergistically killed LNCaP cells during androgen deprivation treatment. Black-Right-Pointing-Pointer Chloroquine inhibited the function of autolysosomes and decreases the cytosolic ATP. Black-Right-Pointing-Pointer Chloroquine induced nuclear and DNA fragmentation in androgen deprived LNCaP. Black-Right-Pointing-Pointer Chloroquine may be an useful adjuvant in hormone ablation therapy in PCa patients. -- Abstract: Modulation of autophagy is a new paradigm in cancer therapeutics. Recently a novel function of chloroquine (CLQ) in inhibiting degradation of autophagic vesicles has been revealed, which raises the question whether CLQ can be used as an adjuvant in targeting autophagic pro-survival mechanism in prostate cancer (PCa). We previously showed that autophagy played a protective role during hormone ablation therapy, in part, by consuming lipid droplets in PCa cells. In addition, blocking autophagy by genetic and pharmacological means in the presence of androgen deprivation caused cell death in PCa cells. To further investigate the importance of autophagy in PCa survival and dissect the role of CLQ in PCa death, we treated hormone responsive LNCaP cells with CLQ in combination with androgen deprivation. We observed that CLQ synergistically killed LNCaP cells during androgen deprivation in a dose- and time-dependent manner. We further confirmed that CLQ inhibited the maturation of autophagic vesicles and decreased the cytosolic ATP. Moreover, CLQ induced nuclear condensation and DNA fragmentation, a hallmark of apoptosis, in androgen deprived LNCaP cells. Taken together, our finding suggests that CLQ may be an useful adjuvant in hormone ablation therapy to improve the therapeutic efficacy.

Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells

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Kaini, Ramesh R.; Hu, Chien-An A.

2012-01-01

Highlights: ► Chloroquine synergistically killed LNCaP cells during androgen deprivation treatment. ► Chloroquine inhibited the function of autolysosomes and decreases the cytosolic ATP. ► Chloroquine induced nuclear and DNA fragmentation in androgen deprived LNCaP. ► Chloroquine may be an useful adjuvant in hormone ablation therapy in PCa patients. -- Abstract: Modulation of autophagy is a new paradigm in cancer therapeutics. Recently a novel function of chloroquine (CLQ) in inhibiting degradation of autophagic vesicles has been revealed, which raises the question whether CLQ can be used as an adjuvant in targeting autophagic pro-survival mechanism in prostate cancer (PCa). We previously showed that autophagy played a protective role during hormone ablation therapy, in part, by consuming lipid droplets in PCa cells. In addition, blocking autophagy by genetic and pharmacological means in the presence of androgen deprivation caused cell death in PCa cells. To further investigate the importance of autophagy in PCa survival and dissect the role of CLQ in PCa death, we treated hormone responsive LNCaP cells with CLQ in combination with androgen deprivation. We observed that CLQ synergistically killed LNCaP cells during androgen deprivation in a dose- and time-dependent manner. We further confirmed that CLQ inhibited the maturation of autophagic vesicles and decreased the cytosolic ATP. Moreover, CLQ induced nuclear condensation and DNA fragmentation, a hallmark of apoptosis, in androgen deprived LNCaP cells. Taken together, our finding suggests that CLQ may be an useful adjuvant in hormone ablation therapy to improve the therapeutic efficacy.

Cold hands, warm feet: sleep deprivation disrupts thermoregulation and its association with vigilance.

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Romeijn, Nico; Verweij, Ilse M; Koeleman, Anne; Mooij, Anne; Steimke, Rosa; Virkkala, Jussi; van der Werf, Ysbrand; Van Someren, Eus J W

2012-12-01

Vigilance is affected by induced and spontaneous skin temperature fluctuations. Whereas sleep deprivation strongly affects vigilance, no previous study examined in detail its effect on human skin temperature fluctuations and their association with vigilance. In a repeated-measures constant routine design, skin temperatures were assessed continuously from 14 locations while performance was assessed using a reaction time task, including eyes-open video monitoring, performed five times a day for 2 days, after a normal sleep or sleep deprivation night. Participants were seated in a dimly lit, temperature-controlled laboratory. Eight healthy young adults (five males, age 22.0 ± 1.8 yr (mean ± standard deviation)). One night of sleep deprivation. Mixed-effect regression models were used to evaluate the effect of sleep deprivation on skin temperature gradients of the upper (ear-mastoid), middle (hand-arm), and lower (foot-leg) body, and on the association between fluctuations in performance and in temperature gradients. Sleep deprivation induced a marked dissociation of thermoregulatory skin temperature gradients, indicative of attenuated heat loss from the hands co-occurring with enhanced heat loss from the feet. Sleep deprivation moreover attenuated the association between fluctuations in performance and temperature gradients; the association was best preserved for the upper body gradient. Sleep deprivation disrupts coordination of fluctuations in thermoregulatory skin temperature gradients. The dissociation of middle and lower body temperature gradients may therefore be evaluated as a marker for sleep debt, and the upper body gradient as a possible aid in vigilance assessment when sleep debt is unknown. Importantly, our findings suggest that sleep deprivation affects the coordination between skin blood flow fluctuations and the baroreceptor-mediated cardiovascular regulation that prevents venous pooling of blood in the lower limbs when there is the orthostatic

Glutathione-binding site of a bombyx mori theta-class glutathione transferase.

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M D Tofazzal Hossain

Full Text Available The glutathione transferase (GST superfamily plays key roles in the detoxification of various xenobiotics. Here, we report the isolation and characterization of a silkworm protein belonging to a previously reported theta-class GST family. The enzyme (bmGSTT catalyzes the reaction of glutathione with 1-chloro-2,4-dinitrobenzene, 1,2-epoxy-3-(4-nitrophenoxy-propane, and 4-nitrophenethyl bromide. Mutagenesis of highly conserved residues in the catalytic site revealed that Glu66 and Ser67 are important for enzymatic function. These results provide insights into the catalysis of glutathione conjugation in silkworm by bmGSTT and into the metabolism of exogenous chemical agents.

Copper ions stimulate the proliferation of hepatic stellate cells via oxygen stress in vitro.

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Xu, San-qing; Zhu, Hui-yun; Lin, Jian-guo; Su, Tang-feng; Liu, Yan; Luo, Xiao-ping

2013-02-01

This study examined the effect of copper ions on the proliferation of hepatic stellate cells (HSCs) and the role of oxidative stress in this process in order to gain insight into the mechanism of hepatic fibrosis in Wilson's disease. LX-2 cells, a cell line of human HSCs, were cultured in vitro and treated with different agents including copper sulfate, N-acetyl cysteine (NAC) and buthionine sulfoximine (BSO) for different time. The proliferation of LX-2 cells was measured by non-radioactive cell proliferation assay. Real-time PCR and Western blotting were used to detect the mRNA and protein expression of platelet-derived growth factor receptor β subunit (PDGFβR), ELISA to determine the level of glutathione (GSH) and oxidized glutathione (GSSG), dichlorofluorescein assay to measure the level of reactive oxygen species (ROS), and lipid hydroperoxide assay to quantify the level of lipid peroxide (LPO). The results showed that copper sulfate over a certain concentration range could promote the proliferation of LX-2 cells in a time- and dose-dependent manner. The effect was most manifest when LX-2 cells were treated with copper sulfate at a concentration of 100 μmol/L for 24 h. Additionally, copper sulfate could dose-dependently increase the levels of ROS and LPO, and decrease the ratio of GSH/GSSG in LX-2 cells. The copper-induced increase in mRNA and protein expression of PDGFβR was significantly inhibited in LX-2 cells pre-treated with NAC, a precursor of GSH, and this phenomenon could be reversed by the intervention of BSO, an inhibitor of NAC. It was concluded that copper ions may directly stimulate the proliferation of HSCs via oxidative stress. Anti-oxidative stress therapies may help suppress the copper-induced activation and proliferation of HSCs.

Oligo-carrageenan kappa increases NADPH, ascorbate and glutathione syntheses and TRR/TRX activities enhancing photosynthesis, basal metabolism, and growth in Eucalyptus trees.

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González, Alberto; Moenne, Fabiola; Gómez, Melissa; Sáez, Claudio A; Contreras, Rodrigo A; Moenne, Alejandra

2014-01-01

In order to analyze the effect of OC kappa in redox status, photosynthesis, basal metabolism and growth in Eucalyptus globulus, trees were treated with water (control), with OC kappa at 1 mg mL(-1), or treated with inhibitors of NAD(P)H, ascorbate (ASC), and glutathione (GSH) syntheses and thioredoxin reductase (TRR) activity, CHS-828, lycorine, buthionine sulfoximine (BSO), and auranofin, respectively, and with OC kappa, and cultivated for 4 months. Treatment with OC kappa induced an increase in NADPH, ASC, and GSH syntheses, TRR and thioredoxin (TRX) activities, photosynthesis, growth and activities of basal metabolism enzymes such as rubisco, glutamine synthetase (GlnS), adenosine 5'-phosphosulfate reductase (APR), involved in C, N, and S assimilation, respectively, Krebs cycle and purine/pyrimidine synthesis enzymes. Treatment with inhibitors and OC kappa showed that increases in ASC, GSH, and TRR/TRX enhanced NADPH synthesis, increases in NADPH and TRR/TRX enhanced ASC and GSH syntheses, and only the increase in NADPH enhanced TRR/TRX activities. In addition, the increase in NADPH, ASC, GSH, and TRR/TRX enhanced photosynthesis and growth. Moreover, the increase in NADPH, ASC and TRR/TRX enhanced activities of rubisco, Krebs cycle, and purine/pyrimidine synthesis enzymes, the increase in GSH, NADPH, and TRR/TRX enhanced APR activity, and the increase in NADPH and TRR/TRX enhanced GlnS activity. Thus, OC kappa increases NADPH, ASC, and GSH syntheses leading to a more reducing redox status, the increase in NADPH, ASC, GSH syntheses, and TRR/TRX activities are cross-talking events leading to activation of photosynthesis, basal metabolism, and growth in Eucalyptus trees.

Oligo-carrageenan kappa increases NADPH, ascorbate and glutathione syntheses and TRR/TRX activities enhancing photosynthesis, basal metabolism, and growth in Eucalyptus trees

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Alberto eGonzález

2014-10-01

Full Text Available In order to analyze the effect of OC kappa in redox status, photosynthesis, basal metabolism and growth in Eucalyptus globulus, trees were treated with water (control, with OC kappa at 1 mg mL-1, or treated with inhibitors of NAD(PH, ascorbate (ASC and glutathione (GSH syntheses and thioredoxin reductase (TRR activity, CHS-828, lycorine, buthionine sulfoximine (BSO and auranofin, respectively, and with OC kappa, and cultivated for 4 months. Treatment with OC kappa induced an increase in NADPH, ASC, and GSH syntheses, TRR and thioredoxin (TRX activities, photosynthesis, growth and activities of basal metabolism enzymes such as rubisco, glutamine synthetase (GlnS, adenosine 5´-phosphosulfate reductase (APR, involved in C, N and S assimilation, respectively, Krebs cycle and purine/pyrimidine synthesis enzymes. Treatment with inhibitors and OC kappa showed that increases in ASC, GSH and TRR/TRX enhanced NADPH synthesis, increases in NADPH and TRR/TRX enhanced ASC and GSH syntheses, and only the increase in NADPH enhanced TRR/TRX activities. In addition, the increase in NADPH, ASC, GSH and TRR/TRX enhanced photosynthesis and growth. Moreover, the increase in NADPH, ASC and TRR/TRX enhanced activities of rubisco, Krebs cycle and purine/pyrimidine synthesis enzymes, the increase in GSH, NADPH, and TRR/TRX enhanced APR activity, and the increase in NADPH and TRR/TRX enhanced GlnS activity. Thus, OC kappa increases NADPH, ASC and GSH syntheses leading to a more reducing redox status, the increase in NADPH, ASC, GSH syntheses and TRR/TRX activities are cross-talking events leading to activation of photosynthesis, basal metabolism and growth in Eucalyptus trees.

Protection of myocytes against free radical-induced damage by accelerated turnover of the glutathione redox cycle

NARCIS (Netherlands)

Le, C. T.; Hollaar, L.; van der Valk, E. J.; Franken, N. A.; van Ravels, F. J.; Wondergem, J.; van der Laarse, A.

1995-01-01

The primary defence mechanism of myocytes against peroxides and peroxide-derived peroxyl and alkoxyl radicals is the glutathione redox cycle. The purpose of the present study was to increase the turnover rate of this cycle by stimulating the glutathione peroxidase catalysed reaction (2GSH-->GSSG),

Evidence That Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain

International Nuclear Information System (INIS)

Volkow, N.D.; Fowler, J.; Volkow, N.D.; Tomasi, D.; Wang, G.-J.; Fowler, J.S.; Logan, J.; Benveniste, H.; Kin, R.; Thanos, P.K.; Sergi, F.

2012-01-01

Dopamine D2 receptors are involved with wakefulness, but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [ 11 C]raclopride in controls) in striatum, but could not determine whether this reflected dopamine increases ([ 11 C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (a drug that increases dopamine by blocking dopamine transporters) during sleep deprivation versus rested sleep, with the assumption that methylphenidate's effects would be greater if, indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [ 11 C]raclopride after rested sleep and after 1 night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared with rested sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans.

Grooming analysis algorithm: use in the relationship between sleep deprivation and anxiety-like behavior.

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Pires, Gabriel N; Tufik, Sergio; Andersen, Monica L

2013-03-05

Increased anxiety is a classic effect of sleep deprivation. However, results regarding sleep deprivation-induced anxiety-like behavior are contradictory in rodent models. The grooming analysis algorithm is a method developed to examine anxiety-like behavior and stress in rodents, based on grooming characteristics and microstructure. This study evaluated the applicability of the grooming analysis algorithm to distinguish sleep-deprived and control rats in comparison to traditional grooming analysis. Forty-six animals were distributed into three groups: control (n=22), paradoxical sleep-deprived (96 h, n=10) and total sleep deprived (6 h, n=14). Immediately after the sleep deprivation protocol, grooming was evaluated using both the grooming analysis algorithm and traditional measures (grooming latency, frequency and duration). Results showed that both paradoxical sleep-deprived and total sleep-deprived groups displayed grooming in a fragmented framework when compared to control animals. Variables from the grooming analysis algorithm were successful in distinguishing sleep-deprived and normal sleep animals regarding anxiety-like behavior. The grooming analysis algorithm and traditional measures were strongly correlated. In conclusion, the grooming analysis algorithm is a reliable method to assess the relationship between anxiety-like behavior and sleep deprivation. Copyright © 2012 Elsevier Inc. All rights reserved.

Effect of cystamine on rat tissue GSH level and glutathione reductase activity

International Nuclear Information System (INIS)

Kovarova, H.; Pulpanova, J.

1979-01-01

Reduced glutathione (GSH) level and glutathione reductase activity were determined by means of the spectrophotometric method in various rat tissues after i.p. administration of cystamine (50 mg/kg and 20 mg/kg). GSH amount dropped in the spleen and kidney at 10 and 20 min; following this interval, an increase of GSH level was observed in the liver at 20-30 min, in the spleen and kidney at 60 min after the treatment with a radioprotective cystamine dose (50 mg/kg). The changes in GSH level induced by a non-radioprotective cystamine dose (20 mg/kg) had an opposite tendency. The activity of glutathione reductase was decreased in all tissues studied. As to the mechanism of the radioprotective action, both the inactivation of glutathione reductase activity and the changes in GSH level seem to be the factors contributing to the radioprotective effect of cystamine by strengthening the cellular radioresistance. (orig.) 891 MG/orig. 892 RKD [de

Monocular deprivation of Fourier phase information boosts the deprived eye's dominance during interocular competition but not interocular phase combination.

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Bai, Jianying; Dong, Xue; He, Sheng; Bao, Min

2017-06-03

Ocular dominance has been extensively studied, often with the goal to understand neuroplasticity, which is a key characteristic within the critical period. Recent work on monocular deprivation, however, demonstrates residual neuroplasticity in the adult visual cortex. After deprivation of patterned inputs by monocular patching, the patched eye becomes more dominant. Since patching blocks both the Fourier amplitude and phase information of the input image, it remains unclear whether deprivation of the Fourier phase information alone is able to reshape eye dominance. Here, for the first time, we show that removing of the phase regularity without changing the amplitude spectra of the input image induced a shift of eye dominance toward the deprived eye, but only if the eye dominance was measured with a binocular rivalry task rather than an interocular phase combination task. These different results indicate that the two measurements are supported by different mechanisms. Phase integration requires the fusion of monocular images. The fused percept highly relies on the weights of the phase-sensitive monocular neurons that respond to the two monocular images. However, binocular rivalry reflects the result of direct interocular competition that strongly weights the contour information transmitted along each monocular pathway. Monocular phase deprivation may not change the weights in the integration (fusion) mechanism much, but alters the balance in the rivalry (competition) mechanism. Our work suggests that ocular dominance plasticity may occur at different stages of visual processing, and that homeostatic compensation also occurs for the lack of phase regularity in natural scenes. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Acute Sleep Deprivation Blocks Short- and Long-Term Operant Memory in Aplysia.

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Krishnan, Harini C; Gandour, Catherine E; Ramos, Joshua L; Wrinkle, Mariah C; Sanchez-Pacheco, Joseph J; Lyons, Lisa C

2016-12-01

Insufficient sleep in individuals appears increasingly common due to the demands of modern work schedules and technology use. Consequently, there is a growing need to understand the interactions between sleep deprivation and memory. The current study determined the effects of acute sleep deprivation on short and long-term associative memory using the marine mollusk Aplysia californica , a relatively simple model system well known for studies of learning and memory. Aplysia were sleep deprived for 9 hours using context changes and tactile stimulation either prior to or after training for the operant learning paradigm, learning that food is inedible (LFI). The effects of sleep deprivation on short-term (STM) and long-term memory (LTM) were assessed. Acute sleep deprivation prior to LFI training impaired the induction of STM and LTM with persistent effects lasting at least 24 h. Sleep deprivation immediately after training blocked the consolidation of LTM. However, sleep deprivation following the period of molecular consolidation did not affect memory recall. Memory impairments were independent of handling-induced stress, as daytime handled control animals demonstrated no memory deficits. Additional training immediately after sleep deprivation failed to rescue the induction of memory, but additional training alleviated the persistent impairment in memory induction when training occurred 24 h following sleep deprivation. Acute sleep deprivation inhibited the induction and consolidation, but not the recall of memory. These behavioral studies establish Aplysia as an effective model system for studying the interactions between sleep and memory formation. © 2016 Associated Professional Sleep Societies, LLC.

Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2α-ATF4-xCT pathway.

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Wang, Sheng-Fan; Chen, Meng-Shian; Chou, Yueh-Ching; Ueng, Yune-Fang; Yin, Pen-Hui; Yeh, Tien-Shun; Lee, Hsin-Chen

2016-11-08

Mitochondrial DNA mutations and defects in mitochondrial enzymes have been identified in gastric cancers, and they might contribute to cancer progression. In previous studies, mitochondrial dysfunction was induced by oligomycin-enhanced chemoresistance to cisplatin. Herein, we dissected the regulatory mechanism for mitochondrial dysfunction-enhanced cisplatin resistance in human gastric cancer cells. Repeated cisplatin treatment-induced cisplatin-resistant cells exhibited high SLC7A11 (xCT) expression, and xCT inhibitors (sulfasalazine or erastin), xCT siRNA, or a GSH synthesis inhibitor (buthionine sulphoximine, BSO) could sensitize these cells to cisplatin. Clinically, the high expression of xCT was associated with a poorer prognosis for gastric cancer patients under adjuvant chemotherapy. Moreover, we found that mitochondrial dysfunction enhanced cisplatin resistance and up-regulated xCT expression, as well as intracellular glutathione (GSH). The xCT inhibitors, siRNA against xCT or BSO decreased mitochondrial dysfunction-enhanced cisplatin resistance. We further demonstrated that the upregulation of the eIF2α-ATF4 pathway contributed to mitochondrial dysfunction-induced xCT expression, and activated eIF2α kinase GCN2, but not PERK, stimulated the eIF2α-ATF4-xCT pathway in response to mitochondrial dysfunction-increased reactive oxygen species (ROS) levels. In conclusion, our results suggested that the ROS-activated GCN2-eIF2α-ATF4-xCT pathway might contribute to mitochondrial dysfunction-enhanced cisplatin resistance and could be a potential target for gastric cancer therapy.

Thioredoxin Reductase Activity may be More Important than GSH Level in Protecting Human Lens Epithelial Cells Against UVA Light

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Padgaonkar, Vanita A.; Leverenz, Victor R.; Bhat, Aparna V.; Pelliccia, Sara E.; Giblin, Frank J.

2014-01-01

This study compares the abilities of the glutathione (GSH) and thioredoxin (Trx) antioxidant systems in defending cultured human lens epithelial cells (LECs) against UVA light. Levels of GSH were depleted with either L-buthionine-(S,R)-sulfoximine (BSO) or 1-chloro-2,4-dinitrobenzene (CDNB). CDNB treatment also inhibited the activity of thioredoxin reductase (TrxR). Two levels of O2, 3% and 20%, were employed during a 1 hr exposure of the cells to 25 J/cm2 of UVA radiation (338-400nm wavelength, peak at 365nm). Inhibition of TrxR activity by CDNB, combined with exposure to UVA light, produced a substantial loss of LECs and cell damage, with the effects being considerably more severe at 20% O2 compared to 3%. In contrast, depletion of GSH by BSO, combined with exposure to UVA light, produced only a slight cell loss, with no apparent morphological effects. Catalase was highly sensitive to UVA-induced inactivation, but was not essential for protection. Although UVA light presented a challenge for the lens epithelium, it was well-tolerated under normal conditions. The results demonstrate an important role for TrxR activity in defending the lens epithelium against UVA light, possibly related to the ability of the Trx system to assist DNA synthesis following UVA-induced cell damage. PMID:25495870

Structures of a putative ζ-class glutathione S-transferase from the pathogenic fungus Coccidioides immitis

International Nuclear Information System (INIS)

Edwards, Thomas E.; Bryan, Cassie M.; Leibly, David J.; Dieterich, Shellie H.; Abendroth, Jan; Sankaran, Banumathi; Sivam, Dhileep; Staker, Bart L.; Van Voorhis, Wesley C.; Myler, Peter J.; Stewart, Lance J.

2011-01-01

The pathogenic fungus C. immitis causes coccidioidomycosis, a potentially fatal disease. Here, apo and glutathione-bound crystal structures of a previously uncharacterized protein from C. immitis that appears to be a ζ-class glutathione S-transferase are presented. Coccidioides immitis is a pathogenic fungus populating the southwestern United States and is a causative agent of coccidioidomycosis, sometimes referred to as Valley Fever. Although the genome of this fungus has been sequenced, many operons are not properly annotated. Crystal structures are presented for a putative uncharacterized protein that shares sequence similarity with ζ-class glutathione S-transferases (GSTs) in both apo and glutathione-bound forms. The apo structure reveals a nonsymmetric homodimer with each protomer comprising two subdomains: a C-terminal helical domain and an N-terminal thioredoxin-like domain that is common to all GSTs. Half-site binding is observed in the glutathione-bound form. Considerable movement of some components of the active site relative to the glutathione-free form was observed, indicating an induced-fit mechanism for cofactor binding. The sequence homology, structure and half-site occupancy imply that the protein is a ζ-class glutathione S-transferase, a maleylacetoacetate isomerase (MAAI)

Evidence That Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain

Energy Technology Data Exchange (ETDEWEB)

Volkow N. D.; Fowler J.; Volkow, N.D.; Tomasi, D.; Wang, G.-J.; Fowler, J.S.; Logan, J.; Benveniste, H.; Kin, R.; Thanos, P.K.; Sergi F.

2012-03-23

Dopamine D2 receptors are involved with wakefulness, but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [{sup 11}C]raclopride in controls) in striatum, but could not determine whether this reflected dopamine increases ([{sup 11}C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (a drug that increases dopamine by blocking dopamine transporters) during sleep deprivation versus rested sleep, with the assumption that methylphenidate's effects would be greater if, indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [{sup 11}C]raclopride after rested sleep and after 1 night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared with rested sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans.

Model of Oxygen and Glucose Deprivation in PC12 Cells and Detection of HSP70 Protein

Science.gov (United States)

He, Jinting; Yang, Le; Shao, Yankun

2018-01-01

Objective: PC12 cell was used to set up a ischemia model by OGD and detected HSP70 protein. Methods: Use of PC12 cells induced by NGF stimulation into nerve cells, oxygen and glucose deprivation to build the nerve cells of oxygen and glucose deprivation model; using Western blot analysis of PC12 cells into neuron-like cells and oxygen-glucose deprivation model established. Results: The application of a final concentration of 50 ng / ml of NGF in DMEM complete mediumPC12 cells showed a typical neuronal morphology with the increase in cell culture time. NGF culture time showed a positive correlation, the establishment of oxygen and glucose deprivation (OGD) training environment, the OGD after nerve element appears different degrees of damage, OGD can effectively induce the expression of HSP70. Conclusion: PC12 cell transformed into cells by NGF; the cell model of OGD was established.

Phosphodiesterase 10A inhibition attenuates sleep deprivation-induced deficits in long-term fear memory.

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Guo, Lengqiu; Guo, Zhuangli; Luo, Xiaoqing; Liang, Rui; Yang, Shui; Ren, Haigang; Wang, Guanghui; Zhen, Xuechu

2016-12-02

Sleep, particularly rapid eye movement (REM) sleep, is implicated in the consolidation of emotional memories. In the present study, we investigated the protective effects of a phosphodiesterase 10A (PDE10A) inhibitor MP-10 on deficits in long-term fear memory induced by REM sleep deprivation (REM-SD). REM-SD caused deficits in long-term fear memory, however, MP-10 administration ameliorated the deleterious effects of REM-SD on long term fear memory. Brain-derived neurotropic factor (BDNF) and phosphorylated cAMP response element-binding protein (pCREB) were altered in specific brain regions associated with learning and memory in REM-SD rats. Accordingly, REM-SD caused a significant decrease of pCREB in hippocampus and striatum and a significant decrease of BDNF in the hippocampus, striatum and amygdala, however, MP-10 reversed the effects of REM-SD in a dose-dependent manner. Our findings suggest that REM-SD disrupts the consolidation of long-term fear memory and that administration of MP-10 protects the REM-SD-induced deficits in fear memory, which may be due to the MP-10-induced expression of BDNF in the hippocampus, striatum and amygdala, and phosphorylation of CREB in the hippocampus and striatum. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Modulation of Sleep Homeostasis by Corticotropin Releasing Hormone in REM Sleep-Deprived Rats

Directory of Open Access Journals (Sweden)

Ricardo Borges Machado

2010-01-01

Full Text Available Studies have shown that sleep recovery following different protocols of forced waking varies according to the level of stress inherent to each method. Sleep deprivation activates the hypothalamic-pituitary-adrenal axis and increased corticotropin-releasing hormone (CRH impairs sleep. The purpose of the present study was to evaluate how manipulations of the CRH system during the sleep deprivation period interferes with subsequent sleep rebound. Throughout 96 hours of sleep deprivation, separate groups of rats were treated i.c.v. with vehicle, CRH or with alphahelical CRH9−41, a CRH receptor blocker, twice/day, at 07:00 h and 19:00 h. Both treatments impaired sleep homeostasis, especially in regards to length of rapid eye movement sleep (REM and theta/delta ratio and induced a later decrease in NREM and REM sleep and increased waking bouts. These changes suggest that activation of the CRH system impact negatively on the homeostatic sleep response to prolonged forced waking. These results indicate that indeed, activation of the HPA axis—at least at the hypothalamic level—is capable to reduce the sleep rebound induced by sleep deprivation.

Glutathione Depletion Induced by c-Myc Downregulation Triggers Apoptosis on Treatment with Alkylating Agents1

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Biroccio, Annamaria; Benassi, Barbara; Fiorentino, Francesco; Zupi, Gabriella

2004-01-01

Abstract Here we investigate the mechanism(s) involved in the c-Myc-dependent drug response of melanoma cells. By using three M14-derived c-Myc low-expressing clones, we demonstrate that alkylating agents, cisplatin and melphalan, trigger apoptosis in the c-Myc antisense transfectants, but not in the parental line. On the contrary, topoisomerase inhibitors, adriamycin and camptothecin, induce apoptosis to the same extent regardless of c-Myc expression. Because we previously demonstrated that c-Myc downregulation decreases glutathione (GSH) content, we evaluated the role of GSH in the apoptosis induced by the different drugs. In control cells treated with one of the alkylating agents or the others, GSH depletion achieved by l-buthionine-sulfoximine preincubation opens the apoptotic pathway. The apoptosis proceeded through early Bax relocalization, cytochrome c release, and concomitant caspase-9 activation, whereas reactive oxygen species production and alteration of mitochondria membrane potential were late events. That GSH was determining in the c-Myc-dependent drug-induced apoptosis was demonstrated by altering the intracellular GSH content of the c-Myc low-expressing cells up to the level of controls. Indeed, GSH ethyl ester-mediated increase of GSH abrogated apoptosis induced by cisplatin and melphalan by inhibition of Bax/cytochrome c redistribution. The relationship among c-Myc, GSH content, and the response to alkylating agent has been also evaluated in the M14 Myc overexpressing clones as well as in the melanoma JR8 c-Myc antisense transfectants. All together, these results demonstrate that GSH plays a key role in governing c-Myc-dependent drug-induced apoptosis. PMID:15153331

Carbon black nanoparticles promote endothelial activation and lipid accumulation in macrophages independently of intracellular ROS production

DEFF Research Database (Denmark)

Cao, Yi; Roursgaard, Martin; Danielsen, Pernille Høgh

2014-01-01

, the concentrations of CB to induce lipid accumulation were lower than the concentrations to promote intracellular ROS production in THP-1a cells. In conclusion, exposure to nano-sized CB induced endothelial dysfunction and foam cell formation, which was not dependent on intracellular ROS production....... and WST-1 assays, especially in THP-1 and THP-1a cells. The CB exposure decreased the glutathione (GSH) content in THP-1 and THP-1a cells, whereas GSH was increased in HUVECs. The reactive oxygen species (ROS) production was increased in all cell types after CB exposure. A reduction of the intracellular...... GSH concentration by buthionine sulfoximine (BSO) pre-treatment further increased the CB-induced ROS production in THP-1 cells and HUVECs. The expression of adhesion molecules ICAM-1 and VCAM-1, but not adhesion of THP-1 to HUVECs or culture dishes, was elevated by CB exposure, whereas these effects...

Effects of Foveal Ablation on Emmetropization and Form-Deprivation Myopia

Science.gov (United States)

Smith, Earl L.; Ramamirtham, Ramkumar; Qiao-Grider, Ying; Hung, Li-Fang; Huang, Juan; Kee, Chea-su; Coats, David; Paysse, Evelyn

2009-01-01

Purpose Because of the prominence of central vision in primates, it has generally been assumed that signals from the fovea dominate refractive development. To test this assumption, the authors determined whether an intact fovea was essential for either normal emmetropization or the vision-induced myopic errors produced by form deprivation. Methods In 13 rhesus monkeys at 3 weeks of age, the fovea and most of the perifovea in one eye were ablated by laser photocoagulation. Five of these animals were subsequently allowed unrestricted vision. For the other eight monkeys with foveal ablations, a diffuser lens was secured in front of the treated eyes to produce form deprivation. Refractive development was assessed along the pupillary axis by retinoscopy, keratometry, and A-scan ultrasonography. Control data were obtained from 21 normal monkeys and three infants reared with plano lenses in front of both eyes. Results Foveal ablations had no apparent effect on emmetropization. Refractive errors for both eyes of the treated infants allowed unrestricted vision were within the control range throughout the observation period, and there were no systematic interocular differences in refractive error or axial length. In addition, foveal ablation did not prevent form deprivation myopia; six of the eight infants that experienced monocular form deprivation developed myopic axial anisometropias outside the control range. Conclusions Visual signals from the fovea are not essential for normal refractive development or the vision-induced alterations in ocular growth produced by form deprivation. Conversely, the peripheral retina, in isolation, can regulate emmetropizing responses and produce anomalous refractive errors in response to abnormal visual experience. These results indicate that peripheral vision should be considered when assessing the effects of visual experience on refractive development. PMID:17724167

Fluorescence detection of glutathione and oxidized glutathione in blood with a NIR-excitable cyanine probe

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Liu, Chang-hui; Qi, Feng-pei; Wen, Fu-bin; Long, Li-ping; Liu, Ai-juan; Yang, Rong-hua

2018-04-01

Cyanine has been widely utilized as a near infrared (NIR) fluorophore for detection of glutathione (GSH). However, the excitation of most of the reported cyanine-based probes was less than 800 nm, which inevitably induce biological background absorption and lower the sensitivity, limiting their use for detection of GSH in blood samples. To address this issue, here, a heptamethine cyanine probe (DNIR), with a NIR excitation wavelength at 804 nm and a NIR emission wavelength at 832 nm, is employed for the detection of GSH and its oxidized form (GSSG) in blood. The probe displays excellent selectivity for GSH over GSSG and other amino acids, and rapid response to GSH, in particular a good property for indirect detection of GSSG in the presence of enzyme glutathione reductase and the reducing agent nicotinamideadenine dinucleotide phosphate, without further separation prior to fluorescent measurement. To the best of our knowledge, this is the first attempt to explore NIR fluorescent approach for the simultaneous assay of GSH and GSSG in blood. As such, we expect that our fluorescence sensors with both NIR excitation and NIR emission make this strategy suitable for the application in complex physiological systems.

Assessing Individual Differences in Adaptation to Extreme Environments: A 36-Hour Sleep Deprivation Study

Science.gov (United States)

Martinez, Jacqueline; Cowings, Patricia S.; Toscano, William B.

2012-01-01

In space, astronauts may experience effects of cumulative sleep loss due to demanding work schedules that can result in cognitive performance impairments, mood state deteriorations, and sleep-wake cycle disruption. Individuals who experience sleep deprivation of six hours beyond normal sleep times experience detrimental changes in their mood and performance states. Hence, the potential for life threatening errors increases exponentially with sleep deprivation. We explored the effects of 36-hours of sleep deprivation on cognitive performance, mood states, and physiological responses to identify which metrics may best predict fatigue induced performance decrements of individuals.

Auranofin induces apoptosis and necrosis in HeLa cells via oxidative stress and glutathione depletion.

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You, Bo Ra; Shin, Hye Rim; Han, Bo Ram; Kim, Suhn Hee; Park, Woo Hyun

2015-02-01

Auranofin (Au), an inhibitor of thioredoxin reductase, is a known anti‑cancer drug. In the present study, the anti‑growth effect of Au on HeLa cervical cancer cells was examined in association with levels of reactive oxygen species (ROS) and glutathione (GSH). Au inhibited the growth of HeLa cells with an IC50 of ~2 µM at 24 h. This agent induced apoptosis and necrosis, accompanied by the cleavage of poly (ADP‑ribose) polymerase and loss of mitochondrial membrane potential. The pan‑caspase inhibitor, benzyloxycarbonyl‑Val‑Ala‑Asp‑fluoromethylketone, prevented apoptotic cell death and each of the assessed caspase inhibitors inhibited necrotic cell death induced by Au. With respect to the levels of ROS and GSH, Au increased intracellular O2•- in the HeLa cells and induced GSH depletion. The pan‑caspase inhibitor reduced the levels of O2•- and GSH depletion in Au‑treated HeLa cells. The antioxidant, N‑acetyl cysteine, not only attenuated apoptosis and necrosis in the Au‑treated HeLa cells, but also decreased the levels of O2•- and GSH depletion in the cells. By contrast, L‑buthionine sulfoximine, a GSH synthesis inhibitor, intensified cell death O2•- and GSH depletion in the Au‑treated HeLa cells. In conclusion, Au induced apoptosis and necrosis in HeLa cells via the induction of oxidative stress and the depletion of GSH.

MicroRNA-132 protects hippocampal neurons against oxygen-glucose deprivation-induced apoptosis.

Science.gov (United States)

Sun, Zu-Zhen; Lv, Zhan-Yun; Tian, Wen-Jing; Yang, Yan

2017-09-01

Hypoxic-ischemic brain injury (HIBI) results in death or long-term neurologic impairment in both adults and children. In this study, we investigated the effects of microRNA-132 (miR-132) dysregulation on oxygen-glucose deprivation (OGD)-induced apoptosis in fetal rat hippocampal neurons, in order to reveal the therapeutic potential of miR-132 on HIBI. MiR-132 dysregulation was induced prior to OGD exposure by transfection of primary fetal rat hippocampal neurons with miR-132 mimic or miR-132 inhibitor. The effects of miR-132 overexpression and suppression on OGD-stimulated hippocampal neurons were evaluated by detection of cell viability, apoptotic cells rate, and the expression of apoptosis-related proteins. Besides, TargetScan database and dual luciferase activity assay were used to seek a target gene of miR-132. As a result, miR-132 was highly expressed in hippocampal neurons following 2 h of OGD exposure. MiR-132 overexpression significantly increased OGD-diminished cell viability and reduced OGD-induced apoptosis at 12, 24, and 48 h post-OGD. MiR-132 overexpression significantly down-regulated the expressions of Bax, cytochrome c, and caspase-9, but up-regulated BCl-2. Caspase-3 activity was also significantly decreased by miR-132 overexpression. Furthermore, FOXO3 was a direct target of miR-132, and it was negatively regulated by miR-132. To conclude, our results provide evidence that miR-132 protects hippocampal neurons against OGD injury by inhibiting apoptosis.

Changes of reduced glutathion, glutathion reductase, and glutathione peroxidase after radiation in guinea pigs

International Nuclear Information System (INIS)

Erden, M.; Bor, N.M.

1984-01-01

In this series of experiments the protective action of reduced glutathion due to ionizing radiation has been studied. In the experimental group 18 guinea pigs were exposed to successive radiations of 150 rad 3 or 4 days apart. Total dose given amounted to 750 rad which is the LD50 for guinea pigs. Blood samples were taken 30 min after each exposure. The control series were sham radiated but otherwise treated identically. The cells of the removed blood samples were separated by centrifugation and were subjected to the reduced glutathion stability test. GSSGR, GPer, and LDH enzyme activities were also measured of which the latter served as a marked enzyme. It was found that LDH did not show any alteration after radiation. The reduced glutathion stability test showed a consistent but minor reduction (P greater than 0.05), in the experimental group. GSSGR enzyme activity on the other hand was reduced significantly (from 176.48 +/- 11.32 to 41.34 +/- 1.17 IU/ml of packed erythrocytes, P less than 0.001) in the same group. GPer activity showed a consistent but minor elevation during the early phase of the experimental group. It was later increased significantly beginning after 600 rad total radiation on the fourth session (P less than 0.050)

Individual Income, Area Deprivation, and Health: Do Income-Related Health Inequalities Vary by Small Area Deprivation?

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Siegel, Martin; Mielck, Andreas; Maier, Werner

2015-11-01

This paper aims to explore potential associations between health inequalities related to socioeconomic deprivation at the individual and the small area level. We use German cross-sectional survey data for the years 2002 and 2006, and measure small area deprivation via the German Index of Multiple Deprivation. We test the differences between concentration indices of income-related and small area deprivation related inequalities in obesity, hypertension, and diabetes. Our results suggest that small area deprivation and individual income both yield inequalities in health favoring the better-off, where individual income-related inequalities are significantly more pronounced than those related to small area deprivation. We then apply a semiparametric extension of Wagstaff's corrected concentration index to explore how individual-level health inequalities vary with the degree of regional deprivation. We find that the concentration of obesity, hypertension, and diabetes among lower income groups also exists at the small area level. The degree of deprivation-specific income-related inequalities in the three health outcomes exhibits only little variations across different levels of multiple deprivation for both sexes. Copyright © 2014 John Wiley & Sons, Ltd.

Establishment of a drug-induced rhabdomyolysis mouse model by co-administration of ciprofloxacin and atorvastatin.

Science.gov (United States)

Matsubara, Akiko; Oda, Shingo; Akai, Sho; Tsuneyama, Koichi; Yokoi, Tsuyoshi

2018-07-01

Rhabdomyolysis is one of the serious side effects of ciprofloxacin (CPFX), a widely used antibacterial drug; and occasionally, acute kidney injury (AKI) occurs. Often, rhabdomyolysis has occurred in patients taking CPFX co-administered with statins. The purpose of this study is to establish a mouse model of drug-induced rhabdomyolysis by co-administration of CPFX and atorvastatin (ATV) and to clarify the mechanisms of its pathogenesis. C57BL/6J mice treated with L-buthionine-(S,R)-sulfoximine (BSO), a glutathione synthesis inhibitor, were orally administered with CPFX and ATV for 4 days. Plasma levels of creatinine phosphokinase (CPK) and aspartate aminotransferase (AST) were significantly increased in the CPFX and ATV-co-administered group. Histopathological examination of skeletal muscle observed degeneration in gastrocnemius muscle and an increased number of the satellite cells. Expressions of skeletal muscle-specific microRNA and mRNA in plasma and skeletal muscle, respectively, were significantly increased. The area under the curve (AUC) of plasma CPFX was significantly increased in the CPFX and ATV-co-administered group. Furthermore, cytoplasmic vacuolization and a positively myoglobin-stained region in kidney tissue and high content of myoglobin in urine were observed. These results indicated that AKI was induced by myoglobin that leaked from skeletal muscle. The established mouse model in the present study would be useful for predicting potential rhabdomyolysis risks in preclinical drug development. Copyright © 2018 Elsevier B.V. All rights reserved.

Silymarin protects PBMC against B(a)P induced toxicity by replenishing redox status and modulating glutathione metabolizing enzymes-An in vitro study

International Nuclear Information System (INIS)

Kiruthiga, P.V.; Pandian, S. Karutha; Devi, K. Pandima

2010-01-01

PAHs are a ubiquitous class of environmental contaminants that have a large number of hazardous consequences on human health. An important prototype of PAHs, B(a)P, is notable for being the first chemical carcinogen to be discovered and the one classified by EPA as a probable human carcinogen. It undergoes metabolic activation to QD, which generate ROS by redox cycling system in the body and oxidatively damage the macromolecules. Hence, a variety of antioxidants have been tested as possible protectors against B(a)P toxicity. Silymarin is one such compound, which has high human acceptance, used clinically and consumed as dietary supplement around the world for its strong anti-oxidant efficacy. Silymarin was employed as an alternative approach for treating B(a)P induced damage and oxidative stress in PBMC, with an emphasis to provide the molecular basis for the effect of silymarin against B(a)P induced toxicity. PBMC cells exposed to either benzopyrene (1 μM) or silymarin (2.4 mg/ml) or both was monitored for toxicity by assessing LPO, PO, redox status (GSH/GSSG ratio), glutathione metabolizing enzymes GR and GPx and antioxidant enzymes CAT and SOD. This study also investigated the protective effect of silymarin against B(a)P induced biochemical alteration at the molecular level by FT-IR spectroscopy. Our findings were quite striking that silymarin possesses substantial protective effect against B(a)P induced oxidative stress and biochemical changes by restoring redox status, modulating glutathione metabolizing enzymes, hindering the formation of protein oxidation products, inhibiting LPO and further reducing ROS mediated damages by changing the level of antioxidant enzymes. The results suggest that silymarin exhibits multiple protections and it should be considered as a potential protective agent for environmental contaminant induced immunotoxicity.

Study of material properties important for an optical property modulation-based radiation detection method for positron emission tomography.

Science.gov (United States)

Tao, Li; Daghighian, Henry M; Levin, Craig S

2017-01-01

We compare the performance of two detector materials, cadmium telluride (CdTe) and bismuth silicon oxide (BSO), for optical property modulation-based radiation detection method for positron emission tomography (PET), which is a potential new direction to dramatically improve the annihilation photon pair coincidence time resolution. We have shown that the induced current flow in the detector crystal resulting from ionizing radiation determines the strength of optical modulation signal. A larger resistivity is favorable for reducing the dark current (noise) in the detector crystal, and thus the higher resistivity BSO crystal has a lower (50% lower on average) noise level than CdTe. The CdTe and BSO crystals can achieve the same sensitivity under laser diode illumination at the same crystal bias voltage condition while the BSO crystal is not as sensitive to 511-keV photons as the CdTe crystal under the same crystal bias voltage. The amplitude of the modulation signal induced by 511-keV photons in BSO crystal is around 30% of that induced in CdTe crystal under the same bias condition. In addition, we have found that the optical modulation strength increases linearly with crystal bias voltage before saturation. The modulation signal with CdTe tends to saturate at bias voltages higher than 1500 V due to its lower resistivity (thus larger dark current) while the modulation signal strength with BSO still increases after 3500 V. Further increasing the bias voltage for BSO could potentially further enhance the modulation strength and thus, the sensitivity.

The protective role of isorhamnetin on human brain microvascular endothelial cells from cytotoxicity induced by methylglyoxal and oxygen-glucose deprivation.

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Li, Wenlu; Chen, Zhigang; Yan, Min; He, Ping; Chen, Zhong; Dai, Haibin

2016-02-01

As the first target of stroke, cerebral endothelial cells play a key role in brain vascular repair and maintenance, and their function is impeded in diabetes. Methylglyoxal (MGO), a reactive dicarbonyl produced during glucose metabolism, accumulates in diabetic patients. MGO and MGO-induced advanced glycation end-products (AGEs) could ameliorate stroke-induced brain vascular damage, closely related with ECs dysfunction. Using MGO plus oxygen-glucose deprivation (OGD) to mimic diabetic stroke, we reported the protective effect of isorhamnetin on OGD-induced cytotoxicity after MGO treatment on primary human brain microvascular endothelial cells (HBMEC) and explored the underlying mechanisms. Treatment of MGO for 24 h significantly enhanced 3-h OGD-induced HBMEC toxic effect, which was inhibited by pretreatment of isorhamnetin (100 μmol/L). Moreover, the protective effect of isorhamnetin is multiple function dependent, which includes anti-inflammation, anti-oxidative stress and anti-apoptosis effects. Besides its well-known inhibition on the mitochondria-dependent or intrinsic apoptotic pathway, isorhamnetin also reduced activation of the extrinsic apoptotic pathway, as characterized by the decreased expression and activity of caspase 3 and caspase 8. Furthermore, pretreatment with isorhamnetin specifically inhibited FAS/FASL expression and suppressed nuclear factor-kappa B nuclear translocation. Taken together, our results indicated that isorhamnetin protected against OGD-induced cytotoxicity after MGO treatment in cultured HBMEC due to its multiple protective effects and could inhibit Fas-mediated extrinsic apoptosis. Therefore, isorhamnetin is a promising reagent for the treatment of hyperglycemia and ischemia-induced cerebral vascular degeneration. A proposed model of the potential protective mechanism of isorhamnetin, a metabolite of quercetin, on methylglyoxal (MGO) treatment plus oxygen-glucose deprivation (OGD) exposure-induced cytotoxicity in cultured human

Glutathione-induced drought stress tolerance in mung bean: coordinated roles of the antioxidant defence and methylglyoxal detoxification systems

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Nahar, Kamrun; Hasanuzzaman, Mirza; Alam, Md. Mahabub; Fujita, Masayuki

2015-01-01

Drought is considered one of the most acute environmental stresses presently affecting agriculture. We studied the role of exogenous glutathione (GSH) in conferring drought stress tolerance in mung bean (Vigna radiata L. cv. Binamoog-1) seedlings by examining the antioxidant defence and methylglyoxal (MG) detoxification systems and physiological features. Six-day-old seedlings were exposed to drought stress (−0.7 MPa), induced by polyethylene glycol alone and in combination with GSH (1 mM) for 24 and 48 h. Drought stress decreased seedling dry weight and leaf area; resulted in oxidative stress as evidenced by histochemical detection of hydrogen peroxide (H2O2) and O2⋅− in the leaves; increased lipid peroxidation (malondialdehyde), reactive oxygen species like H2O2 content and O2⋅− generation rate and lipoxygenase activity; and increased the MG level. Drought decreased leaf succulence, leaf chlorophyll and relative water content (RWC); increased proline (Pro); decreased ascorbate (AsA); increased endogenous GSH and glutathione disulfide (GSSG) content; decreased the GSH/GSSG ratio; increased ascorbate peroxidase and glutathione S-transferase activities; and decreased the activities of monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR) and catalase. The activities of glyoxalase I (Gly I) and glyoxalase II (Gly II) increased due to drought stress. In contrast to drought stress alone, exogenous GSH enhanced most of the components of the antioxidant and glyoxalase systems in drought-affected mung bean seedlings at 24 h, but GSH did not significantly affect AsA, Pro, RWC, leaf succulence and the activities of Gly I and DHAR after 48 h of stress. Thus, exogenous GSH supplementation with drought significantly enhanced the antioxidant components and successively reduced oxidative damage, and GSH up-regulated the glyoxalase system and reduced MG toxicity, which played a significant role in improving the physiological features and drought

Behavioral responses and fluid regulation in male rats after combined dietary sodium deficiency and water deprivation.

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Lucia, Kimberly J; Curtis, Kathleen S

2018-02-01

Most investigators use a single treatment such as water deprivation or dietary sodium deficiency to evaluate thirst or sodium appetite, which underlie behavioral responses to body fluid challenges. The goal of the present experiments was to assess the effects of combined treatments in driving behaviors. Therefore, we evaluated the effect of combined overnight water deprivation and dietary sodium deficiency on water intake and salt intake by adult male rats in 2-bottle (0.5M NaCl and water) tests. Overnight water deprivation alone increased water intake, and 10days of dietary sodium deficiency increased 0.5M NaCl intake, with a secondary increase in water intake. During combined water deprivation and dietary sodium deficiency, water intake was enhanced and 0.5M NaCl was reduced, but not eliminated, suggesting that physiologically relevant behavioral responses persist. Nonetheless, the pattern of fluid intake was altered by the combined treatments. We also assessed the effect of these behaviors on induced deficits in body sodium and fluid volume during combined treatments and found that, regardless of treatment, fluid ingestion partially repleted the induced deficits. Finally, we examined urine volume and sodium excretion during dietary sodium deficiency with or without overnight water deprivation and found that, whether or not rats were water deprived, and regardless of water consumption, sodium excretion was minimal. Thus, the combination of water deprivation and dietary sodium deficiency appears to arouse drives that stimulate compensatory behavioral responses. These behaviors, in conjunction with physiological adaptations to the treatments, underlie body sodium and volume repletion in the face of combined water deprivation and dietary sodium deficiency. Copyright © 2017 Elsevier Inc. All rights reserved.

Distinct unfolded protein responses mitigate or mediate effects of nonlethal deprivation of C. elegans sleep in different tissues.

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Sanders, Jarred; Scholz, Monika; Merutka, Ilaria; Biron, David

2017-08-28

Disrupting sleep during development leads to lasting deficits in chordates and arthropods. To address lasting impacts of sleep deprivation in Caenorhabditis elegans, we established a nonlethal deprivation protocol. Deprivation triggered protective insulin-like signaling and two unfolded protein responses (UPRs): the mitochondrial (UPR mt ) and the endoplasmic reticulum (UPR ER ) responses. While the latter is known to be triggered by sleep deprivation in rodent and insect brains, the former was not strongly associated with sleep deprivation previously. We show that deprivation results in a feeding defect when the UPR mt is deficient and in UPR ER -dependent germ cell apoptosis. In addition, when the UPR ER is deficient, deprivation causes excess twitching in vulval muscles, mirroring a trend caused by loss of egg-laying command neurons. These data show that nonlethal deprivation of C. elegans sleep causes proteotoxic stress. Unless mitigated, distinct types of deprivation-induced proteotoxicity can lead to anatomically and genetically separable lasting defects. The relative importance of different UPRs post-deprivation likely reflects functional, developmental, and genetic differences between the respective tissues and circuits.

Rhabdomyolysis-Induced Acute Kidney Injury Under Hypoxia and Deprivation of Food and Water

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Jingwen Wang

2013-10-01

Full Text Available Background: To investigate the renal pathophysiologyin rhabdomyolysis-induced acute kidney injury (AKI in rats under hypoxia and deprivation of food and water (HDFW, thus broadening the knowledge about rhabdomyolysis-induced AKI in massive earthquake. Methods: Male Wistar rats weighing 200-230g were randomized into control, rhabdomyolysis (R, HDFW and rhabdomyolysis in combination with HDFW (R/HDFW group. Experimental rhabdomyolysis rat model was established through clamping hind limb muscles, HDFW model rats were kept in 10% hypoxic chamber unavailable to food and water. At 1, 3, 5, 7, 9, 11d after treatment, serum creatinine (Scr level, renal index, renal structural changes and cell apoptosis were analyzed. Results: After R, HDFW, R/HDFW treatment, the animals showed significantly higher Scr levels than the control group. Renal index in R and R/HDFW groups elevated remarkably compared with that in control and HDFW group. The results of histopathology, ultra-structure and apoptosis assay suggested that rhabdomyolysis caused renal tubular injury, HDFW treatment resulted in renal vascular dilation, tissue congestion and tubular cell damage. In addition, more severe renal lesion appeared in R/HDFW. Conclusions: We conclude that the association of experimental rhabdomyolysis with HDFW results in a different functional and histological pattern. The rhabdomyolysis-HDFW combination causes more severe renal injury.

Deletion of glutathione peroxidase-2 inhibits azoxymethane-induced colon cancer development.

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Mike F Müller

Full Text Available The selenoprotein glutathione peroxidase-2 (GPx2 appears to have a dual role in carcinogenesis. While it protected mice from colon cancer in a model of inflammation-triggered carcinogenesis (azoxymethane and dextran sodium sulfate treatment, it promoted growth of xenografted tumor cells. Therefore, we analyzed the effect of GPx2 in a mouse model mimicking sporadic colorectal cancer (azoxymethane-treatment only. GPx2-knockout (KO and wild-type (WT mice were adjusted to an either marginally deficient (-Se, adequate (+Se, or supranutritional (++Se selenium status and were treated six times with azoxymethane (AOM to induce tumor development. In the -Se and ++Se groups, the number of tumors was significantly lower in GPx2-KO than in respective WT mice. On the +Se diet, the number of dysplastic crypts was reduced in GPx2-KO mice. This may be explained by more basal and AOM-induced apoptotic cell death in GPx2-KO mice that eliminates damaged or pre-malignant epithelial cells. In WT dysplastic crypts GPx2 was up-regulated in comparison to normal crypts which might be an attempt to suppress apoptosis. In contrast, in the +Se groups tumor numbers were similar in both genotypes but tumor size was larger in GPx2-KO mice. The latter was associated with an inflammatory and tumor-promoting environment as obvious from infiltrated inflammatory cells in the intestinal mucosa of GPx2-KO mice even without any treatment and characterized as low-grade inflammation. In WT mice the number of tumors tended to be lowest in +Se compared to -Se and ++Se feeding indicating that selenium might delay tumorigenesis only in the adequate status. In conclusion, the role of GPx2 and presumably also of selenium depends on the cancer stage and obviously on the involvement of inflammation.

Relative deprivation and intergroup prejudice

NARCIS (Netherlands)

Pettigrew, T.F.; Christ, O.; Wagner, U.; Meertens, R.W.; van Dick, R.; Zick, A.

2008-01-01

Using three diverse European surveys, we test the relationship between relative deprivation (RD) and anti-immigrant prejudice. We find that both group relative deprivation (GRD) and individual relative deprivation (IRD) are found primarily among working-class respondents who are politically

Balneotherapy and platelet glutathione metabolism in type II diabetic patients

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Ohtsuka, Yoshinori; Yabunaka, Noriyuki; Watanabe, Ichiro; Noro, Hiroshi; Agishi, Yuko

1996-09-01

Effects of balneotherapy on platelet glutathione metabolism were investigated in 12 type II (non-insulin-dependent) diabetic patients. Levels of the reduced form of glutathione (GSH) on admission were well correlated with those of fasting plasma glucose (FPG; r=0.692, Pbalneotherapy, the mean level of GSH showed no changes; however, in well-controlled patients (FPG 150 mg/dl), the value decreased ( Pbalneotherapy, the activity increased in 5 patients, decreased in 3 patients and showed no changes (alteration within ±3%) in all the other patients. From these findings in diabetic patients we concluded: (1) platelet GSH synthesis appeared to be induced in response to oxidative stress; (2) lowered GPX activities indicated that the antioxidative defense system was impaired; and (3) platelet glutathione metabolism was partially improved by 4 weeks balneotherapy, an effect thought to be dependent on the control status of plasma glucose levels. It is suggested that balneotherapy is beneficial for patients whose platelet antioxidative defense system is damaged, such as those with diabetes mellitus and coronary heart disease.

Kale Extract Increases Glutathione Levels in V79 Cells, but Does not Protect Them against Acute Toxicity Induced by Hydrogen Peroxide

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Paula B. Andrade

2012-05-01

Full Text Available This study aims to evaluate the antioxidant potential of extracts of Brassica oleracea L. var. acephala DC. (kale and several materials of Pieris brassicae L., a common pest of Brassica cultures using a cellular model with hamster lung fibroblast (V79 cells under quiescent conditions and subjected to H₂O₂-induced oxidative stress. Cytotoxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide (MTT assay and glutathione was determined by the 5,5'-dithiobis(2-nitrobenzoic acid (DTNB-oxidized glutathione (GSSG reductase recycling assay. The phenolic composition of the extracts was also established by HPLC-DAD. They presented acylated and non acylated flavonoid glycosides, some of them sulfated, and hydroxycinnamic acyl gentiobiosides. All extracts were cytotoxic by themselves at high concentrations and failed to protect V79 cells against H₂O₂ acute toxicity. No relationship between phenolic composition and cytotoxicity of the extracts was found. Rather, a significant increase in glutathione was observed in cells exposed to kale extract, which contained the highest amount and variety of flavonoids. It can be concluded that although flavonoids-rich extracts have the ability to increase cellular antioxidant defenses, the use of extracts of kale and P. brassicae materials by pharmaceutical or food industries, may constitute an insult to health, especially to debilitated individuals, if high doses are consumed.

Aging Worsens the Effects of Sleep Deprivation on Postural Control

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Robillard, Rébecca; Prince, François; Filipini, Daniel; Carrier, Julie

2011-01-01

Falls increase with age and cause significant injuries in the elderly. This study aimed to determine whether age modulates the interactions between sleep deprivation and postural control and to evaluate how attention influences these interactions in the elderly. Fifteen young (24±2.7 y.o.) and 15 older adults (64±3.2 y.o.) stood still on a force plate after a night of sleep and after total sleep deprivation. Center of pressure range and velocity were measured with eyes open and with eyes closed while participants performed an interference task, a control task, and no cognitive task. Sleep deprivation increased the antero-posterior range of center of pressure in both age groups and center of pressure speed in older participants only. In elderly participants, the destabilizing effects of sleep deprivation were more pronounced with eyes closed. The interference task did not alter postural control beyond the destabilization induced by sleep loss in older subjects. It was concluded that sleep loss has greater destabilizing effects on postural control in older than in younger participants, and may therefore increase the risk of falls in the elderly. PMID:22163330

Aging worsens the effects of sleep deprivation on postural control.

Science.gov (United States)

Robillard, Rébecca; Prince, François; Filipini, Daniel; Carrier, Julie

2011-01-01

Falls increase with age and cause significant injuries in the elderly. This study aimed to determine whether age modulates the interactions between sleep deprivation and postural control and to evaluate how attention influences these interactions in the elderly. Fifteen young (24±2.7 y.o.) and 15 older adults (64±3.2 y.o.) stood still on a force plate after a night of sleep and after total sleep deprivation. Center of pressure range and velocity were measured with eyes open and with eyes closed while participants performed an interference task, a control task, and no cognitive task. Sleep deprivation increased the antero-posterior range of center of pressure in both age groups and center of pressure speed in older participants only. In elderly participants, the destabilizing effects of sleep deprivation were more pronounced with eyes closed. The interference task did not alter postural control beyond the destabilization induced by sleep loss in older subjects. It was concluded that sleep loss has greater destabilizing effects on postural control in older than in younger participants, and may therefore increase the risk of falls in the elderly.

Pitavastatin treatment induces neuroprotection through the BDNF-TrkB signalling pathway in cultured cerebral neurons after oxygen-glucose deprivation.

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Cui, Xiaoyan; Fu, Zhenqiang; Wang, Menghan; Nan, Xiaofei; Zhang, Boai

2018-05-01

Along with their lipid-lowering effect, statins have been reported to have neuroprotective function in both in vivo and in vitro models of neurodegenerative diseases. We conducted this study in order to uncover the he neuroprotective effect of the lipophilic statin pitavastatin (PTV) and investigate the underlying molecular mechanisms using primary cultured cerebral neurons exposed to oxygen-glucose deprivation (OGD). The primary cultured cerebral neurons were randomly assigned into four groups: the control group, the pitavastatin treatment group, the OGD group and the OGD + pitavastatin treatment group. The pitavastatin's concentration were set as follows: 1μM, 15μM, 30μM. After 3 hours OGD treatment, we use MTT method to assessment cell viability, immunofluorescence to observe neuron morphology and western blot method analysis the BDNF, TrkB. PTV at concentrations of 1 μM and 15 μM elevated the survival rate of cortical neurons exposed to OGD, whereas 30 μM PTV did not show such an effect. Moreover, PTV promoted neuronal dendrite growth at concentrations of 1 μM and 15 μM. Increased expression levels of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) were observed in both of the following two scenarios: when neurons were treated with PTV for 48 hours and when PTV was added after the OGD procedure. Pitavastatin treatment induces neuroprotection in cultured cerebral neurons after oxygen-glucose deprivation this neuroprotection induced by PTV involves the BDNF-TrkB signalling pathway.

Subcellular distribution of glutathione and cysteine in cyanobacteria.

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Zechmann, Bernd; Tomasić, Ana; Horvat, Lucija; Fulgosi, Hrvoje

2010-10-01

Glutathione plays numerous important functions in eukaryotic and prokaryotic cells. Whereas it can be found in virtually all eukaryotic cells, its production in prokaryotes is restricted to cyanobacteria and proteobacteria and a few strains of gram-positive bacteria. In bacteria, it is involved in the protection against reactive oxygen species (ROS), osmotic shock, acidic conditions, toxic chemicals, and heavy metals. Glutathione synthesis in bacteria takes place in two steps out of cysteine, glutamate, and glycine. Cysteine is the limiting factor for glutathione biosynthesis which can be especially crucial for cyanobacteria, which rely on both the sufficient sulfur supply from the growth media and on the protection of glutathione against ROS that are produced during photosynthesis. In this study, we report a method that allows detection and visualization of the subcellular distribution of glutathione in Synechocystis sp. This method is based on immunogold cytochemistry with glutathione and cysteine antisera and computer-supported transmission electron microscopy. Labeling of glutathione and cysteine was restricted to the cytosol and interthylakoidal spaces. Glutathione and cysteine could not be detected in carboxysomes, cyanophycin granules, cell walls, intrathylakoidal spaces, periplasm, and vacuoles. The accuracy of the glutathione and cysteine labeling is supported by two observations. First, preadsorption of the antiglutathione and anticysteine antisera with glutathione and cysteine, respectively, reduced the density of the gold particles to background levels. Second, labeling of glutathione and cysteine was strongly decreased by 98.5% and 100%, respectively, in Synechocystis sp. cells grown on media without sulfur. This study indicates a strong similarity of the subcellular distribution of glutathione and cysteine in cyanobacteria and plastids of plants and provides a deeper insight into glutathione metabolism in bacteria.

Boron deprivation alters rat behaviour and brain mineral composition differently when fish oil instead of safflower oil is the diet fat source.

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Nielsen, Forrest H; Penland, James G

2006-01-01

To determine whether boron deprivation affects rat behaviour and whether behavioural responses to boron deprivation are modified by differing amounts of dietary long-chain omega-3 fatty acids. Female rats were fed diets containing 0.1 mg (9 micromol)/kg boron in a factorial arrangement with dietary variables of supplemental boron at 0 and 3mg (278 micromol)/kg and fat sources of 75 g/kg safflower oil or 65 g/kg fish (menhaden) oil plus 10 g/kg linoleic acid. After 6 weeks, six females per treatment were bred. Dams and pups continued on their respective diets through gestation, lactation and after weaning. Between ages 6 and 20 weeks, behavioural tests were performed on 13-15 male offspring from three dams in each dietary treatment. The rats were euthanized at age 21 weeks for the collection of tissues and blood. At ages 6 and 19 weeks, auditory startle was evaluated with an acoustic startle system and avoidance behaviour was evaluated by using an elevated plus maze. At ages 7 and 20 weeks, spontaneous behaviour activity was evaluated with a photobeam activity system. A brightness discrimination test was performed on the rats between age 15 and 16 weeks. Brain mineral composition was determined by coupled argon plasma atomic emission spectroscopy. Plasma total glutathione was determined by HPLC and total cholesterol and 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) were determined by using commercially available kits. Boron-deficient rats were less active than boron-adequate rats when fed safflower oil based on reduced number, distance and time of horizontal movements, front entries, margin distance and vertical breaks and jumps in the spontaneous activity evaluation. Feeding fish oil instead of safflower oil attenuated the activity response to boron deprivation. In the plus maze evaluation, the behavioural reactivity of the boron-deficient rats fed fish oil was noticeably different than the other three treatments. They made more entries into both open and closed

Glucose-6-phosphate dehydrogenase is required for hpa1xoo (harpin protein fragment)-mediated salt stress tolerance in transgenic arabidopsis thaliana

International Nuclear Information System (INIS)

Sang, S.L.; Xie, L.L.; Cui, X.W.; Wang, Z.Y.

2018-01-01

Harpin induces salicylic acid and abscisic acid signaling in plants under biotic and abiotic stress, respectively. Our previous report showed that the effective harpin fragment Hpa1xoo enhanced H2O2 production and pathogen resistance in a transgenic Arabidopsis mutant. In this study, we examined contents of thiobarbituric acid reactive substance (TBARS), H2O2 and glutathione, and glucose-6-phosphate dehydrogenase (G6PDH), glutathione reductase (GR) and glutathione peroxidase (GPX) enzyme activity in Hpa1xoo-expressing Arabidopsis under salt stress. The results revealed increased amounts of TBARS and H2O2 in wild-type (WT) compared to mutant plants under salt stress conditions. In contrast, increased levels were observed in the mutant under stress-free conditions. Moreover, a higher reduced glutathione (GSH) content and ratio of GSH/oxidized glutathione (GSSG) was observed in mutant compared to WT plants under both stress-free and salt stress conditions. In addition, mutant plants exhibited significantly higher G6PDH, GR and GPX activity than WT plants under salt stress. Suppression of G6PDH activity via 6-aminonicotinamide (6-AN, a specific inhibitor of G6PDH) was partly reversed by L-buthionine-sulfoximine (BSO, a specific inhibitor of GSH regeneration) and aggravated by GSH. Combined with previous reports, these findings suggest that the G6PDH enzyme plays a key role in harpin fragment (Hpa1xoo)-mediated salt stress tolerance in transgenic Arabidopsis. (author)

Lithium ameliorates sleep deprivation-induced mania-like behavior, hypothalamic-pituitary-adrenal (HPA) axis alterations, oxidative stress and elevations of cytokine concentrations in the brain and serum of mice.

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Valvassori, Samira S; Resende, Wilson R; Dal-Pont, Gustavo; Sangaletti-Pereira, Heron; Gava, Fernanda F; Peterle, Bruna R; Carvalho, André F; Varela, Roger B; Dal-Pizzol, Felipe; Quevedo, João

2017-06-01

The goal of the present study was to investigate the effects of lithium administration on behavior, oxidative stress parameters and cytokine levels in the periphery and brain of mice subjected to an animal model of mania induced by paradoxical sleep deprivation (PSD). Male C57 mice were treated with saline or lithium for 7 days. The sleep deprivation protocol started on the 5th day during for the last 36 hours of the treatment period. Immediately after the sleep deprivation protocol, animals locomotor activity was evaluated and serum and brain samples was extracted to evaluation of corticosterone and adrenocorticotropic hormone circulating levels, oxidative stress parameters and citokynes levels. The results showed that PSD induced hyperactivity in mice, which is considered a mania-like behavior. PSD increased lipid peroxidation and oxidative damage to DNA, as well as causing alterations to antioxidant enzymes in the frontal cortex, hippocampus and serum of mice. In addition, PSD increased the levels of cytokines in the brains of mice. Treatment with lithium prevented the mania-like behavior, oxidative damage and cytokine alterations induced by PSD. Improving our understanding of oxidative damage in biomolecules, antioxidant mechanisms and the inflammatory system - alterations presented in the animal models of mania - is important in helping us to improve our knowledge concerning the pathophysiology of BD, and the mechanisms of action employed by mood stabilizers. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A regulatory review for products containing glutathione

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Nur Hidayah Abd Rahim

2016-01-01

Full Text Available Glutathione is a potent antioxidant as well as has important role for DNA synthesis and repair, protein synthesis, amino acid transport, and enzyme activation. Besides this, Glutathione products are now mainly selling as whitening agent which are mainly marketing through social media (Facebook and different websites. Information is not available whether glutathione product are following the regulatory guidelines of National Pharmaceutical Control Bureau of Malaysia (NPCB for selling, advertisement and promotion. This review was carried out by extracting information about glutathione from scientific database using PubMed, Cochrane Library and Embase. Analysis of the available information, case example of glutathione products showed that a brand of glutathione (Glutacaps HQ did not show the product's registration number from NPCB, and also did not show the name, address, contact number of the advertiser, and even not found the name of the manufacture. Without providing the above mentioned information, the product is selling and promoting through social media (fb which is not allowed by the NPCB guidelines part 4.14. So far, only two clinical trials were conducted on glutathione supplementation for 4 weeks duration. There was no serious or systematic adverse effects reported in clinical trials. As the two clinic trials resulted contradictory outcomes, further studies needed for conformation of the clinic benefits of glutathione. Otherwise, random use of glutathione may be risk for the health of the people. Besides, the marketer mainly promoting glutathione as the skin whitening beauty product instead of using as health supplement, it may cause additional and serious risk to the users as the manufacturer not providing sufficient information about the product, its registration number, manufacturing company, etc.

Astrocytic mitochondrial membrane hyperpolarization following extended oxygen and glucose deprivation.

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Andrej Korenić

Full Text Available Astrocytes can tolerate longer periods of oxygen and glucose deprivation (OGD as compared to neurons. The reasons for this reduced vulnerability are not well understood. Particularly, changes in mitochondrial membrane potential (Δψ(m in astrocytes, an indicator of the cellular redox state, have not been investigated during reperfusion after extended OGD exposure. Here, we subjected primary mouse astrocytes to glucose deprivation (GD, OGD and combinations of both conditions varying in duration and sequence. Changes in Δψ(m, visualized by change in the fluorescence of JC-1, were investigated within one hour after reconstitution of oxygen and glucose supply, intended to model in vivo reperfusion. In all experiments, astrocytes showed resilience to extended periods of OGD, which had little effect on Δψ(m during reperfusion, whereas GD caused a robust Δψ(m negativation. In case no Δψ(m negativation was observed after OGD, subsequent chemical oxygen deprivation (OD induced by sodium azide caused depolarization, which, however, was significantly delayed as compared to normoxic group. When GD preceded OD for 12 h, Δψ(m hyperpolarization was induced by both GD and subsequent OD, but significant interaction between these conditions was not detected. However, when GD was extended to 48 h preceding OGD, hyperpolarization enhanced during reperfusion. This implicates synergistic effects of both conditions in that sequence. These findings provide novel information regarding the role of the two main substrates of electron transport chain (glucose and oxygen and their hyperpolarizing effect on Δψ(m during substrate deprivation, thus shedding new light on mechanisms of astrocyte resilience to prolonged ischemic injury.

The use of drugs which deplete intracellular glutathione in hypoxic cell radiosensitization

International Nuclear Information System (INIS)

Bump, E.A.; Yu, N.Y.; Brown, J.M.

1982-01-01

Diethylmaleate (DEM) is a thiol-biding reagent with specificity toward glutathione. Treatment of chinese hamster ovary (CHO) cells in vitro with 2 x 10 -4 M DEM for one hour results in a decrease in glutathione content to less than 5% of control, without cytotoxicity. This treatment results in dose-modifying sensitization to radiation under hypoxic conditions, with no effect on the shoulder of the radiation survival curve. No effect on the radiation sensitivity of oxygenated cells was seen. DEM pretreatment enhances the radiosensitization of hypoxic cells by misonidazole, as well. Similar results were obtained in vivo with EMT6 tumors in BALB/c mice. Analysis of DNA damage by the alkaline elution assay indicates that DEM enhances radiation-induced single-strand breaks, but does not significantly affect repair, while diamide and N-ethylmaleimide inhibit repair, in addition to enhancing radiation-induced single-strand breaks

Progressive paradoxical sleep deprivation impairs partial memory following learning tasks in rats

Institute of Scientific and Technical Information of China (English)

Chunmin Zhu; Xiangrong Yao; Weisheng Zhang; Yanfeng Song; Yiping Hou

2008-01-01

BACKGROUND: Complex learning tasks result in a greater number of paradoxical sleep phases, which can improve memory. The effect of paradoxical sleep deprivation, induced by "flower pot" technique, on spatial reference memory and working memory require further research. OBJECTIVE: To observe the effect of progressive paradoxical sleep deprivation in rats, subsequent to learning, on memory using the Morris Water Maze. DESIGN, TIME AND SETTING: Controlled observation experiment. The experiment was performed at the Laboratory of Neurobiology, Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Lanzhou University from December 2006 to October 2007. MATERIALS: Twenty-eight, male, Wistar rats, 3-4 months old, were provided by the Experimental Animal Center of Lanzhou University. The Morris Water Maze and behavioral analyses system was purchased from Genheart Company, Beijing, China. METHODS: All animals, according to a random digits table, were randomly divided into paradoxical sleep deprivation, tank control, and home cage control groups. Paradoxical sleep deprivation was induced by the "flower pot" technique for 72 hours, housing the rats on small platforms over water. Rats in the "tank control" and "home cage control" groups were housed either in a tank with large platforms over the water or in normal cages without paradoxical sleep deprivation. MAIN OUTCOME MEASURES: Morris Water Maze was employed for task learning and spatial memory testing. Rats in all groups were placed at six random starting points each day for four consecutive days. Each placement was repeated for two trials; the first trial represented reference memory and the second working memory. Rats in the first trial were allowed to locate the submerged platform within 120 seconds. Data, including swimming distance, escape latency, swimming velocity, percentage of time in correct quarter, and memory scores were recorded and analyzed automatically by behavioral analyses

Reverse Transcriptase-Containing Particles Induced in Rous Sarcoma Virus-Transformed Rat Cells by Arginine Deprivation

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Kotler, Moshe; Weinberg, Eynat; Haspel, Osnat; Becker, Yechiel

1972-01-01

Incubation of rat cells transformed by Rous sarcoma virus (RSV) in an arginine-deficient medium resulted in accumulation of particles in the culture medium. Such particles did not appear when the transformed rat cells were incubated in a complete medium nor in the medium of primary rat cells which were incubated either in arginine-deficient or complete media. The particles which were released from the arginine-deprived transformed rat cells resemble C-type particles in their properties. These particles band in sucrose gradients at a density of 1.16 g/ml and contain 35S ribonucleic acid (RNA) molecules and a reverse transcriptase activity. Analysis of the cytoplasm of transformed and primary rat cells, deprived and undeprived of arginine, revealed the presence of reverse transcriptase-containing particles which banded in sucrose gradients at a density of 1.14 g/ml. These particles differed from the particles released into the medium by the arginine-deprived RSV-transformed rat cells. The deoxyribonucleic acid (DNA) molecules synthesized in vitro by the reverse transcriptase present in the particles isolated from the medium of arginine-deprived cells hybridized to RSV RNA, whereas the DNA synthesized by the cell-bound enzyme had no homology to RSV RNA. PMID:4116137

Practice Patterns Compared with Evidence-based Strategies for the Management of Androgen Deprivation Therapy-Induced Side Effects in Prostate Cancer Patients: Results of a European Web-based Survey

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Bultijnck, R.; Surcel, C.; Ploussard, G.; Briganti, A.; Visschere, P. De; Futterer, J.J.; Ghadjar, P.; Giannarini, G.; Isbarn, H.; Massard, C.; Sooriakumaran, P.; Valerio, M.; Bergh, R. van den; Ost, P.

2016-01-01

BACKGROUND: Evidence-based recommendations are available for the management of androgen deprivation therapy (ADT)-induced side effects; however, there are no data on the implementation of the recommendations into daily practice patterns. OBJECTIVE: To compare practice patterns in the management of

Daily acclimation handling does not affect hippocampal long-term potentiation or cause chronic sleep deprivation in mice.

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Vecsey, Christopher G; Wimmer, Mathieu E J; Havekes, Robbert; Park, Alan J; Perron, Isaac J; Meerlo, Peter; Abel, Ted

2013-04-01

Gentle handling is commonly used to perform brief sleep deprivation in rodents. It was recently reported that daily acclimation handling, which is often used before behavioral assays, causes alterations in sleep, stress, and levels of N-methyl-D-aspartate receptor subunits prior to the actual period of sleep deprivation. It was therefore suggested that acclimation handling could mediate some of the observed effects of subsequent sleep deprivation. Here, we examine whether acclimation handling, performed as in our sleep deprivation studies, alters sleep/wake behavior, stress, or forms of hippocampal synaptic plasticity that are impaired by sleep deprivation. Adult C57BL/6J mice were either handled daily for 6 days or were left undisturbed in their home cages. On the day after the 6(th) day of handling, long-term potentiation (LTP) was induced in hippocampal slices with spaced four-train stimulation, which we previously demonstrated to be impaired by brief sleep deprivation. Basal synaptic properties were also assessed. In three other sets of animals, activity monitoring, polysomnography, and stress hormone measurements were performed during the 6 days of handling. Daily gentle handling alone does not alter LTP, rest/activity patterns, or sleep/wake architecture. Handling initially induces a minimal stress response, but by the 6(th) day, stress hormone levels are unaltered by handling. It is possible to handle mice daily to accustom them to the researcher without causing alterations in sleep, stress, or synaptic plasticity in the hippocampus. Therefore, effects of acclimation handling cannot explain the impairments in signaling mechanisms, synaptic plasticity, and memory that result from brief sleep deprivation.

Oxygen-Glucose-Deprivation/Reoxygenation-Induced Autophagic Cell Death Depends on JNK-Mediated Phosphorylation of Bcl-2

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Jin Fan

2016-03-01

Full Text Available Background/Aims: The purpose of this study was to investigate the role of autophagy in oxygen-glucose-deprivation/reoxygenation (OGD/R injury in rat neurons. Methods and results: Cortical neurons were isolated from Sprague-Dawley rats and identified by immunofluorescence. The cortical neurons were randomly assigned to one of four groups: control group (I, experimental group (OGD/R group, II, JNK inhibitor pretreatment group (III and JNK inhibitor pretreatment + OGD/R group (IV. Neuronal cell viability significantly decreased after 6h and 12h of reoxygenation in Group IV (P P Conclusion: The regulation of the JNK/Bcl-2/Beclin-1 signaling pathway may be one of the mechanisms underlying the OGD/R-induced autophagic cell death of neurons.

[Dinitrosyl iron complexes with glutathione recover rats with experimental endometriosis].

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Adamian, L V; Burgova, E N; Tkachev, N A; Mikoian, V D; Stepanian, A A; Sonova, M M; Vanin, A F

2013-01-01

The effect of binuclear dinitrosyl iron complexes (DNIC) with glutathione on endometrioid tumors in rats with experimental endometriosis has been studied. The latter was induced by an autotransplantation model, where two fragments of endometrium with myometrium (2 x 2 mm) from the left uterine horn was grafted to the inner surface of the anterior abdominal wall. The test animals received intraperitoneal injections of 0.5 ml DNIC-glutathione at the dose of 12.5 micromole per kg daily for 12 days 28 days after operation. The injections resulted in more than a 2-fold decrease in the total volume of both large tumors formed from grafts and small additive tumors formed nearby grafts. The disappearance of the additive tumors was also observed in test animals. The EPR signal with g(av) = 2.03 characteristic of protein bound DNIC with thiol-containing ligands was recorded in livers, graft and additive tumors of test and control animals pointing out intensive generation of nitric oxide in rats with experimental endometriosis. Ribonucleotide reductase activation discovered by doublet the EPR signal at g = 2.0 with 2.3 mT hyperfine structure splitting was found in small tumors. The cytotoxic effect of DNIC-glutathione on endometrioid tumors was suggested to be due to DNIC degradation nearby the tumors induced by iron chelating compounds released from the tumors. The degradation resulted in release of a high amount of nitric oxide molecules and nitrosonium ions from DNICs affecting the tumors by way of the cytotoxic effect.

Effects of cellular non-protein sulfhydryl depletion in radiation induced oncogenic transformation and genotoxicity in mouse C3H 10T1/2 cells

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Hei, T.K.; Geard, C.R.; Hall, E.J.

1984-01-01

A study was made of the effects of cellular non-protein sulfhydryl (NPSH) depletion on cytotoxicity, cell cycle kinetics, oncogenic transformation and sister chromatid exchange (SCE) in C 3 H 10T1/2 cells. Using DL-Buthionine S-R-Sulfoximine (BSO) to deplete thiols, it was found spectrophotometrically that less than 5% of control NPSH level remained in the cells after 24-hour treatment under aerated conditions. Such NPSH depleted cells, when subject to a 3 Gy γ-ray treatment, were found to have no radiosensitizing response either in terms of cell survival or oncogenic transformation. In addition, decreased levels of NPSH had no effect on spontaneous or radiation-induced SCE nor were cell cycle kinetics additionally altered. Therefore, the inability of NPSH depletion to alter γ-ray induced cellular transformation was unrelated to any possible effect of BSO on the cell cycle. These results suggest that such depletion may result in little or no additional oncogenic or genotoxic effects on aerated normal tissues

Effects of combinations of curcumin, linalool, rutin, safranal, and thymoquinone on glucose/serum deprivation-induced cell death

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Bagher Alinejad

2013-07-01

Full Text Available Objective: Several phytochemical agents have been known to exhibit a neuroprotective effect. Among them, curcumin, linalool, rutin, safranal, and thymoquinonewere widely investigated and neuroprotective activity of each of them was shown by several studies. This work was planned to investigate whether different combinations of them could induce better neuroprotective effect against glucose/serum deprivation (GSD-induced cytotoxicity. Materials and Methods: PC12 cells were cultivated for 8 h in GSD condition in both the absence and presence of curcumin, linalool, rutin, safranal, thymoquinone, or combinations of them. At the end of the experiment, the cell viability was determined using MTT assay. Results: The cells cultured in GSD condition showed a significant decrease in viability (28±1% as compared with those cultured in standard condition (100±2%. In the presence of curcumin (10 µg/ml, linalool (16 µg/ml, rutin (200 µg/ml, safranal (50 µg/ml, and thymoquinone (1 µg/ml, the cell viability increased to 69±3.4% (p

Involvement of human glutathione S-transferase isoenzymes in the conjugation of cyclophosphamide metabolites with glutathione

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Dirven, H.A.A.M.; Ommen, B. van; Bladeren, P.J. van

1994-01-01

Alkylating agents can be detoxified by conjugation with glutathione (GSH). One of the physiological significances of this lies in the observation that cancer cells resistant to the cytotoxic effects of alkylating agents have higher levels of GSH and high glutathione S-transferase (GST) activity.

Determination of glutathione and glutathione disulfide in biological samples: an in-depth review.

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Monostori, Péter; Wittmann, Gyula; Karg, Eszter; Túri, Sándor

2009-10-15

Glutathione (GSH) is a thiol-containing tripeptide, which plays central roles in the defence against oxidative damage and in signaling pathways. Upon oxidation, GSH is transformed to glutathione disulfide (GSSG). The concentrations of GSH and GSSG and their molar ratio are indicators of cell functionality and oxidative stress. Assessment of redox homeostasis in various clinical states and medical applications for restoration of the glutathione status are of growing importance. This review is intended to provide a state-of-the-art overview of issues relating to sample pretreatment and choices for the separation and detection of GSH and GSSG. High-performance liquid chromatography, capillary electrophoresis and gas chromatography (as techniques with a separation step) with photometric, fluorimetric, electrochemical and mass spectrometric detection are discussed, stress being laid on novel approaches.

Chrysin enhances doxorubicin-induced cytotoxicity in human lung epithelial cancer cell lines: The role of glutathione

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Brechbuhl, Heather M. [Pediatrics, National Jewish Health, Denver, Colorado (United States); Kachadourian, Remy; Min, Elysia [Department of Medicine, National Jewish Health, Denver, Colorado (United States); Chan, Daniel [Medical Oncology, University of Colorado Denver Health Sciences Center (United States); Day, Brian J., E-mail: dayb@njhealth.org [Department of Medicine, University of Colorado Denver Health Sciences Center (United States); Immunology, University of Colorado Denver Health Sciences Center (United States); Pharmaceutical Sciences, University of Colorado Denver Health Sciences Center (United States); Department of Medicine, National Jewish Health, Denver, Colorado (United States)

2012-01-01

We hypothesized that flavonoid-induced glutathione (GSH) efflux through multi-drug resistance proteins (MRPs) and subsequent intracellular GSH depletion is a viable mechanism to sensitize cancer cells to chemotherapies. This concept was demonstrated using chrysin (5–25 μM) induced GSH efflux in human non-small cell lung cancer lines exposed to the chemotherapeutic agent, doxorubicin (DOX). Treatment with chrysin resulted in significant and sustained intracellular GSH depletion and the GSH enzyme network in the four cancer cell types was predictive of the severity of chrysin induced intracellular GSH depletion. Gene expression data indicated a positive correlation between basal MRP1, MRP3 and MRP5 expression and total GSH efflux before and after chrysin exposure. Co-treating the cells for 72 h with chrysin (5–30 μM) and DOX (0.025–3.0 μM) significantly enhanced the sensitivity of the cells to DOX as compared to 72-hour DOX alone treatment in all four cell lines. The maximum decrease in the IC{sub 50} values of cells treated with DOX alone compared to co-treatment with chrysin and DOX was 43% in A549 cells, 47% in H157 and H1975 cells and 78% in H460 cells. Chrysin worked synergistically with DOX to induce cancer cell death. This approach could allow for use of lower concentrations and/or sensitize cancer cells to drugs that are typically resistant to therapy. -- Graphical abstract: Possible mechanisms by which chrysin enhances doxorubicin-induced toxicity in cancer cells. Highlights: ► Chyrsin sustains a significant depletion of GSH levels in lung cancer cells. ► Chyrsin synergistically potentiates doxorubicin-induced cancer cell cytotoxicity. ► Cancer cell sensitivity correlated with GSH and MRP gene network expression. ► This approach could allow for lower side effects and targeting resistant tumors.

Water deprivation induces appetite and alters metabolic strategy in Notomys alexis: unique mechanisms for water production in the desert.

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Takei, Yoshio; Bartolo, Ray C; Fujihara, Hiroaki; Ueta, Yoichi; Donald, John A

2012-07-07

Like many desert animals, the spinifex hopping mouse, Notomys alexis, can maintain water balance without drinking water. The role of the kidney in producing a small volume of highly concentrated urine has been well-documented, but little is known about the physiological mechanisms underpinning the metabolic production of water to offset obligatory water loss. In Notomys, we found that water deprivation (WD) induced a sustained high food intake that exceeded the pre-deprivation level, which was driven by parallel changes in plasma leptin and ghrelin and the expression of orexigenic and anorectic neuropeptide genes in the hypothalamus; these changed in a direction that would stimulate appetite. As the period of WD was prolonged, body fat disappeared but body mass increased gradually, which was attributed to hepatic glycogen storage. Switching metabolic strategy from lipids to carbohydrates would enhance metabolic water production per oxygen molecule, thus providing a mechanism to minimize respiratory water loss. The changes observed in appetite control and metabolic strategy in Notomys were absent or less prominent in laboratory mice. This study reveals novel mechanisms for appetite regulation and energy metabolism that could be essential for desert rodents to survive in xeric environments.

Glutathione and Mitochondria

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Vicent eRibas

2014-07-01

Full Text Available Glutathione (GSH is the main nonprotein thiol in cells whose functions are dependent on the redox-active thiol of its cysteine moiety that serves as a cofactor for a number of antioxidant and detoxifying enzymes. While synthesized exclusively in the cytosol from its constituent amino acids, GSH is distributed in different compartments, including mitochondria where its concentration in the matrix equals that of the cytosol. This feature and its negative charge at physiological pH imply the existence of specific carriers to import GSH from the cytosol to the mitochondrial matrix, where it plays a key role in defense against respiration-induced reactive oxygen species and in the detoxification of lipid hydroperoxides and electrophiles. Moreover, as mitochondria play a central strategic role in the activation and mode of cell death, mitochondrial GSH has been shown to critically regulate the level of sensitization to secondary hits that induce mitochondrial membrane permeabilization and release of proteins confined in the intermembrane space that once in the cytosol engage the molecular machinery of cell death. In this review, we summarize recent data on the regulation of mitochondrial GSH and its role in cell death and prevalent human diseases, such as cancer, fatty liver disease and Alzheimer’s disease.

Effects of sleep deprivation on retrieval and reconsolidation of morphine reward memory in rats.

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Shi, Hai-Shui; Luo, Yi-Xiao; Xue, Yan-Xue; Wu, Ping; Zhu, Wei-Li; Ding, Zeng-Bo; Lu, Lin

2011-04-01

Relapse induced by exposure to cues associated with drugs of abuse is a major challenge to the treatment of drug addiction. Drug seeking can be inhibited by manipulation of the reconsolidation of drug-related memory. Sleep has been proposed to be involved in various memory processes. However, the role of sleep in drug reward memory is not clear. The present study used conditioned place preference to examine the effects of total sleep deprivation on retrieval and reconsolidation of morphine reward memory in rats. Six-hour total sleep deprivation had no effect on the retrieval of morphine reward memory. However, sleep deprivation from 0-6 h, but not 6-12 h, after re-exposure disrupted the reconsolidation of morphine reward memory. This impairment was not attributable to the formation of an aversive associative memory between the drug-paired context and sleep deprivation. Our findings suggest that sleep plays a critical role in morphine reward memory reconsolidation, and sleep deprivation may be a potential non-pharmacotherapy for the management of relapse associated with drug-related memory. Copyright © 2011 Elsevier Inc. All rights reserved.

Delayed maturation and altered proliferation within the rat rostral migratory stream following maternal deprivation

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K. Lievajova

2011-10-01

Full Text Available The objective of this study was to investigate whether stressful experience during early postnatal period may influence morphological characteristics of the rat neurogenic pathway – the rostral migratory stream (RMS and proliferation of neuronal precursors in three successive areas of the RMS: in the vertical arm, the elbow and the horizontal arm. To induce stress, the pups were subjected to repeated maternal deprivation during the first postnatal week after birth. Brains were analyzed at the seventh postnatal day. The controls matched the age of maternally deprived animals. Observation of hematoxylin-eosin stained sections showed that maternal deprivation did not affect the general morphological appearance of the RMS. The shape of the RMS of maternally deprived rats resembles the RMS of control animals. Maternal deprivation caused slight, not significant increase in the RMS thickness in comparison with control rats. Significant difference between the control and maternally deprived rats concerns the olfactory ventricle. While in seven days old control rats the olfactory ventricle is completely closed, in maternally deprived rats of the same age the olfactory ventricle was regularly visible as a narrow lumen at the axis of the RMS horizontal arm. This finding indicates delayed maturation of the migratory pathway as a consequence of stress. Proliferation activity has been assessed by immunoreactivity of the endogenous cell cycle protein Ki-67. The results of Ki-67 immunohistochemistry showed that seven days’ maternal separation for 3 h daily induces significant quantitative changes in the number of proliferating cells within the RMS. The response of Ki-67-positive cells to stress differed in individual part of the RMS, with a marked decrease in the vertical arm and a significant increase in the elbow, suggesting heterogeneity of neural stem cells along the RMS; while in the RMS vertical arm the number of dividing cells significantly decreased

Sensitivity and validity of psychometric tests for assessing driving impairment: effects of sleep deprivation.

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Jongen, Stefan; Perrier, Joy; Vuurman, Eric F; Ramaekers, Johannes G; Vermeeren, Annemiek

2015-01-01

To assess drug induced driving impairment, initial screening is needed. However, no consensus has been reached about which initial screening tools have to be used. The present study aims to determine the ability of a battery of psychometric tests to detect performance impairing effects of clinically relevant levels of drowsiness as induced by one night of sleep deprivation. Twenty four healthy volunteers participated in a 2-period crossover study in which the highway driving test was conducted twice: once after normal sleep and once after one night of sleep deprivation. The psychometric tests were conducted on 4 occasions: once after normal sleep (at 11 am) and three times during a single night of sleep deprivation (at 1 am, 5 am, and 11 am). On-the-road driving performance was significantly impaired after sleep deprivation, as measured by an increase in Standard Deviation of Lateral Position (SDLP) of 3.1 cm compared to performance after a normal night of sleep. At 5 am, performance in most psychometric tests showed significant impairment. As expected, largest effect sizes were found on performance in the Psychomotor Vigilance Test (PVT). Large effects sizes were also found in the Divided Attention Test (DAT), the Attention Network Test (ANT), and the test for Useful Field of View (UFOV) at 5 and 11 am during sleep deprivation. Effects of sleep deprivation on SDLP correlated significantly with performance changes in the PVT and the DAT, but not with performance changes in the UFOV. From the psychometric tests used in this study, the PVT and DAT seem most promising for initial evaluation of drug impairment based on sensitivity and correlations with driving impairment. Further studies are needed to assess the sensitivity and validity of these psychometric tests after benchmark sedative drug use.

Sensitivity and validity of psychometric tests for assessing driving impairment: effects of sleep deprivation.

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Stefan Jongen

Full Text Available To assess drug induced driving impairment, initial screening is needed. However, no consensus has been reached about which initial screening tools have to be used. The present study aims to determine the ability of a battery of psychometric tests to detect performance impairing effects of clinically relevant levels of drowsiness as induced by one night of sleep deprivation.Twenty four healthy volunteers participated in a 2-period crossover study in which the highway driving test was conducted twice: once after normal sleep and once after one night of sleep deprivation. The psychometric tests were conducted on 4 occasions: once after normal sleep (at 11 am and three times during a single night of sleep deprivation (at 1 am, 5 am, and 11 am.On-the-road driving performance was significantly impaired after sleep deprivation, as measured by an increase in Standard Deviation of Lateral Position (SDLP of 3.1 cm compared to performance after a normal night of sleep. At 5 am, performance in most psychometric tests showed significant impairment. As expected, largest effect sizes were found on performance in the Psychomotor Vigilance Test (PVT. Large effects sizes were also found in the Divided Attention Test (DAT, the Attention Network Test (ANT, and the test for Useful Field of View (UFOV at 5 and 11 am during sleep deprivation. Effects of sleep deprivation on SDLP correlated significantly with performance changes in the PVT and the DAT, but not with performance changes in the UFOV.From the psychometric tests used in this study, the PVT and DAT seem most promising for initial evaluation of drug impairment based on sensitivity and correlations with driving impairment. Further studies are needed to assess the sensitivity and validity of these psychometric tests after benchmark sedative drug use.

OXIDATIVE MODIFICATION OF PROTEINS AND GLUTATHIONE SYSTEM IN ADIPOCYTES UNDER DIABETES

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Ye. V. Shakhristova

2014-01-01

Full Text Available Currently, diabetes ranks third in relation to medical and social significance after cardiovascular diseases and cancer and is the leading cause of blindness; it greatly increases the risk of myocardial infarction, coronary heart disease, nephropathy and hypertension in patients with this disorder; therefore clinical and experimental studies aimed at investigation of diabetes emergence and development mechanisms are urgent.The aim of the study was to investigate the status of oxidative modification of proteins and glutathionedependent antioxidant defense system in adipocytes of rats with alloxan diabetes under conditions of oxidative stress.Material and methods. Development of type 1 diabetes was induced in rats by alloxan administration (90 mg/kg of body mass. Adipocytes were obtained from epididymal adipose tissue of rats. The level of carbonyl derivatives of proteins, oxidized tryptophan, bityrosine, general, reduced, oxygenated and protein-bound glutathione, as well as glutathione peroxidase activity in adipocytes of rats was determined.Results. In adipocytes of rats with alloxan diabetes, concentration of carbonyl derivatives of proteins, bityrosine and oxidized tryptophan increased on the background of redox-potential of glutathione system and glutathione peroxidase activity decrease.Conclusion. The obtained data indicate the activation of free-radical oxidation of proteins and reduction of antioxidant defense under conditions of oxidative stress in the adipose tissue of rats with alloxan diabetes; this process plays an important role in pathogenesis of diabetes and its complications development.

Serum deprivation induces glucose response and intercellular coupling in human pancreatic adenocarcinoma PANC-1 cells.

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Hiram-Bab, Sahar; Shapira, Yuval; Gershengorn, Marvin C; Oron, Yoram

2012-03-01

This study aimed to investigate whether the previously described differentiating islet-like aggregates of human pancreatic adenocarcinoma cells (PANC-1) develop glucose response and exhibit intercellular communication. Fura 2-loaded PANC-1 cells in serum-free medium were assayed for changes in cytosolic free calcium ([Ca]i) induced by depolarization, tolbutamide inhibition of K(ATP) channels, or glucose. Dye transfer, assayed by confocal microscopy or by FACS, was used to detect intercellular communication. Changes in messenger RNA (mRNA) expression of genes of interest were assessed by quantitative real-time polymerase chain reaction. Proliferation was assayed by the MTT method. Serum-deprived PANC-1 cell aggregates developed [Ca]i response to KCl, tolbutamide, or glucose. These responses were accompanied by 5-fold increase in glucokinase mRNA level and, to a lesser extent, of mRNAs for K(ATP) and L-type calcium channels, as well as increase in mRNA levels of glucagon and somatostatin. Trypsin, a proteinase-activated receptor 2 agonist previously shown to enhance aggregation, modestly improved [Ca]i response to glucose. Glucose-induced coordinated [Ca]i oscillations and dye transfer demonstrated the emergence of intercellular communication. These findings suggest that PANC-1 cells, a pancreatic adenocarcinoma cell line, can be induced to express a differentiated phenotype in which cells exhibit response to glucose and form a functional syncytium similar to those observed in pancreatic islets.

Materialistic Cues Boosts Personal Relative Deprivation

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Hong Zhang

2016-08-01

Full Text Available Three studies investigated whether exposure to materialistic cues would increase perceptions of personal relative deprivation and related emotional reactions. In Study 1, individuals who were surveyed in front of a luxury store reported higher levels of personal relative deprivation than those surveyed in front of an ordinary building. In Study 2, participants who viewed pictures of luxurious goods experienced greater personal relative deprivation than those viewed pictures of neutral scenes. Study 3 replicated the results from Study 2, with a larger sample size and a more refined assessment of relative deprivation. Implications of these findings for future studies on relative deprivation and materialism are discussed.

Materialistic Cues Boosts Personal Relative Deprivation.

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Zhang, Hong; Zhang, Wen

2016-01-01

Three studies investigated whether exposure to materialistic cues would increase perceptions of personal relative deprivation and related emotional reactions. In Study 1, individuals who were surveyed in front of a luxury store reported higher levels of personal relative deprivation than those surveyed in front of an ordinary building. In Study 2, participants who viewed pictures of luxurious goods experienced greater personal relative deprivation than those viewed pictures of neutral scenes. Study 3 replicated the results from Study 2, with a larger sample size and a more refined assessment of relative deprivation. Implications of these findings for future studies on relative deprivation and materialism are discussed.

Characterization of glutathione transferases involved in the pathogenicity of Alternaria brassicicola.

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Calmes, Benoit; Morel-Rouhier, Mélanie; Bataillé-Simoneau, Nelly; Gelhaye, Eric; Guillemette, Thomas; Simoneau, Philippe

2015-06-18

Glutathione transferases (GSTs) represent an extended family of multifunctional proteins involved in detoxification processes and tolerance to oxidative stress. We thus anticipated that some GSTs could play an essential role in the protection of fungal necrotrophs against plant-derived toxic metabolites and reactive oxygen species that accumulate at the host-pathogen interface during infection. Mining the genome of the necrotrophic Brassica pathogen Alternaria brassicicola for glutathione transferase revealed 23 sequences, 17 of which could be clustered into the main classes previously defined for fungal GSTs and six were 'orphans'. Five isothiocyanate-inducible GSTs from five different classes were more thoroughly investigated. Analysis of their catalytic properties revealed that two GSTs, belonging to the GSTFuA and GTT1 classes, exhibited GSH transferase activity with isothiocyanates (ITC) and peroxidase activity with cumene hydroperoxide, respectively. Mutant deficient for these two GSTs were however neither more susceptible to ITC nor less aggressive than the wild-type parental strain. By contrast mutants deficient for two other GSTs, belonging to the Ure2pB and GSTO classes, were distinguished by their hyper-susceptibility to ITC and low aggressiveness against Brassica oleracea. In particular AbGSTO1 could participate in cell tolerance to ITC due to its glutathione-dependent thioltransferase activity. The fifth ITC-inducible GST belonged to the MAPEG class and although it was not possible to produce the soluble active form of this protein in a bacterial expression system, the corresponding deficient mutant failed to develop normal symptoms on host plant tissues. Among the five ITC-inducible GSTs analyzed in this study, three were found essential for full aggressiveness of A. brassicicola on host plant. This, to our knowledge is the first evidence that GSTs might be essential virulence factors for fungal necrotrophs.

Neurophysiological effects of sleep deprivation in healthy adults, a pilot study

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U.M.H. Klumpers (Ursula); D.J. Veltman (Dick); M.J.D. van Tol (Marie-José); R.W. Kloet (Reina); R. Boellaard (Ronald); Lammertsma, A.A. (Adriaan A.); W.J.G. Hoogendijk (Witte)

2015-01-01

textabstractTotal sleep deprivation (TSD) may induce fatigue, neurocognitive slowing and mood changes, which are partly compensated by stress regulating brain systems, resulting in altered dopamine and cortisol levels in order to stay awake if needed. These systems, however, have never been studied

Blood selenium concentrations and enzyme activities related to glutathione metabolism in wild emperor geese

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Franson, J. Christian; Hoffman, David J.; Schmutz, Joel A.

2002-01-01

In 1998, we collected blood samples from 63 emperor geese (Chen canagica) on their breeding grounds on the Yukon-Kuskokwim Delta (YKD) in western Alaska, USA. We studied the relationship between selenium concentrations in whole blood and the activities of glutathione peroxidase and glutathione reductase in plasma. Experimental studies have shown that plasma activities of these enzymes are useful biomarkers of selenium-induced oxidative stress, but little information is available on their relationship to selenium in the blood of wild birds. Adult female emperor geese incubating their eggs in mid-June had a higher mean concentration of selenium in their blood and a greater activity of glutathione peroxidase in their plasma than adult geese or goslings that were sampled during the adult flight feathermolting period in late July and early August. Glutathione peroxidase activity was positively correlated with the concentration of selenium in the blood of emperor geese, and the rate of increase relative to selenium was greater in goslings than in adults. The activity of glutathione reductase was greatest in the plasma of goslings and was greater in molting adults than incubating females but was not significantly correlated with selenium in the blood of adults or goslings. Incubating female emperor geese had high selenium concentrations in their blood, accompanied by increased glutathione peroxidase activity consistent with early oxidative stress. These findings indicate that further study of the effects of selenium exposure, particularly on reproductive success, is warranted in this species.

Wnt signaling in form deprivation myopia of the mice retina.

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Mingming Ma

Full Text Available BACKGROUND: The canonical Wnt signaling pathway plays important roles in cellular proliferation and differentiation, axonal outgrowth, cellular maintenance in retinas. Here we test the hypothesis that elements of the Wnt signaling pathway are involved in the regulation of eye growth and prevention of myopia, in the mouse form-deprivation myopia model. METHODOLOGY/PRINCIPAL FINDINGS: (1 One hundred twenty-five C57BL/6 mice were randomly distributed into form-deprivation myopia and control groups. Form-deprivation myopia (FDM was induced by suturing the right eyelid, while the control group received no treatment. After 1, 2, and 4 weeks of treatment, eyes were assessed in vivo by cycloplegic retinoscopic refraction and axial length measurement by photography or A-scan ultrasonography. Levels of retinal Wnt2b, Fzd5 and β-catenin mRNA and protein were evaluated using RT-PCR and western blotting, respectively. (2 Another 96 mice were divided into three groups: control, drugs-only, and drugs+FDM (by diffuser. Experimentally treated eyes in the last two groups received intravitreal injections of vehicle or the proteins, DKK-1 (Wnt-pathway antagonist or Norrin (Wnt-pathway agonist, once every three days, for 4 injections total. Axial length and retinoscopic refraction were measured on the 14th day of form deprivation. Following form-deprivation for 1, 2, and 4 weeks, FDM eyes had a relatively myopic refractive error, compared with contralateral eyes. There were no significant differences in refractive error between right and left eye in control group. The amounts of Wnt2b, Fzd5 and β-catenin mRNA and protein were significantly greater in form-deprived myopia eyes than in control eyes.DKK-1 (antagonist reduced the myopic shift in refractive error and increase in axial elongation, whereas Norrin had the opposite effect in FDM eyes. CONCLUSIONS/SIGNIFICANCE: Our studies provide the first evidence that the Wnt2b signaling pathway may play a role in the

Acute versus chronic partial sleep deprivation in middle-aged people: differential effect on performance and sleepiness.

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Philip, Pierre; Sagaspe, Patricia; Prague, Mélanie; Tassi, Patricia; Capelli, Aurore; Bioulac, Bernard; Commenges, Daniel; Taillard, Jacques

2012-07-01

To evaluate the effects of acute sleep deprivation and chronic sleep restriction on vigilance, performance, and self-perception of sleepiness. Habitual night followed by 1 night of total sleep loss (acute sleep deprivation) or 5 consecutive nights of 4 hr of sleep (chronic sleep restriction) and recovery night. Eighteen healthy middle-aged male participants (age [(± standard deviation] = 49.7 ± 2.6 yr, range 46-55 yr). Multiple sleep latency test trials, Karolinska Sleepiness Scale scores, simple reaction time test (lapses and 10% fastest reaction times), and nocturnal polysomnography data were recorded. Objective and subjective sleepiness increased immediately in response to sleep restriction. Sleep latencies after the second and third nights of sleep restriction reached levels equivalent to those observed after acute sleep deprivation, whereas Karolinska Sleepiness Scale scores did not reach these levels. Lapse occurrence increased after the second day of sleep restriction and reached levels equivalent to those observed after acute sleep deprivation. A statistical model revealed that sleepiness and lapses did not progressively worsen across days of sleep restriction. Ten percent fastest reaction times (i.e., optimal alertness) were not affected by acute or chronic sleep deprivation. Recovery to baseline levels of alertness and performance occurred after 8-hr recovery night. In middle-aged study participants, sleep restriction induced a high increase in sleep propensity but adaptation to chronic sleep restriction occurred beyond day 3 of restriction. This sleepiness attenuation was underestimated by the participants. One recovery night restores daytime sleepiness and cognitive performance deficits induced by acute or chronic sleep deprivation. Philip P; Sagaspe P; Prague M; Tassi P; Capelli A; Bioulac B; Commenges D; Taillard J. Acute versus chronic partial sleep deprivation in middle-aged people: differential effect on performance and sleepiness. SLEEP 2012;35(7):997-1002.

Combined Effect of food deprivation and serotonin injection on plasma prolactin and glucose levels in irradiated rats

International Nuclear Information System (INIS)

Girgis, R.B.; Abdel-Fattah, K.I.; Khamis, F.I.; Abu Zaid, N.M.

2004-01-01

The present study aims to investigate the role of serotonin (5-HT) on the homeostasis of plasma prolactin and glucose in rats induced by gamma irradiation and food deprivation. Animals were divided into seven groups; control, irradiated at a dose level of 6 Gy, injected with 500 mg/kg b.wt. 5-HT intra-peritoneally, injected with 5-HT before irradiation food deprived for 48 hrs then irradiated, food deprived then injected with 5-HT, and food deprived then injected with 5-HT before whole body irradiation. Samples were collected at 1,3, 7 and 14 days post irradiation. The results showed that gamma irradiation firstly elevated prolactin (PRL) levels in plasma (1 and 3 days) then the levels decreased after 7 and 14 days as compared to control values. Rats received serotonin before irradiation exhibited an increased level of PRL after 14 days post irradiation compared to control value, while the level decreased after 1, 3, 7 days post irradiation. Food deprivation for 48 hrs altered the effect of serotonin and /or irradiation on PRL levels in plasma. Rats injected with serotonin showed a decreased level of plasma prolactin in food deprived rats, 3 days post injection. The obtained results showed that serotonin causes variable effects on plasma prolactin compared to control values. Glucose plasma levels were increased in both irradiated and serotonin injected rats before irradiation, and also in serotonin injected rats as compared to control values. Irradiation of rats after 48 hrs food deprivation induced an increase in plasma glucose levels measured throughout the different experimental periods. Injection of serotonin to rats after 48 hrs food deprivation before irradiation increased plasma glucose levels after 1, 3, 7 and 14 days compared to control value. Also, injection of serotonin to 48 hrs food deprived rats increased glucose levels during all examined days of experiment.It could be concluded that serotonin may have a variable mechanism controlling prolactin

H2O2 mediates ALA-induced glutathione and ascorbate accumulation in the perception and resistance to oxidative stress in Solanum lycopersicum at low temperatures.

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Liu, Tao; Hu, Xiaohui; Zhang, Jiao; Zhang, Junheng; Du, Qingjie; Li, Jianming

2018-02-15

Low temperature is a crucial factor influencing plant growth and development. The chlorophyll precursor, 5-aminolevulinic acid (ALA) is widely used to improve plant cold tolerance. However, the interaction between H 2 O 2 and cellular redox signaling involved in ALA-induced resistance to low temperature stress in plants remains largely unknown. Here, the roles of ALA in perceiving and regulating low temperature-induced oxidative stress in tomato plants, together with the roles of H 2 O 2 and cellular redox states, were characterized. Low concentrations (10-25 mg·L - 1 ) of ALA enhanced low temperature-induced oxidative stress tolerance of tomato seedlings. The most effective concentration was 25 mg·L - 1 , which markedly increased the ratio of reduced glutathione and ascorbate (GSH and AsA), and enhanced the activities of superoxide dismutase, catalase, ascorbate peroxidase, dehydroascorbate reductase, and glutathione reductase. Furthermore, gene expression of respiratory burst oxidase homolog1 and H 2 O 2 content were upregulated with ALA treatment under normal conditions. Treatment with exogenous H 2 O 2 , GSH, and AsA also induced plant tolerance to oxidative stress at low temperatures, while inhibition of GSH and AsA syntheses significantly decreased H 2 O 2 -induced oxidative stress tolerance. Meanwhile, scavenging or inhibition of H 2 O 2 production weakened, but did not eliminate, GSH- or AsA- induced tomato plant tolerance to oxidative stress at low temperatures. Appropriate concentrations of ALA alleviated the low temperature-induced oxidative stress in tomato plants via an antioxidant system. The most effective concentration was 25 mg·L - 1 . The results showed that H 2 O 2 induced by exogenous ALA under normal conditions is crucial and may be the initial step for perception and signaling transmission, which then improves the ratio of GSH and AsA. GSH and AsA may then interact with H 2 O 2 signaling, resulting in enhanced antioxidant capacity

Naoxintong Protects Primary Neurons from Oxygen-Glucose Deprivation/Reoxygenation Induced Injury through PI3K-Akt Signaling Pathway

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Yan Ma

2016-01-01

Full Text Available Naoxintong capsule (NXT, developed from Buyang Huanwu Decoction, has shown the neuroprotective effects in cerebrovascular diseases, but the neuroprotection mechanisms of NXT on ischemia/reperfusion injured neurons have not yet been well known. In this study, we established the oxygen-glucose deprivation/reoxygenation (OGD/R induced neurons injury model and treat the neurons with cerebrospinal fluid containing NXT (BNC to investigate the effects of NXT on OGD/R induced neurons injury and potential mechanisms. BNC improved neuron viability and decreased apoptotic rate induced by OGD/R. BNC attenuated OGD/R induced cytosolic and mitochondrial Ca2+ overload, ROS generation, intracellular NO levels and nNOS mRNA increase, and cytochrome-c release when compared with OGD/R group. BNC significantly inhibited both mPTP opening and ΔΨm depolarization. BNC increased Bcl-2 expression and decreased Bax expression, upregulated the Bcl-2/Bax ratio, downregulated caspase-3 mRNA and caspase-9 mRNA expression, and decreased cleaved caspase-3 expression and caspase-3 activity. BNC increased phosphorylation of Akt following OGD/R, while LY294002 attenuated BNC induced increase of phosphorylated Akt expression. Our study demonstrated that NXT protected primary neurons from OGD/R induced injury by inhibiting calcium overload and ROS generation, protecting mitochondria, and inhibiting mitochondrial apoptotic pathway which was mediated partially by PI3K-Akt signaling pathway activation.

Recovery of neurofilament following early monocular deprivation

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Timothy P O'Leary

2012-04-01

Full Text Available A brief period of monocular deprivation in early postnatal life can alter the structure of neurons within deprived-eye-receiving layers of the dorsal lateral geniculate nucleus. The modification of structure is accompanied by a marked reduction in labeling for neurofilament, a protein that composes the stable cytoskeleton and that supports neuron structure. This study examined the extent of neurofilament recovery in monocularly deprived cats that either had their deprived eye opened (binocular recovery, or had the deprivation reversed to the fellow eye (reverse occlusion. The degree to which recovery was dependent on visually-driven activity was examined by placing monocularly deprived animals in complete darkness (dark rearing. The loss of neurofilament and the reduction of soma size caused by monocular deprivation were both ameliorated equally following either binocular recovery or reverse occlusion for 8 days. Though monocularly deprived animals placed in complete darkness showed recovery of soma size, there was a generalized loss of neurofilament labeling that extended to originally non-deprived layers. Overall, these results indicate that recovery of soma size is achieved by removal of the competitive disadvantage of the deprived eye, and occurred even in the absence of visually-driven activity. Recovery of neurofilament occurred when the competitive disadvantage of the deprived eye was removed, but unlike the recovery of soma size, was dependent upon visually-driven activity. The role of neurofilament in providing stable neural structure raises the intriguing possibility that dark rearing, which reduced overall neurofilament levels, could be used to reset the deprived visual system so as to make it more ameliorable with treatment by experiential manipulations.

Globular Adiponectin Inhibits the Apoptosis of Mesenchymal Stem Cells Induced by Hypoxia and Serum Deprivation via the AdipoR1-Mediated Pathway

OpenAIRE

Xia-Qiu Tian; Yue-Jin Yang; Qing Li; Pei-Sen Huang; Xiang-Dong Li; Chen Jin; Kang Qi; Lei-Pei Jiang; Gui-Hao Chen

2016-01-01

Background/Aims: Poor viability of transplanted mesenchymal stem cells (MSCs) within the ischemic heart limits their therapeutic potential for cardiac repair. Globular adiponectin (gAPN) exerts anti-apoptotic effects on several types of stem cells. Herein, we investigated the effect of gAPN on the MSCs against apoptosis induced by hypoxia and serum deprivation (H/SD). Methods: MSCs exposed to H/SD conditions were treated with different concentrations of gAPN. To identify the main type of rece...

The influence of sleep deprivation and obesity on DNA damage in female Zucker rats.

Science.gov (United States)

Tenorio, Neuli M; Ribeiro, Daniel A; Alvarenga, Tathiana A; Fracalossi, Ana Carolina C; Carlin, Viviane; Hirotsu, Camila; Tufik, Sergio; Andersen, Monica L

2013-01-01

The aim of this study was to evaluate overall genetic damage induced by total sleep deprivation in obese, female Zucker rats of differing ages. Lean and obese Zucker rats at 3, 6, and 15 months old were randomly distributed into two groups for each age group: home-cage control and sleep-deprived (N = 5/group). The sleep-deprived groups were deprived sleep by gentle handling for 6 hours, whereas the home-cage control group was allowed to remain undisturbed in their home-cage. At the end of the sleep deprivation period, or after an equivalent amount of time for the home-cage control groups, the rats were brought to an adjacent room and decapitated. The blood, brain, and liver tissue were collected and stored individually to evaluate DNA damage. Significant genetic damage was observed only in 15-month-old rats. Genetic damage was present in the liver cells from sleep-deprived obese rats compared with lean rats in the same condition. Sleep deprivation was associated with genetic damage in brain cells regardless of obesity status. DNA damage was observed in the peripheral blood cells regardless of sleep condition or obesity status. Taken together, these results suggest that obesity was associated with genetic damage in liver cells, whereas sleep deprivation was associated with DNA damage in brain cells. These results also indicate that there is no synergistic effect of these noxious conditions on the overall level of genetic damage. In addition, the level of DNA damage was significantly higher in 15-month-old rats compared to younger rats.

Neurophysiological Effects of Sleep Deprivation in Healthy Adults, a Pilot Study

NARCIS (Netherlands)

Klumpers, Ursula M. H.; Veltman, Dick J.; van Tol, Marie-Jose; Kloet, Reina W.; Boellaard, Ronald; Lammertsma, Adriaan A.; Hoogendijk, Witte J. G.

2015-01-01

Total sleep deprivation (TSD) may induce fatigue, neurocognitive slowing and mood changes, which are partly compensated by stress regulating brain systems, resulting in altered dopamine and cortisol levels in order to stay awake if needed. These systems, however, have never been studied in concert.

Oxidative-stress detoxification and signalling in cyanobacteria: the crucial glutathione synthesis pathway supports the production of ergothioneine and ophthalmate.

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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.

Effects of Combined Low Glutathione with Mild Oxidative and Low Phosphorus Stress on the Metabolism of Arabidopsis thaliana

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Atsushi Fukushima

2017-08-01

Full Text Available Plants possess highly sensitive mechanisms that monitor environmental stress levels for a dose-dependent fine-tuning of their growth and development. Differences in plant responses to severe and mild abiotic stresses have been recognized. Although many studies have revealed that glutathione can contribute to plant tolerance to various environmental stresses, little is known about the relationship between glutathione and mild abiotic stress, especially the effect of stress-induced altered glutathione levels on the metabolism. Here, we applied a systems biology approach to identify key pathways involved in the gene-to-metabolite networks perturbed by low glutathione content under mild abiotic stress in Arabidopsis thaliana. We used glutathione synthesis mutants (cad2-1 and pad2-1 and plants overexpressing the gene encoding γ-glutamylcysteine synthetase, the first enzyme of the glutathione biosynthetic pathway. The plants were exposed to two mild stress conditions—oxidative stress elicited by methyl viologen and stress induced by the limited availability of phosphate. We observed that the mutants and transgenic plants showed similar shoot growth as that of the wild-type plants under mild abiotic stress. We then selected the synthesis mutants and performed multi-platform metabolomics and microarray experiments to evaluate the possible effects on the overall metabolome and the transcriptome. As a common oxidative stress response, several flavonoids that we assessed showed overaccumulation, whereas the mild phosphate stress resulted in increased levels of specific kaempferol- and quercetin-glycosides. Remarkably, in addition to a significant increased level of sugar, osmolytes, and lipids as mild oxidative stress-responsive metabolites, short-chain aliphatic glucosinolates over-accumulated in the mutants, whereas the level of long-chain aliphatic glucosinolates and specific lipids decreased. Coordinated gene expressions related to glucosinolate and

Comparison of plasma malondialdehyde, glutathione, glutathione peroxidase, hydroxyproline and selenium levels in patients with vitiligo and healthy controls

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Ozturk I

2008-01-01

Full Text Available Background: The etiology and pathophysiologic mechanism of vitiligo are still unclear. The relationship between increased oxidative stress due to the accumulation of radicals and reactive oxygen species and the associated changes in blood and epidermal component of vitiliginous skin have been reported many times. We investigated the possible changes of plasma malondialdehyde, glutathione, selenium, hydroxyproline and glutathione peroxidase activity levels in patients with vitiligo in order to evaluate the relationship between oxidative stress and etiopathogenesis of vitiligo. Materials and Methods: Plasma malondialdehyde, glutathione, hydroxyproline and glutathione peroxidase activity levels were measured by spectrophotometric methods, and HPLC was used for measurement of selenium concentrations. Results: Our results showed increased malondialdehyde, hydroxyproline and glutathione peroxidase activity levels in plasma of vitiligo group ( P < 0.05. Conclusion: Support of antioxidant system via nonenzymatic antioxidant compounds and antioxidant enzymes may be useful to prevent of melanocyte degeneration which occur due to oxidative damage in vitiligo.

Superoxide dismutase/catalase mimetics but not MAP kinase inhibitors are neuroprotective against oxygen/glucose deprivation-induced neuronal death in hippocampus.

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Zhou, Miou; Dominguez, Reymundo; Baudry, Michel

2007-12-01

Although oxygen/glucose deprivation (OGD) has been widely used as a model of ischemic brain damage, the mechanisms underlying acute neuronal death in this model are not yet well understood. We used OGD in acute hippocampal slices to investigate the roles of reactive oxygen species and of the mitogen-activated protein kinases (MAPKs) in neuronal death. In particular, we tested the neuroprotective effects of two synthetic superoxide dismutase/catalase mimetics, EUK-189 and EUK-207. Acute hippocampal slices prepared from 2-month-old or postnatal day 10 rats were exposed to oxygen and glucose deprivation for 2 h followed by 2.5 h reoxygenation. Lactate dehydrogenase (LDH) release in the medium and propidium iodide (PI) uptake were used to evaluate cell viability. EUK-189 or EUK-207 applied during the OGD and reoxygenation periods decreased LDH release and PI uptake in slices from 2-month-old rats. EUK-189 or EUK-207 also partly blocked OGD-induced ATP depletion and extracellular signal-regulated kinases 1 and 2 (ERK1/2) dephosphorylation, and completely eliminated reactive oxygen species generation. The MEK inhibitor U0126 applied together with EUK-189 or EUK-207 completely blocked ERK1/2 activation, but had no effect on their protective effects against OGD-induced LDH release. U0126 alone had no effect on OGD-induced LDH release. EUK-207 had no effect on OGD-induced p38 or c-Jun N-terminal kinase dephosphorylation, and when the p38 inhibitor SB203580 was applied together with EUK-207, it had no effect on the protective effects of EUK-207. SB203580 alone had no effect on OGD-induced LDH release either. In slices from p10 rats, OGD also induced high-LDH release that was partly reversed by EUK-207; however, neither OGD nor EUK-207 produced significant changes in ERK1/2 and p38 phosphorylation. OGD-induced spectrin degradation was not modified by EUK-189 or EUK-207 in slices from p10 or 2-month-old rats, suggesting that their protective effects was not mediated through

Sleep deprivation increases blood pressure in healthy normotensive elderly and attenuates the blood pressure response to orthostatic challenge.

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Robillard, Rébecca; Lanfranchi, Paola A; Prince, François; Filipini, Daniel; Carrier, Julie

2011-03-01

To determine how aging affects the impact of sleep deprivation on blood pressure at rest and under orthostatic challenge. Subjects underwent a night of sleep and 24.5 h of sleep deprivation in a crossover counterbalanced design. Sleep laboratory. Sixteen healthy normotensive men and women: 8 young adults (mean 24 years [SD 3.1], range 20-28 years) and 8 elderly adults (mean 64.1 years [SD 3.4], range 60-69 years). Sleep deprivation. Brachial cuff arterial blood pressure and heart rate were measured in semi-recumbent and upright positions. These measurements were compared across homeostatic sleep pressure conditions and age groups. Sleep deprivation induced a significant increase in systolic and diastolic blood pressure in elderly but not young adults. Moreover, sleep deprivation attenuated the systolic blood pressure orthostatic response in both age groups. Our results suggest that sleep deprivation alters the regulatory mechanisms of blood pressure and might increase the risk of hypertension in healthy normotensive elderly.

Effects of cisplatin on lipid peroxidation and the glutathione redox status in the liver of male rats: The protective role of selenium

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Trbojević Ivana S.

2010-01-01

Full Text Available The role of oxidative stress in cisplatin (CP toxicity and its prevention by pretreatment with selenium (Se was investigated. Male Wistar albino rats were injected with a single dose of cisplatin (7.5 mg CP/kg b.m., i.p. and selenium (6 mg Se/kg b.m, as Na2SeO3, i.p. alone or in combination. The results suggest that CP intoxication induces oxidative stress and alters the glutathione redox status: reduced glutathione (GSH, oxidized glutathione (GSSG and the GSH/GSSG ratio (GSH RI, resulting in increased lipid peroxidation (LPO in rat liver. The pretreatment with selenium prior to CP treatment showed a protective effect against the toxic influence of CP on peroxidation of the membrane lipids and an altering of the glutathione redox status in the liver of rats. From our results we conclude that selenium functions as a potent antioxidant and suggest that it can control CP-induced hepatotoxicity in rats.

Low levels of glutathione are sufficient for survival of keratinocytes after UV irradiation and for healing of mouse skin wounds.

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Telorack, Michèle; Abplanalp, Jeannette; Werner, Sabine

2016-08-01

Reduced levels of the cellular antioxidant glutathione are associated with premature skin aging, cancer and impaired wound healing, but the in vivo functions of glutathione in the skin remain largely unknown. Therefore, we analyzed mice lacking the modifier subunit of the glutamate cysteine ligase (Gclm), the enzyme that catalyzes the rate-limiting step of glutathione biosynthesis. Glutathione levels in the skin of these mice were reduced by 70 %. However, neither skin development and homeostasis, nor UVA- or UVB-induced apoptosis in the epidermis were affected. Histomorphometric analysis of excisional wounds did not reveal wound healing abnormalities in young Gclm-deficient mice, while the area of hyperproliferative epithelium as well as keratinocyte proliferation were affected in aged mice. These findings suggest that low levels of glutathione are sufficient for wound repair in young mice, but become rate-limiting upon aging.

Protective effects of exercise training on endothelial dysfunction induced by total sleep deprivation in healthy subjects.

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Sauvet, Fabien; Arnal, Pierrick J; Tardo-Dino, Pierre Emmanuel; Drogou, Catherine; Van Beers, Pascal; Bougard, Clément; Rabat, Arnaud; Dispersyn, Garance; Malgoyre, Alexandra; Leger, Damien; Gomez-Merino, Danielle; Chennaoui, Mounir

2017-04-01

Sleep loss is a risk factor for cardiovascular events mediated through endothelial dysfunction. To determine if 7weeks of exercise training can limit cardiovascular dysfunction induced by total sleep deprivation (TSD) in healthy young men. 16 subjects were examined during 40-h TSD, both before and after 7weeks of interval exercise training. Vasodilatation induced by ACh, insulin and heat (42°C) and pulse wave velocity (PWV), blood pressure and heart rate (HR) were assessed before TSD (controlday), during TSD, and after one night of sleep recovery. Biomarkers of endothelial activation, inflammation, and hormones were measured from morning blood samples. Before training, ACh-, insulin- and heat-induced vasodilatations were significantly decreased during TSD and recovery as compared with the control day, with no difference after training. Training prevented the decrease of ACh-induced vasodilation related to TSD after sleep recovery, as well as the PWV increase after TSD. A global lowering effect of training was found on HR values during TSD, but not on blood pressure. Training induces the decrease of TNF-α concentration after TSD and prevents the increase of MCP-1 after sleep recovery. Before training, IL-6 concentrations increased. Cortisol and testosterone decreased after TSD as compared with the control day, while insulin and E-selectin increased after sleep recovery. No effect of TSD or training was found on CRP and sICAM-1. In healthy young men, a moderate to high-intensity interval training is effective at improving aerobic fitness and limiting vascular dysfunction induced by TSD, possibly through pro-inflammatory cytokine responses.(ClinicalTrial:NCT02820649). Copyright © 2017 Elsevier B.V. All rights reserved.

Is Entrepreneurship a Route Out of Deprivation?

DEFF Research Database (Denmark)

Frankish, Julian S.; Roberts, Richard G.; Coad, Alexander Jean-Luc

2014-01-01

Frankish J. S., Roberts R. G., Coad A. and Storey D. J. Is entrepreneurship a route out of deprivation?, Regional Studies. This paper investigates whether entrepreneurship constitutes a route out of deprivation for those living in deprived areas. The measure of income/wealth used is based...... the wealth distribution. Hence, entrepreneurship can be a route out of deprivation....

Garlic protects the glutathione redox cycle in irradiated rats

International Nuclear Information System (INIS)

Abu-Ghadeer, A.R.M.; Osman, S.A.A.; Abbady, M.M.

1999-01-01

The aim of the present study is to evaluate the possible radioprotective role of garlic oil on the glutathione redox cycle (GSH, GSH-Px, GR and G6-PD) in blood and tissues (liver, spleen and intestine) of irradiated rats. Garlic oil was orally administered to rats (100 mg/Kg- b.w.) for 7 days before exposure to a fractionated of whole body gamma irradiation up to 9 Gy (3 Gy X 3 at 2 days intervals) and during the whole period of irradiation. The data showed that radiation exposure caused significant inhibition of the biochemical parameters in blood and tissue of irradiated rats all over the investigation periods (3,7 and 15 days). Garlic oil ameliorated the decrease in the tested parameters with noticeable effect on the 15 Th. day after radiation exposure. It is concluded that garlic oil could control the radiation induced changes in the glutathione redox cycle and provided some radioprotective effect

Near infrared radiation rescues mitochondrial dysfunction in cortical neurons after oxygen-glucose deprivation.

Science.gov (United States)

Yu, Zhanyang; Liu, Ning; Zhao, Jianhua; Li, Yadan; McCarthy, Thomas J; Tedford, Clark E; Lo, Eng H; Wang, Xiaoying

2015-04-01

Near infrared radiation (NIR) is known to penetrate and affect biological systems in multiple ways. Recently, a series of experimental studies suggested that low intensity NIR may protect neuronal cells against a wide range of insults that mimic diseases such as stroke, brain trauma and neurodegeneration. However, the potential molecular mechanisms of neuroprotection with NIR remain poorly defined. In this study, we tested the hypothesis that low intensity NIR may attenuate hypoxia/ischemia-induced mitochondrial dysfunction in neurons. Primary cortical mouse neuronal cultures were subjected to 4 h oxygen-glucose deprivation followed by reoxygenation for 2 h, neurons were then treated with a 2 min exposure to 810-nm NIR. Mitochondrial function markers including MTT reduction and mitochondria membrane potential were measured at 2 h after treatment. Neurotoxicity was quantified 20 h later. Our results showed that 4 h oxygen-glucose deprivation plus 20 h reoxygenation caused 33.8 ± 3.4 % of neuron death, while NIR exposure significantly reduced neuronal death to 23.6 ± 2.9 %. MTT reduction rate was reduced to 75.9 ± 2.7 % by oxygen-glucose deprivation compared to normoxic controls, but NIR exposure significantly rescued MTT reduction to 87.6 ± 4.5 %. Furthermore, after oxygen-glucose deprivation, mitochondria membrane potential was reduced to 48.9 ± 4.39 % of normoxic control, while NIR exposure significantly ameliorated this reduction to 89.6 ± 13.9 % of normoxic control. Finally, NIR significantly rescued OGD-induced ATP production decline at 20 min after NIR. These findings suggest that low intensity NIR can protect neurons against oxygen-glucose deprivation by rescuing mitochondrial function and restoring neuronal energetics.

The role of thiols in cellular response to radiation and drugs

International Nuclear Information System (INIS)

Biaglow, J.E.; Varnes, M.E.; Clark, E.P.; Epp, E.R.

1983-01-01

Cellular nonprotein thiols (NPSH) consist of glutathione (GSH) and other low molecular weight species such as cysteine, cysteamine, and coenzyme A. GSH is usually less than the total cellular NPSH, and with thiol reactive agents, such as diethyl maleate (DEM), its rate of depletion is in part dependent upon the cellular capacity for its resynthesis. If resynthesis is blocked by buthionine-S,R-sulfoximine(BSO), the NPSH, including GSH, is depleted more rapidly, Cellular thiol depletion by diamide, N-ethylmaleimide, and BSO may render oxygenated cells more sensitive to radiation. These cells may or may not show a reduction in the oxygen enhancement ratio (OER). Human A549 lung carcinoma cells depleted of their NPSH either by prolonged culture or by BSO treatment do not show a reduced OER but do show increased aerobic responses to radiation. Some nitroheterocyclic radiosensitizing drugs also deplete cellular thiols under aerobic conditions. Such reactivity may be the reason that they show anomalous radiation sensitization (i.e., better than predicted on the basis of electron affinity). Other nitrocompounds, such as misonidazole, are activated under hypoxic conditions to radical intermediates. When cellular thiols are depleted peroxide is formed. Under hypoxic conditions thiols are depleted because metabolically reduced intermediates react with GSH instead of oxygen. Thiol depletion, under hypoxic conditions, may be the reason that misonidazole and other nitrocompounds show an extra enhancement ratio with hypoxic cells. Thiol depletion by DEM or BSO alters the radiation response of hypoxic cells to misonidazole

Role of thiols in cellular response to radiation and drugs. Symposium: thiols

International Nuclear Information System (INIS)

Biaglow, J.E.; Varnes, M.E.; Clark, E.P.; Epp, E.R.

1983-01-01

Cellular nonprotein thiols (NPSH) consist of glutathione (GSH) and other low molecular weight species such as cysteine, cysteamine, and coenzyme. A GSH is usually less than the total cellular NPSH, and with thiol reactive agents, such as diethyl maleate (DEM), its rate of depletion is in part dependent upon the cellular capacity for its resynthesis. If resynthesis is blocked by buthionine-S,R-sulfoximine(BSO), the NPSH, including GSH, is depleted more rapidly, Cellular thiol depletion by diamide, N-ethylmaleimide, and BSO may render oxygenated cells more sensitive to radiation. These cells may or may not show a reduction in the oxygen enhancement ratio (OER). Human A549 lung carcinoma cells depleted of their NPSH either by prolonged culture or by BSO treatment do not show a reduced OER but do show increased aerobic responses to radiation. Other nitrocompounds, such as misonidazole, are activated under hypoxic conditions to radical intermediates. When cellular thiols are depleted peroxide is formed. Under hypoxic conditions thiols are depleted because metabolically reduced intermediates react with GSH instead of oxygen. Thiol depletion, under hypoxic conditions, may be the reason that misonidazole and other nitrocompounds show an extra enhancement ratio with hypoxic cells. Thiol depletion by DEM or BSO alters the radiation response of hypoxic cells to misonidazole. In conclusion, we propose an altered thiol model which includes a mechanism for thiol involvement in the aerobic radiation response of cells

Glutathione content in sperm cells of infertile men

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R. V. Fafula

2017-04-01

Full Text Available Hyperproduction of reactive oxygen species can damage sperm cells and is considered to be one of the mechanisms of male infertility. Cell protection from the damaging effects of free radicals and lipid peroxidation products is generally determined by the degree of antioxidant protection. Glutathione is non-enzymatic antioxidant which plays an important protective role against oxidative damages and lipid peroxidation. The aim of the present work is to determine the content of reduced and oxidized glutathione in sperm cells of infertile men. Semen samples from 20 fertile men (normozoospermics and 72 infertile patients (12 oligozoospermics, 17 asthenozoospermics, 10 oligoasthenozoosper­mics and 33 leucocytospermic were used. The total, oxidized (GSSG and reduced (GSH glutathione levels were measured spectrophotometrically. The levels of total glutathione were significantly lower in the spermatozoa of patients with oligozoo-, asthenozoo- and oligoasthenozoospermia than in the control. Infertile groups showed significantly decreased values of reduced glutathione in sperm cells vs. fertile men, indicating an alteration of oxidative status. The oxidized glutathione levels in sperm cells of infertile men did not differ from those of normozoospermic men with proven fertility. The GSH/GSSG ratio was significantly decreased in the oligo-, astheno- and oligoasthenozoospermic groups compared to the normozoospermic group. In patients with leucocytospermia the GSH/GSSG ratio was lower but these changes were not significant. In addition, glutathione peroxidase activity in sperm cells was decreased in patients with oligozoo-, astenozoo-, oligoastenozoospermia and with leucocytospermia. The most significant changes in glutathione peroxidase activity were observed in infertile men with leucocytospermia. Decreased GSH/GSSG ratio indicates a decline in redox-potential of the glutathione system in sperm cells of men with decreased fertilizing potential

Arsenite enhances tumor necrosis factor-α-induced expression of vascular cell adhesion molecule-1

International Nuclear Information System (INIS)

Tsou, T.-C.; Yeh, Szu Ching; Tsai, E.-M.; Tsai, F.-Y.; Chao, H.-R.; Chang, Louis W.

2005-01-01

Epidemiological studies demonstrated a high association of vascular diseases with arsenite exposure. We hypothesize that arsenite potentiates the effect of proinflammatory cytokines on vascular endothelial cells, and hence contributes to atherosclerosis. In this study, we investigated the effect of arsenite and its induction of glutathione (GSH) on vascular cell adhesion molecule-1 (VCAM-1) protein expression in human umbilical vein endothelial cells (HUVECs) in response to tumor necrosis factor-α (TNF-α), a typical proinflammatory cytokine. Our study demonstrated that arsenite pretreatment potentiated the TNF-α-induced VCAM-1 expression with up-regulations of both activator protein-1 (AP-1) and nuclear factor-κB (NF-κB). To elucidate the role of GSH in regulation of AP-1, NF-κB, and VCAM-1 expression, we employed L-buthionine (S,R)-sulfoximine (BSO), a specific γ-glutamylcysteine synthetase (γ-GCS) inhibitor, to block intracellular GSH synthesis. Our investigation revealed that, by depleting GSH, arsenite attenuated the TNF-α-induced VCAM-1 expression as well as a potentiation of AP-1 and an attenuation of NF-κB activations by TNF-α. Moreover, we found that depletion of GSH would also attenuate the TNF-α-induced VCAM-1 expression with a down-regulation of the TNF-α-induced NF-κB activation and without significant effect on AP-1. On the other hand, the TNF-α-induced VCAM-1 expression could be completely abolished by inhibition of AP-1 or NF-κB activity, suggesting that activation of both AP-1 and NF-κB was necessary for VCAM-1 expression. In summary, we demonstrate that arsenite enhances the TNF-α-induced VCAM-1 expression in HUVECs via regulation of AP-1 and NF-κB activities in a GSH-sensitive manner. Our present study suggested a potential mechanism for arsenite in the induction of vascular inflammation and vascular diseases via modulating the actions of proinflammatory cytokines

Changes in glutathione system and lipid peroxidation in rat blood during the first hour after chlorpyrifos exposure

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V. P. Rosalovsky

2015-10-01

Full Text Available Chlorpyrifos (CPF is a highly toxic organophosphate compound, widely used as an active substance of many insecticides. Along with the anticholinesterase action, CPF may affect other biochemical mechanisms, particularly through disrupting pro- and antioxidant balance and inducing free-radical oxidative stress. Origins and occurrence of these phenomena are still not fully understood. The aim of our work was to investigate the effects of chlorpyrifos on key parameters of glutathione system and on lipid peroxidation in rat blood in the time dynamics during one hour after exposure. We found that a single exposure to 50 mg/kg chlorpyrifos caused a linear decrease in butyryl cholinesterase activity, increased activity of glutathione peroxidase and glutathione reductase, alterations in the levels of glutathione, TBA-active products and lipid hydroperoxides during 1 hour after poisoning. The most significant changes in studied parameters were detected at the 15-30th minutes after chlorpyrifos exposure.

Profiling the transcriptome of Gracilaria changii (Rhodophyta) in response to light deprivation.

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Ho, Chai-Ling; Teoh, Seddon; Teo, Swee-Sen; Rahim, Raha Abdul; Phang, Siew-Moi

2009-01-01

Light regulates photosynthesis, growth and reproduction, yield and properties of phycocolloids, and starch contents in seaweeds. Despite its importance as an environmental cue that regulates many developmental, physiological, and biochemical processes, the network of genes involved during light deprivation are obscure. In this study, we profiled the transcriptome of Gracilaria changii at two different irradiance levels using a cDNA microarray containing more than 3,000 cDNA probes. Microarray analysis revealed that 93 and 105 genes were up- and down-regulated more than 3-fold under light deprivation, respectively. However, only 50% of the transcripts have significant matches to the nonredundant peptide sequences in the database. The transcripts that accumulated under light deprivation include vanadium chloroperoxidase, thioredoxin, ferredoxin component, and reduced nicotinamide adenine dinucleotide dehydrogenase. Among the genes that were down-regulated under light deprivation were genes encoding light harvesting protein, light harvesting complex I, phycobilisome 7.8 kDa linker polypeptide, low molecular weight early light-inducible protein, and vanadium bromoperoxidase. Our findings also provided important clues to the functions of many unknown sequences that could not be annotated using sequence comparison.

Intracellular Glutathione Depletion by Oridonin Leads to Apoptosis in Hepatic Stellate Cells

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Liang-Mou Kuo

2014-03-01

Full Text Available Proliferation of hepatic stellate cells (HSCs plays a key role in the pathogenesis of liver fibrosis. Induction of HSC apoptosis by natural products is considered an effective strategy for treating liver fibrosis. Herein, the apoptotic effects of 7,20-epoxy-ent-kaurane (oridonin, a diterpenoid isolated from Rabdosia rubescens, and its underlying mechanisms were investigated in rat HSC cell line, HSC-T6. We found that oridonin inhibited cell viability of HSC-T6 in a concentration-dependent manner. Oridonin induced a reduction in mitochondrial membrane potential and increases in caspase 3 activation, subG1 phase, and DNA fragmentation. These apoptotic effects of oridonin were completely reversed by thiol antioxidants, N-acetylcysteine (NAC and glutathione monoethyl ester. Moreover, oridonin increased production of reactive oxygen species (ROS, which was also inhibited by NAC. Significantly, oridonin reduced intracellular glutathione (GSH level in a concentration- and time-dependent fashion. Additionally, oridonin induced phosphorylations of extracellular signal-regulated kinase (ERK, c-Jun N-terminal kinase (JNK, and p38 mitogen-activated protein kinase (MAPK. NAC prevented the activation of MAPKs in oridonin-induced cells. However, selective inhibitors of MAPKs failed to alter oridonin-induced cell death. In summary, these results demonstrate that induction of apoptosis in HSC-T6 by oridonin is associated with a decrease in cellular GSH level and increase in ROS production.

Sleep deprivation suppresses aggression in Drosophila

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Kayser, Matthew S; Mainwaring, Benjamin; Yue, Zhifeng; Sehgal, Amita

2015-01-01

Sleep disturbances negatively impact numerous functions and have been linked to aggression and violence. However, a clear effect of sleep deprivation on aggressive behaviors remains unclear. We find that acute sleep deprivation profoundly suppresses aggressive behaviors in the fruit fly, while other social behaviors are unaffected. This suppression is recovered following post-deprivation sleep rebound, and occurs regardless of the approach to achieve sleep loss. Genetic and pharmacologic approaches suggest octopamine signaling transmits changes in aggression upon sleep deprivation, and reduced aggression places sleep-deprived flies at a competitive disadvantage for obtaining a reproductive partner. These findings demonstrate an interaction between two phylogenetically conserved behaviors, and suggest that previous sleep experiences strongly modulate aggression with consequences for reproductive fitness. DOI: http://dx.doi.org/10.7554/eLife.07643.001 PMID:26216041

Efficacy of Jian'ganle () versus Hugan Pian (), glucuronolactone and reduced glutathione in prevention of antituberculosis drug-induced liver injury.

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Zhang, Quan; Zhong, Fang-ying; Wu, Meng; Zhang, Xin-ping

2014-06-01

Evidence-based medicine is advocated by WHO and adopted by developed countries for many years. In China, however, the selection of essential medicine and various medical insurance reimbursement schemes medicine is usually based on experts' experience of prescription practice which is under heavy critics resulting from the lack of related comparative efficacy and evidence-based research. The efficacy of Jian'ganle in prevention of drug-induced liver injury (DILI) caused by antituberculotics was evaluated in this study by comparison with Hugan Pian, glucuronolactone and reduced glutathione. Evidence was provided for relevant sectors such as Ministry for Human Resources and Social Security of the People's Republic of China and National Health and Family Planning Commission of the People's Republic of China to select and renew the Essential Medicine List (EML), the new rural cooperative medical scheme in China (NRCMS) list or the reimbursement list of industrial injury insurance. A total of 189 patients with initial pulmonary tuberculosis were divided into four groups who took antituberculotics combined with Jian'ganle, Hugan Pian, glucuronolactone and reduced glutathione respectively. Their liver function profile including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), total protein (TP), albumin (A) and globulin (G) were detected at admission as baseline and after treatment. The Jian'ganle group was compared with the three others by chi-square tests. In an aspect of maintaining bilirubin indexes normal, Jian'ganle was more efficacious than glucuronolactone. And Jian'ganle had a little more efficacy than reduced glutathione to maintain protein indexes normal as well. And the therapeutic regimen of antituberculotics combined with Jian'ganle was the best in treating tuberculosis and preventing DILI at the same time. The study showed that among the four hepatinicas which demonstrated similar prevention

Microsomal Glutathione Transferase 1 Protects Against Toxicity Induced by Silica Nanoparticles but Not by Zinc Oxide Nanoparticles

Science.gov (United States)

2012-01-01

Microsomal glutathione transferase 1 (MGST1) is an antioxidant enzyme located predominantly in the mitochondrial outer membrane and endoplasmic reticulum and has been shown to protect cells from lipid peroxidation induced by a variety of cytostatic drugs and pro-oxidant stimuli. We hypothesized that MGST1 may also protect against nanomaterial-induced cytotoxicity through a specific effect on lipid peroxidation. We evaluated the induction of cytotoxicity and oxidative stress by TiO2, CeO2, SiO2, and ZnO in the human MCF-7 cell line with or without overexpression of MGST1. SiO2 and ZnO nanoparticles caused dose- and time-dependent toxicity, whereas no obvious cytotoxic effects were induced by nanoparticles of TiO2 and CeO2. We also noted pronounced cytotoxicity for three out of four additional SiO2 nanoparticles tested. Overexpression of MGST1 reversed the cytotoxicity of the main SiO2 nanoparticles tested and for one of the supplementary SiO2 nanoparticles but did not protect cells against ZnO-induced cytotoxic effects. The data point toward a role of lipid peroxidation in SiO2 nanoparticle-induced cell death. For ZnO nanoparticles, rapid dissolution was observed, and the subsequent interaction of Zn2+ with cellular targets is likely to contribute to the cytotoxic effects. A direct inhibition of MGST1 by Zn2+ could provide a possible explanation for the lack of protection against ZnO nanoparticles in this model. Our data also showed that SiO2 nanoparticle-induced cytotoxicity is mitigated in the presence of serum, potentially through masking of reactive surface groups by serum proteins, whereas ZnO nanoparticles were cytotoxic both in the presence and in the absence of serum. PMID:22303956

Functional and structural changes in internal pudendal arteries underlie erectile dysfunction induced by androgen deprivation

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Rhéure Alves-Lopes

2017-01-01

Full Text Available Androgen deficiency is strongly associated with erectile dysfunction (ED. Inadequate penile arterial blood flow is one of the major causes of ED. The blood flow to the corpus cavernosum is mainly derived from the internal pudendal arteries (IPAs; however, no study has evaluated the effects of androgen deprivation on IPA′s function. We hypothesized that castration impairs IPAs reactivity and structure, contributing to ED. In our study, Wistar male rats, 8-week-old, were castrated and studied 30 days after orchiectomy. Functional and structural properties of rat IPAs were determined using wire and pressure myograph systems, respectively. Protein expression was determined by Western blot and immunohistochemistry. Plasma testosterone levels were determined using the IMMULITE 1000 Immunoassay System. Castrated rats exhibited impaired erectile function, represented by decreased intracavernosal pressure/mean arterial pressure ratio. IPAs from castrated rats exhibited decreased phenylephrine- and electrical field stimulation (EFS-induced contraction and decreased acetylcholine- and EFS-induced vasodilatation. IPAs from castrated rats exhibited decreased internal diameter, external diameter, thickness of the arterial wall, and cross-sectional area. Castration decreased nNOS and α-actin expression and increased collagen expression, p38 (Thr180/Tyr182 phosphorylation, as well as caspase 3 cleavage. In conclusion, androgen deficiency is associated with impairment of IPA reactivity and structure and increased apoptosis signaling markers. Our findings suggest that androgen deficiency-induced vascular dysfunction is an event involving hypotrophic vascular remodeling of IPAs.

Activity-Based Probes for Isoenzyme- and Site-Specific Functional Characterization of Glutathione S -Transferases

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Stoddard, Ethan G. [Chemical Biology and Exposure; Killinger, Bryan J. [Chemical Biology and Exposure; Nair, Reji N. [Chemical Biology and Exposure; Sadler, Natalie C. [Chemical Biology and Exposure; Volk, Regan F. [Chemical Biology and Exposure; Purvine, Samuel O. [Chemical Biology and Exposure; Shukla, Anil K. [Chemical Biology and Exposure; Smith, Jordan N. [Chemical Biology and Exposure; Wright, Aaron T. [Chemical Biology and Exposure

2017-11-01

Glutathione S-transferases (GSTs) comprise a highly diverse family of phase II drug metabolizing enzymes whose shared function is the conjugation of reduced glutathione to various endo- and xenobiotics. Although the conglomerate activity of these enzymes can be measured by colorimetric assays, measurement of the individual contribution from specific isoforms and their contribution to the detoxification of xenobiotics in complex biological samples has not been possible. For this reason, we have developed two activity-based probes that characterize active glutathione transferases in mammalian tissues. The GST active site is comprised of a glutathione binding “G site” and a distinct substrate binding “H site”. Therefore, we developed (1) a glutathione-based photoaffinity probe (GSH-ABP) to target the “G site”, and (2) a probe designed to mimic a substrate molecule and show “H site” activity (GST-ABP). The GSH-ABP features a photoreactive moiety for UV-induced covalent binding to GSTs and glutathione-binding enzymes. The GST-ABP is a derivative of a known mechanism-based GST inhibitor that binds within the active site and inhibits GST activity. Validation of probe targets and “G” and “H” site specificity was carried out using a series of competitors in liver homogenates. Herein, we present robust tools for the novel characterization of enzyme- and active site-specific GST activity in mammalian model systems.

The influence of sleep deprivation and obesity on DNA damage in female Zucker rats

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Neuli M. Tenorio

2013-01-01

Full Text Available OBJECTIVE: The aim of this study was to evaluate overall genetic damage induced by total sleep deprivation in obese, female Zucker rats of differing ages. METHOD: Lean and obese Zucker rats at 3, 6, and 15 months old were randomly distributed into two groups for each age group: home-cage control and sleep-deprived (N = 5/group. The sleep-deprived groups were deprived sleep by gentle handling for 6 hours, whereas the home-cage control group was allowed to remain undisturbed in their home-cage. At the end of the sleep deprivation period, or after an equivalent amount of time for the home-cage control groups, the rats were brought to an adjacent room and decapitated. The blood, brain, and liver tissue were collected and stored individually to evaluate DNA damage. RESULTS: Significant genetic damage was observed only in 15-month-old rats. Genetic damage was present in the liver cells from sleep-deprived obese rats compared with lean rats in the same condition. Sleep deprivation was associated with genetic damage in brain cells regardless of obesity status. DNA damage was observed in the peripheral blood cells regardless of sleep condition or obesity status. CONCLUSION: Taken together, these results suggest that obesity was associated with genetic damage in liver cells, whereas sleep deprivation was associated with DNA damage in brain cells. These results also indicate that there is no synergistic effect of these noxious conditions on the overall level of genetic damage. In addition, the level of DNA damage was significantly higher in 15-month-old rats compared to younger rats.

Iron in intracellular infection: to provide or to deprive?

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Sandro eSilva-Gomes

2013-12-01

Full Text Available Due to their chemical versatility, transition metals were incorporated as cofactors for several basic metabolic pathways in living organisms. This same characteristic makes them potentially harmful, since they can be engaged in deleterious reactions like Fenton chemistry. As such, organisms have evolved highly specialized mechanisms to supply their own metal needs while keeping their toxic potential in check.This dual character comes into play in host-pathogen interactions, given that the host can either deprive the pathogen of these key nutrients or exploit them to induce toxicity towards the invading agent. Iron stands as the prototypic example of how a metal can be used to limit the growth of pathogens by nutrient deprivation, a mechanism widely studied in Mycobacterium infections. However, the host can also take advantage of iron-induced toxicity to control pathogen proliferation, as observed in infections caused by Leishmania. Whether we may harness either of the two pathways for therapeutical purposes is still ill-defined.In this review, we discuss how modulation of the host iron availability impacts the course of infections, focusing on those caused by two relevant intracellular pathogens, Mycobacterium and Leishmania.

Epidermal growth factor regulation of glutathione S-transferase gene expression in the rat is mediated by class Pi glutathione S-transferase enhancer I.

OpenAIRE

Matsumoto, M; Imagawa, M; Aoki, Y

2000-01-01

Using chloramphenicol acetyltransferase assays we showed that epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), and 3,3',4,4',5-pentachlorobiphenyl (PenCB) induce class Pi glutathione S-transferase (GSTP1) in primary cultured rat liver parenchymal cells. GSTP1 enhancer I (GPEI), which is required for the stimulation of GSTP1 expression by PenCB, also mediates EGF and TGF alpha stimulation of GSTP1 gene expression. However, hepatocyte growth factor and insulin did no...

Cardioprotective Effects of HuoxueAnshen Recipe against Myocardial Injuries Induced by Sleep Deprivation in Rats

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Rong Yuan

2017-01-01

Full Text Available Background. Traditional Chinese Medicine is extensively used in China and HuoxueAnshen Recipe (HAR was formulated according to its method in treating CHD accompanied with insomnia in clinic. However, there are few studies related to the effect of HAR on myocardial injury and sleep disorders. Purpose. To investigate the effects of HAR on sleep deprivation- (SD- induced myocardial I/R injury. Methods. Male Wistar rats receiving a daily gavage of HAR or vehicle were exposed to SD intervention while control rats had normal sleep. Then all rats were exposed to myocardial I/R. Hormone, vascular endothelial, and inflammatory related factors were detected before and after I/R, while cardiac injury, cardiac function, myocardial infarct size, and apoptosis were detected after I/R. Results. Levels of neuropeptide Y, vascular endothelial and inflammatory related factors were significantly increased while melatonin was decreased in vehicle-treated SD rats but not in HAR-treated SD rats after SD. In addition, cardiac injury, cardiac dysfunction, myocardial infarct size, and myocardial apoptosis were deteriorated in vehicle-treated SD rats but were ameliorated in HAR-treated SD rats after I/R. Conclusion. HAR not only improved SD-induced hormone disorders, inflammation, and endothelial dysfunction, but also alleviated I/R injury, which supports protective usage in CHD and psychocardiology.

Detection of glutathione based on MnO2 nanosheet-gated mesoporous silica nanoparticles and target induced release of glucose measured with a portable glucose meter.

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Tan, Qingqing; Zhang, Ruirui; Kong, Rongmei; Kong, Weisu; Zhao, Wenzhi; Qu, Fengli

2017-12-08

The authors describe a novel method for the determination of glutathione (GSH). Detection is based on target induced release of glucose from MnO 2 nanosheet-gated aminated mesoporous silica nanoparticles (MSNs). In detail, glucose is loaded into the pores of MSNs. Negatively charged MnO 2 nanosheets are assembled on the MSNs through electrostatic interactions. The nanosheets are reduced by GSH, and this results in the release of glucose which is quantified by using a commercial electrochemical glucose meter. GSH can be quantified by this method in the 100 nM to 10 μM concentration range, with a 34 nM limit of detection. Graphical abstract Glucose is loaded into the pores of mesoporous silica nanoparticles (MSNs). MnO 2 nanosheets are assembled on MSNs through electrostatic interactions. Glutathione (GSH) can reduce the nanosheets, and this results in the release of glucose which is quantified by using a commercial glucose meter.

Levodopa inhibits the development of form-deprivation myopia in guinea pigs.

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Mao, Junfeng; Liu, Shuangzhen; Qin, Wenjuan; Li, Fengyun; Wu, Xiaoying; Tan, Qian

2010-01-01

It has been shown that visual deprivation leads to a myopic refractive error and also reduces the retinal concentration of dopamine. Exogenously 3,4-dihydroxy-L-phenylalanine (levodopa, L-DOPA) can be converted into dopamine in vivo, which safely and effectively treats Parkinson disease. Moreover, L-DOPA was also used in the treatment of amblyopia in clinical studies. However, the effect of L-DOPA on the development of myopia has not been studied. The aim of this study was to investigate whether intraperitoneal injection of L-DOPA could inhibit form-deprivation myopia in guinea pigs and to explore a new strategy for drug treatment of myopia. Sixty guinea pigs, at age of 4 weeks, were randomly divided into six groups: normal control, L-DOPA group, saline group, deprived group, deprived plus L-DOPA group, and deprived plus saline group. Form deprivation was induced with translucent eye shields on the right eye and lasted for 10 days. L-DOPA was injected intraperitoneally into the guinea pig once a day. The corneal radius of curvature, refraction, and axial length were measured in all animals. Subsequently, retinal dopamine content was evaluated by high-performance liquid chromatography with electrochemical detection. Ten days of eye occlusion caused the form-deprived eyes to elongate and become myopic, and retinal dopamine content to decrease, but the corneal radius of curvature was not affected. Repeated intraperitoneal injection of L-DOPA could inhibit the myopic shift (from -3.62 +/- 0.98 D to -1.50 +/- 0.38 D; p < 0.001) due to goggles occluding and compensate retinal dopamine (from 0.65 +/- 0.10 ng to 1.33 +/- 0.23 ng; p < 0.001). Administration of L-DOPA to the unoccluded animals had no effect on its ocular refraction. There was no effect of intraperitoneal saline on the ocular refractive state and retinal dopamine. Systemic L-DOPA was partly effective in this guinea pig model and, therefore, is worth testing for effectiveness in progressing human myopes.

Feedback Blunting: Total Sleep Deprivation Impairs Decision Making that Requires Updating Based on Feedback.

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Whitney, Paul; Hinson, John M; Jackson, Melinda L; Van Dongen, Hans P A

2015-05-01

To better understand the sometimes catastrophic effects of sleep loss on naturalistic decision making, we investigated effects of sleep deprivation on decision making in a reversal learning paradigm requiring acquisition and updating of information based on outcome feedback. Subjects were randomized to a sleep deprivation or control condition, with performance testing at baseline, after 2 nights of total sleep deprivation (or rested control), and following 2 nights of recovery sleep. Subjects performed a decision task involving initial learning of go and no go response sets followed by unannounced reversal of contingencies, requiring use of outcome feedback for decisions. A working memory scanning task and psychomotor vigilance test were also administered. Six consecutive days and nights in a controlled laboratory environment with continuous behavioral monitoring. Twenty-six subjects (22-40 y of age; 10 women). Thirteen subjects were randomized to a 62-h total sleep deprivation condition; the others were controls. Unlike controls, sleep deprived subjects had difficulty with initial learning of go and no go stimuli sets and had profound impairment adapting to reversal. Skin conductance responses to outcome feedback were diminished, indicating blunted affective reactions to feedback accompanying sleep deprivation. Working memory scanning performance was not significantly affected by sleep deprivation. And although sleep deprived subjects showed expected attentional lapses, these could not account for impairments in reversal learning decision making. Sleep deprivation is particularly problematic for decision making involving uncertainty and unexpected change. Blunted reactions to feedback while sleep deprived underlie failures to adapt to uncertainty and changing contingencies. Thus, an error may register, but with diminished effect because of reduced affective valence of the feedback or because the feedback is not cognitively bound with the choice. This has important

Prior regular exercise reverses the decreased effects of sleep deprivation on brain-derived neurotrophic factor levels in the hippocampus of ovariectomized female rats.

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Saadati, Hakimeh; Sheibani, Vahid; Esmaeili-Mahani, Saeed; Darvishzadeh-Mahani, Fatemeh; Mazhari, Shahrzad

2014-11-01

Previous studies indicated that brain-derived neurotrophic factor (BDNF) is the main candidate to mediate the beneficial effects of exercise on cognitive function in sleep deprived male rats. In addition, our previous findings demonstrate that female rats are more vulnerable to the deleterious effects of sleep deprivation on cognitive performance and synaptic plasticity. Therefore, the current study was designed to investigate the effects of treadmill exercise and/or sleep deprivation (SD) on the levels of BDNF mRNA and protein in the hippocampus of female rats. Intact and ovariectomized (OVX) female Wistar rats were used in the present experiment. The exercise protocol was four weeks treadmill running and sleep deprivation was accomplished using the multiple platform method. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblot analysis were used to evaluate the level of BDNF mRNA and protein in the rat hippocampus respectively. Our results showed that protein and mRNA expression of BDNF was significantly (psleep deprived OVX rats under exercise conditions had a significant (peffect against hippocampus-related functions and impairments induced by sleep deprivation probably by inducing BDNF expression. Copyright © 2014 Elsevier B.V. All rights reserved.

Efficacy of free glutathione and niosomal glutathione in the treatment of acetaminophen-induced hepatotoxicity in cats

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L.A. Denzoin Vulcano

2013-06-01

Full Text Available Acetaminophen (APAP administration results in hepatotoxicity and hematotoxicity in cats. The response to three different treatments against APAP poisoning was evaluated. Free glutathione (GSH (200mg/kg, niosomal GSH (14 mg/kg and free amino acids (180 mg/kg of N-acetylcysteine and 280 mg/kg of methionine were administered to cats that were intoxicated with APAP (a single dose of 150 mg/kg, p.o.. Serum concentration of alanine aminotransferase (ALT along with serum, liver and erythrocyte concentration of GSH and methemoglobin percentage were measured before and 4, 24 and 72 hours after APAP administration. Free GSH (200 mg/kg and niosomal GSH (14 mg/kg were effective in reducing hepatotoxicity and hematotoxicity in cats intoxicated with a dose of 150 mg/kg APAP. We conclude that both types of treatments can protect the liver and haemoglobin against oxidative stress in APAP intoxicated cats. Furthermore, our results showed that treatment with niosomal GSH represents an effective therapeutic approach for APAP poisoning.

Alkylating Agent-Induced NRF2 Blocks Endoplasmic Reticulum Stress-Mediated Apoptosis via Control of Glutathione Pools and Protein Thiol Homeostasis.

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Zanotto-Filho, Alfeu; Masamsetti, V Pragathi; Loranc, Eva; Tonapi, Sonal S; Gorthi, Aparna; Bernard, Xavier; Gonçalves, Rosângela Mayer; Moreira, José C F; Chen, Yidong; Bishop, Alexander J R

2016-12-01

Alkylating agents are a commonly used cytotoxic class of anticancer drugs. Understanding the mechanisms whereby cells respond to these drugs is key to identify means to improve therapy while reducing toxicity. By integrating genome-wide gene expression profiling, protein analysis, and functional cell validation, we herein demonstrated a direct relationship between NRF2 and Endoplasmic Reticulum (ER) stress pathways in response to alkylating agents, which is coordinated by the availability of glutathione (GSH) pools. GSH is essential for both drug detoxification and protein thiol homeostasis within the ER, thus inhibiting ER stress induction and promoting survival, an effect independent of its antioxidant role. NRF2 accumulation induced by alkylating agents resulted in increased GSH synthesis via GCLC/GCLM enzyme, and interfering with this NRF2 response by either NRF2 knockdown or GCLC/GCLM inhibition with buthionine sulfoximine caused accumulation of damaged proteins within the ER, leading to PERK-dependent apoptosis. Conversely, upregulation of NRF2, through KEAP1 depletion or NRF2-myc overexpression, or increasing GSH levels with N-acetylcysteine or glutathione-ethyl-ester, decreased ER stress and abrogated alkylating agents-induced cell death. Based on these results, we identified a subset of lung and head-and-neck carcinomas with mutations in either KEAP1 or NRF2/NFE2L2 genes that correlate with NRF2 target overexpression and poor survival. In KEAP1-mutant cancer cells, NRF2 knockdown and GSH depletion increased cell sensitivity via ER stress induction in a mechanism specific to alkylating drugs. Overall, we show that the NRF2-GSH influence on ER homeostasis implicates defects in NRF2-GSH or ER stress machineries as affecting alkylating therapy toxicity. Mol Cancer Ther; 15(12); 3000-14. ©2016 AACR. ©2016 American Association for Cancer Research.

Measurement of glutathione-protein mixed disulfides

International Nuclear Information System (INIS)

Livesey, J.C.; Reed, D.J.

1984-01-01

The development of a sensitive and highly specific assay for the presence of mixed disulfides between protein thiol groups and endogenous thiols has been undertaken. Previous investigations on the concentrations of glutathione (GSH), glutathione disulfide (GSSG) and protein glutathione mixed disulfides (ProSSG) have been of limited usefulness because of the poor specificity of the assays used. Our assay for these forms of glutathione is based on high performance liquid chromatography (HPLC) and is an extension of an earlier method. After perchloric acid precipitation, the protein sample is washed with an organic solvent to fully denature the protein. Up to a 10-fold increase in GSH released from fetal bovine serum (FBS) protein has been found when the protein precipitate is washed with ethanol rather than ether, as earlier suggested. Similar effects have been observed with an as yet unidentified thiol which elutes in the chromatography system with a retention volume similar to cysteine

Paradoxical sleep deprivation changes testicular malondialdehyde and caspase-3 expression in male rats

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Fitranto Arjadi

2015-08-01

Full Text Available BACKGROUND Sleep deprivation is a significant problem among adult men and is considered as a risk factor for several diseases. Paradoxical sleep deprivation (PSD induces Leydig cell apoptosis through elevation of corticosterone, with testicular malondialdehyde (MDA and Leydig cell caspase-3 expression as parameters. The aim of this study was to observe testicular MDA level and caspase-3 expression treated with paradoxical sleep deprivation (PSD, immobilization, and footshock stress and to determine the stress model with a significant effect in white male rats (Rattus norvegicus . METHODS This experimental randomized study of posttest only with control group design was conducted on 24 white male Wistar strain rats, randomly allocated into four treatment groups, i.e. control (K1 without any stress treatment, PSD (KII, immobilization (KIII, and footshock stress (KIV. Treatments were given for 25 days to produce chronic stress. Testicular MDA concentration was examined by the ELISA method while caspase-3 was examined by the TUNEL method. RESULTS Mean testicular MDA concentration with one-way ANOVA test showed differences in means between the groups (p=0.000 and post hoc Tukey-HSD test showed significant results between PSD stress group versus control, immobilization and footshock stress groups. One-way ANOVA test showed a significant difference in caspase-3 expression in at least two treatment groups (p=0.008 and post-hoc Tuckey-LSD test showed significant differences between controls and all stress groups. CONCLUSION Sleep deprivation is a type of stress inducing changes in testicular MDA concentration and caspase-3 expression in male rat testes.

Effects of stem cell factor on hypoxia-inducible factor 1 alpha accumulation in human acute myeloid leukaemia and LAD2 mast cells.

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Bernhard F Gibbs

Full Text Available Stem cell factor (SCF is a hematopoietic growth factor that exerts its activity by signalling through the tyrosine kinase receptor known as Kit or CD117. SCF-Kit signalling is crucial for the survival, proliferation and differentiation of hematopoietic cells of myeloid lineage. Furthermore, since myeloid leukaemia cells express the Kit receptor, SCF may play an important role in myeloid leukaemia progression too. However, the mechanisms of this pathophysiological effect remain unclear. Recent evidence shows that SCF triggers accumulation of the inducible alpha subunit of hypoxia-inducible factor 1 (HIF-1 in hematopoietic cells--a transcription complex that plays a pivotal role in cellular adaptation to low oxygen availability. However, it is unknown how SCF impacts on HIF-1α accumulation in human myeloid leukaemia and mast cells. Here we show that SCF induces HIF-1α accumulation in THP-1 human myeloid leukaemia cells but not in LAD2 mast cells. We demonstrated that LAD2 cells have a more robust glutathione (GSH-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner. BSO-induced GSH depletion led to a significant decrease in HIF-1α prolyl hydroxylase (PHD activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells, SCF-induced HIF-1α accumulation is controlled via ERK, PI3 kinase/PKC-δ/mTOR-dependent and to a certain extent by redox-dependent mechanisms. These results demonstrate for the first time an important cross-talk of signalling pathways associated with HIF-1 activation--an important stage of the myeloid leukaemia cell life cycle.

Active biomonitoring of a subtropical river using glutathione-S ...

African Journals Online (AJOL)

Active biomonitoring of a subtropical river using glutathione-S-transferase (GST) and heat shock proteins (HSP 70) in. Oreochromis niloticusas surrogate biomarkers of metal contamination. Victor Kurauone Muposhi1, Beaven Utete1*, Idah Sithole-Niang2 and Stanley Mukangenyama2. 1Wildlife Ecology and Conservation, ...

Effect of asoka on the intracellular glutathione levels and skin tumour promotion in mice.

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Varghese, C D; Nair, S C; Panikkar, B; Panikkar, K R

1993-04-15

The bark of Saraka asoca (asoka) is commonly used to treat various diseases by the Indian system of medicine and in Sri Lanka. Further purification and chemical analysis of the active compound from the bark extract of asoka showed that (-)-epicatechin was responsible for the observed antitumour/anticarcinogenic activity. Papilloma formation in mice initiated with 7,12-dimethylbenz[a]anthracene (DMBA) and promoted using croton oil was inhibited by the topical application of 100 mg/kg body weight (b.w.) of (-)-epicatechin isolated from asoka bark extract. Oral administration of the same dose restricted the growth of s.c. injected 20 methylcholanthrene (MCA) induced soil tissue fibrosarcomas significantly in mice. Elevations of almost 2-4-fold in the intracellular reduced glutathione and related enzymes viz., glutathione reductase and glutathione S-transferase of sarcoma-180 tumour cells were noted in the presence of 1 microgram/ml of (-)-epicatechin, further highlighting its antiproliferative effect.

Feedback Blunting: Total Sleep Deprivation Impairs Decision Making that Requires Updating Based on Feedback

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Whitney, Paul; Hinson, John M.; Jackson, Melinda L.; Van Dongen, Hans P.A.

2015-01-01

or because the feedback is not cognitively bound with the choice. This has important implications for understanding and managing sleep loss-induced cognitive impairment in emergency response, disaster management, military operations, and other dynamic real-world settings with uncertain outcomes and imperfect information. Citation: Whitney P, Hinson JM, Jackson ML, Van Dongen HPA. Feedback blunting: total sleep deprivation impairs decision making that requires updating based on feedback. SLEEP 2015;38(5):745–754. PMID:25515105

Monocular Perceptual Deprivation from Interocular Suppression Temporarily Imbalances Ocular Dominance.

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Kim, Hyun-Woong; Kim, Chai-Youn; Blake, Randolph

2017-03-20

Early visual experience sculpts neural mechanisms that regulate the balance of influence exerted by the two eyes on cortical mechanisms underlying binocular vision [1, 2], and experience's impact on this neural balancing act continues into adulthood [3-5]. One recently described, compelling example of adult neural plasticity is the effect of patching one eye for a relatively short period of time: contrary to intuition, monocular visual deprivation actually improves the deprived eye's competitive advantage during a subsequent period of binocular rivalry [6-8], the robust form of visual competition prompted by dissimilar stimulation of the two eyes [9, 10]. Neural concomitants of this improvement in monocular dominance are reflected in measurements of brain responsiveness following eye patching [11, 12]. Here we report that patching an eye is unnecessary for producing this paradoxical deprivation effect: interocular suppression of an ordinarily visible stimulus being viewed by one eye is sufficient to produce shifts in subsequent predominance of that eye to an extent comparable to that produced by patching the eye. Moreover, this imbalance in eye dominance can also be induced by prior, extended viewing of two monocular images differing only in contrast. Regardless of how shifts in eye dominance are induced, the effect decays once the two eyes view stimuli equal in strength. These novel findings implicate the operation of interocular neural gain control that dynamically adjusts the relative balance of activity between the two eyes [13, 14]. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1

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Havekes, Robbert; Park, Alan J; Tudor, Jennifer C; Luczak, Vincent G; Hansen, Rolf T; Ferri, Sarah L; Bruinenberg, Vibeke M; Poplawski, Shane G; Day, Jonathan P; Aton, Sara J; Radwańska, Kasia; Meerlo, Peter; Houslay, Miles D; Baillie, George S; Abel, Ted

2016-01-01

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density. DOI: http://dx.doi.org/10.7554/eLife.13424.001 PMID:27549340

The NADPH oxidase inhibitor apocynin (acetovanillone) induces oxidative stress

International Nuclear Information System (INIS)

Riganti, Chiara; Costamagna, Costanzo; Bosia, Amalia; Ghigo, Dario

2006-01-01

Apocynin (acetovanillone) is often used as a specific inhibitor of NADPH oxidase. In N11 glial cells, apocynin induced, in a dose-dependent way, a significant increase of both malonyldialdehyde level (index of lipid peroxidation) and lactate dehydrogenase release (index of a cytotoxic effect). Apocynin evoked also, in a significant way, an increase of H 2 O 2 concentration and a decrease of the intracellular glutathione/glutathione disulfide ratio, accompanied by augmented efflux of glutathione and glutathione disulfide. Apocynin induced the activation of both pentose phosphate pathway and tricarboxylic acid cycle, which was blocked when the cells were incubated with glutathione together with apocynin. The cell incubation with glutathione prevented also the apocynin-induced increase of malonyldialdehyde generation and lactate dehydrogenase leakage. Apocynin exerted an oxidant effect also in a cell-free system: indeed, in aqueous solution, it evoked a faster oxidation of the thiols glutathione and dithiothreitol, and elicited the generation of reactive oxygen species, mainly superoxide anions. Our results suggest that apocynin per se can induce an oxidative stress and exert a cytotoxic effect in N11 cells and other cell types, and that some effects of apocynin in in vitro and in vivo experimental models should be interpreted with caution

Activation of cathepsin L contributes to the irreversible depolarization induced by oxygen and glucose deprivation in rat hippocampal CA1 neurons.

Science.gov (United States)

Kikuta, Shogo; Murai, Yoshinaka; Tanaka, Eiichiro

2017-01-01

Oxygen and glucose deprivation (OGD) elicits a rapid and irreversible depolarization with a latency of ∼5min in intracellular recordings of hippocampal CA1 neurons in rat slice preparations. In the present study, we examined the role of cathepsin L in the OGD-induced depolarization. OGD-induced depolarizations were irreversible as no recovery of membrane potential was observed. The membrane potential reached 0mV when oxygen and glucose were reintroduced immediately after the onset of the OGD-induced rapid depolarization. The OGD-induced depolarizations became reversible when the slice preparations were pre-incubated with cathepsin L inhibitors (types I and IV at 0.3-2nM and 0.3-30nM, respectively). Moreover, pre-incubation with these cathepsin inhibitors prevented the morphological changes, including swelling of the cell soma and fragmentation of dendrites, observed in control neurons after OGD. These findings suggest that the activation of cathepsin L contributes to the irreversible depolarization produced by OGD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The influence of sleep deprivation on expression of apoptosis regulatory proteins p53, bcl-2 and bax following rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide

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Juliana Noguti

2013-01-01

Full Text Available Background: The aim of this study was to evaluate whether paradoxical sleep deprivation could affects the mechanisms and pathways essentials for cancer cells in tongue cancer induced by 4-nitroquinole 1-oxide in Wistar rats. Materials and Methods: For this purpose, the animals were distributed into 4 groups of 5 animals each treated with 50 ppm 4 nitroquinoline 1 oxide (4 NQO solution through their drinking water for 4 and 12 weeks. The animals were submitted to paradoxical sleep deprivation (PSD for 72 h using the modified multiple platform method, which consisted of placing 5 mice in a cage (41 × 34 × 16 cm containing 10 circular platforms (3.5 cm in diameter with water 1 cm below the upper surface. The investigations were conducted using immunohistochemistry of p53, Bax and Bcl-2 proteins related to apoptosis and its pathways. Statistical analysis was performed by Kruskal-Wallis non-parametric test followed by the Dunn′s test using SPSS software pack (version 1.0. P value < 0.05 was considered for statistic significance. Results: Although no histopathological abnormalities were induced in the epithelium after 4 weeks of carcinogen exposure in all groups, in 12 weeks were observed pre-neoplasic lesions. Data analysis revealed statistically significant differences ( P < 0.05 in 4 weeks group for p53 and for bcl-2 and for all immunomarkers after 12 weeks of 4NQO administration. Conclusion: Our results reveal that sleep deprivation exerted alterations in proteins associated with proliferation and apoptosis in carcinogenesis.

Brain Networks are Independently Modulated by Donepezil, Sleep, and Sleep Deprivation.

Science.gov (United States)

Wirsich, Jonathan; Rey, Marc; Guye, Maxime; Bénar, Christian; Lanteaume, Laura; Ridley, Ben; Confort-Gouny, Sylviane; Cassé-Perrot, Catherine; Soulier, Elisabeth; Viout, Patrick; Rouby, Franck; Lefebvre, Marie-Noëlle; Audebert, Christine; Truillet, Romain; Jouve, Elisabeth; Payoux, Pierre; Bartrés-Faz, David; Bordet, Régis; Richardson, Jill C; Babiloni, Claudio; Rossini, Paolo Maria; Micallef, Joelle; Blin, Olivier; Ranjeva, Jean-Philippe

2018-05-01

Resting-state connectivity has been widely studied in the healthy and pathological brain. Less well-characterized are the brain networks altered during pharmacological interventions and their possible interaction with vigilance. In the hopes of finding new biomarkers which can be used to identify cortical activity and cognitive processes linked to the effects of drugs to treat neurodegenerative diseases such as Alzheimer's disease, the analysis of networks altered by medication would be particularly interesting. Eleven healthy subjects were recruited in the context of the European Innovative Medicines Initiative 'PharmaCog'. Each underwent five sessions of simultaneous EEG-fMRI in order to investigate the effects of donepezil and memantine before and after sleep deprivation (SD). The SD approach has been previously proposed as a model for cognitive impairment in healthy subjects. By applying network based statistics (NBS), we observed altered brain networks significantly linked to donepezil intake and sleep deprivation. Taking into account the sleep stages extracted from the EEG data we revealed that a network linked to sleep is interacting with sleep deprivation but not with medication intake. We successfully extracted the functional resting-state networks modified by donepezil intake, sleep and SD. We observed donepezil induced whole brain connectivity alterations forming a network separated from the changes induced by sleep and SD, a result which shows the utility of this approach to check for the validity of pharmacological resting-state analysis of the tested medications without the need of taking into account the subject specific vigilance.

Membrane accessibility of glutathione

DEFF Research Database (Denmark)

Garcia, Almudena; Eljack, N., D.; Sani, ND

2015-01-01

Regulation of the ion pumping activity of the Na(+),K(+)-ATPase is crucial to the survival of animal cells. Recent evidence has suggested that the activity of the enzyme could be controlled by glutathionylation of cysteine residue 45 of the β-subunit. Crystal structures so far available indicate...... that this cysteine is in a transmembrane domain of the protein. Here we have analysed via fluorescence and NMR spectroscopy as well as molecular dynamics simulations whether glutathione is able to penetrate into the interior of a lipid membrane. No evidence for any penetration of glutathione into the membrane...

Nitric oxide induces the alternative oxidase pathway in Arabidopsis seedlings deprived of inorganic phosphate.

Science.gov (United States)

Royo, Beatriz; Moran, Jose F; Ratcliffe, R George; Gupta, Kapuganti J

2015-10-01

Phosphate starvation compromises electron flow through the cytochrome pathway of the mitochondrial electron transport chain, and plants commonly respond to phosphate deprivation by increasing flow through the alternative oxidase (AOX). To test whether this response is linked to the increase in nitric oxide (NO) production that also increases under phosphate starvation, Arabidopsis thaliana seedlings were grown for 15 d on media containing either 0 or 1mM inorganic phosphate. The effects of the phosphate supply on growth, the production of NO, respiration, the AOX level and the production of superoxide were compared for wild-type (WT) seedlings and the nitrate reductase double mutant nia. Phosphate deprivation increased NO production in WT roots, and the AOX level and the capacity of the alternative pathway to consume electrons in WT seedlings; whereas the same treatment failed to stimulate NO production and AOX expression in the nia mutant, and the plants had an altered growth phenotype. The NO donor S-nitrosoglutathione rescued the growth phenotype of the nia mutants under phosphate deprivation to some extent, and it also increased the respiratory capacity of AOX. It is concluded that NO is required for the induction of the AOX pathway when seedlings are grown under phosphate-limiting conditions. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Thiol-Disulfide Exchange between Glutaredoxin and Glutathione

DEFF Research Database (Denmark)

Iversen, Rasmus; Andersen, Peter Anders; Jensen, Kristine Steen

2010-01-01

Glutaredoxins are ubiquitous thiol-disulfide oxidoreductases which catalyze the reduction of glutathione-protein mixed disulfides. Belonging to the thioredoxin family, they contain a conserved active site CXXC motif. The N-proximal active site cysteine can form a mixed disulfide with glutathione ...... has been replaced with serine. The exchange reaction between the reduced protein and oxidized glutathione leading to formation of the mixed disulfide could readily be monitored by isothermal titration calorimetry (ITC) due to the enthalpic contributions from the noncovalent interactions...

Prostate Cancer Metastases to Bone: Role of High Bone Turnover Induced by Androgen Deprivation

National Research Council Canada - National Science Library

Padalecki, Susan

2002-01-01

.... Treatment with androgen deprivation therapy leads to an increase in bone turnover as indicated by the loss of bone mineral density and the increase in markers of bone turnover in patients on treatment...

Changes in attention to an emotional task after sleep deprivation: neurophysiological and behavioral findings.

Science.gov (United States)

Alfarra, Ramey; Fins, Ana I; Chayo, Isaac; Tartar, Jaime L

2015-01-01

While sleep loss is shown to have widespread effects on cognitive processes, little is known about the impact of sleep loss on emotion processes. In order to expand on previous behavioral and physiological findings on how sleep loss influences emotion processing, we administered positive, negative, and neutral affective visual stimuli to individuals after one night of sleep deprivation while simultaneously acquiring EEG event related potential (ERP) data and recording affective behavioral responses. We compared these responses to a baseline testing session. We specifically looked at the late positive potential (LPP) component of the visual ERP as an established sensitive measure of attention to emotionally-charged visual stimuli. Our results show that after sleep deprivation, the LPP no longer discriminates between emotional and non-emotional pictures; after sleep deprivation the LPP amplitude was of similar amplitude for neutral, positive, and negative pictures. This effect was driven by an increase in the LPP to neutral pictures. Our behavioral measures show that, relative to baseline testing, emotional pictures are rated as less emotional following sleep deprivation with a concomitant reduction in emotional picture-induced anxiety. We did not observe any change in cortisol concentrations after sleep deprivation before or after emotional picture exposure, suggesting that the observed changes in emotion processing are independent of potential stress effects of sleep deprivation. Combined, our findings suggest that sleep loss interferes with proper allocation of attention resources during an emotional task. Copyright © 2014 Elsevier B.V. All rights reserved.

Rubber hand illusion induced by touching the face ipsilaterally to a deprived hand: evidence for plastic ‘somatotopic’ remapping in tetraplegics

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Michele eScandola

2014-06-01

Full Text Available Background: Studies in animals and humans indicate that the interruption of body-brain connections following spinal cord injury (SCI leads to plastic cerebral reorganization.Objective: To explore whether inducing the Rubber Hand Illusion (RHI via synchronous multisensory visuo-tactile bodily stimulation may reveal any perceptual correlates of plastic remapping in SCI.Methods: In 16 paraplegic, 16 tetraplegic and 16 healthy participants we explored whether RHI may be induced by tactile stimuli involving not only the left hand but also the left hemi-face. Touching the participant’s actual hand or face was either synchronous or asynchronous with tactile stimuli seen on a rubber hand. We assessed two components of the illusion, namely perceived changes in the real hand in space (indexed by proprioceptive drift and ownership of the rubber hand (indexed by subjective responses to an ad-hoc questionnaire.Results: Proprioceptive drift and ownership were found in the healthy group only in the condition where the left real and fake hand were touched simultaneously. In contrast, no drift was found in the SCI patients who, however, showed ownership after both synchronous and asynchronous hand stroking. Importantly, only tetraplegics showed the effect also after synchronous face stroking. Conclusions: RHI may reveal plastic phenomena in SCI. In hand representation-deprived tetraplegics, stimuli on the face (represented contiguously in the somatic and motor systems, drive the sense of hand ownership. This hand-face remapping phenomenon may be useful for restoring a sense of self in massively deprived individuals.

[Is the socioeconomic deprivation EPICES score useful in obstetrics?].

Science.gov (United States)

Convers, M; Langeron, A; Sass, C; Moulin, J-J; Augier, A; Varlet, M-N; Seffert, P; Chêne, G

2012-04-01

To describe a validated and multifactorial deprivation score to study the relationship between socioeconomic deprivation and perinatal risks. The index of deprivation EPICES (Evaluation of Precarity and Inequalities in Health Examination Centers) was used to characterize the deprivation status of 234 women in post-partum in comparison with perinatal morbidity. The cutoff value of 30.7 was the threshold to define deprivation. Two hundred and eight patients were included in this retrospective study from whom 48 (23%) had a score of deprivation higher than 30.7. Maternofetal morbidity was more severe in deprived patients. The current results show that the EPICES score could be a useful obstetrical tool for the identification of deprived women during pregnancy. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Fasting or fear: disentangling the roles of predation risk and food deprivation in the nitrogen metabolism of consumers.

Science.gov (United States)

Dalton, Christopher M; Tracy, Karen E; Hairston, Nelson G; Flecker, Alexander S

2018-03-01

Predators can alter nutrient cycles simply by inducing stress in prey. This stress accelerates prey's protein catabolism, nitrogen waste production, and nitrogen cycling. Yet predators also reduce the feeding rates of their prey, inducing food deprivation that is expected to slow protein catabolism and nitrogen cycling. The physiology of prey under predation risk thus balances the influences of predation risk and food deprivation, and this balance is central to understanding the role of predators in nutrient cycles. We explored the separate and combined effects of predation risk and food deprivation on prey physiology and nutrient cycling by exposing guppies (Poecilia reticulata) to predation risk and food deprivation in a 2 × 2 design. We simulated predation risk using chemical cues from a natural predator of guppies, and we created food deprivation by rationing food availability. We measured guppy response as food consumption, growth, tissue energy density, tissue carbon:nitrogen, and nitrogen (N) excretion and assimilation. We found that N-linked physiological processes (N consumption, assimilation, excretion) were strongly affected by predation risk, independent of food consumption. Guppies excreted substantially less under predation risk than they did under food deprivation or control conditions. These results suggest that predation risk, per se, triggers physiological changes in guppies that increase N retention and decrease N excretion. We suggest that slower N metabolism under predation risk is an adaptive response that minimizes protein loss in the face of predictable, predator-induced food restriction. Notably, N metabolism shares common hormonal control with food seeking behavior, and we speculate that increased N retention is a direct and immediate result of reduced food seeking under predation risk. Contrary to predation-stress-based hypotheses for how predators affect nutrient cycling by prey, our result indicates that even short-term exposure to

Arctigenin induces the apoptosis of primary effusion lymphoma cells under conditions of glucose deprivation.

Science.gov (United States)

Baba, Yusuke; Shigemi, Zenpei; Hara, Naoko; Moriguchi, Misato; Ikeda, Marina; Watanabe, Tadashi; Fujimuro, Masahiro

2018-02-01

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of primary effusion lymphoma (PEL) and Kaposi's sarcoma. PEL is a type of non-Hodgkin's B-cell lymphoma, affecting immunosuppressed individuals, such as post-transplant or AIDS patients. However, since PEL is resistant to chemotherapeutic regimens, new effective treatment strategies are required. Arctigenin, a natural lignan compound found in the plant Arctium lappa, has been widely investigated as a potential anticancer agent in the clinical setting. In the present study, we examined the cytotoxic effects of arctigenin by cell viability assay and found that arctigenin markedly inhibited the proliferation of PEL cells compared with KSHV-uninfected B-lymphoma cells under conditions of glucose deprivation. Arctigenin decreased cellular ATP levels, disrupted mitochondrial membrane potential and triggered caspase-9-mediated apoptosis in the glucose-deprived PEL cells. In addition, western blot analysis using phospho-specific antibodies were used to evaluate activity changes in the signaling pathways of interest. As a result, arctigenin suppressed the activation of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways by inhibiting ERK and p38 MAPK phosphorylation in the glucose-deprived PEL cells. We confirmed that an inhibitor of ERK (U0126) or p38 MAPK (SB202190 and SB203580) suppressed the proliferation of the BC3 PEL cells compared with the KSHV-negative DG75 cells. Moreover, RT-PCR and luciferase reporter assay revealed that arctigenin and p38 MAPK inhibition by SB202190 or SB203580 downregulated the transcriptional expression of unfolded protein response (UPR)‑related molecules, including GRP78 and ATF6α under conditions of glucose deprivation. Finally, we confirmed that arctigenin did not affect KSHV replication in PEL cells, suggesting that arctigenin treatment for PEL does not contribute to the risk of de novo KSHV

The Effects of Sleep Deprivation on Pain

Directory of Open Access Journals (Sweden)

Bernd Kundermann

2004-01-01

Full Text Available Chronic pain syndromes are associated with alterations in sleep continuity and sleep architecture. One perspective of this relationship, which has not received much attention to date, is that disturbances of sleep affect pain. To fathom this direction of cause, experimental human and animal studies on the effects of sleep deprivation on pain processing were reviewed. According to the majority of the studies, sleep deprivation produces hyperalgesic changes. Furthermore, sleep deprivation can counteract analgesic effects of pharmacological treatments involving opioidergic and serotoninergic mechanisms of action. The heterogeneity of the human data and the exclusive interest in rapid eye movement sleep deprivation in animals so far do not allow us to draw firm conclusions as to whether the hyperalgesic effects are due to the deprivation of specific sleep stages or whether they result from a generalized disruption of sleep continuity. The significance of opioidergic and serotoninergic processes as mediating mechanisms of the hyperalgesic changes produced by sleep deprivation are discussed.

BDNF in sleep, insomnia, and sleep deprivation.

Science.gov (United States)

Schmitt, Karen; Holsboer-Trachsler, Edith; Eckert, Anne

2016-01-01

The protein brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors involved in plasticity of neurons in several brain regions. There are numerous evidence that BDNF expression is decreased by experiencing psychological stress and that, accordingly, a lack of neurotrophic support causes major depression. Furthermore, disruption in sleep homeostatic processes results in higher stress vulnerability and is often associated with stress-related mental disorders. Recently, we reported, for the first time, a relationship between BDNF and insomnia and sleep deprivation (SD). Using a biphasic stress model as explanation approach, we discuss here the hypothesis that chronic stress might induce a deregulation of the hypothalamic-pituitary-adrenal system. In the long-term it leads to sleep disturbance and depression as well as decreased BDNF levels, whereas acute stress like SD can be used as therapeutic intervention in some insomniac or depressed patients as compensatory process to normalize BDNF levels. Indeed, partial SD (PSD) induced a fast increase in BDNF serum levels within hours after PSD which is similar to effects seen after ketamine infusion, another fast-acting antidepressant intervention, while traditional antidepressants are characterized by a major delay until treatment response as well as delayed BDNF level increase. Key messages Brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology of stress-related mood disorders. The interplay of stress and sleep impacts on BDNF level. Partial sleep deprivation (PSD) shows a fast action on BDNF level increase.

Sleep deprivation as an experimental model system for psychosis: Effects on smooth pursuit, prosaccades, and antisaccades.

Science.gov (United States)

Meyhöfer, Inga; Kumari, Veena; Hill, Antje; Petrovsky, Nadine; Ettinger, Ulrich

2017-04-01

Current antipsychotic medications fail to satisfactorily reduce negative and cognitive symptoms and produce many unwanted side effects, necessitating the development of new compounds. Cross-species, experimental behavioural model systems can be valuable to inform the development of such drugs. The aim of the current study was to further test the hypothesis that controlled sleep deprivation is a safe and effective model system for psychosis when combined with oculomotor biomarkers of schizophrenia. Using a randomized counterbalanced within-subjects design, we investigated the effects of 1 night of total sleep deprivation in 32 healthy participants on smooth pursuit eye movements (SPEM), prosaccades (PS), antisaccades (AS), and self-ratings of psychosis-like states. Compared with a normal sleep control night, sleep deprivation was associated with reduced SPEM velocity gain, higher saccadic frequency at 0.2 Hz, elevated PS spatial error, and an increase in AS direction errors. Sleep deprivation also increased intra-individual variability of SPEM, PS, and AS measures. In addition, sleep deprivation induced psychosis-like experiences mimicking hallucinations, cognitive disorganization, and negative symptoms, which in turn had moderate associations with AS direction errors. Taken together, sleep deprivation resulted in psychosis-like impairments in SPEM and AS performance. However, diverging somewhat from the schizophrenia literature, sleep deprivation additionally disrupted PS control. Sleep deprivation thus represents a promising but possibly unspecific experimental model that may be helpful to further improve our understanding of the underlying mechanisms in the pathophysiology of psychosis and aid the development of antipsychotic and pro-cognitive drugs.

Hsp20 Protects against Oxygen-Glucose Deprivation/Reperfusion-Induced Golgi Fragmentation and Apoptosis through Fas/FasL Pathway

Directory of Open Access Journals (Sweden)

Bingwu Zhong

2015-01-01

Full Text Available Cerebral ischemia-reperfusion injury plays an important role in the development of tissue injury after acute ischemic stroke. Finding effective neuroprotective agents has become a priority in the treatment of ischemic stroke. The Golgi apparatus (GA is a pivotal organelle and its protection is an attractive target in the treatment of cerebral ischemia-reperfusion injury. Protective effects of Hsp20, a potential cytoprotective agent due to its chaperone-like activity and involvement in regulation of many vital processes, on GA were assessed in an ischemia-reperfusion injury model. Mouse neuroblastoma Neuro2a (N2a cells were subjected to oxygen-glucose deprivation/reperfusion (OGDR insult. OGDR induces Golgi fragmentation, apoptosis, and p115 cleavage in N2a cells. However, transfection with Hsp20 significantly attenuates OGDR-induced Golgi fragmentation and apoptosis. Hsp20 interacts with Bax, decreases FasL and Bax expression, and inhibits caspases 3 and p115 cleavage in N2a cells exposed to OGDR. Our data demonstrate that increased Hsp20 expression protects against OGDR-induced Golgi fragmentation and apoptosis, likely through interaction with Bax and subsequent amelioration of the OGDR-induced elevation in p115 cleavage via the Fas/FasL signaling pathway. This neuroprotective potential of Hsp20 against OGDR insult and the underlying mechanism will pave the way for its potential clinical application for cerebral ischemia-reperfusion related disorders.

Glutathione peroxidase 4 overexpression inhibits ROS-induced cell death in diffuse large B-cell lymphoma.

Science.gov (United States)

Kinowaki, Yuko; Kurata, Morito; Ishibashi, Sachiko; Ikeda, Masumi; Tatsuzawa, Anna; Yamamoto, Masahide; Miura, Osamu; Kitagawa, Masanobu; Yamamoto, Kouhei

2018-02-20

Regulation of oxidative stress and redox systems has important roles in carcinogenesis and cancer progression, and for this reason has attracted much attention as a new area of cancer therapeutic targets. Glutathione peroxidase 4 (GPX4), an antioxidant enzyme, has biological important functions such as signaling cell death by suppressing peroxidation of membrane phospholipids. However, few studies exist on the expression and clinical relevance of GPX4 in malignant lymphomas such as diffuse large B-cell lymphoma. In this study, we assessed the expression of GPX4 immunohistochemically. GPX4 was expressed in 35.5% (33/93) cases of diffuse large B-cell lymphoma. The GPX4-positive group had poor overall survival (P = 0.0032) and progression-free survival (P = 0.0004) compared with those of the GPX4-negative group. In a combined analysis of GPX4 and 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, there was a negative correlation between GPX4 and 8-hydroxydeoxyguanosine (P = 0.0009). The GPX4-positive and 8-hydroxydeoxyguanosine-negative groups had a significantly worse prognosis than the other groups in both overall survival (P = 0.0170) and progression-free survival (P = 0.0005). These results suggest that the overexpression of GPX4 is an independent prognostic predictor in diffuse large B-cell lymphoma. Furthermore, in vitro analysis demonstrated that GPX4-overexpressing cells were resistant to reactive oxygen species-induced cell death (P = 0.0360). Conversely, GPX4-knockdown cells were sensitive to reactive oxygen species-induced cell death (P = 0.0111). From these data, we conclude that GPX4 regulates reactive oxygen species-induced cell death. Our results suggest a novel therapeutic strategy using the mechanism of ferroptosis, as well as a novel prognostic predictor of diffuse large B-cell lymphoma.

Chemiluminescence of carbon dots induced by diperiodato-nicklate (IV) in alkaline solution and its application to a quenchometric flow-injection assays of paracetamole, L-cysteine and glutathione

International Nuclear Information System (INIS)

Dong, Yajuan; Su, Ming; Chen, Peiyun; Sun, Hanwen

2015-01-01

Aqueous solutions of carbon dots (C-dots) were prepared by microwave-assisted thermal carbonization of poly(ethylene glycol). They were investigated by transmission electron microscopy, absorption and fluorescence spectra. It is shown that diperiodato-nicklate(IV), a strong oxidant, induces the chemiluminescence (CL) of C-dots in strongly alkaline solution without use of an additional reagent. A mechanism for this reaction is suggested. It is also found that the CL of the system is quenched by paracetamole, L-cysteine and glutathione. Under the optimized conditions, the calibration plot is linear with a correlation coefficient (r) of >0.995. The limits of detection are 90, 8, and 60 µg L -1 for paracetamole, L-cysteine, and glutathione, respectively. Spiked urine and serum samples were analyzed and gave recoveries in the range from 84.38 to 116.0 %, with an RSD of 1.2–2.7 %. (author)

Human glutathione S-transferase-mediated glutathione conjugation of curcumin and efflux of these conjugates in Caco-2 cells

NARCIS (Netherlands)

Usta, M.; Wortelboer, H.M.; Vervoort, J.J.M.; Boersma, M.G.; Rietjens, I.M.C.M.; Bladeren, van P.J.; Cnubben, N.H.P.

2007-01-01

Curcumin, an alpha,beta-unsaturated carbonyl compound, reacts with glutathione, leading to the formation of two monoglutathionyl curcumin conjugates. In the present study, the structures of both glutathione conjugates of curcumin were identified by LC-MS and one- and two-dimensional H-1 NMR

Patterns of Subjective Deprivation in Adulthood

Science.gov (United States)

Bortner, Rayman, W.; Hultsch, David F.

1974-01-01

Investigated the number and characteristics of adults experiencing different types of subjective deprivation, and evaluated Cantril's assertion that some of these types of deprivation are ontogenetic in nature. (DP)

DL-2-amino-3-phosphonopropionic acid protects primary neurons from oxygen-glucose deprivation induced injury

Directory of Open Access Journals (Sweden)

Di Cui

2017-02-01

Full Text Available Cerebral infarction is a type of ischemic stroke and is one of the main causes of irreversible brain damage. Although multiple neuroprotective agents have been investigated recently, the potential of DL-2-amino-3-phosphonopropionic acid (DL-AP3 in treating oxygen-glucose deprivation (OGD-induced neuronal injury, has not been clarified yet. This study was aimed to explore the role of DL-AP3 in primary neuronal cell cultures. Primary neurons were divided into four groups: (1 a control group that was not treated; (2 DL-AP3 group treated with 10 μM of DL-AP3; (3 OGD group, in which neurons were cultured under OGD conditions; and (4 OGD + DL-AP3 group, in which OGD model was first established and then the cells were treated with 10 μM of DL-AP3. Neuronal viability and apoptosis were measured using Cell Counting Kit-8 and flow cytometry. Expressions of phospho-Akt1 (p-Akt1 and cytochrome c were detected using Western blot. The results showed that DL-AP3 did not affect neuronal viability and apoptosis in DL-AP3 group, nor it changed p-Akt1 and cytochrome c expression (p > 0.05. In OGD + DL-AP3 group, DL-AP3 significantly attenuated the inhibitory effects of OGD on neuronal viability (p < 0.001, and reduced OGD induced apoptosis (p < 0.01. Additionally, the down-regulation of p-Akt1 and up-regulation of cytochrome c, induced by OGD, were recovered to some extent after DL-AP3 treatment (p < 0.05 or p < 0.001. Overall, DL-AP3 could protect primary neurons from OGD-induced injury by affecting the viability and apoptosis of neurons, and by regulating the expressions of p-Akt1 and cytochrome c.

Effects of Ionizing Radiation and Glutathione Precursor on Antioxidant Enzyme and Cell Survival in Yeast

Energy Technology Data Exchange (ETDEWEB)

Kim, Jinkyu; Roh, Changhyun; Ryu, Taeho; Park, Jiyoung [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Nili, Michael A. [Oxiage Cosmeceutical Research Institute, Virginia (United States)

2013-05-15

Cells react to such an induced oxidative stress through scavenging the generated reactive oxygen species to reduce oxidative damage. Antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase are immediately triggered for reactive oxygen species. N-acetyl-L-cysteine (NAC), a precursor of glutathione, is one of the antioxidants. The effect of NAC as an antioxidant and/or a cell rescue agent was investigated in the present study. Glutathione (GSH) is the most abundant intracellular thiol, which involves in antioxidant defense via direct interaction with ROS or via activities of detoxication enzymes like glutathione peroxidases (GPx). NAC flowed in the cell is converted to cysteine by deacetylation, that is supplied to the depleted GSH by oxidative stress. NAC prevents the depletion of GSH by radiation, increases the production of GSH, and improves enzymes activity such as GPx and alkaline phosphatase. Cell growth and survivorship and transcriptional level of glutathione gene are analyzed in two yeast strains exposed to combined treatment of NAC with gamma-rays. The effect of NAC on cell growth was measured during 72 hours. The cell growth was hampered by higher concentrations of NAC at stationary phase. NAC, however, didn't affect the cell division at the exponential phase. The survival of the cells decreased with radiation dose. The cell viability of the strain W303-1A was reduced significantly at the low dose (10 and 30 Gy). By comparison, the strain W303-1A was more sensitive to radiation with having a half lethal dose (LD{sub 50}) of about 20 Gy. The quantitative RT-PCR analysis showed that the transcriptional expression of antioxidant enzyme gene GPX1 increased after irradiation while the expression of the gene decreased by the combined treatment of NAC with 100 Gy radiation. The present study shows that NAC can directly scavenge ROS against oxidative stress in vivo. In conclusion, NAC can prevent radiation-induced oxidative

Effects of Ionizing Radiation and Glutathione Precursor on Antioxidant Enzyme and Cell Survival in Yeast

International Nuclear Information System (INIS)

Kim, Jinkyu; Roh, Changhyun; Ryu, Taeho; Park, Jiyoung; Nili, Michael A.

2013-01-01

Cells react to such an induced oxidative stress through scavenging the generated reactive oxygen species to reduce oxidative damage. Antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase are immediately triggered for reactive oxygen species. N-acetyl-L-cysteine (NAC), a precursor of glutathione, is one of the antioxidants. The effect of NAC as an antioxidant and/or a cell rescue agent was investigated in the present study. Glutathione (GSH) is the most abundant intracellular thiol, which involves in antioxidant defense via direct interaction with ROS or via activities of detoxication enzymes like glutathione peroxidases (GPx). NAC flowed in the cell is converted to cysteine by deacetylation, that is supplied to the depleted GSH by oxidative stress. NAC prevents the depletion of GSH by radiation, increases the production of GSH, and improves enzymes activity such as GPx and alkaline phosphatase. Cell growth and survivorship and transcriptional level of glutathione gene are analyzed in two yeast strains exposed to combined treatment of NAC with gamma-rays. The effect of NAC on cell growth was measured during 72 hours. The cell growth was hampered by higher concentrations of NAC at stationary phase. NAC, however, didn't affect the cell division at the exponential phase. The survival of the cells decreased with radiation dose. The cell viability of the strain W303-1A was reduced significantly at the low dose (10 and 30 Gy). By comparison, the strain W303-1A was more sensitive to radiation with having a half lethal dose (LD 50 ) of about 20 Gy. The quantitative RT-PCR analysis showed that the transcriptional expression of antioxidant enzyme gene GPX1 increased after irradiation while the expression of the gene decreased by the combined treatment of NAC with 100 Gy radiation. The present study shows that NAC can directly scavenge ROS against oxidative stress in vivo. In conclusion, NAC can prevent radiation-induced oxidative stress by

Human glutathione S-transferase-mediated glutathione conjugation of curcumin and efflux of these conjugates in caco-2 cells

NARCIS (Netherlands)

Usta, M.; Wortelboer, H.M.; Vervoort, J.; Boersma, M.G.; Rietjens, I.M.C.M.; Bladeren, P.J. van; Cnubben, N.H.P.

2007-01-01

Curcumin, an α,β-unsaturated carbonyl compound, reacts with glutathione, leading to the formation of two monoglutathionyl curcumin conjugates. In the present study, the structures of both glutathione conjugates of curcumin were identified by LC-MS and one- and two-dimensional 1H NMR analysis, and

Protective Effect of Diospyros kaki against Glucose-Oxygen-Serum Deprivation-Induced PC12 Cells Injury

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Fatemeh Forouzanfar

2016-01-01

Full Text Available Ischemic cerebrovascular disease is one of the most common causes of death in the world. Recent interests have been focused on natural antioxidants and anti-inflammatory agents as potentially useful neuroprotective agents. Diospyros kaki (persimmon has been shown to exert anti-inflammatory, antioxidant, and antineoplastic effects. However, its effects on ischemic damage have not been evaluated. Here, we used an in vitro model of cerebral ischemia and studied the effects of hydroalcoholic extract of peel (PeHE and fruit pulp (PuHE of persimmon on cell viability and markers of oxidative damage mainly intracellular reactive oxygen species (ROS induced by glucose-oxygen-serum deprivation (GOSD in PC12 cells. GOSD for 6 h produced significant cell death which was accompanied by increased levels of ROS. Pretreatment with different concentrations of PeHE and PuHE (0–500 μg/mL for 2 and 24 h markedly restored these changes only at high concentrations. However, no significant differences were seen in the protection against ischemic insult between different extracts and the time of exposure. The experimental results suggest that persimmon protects the PC12 cells from GOSD-induced injury via antioxidant mechanisms. Our findings might raise the possibility of potential therapeutic application of persimmon for managing cerebral ischemic and other neurodegenerative disorders.

Neuroglobin overexpression inhibits oxygen-glucose deprivation-induced mitochondrial permeability transition pore opening in primary cultured mouse cortical neurons.

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Yu, Zhanyang; Liu, Ning; Li, Yadan; Xu, Jianfeng; Wang, Xiaoying

2013-08-01

Neuroglobin (Ngb) is an endogenous neuroprotective molecule against hypoxic/ischemic brain injury, but the underlying mechanisms remain largely undefined. Our recent study revealed that Ngb can bind to voltage-dependent anion channel (VDAC), a regulator of mitochondria permeability transition (MPT). In this study we examined the role of Ngb in MPT pore (mPTP) opening following oxygen-glucose deprivation (OGD) in primary cultured mouse cortical neurons. Co-immunoprecipitation (Co-IP) and immunocytochemistry showed that the binding between Ngb and VDAC was increased after OGD compared to normoxia, indicating the OGD-enhanced Ngb-VDAC interaction. Ngb overexpression protected primary mouse cortical neurons from OGD-induced neuronal death, to an extent comparable to mPTP opening inhibitor, cyclosporine A (CsA) pretreatment. We further measured the role of Ngb in OGD-induced mPTP opening using Ngb overexpression and knockdown approaches in primary cultured neurons, and recombinant Ngb exposure to isolated mitochondria. Same as CsA pretreatment, Ngb overexpression significantly reduced OGD-induced mPTP opening markers including mitochondria swelling, mitochondrial NAD(+) release, and cytochrome c (Cyt c) release in primary cultured neurons. Recombinant Ngb incubation significantly reduced OGD-induced NAD(+) release and Cyt c release from isolated mitochondria. In contrast, Ngb knockdown significantly increased OGD-induced neuron death, and increased OGD-induced mitochondrial NAD(+) release and Cyt c release as well, and these outcomes could be rescued by CsA pretreatment. In summary, our results demonstrated that Ngb overexpression can inhibit OGD-induced mPTP opening in primary cultured mouse cortical neurons, which may be one of the molecular mechanisms of Ngb's neuroprotection. Copyright © 2013 Elsevier Inc. All rights reserved.

Potential involvement of oxygen intermediates and glutathione depletion in UV-induced epidermal cell injury in vitro

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Hsieh, G.C.; Acosta, D.

1991-01-01

Generation of reactive oxygen species (ROS) and depletion of glutathione (GSH) are suggested as the cytotoxic mechanisms for UVB-induced cellular damage. Primary monolayer cultures of epidermal keratinocytes (KCs) prepared from the skin of neonatal rats were irradiated with UVB at levels of 0.25-3.0 J/cm 2 . Cytotoxicity was measured at 3, 6, and 12 hr after UVB radiation. Exposure of KCs to UVB resulted in time- and dose-related toxic responses as determined by plasma membrane integrity, lysosomal function and mitochondrial metabolic activity. Irradiated KCs generated superoxide in a dose-dependent manner when compared to sham-irradiated cells. Superoxide formation, which occurred before and concomitant with cell injury, was decreased by superoxide dismutase (SOD). Cell injury was also significantly prevented by ROS scavengers, SOD and catalase. Pretreatment of cells with endocytosis inhibitors, cytochalasin B and methylamine, suppressed the ability of SOD and catalase to protect keratinocytes from UVB-induced toxicity. Irradiation of cells with UVB caused rapid depletion of GSH to about 30% of unirradiated levels within 15 min. UVB-irradiation led to a rapid transient increase in GSH peroxidase activity, concomitant with a marked decrease in the GSH/GSSG ratio. After 1 hr., while the GSH/GSSG ratio remained low, the GSH peroxidase activity declined below the control levels in UVB-treated epidermal cells. Following extensive GSH depletion in cells preincubated with 0.1 mM buthiomine sulfoximine, KCs became strongly sensitized to the cytotoxic action of UVB. These results indicate that UVB-induced cell injury in cultured KCs may be mediated by ROs and that endogenous GSH may play an important protective role against the cytotoxic action of UVB

Vacuolar H+ -ATPase c protects glial cell death induced by sodium nitroprusside under glutathione-depleted condition.

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Byun, Yu Jeong; Lee, Seong-Beom; Lee, Hwa Ok; Son, Min Jeong; Kim, Ho-Shik; Kwon, Oh-Joo; Jeong, Seong-Whan

2011-08-01

We examined the role of the c subunit (ATP6L) of vacuolar H(+) -ATPase and its molecular mechanisms in glial cell death induced by sodium nitroprusside (SNP). ATP6L siRNA-transfected cells treated with SNP showed a significant increase in cytotoxicity under glutathione (GSH)-depleted conditions after pretreatment with buthionine sulfoximine, but reduction of ATP6L did not affect the regulation of lysosomal pH in analyses with lysosomal pH-dependent fluorescence probes. Photodegraded SNP and ferrous sulfate induced cytotoxicity with the same pattern as that of SNP, but SNAP and potassium cyanide did not show activity. Pretreatment of the transfected cells with deferoxamine (DFO) reduced ROS production and significantly inhibited the cytotoxicity, which indicates that primarily iron rather than nitric oxide or cyanide from SNP contributes to cell death. Involvement of apoptotic processes in the cells was not shown. Pretreatment with JNK or p38 chemical inhibitor significantly inhibited the cytotoxicity, and we also confirmed that the MAPKs were activated in the cells by immunoblot analysis. Significant increase of LC3-II conversion was observed in the cells, and the conversions were inhibited by cotransfection of the MAPK siRNAs and pretreatment with DFO. Introduction of Atg5 siRNA inhibited the cytotoxicity and inhibited the activation of MAPKs and the conversion of LC3. We finally confirmed autophagic cell death and involvement of MAPKs by observation of autophagic vacuoles via electron microscopy. These data suggest that ATP6L has a protective role against SNP-induced autophagic cell death via inhibition of JNK and p38 in GSH-depleted glial cells. Copyright © 2011 Wiley-Liss, Inc.

Sleep Deprivation and Oxidative Stress in Animal Models: A Systematic Review

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Gabriel Villafuerte

2015-01-01

Full Text Available Because the function and mechanisms of sleep are partially clear, here we applied a meta-analysis to address the issue whether sleep function includes antioxidative properties in mice and rats. Given the expansion of the knowledge in the sleep field, it is indeed ambitious to describe all mammals, or other animals, in which sleep shows an antioxidant function. However, in this paper we reviewed the current understanding from basic studies in two species to drive the hypothesis that sleep is a dynamic-resting state with antioxidative properties. We performed a systematic review of articles cited in Medline, Scopus, and Web of Science until March 2015 using the following search terms: Sleep or sleep deprivation and oxidative stress, lipid peroxidation, glutathione, nitric oxide, catalase or superoxide dismutase. We found a total of 266 studies. After inclusion and exclusion criteria, 44 articles were included, which are presented and discussed in this study. The complex relationship between sleep duration and oxidative stress is discussed. Further studies should consider molecular and genetic approaches to determine whether disrupted sleep promotes oxidative stress.

Bystander effects in UV-induced genomic instability: Antioxidants inhibit delayed mutagenesis induced by ultraviolet A and B radiation

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Dahle Jostein

2005-01-01

Full Text Available Abstract Background Genomic instability is characteristic of many types of human cancer. Recently, we reported that ultraviolet radiation induced elevated mutation rates and chromosomal instability for many cell generations after ultraviolet irradiation. The increased mutation rates of unstable cells may allow them to accumulate aberrations that subsequently lead to cancer. Ultraviolet A radiation, which primarily acts by oxidative stress, and ultraviolet B radiation, which initially acts by absorption in DNA and direct damage to DNA, both produced genomically unstable cell clones. In this study, we have determined the effect of antioxidants on induction of delayed mutations by ultraviolet radiation. Delayed mutations are indicative of genomic instability. Methods Delayed mutations in the hypoxanthine phosphoribosyl transferase (hprt gene were detected by incubating the cells in medium selectively killing hprt mutants for 8 days after irradiation, followed by a 5 day period in normal medium before determining mutation frequencies. Results The UVB-induced delayed hprt mutations were strongly inhibited by the antioxidants catalase, reduced glutathione and superoxide dismutase, while only reduced glutathione had a significant effect on UVA-induced delayed mutations. Treatment with antioxidants had only minor effects on early mutation frequenies, except that reduced glutathione decreased the UVB-induced early mutation frequency by 24 %. Incubation with reduced glutathione was shown to significantly increase the intracellular amount of reduced glutathione. Conclusion The strong effects of these antioxidants indicate that genomic instability, which is induced by the fundamentally different ultraviolet A and ultraviolet B radiation, is mediated by reactive oxygen species, including hydrogen peroxide and downstream products. However, cells take up neither catalase nor SOD, while incubation with glutathione resulted in increased intracellular levels of

The Incomplete Glutathione Puzzle: Just Guessing at Numbers and Figures?

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Deponte, Marcel

2017-11-20

Glutathione metabolism is comparable to a jigsaw puzzle with too many pieces. It is supposed to comprise (i) the reduction of disulfides, hydroperoxides, sulfenic acids, and nitrosothiols, (ii) the detoxification of aldehydes, xenobiotics, and heavy metals, and (iii) the synthesis of eicosanoids, steroids, and iron-sulfur clusters. In addition, glutathione affects oxidative protein folding and redox signaling. Here, I try to provide an overview on the relevance of glutathione-dependent pathways with an emphasis on quantitative data. Recent Advances: Intracellular redox measurements reveal that the cytosol, the nucleus, and mitochondria contain very little glutathione disulfide and that oxidative challenges are rapidly counterbalanced. Genetic approaches suggest that iron metabolism is the centerpiece of the glutathione puzzle in yeast. Furthermore, recent biochemical studies provide novel insights on glutathione transport processes and uncoupling mechanisms. Which parts of the glutathione puzzle are most relevant? Does this explain the high intracellular concentrations of reduced glutathione? How can iron-sulfur cluster biogenesis, oxidative protein folding, or redox signaling occur at high glutathione concentrations? Answers to these questions not only seem to depend on the organism, cell type, and subcellular compartment but also on different ideologies among researchers. A rational approach to compare the relevance of glutathione-dependent pathways is to combine genetic and quantitative kinetic data. However, there are still many missing pieces and too little is known about the compartment-specific repertoire and concentration of numerous metabolites, substrates, enzymes, and transporters as well as rate constants and enzyme kinetic patterns. Gathering this information might require the development of novel tools but is crucial to address potential kinetic competitions and to decipher uncoupling mechanisms to solve the glutathione puzzle. Antioxid. Redox Signal

DRAM1 Protects Neuroblastoma Cells from Oxygen-Glucose Deprivation/Reperfusion-Induced Injury via Autophagy

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Mengqiang Yu

2014-10-01

Full Text Available DNA damage-regulated autophagy modulator protein 1 (DRAM1, a multi-pass membrane lysosomal protein, is reportedly a tumor protein p53 (TP53 target gene involved in autophagy. During cerebral ischemia/reperfusion (I/R injury, DRAM1 protein expression is increased, and autophagy is activated. However, the functional significance of DRAM1 and the relationship between DRAM1 and autophagy in brain I/R remains uncertain. The aim of this study is to investigate whether DRAM1 mediates autophagy activation in cerebral I/R injury and to explore its possible effects and mechanisms. We adopt the oxygen-glucose deprivation and reperfusion (OGD/R Neuro-2a cell model to mimic cerebral I/R conditions in vitro, and RNA interference is used to knock down DRAM1 expression in this model. Cell viability assay is performed using the LIVE/DEAD viability/cytotoxicity kit. Cell phenotypic changes are analyzed through Western blot assays. Autophagy flux is monitored through the tandem red fluorescent protein–Green fluorescent protein–microtubule associated protein 1 light chain 3 (RFP–GFP–LC3 construct. The expression levels of DRAM1 and microtubule associated protein 1 light chain 3II/I (LC3II/I are strongly up-regulated in Neuro-2a cells after OGD/R treatment and peaked at the 12 h reperfusion time point. The autophagy-specific inhibitor 3-Methyladenine (3-MA inhibits the expression of DRAM1 and LC3II/I and exacerbates OGD/R-induced cell injury. Furthermore, DRAM1 knockdown aggravates OGD/R-induced cell injury and significantly blocks autophagy through decreasing autophagosome-lysosome fusion. In conclusion, our data demonstrate that DRAM1 knockdown in Neuro-2a cells inhibits autophagy by blocking autophagosome-lysosome fusion and exacerbated OGD/R-induced cell injury. Thus, DRAM1 might constitute a new therapeutic target for I/R diseases.

Fibroblast growth factor 10 protects neuron against oxygen–glucose deprivation injury through inducing heme oxygenase-1

International Nuclear Information System (INIS)

Li, Yong-Hua; Yang, Li-Ye; Chen, Wei; Li, Ying-Ke; Yuan, Hong-Bin

2015-01-01

Highlights: • FGF10 attenuates OGD induced injury in cortical neuron. • FGF10 reduces OGD triggered ROS level in cortical neuron. • FGF10 induces HO-1 expression upon OGD stimuli in cortical neuron. • Knockdown of HO-1 impairs the neuroprotection of FGF10 in OGD model. - Abstract: Fibroblast growth factors (FGFs) are a family of structurally related heparin-binding proteins with diverse biological functions. FGFs participate in mitogenesis, angiogenesis, cell proliferation, development, differentiation and cell migration. Here, we investigated the potential effect of FGF10, a member of FGFs, on neuron survival in oxygen–glucose deprivation (OGD) model. In primary cultured mouse cortical neurons upon OGD, FGF10 treatment (100 and 1000 ng/ml) attenuated the decrease of cell viability and rescued the LDH release. Tuj-1 immunocytochemistry assay showed that FGF10 promoted neuronal survival. Apoptosis assay with Annexin V + PI by flow cytometry demonstrated that FGF10 treatment reduced apoptotic cell proportion. Moreover, immunoblotting showed that FGF10 alleviated the cleaved caspase-3 upregulation caused by OGD. FGF10 treatment also depressed the OGD-induced increase of caspase-3, -8 and -9 activities. At last, we found FGF10 triggered heme oxygenase-1 (HO-1) protein expression rather than hypoxia-inducible factor-1 (HIF-1), AMP-activated protein kinase (AMPK) signaling and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling. Knockdown of HO-1 by siRNA partly abolished the neuroprotection of FGF10 in OGD model. In summary, our observations provide the first evidence for the neuroprotective function of FGF10 against ischemic neuronal injury and suggest that FGF10 may be a promising agent for treatment of ischemic stroke

Fibroblast growth factor 10 protects neuron against oxygen–glucose deprivation injury through inducing heme oxygenase-1

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Li, Yong-Hua; Yang, Li-Ye; Chen, Wei; Li, Ying-Ke, E-mail: liyingke6f@126.com; Yuan, Hong-Bin, E-mail: yuanhongbin6f@126.com

2015-01-02

Highlights: • FGF10 attenuates OGD induced injury in cortical neuron. • FGF10 reduces OGD triggered ROS level in cortical neuron. • FGF10 induces HO-1 expression upon OGD stimuli in cortical neuron. • Knockdown of HO-1 impairs the neuroprotection of FGF10 in OGD model. - Abstract: Fibroblast growth factors (FGFs) are a family of structurally related heparin-binding proteins with diverse biological functions. FGFs participate in mitogenesis, angiogenesis, cell proliferation, development, differentiation and cell migration. Here, we investigated the potential effect of FGF10, a member of FGFs, on neuron survival in oxygen–glucose deprivation (OGD) model. In primary cultured mouse cortical neurons upon OGD, FGF10 treatment (100 and 1000 ng/ml) attenuated the decrease of cell viability and rescued the LDH release. Tuj-1 immunocytochemistry assay showed that FGF10 promoted neuronal survival. Apoptosis assay with Annexin V + PI by flow cytometry demonstrated that FGF10 treatment reduced apoptotic cell proportion. Moreover, immunoblotting showed that FGF10 alleviated the cleaved caspase-3 upregulation caused by OGD. FGF10 treatment also depressed the OGD-induced increase of caspase-3, -8 and -9 activities. At last, we found FGF10 triggered heme oxygenase-1 (HO-1) protein expression rather than hypoxia-inducible factor-1 (HIF-1), AMP-activated protein kinase (AMPK) signaling and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling. Knockdown of HO-1 by siRNA partly abolished the neuroprotection of FGF10 in OGD model. In summary, our observations provide the first evidence for the neuroprotective function of FGF10 against ischemic neuronal injury and suggest that FGF10 may be a promising agent for treatment of ischemic stroke.

[Effect of acupuncture on pattern-visual evoked potential in rats with monocular visual deprivation].

Science.gov (United States)

Yan, Xing-Ke; Dong, Li-Li; Liu, An-Guo; Wang, Jun-Yan; Ma, Chong-Bing; Zhu, Tian-Tian

2013-08-01

To explore electrophysiology mechanism of acupuncture for treatment and prevention of visual deprivation effect. Eighteen healthy 15-day Evans rats were randomly divided into a normal group, a model group and an acupuncture group, 6 rats in each one. Deprivation amblyopia model was established by monocular eyelid suture in the model group and acupuncture group. Acupuncture was applied at "Jingming" (BL 1), "Chengqi" (ST 1), "Qiuhou" (EX-HN 7) and "Cuanzhu" (BL 2) in the acupuncture group. The bilateral acupoints were selected alternately, one side for a day, and totally 14 days were required. The effect of acupuncture on visual evoked potential in different spatial frequencies was observed. Under three different kinds of spatial frequencies of 2 X 2, 4 X 4 and 8 X 8, compared with normal group, there was obvious visual deprivation effect in the model group where P1 peak latency was delayed (P0.05). Under spatial frequency of 4 X 4, N1-P1 amplitude value was maximum in the normal group and acupuncture group. With this spatial frequency the rat's eye had best resolving ability, indicating it could be the best spatial frequency for rat visual system. The visual system has obvious electrophysiology plasticity in sensitive period. Acupuncture treatment could adjust visual deprivation-induced suppression and slow of visual response in order to antagonism deprivation effect.

State dependent valuation: the effect of deprivation on risk preferences.

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Dino J Levy

Full Text Available The internal state of an organism affects its choices. Previous studies in various non-human animals have demonstrated a complex, and in some cases non-monotonic, interaction between internal state and risk preferences. Our aim was to examine the systematic effects of deprivation on human decision-making across various reward types. Using both a non-parametric approach and a classical economic analysis, we asked whether the risk attitudes of human subjects towards money, food and water rewards would change as a function of their internal metabolic state. Our findings replicate some previous work suggesting that, on average, humans become more risk tolerant in their monetary decisions, as they get hungry. However, our specific approach allowed us to make two novel observations about the complex interaction between internal state and risk preferences. First, we found that the change in risk attitude induced by food deprivation is a general phenomenon, affecting attitudes towards both monetary and consumable rewards. But much more importantly, our data indicate that rather than each subject becoming more risk tolerant as previously hypothesized based on averaging across subjects, we found that as a population of human subjects becomes food deprived the heterogeneity of their risk attitudes collapses towards a fixed point. Thus subjects who show high-risk aversion while satiated shift towards moderate risk aversion when deprived but subjects who are risk tolerant become more risk averse. These findings demonstrate a more complicated interaction between internal state and risk preferences and raise some interesting implications for both day-to-day decisions and financial market structures.

State dependent valuation: the effect of deprivation on risk preferences.

Science.gov (United States)

Levy, Dino J; Thavikulwat, Amalie C; Glimcher, Paul W

2013-01-01

The internal state of an organism affects its choices. Previous studies in various non-human animals have demonstrated a complex, and in some cases non-monotonic, interaction between internal state and risk preferences. Our aim was to examine the systematic effects of deprivation on human decision-making across various reward types. Using both a non-parametric approach and a classical economic analysis, we asked whether the risk attitudes of human subjects towards money, food and water rewards would change as a function of their internal metabolic state. Our findings replicate some previous work suggesting that, on average, humans become more risk tolerant in their monetary decisions, as they get hungry. However, our specific approach allowed us to make two novel observations about the complex interaction between internal state and risk preferences. First, we found that the change in risk attitude induced by food deprivation is a general phenomenon, affecting attitudes towards both monetary and consumable rewards. But much more importantly, our data indicate that rather than each subject becoming more risk tolerant as previously hypothesized based on averaging across subjects, we found that as a population of human subjects becomes food deprived the heterogeneity of their risk attitudes collapses towards a fixed point. Thus subjects who show high-risk aversion while satiated shift towards moderate risk aversion when deprived but subjects who are risk tolerant become more risk averse. These findings demonstrate a more complicated interaction between internal state and risk preferences and raise some interesting implications for both day-to-day decisions and financial market structures.

The antioxidant master glutathione and periodontal health

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Vivek Kumar Bains

2015-01-01

Full Text Available Glutathione, considered to be the master antioxidant (AO, is the most-important redox regulator that controls inflammatory processes, and thus damage to the periodontium. Periodontitis patients have reduced total AO capacity in whole saliva, and lower concentrations of reduced glutathione (GSH in serum and gingival crevicular fluid, and periodontal therapy restores the redox balance. Therapeutic considerations for the adjunctive use of glutathione in management of periodontitis, in limiting the tissue damage associated with oxidative stress, and enhancing wound healing cannot be underestimated, but need to be evaluated further through multi-centered randomized controlled trials.

Glutathione Transferases Superfamily: Cold-Inducible Expression of Distinct GST Genes in Brassica oleracea

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Harshavardhanan Vijayakumar

2016-07-01

Full Text Available Plants, as sessile organisms, can suffer serious growth and developmental consequences under cold stress conditions. Glutathione transferases (GSTs, EC 2.5.1.18 are ubiquitous and multifunctional conjugating proteins, which play a major role in stress responses by preventing oxidative damage by reactive oxygen species (ROS. Currently, understanding of their function(s during different biochemical and signaling pathways under cold stress condition remain unclear. In this study, using combined computational strategy, we identified 65 Brassica oleracea glutathione transferases (BoGST and characterized them based on evolutionary analysis into 11 classes. Inter-species and intra-species duplication was evident between BoGSTs and Arabidopsis GSTs. Based on localization analyses, we propose possible pathways in which GST genes are involved during cold stress. Further, expression analysis of the predicted putative functions for GST genes were investigated in two cold contrasting genotypes (cold tolerance and susceptible under cold condition, most of these genes were highly expressed at 6 h and 1 h in the cold tolerant (CT and cold susceptible (CS lines, respectively. Overall, BoGSTU19, BoGSTU24, BoGSTF10 are candidate genes highly expressed in B. oleracea. Further investigation of GST superfamily in B. oleracea will aid in understanding complex mechanism underlying cold tolerance in plants.

Sleep Deprivation and Time-Based Prospective Memory.

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Esposito, Maria José; Occhionero, Miranda; Cicogna, PierCarla

2015-11-01

To evaluate the effect of sleep deprivation on time-based prospective memory performance, that is, realizing delayed intentions at an appropriate time in the future (e.g., to take a medicine in 30 minutes). Between-subjects experimental design. The experimental group underwent 24 h of total sleep deprivation, and the control group had a regular sleep-wake cycle. Participants were tested at 08:00. Laboratory. Fifty healthy young adults (mean age 22 ± 2.1, 31 female). 24 h of total sleep deprivation. Participants were monitored by wrist actigraphy for 3 days before the experimental session. The following cognitive tasks were administered: one time-based prospective memory task and 3 reasoning tasks as ongoing activity. Objective and subjective vigilance was assessed by the psychomotor vigilance task and a visual analog scale, respectively. To measure the time-based prospective memory task we assessed compliance and clock checking behavior (time monitoring). Sleep deprivation negatively affected time-based prospective memory compliance (P sleep deprivation on human behavior, particularly the ability to perform an intended action after a few minutes. Sleep deprivation strongly compromises time-based prospective memory compliance but does not affect time check frequency. Sleep deprivation may impair the mechanism that allows the integration of information related to time monitoring with the prospective intention. © 2015 Associated Professional Sleep Societies, LLC.

Sleep deprivation affects reactivity to positive but not negative stimuli.

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Pilcher, June J; Callan, Christina; Posey, J Laura

2015-12-01

The current study examined the effects of partial and total sleep deprivation on emotional reactivity. Twenty-eight partially sleep-deprived participants and 31 totally sleep-deprived participants rated their valence and arousal responses to positive and negative pictures across four testing sessions during the day following partial sleep deprivation or during the night under total sleep deprivation. The results suggest that valence and arousal ratings decreased under both sleep deprivation conditions. In addition, partial and total sleep deprivation had a greater negative effect on positive events than negative events. These results suggest that sleep-deprived persons are more likely to respond less to positive events than negative events. One explanation for the current findings is that negative events could elicit more attentive behavior and thus stable responding under sleep deprivation conditions. As such, sleep deprivation could impact reactivity to emotional stimuli through automated attentional and self-regulatory processes. Copyright © 2015 Elsevier Inc. All rights reserved.

Glutathione-mediated detoxification of halobenzoquinone drinking water disinfection byproducts in T24 cells.

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Li, Jinhua; Wang, Wei; Zhang, Hongquan; Le, X Chris; Li, Xing-Fang

2014-10-01

Halobenzoquinones (HBQs) are a new class of drinking water disinfection byproducts (DBPs) and are capable of producing reactive oxygen species and causing oxidative damage to proteins and DNA in T24 human bladder carcinoma cells. However, the exact mechanism of the cytotoxicity of HBQs is unknown. Here, we investigated the role of glutathione (GSH) and GSH-related enzymes including glutathione S-transferase (GST) and glutathione peroxidase (GPx) in defense against HBQ-induced cytotoxicity in T24 cells. The HBQs are 2,6-dichloro-1,4-benzoquinone (DCBQ), 2,6-dichloro-3-methyl-1,4-benzoquinone (DCMBQ), 2,3,6-trichloro-1,4-benzoquinone (TriCBQ), and 2,6-dibromobenzoquinone (DBBQ). We found that depletion of cellular GSH could sensitize cells to HBQs and extracellular GSH supplementation could attenuate HBQ-induced cytotoxicity. HBQs caused significant cellular GSH depletion and increased cellular GST activities in a concentration-dependent manner. Our mass spectrometry study confirms that HBQs can conjugate with GSH, explaining in part the mechanism of GSH depletion by HBQs. The effects of HBQs on GPx activity are compound dependent; DCMBQ and DBBQ decrease cellular GPx activities, whereas DCBQ and TriCBQ have no significant effects. Pearson correlation analysis shows that the cellular GSH level is inversely correlated with ROS production and cellular GST activity in HBQ-treated cells. These results support a GSH and GSH-related enzyme-mediated detoxification mechanism of HBQs in T24 cells. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Exercise attenuates negative effects of abstinence during 72 hours of smoking deprivation.

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Conklin, Cynthia A; Soreca, Isabella; Kupfer, David J; Cheng, Yu; Salkeld, Ronald P; Mumma, Joel M; Jakicic, John M; Joyce, Christopher J

2017-08-01

Exercise is presumed to be a potentially helpful smoking cessation adjunct reputed to attenuate the negative effects of deprivation. The present study examined the effectiveness of moderate within-session exercise to reduce 4 key symptoms of smoking deprivation during 3 72-hr nicotine abstinence blocks in both male and female smokers. Forty-nine (25 male, 24 female) sedentary smokers abstained from smoking for 3 consecutive days on 3 separate occasions. At each session, smokers' abstinence-induced craving, cue-induced craving, negative mood, and withdrawal symptom severity were assessed prior to and after either exercise (a.m. exercise, p.m. exercise) or a sedentary control activity (magazine reading). Abstinence-induced craving and negative mood differed as a function of condition, F(2, 385) = 21, p exercise, but exercise overall led to greater pre-post reduction in abstinence-induced craving, t(385) = 6.23, p exercise also led to a larger pre-post reduction in cue-induced craving in response to smoking cues, F(2, 387) = 8.94, p = .0002; and withdrawal severity, F(2, 385) = 3.8, p = .02. Unlike the other 3 measures, p.m. exercise reduced withdrawal severity over control, t(385) = 2.64, p = .009, d = 0.27, whereas a.m. exercise did not. The results support the clinical potential of exercise to assist smokers in managing common and robust negative symptoms experienced during the first 3 days of abstinence. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Glutathione deficiency induced by cystine and/or methionine deprivation does not affect thyroid hormone deiodination in cultured rat hepatocytes and monkey hepatocarcinoma cells

International Nuclear Information System (INIS)

Sato, K.; Robbins, J.

1981-01-01

To elucidate the recently advanced hypothesis that glutathione [L-gamma-glutamyl-L-cysteinyl glycine (GSH)] regulates deiodinating enzyme activities, accounting for the decreased conversion of T4 to T3 in the liver of fetal and starved animals, we investigated thyroid hormone metabolism in GSH-depleted neoplastic and normal hepatocytes. In monkey hepatocarcinoma cells, intracellular total GSH decreased below 10% of the control value (approximately 25 micrograms/mg protein) when cells were grown for 44 h in medium deficient in cystine and methionine or in cystine alone. The latter finding indicated that transsulfuration from methionine to cysteine was defective in these neoplastic cells. In primary cultured adult rat hepatocytes, on the other hand, the transsulfuration pathway was intact, and total GSH decreased below 10% of control (approximately 20 micrograms/mg protein) only in cells grown in cystine- and methionine-deficient medium. In both cell types, the oxidized GSH fraction remained constant (2-5% of total). Incubation with 125I-labeled T4 and T3, followed by chromatography, was used to evaluate 5-deiodination in hepatocarcinoma cells and both 5- and 5'-deiodination in normal hepatocytes. Deiodination was not decreased by GSH deficiency in either case, but was actually increased in hepatocarcinoma cells. This resulted from an increase in the Vmax of 5-deiodinase related to growth arrest. Diamide at 2 mM reversibly inhibited both 5'- and 5'-deiodination in rat hepatocytes, accompanied by decreased total GSH as well as increased GSH disulfide (27% of total). The data suggest that GSH is so abundant in the liver that hepatocytes can tolerate a greater than 90% decrease in intracellular concentration without any change in thyroid hormone deiodination and indicate that altered thyroid hormone metabolism in the fetus and in starvation cannot be accounted for by a decreased hepatic GSH concentration

TNFα G308A polymorphism is associated with resilience to sleep deprivation-induced psychomotor vigilance performance impairment in healthy young adults.

Science.gov (United States)

Satterfield, Brieann C; Wisor, Jonathan P; Field, Stephanie A; Schmidt, Michelle A; Van Dongen, Hans P A

2015-07-01

Cytokines such as TNFα play an integral role in sleep/wake regulation and have recently been hypothesized to be involved in cognitive impairment due to sleep deprivation. We examined the effect of a guanine to adenine substitution at position 308 in the TNFα gene (TNFα G308A) on psychomotor vigilance performance impairment during total sleep deprivation. A total of 88 healthy women and men (ages 22-40) participated in one of five laboratory total sleep deprivation experiments. Performance on a psychomotor vigilance test (PVT) was measured every 2-3h. The TNFα 308A allele, which is less common than the 308G allele, was associated with greater resilience to psychomotor vigilance performance impairment during total sleep deprivation (regardless of time of day), and also provided a small performance benefit at baseline. The effect of genotype on resilience persisted when controlling for between-subjects differences in age, gender, race/ethnicity, and baseline sleep duration. The TNFα G308A polymorphism predicted less than 10% of the overall between-subjects variance in performance impairment during sleep deprivation. Nonetheless, the differential effect of the polymorphism at the peak of performance impairment was more than 50% of median performance impairment at that time, which is sizeable compared to the effects of other genotypes reported in the literature. Our findings provided evidence for a role of TNFα in the effects of sleep deprivation on psychomotor vigilance performance. Furthermore, the TNFα G308A polymorphism may have predictive potential in a biomarker panel for the assessment of resilience to psychomotor vigilance performance impairment due to sleep deprivation. Copyright © 2014 Elsevier Inc. All rights reserved.

Sleep deprived and sweating it out: the effects of total sleep deprivation on skin conductance reactivity to psychosocial stress.

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Liu, Jean C J; Verhulst, Silvan; Massar, Stijn A A; Chee, Michael W L

2015-01-01

We examined how sleep deprivation alters physiological responses to psychosocial stress by evaluating changes in skin conductance. Between-subjects design with one group allocated to 24 h of total sleep deprivation and the other to rested wakefulness. The study took place in a research laboratory. Participants were 40 healthy young adults recruited from a university. Sleep deprivation and feedback. Electrodermal activity was monitored while participants completed a difficult perceptual task with false feedback. All participants showed increased skin conductance levels following stress. However, compared to well-rested participants, sleep deprived participants showed higher skin conductance reactivity with increasing stress levels. Our results suggest that sleep deprivation augments allostatic responses to increasing psychosocial stress. Consequentially, we propose sleep loss as a risk factor that can influence the pathogenic effects of stress. © 2014 Associated Professional Sleep Societies, LLC.

Long-Term Effects of Maternal Deprivation on Redox Regulation in Rat Brain: Involvement of NADPH Oxidase

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Branka Marković

2017-01-01

Full Text Available Maternal deprivation (MD causes perinatal stress, with subsequent behavioral changes which resemble the symptoms of schizophrenia. The NADPH oxidase is one of the major generators of reactive oxygen species, known to play a role in stress response in different tissues. The aim of this study was to elucidate the long-term effects of MD on the expression of NADPH oxidase subunits (gp91phox, p22phox, p67phox, p47phox, and p40phox. Activities of cytochrome C oxidase and respiratory chain Complex I, as well as the oxidative stress parameters using appropriate spectrophotometric techniques were analyzed. Nine-day-old Wistar rats were exposed to a 24 h maternal deprivation and sacrificed at young adult age. The structures affected by perinatal stress, cortex, hippocampus, thalamus, and caudate nuclei were investigated. The most prominent findings were increased expressions of gp91phox in the cortex and hippocampus, increased expression of p22phox and p40phox, and decreased expression of gp91phox, p22phox, and p47phox in the caudate nuclei. Complex I activity was increased in all structures except cortex. Content of reduced glutathione was decreased in all sections while region-specific changes of other oxidative stress parameters were found. Our results indicate the presence of long-term redox alterations in MD rats.

Spontaneous sleep-wake cycle and sleep deprivation differently induce Bdnf1, Bdnf4 and Bdnf9a DNA methylation and transcripts levels in the basal forebrain and frontal cortex in rats.

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Ventskovska, Olena; Porkka-Heiskanen, Tarja; Karpova, Nina N

2015-04-01

Brain-derived neurotrophic factor (Bdnf) regulates neuronal plasticity, slow wave activity and sleep homeostasis. Environmental stimuli control Bdnf expression through epigenetic mechanisms, but there are no data on epigenetic regulation of Bdnf by sleep or sleep deprivation. Here we investigated whether 5-methylcytosine (5mC) DNA modification at Bdnf promoters p1, p4 and p9 influences Bdnf1, Bdnf4 and Bdnf9a expression during the normal inactive phase or after sleep deprivation (SD) (3, 6 and 12 h, end-times being ZT3, ZT6 and ZT12) in rats in two brain areas involved in sleep regulation, the basal forebrain and cortex. We found a daytime variation in cortical Bdnf expression: Bdnf1 expression was highest at ZT6 and Bdnf4 lowest at ZT12. Such variation was not observed in the basal forebrain. Also Bdnf p1 and p9 methylation levels differed only in the cortex, while Bdnf p4 methylation did not vary in either area. Factorial analysis revealed that sleep deprivation significantly induced Bdnf1 and Bdnf4 with the similar pattern for Bdnf9a in both basal forebrain and cortex; 12 h of sleep deprivation decreased 5mC levels at the cortical Bdnf p4 and p9. Regression analysis between the 5mC promoter levels and the corresponding Bdnf transcript expression revealed significant negative correlations for the basal forebrain Bdnf1 and cortical Bdnf9a transcripts in only non-deprived rats, while these correlations were lost after sleep deprivation. Our results suggest that Bdnf transcription during the light phase of undisturbed sleep-wake cycle but not after SD is regulated at least partially by brain site-specific DNA methylation. © 2014 European Sleep Research Society.

Iron deprivation induces apoptosis independently of p53 in human and murine tumour cells

Czech Academy of Sciences Publication Activity Database

Truksa, Jaroslav; Kovář, Jan; Valenta, Tomáš; Ehrlichová, Marie; Polák, J.; Naumann, P. W.

2003-01-01

Roč. 36, č. 4 (2003), s. 199-213 ISSN 0960-7722 R&D Projects: GA ČR GA301/01/0041 Keywords : iron deprivation * p53 * apoptosis induction Subject RIV: EB - Gene tics ; Molecular Biology Impact factor: 1.529, year: 2003

Relative deprivation and disordered gambling in youths.

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Elgar, Frank J; Canale, Natale; Wohl, Michael J A; Lenzi, Michela; Vieno, Alessio

2018-03-07

Previous research has found that area-level income inequality and individual-level relative deprivation both contribute to disordered gambling in adults. However, the socioeconomic factors that contribute to disordered gambling in youths and protective factors in their social environment have not been fully explored. This study examined the association between relative deprivation and youth disordered gambling and the potential moderating role of social support in this association. We used data on family material assets and self-reported symptoms of disordered gambling symptoms in 19 321 participants of the 2013/2014 Italian Health Behaviour in School-aged Children study. Relative deprivation was measured using the Yitzhaki index and classmates as a social reference group. Its association with disordered gambling was tested using multilevel negative binomial regression analyses. We also tested moderated effects of relative deprivation on disordered gambling by four sources of social support: families, peers, teachers and classmates. Relative deprivation related to a fourfold increase in the rate of disordered gambling symptoms (incidence rate ratio=4.18) after differences in absolute family wealth and other variables were statistically controlled. Symptoms were also more prevalent in males, first-generation immigrants and less supported youth. Peer support moderated the association between relative deprivation and symptoms, suggesting that high deprivation and low peer support have interactive links to disordered gambling. Relative deprivation among classmates relate to youth symptoms of disordered gambling. Youth who live in economically unequal settings and perceive a lack of social support may be at greatest risk. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Oxytocin is implicated in social memory deficits induced by early sensory deprivation in mice.

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Zhang, Jin-Bao; Chen, Ling; Lv, Zhu-Man; Niu, Xue-Yuan; Shao, Can-Can; Zhang, Chan; Pruski, Michal; Huang, Ying; Qi, Cong-Cong; Song, Ning-Ning; Lang, Bing; Ding, Yu-Qiang

2016-12-13

Early-life sensory input plays a crucial role in brain development. Although deprivation of orofacial sensory input at perinatal stages disrupts the establishment of the barrel cortex and relevant callosal connections, its long-term effect on adult behavior remains elusive. In this study, we investigated the behavioral phenotypes in adult mice with unilateral transection of the infraorbital nerve (ION) at postnatal day 3 (P3). Although ION-transected mice had normal locomotor activity, motor coordination, olfaction, anxiety-like behaviors, novel object memory, preference for social novelty and sociability, they presented deficits in social memory and spatial memory compared with control mice. In addition, the social memory deficit was associated with reduced oxytocin (OXT) levels in the hypothalamus and could be partially restored by intranasal administration of OXT. Thus, early sensory deprivation does result in behavioral alterations in mice, some of which may be associated with the disruption of oxytocin signaling.

Predicting Psychotic-Like Experiences during Sensory Deprivation

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Daniel, Christina; Mason, Oliver J.

2015-01-01

Aims. This study aimed to establish the contribution of hallucination proneness, anxiety, suggestibility, and fantasy proneness to psychotic-like experiences (PLEs) reported during brief sensory deprivation. Method. Twenty-four high and 22 low hallucination-prone participants reported on PLEs occurring during brief sensory deprivation and at baseline. State/trait anxiety, suggestibility, and fantasy proneness were also measured. Results. Both groups experienced a significant increase in PLEs in sensory deprivation. The high hallucination prone group reported more PLEs both at baseline and in sensory deprivation. They also scored significantly higher on measures of state/trait anxiety, suggestibility, and fantasy proneness, though these did not explain the effects of group or condition. Regression analysis found hallucination proneness to be the best predictor of the increase in PLEs, with state anxiety also being a significant predictor. Fantasy proneness and suggestibility were not significant predictors. Conclusion. This study suggests the increase in PLEs reported during sensory deprivation reflects a genuine aberration in perceptual experience, as opposed to increased tendency to make false reports due to suggestibility of fantasy proneness. The study provides further support for the use of sensory deprivation as a safe and effective nonpharmacological model of psychosis. PMID:25811027

Predicting Psychotic-Like Experiences during Sensory Deprivation

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Christina Daniel

2015-01-01

Full Text Available Aims. This study aimed to establish the contribution of hallucination proneness, anxiety, suggestibility, and fantasy proneness to psychotic-like experiences (PLEs reported during brief sensory deprivation. Method. Twenty-four high and 22 low hallucination-prone participants reported on PLEs occurring during brief sensory deprivation and at baseline. State/trait anxiety, suggestibility, and fantasy proneness were also measured. Results. Both groups experienced a significant increase in PLEs in sensory deprivation. The high hallucination prone group reported more PLEs both at baseline and in sensory deprivation. They also scored significantly higher on measures of state/trait anxiety, suggestibility, and fantasy proneness, though these did not explain the effects of group or condition. Regression analysis found hallucination proneness to be the best predictor of the increase in PLEs, with state anxiety also being a significant predictor. Fantasy proneness and suggestibility were not significant predictors. Conclusion. This study suggests the increase in PLEs reported during sensory deprivation reflects a genuine aberration in perceptual experience, as opposed to increased tendency to make false reports due to suggestibility of fantasy proneness. The study provides further support for the use of sensory deprivation as a safe and effective nonpharmacological model of psychosis.

Effects of acetylcysteine and probucol on contrast medium-induced depression of intrinsic renal glutathione peroxidase activity in diabetic rats.

Science.gov (United States)

Yen, Hsueh-Wei; Lee, Hsiang-Chun; Lai, Wen-Te; Sheu, Sheng-Hsiung

2007-04-01

Antioxidants such as N-acetylcysteine and probucol have been used to protect patients from contrast media-induced nephrotoxicity. The mechanisms underlying these protective effects are not well understood. We hypothesized that acetylcysteine and probucol alter the activity of endogenous antioxidant enzyme activity. Four weeks after induction of diabetes with streptozotocin, diabetic and nondiabetic rats were divided into three groups. Group 1 rats did not receive any antioxidant agents. Group 2 rats were treated with acetylcysteine and group 3 rats with probucol for 1 week before injection of the contrast medium diatrizoate (DTZ). We found that diabetic rats had higher renal glutathione peroxidase (GPx) activity than normal rats. DTZ suppressed renal GPx activity significantly in both group 1 diabetic and normal rats. Interestingly, renal GPx activity in both diabetic and normal rats pretreated with acetylcysteine or probucol was not inhibited by DTZ. Renal superoxide dismutase (SOD) increased significantly in normal rats after DTZ injection, but not in diabetic rats. Finally, acetylcysteine or probucol did not significantly influence renal SOD. These findings suggest that the renal protective effects of acetylcysteine and probucol against contrast-induced oxidative stress and nephrotoxicity may be mediated by altering endogenous GPx activity.

21 CFR 864.7375 - Glutathione reductase assay.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Glutathione reductase assay. 864.7375 Section 864.7375 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Kits and Packages § 864.7375 Glutathione...

Augmented Reality as a Countermeasure for Sleep Deprivation.

Science.gov (United States)

Baumeister, James; Dorrlan, Jillian; Banks, Siobhan; Chatburn, Alex; Smith, Ross T; Carskadon, Mary A; Lushington, Kurt; Thomas, Bruce H

2016-04-01

Sleep deprivation is known to have serious deleterious effects on executive functioning and job performance. Augmented reality has an ability to place pertinent information at the fore, guiding visual focus and reducing instructional complexity. This paper presents a study to explore how spatial augmented reality instructions impact procedural task performance on sleep deprived users. The user study was conducted to examine performance on a procedural task at six time points over the course of a night of total sleep deprivation. Tasks were provided either by spatial augmented reality-based projections or on an adjacent monitor. The results indicate that participant errors significantly increased with the monitor condition when sleep deprived. The augmented reality condition exhibited a positive influence with participant errors and completion time having no significant increase when sleep deprived. The results of our study show that spatial augmented reality is an effective sleep deprivation countermeasure under laboratory conditions.

PERK pathway is involved in oxygen-glucose-serum deprivation-induced NF-kB activation via ROS generation in spinal cord astrocytes.

Science.gov (United States)

Liu, Jinbo; Du, Lijian

2015-11-13

Mitochondrial dysfunction is a direct target of hypoxic/ischemic stress in astrocytes, which results in the increased production of reactive oxygen species (ROS). Previous reports showed that ROS can activate NF-kB in spinal cord astrocytes, which occurs as a secondary injury during the pathological process of spinal cord injury (SCI). Protein kinase RNA (PKR)-like ER kinase (PERK) plays an important role in mitochondrial dysfunction. To elucidate the specific role of PERK in hypoxic/ischemic-induced NF-kB activation in spinal astrocytes, we utilized an in vitro oxygen-glucose deprivation (OGD) model, which showed an enhanced formation of ROS and NF-kB activation. Knockdown of PERK resulted in reduced activation of PERK and ROS generation in astrocytes under OGD conditions. Notably, the knockdown of PERK also induced NF-kB activation in astrocytes. These data suggest that PERK is required for the hypoxic/ischemic-induced-dependent regulation of ROS and that it is involved in NF-kB activation in the astrocytes. Copyright © 2015 Elsevier Inc. All rights reserved.

A Lipid Transfer Protein Increases the Glutathione Content and Enhances Arabidopsis Resistance to a Trichothecene Mycotoxin.

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John E McLaughlin

Full Text Available Fusarium head blight (FHB or scab is one of the most important plant diseases worldwide, affecting wheat, barley and other small grains. Trichothecene mycotoxins such as deoxynivalenol (DON accumulate in the grain, presenting a food safety risk and health hazard to humans and animals. Despite considerable breeding efforts, highly resistant wheat or barley cultivars are not available. We screened an activation tagged Arabidopsis thaliana population for resistance to trichothecin (Tcin, a type B trichothecene in the same class as DON. Here we show that one of the resistant lines identified, trichothecene resistant 1 (trr1 contains a T-DNA insertion upstream of two nonspecific lipid transfer protein (nsLTP genes, AtLTP4.4 and AtLTP4.5. Expression of both nsLTP genes was induced in trr1 over 10-fold relative to wild type. Overexpression of AtLTP4.4 provided greater resistance to Tcin than AtLTP4.5 in Arabidopsis thaliana and in Saccharomyces cerevisiae relative to wild type or vector transformed lines, suggesting a conserved protection mechanism. Tcin treatment increased reactive oxygen species (ROS production in Arabidopsis and ROS stain was associated with the chloroplast, the cell wall and the apoplast. ROS levels were attenuated in Arabidopsis and in yeast overexpressing AtLTP4.4 relative to the controls. Exogenous addition of glutathione and other antioxidants enhanced resistance of Arabidopsis to Tcin while the addition of buthionine sulfoximine, an inhibitor of glutathione synthesis, increased sensitivity, suggesting that resistance was mediated by glutathione. Total glutathione content was significantly higher in Arabidopsis and in yeast overexpressing AtLTP4.4 relative to the controls, highlighting the importance of AtLTP4.4 in maintaining the redox state. These results demonstrate that trichothecenes cause ROS accumulation and overexpression of AtLTP4.4 protects against trichothecene-induced oxidative stress by increasing the glutathione

Molecularly imprinted solid-phase extraction of glutathione from urine samples

International Nuclear Information System (INIS)

Song, Renyuan; Hu, Xiaoling; Guan, Ping; Li, Ji; Zhao, Na; Wang, Qiaoli

2014-01-01

Molecularly imprinted polymer (MIP) particles for glutathione were synthesized through iniferter-controlled living radical precipitation polymerization (IRPP) under ultraviolet radiation at ambient temperature. Static adsorption, solid-phase extraction, and high-performance liquid chromatography were carried out to evaluate the adsorption properties and selective recognition characteristics of the polymers for glutathione and its structural analogs. The obtained IRPP-MIP particles exhibited a regularly spherical shape, rapid binding kinetics, high imprinting factor, and high selectivity compared with the MIP particles prepared using traditional free-radical precipitation polymerization. The selective separation and enrichment of glutathione from the mixture of glycyl-glycine and glutathione disulfide could be achieved on the IRPP-MIP cartridge. The recoveries of glutathione, glycyl-glycine, and glutathione disulfide were 95.6% ± 3.65%, 29.5% ± 1.26%, and 49.9% ± 1.71%, respectively. The detection limit (S/N = 3) of glutathione was 0.5 mg·L −1 . The relative standard deviations (RSDs) for 10 replicate detections of 50 mg·L −1 of glutathione were 5.76%, and the linear range of the calibration curve was 0.5 mg·L −1 to 200 mg·L −1 under optimized conditions. The proposed approach was successfully applied to determine glutathione in spiked human urine samples with recoveries of 90.24% to 96.20% and RSDs of 0.48% to 5.67%. - Highlights: • Imprinted polymer particles were prepared by IRPP at ambient temperature. • High imprinting factor, high selectivity, and rapid binding kinetics were achieved. • Selective solid-phase extraction of glutathione from human urine samples

Effect of glutathione on phytochelatin synthesis in tomato cells. [Lycopersicon esculentum

Energy Technology Data Exchange (ETDEWEB)

Mendum, M.L.; Gupta, S.C.; Goldsbrough, P.B. (Purdue Univ., West Lafayette, IN (USA))

1990-06-01

Growth of cell suspension cultures of tomato, Lycopersicon esculentum Mill. cv VFNT-Cherry, in the presence of cadmium is inhibited by buthionine sulfoximine, an inhibitor of glutathione synthesis. Cell growth and phytochelatin synthesis are restored to cells treated with buthionine sulfoximine by the addition of glutathione to the medium. Glutathione stimulates the accumulation of phytochelatins in cadmium treated cells, indicating that availability of glutathione can limit synthesis of these peptides. Exogenous glutathione causes a disproportionate increase in the level of smaller phytochelatins, notably ({gamma}-Glu-Cys){sub 2}-Gly. In the presence of buthionine sulfoximine and glutathione, phytochelatins that are produced upon exposure to cadmium incorporate little ({sup 35}S)cysteine, indicating that these peptides are probably not synthesized by sequential addition of cysteine and glutamate to glutathione.

1,8-Cineole ameliorates oxygen-glucose deprivation/reoxygenation-induced ischaemic injury by reducing oxidative stress in rat cortical neuron/glia.

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Ryu, Sangwoo; Park, Hyeon; Seol, Geun Hee; Choi, In-Young

2014-12-01

1,8-Cineole, the main monoterpene in many essential oils, has been used as an ingredient in flavourings and medicine. 1,8-Cineole has been shown to possess pharmacological properties, including anti-oxidative, anti-inflammatory and anti-nociceptive actions. However, to date, no studies have examined the potential of 1,8-cineole to protect against cerebral ischaemic injury. In this study, we investigated the neuroprotective effects of 1,8-cineole against cortical neuronal/glial cell injury caused by oxygen-glucose deprivation/reoxygenation (OGD/R) in an in-vitro model of ischaemia. 1,8-Cineole significantly attenuated OGD/R-induced cortical cell injury, as well as reduced n-methyl-d-aspartate (NMDA)-induced cell injury. However, it did not inhibit NMDA-induced cytosolic calcium overload. Nevertheless, 1,8-cineole significantly reduced the OGD/R- and NMDA-induced overproduction of reactive oxygen species (ROS). These results indicate that 1,8-cineole exerts neuroprotection through its anti-oxidative rather than its anti-excitotoxic, properties. The decrease in OGD/R-induced intracellular superoxide in 1,8-cineole-treated cortical cells was associated with the upregulation of superoxide dismutase activity. Moreover, 1,8-cineole showed direct ROS scavenging activity in an assay of oxygen radical absorbance capacity. Collectively, these results suggest 1,8-cineole as a potentially effective neuroprotective and anti-oxidative candidate for the treatment of patients with ischaemic stroke. © 2014 Royal Pharmaceutical Society.

Mild hypothermia protects hippocampal neurons against oxygen-glucose deprivation/reperfusion-induced injury by improving lysosomal function and autophagic flux.

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Zhou, Tianen; Liang, Lian; Liang, Yanran; Yu, Tao; Zeng, Chaotao; Jiang, Longyuan

2017-09-15

Mild hypothermia has been proven to be useful to treat brain ischemia/reperfusion injury. However, the underlying mechanisms have not yet been fully elucidated. The present study was undertaken to determine whether mild hypothermia protects hippocampal neurons against oxygen-glucose deprivation/reperfusion(OGD/R)-induced injury via improving lysosomal function and autophagic flux. The results showed that OGD/R induced the occurrence of autophagy, while the acidic environment inside the lysosomes was altered. The autophagic flux assay with RFP-GFP tf-LC3 was impeded in hippocampal neurons after OGD/R. Mild hypothermia recovered the lysosomal acidic fluorescence and the lysosomal marker protein expression of LAMP2, which decreased after OGD/R.Furthermore, we found that mild hypothermia up-regulated autophagic flux and promoted the fusion of autophagosomes and lysosomes in hippocampal neurons following OGD/R injury, but could be reversed by treatment with chloroquine, which acts as a lysosome inhibitor. We also found that mild hypothermia improved mitochondrial autophagy in hippocampal neurons following OGD/R injury. Finally,we found that chloroquine blocked the protective effects of mild hypothermia against OGD/R-induced cell death and injury. Taken together, the present study indicates that mild hypothermia protects hippocampal neurons against OGD/R-induced injury by improving lysosomal function and autophagic flux. Copyright © 2017. Published by Elsevier Inc.

Do glutathione levels decline in aging human brain?

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Tong, Junchao; Fitzmaurice, Paul S; Moszczynska, Anna; Mattina, Katie; Ang, Lee-Cyn; Boileau, Isabelle; Furukawa, Yoshiaki; Sailasuta, Napapon; Kish, Stephen J

2016-04-01

For the past 60 years a major theory of "aging" is that age-related damage is largely caused by excessive uncompensated oxidative stress. The ubiquitous tripeptide glutathione is a major antioxidant defense mechanism against reactive free radicals and has also served as a marker of changes in oxidative stress. Some (albeit conflicting) animal data suggest a loss of glutathione in brain senescence, which might compromise the ability of the aging brain to meet the demands of oxidative stress. Our objective was to establish whether advancing age is associated with glutathione deficiency in human brain. We measured reduced glutathione (GSH) levels in multiple regions of autopsied brain of normal subjects (n=74) aged one day to 99 years. Brain GSH levels during the infancy/teenage years were generally similar to those in the oldest examined adult group (76-99 years). During adulthood (23-99 years) GSH levels remained either stable (occipital cortex) or increased (caudate nucleus, frontal and cerebellar cortices). To the extent that GSH levels represent glutathione antioxidant capacity, our postmortem data suggest that human brain aging is not associated with declining glutathione status. We suggest that aged healthy human brains can maintain antioxidant capacity related to glutathione and that an age-related increase in GSH levels in some brain regions might possibly be a compensatory response to increased oxidative stress. Since our findings, although suggestive, suffer from the generic limitations of all postmortem brain studies, we also suggest the need for "replication" investigations employing the new (1)H MRS imaging procedures in living human brain. Copyright © 2016 Elsevier Inc. All rights reserved.

Restorative effects of curcumin on sleep-deprivation induced memory impairments and structural changes of the hippocampus in a rat model.

Science.gov (United States)

Noorafshan, Ali; Karimi, Fatemeh; Kamali, Ali-Mohammad; Karbalay-Doust, Saied; Nami, Mohammad

2017-11-15

The present study examined the consequences of rapid eye-movement sleep-deprivation (REM-SD) with or without curcumin treatment. The outcome measures comprised quantitative features in the three-dimensional reconstruction (3DR) CA1 and dentate gyrus in experimental and control animals using stereological procedures. Male rats were arbitrarily assigned to nine groups based on the intervention and treatment administered including: 1-cage control+distilled water, 2-cage control+curcumin (100mg/kg/day), 3-cage control+olive oil, 4-REM-SD+distilled water, 5-REM-SD+curcumin, 6-REM-SD+olive oil, 7-grid-floor control+distilled water, 8-grid-floor control+curcumin, and 9-grid-floor control+olive oil. Animals in the latter three groups were placed on wire-mesh grids in the sleep-deprivation box. REM-SD was induced by an apparatus comprising a water tank and multiple platforms. After a period of 21days, rats were submitted to the novel object-recognition task. Later, their brains were excised and evaluated using stereological methods. Our results indicated a respective 29% and 31% reduction in the total volume of CA1, and dentate gyrus in REM-SD+distilled water group as compared to the grid-floor control+distilled water group (pcurcumin compared to the REM-SD+distilled water group. This suggests the potential neuro-restorative effects of curcumin in our model. Copyright © 2017 Elsevier Inc. All rights reserved.

The Roles of Glutathione Peroxidases during Embryo Development.

Science.gov (United States)

Ufer, Christoph; Wang, Chi Chiu

2011-01-01

Embryo development relies on the complex interplay of the basic cellular processes including proliferation, differentiation, and apoptotic cell death. Precise regulation of these events is the basis for the establishment of embryonic structures and the organ development. Beginning with fertilization of the oocyte until delivery the developing embryo encounters changing environmental conditions such as varying levels of oxygen, which can give rise to reactive oxygen species (ROS). These challenges are met by the embryo with metabolic adaptations and by an array of anti-oxidative mechanisms. ROS can be deleterious by modifying biological molecules including lipids, proteins, and nucleic acids and may induce abnormal development or even embryonic lethality. On the other hand ROS are vital players of various signaling cascades that affect the balance between cell growth, differentiation, and death. An imbalance or dysregulation of these biological processes may generate cells with abnormal growth and is therefore potentially teratogenic and tumorigenic. Thus, a precise balance between processes generating ROS and those decomposing ROS is critical for normal embryo development. One tier of the cellular protective system against ROS constitutes the family of selenium-dependent glutathione peroxidases (GPx). These enzymes reduce hydroperoxides to the corresponding alcohols at the expense of reduced glutathione. Of special interest within this protein family is the moonlighting enzyme glutathione peroxidase 4 (Gpx4). This enzyme is a scavenger of lipophilic hydroperoxides on one hand, but on the other hand can be transformed into an enzymatically inactive cellular structural component. GPx4 deficiency - in contrast to all other GPx family members - leads to abnormal embryo development and finally produces a lethal phenotype in mice. This review is aimed at summarizing the current knowledge on GPx isoforms during embryo development and tumor development with an emphasis on

Nrf2-mediated antioxidant response by ethanolic extract of Sida cordifolia provides protection against alcohol-induced oxidative stress in liver by upregulation of glutathione metabolism.

Science.gov (United States)

Rejitha, S; Prathibha, P; Indira, M

2015-03-01

Objective The study aimed to evaluate the antioxidant property of ethanolic extract of Sida cordifolia (SAE) on alcohol-induced oxidative stress and to elucidate its mechanism of action. Methods Male albino rats of the Sprague-Dawley strain were grouped into four: (1) control, (2) alcohol (4 g/kg body weight), (3) SAE (50 mg/100 g body weight), and (4) alcohol (4 g/kg body weight) + SAE (50 mg/100 g body weight). Alcohol and SAE were given orally each day by gastric intubation. The duration of treatment was 90 days. Results The activities of toxicity markers in liver and serum increased significantly in alcohol-treated rats and to a lesser extent in the group administered SAE + alcohol. The activity of alcohol dehydrogenase and the reactive oxygen species level were increased significantly in alcohol-treated rats but attenuated in the SAE co-administered group. Oxidative stress was increased in alcohol-treated rats as evidenced by the lowered activities of antioxidant enzymes, decreased level of reduced glutathione (GSH), increased lipid peroxidation products, and decreased expression of γ-glutamyl cysteine synthase in liver. The co-administration of SAE with alcohol almost reversed these changes. The activity of glutathione-S-transferase and translocation of Nrf2 from cytosol to nucleus in the liver was increased in both the alcohol and alcohol + SAE groups, but the maximum changes were observed in the latter group. Discussion The SAE most likely elicits its antioxidant potential by reducing oxidative stress, enhancing the translocation of Nrf2 to nucleus and thereby regulating glutathione metabolism, leading to enhanced GSH content.

7-Glutathione-pyrrole and 7-cysteine-pyrrole are potential carcinogenic metabolites of pyrrolizidine alkaloids.

Science.gov (United States)

He, Xiaobo; Xia, Qingsu; Fu, Peter P

2017-04-03

Many pyrrolizidine alkaloids (PAs) are hepatotoxic, genotoxic, and carcinogenic phytochemicals. Metabolism of PAs in vivo generates four (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-DNA adducts that have been proposed to be responsible for PA-induced liver tumor formation in rats. In this present study, we determined that the same set of DHP-DNA adducts was formed upon the incubation of 7-glutathione-DHP and 7-cysteine-DHP with cultured human hepatocarcinoma HepG2 cells. These results suggest that 7-glutathione-DHP and 7-cysteine-DHP are reactive metabolites of PAs that can bind to cellular DNA to form DHP-DNA adducts in HepG2 cells, and can potentially initiate liver tumor formation.

Neuroprotective effects of scutellarin against hypoxic-ischemic-induced cerebral injury via augmentation of antioxidant defense capacity.

Science.gov (United States)

Guo, Hong; Hu, Li-Min; Wang, Shao-Xia; Wang, Yu-Lin; Shi, Fang; Li, Hui; Liu, Yang; Kang, Li-Yuan; Gao, Xiu-Mei

2011-12-31

An increasing number of studies has indicated that hypoxic-ischemic-induced cerebral injury is partly mediated via oxidative stress. Recent researches have focused on searching for drug and herbal manipulations to protect against hypoxic-ischemic-induced oxidative cell damage. Scutellarin is a flavonoid derived from the Erigeron breviscapus (vant.) and has been reported to exhibit neuroprotective properties. However, its precise mechanism, particularly its antioxidation mechanism, remains elusive. In the present study, we investigated the neuroprotective effects of scutellarin on middle cerebral artery occlusion (MCAO)-induced brain damage in rats, and oxygen-glucose deprivation (OGD)-induced toxicity in primary culture of rat cortical neurons. In vivo, intraperitoneal injections of scutellarin (20 and 60 mg/kg) improved the neurological score and diminished the percentage of brain infarct volume. At the same time, scutellarin significantly increased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) level in ischemic brain tissues, enhancing endogenous antioxidant activity. Moreover, pretreatment of scutellarin (25, 50 and 100 μM) protected neurons against lethal stimuli, decreased the percentage of apoptotic cells and inhibited reactive oxygen species (ROS) generation in OGD-induced primary cortical neurons in vitro. These results suggest that the preventive and therapeutic potential of scutellarin in cerebral injury patients is, at least in part, ascribed to augmentation of cellular antioxidant defense capacity.

Perceived deprivation in active duty military nurse anesthetists.

Science.gov (United States)

Pearson, Julie A; Fallacaro, Michael D; Pellegrini, Joseph E

2009-02-01

There is a shortage of military Certified Registered Nurse Anesthetists (CRNAs). Relative deprivation is a perception of unfairness due to discrepancies between what one has and what one could or should have that is dependent on feelings (subjective data) and facts (objective data). Feelings of relative deprivation could contribute to the military CRNA shortage. The purposes of this study were to measure relative deprivation in active-duty military CRNAs and explore variables that correlate with relative deprivation. The descriptive, correlational study was conducted using a self-administered survey sent to 435 active-duty Army, Navy, and Air Force CRNAs. Surveys were distributed to subjects by mail and could be answered by mail or by secured website. Data were analyzed using descriptive and inferential statistics. Analysis of the data revealed a calculated response rate of 57.7%. There was no significant correlation (P pay, promotion opportunity, or scope of practice/autonomy and relative deprivation. Correlations of the psychological factors "wanting" and "deserving" with relative deprivation were significant (P < .001). Further research is indicated to identify definitive factors that can be modified to improve feelings of deprivation as they relate to retention and recruitment of military CRNAs.

Nrf1 CNC-bZIP protein promotes cell survival and nucleotide excision repair through maintaining glutathione homeostasis.

Science.gov (United States)

Han, Weinong; Ming, Mei; Zhao, Rui; Pi, Jingbo; Wu, Chunli; He, Yu-Ying

2012-05-25

Skin cancer is the most common cancer in the United States. Its major environmental risk factor is UVB radiation in sunlight. In response to UVB damage, epidermal keratinocytes activate a specific repair pathway, i.e. nucleotide excision repair, to remove UVB-induced DNA lesions. However, the regulation of UVB response is not fully understood. Here we show that the long isoform of the nuclear factor erythroid 2-related factor 1 (Nrf1, also called NFE2L1), a cytoprotective transcription factor critical for the expression of multiple antioxidant response element-dependent genes, plays an important role in the response of keratinocytes to UVB. Nrf1 loss sensitized keratinocytes to UVB-induced apoptosis by up-regulating the expression of the proapoptotic Bcl-2 family member Bik through reducing glutathione levels. Knocking down Bik reduced UVB-induced apoptosis in Nrf1-inhibited cells. In UVB-irradiated surviving cells, however, disruption of Nrf1 impaired nucleotide excision repair through suppressing the transcription of xeroderma pigmentosum C (XPC), a factor essential for initiating the global genome nucleotide excision repair by recognizing the DNA lesion and recruiting downstream factors. Nrf1 enhanced XPC expression by increasing glutathione availability but was independent of the transcription repressor of XPC. Adding XPC or glutathione restored the DNA repair capacity in Nrf1-inhibited cells. Finally, we demonstrate that Nrf1 levels are significantly reduced by UVB radiation in mouse skin and are lower in human skin tumors than in normal skin. These results indicate a novel role of Nrf1 in UVB-induced DNA damage repair and suggest Nrf1 as a tumor suppressor in the skin.

The effect of intra- and extracellular GSH depletion on aerobic radiosensitization in three cell lines

International Nuclear Information System (INIS)

Clark, E.P.; Epp, E.R.; Morse-Gaudio, M.; Biaglow, J.E.

1985-01-01

The effect of changes in the intra- and extracellular glutathione (GSH) concentrations on aerobic radiosensitization was studied in thee cell lines: CHO, V79 and A549. Intracellular GSH was metabolically depleted after the inhibition of GSH synthesis by buthionine sulfoximine (BSO) treatment of attached cell cultures. Extracellular GSH was controlled through the replacement of growth medium with a thiol-free salt solution and, where desired, by the exogenous addition of GSH. Each of the cell lines examined exhibited an enhanced aerobic radioresponse when the intracellular GSH was extensively depleted (GSH < 5% of control after 1.0 mM BSO/24 hr treatment) and the extracellular GSH concentration was zero. However, this enhanced radiosensitivity was eliminated by the addition of exogenous GSH, albeit at a high concentration (5 mM). Most interesting and as yet unexplained is the observation that GSH appears to affect restoration of the control radioresponse without increasing the intracellular GSH concentration

[TRPM8 mediates PC-12 neuronal cell apoptosis induced by oxygen-glucose deprivation through cAMP-PKA/UCP4 signaling].

Science.gov (United States)

Li, Hong-Wei; Zhou, Bin; Zhang, Hai-Hong

2016-08-20

To explore the molecular mechanism responsible for apoptosis of PC-12 neuronal cells induced by oxygen-glucose deprivation (OGD). PC12 cells were exposed to OGD for 24 h to simulate ischemia-reperfusion injury. Flow cytometry was employed detect the cell apoptosis, and the expresions of TRPM8, UCP4, cAMP and PKA in the exposed cells were detected with RT-PCR and Western blotting. The changes in the expressions of Bax, Bcl-2, cAMP, PKA and UCP4 proteins were detected in the exposed cells in resposne to inhibition of TRPM8 and cAMP-PKA signal or over-expression of UCP4. OGD for 24 induced obvious apoptosis in PC-12 cells and caused TRPM8 over-expression and inhibition of UCP4 and cAMP-PKA signaling. Inhibiting TRPM8 expression reduced the cell apoptosis and up-regulated cAMP, p-PKA and UCP4 in the cells exposed to OGD. In cells exposed to OGD, inhibition of TRPM8 and cAMP-PKA signaling suppressed the expressio of UCP4 and increased the cell apoptosis. TRPM8 mediates OGD-induced PC12 cell apoptosis through cAMP-PKA/UCP4 signaling.

Glutathione, cell proliferation and differentiation | Ashtiani | African ...

African Journals Online (AJOL)

All organisms require an equivalent source for living. Reduced glutathione is the most abundant thiol containing protein in mammalian cells and organs. Glutathione was discovered by Hopkins in 1924 who published his findings in JBC. It is a three peptide containing glutamic acid, cystein and glycin and is found in reduced ...

Homeostatic & Circadian Regulation of Wakefulness During Jet Lag and Sleep. Sleep Deprivation: Effect of Wake-Promoting Countermeasures

National Research Council Canada - National Science Library

Dinges, David

2000-01-01

.... Major human research projects on the effects of induced jet lag and sleep deprivation and their mitigation by sustained low-dose caffeine and naps were undertaken at the University of Pennsylvania...

Glutathione Metabolism and Parkinson’s Disease

OpenAIRE

Smeyne, Michelle; Smeyne, Richard Jay

2013-01-01

It has been established that oxidative stress, defined as the condition when the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson’s disease. Glutathione is a ubiquitous thiol tripeptide that acts alone, or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals and peroxynitrites. In this review, we examine the synthesis, metabolism and functional interactions of glutathione, and discuss how...

DL-2-amino-3-phosphonopropionic acid protects primary neurons from oxygen-glucose deprivation induced injury.

Science.gov (United States)

Cui, Di; Xu, Jun; Xu, Quanyi; Zuo, Guokun

2017-02-21

Cerebral infarction is a type of ischemic stroke and is one of the main causes of irreversible brain damage. Although multiple neuroprotective agents have been investigated recently, the potential of DL-2-amino-3-phosphonopropionic acid (DL-AP3) in treating oxygen-glucose deprivation (OGD)-induced neuronal injury, has not been clarified yet. This study was aimed to explore the role of DL-AP3 in primary neuronal cell cultures. Primary neurons were divided into four groups: (1) a control group that was not treated; (2) DL-AP3 group treated with 10 μM of DL-AP3; (3) OGD group, in which neurons were cultured under OGD conditions; and (4) OGD + DL-AP3 group, in which OGD model was first established and then the cells were treated with 10 μM of DL-AP3. Neuronal viability and apoptosis were measured using Cell Counting Kit-8 and flow cytometry. Expressions of phospho-Akt1 (p-Akt1) and cytochrome c were detected using Western blot. The results showed that DL-AP3 did not affect neuronal viability and apoptosis in DL-AP3 group, nor it changed p-Akt1 and cytochrome c expression (p > 0.05). In OGD + DL-AP3 group, DL-AP3 significantly attenuated the inhibitory effects of OGD on neuronal viability (p neurons from OGD-induced injury by affecting the viability and apoptosis of neurons, and by regulating the expressions of p-Akt1 and cytochrome c.

Application of superparamagnetic microspheres for affinity adsorption and purification of glutathione

International Nuclear Information System (INIS)

Wang Qiang; Guan Yueping; Yang Mingzhu

2012-01-01

The superparamagnetic poly-(MA–DVB) microspheres with micron size were synthesized by the modified suspension polymerization method. Adsorption of glutathione by magnetic poly-(MA–DVB) microspheres with IDA-copper was investigated. The effect of solution pH value, affinity adsorption and desorption of glutathione was studied. The results showed that the optimum pH value for glutathione adsorption was found at pH=3.5, the maximum capacity for glutathione of magnetic poly-(MA–DVB) microspheres was estimated at 42.4 mg/g by fitting the experimental data to the Langmuir equation. The adsorption equilibrium of glutathione was obtained in about 10 min and the adsorbed glutathione was desorbed from the magnetic microspheres in about 30 min using NaCl buffer solution. The magnetic microspheres could be repeatedly utilized for the affinity adsorption of glutathione. - Highlights: ► The magnetic microsphere with surface IDA–Cu groups was synthesized. ► The magnetic microspheres were applied for adsorption of GSH. ► The adsorption–desorption of glutathione was investigated. ► The maximum adsorption capacity of GSH was fitted at 42.4 mg/g.

Effect of Vitamin C on Glutathione Peroxidase Activities in Pregnant ...

African Journals Online (AJOL)

Glutathione peroxidase is one of the most important antioxidant enzymes in humans. We studied the relationship between serum glutathione peroxidase activity and vitamin C ingestion during normal pregnancy in women attending antenatal clinic in the University of Ilorin Teaching Hospital, Ilorin. Glutathione peroxidase ...

Compartment specific importance of glutathione during abiotic and biotic stress

Directory of Open Access Journals (Sweden)

Bernd eZechmann

2014-10-01

Full Text Available The tripeptide thiol glutathione (γ-L-glutamyl-L-cysteinyl-glycine is the most important sulfur containing antioxidant in plants and essential for plant defense against abiotic and biotic stress conditions. It is involved in the detoxification of reactive oxygen species, redox signaling, the modulation of defense gene expression and important for the regulation of enzymatic activities. Even though changes in glutathione contents are well documented in plants and its roles in plant defense are well established, still too little is known about its compartment specific importance during abiotic and biotic stress conditions. Due to technical advances in the visualization of glutathione and the redox state of plants through microscopical methods some progress was made in the last few years in studying the importance of subcellular glutathione contents during stress conditions in plants. This review summarizes the data available on compartment specific importance of glutathione in the protection against abiotic and biotic stress conditions such as high light stress, exposure to cadmium, drought, and pathogen attack (Pseudomonas, Botrytis, Tobacco Mosaic Virus. The data will be discussed in connection with the subcellular accumulation of ROS during these conditions and glutathione synthesis which are both highly compartment specific (e.g. glutathione synthesis takes place in chloroplasts and the cytosol. Thus this review will reveal the compartment specific importance of glutathione during abiotic and biotic stress conditions.

Deprivation of L-Arginine Induces Oxidative Stress Mediated Apoptosis in Leishmania donovani Promastigotes: Contribution of the Polyamine Pathway

Science.gov (United States)

Mandal, Abhishek; Das, Sushmita; Roy, Saptarshi; Ghosh, Ayan Kumar; Sardar, Abul Hasan; Verma, Sudha; Saini, Savita; Singh, Ruby; Abhishek, Kumar; Kumar, Ajay; Mandal, Chitra; Das, Pradeep

2016-01-01

The growth and survival of intracellular parasites depends on the availability of extracellular nutrients. Deprivation of nutrients viz glucose or amino acid alters redox balance in mammalian cells as well as some lower organisms. To further understand the relationship, the mechanistic role of L-arginine in regulation of redox mediated survival of Leishmania donovani promastigotes was investigated. L-arginine deprivation from the culture medium was found to inhibit cell growth, reduce proliferation and increase L-arginine uptake. Relative expression of enzymes, involved in L-arginine metabolism, which leads to polyamine and trypanothione biosynthesis, were downregulated causing decreased production of polyamines in L-arginine deprived parasites and cell death. The resultant increase in reactive oxygen species (ROS), due to L-arginine deprivation, correlated with increased NADP+/NADPH ratio, decreased superoxide dismutase (SOD) level, increased lipid peroxidation and reduced thiol content. A deficiency of L-arginine triggered phosphatidyl serine externalization, a change in mitochondrial membrane potential, release of intracellular calcium and cytochrome-c. This finally led to DNA damage in Leishmania promastigotes. In summary, the growth and survival of Leishmania depends on the availability of extracellular L-arginine. In its absence the parasite undergoes ROS mediated, caspase-independent apoptosis-like cell death. Therefore, L-arginine metabolism pathway could be a probable target for controlling the growth of Leishmania parasites and disease pathogenesis. PMID:26808657

Differential effects of total and partial sleep deprivation on salivary factors in Wistar rats.

Science.gov (United States)

Lasisi, Dr T J; Shittu, S T; Meludu, C C; Salami, A A

2017-01-01

Aim of this study was to investigate the effects of sleep deprivation on salivary factors in rats. Animals were randomly assigned into three groups of 6 animals each as control, total sleep deprivation (TSD) and partial sleep deprivation (PSD) groups. The multiple platform method was used to induce partial and total sleep deprivation for 7days. On the 8th day, stimulated saliva samples were collected for the analysis of salivary lag time, flow rate, salivary amylase activity, immunoglobulin A secretion rate and corticosterone levels using ELISA and standard kinetic enzyme assay. Data were analyzed using ANOVA with Dunnett T3 post hoc tests. Salivary flow rate reduced significantly in the TSD group compared with the PSD group as well as the control group (p=0.01). The secretion rate of salivary IgA was significantly reduced in the TSD group compared with the control group (p=0.04). Salivary amylase activity was significantly elevated in the TSD group compared with the PSD group as well as control group (psalivary lag time and levels of corticosterone among the groups. These findings suggest that total sleep deprivation is associated with reduced salivary flow rate and secretion rate of IgA as well as elevated levels of salivary amylase activity in rats. However, sleep recovery of four hours in the PSD group produced ameliorative effects on the impaired functions of salivary glands. Copyright © 2016 Elsevier Ltd. All rights reserved.

Superoxide radical (O2-) reactivity with respect to glutathione

International Nuclear Information System (INIS)

Sekaki, A.; Gardes-Albert, M.; Ferradini, C.

1984-01-01

Influence of superoxide radicals formed during gamma irradiation of glutathione in aerated aqueous solutions is examined. Solutions are buffered at pH7 and contain sodium formate for capture of H and OH radicals which are transformed in COO - radicals and then O 2 - radicals. G value of glutathione disparition vs glutathione concentration are given with and without enzyme or catalase. Reaction mechanism are interpreted [fr

Induction of glutathione synthesis in human hepatocytes by acute and chronic arsenic exposure: Differential roles of mitogen-activated protein kinases

International Nuclear Information System (INIS)

Hou, Yongyong; Wang, Yi; Wang, Huihui; Xu, Yuanyuan

2014-01-01

Highlights: • Arsenic exposure increased intracellular levels of glutathione. • Mitogen-activated protein kinases were involved in glutathione homeostasis. • ERK contributed to glutathione synthesis during acute arsenic exposure. • Glutathione synthesis was regulated by p38 at least in part independent of NRF2 during chronic arsenic exposure. - Abstract: Glutathione (GSH) is a vital component of antioxidant defense which protects cells from toxic insults. Previously we found intracellular GSH was involved in cell resistance against arsenic-induced cytotoxicity. However, molecular mechanisms of GSH homeostasis during arsenic exposure are largely undefined. Here, we investigated roles of mitogen-activated protein kinases (MAPKs) in GSH synthesis pathway with two arsenic exposure strategies by using Chang human hepatocytes. In one strategy, acute arsenic exposure (20 μM, 24 h) was applied, as MAPK signaling is generally considered to be transient. In the other one, chronic arsenic exposure (500 nM, 20 weeks) was applied, which mimicked the general human exposure to arsenic. We found that acute arsenic exposure activated extracellular signal-regulated 1/2 kinases (ERK1/2) and c-Jun N-terminal kinase (JNK) in parallel with increased transcription and nuclear translocation of factor-erythroid 2-related factor 2 (NRF2) and enhanced expression of γ-glutamyl cysteine ligase catalytic subunit (GCLC), resulting in elevated intracellular GSH levels. Specific ERK inhibitor abolished arsenic-induced NRF2 nuclear translocation and GSH synthesis. During chronic arsenic exposure which induced a malignant cellular phenotype, continuous p38 activation and NRF2 nuclear translocation were observed with enhanced GSH synthesis. Specific p38 inhibitor attenuated arsenic-enhanced GSH synthesis without changing NRF2 nuclear translocation. Taken together, our results indicate MAPK pathways play an important role in cellular GSH homeostasis in response to arsenic. However, the

The Effects of Sleep Deprivation on Pain

OpenAIRE

Kundermann, Bernd; Krieg, Jürgen-Christian; Schreiber, Wolfgang; Lautenbacher, Stefan

2004-01-01

Chronic pain syndromes are associated with alterations in sleep continuity and sleep architecture. One perspective of this relationship, which has not received much attention to date, is that disturbances of sleep affect pain. To fathom this direction of cause, experimental human and animal studies on the effects of sleep deprivation on pain processing were reviewed. According to the majority of the studies, sleep deprivation produces hyperalgesic changes. Furthermore, sleep deprivation can c...

Taurine Protected Against the Impairments of Neural Stem Cell Differentiated Neurons Induced by Oxygen-Glucose Deprivation.

Science.gov (United States)

Xiao, Bo; Liu, Huazhen; Gu, Zeyun; Liu, Sining; Ji, Cheng

2015-11-01

Cell transplantation of neural stem cells (NSCs) is a promising approach for neurological recovery both structurally and functionally. However, one big obstacle is to promote differentiation of NSCs into neurons and the followed maturation. In the present study, we aimed to investigate the protective effect of taurine on the differentiation of NSCs and subsequent maturation of their neuronal lineage, when exposed to oxygen-glucose deprivation (OGD). The results suggested that taurine (5-20 mM) promoted the viability and proliferation of NSCs, and it protected against 8 h of OGD induced impairments. Furthermore, 20 mM taurine promoted NSCs to differentiate into neurons after 7 days of culture, and it also protected against the suppressive impairments of 8 h of OGD. Consistently, taurine (20 mM) promoted the neurite sprouting and outgrowth of the NSC differentiated neurons after 14 days of differentiation, which were significantly inhibited by OGD (8 h). At D21, the mushroom spines and spine density were promoted or restored by 20 mM taurine. Taken together, the enhanced viability and proliferation of NSCs, more differentiated neurons and the promoted maturation of neurons by 20 mM taurine support its therapeutic application during stem cell therapy to enhance neurological recovery. Moreover, it protected against the impairments induced by OGD, which may highlight its role for a more direct therapeutic application especially in an ischemic stroke environment.

Glutathione level after long-term occupational elemental mercury exposure

International Nuclear Information System (INIS)

Kobal, Alfred Bogomir; Prezelj, Marija; Horvat, Milena; Krsnik, Mladen; Gibicar, Darija; Osredkar, Josko

2008-01-01

Many in vitro and in vivo studies have elucidated the interaction of inorganic mercury (Hg) and glutathione. However, human studies are limited. In this study, we investigated the potential effects of remote long-term intermittent occupational elemental Hg vapour (Hg o ) exposure on erythrocyte glutathione levels and some antioxidative enzyme activities in ex-mercury miners in the period after exposure. The study included 49 ex-mercury miners divided into subgroups of 28 still active, Hg o -not-exposed miners and 21 elderly retired miners, and 41 controls, age-matched to the miners subgroup. The control workers were taken from 'mercury-free works'. Reduced glutathione (GSH) and oxidized disulphide glutathione (GSSG) concentrations in haemolysed erythrocytes were determined by capillary electrophoresis, while total glutathione (total GSH) and the GSH/GSSG ratio were calculated from the determined values. Catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) activities in erythrocytes were measured using commercially available reagent kits, while urine Hg (U-Hg) concentrations were determined by cold vapour atomic absorption (CVAAS). No correlation of present U-Hg levels, GSH, GSSG, and antioxidative enzymes with remote occupational biological exposure indices were found. The mean CAT activity in miners and retired miners was significantly higher (p o could be an inductive and additive response to maintain the balance between GSH and antioxidative enzymes in interaction with the Hg body burden accumulated during remote occupational exposure, which does not represent a severely increased oxidative stress

Persistent short-term memory defects following sleep deprivation in a drosophila model of Parkinson disease.

Science.gov (United States)

Seugnet, Laurent; Galvin, James E; Suzuki, Yasuko; Gottschalk, Laura; Shaw, Paul J

2009-08-01

Parkinson disease (PD) is the second most common neurodegenerative disorder in the United States. It is associated with motor deficits, sleep disturbances, and cognitive impairment. The pathology associated with PD and the effects of sleep deprivation impinge, in part, upon common molecular pathways suggesting that sleep loss may be particularly deleterious to the degenerating brain. Thus we investigated the long-term consequences of sleep deprivation on shortterm memory using a Drosophila model of Parkinson disease. Transgenic strains of Drosophila melanogaster. Using the GAL4-UAS system, human alpha-synuclein was expressed throughout the nervous system of adult flies. Alpha-synuclein expressing flies (alpha S flies) and the corresponding genetic background controls were sleep deprived for 12 h at age 16 days and allowed to recover undisturbed for at least 3 days. Short-term memory was evaluated using aversive phototaxis suppression. Dopaminergic systems were assessed using mRNA profiling and immunohistochemistry. MEASURMENTS AND RESULTS: When sleep deprived at an intermediate stage of the pathology, alpha S flies showed persistent short-term memory deficits that lasted > or = 3 days. Cognitive deficits were not observed in younger alpha S flies nor in genetic background controls. Long-term impairments were not associated with accelerated loss of dopaminergic neurons. However mRNA expression of the dopamine receptors dDA1 and DAMB were significantly increased in sleep deprived alpha S flies. Blocking D1-like receptors during sleep deprivation prevented persistent shortterm memory deficits. Importantly, feeding flies the polyphenolic compound curcumin blocked long-term learning deficits. These data emphasize the importance of sleep in a degenerating/reorganizing brain and shows that pathological processes induced by sleep deprivation can be dissected at the molecular and cellular level using Drosophila genetics.

Effect of rosella ( Hibiscus sabdariffa L ) extract on glutathione-S ...

African Journals Online (AJOL)

Purpose: To determine the effect of rosella (Hibiscus sabdariffa L) extract on glutathione-S-trasferase (GST) activity and its hepatoprotective effect. Methods: A total of 25 rats were divided randomly into 5 groups (5 rats per group). Group I served as the baseline, group II was the negative control group, while groups III, IV and ...

Meta-Analysis of the Antidepressant Effects of Acute Sleep Deprivation.

Science.gov (United States)

Boland, Elaine M; Rao, Hengyi; Dinges, David F; Smith, Rachel V; Goel, Namni; Detre, John A; Basner, Mathias; Sheline, Yvette I; Thase, Michael E; Gehrman, Philip R

To provide a quantitative meta-analysis of the antidepressant effects of sleep deprivation to complement qualitative reviews addressing response rates. English-language studies from 1974 to 2016 using the keywords sleep deprivation and depression searched through PubMed and PsycINFO databases. A total of 66 independent studies met criteria for inclusion: conducted experimental sleep deprivation, reported the percentage of the sample that responded to sleep deprivation, provided a priori definition of antidepressant response, and did not seamlessly combine sleep deprivation with other therapies (eg, chronotherapeutics, repetitive transcranial magnetic stimulation). Data extracted included percentage of responders, type of sample (eg, bipolar, unipolar), type of sleep deprivation (eg, total, partial), demographics, medication use, type of outcome measure used, and definition of response (eg, 30% reduction in depression ratings). Data were analyzed with meta-analysis of proportions and a Poisson mixed-effects regression model. The overall response rate to sleep deprivation was 45% among studies that utilized a randomized control group and 50% among studies that did not. The response to sleep deprivation was not affected significantly by the type of sleep deprivation performed, the nature of the clinical sample, medication status, the definition of response used, or age and gender of the sample. These findings support a significant effect of sleep deprivation and suggest the need for future studies on the phenotypic nature of the antidepressant response to sleep deprivation, on the neurobiological mechanisms of action, and on moderators of the sleep deprivation treatment response in depression. © Copyright 2017 Physicians Postgraduate Press, Inc.

Glutathione attenuates uranyl toxicity in Lactococcus lactis

International Nuclear Information System (INIS)

Fahmy, Karim; Oertel, Jana; Solioz, M.

2017-01-01

We investigated the role of intracellular glutathione (GSH), which in a large number of taxa plays a role in the protection against the toxicity of heavy metals. Anaerobically grown Lactococcus lactis containing an inducible GSH synthesis pathway was used as a model organism allowing the study of GSH-dependent uranyl detoxification without interference from additional reactive oxygen species. Microcalorimetric measurements of the metabolic heat showed that intracellular GSH attenuates the toxicity of uranium at a concentration in the range of 10-150 μM. Isothermal titration calorimetry revealed the endothermic binding of U(VI) to the carboxyl group(s) of GSH. The data indicate that the primary detoxifying mechanism is the intracellular sequestration of carboxyl-coordinated U(VI) into an insoluble complex with GSH.

Glutathione attenuates uranyl toxicity in Lactococcus lactis

Energy Technology Data Exchange (ETDEWEB)

Fahmy, Karim; Oertel, Jana [Helmholtz-Zentrum Dresden-Rossendorf e.V., Dresden (Germany). Biophysics; Obeid, M. [Technische Univ. Dresden (Germany); Solioz, M. [Bern Univ. (Switzerland)

2017-06-01

We investigated the role of intracellular glutathione (GSH), which in a large number of taxa plays a role in the protection against the toxicity of heavy metals. Anaerobically grown Lactococcus lactis containing an inducible GSH synthesis pathway was used as a model organism allowing the study of GSH-dependent uranyl detoxification without interference from additional reactive oxygen species. Microcalorimetric measurements of the metabolic heat showed that intracellular GSH attenuates the toxicity of uranium at a concentration in the range of 10-150 μM. Isothermal titration calorimetry revealed the endothermic binding of U(VI) to the carboxyl group(s) of GSH. The data indicate that the primary detoxifying mechanism is the intracellular sequestration of carboxyl-coordinated U(VI) into an insoluble complex with GSH.

The behavioral and health consequences of sleep deprivation among U.S. high school students: relative deprivation matters.