Control of sulphate assimilation and glutathione synthesis: interaction with N and C metabolism

Enhanced oxidative stress is closely related to aging and impaired metabolic health and is influenced by diet-derived nutrients and energy. Recent studies have shown that methionine restriction (MetR) is related to longevity and metabolic health in organisms from yeast to rodents. The effect of MetR on lifespan extension and metabolic health is mediated partially through a reduction in oxidative stress. Methionine metabolism is involved in the supply of methyl donors such as S-adenosyl-methionine (SAM), glutathione synthesis and polyamine metabolism. SAM, a methionine metabolite, activates mechanistic target of rapamycin complex 1 and suppresses autophagy; therefore, MetR can induce autophagy. In the process of glutathione synthesis in methionine metabolism, hydrogen sulfide (H2S) is produced through cystathionine-β-synthase and cystathionine-γ-lyase; however, MetR can induce increased H2S production through this pathway. Similarly, MetR can increase the production of polyamines such as spermidine, which are involved in autophagy. In addition, MetR decreases oxidative stress by inhibiting reactive oxygen species production in mitochondria. Thus, MetR can attenuate oxidative stress through multiple mechanisms, consequently associating with lifespan extension and metabolic health. In this review, we summarize the current understanding of the effects of MetR on lifespan extension and metabolic health, focusing on the reduction in oxidative stress.

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Niujiaodihuang Detoxify Decoction inhibits ferroptosis by enhancing glutathione synthesis in acute liver failure models

Journal of Ethnopharmacology ◽

10.1016/j.jep.2021.114305 ◽

2021 ◽

pp. 114305

Author(s):

Yichun Ji ◽

Wenwen Si ◽

Juan Zeng ◽

Liqiao Huang ◽

Zifeng Huang ◽

...

Keyword(s):

Liver Failure ◽

Acute Liver Failure ◽

Glutathione Synthesis ◽

Failure Models

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Impact of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behaviors and BDNF mRNA expression in the adult Sprague–Dawley rats exposed to glutathione deficit during early postnatal development of the brain

Pharmacological Reports ◽

10.1007/s43440-021-00318-z ◽

2021 ◽

Author(s):

Marta A. Lech ◽

Kinga Kamińska ◽

Monika Leśkiewicz ◽

Elżbieta Lorenc-Koci ◽

Zofia Rogóż

Keyword(s):

Mrna Expression ◽

Postnatal Development ◽

Repeated Treatment ◽

Sprague Dawley ◽

Biochemical Tests ◽

Bdnf Mrna ◽

Adult Rats ◽

Behavioral Deficits ◽

Glutathione Synthesis ◽

Early Postnatal Development

Abstract Background Preclinical and clinical studies have indicated that impaired endogenous synthesis of glutathione during early postnatal development plays a significant role in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and cognitive symptoms of schizophrenia. Methods In the present study, we investigated the influence of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behavior and BDNF mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Male pups between the postnatal days p5–p16 were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12,909 alone or in combination. Escitalopram and aripiprazole were given repeatedly for 21 days before the tests. On p90–92 rats were evaluated in the behavioral and biochemical tests. Results BSO given alone and together with GBR 12,909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with aripiprazole and an ineffective dose of escitalopram also abolished the behavioral deficits in the studied tests. Conclusion The obtained data indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioral deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with aripiprazole and ineffective dose of escitalopram.

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FORMATION AND UTILIZATION OF γ-GLUTAMYLCYSTEINE IN GLUTATHIONE SYNTHESIS

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)44849-1 ◽

1952 ◽

Vol 199 (1) ◽

pp. 407-414 ◽

Cited By ~ 8

Author(s):

John E. Snoke ◽

Konrad Bloch

Keyword(s):

Glutathione Synthesis

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Regulation of intracellular glutathione levels in erythrocytes infected with chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum

Biochemical Journal ◽

10.1042/bj20020962 ◽

2002 ◽

Vol 368 (3) ◽

pp. 761-768 ◽

Cited By ~ 73

Author(s):

Svenja MEIERJOHANN ◽

Rolf D. WALTER ◽

Sylke MÜLLER

Keyword(s):

Oxidative Stress ◽

Red Blood Cells ◽

Blood Cells ◽

Differential Susceptibility ◽

Protozoan Parasite ◽

Chloroquine Resistance ◽

Glutathione Metabolism ◽

Glutathione Synthesis ◽

Intracellular Glutathione ◽

Glutamylcysteine Synthetase

Malaria is one of the most devastating tropical diseases despite the availability of numerous drugs acting against the protozoan parasite Plasmodium in its human host. However, the development of drug resistance renders most of the existing drugs useless. In the malaria parasite the tripeptide glutathione is not only involved in maintaining an adequate intracellular redox environment and protecting the cell against oxidative stress, but it has also been shown that it degrades non-polymerized ferriprotoporphyrin IX (FP IX) and is thus implicated in the development of chloroquine resistance. Glutathione levels in Plasmodium-infected red blood cells are regulated by glutathione synthesis, glutathione reduction and glutathione efflux. Therefore the effects of drugs that interfere with these metabolic processes were studied to establish possible differences in the regulation of the glutathione metabolism of a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodiumfalciparum. Growth inhibition of P. falciparum 3D7 by d,l-buthionine-(S,R)sulphoximine (BSO), an inhibitor of γ-glutamylcysteine synthetase (γ-GCS), and by Methylene Blue (MB), an inhibitor of gluta thione reductase (GR), was significantly more pronounced than inhibition of P.falciparum Dd2 growth by these drugs. These results correlate with the higher levels of total glutathione in P. falciparum Dd2. Short-term incubations of Percoll-enriched trophozoite-infected red blood cells in the presence of BSO, MB and N,N1-bis(2-chloroethyl)-N-nitrosourea and subsequent determinations of γ-GCS activities, GR activities and glutathione disulphide efflux revealed that maintenance of intracellular glutathione in P. falciparum Dd2 is mainly dependent on glutathione synthesis whereas in P. falciparum 3D7 it is regulated via GR. Generally, P. falciparum Dd2 appears to be able to sustain its intracellular glutathione more efficiently than P. falciparum 3D7. In agreement with these findings is the differential susceptibility to oxidative stress of both parasite strains elicited by the glucose/glucose oxidase system.

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Auranofin-Mediated NRF2 Induction Attenuates Interleukin 1 Beta Expression in Alveolar Macrophages

Antioxidants ◽

10.3390/antiox10050632 ◽

2021 ◽

Vol 10 (5) ◽

pp. 632

Author(s):

Stephanie B. Wall ◽

Rui Li ◽

Brittany Butler ◽

Ashley R. Burg ◽

Hubert M. Tse ◽

...

Keyword(s):

Alveolar Macrophages ◽

Inflammatory Responses ◽

Interleukin 1 ◽

Direct Interaction ◽

Synthesis Methods ◽

Related Factor ◽

Gold Compound ◽

Nuclear Factor ◽

Glutathione Synthesis ◽

Gold Compounds

Background: Alveolar macrophages (AMs) are resident inflammatory cells in the lung that serve as early sentinels of infection or injury. We have identified thioredoxin reductase 1 inhibition by gold compounds increases activation of nuclear factor erythroid 2-related factor 2 (NRF2)-dependent pathways to attenuate inflammatory responses. The present studies utilized murine alveolar macrophages (MH-S) to test the hypothesis that the gold compound, auranofin (AFN), decreases interleukin (IL)-1β expression through NRF2-mediated interactions with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway genes and/or increases in glutathione synthesis. Methods: MH-S cells were treated with AFN and lipopolysaccharide (LPS) and analyzed at 6 and 24 h. The Il1b promoter was analyzed by chromatin immunoprecipitation for direct interaction with NRF2. Results: Expression of IL-1β, p-IκBα, p-p65 NF-kB, and NOD-, LRR-, and pyrin domain-containing protein 3 were elevated by LPS exposure, but only IL-1β expression was suppressed by AFN treatment. Both AFN and LPS treatments increased cellular glutathione levels, but attenuation of glutathione synthesis by buthionine sulfoximine (BSO) did not alter expression of Il-1β. Analysis revealed direct NRF2 binding to the Il1b promoter which was enhanced by AFN and inhibited the transcriptional activity of DNA polymerase II. Conclusions: Our data demonstrate that AFN-induced NRF2 activation directly suppresses IL-1β synthesis independent of NFκB and glutathione-mediated antioxidant mechanisms. NRF2 binding to the promoter region of IL1β directly inhibits transcription of the IL1β gene. Collectively, our research suggests that gold compounds elicit NRF2-dependent pulmonary protection by suppressing macrophage-mediated inflammation.

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