ArticleLiterature Review

Glutathione and immune function

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Abstract

The immune system works best if the lymphoid cells have a delicately balanced intermediate level of glutathione. Even moderate changes in the intracellular glutathione level have profound effects on lymphocyte functions. Certain functions, such as the DNA synthetic response, are exquisitely sensitive to reactive oxygen intermediates and, therefore, are favoured by high levels of the antioxidant glutathione. Certain signal pathways, in contrast, are enhanced by oxidative conditions and favoured by low intracellular glutathione levels. The available evidence suggests that the lymphocytes from healthy human subjects have, on average, an optimal glutathione level. There is no indication that immunological functions such as resistance to infection or the response to vaccination may be enhanced in healthy human subjects by administration of glutathione or its precursor amino acid cysteine. However, immunological functions in diseases that are associated with a cysteine and glutathione deficiency may be significantly enhanced and potentially restored by cysteine supplementation. This factor has been studied most extensively in the case of human immunodeficiency virus (HIV)-infected patients who were found to experience, on average, a massive loss of S equivalent to a net loss of approximately 4 g cysteine/d. Two randomized placebo-controlled trials have shown that treatment of HIV-infected patients with N-acetyl-cysteine caused in both cases a significant increase in all immunological functions under test, including an almost complete restoration of natural killer cell activity. It remains to be tested whether cysteine supplementation may be useful also in other diseases and conditions that are associated with a low mean plasma cystine level and impaired immunological functions.

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... Numerous disorders of cellular redox homeostasis are due to decreased GSH levels. Many different disorders and diseases in human medicine are accompanied by GSH deficiency (2,4,(12)(13)(14). ...
... Clinical studies in HIV-infected individuals receiving ART are not conclusive (3)(4)(5)12,15,(17)(18)(19). The results of the current study are in line with the conclusions of Musisi (3). ...
... However, Mandas et al. describes the significantly higher levels of ROS in treated than naive (4,17). In contrast to our findings the Awodele et al. study found that HIV-naïve patients had lower systemic GSH levels and higher lipid peroxidation compared with HIV-positive patients with antiretroviral drugs (12,15,19). But the number of patients in these individual studies was low and some parameters were examined using methods different from ours; therefore, a comparison between the current study and previous studies is limited. ...
... The glutathione cycle is one of the main intracellular mechanisms to preserve an adequate intracellular redox state [11,60]. In fact, GSH is the major antioxidant involving in cell-signaling regulation, whereas GSSG is highly toxic to cells [60]. ...
... The glutathione cycle is one of the main intracellular mechanisms to preserve an adequate intracellular redox state [11,60]. In fact, GSH is the major antioxidant involving in cell-signaling regulation, whereas GSSG is highly toxic to cells [60]. Therefore, an optimal GSSG/GSH balance is essential for the preservation of oxidative damage and the maintenance of immune functions [11,60]. ...
... In fact, GSH is the major antioxidant involving in cell-signaling regulation, whereas GSSG is highly toxic to cells [60]. Therefore, an optimal GSSG/GSH balance is essential for the preservation of oxidative damage and the maintenance of immune functions [11,60]. In our study, NDD-CKD patients showed in PMNs and MNs lower GSH content, together with higher GSSG and GSSG/GSH ratios, compared with controls. ...
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Oxidative stress plays a key role in the pathophysiology of chronic kidney disease (CKD). Most studies have investigated peripheral redox state focus on plasma, but not in different immune cells. Our study analyzed several redox state markers in plasma and isolated peripheral polymorphonuclear (PMNs) and mononuclear (MNs) leukocytes from advanced-CKD patients, also evaluating differences of hemodialysis (HD) and peritoneal dialysis (PD) procedures. Antioxidant (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH)) and oxidant parameters (xanthine oxidase (XO), oxidized glutathione (GSSG), malondialdehyde (MDA)) were assessed in plasma, PMNs and MNs from non-dialysis-dependent-CKD (NDD-CKD), HD and PD patients and healthy controls. Increased oxidative stress and damage were observed in plasma, PMNs and MNs from NDD-CKD, HD and PD patients (increased XO, GSSG and MDA; decreased SOD, CAT, GPX and GSH; altered GSSG/GSH balance). Several oxidative alterations were more exacerbated in PMNs, whereas others were only observed in MNs. Dialysis procedures had a positive effect on preserving the GSSG/GSH balance in PMNs. Interestingly, PD patients showed greater oxidative stress than HD patients, especially in MNs. The assessment of redox state parameters in PMNs and MNs could have potential use as biomarkers of the CKD progression.
... Furthermore, GSH affects the production of most inflammatory cytokines and is required to maintain adequate interferon (IFN)-γ production by dendritic cells [82]. Based on these data, Dröge and Breitkreutz [83] claimed that the immune system is highly affected by the level of GSH in the body. However, for many years, it was not known whether disrupted GSH levels alter a complex ...
... Furthermore, GSH affects the production of most inflammatory cytokines and is required to maintain adequate interferon (IFN)-γ production by dendritic cells [82]. Based on these data, Dröge and Breitkreutz [83] claimed that the immune system is highly affected by the level of GSH in the body. ...
... GSH is an antioxidant that, according to a growing body of evidence, is an important signaling molecule engaged in immunological processes [75][76][77]83]. Most papers indicate that increased GSH levels lead to a decrease in inflammation [102,103]. ...
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Glutathione is one of the most important and potent antioxidants. The development of pharmacological compounds that can either increase or decrease glutathione concentrations has allowed investigation into the role of glutathione in various biological processes, including immune responses. Recent findings have shown that glutathione not only affects certain factors involved in immunological processes but also modifies complex immune reactions such as fever. Until recently, it was not known why some patients do not develop fever during infection. Data suggest that fever induction is associated with oxidative stress; therefore, antioxidants such as glutathione can reduce pyrexia. Surprisingly, new studies have shown that low glutathione levels can also inhibit fever. In this review, we focus on recent advances in this area, with an emphasis on the role of glutathione in immune responses accompanied by fever. We describe evidence showing that disturbed glutathione homeostasis may be responsible for the lack of fever during infections. We also discuss the biological significance of the antipyretic effects produced by pharmacological glutathione modulators.
... As summarized in Table 1, decreased levels of antioxidants have been reported in both acute COVID-19 and ME/CFS. Foremost among these small molecules is glutathione, which helps modulate immune activation (76,77). Glutathione also enhances vitamin D metabolism (78) and vitamin D, in turn, reciprocally increases glutathione and decreases oxidative stress and levels of inflammatory cytokines and chemokines (79). ...
... Glutathione plays a particularly important role in enabling and modulating the immune response (76). It is vital for proliferation of T lymphocytes; T cell activation, in turn, generates glutathione, which counters ROS levels and mediates a metabolic shift toward aerobic glycolysis and glutaminolysis (113) Other connections between inflammation and redox imbalance exist as well. ...
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Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called “long COVID-19,” reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics.
... This is, in part, attributed to the lower capacity of calf lymphocytes to respond to stimuli compared to lymphocytes from mature animals [4][5][6][7]. Critical functions of lymphocytes that are altered during the neonatal period in calves include, among others, activation capacity, cytokine production, and antibody production [8][9][10]. ...
... In humans, compelling evidence in the last three decades shows that changes in redox balance (RB) result in decreased lymphocyte responses to stimuli, particularly in T lymphocytes [8][9][10]. Redox balance reflects the equilibrium between the concentration of pro-oxidants and the availability of antioxidant defenses [11]. ...
Article
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Dairy calves are unable to mount an effective immune response during their first weeks of life, which contributes to increased disease susceptibility during this period. Oxidative stress (OS) diminishes the immune cell capabilities of humans and adult cows, and dairy calves also experience OS during their first month of life. However, the impact that OS may have on neonatal calf immunity remains unexplored. Thus, we aimed to evaluate the impact of OS on newborn calf lymphocyte functions. For this, we conducted two experiments. First, we assessed the association of OS status throughout the first month of age and the circulating concentrations of the cytokines interferon-gamma (IFN-γ) and interleukin (IL) 4, as well as the expression of cytokine-encoding genes IFNG, IL2, IL4, and IL10 in peripheral mononuclear blood cells (PBMCs) of 12 calves. Subsequently, we isolated PBMCs from another 6 neonatal calves to investigate in vitro the effect of OS on immune responses in terms of activation of lymphocytes, cytokine expression, and antibody production following stimulation with phorbol 12-myristate 13-acetate or bovine herpesvirus-1. The results were compared statistically through mixed models. Calves exposed to high OS status in their first month of age showed higher concentrations of IL-4 and expression of IL4 and IL10 and lower concentrations of IFN-γ and expression of IFNG and IL2 than calves exposed to lower OS. In vitro, OS reduced lymphocyte activation, production of antibodies, and protein and gene expression of key cytokines. Collectively, our results demonstrate that OS can compromise some immune responses of newborn calves. Hence, further studies are needed to explore the mechanisms of how OS affects the different lymphocyte subsets and the potential of ameliorating OS in newborn calves as a strategy to augment the functional capacity of calf immune cells, as well as enhance calves’ resistance to infections.
... Ebselen uses a glutathione peroxidase-1 (GPx1) mimetic to reduce influenza A virus-induced lung inflammation [143]. Given that GSH is important for immune responses due to the activation of antioxidant mechanisms and optimal functioning of lymphocytes and other immune cells [144], natural compounds that activate the Nrf2-antioxidant response element (ARE) pathway and thus glutathione and other antioxidant elements may be promising targets. ...
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The phenomenon of oxidative stress, characterized as an imbalance in the production of reactive oxygen species and antioxidant responses, is a well-known inflammatory mechanism and constitutes an important cellular process. The relationship of viral infections, reactive species production, oxidative stress, and the antiviral response is relevant. Therefore, the aim of this review is to report studies showing how reactive oxygen species may positively or negatively affect the pathophysiology of viral infection. We focus on known respiratory viral infections, especially severe acute respiratory syndrome coronaviruses (SARS-CoVs), in an attempt to provide important information on the challenges posed by the current COVID-19 pandemic. Because antiviral therapies for severe acute respiratory syndrome coronaviruses (e.g., SARS-CoV-2) are rare, knowledge about relevant antioxidant compounds and oxidative pathways may be important for understanding viral pathogenesis and identifying possible therapeutic targets.
... The immune system must be exhausted in-order for cancer to initiate and progress. The exhaustion of the immune system relies on the availability of glutathione because the lymphoid cells function best on a balanced level of glutathione (122). ...
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Cancer is the major cause of morbidity and mortality in the world today. The third most common cancer and which is most diet related is colorectal cancer (CRC). Although there is complexity and limited understanding in the link between diet and CRC, the advancement in research methods have demonstrated the involvement of non-coding RNAs (ncRNAs) as key regulators of gene expression. MicroRNAs (miRNAs) which are a class of ncRNAs are key players in cancer related pathways in the context of dietary modulation. The involvement of ncRNA in cancer progression has recently been clarified throughout the last decade. ncRNAs are involved in biological processes relating to tumor onset and progression. The advances in research have given insights into cell to cell communication, by highlighting the pivotal involvement of extracellular vesicle (EV) associated-ncRNAs in tumorigenesis. The abundance and stability of EV associated ncRNAs act as a new diagnostic and therapeutic target for cancer. The understanding of the deranging of these molecules in cancer can give access to modulating the expression of the ncRNAs, thereby influencing the cancer phenotype. Food derived exosomes/ vesicles (FDE) are gaining interest in the implication of exosomes in cell-cell communication with little or no understanding to date on the role FDE plays. There are resident microbiota in the colon; to which the imbalance in the normal intestinal occurrence leads to chronic inflammation and the production of carcinogenic metabolites that lead to neoplasm. Limited studies have shown the implication of various types of microbiome in CRC incidence, without particular emphasis on fungi and protozoa. This review discusses important dietary factors in relation to the expression of EV-associated ncRNAs in CRC, the impact of diet on the colon ecosystem with particular emphasis on molecular mechanisms of interactions in the ecosystem, the Frontiers in Oncology | www.frontiersin.org influence of homeostasis regulators such as glutathione, and its conjugating enzyme-glutathione S-transferase (GST) polymorphism on intestinal ecosystem, oxidative stress response, and its relationship to DNA adduct fighting enzyme-0-6-methylguanine-DNA methyltransferase. The understanding of the molecular mechanisms and interaction in the intestinal ecosystem will inform on the diagnostic, preventive and prognosis as well as treatment of CRC.
... With more than 2000 approved patents worldwide related to GSH production, this intracellular tripeptide showed a great potential for tremendous industrial applications. In medicine, it serves as a drug or drug-precursor for the treatment of high-reactive oxygen species (ROS) related diseases including cardiovascular and neurodegenerative diseases but also cancer, diabities, and aged-related diseases (Droge and Breitkreutz 2000;Ballatori et al. 2009;Bajic et al. 2019). Recently, GSH D. T. H. Do Á P. Fickers (&) Á I. Ben Tahar Microbial Processes and Interactions, TERRA Teaching and Research Centre, University of Liège -Gembloux Agro-Bio Tech, Av. de la Faculté, 2B, 5030 Gembloux, Belgium e-mail: pfickers@uliege.be ...
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Objective In this study, we aimed to maximize glutathione (GSH) production by a metabolically engineered Yarrowia lipolytica strain using a small-scale optimization approach. Results A three levels four factorial Box–Behnken Design was used to assess the effect of pH, inulin extract, yeast extract and ammonium sulfate concentrations on cell growth and to generate a mathematical model which predict optimal conditions to maximize biomass production and thus GSH titer. The obtained results revealed that only yeast and inulin extract concentrations significantly affect biomass production. Based on the generated model, a medium composed of 10 g/L of yeast extract and 10 g/L of inulin extract from Jerusalem artichoke was used to conduct batch cultures in 2 L bioreactor. After 48 h of culture, the biomass and the glutathione titer increased by 55% (5.8 gDCW/L) and 61% (1011.4 mg/L), respectively, as compared to non-optimized conditions. Conclusion From the obtained results, it could be observed that the model established from small scale culture (i.e. 2 mL) is able to predict performance at larger scale (i.e. 2 L bioreactor, two orders of magnitude scale-up). Moreover, the results highlight the ability of the optimized process to ensure high titer of glutathione using a low-cost carbon source.
... It has been proposed that Se-deficiency in HT patients is associated with an array of adverse effects, such as compromised antioxidant state, increased expression of harmful epitopes and apoptosis [8,9,31]. However, the absence of adequate laboratory evidence has hampered the clarification of the underlying molecular mechanisms. ...
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Selenium (Se) deficiency has been implicated in the pathogenesis of Hashimoto’s thyroiditis (HT), although the available evidence is limited. The present study aimed to explore the interrelationships between serum Se status with measures of thyroid function and antioxidant defense in new cases of HT patients with hypoechogenic thyroid. HT patients (n = 49) and matched controls (n = 50) were recruited. Selenium, thyroid hormone panel, thyroid volume (TVol), glutathione (GSH), glutathione peroxidase3 (GPx3) activity, urinary iodine concentration (UIC), and urinary creatinine (Cr) were assessed. HT patients exhibited lower Se levels compared to controls (p < 0.001) with the rates of Se-deficient (<0.85 µmol/L) participants being 58.8% and 34%, respectively. Se-deficient patients exhibited higher thyroid stimulating hormone (TSH), Thyroid volume (TVol), thyroglobulin, antibody-titers, GPx3 activity and UIC/Cr compared to Se-sufficient patients (all p < 0.001). In the Se-deficient patients, inverse correlations were seen between Se-levels with TSH, TVol, and Thyroid peroxidase antibody (TPO-Ab) (all p < 0.001). This study is the first to uncover that coexisting Se-deficiency and elevated iodine in HT may enhance autoimmune reactions and accelerate the deterioration of thyroid function through oxidative stress. Our study also highlights the importance of optimal Se status in this disease, thus providing a rationale for the execution of intervention trials for the evaluation of the clinical benefits of antioxidant-status improvement in HT.
... In this regard, it was shown that the mean concentration of free reduced glutathione (GSH), a crucial intracellular antioxidant, was significantly reduced, and the oxidized form of glutathione (GSSG) was significantly augmented, leading to decreased glutathione redox status and increased oxidative stress [29,30]. Folinic acid has been substantiated to alleviate oxidative stress in patients with ASD, which might lead to better immune function, increased detoxification capacity, and membrane redox signaling [31][32][33][34]. ...
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This is a double-blind, placebo-controlled randomized trial to investigate the potential therapeutic effects of folinic acid/placebo as an adjuvant to risperidone on inappropriate speech and other behavioral symptoms of autism spectrum disorder (ASD). Fifty-five ASD children (age (mean ± standard deviation) = 13.40 ± 2.00; male/female: 35/20) were evaluated for behavioral symptoms at baseline, week 5, and week 10 using the aberrant behavior checklist-community (ABC-C). Folinic acid dosage was 2 mg/kg up to 50 mg per day for the entire course of the study. The repeated measures analysis showed significant effect for time × treatment interaction on inappropriate speech (F = 3.51; df = 1.61; P = 0.044), stereotypic behavior (F = 4.02; df = 1.37; P = 0.036), and hyperactivity/noncompliance (F = 6.79; df = 1.66; P = 0.003) subscale scores. In contrast, no significant effect for time × treatment interaction was found on lethargy/social withdrawal (F = 1.06; df = 1.57; P = 0.336) and irritability (F = 2.86; df = 1.91; P = 0.064) subscale scores. Our study provided preliminary evidence suggesting that folinic acid could be recommended as a beneficial complementary supplement for alleviating speech and behavioral symptoms in children with ASD. Clinical trial registeration: This trial was registered in the Iranian Registry of Clinical Trials (www.irct.ir; No. IRCT20090117001556N114).
... Glutathione (y-glutamylcysteinylglycine, GSH) is a tripeptide, which has many functions in biological systems (Meister & Anderson, 1983;Meister, 1992;Droge & Breitkreutz, 2000). It ...
Thesis
Aims/Hypothesis: Oxidative stress has been implicated in the development of diabetic neuropathy. The objective of this study was to establish if type 1 or type 2 diabetes in the presence of polyneuropathy (PNP) and/or cardiovascular autonomic neuropathy (CAN) is associated with alterations in plasma and urinary measures of oxidative stress. Studied population: Diabetic patients (n=185; type1: n=61 and type 2: n=124) were recruited. Of these, 60 patients were without PNP and CAN, 103 patients with PNP but without CAN and 22 patients with PNP and CAN. Non-diabetic subjects (n=70) were employed as controls. Methods: Plasma and urinary 8-epi-PGF2α and its metabolites were measured by gas- chromatography/mass-spectrometry. Plasma total antioxidant capacity (TAC) was assessed by quenching of peroxiynitrite Pholasin® chemiluminescence (peroxynitrite-QPC), quenching of superoxide anion Pholasin® chemiluminescence (superoxide anion-QPC) and quenching of hypochlorous acid Pholasin® chemiluminescence (hypochlorous acid-QPC). Plasma vitamin C was assayed spectrofluorometrically. Plasma vitamin E was determined by HPLC with fluorometric detection. Results: Type 1 diabetic patients (PNP-/CAN-) had lower TAC (peroxynitrite-QPC, superoxide anion-QPC), vitamin C levels, vitamin E cholesterol/ratios, and 8-epi-PGF2α concentrations than in control subjects. Lower TAC (superoxide anion-QPC) and increased 8-epi-PGF2α concentrations were seen in the presence PNP. The additional presence of CAN was associated with further reductions in TAC (peroxynitrite-QPC and superoxide anion-QPC) and vitamin E/cholesterol ratios. Type 2 diabetic patients (PNP-/CAN-) exhibited lower TAC (peroxynitrite-QPC, superoxide anion-QPC), and vitamin E cholesterol/ratios compared to control subjects. Lower TAC (peroxynitrite-QPC and superoxide anion-QPC), vitamin C levels and vitamin E/cholesterol ratios, and increased 8-epi-PGP2α concentrations were observed the presence of PNP. Lower TAC (superoxide anion-QPC) was seen in the presence of additional CAN. Correlations occurred between neurological impairment score of the lower limb (NIS-LL) and peroxynitrite-QPC, superoxide anion-QPC as well as vitamin C levels. Multiple regression analysis revealed that peroxynitrite-QPC was independently associated with the neurological impairment score of the lower limb. Urinary 8-epi-PGF2α and its metabolites levels were lower in diabetic patients than in control subjects. However, no firm conclusion could be drawn concerning urinary 8-epi-PGF2α and its metabolites because the results exhibited substantial variability. Conclusions: This study has revealed that oxidative stress is enhanced in diabetic patients (PNP-/CAN-). Oxidative stress was more pronounced in patients with PNP and that the additional presence of CAN was without influence. Measurement of TAC, as assessed by peroxynitrite-QPC or superoxide anion-QPC, was superior in the terms of simplicity, cost and diagnostic value to nutrient antioxidants and lipid-oxidation products in assessing oxidative stress. These results indicate improved strategies for patient selection for clinical trials involving antioxidants aimed at the prevention or treatment of diabetic neuropathy.
... High levels of glutathione in body cells is associated with numerous health benefits such as support of immune function, making of DNA, formation of sperm cells, breaking down free radicals, assisting in apoptosis, increase in insulin resistance in aged people, wound healing and reduction in the symptoms of Parkinson's disease amongst other notable profits [23][24][25]. Furthermore, low levels of glutathione has been linked with several diseases such as Parkinson's disease, autoimmune diseases, Alzheimer's disease, several heart complications and chronic kidney diseases [26]. ...
... Glutathione (GSH), is the most potent antioxidant or detoxifier in cells, is responsible for maintaining redox status, as well as many cellular processes, including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, and immune response [39,40]. RNAseq of bone marrow neutrophils revealed an increase in expression of enzymes involved in glutathione metabolism/synthesis in neutrophils treated with C42B CM, compared to LNCaP media (Fig. 3E). ...
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Bone metastatic prostate cancer (BM-PCa) remains one of the most difficult cancers to treat due to the complex interactions of cancer and stromal cells. We previously showed that bone marrow neutrophils elicit an anti-tumor immune response against BM-PCa. Further, we demonstrated that BM-PCa induces neutrophil oxidative burst, which has previously been identified to promote primary tumor growth of other cancers, and a goal of this study was to define the importance of neutrophil oxidative burst in BM-PCa. To do this, we first examined the impact of depletion of reactive oxygen species (ROS), via systemic deletion of the main source of ROS in phagocytes, NADPH oxidase (Nox)2, which we found to suppress prostate tumor growth in bone. Further, using pharmacologic ROS inhibitors and Nox2-null neutrophils, we found that ROS depletion specifically suppresses growth of androgen-insensitive prostate cancer cells. Upon closer examination using bulk RNA sequencing analysis, we identified that metastatic prostate cancer induces neutrophil transcriptomic changes that activates pathways associated with response to oxidative stress. In tandem, prostate cancer cells resist neutrophil anti-tumor response via extracellular (i.e., regulation of neutrophils) and intracellular alterations of glutathione synthesis, the most potent cellular antioxidant. These findings demonstrate that BM-PCa thrive under oxidative stress conditions and such that regulation of ROS and glutathione programming could be leveraged for targeting of BM-PCa progression.
... For instance, its ability to suppress melanin synthesis through tyrosinase inhibition allows it to be used as a skin whitening agent in cosmeceuticals [5][6][7]. In addition, GSH may be used as an immune booster, an antidote for metal poisoning, and for the treatment of diseases such as fibrosis, glaucoma, and arthritis [8][9][10][11]. Unfortunately, its poor bioavailability and unpleasant odor limit the use of GSH in clinics despite its many therapeutic applications. ...
Article
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Glutathione is a natural anti-aging substance that prevents the oxidation of protein thiols from reactive oxygen species. In the pharmaceutical industry, reduced glutathione (GSH) has been widely used for skin whitening due to its ability to inhibit tyrosinase. However, its poor permeability and foul odor limit its use in skin applications. Herein, we report a GSH-loaded dissolving microneedle (MN) patch prepared with hyaluronic acid (HA) that enables enhanced permeation across the skin and reduces the foul odor of GSH. HA was selected to prepare odorless GSH solutions and used for MN fabrications as a carrier of GSH. GSH-loaded MN (GSH-MN) arrays prepared from MN-forming solution containing up to 10% GSH showed good pattern uniformity and appropriate mechanical properties for insertion into the skin. The GSH-MNs with a loading capacity of 17.4% dissolve within10 min following insertion into porcine skin and release the loaded GSH without being oxidized. This new approach combines functional biopolymers to reduce the characteristic GSH odor and advanced transdermal delivery based on MN technology to enhance skin permeation without pain. We believe this technique could expand the application of GSH in many cosmeceutical fields.
... [5] The enhanced by oxidative conditions and favored by low intracellular glutathione levels. [26] GENERAL MULTIPLE FUNCTIONS OF GSH [5,17] Reducing agent, antioxidant ...
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In this review article would selected and talk in some sides related to Glutathione and highlights the some points as general. Glutathione (γ-glutamyl-cysteinylglycine) is an endogenous peptide with antioxidant plays many useful functions in human body and therefore determination of this small molecule is very important for present-day medicine and pharmacy. General multiple functions of GSH A.
... For instance, its ability to suppress melanin synthesis through tyrosinase inhibition allows it to be used as a skin whitening agent in cosmeceuticals [5][6][7]. In addition, GSH may be used as an immune booster, an antidote for metal poisoning, and for the treatment of diseases such as fibrosis, glaucoma, and arthritis [8][9][10][11]. Unfortunately, its poor bioavailability and unpleasant odor limit the use of GSH in clinics despite its many therapeutic applications. ...
Article
Full-text available
Glutathione is a natural anti-aging substance that prevents the oxidation of protein thiols from reactive oxygen species. In the pharmaceutical industry, reduced glutathione (GSH) has been widely used for skin whitening due to its ability to inhibit tyrosinase. However, its poor permeability and foul odor limit its use in skin applications. Herein, we report a GSH-loaded dissolving microneedle (MN) patch prepared with hyaluronic acid (HA) that enables enhanced permeation across the skin and reduces the foul odor of GSH. HA was selected to prepare odorless GSH solutions and used for MN fabrications as a carrier of GSH. GSH-loaded MN (GSH-MN) arrays prepared from MN-forming solution containing up to 10% GSH showed good pattern uniformity and appropriate mechanical properties for insertion into the skin. The GSH-MNs with a loading capacity of 17.4% dissolve within 10 min following insertion into porcine skin and release the loaded GSH without being oxidized. This new approach combines functional biopolymers to reduce the characteristic GSH odor and advanced transdermal delivery based on MN technology to enhance skin permeation without pain. We believe this technique could expand the application of GSH in many cosmeceutical fields.
... Механизм биохимического действия тиолов заключается в способности восстанавливать дисульфидные связи при патологических нарушениях, инактивировать токсические агенты, а также повышать содержание сульфгидрильных групп, обеспечивая антиоксидантный эффект (16,17). Тиольные соединения в первую очередь подвергаются воздействию активных кислородных радикалов, что предохраняет от их влияния функциональные группы биологических молекул и клеточных мембран (18,19). ...
... Механизм биохимического действия тиолов заключается в способности восстанавливать дисульфидные связи при патологических нарушениях, инактивировать токсические агенты, а также повышать содержание сульфгидрильных групп, обеспечивая антиоксидантный эффект (16,17). Тиольные соединения в первую очередь подвергаются воздействию активных кислородных радикалов, что предохраняет от их влияния функциональные группы биологических молекул и клеточных мембран (18,19). ...
... In particular, some lymphocyte functions, such as DNA synthesis, are favored by high levels of GSH, while other redox-sensitive pathways are favored by low intracellular GSH. However, immunological functions in the diseases characterized by oxidative stress can be restored by cysteine or GSH supplementation [27,28]. The brain generates high levels of ROS due to its high oxygen consumption, hence it is more susceptible to the damaging effects of ROS than other tissues [29,30]. ...
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Glutathione (GSH) has poor pharmacokinetic properties; thus, several derivatives and biosynthetic precursors have been proposed as GSH-boosting drugs. I-152 is a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-β-mercaptoethylamine (SMEA) designed to release the parent drugs (i.e., NAC and β-mercaptoethylamine or cysteamine, MEA). NAC is a precursor of L-cysteine, while MEA is an aminothiol able to increase GSH content; thus, I-152 represents the very first attempt to combine two pro-GSH molecules. In this review, the in-vitro and in-vivo metabolism, pro-GSH activity and antiviral and immunomodulatory properties of I-152 are discussed. Under physiological GSH conditions, low I-152 doses increase cellular GSH content; by contrast, high doses cause GSH depletion but yield a high content of NAC, MEA and I-152, which can be used to resynthesize GSH. Preliminary in-vivo studies suggest that the molecule reaches mouse organs, including the brain, where its metabolites, NAC and MEA, are detected. In cell cultures, I-152 replenishes experimentally depleted GSH levels. Moreover, administration of I-152 to C57BL/6 mice infected with the retroviral complex LP-BM5 is effective in contrasting virus-induced GSH depletion, exerting at the same time antiviral and immunomodulatory functions. I-152 acts as a pro-GSH agent; however, GSH derivatives and NAC cannot completely replicate its effects. The co-delivery of different thiol species may lead to unpredictable outcomes, which warrant further investigation.
... Dietary supplements containing S (chondroitin sulfate, glucosamine sulfate, methylsulfonylmethane) can be benefi cial in the treatment of joint diseases (Nimini et al., 2006). Glutathione (GSH) takes care of free oxygen radicals and peroxides (Dorge and Bretkreutz, 2000;Townsend et al., 2004). GSH is also the form S is stored in the liver. ...
... For instance, NAC ingestion is proposed to result in an anti-oxidant effect that minimizes the oxidative stress and inflammatory response imposed from physical activity [151] (see Sect. 4.2). Furthermore, NAC is proposed to enhance fatigue resistance [152] and improve athletic performance [151]; to enhance immune system function [153], hemodynamics and muscle blood flow [154]; and to modulate EPO production and the hypoxic ventilatory response [155]. Intuitively, each of these mechanisms appears likely to support a positive adaptation to hypoxic environments such as altitude exposure. ...
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Training at low to moderate altitudes (~ 1600-2400 m) is a common approach used by endurance athletes to provide a distinctive environmental stressor to augment training stimulus in the anticipation of increasing subsequent altitude- and sea-level-based performance. Despite some scientific progress being made on the impact of various nutrition-related changes in physiology and associated interventions at mountaineering altitudes (> 3000 m), the impact of nutrition and/or supplements on further optimization of these hypoxic adaptations at low-moderate altitudes is only an emerging topic. Within this narrative review we have highlighted six major themes involving nutrition: altered energy availability, iron, carbohydrate, hydration, antioxidant requirements and various performance supplements. Of these issues, emerging data suggest that particular attention be given to the potential risk for poor energy availability and increased iron requirements at the altitudes typical of elite athlete training (~ 1600-2400 m) to interfere with optimal adaptations. Furthermore, the safest way to address the possible increase in oxidative stress associated with altitude exposure is via the consumption of antioxidant-rich foods rather than high-dose antioxidant supplements. Meanwhile, many other important questions regarding nutrition and altitude training remain to be answered. At the elite level of sport where the differences between winning and losing are incredibly small, the strategic use of nutritional interventions to enhance the adaptations to altitude training provides an important consideration in the search for optimal performance.
... Decreased level of CoQ10 is linked with the development of the cardiovascular disease. Glutathione (GSH) is an intracellular antioxidant essential for the immune cells functioning [201]. Low level of GSH is correlated with chronic heart failure and myocardial infarction [189,202,203]. ...
Article
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Inflammation is one of the common events in the majority of acute as well as chronic debilitating diseases and represent a chief cause of morbidity in today’s era of modern lifestyle. If unchecked, inflammation leads to development of rheumatoid arthritis, diabetes, cancer, Alzheimer’s disease, and atherosclerosis along with pulmonary, autoimmune and cardiovascular diseases. Inflammation involves a complex network of many mediators, a variety of cells, and execution of multiple pathways. Current therapy for inflammatory diseases is limited to the steroidal and non-steroidal anti-inflammatory agents. The chronic use of these drugs is reported to cause severe adverse effects like gastrointestinal, cardiovascular, and renal abnormalities. There is a massive need to explore new anti-inflammatory agents with selective action and lesser toxicity. Plants and isolated phytoconstituents are promising and interesting sources of new anti-inflammatories. However, drug development from natural sources has been linked with hurdles like the complex nature of extracts, difficulties in isolation of pure phytoconstituents, and the yield of isolated compounds in minute quantities that is insufficient for subsequent lead development. Although various in-vivo and in-vitro models for anti-inflammatory drug development are available, judicious selection of appropriate animal models is a vital step in the early phase of drug development. Systematic evaluation of phytoconstituents can facilitate the identification and development of potential anti-inflammatory leads from natural sources. The present review describes various techniques of anti-inflammatory drug screening with its advantages and limitations, elaboration on biological targets of phytoconstituents in inflammation and biomarkers for the prediction of adverse effects of anti-inflammatory drugs. The systematic approach proposed through present article for anti-inflammatory drug screening can rationalize the identification of novel phytoconstituents at the initial stage of drug screening programs.
... Thus, it is understandable to think that the higher the GSH concentration and the higher Glutathione Peroxidase activity in immune cells together with the lower one of MDA, the better the redox balance of these cells, and therefore their function. In fact, GSH has been shown to be essential for proper immune cell functioning given that even a moderate depletion of GSH has been shown to impair several leukocyte functions (Dröge and Breitkreutz, 2000). MDA, which is an end-product of reactive oxygen species (ROS)-induced peroxidation and therefore is used as a marker of oxidative stress, has also been shown to play an active role by inducing the cross-links in proteins and forming irreversible advanced glycated end-products (AGEs) (Esterbauer et al., 1990). ...
... Glutathione (GSH) is a major intracellular antioxidant capable of scavenging free radicals and detoxifying electrophiles from endogenous and exogenous sources via the free thiol group. Several studies have investigated GSH efficacy in immune diseases [22][23][24][25][26], but no studies have been published regarding its use in CAD, HLH, and PMR. We tested GSH prophylactic antibiotics, and a prednisone taper for long-term management. ...
Article
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Cold agglutinins disease (CAD) is a rare type of autoimmune hemolytic anemia. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease eventually caused or reactivated by a viral infection which can lead to the production of cold agglutinins. Narcolepsy is a sleep disorder caused by a lack of a brain chemical called hypocretin (orexin) secondary to immune attack related to Human Leukocyte Antigen DQB1 (HLA-DQB1). Polymyalgia rheumatica (PMR) is an inflammatory disorder that can be hard to diagnose and usually occurs with another serious condition called giant cell arteritis. We report a case of a 78-years-old male patient with an atypical presentation of possible associated to past Epstein Bar Virus (EBV) or Cytomegalovirus (CMV) and/or HLA. The purpose of this case is defining the first association within all four conditions as well as its biological and clinical manifestations plus the management with glutathione (GSH) as part of integrative therapeutically approach.
... Glutathione, a crucial antioxidant, is well known to modulate the behavior of many cells including the cells of the immune system, augmenting the innate and the adaptive immunity as well as conferring protection against microbial, viral and parasitic infections [42,43]. Interaction between GSH metabolism and several diseases were also well described [44]. ...
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Background: A key role of oxidative stress has been highlighted in the pathogenesis of COVID-19. However, little has been said about oxidative stress status (OSS) of COVID-19 patients hospitalized in intensive care unit (ICU). Material and methods: Biomarkers of the systemic OSS included antioxidants (9 assays), trace elements (3 assays), inflammation markers (4 assays) and oxidative damage to lipids (3 assays). Results: Blood samples were drawn after 9 (7-11) and 41 (39-43) days of ICU stay, respectively in 3 and 6 patients. Vitamin C, thiol proteins, reduced glutathione, γ-tocopherol, β-carotene and PAOT® score were significantly decreased compared to laboratory reference values. Selenium concentration was at the limit of the lower reference value. By contrast, the copper/zinc ratio (as a source of oxidative stress) was higher than reference values in 55% of patients while copper was significantly correlated with lipid peroxides (r = 0.95, p < 0.001). Inflammatory biomarkers (C-reactive protein and myeloperoxidase) were significantly increased when compared to normals. Conclusions: The systemic OSS was strongly altered in critically ill COVID-19 patients as evidenced by increased lipid peroxidation but also by deficits in some antioxidants (vitamin C, glutathione, thiol proteins) and trace elements (selenium).
... By enhancing all lines of host defense that include soluble and cellular components of innate immunity, cellular components of both innate and adaptive immunity and soluble and cellular components of the adaptive immune system will certainly help humans defeat this pandemic killer (2). Considering the impact that cytokine storm and oxidative stress have during SARS-CoV-2 infection toward development of a severe disease, the concomitant administration of both nuclear factor erythroid 2 p45-related factor 2 (Nrf2) activators such as sulforaphane and glutathione (GSH) synthesis precursors such as N-acetyl cysteine, cysteine, and cystine can increase (a) nuclear Nrf2 translocation and antioxidant response element transcription and (b) synthesis of GSH, the most powerful antioxidant of the body, respectively (11)(12)(13), facilitating prevention against oxidative stress, inflammation, and cell and tissue damage in SARS-CoV-2 infection and COVID-19 disease. Replenishing the nutritional status of the host by (a) increasing vital amino acids such as cysteine and/or (b) providing GSH itself, through liposomal administration (14) to enhance GSH levels, and (c) supplementing selenium to improve selenium deficiency and facilitate selenoprotein (GSH peroxidases, thioredoxin reductases) expression (15) can inhibit oxidative stress, modulating inflammation and endothelial dysfunction. ...
... Intracellular concentrations of reduced glutathione are maintained at the highest (millimolar) levels suggesting its vital and multifaceted roles, not solely limited by antioxidant defense [20]. Glutathione possesses a plethora of functions essential for whole-body homeostasis including the detoxification of both xenobiotic and endogenous compounds as well as the maintenance of the mitochondrial redox environment, antiviral defense by fine-tuning the innate immune response to antiviral pathways, the regeneration of vitamins C and E and the regulation of cellular proliferation, apoptosis and protein folding [20,[111][112][113][114][115][116][117]. Glutathione deficiency is well known for increasing oxidative stress, a pathological condition capable of disturbing the redox state in the endoplasmic reticulum and disrupt disulfide bond formation, adaptively activating ER stress and unfolded protein response [118,119]. ...
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The present study investigated whether type 2 diabetes (T2D) is associated with polymor-phisms of genes encoding glutathione-metabolizing enzymes such as glutathione synthetase (GSS) and gamma-glutamyl transferase 7 (GGT7). A total of 3198 unrelated Russian subjects including 1572 T2D patients and 1626 healthy subjects were enrolled. Single nucleotide polymorphisms (SNPs) of the GSS and GGT7 genes were genotyped using the MassArray-4 system. We found that the GSS and GGT7 gene polymorphisms alone and in combinations are associated with T2D risk regardless of sex, age, and body mass index, as well as correlated with plasma glutathione, hydrogen peroxide, and fasting blood glucose levels. Polymorphisms of GSS (rs13041792) and GGT7 (rs6119534 and rs11546155) genes were associated with the tissue-specific expression of genes involved in unfolded protein response and the regulation of proteostasis. Transcriptome-wide association analysis has shown that the pancreatic expression of some of these genes such as EDEM2, MYH7B, MAP1LC3A, and CPNE1 is linked to the genetic risk of T2D. A comprehensive analysis of the data allowed proposing a new hypothesis for the etiology of type 2 diabetes that endogenous glutathione deficiency might be a key condition responsible for the impaired folding of proinsulin which triggered an unfolded protein response, ultimately leading to beta-cell apoptosis and disease development.
... It is a ubiquitous molecule and provides defence against free radicals, hydroperoxides and other harmful oxidants. However, its production declines with age, and is often given orally or administered intravenously [24][25][26] , which causes its increased plasma concentration. Our studies show that incubation of α2M with GSH (20-100 µM) results in loss of functional status of this antiproteinase. ...
Article
Background: Glutathione (GSH) is a principle thiol-containing tripeptide (cysteine, glutamic acid and glycine) antioxidant against free radicals and other harmful oxidants in cellular defence. The alpha-2-macroglobulin (α2M) is large tetrameric zinc-binding glycoprotein which inhibits proteinases regardless of their specificity and catalytic mechanism. Materials and Methods: The interaction of GSH was analyzed with α2M including the structural and functional alterations in α2M using various biochemical and biophysical methods. UV-visible and fluorescence spectroscopy were used to study the binding of α2M with GSH and Fourier transform infrared (FT-IR) spectroscopy was explored to study the structural change induced in α2M. Results: The results suggest that exposure of α2M to GSH decreases the antiproteolytic potential as suggested by the amidase assay. The UV-spectroscopic study showed the formation of α2M-GSH complex and fluorescence analysis showed significant quenching in fluorescence intensity of α2M suggesting GSH binding and structural alteration in the protein. FT-IR spectroscopy was explored to study the structural change induced in α2M which suggest that the secondary structure of α2M changes upon complex formation. Conclusion: Our studies show that interaction of α2M with photoilluminated GSH results in functional and conformational changes of the protein. Keywords: glutathione, GSH, alpha-2-macroglobulin, photo-illumination, ITC, FTIR
... Glutathione, a crucial antioxidant, is well known to modulate the behavior of many cells including the cells of the immune system, augmenting the innate and the adaptive immunity as well as conferring protection against microbial, viral and parasitic infections [42,43]. Interaction between GSH metabolism and several diseases were also well described [44]. ...
... Role of GSH Reference Enhancement of immune system function Protects against inflammatory pathologies Impaired immunological function caused by cysteine and glutathione deficiency is restored when supplemented with cysteine [7,8] Prevention of oxidative cell damage Serves as an antioxidant [9,10] Prostaglandin synthesis Inhibits prostaglandin synthesis at elevated levels [11] Transport of metals across membranes ...
Article
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Glutathione is a remarkably functional molecule with diverse features, which include being an antioxidant, a regulator of DNA synthesis and repair, a protector of thiol groups in proteins, a stabilizer of cell membranes, and a detoxifier of xenobiotics. Glutathione exists in two states—oxidized and reduced. Under normal physiological conditions of cellular homeostasis, glutathione remains primarily in its reduced form. However, many metabolic pathways involve oxidization of glutathione, resulting in an imbalance in cellular homeostasis. Impairment of glutathione function in the brain is linked to loss of neurons during the aging process or as the result of neurological diseases such as Huntington’s disease, Parkinson’s disease, stroke, and Alzheimer’s disease. The exact mechanisms through which glutathione regulates brain metabolism are not well understood. In this review, we will highlight the common signaling cascades that regulate glutathione in neurons and glia, its functions as a neuronal regulator in homeostasis and metabolism, and finally a mechanistic recapitulation of glutathione signaling. Together, these will put glutathione’s role in normal aging and neurological disorders development into perspective.
... Glutathione is considered as an important antioxidant in the immune system for two causes; first, it protects the immune cells of the host through its antioxidant mechanism against different types of reactive oxygen species as in Table 1 [20] , second, it provides the best working of immune system cells like lymphocytes and other cells. [21] It is considered as an essential factor for the proliferation of T-cell, neutrophil phagocytic activity, and dendritic cell function. [22] So, the decreasing of glutathione levels is associated with an increased susceptibility to infection and disease such as G6DP, [23] cystic fibrosis, [24] and influenza infection. ...
Article
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The immune system is a complicated system; it is consisted from network of specialized organs, tissues, cells, proteins, and chemicals which it has the function to protect the host from various types of pathogens such as bacteria, virus, fungi, and parasite in addition to cancer cells. Antioxidants are defined as agents that can prevent the damage that is caused by free radicals through scavenging of them. They decrease the damage by neutralizing to the free radicals before they attack any of the cells and can prevent lipids, enzymes, proteins, carbohydrates, and DNA damage.
... Glutathione is considered as an important antioxidant in the immune system for two causes; first, it protects the immune cells of the host through its antioxidant mechanism against different types of reactive oxygen species as in Table 1 [20] , second, it provides the best working of immune system cells like lymphocytes and other cells. [21] It is considered as an essential factor for the proliferation of T-cell, neutrophil phagocytic activity, and dendritic cell function. [22] So, the decreasing of glutathione levels is associated with an increased susceptibility to infection and disease such as G6DP, [23] cystic fibrosis, [24] and influenza infection. ...
Article
Full-text available
The immune system is a complicated system; it is consisted from network of specialized organs, tissues, cells, proteins, and chemicals which it has the function to protect the host from various types of pathogens such as bacteria, virus, fungi, and parasite in addition to cancer cells. Antioxidants are defined as agents that can prevent the damage that is caused by free radicals through scavenging of them. They decrease the damage by neutralizing to the free radicals before they attack any of the cells and can prevent lipids, enzymes, proteins, carbohydrates, and DNA damage
... The products of amino acid metabolism were the substrates of the citrate cycle, which may also be one of the reasons to accelerate the citrate cycle in the rumen epithelia. Glutathione metabolism plays a key role in the pathogenesis of many diseases, and is related to oxidative stress (Droge and Breitkreutz, 2000;Liang et al., 2019). Thus, appropriate regulation of glutathione metabolism is necessary for host health (Wu et al., 2004). ...
Article
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The present study aimed to comparatively characterize the ruminal epithelial protein expression profiles in lambs fed ewe milk or milk plus starter diet using proteome analysis. twenty new-born lambs were randomly divided into a group receiving ewe milk (M, n = 10) and a group receiving milk plus starter diet (M + S, n = 10). From 10-d-old, M group lambs remained with the ewe and suckled ewe milk without receiving the starter diet. The lambs in the M + S group were separated from the ewe and received starter feed. All lambs were slaughtered at 56-d-old. Eight rumen epithelia samples (4 per group) were collected to characterize their protein expression profiles using proteomic technology. Proteome analysis showed that 31 upregulated proteins and 40 downregulated proteins were identified in the rumen epithelium of lambs in response to starter diet supplementation. The results showed that starter feeding regulates a variety of biological processes in the epithelium, especially blood vessel development and extracellular matrix protein expression. Meanwhile, the expression of proteins associated with synthesis and degradation of ketone bodies, butanoate metabolism, and citrate cycle signaling transduction pathway were upregulated in the group with starter diet supplementation, including 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMGCS2, fold change [FC] = 1.93), 3-hydroxybutyrate dehydrogenase 1 (BDH1, FC = 1.91), and isocitrate dehydrogenase 1 (IDH1, FC = 8.12). The metabolic processes associated with ammonia detoxification and antioxidant stress were also affected by starter diet supplementation, with proteins, microsomal glutathione S-transferase 3 (MGST3, FC = 2.37) and IDH1, linked to the biosynthesis of glutamate and glutathione metabolism pathway being upregulated in the group with starter diet supplementation. In addition, starter feeding decreased the expression of Ras-related protein rap-1A (RAP1A, FC = 0.48) enriched in Rap1 signaling pathway, Ras signaling pathway, cyclic adenosine monophosphate (cAMP) signaling pathway, and mitogen-activated protein kinase (MAPK) signaling pathway. In summary, starter feed supplementation changed the expression of proteins related to energy production, ammonia detoxification, antioxidant stress, and signaling pathways related to proliferation and apoptosis, which facilitates the rumen epithelia development in lambs. The results provide new insights into the molecular adaptation of rumen epithelia in response to starter diet supplementation at the protein level in lambs.
... Human plasma or serum contains nearly 250 lM of Cys [5]. Reactive oxygen species (ROS) can damage the victim severely when the Cys level decreases [6]. Detection of both high and low levels of Cys is needed to investigate chronic illness like hemolytic anemia, motor neuron disease, depression, autism, irritable bowel syndrome, myalgic encephalomyelitis and multiple sclerosis. ...
Article
A selective and sensitive detection of L-cysteine (Cys) is an important tool for various biological studies. Here, Au nanoparticles (NPs) were prepared by chemical reduction technique. The probe was developed to detect and quantify Cys in the presence of Cr3+ ions which acts as a cross linker. The citrate capped Au NPs probe was analyzed by UV-visible spectrophotometry, TEM, EDAX, FTIR, DLS, XPS and zetasize. The zeta potential and effective size of Au NPs were -41.22 mV and 12 nm, respectively. The Cys interaction with Au NPs showed drastic colour variation from red to purple and colourless with rapid response time of 1 min. The limit of detection (LOD) of Au NPs probe was as low as 0.012 nM. The TEM image of Au NPs after Cys interaction verified the aggregation that resulted in colour change. The XPS core level scans of Au 4f showed 0.3 eV red shift when Cyswas interacted. The Au NPs sensor is highly selective for Cys with excellent reproducibility. Acidic pH slightly favored Cys detection. Further, the probe was applied to estimate Cys quantity from milk, urine, blood and environmental augmented samples in the presence of other amino acids . The study suggests that the proposed Au NPs could detect Cys with high accuracy from various biological samples.
... GSH concentration in immune cells, in addition to acting as a scavenger of reactive oxygen species (ROS) is of paramount importance for these cells to carry out their proper functions. It has been reported that even transient GSH deprivation affect several functions of immune cells, such as lymphocyte proliferation (Hamilos et al., 1989;Dröge and Breitkreutz, 2000;Rodrigues and Percival, 2019). ...
Article
Chronic obstructive pulmonary disease (COPD) is characterised by inflammatory and oxidative alterations in the lung and extrapulmonary compartments, through involvement of the immune system. Several leukocyte functions are health markers and good predictors of longevity, and high pro-inflammatory and oxidative states are related to more aged profiles. Here, we aimed to investigate the aging rate in terms of immunosenescence in COPD men with respect to healthy age-matched controls. Several neutrophil (adherence, chemotaxis, phagocytosis, superoxide anion stimulated production) and lymphocyte (adherence, chemotaxis, lymphoproliferation, natural killer activity) functions, cytokine concentrations released in response to lipopolysaccharide (tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, IL-10) and redox parameters (intracellular glutathione content, basal superoxide anion level) were assessed in circulating leukocytes of men with moderate and severe stages of COPD, and compared to healthy age-matched volunteers. The biological age or aging rate in each participant was determined using the values of leukocyte functions. The results indicated impairment of immune functions in COPD patients, both in innate and adaptive immunity, and higher pro-inflammatory and oxidative states in peripheral leukocytes than controls. In general, these changes were more remarkable at the severe stage of airway obstruction. Importantly, COPD patients were found to be aging at a faster rate than age-matched healthy counterparts.
... [1][2][3] The imbalance of GSH homeostasis is concerned with various clinical diseases, such as liver or lung damage, cancer, AIDS, Alzheimer's and Parkinson's disease. [4][5][6][7] Therefore, analysis of GSH in biological samples is of continuous interest and great significance in biomedical applications. ...
Article
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A bioinspired fluorometric method has been developed for the detection of glutathione (GSH) in biological fluids. It is based on the use of near-infrared fluorescent semiconducting polymer dots (P-dots) and of the dopamine (DA)-melanin nanosystem. The P-dots were prepared from poly(styrene-co-maleic anhydride), the semiconducting polymer poly[(9,9′-dioctyl-2,7-divinylenefluorenylene)-alt-2-methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylene] and the fluorescent dye tetraphenylporphyrin. They have excitation/emission maxima at 458/656 nm, and this enables measurement to be performed with low autofluorescence and scattering background. DA can self-polymerize on the surface of the P-dots to yield a poly-DA coating. This coating, at weak alkaline pH values, causes the quenching of the fluorescence of the P-dots. However, the polymerization of DA is inhibited by GSH. Hence, quenching of fluorescence is prevented. This effect was used to design a fluorometric assay for GSH that has good selectivity and sensitivity. Under optimal conditions, the method has a linear response in the 0.2 to 20 μM GSH concentration range and a 60 nM detection limit. It was successfully applied to the determination of GSH in HepG2 cells and in spiked human serum. Graphical abstractSchematic representation of using a NIR fluorescent P-dots and dopamine (DA)-melanin nanohybrid as a probe for glutathione (GSH) detection. The P-dots were prepared from poly(styrene-co-maleic anhydride) (PSMA), the semiconducting polymer poly[(9,9′-dioctyl-2,7-divinylenefluorenylene)-alt-2-methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylene] (PEPV) and the fluorescent dye tetraphenylporphyrin (TPP).The GSH can inhibit the dopamine self-polymerization and prevented the formation of PDA and fluorescence quenching of P-dots.
... Glutathione possesses a plethora of functions essential for whole-body homeostasis including the detoxification of both xenobiotic and endogenous compounds, maintenance of the mitochondrial redox environment, antiviral defense by fine-tuning the innate immune response to antiviral pathways, regeneration of vitamins C and E as well as the regulation of cellular proliferation, apoptosis and protein folding [20,286,287,288,289,290,291,292]. Despite an existence of numerous non-antioxidant functions of glutathione, nevertheless, their relationship with the pathogenesis of type 2 diabetes did not become an area of active research. ...
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The present study was designed to investigate whether the genetic predisposition to type 2 diabetes (T2D) is associated with polymorphisms of genes encoding glutathione-metabolizing enzymes such as glutathione synthetase (GSS) and gamma-glutamyl transferase 7 (GGT7), and also to analyze in silico the molecular mechanisms of their involvement in disease pathogenesis. A total of 3198 unrelated Russian subjects including 1572 T2D patients and 1626 healthy subjects were enrolled. Single nucleotide polymorphisms (SNP) of the GSS and GGT7 genes were genotyped using the MALDI-TOF mass spectrometry iPLEX platform. We found for the first time that SNPs rs11546155 (OR 0.42, 95%CI 0.22-0.80, P=0.022) and rs6119534 (OR 0.73, 95%CI 0.53-0.99, P=0.0003) of the GGT7 are significantly associated with T2D regardless of sex, age, and body mass index. The association of SNP rs11546155 with diabetes risk has been replicated in a large ethnically diverse cohort (P=0.018). The GSS and GGT7 polymorphisms in diabetics correlated with the levels of plasma glutathione, hydrogen peroxide, and fasting blood glucose in a gender-specific manner. Epistatic interactions between the gene polymorphisms determining disease susceptibility have been observed with strong protective effects of genotype combinations such as GGT7 rs6119534-C/T × GSS rs1801310-A/A and GGT7 rs6119534-C/T × GSS rs13041792-G/G against disease risk (FDR<1.8×10-5). The risk alleles of GSS and GGT7 correlated with tissue-specific expression of genes located at genomic region 20q11.22 that spans numerous genes involved in the unfolded protein response pathway and regulation of proteostasis. Transcriptome-wide association analysis has shown that pancreatic expression of some of these genes such as EDEM2, MYH7B, MAP1LC3A, and CPNE1 is linked with the genetic susceptibility to type 2 diabetes. Taken together the study findings along with our previous results allowed proposing a new hypothesis for the etiology of type 2 diabetes that endogenous deficiency of glutathione is a key condition responsible for impaired folding of proinsulin and triggering unfolded protein response which ultimately leads to β-cell apoptosis, disease development, and progression.
... Интерес к использованию NAC в лечении ВИЧ инфицированных больных появился около 15 лет на зад, когда появились первые публикации о выражен ном снижении концентрации цистеина и глютатиона в плазме и моноцитах крови и жидкости БАС у этих пациентов [133][134][135][136]. С этими процессами связы вают прогрессирование болезни даже на ранней (асимптоматической) стадии, поскольку глютатион принимает участие в регуляции функций Т лимфо цитов [133,137]. ...
Article
Обзор формально посвящен одному из наиболее "старых" лекарственных средств – ацетилцистеину. Действительно, его клиническое применение охватывает более чем 30-летний период, в котором можно выделить несколько этапов в изучении механизмов его фармакологической активности. Особое внимание к нему было проявлено в связи с поиском антидотов при радиационном воздействии. Ацетилцистеин вошел в список жизненно необходимых лекарственных средств при радиационном поражении человека. Одним из важных этапов в исследовании его механизмов стало применение в области респираторной медицины. Так, исходно ацетилцистеин был предложен как секретолитик, регулирующий образование муцина и стимулирующий его транспорт по дыхательным путям. В последующем была открыта его способность снижать повреждение клеточных структур свободными радикалами. Дисбаланс в системе оксиданты–антиоксиданты играет ведущую патогенетическую роль при таких заболеваниях, как хроническая обструктивная болезнь легких (ХОБЛ), респираторный дистресс-синдром и некоторых других. Необходимо подчеркнуть, что ацетилцистеин с успехом применяется при инфекционных заболеваниях как верхних, так и нижних отделов дыхательных путей. Значительный прогресс был достигнут и при таких прогностически неблагоприятных заболеваниях, какими является разнообразная группа интерстициальных заболеваний легких. Современный этап клинического применения охватил такие области как кардиология, диабетология, химиотерапия, трансплантация органов и тканей, токсикология и некоторые другие. Читатель найдет в обзоре С.Ю.Чикиной новую информацию, которая позволит прийти к выводу о том, что ацетилцистеин, начиная с 70-х гг. прошлого столетия, всегда остается современным лекарственным средством. Академик РАМН профессор А.Г.Чучалин
... Table 3. Evidences related to lactoferrin's role in T1D, and its possible association with COVID-19. Glutathione is an antioxidant that counteracts oxidative stress and improves immune cell function [77]. It has been reported that glutathione levels are dramatically reduced in young subjects with poorly controlled T1D because it is used up at an increased rate [78]. ...
Article
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COVID-19 is without any doubt the worst pandemic we have faced since the H1N1 virus outbreak. Even if vaccination against SARS-CoV-2 infection is becoming increasingly available, a more feasible approach for COVID-19 prevention and therapy is still needed. Evidence of a pathological link between metabolic diseases and severe forms of COVID-19 has stimulated critical reflection and new considerations. In particular, an abnormal immune response observed in certain patients with SARS-CoV-2 infection suggested possible common predisposing risk factors with autoimmune diseases such as Type 1 Diabetes (T1D). Correct supplementation with dietary factors may be key to preventing and counteracting both the underlying metabolic impairment and the complications of COVID-19. A set of agents may inhibit the cytokine storm and hypercoagulability that characterize severe COVID-19 infection: vitamin D3, omega-3 polyunsaturated fatty acids, polyphenols like pterostilbene, polydatin and honokiol, which can activate anti-inflammatory and antioxidant sirtuins pathways, quercetin, vitamin C, zinc, melatonin, lactoferrin and glutathione. These agents could be highly beneficial for subjects who have altered immune responses. In this review, we discuss the antiviral and metabolic effects of these dietary factors and propose their combination for potential applications in the prevention and treatment of COVID-19. Rigorous studies will be fundamental for validating preventive and therapeutic protocols that could be of assistance to mitigate disease progression following SARS-CoV-2 infection.
... Betaine ameliorates oxidative stress, inhibits NLRP3 inflammasome activation, and regulates energy metabolism (Hassan et al., 2011;Zhao et al., 2018). Glutathione plays essential role in maintaining a healthy immune system and contributes to antioxidation and detoxication (Dröge and Breitkreutz, 2000;Ming et al., 2019). Gluten exorphin is a food-derived opioid peptide obtained through the digestion of wheat gluten and plays essential roles in immune response; it may be a good candidate adjuvant for vaccine development (Pruimboom and de Punder, 2015;Zhou and Zhou, 2016). ...
Article
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Ctenopharyngodon idellus and Leuciscus idus are two closely related Leuciscinae fish with dramatically different physiologies, especially in terms of immunological performance. However, the intrinsic metabolic difference between these two species has not been fully discovered. In this study, the immunological indexes, such as lysozyme, superoxide dismutase, and alkaline phosphatase activities, and plasma metabolomic profiles of the two species were compared. Our study revealed significant differences in immunological indexes and metabolomic profiles between them. In C. idellus, highly abundant metabolites were enriched in galactose metabolism, pyruvate metabolism, choline metabolism, and ether lipid metabolism. By contrary, in L. idus, highly abundant metabolites were enriched in taurine and hypotaurine metabolism, glycine, serine and threonine metabolism, and glycerophospholipid metabolism. We also identified that the abundances of key immune-performance-related metabolites, such as taurine, betaine, glutathione, gluten exorphin, and fistuloside A were higher in L. idus than in C. idellus. This result indicated that the two species presented distinct immunological performance at metabolomic level. Our study provided a snapshot of the metabolic difference between C. idellus and L. idus, and the key metabolites identified here could be utilized as immunological biomarkers for the aquaculture and selective breeding of C. idellus in the future.
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Objective: The research was aimed to determine the effects of glutathione extracts and some biological agents on immune and oxidative stress parameters in male rats induced Immunosuppression used Sandimmune. Methods: Glutathione was extract from spinach leaves and estimated the concentration used a high-performance liquid chromatography (HPLC) and determined the effect of orally dosage at one mg/ml alone or with both Zinc or Vit C or cell concentration of Lactobacillus plantarum (CCLP) on the immunity and biological parameters of male rats induced Immunosuppression used Sandimmune and breeding for 28 days. Results: The results indicated that aqueous spinach extract was contained glutathione at a concentration of 246 µg/g in the case of extraction using aqueous extract. The Immunosuppression induced was significantly (p<0.05) decreased of IgA, IgG and IgM values and became at 1022, 2031 and 121.5 mg/dl respectively compared with the control rats group which at 1564, 3206 and 174.7 mg/dl respectively while the orally dosage from biological parameters was caused in amelioration of immunity parameters to became similar of values with the control rats group. Also the oxidative stress parameters value as GSH, GPx, SOD and catalase enzyme were significantly decreased to 222, 0.17, 375 and 0.31µmol/L respectively and increased in MDA value to 4.6 µmol/L compared with the rats in control group, and the used of glutathione alone or with the biological parameters were done improvement to similar values in control group. Conclusion: It was concluded that oral dosage of glutathione alone or with biological agents was significantly effective in improving immunity and decreasing the oxidative stress values in the laboratory rats that induced immunosuppression. Abdel-Hamid ZD, Thalij KM (2020) The effects of oral dosage of glutathione and some biological agents on immunity and oxidative stress parameters in male rats induced with immunosuppression.
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Despite the prevalence of autism and its extensive impact on our society, no U.S. Food and Drug Administration-approved treatment is available for this complex neurobiological disorder. Based on mounting evidences that support a link between autism and the gut microbiome, we previously performed a pioneering open-label clinical trial using intensive fecal microbiota transplant. The therapy significantly improved gastrointestinal and behavioral symptoms. Comprehensive metabolomic measurements in this study showed that children with autism spectrum disorder (ASD) had different levels of many plasma metabolites at baseline compared to those in typically developing children. Microbiota transfer therapy (MTT) had a systemic effect, resulting in substantial changes in plasma metabolites, driving a number of metabolites to be more similar to those from typically developing children. Our results provide evidence that changes in metabolites are one mechanism of the gut-brain connection mediated by the gut microbiota and offer plausible clinical evidence for a promising autism treatment and biomarkers.
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Background: Despite the crucial role of educators in encourage students' academic learning, addressing educator stress inside the classroom remains a significant challenge in the educational context. Mindfulness Meditation training (MM) has been recommended as an environmental enrichment strategy in schools to help teachers cope with stress and cultivating a state of awareness in daily life. Although studies have shown that MM can improve immune system dynamics the biological mechanism underlying glutathione metabolism in a healthy human is unclear. Objective: The purpose of this study was to determine whether MM training benefits psychological and behavioral response, immunological functions and glutathione metabolism in service healthy female teachers from public schools. Methods: We randomly assigned 76 teachers to an 8-week Mindfulness-Based Health Program for Educators (MBHPEduca) or Neuroscience for Education program (Neuro-Educa; active control group). Using the quality of life as our primary outcome, perceived stress, negative affectivity, and resilience as our secondary outcome, and pro-inflammatory cytokines and glutathione levels as our third outcome at baseline and post-intervention that occurred in public schools. Blood samples were collected for the measurement of three proinflammatory markers, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) and three GSH metabolism, including Cysteine (Cys), Homocysteine (HCys) and GSH were conducted at pre-and post-intervention, with selfreported assessments over time. Treatment effects were analyzed using generalized estimating equations (GEE) with to intention to treat. Results: We observed statistically significant improvements to the MBHP-Educa group compared to active control in perceived stress, resilience, positive and negative affect, and quality of life after 8-weeks MM (p < 0.0001). Further, the MBHP-Educa group exhibited lower circulating IL-6 production accompanied by high circulating GSH, and Cys (p < 0.0001). Additional analyses indicated that enhancing quality of life through mindfulness meditation training was mediated by reducing perceived stress and serum levels of IL- 6 and increasing resilience and teachers 'plasma GSH levels. Conclusions: The present study is a pilot trial with low-power and provides preliminary evidence that mindfulness meditation training help teachers to cope with stress in the school environment with an impact on the quality of life, immune function, and glutathione metabolism.
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Epidemiological studies have identified dairy foods as providing significant protection against colon cancer. Though the interpretation of such data is complicated by the presence of many confounding factors, the effect of milk intake on colon cancer has been reasonably consistent. Calcium, present in milk in a highly bioavailable form, has usually been considered the milk constituent most likely to confer this benefit, however, data from in vitro studies and animal models point to the effect of milk and milk products independent of calcium, including vitamin D, lactoferrin, lactalbumin, conjugated linoleic acid, sphingolipids, lactose, probiotics, butyrate and milk fat globule membrane. Data on the clinical impact of these components in very limited.
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Maintenance of intracellular glutathione (GSH) levels has been implicated in blocking cytokine-stimulated HIV replication in vitro, in both acute and latent infection models. We demonstrate here that subsets of human peripheral blood mononuclear cells differ substantially in mean GSH levels, as measured on a cell-by-cell basis with the fluorescence-activated cell sorter (FACS): B cells have the lowest GSH levels; T cells are intermediate; and monocytes and macrophages have the highest levels. Furthermore, GSH levels subdivide the CD4 and CD8 T cell subsets into two classes each: high- and low-GSH cells, which cannot be distinguished by cell size or by currently known surface markers. Significantly, the high-GSH T cells are selectively depleted early during the HIV infection, and are effectively missing in all ARC and AIDS patients.
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Hydrogen peroxide and oxygen radicals are agents commonly produced during inflammatory processes. In this study, we show that micromolar concentrations of H2O2 can induce the expression and replication of HIV-1 in a human T cell line. The effect is mediated by the NF-kappa B transcription factor which is potently and rapidly activated by an H2O2 treatment of cells from its inactive cytoplasmic form. N-acetyl-L-cysteine (NAC), a well characterized antioxidant which counteracts the effects of reactive oxygen intermediates (ROI) in living cells, prevented the activation of NF-kappa B by H2O2. NAC and other thiol compounds also blocked the activation of NF-kappa B by cycloheximide, double-stranded RNA, calcium ionophore, TNF-alpha, active phorbol ester, interleukin-1, lipopolysaccharide and lectin. This suggests that diverse agents thought to activate NF-kappa B by distinct intracellular pathways might all act through a common mechanism involving the synthesis of ROI. ROI appear to serve as messengers mediating directly or indirectly the release of the inhibitory subunit I kappa B from NF-kappa B.
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Activation of the CD28 surface receptor provides a major costimulatory signal for T cell activation resulting in enhanced production of interleukin-2 (IL-2) and cell proliferation. In primary T lymphocytes we show that CD28 ligation leads to the rapid intracellular formation of reactive oxygen intermediates (ROIs) which are required for CD28-mediated activation of the NF-kappa B/CD28-responsive complex and IL-2 expression. Delineation of the CD28 signaling cascade was found to involve protein tyrosine kinase activity, followed by the activation of phospholipase A2 and 5-lipoxygenase. Our data suggest that lipoxygenase metabolites activate ROI formation which then induce IL-2 expression via NF-kappa B activation. These findings should be useful for therapeutic strategies and the development of immunosuppressants targeting the CD28 costimulatory pathway.
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The transcription factors NF-kappa B and AP-1 have been implicated in the inducible expression of a variety of genes involved in responses to oxidative stress and cellular defense mechanisms. Here, we report that thioredoxin, an important cellular protein oxidoreductase with antioxidant activity, exerts different effects on the activation of NF-kappa B and AP-1. Transient expression or exogenous application of thioredoxin resulted in a dose-dependent inhibition of NF-kappa B activity, as demonstrated in gel shift and transactivation experiments. AP-1-dependent transactivation, in contrast was strongly enhanced by thioredoxin. A similar increase of AP-1 activity was also observed with other, structurally unrelated antioxidants such as pyrrolidine dithiocarbamate and butylated hydroxyanisole, indicating that the thioredoxin-induced increase of AP-1 activation was indeed based on an antioxidant effect. Moreover, the stimulatory effect on AP-1 activity was found to involve de novo transcription of the c-jun and c-fos components but to be independent of protein kinase C activation. These results suggest that thioredoxin plays an important role in the regulation of transcriptional processes and oppositely affects NF-kappa B and AP-1 activation.
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We show that AP-1 is an antioxidant-responsive transcription factor. DNA binding and transactivation by AP-1 were induced in HeLa cells upon treatment with the antioxidants pyrrolidine dithiocarbamate (PDTC) and N-acetyl-L-cysteine (NAC), and upon transient expression of the antioxidative enzyme thioredoxin. While PDTC and NAC enhanced DNA binding and transactivation of AP-1 in response to phorbol ester, the oxidant H2O2 suppressed phorbol ester activation of the factor. H2O2 on its own was only a weak inducer of AP-1. Activation of AP-1 by PDTC was dependent on protein synthesis and involved transcriptional induction of c-jun and c-fos genes. Transcriptional activation of c-fos by PDTC was conferred by the serum response element, suggesting that serum response factor and associated proteins function as primary antioxidant-responsive transcription factors. In the same cell line, the oxidative stress-responsive transcription factor NF-kappa B behaved in a manner strikingly opposite to AP-1. DNA binding and transactivation by NF-kappa B were strongly activated by H2O2, while the antioxidants alone were ineffective. H2O2 potentiated the activation of NF-kappa B by phorbol ester, while PDTC and NAC suppressed PMA activation of the factor. PDTC did not influence protein kinase C (PKC) activity and PKC activation by PMA, indicating that the antioxidant acted downstream of and independently from PKC.
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In a double-blind placebo-controlled trial, human immunodeficiency virus (HIV)-seropositive patients with a CD4 lymphocyte cell count of more than 200 x 10(6) . l-1 were randomised to receive either 800 mg N-acetylcysteine (NAC) or placebo for 4 months. Before treatment low plasma cysteine levels, high free radical activity in neutrophils in the presence of autologous plasma-measured by the nitroblue tetrazolium (NBT) test- and increased tumor necrosis factor (TNF)-alpha levels were found in the HIV positive patients. After treatment the low plasma cysteine level in the NAC group increased to normal, and the decline of the CD4+ lymphocyte count before the study start, was less steep in the NAC group than in the placebo group after treatment. There was also a reduction in TNF-alpha level. However, NAC had no effect on the radical production by neutrophils, and although it did not increase the CD4+ cell count, it may have decreased the decline in CD4+ cells. Further controlled trials with NAC are needed to determine whether it has a beneficial effect in the treatment of asymptomatic HIV-infected individuals.
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Patients with skeletal muscle catabolism (cachexia) fail to conserve the skeletal muscle protein and release large amounts of nitrogen as urea. Previous studies suggest that the threshold for the conversion of amino acids into other forms of chemical energy and the concomitant production of urea are regulated by the plasma cystine level and hepatic cysteine catabolism. Studies of plasma amino acid exchange rates in the lower extremities now show that healthy young subjects regulate their plasma cystine level in a process that may be described as controlled constructive catabolism. The term controlled describes the fact that the release of cystine and other amino acids from the peripheral tissue is negatively correlated with (certain) plasma amino acid levels. The term constructive describes the fact that the release of cystine is correlated with an increase of the plasma cystine level. The regulation of the plasma cystine level is disturbed in conditions with progressive skeletal muscle catabolism including cancer, HIV infection, and old age. These conditions show also a low plasma glutamine:cystine ratio indicative of an impaired hepatic cystine catabolism. In HIV+ patients and SIV-infected macaques, a decrease of the plasma cystine level was found to coincide with the decrease of CD4+ T cells.
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Growing evidence has indicated that cellular reduction/oxidation (redox) status regulates various aspects of cellular function. Oxidative stress can elicit positive responses such as cellular proliferation or activation, as well as negative responses such as growth inhibition or cell death. Cellular redox status is maintained by intracellular redox-regulating molecules, including thioredoxin (TRX). TRX is a small multifunctional protein that has a redox-active disulfide/dithiol within the conserved active site sequence: Cys-Gly-Pro-Cys. Adult T cell leukemia-derived factor (ADF), which we originally defined as an IL-2 receptor alpha-chain/Tac inducer produced by human T cell lymphotrophic virus-I (HTLV-I)-transformed T cells, has been identified as human TRX. TRX/ADF is a stress-inducible protein secreted from cells. TRX/ADF has both intracellular and extracellular functions as one of the key regulators of signaling in the cellular responses against various stresses. Extracellularly, TRX/ADF shows a cytoprotective activity against oxidative stress-induced apoptosis and a growth-promoting effect as an autocrine growth factor. Intracellularly, TRX/ADF is involved in the regulation of protein-protein or protein-nucleic acid interactions through the reduction/oxidation of protein cysteine residues. For example, TRX/ADF translocates from the cytosol into the nucleus by a variety of cellular stresses, to regulate the expression of various genes through the redox factor-1 (Ref-1)/APEX. Further studies to clarify the regulatory roles of TRX/ADF and its target molecules may elucidate the intracellular signaling pathways in the responses against various stresses. The concept of "redox regulation" is emerging as an understanding of the novel mechanisms in the pathogenesis of several disorders, including viral infections, immunodeficiency, malignant transformation, and degenerative disease.
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Initial investigations demonstrated a deficiency of glutathione (GSH) in the epithelial lining fluid (ELF) of HIV-seropositive patients. In a recent study, our laboratory was unable to document such a deficiency. The current study was performed in an attempt to reconcile those disparate findings. To determine if ELF GSH decreases over time in asymptomatic HIV-seropositive subjects. Prospective, longitudinal study. Major university medical center. Thirty-three asymptomatic HIV-seropositive volunteers. None. BAL was performed on 33 asymptomatic HIV-seropositive subjects at baseline, 6 months later, and 12 months later. The volume of ELF and the concentration of GSH and oxidized GSH were determined. The concentration of total GSH in ELF was 689.0+/-100.4 microM. This significantly decreased when measured 6 and 12 months later (355.9+/-41.7 microM, and 397.9+/-52.7 microM, respectively, p=0.01, compared with baseline, both comparisons). Significant decreases were also noted in the HIV-seropositive subjects who smoked cigarettes (baseline--762.6+/-142.4 microM; 6 months--373.7+/-45.9 microM; 12 months--459.3+/-73.8 microM, p<0.03, for baseline vs 6 months, and baseline vs 12 months). In nonsmoking HIV-seropositive subjects, there was a decrease in ELF GSH over time, but it did not reach statistical significance (baseline--589.1+/-138.2 microM; 6 months--335.3+/-74.1 microM; 12 months--345.8+/-74.0 microM, p>0.1, all comparisons). The percentage of total GSH in the oxidized form was similar at all three time points (baseline--3.8+/-0.5%; 6 months--3.1+/-0.5%; 12 months--3.9+/-0.9%, p>0.1, all comparisons). The current study demonstrates that the GSH level in ELF is significantly decreased in HIV-seropositive subjects 6 and 12 months after the initial determination.
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We show that AP-1 is an antioxidant-responsive transcription factor. DNA binding and transactivation by AP-1 were induced in HeLa cells upon treatment with the antioxidants pyrrolidine dithiocarbamate (PDTC) and N-acetyl-L-cysteine (NAC), and upon transient expression of the antioxidative enzyme thioredoxin. While PDTC and NAC enhanced DNA binding and transactivation of AP-1 in response to phorbol ester, the oxidant H2O2 suppressed phorbol ester activation of the factor. H2O2 on its own was only a weak inducer of AP-1. Activation of AP-1 by PDTC was dependent on protein synthesis and involved transcriptional induction of c-jun and c-fos genes. Transcriptional activation of c-fos by PDTC was conferred by the serum response element, suggesting that serum response factor and associated proteins function as primary antioxidant-responsive transcription factors. In the same cell line, the oxidative stress-responsive transcription factor NF-kappa B behaved in a manner strikingly opposite to AP-1. DNA binding and transactivation by NF-kappa B were strongly activated by H2O2, while the antioxidants alone were ineffective. H2O2 potentiated the activation of NF-kappa B by phorbol ester, while PDTC and NAC suppressed PMA activation of the factor. PDTC did not influence protein kinase C (PKC) activity and PKC activation by PMA, indicating that the antioxidant acted downstream of and independently from PKC.
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Activation of the CD28 surface receptor provides a major costimulatory signal for T cell activation resulting in enhanced production of interleukin‐2 (IL‐2) and cell proliferation. In primary T lymphocytes we show that CD28 ligation leads to the rapid intracellular formation of reactive oxygen intermediates (ROIs) which are required for CD28‐mediated activation of the NF‐kappa B/CD28‐responsive complex and IL‐2 expression. Delineation of the CD28 signaling cascade was found to involve protein tyrosine kinase activity, followed by the activation of phospholipase A2 and 5‐lipoxygenase. Our data suggest that lipoxygenase metabolites activate ROI formation which then induce IL‐2 expression via NF‐kappa B activation. These findings should be useful for therapeutic strategies and the development of immunosuppressants targeting the CD28 costimulatory pathway.
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In studies on fatty livers due to amino acid imbalances, it was found that addition of 0.3% of methionine and threonine to a protein free diet significantly reduced the loss of body weight and urinary nitrogen excretion of young adult female rats. Addition of methionine alone or of a combination of methionine and an essential amino acid other than threonine had a little effect in reducing urinary nitrogen excretion. Supplemented amount and the ratio of methionine and threonine was also investigated and the nitrogen sparing action of methionine and threonine was observed in fairly wide range of the supplemented amount and the ratio of the two amino acids. Effect of supplementation of methionine and threonine on some amino acid catabolizing enzymes in the livers of rats was also investigated.
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Purified CD4+ and CD8+ T cells, prepared from seven aged rhesus monkeys (>20 years), were 40-97% suppressed in their mitogenic responses to Con A or anti-CD3 (with PMA) when compared to T cell responses from four young control animals. The suppressed mitogenic responses were paralleled by diminished synthesis of interleukin-2 (IL-2). The CD4+ and CD8+ T cells from a given aged animal were suppressed approximately the same degree. Addition of NAC (5 mM) enhanced the aged T cell proliferative response and IL-2 production from 4-15 fold; the more strongly suppressed cells generally were more responsive to NAC Control T cell responses were modestly enhanced from 1.5-3 fold. Since the cysteine of NAC readily incorporates into glutathione, the observation that NAC restores aged T cell responses suggests that glutathioneassociated metabolism, an important component for T cell mitogenesis, may be altered in aged rhesus T cells. Supported by NIH grants 1-S06RR08239 and 1G12RR03050.
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The nitrogen sparing action of methionine and arginine supplementations to a protein-free diet were studied with colostomized adult cocks.Body weight loss of the cocks fed a protein-free diet was alleviated with methionine or arginine supplementation, but neither effect was significant. Faecal nitrogen showed comparable values and urinary nitrogen of the cocks fed the methionine supplemented diet was the lowest of the 3 groups. The nitrogen balance were, in the order of increasing, methionine supplemented, arginine supplemented and protein-free groups.Each of the major urinary nitrogenous compounds of cocks fed the methionine supplemented diet showed lower values than the corresponding values for the cocks fed a protein-free diet. From the result of faecal nitrogen and faecal amino acid analysis, there was no evidence that the re-utilization of endogenous nitrogen of the birds fed a protein-free diet was enhanced by the addition of methionine or arginine.
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To establish whether the low cysteine and glutathione levels in HIV-infected patients and SIV-infected rhesus macaques may be consequences of an abnormal cysteine catabolism, we analyzed sulfate and glutathione levels in macaques. Muscle tissue (m. vastus lateralis and m. gastrocnemius) of SIV-infected macaques (n = 25) had higher sulfate and lower glutathione and glutamate levels than that of uninfected controls (n = 9). Hepatic tissue, in contrast, showed decreased sulfate and glutathione disulfide (GSSG) levels, and increased γ-glutamylcysteine synthetase (γ-GCS) activity. These findings suggest drainage of the cysteine pool by increased cysteine catabolism in skeletal muscle tissue, and by increased hepatic glutathione biosynthesis. Cachectic macaques also showed increased urea levels and decreased glutamine/urea ratios in the liver, which are obviously related to the abnormal urea excretion and negative nitrogen balance commonly observed in cachexia. As urea production and net glutamine synthesis in the liver are strongly influenced by proton-generating processes, the abnormal hepatic urea production may be the direct consequence of the cysteine deficiency and the decreased catabolic conversion of cysteine into sulfate and protons in the liver. To establish whether the low cysteine and glutathione levels in HIV-infected patients and SIV-infected rhesus macaques may be consequences of an abnormal cysteine catabolism, we analyzed sulfate and glutathione levels in macaques. Muscle tissue (m. vastus lateralis and m. gastrocnemius) of SIV-infected macaques (n = 25) had higher sulfate and lower glutathione and glutamate levels than that of uninfected controls (n = 9). Hepatic tissue, in contrast, showed decreased sulfate and glutathione disulfide (GSSG) levels, and increased γ-glutamylcysteine synthetase (γ-GCS) activity. These findings suggest drainage of the cysteine pool by increased cysteine catabolism in skeletal muscle tissue, and by increased hepatic glutathione biosynthesis. Cachectic macaques also showed increased urea levels and decreased glutamine/urea ratios in the liver, which are obviously related to the abnormal urea excretion and negative nitrogen balance commonly observed in cachexia. As urea production and net glutamine synthesis in the liver are strongly influenced by proton-generating processes, the abnormal hepatic urea production may be the direct consequence of the cysteine deficiency and the decreased catabolic conversion of cysteine into sulfate and protons in the liver.
Article
HIV-1 proviral DNA contains two binding sites for the transcription factor NF-x B. HIV-1-infected individuals have, on average, abnormally high levels of tumour necrosis factor [alpha] (TNF[alpha]) and abnormally low plasma cysteine levels. We therefore investigated the effects of cysteine and related thiols on HIV-1 replication and NF-x B expression. The experiments in this report show that cysteine or N-acetylcysteine (NAC) raise the intracellular glutathione (GSH) level and inhibit HIV-1 replication in persistently infected Molt-4 and U937 cells. However, inhibition of HIV-1 replication appears not to be directly correlated with CSH levels. Cysteine and NAC also inhibit NF-x B activity as determined by electrophoretic mobility shift assays and chloramphenicol acetyl-transferase (CAT) gene expression under control of NF-x B binding sites in uninfected cells. This suggests that the cysteine deficiency in HIV-1-infected individuals may cause an over-expression of NF-x B-dependent genes and enhance HIV-1 replication. NAC may be considered for the treatment of HIV-1-infected individuals. (C) Lippincott-Raven Publishers.
Article
Three bioassays were conducted to determine the limiting order of amino acids for endogenous amino acid utilization in chicks fed a protein-free diet. The studies were conducted during the period 10 to 21 d posthatching. Experiment 1 was a deletion assay in which a protein-free basal diet was supplemented with an amino acid mixture containing methionine, cystine, threonine, arginine, phenylalanine and glutamine. Each amino acid, or methionine + cystine together, was then deleted singly from the amino acid mixture. Supplementing the protein-free basal diet with the amino acid mixture reduced weight loss. Deletion of methionine and cystine from the amino acid mixture increased (P < 0.05) weight loss. Deleting threonine from the amino acid mixture also resulted in weight loss that was intermediate between the amino acid-supplemented diet and the protein-free basal diet, indicating it was second limiting after sulfur amino acids. Experiments 2 and 3 were amino acid addition assays. Additions of methionine or cystine to the protein-free basal diet, either singly or in combination, resulted in lower rates of weight loss and protein depletion. Addition of threonine to the diet supplemented with methionine and cystine further reduced weight loss. These studies indicate that sulfur amino acids are the first-limiting amino acids for utilization of endogenous amino acids. However, our results clearly demonstrate that the primary need is for cystine, and not for methionine per se.
Article
Cocks were fed a protein-free diet supplemented with methionine plus arginine or glutamic acid for 25 days to investigate the effect of these amino acids on fecal and urinary nitrogen excretion. Addition of either methionine plus arginine or glutamic acid did not change the fecal nitrogen excretion. Methionine plus arginine supplementation reduced the urniary nitrogen excretion compared to the protein-free diet, whereas glutamic acid supplementation increased it. The reduced urinary nitrogen excretion resulting from supplementation with methionine plus arginine was mostly accounted for by a reduction in uric acid excretion. In the methionine plus arginine group, free amino acid analysis showed that free glutamine and glutamic acid content significantly decreased in liver while no differences were found in plasma. Since glutamine may play an important role in the formation of uric acid for chickens, the reduced amount of free glutamine and glutamic acid in the liver of cocks fed the diet suplemented with methionine plus arginine might account for the reduced excretion of uric acid, and therefore for the nitrogen sparing action of methionine plus arginine in chickens fed a protein-free diet.
Article
It was previously reported that methionine and threonine supplementation of a protein free diet had a greater nitrogen sparing action than methionine supplementation alone. Investigated in this study were (1) effects of depletion of labile body protein on the nitrogen sparing action of methionine and threonine supplementation of a protein free diet, (2) the effects of graded levels of methionine and threonine on urinary nitrogen excretion, (3) the effect of supplementation of other amino acids to the protein free diet plus methionine and threonine on the urinary excretion of nitrogen and (4) sex differences in the nitrogen sparing action of methionine and threonine supplementation of a protein free diet. After 10 days of feeding a protein free diet to deplete the body labile proteins, nitrogen excretion in urine of female rats was significantly reduced within the first 2 days of feeding a protein free diet supplemented with methionine and threonine. After 7 days of feeding a protein free diet supplemented with methionine and threonine, nitrogen excretion was reduced when even as little as 0.0188% of each amino acid was added. The supplementation of all essential amino acids to the protein free diet did not reduce the urinary excretion of nitrogen further than the supplementation of methionine and threonine, but improved the nitrogen balance slightly. The excretion of urinary nitrogen by female rats fed the protein free diet supplemented with small amounts (0.0188%) of methionine and threonine was significantly reduced after 7 to 14 days of feeding. In males, small amounts of methionine and threonine had no significant effect at either 7 or 14 days.
Article
Markedly decreased plasma cystine and cysteine concentrations have been found in HIV-infected patients at all stages of the disease and in SIV-infected rhesus macaques. The elevated glutamate levels found in the same patients aggravate the cysteine deficiency by inhibiting the membrane transport activity for cystine. The intact immune system appears to require a delicate balance between pro-oxidant and antioxidant conditions, maintained by a limited and well-regulated supply of cysteine. This balance is obviously disturbed in HIV infection and may contribute to the pathogenesis of AIDS.
Article
To determine whether a single oral dose of N-acetylcysteine corrects the deficiency of cysteine and glutathione in plasma and mononuclear cells of HIV-infected patients. Pharmacokinetic and pharmacodynamic study. Cysteine and glutathione were measured in plasma and peripheral blood mononuclear cells of patients at different stages of HIV infection before and after a single oral dose of N-acetylcysteine. At baseline, the plasma concentrations of glutathione and cysteine were significantly lower in HIV-infected patients than in healthy controls. The intracellular concentration of glutathione correlated with the absolute CD4 lymphocyte counts: the concentration of glutathione in mononuclear cells was significantly lower in patients with more advanced immunodeficiency. A single oral dose of N-acetylcysteine increased the concentration of cysteine in plasma and mononuclear cells of HIV-infected patients. Four hours after N-acetylcysteine administration, intracellular glutathione concentrations in the patients were moderately higher than at baseline and at 2 h. Oral N-acetylcysteine transiently increases the concentrations of cysteine and glutathione in mononuclear cells of patients with HIV infection. A sustained increase in intracellular cysteine may be necessary to normalize intracellular glutathione. This may be accomplished by repeat administration of N-acetylcysteine.
Article
Even moderate variations of the extracellular cysteine concentration were previously shown to affect T cell functions in vitro despite high concentrations of cystine. We therefore analyzed the membrane transport activities of T cells for cysteine and cystine, and the role of low molecular weight thiol in T cell-mediated host responses against a T cell tumor in vivo. A series of T cell clones and tumors including the highly malignant lymphoma L5178Y ESb and its strongly immunogenic variant ESb-D was found to express extremely weak transport activity for cystine but strong transport activity for cysteine. However, not all cells showed the expected requirement for cysteine (or 2-mercaptoethanol (2-ME)) in the culture medium. One group of clones and tumors including the malignant ESb-lymphoma did not respond to changes of extracellular cystine concentrations and was strongly thiol dependent. This group released only little acid soluble thiol (cysteine) if grown in cystine-containing cultures. The other T cell lines, in contrast, were able to maintain high intracellular GSH levels and DNA synthesis activity in cystine-containing culture medium without cystein or 2-ME and released substantial amounts of thiol. This group included the immunogenic ESb-D line. Additional thiol-releasing ESb variants were obtained by culturing large numbers of L5178Y ESb tumor cells in cultures without cysteine or 2-ME. All of these ESb variants showed a significantly decreased tumorigenicity and some of them induced cytotoxic and protective host responses even against the malignant ESb parent tumor. Taken together, our experiments suggest that the host response against a tumor may be limited in certain cases by the failure of the stimulator (i.e., the tumor) cell to deliver sufficient amounts of cysteine to the responding T cells.
Article
To establish whether the high plasma glutamate and low acid-soluble thiol (mainly cysteine) concentrations previously found in patients with HIV-1 infection are a consequence of the infection or a risk factor for its development, a closely related animal model, rhesus and fascicularis macaques infected with simian immunodeficiency virus (SIVmac251), was studied. The 23 infected macaques had significantly lower mean plasma thiol and higher glutamate concentrations than 18 uninfected controls (p less than 0.001). The changes were apparent by 1 week after infection. Thus, abnormal plasma glutamate and thiol concentrations are, at least in this model, a direct and early consequence of the retroviral infection.
Article
The concentration of L-lactate in the blood plasma of higher vertebrates is about 1 mM but can be as high as 30 mM under certain physiological and pathological conditions or in the vicinity of glycolytically active cells including macrophages. Here we report that high but physiologically relevant concentrations of lactate increase the expression of interleukin 2 (IL 2)-specific mRNA and the production of IL 2 activity in cultures of mitogenically stimulated T cells. Lactate supports IL 2 production most effectively if added 0-8 h after T cell stimulation and only in cultures of CD4+ but not of CD8+ T cells. In contrast to the DNA synthesis activity in these cell cultures, IL 2 production is not augmented but rather inhibited by exogenous glutathione (GSH). Lactate causes a reduction of intracellular GSH levels, and lactate-containing cultures require accordingly higher extracellular cysteine concentrations than control cultures to achieve similar intracellular GSH levels. In view of the strong variations of extracellular lactate concentrations in vivo, our experiments suggest that lactate may be part of a previously unknown mechanism by which the metabolic microenvironment modulates gene expression in T cells.