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Glutathione and immune function
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.
... Glutathione is fundamental to sustain an adequate function of the immune system, particularly affecting the lymphocyte activity since low GSH levels inhibit T-cell proliferation and immune response (Dröge and Breitkreutz, 2000;Ghezzi, 2011;Moro-García et al., 2018;Kelly and Pearce, 2020;Khanfar and Al Qaroot, 2020;Shyer et al., 2020). GSH depletion is strongly associated with impaired immune function and with disease development including viral diseases, cancer, cardiovascular diseases, arthritis and diabetes (Sinha et al., 2018;Sharifi-Rad et al., 2020;Silvagno et al., 2020;Fraternale et al., 2021;Matuz-Mares et al., 2021). ...
... GSH is essential for immunomodulation of both innate and adaptive immune system functions, including T-lymphocyte proliferation, polymorphonuclear neutrophil phagocytosis, and dendritic cell functions, and is also important for fine-tuning the innate immune response to infection and for the first step of adaptive immunity involving antigen-presenting cell (macrophages, dendritic cells)related antigen presentation (Morris et al., 2013;Diotallevi et al., 2017). GSH works to modulate the behavior of many immune cells, augmenting both, innate immunity (and trained innate immunity or innate immune memory; Netea et al., 2020;Chumakov et al., 2021;Ferreira et al., 2021;Gong et al., 2021;Brueggeman et al., 2022), severely affected by SARS-CoV-2 viral infection (Polonikov, 2020;Rodrigues et al., 2020;Forcados et al., 2021;Kozlov et al., 2021;Bellanti et al., 2022;Paludan and Mogensen, 2022), and adaptive immunity (Dröge et al., 1991;Dröge and Breitkreutz, 2000;Dröge, 2002c;Ghezzi, 2011;Morris et al., 2013;Fraternale et al., 2017), as well as conferring protection against oxidative stress caused by microbial, parasitic and viral infections such as SARS-CoV-2 that causes COVID-19 disease (Morris et al., 2013;Diotallevi et al., 2017;Derouiche, 2020;Polonikov, 2020;Silvagno et al., 2020;Suhail et al., 2020;Forcados et al., 2021;Pérez de la Lastra et al., 2021;Bellanti et al., 2022;Kumar P. et al., 2022). Persistent and uncontrolled oxidative stress and exacerbating NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome activation during severe COVID-19 disease (Lage et al., 2022), induce production of pro-inflammatory cytokines, such as IL-1β and IL-18, that can be explained because of sharply decreased macrophage GSH intracellular levels associated with increased GSH efflux (Zhang T. et al., 2021). ...
... GSH is capable of scavenging ROS through Nrf2-mediated heme oxygenase-1 induction and enhancing M1-like macrophage polarization regulation, showing that GSH may be a useful strategy to increase the human defense system (Mittal et al., 2014;Kwon et al., 2019;Funes et al., 2020). Strategies to enhance intracellular GSH levels such as supplementation of additional sources of cysteine (Deneke and Fanburg, 1989;Dröge et al., 1991;Lands et al., 1999;Dröge and Breitkreutz, 2000;Ghezzi et al., 2019;Gould and Pazdro, 2019;Minich and Brown, 2019;Castejon et al., 2021), oral and intravenous GSH (Cazzola et al., 2021), and sublingual and/or oral liposomal GSH administration (Schmitt et al., 2015;Campolo et al., 2017;Sinha et al., 2018;Guloyan et al., 2020; will also help to improve the immunological functions. The GSH and NAC digestive degradation occurring during oral treatments lead to consider GSH and NAC nebulization as a viable alternative to manage early stages of COVID-19 disease (Santos Duarte Lana et al., 2021). ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 19 (COVID-19) has numerous risk factors leading to severe disease with high mortality rate. Oxidative stress with excessive production of reactive oxygen species (ROS) that lower glutathione (GSH) levels seems to be a common pathway associated with the high COVID-19 mortality. GSH is a unique small but powerful molecule paramount for life. It sustains adequate redox cell signaling since a physiologic level of oxidative stress is fundamental for controlling life processes via redox signaling, but excessive oxidation causes cell and tissue damage. The water-soluble GSH tripeptide (γ-L-glutamyl-L-cysteinyl-glycine) is present in the cytoplasm of all cells. GSH is at 1–10 mM concentrations in all mammalian tissues (highest concentration in liver) as the most abundant non-protein thiol that protects against excessive oxidative stress. Oxidative stress also activates the Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) redox regulator pathway, releasing Nrf2 to regulate the expression of genes that control antioxidant, inflammatory and immune system responses, facilitating GSH activity. GSH exists in the thiol-reduced and disulfide-oxidized (GSSG) forms. Reduced GSH is the prevailing form accounting for >98% of total GSH. The concentrations of GSH and GSSG and their molar ratio are indicators of the functionality of the cell and its alteration is related to various human pathological processes including COVID-19. Oxidative stress plays a prominent role in SARS-CoV-2 infection following recognition of the viral S-protein by angiotensin converting enzyme-2 receptor and pattern recognition receptors like toll-like receptors 2 and 4, and activation of transcription factors like nuclear factor kappa B, that subsequently activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) expression succeeded by ROS production. GSH depletion may have a fundamental role in COVID-19 pathophysiology, host immune response and disease severity and mortality. Therapies enhancing GSH could become a cornerstone to reduce severity and fatal outcomes of COVID-19 disease and increasing GSH levels may prevent and subdue the disease. The life value of GSH makes for a paramount research field in biology and medicine and may be key against SARS-CoV-2 infection and COVID-19 disease.
... Evidencia en inmunización. La evidencia disponible sugiere que los linfocitos de sujetos humanos sanos mantienen, en promedio, una concentración óptima de glutatión y un balance estrecho de sus cantidades (29). Los cambios en el glutatión intracelular afectarían las funciones de los linfocitos. ...
... Los cambios en el glutatión intracelular afectarían las funciones de los linfocitos. Sin embargo, no hay hallazgos directos de que la respuesta de las células linfoides a la vacunación se potencie mediante la administración de glutatión o su precursor de cisteína en sujetos sanos (29). Las funciones inmunológicas en enfermedades que están asociadas con una deficiencia de cisteína y glutatión, en teoría, mejorarían y potencialmente se restaurarían mediante la suplementación con cisteína. ...
... Las funciones inmunológicas en enfermedades que están asociadas con una deficiencia de cisteína y glutatión, en teoría, mejorarían y potencialmente se restaurarían mediante la suplementación con cisteína. Esto se ha estudiado más extensamente en el caso de pacientes con VIH y pérdida masiva de cisteína (29,30). Dos ensayos aleatorizados controlados con placebo reportaron que el tratamiento con la NAC de pacientes con VIH se asoció con un aumento significativo de las funciones inmunológicas, incluida una restauración casi completa de la actividad de las células natural killer (NK). ...
Introducción: La N-acetilcisteína (NAC) es uno de los medicamentos que se ha propuesto en el manejo de pacientes con covid-19. Este fármaco cuenta con más de cincuenta años de uso en profilaxis y terapia de varias condiciones clínicas. Objetivo: Revisar la literatura que recoja la evidencia disponible sobre el uso de NAC como adyuvante en inmunización y tratamiento de covid-19, así como sobre su uso en infecciones causadas por otros virus ARN. Métodos: Se revisó Medline y la base de datos de estudios clínicos Clinical Tril con los términos clave n-acetyl cysteine, covid-19 y vaccination. Se examinaron las referencias de los artículos incluidos para obtener evidencia adicional relevante. Resultados: Se encontraron 151 referencias, de las cuales fueron incluidas 42. Estas incluyeron evidencia sobre los planteamientos teóricos, resultados de estudios clínicos y experimentación básica que describen la utilización de NAC en tratamiento, prevención de covid-19, así como sobre los mecanismos de acción, uso, eficacia y seguridad en esta y otras infecciones causadas por virus ARN. Conclusiones: La administración de NAC podría mejorar ciertos desenlaces clínicos en covid-19. Se requieren ensayos clínicos adicionales que investiguen su efectividad en pacientes con covid-19 o durante la vacunación.
... 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. ...
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.
... 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. ...
... Because certain activities, such as the DNA synthesis response, are extremely sensitive to reactive oxygen intermediates, high amounts of the antioxidant glutathione are beneficial. Conversely, oxidative circumstances and low intracellular glutathione levels encourage certain signal pathways [6]. In general glutathione has many functions [5,7]. ...
... Many human disorders have been linked to low glutathione levels, according to extensive study in numerous fields, such as emphysema, asthma, allergy disorders, medication toxicity, metabolic disorders, cancer, chemotherapy, and human immunodeficiency virus-acquired immune deficiency syndrome are only a few of the conditions and causes. [6,7] There is little research on the role of glutathione supplementation in these disorders, the majority of the research has focused on autism and cystic fibrosis. [9,10] The degree of inconstancy in a person's ability to provide glutathione, which is mostly owing to hereditary changeability in chemical components involved in its formation and recovery, is a factor influencing glutathione renown, glutathione stransferase and gamma-glutamyltransferase are two enzymes that convert glutathione to glutamate and have received a lot of attention in the logical writing and internal clinical medicinal drug, one of those catalysts requires complement cofactors [11]. ...
Abstract
Glutathione is a thiol-tripeptide with a low molecular weight that is important
for maintaining intracellular redox balance. Its antimelanogenic qualities have led to
its promotion as a skin-lightening agent, in addition to its exceptional antioxidant
properties. In some ethnic groups, it is commonly utilized for this purpose. There is,
however, a discrepancy between the evidence supporting its efficacy and safety. The
marketing gimmick surrounding its depigmenting properties could be a pharma�cosmeceutical company's marketing ploy. This article examines the different
characteristics of glutathione, including its metabolism, mechanism of action, and
scientific evidence to assess its usefulness as a systemic skin-lightening agent.
Glutathione, in its reduced form, is found within cells and plays a crucial part in a
variety of physiological functions. The direct and indirect suppression of the
tyrosinase enzyme, as well as the switch from eumelanin to phaeomelanin production,
are responsible for its skin-lightening effects. It can be taken orally, parent rally, or
topically. Although intravenous glutathione injections are widely used, there is little
proof that they are effective. Indeed, the Philippines' Food and Drug Administration
has issued a public warning denouncing intravenous glutathione's usage for off-label
applications such as skin whitening due to its negative consequences. There are now
three randomized controlled trials that support topical and oral glutathione's skin�lightening impact and good safety profile. However, important questions such as
treatment duration, skin-lightening impact lifetime, and maintenance regimens remain
unsolved. To establish the importance of this chemical in hyperpigmentation and skin
lightening diseases, more randomized, double-blind, placebo-controlled trials with
bigger sample sizes, long-term follow-up, and well-defined efficacy outcomes are
needed.
... 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. ...
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]. ...
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.
... It involves the invasion of the brain by circulating immune cells. Due to blood-brain barrier (BBB) failure and microglial activation, such immune cell infiltrations happen throughout the development of many diseases 14,15 . ...
Endotoxin Lipopolysaccharide (LPS) induces an innate immune response and activates sickness behavior. During neuroinflammation, the activated microglial cells change its morphology and release various chemicals that could be harmful such as nitric oxide (NO), reactive oxygen species (ROS) and enzymes for proteolysis. Through the buildup of free radicals and ROS, these neuroinflammations can also result in oxidative stress. This ROS reacts with cellular macromolecules, triggering a cascade that results in membrane porosity caused by membrane lipid peroxidation (LPO), which is measured by the quantity of malondialdehyde (MDA). On LPS challenge, the complex behaviour that decreased common activities and explorations, is noticed and with rising anxiety, cognitive impairment and decreased social activities. It also decreased closed arm time, although closed arm entries were higher which may be related to the increased locomotion. It raised open arm time and open arm entries, suggesting of reduced anxiety and also increased exploratory behaviour. AChE and nNOS were increased in the forebrain part. Reduction in brainstem and MDA activity decreased on both forebrain and brain stem. MDA in the liver increased by LPS challenge indicating upregulated hepatic tissue damage and oxidative stress. As a result of LPS-induced lipid peroxidation and oxidative stress, brain Glutathione (GSH), a substrate for cytosolic Glutathione peroxidase, increased in the forebrain and decreased in the brainstem. Decreased scavenging of ROS was indicated by the LPS-induced decrease in liver GSH levels.
... Glutathione possesses a wide range of effects on the immune system, either activating or suppressing the immune response to control inflammation. In particular, reduced glutathione is required for the control of innate and adaptive immunological processes such as T-lymphocyte proliferation, the phagocytic activity of polymorphonuclear neutrophils, and dendritic cell functions, as well as antigen presentation by antigen-presenting cells [80][81][82]. Changes in glutathione concentrations may be critical in many autoimmune disease disorders, in-cluding psoriasis [83]. In particular, glutathione may suppress the immune reaction in mice with allergic contact dermatitis [84], inhibit the production of inflammatory cytokines, and maintain the adequate production of interferon-gamma by dendritic cells [80]. ...
The aim of this pilot study was to investigate whether single nucleotide polymorphisms (SNP) in the gene encoding the catalytic subunit of glutamate cysteine ligase (GCLC) are associated with the risk and clinical features of psoriasis. A total of 944 unrelated individuals, including 474 patients with a diagnosis of psoriasis and 470 healthy controls, were recruited for the study. Six common SNPs in the GCLC gene were genotyped using the MassArray-4 system. Polymorphisms rs648595 (OR = 0.56, 95% CI 0.35–0.90; Pperm = 0.017) and rs2397147 (OR = 0.54, 95% CI 0.30–0.98; Pperm = 0.05) were associated with susceptibility to psoriasis in males. In the male group, diplotype rs2397147-C/C × rs17883901-G/G was associated with a decreased risk of psoriasis (FDR-adjusted p = 0.014), whereas diplotype rs6933870-G/G × rs17883901-G/G (FDR-adjusted p = 0.045) showed an association with an increased disease risk in females. The joint effects of SNPs with tobacco smoking (rs648595 and rs17883901) and alcohol abuse (rs648595 and rs542914) on psoriasis risk were observed (Pperm ≤ 0.05). We also found multiple sex-independent associations between GCLC gene polymorphisms and various clinical features such as earlier disease onset, the psoriatic triad, and specific localizations of skin lesions. The present study is the first to show that polymorphisms of the GCLC gene are significantly associated with the risk of psoriasis and related to its clinical features.
... Glutathione has been shown to have a wide range of effects on the immune system, either activating or suppressing the immune response to control inflammation. In particular, reduced glutathione is required for the control of innate and adaptive immunological processes such as T-lymphocyte proliferation, phagocytic activity of polymorphonuclear neutrophils, and dendritic cell functions, as well as antigen presentation by antigen-presenting cells [80,81,82]. Changes in glutathione concentrations may be critical in many autoimmune disease disorders, including psoriasis, that are commonly induced, detrimented, and perpetuated by inflammatory or immune responses mediated by ROS [83]. ...
The aim of this pilot study was to investigate whether single nucleotide polymorphisms (SNP) in the gene encoding the catalytic subunit of glutamate cysteine ligase (GCLC) are associated with the risk and clinical features of psoriasis. A total of 944 unrelated individuals, including 474 patients with a diagnosis of psoriasis and 470 healthy controls, were recruited for the study. Six common SNPs in the GCLC gene were genotyped using the MassArray-4 system. Polymorphisms rs648595 (OR=0.56 95%CI 0.35-0.90, Pperm=0.017) and rs2397147 (OR=0.54 95%CI 0.30-0.98, Pperm=0.05) were associated with susceptibility to psoriasis in males. In the male group, diplotype rs2397147-C/C×rs17883901-G/G was associated with decreased risk of psoriasis (FDR-adjusted P=0.014), whereas diplotype rs6933870-G/G×rs17883901-G/G (FDR-adjusted P=0.045) showed association with increased disease risk in females. Joint effects of SNPs with tobacco smoking (rs648595 and rs17883901) and alcohol abuse (rs648595 and rs542914) on the risk of psoriasis were observed (Pperm≤0.05). Furthermore, we found multiple sex-independent associations between GCLC gene polymorphisms and various clinical features such as earlier disease onset, the psoriatic triad, and specific localizations of skin lesions. The present study is the first to show that polymorphisms of the GCLC gene are significantly associated with the risk of psoriasis and related to its clinical features.
... In light of this mechanism, it is possible that some of the pathologies of viral infection may simply be "collateral damage" consequent to this primary goal of enhancing viral replication. Given their multiple roles in antioxidant defense, maintenance of redox homeostasis, and immune cell functioning [58][59][60][61], it is obvious that if these two essential biological reducing agents (TXNRD1 and GSH) are disrupted, the resulting increased oxidative stress and pro-inflammatory conditions, with pathological consequences, are to be expected. ...
Associations between dietary selenium status and the clinical outcome of many viral infections, including SARS-CoV-2, are well established. Multiple independent studies have documented a significant inverse correlation between selenium status and the incidence and mortality of COVID-19. At the molecular level, SARS-CoV-2 infection has been shown to decrease the expression of certain selenoproteins, both in vitro and in COVID-19 patients. Using computational methods, our group previously identified a set of six host proteins that contain potential SARS-CoV-2 main protease (Mpro) cleavage sites. Here we show experimentally that Mpro can cleave four of the six predicted target sites, including those from three selenoproteins: thioredoxin reductase 1 (TXNRD1), selenoprotein F, and selenoprotein P, as well as the rate-limiting enzyme in glutathione synthesis, glutamate-cysteine ligase catalytic subunit (GCLC). Cleavage was assessed by incubating recombinant SARS-CoV-2 Mpro with synthetic peptides spanning the proposed cleavage sites, and analyzing the products via UPLC-MS. Furthermore, upon incubation of a recombinant Sec498Ser mutant of the full TXNRD1 protein with SARS-CoV-2 Mpro, the predicted cleavage was observed, destroying the TXNRD1 C-terminal redox center. Mechanistically, proteolytic knockdown of both TXNRD1 and GCLC is consistent with a viral strategy to inhibit DNA synthesis, conserving the pool of ribonucleotides for increased virion production. Viral infectivity could also be enhanced by GCLC knockdown, given the ability of glutathione to disrupt the structure of the viral spike protein via disulfide bond reduction. These findings shed new light on the importance of dietary factors like selenium and glutathione in COVID-19 prevention and treatment.
... Reduced glutathione portrays a higher affinity for different NMs, and it further reduces available GSH. Decreased glutathione is linked with a lowered immune function [154,156]. Increased levels of GSH in the cadmium-exposed group (G2) might be linked with an elevated immune response. The alteration in the level of MTs referred to metals-induced toxicity in animal tissues. ...
Biomolecules-based surface modifications of nanomaterials may yield effective and biocompatible nanoconjugates. This study was designed to evaluate gold nanoconjugates (AuNCs) for their altered antioxidant potential. Gold nanoparticles (AuNPs) and their conjugates gave SPR peaks in the ranges of 512–525 nm, with red or blueshift for different conjugates. Cys-AuNCs demonstrated enhanced (p < 0.05) and Gly-AuNCs (p > 0.05) displayed reduced DPPH activity. Gly-AuNCs and Tyr-AuNCs displayed enhanced ferric-reducing power and hydrogen peroxide scavenging activity, respectively. Cadmium-intoxicated mice were exposed to gold nanomaterials, and the level of various endogenous parameters, i.e., CAT, GST, SOD, GSH, and MTs, was evaluated. GSH and MTs in liver tissues of the cadmium-exposed group (G2) were elevated (p < 0.05), while other groups showed nonsignificance deviations than the control group. It is concluded that these nanoconjugates might provide effective nanomaterials for biomedical applications. However, more detailed studies for their safety profiling are needed before their practical applications.
... Moreover, it may be suggested that the natural antioxidants in CM play an important role in mitochondrial bioenergetics. The ability of CM to improve GSH production can also be traced to its high content of polyphenols which enhance the uptake of L-cysteine (the limiting substrate for GSH synthesis) (Dröge and Breitkreutz, 2000;Maher et al., 2008). ...
Context: Parkinson's disease (PD) is a multisystem neurodegenerative disorder associated with oxidative stress and disrupted mitochondrial function. It is characterized by motor and non-motor symptoms due to multi-factors. Coconut (Cocos nucifera) milk contains a complex mixture of highly nutritional constituents such as carbohydrates, vitamins, and minerals which have remarkable health benefits. Lauric acid (LA) which makes up 54.5% of the total nutrient composition of coconut milk (CM) possesses strong antioxidant properties. Objectives: This study evaluated the effect of CM on PD-associated motor and non-motor deficits in alpha-synuclein (α-syn) transgenic Drosophila melanogaster (D. melanogaster). Methods: W 1118 strain (control) and α-syn transgenic (PD strain) of D. melanogaster aged between 1 to 3 days were randomized into various groups. The control flies were fed on untreated diets, while the PD flies were orally exposed to varying concentrations (0, 5, 10, and 15% v/v) of the coconut milk diet for 14 days. Subsequently, longevity, behavioral, fecundity, and biochemical analyses were conducted across the groups. Results: The results showed that CM significantly increased longevity, climbing ability, egg count, and the rate of emergence (P< 0.05). In addition, MDA and NO levels as well as AChE activity were significantly decreased, while GSH levels alongside SOD and CAT activities were increased (P< 0.05) in the CM-treated PD flies in a concentration-dependent manner. Conclusions: CM ameliorated PD-associated deficits in D. melanogaster by prolonging lifespan, and improving locomotor function, fecundity, and redox status.
... En este sentido, son varios los reportes en la literatura que relacionan las alteraciones de la homeostasis del GSH con la aparición y progresión de estados inflamatorios y autoinmunes. (4,5) Revista Cubana de Hematología, Inmunología y Hemoterapia. 2022;38(2):e1602 4 Esta obra está bajo una licencia https://creativecom m ons.org/licenses/b y -nc/4.0/deed.es_E ...
Introducción:
Las alteraciones en el estado redox celular se han descrito como factores causales en diversas enfermedades. La depleción del glutatión reducido se ha asociado fundamentalmente a enfermedades neurodegenerativas, pulmonares, hepáticas, cardiovasculares e inmunológicas.
Objetivo:
Determinar las concentraciones de glutatión reducido y el estado redox celular en pacientes pediátricos con inmunodeficiencias.
Métodos:
Se estudiaron 21 pacientes con inmunodeficiencias procedentes de la consulta de Inmunogenética, en edades comprendidas entre 1 y 8 años, de ambos sexos, y 8 niños en el mismo rango de edad de los pacientes, como grupo control, con estudios de inmunidad humoral y celular normales. Los pacientes con diagnóstico de inmunodeficiencia se dividieron para su estudio en 2 grupos según el componente afectado de la respuesta inmune: humoral y celular. Fueron determinadas las concentraciones intraeritrocitarias de glutatión reducido y oxidado, mediante un método de HPLC-UV. Para evaluar el estado redox celular se calculó la relación entre las formas reducidas y oxidadas del glutatión (GSH/GSSG).
Resultados:
Las concentraciones de glutatión reducido y el estado redox celular se encontraron disminuidos en ambos grupos de pacientes en relación con los niños sin inmunodeficiencia (p=0,031 y p=0,03; respectivamente). El glutatión oxidado no mostró diferencias entre los grupos.
Conclusiones:
En los pacientes con inmunodeficiencia se evidenció la afectación del estado redox celular como consecuencia de la disminución del glutatión reducido. Este primer acercamiento ofreció las potencialidades del empleo de estos biomarcadores en la evaluación integral de pacientes con inmunodeficiencia.
... Glutathione level was increased using the other treatments, mainly when rats were fed turmeric supplement which gave the highest glutathione content in both the liver and kidneys. In addition, turmeric supplements had critical Immunological functions including prohibiting the disorders connected with the reduction of glutathione levels [50]. Despite feeding a meal containing cysteine and methionine supplements, either individually or in combination, as in groups (2, 3 and 4), the group fed a meal containing spirulina, which the protein may reach about 65 to 70% records higher glutathione. ...
Background: Oxidative stress occurs due to decreased glutathione inside the body. Some supplements may promote and stimulate glutathione production in the liver. This article aims to investigate the impact of different supplements on enhancing glutathione synthesis in rats’ livers. For this purpose 42 rats (male albino) were separated into 7 groups, each including 6 animals with average weights ranging between 150 and 160 g. Group 1 (control) and different groups consumed a basal diet for 8 weeks, whereas group 2 received 500 mg/kg bw of L-cysteine daily. Group 3 received 250 mg/kg bw of methionine, while group 4 got 250 mg/kg of L cysteine plus 125 mg/kg of methionine daily. Spirulina (20 mg/kg bw), turmeric (500 mg/kg bw), and dried garlic (500 mg/kg bw), respectively, were given to groups 5, 6, and 7. Results: Utilizing the various dietary supplements decreased levels of liver function enzymes, bilirubin, urea, creatinine, and malondialdehyde while enhancing levels antioxidant enzymes of liver, and increased glutathione of kidneys and liver. However, cysteine alone at 500 mg/kg bw decreased glutathione formation in the liver and kidneys. Compared to the amino acid supplements (group 2, 3, 4) used, spirulina, turmeric, and dried garlic had a significant impact on reducing liver function enzymes, bilirubin, uric acid, creatinine, urea, and malondialdehyde and increasing antioxidant enzymes, and glutathione while turmeric supplement showed the best influence. Using dietary supplements did not result in any pathological modifications in the liver tissues, but there were some unsatisfactory minor alterations. However, group 2 showed considerable pathological developments in the liver tissues. Conclusion: According to the findings, using the suggested dietary supplement except for cysteine alone can promote and encourage glutathione synthesis in different organs, especially the liver, hence alleviating the effects of oxidative stress associated with several illnesses.
... Glutathione is the most abundant non-protein thiol compound in all living organisms [1]. Because of its important physiological functions including its ability to act as an antioxidant, a detoxifier of xenobiotics, and an immune booster [2][3][4][5][6][7][8], glutathione has been widely used in the medical, food and cosmetic industries [9,10]. Therefore, the demand for glutathione has increased in recent years. ...
Background
Glutathione is a valuable tri-peptide that is industrially produced by fermentation using the yeast Saccharomyces cerevisiae , and is widely used in the pharmaceutical, food, and cosmetic industries. It has been reported that addition of l -serine ( l -Ser) is effective at increasing the intracellular glutathione content because l -Ser is the common precursor of l -cysteine ( l -Cys) and glycine (Gly) which are substrates for glutathione biosynthesis. Therefore, we tried to enhance the l -Ser biosynthetic pathway in S . cerevisiae for improved glutathione production.
Results
The volumetric glutathione production of recombinant strains individually overexpressing SER2 , SER1 , SER3 , and SER33 involved in l -Ser biosynthesis at 48 h cultivation was increased 1.3, 1.4, 1.9, and 1.9-fold, respectively, compared with that of the host GCI strain, which overexpresses genes involved in glutathione biosynthesis. We further examined simultaneous overexpression of SHM2 and/or CYS4 genes involved in Gly and l -Cys biosynthesis, respectively, using recombinant GCI strain overexpressing SER3 and SER33 as hosts. As a result, GCI overexpressing SER3 , SHM2 , and CYS4 showed the highest volumetric glutathione production (64.0 ± 4.9 mg/L) at 48 h cultivation, and this value is about 2.5-fold higher than that of the control strain.
Conclusions
This study first revealed that engineering of l -Ser and Gly biosynthetic pathway are useful strategies for fermentative glutathione production by S. cerevisiase .
... In healthy cells and tissue, more than 90% of the total glutathione pool is in the reduced form and less than 10% exists in the disulfide form [7]. A shift in the ratio of these two forms can be an indication of cellular oxidative stress, when glutathione changes from the reduced form (GSH) to the oxidized form (GSSG) [8]. Recently, many studies have shown that alteration in glutathione concentration in human fluids directly leads to several pathological diseases such as diabetes, Parkinson's disease, macular degeneration, HIV disease, and numerous types of cancers [9][10][11]. For these reasons, the use of sensitive detection methods for monitoring glutathione levels in physiological systems is highly demanded. ...
Oxidation of the reduced form of glutathione based on the 1:1 copper(Cu⁺²)-glutathione(GSH) complexes was found to occur at a decreased overpotential at a glassy carbon electrode modified with highly ordered mesoporous silica thin films (MSTFs) by means of the electrochemically assisted self-assembly (EASA) process. Adsorption of complexes can be performed on the electrode by taking advantage of the anionic nature of the silica walls of the MSTF which provide an excellent fixation site for accumulation of the Cu⁺²-GSH complex. The current response of voltammetric glutathione sensor is monitored at low oxidation potential of − 0.10 V versus standard mercury/mercurous sulfate reference electrode which makes the proposed sensor applicable to minimize interference from easily oxidizable species in the analysis of biological fluids. The proposed method represents a sensitive voltammetric sensor with a good linear detection range of 1.0–35.0 µM, which is in the range of GSH concentration in physiological fluids reported in literature with a suitable limit of detection of 0.08 µM. The proposed sensor offers several advantages such as being rapid and cost-effective, having good reproducibility, simple operation, and nontoxicity for glutathione detection.
... Glutathione also plays a critical role in immune system function and has been demonstrated to possess antioxidant and detoxifying activities by binding to drugs or toxins through sulfhydryl (Dröge and Breitkreutz 2000, Wu et al. 2004, Forman et al. 2009). Glutathionerelated indicators, such as glutathione-S-transferase and total glutathione, are considered as biomarkers correlated with critical insect physiological functions; furthermore, glutathione-related indicators reportedly participate in chlorantraniliprole resistance. ...
Parasitic Trichogramma chilonis Ishii, an egg parasitoid of Grapholita molesta, is a critical agent for biological control of insect pests in crop plants. However, the efficiency of T. chilonis is influenced by its resistance to the common pesticide chlorantraniliprole. To elucidate the chlorantraniliprole detoxification mechanism, differentially expressed genes (DEGs) related to chlorantraniliprole resistance were studied at different developmental stages of the wasp. Individuals of T. chilonis were grouped and treated with chlorantraniliprole at different developmental stages. Untreated wasps were used as controls. Transcriptomic analysis identified the DEGs associated with chlorantraniliprole resistance and detoxification in T. chilonis. A total of 1,483 DEGs were associated with chlorantraniliprole resistance at all developmental stages. DEGs that correlated with chlorantraniliprole sensitivity of T. chilonis at different developmental stages were distinct and had various functions. The newly identified DEGs are involved in cytochrome P450- and glutathione metabolism-related pathways, which were predicted to contribute to chlorantraniliprole detoxification. Chlorantraniliprole detoxification by T. chilonis was associated with cytochrome P450- and glutathione-related pathways. Our findings may be useful for balancing chemical and biological control practices aimed to optimize agricultural production.
... 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). ...
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.
... 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. ...
... 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. ...
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 ...
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. ...
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. ...
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). ...
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. ...
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). ...
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.
... 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]. ...
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.
... 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]. ...
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
... 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. ...
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.
... 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]. ...
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). ...
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.
... 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]. ...
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).
... 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. ...
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.
... 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. ...
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). ...
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.
Background:
Allergic diseases affect about 10-30% of the population in low- or middle-income tropical countries. Few studies describe the factors associated with allergic diseases in adult patients undergoing immunotherapy in Latin American countries.
Objective:
This study aimed to determine the factors associated with allergic rhinitis (AR) and AR in comorbidity with asthma (CARAS) in adults treated with immunotherapy in two allergy referral centers in Bogotá (Colombia).
Material and methods:
Observational, cross-sectional study conducted between January 2018 and January 2019. ISAAC-III and sociodemographic questionnaires were applied to determine the factors associated with AR and CARAS in adults treated with immunotherapy who attended the allergy consult at the Fundación Santa Fe de Bogotá and Unimeq-Orl.
Results:
Among 416 adults aged 18-68 years, 71.4% (n = 297) were women. Regarding the sensitization results obtained by skin prick test, the most frequent allergens were house dust mites (64.18%): 49.03% were positive for both Dermatophagoides pteronyssinus and Dermatophagoides farinae, while 28.61% were positive for Blomia tropicalis. Excluding house dust mites, the most frequent allergens were dog hair (31.01%), cat hair (15.1%), grasses (15.9%), and food (15.9%). The main factor associated with exclusive AR was regular acetaminophen use more than four times a year: Prevalence ratio (PR) = 1.77 (95% CI: 1.12-2.25). The main factor associated with CARAS was cesarean delivery PR: 1.44 (95% CI: 1.09-1.78).
Conclusion:
The main factor associated with AR was regular acetaminophen use, while that associated with CARAS was cesarean delivery. The ISAAC-III questionnaire can be a useful low-cost tool to assess the factors associated with allergic diseases in adults in tropical countries.
COVID-19 has become the first modern-day pandemic of historic proportion, affecting >600 million individuals worldwide and causing >6.5 million deaths. While acute infection has had devastating consequences, postacute sequelae of SARS-CoV-2 infection appears to be a pandemic of its own, impacting up to one-third of survivors and often causing symptoms suggestive of cardiovascular phenomena. This review will highlight the suspected pathophysiology of postacute sequelae of SARS-CoV-2, its influence on the cardiovascular system, and potential treatment strategies.
In recent years, there has been a great deal of attention toward the field of free radical chemistry. Free radicals reactive oxygen species and reactive nitrogen species are generated by our body by various endogenous systems, exposure to different physiochemical conditions or pathological states. A balance between free radicals and antioxidants is necessary for proper physiological function. If free radicals overwhelm the body’s ability to regulate them, a condition known as oxidative stress ensues. Free radicals thus adversely alter lipids, proteins, and DNA and trigger a number of human diseases. This study was designed to determine the influence of Glutathione to reduce the pathological changes induced by estrogen. In this study 40 female and male mice are taken at age of 21days with groups of control (10 mouse in each group).The group of experimental animals was treated with estrogen and glutathione diluted with distilled water, as a vehicle, and injected intraperitonially for 12 weeks, once weekly. Each control group was injected with the vehicle of it in the same manner of injection and for the same period.
Recent data suggest that there is a continuous need to develop safer and less toxic nanomaterials (NMs). For this, the surface chemistry of commonly used NMs may be modified using several biomolecules/conjugates. The current study has been designed to develop silver nanoconjugates (AgNCs) capped with different amino acids. Characterization of the same was performed using different techniques. During in vitro analysis, l-tyrosine and l-cystine capped AgNCs exhibited antioxidant activity, while l-glycine capped AgNCs showed prooxidant activity. l-cystine and l-tyrosine capped AgNCs also demonstrated good in vivo results. The level of catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), and metallothioneins (MTs) in different organs was evaluated. It is assumed that newly developed nanoconjugates can be utilized as nano-tools for different applications. However, more detailed studies with resolution techniques for safety, the risk associated, and their accuracy are needed for the utilization of these nanoconjugates for specific biomedical uses.Graphical abstract
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.
The incidence of autoimmunity is growing rapidly worldwide. Many epidemiological studies have found environmental factors, such as toxic chemicals (persistent organic pollutants, toxic metals, solvents, endocrine disruptors), to be a key factor in this rapid progression. Numerous mechanisms have been identified that can cause immune dysregulation and autoimmune reactivity from toxic chemical exposure to subsets of individuals who have genetic susceptibility in immune regulatory genes. In susceptible genotypes, toxic chemicals can induce epigenetic expressions, bind to immune and endocrine receptors throughout the body and promote immune dysregulation, bind to nucleic acids and promote anti-nuclear autoimmunity, deplete antioxidant reserves, promote immune barrier degradation, induce lymphocyte dysregulation, and alter normal antigen-presenting responses. This paper provides a detailed review of the specific immunological pathways involved with exposure to environmental toxins and autoimmunity.
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.
Biothiols, including homocysteine (Hcy), cysteine (Cys) and reduced glutathione (GSH), play various roles in physiological and pathological processes. Because these biothiols possess similar in structures, it is difficult to discriminate Hcy, Cys and GSH from one another. In this work, a novel fluorescent probe, 4-BrCP, based on coumarin as a fluorophore to discriminate GSH from Hcy and Cys was rationally designed and synthesized in three steps with good total yield. The benzothiazol ring played the role of a fluorescent emission wavelength adjuster, while the ester part served as a fluorescent quencher and reactive sites with Hcy, Cys and GSH. The results of responsive experiment indicated that the probe could discriminate GSH from Hcy and Cys distinctly and exhibited a relatively high fluorescence quantum yield (0.84) and low detection limit (9.8 nM). In addition, the probe 4-BrCP also showed good stability and low toxicity. The reaction mechanism of 4-BrCP with GSH was speculated on according to the LC-MS data. Most importantly, because of the length of the skeletons of Hcy, Cys and GSH, different dynamic fluorescent phenomena were observed. Furthermore, imaging experiments suggested that the probe could be used to monitor GSH in living cells and organisms.
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.
Objective:
Since the emergence of coronavirus disease (COVID-19), the death toll has been increasing daily. Many risk factors are associated with a high mortality rate in COVID-19. Establishment of a common pathway among these risk factors could improve our understanding of COVID-19 severity and mortality. This review aims at establishing this common pathway and its possible effect on COVID-19 mortality.
Materials and methods:
The current review was executed in five consecutive stages starting from determining the risk factors of COVID-19 mortality and trying to find a common pathway among them depending on the available literature. This was followed by proposing a mechanism explaining how this common pathway could increase the mortality. Finally, its potential role in managing COVID-19 was proposed.
Results:
This review identified this common pathway to be a low baseline of reduced glutathione (i.e., GSH) level. In particular, this review provided an in-depth discussion regarding the pathophysiology by which COVID-19 leads to GSH depletion, tissue damage, and acute respiratory distress syndrome. In addition, the current review demonstrated how GSH depletion could result in failure of the immune system and rendering the end organs vulnerable to damage from the oxidative stress.
Conclusions:
This preclinical study shows that GSH depletion may have a central role in COVID-19 mortality and pathophysiology. Therefore, elevating the GSH level in tissues may decrease the severity and mortality rates of COVID-19.
Today, the arrival of agricultural pesticides in surface water is one of the biggest
environmental problems that can threaten aquatic life. The impact of these pollutants on
the immune system of fish has caused weakening it and increasing fish sensitivity to
pathogens. Diazinon is one of the most important organophosphates used in many
agricultural areas and found in Iran’s surface water. This study aimed to evaluate the
effect of diazinon on the immune system of fish and the use of Vitis vinifera extract to
reduce the adverse effects of the pesticide in the immune system of rainbow trout
(Oncorhynchus mykiss). Feeding was done by adding plant extract supplement of 400
mg/kg of food. After sampling of fish on days 7, 14 and 28 after the start of the
experiment and separate the plasma levels of peroxidase, immunoglobulins and
complement were measured. The reduction in the level of plasma peroxides, IgM, total
complement and lysozyme in fishes exposed to diazinon shows the effect of diazinon on
the immune system of fish in the long term well. While in fishes fed by Milk thistle
plant V. vinifera extract and exposed to toxin, no significant difference (p <0.05) was
observed compared to the fishes in the control group which reflects the strengthening
and protective impact of Milk thistle plant V. vinifera extract on the immune system of
rainbow trout.
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.
HIV-1 proviral DNA contains two binding sites for the transcription factor NF-kappa 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-kappa 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 GSH levels. Cysteine and NAC also inhibit NF-kappa B activity as determined by electrophoretic mobility shift assays and chloramphenicol acetyl-transferase (CAT) gene expression under control of NF-kappa B binding sites in uninfected cells. This suggests that the cysteine deficiency in HIV-1-infected individuals may cause an over-expression of NF-kappa B-dependent genes and enhance HIV-1 replication. NAC may be considered for the treatment of HIV-1-infected individuals.
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.
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.
Plasma concentrations of 21 amino acids were determined for 20 control subjects and 20 subjects infected with human immunodeficiency virus type 1 (HIV). Compared with the control subjects, the HIV-infected group had lower cystine, tryptophan, and methionine (decreased 67%, 52%, and 32%, respectively, P < 0.001 for each) and increased taurine (230%, P < 0.001) and lysine concentrations (30%, P < 0.001). Other amino acid concentrations changed modestly. Amounts of cystine, tryptophan, methionine, taurine, and lysine did not differ significantly between subgroups of HIV-infected subjects with > 200 (n = 6) or < 200 (n = 14) CD4+ lymphocytes per microliter, suggesting that the concentrations decrease soon after infection and change little thereafter. Activation of metabolism of cystine to taurine may explain reciprocal changes in these amino acids and known depletion of cystine and glutathione. The selective changes in amino acid profiles observed during HIV infection differ from those recognized for malnutrition or other pathological processes.
HIV-infected individuals and SIV-infected rhesus macaques have, on the average, decreased plasma cysteine and cystine concentrations and decreased intracellular glutathione levels. We show that the cysteine supply and the intracellular glutathione levels have a strong influence on the T cell system. A study of healthy human subjects revealed that persons with intracellular glutathione levels of 20-30 nmol/mg protein had significantly higher numbers of CD4+ T cells than persons with either lower or higher glutathione levels. Persons who moved during a 4-week observation period from the optimal to the suboptimal range (10-20 nmol/mg) experienced, on the average, a 30% decrease in CD4+ T cell numbers. This decrease was prevented by treatment with N-acetyl-cysteine (NAC). NAC caused this relative increase of CD4+ T cell numbers in spite of decreasing glutathione levels and not by increasing the glutathione level. Our studies suggest that the immune system may be exquisitely sensitive not only against a cysteine and glutathione deficiency but also against an excess of cysteine.
Even a moderate increase in the cellular cysteine supply elevates the intracellular glutathione (GSH) and glutathione disulfide (GSSG) levels and potentiates immunological functions of lymphocytes in vitro. At low GSSG levels, T cells cannot optimally activate the immunologically important transcription factor NF kappa B, whereas high GSSG levels inhibit the DNA binding activity of NF kappa B. The effects of GSSG are antagonized by reduced thioredoxin (TRX). As the protein tyrosine kinase activities p56lck and p59fyn are activated in intact cells by hydrogen peroxide, they are likely targets for GSSG action. These redox-regulated enzymes trigger signal cascades for NF kappa B activation and transduce signals from the T cell antigen receptor, from CD4 and CD8 molecules, and from the IL-2 receptor beta-chain. The effector phase of cytotoxic T cell responses and IL-2-dependent functions are inhibited even by a partial depletion of the intracellular GSH pool. As signal transduction is facilitated by prooxidant conditions, we propose that the well-known immunological consequences of GSH depletion ultimately may be results of the accompanying GSSG deficiency. As HIV-infected patients and SIV-infected rhesus macaques have, on the average, significantly decreased plasma cyst(e)ine and intracellular GSH levels, we also hypothesize that AIDS may be the consequence of a GSSG deficiency as well.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.