RESUMEN
The effects of reduced glutathione (GSH) on skeletal muscle fatigue were investigated. GSH was depressed by buthionine sulfoximine (BSO) (100 mg/kg body wt/day) treatment for 5 days, which decreased GSH content to â¼10%. Male Wistar rats were assigned to the control (N = 18) and BSO groups (N = 17). Twelve hours after BSO treatment, the plantar flexor muscles were subjected to fatiguing stimulation (FS). Eight control and seven BSO rats were rested for 0.5 h (early stage of recovery), and the remaining were rested for 6 h (late stage of recovery). Forces were measured before FS and after rest, and physiological functions were estimated using mechanically skinned fibers. The force at 40 Hz decreased to a similar extent in both groups in the early stage of recovery and was restored in the control but not in the BSO group in the late stage of recovery. In the early stage of recovery, sarcoplasmic reticulum (SR) Ca2+ release was decreased in the control greater than in the BSO group, whereas myofibrillar Ca2+ sensitivity was increased in the control but not in the BSO group. In the late stage of recovery, SR Ca2+ release decreased and SR Ca2+ leakage increased in the BSO group but not in the control group. These results indicate that GSH depression alters the cellular mechanism of muscle fatigue in the early stage and delays force recovery in the late stage of recovery, due at least in part, to the prolonged Ca2+ leakage from the SR.
Asunto(s)
Depresión , Fatiga Muscular , Ratas , Masculino , Animales , Fatiga Muscular/fisiología , Ratas Wistar , Glutatión/farmacología , Glutatión/fisiología , Músculo Esquelético , Butionina Sulfoximina/farmacologíaRESUMEN
Individual differences in the development of uncontrollable fear in response to traumatic stressors have been observed in clinic, but the underlying mechanisms remain unknown. In the present study we first conducted a meta-analysis of published clinical data and found that malondialdehyde, an oxidative stress biomarker, was significantly elevated in the blood of patients with fear-related anxiety disorders. We then carried out experimental study in rats subjected to fear conditioning. We showed that reestablishing redox homeostasis in basolateral amygdale (BLA) after exposure to fear stressors determined the capacity of learned fear inhibition. Intra-BLA infusion of buthionine sulfoximine (BSO) to deplete the most important endogenous antioxidant glutathione (GSH) blocked fear extinction, whereas intra-BLA infusion of dithiothreitol or N-acetylcysteine (a precursor of GSH) facilitated extinction. In electrophysiological studies conducted on transverse slices, we showed that fear stressors induced redox-dependent inhibition of NMDAR-mediated synaptic function, which was rescued by extinction learning or reducing agents. Our results reveal a novel pharmacological strategy for reversing impaired fear inhibition and highlight the role of GSH in the treatment of psychiatric disorders.
Asunto(s)
Acetilcisteína/farmacología , Complejo Nuclear Basolateral/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Miedo/efectos de los fármacos , Glutatión/metabolismo , Memoria/efectos de los fármacos , Animales , Complejo Nuclear Basolateral/metabolismo , Complejo Nuclear Basolateral/fisiología , Butionina Sulfoximina/farmacología , Condicionamiento Clásico , Señales (Psicología) , Ditiotreitol/farmacología , Glutatión/fisiología , Homeostasis/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Plant growth and development and interactions with the environment are regulated by phytohormones and other signaling molecules. During their evolution, plants have developed strategies for efficient signal perception and for the activation of signal transduction cascades to maintain proper growth and development, in particular under adverse environmental conditions. Abscisic acid (ABA) is one of the phytohormones known to regulate plant developmental events and tolerance to environmental stresses. The role of ABA is mediated by both its accumulated level, which is regulated by its biosynthesis and catabolism, and signaling, all of which are influenced by complex regulatory mechanisms. Under stress conditions, plants employ enzymatic and non-enzymatic antioxidant strategies to scavenge excess reactive oxygen species (ROS) and mitigate the negative effects of oxidative stress. Glutathione (GSH) is one of the main antioxidant molecules playing a critical role in plant survival under stress conditions through the detoxification of excess ROS, maintaining cellular redox homeostasis and regulating protein functions. GSH has recently emerged as an important signaling molecule regulating ABA signal transduction and associated developmental events, and response to stressors. This review highlights the current knowledge on the interplay between ABA and GSH in regulating seed dormancy, germination, stomatal closure and tolerance to drought.
Asunto(s)
Ácido Abscísico/metabolismo , Adaptación Fisiológica , Sequías , Glutatión/fisiología , Semillas/crecimiento & desarrollo , Semillas/fisiología , Transducción de Señal/fisiologíaRESUMEN
The cellular trafficking pathways that conduct zinc to its sites of binding in functional proteins remain largely unspecified. In this study, the hypothesis was investigated that nonspecific proteomic binding sites serve as intermediates in zinc trafficking. Proteome from pig kidney LLC-PK1 cells contains a large concentration of such sites, displaying an average conditional stability constant of 1010-11, that are dependent on sulfhydryl ligands to achieve high-affinity binding of zinc. As a result, the proteome competes effectively with induced metallothionein for Zn2+ upon exposure of cells to extracellular Zn2+ or during in vitro direct competition. The reaction of added Zn2+ bound to proteome with apo-carbonic anhydrase was examined as a potential model for intracellular zinc trafficking. The extent of this reaction was inversely dependent upon proteome concentration and under cellular conditions thought to be negligible. The rate of reaction was strictly first order in both Zn2+ and apo-carbonic anhydrase, and also considered to be insignificant in cells. Adding the low molecular weight fraction of cell supernatant to the proteome markedly enhanced the speed of this reaction, a phenomenon dependent on the presence of glutathione (GSH). In agreement, inclusion of GSH accelerated the reaction in a concentration-dependent manner. The implications of abundant high-affinity binding sites for Zn2+ within the proteome are considered in relation to their interaction with GSH in the efficient delivery of Zn2+ to functional binding sites and in the operation of fluorescent zinc sensors as a tool to observe zinc trafficking.
Asunto(s)
Glutatión/fisiología , Metalotioneína/fisiología , Proteoma/fisiología , Zinc/metabolismo , Sitios de Unión , Transporte Iónico , Espectrometría de Masas/métodos , Sondas Moleculares , Espectrofotometría Atómica/métodosRESUMEN
Organs from donors after controlled circulatory death (DCD III) exhibit a higher risk for graft dysfunction due to an initial period of warm ischemia. This procurement condition can also affect the yield of beta cells in islet isolates from donor pancreases, and hence their use for transplantation. The present study uses data collected and generated by our Beta Cell Bank to compare the number of beta cells in isolates from DCD III (n = 141) with that from donors after brain death (DBD, n = 609), before and after culture, and examines the influence of donor and procurement variables. Beta cell number per DCD III-organ was significantly lower (58 x 106 versus 84 x 106 beta cells per DBD-organ; p < 0.001) but their purity (24% insulin positive cells) and insulin content (17 µg / 106 beta cells in DCD III-organs versus 19 µg / 106 beta cells in DBD-organs) were similar. Beta cell number correlated negatively with duration of acirculatory warm ischemia time above 10 min; for shorter acirculatory warm ischemia time, DCD III-organs did not exhibit a lower beta cell yield (74 x 106 beta cells). Use of Institut Georges Lopez-1 cold preservation solution instead of University of Wisconsin solution or histidine-tryptophan-ketoglutarate also protected against the loss in beta cell yield from DCD III-organs (86 x 106 for IGL-1 versus 54 x 106 and 65 x 106 beta cells respectively, p = 0.042). Multivariate analysis indicates that both limitation of acirculatory warm ischemia time and use of IGL-1 prevent the reduced beta cell yield in islet cell isolates from DCD III-organs.
Asunto(s)
Muerte Encefálica/metabolismo , Muerte Encefálica/patología , Supervivencia de Injerto/fisiología , Células Secretoras de Insulina/fisiología , Soluciones Preservantes de Órganos/metabolismo , Adenosina/metabolismo , Adenosina/fisiología , Adulto , Alopurinol/metabolismo , Femenino , Glutaratos/metabolismo , Glutatión/metabolismo , Glutatión/fisiología , Histidina/metabolismo , Humanos , Insulina/metabolismo , Insulina/fisiología , Células Secretoras de Insulina/metabolismo , Trasplante de Hígado/métodos , Masculino , Persona de Mediana Edad , Rafinosa/metabolismo , Rafinosa/fisiología , Donantes de Tejidos , Obtención de Tejidos y Órganos/métodos , Triptófano/metabolismo , Isquemia Tibia/métodosRESUMEN
The hydropersulfide (RSSH) functional group has received significant recent interest due to its unique chemical properties that set it apart from other biological species. The chemistry of RSSH predicts that one possible biological role may be as a protectant against cellular oxidative and electrophilic stress. That is, RSSH has reducing and nucleophilic properties that may combat the potentially destructive biochemistry of toxicologically relevant oxidants and electrophiles. However, there are currently numerous other molecules that have established roles in this regard. For example, ascorbate and tocopherols are potent antioxidants that quench deleterious oxidative reactions and glutathione (GSH) is a well-established and highly prevalent biological protectant against electrophile toxicity. Thus, in order to begin to understand the possible role of RSSH species as protectants against oxidative/electrophilic stress, the inherent chemical properties of RSSH versus these other protectants will be discussed and contrasted.
Asunto(s)
Antioxidantes/fisiología , Estrés Oxidativo/fisiología , Sulfuros/metabolismo , Animales , Antioxidantes/química , Ácido Ascórbico/química , Ácido Ascórbico/fisiología , Glutatión/química , Glutatión/fisiología , Humanos , Sulfuro de Hidrógeno/química , Sulfuro de Hidrógeno/metabolismo , Óxido Nítrico/química , Óxido Nítrico/fisiología , Oxidación-Reducción , Sulfuros/químicaRESUMEN
Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concentrations in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and xenobiotics. Recent studies have highlighted the importance of GSH in key signal transduction reactions as a controller of cell differentiation, proliferation, apoptosis, ferroptosis and immune function. Molecular changes in the GSH antioxidant system and disturbances in GSH homeostasis have been implicated in tumor initiation, progression, and treatment response. Hence, GSH has both protective and pathogenic roles. Although in healthy cells it is crucial for the removal and detoxification of carcinogens, elevated GSH levels in tumor cells are associated with tumor progression and increased resistance to chemotherapeutic drugs. Recently, several novel therapies have been developed to target the GSH antioxidant system in tumors as a means for increased response and decreased drug resistance. In this comprehensive review we explore mechanisms of GSH functionalities and different therapeutic approaches that either target GSH directly, indirectly or use GSH-based prodrugs. Consideration is also given to the computational methods used to describe GSH related processes for in silico testing of treatment effects.
Asunto(s)
Glutatión/fisiología , Neoplasias/etiología , Neoplasias/terapia , Animales , Ensayos de Selección de Medicamentos Antitumorales/métodos , Ensayos de Selección de Medicamentos Antitumorales/tendencias , Homeostasis , Humanos , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , Oxidación-Reducción , Transducción de Señal/fisiologíaRESUMEN
Gefitinib (GEF) is the first selective tyrosine kinase inhibitor of epidermal growth factor receptor. It is associated with the occurrence of clinical drug-induced liver injury. Although GEF is metabolized to chemically reactive metabolites by cytochrome P450 3A and 1A enzymes and then conjugated to glutathione (GSH), whether these reactive metabolites contribute to GEF-induced toxicity remains unknown. In this study, we investigated whether GSH depletion can sensitize mice to liver injury caused by GEF. Male C57BL/6J mice were intraperitoneally pretreated with L-buthionine (S,R)-sulfoximine (BSO) at 700 mg/kg to inhibit GSH synthesis and then orally administered GEF at 500 mg/kg every 24 hr for 4 consecutive days. The coadministration of BSO and GEF increased plasma alanine aminotransferase (ALT) levels to approximately 700 U/L and 1600 U/L at 72 and 96 hr after the first administration, respectively, whereas the increase in plasma ALT levels in mice receiving GEF at 500 mg/kg alone was limited, suggesting that GSH plays a protective role in GEF-induced liver injury. Histological examination showed nuclear karyorrhexis and sporadic single hepatocyte death in the livers of BSO+GEF coadministered mice. In these mice, the hepatic expression levels of heme oxygenase 1 (Hmox1) and metallothionein 2 (Mt2) mRNA, caspase 3/7 enzymatic activity, and the amounts of 2-thiobarbiuric acid reactive substances were significantly increased, suggesting the presence of oxidative stress, which may be associated with hepatocellular death. Together, these results show that oxidative stress as well as the reactive metabolites of GEF are involved in GEF-induced liver injury in GSH-depleted mice.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Gefitinib/efectos adversos , Gefitinib/toxicidad , Glutatión/deficiencia , Glutatión/metabolismo , Hígado/metabolismo , Hígado/patología , Estrés Oxidativo , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/toxicidad , Animales , Butionina Sulfoximina/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocromo P-450 CYP3A/fisiología , Progresión de la Enfermedad , Gefitinib/metabolismo , Glutatión/fisiología , Ratones Endogámicos C57BL , Inhibidores de Proteínas Quinasas/metabolismoRESUMEN
Glutathione (GSH) is an important player in plant responses to cadmium (Cd) through its dual function as an antioxidant and precursor for metal-chelating phytochelatins (PCs). In addition, it was shown to be involved in cell cycle regulation in Arabidopsis thaliana roots, but its involvement in this process in leaves is largely unknown and has never been evaluated in Cd-exposed plants. This study aimed to elucidate the role of GSH in leaf growth and development, metal chelation, nutrient homeostasis and cell cycle regulation in A. thaliana plants upon prolonged Cd exposure. Responses were compared between wild-type (WT) plants and three GSH-deficient mutants. Our results indicate that PC production remains important in plants exposed to Cd for an extended duration. Furthermore, an important role for GSH in regulating nutrient homeostasis in Cd-exposed plants was revealed. Cell cycle analysis demonstrated that negative effects of Cd exposure on cell division and endoreplication were more pronounced in leaves of the GSH-deficient cadmium-sensitive 2-1 (cad2-1) mutant in comparison to the WT, indicating the involvement of GSH in cell cycle regulation. Finally, a crucial role for GSH in transcriptional activation of the Cd-induced DNA damage response (DDR) was revealed, as the Cd-induced upregulation of DDR-related genes was either less pronounced or completely abolished in leaves of the GSH-deficient mutants.
Asunto(s)
Arabidopsis/efectos de los fármacos , Cadmio/toxicidad , Daño del ADN , Glutatión/fisiología , Arabidopsis/fisiología , Ciclo Celular , Homeostasis , Nutrientes , Fitoquelatinas/fisiología , Hojas de la Planta/efectos de los fármacos , Hojas de la Planta/fisiologíaRESUMEN
Chymotrypsinogen, when reduced and taken to its molten globule-like conformation, displays a single cysteine with an unusual kinetic propensity toward oxidized glutathione (GSSG) and other organic thiol reagents. A single residue, identified by mass spectrometry like Cys1, reacts with GSSG about 1400 times faster than an unperturbed protein cysteine. A reversible protein-GSSG complex and a low pKa (8.1 ± 0.1) make possible such astonishing kinetic property which is absent toward other natural disulfides like cystine, homocystine and cystamine. An evident hyper-reactivity toward 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) and 1-chloro-2,4-dinitrobenzene (CDNB) was also found for this specific residue. The extraordinary reactivity toward GSSG is absent in two proteins of the thermophilic archaeon Sulfolobus solfataricus, an organism lacking glutathione: the Protein Disulphide Oxidoreductase (SsPDO) and the Bacterioferritin Comigratory Protein 1 (Bcp1) that displays Cys residues with an even lower pKa value (7.5 ± 0.1) compared to chymotrypsinogen. This study, which also uses single mutants in Cys residues for Bcp1, proposes that this hyper-reactivity of a single cysteine, similar to that found in serum albumin, lysozyme, ribonuclease, may have relevance to drive the "incipit" of the oxidative folding of proteins from organisms where the glutathione/oxidized glutathione (GSH/GSSG) system is present.
Asunto(s)
Proteínas Arqueales/metabolismo , Quimotripsinógeno/metabolismo , Glutatión/metabolismo , Secuencia de Aminoácidos , Archaea/metabolismo , Quimotripsinógeno/fisiología , Cisteína/metabolismo , Disulfuros/química , Glutatión/fisiología , Disulfuro de Glutatión/metabolismo , Oxidación-Reducción , Oxidorreductasas/metabolismo , Pliegue de Proteína , Compuestos de Sulfhidrilo/química , Reactivos de Sulfhidrilo/química , Sulfolobus solfataricus/metabolismoAsunto(s)
Glutatión/fisiología , Neoplasias/tratamiento farmacológico , Compuestos de Sulfhidrilo/fisiología , Tiorredoxinas/fisiología , Antibacterianos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Reparación del ADN , Resistencia a Antineoplásicos , Homeostasis , Humanos , Oxidación-Reducción , Especies Reactivas de Oxígeno , Reductasa de Tiorredoxina-DisulfuroRESUMEN
In plants, investigation on heavy metal toxicity and its mitigation by nutrient elements have gained much attention. However, mechanism(s) associated with nutrients-mediated mitigation of metal toxicity remain elusive. In this study, we have investigated the role and interrelation of glutathione (GSH) and hydrogen sulfide (H2 S) in the regulation of hexavalent chromium [Cr(VI)] toxicity in tomato (Solanum lycopersicum), pea (Pisum sativum) and brinjal (Solanum melongena) seedlings, supplemented with additional sulfur (S). The results show that Cr(VI) significantly reduced growth, total chlorophyll and photosynthetic quantum yield of tomato, pea and brinjal seedlings which was accompanied by enhanced intracellular accumulation of Cr(VI) in roots. Moreover, Cr(VI) enhanced the generation of reactive oxygen species in the studied vegetables, while antioxidant defense system exhibited differential responses. However, additional supply of S alleviated Cr(VI) toxicity. Interestingly, addition of l-buthionine sulfoximine (BSO, a glutathione biosynthesis inhibitor) further increased Cr(VI) toxicity even in the presence of additional S but GSH addition reverses the effect of BSO. Under similar condition, endogenous H2 S, l-cysteine desulfhydrase (DES) activity and cysteine content did not significantly differ when compared to controls. Hydroxylamine (HA, an inhibitor of DES) also increased Cr(VI) toxicity even in the presence of additional S but sodium hydrosulfide (NaHS, an H2 S donor) reverses the effect of HA. Moreover, Cr(VI) toxicity amelioration by NaHS was reversed by the addition of hypotaurine (HT, an H2 S scavenger). Taken together, the results show that GSH which might be derived from supplied S is involved in the mitigation of Cr(VI) toxicity in which H2 S signaling preceded GSH biosynthesis.
Asunto(s)
Cromo/toxicidad , Glutatión/fisiología , Sulfuro de Hidrógeno/metabolismo , Pisum sativum/fisiología , Solanum lycopersicum/fisiología , Solanum melongena/fisiología , Solanum lycopersicum/efectos de los fármacos , Pisum sativum/efectos de los fármacos , Plantones/efectos de los fármacos , Plantones/fisiología , Solanum melongena/efectos de los fármacosRESUMEN
Objectives: Schizophrenia is a debilitating psychiatric illness associated with positive and negative symptoms as well as significant impairments in cognition. Current antipsychotic medications do not alleviate these cognitive deficits, and more effective therapeutic options are required. Increased oxidative stress and altered antioxidant levels, including glutathione (GSH) have been observed both in individuals with cognitive impairment and in people with schizophrenia. A GSH precursor, the antioxidant N-acetylcysteine (NAC) has been investigated as a novel treatment for the cognitive symptoms of schizophrenia, and recent research suggests that NAC may be a promising adjunctive treatment option. However, the current literature lacks integration as to why NAC may effectively improve cognition in schizophrenia. The present theoretical synthesis aimed to address this gap by examining the processes by which NAC may improve cognitive function in schizophrenia. Methods: The schizophrenia literature was reviewed in three key domains: cognitive impairment, the relationship between oxidative stress and cognition, and the efficacy of NAC as a novel treatment. This led to a theoretical analysis of the neurobiological processes by which NAC may improve cognition in schizophrenia. Results: This theoretical review concluded that improved cognition may result from a combination of factors, including decreased oxidative stress, neuroprotection of cognitive networks and an increase in glutamatergic modulation of the N-methyl-d-aspartate receptor system. Whilst a number of mechanisms by which NAC may improve cognition and symptoms in schizophrenia have been proposed, there is still limited understanding of the specific metabolic pathways involved and how they interrelate and modify specific symptomology. Discussion: Exploration of how NAC treatment may act to improve cognitive function could guide clinical trials by investigation of the specific neurotransmitter systems and processes involved, allowing for targeted neurological outcome measures. Future research would benefit from the investigation of both in vivo cortical GSH concentration and peripheral plasma GSH in a population of individuals with chronic schizophrenia.
Asunto(s)
Acetilcisteína/uso terapéutico , Cognición/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Cognición/fisiología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/fisiopatología , Glutatión/fisiología , Humanos , Fármacos Neuroprotectores , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiologíaRESUMEN
Acrolein, known as one of the most common reactive carbonyl species, is a toxic small molecule affecting human health in daily life. This study is focused on the scavenging abilities and mechanism of ferulic acid and some other phenolic acids against acrolein. Among the 13 phenolic compounds investigated, ferulic acid was found to have the highest efficiency in scavenging acrolein under physiological conditions. Ferulic acid remained at (3.04±1.89)% and acrolein remained at (29.51±4.44)% after being incubated with each other for 24 h. The molecular mechanism of the detoxifying process was also studied. Detoxifying products, namely 2-methoxy-4-vinylphenol (product 21) and 5-(4-hydroxy-3-methoxyphenyl)pent-4-enal (product 22), were identified though nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC-MS), after the scavenging process. Ferulic acid showed significant activity in scavenging acrolein under physiological conditions. This study indicates a new method for inhibiting damage from acrolein.
Asunto(s)
Acroleína/toxicidad , Ácidos Cumáricos/farmacología , Acroleína/química , Ácidos Cumáricos/química , Glutatión/fisiología , Hidroxibenzoatos/farmacología , Espectroscopía de Resonancia Magnética , Relación Estructura-ActividadAsunto(s)
Circulación Cerebrovascular/fisiología , Glutatión/fisiología , Estrés Oxidativo/fisiología , Choque Séptico/complicaciones , Anciano , Enfermedad Crítica/terapia , Femenino , Glutatión/análisis , Homeostasis/efectos de los fármacos , Homeostasis/fisiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Ácido Pirrolidona Carboxílico/análisis , Ácido Pirrolidona Carboxílico/sangre , Ácido Pirrolidona Carboxílico/orina , Choque Séptico/fisiopatología , EspañaRESUMEN
AIM: The aim of this study was to evaluate oxidative stress from glutathione depletion in critically ill patients with a septic shock through the abnormal presence of pyroglutamic acid (PyroGlu) in the urine (indirectly) and through its serum level (directly). METHODS: This was a prospective analytical study of 28 critically ill patients with a septic shock who were monitored from admission (initial) to 3 days of stay (final) in the intensive care unit (ICU). Data collected included PyroGlu and glutamic acid (Glu) using liquid chromatography/mass spectrometry, and glutathione peroxidase (GPX) activity with a colorimetric assay. The differences in Glu, PyroGlu, and GPX activity between the septic shock group and healthy control group serving as reference values were evaluated using the Mann-Whitney test. The correlations between Glu, PyroGlu, and GPX activity and clinical outcomes were determined using Spearman's correlation coefficient. RESULTS: In patients with septic shock, serum and urine PyroGlu levels were higher, erythrocyte GPX activity/gr Hb was lower, and urine Glu levels were lower compared to healthy control reference values, for both initial and final values. Initial serum Glu levels were also lower. Serum PyroGlu levels had a correlation with both initial and final serum Glu levels; levels also correlated in the urine. Initial serum Glu correlated with the days of mechanical ventilation (P = 0.016) and the days of ICU stay (P = 0.05). Urine Glu/mg creatinine correlated with APACHE II (P = 0.030). This positive correlation observed for serum Glu was not observed for PyroGlu. CONCLUSIONS: The current study found that septic patients have higher levels of PyroGlu, lower levels of Glu, and lower erythrocyte GPX activity, suggesting that these biomarkers could be used as an indicator of glutathione depletion. In addition, Glu is related to severity parameters. This study can guide future studies on the importance of monitoring the levels of pyroglutamic acidosis in critical patients with septic shock in order to preserve the oxidative status and its evolution during the stay in the ICU.
Asunto(s)
Circulación Cerebrovascular/fisiología , Glutatión/fisiología , Estrés Oxidativo/fisiología , Choque Séptico/complicaciones , APACHE , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Enfermedad Crítica/terapia , Femenino , Glutatión/análisis , Homeostasis/efectos de los fármacos , Homeostasis/fisiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Ácido Pirrolidona Carboxílico/análisis , Ácido Pirrolidona Carboxílico/sangre , Ácido Pirrolidona Carboxílico/orina , Choque Séptico/fisiopatología , EspañaRESUMEN
Glutathione (GSH) is one of the most extensively studied tripeptides. The roles for GSH in redox signaling, detoxification of xenobiotics and antioxidant defense have been investigated. A drug-induced rhabdomyolysis mouse model was recently established in L-buthionine-(S,R)-sulfoximine (BSO; a GSH synthesis inhibitor)-treated normal mice by co-administration of antibacterial drug and statin. In these models, mild kidney injury was observed in the BSO only-treated mice. Therefore, in this study, we studied kidney injury in the GSH-depleted mouse. BSO was intraperitoneally administered twice a day for 7 days to normal mice. The maximum level of plasma creatine phosphokinase (351 487 ± 53 815 U/L) was shown on day 8, and that of aspartate aminotransferase was shown on day 6. Increased levels of blood urea nitrogen, plasma creatinine, urinary kidney injury molecule-1 and urinary creatinine were observed. An increase of mRNA expression level of renal lipocalin 2/neutrophil gelatinase-associated lipocalin was observed. Degeneration and necrosis in the skeletal muscle and high concentrations of myoglobin (Mb) in blood (347-203 925 ng/mL) and urine (2.5-68 583 ng/mL) with large interindividual variability were shown from day 5 of BSO administration. Mb-stained regions in the renal tubule and renal cast were histologically observed. In this study, the GSH-depletion treatment established an acute kidney injury mouse model due to Mb release from the damaged skeletal muscle. This mouse model would be useful for predicting potential acute kidney injury risks in non-clinical drug development.
Asunto(s)
Lesión Renal Aguda/etiología , Butionina Sulfoximina/toxicidad , Glutatión/fisiología , Alanina Transaminasa/sangre , Animales , Modelos Animales de Enfermedad , Glutatión/análisis , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Mioglobina/sangreRESUMEN
BACKGROUND: Hepatotoxicity is one of the most life-threatening side-effects of Methotrexate therapy. Former studies highlighted the significance of oxidative stress in promoting Methotrexate-induced hepatotoxicity (MIH). Hence, the current study investigated the protective effect of Ellagic acid (EA), a poly-phenolic antioxidant, against MIH. METHODS: Twenty-eight male Wistar rats were grouped into four sets: group 1 (control), group 2 (injected intraperitoneally with 20 mg/kg of Methotrexate on the 9th day), group 3 (treated orally with 10 mg/kg/day of EA for 10 days and injected with Methotrexate on the 9th day) and group 4 (treated with EA for 10 days). Subsequently, biochemical and histopathological parameters were evaluated in serum samples and liver tissues. RESULTS: Methotrexate significantly increased activities of aminotransferases and ALP enzymes as well as levels of oxidative stress parameters in liver tissue. Likewise, Methotrexate decreased hepatic reduced glutathione level and activities of antioxidant enzymes. EA pre-treatment markedly attenuated the activities of aminotransferases and ALP, levels of oxidative stress parameters and augmented activities of antioxidant enzymes. Similarly, the remarkable protective effect of EA on liver has been confirmed by histological examination. CONCLUSION: In sum, the current study supports the hypothesis that EA may be used as a promising pre-therapy to prevent the MIH.
Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Antioxidantes/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Ácido Elágico/administración & dosificación , Metotrexato/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Modelos Animales de Enfermedad , Glutatión/análisis , Glutatión/fisiología , Inmunosupresores/efectos adversos , Hígado/química , Hígado/efectos de los fármacos , Hígado/fisiopatología , Masculino , Estrés Oxidativo/fisiología , Ratas , Ratas WistarRESUMEN
We hypothesized that thiols and particularly glutathione (GSH) are essential for the regulation of stallion sperm functionality. To test this hypothesis, we initially investigated the relationship between sperm function and GSH content, revealing highly significant correlations between GSH, sperm viability, motility, and velocity parameters (P < 0.001). Furthermore, the deleterious effects of GSH depletion using menadione and 1,3 dimethoxy 1,4, naphtoquinone (DMNQ) were able to be prevented by the addition of cysteine, but no other antioxidant. Pre-incubation with cysteine prevented menadione and DMNQ induced damage to sperm membranes after 1 h (P < 0.001; P < 0.05) and after 3 h of incubation (P < 0.001, P < 0.05). Pre-incubation with cysteine ameliorated both the menadione- and DMNQ-induced increase in 4-hydroxynonenal (P < 0.001). As cysteine is a precursor of GSH, we hypothesized that stallion spermatozoa are able to synthesize this tripeptide using exogenous cysteine. To test this hypothesis, we investigated the presence of two enzymes required to synthesize GSH (GSH and GCLC) and using western blotting and immunocytochemistry we detected both enzymes in stallion spermatozoa. The inhibition of GCLC reduced the recovery of GSH by addition of cysteine after depletion, suggesting that stallion spermatozoa may use exogenous cysteine to regulate GSH. Other findings supporting this hypothesis were changes in sperm functionality after BSO treatment and changes in GSH and GSSG validated using HPLC-MS, showing that BSO prevented the increase in GSH in the presence of cysteine, although important stallion to stallion variability occurred and suggested differences in expression of glutamate cysteine ligase. Mean concentration of GSH in stallion spermatozoa was 8.2 ± 2.1 µM/109 spermatozoa, well above the nanomolar ranges per billion spermatozoa reported for other mammals.
Asunto(s)
Aldehídos/metabolismo , Senescencia Celular , Glutatión/fisiología , Espermatozoides/fisiología , Compuestos de Sulfhidrilo/metabolismo , Aldehídos/farmacología , Animales , Senescencia Celular/efectos de los fármacos , Glutatión/metabolismo , Caballos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismo , Análisis de Semen , Preservación de Semen , Motilidad Espermática , Espermatozoides/química , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismoRESUMEN
Acrolein, known as one of the most common reactive carbonyl species, is a toxic small molecule affecting human health in daily life. This study is focused on the scavenging abilities and mechanism of ferulic acid and some other phenolic acids against acrolein. Among the 13 phenolic compounds investigated, ferulic acid was found to have the highest efficiency in scavenging acrolein under physiological conditions. Ferulic acid remained at (3.04±1.89)% and acrolein remained at (29.51±4.44)% after being incubated with each other for 24 h. The molecular mechanism of the detoxifying process was also studied. Detoxifying products, namely 2-methoxy-4-vinylphenol (product 21) and 5-(4-hydroxy-3-methoxyphenyl)pent-4-enal (product 22), were identified though nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC-MS), after the scavenging process. Ferulic acid showed significant activity in scavenging acrolein under physiological conditions. This study indicates a new method for inhibiting damage from acrolein.