Glutathione-dependent system in the blood of gastric cancer patients with various tumor histotypes and prevalence of the disease

Purpose of the study. Exploring the erythrocyte glutathione system functioning in patients with gastric cancer in a comparative aspect, depending on tumor histotype and disease prevalence.Patients and methods. The study included 89 patients with gastric cancer, divided into 6 groups depending on the histotype of the tumor. Separately, the results of the study were analyzed in patients with T4 status according to TNM and in patients at stage 4. The content of reduced glutathione and the activity of glutathione-dependent enzymes in the erythrocytes of the patients' blood were studied by conventional spectrophotometric methods. Statistical processing of the results was carried out using the Statistika 6.0 software package according to the Student's t-test and the nonparametric Wilcoxon-Mann-Whitney test for two independent samples.Results. An increase in the content of glutathione was revealed in patients with gastric cancer compared with the group without oncopathology. The maximum increase was observed in patients with low-grade adenocarcinoma - by 42.5 %, while in signet ring cell carcinoma (SRCC) there was only a tendency to increase by 17.8 %. Glutathione reductase activity was decreased in adenocarcinoma by 23.4-26.2 % and did not change in SRCC. The activity of the antioxidant enzymes glutathione peroxidase and glutathione transferase was increased in all groups, and especially in SRCC - by 76 % and 23-29 %, respectively. In patients with the T4 status and at stage IV of the process, a lower activity of the studied glutathione-dependent enzymes was revealed in comparison with all other groups of patients.Conclusions. The data obtained indicate a greater functional potential of the glutathione system in SRCC. A significant increase in glutathione transferase activity at a sufficiently high level of reduced glutathione can contribute to the development of treatment resistance in SRCC patients.

Effects of Panthenol and N-Acetylcysteine on Changes in the Redox State of Brain Mitochondria under Oxidative Stress In Vitro

The glutathione system in the mitochondria of the brain plays an important role in maintaining the redox balance and thiol–disulfide homeostasis, whose violations are the important component of the biochemical shifts in neurodegenerative diseases. Mitochondrial dysfunction is known to be accompanied by the activation of free radical processes, changes in energy metabolism, and is involved in the induction of apoptotic signals. The formation of disulfide bonds is a leading factor in the folding and maintenance of the three-dimensional conformation of many specific proteins that selectively accumulate in brain structures during neurodegenerative pathology. In this study, we estimated brain mitochondria redox status and functioning during induction of oxidative damage in vitro. We have shown that the development of oxidative stress in vitro is accompanied by inhibition of energy metabolism in the brain mitochondria, a shift in the redox potential of the glutathione system to the oxidized side, and activation of S-glutathionylation of proteins. Moreover, we studied the effects of pantothenic acid derivatives—precursors of coenzyme A (CoA), primarily D-panthenol, that exhibit high neuroprotective activity in experimental models of neurodegeneration. Panthenol contributes to the significant restoration of the activity of enzymes of mitochondrial energy metabolism, normalization of the redox potential of the glutathione system, and a decrease in the level of S-glutathionylated proteins in brain mitochondria. The addition of succinate and glutathione precursor N-acetylcysteine enhances the protective effects of the drug.

Glutathione system activity in the blood of overweight postmenopausal women

One of the important components of the antioxidant defense system is the glutathione system, the activity of which, when overweight, changes direction depending on gender and ethnicity. The results of studies involving overweight menopausal women are mixed. The study involved 61 postmenopausal women, who, after clinical and anamnestic examination, were divided into 2 groups: control (BMI = 19-24.9 kg / m2) and overweight group (BMI = 25-29.9 kg/m2). The use of hormone replacement therapy; the use of antioxidant drugs; diseases of endocrine genesis; exacerbation of chronic diseases; premature early menopause; surgical menopause was the exclusion criteria for women from the study. The lipid profile parameters with the calculation of the atherogenic coefficient; reduced and oxidized glutathione levels with the calculation of their ratio, the glutathione S-transferase and glutathione reductase activities were determined in the blood. Overweight women showed an increase in the triacylglycerols (p = 0.041) and cholesterol in very low density lipoproteins levels (p = 0.044). When assessing the glutathione system activity in women of the main group, compared with the control, an increase in the glutathione-S-transferase (p = 0.023) and glutathione reductase (p = 0.022) activities was noted, however, the reduced and oxidized glutathione levels, as well as their ratio did not differ from the control values. The results obtained indicate the activation of the glutathione system enzymatic link in response to changes in lipid status in postmenopausal women with overweight.

Protective effect of ademetionine, cytoflavinum and dihydroquercetin in the liver of rats exposed to toxic effects of valproate sodium

Введение. Вальпроат натрия влияет на метаболизм гамма-аминомасляной кислоты, предотвращая развитие эпилептических приступов. Многие метаболиты вальпроата натрия потенцируют его клинический эффект, однако, именно они могут приводить к развитию хронической интоксикации с поражением печени. Цель - оценка протекторного эффекта адеметионина (гептрала), цитофлавина и дигидрокверцетина у крыс, подвергнутых токсическому влиянию вальпроата натрия (депакина). Методика. Животным контрольной группы вводили вальпроат натрия в токсической дозе 600 мг/кг интрагастрально 1 раз в день в течение 28 сут. Крысам опытных групп вводили вальпроат натрия в той же дозе с одновременным введением адеметионина, цитофлавина или дигидрокверцетина. Животные выводились из эксперимента на 7-, 14-, 21- и 28-е сут. В гомогенате печени определяли стандартными спектрофотометрическими методами концентрацию диеновых конъюгатов, малонового диальдегида, восстановленного глутатиона и активность ферментов метаболизма глутатиона: глутатионредуктазы, глутатионпероксидазы и глутатионтрансферазы. Результаты. При токсическом воздействии вальпроата натрия в ткани печени развивались процессы гиперпероксидации липидов, которые подтверждались значительным повышением уровня диеновых конъюгатов и малонового диальдегида. Концентрация глутатиона снижалась начиная с 14-х сут эксперимента. Активность глутатионредуктазы повышалась к 14-м сут, а затем к 28-м сут практически достигала значений интактных животных. Активность глутатионтрансферазы начинала снижаться с 14-х сут и сохранялась низкой до конца исследования. Активность глутатионпероксидазы повышалась с 14-х сут эксперимента, достигая максимума к 28-м сут. Протекторный эффект адеметионина при токсическом воздействии вальпроата натрия выражался в снижении содержания диеновых конъюгатов и малонового диальдегида. Одновременно происходила активация системы глутатиона: повышалась активность глутатионтрансферазы и глутатионредуктазы. Антиокислительное действие цитофлавина проявлялось в основном на 1-й нед эксперимента: концентрация диеновых конъюгатов и малонового диальдегида снижалась, активность глутатионредуктазы и глутатионтрансферазы повышалась. Дигидрокверцетин также оказывал антиокислительное действие: концентрация диеновых конъюгатов и малонового диальдегида снижалась. Активность глутатионредуктазы и глутатионтрансферазы увеличивалась по сравнению с контрольными животными. Заключение. Вальпроат натрия в токсической дозе приводит к статистически значимому повышению уровня продуктов перекисного окисления липидов и снижению антиокислительной защиты системы глутатиона в печени крыс. Адеметионин, цитофлавин и дигидрокверцетин способствуют восстановлению баланса системы перекисного окисления липидов и антиоксидантной защиты в печени крыс при токсическом влиянии вальпроата натрия. Наиболее перспективным препаратом защиты является адеметионин, так как он наиболее существенно снижает концентрацию диеновых конъюгатов, малонового диальдегид и повышает активность системы глутатиона на протяжении 28 сут эксперимента. Background. Sodium valproate affects metabolism of gamma-aminobutyric acid to prevent the development of epileptic seizures. Many valproic acid metabolites potentiate its clinical effect; however, specifically these metabolites may result in chronic intoxication with liver damage. Aim: To evaluate the protective effect of ademetionine (Heptral), cytoflavin, and dihydroquircetin in rats exposed to the toxic action of sodium valproate (Depakene). Methods. Animals of the control group were administered valproate sodium at a toxic dose of 600 mg/kg, intragastrically. Rats of the experimental group were administered valproate sodium at a dose of 600 mg/kg with simultaneous administration of ademetionine, cytoflavin and dihydroquercetin. The duration of drug administration in all groups was 7 days, 14 days, 21 days, or 28 days. The contents of diene conjugates, malonic dialdehyde, reduced glutathione, and the activity of glutathione reductase, glutathione peroxidase, and glutathione transferase were measured in liver homogenates with standard spectrophotometric methods. Results. Under the toxic effects of valproate sodium in liver tissue, a significant increase in the contents of diene conjugates and malonic dialdehyde was found. The glutathione concentration decreased starting from day 14 of the experiment. The glutathione reductase activity increased by day 14 and practically reached the values of intact animals by day 28. The glutathione transferase activity began decreasing on day 14 and remained low until the end of study. The glutathione peroxidase activity increased starting from day 14 and reached maximum by day 28. The protective effect of ademetionine was manifested by a decrease in the contents of diene conjugates and malonic dialdehyde. There was a simultaneous activation of the glutathione system evident as increased activities of glutathione transferase and glutathione reductase. An antioxidant effect of cytoflavin was manifested mainly at the 1st wk of the experiment. The concentration of diene conjugates and malonic dialdehyde decreased, the activity of glutathione reductase increased, and the activity of glutathione transferase increased. Dihydroquercetin also had an antioxidant effect since the concentration of diene conjugates and malonic dialdehyde decreased. The activity of glutathione reductase and glutathione transferase increased. Conclusion. Sodium valproate significantly increased concentrations of lipid peroxidation products and impaired the glutathione antioxidant defense in the rat liver. Ademetionine, cytoflavin and dihydroquercetin help to restore the balance of lipid peroxidation and antioxidant protection in the rat liver during the toxic effects of valproate sodium. The most effective drug was ademetionine, since within 28 days, it significantly decreased the concentration of diene conjugates and malonic dialdehyde, and it increased the activity of the glutathione system.

THE ROLE OF THE GLUTATHIONE SYSTEM IN MAINTAINING REDOX-HOMEOSTASIS AND ANTIOXIDANT PROTECTION IN INFLAMMATORY AND DEGENERATIVE DISEASES OF THE ORGAN OF VISION

Objective. To review and analyze literature data as well as evaluate the role of the glutathione antioxidant system in inflammatory and degenerative diseases of the organ of vision. Material and Methods. Multiple sources of foreign and domestic literature concerning the problem of oxidative stress, antioxidant protection system, glutathione and their role in inflammatory and degenerative diseases of the organ of vision were analyzed using main scientific and medical databases. More than 120 sources in the medical literature over the past 15 years were evaluated, 50 of them have been selected for final summary. Results. It was found that oxidative stress, based on free radical oxidation reactions, including LPO processes, plays a leading role in the development of inflammatory and degenerative diseases of the organ of vision. The key link in the eye’s antioxidant protection system is the glutathione system, which includes glutathione itself (GSH) and glutathionedependent enzymes: glutathione peroxidase (GPO), glutathione reductase (GR), glutathione-S-transferase (GST). Inflammatory and degenerative diseases of the eye are accompanied by reduction of the intracellular glutathione pool and imbalance between its reduced and oxidized forms (GSH / GSSG). Conclusions. Oxidative stress has a high correlation with inflammation and is the most important pathogenetic mechanism in inflammatory and degenerative diseases of the eye. The key role in antioxidant protection and maintenance of redox homeostasis of eye tissues belongs to the glutathione system, which includes GSH itself and glutathione-dependent enzymes (GPO, GR, GST). Inflammatory and degenerative processes in the eye are accompanied by decrease of the intracellular glutathione pool (GSH) and imbalance between its reduced and oxidized forms (GSH / GSSG). A shift in this balance significantly affects normal cell functioning, up to its apoptosis, and triggers multiple pathological conditions within the body, including diseases of the organ of vision.

Energy metabolism and redox status of the glutathione system in experimental brain ischemia and its correction by metabolic neuroprotectors

The changes in the parameters of oxidative stress, energy metabolism, and redox potential of the glutathione system in the rat brain following cerebral ischemia were studied. To correct metabolic disorders, the pantothenic acid derivatives were used in combination with precursors of glutathione biosynthesis and selenium substances.Cerebral ischemia was modeled by ligating the both common carotid arteries in rats for 2 h. Drugs were administered i.p. in the following doses: panthenol – 400 mg/kg, N-acetylcysteine – 150, nanoselen – 1 mg/kg, three times: 1 h before ligation of the carotid arteries, at the time of ligation and 1 hour after ligation. We showed that the development of oxidative stress caused by ischemia is accompanied by the changes in the parameters of energy metabolism and the pentose phosphate pathway in the cerebral hemispheres. Simultaneously, there are a decrease in the GSH level, an increase in the GSSG content, a decrease in the GSH/GSSG ratio, and the activation of enzymes of redox transformations of glutathione.The redox potential of the glutathione system decreases and shifts towards oxidation, while the level of S-glutathionylated proteins increases. Thus, the value of the GSH/GSSG ratio and the protein glutathionylation intensity are the sensitive indicators of the redox potential in the brain tissue and can be used as markers of the extent of changes in the redox balance. The panthenol injection to animals leads to a decrease in the content of free radical oxidation products, violations of oxidative phosphorylation and restoration of thiol-disulfide balance in the brain. When panthenol is administered together with N-acetylcysteine and nanoselen, the corrective effect of panthenol is enhanced.

The glutathione system in bone tissue under the action of copper-zinc ore components and antioxidants administration

Aim. To study changes in the glutathione system in bone tissue during chronic intoxication with elements contained in copper-zinc pyrite ore and antioxidant vitamin administration. Methods. 36 mature male white rats were divided into three groups (control, comparison, experimental). The rats of the experimental and comparison groups received intragastrically copper-zinc pyrite ore powder in a 2% starch solution as a suspension at a dosage of 60 mg/100 g bodyweight daily for three months. During the last month, the experimental group received an antioxidant vitamin preparation (the complex of vitamins with a trace element) containing -tocopherol, -carotene, ascorbic acid and selenium. The content of reduced glutathione, free thiol groups in proteins, the activity of glutathione peroxidase, glutathione transferase, glutathione reductase, gamma-glutamyl transferase, and glucose-6-phosphate dehydrogenase were determined in homogenates derived from femoral epiphysis. The statistical analysis of the results was performed using Statistica 6.0 software. The median (Me) and percentiles (Q1 and Q2) were calculated, a non-parametric MannWhitney U test was carried out to compare study groups. Results. Chronic intoxication with elements contained in copper-zinc pyrite ore causes impairment of the glutathione system in bone tissue. Intoxicated rats showed a decrease in the reduced glutathione content to 71.9% (р=0.014) and free sulfhydryl groups of proteins to 77.8% (р=0.0143), inhibition of glutathione-dependent antioxidant enzymes activities, and disruption of the glutathione reduction system in tissues, compared to the control group. Antioxidant vitamin administration increased the levels of reduced glutathione and free thiol groups of proteins, activated the enzymes involved in the glutathione system: the reduced glutathione content increased to 94.8% (p=0.2132), glutathione peroxidase activity to 85.7% (p=0.0432), glutathione transferase up to 94.3% (p=0.5251), glutathione reductase up to 86.1% (p=0.0442) compared to the control group. Conclusion. Chronic intoxication with metals contained in copper-zinc pyrite ore leads to decreasing the content of reduced glutathione and free thiol groups of proteins in bones along with reducing glutathione reductase and glucose-6-phosphate dehydrogenase activities, inhibition of glutathione peroxidase and glutathione transferase; an antioxidant vitamin administration increases the activity of glutathione reduction enzymes in bone tissue, the content of reduced glutathione and free sulfhydryl groups of proteins, the activities of glutathione peroxidase and glutathione transferase.

Biological and medical value of antioxidant protection system of the human body

The article is devoted to the antioxidant system of the human body in the context of biological and medical significance. The classification of antioxidants in terms of their physical and chemical properties, bioorganic compounds, biochemical effects, mechanisms of implementation of antioxidant protection is presented. The given processes of extreme radical oxidation and mechanisms of antioxidant defense in physiological and pathological conditions. The characteristics of the components of the glutathione system, namely glutathione and enzymes – glutathione peroxidase, glutathione reductase and glutathione transferase are presented. Much attention is paid to manganese superoxide dismutase, an antiradical defense enzyme, as a fundamental regulator of cell proliferation, a mediator of metabolism and apoptosis. Interpretation of changes in the antioxidant enzyme of mitochondrial origin from a prognostic point of view is interpreted on the basis of the results of clinical observations carried out by scientists in various human diseases. The expediency of determining manganese superoxide dismutase in clinical practice for the diagnostic search for the direction of the pathological process, the timely detection of complications and the appointment of adequate therapy is emphasized. Keywords: antioxidant system, classification, glutathione system, manganese superoxide dismutase.