Enzymes Of Glutathione Metabolism Research Articles

Modelling the redox imbalance and oxidative stress in the hippocampus at aluminum neurotoxicity and initiating the coenzyme А biosynthesis

An Alzheimer-like pathological process was induced in mature female Wistar CRL: (WI) WUBR rats using aluminum chloride (200 mg/kg, intragastrically, 6 weeks) in order to model redox imbalance and oxidative stress (OS) in the hippocampus and study the possibilities of their correction 2 weekly administration of coenzyme A biosynthesis modulators (panthenol – PL, pantethine – PT, homopantothenate – HP) at a dose of 200 mg/kg intragastrically for 2 weeks). Against the background of activation of peroxidation processes and a decrease in acetylcholinesterase activity, a decrease in the reduction potential of glutathione and the level of the acid-soluble fraction of CoA was observed with a simultaneous increase in the activity of glutathione-metabolizing enzymes (GR, GPx, GST), the process of S-glutathionylation of proteins and the level of protein thiols. The consumption of the precursors of CoA biosynthesis in full (PL, PT) or in part (HP) had an antioxidant effect, restored the activity of AChE, the level and reduction potential of glutathione and glutathione-metabolizing enzymes, the process of S-glutathionylation, and stimulated the activity of enzymes generating NADPH+. Taking into account the low modulating effect of coenzyme precursors on the level of CoA in the hippocampus and their high redox pharmacological activity, their non-coenzymatic effect on redox mechanisms leading to an increase in the bioavailability of reducing equivalents and energy status is assumed.

Proinflammatory activity of monocytes and activity of glutathione-dependent enzymes in red blood cells in women with depressive conditions

To search for possible connections between the anti-inflammatory activity of monocytes (PAM) and the activity of glutathione metabolic enzymes: glutathione reductase (GR) and glutathione-S-transferase (GT) in patients with depressive states (DS) within various mental pathologies, as well as between the studied biological parameters and clinical condition of patients. Sixty-one women, aged 18-56 years, with DC were examined before and after treatment. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depressive Symptom Rating Scale (HDRS-21). The control group included 23 women of the corresponding age without mental pathology. Biological parameters were assessed in the peripheral blood of patients and healthy people. Patients with a high level of PAM compared to the control (p<0.001) (subgroup 1, n=31) and with a low (at the control level) level (subgroup 2, n=30) were identified. In the subgroup 1, the values of GR and GT were significantly lower than in patients of subgroup 2 (p<0.05 and p<0.01, respectively). Negative correlations between the level of PAM before treatment and GR before and after treatment were revealed in patients who responded to treatment (r=-0.67; p=0.0041; r=-0.76; p=0.0001). The results may indicate the inverse relationship between the level of PAM and the activity of GR and GT, which are involved in the pathogenesis of DC, and can also serve as criteria for assessing the response of patients to treatment.

Late onset psychosis treatment with adjunctive medicines.

A number of studies have shown the feasibility of using adjunctive drugs in late onset psychosis (LOP). Testing hypothesis that among LOP people treated with antipsychotics and antidepressants, basing on certain clinical characteristics a subgroup of patients might be distinguished, for whom adjunctive therapy is advantageous. This subgroup might be identified by measurement of blood biochemical parameters. 59 in-patients with LOP, treated neuroleptics and antidepressants, were included, and followed in real clinical practice. Database containing demographic, clinical data (scores by PANSS, CDSS, CGI-S, HAMD-17), prescribed therapy, adverse effects of antipsychotic and antidepressant treatment, and blood biochemical parameters (enzymatic activities of glutamate- and glutathione metabolism enzymes in platelets and erythrocytes) at baseline and after the treatment course was created. Three groups of patients (Gr1, Gr2, and Gr3), based on the adjunctive therapy usage were identified: Gr1 (n = 16) was without adjunctive therapy, two other groups (Gr2 and Gr3) were with adjunctive medicines, such as 2-ethyl-6-methyl-3-hydroxypyridine succinate (EMHS; Gr2, n = 20), or other drugs, such as citicoline, cerebrolysin, cortexin, actovegin, gliatilin (choline alfoscerate; Gr3, n = 23). The enzymatic activities were assessed also in the matched control group (n = 38). In all three patient groups, as compared with controls, activity of erythrocyte glutathione reductase was decreased at baseline and after the treatment course. In Gr2, unlike Gr1 or Gr3, there was a significant decrease in baseline glutamate dehydrogenase and glutathione-S-transferase activities. Certain clinical criteria were also elucidated for prescription of EMHS as adjunctive therapy for patients of Gr2. Glutamate dehydrogenase and glutathione-S-transferase activities returned closer to control levels after the treatment course in Gr2, unlike Gr1, where they declined yet more after psychotropic treatment without adjunctive medicine. Different significant links between biochemical parameters and scores by clinical scales were observed in Gr1, Gr2, and Gr3, some having predictive value for evaluation of antipsychotic treatment efficacy. We demonstrate the validity of adjunctive neuroprotective medicines' usage in addition to antipsychotic and antidepressant therapy in distinct subgroups of patients suffering with LOP, especially those who have prominent side effects accompanying their psychotropic treatment. Returning of biochemical parameters to control range following the treatment course observed in patients of the subgroup treated with adjunctive EMHS is evidence for their metabolism normalization.

Melatonin treatment prevents carbon-tetrachloride induced rat brain injury.

Herein the neuroprotective properties of melatonin, a highly effective antioxidant, administered in a single dose 50mg/kg intraperitoneally, were investigated in the brain tissue of Wistar rats acutely exposed to the toxin carbon-tetrachloride (1mL/kg, intraperitoneally). To assess the degree of whole encephalic mass damage, biochemical parameters related to lipid and protein oxidation, antioxidant enzymes (catalase and superoxide dismutase), glutathione and inducible nitric oxide/arginase pathways were determined. The results showed that carbon-tetrachloride impaired the function of antioxidant enzymes (reduced catalase and superoxide dismutase activities) and reduced glutathione-metabolizing enzymes (reduced glutathione, glutathione S-transferase and peroxidase activity). Furthermore, carbon-tetrachloride increased lipid peroxidation and protein oxidative damage in the brain tissue, as well as myeloperoxidase and inducible nitric oxide synthase content/activities. The application of a single dose of melatonin post intoxication has been able to reverse the disturbance in the function of antioxidant enzymes and alleviate the tissue damage caused by oxidative stress, indicating that melatonin could be a potential therapeutic agent in oxidative-damage related neurodegenerative disorders.

Biochemical responses of the Dreissena polymorpha from municipal pond to caffeine, microplastics, and heating in single and combined exposures

Background. Pharmaceuticals have become the aquatic pollutants of growing concern. Caffeine is one of the most widely distributed in the surface waters among them. However, the environmentally relevant models of its effect, which include combined exposures with probable confounding factors, are unknown. Microplastics are a suspected vector that influences caffeine bioavailability. The temperature dependence of response, considering the increase of temperature in surface waters, can also be anticipated. The aim of this study was to analyze the input of caffeine, microplastics and elevated temperature into their combined effect on the zebra mussel Dreissena polymorpha (Pallas, 1771). Materials and Methods. Molluscs were exposed to caffeine (Caf, 20.0 μg·L−1), microplastics (MP, 1 mg·L−1, 2 μm in size), or elevated temperature (T, 25 °C) in the single and combined (Mix- and MixT-) exposures for 14 days. The concentrations of metallothioneins, metallothioneins-bound zinc, total Zn and Cu concentration in the tissue, total glutathione level, antioxidant (superoxide dismutase) and metabolic (citrate synthase) enzymes activities, acid phosphatase activity as the lysosomal functionality marker were determined. Results and Discussion. The decrease in Zn/Cu concentrations ratio in the soft tissues shared the common response in all exposures, reflecting the metal imbalance as the most sensitive marker. The MP-group was distinguished by the decrease in the levels of total Zn and extra lysosomal acid phosphatase activity, proving injury of Zn transportation and Zn-related enzyme activities. All other exposures (T-, Mix-, MixT-) caused citrate synthase and superoxide dismutase activation. Caf-related groups demonstrated the elevation of the levels of phosphatase lysosomal membrane-linked latency, metallothionein total protein and its apo-form. However, glutathione level was stable in all exposures. Conclusion. These data revealed the adverse effect of MP and shared beneficial effects in the exposures that involved caffeine, which can be explained by the antioxidant activity of this substance. Exposure to elevated temperature partially alleviated the effect of caffeine in the mixture. Thus, the results indicate the importance of multi-stress exposures modeling, which allows the evaluation of environmentally realistic responces of an organism to xenobiotics.

Effect of 6-hydroxydopamine increase the glutathione level in SH-SY5Y human neuroblastoma cells.

Treatment of human neuroblastoma SH-SY5Y cells with a catecholaminergic neurotoxin, 6-hydroxydopamine (6-OHDA) is an acknowledged in vitro experimental model of Parkinson disease (PD). A decrease in the glutathione content occurs in PD. Higher concentrations of 6-OHDA lowered the glutathione level in SH-SY5Y cells, nonetheless, we and other authors found a considerable increase in these cells' glutathione content after 24 h treatment with 60 μM 6-OHDA. A synthetic antioxidant, 4-aminotetramethylpiperidine-1-oxyl (4-AT) exerted a similar effect. The aim of the present study was to explain this surprising effect by monitoring the time course of changes in the levels of reduced (GSH) and oxidized glutathione (GSSG), total antioxidant activity (TAC) of human neuroblastoma cell SH-SY5Y extracts as well as the level of reactive oxygen species and activities of enzymes of glutathione metabolism after treatment of the cells with 60 µM 6-OHDA and/or 4-AT for 30 min - 24 h. A transient decrease in the level of GSH and TAC of cell extracts, increase in the level of GSSG, and decrease in the activities of glutathione peroxidase, glutathione reductase, glutathione S-transferase and γ-glutamyl-cysteine ligase activities were found followed by normalization or overshoot of the GSH level, TAC and enzyme activities. Increased activity of γ-glutamyl-cysteine ligase activity starting after 4-6 h was responsible for the elevation of the level of GSH and TAC in cells treated with 6-OHDA, 4-AT, and both compounds. The 6-OHDA-induced increase in the GSH content is a result of an overcompensatory response. The antioxidant 4-AT may be useful for the induction of an increase in the level of GSH in neural cells, without the negative effect of 6-OHDA.

The Effects of Sodium Tetraborate against Lead Toxicity in Rats: The Behavior of Some Metabolic Enzymes.

This study was planned to research the in vivo effects of lead (Pb) ions and sodium tetraborate (Na2B4O7) on G6PD and 6PGD, which are some of the enzymes of the pentose phosphate pathway, which carries vital importance for metabolism, and GR and GST, which are glutathione metabolism enzymes, and the in vitro effects of the same agents on the 6PGD enzyme. According to the in vivo analysis results, in comparison to the control group, the rat liver G6PD (p < 0.05), and 6PGD (p < 0.01) enzyme activities in the Na2B4O7 group were significantly lower. In addition, GR and GST enzyme activities were insignificantly lower in the Na2B4O7 group compared to the control group (p > 0.05). The Pb group had lower G6PD and 6PGD enzyme activity levels and higher GR and GST enzyme activity levels compared to the control group, while these changes did not reach statistical significance (p > 0.05). In the in vitro analyses of the effects of Pb ions on the 6PGD enzyme that was purified out of rat liver with the 2',5'-ADP-Sepharose 4B affinity chromatography method, it was determined that Pb ions (200-1200 μM) increased the rat liver 6PGD enzyme activity levels by 33%. On the other hand Na2B4O7 was not significantly effective on 6PGD activity. These results will also contribute to future studies in understanding the physiopathology of the states triggered by Pb ions and sodium tetraborate (Na2B4O7).

Correlations between biochemical and clinical parameters in patients at risk for schizophrenia spectrum disorders

Integrated clinical and biological approach to the early detection of attenuated psychotic symptoms within the frames of affective disorders makes it possible to detect the initial stage of the psychosis development and begin timely therapeutic intervention. The aim of the study was to evaluate the activity of glutamate, glutathione, and energy metabolism enzymes in the blood of patients who are at risk for the development of schizophrenia and to search for clinical and biological correlations. Clinical, psychometric (SOPS and HDRS-21), and biochemical examinations were made in 60 young men aged 16–25 years belonging to the risk group for the development of schizophrenia and in 21 young men from the comparison group without signs of risk of schizophrenia. The control group consisted of 25 healthy young men aged 19–25 years. The activities of cytochrome c oxidase, glutamate dehydrogenase, glutathione reductase, and glutathione-S-transferase were determined in platelets and erythrocytes. Decreased activities of platelet glutamate dehydrogenase, glutathione reductase, and glutathione-S-transferase were observed in all groups of examined patients compared with the control group. In erythrocytes, changed activities of glutathione reductase were observed only in the group of patients without attenuated psychotic symptoms, and glutathione-S-transferase — in the group of patients with attenuated symptoms. The revealed correlations between biochemical and clinical parameters differed in the examined groups of patients. The obtained results reflect the features of the pathogenic mechanisms in the schizophrenia risk group in terms of the activity levels of blood enzymes involved in glutamate, energy, and glutathione metabolism.

Comparative Transcriptomics Reveal Metabolic Rather than Genetic Control of Divergent Antioxidant Metabolism in the Primary Root Elongation Zone of Water-Stressed Cotton and Maize.

Under water stress, the primary root elongation zones of cotton and maize exhibit both conserved and divergent metabolic responses, including variations in sulfur and antioxidant metabolism. To explore the relative importance of metabolic and genetic controls of these responses for each species, and the extent to which responses are mediated by similar gene expression networks within the framework of ortholog groups, comparative transcriptomics analyses were conducted under conditions of equivalent tissue water stress. Ortholog analysis revealed that 86% of the transcriptome response to water stress was phylogenetically unrelated between cotton and maize. Elevated transcript abundances for genes involved in abscisic acid (ABA) biosynthesis and signaling, as well as key enzymes that enable osmotic adjustment, were conserved between the species. In contrast, antioxidant responses, at least with regard to glutathione metabolism and anti-oxidative enzymes, did not exhibit such a transcript abundance adaptive signature. In particular, previously characterized differential responses of the glutathione and sulfur metabolic pathways between cotton and maize were not evident in the transcriptomic responses. The findings indicate that the antioxidant response in both species results from a metabolic acclimation to water stress, and thus represents an example of water stress-related metabolic plasticity.

Molecular Mechanisms Underlying Flax (Linum usitatissimum L.) Tolerance to Cadmium: A Case Study of Proteome and Metabolome of Four Different Flax Genotypes.

Cadmium is one of the most toxic heavy metal pollutants, and its accumulation in the soil is harmful to agriculture. Plants have a higher cadmium tolerance than animals, and some species can be used for phytoremediation. Flax (Linum usitatissimum L.) can accumulate high amounts of cadmium, but the molecular mechanism behind its tolerance is unknown. Here, we employed four genotypes representing two fiber cultivars, an oilseed breeding line, and a transgenic line overexpressing the metallothionein domain for improved cadmium tolerance. We analyzed the proteome of suspensions and the proteome and metabolome of seedling roots in response to cadmium. We identified more than 1400 differentially abundant proteins representing putative mechanisms in cadmium tolerance, including metal-binding proteins and transporters, enzymes of flavonoid, jasmonate, polyamine, glutathione metabolism, and HSP70 proteins. Our data indicated the role of the phytohormone cytokinin in the observed responses. The metabolome profiling found that pipecolinic acid could be a part of the cadmium accumulation mechanism, and the observed accumulation of putrescine, coumaric acid, cinnamic acid, and coutaric acid confirmed the role of polyamines and flavonoids in tolerance to cadmium. In conclusion, our data provide new insight into cadmium tolerance and prospective targets for improving cadmium tolerance in other plants.

Far-Red Light Coordinates the Diurnal Changes in the Transcripts Related to Nitrate Reduction, Glutathione Metabolism and Antioxidant Enzymes in Barley.

Spectral quality, intensity and period of light modify many regulatory and stress signaling pathways in plants. Both nitrate and sulfate assimilations must be synchronized with photosynthesis, which ensures energy and reductants for these pathways. However, photosynthesis is also a source of reactive oxygen species, whose levels are controlled by glutathione and other antioxidants. In this study, we investigated the effect of supplemental far-red (735 nm) and blue (450 nm) lights on the diurnal expression of the genes related to photoreceptors, the circadian clock, nitrate reduction, glutathione metabolism and various antioxidants in barley. The maximum expression of the investigated four photoreceptor and three clock-associated genes during the light period was followed by the peaking of the transcripts of the three redox-responsive transcription factors during the dark phase, while most of the nitrate and sulfate reduction, glutathione metabolism and antioxidant-enzyme-related genes exhibited high expression during light exposure in plants grown in light/dark cycles for two days. These oscillations changed or disappeared in constant white light during the subsequent two days. Supplemental far-red light induced the activation of most of the studied genes, while supplemental blue light did not affect or inhibited them during light/dark cycles. However, in constant light, several genes exhibited greater expression in blue light than in white and far-red lights. Based on a correlation analysis of the gene expression data, we propose a major role of far-red light in the coordinated transcriptional adjustment of nitrate reduction, glutathione metabolism and antioxidant enzymes to changes of the light spectrum.

Late onset schizophrenia and delusional disorder: activity of platelet energy, glutamate, and glutathione metabolizing enzymes

IntroductionAlterations of glutamate, energy and glutathione metabolism contribute to the pathogenesis of psychotic disordersObjectivesRevealing clinical-biological correlations in patients with late onset schizophrenia and delusional disorder by determining clinical parameters and activity of platelet enzymes of energy, glutamate, and glutathione metabolism.Methods27 women of 45-80 years old were studied, with late onset schizophrenia or delusional disorder. Activity of platelet cytochrome c-oxidase (COX), glutamate dehydrogenase (GDH), glutathione reductase (GR) and glutathione-S-transferase (GST), and scores by PANSS, HAMD, MMSE, and CGI-S were evaluated twice: before and after the 28-th day of treatment. Activity of COX, GDH, GR, and GST was measured once in 23 women of 44-81 years old comprising the control group.ResultsAs compared with controls, only GDH activity was found significantly decreased (before and after treatment, p&lt;0.001). Clusterisation of patients by enzymatic activities resulted in 3 clusters significantly different by COX, GDH and GST. Significant correlations were found between enzymatic activities and scores by psychometric scales: in the cluster 1 (n=9) baseline COX activity correlated with scores by PANSS positive subscale (R=0.9, p=0.001) and with scores by MMSE (R=-0.9, p=0.002); in the cluster 2 (n=12) GR activity after treatment negatively correlated with scores by PANSS (R=-0.9, p=0.001), PANSS negative subscale (R=-0.8, p=0.004), and CGI-S (R=-0.9, p=0.001).ConclusionsThe revealed correlations between enzymatic activities and clinical parameters give hope on detection of useful biochemical markers which, after enlargement of patients’ group with late onset psychotic disorders, would be validated for prediction of the pharmacotherapy efficiency and outcome of treatment.DisclosureNo significant relationships.

Activity of energy, glutamate, and glutathione metabolism enzymes in blood cells of elderly patients with depression

Heterogeneity of depression in older adults is a challenge for the development of person-centered treatment. To address this, we studied glutamate and glutathione metabolism enzymes in blood cells in 53 older adult patients with depression and 20 controls. Patients with depression had decreased platelet glutathione-S-transferase and erythrocyte glutathione reductase. The biochemical and clinical data contributed to three clinical clusters that are not linked to the onset of depression or its duration but were related to anxiety, cerebrovascular and cardiovascular comorbidities, including parkinsonian features such as tremor, akathisia, and rigidity. These findings could aid person-centered diagnosis and outcomes and timely successful treatment(s) of depression in older adults.

Activity of enzymes of glutamate, energy and glutathione metabolism in the first juvenile depression with attenuated symptoms of schizophrenia

To reveal clinical and biological correlations in patients with attenuated symptoms of schizophrenia in the first juvenile depression, namely, the correlation between SOPS and HDRS-21 scores and the levels of activities of glutathione, glutamate and energy metabolism enzymes in the blood of patients. The study included 81 young men, aged 16-25 years, with the first depressive episode (ICD-10 items F32.1, F32.2, F32.38, F32.8), from which the groups with predominantly attenuated positive symptoms (group 1, n=36) and predominantly attenuated negative symptoms (group 2, n=24), and a group without attenuated schizophrenia symptoms (group 3, n=21) were selected. The control group consisted of 20 mentally healthy men aged 19-25 years. Psychometric methods (SOPS and HDRS-21) and psychopathological methods were used. Activities of cytochrome c oxidase (COX), glutamate dehydrogenase (GDH), glutathione reductase (GR), and glutathione S-transferase (GST) enzymes were determined spectrophotometrically in blood cells. When compared with the control group, activities of platelet GDH, GR, and GST (before and after treatment) were significantly reduced in groups 1, 2, 3 (Mann-Whitney U-test, p<0.0002, p<0.001 and p<0.0001, respectively); the activity of erythrocyte GST was reduced in group 1, and the activities of erythrocyte GR and GST were reduced in group 3 (p<0.05). In group 1, baseline COX (before treatment) was positively correlated with post-treatment SOPS-N scores (R=0.580, p=0.0003), while baseline erythrocyte GR was negatively correlated with post-treatment HDRS-21 scores (R=-0.591, p=0.0004). In group 2, baseline GDH levels were positively correlated with post-treatment scores on SOPS-P (R=0.425, p=0.0384), SOPS-N (R=0.500, p=0.0129), SOPS total (R=0.526, p=0.0083) and HDRS-21 (R=0.479, p=0.0180). The discovery of clinical and biological correlations in groups of patients with attenuated symptoms of schizophrenia in the structure of juvenile depression contributes to understanding the pathogenetic mechanisms of the formation of a high clinical risk of psychosis and contributes to the search for markers of the initial stages of schizophrenia.

Reactivity of γ-glutamyl-cysteine with intracellular and extracellular glutathione metabolic enzymes.

Gamma-glutamyl-cysteine (γ-EC) is a precursor of glutathione (GSH) biosynthesis. We investigated whether it functions as a substrate for three intracellular and one extracellular GSH metabolic enzymes, which mediate the antioxidant defence function of GSH. Among them, glutathione peroxidase, glutathione S-transferase and γ-glutamyl transferase (GGT) exhibited substrate specificity for γ-EC, whereas glutathione reductase did not. The specificities of γ-EC and its disulphide form to GGT were comparable to GSH and its oxidized form, GSSG respectively. These results indicate that they can supply GSH constituent amino acids, glutamate, cysteine and cystine through degradation by GGT. γ-EC may contribute valuable antioxidant defence properties as a food and cosmetic additive.

ITRAQ and RNA-seq analyses provide an insight into mechanisms of recalcitrance in a medicinal plant Panax notoginseng seeds during the after-ripening process.

Panax notoginseng (Burk) F.H. Chen is an important economic and medicinal plant from the family of Araliaceae, and its seed is characterised by the recalcitrance and after-ripening process. However, the molecular mechanism on the dehydration sensitivity is not clear in recalcitrant seeds. In the present study, isobaric tag for relative and absolute quantification (iTRAQ) and RNA-seq were used to analyse the proteomic and transcriptomic changes in seeds of P. notoginseng in days after-ripening (DAR). A total of 454 differentially expressed proteins (DEPs) and 12000 differentially expressed genes (DEGs) were obtained. The activity of enzymes related to antioxidant system were significantly increased, and the late embryogenesis abundant (LEA) protein family and most members of glutathione metabolism enzymes have been downregulated during the after-ripening process. The lack or inadequate accumulation of LEA proteins in the embryo and the low activity of antioxidant defense in glutathione metabolism might be the key factors leading to the dehydration sensitivity in recalcitrant seeds of P. notoginseng. In addition, the increased activity of elycolysis (EMP), citric acid cycle (TCA) and pentose phosphate pathway (PPP) pathways might be one of important signals to complete the after-ripening process. Overall, our study might provide a new insight into the molecular mechanism on dehydration sensitivity of recalcitrant seeds.

Metabolomic Profiling in Renal Cell Carcinoma Patients: News and Views.

Simple SummaryUnderstanding the metabolic basis of renal cell carcinoma (RCC) has been of paramount importance in defining therapeutic management in clinical practice. Unfortunately, cancer drug resistance continues to be a major cause of treatment failure. Accordingly, developing new treatment perspectives targeting new metabolisms can contribute to overcoming the development of multidrug resistance, and thus optimize patient cure. In this review, we will define and discuss the outline of RCC metabolism, and we will describe certain therapeutic strategies targeting metabolic pathways. The PI3K/Akt signaling pathway continues to be the main target of clinical investigation in RCC patients. Data from metabolic pathways such as c-Met, GSH, and HDAC, variously targeted in combination with PI3K/Akt inhibitors, seem to offer new potential treatment opportunities for the research community. In this view, further studies are warranted.Background: We address novelty regarding metabolomic profiling in renal cell carcinoma (RCC) patients, in an attempt to postulate potential treatment strategies. Methods: A large-scale literature search in existing scientific websites focusing on the keywords “renal cell carcinoma”, “clear cell histology”, “papillary histology”, “metabolomic profiling”, and “therapeutics” was performed. Results: The PI3K/Akt signaling pathway is key in clear cell RCC metabolism and accordingly several drugs are presently available for routine use in clinical practice. Along this line, new treatment combinations against PI3K/Akt family members are currently under clinical investigation. On the other hand, new developed targets such as c-Met tyrosine kinase domain, glutathione (GSH) metabolism, and histone deacetylases enzymes (HDAC), as well as therapeutic strategies targeting them are currently being tested in clinical trials and here discussed. Conclusions: In RCC patients, the PI3K/Akt signaling is still the most effective targetable pathway. Targeting other metabolic pathways such as c-Met, GSH, and HDAC appears to be a promising approach and deserve further insights.

The Link between Type 2 Diabetes Mellitus and the Polymorphisms of Glutathione-Metabolizing Genes Suggests a New Hypothesis Explaining Disease Initiation and Progression.

The present study investigated whether 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). 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.

The relationship of folate deficiency, hyperhomocysteinemia and glutathione metabolism in hypertensive patients

Hypertension (HTN) is often accompanied by folic acid (FA) deficiency and hyperhomocysteinemia (HHcy). Reduced glutathione (GSH) and dependent enzymes determine the state of cellular antioxidant and redox systems in cardiovascular pathology. The aim of our work is to assess the relationship between the status of FA and the presence of HHcy with enzymes of glutathione metabolism and the redox state of erythrocyte glutathione in HTN. Design and methods. In blood plasma samples from 43 HTN patients admitted to the clinic of Pavlov University, the concentration of FA and total homocysteine (oHcy) was determined. We also evaluated the level of GSH, the activity of glutathione peroxidase and glutathione reductase (GR) in erythrocytes. Results. In the whole group, GR activity positively correlated with the concentration of FA (R = 0,415; p = 0,001). A significant decrease in GR activity (U/g Hb) was found in the subgroup with the low level of FA [0,8 (0,5–1,1)] compared with the subgroup without a FA deficiency [1,2 (0,9–2,0)]. The GSH level (μM/g Hb) was also lower (p &lt; 0,018) in the subgroup with FA deficiency [1,3 (0,9–2,1)] compared with the subgroup with normal FA levels [1,8 (1,5–4,6)]. A significant decrease in the level of GSH and GR activity in the subgroup with HHcy was found compared with the corresponding parameters in the subgroup without HHcy. However, even in the absence of HHcy patients with FA deficiency demonstrated a significant decrease in GR activity compared to patients without FA deficiency. In this case, GR positively correlated with FA (R = 0,564; p = 0,03). Conclusions. The deficiency of FA can increase the deficiency of GR activity, regardless of the level of oHcy. The indicator of GR activity in erythrocytes can be considered as a possible marker of functional deficiency of FA in the absence of HHcy.

Platelet glutathione reductase and glutathione-S-transferase in elderly patients with depression

To compare the activity of platelet glutathione reductase (GR) and glutathione-S-transferase (GST) in elderly patients with depression and in the control group, and to identify a possible relationship between the activity of these enzymes and clinical parameters of the disease. We examined 42 elderly patients (60-86 years old) with depressive episodes of various nosological categories according to ICD-10: a single depressive episode (F32.0, F32.1), a depressive episode in recurrent depressive disorder (RDR - F33.0, F33.1), and a depressive episode in bipolar disorder (BD - F31.3). The GR, GST activity and the severity of depression were assessed twice: before the beginning of the course of 28-day antidepressant therapy (day 0) and on the 28th day of the course of therapy, using the Hamilton Depressive Scale (HAMD-17) and the Hamilton Anxiety Scale (HARS). As compared with the control group, a significant decrease in GST activity was found in patients before and after the course of therapy (p<0.0001 and p<0.0003, respectively), no significant difference in GR activity was found. Significant correlations of the platelet GR activity in patients before thetreatment course with the age of disease manifestation (R= -0.44; p=0.004, inverse correlation) and with its duration (R=0.43, p=0.004, direct correlation), estimated after a 28-day course of therapy. A significant inverse correlation of the baseline (before treatment) GR activity with the HAMD score estimated after the course of therapy (R=-0.440; p=0.009) was found only in women subgroup (n=33). A pilot study has revealed a decrease in platelet GST activity, and a link between platelet GR activity and the severity of depression after a course of therapy. The results obtained indicate the promise of further study of glutathione metabolism enzymes as a biomarker for assessing the state.