Lower GSH Research Articles

Taurine regulates mucosal barrier function to alleviate lipopolysaccharide-induced duodenal inflammation in chicken.

The objective of the study was to investigate how taurine alleviates mucosal injury. Young chickens were fed with taurine for 1week and then challenged with lipopolysaccharide. We found that, under lipopolysaccharide challenge, taurine could attenuate diarrhea and mucosal inflammation. Additionally, under LPS challenge, taurine could enhance epithelial proliferation and goblet cell function, could also decrease epithelial apoptosis by improving the mitochondrial membrane permeability. The high-performance liquid chromatography assay showed that taurine feeding could elevate taurine concentration in duodenum obviously. The antioxidant assay showed that taurine could reverse lipopolysaccharide-induced low GSH level, GSH/GSSG ratio, GSH-Px activity and SOD activity, high GSSG and MDA content. In summary, we suggested that taurine could enhance duodenal antioxidant status locally and further ameliorated lipopolysaccharide-induced chicken duodenal inflammation by improving mitochondrial membrane permeability and goblet cell function.

Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models.

Friedreich’s Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder, affecting dorsal root ganglia (DRG), cerebellar dentate nuclei and heart. It is caused by a GAA repeat expansion mutation within the frataxin gene (FXN). This impedes FXN transcription resulting in a progressive decrease of the mitochondrial protein, frataxin. Increased oxidative stress leading to a chronic depletion of endogenous antioxidants affects the survival of the cells and causes neurodegeneration. In particular, cerebellar granule neurons (CGNs) show a significant increase of reactive oxygen species (ROS), lipid peroxidation and lower level of reduced glutathione (GSH). In FRDA, one of the major pathways of oxidant scavengers, the Nrf2 antioxidant pathway, is defective. Previous studies on FRDA-like CGNs showed that the reduced level of frataxin and the oxidative stress induce mitochondrial impairments. By triggering the Nrf2 endogenous pathway pharmacologically we determined whether this could promote mitochondrial fitness and counteract oxidative stress. In this work, we sought to investigate the beneficial effect of a promising Nrf2-inducer, omaveloxolone (omav), in CGNs from two FRDA mouse models, KIKO and YG8R, and human fibroblasts from patients. We found that CGNs from both KIKO and YG8R presented Complex I deficiency and that omav was able to restore substrate availability and Complex I activity. This was also confirmed in human primary fibroblasts from FRDA patients. Although fibroblasts are not the major tissue affected, we found that they show significant differences recapitulating the disease; this is therefore an important tool to investigate patients’ pathophysiology. Interestingly, we found that patient fibroblasts had an increased level of endogenous lipid peroxidation and mitochondrial ROS (mROS), and lower GSH at rest. Omav was able to reverse this phenotype, protecting the cells against oxidative stress. By stimulating the cells with hydrogen peroxide (H2O2) and looking for potential mitochondrial pathophysiology, we found that fibroblasts could not maintain their mitochondrial membrane potential (ΔΨm). Remarkably, omav was protective to mitochondrial depolarization, promoting mitochondrial respiration and preventing cell death. Our results show that omav promotes Complex I activity and protect cells from oxidative stress. Omav could, therefore, be used as a novel therapeutic drug to ameliorate the pathophysiology of FRDA.

Detoxication mechanisms of Radix Tripterygium wilfordii via compatibility with Herba Lysimachia christinae in S180-bearing mice by involving Nrf2.

The combined administration between Radix Tripterygium wilfordii Hook F (LGT) and Herba Lysimachia christinae Hance (JQC) belongs to mutual detoxication compatibility of seven emotions in traditional Chinese medicine (TCM) theory. However, until now, the compatibility detoxication mechanisms remain unknown. The present study was undertaken to observe detoxication mechanisms of LGT through compatibility with JQC in tumor-bearing mice by involving NF-E2-related factor 2 (Nrf2)-mediated antioxidant defenses. In addition, influence of compatibility on antitumor activity was also investigated here. Our results demonstrated that compatibility with JQC administration significantly reversed LGT-elevated serum alanine/aspartate transaminase (ALT/AST) levels and alleviated hepatocytes’ swelling or degeneration damage, and at the ratio 2/1 (LGT/JQC) produced the strongest detoxication effect. Besides, compatibility with JQC administration reversed not only LGT-elevated hepatic malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α) but also the LGT lowered GSH, glutathione-s transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and interleukin (IL)-10 levels. Furthermore, compatibility with JQC administration significantly up-regulated protein expression of Nrf2 and mRNA expression of it regulated downstream antioxidant genes such as heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase-1 (NQO1), and glutamate cysteine ligase catalytic subunit (GCLC). In addition, compatibility with JQC further decreased LGT-decreased tumor weight and at the ratio 2/1 (LGT/JQC) also exerted the strongest synergistic effect. Collectively, through compatibility with JQC exerted detoxication effect on LGT-induced hepatotoxicity and the mechanisms could be at least partly attributed to up-regulation of Nrf2 and its downstream signals, thereby enhancing antioxidant defenses, and inhibiting lipid peroxidation, oxidative stress, and inflammation. Additionally, at the ratio 2/1 (LGT/JQC) exerted the strongest effects on both detoxication and synergism.

Glutathione metabolism in type 2 diabetes and its relationship with microvascular complications and glycemia.

Aims/HypothesesWe hypothesized that there is decreased synthesis of glutathione (GSH) in type 2 diabetes (T2DM) especially in the presence of microvascular complications, and this is dependent on the degree of hyperglycemia.MethodsIn this case-control study, we recruited 16 patients with T2DM (7 without and 9 with microvascular complications), and 8 age- and sex-matched non-diabetic controls. We measured GSH synthesis rate using an infusion of [2H2]-glycine as isotopic tracer and collection of blood samples for liquid chromatography mass spectrometric analysis.ResultsCompared to the controls, T2DM patients had lower erythrocyte GSH concentrations (0.90 ± 0.42 vs. 0.35 ± 0.30 mmol/L; P = 0.001) and absolute synthesis rates (1.03 ± 0.55 vs. 0.50 ± 0.69 mmol/L/day; P = 0.01), but not fractional synthesis rates (114 ± 45 vs. 143 ± 82%/day; P = 0.07). The magnitudes of changes in patients with complications were greater for both GSH concentrations and absolute synthesis rates (P-values ≤ 0.01) compared to controls. There were no differences in GSH concentrations and synthesis rates between T2DM patients with and without complications (P-values > 0.1). Fasting glucose and HbA1c did not correlate with GSH concentration or synthesis rates (P-values > 0.17).ConclusionsCompared to non-diabetic controls, patients with T2DM have glutathione deficiency, especially if they have microvascular complications. This is probably due to reduced synthesis and increased irreversible utilization by non-glycemic mechanisms.

Is serum glutathione level in combination with serum PSA useful for early detection of prostatic carcinoma? A local study of Iraq

Background: Prostate cancer is the most common cancer and the second leading cause of cancer-related death among men of western countries. The aim of this study is to develop non-invasive diagnostic tools for the early detection of prostate cancer (PCa) through detection of low level of Serum reduced Glutathione (GSH).Methods: Serum samples from men being evaluated for PCa were analyzed for reduced Glutathione (GSH) level. The results were compared with the prostate needle biopsy findings and (PSA) level combined with Digital Rectal Examination (DRE). Samples were obtained from 59 cases including 18 controls.Results: The maximum sensitivity of the test was observed in the first category of confirmed cases with 93.33% turs positive detected with low GSH. Among those highly suspected Ca prostate there was 87.5% true positive test and 12.5% false negative results. Among those in grey zone where PSA between is 4 and 10, and DRE is suggestive, the proportion of true positive was 50%.Conclusions: These results demonstrate that serum reduced Glutathione (GSH) level is helpful in patient with definite carcinoma. This test could be useful in augmenting current PCa diagnostic procedures. For example, the examination test for reduced Glutathione (GSH) level with an elevated prostate- specific antigen level might be used in predicting which patients will have negative biopsies and may be used as treatment modality for PCa.

GSH levels affect weight loss in individuals with metabolic syndrome and obesity following dietary therapy

This study examined the effects of redox status markers on metabolic syndrome (MetS) and obesity before and after dietary intervention and exercise for weight loss. A total of 103 adults suffering from MetS and obesity participated in this study and followed a personalized diet plan for 6 months. Body weight, body fat (BF) percentage (BF%), respiratory quotient (RQ) and the redox status markers, reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and protein carbonyls (CARB), were measured twice in each individual, before and after intervention. Dietary intervention resulted in weight loss, a reduction in BF% and a decrease in RQ. The GSH levels were significantly decreased following intervention, while the levels of TBARS and CARB were not affected. Based on the initial GSH levels, the patients were divided into 2 groups as follows: The high GSH group (GSH, >3.5 µmol/g Hb) and the low GSH group (GSH <3.5 µmol/g Hb). Greater weight and BF loss were observed in patients with high GSH levels. It was observed that patients with MetS and obesity with high GSH values responded better to the dietary therapy, exhibiting more significant changes in weight and BF%. This finding underscores the importance of identifying redox status markers, particularly GSH, in obese patients with MetS. Knowing the levels of GSH may aid in developing a better design of an individualized dietary plan for individuals who wish to lose weight.

Effect of L-carnitine on the skeletal muscle contractility in simvastatin-induced myopathy in rats.

Abstract Background Statins therapy is effective in the prevention of cardiovascular events. However, its use is associated with skeletal muscle myopathy, which may be severe enough to discontinue statin therapy, thus exposing patients to more morbidity and mortality. This study was conducted to assess the effect of L-carnitine on the skeletal muscle contractility in a rat model of statin-induced myopathy and to clarify its possible mechanisms. Methods Twenty-one female Sprague Dawley rats were used throughout this study. The rats were divided into the normal control group, statin-induced myopathy group and statin/L-carnitine-treated group. The assessment of gastrocnemius muscle contractility, plasma creatine kinase (CK) levels and oxidative stress markers (malondialdehyde, reduced glutathione) was also carried out done. Results The results of the current study suggest that simvastatin decreased the skeletal muscle mass and altered the muscle contractile properties. It also significantly increased plasma CK level and induced a state of oxidative stress state (high MDA, low GSH). Meanwhile, concurrent L-carnitine significantly reduced statin-induced myopathy and improved the oxidative stress markers and skeletal muscle contractile parameters. Conclusions Statin myopathy is postulated to be due to mitochondrial dysfunction, cellular oxidative stress, induction of apoptosis, reduction in the expression of chloride channel and its related conductance, in addition to the alteration of Ca2+ homeostasis. L-carnitine has an antioxidant effect, reduces skeletal muscle atrophy and improves the skeletal muscle contractility in simvastatin-induced myopathy.

Neuroprotective efficiency of Mangifera indica leaves extract on cadmium-induced cortical damage in rats.

Due to the high ability of cadmium to cross the blood-brain barrier, cadmium (Cd) causes severe neurological damages. Hence, the purpose of this study was to investigate the possible protective effect of Mangifera indica leaf extract (MLE) against Cd-induced neurotoxicity. Rats were divided into eight groups. Group 1 served as vehicle control group, groups 2, 3 and 4 received MLE (100, 200, 300mg /kg b.wt, respectively). Group 5 was treated with CdCl2 (5mg/kg b.wt). Groups 6, 7 and 8 were co-treated with MLE and CdCl2 using the same doses. All treatments were orally administered for 28days. Cortical oxidative stress biomarkers [Malondialdehyde (MDA), nitric oxide (NO), glutathione content (GSH), oxidized form of glutathione (GSSG), 8-hydroxy-2-deoxyguanosine (8-OHdG), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)], inflammatory cytokines [tumor necrosis factor (TNF-α) and interlukin-1β (IL-1β)], biogenic amines [norepinephrine (NE), dopamine (DA) and serotonin (5-HT)], some biogenic metabolites [3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA)], acetylcholine esterase activity (AChE) and purinergic compound [adenosine triphosphate (ATP)] were determined in frontal cortex of rats. Results indicated that Cd increased levels of the oxidative biomarkers (MDA, NO, GSSG and 8-OHdG) and the inflammatory mediators (TNF-α and IL-1β), while lowered GSH, SOD, CAT, GPx and ATP levels. Also, Cd significantly decreased the AChE activity and the tested biogenic amines while elevated the tested metabolites in the frontal cortex. Levels of all disrupted cortical parameters were alleviated by MLE co-administration. The MLE induced apparent protective effect on Cd-induced neurotoxicity in concern with its medium and higher doses which may be due to its antioxidant and anti-inflammatory activities.

Double-Sensitive Drug Release System Based on MnO2 Assembled Upconversion Nanoconstruct for Double-Model Guided Chemotherapy

A double-sensitive drug release system based on MnO2 nanosheets was synthesized using a facile method for imaging guided chemotherapy in cancer cells. The upconversion nanoparticles (UCNPs) as core are used for upconversion luminescence (UCL) imaging, and the coating of mesoporous silica shows excellent ability for loading drug. The assembly with MnO2 nanosheets can respond to low intracellular pH and GSH in cancer cells. The obtained UCNPs@mSiO2–MnO2 nanoparticles with excellent biocompatibility can be applied as drug carriers. As expected, the UCNPs@mSiO2(DOX)–MnO2 (UCDMs) nanoconstruct loading with DOX offer practical chemotherapeutic effects in vitro, suggesting the active drug release in cancer cells. The luminescence intensity and magnetic resonance signals increased with the decomposition of the MnO2 nanosheets and the release of DOX under low pH and high levels of GSH. In addition, the UCDMs exhibit excellent intracellular UCL imaging, indicating that they can be used as a selective imaging agent in a cancerous environment. Thus, the UCDMs present potential application for use as theranostic agents in imaging guided therapy.

Changes in Oxidant Defense, Apoptosis, and Cognitive Abilities During Treatment for Childhood Leukemia.

Aggressive central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia (ALL), the most prevalent cancer among children and adolescents, prevents metastasis of leukemia cells into the brain. Up to 60% of survivors experience cognitive problems, but knowledge about risk factors for and mechanisms of neurologic injury is lacking. Objectives of the present study were to (1) quantify changes in oxidant defense and apoptosis over the course of ALL therapy and (2) elucidate risk factors for long-term cognitive problems. The sample included 71 children with ALL. Cerebrospinal fluid (CSF) samples were collected at diagnosis and during intrathecal chemotherapy administration. Oxidant defense was measured by reduced glutathione (GSH), oxidized glutathione (GSSG), and the ratio of GSH:GSSG. Apoptosis was measured by activity of several cysteine-dependent aspartate-specific protease (abbreviated as caspase) enzymes that initiate (caspases 8 and 9) or execute (caspases 3/7) apoptosis. Cognitive abilities were assessed by standardized measures of short-term memory, visual-motor integration, and attention 3 years after ALL diagnosis. GSH and GSSG concentration increased significantly during ALL therapy, and a low GSH:GSSG ratio was indicative of an oxidized extracellular environment. Caspase enzyme activity increased significantly, and caspases 3/7 activity was significantly and negatively associated with performance on measures of cognitive abilities. Younger age at time of ALL diagnosis was associated with some measures of attention. Efflux of glutathione into CSF maintains oxidant defense by scavenging free radicals and other reactive oxygen species and is an early event in apoptosis. These mechanisms may be involved in neurologic injury associated with CNS-directed treatment and subsequent cognitive problems.

Trace elements and oxidative stress in children with type 1 diabetes mellitus.

BackgroundThe early imbalances of trace elements in type 1 diabetes (T1D) may cause disturbance of glucose metabolism and more oxidative stress that may enhance the development of insulin resistance and diabetic complications. We aim to evaluate the serum level of selenium (Se), zinc (Zn), magnesium (Mg), and copper (Cu), the degree of oxidative stress and evaluate their relations to glycemic control in children with T1D.MethodsA case–control study which included 100 diabetic children and 40 healthy children age, sex, and ethnicity-matched as a control group. The diabetic children were divided into poor and good controlled patients according to glycosylated hemoglobin (A1c %). Studied children underwent history taking, clinical examination and laboratory measurement of serum Se, Zn, Mg, and Cu levels, erythrocyte reduced glutathione (GSH) and peroxidase enzyme activity (GPx).ResultsSerum Se, Zn, Mg, Cu, erythrocyte GSH, and GPx were significantly lower in the diabetic group in comparison to the control group (P<0.05) and their levels were lower in poorly controlled patients compared to good controlled patients (P<0.05). The serum Se, Zn, Mg, erythrocyte GSH, and GPx showed a negative correlation with A1c %. The serum Se showed a positive correlation with erythrocyte GSH and GPx ([r=0.56, P<0.001], [r=0.78, P<0.001], respectively).ConclusionChildren with T1D, especially poorly controlled cases, had low serum Se, Zn, Mg, Cu, GSH, and GPx. Low serum Se in diabetic children may affect the erythrocyte GSH-GPx system.

Impact of Glutathione Modulation on Stability and Pharmacokinetic Profile of Redox‐Sensitive Nanogels

Nanoparticles degradable upon external stimuli combine pharmacokinetic features of both small molecules as well as large nanoparticles. However, despite promising preclinical results, several redox responsive disulphide-linked nanoparticles failed in clinical translation, mainly due to their unexpected in vivo behavior. Glutathione (GSH) is one of the most evaluated antioxidants responsible for disulfide degradation. Herein, the impact of GSH on the in vivo behavior of redox-sensitive nanogels under physiological and modulated conditions is investigated. Labelling of nanogels with a DNA-intercalating dye and a radioisotope allows visualization of the redox responsiveness at the cellular and the systemic levels, respectively. In vitro, efficient cleavage of disulphide bonds of nanogels is achieved by manipulation of intracellular GSH concentration. While in vivo, the redox-sensitive nanogels undergo, to a certain extent, premature degradation in circulation leading to rapid renal elimination. This instability is modulated by transient inhibition of GSH synthesis with buthioninsulfoximin. Altered GSH concentration significantly changes the in vivo pharmacokinetics. Lower GSH results in higher elimination half-life and altered biodistribution of the nanogels with a different metabolite profile. These data provide strong evidence that decreased nanogel degradation in blood circulation can limit the risk of premature drug release and enhance circulation half-life of the nanogel.

Dual redox/pH-responsive hybrid polymer-lipid composites: Synthesis, preparation, characterization and application in drug delivery with enhanced therapeutic efficacy

The development of intelligent drug delivery system that can efficiently deliver drug to targeted site and release the cargo in a controlled manner is of great significance for cancer chemotherapy. In the present study, dual redox/pH-sensitive amphiphilic copolymer, cholesterol modified poly (β-amino esters)-grafted disulfide poly (ethylene glycol) methyl ether (PAE(-ss-mPEG)-g-Chol), is successfully synthesized via Michael-type step polymerization using disulfide linkage-containing PEG segment. PEGylated lipid is introduced to fabricate the doxorubicin (DOX)-loaded hybrid polymer-lipid nanoparticles (NPs) with (DOX-HDPLNPs) or without (DOX-HPLNPs) disulfides to receive stable NPs with enhanced loading capacity and improved cellular uptake ability as well as serum stability. The HDPLNPs show not only pH-sensitivity because of poly(β-amino esters) (PAE) residues in main chain but also the redox-responsivity due to the disulfides on the side chains with PEG segments. As expected, the DOX-HDPLNPs exhibited the extended blood circulation time and higher serum stability in normal physiological environment, but once deposited in the tumor microenvironment (e.g. low pH value and high GSH concentration), they underwent a dramatic size transition and charge reversal. These features not only can facilitate the NPs accumulation through the enhanced permeability and retention (EPR) effect and endocytosis by tumor cells but also realize the drug controlled release and more efficient tumor inhibition. The in vitro and in vivo results demonstrate that the DOX-HDPLNPs possess the highest therapeutic efficacy with high cellular uptake and negligible cytotoxicity compared to the controls and free drug. Therefore, the HDPLNPs have good potential as smart delivery platforms for hydrophobic anticancer drug delivery due to high uptake by tumor cells and redox/pH-triggered drug release.

Influence of in vitro digestion process on polyphenolic profile of skin grape (cv. Italia) and on antioxidant activity in basal or stressed conditions of human intestinal cell line (HT-29)

White table grape cv. Italia is a typical component of the Mediterranean diet and a source of phenolic compounds, particularly abundant in the skin portion. The aim of this study was to characterize the phenolic profile of the table grape skin and to assess its stability after the in vitro digestion process. The main phenolic compounds identified by the HPLC-DAD analysis were: procyanidin B1, caftaric acid, catechin, coutaric acid, quercetin 3-glucuronide and quercetin 3-glucoside. All compounds showed a good stability after in vitro digestion (from 43 to 80%). Moreover, the influence of grape skin polyphenols on the modulation of ROS and GSH levels was evaluated in basal and in stressed conditions on human intestinal cells (HT-29). In basal conditions, a higher polyphenol concentrations exerted pro-oxidant effect corresponding to high ROS level and low GSH content. This effect was probably due to the polyphenolic oxidation in cell culture condition with consequent production of hydrogen peroxide. Otherwise, in stressed conditions, grape skin polyphenols exerted antioxidant effects up to 1.3 × 10−6 μg/g and restored the stress-related GSH reduction. The in vitro digestion process attenuated the biological effect of grape skin polyphenols on intestinal cell line (HT-29). In conclusion, grape skin polyphenols showed different behavior in relation to their concentrations and to the intracellular ROS levels.

Sulfur amino acid restriction-induced changes in redox-sensitive proteins are associated with slow protein synthesis rates.

The mechanisms underlying life span extension by sulfur amino acid restriction (SAAR) are unclear. Cysteine and methionine are essential for the biosynthesis of proteins and glutathione (GSH), a major redox buffer in the endoplasmic reticulum (ER). We hypothesized that SAAR alters protein synthesis by modulating the redox milieu. Male F344-rats were fed control (CD: 0.86% methionine without cysteine) and SAAR diets (0.17% methionine without cysteine) for 12 weeks. Growth rates, food intake, cysteine and GSH levels, proteins associated with redox status and translation, and fractional protein synthesis rates (FSRs) were determined in liver. Despite a 40% higher food intake, growth rates for SAAR rats were 27% of those fed CD. Hepatic free cysteine in SAAR rats was 55% compared with CD rats. SAAR altered tissue distribution of GSH, as hepatic and erythrocytic levels were 56% and 196% of those in CD rats. Lower GSH levels did not induce ER stress (i.e., unchanged expression of Xbp1s , Chop, and Grp78), but activated PERK and its substrates eIF2-α and NRF2. SAAR-induced changes in translation-initiation machinery (higher p-eIF2-α and 4E-BP1, and lower eIF4G-1) resulted in slower protein synthesis rates (53% of CD). Proteins involved in the antioxidant response (NRF2, KEAP1, GCLM, and NQO1) and protein folding (PDI and ERO1-α) were increased in SAAR. Lower FSR and efficient protein folding might be improving proteostasis in SAAR.

Reactivity Toward Ag+: A General Strategy to Generate a New Emissive Center from NIR-Emitting Gold Nanoparticles.

We report a facile strategy for the transformation of single NIR-emitting AuNPs to dual-NIR-emitting bimetallic Ag@AuNPs based on the robust reactivity toward Ag(I) ions under mild conditions. The reactivities toward Ag(I) ions were found to be significantly different between visible- and NIR-emitting glutathione (GSH)-coated AuNPs: the high GSH surface coverage on the 610 nm-emitting AuNPs resulted in a reversible interaction due to enough surface steric hindrance to resist Ag(I) ions from interaction with the Au(0) core, whereas the low GSH surface coverage on the 810 nm-emitting AuNPs led to both antigalvanic reaction and Ag(I)-carboxylate shell formation on the surface of the AuNPs, which were responsible for the formation of a new emissive center at 705 nm. This strategy was also demonstrated to exhibit excellent generalization toward various NIR-emitting AuNPs with surface chemistries containing carboxyl groups, opening a new pathway of tailoring the optical properties of metallic NPs through surface reactivity.

Metabolic syndrome-associated cognitive decline in mice: Role of minocycline.

OBJECTIVE:The objective of the study was to characterize the mechanism associated with metabolic syndrome (MetS)-associated cognitive decline and determine the effect of minocycline on the above condition in mice.MATERIALS AND METHODS:We developed a HFHC diet-induced MetS model in mice. Diagnostic characteristics of MetS including waist circumference, lipid levels, blood pressure, and fasting blood glucose were measured in these Swiss albino mice. Cognitive parameters were measured using passive avoidance and elevated plus maze test. Hippocampal acetylcholine esterase (AchE), reduced glutathione (GSH), and cytokine levels were measured and histopathological evaluation conducted. The MetS animals were administered minocycline (50 mg/kg; 10 days) and the above parameters were measured.RESULTS:We successfully induced MetS using HFHC diet in mice. Animals showed significantly higher fasting blood glucose levels (P < 0.001), systolic blood pressure (P < 0.01), waist circumference (P < 0.001), low-density lipoprotein (P < 0.001), and triglyceride (P < 0.01) and reduced high density lipoprotein levels (P < 0.05) compared to control animals. Both scopolamine and MetS significantly lowered (P < 0.01) step-down latency and increased transfer latency (P < 0.001). MetS animals showed significantly higher AchE (P < 0.001) and tumor necrosis factor-α (P < 0.001) and Interleukin-1 β (P < 0.01) and lower GSH (P < 0.001) levels and reduced both CA1 (P < 0.001) and CA3 (P < 0.01) neuronal density compared to controls. Minocycline treatment partially reversed the above neurobehavioral and biochemical changes and improved hippocampal neuronal density in MetS animals.CONCLUSION:MetS led to hippocampal oxidative stress and neuroinflammatory changes with a corresponding loss of hippocampal neuronal density and cognitive decline. Anti-inflammatory and antioxidant property of minocycline may be responsible for its neuroprotective actions in these animals.

Chronic Carrageenan Toxicity and the Possible Ameliorative Role of Diacerein in Experimental Animals

Carrageenan, is one of the food additives and is used as a firming agent in healthcare products like toothpaste. The aim of this study was to analyze the chronic toxic effects of kappa carregeenan (k- CGN) on the thyroid gland and pancreas in experimental rats and to evaluate the possible ameliorative effect of Diacerein. This study was done on fifty adult male albino rats. The rats were divided into 5 groups (10 rats in each group) in the form of; control group, Carboxymethylcellulose group (1.2ml/Kg), Diacerein group (30mg/Kg), Carrageenan group (50mg/Kg), and Diacerein( 30mg/kg) + Carrageenan (50mg/kg) combination group All drugs were given orally for 3 months. By the end of the 3rd month, thyroid and pancreatic functions were assessed by biochemical, histological, and immunohistochemical investigations. Rats group that were given Carrageenan alone had significantly higher thyroid MDA (malondialdehyde), lower thyroid GSH (reduced glutathione) and serum T4 levels than the untreated control rats group, but co- treatment of Carrageenan- exposed rats with diacerein had an ameliorative effect on the previous results. Light microscopic examinations of thyroid gland sections revealed that Carrageenan caused significant marked hypothyroid changes, and significant mild hypothyroid changes were observed in the rats which received Carrageenan + diacerein combination. Immunohistochemical studies of thyroid gland showed that carrageenan caused significant marked expression of PCNA and significant mild expression was observed in rats received combination of diacerein + carrageenan. Regarding pancreas, this study revealed no significant statistical changes in serum amylase level, MDA and GSH levels. Also, there were not any significant pathological changes of pancreatic tissues of carrageenan group. Thus, it appears that carrageenan can induce oxidative damage in the thyroid gland of rats and diacerein has an ameliorative effect against this damage.

Protective Effects of Quercetin on Necrotizing Enterocolitis in a Neonatal Rat Model.

Necrotizing enterocolitis (NEC) is one of the major health problems of newborn period. To date, a large amount of chemicals have been tested for NEC and some showed limited beneficial effects. The research for better results still continues. This study aims to investigate the effects of quercetin (QE) on NEC treatment in rats. Newborn rats were divided into control, NEC, and NEC + QE groups. In NEC and NEC + QE groups, experimental NEC was induced. NEC + QE group animals were also given QE. Weight changes of the animals were recorded, and serum total antioxidant status (TAS), total oxidant status (TOS), malondialdehyde (MDA), and glutathione (GSH) levels were measured. Histologic evaluation of the distal ileum and the terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. A significant increase in the TAS levels was observed in NEC + QE group. Only NEC group exhibited significantly higher TOS and MDA levels and lower GSH levels. Rats in the NEC + QE group had better histopathology and less apoptosis than NEC group. QE is effective in enhancing antioxidant defense mechanism, limiting oxidative stress, reducing intestinal damage, and preventing NEC development.

A role for glutathione reductase and glutathione in the tolerance of Chlamydomonas reinhardtii to photo-oxidative stress.

The role of glutathione reductase (GR; EC 1.6.4.2) in the tolerance of Chlamydomonas reinhardtii P.A. Dangeard to high-intensity light stress (HL, 1400 μmol m-2 s-1 ) was examined. Cells survived under high light (HL) stress, although their growth was inhibited after long-term treatment (9-24 h). GR activity increased 1 h after HL treatment. The contents of total glutathione, reduced glutathione (GSH) and glutathione disulfide (GSSG) increased 1-3 h after HL treatment and then decreased after 24 h, while the GSH:GSSG ratio (glutathione redox potential) decreased after 3-9 h and recovered after 24 h. The transcript abundance of GR, CrGR1 (Cre06.g262100) and CrGR2 (Cre09.g396252) as well as glutathione synthesis-related genes, CrGSH1 (Cre02g077100.t1.1) and CrGSH2 (Cre17.g70800.t1.1), increased with a peak near 1 h after HL treatment. Except for enhanced glutathione synthesis, the GR-mediated glutathione redox machinery is also critical for the tolerance of C. reinhardtii cells to HL stress. Therefore, GR was downregulated or upregulated to investigate the importance of GR in HL tolerance. The CrGR1 knockdown amiRNA line exhibited low GR transcript abundance, GR activity and GSH:GSSG ratio and could not survive under HL conditions. Over-expression of CrGR1 or CrGR2 driven by a HSP70A:RBCS2 fusion promoter resulted in a higher GR transcript abundance, GR activity and GSH:GSSG ratio and led to cell survival when exposed to high-intensity illumination, i.e. 1800 μmol m-2 s-1 . In conclusion, GR-mediated modulation of the glutathione redox potential plays a role in the tolerance of Chlamydomonas cells to photo-oxidative stress.