Decrease In GSH Content Research Articles

Lipopolysaccharide-Elicited Systemic Inflammation Induces Selective Vulnerability of Cerebral Cortex and Striatum of Developing Glutaryl-CoA Dehydrogenase Deficient (Gcdh−/−) Mice to Oxidative Stress

We investigated redox homeostasis in cerebral and peripheral tissues of wild type (WT) and glutaryl-CoA dehydrogenase knockout mice (Gcdh-/-) submitted to inflammation induced by lipopolysaccharide (LPS) since patients with glutaric aciduria type I (GA I) manifest acute encephalopathy during catabolic events triggered by inflammation. WT and Gcdh-/- mice fed a low (0.9%) or high (4.7%) Lys chow were euthanized 4h after LPS intraperitoneal injection. Cerebral cortex of Lys-restricted Gcdh-/- animals presented no alterations of redox homeostasis, whereas those fed a high Lys chow showed increased malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity, compared to WT mice. Furthermore, Gcdh-/- mice receiving low Lys and injected with LPS presented elevated MDA levels and decreased reduced glutathione (GSH) concentrations, glutathione peroxidase (GPx), and glutathione reductase (GR) activities in cerebral cortex. LPS administration also decreased GSH values, as well as GPx and GR activities in cerebral cortex of Gcdh-/- mice receiving Lys overload. Further experiments performed in WT and Gcdh-/- mice injected with LPS and receiving either a low or high Lys chow revealed increased MDA levels and decreased GSH concentrations in cerebral cortex and striatum, but not in hippocampus, liver and heart of Gcdh-/- mice, suggesting a selective vulnerability of these cerebral structures to oxidative stress during an inflammatory process. LPS administration also increased S100B and NF-κF protein levels in brain of Gcdh-/- mice receiving high Lys. These data support the hypothesis that low Lys diet is beneficial in GA I by preventing redox imbalance, whereas a high Lys diet or systemic inflammation per se or combined induce oxidative stress in striatum and cerebral cortex that are mainly damaged in this disorder.

Fostered Nrf2 expression antagonizes iron overload and glutathione depletion to promote resistance of neuron-like cells to ferroptosis

Neurological diseases were often characterized by progressive neuronal death, and emerging evidences suggested that ferroptosis may be an active driver of multiple neurodegenerative diseases. However, the mechanisms underlying ferroptosis in neuron cells are unclear. Here, we demonstrated that ferroptotic stimuli caused injury in neuron-like PC12 cells by modulating the expression of proteins involved in iron metabolism and lipid peroxidation at multiple levels, such as altering iron import/export, activating ferritinophagy, and decreasing glutathione (GSH) level. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple genes involved in ferroptosis, however, its exact role remain elusive. Our mechanistic inquiry revealed that Nrf2 expression enhanced iron storage capacity by increasing ferritin heavy chain 1 (FTH1) expression in PC12 cells. Moreover, Nrf2 alleviated the decrease in GSH level by promoting the expression of genes related to GSH synthesis, including solute carrier family 7 member 11 (SLC7A11) and cysteine ligase (GCL). The contribution of Nrf2 on ferroptosis resistance was further verified by increasing cell tolerance to oxidative stress. Furthermore, Nfe2l2 (Nrf2) knockdown sensitized cells to ferroptotic cell death. Taken together, our findings suggested that iron accumulation caused by altering iron metabolism and the decrease of GSH content are key factors in determining ferroptosis in PC12 cells, and Nrf2 inhibits ferroptosis by combating iron-induced oxidative stress. Our present study provided new clues for the intervention and prevention against ferroptosis-associated neurological diseases.

Molecular and biochemical effects of the antifouling DCOIT in the mussel Perna perna

Biological fouling is an unwanted phenomenon that results in economic losses to the shipping industry. To prevent fouling, antifouling paints are used. DCOIT (4,5- dichloro-2-n-octyl-4-isothiazolin-3-one) is a biocide present in many antifouling paint formulations, and is toxic to a wide range of organisms. The aim of the present study was to evaluate the effects of DCOIT on oxidative stress indicators of the brown mussel, Perna perna. Molecular (SOD-like, GSTO-like and MGST-like mRNA levels) and biochemical (activities of superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST), and levels of glutathione (GSH), reactive oxygen species (ROS) and protein carbonyls (PCO)) components were evaluated. Further, levels of biomarkers were assessed in the gills and digestive glands of mussels. Bivalves were exposed to DCOIT (control, 0.1 μg/L and 10 μg/L) for up to 96 h. DCOIT exposure decreased GSH content in gills. Moreover, exposure to DCOIT also decreased CAT activity in the gills and digestive glands of mussels. GST activity increased in digestive gland after exposure for 24 h to both concentrations of DCOIT tested. SOD activity, ROS levels and PCO content were not affected by exposure to the contaminant. Regarding the molecular biomarkers evaluated, DCOIT exposure altered mRNA levels of SOD-like in both tissues after 24 and 96 h of exposure, and decreased MGST-like mRNA levels in the digestive gland after 96 h of exposure to the chemical. These findings suggested that exposure to DCOIT may alter the biochemical and molecular functioning of P. perna, which may harm the species.

Cytoplasmic glucose-6-phosphate dehydrogenase plays an important role in the silicon-enhanced alkaline tolerance in highland barley

Glucose-6-phosphate dehydrogenase (G6PDH), as a key enzyme in the pentose phosphate pathway, extensively responds to the biotic and abiotic stresses. In this study we focussed on the G6PDH role in the alleviation of alkaline stress induced by silicon (Si) in highland barley. Application of Si reduced the water loss and malondialdehyde (MDA) and reactive oxygen species (ROS) contents, improved the fresh weight, photosynthesis, K+ content, and the superoxide dismutase (SOD) and catalase (CAT) activities, thus alleviating the damage caused by alkaline stress. The G6PDH activity, especially the cytoplasmic G6PDH, significantly increased under alkaline stress, and was further stimulated by the addition of exogenous Si. Meanwhile, the levels of NADPH and reduced glutathione (GSH) showed similar profiles to G6PDH activity under NaHCO3 and NaHCO3 + Si treatments. The inhibition of G6PDH activity by glucosamine abolished the relieving effect of Si on alkaline stress, which was manifested in the increase of ROS and the decrease of GSH content. Together, our results suggest that Si-enhanced tolerance of alkaline stress may be related to the regulation of GSH levels by the cytoplasmic G6PDH in highland barley.

Effects of Diclofenac Versus Meloxicam in Pentylenetetrazol-Kindled Mice.

Epilepsy comes after stroke as the most common chronic neurological disorder worldwide. Inflammation enhances neuronal hyperexcitability that could provide a background setting for the development of epilepsy. The aim of this study was to assess the effect of valproate (VAL), diclofenac (DIC), meloxicam (MEL), VAL + MEL and VAL + DIC in pentylenetetrazol (PTZ) kindled mice. Seventy mice were randomly allocated into 7 equal groups; Control, PTZ, VAL, DIC, MEL, VAL + MEL and VAL + DIC groups. Kindling was induced by PTZ (40mg/kg, i.p.) injection every other day for 17days. The drugs were administered, 30min before each PTZ injection till the end of the schedule. Seizure score, latency, duration and mortality rate were recorded in all groups. Tumor necrosis factor- α (TNF-α), interleukin-1β (IL-1β), malondialdehyde (MDA) and prostaglandin E2 (PGE2) levels as well as reduced glutathione (GSH) content were assessed in brain homogenate at the end of the schedule. VAL, DIC, MEL, VAL + MEL and VAL + DIC decreased seizure score and duration. Meanwhile, they increased the latency period. PTZ increased TNF-α, IL-1β, MDA, and PGE2 levels meanwhile, it decreased GSH content. Administration of VAL, DIC, MEL, VAL + MEL and VAL + DIC decreased TNF-α, IL-1β, MDA, and PGE2 levels meanwhile, they increased GSH content in the brain homogenates. Effects of VAL + DIC combination on the studied parameters were significant in relation to VAL. VAL, DIC, MEL, VAL + MEL and VAL + DIC produced anticonvulsant effect and mitigated inflammation and oxidative stress in PTZ-kindled mice. Interestingly, DIC rather than MEL enhanced the anticonvulsant effect VAL.

Frataxin-deficient cardiomyocytes present an altered thiol-redox state which targets actin and pyruvate dehydrogenase

Friedreich ataxia (FA) is a cardioneurodegenerative disease caused by deficient frataxin expression. This mitochondrial protein has been related to iron homeostasis, energy metabolism, and oxidative stress. Previously, we set up a cardiac cellular model of FA based on neonatal rat cardiac myocytes (NRVM) and lentivirus-mediated frataxin RNA interference. These frataxin-deficient NRVMs presented lipid droplet accumulation, mitochondrial swelling and signs of oxidative stress. Therefore, we decided to explore the presence of protein thiol modifications in this model. With this purpose, reduced glutathione (GSH) levels were measured and the presence of glutathionylated proteins was analyzed. We observed decreased GSH content and increased presence of glutahionylated actin in frataxin-deficient NRVMs. Moreover, the presence of oxidized cysteine residues was investigated using the thiol-reactive fluorescent probe iodoacetamide-Bodipy and 2D-gel electrophoresis. With this approach, we identified two proteins with altered redox status in frataxin-deficient NRVMs: electron transfer flavoprotein-ubiquinone oxidoreductase and dihydrolipoyl dehydrogenase (DLDH). As DLDH is involved in protein-bound lipoic acid redox cycling, we analyzed the redox state of this cofactor and we observed that lipoic acid from pyruvate dehydrogenase was more oxidized in frataxin-deficient cells. Also, by targeted proteomics, we observed a decreased content on the PDH A1 subunit from pyruvate dehydrogenase. Finally, we analyzed the consequences of supplementing frataxin-deficient NRVMs with the PDH cofactors thiamine and lipoic acid, the PDH activator dichloroacetate and the antioxidants N-acetyl cysteine and Tiron. Both dichloroacetate and Tiron were able to partially prevent lipid droplet accumulation in these cells. Overall, these results indicate that frataxin-deficient NRVMs present an altered thiol-redox state which could contribute to the cardiac pathology.

Synergistic anti-atherosclerotic role of combined treatment of omega-3 and co-enzyme Q10 in hypercholesterolemia-induced obese rats

Hypercholesterolemia is a metabolic disorder associated with atherosclerosis. This study aimed to investigate the effects of omega-3 and/or coenzyme Q10 (CoQ10) on hypercholesterolemia-induced atherosclerosis. Rats were divided into five groups; (1): served as the negative control, (2): served as hypercholesterolemic (HC) control, (3): HC-rats administrated omega-3 orally, (4): HC-rats administrated CoQ10 orally, and (5): HC-rats administered the combination treatment of both omega-3 and CoQ10. Lipid profile was assayed and cardiovascular risk indices were calculated. Serum levels of Adiponectin (APN) and creatine kinase (CK-MB) were determined using ELISA. Besides, oxidative stress markers, malondialdehyde (MDA), nitric oxide (NO) and glutathione (GSH) were assayed in the heart homogenate. Histopathological investigation of the aortae and heart tissues were investigated. The results revealed that atherogenic HC-rats demonstrated a significant elevation in lipid profiles, except for HDL-C, along with decreased levels of APN, but increased CK-MB activities. Hypercholesterolemia increased lipid peroxidation, reduced NO production, and decreased GSH content in the cardiac tissue. Treatment of atherogenic HC-rats with omega-3 and/or CoQ10 improved dyslipidemia and ameliorated most of the HC-induced biochemical and histopathological changes. The histological observations of aortae and cardiac tissues validated our biochemical results. We concluded that the combined treatment of nutraceuticals such as omega-3 and CoQ10 demonstrated the best outcome, demonstrating their anti-hyperlipidemic, cardioprotective, and atheroprotective potentials. Together, this study supports a beneficial role of dietary co-administration of omega-3 and CoQ10 in obese patients who are prone to develop cardiovascular disorders.

Effects of Low Concentration Hydrogen Inhalation on Asthma and Sleep Function in Mice

This study was designed to investigate the effects of low concentration hydrogen inhalation on asthma and sleep function in mice and the potential mechanism. In the asthma experiment, BALB/c mice were randomly divided into normal control group, asthma model group and hydrogen treatment group. After establishing ovalbumin (OVA)-induced asthma model, the hydrogen treatment group mice were treated by inhalation of hydrogen (24-26 mL/L per day) for 7 consecutive days, and the normal control group and asthma model group mice received similar treatment by inhalation of air. The levels of interleukin (IL)-4, IL-13, and interferon-γ (IFN-γ) in bronchoalveolar lavage fluid (BALF) were measured by commercially available ELISA kits. The levels of malondialdehyde (MDA) and glutathione (GSH), as well as the activity of superoxide dismutase (SOD) in lung tissue were detected by colorimetric assays. The pathological changes in lung tissue were assessed by HE staining. In the sleep experiment, ICR mice were randomly divided into blank control group and 1 d, 3 d, 5 d hydrogen treatment groups and diazepam group. The effects of inhalation of 24-26 mL/L per day hydrogen on the sleep duration induced by intraperitoneal injection of upper-threshold dose of sodium pentobarbital and the sleep latency in response to subthreshold dose were evaluated. In the asthma experiment, the asthma model group showed higher levels of IL-4 and IL-13 ( P<0.05) and lower levels of IFN-γ ( P<0.001) in BALF, as compared to the normal control group. The content of MDA in lung tissue was also significantly increased ( P<0.01), companied by a decreased GSH concentration ( P <0.05) and a mildly reduced SOD activity ( P>0.05). Compared to the asthma model group, treatment with hydrogen significantly decreased the levels of IL-4 and IL-13 and increased the level of IFN-γ in BALF ( P<0.05). Moreover, without alteration of the MDA production ( P>0.05), hydrogen inhalation greatly increased GSH level and restored the SOD activity ( P<0.05) in lung tissue. Additionally, the HE staining data showed that the hydrogen treatment attenuated the pulmonary histopathological changes. In the sleep experiment, compared with the blank control group, the sleep latency was significantly shorter ( P<0.05) and the sleep duration was longer ( P<0.001) in all the hydrogen treatment groups after receiving an upper-threshold dose of sodium pentobarbital. Meanwhile, in all the hydrogen treatment groups, the sleep latency was significantly longer ( P<0.001) and the sleep duration was shorter ( P<0.001) when compared to the diazepam group. Compared with the blank control group, after intraperitoneal injection of a subthreshold dose of sodium pentobarbital, the sleep latency was significantly increased in both 1 d and 5 d hydrogen treatment groups, and there was no significant difference as compared to the diazepam group. In the 3 d hydrogen treatment group, the sleep latency was only slightly increased ( P>0.05), which was significantly lower than that of the diazepam group ( P<0.05). Low concentration hydrogen inhalation could alleviate OVA-induced asthma in mice, and the mechanism might be related to the anti-oxidative and anti-inflammatory effects of hydrogen. Also, low concentration hydrogen inhalation could improve sleep function in mice.

Sorafenib sensitizes melanoma cells to vemurafenib through ferroptosis.

BackgroundBRAF gene mutation causes melanoma patients to develop drug resistance after 8–9 months BRAF inhibitors treatment. Therefore, overcoming BRAF inhibitor resistance has important implications for improving patient survival. Sorafenib directly inhibits tumor cell proliferation by blocking the RAF/MEK/ERK-mediated cell signaling pathway. It remains unknown that whether the combination of sorafenib with vemurafenib could sensitize melanoma cells to vemurafenib, and the underlying mechanism needs to be clarified.MethodsVemurafenib resistant melanoma cells A375/Vem and SK-Mel-28/Vem were established by exposing to a series of concentration of vemurafenib. Cell viability was measured when A375 and SK-Mel-28 cells treated with vemurafenib or combined with sorafenib. Meanwhile the levels of Iron, GSH, MDA and reactive oxygen species (ROS) were detected. Finally we examined that whether sorafenib sensitizes melanoma cells to vemurafenib through ferroptosis.ResultsWe found that sorafenib sensitized melanoma cells to vemurafenib. Sorafenib treatment did not significantly alter the production of ROS and the content of iron, GSH and MDA in vemurafenib resistant cells, but cotreatment of sorafenib and vemurafenib dramatically upregulated ROS production, MDA and iron, but decreased GSH concentration. Interestingly, sorafenib strongly promoted vemurafenib-induced cell death, which was blocked by lipid peroxidation inhibitors ferrostatin-1 but not ZVAD-FMK or necrosulfonamid.ConclusionsSorafenib sensitized melanoma cells to vemurafenib by increasing ROS production through ferroptosis. Our study reveals that the combination of sorafenib may provide a novel strategy of vemurafenib resistant melanoma therapy.

Effects of waterborne exposure to cadmium on biochemical responses in the freshwater gastropod, Bellamya aeruginosa.

The biochemical responses of Bellamya aeruginosa as a dominant and widespread freshwater gastropod throughout China to waterborne cadmium (Cd) were investigated to explore the impacts of exposure concentration and duration in this potential sentinel species. After the 7 days' test of dosage-mortality relationship, gastropods were exposed for either 7 days at the LC50 (1.7mg/L), the LC10 (0.7mg/L) and 0.02mg/L Cd, or 28 days at 0.02mg/L Cd. A suite of biochemical indicators including metallothionein-like protein (MTLP), reduced glutathione (GSH), catalase (CAT), contents of tissue metal (Cd, Fe, Mn, Cu, Zn), and the compartments of these metals bound to MTLP were examined. The treatment of 0.02mg/L Cd led to the increase of Cd bound to MTLP (Cd-MTLP) levels, the decrease of GSH content, and the upregulation of CAT activity, but no induction of MTLP, indicating that the intrinsic MTLP and GSH worked together for the detoxification of Cd at the low exposure. When the exposure concentration increased, GSH was depleted severely and synthesis of MTLP was triggered, leading to a strong and significant relationship between MTLP level and Cd accumulation. At the lethal concentrations (1.7mg/L), both MTLP induction and CAT activity were inhibited while the proportion of Cd-MTLP to total Cd were increased, suggesting more intrinsic MTLP were utilized to sequester free Cd ions. Therefore, the content of Cd-MTLP in digestive glands of B. aeruginosa was recommended as a reliable biomarker for Cd contamination.

Antioxidant supplementation partially rescues accelerated ovarian follicle loss, but not oocyte quality, of glutathione-deficient mice†.

The tripeptide thiol antioxidant glutathione (GSH) has multiple physiological functions. Female mice lacking the modifier subunit of glutamate cysteine ligase (GCLM), the rate-limiting enzyme in GSH synthesis, have decreased GSH concentrations, ovarian oxidative stress, preimplantation embryonic mortality, and accelerated age-related decline in ovarian follicles. We hypothesized that supplementation with thiol antioxidants, N-acetyl cysteine (NAC), or α-lipoic acid (ALA) will rescue this phenotype. Gclm-/- and Gclm+/+ females received 0 or 80mM NAC in drinking water from postnatal day (PND) 21-30; follicle growth was induced with equine chorionic gonadotropin (eCG) on PND 27, followed by an ovulatory dose of human CG and mating with a wild type male on PND 29 and zygote harvest 20h after hCG. N-acetyl cysteine supplementation failed to rescue the low rate of second pronucleus formation in zygotes from Gclm-/- versus Gclm+/+ females. In the second study, Gclm-/- and Gclm+/+ females received diet containing 0, 150, or 600mg/kg ALA beginning at weaning and were mated with wild type males from 8 to 20 weeks of age. α-Lipoic acid failed to rescue the decreased offspring production of Gclm-/- females. However, 150mg/kg diet ALA partially rescued the accelerated decline in primordial follicles, as well as the increased recruitment of follicles into the growing pool and the increased percentages of follicles with γH2AX positive oocytes or granulosa cells of Gclm-/- females. We conclude that ovarian oxidative stress is the cause of accelerated primordial follicle decline, while GSH deficiency per se may be responsible for preimplantation embryonic mortality in Gclm-/- females.

Antioxidant System Response of Freshwater Mussel Anodontacygnea to Cadmium Exposure

Cadmium is one of the widespread toxic substances being hazardous for man as it capable to enter from the environment into animal and plant tissues and spreading along the food chain. We have studied the effect of Cd on the gills and hepatopancreas of the fresh water bivalve mollusks Anodontacygnea. After 12-day acclimation the mollusks were kept for 24 and 72 hours in aquariums with Cd2+ concentrations of 10, 50 and 100 μg/L. Mass-spectrometric analysis has shown that Cd accumulation rate increased with increasing metal concentration in the water. At cadmium concentration of 100 μg/L the mollusk was capable of accumulating up to 0.44 μg of Cd per day. The accumulation of such high metal concentrations in the mollusk tissues did not kill the animals, but signs of oxidative stress, more pronounced in the gills than in the digestive gland, were observed. Exposure to cadmium ions decreased GSH concentration and increase Рx activity in the mollusk gills as early as 24 hours after the beginning of the experiment. Changing the water in the aquarium had a considerable influence on SOD activity in the gills comparable with the effect of the addition of Cd.

Fullerene C60Nanoparticles Decrease Liver Oxidative Stress through Increment of Liver Antioxidant Capacity in Streptozotocin-Induced Diabetes in Rats

Chronic hyperglycemia causes oxidative stress in the liver and enhances the hepatic vulnerability to oxidative damage in diabetes mellitus. Since an excellent antioxidative stress property of fullerene C60 nanoparticles has been demonstrated in a wide range of in vitro and in vivo studies, we examined the effect of fullerene C60 nanoparticles on the oxidative stress markers in the liver of streptozotocin-induced diabetes in rats. Male Wistar rats were randomly divided into 4 groups (n = 8 for each group): normal, treated normal, diabetic, and treated diabetic groups. The rats were made diabetic by a single intravenous injection of streptozotocin (50 mg/kg). Treated (normal and diabetic) rats received orally fullerene C60 nanoparticles (1 mg/kg/day) by a gavage tube for 8 weeks. At termination of the study, the oxidative stress parameters were determined in liver tissues, including malondialdehyde (MDA) levels and the activities of catalase (CAT) and superoxide dismutase (SOD) as well as the content of the reduced form of glutathione (GSH). Treatment with fullerene C60 did not change blood glucose of normal and diabetic rats. Diabetes increased MDA levels and CAT activity but decreased GSH content in the liver. Fullerene C60 administration significantly decreased MDA levels and increased the activities of CAT and SOD as well as ameliorated the histopathological changes in the liver of diabetic rats. Taken together, the results of the present study indicated that fullerene C60 nanoparticles could decrease oxidative stress injury in the liver of diabetic rats likely through potentiation of the hepatic antioxidant capacity.

Vitamin C controls neuronal necroptosis under oxidative stress

Under physiological conditions, vitamin C is the main antioxidant found in the central nervous system and is found in two states: reduced as ascorbic acid (AA) and oxidized as dehydroascorbic acid (DHA). However, under pathophysiological conditions, AA is oxidized to DHA. The oxidation of AA and subsequent production of DHA in neurons are associated with a decrease in GSH concentrations, alterations in glucose metabolism and neuronal death. To date, the endogenous molecules that act as intrinsic regulators of neuronal necroptosis under conditions of oxidative stress are unknown. Here, we show that treatment with AA regulates the expression of pro- and antiapoptotic genes. Vitamin C also regulates the expression of RIPK1/MLKL, whereas the oxidation of AA in neurons induces morphological alterations consistent with necroptosis and MLKL activation. The activation of necroptosis by AA oxidation in neurons results in bubble formation, loss of membrane integrity, and ultimately, cellular explosion. These data suggest that necroptosis is a target for cell death induced by vitamin C.

Glutathione Deficiency and Alterations in the Sulfur Amino Acid Homeostasis during Early Postnatal Development as Potential Triggering Factors for Schizophrenia-Like Behavior in Adult Rats.

Impaired glutathione (GSH) synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Our research aimed to assess the effects of l-buthionine-(S,R)-sulfoximine (BSO), a GSH synthesis inhibitor, and GBR 12909, a dopamine reuptake inhibitor, administered alone or in combination, to Sprague–Dawley rats during early postnatal development (p5–p16), on the levels of GSH, sulfur amino acids, global DNA methylation, and schizophrenia-like behavior. GSH, methionine (Met), homocysteine (Hcy), and cysteine (Cys) contents were determined in the liver, kidney, and in the prefrontal cortex (PFC) and hippocampus (HIP) of 16-day-old rats. DNA methylation in the PFC and HIP and schizophrenia-like behavior were assessed in adulthood (p90–p93). BSO caused the tissue-dependent decreases in GSH content and alterations in Met, Hcy, and Cys levels in the peripheral tissues and in the PFC and HIP. The changes in these parameters were accompanied by alterations in the global DNA methylation in the studied brain structures. Parallel to changes in the global DNA methylation, deficits in the social behaviors and cognitive functions were observed in adulthood. Only BSO + GBR 12909-treated rats exhibited behavioral alterations resembling positive symptoms in schizophrenia patients. Our results suggest the usefulness of this neurodevelopmental model for research on the pathomechanism of schizophrenia.

Targeting AngII/AT1R signaling pathway by perindopril inhibits ongoing liver fibrosis in rat.

The renin-angiotensin system (RAS) has a substantial role in liver fibrosis, cirrhosis, and portal hypertension. Hence, targeting RAS through angiotensin-converting enzyme (ACE) inhibitors can mend hepatic fibrosis; the current study was designed to examine the potential fibrosis inhibition activity of perindopril using a rat model of liver fibrosis induced by thioacetamide (TAA). Four groups of rats were used throughout this study, Group I (control group); rats received the vehicle. TAA was used for inducing liver fibrosis in rats by intraperitoneal injection of 200-mg/kg body weight twice a week for 6 weeks. Group II served as (TAA group). Rats of Groups III and IV were given perindopril at doses of 2 and 8 mg/kg 2 weeks after TAA administration and continued concomitantly with TAA till the end of the experiment. Injection of TAA resulted in a significant increase in aminotransferases' activities and bilirubin with a significant decrease in serum albumin and total protein and a significant decrease in hepatic content of GSH and SOD. Additionally, TAA injection raised the hepatic content of TGF-β1, α-SMA, TNF-α, and level of MDA. Histological and immunohistochemical data presented marked fibrosis in liver sections of TAA-administrated rats with increased collagen deposition, elevated METAVIR scoring, and increased expression of α-SMA, caspase-3, and AT1R. Oral dosing of perindopril for 4 weeks concomitant with TAA could mend the altered parameters near to normal values and abolished the ongoing fibrosis extension. In conclusion, these results demonstrated that perindopril, as ACE inhibitor, could grant a superior remedial nominee in preventing liver fibrosis progression through targeting angiotensin II formation.

The role of DFO in Al (mal) (3)-induced ferroptosis in PC12 cells

Objective: To investigate the mechanism of Al (mal) (3)-induced ferroptosis in rat adrenal pheochromocytoma cells (PC12), to explore the effect of deferoxamine (DFO) . Methods: Taken PC12 cells growing at logarithmic phase and divided into 6 groups: control group, 200 μmol/L Al (mal) (3) group, 0.5% DMSO group, 200 μmol/L DFO group, Al (mal) (3)+DMSO group, Al (mal) (3)+DFO group. DMSO and DFO were added to the DMSO group and the Al (mal) (3)+DMSO group, the DFO group and the Al (mal) (3)+DFO group for 2 h, respectively, Al (mal) (3) was then added to the Al (mal) (3) group, Al (mal) (3)+DMSO group, and the Al (mal) (3)+DFO group to a final concentration of 200 μmol/L. The cell viability was detected by CCK8, the morphology and ROS levels of PC12 cells was observed by inverted microscope, the cell proliferation toxicity and intracellular iron ion content were detected by colorimetry, the GSH content and GSH-PX activity were detected by biochemical method. Results: Al (mal) (3) exposure significantly inhibited the growth of PC12 cells and destroyed the cell morphological structure, resulting in increased LDH activity and intracellular iron ion content in PC12 cells, decreased GSH content and GSH-PX activity, increased ROS levels; the combined treatment of Al (mal) (3)+DFO can significantly improve the cell viability of PC12 cells, improved cell morphology, decreased cell LDH activity and intracellular iron ion content (P>0.05), increased GSH content and GSH-PX activity, decreased ROS levels. Conclusion: Al (mal) (3) can induce ferroptosis in PC12 cells, DFO may inhibit ferroptosis by reducing intracellular iron levels and reducing oxidative damage.

Ameliorative Effect Of Zinc Oxide Nanoparticles Against Dermal Toxicity Induced By Lead Oxide In Rats.

BackgroundRecently, several studies demonstrate the possible role of zinc oxide (ZnO) in the protection of several skin diseases, but less is known about the role of ZnO nanoparticles in the inflammatory skin disease. So, this study was designed to confirm the pivotal role of the nano zinc oxide cream in the alleviation of lead oxide (PbO) induced-allergic dermatitis in rats.Materials and methodsTwo concentrations (1% and 6%) of ZnONPs creams were prepared and characterized prior to being used in the study. A total number of 30 male Wistar rats were randomly divided into six groups. Group 1 (negative control), groups 2&3 (either 1% or 6% ZnONPs control groups), group 4 (PbO), groups 5&6 (co-treatment of each ZnONPs concentration+PbO). All rats in different groups were observed daily to determine the severity of dermal gross lesions. Histopathological studies, mRNA analysis, and oxidative stress evaluations were performed on the affected skin tissue. Immunohistochemical studies were performed to evaluate the expression of cluster of differentiation CD4, CD8 and intercellular adhesion molecules ICAM-1 in different groups.ResultsPbO caused extensive skin oxidative damage manifested by a significant increase in MDA level with a decrease in GSH content and CAT activity. The results of histopathological and immunohistochemical examinations revealed that topical application of PbO for 14 days led to severe allergic dermatitis with remarkable elevations in the number of CD4+ T-helper, CD8+ T-cytotoxic lymphocytes, and ICAM-1 expression. On the other hand, noticeable improvements were recorded in all the previous toxicopathological parameters among the groups treated by either 1% or 6% ZnO-NPs cream. However, the best results were observed in the group treated with 1% ZnO-NPs cream.ConclusionOur findings suggest that 1% of ZnO-NPs cream is safe when applied topically on the inflamed skin. Moreover, it had anti-inflammatory and antioxidant effects so that, it is recommended to use the 1% ZnO-NPs cream to avert the dermal toxicity-induced by PbO.

Brain oxidative stress in rat with chronic iron or copper overload

Male rats of 80–90 g that were fed 42 days with a commercial rodent diet of 2780 kcal/100 g and received chronic overloads of either Fe(II) or Cu(II) in the drinking water. The two metals produced brain oxidative stress and damage with marked increases in the indicators of oxidative processes: in vivo brain surface chemiluminescence (the sensitive organ non-invasive assay for oxidative free radical reactions), and the ex vivo processes of phospholipid peroxidation and protein oxidation. Brain redox imbalance was also indicated by marked decreases in the cellular indicators of oxidative metabolic stress: reduced glutathione (GSH) content and reduced/oxidized glutathione ratio (GSH/GSSG). Brain decreased GSH content has a central role in the biochemical oxidative processes associated with Fe and Cu chronic damage. The understanding of biochemical oxidative imbalances in the rat brain with chronic Fe(II) or Cu(II) overloads may be useful for the establishment of pharmacological therapies for human pathologies associated to Fe and Cu cellular imbalances.

Influence of N-acetyl-L-cysteine against bisphenol a on the maturation of mouse oocytes and embryo development: in vitro study

BackgroundBisphenol A (BPA), an endocrine disruptor, is a widely used chemical that has adverse effects on animal development and reproduction. The current research aimed to evaluate the effect of BPA on the in vitro maturation (IVM) and subsequent embryo development of mouse oocytes following in vitro fertilization (IVF).MethodsIVM was performed in the presence of different concentrations (0, 20, 50, or 100 μg/mL) of BPA. Nuclear maturation, IVF efficiency and embryonic development were determined. The levels of reactive oxygen species (ROS) and glutathione (GSH) in the BPA (50 μg/mL) group were evaluated. We explored the ability of N-acetyl-L-cysteine (NAC) in the IVM medium to rescue the BPA-induced damage by examining changes in nuclear maturation, IVF rate, blastocyst formation, ROS levels and GSH content.ResultsCompared with the control, BPA (50 μg/mL) supplementation during oocyte IVM significantly inhibited nuclear maturation and decreased fertilization and blastocyst formation rates. In addition, BPA exposure increased ROS levels and decreased GSH content in oocytes. The addition of NAC weakened the BPA-induced suppression of nuclear maturation, relieved the BPA-induced downregulation of the fertilization and blastocyst formation rates, and mitigated the increased ROS levels and decreased GSH content.ConclusionBPA affects mouse oocyte maturation and subsequent early embryonic developmental competence following IVF by increasing intracytoplasmic oxidative stress in mature oocytes. NAC can reduce these harmful effects to a certain extent.