Uric acid is negatively associated with cognition in the first- episode of schizophrenia.

BACKGROUND: We explored the relationship between levels of serum uric acid (UA) and cognitive impairment in people with schizophrenia to order to better protect and improve cognitive function in such patients. METHODS: A uricase method evaluated serum UA levels in 82 individuals with first-episode schizophrenia and in 39 healthy controls. The Brief Psychiatric Rating Scale (BPRS) and the event-related potential P300 were used to assess the patient's psychiatric symptoms and cognitive functioning. The link between serum UA levels, BPRS scores, and P300 was investigated. RESULTS: Prior to treatment, serum UA levels and latency N3 in the study group were significantly higher than in the control group, whereas the amplitude P3 was considerably lower. After therapy, the study group's BPRS scores, serum UA levels, latency N3, and amplitude P3 were lower than before treatment. According to correlation analysis, serum UA levels in the pre-treatment study group significantly positively correlated with BPRS score and latency N3 but not amplitude P3. After therapy, serum UA levels were no longer substantially related to the BPRS score or amplitude P3 but strongly and positively correlated with latency N3. CONCLUSIONS: First-episode schizophrenia patients have higher serum UA levels than the general population which partly reflects poor cognitive performance. Improving patients' cognitive function may be facilitated by lowering serum UA levels.

Protective effect of Enicostemma axillare - Swertiamarin on oxidative stress against nicotine-induced liver damage in SD rats.

OBJECTIVE: The current investigation was aimed to determine the hepatoprotective benefits of Swertiamarin (ST) administration against nicotine-induced hepatotoxicity in SD rats. MATERIAL AND METHODS: A total of 48 adult male SD rats were allocated into six groups using a fully randomised approach. As a control, group I was given oral (PO) normal saline. For 65 days, the animals in groups II, III, IV, V and VI received 2.5mg/kg/day of nicotine intraperitoneally (IP), 100mg/kg/day of ST orally (PO), 200mg/kg/day of ST orally (PO), 2.5mg/kg/day of nicotine (IP)+100mg/kg/day of ST (PO), and 2.5mg/kg/day of nicotine (IP)+200mg/kg/day of ST (PO), respectively. Animals were killed on 66thday, liver tissue was removed and used for histopathological analysis as well as biochemical testing (oxidative stress parameters and liver function enzymes). RESULTS: When compared to control animals, the animals in group II showed a substantial rise in their aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine levels (P˂0.001). Furthermore, compared to control animals, these animals displayed enhanced hepatic oxidative stress as indicated by significantly higher Malondialdehyde (MDA) levels (P˂0.001) and lower levels of Catalase (CAT), Glutathione (GSH), Glutathione peroxidase (GSH-Px) and Superoxide dismutase (SOD) (P˂0.001). Further, more histological anomalies were seen in the liver of nicotine-treated rats compared to control rats, including significant vacuolization, poor tissue architecture, the growth of pycnotic nuclei, and dilated sinusoids. Contrary to nicotine-treated rats, the co-administration of ST and nicotine was observed to prevent the abnormalities caused by nicotine (groups V and VI). CONCLUSION: The results of the current study show that nicotine can seriously harm liver tissue and that swertiamarin can prevent the harmful effects of nicotine on rat liver. Future research is necessary to delve deeply into the mechanisms behind swertiamarin protective impact against nicotine-induced hepatotoxicity.

Reproducible method for assessing the effects of blue light using in vitro human skin tissues.

INTRODUCTION: High-intensity visible light (HEV), also referred to as blue light, has a wavelength of 400-500 nm and accounts for approximately one-third of the visible light. Blue light is also emitted from electronic devices and artificial indoor lighting. Studies have shown that exposure of human skin cells to light emitted from electronic devices, even as short as 1 h, can cause an increase in reactive oxygen species (ROS), apoptosis and necrosis. Despite comprising a significant portion of the light spectrum, the effects of HEV light have not been studied as extensively. This is in part due to a lack of suitable in vitro testing methods. This work was conducted in order to develop a reproducible testing method for assessing the effects of blue light on the skin. METHODS: Testing was performed using a full thickness, 3D in vitro skin tissue model. Different exposure protocols were tested to (1) determine the biological effects of blue light on the skin and (2) to identify an appropriate exposure for routine testing of cosmetic materials that may protect the skin from blue light damage. Gene expression and protein biomarkers were measured using qPCR, ELISA and immunohistochemical (IHC) methods. RESULTS: Our work demonstrates that daily exposure to blue light produced dose-and-time-dependent changes in biomarkers associated with skin damage. Exposure to blue light for 6 h for 5 consecutive days (total intensity of 30 J/cm2 ) increased the expression of genes that regulate inflammation and oxidative stress pathways and decreased the expression of genes that maintain skin barrier and tissue integrity. Exposure to blue light significantly increased protein biomarkers associated with ageing, inflammation and tissue damage. IHC staining confirmed changes in collagen, filaggrin and NQO1 protein expression. Treatment with ascorbic acid inhibited the effects of blue light, demonstrating a role in protection from blue light. CONCLUSION: Our results showed that consistent blue light exposure produced skin damage via alterations in biological pathways that are associated with skin ageing. This work provides a new, reproducible in vitro testing method for assessing the effects of blue light on human skin using gene expression, protein ELISA and IHC staining.

INTRODUCTION: La lumière visible à haute énergie (VHE), également appelée lumière bleue, a une longueur d'onde de 400 à 500 nm et représente environ un tiers de la lumière visible. La lumière bleue est également émise par les appareils électroniques et l'éclairage intérieur artificiel. Des études ont montré que l'exposition des cellules cutanées humaines à la lumière émise par les appareils électroniques, même pour une période de seulement 1 h, peut entraîner une augmentation des dérivés réactifs de l'oxygène (DRO), de l'apoptose et de la nécrose. Bien qu'ils représentent une partie importante du spectre lumineux, les effets de la lumière VHE n'ont pas été étudiés aussi largement. Cela est en partie dû à un manque de méthodes de test in vitro appropriées. Ces travaux ont été réalisé afin de développer une méthode de test reproductible pour évaluer les effets de la lumière bleue sur la peau. MÉTHODES: Les tests ont été réalisés à l'aide d'un modèle de tissu cutané 3D in vitro de pleine épaisseur. Différents protocoles d'exposition ont été testés pour (1) déterminer les effets biologiques de la lumière bleue sur la peau et (2) identifier une exposition appropriée pour les tests de routine des produits cosmétiques susceptibles de protéger la peau des dommages causés par la lumière bleue. L'expression génique et les biomarqueurs protéiques ont été mesurés à l'aide des méthodes de PCR quantitative, de dosage par la méthode immuno-enzymatique ELISA et immunohistochimiques (IHC). RÉSULTATS: Nos travaux démontrent que l'exposition quotidienne à la lumière bleue a produit des modifications dépendantes de la dose et du temps dans les biomarqueurs associés aux lésions cutanées. L'exposition à la lumière bleue pendant 6 h au cours de 5 jours consécutifs (intensité totale de 30 J/cm2) a augmenté l'expression des gènes qui régulent l'inflammation et les voies du stress oxydatif, et a diminué l'expression des gènes qui maintiennent la barrière cutanée et l'intégrité tissulaire. L'exposition à la lumière bleue a significativement augmenté les biomarqueurs protéiques associés au vieillissement, à l'inflammation et aux lésions tissulaires. La coloration par IHC a confirmé les modifications de l'expression du collagène, de la filaggrine et de la protéine NQO1. Le traitement par acide ascorbique a inhibé les effets de la lumière bleue, démontrant un rôle dans la protection contre la lumière bleue. CONCLUSION: Nos résultats ont montré qu'une exposition continue à la lumière bleue produisait des lésions cutanées par le biais d'altérations des voies biologiques associées au vieillissement de la peau. Ces travaux fournissent une nouvelle méthode de test in vitro reproductible pour évaluer les effets de la lumière bleue sur la peau humaine à l'aide de l'expression des gènes, du test ELISA de détection de protéines et de la coloration IHC.

Stem bark chloroform extract of Bombax costatum Pellegr. & Vuillet exhibit anticonvulsant and neuroprotective effects in pentylenetetrazole-induced seizures in rats.

AIM OF THE STUDY: The study aimed at evaluating the potentials of stem bark extracts of Bombax costatum (B. costatum) on seizure, pentylenetetrazole (PTZ) induced kindling and associated changes in wistar albino rats. MATERIALS AND METHODS: Phase 1 evaluated which extract of B. costatum (chloroform, ethanol and n-hexane) is most effective in preventing seizure in acute PTZ-induced (85mg/kg) seizure in rats. Phase 2 evaluated the potentials of stem bark chloroform extract of B. costatum in PTZ-kindled rats at a dose 250 and 500mg/kg in comparison to diazepam. As its effects on memory, oxidative stress markers, neurotransmitters and brain histology were evaluated. Phase 3 determined the probable curative effects of B. costatum on fully kindled rats. RESULTS: In phase 1, Chloroform extract of B. coststum 500mg/kg is the most effective (P<0.05) in preventing seizure as compared to ethanol and n-hexane extracts. In phase 2, chloroform extract of B. costatum delayed the development of kindling, improved kindling associated cognitive impairment and alterations of glutamate and gamma-aminobutyric acid (GABA). Further, it attenuated oxidative stress besides the maintenance of neuronal architecture of the hippocampus. CONCLUSION: Conclusively, chloroform stem bark extract of B. costatum antagonizes PTZ-induced seizure progression, protects against kindling induced cognitive impairment and oxidative stress. Additionally, it also increases the brain level of GABA at high dose and prevented against kindling-induced hippocampal disruptions. Hence, this justifies its use traditionally in the treatment of epileptic seizures.

Cadmium chloride generates cytotoxic reactive species that cause oxidative damage and morphological changes in human erythrocytes.

Cadmium chloride (CdCl2) is a widely used industrial compound that exhibits multiple organ toxicity. Cadmium is transported through blood where erythrocytes are exposed to its action. Here the effect of CdCl2 on human erythrocytes was examined under in vitro conditions. Human erythrocytes were treated with 0.01-0.5 mM CdCl2 for 24 h at 37 °C. Lysates were made from CdCl2 treated and untreated (control) cells and used for further analysis. CdCl2 treatment resulted in marked hemolysis of erythrocytes and oxidation of hemoglobin to methemoglobin. This will result in anemia and also reduce the oxygen carrying ability of erythrocytes. Hemoglobin oxidation was accompanied by degradation of heme and release of free ferrous iron moiety. Further analysis showed elevated lipid hydroperoxides and formation of advanced oxidation protein products along with reduction in total sulfhydryl content, indicating the generation of oxidative stress condition in the cell. Incubation of erythrocytes with CdCl2 enhanced generation of reactive oxygen and nitrogen species, decreased the antioxidant power and inhibited pathways of glucose metabolism. Plasma membrane was damaged as indicated by enhanced osmotic fragility and inhibition of membrane bound enzymes. This was confirmed by electron microscopy which showed formation of echinocytes. These results show that CdCl2 generates reactive species which impair the antioxidant system resulting in oxidative damage to erythrocytes.

Hemostasis and oxidative stress in chronic kidney disease in children and adolescents.

Chronic kidney disease (CKD) can be defined as the progressive loss of renal function, characterized by a decreased glomerular filtration rate (GFR). The etiology of CKD in childhood is mainly associated with congenital anomalies of the kidneys and urinary tract (CAKUT) and with glomerular diseases. The goal of this study was to investigate the hemostasis and oxidative stress in pediatric CKD of different etiologies. Fifty-four CKD children and adolescents and 52 controls were enrolled in this study. The evaluation of hemostasis was carried out by determination of D-dimer (D-Di) and plasminogen activator inhibitor (PAI-1) plasma levels, while oxidative stress was evaluated by thiobarbituric acid reactive substance (TBARS) levels, protein carbonyl content, plasma antioxidant capacity (MTT), and ascorbate. The D-Di was increased in CAKUT stage 3 or 4 patients compared with those with glomerular disease. PAI-1 was increased in patients with glomerular disease compared with CAKUT. Carbonyl protein content was higher in the control group compared with glomerular disease stage 3 or 4 patients. Our findings showed that the reduction in GFR is associated with a state of hypercoagulability. The analysis of integrated networks showed an expansion of connections among hemostatic and oxidative stress markers in CKD children and adolescents compared with controls.

Low-dose spironolactone abates cardio-renal disorder by reduction of BAX/inflammasome expression in experimentally induced polycystic ovarian syndrome rat model.

The impact of low-dose spironolactone (LSPL) on polycystic ovarian syndrome (PCOS)-associated cardio-renal disorder is unknown. Therefore, the present study hypothesized that LSPL would ameliorate cardio-renal disorders in experimental PCOS animals. Eight-week-old female Wistar rats were allotted into three groups. The control group received vehicle (distilled water; per os (p.o.)), the letrozole (LET)-treated group designated as PCOS group received LET (1 mg/kg; p.o.), and PCOS+LSPL received LET and LSPL (0.25 mg/kg, p.o.). The treatment was done once daily for 21 days uninterrupted. The experimental PCOS rats were characterized with insulin resistance, as well as elevated testosterone and luteinizing hormone/follicle-stimulating hormone, with a significant increase in cardiac and renal lipid profile, oxidative stress, inflammatory biomarkers (nuclear factor-κB and tumor necrosis factor-α), lactate dehydrogenase and lactate content and decrease in cardiac and renal antioxidant system (glutathione peroxidase and reduced glutathione) compared with the control rats. In addition, immunohistochemical assessment of cardiac and renal tissue showed significant expression of inflammasome and B-cell lymphoma-2 associated X-protein (BAX) in animals with PCOS. Nevertheless, these perturbations were attenuated following the administration of LSPL. Collectively, the present results suggest that LSPL attenuates PCOS-associated cardio-renal disorders by reduction of oxidative stress and BAX/inflammasome expression.

Potential role of d-chiro-inositol in reducing oxidative stress in the blood of nonobese women with polycystic ovary syndrome.

d-chiro-Inositol (DCI), an isomer of inositol, possesses antioxidative and endothelial protective properties. Possibly due to a deficiency of insulin mediators, polycystic ovary syndrome (PCOS) is often associated with insulin resistance (IR) and hyperinsulinemia, likely responsible for an elevated production of reactive oxygen species. We investigated oxidative-related alterations of inositol in the blood of women with PCOS before and after treatment with DCI. A total of 38 normal-weight PCOS women were investigated before and after DCI administration (500 mg/day for 12 weeks; n = 38) by evaluating serum testosterone, serum androstenedione, fasting serum insulin, fasting serum glucose, and parameters of IR. From the blood, we determined biomarkers of oxidative stress: superoxide anion radicals, hydrogen peroxide, nitric oxide, and the index of lipid peroxidation. The activity of catalase and superoxide dismutase and the reduced glutathione (GSH) content in the hemolysate were also assessed. Data showed that PCOS patients' plasma underwent oxidative stress, as indicated by the higher level of prooxidants and reduced cytosolic GSH content. DCI treatment significantly improved the metabolic parameters. Also, serum values of testosterone were reduced. In conclusion, PCOS patients suffer from a systemic oxidative stress that induces endothelial dysfunction. Treatment with DCI is effective in reducing hormonal, metabolic, and oxidative abnormalities in PCOS patients by improving IR.

Transgenerational impact of topical steroid application on superoxide dismutase activities of hypothalamus-pituitary-adrenal axis in rats.

Topical steroids (TS) have been widely prescribed since the 1950s. This study investigated for the first time the transgenerational effects of TS on the antioxidant mechanism of the hypothalamus-pituitary-adrenal (HPA) axis, both in prenatal and infancy. Three generations (F1, F2, and F3) and prenatal group (P) were investigated in both sexes with two different time points; P45th and P75th day were accepted as puberty and early adulthood, respectively. Clobetasol propionate 0.05% was used as TS. Quantitative real-time PCR was performed to expressional analyses of Sod1, Sod2, and Sod3 genes in the HPA tissues. The Sod mRNA expression of the HPA belonging to P and F1 groups revealed similar results in both genders. The downregulation in the adrenal Sod level was determined in P and F1, F2, and F3 generations in both genders, especially in females (p < 0.05). The Sod activities in the pituitary of all groups were downregulated in female rats (p < 0.05). Interestingly, in male rats, Sod2 and Sod3 were not expressed in the pituitary compared with the control on the day P45, while Sod2 and Sod3 expressions were determined in all the groups on day P75. Sod1 overexpression was found in pituitary and hypothalamus of males in the F3 generation. This study showed that TS applied in infancy had a transgenerational adverse effect on antioxidant defense mechanisms, especially in the adrenal gland.

Wnt/ß-catenin inhibitor pyrivinium attenuates cisplatin-induced acute kidney injury by possibly reducing platinum uptake and accumulation mediated by reduced organic cation transporter-2 expressions.

Aberrant activation of Wnt/ß-catenin induces renal dysfunction by initiating pro-apoptotic cascades, fibrosis, oxidative and inflammatory burden. This study tested the therapeutic effects of Wnt/ß-catenin inhibitor pyrvinium against cisplatin-induced acute kidney injury (AKI) in rats. Cisplatin was administered at a single dose of 5 mg/kg (i.p.) and renal cisplatin accumulation and uptake in cortical slices were determined after the fifth day by atomic absorption spectroscopy. Levels of pro-inflammatory cytokines were checked by ELISA, and organic cation transporter-2 (OCT-2) transcription and expression in renal tissue were evaluated by RT-PCR and immunohistochemical technique. Cisplatin administration produced renal dysfunction manifested as increase in serum creatinine, blood urea nitrogen, proteinuria, reduced clearance and electrolyte imbalance. Oxidative stress indices, pro-inflammatory cytokines, fibronectin, and caspase-3 activity were elevated in cisplatin-challenged rats. Moreover, increased renal OCT-2 transcription and immunostaining were detected in cisplatin kidneys which resulted in platinum accumulation. Additional docking studies depicted strong interaction between the ß-catenin and OCT-2 protein. These manifestations induced mitochondrial dysfunction, histological damage and fibrosis. Notably, Wnt/ß-catenin inhibitor pyrvinium (60 µg/kg; p.o.) treatment reduced the renal OCT-2 gene transcription causing a decline in platinum levels. Thus, the present study concludes that Wnt/ß-catenin inhibition attenuates cisplatin-induced AKI in rats, partly by down-regulating OCT-2 expression.

Senescence and oxidative stress toxicities induced by lamivudine and tenofovir in Drosophila melanogaster.

BACKGROUND: Lamivudine and tenofovir disoproxil fumarate act against the replication of hepatitis B and human immunodeficiency viruses via inhibition of the reverse transcriptase enzyme activity, thereby preventing the synthesis of viral DNA. Chronic administration of these drugs has been associated with toxicities, including senescence, oxidative stress and premature death. A study of these toxicities in Drosophila melanogaster, which share 75% genomic similarity with humans could help to develop a pharmacologic intervention. METHODS: Susceptibility of D. melanogaster for lamivudine and tenofovir-induced toxicities were investigated. First, flies (≤3 days old) were fed with drugs-supplemented diet at varying concentrations (1mg to 300mg/10-gram diet) or distilled water for seven days to determine LD50. Secondly, five groups of 60 flies were fed with four concentrations of test drugs: 2.9mg, 5.82mg, 11.64mg and 23.28mg each per 10-gram diet for 28 days survival and lifespan assays. Then 5-day treatment plan was utilized to determine drugs toxicities on climbing ability and some biomarkers of oxidative stress. Finally, molecular docking was carried out using the Auto-dock vina mode to predict the biological interactions between the test drugs and D. melanogaster acetylcholinesterase (AChE) or glutathione-S-transferase (GST). RESULTS: The LD50 of lamivudine or tenofovir was 47.07 or 43.95mg/10g diet, respectively. Each drug significantly (P<0.05) reduced the survival rate, longevity and climbing performance of the flies dose-dependently. These drugs also altered levels of biochemical parameters: AChE, GST, superoxide dismutase (SOD), catalase (CAT), total thiol (T-SH), and malondialdehyde (MDA) of the flies significantly (P<0.05). In silico molecular analysis showed that the test drugs interacted with significantly (P<0.05) higher binding affinities at the same catalytic sites of D. melanogaster GST and AChE compared with substrates (glutathione or acetylcholine). CONCLUSION: The significant lamivudine and tenofovir-induced toxicities observed as increased mortality, climbing deficits and compromised antioxidant defence in D. melanogaster demands further research for possible pharmacological intervention.

Evaluation of antioxidant potential of Heliotropium bacciferum Forssk extract and wound healing activity of its topical formulation in rat.

Wound healing is a dynamic process that occurs in the tissue under the skin. During this process, oxidative stress biomarkers are excessively produced, which finally lead to inflammation and cellular damage. In this study, efforts have been made to evaluate the antioxidant effect and wound healing activity topical formulation containing Heliotropium bacciferum Forssk extract. The in vitro antioxidant properties were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activities and the ferric reducing antioxidant power (FRAP) assay. The herbal ointments (2.5% w/w and 5% w/w) were prepared from the hydroalcoholic extract of H. bacciferum Forssk and administrated on the induced wounds in Wistar rats. The chromatic assay, percentage of wound contraction, and histopathological studies were used for evaluating the wound healing activity. For the evaluation of reactive oxygen species (ROS), catalase (CAT) activity, superoxide dismutase (SOD), and glutathione (GSH) levels were examined. The DPPH method showed tremendous radical scavenging activities at the corresponding concentrations with EC50 value of 80µg/mL. Topical application of the ointment (5% w/w) showed the highest wound contraction in comparison to the positive control (treated with CICALFATE™) and the control group (treated with normal saline). Similarly, the histological study of the group treated with the extract ointment (5% w/w) showed full collagen tissue deposition with a complete epidermal regeneration. The results of the assessment of GSH levels as well as CAT and SOD activities in the treated group (5% w/w) confirmed the scavenging property of the extract ointment. Our findings indicated the proper wound healing impact of the topical formulation of H. bacciferum Forssk due to its notable antioxidant capacity.

7-Chloro-4-(phenylselanyl) quinoline reduces renal oxidative stress induced by oxaliplatin in mice.

The object of this study was to evaluate the relationship between oxidative damage induced by oxaliplatin (OXA) and the therapeutic potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) in kidney of mice. Mice received OXA (10 mg/kg) or vehicle intraperitoneally (days 0 and 2). Oral administration of 4-PSQ (1 mg/kg) or vehicle was performed on days 2 to 14. On day 15 the animals were euthanized and the kidneys and blood were collected. The effect of OXA and (or) 4-PSQ on urea, thiobarbituric acid reactive species, nonprotein thiol (NPSH), and protein carbonyl (PC) levels were investigated. Moreover, renal superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), δ-aminolevulinic acid dehydratase (δ-ALA-D), and Na+,K+ ATPase activities were evaluated. Our findings revealed an increase on urea levels and significant renal oxidative damage in OXA-induced mice. OXA exposure increased SOD, GPx, and GST activities and caused a reduction on NPSH levels and CAT and GR activities. Na+,K+ ATPase and δ-ALA-D activities were reduced by OXA. 4-PSQ decreased plasmatic urea levels and renal oxidative damage. SOD, GPx, CAT, GR, and Na+,K+ ATPase activities were restored by 4-PSQ. 4-PSQ may be a good prototype for the treatment of OXA-induced renal injury.

Inducible nitric oxide synthase (iNOS) mediates ethanol-induced redox imbalance and upregulation of inflammatory cytokines in the kidney.

Overexpression of the inducible isoform of the enzyme nitric oxide synthase (iNOS) has been associated to pathological processes in the kidney. Ethanol consumption induces the renal expression of iNOS; however, the contribution of this enzyme to the deleterious effects of ethanol in the kidney remains elusive. We examined whether iNOS plays a role in the renal dysfunction and oxidative stress induced by ethanol consumption. With this purpose, male C57BL/6 wild-type (WT) or iNOS-deficient (iNOS-/-) mice were treated with ethanol (20% v/v) for 10 weeks. Treatment with ethanol increased the expression of Nox4 as well as the concentration of thiobarbituric acid reactive substances and the levels of tumor necrosis factor α in the renal cortex of WT but not iNOS-/- mice. Augmented serum levels of creatinine and increased systolic blood pressure were found in WT and iNOS-/- mice treated with ethanol. WT mice treated with ethanol showed increased production of reactive oxygen species and myeloperoxidase activity, but these responses were attenuated in iNOS-/- mice. We concluded that iNOS played a role in ethanol-induced oxidative stress and pro-inflammatory cytokine production in the kidney. These are mechanisms that may contribute to the renal toxicity induced by ethanol.

mTOR inhibition as a possible pharmacological target in the management of systemic inflammatory response and associated neuroinflammation by lipopolysaccharide challenge in rats.

Neuroinflammation plays a critical role during sepsis triggered by microglial activation. Mammalian target of rapamycin (mTOR) has gained attraction in neuroinflammation, however, the mechanism remains unclear. Our goal was to assess the effects of mTOR inhibition by rapamycin on inflammation, microglial activation, oxidative stress, and apoptosis associated with the changes in the inhibitor-κB (IκB)-α/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α) pathway activity following a systemic challenge with lipopolysaccharide (LPS). Rats received saline (10 mL/kg), LPS (10 mg/kg), and (or) rapamycin (1 mg/kg) intraperitoneally. Inhibition of mTOR by rapamycin blocked phosphorylated form of ribosomal protein S6, NF-κB p65 activity by increasing degradation of IκB-α in parallel with HIF-1α expression increased by LPS in the kidney, heart, lung, and brain tissues. Rapamycin attenuated the increment in the expression of tumor necrosis factor-α and interleukin-1ß, the inducible nitric oxide synthase, gp91phox, and p47phox in addition to nitrite levels elicited by LPS in tissues or sera. Concomitantly, rapamycin treatment reduced microglial activation, brain expression of caspase-3, and Bcl-2-associated X protein while it increased expression of B cell lymphoma 2 induced by LPS. Overall, this study supports the hypothesis that mTOR contributes to the detrimental effect of LPS-induced systemic inflammatory response associated with neuroinflammation via IκB-α/NF-κB/HIF-1α signaling pathway.

Rosuvastatin corrects oxidative stress and inflammation induced by LPS to attenuate cardiac injury by inhibiting the NLRP3/TLR4 pathway.

Rosuvastatin has been found to possess antioxidant and anti-inflammatory properties. The aim of the current study was to evaluate whether rosuvastatin was effective in attenuating cardiac injury in lipopolysaccharide (LPS) - challenged mice and H9C2 cells and identify the underlying mechanisms, focusing on the nod-like receptor protein 3 (NLRP3)/toll-like receptor 4 (TLR4) pathway. Cardiac injury, cardiac function, apoptosis, oxidative stress, inflammatory response, and the NLRP3/TLR4 pathway were evaluated in both in vivo and in vitro studies. LPS-induced cardiomyocyte injury was markedly attenuated by rosuvastatin treatment, evidenced by increased cell proliferation of H9C2 cells, rescued cardiac function, and improved morphological changes in mice and reduced lactate dehydrogenase (LDH), creatine kinase MB fraction (CK-MB), and troponin I (cTnI) in serum. Apoptosis was clearly ameliorated in myocardial tissue and H9C2 cells co-treated with rosuvastatin. In addition, after LPS challenge, excessive oxidative stress was present, indicated by increases in malondialdehyde (MDA) content, NADPH activity, and reactive oxygen species (ROS) production and decreased superoxide dismutase (SOD) activity. Rosuvastatin improved all the indicators of oxidative stress, with an effect similar to that of N-acetylcysteine (NAC) (an ROS scavenger). Notably, LPS-exposed H9C2 cells and mice showed significant NLRP3 and TLR4/nuclear factor-κB (NF-κB) pathway activation and inflammatory responses. Administration of rosuvastatin reduced the increases in NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), pro-caspase-1, TLR4, and p65 expression and decreased the tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), IL-18, and IL-6 contents, with an effect similar to that of MCC950 (an NLRP3 inhibitor). In conclusion, inhibition of the inflammatory response and oxidative stress contributes to cardioprotective effect of rosuvastatin against cardiac injury induced by LPS, and the effect of rosuvastatin was achieved through inactivation of the NF-κB/NLRP3 pathway.

4,4'-Dichloro-diphenyl diselenide modulated oxidative stress that differently affected peripheral tissues in streptozotocin-exposed mice.

Streptozotocin (STZ) is a substance used experimentally to induce a diabetes model, a metabolic disease associated with oxidative tissue damage. This study evaluated if 4-4'-dichloro-diphenyl diselenide (p-ClPhSe)2 modulates oxidative stress in peripheral tissues of diabetic mice. Male Swiss mice received a single STZ injection (i.p.) at a dose of 200 mg/kg or its vehicle and were treated with (p-ClPhSe)2 (7 days, 5 mg/kg) or metformin (200 mg/kg, twice per day). After, the mice were euthanized to collect liver, kidney, and skeletal muscle samples. In the liver, (p-ClPhSe)2 reduced thiobarbituric acid reactive substances (TBARS) and protein carbonyl levels and normalized the superoxide dismutase activity in STZ-treated mice. In the kidney, (p-ClPhSe)2 reversed the increase in the reactive species levels but not the catalase (CAT) activity reduction in STZ-treated mice. There was no evidence of oxidative damage in the skeletal muscle of STZ-treated mice, but an increase in the CAT activity and a reduction in non-protein thiol levels were found. (p-ClPhSe)2 did not reverse a decrease in hepatic and renal δ-aminolevulinic acid dehydratase activity in STZ-treated mice. The results show that the liver and kidney of STZ-treated mice were more susceptible to oxidative stress. This study reveals that (p-ClPhSe)2 modulated oxidative stress, which differently affected peripheral tissues of diabetic mice.

Molecular hydrogen downregulates acute exhaustive exercise-induced skeletal muscle damage.

Physical exercise-induced skeletal muscle damage may be characterized by increased oxidative stress, inflammation, and apoptosis which may be beneficial when exercise is regular, but it is rather harmful when exercise is exhaustive and performed acutely by unaccustomed individuals. Molecular hydrogen (H2) has emerged as a potent antioxidant, anti-inflammatory, and anti-apoptotic agent, but its action on the deleterious effects of acute exhaustive exercise in muscle damage remain unknown. Therefore, we tested the hypothesis that H2 decreases acute exhaustive exercise-induced skeletal muscle damage of sedentary rats. Rats ran to exhaustion on a sealed treadmill inhaling an H2-containing mixture or the control gas. We measured oxidative stress (SOD, GSH, and TBARS), inflammatory (TNF-α, IL-1ß, IL-6, IL-10, and NF-κB phosphorylation), and apoptotic (expression of caspase-3, Bcl-2, and HSP70) markers. Exercise caused no changes in SOD activity but increased TBARS levels. H2 caused increases in exercise-induced SOD activity and blunted exercise-induced increased TBARS levels. We observed exercise-induced TNF-α and IL-6 surges as well as NF-κB phosphorylation, which were blunted by H2. Exercise increased cleaved caspase-3 expression, and H2 reduced this response. In conclusion, H2 effectively downregulates muscle damage, reducing oxidative stress, inflammation, and apoptosis after acute exhaustive exercise performed by an unaccustomed organism.

CF3-substituted diselenide modulatory effects on oxidative stress, induced by single and repeated morphine administrations, in susceptible tissues of mice.

Studies reveal that oxidative stress is associated with adverse effects of long-term morphine treatment. The m-trifluoromethyl-diphenyl diselenide (CF3) is a multi-target organoselenium compound that has antioxidant properties in different experimental models. This study aimed to investigate the CF3 effects against redox imbalance in peripheral and central tissues of mice, after single or multiple morphine doses. Swiss male mice received a single dose of morphine (5 mg/kg, s.c.) and CF3 (10 mg/kg, i.g.), or morphine was repeatedly injected (5 mg/kg, s.c.) and CF3 (10 mg/kg, i.g.) administered twice daily for 7 days. Oxidative stress was determined in the hippocampus, liver, and kidney. CF3 reversed the increase in reactive species caused by single and multiple morphine doses in the peripheral tissues. CF3 increased hepatic non-protein thiol levels and the superoxide dismutase (SOD) activity decreased by a single morphine dose. CF3 reversed the reduction in SOD activity in the kidney of mice repeatedly exposed to morphine. The study demonstrates that peripheral tissues were more susceptible than the hippocampus to oxidative stress induced by morphine in mice. The results show that CF3 modulated parameters of oxidative stress modified by single and multiple morphine administrations in peripheral and central tissues of mice.

Early predictive blood markers of hemorrhagic stroke - influence of cytoflavin therapy.

Examination of the patterns of free-radical processes (FRP) and changes of the early screening markers to predict the course of hemorrhagic stroke (HS) and applied pathophysiologically based therapy can be of great practical importance. This study aimed to determine early changes in the parameters of oxidative stress and routine biochemistry blood tests in patients with HS and to assess their relationship with clinical outcome. The effects of early applied cytoflavin were also investigated. The prospective study included 151 patients with HS. Forty-eight percent of patients in the standard conservative therapy were given cytoflavin antioxidant energy therapy from the first day of hospitalization. The neurological status, neuroimaging, biochemical blood tests and FRP were assessed on days 1, 5, 10, and 20 of hospitalization. In patients with HS, an imbalance of all stages of FRP was detected proportionately to the severity of HS. The malondialdehyde concentration above 5.3 µmol/L, the number of leukocytes above 15 800, glucose above 11.9 mmol/L, lactate dehydrogenase above 574 IU/L, and lactate above 2.5 mmol/L, detected on the first day, predetermined a high risk of death. Additional cytoflavin treatment allowed stabilizing the clinical laboratory picture of HS, improved the treatment results, and reduced hospital mortality rate.