Oxidative Stress In Mice Research Articles

The effects of decabromodiphenyl ether on glycolipid metabolism and related signaling pathways in mice

Decabromodiphenyl ether (BDE-209), an addictive type flame retardant, is widely found in environments, and could affect the glycolipid metabolism. The present study was designed to investigate the potential mechanism of BDE-209 affecting glycolipid metabolism. Forty mice were randomly divided into four groups, and they were exposed to BDE-209 at dosages of 0, 7.5, 25 and 75 mg kg−1·d−1 for 28 d, respectively. The results showed that BDE-209 increased the serum levels of glucose, insulin, and triglyceride, also decreased the level of high-density lipoprotein, and damaged the structures of liver and adipose tissue in mice. BDE-209 significantly increased the protein expression of p-IRS, markedly decreased the expressions of PI3K, p-AKT, and GLUT4, significantly improved the lipid metabolism related factor expressions of p-mTOR, mTOR, PPARγ and RXRɑ, also inhibited the activity of antioxidant enzymes in the liver of mice. These results suggested that BDE-209 could affect glucose metabolism and inhibiting PI3K/AKT/GLUT4 signaling pathway resulting from improving the p-IRS expression, and interfered with lipid metabolism through activate mTOR/PPARγ/RXRα resulting from oxidative stress in mice.

Maltol Mitigates Thioacetamide-induced Liver Fibrosis through TGF-β1-mediated Activation of PI3K/Akt Signaling Pathway.

Our previous study has confirmed that maltol can attenuate alcohol-induced acute hepatic damage and prevent oxidative stress in mice. Therefore, maltol might have the capacity to improve thioacetamide (TAA)-induced liver fibrosis. The purpose of this work was to explore the antifibrotic efficacy and underlying mechanisms of maltol for TAA-treated mice. Progressive liver fibrosis was established with a dose-escalating protocol in which the mice received TAA intraperitoneal three times a week for a total duration of 9 weeks. The injection doses of TAA were 50 mg/kg for the first week, 100 mg/kg for the second and third weeks, and 150 mg/kg for the rest of the injections. Maltol with doses of 50 and 100 mg/kg was given by gavage after 4 weeks of intraperitoneal injection of TAA, respectively, once daily for 5 weeks. Results indicated that TAA intraperitoneal injection significantly increased serum activities of alanine aminotransferase (ALT) (52.93 ± 13.21 U/L vs 10.22 ± 3.36 U/L) and aspartate aminotransferase (AST) (67.58 ± 25.84 U/L vs 39.34 ± 3.89 U/L); these elevations were significantly diminished by pretreatment with maltol. Additionally, maltol ameliorated TAA-induced oxidative stress with attenuation in MDA ( p < 0.05 or p < 0.01) content; evident elevation in the GSH levels, GSH/GSSG ratio ( p < 0.05 or p < 0.01), and superoxide dismutase (SOD) ( p < 0.01); and restored liver histology accompanied by a decrease of α-smooth muscle actin (α-SMA) expression. Furthermore, maltol significantly suppressed the transforming growth factor-β1 (TGF-β1) expression and the PI3K/Akt pathway. This study suggested that maltol alleviated experimental liver fibrosis by suppressing the activation of HSCs and inducing apoptosis of activated HSCs through TGF-β1-mediated PI3K/Akt signaling pathway. These findings further clearly suggested that maltol is a potent therapeutic candidate for the alleviation of liver fibrosis.

Taurine Supplementation Ameliorates Arsenic-Induced Hepatotoxicity and Oxidative Stress in Mouse.

We previously reported that taurine treatment inhibited arsenic (As)-induced apoptosis in the liver of mice. This study was designed to explore the effect of taurine on liver function and its underlying mechanism in As-exposed mice. Mice were randomly divided into 3 groups, ten mice in each group. Group 1, control group, only orally received drinking water alone. Group 2, As intoxication group, was exposed to 4mg/L As2O3 via drinking water for 60days. Group 3, taurine protection group, was treated with 4mg/L As2O3 and 150mg/kg both. Taurine administration significantly revered the increases of alanine transaminase (ALT) and aspartate transaminase (AST) activities in serum. The decrease of glutathione (GSH) was inhibited with taurine treatment in the liver of As-exposed mice. At the same time, taurine significantly inhihibited As-induced enhancement of malondialdehyde (MDA) in the liver. Here we show that taurine protective effect on liver function in As-exposed mice maybe involve lipid peroxidation.

Hepatoprotective and antioxidant potential of radish seed aqueous extract on cadmium-induced hepatotoxicity and oxidative stress in mice

Background: Exposure to cadmium (Cd) is a major environmental pollutant that causes injury on many organs and tissues, particularly the liver. However, the protection of radish seed aqueous extract (RSE) against hepatic injury in Cd-exposed mice yet remains unclear. Objective: The research aimed to investigate the mitigation effect of RSE against Cd-induced hepatotoxicity in experimental animals. Materials and Methods: The mice were administered intraperitoneally with Cd Chloride (CdCl2, 75 mg/kg b. wt) as a positive control to compare RSE. The hepatic function and antioxidant status were assessed in liver tissue of poisoned and control mice. Results: Levels of serum hepatic enzymes (aspartate transaminase: AST and alanine transaminase: ALT) as well as total bilirubin were significantly increased in Cd-exposed mice. In addition, Cd exposure elicited enhancement of oxidative stress level. Co-treatment with RSE (200 and 400 mg/kg b. wt) significantly decreased the serum levels of liver function biomarkers. Furthermore, RSE treatment showed a significant reduction of lipid peroxidation and increase of enzyme and glutathione concentrations. Histopathological analysis was parallel to these biochemical findings. Conclusion: The results clearly demonstrated that RSE is effective for ameliorating hepatic cytotoxicity and oxidative damage arising from Cd exposure. Abbreviations used: Cd: Cadmium; ROS: Reactive oxygen species; RS: Radish seed; RSE: Radish seed aqueous extract; HPLC: High-performance liquid chromatography; SAE: Sulforaphene; SFE: Sulforaphene; TFC: Total flavonoids content; TPC: Total phenolics content; AST: Glutamic-oxalacetic transaminase; ALT: Glutamic pyruvic transaminase; TB: Total bilirubin; MDA: Malondialdehyde; CAT: Catalase; GPX: Glutathione peroxidase; NOx: Nitrates and nitrites; NO: Nitric oxide; LRS: Low dose of radish seed extract; HRS: High dose of radish seed extract; LPO: Lipid peroxidation; ONOO−: Peroxynitrite radical; iNOS: Nitric oxide synthase.

C-glycosyl flavonoid orientin alleviates learning and memory impairment by radiofrequency electromagnetic radiation in mice via improving antioxidant defence mechanism

Objective: To investigate the antioxidant efficacy of oral orientin on 900 MHz radiofrequency-electromagnetic radiation-induced oxidative stress in mice. Methods: The mice were randomly allotted into 5 groups consisting of 7 mice each. The deionised water and radiofrequency electromagnetic radiations (RF-EMR) groups were administered with deionised water while orientin was administered to the RF-EMR + low dose of orientin group (10 mg/kg), RF-EMR + high dose of orientin group (20 mg/kg) and high dose of orientin group (20 mg/kg). All the groups except deionised water and high dose groups were exposed to 900 MHz radiofrequency-electromagnetic radiation for 28 consecutive days (1 h/day). Learning and memory was assessed via the step-down inhibitory avoidance task. Activities of lipid prexidation and antioxidant enzymes were measured using kits. Results: Radiofrequency electromagnetic radiation caused impairment in learning and memory and reduced activities of brain antioxidant enzymes, increased lipoperoxidation and corticosterone concentration as well as histopathological aberrations in the hippocampal tissues. Conversely, orientin alleviated learning and memory deficit, improved the activities of endogenous antioxidant enzymes and mitigated brain lipoperoxidation and neuronal degeneration in mice exposed to radiofrequency electromagnetic radiation. Conclusions: Orientin alleviates learning and memory impairment due to radiofrequency electromagnetic radiation in mice by improving antioxidant defence mechanism and may be considered as a promising therapeutic agent for improving the antioxidant system of people living in radiofrequency electromagnetic radiation-prone environment.

Osteonecrosis of the jaws caused by bisphosphonate treatment and oxidative stress in mice.

Aging is a significant risk factor for the development of bisphosphonate-related osteonecrosis of the jaws (BRONJ). Accumulating evidence suggests that bone aging is associated with oxidative stress (OS), and OS is associated with osteonecrosis. To elucidate the mechanisms of the onset of BRONJ, the present study focused on OS and the effects of treatment with the pro-oxidant DL-buthionine-(S,R)-sulfoximine (BSO), an oxidative stressor, on healing of a surgically induced penetrating injury of the palate. Six-week-old C57BL/6J mice were randomly divided into four groups (n=5 each) and treated with or without zoledronic acid (ZOL) and with or without BSO (experimental groups: ZOL, BSO, and ZOL+BSO; control group: saline solution). A penetrating injury of the midline palate was surgically created using a root elevator. ZOL (250 µg/kg/day) was injected intraperitoneally every day from 7 days prior to the surgical treatment to 4 days following the surgical treatment. BSO (500 µg/kg/day) was administered 7 days prior to the surgical treatment as a single intraperitoneal injection. The maxillae were harvested at 5 days following the surgical treatment for histological and histochemical studies. The presence of empty osteocyte lacunae in the palatal bone was increased by ZOL and BSO treatment. The highest number of empty osteocyte lacunae was observed in the ZOL+BSO group. The number of tartrate-resistant acid phosphatase-positive cells was decreased by ZOL treatment and increased by BSO treatment. The number of canaliculi per osteocyte lacuna was significantly decreased by BSO treatment. The mineral apposition rate was significantly lower in the treatment groups than the control group. Bisphosphonates and OS suppressed bone turnover. The present study has demonstrated that BSO treatment affects osteocytes, and OS in osteocytes exacerbates impairment of the osteocytic canalicular networks. As a result, bisphosphonates and OS may induce osteonecrosis following invasive dentoalveolar surgery. OS has been identified as an additional risk factor for the development of BRONJ.

MicroRNA-140-5p aggravates hypertension and oxidative stress of atherosclerosis via targeting Nrf2 and Sirt2.

In the present study, the function of microRNA (miR)-140-5p on oxidative stress in mice with atherosclerosis was investigated. A reverse transcription-quantitative polymerase chain reaction assay was used to determine the expression of miR-140-5p. Oxidative stress kits and reactive oxygen species (ROS) kits were used to analyze alterations in oxidative stress and ROS levels. The alterations in protein expression were determined using western blot analysis and an immunofluorescence assay. miR-140-5p expression was increased in mice with atherosclerosis with hypertension. Consistently, miR-140-5p expression was also increased in mice with atherosclerosis. Upregulation of miR-140-5p increased oxidative stress and ROS levels by suppressing the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuin 2 (Sirt2), Kelch-like enoyl-CoA hydratase-associated protein 1 (Keap1) and heme oxygenase 1 (HO-1) in vitro. By contrast, downregulation of miR-140-5p decreased oxidative stress and ROS levels by activating the protein expression of Nrf2, Sirt2, Keap1 and HO-1 in vitro. Sirt2 agonist or Nrf2 agonist inhibited the effects of miR-140-5p on oxidative stress in vitro. Collectively, these results suggested that miR-140-5p aggravated hypertension and oxidative stress of mice with atherosclerosis by targeting Nrf2 and Sirt2.

Protective effect of N-acetylcysteine on MK-801-induced testicular oxidative stress in mice

Experimental studies indicate that MK-801 causes organ injury in schizophrenic mice testes although it is molecular mechanism has not been clearly defined. In this study, we investigated the probable protective effect of N-Acetylcysteine (NAC) against MK-801- induced testicular toxicity in mice. In total, 24 Balb/C male mice were divided into 4 equal groups: the animals in the control group (vehicle treated) were intraperitoneally given 10 mL/kg/day saline solution, the animals in the experiment groups were intraperitoneally given 1 mg/kg/day MK-801 alone, 100 mg/kg/day NAC alone and MK-801 by 1 mg/kg/day for 14 days. The level of the testes’ total oxidant status (TOS) in mice that were treated with MK-801 was significantly higher than those level in the other groups while the total antioxidant status (TAS) levels decreased. In comparison to the MK-801 group, the TOS levels were lower, and the TAS levels increased in the MK-801 + NAC group. In the morphometric analysis, the diameter and epithelial height of the seminiferous tubules of the testes showed no significant changes after MK-801 administration. Conversely, the weights of the testes decreased significantly. In the treatment with NAC, the weights of testes significantly increased in comparison to the MK-801 group. The histopathological examination revealed necrobiotic and degenerative changes in the epithelial cells, vacuole formation within the seminiferous tubules, a decrease in the number of the spermatozoid, and disorganization in the basement membrane of the seminiferous tubules in the MK-801 group in comparison to the control group. Administration of NAC alleviated several negative effects of MK-801 on the testicular damage in mice. In conclusion, our results showed that NAC protected the mice against the testicular toxicity of MK-801 when it was administrated intraperitoneally.

Ginsenoside Rd contributes the attenuation of cardiac hypertrophy in vivo and in vitro

Cardiac hypertrophy are the major health challenges in the whole world. Ginsenoside Rd is an important component of cell growth and tumorigenesis, but the role and mechanism of ginsenoside Rd in pressure overload induced cardiac dysfunction and remodeling are still not fully illuminated. Here, cardiac hypertrophic remodeling and dysfunction were induced by pressure overload in mice. Myocardial histology was detected by Masson's trichrome staining and hematoxylin-eosin staining (H&E). Western blot was used to detect protein levels of signal mediators. Cardiac function was evaluated by echocardiography, and qPCR analysis was used to detect mRNA expression of hypertrophy and fibrosis markers. Cardiomyocyte size was detected by Wheat germ agglutinin (WGA) staining. Dihydroethidine (DHE) staining was used to detect oxidative stress. We also detected the influence of Ginsenoside Rd on rat neonatal cardiac myocytes (NRCMs) treated by Phenylephrine (PE). Our results showed that Ginsenoside Rd significantly improved pressure overload induced contractile dysfunction, fibrosis, cardiac hypertrophy, inflammation and oxidative stress in mice. Moreover, protein levels of AKT, calcineurin A, ERK1/2 and TGF-β1 were significantly decreased in the Ginsenoside Rd-treated hearts as compared to control. Ginsenoside Rd treated in cardiomyocytes inhibited PE-induced cardiomyocyte hypertrophy. These results revealed that ginsenoside Rd improved cardiac dysfunction and remodeling induced by pressure overload, which is related to the inhibition of a variety of signaling pathways.

Hyperoxia reduces salivary secretion by inducing oxidative stress in mice

Objective: The aim of this study was to determine the effects of prolonged hyperoxia on salivary glands and salivary secretion in mice.Design: Male C57BL/6 J mice were kept in a 75% oxygen chamber (hyperoxia group) or a 21% oxygen chamber for 5 days. We measured the secretion volume, protein concentration, and amylase activity of saliva after the injection of pilocarpine. In addition, we evaluated the histological changes induced in the submandibular glands using hematoxylin and eosin and Alcian blue staining and assessed apoptotic changes using the TdT-mediated dUTP nick end labeling (TUNEL) assay. We also compared the submandibular gland expression levels of heme oxygenase-1 (HO-1), superoxide dismutase (SOD)-1, and SOD-2 using the real-time polymerase chain reaction.Results: In the hyperoxia group, salivary secretion was significantly inhibited at 5 and 10 min after the injection of pilocarpine, and the total salivary secretion volume was significantly decreased. The salivary protein concentration and amylase activity were also significantly higher in the hyperoxia group. In the histological examinations, enlargement of the mucous acini and the accumulation of mucins were observed in the submandibular region in the hyperoxia group, and the number of TUNEL-positive cells was also significantly increased in the hyperoxia group. Moreover, the expression levels of HO-1, SOD-1, and SOD-2 were significantly higher in the hyperoxia group.Conclusion: Our results suggest that hyperoxia reduces salivary secretion, and oxidative stress reactions might be involved in this.

Protective effects of Aporosa octandra bark extract against D-galactose induced cognitive impairment and oxidative stress in mice

Aporosa octandra (Buch.-Ham. ex D.Don) Vickery is a native species of India. Different parts of the plant are used for the medicinal purpose by the tribal peoples of south-eastern part of India. However, the biological properties of A. octandra have not been studied well. The extracts obtained from the bark of A. octandra were evaluated to determine their protective effect on cognitive impairment and oxidative stress in mice induced by D-galactose using the standard protocol. Different dosages of extract AOE-4 (100, 200, and 300 mg/kg, p.o.) were administered to mice, which were previously treated for six weeks with D-galactose (100 mg/kg s.c.). The D-galactose-induced mice showed significantly impaired cognitive behavior, i.e., oxidative defense, compared to the sham group. Six weeks of treatment with A. octandra extract AOE-4 (100, 200 and 300 mg/kg, p.o.) considerably improved the cognitive behavior and oxidative impairment of mice compared to the control alone (D-galactose). For the phytochemical investigation, the bark of A. octandra was successively extracted with dichloromethane and methanol. The chemical constituents of A. octandra were isolated by multiple column chromatography and characterized by different spectral analyses. (R)-Coclaurine (AO-5), an alkaloid, was isolated along with two other compounds from the AOE-4 extract; three more compounds were also isolated from the AOE-1 extract of the bark of A. octandra. All the compounds were isolated for the first time from the bark of A. octandra, and their structures were established by detailed spectral studies. The structure of compound AO-5 was also investigated and confirmed by X-ray diffraction and DFT studies. This study highlights the protective effect of A. octandra bark extract against D-galactose-induced biochemically dysfunction in mice. (R)-Coclaurine (AO-5) was isolated as one of the major components of A. octandra bark from AOE-4 extract; this compound could be further evaluated for the development of new potential drug candidates.

Tartrazine induced oxidative damage in mice liver and kidney

Tartrazine is an azo dye which is widely used as colorant in foods, drugs and cosmetics.The aim of this study was to investigate the effect of tartrazine on biochemical and oxidative stress biomarkers on Swiss mice. Tartrazine was administered in drinking water at doses of 0%, 0.005% and 0.05% for 90 days. Both doses of tartrazine declined the body weight gain. In contrary, high dose increased glucose, total cholesterol (TC), triglycerides (TG), LDL, LDL/HDL and CT/HDL, transaminases, total protein (TP), total and direct bilirubin, , urea, creatinine, sodium and potassium levels. However, high dose of tartrazine decreased HDL, chloride, phosphorus and magnesium levels, whereas, tartrazine decreased calcium levels only in female. Both doses of tartrazine declined total antioxidant capacity. Protein carbonyls were in-creased in liver and kidney whith high dose. Liver and kidney superoxide dismutase (SOD) was decreased in male at low and high doses. However, liver SOD was reduced only in female at high dose. Oral administration of tartrazine affects liver and kidney functions as well as induces oxidative stress in mice. So, tartrazine consumption might be harmful to human health. It is necessary that people should be carefully consumed foods containing tartrazine.

Decreased plasma neuregulin 4 levels are associated with peripheral neuropathy in Chinese patients with newly diagnosed type 2 diabetes: A cross-sectional study

Neuregulin-4 (Nrg4) is a novel adipokine associated with obesity, hyperglycemia, insulin resistance, dislipidemia, inflammation, and oxidative stress in mice and humans. However, no report has demonstrated the relationship of circulating Nrg4 with diabetic peripheral neuropathy (DPN). The objective of our study was to investigate the relationship between circulating Nrg4 and DPN in a cross-sectional study. Circulating Nrg4 levels were determined with an enzyme-linked immunosorbent assays kit in 132 newly diagnosed type 2 diabetes mellitus (nT2DM) patients and 41 normal controls (NC group). The associations of circulating Nrg4 with other parameters were also analyzed. Circulating Nrg4 levels were significantly lower in nT2DM patients with no DPN than in NC subjects, and were further markedly decreased in nT2DM patients with DPN (P < 0.01 or P < 0.05). Circulating Nrg4 levels were progressively decreased with an increasing number of abnormal DPN screening (P for trend < 0.01). Circulating Nrg4 levels correlated negatively with 8-iso-prostaglandin F2α (8-iso-PGF2α), high-sensitivity C-reactive protein (hs-CRP) and vibration perception threshold (VPT) (all P < 0.01), and 8-iso-PGF2α, hs-CRP, glycated hemoglobin A1c and VPT were independently related factors to circulating Nrg4 in nT2DM patients (P < 0.01 or P < 0.05). Moreover, circulating Nrg4 was significantly associated with the development of DPN even after controlling for anthropometric, biochemical and clinical parameters. Additionally, the analysis of receiver operating characteristic curves revealed that the best cutoff value for circulating Nrg4 to predict DPN was 1.58 ng/mL (sensitivity 90.91%, specificity 54.55%, and area under the curve 0.716). These findings together suggested that circulating Nrg4 levels were reduced in DPN patients and Nrg4 may be a novel adipokine associated with inflammation, oxidative stress, and long-term glycemic control in nT2DM patients.

Histopathological Changes Caused by Inflammation and Oxidative Stress in Diet-Induced-Obese Mouse following Experimental Lung Injury

Obesity has been identified as a risk factor for adverse outcomes of various diseases. However, information regarding the difference between the response of obese and normal subjects to pulmonary inflammation is limited. Mice were fed with the control or high-fat diet to establish the lean and diet-induced obese (DIO) mice. Escherichia coli was intranasally instilled to reproduce non-fatal acute pneumonia model. After infection, serum samples and lung tissues were obtained at 0, 12, 24, and 72 h. DIO mice exhibited increased serum triglyceride (TG) and total cholesterol (TC) contents as well as pulmonary resistin, IL-6, and leptin levels compared with lean mice. E. coli infection caused an acute suppurative inflammation in the lung with increased lung index and serum TG and TC contents; elevated pulmonary tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, and leptin levels; and oxidative stress in mice. Interestingly, almost all the above-mentioned parameters peaked at 12 h after infection in the lean-E. coli group but after 12 h in the DIO-E. coli group. These results indicated that the DIO mice presented a delayed inflammatory response and oxidative stress in non-fatal acute pneumonia induced by E. coli infection.

Hypolipidemic, Antioxidant, and Antiapoptotic Effects of Polysaccharides Extracted from Reishi Mushroom, Ganoderma lucidum (Leysser: Fr) Karst, in Mice Fed a High-Fat Diet.

The mechanisms underlying the effect of Ganoderma lucidum (Reishi mushroom) polysaccharides (GLP) on obesity are not clear. In this study, GLP were found to attenuate the oleic acid-induced cell viability loss and apoptosis dose dependently in splenic lymphocytes in vitro. The effects of GLP on lipid metabolism, oxidative stress, and apoptosis in mice fed a high-fat diet (HD) were determined. GLP administration (200 and 400 mg/kg bw) significantly lowered the body-weight increases; liver, heart, and white adipose tissues indexes; serum lipid accumulation; and serum and small intestine oxidative stress in mice fed a HD. Moreover, GLP inhibited HD-induced apoptosis by decreasing the Bax/Bcl-2 ratio and suppressing caspase-3 activation in splenic lymphocytes. These findings indicate that GLP can exert hypolipidemic, antioxidant, and antiapoptotic effects in HD-induced obese mice.

Effect of Anti-IL17 Antibody Treatment Alone and in Combination With Rho-Kinase Inhibitor in a Murine Model of Asthma.

Background: Interleukin-17 (IL-17) and Rho-kinase (ROCK) play an important role in regulating the expression of inflammatory mediators, immune cell recruitment, hyper-responsiveness, tissue remodeling, and oxidative stress. Modulation of IL-17 and ROCK proteins may represent a promising approach for the treatment of this disease.Objective: To study the effects of an anti-IL17 neutralizing antibody and ROCK inhibitor treatments, separately and in combination, in a murine model of chronic allergy-induced lung inflammation.Methods: Sixty-four BALBc mice, were divided into eight groups (n = 8): SAL (saline-instilled); OVA (exposed-ovalbumin); SAL-RHOi (saline and ROCK inhibitor), OVA-RHOi (exposed-ovalbumin and ROCK inhibitor); SAL-anti-IL17 (saline and anti-IL17); OVA-anti-IL17 (exposed-ovalbumin and anti-IL17); SAL-RHOi-anti-IL17 (saline, ROCK inhibitor and anti-IL17); and OVA-RHOi-anti-IL17 (exposed-ovalbumin, anti-IL17, and ROCK inhibitor). A 28-day protocol of albumin treatment was used for sensitization and induction of pulmonary inflammation. The anti-IL17A neutralizing antibody (7.5 μg per treatment) was administered by intraperitoneal injection and ROCK inhibitor (Y-27632) intranasally (10 mg/kg), 1 h prior to each ovalbumin challenge (days 22, 24, 26, and 28).Results: Treatment with the anti-IL17 neutralizing antibody and ROCK inhibitor attenuated the percentage of maximal increase of respiratory system resistance and respiratory system elastance after challenge with methacholine and the inflammatory response markers evaluated (CD4+, CD8+, ROCK1, ROCK2, IL-4, IL-5, IL-6, IL-10 IL-13, IL-17, TNF-α, TGF-β, NF-κB, dendritic cells, iNOS, MMP-9, MMP-12, TIMP-1, FOXP3, isoprostane, biglycan, decorin, fibronectin, collagen fibers content and gene expression of IL-17, VAChT, and arginase) compared to the OVA group (p < 0.05). Treatment with anti-IL17 and the ROCK inhibitor together resulted in potentiation in decreasing the percentage of resistance increase after challenge with methacholine, decreased the number of IL-5 positive cells in the airway, and reduced, IL-5, TGF-β, FOXP3, ROCK1 and ROCK2 positive cells in the alveolar septa compared to the OVA-RHOi and OVA-anti-IL17 groups (p < 0.05).Conclusion: Anti-IL17 treatment alone or in conjunction with the ROCK inhibitor, modulates airway responsiveness, inflammation, tissue remodeling, and oxidative stress in mice with chronic allergic lung inflammation.

Chronic psychosocial defeat differently affects lipid metabolism in liver and white adipose tissue and induces hepatic oxidative stress in mice fed a high-fat diet.

It is widely accepted that chronic stress may alter the homeostatic mechanisms of body weight control. In this study, we followed the metabolic changes occurring in mice when chronic stress caused by psychosocial defeat (CPD) is associated with ad libitum exposure to a palatable high-fat diet (HFD). In this model, CPD mice consumed more HFD than unstressed (Un) mice without gaining body weight. We focused on metabolic processes involved in weight control, such as de novo lipogenesis (DNL), fatty acid β-oxidation (FAO), and thermogenesis. The activity and expression of DNL enzymes were reduced in the liver and white adipose tissue of mice consuming the HFD. Such effects were particularly evident in stressed mice. In both CPD and Un mice, HFD consumption increased the hepatic expression of the mitochondrial FAO enzyme carnitine palmitoyltransferase-1. In the liver of mice consuming the HFD, stress exposure prevented accumulation of triacylglycerols; however, accumulation of triacylglycerols was observed in Un mice under the same dietary regimen. In brown adipose tissue, stress increased the expression of uncoupling protein-1, which is involved in energy dissipation, both in HFD and control diet-fed mice. We consider increased FAO and energy dissipation responsible for the antiobesity effect seen in CPD/HFD mice. However, CPD associated with HFD induced hepatic oxidative stress.-Giudetti, A. M., Testini, M., Vergara, D., Priore, P., Damiano, F., Gallelli, C. A., Romano, A., Villani, R., Cassano, T., Siculella, L., Gnoni, G. V., Moles, A., Coccurello, R., Gaetani, S. Chronic psychosocial defeat differently affects lipid metabolism in liver and white adipose tissue and induces hepatic oxidative stress in mice fed a high-fat diet.

Mitohormesis in Mice via Sustained Basal Activation of Mitochondrial and Antioxidant Signaling

Transient mitochondrial stress can promote beneficial physiological responses and longevity, termed "mitohormesis." To interrogate mitohormetic pathways in mammals, we generated mice in which mitochondrial superoxide dismutase 2 (SOD2) can be knocked down in an inducible and reversible manner (iSOD2-KD mice). Depleting SOD2 only during embryonic development did not cause post-natal lethality, allowing us to probe adaptive responses to mitochondrial oxidant stress in adult mice. Liver from adapted mice had increased mitochondrial biogenesis and antioxidant gene expression and fewer reactive oxygen species. Gene expression analysis implicated non-canonical activation of the Nrf2 antioxidant and PPARγ/PGC-1α mitochondrial signaling pathways in this response. Transient SOD2 knockdown in embryonic fibroblasts from iSOD2-KD mice also resulted in adaptive mitochondrial changes, enhanced antioxidant capacity, and resistance to a subsequent oxidant challenge. We propose that mitohormesis in response to mitochondrial oxidative stress in mice involves sustained activation of mitochondrial and antioxidant signaling pathways to establish a heightened basal antioxidant state.

Flavonoid-Rich Fraction of Ocimum gratissimum Attenuates Lipopolysaccharide-Induced Sickness Behavior, Inflammatory and Oxidative Stress in Mice.

Ocimum gratissimum L. leaves has been traditionally used for management of febrile illnesses and symptoms typified of sickness behavior. In this work we investigated the modulatory effect of flavonoid-rich fraction of O. gratissimum leaves (EAFOg) on sickness behavior, inflammatory and oxidative stress responses in LPS-challenged mice. O. gratissimum leaf was first extracted with n-hexane, chloroform and methanol, and EAFOg was obtained by ethylacetate partitioning of a sequentially resultant methanol extract. The effect of EAFOg (25-100 mg/kg) on acute LPS-induced neurobehavioral impairment in an open field test (OFT) and depressive-like behavior in forced swimming test (FST) was investigated. Serum nitrite and TNF-α, as well as myeloperoxidase (MPO), malondialdehyde (MDA), and reduced glutathione (GSH) levels were determined in liver and brain tissues. EAFOg prevented the reduction in locomotor and rearing activity in OFT and the increase in immobility time in FST. The fraction significantly attenuated the elevation of serum TNF- α and nitrite levels. EAFOg reversed LPS-induced increase in MDA, MPO, and nitrite levels and attenuated GSH depletion in liver and brain tissues of mice. Flavonoid-rich fraction of O. gratissimum leaf demonstrated significant modulation of LPS-induced sickness behavior, inflammatory and oxidative stress response in mice. This suggests an important therapeutic strategy in slowing down LPS-mediated hepatic and neuronal disease processes.

Synergistic action of ursolic acid and metformin in experimental model of insulin resistance and related behavioral alterations

Chronic restraint stress (CRS) is known to cause metabolic and neurological complications in a number of ways. Prolonged exposure to stress evident by increased corticosterone level led to impaired altered insulin signaling and oxidative stress in mice, in the present study. Impaired insulin signaling or insulin resistance was characterized by hyperglycemia, hyperinsulinemia, hyperlipidemia, hypoadiponectinemia, increased glycosylated haemoglobin and HOMA-IR. It was also associated with increased proinflammatory cytokine TNF-α levels. CRS also caused significant increase in acetylcholinesterase activity and oxidative stress in brain along with cognitive impairment in behavioral test. Ursolic acid, metformin, gliclazide and their combinations when administered daily for 30 days significantly improved insulin sensitivity apart from behavioral and biochemical alterations in stressed mice. Treatment with drugs also decreased serum corticosterone and TNF-α levels. The findings of our study revealed that improvement in insulin sensitivity, learning and cognitive performance in stressed mice was attributed to attenuation of proinflammatory cytokines and oxidative stress. Moreover, combination of [Metformin (150 mg/kg) + Ursolic acid (10 mg/kg)] produced enhanced improvement in insulin sensitivity and cognitive impairment as compared to their individual effects, suggesting possibly the common mode of anti-inflammatory and antioxidant mechanisms.