Oropouche virus infection induces ROS production and oxidative stress in liver and spleen of mice.

Oropouche virus (OROV) is the aetiological agent of Oropouche fever, the symptoms of which are common to most arboviruses, such as fever, headache, malaise, nausea and vomiting. More than half a million people have been infected with OROV since its isolation in 1955. Although Oropouche fever is classified as a neglected and emerging disease, to date, there are no antiviral drugs or vaccines available against the infection and little is known about its pathogenicity. Therefore, it is essential to elucidate the possible mechanisms involved in its pathogenesis. Since oxidative stress plays a pivotal role in the progression of various viral diseases, in this study, redox homeostasis in the target organs of OROV infection was evaluated using an animal model. Infected BALB/c mice exhibited reduced weight gain, splenomegaly, leukopenia, thrombocytopenia, anaemia, development of anti-OROV neutralizing antibodies, increased liver transaminases, and serum levels of pro-inflammatory cytokines tumour necrosis factor (TNF-α) and interferon-γ (IFN-γ). The OROV genome and infectious particles were detected in the liver and spleen of infected animals, with liver inflammation and an increase in the number and total area of lymphoid nodules in the spleen. In relation to redox homeostasis in the liver and spleen, infection led to an increase in reactive oxygen species (ROS) levels, increased oxidative stress biomarkers malondialdehyde (MDA) and carbonyl protein, and decreased activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Taken together, these results help elucidate some important aspects of OROV infection that may contribute to the pathogenesis of Oropouche.

High-fat diet increases mortality and intensifies immunometabolic changes in septic mice.

Immunometabolic changes in the liver and white adipose tissue caused by high-fat (HF) diet intake may worse metabolic adaptation and protection against pathogens in sepsis. We investigate the effect of chronic HF diet (15 weeks) on mortality and immunometabolic responses in female mice after sepsis induced by cecum ligation and perforation (CLP). At week 14, animals were divided into four groups: sham C diet, sepsis C diet (C-Sp), sham HF diet (HF-Sh) and sepsis HF diet (HF-Sp). The surviving animals were euthanized on the 7th day. The HF diet decreased survival rate (58.3% vs. 76.2% C-Sp group), increased serum cytokine storm (IL-6 [1.41 ×; vs. HF-Sh], IL-1ß [1.37 ×; vs. C-Sp], TNF [1.34 ×; vs. C-Sp and 1.72 ×; vs. HF-Sh], IL-17 [1.44 ×; vs. HF-Sh], IL-10 [1.55 ×; vs. C-Sp and 1.41 ×; HF-Sh]), white adipose tissue inflammation (IL-6 [8.7 ×; vs. C-Sp and 2.4 ×; vs. HF-Sh], TNF [5 ×; vs. C-Sp and 1.7 ×; vs. HF-Sh], IL-17 [1.7 ×; vs. C-Sp], IL-10 [7.4 ×; vs. C-Sp and 1.3 ×; vs. HF-Sh]), and modulated lipid metabolism in septic mice. In the HF-Sp group liver's, we observed hepatomegaly, hydropic degeneration, necrosis, an increase in oxidative stress (reduction of CAT activity [-81.7%; vs. HF-Sh]; increase MDA levels [82.8%; vs. HF-Sh], and hepatic IL-6 [1.9 ×; vs. HF-Sh], and TNF [1.3 × %; vs. HF-Sh]) production. Furthermore, we found a decrease in the total number of inflammatory, mononuclear cells, and in the regenerative processes, and binucleated hepatocytes in a HF-Sp group livers. Our results suggested that the organism under metabolic stress of a HF diet during sepsis may worsen the inflammatory landscape and hepatocellular injury and may harm the liver regenerative process.

Repositioning of Tamoxifen in Surface-Modified Nanocapsules as a Promising Oral Treatment for Visceral Leishmaniasis.

Standards of care for human visceral leishmaniasis (VL) are based on drugs used parenterally, and oral treatment options are urgently needed. In the present study, a repurposing strategy was used associating tamoxifen (TMX) with polyethylene glycol-block-polylactide nanocapsules (NC) and its anti-leishmanial efficacy was reported in vivo. Stable surface modified-NC (5 mg/mL of TMX) exhibited 200 nm in size, +42 mV of zeta potential, and 98% encapsulation efficiency. Atomic force microscopy evidenced core-shell-NC. Treatment with TMX-NC reduced parasite-DNA quantified in liver and spleen compared to free-TMX; and provided a similar reduction of parasite burden compared with meglumine antimoniate in mice and hamster models. Image-guided biodistribution showed accumulation of NC in liver and spleen after 30 min post-administration. TMX-NC reduced the number of liver granulomas and restored the aspect of capsules and trabeculae in the spleen of infected animals. TMX-NC was tested for the first time against VL models, indicating a promising formulation for oral treatment.

Oral administration of angiotensin-(1-7) decreases muscle damage and prevents the fibrosis in rats after eccentric exercise.

NEW FINDINGS: What is the central question of this study? Eccentric contraction exercises cause damage to muscle fibres and induce inflammatory responses. The exacerbation of this process can induce deposition of fibrous connective tissue, leading to decreased muscle function. The aim of this study was to examine the role of angiotensin-(1-7) in this context. What is the main finding and its importance? Our results show that oral treatment with angiotensin-(1-7) decreases muscle damage induced by eccentric exercise, reducing inflammation and fibrosis in the gastrocnemius and soleus muscles. This study shows a potential effect of angiotensin-(1-7) for the prevention of muscle injuries induced by physical exercise. ABSTRACT: Eccentric contraction exercises cause damage to the muscle fibres and induce an inflammatory reaction. The protective effect of angiotensin-(1-7) [Ang-(1-7)] in skeletal muscle has led us to examine the role of this peptide in modifying processes associated with inflammation and fibrogenesis induced by eccentric exercise. In this study, we sought to investigate the effects of oral administration of Ang-(1-7) formulated in hydroxypropyl ß-cyclodextrin (HPß-CD) in prevention and treatment of muscle damage after downhill running. Male Wistar rats were divided into three groups: control (untreated and not exercised; n = 10); treated/exercised HPß-CD Ang-(1-7) (n = 40); and treated/exercised HPß-CD (n = 40). Exercised groups were subjected to a single eccentric contraction exercise session on a treadmill inclined to -13° at a constant speed of 20 m/min, for 60 min. Oral administration of HPß-CD Ang-(1-7) and HPß-CD was performed 3 h before the exercise protocol and daily as a single dose, until the end of the experiment. Samples were collected 4, 12, 24, 48 and 72 h after the exercise session. The animals treated with the Ang-(1-7) showed lower levels of creatine kinase, lower levels of tumor necrosis factor-α in soleus muscle and increased levels of interleukin-10 cytokines. The inflammatory cells and deposition of fibrous connective tissue in soleus and gastrocnemius muscles were lower in the group treated with Ang-(1-7). The results of this study show that treatment with an oral formulation of Ang-(1-7) enhances the process of repair of muscle injury induced by eccentric exercise.

High-Density-Immune-Complex Regulatory Macrophages Promote Recovery of Experimental Colitis in Mice.

Macrophages not only play a fundamental role in the pathogenesis of inflammatory bowel disease (IBD), but they also play a major role in preserving intestinal homeostasis. In this work, we evaluated the role of macrophages in IBD and investigated whether the functional reprogramming of macrophages to a very specific phenotype could decrease disease pathogenesis. Thus, macrophages were stimulated in the presence of high-density immune complexes which strongly upregulate their production of IL-10 and downregulate pro-inflammatory cytokines. The transfer of these high-density-immune-complex regulatory macrophages into mice with colitis was examined as a potential therapy proposal to control the disease. Animals subjected to colitis induction received these high-density-immune-complex regulatory macrophages, and then the Disease Activity Index (DAI), and macroscopic and microscopic lesions were measured. The treated group showed a dramatic improvement in all parameters analyzed, with no difference with the control group. The colon was macroscopically normal in appearance and size, and microscopically colon architecture was preserved. The immunofluorescence migration assay showed that these cells migrated to the inflamed intestine, being able to locally produce the cytokine IL-10, which could explain the dramatic improvement in the clinical and pathological condition of the animals. Thus, our results demonstrate that the polarization of macrophages to a high IL-10 producer profile after stimulation with high-density immune complexes was decisive in controlling experimental colitis, and that macrophages are a potential therapeutic target to be explored in the control of colitis.

Silymarin Attenuates Hepatic and Pancreatic Redox Imbalance Independent of Glycemic Regulation in the Alloxan-induced Diabetic Rat Model.

OBJECTIVE: To evaluate the efficiency of silymarin (SMN) in modulating metabolic parameters and redox status in rats with type 1 diabetes mellitus (T1DM). METHODS: Diabetes was induced by intraperitoneal injection of alloxan. The diabetic rats were administered with SMN at doses of 50 and 100 mg/kg body weight/d for 30 consecutive days. The rats were divided into the following four groups: vehicle control, diabetic (alloxan-treated), DS50 (alloxan + 50 mg/kg body weight/d of SMN), and DS100 (alloxan + 100 mg/kg body weight/d of SMN) groups. The bodyweight and food and water intake were evaluated. After 30 d, the animals were euthanized and the blood was collected for measuring the serum levels of glucose, triacylglycerol (TAG), urea, and creatinine. The liver and pancreas were collected for measuring the activities of superoxide dismutase (SOD) and catalase (CAT), and the levels of carbonylated protein (PC). The pancreas sample was also used for histological analysis. RESULTS: SMN reduced hepatic ( P < 0.001) and pancreatic ( P < 0.001) protein damage and creatinine levels ( P = 0.0141) in addition to decreasing food ( P < 0.001) and water intake ( P < 0.001). However, treatment with SMN did not improve beta-cell function or decrease blood glucose levels in diabetic rats. CONCLUSION: SMN improved polyphagia and polydipsia, renal function, and protected the liver and pancreas against protein damage without affecting hyperglycemia in diabetic animals.

Effects of açai on oxidative stress, ER stress, and inflammation-related parameters in mice with high fat diet-fed induced NAFLD.

Non-alcoholic fatty liver disease (NAFLD), the most predominant liver disease worldwide, is a progressive condition that encompasses a spectrum of disorders ranging from steatosis to steatohepatitis, and, ultimately, cirrhosis and hepatocellular carcinoma. Although the underlying mechanism is complex and multifactorial, several intracellular events leading to its progression have been identified, including oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, and altered endoplasmic reticulum (ER) homeostasis. Phenolic compounds, such as those present in açai (Euterpe oleracea Mart.), are considered promising therapeutic agents due to their possible beneficial effects on the prevention and treatment of NAFLD. We tested in vitro effects of aqueous açai extract (AAE) in HepG2 cells and its influence on oxidative stress, endoplasmic reticulum stress, and inflammation in a murine model of high fat diet-induced NAFLD. In vitro AAE exhibited high antioxidant capacity, high potential to inhibit reactive oxygen species production, and no cytotoxicity. In vivo, AAE administration (3 g/kg) for six weeks attenuated liver damage (alanine aminotransferase levels), inflammatory process (number of inflammatory cells and serum TNFα), and oxidative stress, through the reduction of lipid peroxidation and carbonylation of proteins determined by OxyBlot and modulation of the antioxidant enzymes: glutathione reductase, SOD and catalase. No change was observed in collagen content indicating an absence of fibrosis, stress-related genes in RE, and protein expression of caspase-3, a marker of apoptosis. With these results, we provide evidence that açai exhibits hepatoprotective effects and may prevent the progression of liver damage related to NAFLD by targeting pathways involved in its progression.

Baccharis trimera protects against ethanol induced hepatotoxicity in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Baccharis trimera has been traditionally used in Brazil to treat liver diseases. AIM OF THE STUDY: To evaluate the protective effect of Baccharis trimera in an ethanol induced hepatotoxicity model. MATERIALS AND METHODS: The antioxidant capacity was evaluated in vitro by the ability to scavenged the DPPH radical, by the quantification of ROS, NO and the transcription factor Nrf2. Hepatotoxicity was induced in animals by administration of absolute ethanol for 2 days (acute) or with ethanol diluted for 28 days (chronic). The biochemical parameters of hepatic function (ALT and AST), renal function (urea and creatinine) and lipid profile (total cholesterol, triglycerides and HDL) were evaluated. In addition to antioxidant defense (SOD, catalase, glutathione), oxidative damage markers (TBARS and carbonylated protein), MMP-2 activity and liver histology. RESULTS: Baccharis trimera promoted a decrease in ROS and NO, and at low concentrations promoted increased transcription of Nrf2. In the acute experiment it promoted increase of HDL, in the activity of SOD and GPx, besides diminishing TBARS and microesteatosis. Already in the chronic experiment B. trimera improved the hepatic and renal profile, decreased triglycerides and MMP-2 activity, in addition to diminishing microesteatosis. CONCLUSION: We believe that B. trimera action is possibly more associated with direct neutralizing effects or inhibition of reactive species production pathways rather than the modulation of the antioxidant enzymes activity. Thus it is possible to infer that the biological effects triggered by adaptive responses are complex and multifactorial depending on the dose, the time and the compounds used.

Biodegradable seeds of holmium don't change neurological function after implant in brain of rats.

AIM: To evaluate the surgical procedure and parenchymal abnormalities related to implantation of ceramic seeds with holmium-165 in rats' brain. BACKGROUND: An effective method of cancer treatment is brachytherapy in which radioactive seeds are implanted in the tumor, generating a high local dose of ionizing radiation that can eliminate tumor cells while protecting the surrounding healthy tissue. Biodegradable Ho166-ceramic-seeds have been addressed recently. METHODS AND MATERIALS: The experiments in this study were approved by the Ethics Committee on Animal Use at the Federal University of Ouro Preto, protocol number 2012/034. Twenty-one adult Fischer rats were divided into Naive Group, Sham Group and Group for seed implants (ISH). Surgical procedures for implantation of biodegradable seeds were done and 30 days after the implant radiographic examination and biopsy of the brain were performed. Neurological assays were also accomplished to exclude any injury resulting from either surgery or implantation of the seeds. RESULTS: Radiographic examination confirmed the location of the seeds in the brain. Neurological assays showed animals with regular spontaneous activity. The histological analysis showed an increase of inflammatory cells in the brain of the ISH group. Electron microscopy evidenced cytoplasmic organelles to be unchanged. Biochemical analyzes indicate there was neither oxidative stress nor oxidative damage in the ISH brain. CAT activity showed no difference between the groups as well as lipid peroxidation measured by TBARS. CONCLUSIONS: The analysis of the data pointed out that the performed procedure is safe as no animal showed alterations of the neurological parameters and the seeds did not promote histological architectural changes in the brain tissue.

Swimming training induces liver adaptations to oxidative stress and insulin sensitivity in rats submitted to high-fat diet.

Oxidative stress, physical inactivity and high-fat (FAT) diets are associated with hepatic disorders such as metabolic syndrome (MS). The therapeutic effects of physical training (PT) were evaluated in rats with MS induced by FAT diet for 13 weeks, on oxidative stress and insulin signaling in the liver, during the last 6 weeks. FAT-sedentary (SED) rats increased body mass, retroperitoneal fat, mean arterial pressure (MAP) and heart rate (HR), and total cholesterol, serum alanine aminotransferase, glucose and insulin. Livers of FAT-SED rats increased superoxide dismutase activity, thiobarbituric acid-reactive substances, protein carbonyl and oxidized glutathione (GSSG); and decreased catalase activity, reduced glutathione/GSSG ratio, and the mRNA expression of insulin receptor substrate 1 (IRS-1) and serine/threonine kinase 2. FAT-PT rats improved in fitness and reduced their body mass, retroperitoneal fat, and glucose, insulin, total cholesterol, MAP and HR; and their livers increased superoxide dismutase and catalase activities, the reduced glutathione/GSSG ratio and the expression of peroxisome proliferator-activated receptor gamma and insulin receptor compared to FAT-SED rats. These findings indicated adaptive responses to PT by restoring the oxidative balance and insulin signaling in the liver and certain biometric and biochemical parameters as well as MAP in MS rats.

Lycopene inhibits reactive oxygen species production in SK-Hep-1 cells and attenuates acetaminophen-induced liver injury in C57BL/6 mice.

Our aim was to investigate the antioxidant potential of lycopene in different experimental liver models: in vitro, to evaluate the influence of lycopene on reactive oxygen species (ROS) production mediated by the PKC pathway and in vivo, to evaluate the protective effects of lycopene in an experimental model of hepatotoxicity. The in vitro study assessed the lycopene antioxidant potential by the quantification of ROS production in SK-Hep-1 cells unstimulated or stimulated by an activator of the PKC pathway. The role of NADPH oxidase was evaluated by measuring its inhibition potential using an inhibitor of this enzyme. In the in vivo study, male C57BL/6 mice received lycopene (10 or 100 mg/kg by oral gavage) and 1 h later, acetaminophen (APAP) (500 mg/kg) was administrated. Lycopene decreased ROS production in SK-Hep-1 cells through inhibition of NADPH oxidase, brought about in the PKC pathway. Lycopene improved hepatotoxicity acting as an antioxidant, reduced GSSG and regulated tGSH and CAT levels, reduced oxidative damage primarily by decreasing protein carbonylation, promoted the downregulation of MMP-2 and reduced areas of necrosis improving the general appearance of the lesion in C57BL/6 mice. Lycopene is a natural compound that was able to inhibit the production of ROS in vitro and mitigate the damage caused by APAP overdose in vivo.

Açai (Euterpe oleracea Mart.) Upregulates Paraoxonase 1 Gene Expression and Activity with Concomitant Reduction of Hepatic Steatosis in High-Fat Diet-Fed Rats.

Açai (Euterpe oleracea Mart.), a fruit from the Amazon region, has emerged as a promising source of polyphenols. Açai consumption has been increasing owing to ascribed health benefits and antioxidant properties; however, its effects on hepatic injury are limited. In this study, we evaluated the antioxidant effect of filtered açai pulp on the expression of paraoxonase (PON) isoforms and PON1 activity in rats with nonalcoholic fatty liver disease (NAFLD). The rats were fed a standard AIN-93M (control) diet or a high-fat (HF) diet containing 25% soy oil and 1% cholesterol with or without açai pulp (2 g/day) for 6 weeks. Our results show that açai pulp prevented low-density lipoprotein (LDL) oxidation, increased serum and hepatic PON1 activity, and upregulated the expression of PON1 and ApoA-I in the liver. In HF diet-fed rats, treatment with açai pulp attenuated liver damage, reducing fat infiltration and triglyceride (TG) content. In rats receiving açai, increased serum PON1 activity was correlated with a reduction in hepatic steatosis and hepatic injury. These findings suggest the use of açai as a potential therapy for liver injuries, supporting the idea that dietary antioxidants are a promising approach to enhance the defensive systems against oxidative stress.

Oxidative effects on lung inflammatory response in rats exposed to different concentrations of formaldehyde.

The formaldehyde (FA) is a crosslinking agent that reacts with cellular macromolecules such as proteins, nucleic acids and molecules with low molecular weight such as amino acids, and it has been linked to inflammatory processes and oxidative stress. This study aimed to analyze the oxidative effects on pulmonary inflammatory response in Fischer rats exposed to different concentrations of FA. Twenty-eight Fischer rats were divided into 4 groups (N = 7). The control group (CG) was exposed to ambient air and three groups were exposed to different concentrations of FA: 1% (FA1%), 5% (FA5%) and 10% (FA10%). In the Bronchoalveolar Lavage Fluid (BALF), the exposure to a concentration of 10% promoted the increase of inflammatory cells compared to CG. There was also an increase of macrophages and lymphocytes in FA10% and lymphocytes in FA5% compared to CG. The activity of NADPH oxidase in the blood had been higher in FA5% and FA10% compared to CG. The activity of superoxide dismutase enzyme (SOD) had an increase in FA5% and the activity of the catalase enzyme (CAT) showed an increase in FA1% compared to CG. As for the glutathione system, there was an increase in total glutathione (tGSH), reduced glutathione (GSH) and oxidized glutathione (GSSG) in FA5% compared to CG. The reduced/oxidized glutathione ratio (GSH/GSSG) had a decrease in FA5% compared to CG. There was an increase in lipid peroxidation compared to all groups and the protein carbonyl formation in FA10% compared to CG. We also observed an increase in CCL2 and CCL5 chemokines in the treatment groups compared to CG and in serum there was an increase in CCL2, CCL3 and CCL5 compared to CG. Our results point out to the potential of formaldehyde in promoting airway injury by increasing the inflammatory process as well as by the redox imbalance.

Short-term exposure to formaldehyde promotes oxidative damage and inflammation in the trachea and diaphragm muscle of adult rats.

Formaldehyde (FA) is an environmental pollutant widely used in industry. Exposure to FA causes irritation of the respiratory mucosa and is associated with inflammation and oxidative stress in the airways. This study aimed at investigating the oxidative effects on the inflammatory response in the trachea and the diaphragm muscle (DM) of rats exposed to different concentrations of formaldehyde. Twenty-eight Fischer male rats were divided into four groups: control group (CG) exposed to the ambient air; and three groups exposed to the following formaldehyde concentrations of 1% (FA1), 5% (FA5) and 10% (FA10), respectively. The exposure occurred for twenty minutes, three times a day for five days. Oxidative stress analyses were performed by carbonyl protein, lipid peroxidation and catalase activity. The assessment of inflammatory cell influx in both organs and the mucus production in the trachea was carried out. There was an increase of lipid peroxidation in the trachea and the DM of FA1 and FA5 groups compared to the CG and FA10. The oxidation of DM proteins increased in FA10 group compared to CG, FA1 and FA5. The catalase enzyme activity in the DM was reduced in FA1, FA5 and FA10 compared to the CG. Meanwhile, there was a reduction in the enzymatic activity of FA10 compared to the CG in the trachea. The morphometric analysis in the DM demonstrated an influx of inflammatory cells in FA10 compared to the CG. In FA10 group, the tracheal epithelium showed metaplasia and ulceration. In addition, the tracheal epithelium showed more mucus deposits in FA5 compared to CG, FA1 and FA10. The results demonstrated that the exposure to formaldehyde at different concentrations in a short period of time promotes oxidative damage and inflammation in the DM and the trachea and causes metaplasia, ulceration and increased mucus at the latter.

Influence of sexual dimorphism on pulmonary inflammatory response in adult mice exposed to chloroform.

Chloroform is an organic solvent used as an intermediate in the synthesis of various fluorocarbons. Despite its widespread use in industry and agriculture, exposure to chloroform can cause illnesses such as cancer, especially in the liver and kidneys. The aim of the study was to analyze the effects of chloroform on redox imbalance and pulmonary inflammatory response in adult C57BL/6 mice. Forty animals were divided into 4 groups (N = 10): female (FCG) and male (MCG) controls, and females (FEG) and males (MEG) exposed to chloroform (7.0 ppm) 3 times/d for 20 minutes for 5 days. Total and differential cell counts, oxidative damage analysis, and protein carbonyl and antioxidant enzyme catalase (CAT) activity measurements were performed. Morphometric analyses included alveolar area (Aa) and volume density of alveolar septa (Vv) measurements. Compared to FCG and MCG, inflammatory cell influx, oxidative damage to lipids and proteins, and CAT activity were higher in FEG and MEG, respectively. Oxidative damage and enzyme CAT activity were higher in FEG than in FCG. The Aa was higher in FEG and MEG than in FCG and MCG, respectively. The Vv was lower in FEG and MEG than in FCG and MCG, respectively. This study highlights the risks of occupational chloroform exposure at low concentrations and the intensity of oxidative damage related to gender. The results validate a model of acute exposure that provides cellular and biochemical data through short-term exposure to chloroform.

Iron dextran increases hepatic oxidative stress and alters expression of genes related to lipid metabolism contributing to hyperlipidaemia in murine model.

The objective of this study was to investigate the effects of iron dextran on lipid metabolism and to determine the involvement of oxidative stress. Fischer rats were divided into two groups: the standard group (S), which was fed the AIN-93M diet, and the standard plus iron group (SI), which was fed the same diet but also received iron dextran injections. Serum cholesterol and triacylglycerol levels were higher in the SI group than in the S group. Iron dextran was associated with decreased mRNA levels of pparα, and its downstream gene cpt1a, which is involved in lipid oxidation. Iron dextran also increased mRNA levels of apoB-100, MTP, and L-FABP indicating alterations in lipid secretion. Carbonyl protein and TBARS were consistently higher in the liver of the iron-treated rats. Moreover, a significant positive correlation was found between oxidative stress products, lfabp expression, and iron stores. In addition, a negative correlation was found between pparα expression, TBARS, carbonyl protein, and iron stores. In conclusion, our results suggest that the increase observed in the transport of lipids in the bloodstream and the decreased fatty acid oxidation in rats, which was promoted by iron dextran, might be attributed to increased oxidative stress.

DBT- and DBTO2-induced dysplasia and their associated proteomic alterations in the small intestines of Wistar rats.

Dibenzothiophene (DBT) and its oxidized derivative dibenzothiophene sulfone (DBTO2) are important representatives of polycyclic aromatic hydrocarbons (PAHs). Due to the importance of PAHs in oncogenesis and the lack of toxicological investigations related to DBT and DBTO2, this work proposes to assess their toxic and molecular effects caused by chronic treatment of Wistar rats. In parallel, their effects were compared to those caused by treatment with 1,2-dimethylhydrazine (DMH), a classic mutagenic agent. At the 14th day post-treatment, the animals were sacrificed and blood withdrawn for hematology and evaluation of liver and pancreatic functions. No significant alterations were observed. Nevertheless, histopathological analyses revealed dysplastic lesions in the intestines of animals treated with DBT and DBTO2. CD44 and carcinoembryonic antigen (CEA) staining demonstrated an approximately 3-fold increase in expression of both tissue markers for animals administered DBT, DBTO2, and DMH. A comparative two-dimensional gel analysis revealed additional 23 proteins exhibiting altered levels in the small intestines caused by exposure to DBT and DBTO2. At last, a protein-metabolite interaction map provided major insights into the metabolism of the dysplastic tissues. Our results provided strong evidence that DBT and its derivative could potentially act as cancer inducers, highlighting their toxicological and environmental relevance.

Protective effect of Baccharis trimera extract on acute hepatic injury in a model of inflammation induced by acetaminophen.

BACKGROUND: Acetaminophen (APAP) is a commonly used analgesic and antipyretic. When administered in high doses, APAP is a clinical problem in the US and Europe, often resulting in severe liver injury and potentially acute liver failure. Studies have demonstrated that antioxidants and anti-inflammatory agents effectively protect against the acute hepatotoxicity induced by APAP overdose. METHODS: The present study attempted to investigate the protective effect of B. trimera against APAP-induced hepatic damage in rats. The liver-function markers ALT and AST, biomarkers of oxidative stress, antioxidant parameters, and histopathological changes were examined. RESULTS: The pretreatment with B. trimera attenuated serum activities of ALT and AST that were enhanced by administration of APAP. Furthermore, pretreatment with the extract decreases the activity of the enzyme SOD and increases the activity of catalase and the concentration of total glutathione. Histopathological analysis confirmed the alleviation of liver damage and reduced lesions caused by APAP. CONCLUSIONS: The hepatoprotective action of B. trimera extract may rely on its effect on reducing the oxidative stress caused by APAP-induced hepatic damage in a rat model. General Significance. These results make the extract of B. trimera a potential candidate drug capable of protecting the liver against damage caused by APAP overdose.

Hypercholesterolemic diet induces hepatic steatosis and alterations in mRNA expression of NADPH oxidase in rat livers.

OBJECTIVE: This study aimed to determine whether a hypercholesterolemic diet induces hepatic steatosis, alterations in mRNA expression of NADPH oxidase subunits, and antioxidant defenses. MATERIALS AND METHODS: Fischer rats were divided into two groups of eight animals according to the treatment, control (C) and hypercholesterolemic diet (H). Those in group C were fed a standard diet (AIN-93M), and those of the group H were fed a hypercholesterolemic diet (25% soybean oil and 1% cholesterol). RESULTS: The hypercholesterolemic diet did not affect body weight, but resulted in the accumulation of lipids in the liver, increased serum activities of aminotransferases and cholesterol levels. Biomarker of lipid peroxidation (TBARS) and mRNA expression of NADPH oxidase subunits p22(phox) and p47(phox) were increased in the liver of animals in group H. Besides, the activity and expression of antioxidant enzymes were altered. CONCLUSION: The results show increased mRNA expression of NADPH oxidase subunits and changes in antioxidant enzyme activities in diet-induced hepatic steatosis.

Caraparu virus induces damage and alterations in antioxidant defenses in the liver of BALB/c mice after subcutaneous infection.

Oxidative stress is a disturbance in the oxidant-antioxidant balance leading to potential cellular damage. Most cells can tolerate a mild degree of oxidative stress because they have a system that counteracts oxidation that includes antioxidant molecules such as glutathione (GSH) and superoxide dismutase (SOD). Disruption of the host antioxidant status has been recognized as an important contributor to the pathogenesis of many viruses. Caraparu virus (CARV) is a member of group C of the Bunyaviridae family of viruses. In South American countries, group C bunyaviruses are among the common agents of human febrile illness and have caused multiple notable outbreaks of human disease in recent decades; nevertheless, little is known about the pathogenic characteristics of these viruses. The purpose of this study was to examine the hepatic pathogenesis of CARV in mice and the involvement of oxidative stress and antioxidant defenses on this pathology. Following subcutaneous infection of BALB/c mice, CARV was detected in the liver, and histopathology revealed acute hepatitis. Increased serum levels of aspartate and alanine aminotransferases (AST/ALT) and greater hepatic expression of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) were found in infected animals. CARV infection did not alter the biomarkers of oxidative stress but caused an increase in GSH content and altered the expression and activity of SOD. This is the first report of an alteration of oxidative homeostasis upon CARV infection, which may, in part, explain the hepatic pathogenesis of this virus, as well as the pathogenesis of other Bunyaviridae members.