Oxidative Damage In Liver Research Articles

Cyclophilin D-dependent mitochondrial permeability transition amplifies inflammatory reprogramming in endotoxemia.

Microorganisms or LPS (lipopolysaccharide), an outer membrane component of Gram‐negative bacteria, can induce a systemic inflammatory response that leads to sepsis, multiple organ dysfunction, and mortality. Here, we investigated the role of cyclophilin D (CypD)‐dependent mitochondrial permeability transition (mPT) in the immunosuppressive phase of LPS‐induced endotoxic shock. The liver plays an important role in immunity and organ dysfunction; therefore, we used liver RNA sequencing (RNA‐seq) data, Ingenuity® Pathway Analysis (IPA ®) to investigate the complex role of mPT formation in inflammatory reprogramming and disease progression. LPS induced significant changes in the expression of 2844 genes, affecting 179 pathways related to mitochondrial dysfunction, defective oxidative phosphorylation, nitric oxide (NO) and reactive oxygen species (ROS) accumulation, nuclear factor, erythroid 2 like 2 (Nrf2), Toll‐like receptors (TLRs), and tumor necrosis factor α receptor (TNFR)‐mediated processes in wild‐type mice. The disruption of CypD reduced LPS‐induced alterations in gene expression and pathways involving TNFRs and TLRs, in addition to improving survival and attenuating oxidative liver damage and the related NO‐ and ROS‐producing pathways. CypD deficiency diminished the suppressive effect of LPS on mitochondrial function, nuclear‐ and mitochondrial‐encoded genes, and mitochondrial DNA (mtDNA) quantity, which could be critical in improving survival. Our data propose that CypD‐dependent mPT is an amplifier in inflammatory reprogramming and promotes disease progression. The mortality in human sepsis and shock is associated with mitochondrial dysfunction. Prevention of mPT by CypD disruption reduces inflammatory reprogramming, mitochondrial dysfunction, and lethality; therefore, CypD can be a novel drug target in endotoxic shock and related inflammatory diseases.

Crosstalk between heat shock proteins, NRF2, NF-κB and different endogenous antioxidants during lead-induced hepatotoxicity in Puntius ticto

Present study aims to investigate interaction of molecular chaperons (heat shock protein 70, heat shock protein 90) with transcriptional factors (nuclear factor kappa B/nuclear factor E2-related factor 2/Kelch-like ECH-associated protein 1) to evaluate their role during metal induced stress in fish hepatocytes. Adult Puntius ticto were exposed to lead nitrate at 0 mg/l (control), 1/50th (0.04 mg/l) and 1/20th (0.12 mg/l) of LC50 for 30 days and sacrificed to collect liver tissues. Activity of selected liver enzymes, antioxidants and metallothionein were analyzed. Levels of heat shock protein 70, heat shock protein 90, nuclear factor kappa B, nuclear factor E2-related factor 2 and Kelch-like ECH-associated protein 1 were also measured. Liver enzymes showed a significant increase (p < 0.05) in both Pb exposed groups indicating that the liver might be at risk of damage. Increased level of lipid peroxidation due to metal stress was marked by significant increase (p < 0.05) in malondialdehyde level in fish exposed to the higher Pb concentration compared to control (+ 13.7 %). Significant increase (p < 0.05) in gluthathione reductase (+ 35 %, + 39.2 %), glutathione s-transferase (+ 22.4 %, + 50.4 %) activities and decrease in reduced glutathione level (− 6.75 %, − 12.25 %) in fish exposed to both lower and higher Pb concentration compared to control also indicated metal induced oxidative damage in fish liver. Super oxide dismutase and catalase activities increased significantly (p < 0.05) during exposure to lower Pb concentration, while decreased significantly (p < 0.05) during exposure to higher Pb concentration compared to those in control. Significant (P < 0.05) increase (+ 52.63 %, + 89.47 %) in metallothionein in Pb exposed groups confirmed its role in detoxification process of the metal. Heat shock protein 70 and heat shock protein 90 expression levels increased significantly (p < 0.05) during metal exposure indicating their role as modulator of stress-induced antioxidant protein remodelling. A positive correlation between nuclear factor kappa B/nuclear factor E2-related factor 2/Kelch-like ECH-associated protein 1 with gluthathione regulatory enzymes (gluthathione reductase and glutathione s-transferase) was noted. Current study effectively illuminates the critical role of different factors (heat shock proteins/nuclear factor kappa B/nuclear factor E2-related factor 2/Kelch-like ECH-associated protein 1) to influence the expression and synthesis of antioxidants and other functional enzymes in lead-exposed fish liver.

Thymoquinone Ameliorate Hepatorenal Toxicity Associated With Propylthiouracil-Induced Hypothyroidism in Juvenile Rats.

An increasing number of studies suggest that hypothyroidism may lead to hepatorenal toxicity. This study examined whether thymoquinone (TQ), the main active Nigella sativa constituent, could prevent the detrimental influences of hepatorenal toxicity of hypothyroidism during the juvenile period in rats. The male rats were randomly divided into four groups (n = 7), including control, propylthiouracil (PTU), PTU-TQ 5 mg/kg, and PTU-TQ 10 mg/kg. PTU was dissolved in drinking water at a concentration of 0.05% and administered for six weeks. In the PTU-TQ5 and PTU-TQ10 groups, animals received PTU plus 5 mg/kg and 10 mg/kg of the TQ (i.p.) for six weeks, respectively. The rats were evaluated after TQ treatment by measuring serum markers of liver and kidney function tests as well as oxidative stress biomarkers in liver and kidney tissues. Administration of TQ (5 and 10 mg/kg) decreased oxidative stress damage in liver and kidney tissue in hypothyroidism rats with improvement in activities of antioxidant enzymes and a decrease in MDA in both liver and kidney homogenates. Furthermore, TQ treatment significantly inhibited the elevation of serum biochemical markers of liver and kidney function associated with this hepatorenal toxicity. These results suggest that the protective effect of TQ in hypothyroidism-induced hepatorenal toxicity in rats is attributed to its ability to reduce oxidative stress in hepatic and renal tissues. However, more studies are recommended to investigate the exact mechanism (s) for the effect of TQ on hepatorenal outcomes of hypothyroidism in human subjects.

Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice.

Simple SummaryAspartame is an artificial sweetener used in foods and beverages worldwide to prevent increasing obesity and diabetes mellitus, acting as a tool to help the control of caloric intake. However, its chronic intake is controversial since it has been linked to some adverse effects including oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. Thus, this work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Aspartame generated liver injury and fibrosis. It also decreased the activity of antioxidant enzymes and increased the levels of lipid peroxidation, thus, probably, triggering inflammation and cell death through the induction of protein 53 (p53). Finally, via p53 activation, aspartame inhibited a transcriptional coactivator, the peroxisome proliferator-activated receptor gamma coactivator 1 alpha, a master regulator of glucose and lipid metabolism, probably leading to changes in lipid profile in serum, total lipid accumulation, as well as an impairment in the gluconeogenesis in mouse liver, thus causing hypoglycemia. Therefore, this study provides new insights to understand the mechanisms related to aspartame-linked adverse effects, showing that its intake should be cautioned.Background: Aspartame is an artificial sweetener used in foods and beverages worldwide. However, it is linked to oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. This work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Methods: Mice were divided into two groups with six animals each: control and aspartame. Aspartame (80 mg/kg, via oral) or vehicle was administrated for 12 weeks. Results: Aspartame caused liver damage and elevated serum transaminase levels. Aspartame also generated liver fibrosis, as evidenced by histology analysis, and pro-fibrotic markers’ upregulation, including transforming growth factor β 1, collagen type I alpha 1, and alpha-smooth muscle actin. Furthermore, aspartame reduced nuclear factor erythroid 2-related factor 2 (Nrf2) activation and enzymatic antioxidant activity and increased lipid peroxidation, which triggered NOD-like receptor containing protein 3 (NLRP3) inflammasome activation and p53 induction. Furthermore, aspartame reduced peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) levels, possibly through p53 activation. This PGC-1α deficiency could be responsible for the changes in lipid profile in serum, total lipid accumulation, and gluconeogenesis impairment in liver, evidenced by the gluconeogenic enzymes’ downregulation, thus causing hypoglycemia. Conclusions: This work provides new insights to understand the mechanisms related to the adverse effects of aspartame on liver tissue.

The antioxidant study proprieties of Thymus munbyanus aqueous extract and its beneficial effect on 2, 4-Dichlorophenoxyacetic acid -induced hepatic oxidative stress in albino Wistar rats

Herein, we investigated the antioxidant and hepatoprotective effects of thyme (Thymus munbyanus: AETM) on 2,4-dichlorophenoxyacetic acid (2,4 -D) - induced liver oxidative damage in rats. The phytochemical study of AETM revealed potent antioxidant properties owed to its richness in phenolic compounds including flavonoids, tannins, and phenolic acids. Further, in vivo animal study was conducted on 24 Wistar rats divided equally into control group and three treated groups, receiving orally AETM (10 ml/kg body weight (b.w), 2,4-D (5 mg/kg (b.w) and AETM + 2,4 – D (combined treatment) for 30 consecutive days. The results showed a significant increase in the enzymatic activity of transaminases (AST, ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (γ-GT), lactate dehydrogenase (LDH), and the levels of malondialdehyde (MDA) and carbonyl proteins (CPO), along with a significant decrease in plasma total protein, albumin, hepatic glutathione (GSH) contents, and the enzymatic activity of the hepatic antioxidant markers (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione- S- transferase (GST)) in 2,4- D treatment compared with control. Moreover, no significant changes in these parameters were noticed in AETM treated animals as compared to control, and hence the combined treatment (AETM + 2,4- D) showed a marked enhancement in the above altered hepatic functional and antioxidant parameters and liver histopathology. In conclusion, AETM, owing to its richness with phenolic compounds proved to be an efficient antioxidant against 2,4-D - induced liver oxidative damage, and hence complementary studies would be needed to appear the use of these compounds as supplements in treating liver impairment.

Effect of Adrenergic Drugs on the Lipopolysaccharide-Induced Oxidative Stress and Liver Damage in the Rat

Aim: We aimed to investigate the effect of the adrenergic system on oxidative stress and liver damage during mild systemic inflammation in rats. Methods: For this purpose, Eschrechia coli lipopolysacchride (LPS; 300μg/kg) was intraperitoneally injected either alone or along with the α-2 adrenoceptor antagonist yohimbine, the non-selective β adrenoceptor antagonist propranolol, the and β-adrenoceptor agonist adrenaline and rats euthanized 4h later. The effects of these drugs in saline-treated rats were also studied. Serum alanine aminotransferase (ALT), aspartate aminotransferase, and alkaline phosphatase activities were measured. Liver tissue levels of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH) were determined and liver histology evaluated. Results: In saline-treated rats (i) yohimbine caused significantly increased ALT, AST and ALP in serum. In addition, yohimbine increased MDA, NO and decreased GSH in liver tissue and caused cytoplasmic vacuolations and cellular infiltration: (ii) adrenaline treatment increased serum ALT, AST, liver MDA, decreased liver GSH and caused minute vacuolar degeneration and foci of necrosis; (iii) in contrast, there were no biochemical or histologic alterations after propranolol treatment. In endotoxaemic rats; (i) serum aminotransferases and alkaline phosphatase were significantly increased by yohimbine together with increased liver MDA, NO and decreased GSH content; (ii) serum ALT decreased by propranolol and adrenaline while serum ALP increased by adrenaline; (iii) liver GSH increased by propranolol; (iv) LPS administration caused acute liver damage in the form of foci of necrosis, vacuolar degeneration and aggregates of inflammatory cellular infiltration. Compared with the LPS only group, treatment with yohimbine increased while propranolol or adrenaline produced less liver damage. Conclusions: Thus, blockade of α-2 adrenoceptors increased while β adrenoceptor antagonism decreased oxidative stress and liver damage following LPS administration in rats. Collectively, these results indicate a benefit from blockade of beta-adrenoceptors in protecting the liver during mild systemic inflammation in part by decreasing oxidative stress.

Effect of Maternal Marginal Zinc Deficiency on Development, Redox Status, and Gene Expression Related to Oxidation and Apoptosis in an Avian Embryo Model.

Maternal severe zinc (Zn) deficiency resulted in growth retardation and high mortality during embryonic development in human. Therefore, this study is aimed at evaluating the effect of maternal marginal Zn deficiency on the development and redox status to avoid severe Zn deficiency using an avian model. A total of 324 laying duck breeders at 214 days old were randomly allotted into 3 dietary Zn levels with 6 replicates of 18 ducks per replicate. The birds were fed experimental diets including 3 dietary supplemental Zn levels of 0 mg/kg (maternal Zn-deficient group, 29.2 mg Zn/kg diet), 60 mg/kg (maternal Zn-adequate group), and 120 mg/kg (maternal Zn-high group) for 6 weeks. Dietary Zn levels had on effect on egg production and fertility (P > 0.05), whereas dietary Zn deficiency decreased breeder plasma Zn concentration and erythrocytic alkaline phosphatase activity at week 6 and inhibited erythrocytic 5′-nucleotidase (5′-NT) activity at weeks 2, 4, and 6 (P < 0.05), indicating that marginal Zn-deficient status occurred after Zn depletion. Maternal marginal Zn deficiency increased embryonic mortality and contents of superoxide anion radical, MDA, and PPC and reduced MT content and CuZnSOD activity in duck embryonic livers on E29. The MDA content was positively correlated with embryonic mortality. Maternal marginal Zn deficiency increased BCL2-associated X protein and Caspase-9 mRNA expressions as well as decreased B-cell lymphoma-2 and MT1 mRNA and signal AKT1 and ERK1 protein expressions (P < 0.05). Breeder plasma Zn concentration and erythrocytic 5′-NT activities at week 6 were positively correlated with GSH-Px activity and GPx, MT1, and BCL2 mRNA expressions in embryonic livers on E29. In conclusion, erythrocytic 5′-NT activity could be more rapid and reliable to monitor marginal Zn-deficient status. Marginal Zn deficiency impaired hatchability and antioxidant defense system and then induced oxidative damage and apoptosis in the embryonic liver, contributing to the greater loss of duck embryonic death.

Garuga pinnata attenuates oxidative stress and liver damage in chemically induced hepatotoxicity in rats

ABSTRACT Aim: The aim of the current research work was to isolate, characterize and evaluate the hepatoprotective activity of Garuga pinnata leaves in both acute and chronic hepatic disorder. Materials and methods: The ethanolic extract of the leaves was evaluated for phytochemical screening, acute oral toxicity studies and In-vivo hepatoprotective activity. Hepatotoxicity was induced by administration of paracetamol, thioacetamide and ethanol in albino wistar rats. Serum and tissue biochemical parameters were estimated. Histopathological studies were performed using hematoxylin and eosin staining. The active principle from plant was isolated using column chromatography and identified by UV, FTIR, NMR, and GC-MS studies. Results: Animal groups treated with hepatotoxicant showed marked alteration in serum and tissue biochemical parameters. However, pretreatment with ethanolic extract significantly restored the biochemical parameters. Garuga pinnata leaves extract showed the dose-dependant hepatoprotective effect. Histopathology of the groups treated with leaves extract showed normal hepatic architecture confirming hepatoprotective activity. Analytical techniques including UV, FTIR, NMR and mass confirmed the presence of rutin flavonoids and hence the hepatoprotective activity was attributed to chemical compound rutin. Conclusion: Ethanolic leaves extracts can serve as promising herbal medicine for the treatment of both acute and chronic hepatotoxicity due to the presence of flavonoids rutin.

The Mechanism Underlying the Extreme Sensitivity of Duck to Aflatoxin B1

Most metabolites of aflatoxin B1 (AFB1), especially exo‐AFB1‐8,9‐epoxide (AFBO), can induce the production of reactive oxygen species (ROS) to vary degrees, causing oxidative stress and liver damage, and ultimately induce liver cancer in humans and animals. Duck is one of the most sensitive animals to AFB1, and severe economic losses are caused by duck AFB1 poisoning every year, but the exact mechanism of this high sensitivity is still unclear. This review highlights significant advances in our understanding of the AFB1 metabolic activation, like cytochrome P450s (CYPs), and AFB1 metabolic detoxification, like glutathione S‐transferases (GSTs) in poultry. In addition, AFB1 may have other metabolic pathways in poultry, such as the mutual conversion of AFB1 and aflatoxicol (AFL) and the process of AFBO to produce AFB1‐8,9‐dihydrodiol (AFB1‐dhd) and further metabolize it into detoxification substances. This review also summarized some exogenous regulatory substances that can alleviate AFB1‐induced oxidative stress.

Pyrroloquinoline quinone (PQQ) alleviated sepsis-induced acute liver injury, inflammation, oxidative stress and cell apoptosis by downregulating CUL3 expression

ABSTRACT PQQ has anti-inflammatory and anti-oxidant effects. PQQ can relieve high glucose-induced renal cell damage by suppressing Keap1 expression. Keap1 can interact with CUL3. Upregulation of CUL3 facilitates the apoptosis of LPS-induced podocytes. Based on knowledge above, this current work was designed to explore the role of PQQ in sepsis and determine the molecular function of CUL3 in the pathogenesis of sepsis. Rats received CLP surgery to establish sepsis models in vivo. Kupffer cells were pretreated with PQQ (10, 50 and 100 nmol/L) for 2 h and then treated with 100 ng/mL LPS for 24 h, simulating sepsis-induced acute liver injury in vitro. H&E staining was performed to evaluate liver injury of SD rats. Levels of inflammatory factors and oxidative stress markers were detected to assess inflammatory response and oxidative stress. Moreover, TUNEL staining, flow cytometric analysis and western blot were applied to determine cell apoptosis. It was confirmed that PQQ treatment relieved acute liver injury, inflammatory and oxidative stress damage and apoptosis of liver tissue cells in sepsis rats. In addition, PQQ therapy could alleviate inflammation, oxidative stress and apoptosis in LPS-induced Kupffer cells. Notably, LPS stimulation enhanced CUL3 expression and PQQ repressed CUL3 expression in Kupffer cells suffered from LPS. Overall, CUL3 overexpression weakened the remission effects of PQQ on LPS-induced inflammatory and oxidative damage and apoptosis of Kupffer cells. Mechanistically, PQQ treatment may mitigate sepsis-induced acute liver injury through downregulating CUL3 expression.

Protective Effect of Alpha-Lipoic Acid against Liver Damage Induced by Cigarette Smoke: An in vivo Study.

Background:Long-term cigarette smoking damages the liver tissue. Alpha-lipoic acid (ALA) is used as a therapeutic agent in a number of conditions and is known to have ameliorative effects against oxidative stress in the liver.Objective:To investigate the ameliorative effects of ALA on cigarette smoke (CS)-induced oxidative liver damage by examining histopathological, immunohistopathological changes and biochemical parameters in an animal model.Materials and Methods:Twenty-eight female Sprague–Dawley rats were randomly divided into three groups. In the control group (n = 8), rats were exposed to fresh air twice a day and given 0.1 ml of saline by gavage once a day for 8 weeks. In the smoking group (n = 10), rats were exposed to CS for 1 h in the morning and afternoon and given 0.1 ml of saline by gavage once a day for 8 weeks. In the smoking + ALA group (n = 10), CS exposure was same as the smoking group in addition to 100 mg/kg of ALA per day for 8 weeks through gavage. Oxidative damage in the liver tissue was determined by evaluating malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD) levels. Aspartate aminotransferase (AST), alanine aminotransaminase (ALT), alkaline phosphatase (ALP), direct bilirubin and total bilirubin levels were measured in the blood. Histopathological and immunohistochemical examinations were performed.Results:MDA (P = 0.011), AST (P = 0.018) and total bilirubin levels (P < 0.001) were increased, while CAT activity (P = 0.009) and the efficiency of SOD (P = 0.010) were decreased in the smoking group compared with the control group. CAT activity was increased (P = 0.017) and AST (P = 0.018) and total bilirubin levels (P < 0.001) were decreased in ALA-treated group compared with the smoking group. We observed vascular dilatation and hemorrhagic areas in the smoking group. TNF-α expression was increased in the smoking group compared with the control group. However, TNF-α expression was high in some preparations in the ALA-treated group.Conclusions:ALA can enhance antioxidant activity, but studies with different doses of ALA are required to determine the extent of its hepatoprotective effect.

Assessment of oxidative DNA damage, oxidative stress responses and histopathological alterations in gill and liver tissues of Oncorhynchus mykiss treated with linuron.

We investigated changes in 8-hydroxy-2-deoxyguanosine (8-OHdG) activity which is a product of oxidative DNA damage, histopathological changes and antioxidant responses in liver and gill tissues of rainbow trout, following a 21-day exposure to three different concentrations of linuron (30 µg/L, 120 µg/L and 240 µg/L). Our results indicated that linuron concentrations caused an increase in LPO levels of liver and gill tissues (p < 0.05). While linuron induced both increases and decreases in GSH levels and SOD activity, CAT activity was decreased by all concentrations of linuron (p < 0.05). The immunopositivity of 8-OHdG was detected in the hepatocytes of liver and in the epithelial and chloride cells of the secondary lamellae of the gill tissues. Our results suggested that linuron could cause oxidative DNA damage by causing an increase in 8-OHdG activity in tissues, and it induces histopathological damage and alterations in the antioxidant parameters of the tissues.

Protective Effect of Tylophora indica against Streptozotocin Induced Pancreatic and Liver Dysfunction in Wistar Rats

The objective of the study is to evaluate the ethanolic leaf extract of Tylophora indica (ELTI) on pancreatic and hepatic oxidative stress in streptozotocin (STZ) induced diabetic rats. The serum blood glucose and liver enzymes (AST, ALT and ALP) were estimated in all the groups. The elevated blood glucose levels and liver enzymes were found to be decreased with ELTI in STZ induced diabetic rats. The activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S- transferase (GST) and the levels of reduced glutathione (GSH) were also decreased, while an increase in the levels of thiobarbituric acid reactive substances (TBARS) were observed in pancreas and liver with ELTI treatment in STZ induced diabetic rats. Histopathology reveals that the protective effect of ELTI over STZ induced oxidative damage in both liver and pancreas. These results indicated that ELTI has more potential antioxidant effects on diabetic-induced oxidative stress.

Antihyperglycemic activity of crude extract and isolation of phenolic compounds with antioxidant activity from Moringa oleifera Lam. leaves grown in Southern Brazil

The antihyperglicemic activity of crude extract from Moringa oleifera leaves and isolation of phenolic compounds with antioxidant activity using bioguided assay were employed by the first time in leaves cultivated in Brazil. The hydroalcoholic extract (HE) was produced by using ethanol:water (80:20 v/v) and purified by solid–liquid procedure using solvents in ascending order of polarity. The ethyl acetate fraction (Fr-EtOAc) presented high antioxidant potential and it was purified using chromatographic techniques rendering isolated compounds that were identified from the spectral data. The HE extract (500 mg kg−1) was adimistrated in diabetic rats induced by streptozotocin and chemical markers and lipid peroxidation in liver and kidney were evaluated. The Fr-EtOAc showed high antioxidant potential by FRAP reduction method (1678 µmol Fe2+ g−1), DPPH and ABTS scavenging methods (526.7 and 671.5 µmol TEAC g−1 respectively) and ORAC assay (3560.6 µmol TEAC g−1). Therefore, the Fr-EtOAc was purified and yielded three bioactive subfractions (S-12, S-13 abd S-15) that were rechromatoghaphed in HPLC-SemiPrep. After that, two main bioactive glycosylated flavonoids (isoquercitrin and astragalin) and phenolic acid (3-O-caffeoylquinic acid) were obtained. Additionally, the HE extract provided protection against oxidative damage in liver and kidney of diabetic rats ameliorating endogenous antioxidant defenses by increase catalase (CAT), glutathione S-transferase (GST) and non-protein thiol groups (NPSH) levels as well as decreased the lipid peroxidation in these tissues. Our results indicate that three phenolic compounds with high antioxidant activity were isolated and, the chemical composition of HE crude extract, rich in flavonoids glycosylated could be intimately related to antihyperglycemic action. So, it is possible to suggest that these compounds may be used as chemical biomarkers for this plant in Brazil, ensuring quality and supporting the use of aerial parts in tradicional medicine.

Dietary squalene supplementation alleviates diquat-induced oxidative stress and liver damage of broiler chickens

The aim of this study was to explore the protective effects of squalene supplementation on growth performance, oxidative status, and liver function of diquat-challenged broilers. One hundred forty-four 1-day-old male Ross 308 broiler chicks were allocated to 3 groups, and each group consisted of 6 replicates of 8 birds each. The three groups were as follows: 1) nonchallenged broilers fed with a basal diet (control group), 2) diquat-challenged broilers fed a basal diet, and 3) diquat-challenged broilers fed with a basal diet supplemented with 1.0 g/kg of squalene. Broilers were intraperitoneally injected with 20 mg/mL of diquat solution at a dosage of 1 mL/kg of BW or an equivalent amount of saline at 20 d. Compared with the control group, weight gain and BW change rate during 24 h after injection were decreased by diquat challenge (P < 0.05), and the diquat-induced compromised growth performance was improved by squalene supplementation (P < 0.05). Diquat administration reduced plasma superoxide dismutase activity and increased malondialdehyde accumulation and glutathione peroxidase activity in both plasma and the liver (P < 0.05). In contrast, plasma glutathione peroxidase activity in diquat-challenged broilers was reduced by squalene supplementation (P < 0.05). The hepatic glutathione level was reduced by diquat administration (P < 0.05), whereas its level in plasma and the liver of diquat-challenged broilers was increased by squalene supplementation (P < 0.05). The relative liver weight of broilers was increased by diquat challenge (P < 0.05), with its value being intermediate in the squalene-supplemented group (P > 0.05). The plasma aminotransferase activities and total bilirubin concentration were increased by diquat challenge (P < 0.05), which were reduced by squalene supplementation (P < 0.05). The mRNA abundance of hepatic nuclear factor erythroid 2–related factor 2 (P < 0.05) was upregulated by diquat treatment, regardless of squalene supplementation. The mRNA abundance of hepatic glutathione peroxidase 1 and B-cell lymphoma/leukemia 2–associated X protein was upregulated by diquat challenge (P < 0.05), which was reversed by squalene administration (P < 0.05). Squalene increased NAD(P)H quinone dehydrogenase 1 mRNA abundance and decreased caspase 3 mRNA abundance in the liver of diquat-challenged broilers (P < 0.05). The results suggested that squalene can increase weight gain, improve oxidative status, and alleviate liver injury in diquat-challenged broilers.

Aceclofenac-induced hepatotoxicity: An ameliorative effect of Terminalia bellirica fruit and ellagic acid.

BACKGROUNDAceclofenac (ACF), a widely used nonsteroidal anti-inflammatory drug, has been associated with a number of severe cases of clinical hepatotoxicity. Terminalia bellirica, an evergreen tree, is known to have several ethnomedicinal uses including antioxidant and hepatoprotective effects. Hence T. bellirica fruit extracts and its phytoconstituent ellagic acid (EA) are expected to provide protection against oxidative stress and liver damage produced by long-term use of ACF. AIMTo evaluate the antioxidant and hepatoprotective activities of T. bellirica fruit extracts and EA against ACF-induced toxicity in albino Wistar rats.METHODSThe in vitro antioxidant activities of T. bellirica fruit ethyl acetate and aqueous extracts were measured by metal ion chelation and nitric oxide radical scavenging assays. The in vivo antioxidant and hepatoprotective effects of T. bellirica extracts (200 mg/kg) and EA (40 mg/kg) in ACF-induced hepatotoxic rats were assessed in serum and liver tissue after oral administration for 21 d. Silymarin (40 mg/kg) was used as a standard control. Oxidative stress markers in the blood (ferric reducing ability of plasma and lipid peroxidation inhibition) and liver tissues (superoxide dismutase, catalase and malondialdehyde) were analyzed using standard protocols. Liver function markers such as alkaline phosphatase, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, lactate dehydrogenase, γ-glutamyl transferase, creatinine, total protein, and uric acid were evaluated in rat serum.RESULTSThe T. bellirica fruit ethyl acetate extract exhibited superior metal ion chelating and nitric oxide radical scavenging abilities during in vitro antioxidant assays as compared to aqueous extracts. Oral administration of ACF in rats (15 mg/kg) for 21 d produced oxidative stress and adversely affected liver function suggesting liver injury. Treatment with extracts (ethyl acetate and aqueous), EA and silymarin accounted for a significant reduction in the adverse effects of ACF on oxidative stress and liver function markers in serum and hepatic tissue in rats. Histopathological evaluation of the liver indicated that the extracts and EA significantly decreased the degree of liver damage. The in vivo efficacy of EA was higher than T. bellirica fruit extracts. Of these extracts, ethyl acetate extract revealed comparatively better antioxidant and hepatoprotective activity.CONCLUSIONEllagic acid and T. bellirica fruit extracts exhibited considerable hepatoprotective and antioxidant activities in long-term ACF-treated rats.

Toxicity reduction and water expelling effect preservation of Shizaotang after its toxic members processing with vinegar on rats with malignant pleural effusions

Ethnopharmacological relevanceShizaotang (SZT), consisted of Euphorbia kansui S.L.Liou ex S.B.Ho (EK), Euphorbia pekinensis Rupr. (EP), Daphne genkwa Sieb. et Zucc. (DG，fried) and Ziziphus jujuba Mill. (ZJ), is usually used for treating malignant pleural effusions (MPE), but the toxicity of EK and EP limits its clinical safe application. It was reported that vinegar processing can reduce the toxicity of EK and EP. Whether EK and EP processing with vinegar can cause the reduced toxicity and retained pharmacological effects of SZT, it still remains unknown.Aim of the study: We aimed to evaluate whether using vinegar processed EK and EP would reduce toxicity and preserve water expelling effect of SZT. Materials and methodsNetwork pharmacology and qualitative analysis of SZT/VSZT were used to construct compound-target-pathway network of their effects and toxicity. Pleural fluid weight, urine volume, uric electrolyte, pH, pro-inflammatory cytokines in pleural fluid, serum Renin-Angiotensin-Aldosterone System (RAAS), anti-diuretic hormone (ADH) and intestinal aquaporin 8 (AQP8) protein were used to evaluate the effect mechanisms involved in rats experiments. And liver damage, oxidative damage and HE staining (liver, stomach, and intestine) were used to determine the toxicity. ResultsNetwork pharmacology analysis reviewed inflammation-related pathways of the effect and toxicity of SZT/VSZT: VEGF-PI3K-AKT pathway inhibited MPE by changing the vasopermeability; PI3K-Akt/Mitogen-activated protein kinase (MAPK)/TNF-NF-κB signaling pathway inhibited MPE by up-regulating expression of AQP8 protein. In vivo experiments displayed that SZT/VSZT could reduce pleural fluid, increase urine volume, lower pro-inflammatory cytokines levels and up-regulate AQP8 protein expression significantly (P < 0.05, P < 0.01). In addition, disorders on electrolyte (Na+, K+ and Cl−) and pH were ameliorated (P < 0.05, P < 0.01). The levels of RAAS and ADH were significantly dose-dependently called back (P < 0.01). These findings were partly consistent with the results of network pharmacology analysis. Results of toxicity experiments demonstrated that SZT and VSZT exhibited certain toxicity on normal rats, and VSZT had lower toxicity than that of SZT. Interestingly, SZT and VSZT exerted alleviation effect to the liver damage and oxidative damage on model rats. ConclusionSZT/VSZT improved MPE by regulating associated inflammation pathways. Besides, compared to SZT, VSZT showed lower toxicity and equivalent expelling MPE effect. This study may provide scientific basis for guiding the clinical application of SZT.

Anti-oxidant and hepatoprotective effects of Salvia officinalis essential oil against vanadium-induced oxidative stress and histological changes in the rat liver.

The present study was designed to evaluate the protective effects of Salvia officinalis essential oil (SOEO) against vanadium-induced hepatotoxicity in Wistar rats. Animals were divided into three groups: the first group served as the control (C), where rats received daily 0.5mL of saline solution (0.9%) given by intraperitoneal (i.p.) way. Rats in the second group (V) received daily by i.p. way 5mg/kg BW of NH4VO3 (V). Rats in the third group (SV) received daily V (5mg/kg BW) by i.p. way and SOEO (15mg/kg BW) by gavage. Animals were sacrificed after 4 or 10days of treatment. Administration of V increased plasma ALT, AST, ALP, and LDH activities, and cholesterol, bilirubin, triglyceride, and NO levels in rats and reduced anti-oxidant enzyme activities in the liver. Treatment with SOEO significantly attenuated these changes. Moreover, the histopathological changes and the overexpression of Hsp72/73 proteins induced by V were significantly improved by SOEO. Therefore, our results suggested that SOEO could protect against V-induced oxidative damage in rat livers. The hepatoprotective effect of SOEO might be attributed to its modulation of detoxification enzymes and/or to its anti-oxidant and free radical scavenging effects.

P2X7 receptor deletion attenuates oxidative stress and liver damage in sepsis.

Sepsis is a severe disease characterized by an uncontrolled systemic inflammation and consequent organ dysfunction generated in response to an infection. Extracellular ATP acting through the P2X7 receptor induces the maturation and release of pro-inflammatory cytokines (i.e., IL-1β) and the production of reactive nitrogen and oxygen species that lead to oxidative tissue damage. Here, we investigated the role of the P2X7 receptor in inflammation, oxidative stress, and liver injury in sepsis. Sepsis was induced by cecal ligation and puncture (CLP) in wild-type (WT) and P2X7 knockout (P2X7-/-) mice. The oxidative stress in the liver of septic mice was assessed by 2',7'-dichlorofluorescein oxidation reaction (DCF), thiobarbituric acid-reactive substances (TBARS), and nitrite levels dosage. The status of the endogenous defense system was evaluated through catalase (CAT) and superoxide dismutase (SOD) activities. The inflammation was assessed histologically and by determining the expression of inflammatory cytokines and chemokines by RT-qPCR. We observed an increase in the reactive species and lipid peroxidation in the liver of septic WT mice, but not in the liver from P2X7-/- animals. We found an imbalance SOD/CAT ratio, also only WT septic animals. The number of inflammatory cells and the gene expression of IL-1 β, IL-6, TNF-α, IL-10, CXCL1, and CXCL2 were higher in the liver of WT septic mice in comparison to P2X7-/- septic animals. In summary, our results suggest that the P2X7 receptor might be a therapeutic target to limit oxidative stress damage and liver injury during sepsis.

Protective effects of vitamin E on aluminium chloride-induced liver and kidney damage in rats

Aluminium is present in many manufactured foods and medicines and is also used in water purification. It is known that aluminium causes oxidative stress. Therefore, the present study was undertaken to determine the effectiveness of vitamin E (VE) in modulating the toxicity of aluminium chloride (AlCl3) on biochemical parameters, antioxidant enzymes and lipid peroxidation in serum and different organs (liver and kidney) of male Wistar rats. 24 rats (150-180g) were divided into four groups of six animals each : control ; Al was administered intraperitoneally (50 mg/kg/bw, one times a week) ; VE was given orally at a daily dose (100 mg/kg/bw) and Al+VE group. The experiment during for 90 days. AlCl3 caused a decreased in body weight consumption along with increased in the absolute and relative liver and kidney weights. TBARS level was increased, and the enzymes activities of CAT and SOD were decreased in liver and kidney of rats treated with AlCl3. While, TBARS was decreased and the antioxidant enzymes were increased in rats treated with VE. The hepatic and renal damage induced by Al was evidenced by a increase in the levels of serum AST, ALT, LDH, ALP, γGT, glucose, urea, creatinine and bilirubin, while total protein and albumin were decreased due to AlCl3 administration. These parameters indicated the extent of oxidative damage in liver and kidney, thus confirming the histology results in these organs. It can be concluded in this study that presence of VE effectively atte-nuated AlCl3 induced hepatotoxicity and nephrotoxicity in rats. It has benefi-cial influences and protective effect against AlCl3 toxicity.