Hepatic Tumor Necrosis Factor-alpha Research Articles

Evening primrose oil enriched with gamma linolenic acid and D/L-alpha tocopherol acetate attenuated carbon tetrachloride-induced hepatic injury model in male rats via TNF-α, IL-1β, and IL-6 pathway

The modulatory role of primrose oil (PO) supplementation enriched with γ-linolenic acid and D/L-alpha tocopherol acetate against a carbon tetrachloride (CCl4)-induced liver damage model was assessed in this study. Twenty male Albino rats were divided into four groups. The control group received corn oil orally. The PO group received 10 mg/kg P O orally. The CCl4 group received 2 mL/kg CCl4 orally and PO/CCl4 group; received PO and 2 mL/kg CCl4 orally. The relative liver weight was recorded. Serum liver enzymes, hepatic malondialdehyde (MDA), hepatic reduced glutathione (GSH) and the expression of hepatic tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) were assessed. The binding affinities of γ-linolenic acid and D/L-alpha tocopherol constituents with IL-1β, IL-6 and TNF-α were investigated using molecular docking simulations. Histopathological and electron microscopic examinations of the liver were performed. The results indicated that CCl4 elevated serum liver enzyme and hepatic MDA levels, whereas GSH levels were diminished. The upregulation of IL-1β, IL-6, and TNF-α gene expressions were induced by CCl4 treatment. The PO/CCl4-treated group showed amelioration of hepatic injury biomarkers and oxidative stress. Restoration of histopathological and ultrastructural alterations while downregulations the gene expressions of TNF-α, IL1-β and IL-6 were observed. In conclusion, evening primrose oil enriched with γ-linolenic acid and D/L-alpha tocopherol acetate elicited a potential amelioration of CCl4-induced hepatic toxicity.

Nilotinib alleviates paraquat-induced hepatic and pulmonary injury in rats via the Nrf2/Nf-kB axis

BackgroundParaquat (PQ, 1,1′-dimethyl-4-4′-bipyridinium dichloride) is a highly toxic quaternary ammonium herbicide widely used in agriculture. It exerts its toxic effects mainly as a result of its redox cycle via the production of superoxide anions in organisms, leading to an imbalance in the redox state of the cell causing oxidative damage and finally cell death. The aim of this study was to estimate the beneficial protective role of nilotinib (NIL) on PQ-induced hepatic and pulmonary toxicity in rats. MethodsMale wistar rats were randomly divided into four groups, namely control, PQ (15 mg/kg), PQ plus NIL (5 mg/kg) and PQ plus NIL (10 mg/kg). NIL (5 and 10 mg/kg/day) was taken by oral syringe for five days followed by a single intra-peritoneal administration of PQ (15 mg/kg) on sixth day. ResultsPretreatment with NIL relieved the histological damage in liver and lung tissues and improved hepatic biochemical markers. It significantly (p < 0.05) reduced serum levels of ALT, AST, ALP, Y-GT and total bilirubin while increased that of albumin. Meanwhile, NIL significantly (p < 0.05) reduced oxidative stress markers via reduction of malondialdhyde (MDA) and elevation of glutathione (GSH) contents in liver and lung tissues. In addition, it significantly (p < 0.05) decreased the inflammation by reducing hepatic and pulmonary tumor necrosis factor alpha (TNF-α) and nuclear transcription factor kappa B (NF-KB/p65) contents. Nilotinib also down-regulated apoptosis by reducing cysteinyl aspartate-specific proteinase-3 (caspase-3). Furthermore, it upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and microtubule-associated protein 1A/1B-light chain 3 II (LC3II) in liver and lung tissues. SignificanceNIL suppressed PQ-induced inflammation, oxidative stress and apoptosis in liver and lung tissues by modulating Nrf2/Nf-kB axis.

Pregnenolone protects the liver against doxorubicin-induced cellular injury by anti-inflammatory, antioxidant, and antiapoptotic mechanisms: role of Keap1/Nrf2/HO-1 and P-glycoprotein.

Doxorubicin (DOX) is a widely used cytotoxic anthracycline antibiotic characterized by increased adverse effects that limit its clinical usefulness. Pregnenolone is a pregnane X receptor (PXR) agonist that increases the expression of xenobiotic transporters with anti-inflammatory and antioxidant potential. Thus, we hypothesized that pregnenolone would protect against DOX-induced hepatotoxicity. Male Wistar rats (180-200 g) were randomized into four groups (n = 7): Control, Control + Pregnenolone (35 mg/kg/day, orally), DOX (15 mg/kg, i.p.) single dose on day five, and Pregnenolone + DOX. All treatments continued for seven consecutive days. Twenty-four hours after the last treatment, serum and liver tissues were collected for biochemical and histopathological assessment. The possible interaction between pregnenolone and DOX on cell viability was tested in HepG2 cells in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. DOX treatment resulted in hepatic damage and fibrosis with increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Liver samples of the DOX-treated group showed increased oxidative stress [malondialdehyde (MDA) and total nitrite/nitrate and decreased reduced glutathione (GSH) and superoxide dismutase (SOD)], increased hepatic tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), transforming growth factor-beta1 (TGF-β1), and mRNA of interleukin-1beta (IL-1β) and interleukin-6 (IL-6). Pretreating the rats with pregnenolone antagonized these DOX-induced effects. Moreover, pregnenolone upregulated the hepatic expression of Nrf2, heme oxygenase-1 (HO-1), and P-glycoprotein and decreased Keap1, opposing the effects of DOX. Moreover, pregnenolone prevented the DOX-induced activation and nuclear translocation of NFκB and increased cleaved caspase-3. Pregnenolone potentiated DOX-mediated cytotoxicity in HepG2 cells. These results illustrate the protective effects of pregnenolone against DOX-induced hepatotoxicity without limiting its anticancer activity.

Sesamin Attenuates Obesity-Associated Nonalcoholic Steatohepatitis in High-Fat and High-Fructose Diet-Fed Mice.

This study explored the effects of sesamin on nonalcoholic steatohepatitis (NASH). High-fat and high-fructose diet-fed mice supplemented with or without sesamin. The results suggested that sesamin-treated mice lost body weight and fat tissue weight, had lower levels of serum metabolic parameters, and insulin resistance was mitigated. Histological examinations showed that sesamin treatment mitigated the progression of hepatic steatosis, and inflammation. In addition, sesamin enhanced hepatic antioxidant capacity, and decreased the activations of hepatic c-jun N-terminal kinase, inhibitor of kappa B kinase α, and insulin receptor substrate 1 as well as hepatic interleukin-6 and tumor necrosis factor-alpha levels. Further experiments indicated that sesamin treatment downregulated GRP78 and phospho-inositol-requiring enzyme 1 (IRE1) expression, and upregulated x-box binding protein 1 (XBP1) expression in hepatic tissue. The aforementioned results suggest that sesamin alleviates obesity-associated NASH, which might be linked to the effect of sesamin on the regulation of the hepatic endoplasmic reticulum stress-IRE1/XBP1 pathway. Thus, sesamin may be a good food functional ingredient in the treatment of obesity-associated NASH.

TLRs-JNK/ NF-κB Pathway Underlies the Protective Effect of the Sulfide Salt Against Liver Toxicity.

Hydrogen sulfide (H2S) is an endogenously gas transmitter signaling molecule with known antioxidant, anti-inflammatory, and cytoprotective properties. Although accumulating evidence shows the therapeutic potential of H2S in various hepatic diseases, its role in cyclophosphamide (CP)-induced hepatotoxicity remains elusive. The present study was undertaken to investigate the impact of endogenous and exogenous H2S on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in CP-induced hepatotoxicity. Either an H2S donor (NaHS (100 μM/kg) or an H2S blocker [dl-propargylglycine (PAG) (30 mg/kg, i. p.)], was administered for 10 days before a single ip injection of CP (200 mg/kg). NaHS attenuated conferred hepatoprotection against CP-induced toxicity, significantly decreasing serum hepatic function tests and improving hepatic histopathology. Additionally, NaHS-treated rats exhibited antioxidant activity in liver tissues compared with the CP group. The upregulated hepatic levels of TLR2/4 and their downstream signaling molecules including c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) were also suppressed by NaHS protective treatment. NaHS showed anti-inflammatory and antiapoptotic effects; reducing hepatic level tumor necrosis factor-alpha (TNF-α) and caspase-3 expression. Interestingly, the cytotoxic events induced in CP-treated rats were not significantly altered upon the blocking of endogenous H2S. Taken together, the present study suggested that exogenously applied H2S rather than the endogenously generated H2S, displayed a hepatoprotective effect against CP-induced hepatotoxicity that might be mediated by TLRs-JNK/NF-κB pathways.

The Acute Hepatic NF-κB-Mediated Proinflammatory Response to Endotoxemia Is Attenuated in Intrauterine Growth-Restricted Newborn Mice.

Intrauterine growth restriction (IUGR) is a relevant predictor for higher rates of neonatal sepsis worldwide and is associated with an impaired neonatal immunity and lower immune cell counts. During the perinatal period, the liver is a key immunological organ responsible for the nuclear factor kappa B (NF-κB)-mediated innate immune response to inflammatory stimuli, but whether this role is affected by IUGR is unknown. Herein, we hypothesized that the newborn liver adapts to calorie-restriction IUGR by inducing changes in the NF-κB signaling transcriptome, leading to an attenuated acute proinflammatory response to intraperitoneal lipopolysaccharide (LPS). We first assessed the hepatic gene expression of key NF-κB factors in the IUGR and normally grown (NG) newborn mice. Real-time quantitative PCR (RT-qPCR) analysis revealed an upregulation of both IκB proteins genes (Nfkbia and Nfkbib) and the NF-κB subunit Nfkb1 in IUGR vs. NG. We next measured the LPS-induced hepatic expression of acute proinflammatory genes (Ccl3, Cxcl1, Il1b, Il6, and Tnf) and observed that the IUGR liver produced an attenuated acute proinflammatory cytokine gene response (Il1b and Tnf) to LPS in IUGR vs. unexposed (CTR). Consistent with these results, LPS-exposed hepatic tumor necrosis factor alpha (TNF-α) protein concentrations were lower in IUGR vs. LPS-exposed NG and did not differ from IUGR CTR. Sex differences at the transcriptome level were observed in the IUGR male vs. female. Our results demonstrate that IUGR induces key modifications in the NF-κB transcriptomic machinery in the newborn that compromised the acute proinflammatory cytokine gene and protein response to LPS. Our results bring novel insights in understanding how the IUGR newborn is immunocompromised due to fundamental changes in NF-κB key factors.

Camellia sinesis leaves extract ameliorates high fat diet-induced nonalcoholic steatohepatitis in rats: analysis of potential mechanisms

Our research aims to address and determine the effect of Camellia sinensis extract in the management of nonalcoholic steatohepatitis (NASH) in rats. Forty adult female albino rats were divided into four groups. Group 1 (G1) served as the control group, while the other three groups received high-fat diet for 32 weeks to induce NASH and then were later assigned to the following groups: (G2) NASH-afflicted group which was left untreated, (G3) NASH-afflicted group treated with Camellia sinensis extract in a dose of 400 mg/kg, and (G4) NASH-afflicted group treated with Camellia sinensis extract in a dose of 200 mg/kg. Significant elevation in serum alanine aminotransferase, albumin, bilirubin (total and direct), cholesterol, low density lipoprotein, triglycerides, leptin, Cox-2, and CD40 values was recorded. Moreover, overexpression of hepatic tumor necrosis factor alpha and hepatocyte growth factor genes were recorded, whereas blood platelet count and serum high density lipoprotein concentration revealed significant depletion, which was paralleled by significant downregulation of hepatic adiponectin gene expression level in NASH group versus the control group. On the opposite side, treatment of NASH groups with two different doses of Camellia sinensis extract reversed the values of the measured biochemical parameters and the targeted gene expression levels when compared with the NASH group. Optical micrograph of liver tissue sections of rats treated with Camellia sinensis extract showed the observed improvement in the studied biochemical and genetic markers. This study provides a clear evidence for the promising therapeutic potential of Camellia sinensis extract against NASH. This could be ascribed to its hepatoprotective activity, hypolipidemic effect, and anti-inflammatory potency.

Protective effect of resveratrol against hepatic damage induced by heat stress in a rat model is associated with the regulation of oxidative stress and inflammation.

Heat stress jeopardizes humans and animals health, and results in enormous economic loss in public health care and livestock production. The aim of this study was to investigate the effects of resveratrol on hepatic oxidative stress and inflammation in heat-stressed rats. Male Sprague-Dawley rats were orally fed with 100 mg resveratrol/kg body weight/day prior to heat stress (40 ∘C per day for 1.5 h) exposure for 3 consecutive days. Serum and liver samples were collected for the analysis of hepatic injury, redox status and immune response. The results showed that the heat-stress-induced increased aspartate aminotransferase activities in the serum, aberrant hepatic histology, excessive hepatic malondialdehyde and tumor necrosis factor alpha concentrations, and up-regulation of heat shock protein 70, superoxide dismutase 1, glutathione peroxidase 1, toll-like receptor 4 and interleukin 10 mRNA expression in the liver were mitigated by oral resveratrol treatment. Collectively, the beneficial effects of resveratrol on hepatic damage induced by heat stress were associated with the regulation of oxidative stress and inflammation.

Antioxidant, antiapoptotic, antigenotoxic, and hepatic ameliorative effects of L-carnitine and selenium on cadmium-induced hepatotoxicity and alterations in liver cell structure in male mice

L-carnitine (LC) and selenium (Se) have significant protective and antioxidant effects on several tissues. Cadmium (Cd), widely used in some industries and emitted from fossil fuels, is a heavy metal having a number of side effects, including hepatotoxicity. This study aims to assess the ameliorative function of both LC and SeCl4 on cadmium chloride (CdCl2)-induced liver toxicity. In total, 70 male mice included in this study were allocated to seven groups: control, CdCl2, LC, SeCl4, CdCl2 plus SeCl4, CdCl2 plus LC, CdCl2 plus SeCl4 and LC groups. Hepatic aminotransferase (aspartate aminotransferase [AST] and alanine transaminase [ALT]) activity and tumor necrosis factor-alpha [TNF-α] levels, as well as the antioxidant biomarkers (superoxide dismutase [SOD], glutathione reductase [GRx], glutathione-S-transferase [GST] and catalase [CAT], were examined. Histological and transmission electron microscopic [TEM] variations in the liver were used as indicators of liver damage after the administration of CdCl2-alone or CdCl2 with LC, SeCl4, or both. Genotoxic effects of CdCl2 were also evaluated and the possible roles of SeCl4 and/or LC on the expression of the antioxidant enzymes were studied. Results showed that administration of LC and SeCl4 decreased CdCl2-induced increase in ALT and AST levels and reduced oxidative stress to normal levels. In addition, LC combined with SeCl4 had a highly synergistic effect and elevated significantly the enzymatic antioxidants and decreased lipid peroxidation levels compared with those in the CdCl2-treated group. It is clear from the data that both LC and SeCl4 inhibit liver injury and improve the redox state in mice.

The therapeutic effects of resveratrol on hepatic steatosis in high-fat diet-induced obese mice by improving oxidative stress, inflammation and lipid-related gene transcriptional expression.

So far, the majority of the previous animal studies have focused on the preventive effects of resveratrol (RSV) on non-alcoholic fatty liver disease (NAFLD) rather than the therapeutic effects. In this study, the therapeutic effects of RSV on hepatic oxidative stress (OS), inflammation, and lipid metabolism-related gene expression of obese mice induced by a high-fat diet (HFD) were investigated. Male C57BL/6 mice were fed a HFD for 8 weeks to induce obesity-related NAFLD model. And then, NAFLD mice were treated with daily RSV oral gavage at the dose of 100mg/kg body weight for an additional 4 weeks. HFD-induced the elevation of serum total cholesterol, high-density lipoprotein cholesterol, glucose, insulin, aspartate aminotransferase and alanine aminotransferase levels, and homeostasis model assessment of insulin resistance, hepatic histology changes, the increases in hepatic triglyceride, malondialdehyde and tumor necrosis factor alpha concentrations, as well as the higher mRNA expression of hepatic toll-like receptor 4 and cluster of differentiation 36 in mice, were restored by RSV. The therapeutic effects of RSV against hepatic steatosis of HFD obese mice were attributed to the reduction of OS, inflammation and free fatty acid uptake.

Lactobacillus plantarum attenuates oxidative stress and liver injury in rats with nonalcoholic steatohepatitis

Pharmacognosy Magazine,2018,14,58,471-476.DOI:10.4103/pm.pm_279_18Published:November 2018Type:Original ArticleAuthors:Duangporn Werawatganon, Kanjana Somanawat, Somying Tumwasorn, Naruemon Klaikeaw, and Prasong Siriviriyakul Author(s) affiliations:Duangporn Werawatganon1, Kanjana Somanawat1, Somying Tumwasorn2, Naruemon Klaikeaw3, Prasong Siriviriyakul1 1 Department of Physiology, Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases Research Unit, Bangkok, Thailand 2 Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand 3 Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Abstract:Background: Steatohepatitis is a morphological pattern of liver injury that, in non-alcoholic patients, may represent a form of chronic liver disease currently known as non-alcoholic steatohepatitis (NASH). Probiotics, Lactobacillus sp. and Bifidobacterium sp., have been proposed to prevent and treat different inflammatory conditions of the gastrointestinal tract. Objective: To examine the effect of Lactobacillus plantarum (L. plantarum) on the liver damage of non-alcoholic steatohepatitis (NASH) rats. Materials and Methods: Male Sprague-Dawley rats were randomly divided into three groups. Group 1 (control, n = 8) was fed with phosphate-buffered saline (PBS) 1 mL/rat. Group 2 (NASH, n = 8) was fed with 100% fat diet for 6 weeks. Group 3 (NASH + L. plantarum, n = 8) was fed with 100% fat diet plus L. plantarum 1.8 × 109 colony-forming unit/mL was suspended in PBS by gavage twice a day at an interval of 4 h for 6 weeks. All rats were sacrificed to collect blood and liver samples at the end of the treatment period. Results: The levels of hepatic malondialdehyde (MDA) and tumor necrosis factor alpha (TNF-α) were increased while the expression of peroxisome proliferator activated receptors gamma (PPAR-γ) was decreased significantly in the NASH group as compared with the control group. Histopathology from the NASH group showed macrovesicular steatosis, hepatocyte ballooning, and lobular inflammation. The NASH + L. plantarum group had attenuated the levels of MDA and TNF-α, enhanced PPAR-γ expression, and improved the histopathology. Conclusion: L. plantarum treatment can attenuate oxidative stress, inflammation, and improvement of histopathology in rats with NASH. Keywords:Lactobacillus plantarum, liver injury, Nonalcoholic steatohepatitis, oxidative stress, ratsView:PDF (1.86 MB)

Prophylactic tributyrin treatment mitigates chronic-binge ethanol-induced intestinal barrier and liver injury.

Impaired gut-liver axis is a potential factor contributing to alcoholic liver disease. Ethanol depletes intestinal integrity and causes gut dysbiosis. Butyrate, a fermentation byproduct of gut microbiota, is altered negatively following chronic ethanol exposure. This study aimed to determine whether prophylactic tributyrin could protect the intestinal barrier and liver in mice during combined chronic-binge ethanol exposure. C57BL/6J mice exposed to 5% v/v ethanol-containing diet for 10days received a single ethanol gavage (5g/kg) 9h before euthanasia. Control mice were isocalorically pair-fed maltose dextrin for ethanol. Diets were supplemented (5mM) with tributyrin or glycerol. Intestine and liver disease activity was assessed histologically. Protein and mRNA expression of tight junction (TJ) proteins, toll-like receptors, and tumor necrosis factor-alpha were assessed. Caco-2 monolayers with or without ethanol exposure and/or sodium butyrate were used to test butyrate's direct effects on intestinal integrity. Chronic-binge ethanol feeding impaired intestinal TJ protein co-localization staining; however, tributyrin co-treatment mitigated these effects. Ethanol depleted TJ and transepithelial electrical resistance in Caco-2 monolayers, but butyrate co-treatment reduced these effects. Hepatic toll-like receptor mRNA expression and tumor necrosis factor-alpha protein expression was induced by ethanol; however, the response was significantly dampened in mice co-treated with tributyrin. Tributyrin altered localization of both neutrophils and single hepatocyte death: Leukocytes and apoptotic hepatocytes localized predominantly around the portal tract in ethanol-only treated mice, whereas localization predominated around the central vein in ethanol-tributyrin mice. Prophylactic tributyrin supplementation mitigated effects of combined chronic-binge ethanol exposure on disruption of intestinal TJ localization and intestinal permeability and liver injury.

Apigenin protects against alcohol-induced liver injury in mice by regulating hepatic CYP2E1-mediated oxidative stress and PPARα-mediated lipogenic gene expression

Alcohol is a major cause of liver injury, and there are currently no ideal pharmacological reagents that can prevent or reverse this disease. Apigenin is one of the most common flavonoids present in numerous plants and has many beneficial effects. But whether or not apigenin may protect against alcohol-induced liver injury remains unknown. Our aim was to examine the effect and potential mechanisms. The experimental mice were given 56% erguotou wine or simultaneously given apigenin 150–300 mg/kg by gavage for 30 days. The results showed that in the apigenin-treated mice, the expression of hepatic cytochrome P450 2E1 (CYP2E1) and nuclear factor kappa B proteins as well as contents of hepatic malondialdehyde and tumor necrosis factor-alpha were reduced, while the levels of hepatic reduced glutathione, glutathione reductase, glutathione peroxidase, and glutathione S-transferase were increased, especially in the 300 mg/kg group. A significant change in hepatic steatosis was also observed in the apigenin 300 mg/kg group. Apigenin pretreatment could increase the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase-1 proteins, and decrease the expression of hepatic sterol regulatory element binding protein-1c, fatty acid synthase, and diacylglycerol acyltransferase proteins. These findings demonstrated that apigenin might exert a protective effect on alcohol-induced liver injury, and its mechanisms might be related to the regulations of hepatic CYP2E1-mediated oxidative stress and PPARα-mediated lipogenic gene expression.

The Effects of Onion Consumption on Prevention of Nonalcoholic Fatty Liver Disease.

It is well known that dietary intakes play a pivotal role in pathogenesis of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH); however, the role of each component of diet has not yet been elucidated. Our objective was to evaluate the effects of onion consumption on prevention of NAFLD/NASH development. Sprague-Dawley rats were fed either high-fat, high sugar diet (model group), or high-fat, high sugar diet plus 7% onion powder (model+onion), or chow diet ad libitum for 7weeks. Serum levels of fasting glucose, triglyceride, cholesterol, liver enzymes, insulin, and hepatic tumor necrosis factor-alpha (TNF-α) gene expression were determined. Hepatic histology was examined by H&E stain. Model+onion group had significantly lower hepatic steatosis, ballooning, lobular inflammation, and portal inflammation (p<0.001), lower hepatic TNF-α gene expression (p<0.001), lower plasma levels of ALT (p=0.026), AST (p=0.041), insulin (p<0.001), TG (p=0.041), and glucose (p=0.009) compared with model group; however, weight gain, food intake, plasma total cholesterol and LDL levels were not significantly different between these two groups. Our data indicate that regular consumption of onion can prevent NAFLD even in the presence of the other risk factors such as obesity, hypercholesterolemia, and high energy, fat, and sugar intakes.

Taurine Inhibits Kupffer Cells Activation Induced by Lipopolysaccharide in Alcoholic Liver Damaged Rats.

Taurine, a β free amino-acid, takes various biological functions including maintain the normal hepatic structure and function. In this study, the regulation mechanism of taurine on lipopolysaccharide (LPS) induced activation of Kupffer cells (KC) in the liver of rats with alcoholic liver disease (ALD) were explored. Male wistar rats were intragastrically administered with alcohol and pyrazole, and ate high-fat diet in order to establish ALD model. Taurine were administered in drinking water simultaneous with and after ALD model establishment. The preventive trial was lasted for 12 weeks, while the curative trial was lasted for 4 weeks. Finally, blood and liver were collected in order to detect the concentrations of plasma LPS and hepatic tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Hepatic total RNA were extracted, gene expressions of LPS binding protein (LBP), leukocyte differentiation antigen 14 (CD14), toll-like receptors (TLR4), nuclear transcription factor (NF-κB) and TNF-α were detected by semi-quantitative RT-PCR. The results showed significant elevated levels of plasma LPS, hepatic TNF-α, IL-1β and IL-6 in ALD rats (P < 0.05), and heightened gene expressions of LBP, CD14, TLR4, NF-κB and TNF-α (P < 0.05); Taurine no matter administered preventively or curatively can reduce the levels of plasma LPS, hepatic TNF-α, IL-1β, IL-6, and down-regulate the gene expressions of LBP, CD14, TLR4, NF-κB and TNF-α. The results demonstrated that taurine can prevent and cure ALD by reducing the production and transformation of LPS as well as inhibiting the opening and the transmission of LPS induced KC activation and the downstream signaling pathway.

Dasatinib prevent hepatic fibrosis induced by carbon tetrachloride (CCl4) via anti-inflammatory and antioxidant mechanism

SummaryObjectives: Dasatinib, a potent and broad-spectrum tyrosine kinase inhibitor, is approved for the treatment of imatinib-resistant chronic myelogenous leukemia. The aim of this study was to evaluate the anti-fibrotic, anti-inflammatory and antioxidant effects of this agent against CCl4-induced hepatic fibrosis and oxidative status.Materials and methods: Experimental fibrosis was induced in Wistar male rats by 12 weeks of CCl4 administration (i.p.). During the last 8 weeks of injection, rats were gavaged daily with Dasatinib (10 mg/kg). To evaluate anti-inflammatory and anti-fibrotic effects of Dasatinib, histopathological examination of liver tissue was performed and serum ALT and AST activities, oxidant, antioxidant parameters and hepatic tumor necrosis factor alpha (TNF-α) were examined. Moreover, transforming growth factor (TGF-β1), platelet derived growth factor (PDGF) and TNF-α mRNA expressions were also evaluated by real time polymerase chain reaction.Results: Dasatinib administration induced a significant reduction of ALT and AST activities (p < .001) and Malondialdehyde (MDA) content in CCl4 injected rats (p < .05). Concomitantly hepatic protein and mRNA expression of TNF-α, mRNA expression of TGF-β1 and PDGF were increased due to CCl4 intoxication (p < .001), but Dasatinib treatment could significantly ameliorate these mediators at the level of gene expression (p < .01) and protein level of TNF-α (p < .001). The necro-inflammatory changes in histopathological finding, nitric oxide and hydroxyproline level were also increased during 12 weeks of CCl4 administration which was significantly attenuated by Dasatinib (p < .01).Discussion and conclusion: Our findings indicate that Dasatinib can be cautiously an anti-fibrotic, anti-inflammatory and anti-oxidative agent in clinical setting.

Immune and metabolic responses in early and late sepsis during mild dietary zinc restriction

BackgroundMild dietary zinc (Zn) deficiency is widespread in human populations, but its influence on recovery after acute illness is poorly understood. In a mouse model of abdominal sepsis (cecal ligation puncture), systemic immune responses and liver metabolism were monitored in early (24 h) and late (5 d) phases, under control conditions and during mild dietary Zn restriction. MethodsMice were fed diets adequate or marginally deficient (ZM) in Zn (30 versus 10 mg zinc/kg diet) for 4 wk, before undergoing laparotomy alone (nonseptic control) or cecal ligation puncture (septic). ResultsAmong nonseptic mice, the ZM state was not associated with differences in inflammation or metabolic responses. Among septic mice, mortality did not differ between the zinc adequate and ZM groups. In the early phase, the ZM state amplified increases in plasma interleukin (IL) 6, tumor necrosis factor alpha, and IL-10, while dampening the interferon gamma response. In the late phase, subtle but significant ZM-associated increases were observed in plasma IL-5 and interferon gamma levels and hepatic protein synthesis, the latter of which appeared to be mammalian target of rapamycin independent and was associated with increased hepatic tumor necrosis factor alpha messenger RNA content. ConclusionsWithout increasing mortality, the ZM state is associated with a more disordered acute systemic inflammatory response and persistence or enhancement of acute phase responses within the liver parenchyma.

Heme oxygenase 1 protects ethanol-administered liver tissue inAldh2 knockout mice.

A genetic polymorphism of the aldehyde dehydrogenase 2 (​ALDH2) gene, ALDH2*2, encodes an enzymatically defective ALDH2 protein. Recent epidemiological studies suggest that possessing ALDH2*2 is a protective factor for liver tissue in healthy individuals, although these studies lack a mechanistic explanation. Our animal studies have shown the same trend: levels of serum alanine transaminase (ALT), hepatic malondialdehyde (MDA), and hepatic tumor necrosis factor alpha (TNF-α) were lower in Aldh2 knockout (Aldh2(-/-)) mice than in wild-type (Aldh2(+/+)) mice after ethanol administration. To propose a mechanistic hypothesis, residual liver specimens from the previous experiment were analyzed. An anti-oxidative protein, heme oxygenase 1 (HO-1), and an oxidative stress-producing protein, cytochrome P450 2E1 (CYP2E1), were detected at higher levels in Aldh2(-/-) mice than in Aldh2(+/+) mice, regardless of ethanol treatment. Other oxidative stress-related proteins and inflammatory cytokines did not show such a significant difference. To conclude, we propose a protective role of HO-1 in individuals with A​LDH2*2. Our continued studies support the epidemiological finding that possession of ALDH2*2 is a protective factor in the liver of the healthy individual.

An Accessible and Pragmatic Experimental Model of Nonalcoholic Fatty Liver Disease.

BACKGROUND There is no convenient cheap pragmatic experimental model for Nonalcoholic Fatty Liver Disease (NAFLD)/Nonalcoholic Steatohepatitis (NASH). Objective: Our objective was to create a pragmatic model of NAFLD/NASH. METHODS Sprague-Dawley rats were fed a high-fat, high sugar homemade diet ad libitum for seven weeks. The high-fat, high sugar diet included 59% of energy derived from fat, 30% from carbohydrates, and 11% from protein. Serum levels of fasting glucose, triglyceride, cholesterol, liver enzymes, insulin, and hepatic tumor necrosis factor-alpha (TNF-α) gene expression were determined. Hepatic histology was examined by H&E stain. RESULTS Rats fed the high-fat, high sugar diet developed hepatic steatosis, and a moderate inflammation, which was associated with increased serum levels of liver enzymes, glucose, insulin, triglyceride, cholesterol, and hepatic TNF-α gene expression. CONCLUSION This rat model resembles the key features of human NAFLD/NASH and provides a simple pragmatic experimental model for elucidating the disease prevention and treatment.

The effects of onion consumption on treatment of metabolic, histologic, and inflammatory features of nonalcoholic fatty liver disease.

BackgroundThe aim of this study was to evaluate the effects of onion powder consumption on treatment of Non-alcoholic Fatty Liver Disease (NAFLD) in an experimental model of disease.MethodsSprague–Dawley rats were fed high-fat (HF) diet for seven weeks to induce the NAFLD. Then, they were treated by either the same diet (HF), or high-fat diet plus 7 % onion powder (HF + onion), or chow diet (control), or chow diet plus 7 % onion powder (control + onion)ad libitum for four weeks. Serum levels of fasting glucose, triglyceride, cholesterol, liver enzymes, insulin, and hepatic tumor necrosis factor-alpha (TNF-α) gene expression were determined. Hepatic histology was examined by Hematoxylin and Eosin stain.ResultsDietary food intakes and weigh gain were significantly more in animals fed control + onion diet in comparison to the other groups. Animals fed control or control + onion diet had significantly lower plasma levels of hepatic enzymes, lipid profile, glycemic indices, and hepatic TNF-α gene expression as compared with HF diet fed groups; however, there was no significant difference in the histopathologic features of NAFLD among different groups.ConclusionOur results indicate that onion consumption can be effective in NAFLD management when it is combined with a healthy diet.Electronic supplementary materialThe online version of this article (doi:10.1186/s40200-016-0248-4) contains supplementary material, which is available to authorized users.