Hepatic Tumor Necrosis Factor Research Articles

Evaluation of antioxidant properties from purple tubers and their ability to improve glucose and lipid metabolism in streptozotocin-induced diabetic rats

BackgroundPurple tubers have been used as a rich-nutrition source and are believed to have antioxidant properties. ObjectivesThe research aimed to evaluate the computational modelling and antioxidant activity of purple sweet potato (PSP), purple yam (PY), and taro. The selected tuber was then evaluated by in vivo experiment using streptozotocin-induced diabetic rats. Material and methodsMolecular docking of α-glucosidase, dipeptidyl peptidase 4 (DPP4), and 3‑hydroxy-3-methylglutaryl coenzyme-A reductase (HMGCR) protein was examined with various active compounds in PSP, PY, and taro. Antioxidant activity was measured using 2,2-diphenyl-1-picryhydrazyl (DPPH). The highest activity of antioxidant was then continued as treatment in streptozotocin (STZ)-induced diabetic rats. ResultsProtein-ligand docking demonstrated that the amino acid residues of α-glucosidase, DPP4, and HMGCR with drug control also appeared in purple tubers active compounds. Antioxidant activity of PSP were higher (77.23 %) than PY (32.22 %) and taro (14.72 %). In diabetic rats, the blood glucose level, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic oxaloacetic transaminase (SGPT), low-density lipoprotein (LDL), total cholesterol (TC), and triglyceride (TG) was higher than normal group while high-density lipoprotein (HDL) levels decreased. The number of hepatic necrosis cells and tumor necrosis factor α (TNF-α) increased compared to normal group, while PSP extract showed a significant decrease in blood glucose, SGOT, SGPT, LDL, TC, and TG and increased HDL. Proinflammatory cytokine TNF-α also decreases following the improvement of hepatic cells structure. ConclusionPurple tubers could be an alternative treatment for hyperglycemia and hyperlipidemia. Purple tubers, especially PSP, have high antioxidant activity and can be promising as an antidiabetic agent.

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.

Orange Peel Extract and Physical Exercise Synergistically Ameliorate Type 2 Diabetes Mellitus-Induced Dysmetabolism by Upregulating GLUT4 Concentration in Male Wistar Rats.

Diabetes mellitus (DM) is a chronic disease and one of the oldest known disorders. It is characterized by dysglycemia, dyslipidemia, insulin resistance (IR), and pancreatic cell dysfunction. Although different drugs, metformin (MET), glipizide, glimepiride, etc., have been introduced to treat type 2 DM (T2DM), these drugs are not without side effects. Scientists are now seeking natural treatments such as lifestyle modification and organic products known with limited side effects. Thirty-six male Wistar rats were randomized into six groups (n = 6 per group): control, DM untreated rats, DM+orange peel extract (OPE), DM+exercise (EX), DM+OPE +EX, and DM+MET. The administration was once daily through the oral route and lasted for 28 days. EX and OPE synergistically ameliorated the diabetic-induced increase in fasting blood sugar, homeostatic model assessment for insulin resistance (HOMA IR), total cholesterol (TC) and triglyceride (TG), TC/high-density lipoprotein (HDL), TG/HDL, triglyceride glucose (TyG) index, and hepatic lactate dehydrogenase, alanine transaminase, malondialdehyde, c-reactive protein, and tumour necrosis factor α when compared with the diabetic untreated group. Also, EX+OPE blunted DM-induced decrease in serum insulin, homeostasis model assessment of β-cell function (HOMA-B), homeostasis model assessment of insulin sensitivity (HOMA S), quantitative insulin-sensitivity check index (QUICK 1), HDL, total antioxidant capacity, superoxide dismutase, and hepatic glycogen. Furthermore, EX+OPE ameliorated the observed DM-induced decrease in glucose transporter type 4 (GLUT 4), expression. This study showed that OPE and EX synergistically ameliorate T2DM-induced dysglycaemia, dyslipidaemia, and down-regulation of GLUT4 expression.

Is oxidative stress involved in the hepatic inflammatory response to apical periodontitis? A comparative study in normal and hyperlipidaemic rat.

The aim of the study was to explore the involvement of oxidative stress (OS) in the hepatic inflammation induced by apical periodontitis (AP). Periapical, systemic and hepatic reaction to AP under hyperlipidaemia was also investigated. A total of 16 male Sprague-Dawley rats were fed with a hyperlipidaemic diet (HD) whereas another 16 rats with a normal diet (ND). After 9 weeks, the first molars of the right maxilla and mandible of 8 HD and 8 ND rats were exposed to induce AP (ND, ND + AP, HD and HD + AP group). After 5 weeks, rats were euthanized, the haematological tissue was collected directly from the heart, and serum levels of inflammatory cytokines were measured. Liver tissue was analysed by haematoxylin-eosin and Masson staining, and reverse transcription-polymerase chain reaction (RT-PCR) was performed to detect mRNA expression of inflammatory cytokines. Serum, periapical, and hepatic OS parameters including total oxidant status (TOS), total antioxidant capacity (TAOC) and oxidative stress index (OSI) were measured by enzyme-linked immunosorbent assay (ELISA). The area of AP lesion in the right maxilla or mandible was radiographically assessed. Student's t-test was performed on the periapical data. A one-way analysis of variance and the Kruskal-Wallis test were analysed for others. The HD + AP group had a larger AP lesion in the maxilla, compared with the ND + AP group (p < .05). The ND + AP group presented higher serum interleukin (IL)-18, IL-1β, TOS, OSI levels, lower serum TOAC levels, higher hepatic tumour necrosis factor (TNF)-α mRNA expression and higher hepatic TOS, and OSI levels, compared with the ND group (p < .05). The HD + AP group had lower serum IL-4 level, higher serum IL-1β level, and higher hepatic IL-6 and transforming growth factor (TGF) -β1 mRNA expression, compared with the HD group (p < .05). Apical periodontitis could activate systemic and liver inflammation by promoting serum IL-18, 1L-1β, TOS and OSI expression, enhancing hepatic TOS and OSI expression and inhibiting serum TOAC expression. AP under hyperlipidaemia led to more profound periapical bone destruction in the maxilla and elicit systemic and liver inflammatory responses through elevating serum levels of IL-1β, descending serum IL-4 level and improving hepatic IL-6 and TGF-β1 expression.

The Preliminary Results for Evaluating Cocoa Butter's Hepatoprotective Effects against Lipid Accumulation and Inflammation in Adult Male Rats Chronically Fed Ethanol.

The purpose of this study was to clarify the role of saturated fats from cocoa butter (plant source) compared with lard (animal source) on alcoholic liver damage in rats. Male Wistar rats were fed either a control diet (C) or an ethanol diet (E), and the dietary fats (corn oil, olive oil, and safflower oil) of these two diets were further replaced by lard (CL, EL) or cocoa butter (CC, EC). After 8-week feeding, plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, hepatic triglyceride (TG) levels, plasma intercellular adhesion molecular (ICAM)-1 levels, hepatic cytochrome P450 2E1 (CYP2E1) protein expression, and hepatic interleukin (IL)-1β significantly increased in the E group compared to the C group. In addition, hepatic histopathological scores of fatty changes, inflammatory cell infiltration, and degeneration and necrosis in the E group were significantly higher compared to those in the C group. However, fatty changes were significantly inhibited only in the EC group as well as hepatic inflammatory cell infiltration, degeneration, and necrosis being significantly lower in the EL and EC groups. Plasma ICAM-1 and hepatic tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-10 levels were significantly lower in the EL and EC groups than those in the E group. Moreover, a correlation analysis showed that hepatic histopathological scores of degeneration and necrosis were significantly positively correlated with erythrocytic oleic acid (C18:1) and were negatively correlated with linoleic acid (C18:2). In conclusion, cocoa butter protected the liver against lipid accumulation and inflammation in rats chronically fed ethanol.

Dunaliella salina Microalga Restores the Metabolic Equilibrium and Ameliorates the Hepatic Inflammatory Response Induced by Zinc Oxide Nanoparticles (ZnO-NPs) in Male Zebrafish.

Simple SummaryDunaliella salina, a type of halophile green unicellular microalgae riches in carotenoids, was used to assess its ability to restore the metabolic equilibrium and mitigate the hepatic inflammation induced by zinc oxide nanoparticles (ZnO-NPs) in the male zebrafish. In our study, after 2 weeks of feeding, the body burdens of zinc residues, fish appetite, intestinal bacteria composition, and energy metabolism were restored. Additionally, the hepatic inflammation and histopathological malformations were ameliorated after D. salina administration.Microalgae are rich in bioactive compounds including pigments, proteins, lipids, polyunsaturated fatty acids, carbohydrates, and vitamins. Due to their non-toxic and nutritious characteristics, these are suggested as important food for many aquatic animals. Dunaliella salina is a well-known microalga that accumulates valuable amounts of carotenoids. We investigated whether it could restore the metabolic equilibrium and mitigate the hepatic inflammation induced by zinc oxide nanoparticles (ZnO-NPs) using male zebrafish which were exposed to 1/5th 96 h-LC50 for 4 weeks, followed by dietary supplementation with D. salina at two concentrations (15% and 30%) for 2 weeks. Collectively, ZnO-NPs affected fish appetite, whole body composition, hepatic glycogen and lipid contents, intestinal bacterial and Aeromonas counts, as well as hepatic tumor necrosis factor- α (TNF-α). In addition, the mRNA expression of genes related to gluconeogenesis (pck1, gys2, and g6pc3), lipogenesis (srepf1, acaca, fasn, and cd36), and inflammatory response (tnf-α, tnf-β, nf-kb2) were modulated. D. salina reduced the body burden of zinc residues, restored the fish appetite and normal liver architecture, and mitigated the toxic impacts of ZnO-NPs on whole-body composition, intestinal bacteria, energy metabolism, and hepatic inflammatory markers. Our results revealed that the administration of D. salina might be effective in neutralizing the hepatotoxic effects of ZnO-NPs in the zebrafish model.

Monascus vinegar alleviates high-fat-diet-induced inflammation in rats by regulating the NF-κB and PI3K/AKT/mTOR pathways

Monascus vinegar (MV) is a typical fermented food with various health-promoting effects. This study aimed to evaluate the role of MV in alleviating high-fat-diet-induced inflammation in rats with hyperlipidemia and elucidate the possible regulatory mechanisms. In the study, serum lipid profiles, liver pathology and liver inflammatory cytokines were analyzed in hyperlipidemia rats with MV (0.5 mL/kg mb, 2 mL/kg mb). Results showed that the administration of MV alleviated dyslipidemia by decreasing the serum and liver levels of triglyceride and total cholesterol. Increase in hepatic lipase and carnitine palmitoyl transferase 1 (CPT-1) levels and decrease in hepatocyte steatosis, nephritis, and intestinal tissue injury in the HD group showed that high-dose MV can significantly suppress hepatic lipid accumulation and steatosis. In addition, compared with the model (MOD) group, the HD group showed significantly down-regulated the level of serum or hepatic alanine aminotransferase (ALT), aspartate aminotransferase (AST), CPT-1, interleukin (IL)-2, IL-6, IL-12, and tumor necrosis factor α (TNF-α). Moreover, the HD group showed repressed hepatic nuclear factor κB (NF-κB) pathway and inactivated phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway mitigated liver inflammation. Similar results were obtained from cell experiments. Collectively, these findings revealed that MV might attenuate high-fat-diet-induced inflammation by inhibiting the NF-κB and PI3K/Akt/mTOR pathways.

Protection of mice against carbon tetrachloride-induced acute liver injury by endogenous and exogenous estrogens

Gender is a crucial factor determining susceptibility to drug-induced liver injury (DILI) in humans and experimental animals. However, no general concept of sex differences in DILI has been established, as metabolic events specific to one DILI model are difficult to apply to other DILI models. Herein, we examined sex differences in carbon tetrachloride (CCl4)-induced hepatotoxicity, a widely employed DILI model. Male and female CD-1 mice were intraperitoneally administered CCl4. Additionally, some male mice were administered genistein or another isoflavone to evaluate the effects of exogenous estrogens. Dose-dependent alanine aminotransferase leakage was observed at a CCl4 range of 0.5–10 mmol/kg, with male-dominant sex differences mainly observed at lower doses. No sex differences in hepatic glutathione levels or thiobarbituric acid-reactive substance formation were detected. CCl4 induced hepatic inflammatory genes, interleukin (IL)-6 and tumor necrosis factor (TNF)-α, predominantly in female mice, which might be involved in DILI resistance, observed in female mice. Treatment of male mice with phytoestrogens, especially genistein, attenuated CCl4-induced hepatotoxicity. Moreover, genistein inhibited IL-6 and TNF-α expression, suggesting possible hepatoprotection via immunosuppression. In conclusion, female mice are resistant to CCl4-induced hepatotoxicity, and male mice were afforded protection by genistein, probably via mechanisms based on anti-estrogenic, antioxidant and/or anti-inflammatory effects.

Rimonabant ameliorates hepatic ischemia/reperfusion injury in rats: Involvement of autophagy via modulating ERK- and PI3K/AKT-mTOR pathways

Hepatic ischemia/reperfusion (HIR), which can result in severe liver injury and dysfunction, is usually associated with autophagy and endocannabinoid system derangements. Whether or not the modulation of the autophagic response following HIR injury is involved in the hepatoprotective effect of the cannabinoid receptor 1(CB1R) antagonist rimonabant remains elusive and is the aim of the current study. Rats pre-treated with rimonabant (3 mg/kg) or vehicle underwent 30 min hepatic ischemia followed by 6 hrs. reperfusion. Liver injury was evaluated by serum ALT, AST, bilirubin (total and direct levels) and histopathological examination. The inflammatory, profibrotic and oxidative responses were investigated by assessing hepatic tumor necrosis factor α (TNFα), nuclear factor kappa B (NF-κB), transforming growth factor (TGF-β), lipid peroxidation and reduced glutathione. The hepatic levels of CB1R and autophagic markers p62, Beclin-1, and LC3 as well as the autophagic signaling inhibitors ERK1/2, PI3K, Akt and mTOR were also determined. Rimonabant significantly attenuated HIR-induced increases in hepatic injury, inflammation, profibrotic responses and oxidative stress and improved the associated pathological features. Rimonabant modulated the expression of p62, Beclin-1, and LC3, down-regulated CB1R, and dcreased pERK1/2, PI3K, Akt, and mTOR activities. The current study suggests that rimonabant can protect the liver from IR injury at least in part by inducing autophagy, probably by modulating ERK- and/or PI3K/AKT-mTOR signaling.

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.

Mesenchymal stem cells alleviate liver injury induced by chronic-binge ethanol feeding in mice via release of TSG6 and suppression of STAT3 activation

BackgroundMesenchymal stem cells (MSCs) are a population of pluripotent cells that might be used for treatment of liver disease. However, the efficacy of MSCs for mice with alcoholic hepatitis (AH) and its underlying mechanism remains unclear.MethodsMSCs were isolated from the bone marrow (BM) of 4–6-week-old male C57BL/6 N mice. AH was induced in female mice by chronic-binge ethanol feeding for 10 days. The mice were given intraperitoneal injections of MSCs with or without transfection or AG490, recombinant mouse tumor necrosis factor (TNF)-α-stimulated gene/protein 6 (rmTSG-6), or saline at day 10. Blood samples and hepatic tissues were collected at day 11. Various assays such as biochemistry, histology, and flow cytometry were performed.ResultsMSCs reduced AH in mice, decreasing liver/body weight ratio, liver injury, blood and hepatic lipids, malondialdehyde, interleukin (IL)-6, and TNF-ɑ, but increasing glutathione, IL-10, and TSG-6, compared to control mice. Few MSCs engrafted into the inflamed liver. Knockdown of TSG-6 in MSCs significantly attenuated their effects, and injection of rmTSG-6 achieved similar effects to MSCs. The signal transducer and activator of transcription 3 (STAT3) was activated in mice with AH, and MSCs and rmTSG-6 inhibited the STAT3 activation. Injection of MSCs plus AG490 obtained more alleviation of liver injury than MSCs alone.ConclusionsBM-MSCs injected into mice with AH do not engraft the liver, but they secrete TSG-6 to reduce liver injury and to inhibit STAT3 activation.

Curcumin prevents high-fat diet-induced hepatic steatosis in ApoE\u2212/\u2212 mice by improving intestinal barrier function and reducing endotoxin and liver TLR4/NF-\u03baB inflammation

BackgroundNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and has become a public health concern worldwide. The hallmark of NAFLD is hepatic steatosis. Therefore, there is an urgent need to develop new therapeutic strategies that are efficacious and have minimal side effects in hepatic steatosis and NAFLD treatment. The present study aimed to investigate the effect of dietary supplement of curcumin on high-fat diet (HFD)-induced hepatic steatosis and the underlying mechanism.MethodsApoE−/− mice were fed a normal diet, high-fat diet (HFD) or HFD supplemented with curcumin (0.1% w/w) for 16 weeks. Body and liver weight, blood biochemical.parameters, and liver lipids were measured. Intestinal permeability, hepatic steatosis and mRNA and protein expressions of TLR4-related inflammatory signaling molecule were analyzed.ResultsThe administration of curcumin significantly prevented HFD-induced body weight gain and reduced liver weight. Curcumin attenuated hepatic steatosis along with improved serum lipid profile. Moreover, curcumin up-regulated the expression of intestinal tight junction protein zonula occluden-1 and occludin, which further improved gut barrier dysfunction and reduced circulating lipopolysaccharide levels. Curcumin also markedly down-regulated the protein expression of hepatic TLR4 and myeloid differentiation factor 88 (MyD88), inhibited p65 nuclear translocation and DNA binding activity of nuclear factor-κB (NF-κB) in the liver. In addition, the mRNA expression of hepatic tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) as well as the plasma levels of TNF-α and IL-1β were also lowered by curcumin treatment.ConclusionThese results indicated that curcumin protects against HFD-induced hepatic steatosis by improving intestinal barrier function and reducing endotoxin and liver TLR4/NF-κB inflammation. The ability of curcumin to inhibit hepatic steatosis portrayed its potential as effective dietry intervention for NAFLD prevention.

Supplementation with Sodium Butyrate Modulates the Composition of the Gut Microbiota and Ameliorates High-Fat Diet-Induced Obesity in Mice

Short-chain fatty acids (SCFAs) have been reported to ameliorate obesity. However, the underlying mechanisms require further investigation. The aim of this study was to determine the role of butyrate, an SCFA, in the regulation of obesity, low-grade chronic inflammation, and alterations of microbiota composition in mice. Male C57BL/6J mice, 4-5 wk of age, were divided into 3 groups (n=8 mice/group): low-fat diet (LFD; 10% energy from fat), high-fat diet (HFD; 45% energy from fat), or high-fat diet plus sodium butyrate (HSB). HSB mice received sodium butyrate at a concentration of 0.1 M in drinking water for 12 wk. Measures of inflammation, obesity, and intestinal integrity were assessed. Serum lipopolysaccharide (LPS) concentrations were measured in the 3 groups. Fecal samples were collected for gut microbiota analysis. In HFD mice, body weight gain and hepatic triglyceride (TG), serum interleukin-6 (IL-6), and serum tumor necrosis factor (TNF)-α levels were 1-4 times higher than those in LFD mice (P<0.05); they were 34-42% lower in HSB mice compared with HFD mice (P<0.05). The HFD group had 28%-48% lower mRNA expression of both Tjp1 and Ocln in the ileum and colon compared with levels in LFD or HSB mice (P<0.05), whereas there was no difference in expression levels between LFD and HSB mice. Furthermore, in HSB mice, serum LPS concentration was 53% lower compared with that in HFD mice but still 23% higher than that in LFD mice (P<0.05). Results from principal component analysis showed that HSB and LFD mice had a similar gut microbiota structure, which was significantly different from that in HFD mice (P<0.05). Sodium butyrate administration beneficially changed HFD-induced gut microbiota composition and improved intestinal barrier, leading to lower serum LPS concentrations. These changes may correspond with improvements in obesity-related lipid accumulation and low-grade chronic inflammation.

Pectin oligosaccharide from hawthorn fruit ameliorates hepatic inflammation via NF-κB inactivation in high-fat diet fed mice

Abstract Effects of pectin oligosaccharide (POS) derived from hawthorn fruit on the nuclear factor kappa-B (NF-κB) pathway-related factors were investigated in the liver of mice fed a high-fat diet. The results showed that POS significantly reduced the total liver fat content and the levels of hepatic pro-inflammatory factors tumor necrosis factor (TNF)-α and interleukin-6 (IL-6), while increased the level of interleukin-10 (IL-10). Moreover, POS significantly down-regulated gene and protein expression of NF-κB, with concomitant decreased mRNA levels of receptor interacting protein kinase 1 (RIP1), NF-κB-inducing kinase (NIK), IκB kinase-α (IKKα), TNFα and its receptors 1 (TNFR1), receptor-associated factor 2 (TRAF2), compared to high fat control (HFC). However, expressions of AMP-activated protein kinase (AMPK) and silent information regulator T 1 (SIRT 1) were up-regulated by POS, compared to HFC. The results indicated that POS had significant inhibition effects on the liver inflammation in vivo, involving the inhibition on NF-kB activation.

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.

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.

Andrographolide impairs alpha-naphthylisothiocyanate-induced cholestatic liver injury in vivo.

To investigate if andrographolide impairs cholestatic liver injury. All rats were randomly divided into six groups-(1) control (n = 6), (2) control + 200mg/kg andrographolide (n = 6), (3) alpha-naphthylisothiocyanate (ANIT)-control (n = 6), (4) ANIT + 50mg/kg andrographolide (n = 6), (5) ANIT + 100mg/kg andrographolide (n = 6), and (6) ANIT + 200mg/kg andrographolide (n = 6). We gavaged 50mg/kg ANIT to mimic cholestatic liver injury in rats. Seven days after treatment, all the rats were killed. Serum biochemistry and hepatic histopathological assays were performed to evaluate liver injury. We observed that 200mg/kg andrographolide significantly decreased the level of alanine transaminase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltranspeptidase, total bilirubin, and total bile acid in the blood. It also markedly decreased hepatic interleukin-6 and tumor necrosis factor α. Furthermore, 200mg/kg andrographolide significantly decreased malondialdehyde but increased superoxide dismutase, glutathione, and erythrocyte glutathione peroxidase. Moreover, 200mg/kg andrographolide effectively increased the accumulation of sirtuin 1 and nuclear erythroid 2-related factor-2. It also attenuated the level of nuclear factor kappa-light-chain-enhancer of activated B and cyclooxygenase-2. These data suggest that andrographolide may impair cholestatic liver injury via anti-inflammatory and anti-oxidative stress.

Olive oil combined with Lycium barbarum polysaccharides attenuates liver apoptosis and inflammation induced by carbon tetrachloride in rats

Olive oil and Lycium barbarum polysaccharides were considered to be hepatoprotective for liver fibrosis. This study investigated anti-apoptotic, anti-inflammatory and anti-fibrotic effects of olive oil and/or Lycium barbarum polysaccharides (LBP) on CCl4-induced liver fibrosis in rats. The results showed that CCl4 caused liver fatty change, cell death, inflammation and collagen accumulation. The olive oil-treated groups reduced hepatic transforming growth factor (TGF)-β1 and tissue inhibitors of metalloproteinase (TIMP)-1 levels. The LBP-treated groups inhibited hepatic caspase-9 and caspase-3 activities, decreased hepatic tumor necrosis factor (TNF)-α levels, increased hepatic interleukin (IL)-10 levels and IL-10/TNF-α ratios, and reduced hepatic TGF-β1 and TIMP-1 levels. Olive oil combined with LBP suppressed liver apoptotic markers, inhibited liver inflammatory markers, and attenuated hepatic TGF-β1 levels. Therefore, LBP improves liver apoptotic, inflammatory and fibrotic markers, while olive oil combined with LBP has better effects on anti-apoptosis and anti-inflammation compared with olive oil treatment in rats with CCl4-induced liver fibrosis.

Spred2 Deficiency Exacerbates D-Galactosamine/Lipopolysaccharide -induced Acute Liver Injury in Mice via Increased Production of TNF\u03b1

Acute liver injury (ALI) is characterized by hepatocyte damage and inflammation. In the present study, we examined whether the absence of Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, influences ALI induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS). Compared to wild-type mice, Spred2−/− mice developed exacerbated liver injury represented by enhanced hepatocyte damage and inflammation. Enhanced ERK activation was observed in Spred2−/−-livers, and the MEK/ERK inhibitor U0126 ameliorated ALI. Hepatic tumour necrosis factor α (TNFα) and interleukin (IL)-1β levels were increased in Spred-2−/−-livers, and the neutralization of TNFα dramatically ameliorated ALI, which was associated with decreased levels of endogenous TNFα and IL-1β. When mice were challenged with D-GalN and TNFα, much severer ALI was observed in Spred2−/− mice with significant increases in endogenous TNFα and IL-1β in the livers. Immunohistochemically, Kupffer cells were found to produce TNFα, and isolated Kupffer cells from Spred2−/− mice produced significantly higher levels of TNFα than those from wild-type mice after LPS stimulation, which was significantly decreased by U0126. These results suggest that Spred2 negatively regulates D-GalN/LPS-induced ALI under the control of TNFα in Kupffer cells. Spred2 may present a therapeutic target for the treatment of ALI.