Liver TNF-α Research Articles

β-Cryptoxanthin ameliorates metabolic risk factors by regulating NF-κB and Nrf2 pathways in insulin resistance induced by high-fat diet in rodents

The aim of this experiment was to determine the effects of β-cryptoxanthin (BCX) on the cardiometabolic health risk factors and NF-κB and Nrf2 pathway in insulin resistance induced by high-fat diet (HFD) in rodents. Twenty-eight Sprague-Dawley rats were allocated into four groups: (1) Control, rats fed a standard diet for 12 weeks; (2) BCX, rats fed a standard diet and supplemented with BCX (2.5 mg/kg BW) for 12 weeks; (3) HFD, rats fed a HFD for 12 weeks, (4) HFD + BCX, rats fed a HFD and supplemented with BCX for 12 weeks. BCX reduced cardio-metabolic health markers and decreased inflammatory markers (P < 0.001). Rats fed a HFD had the lower total antioxidant capacity and antioxidant enzymes activities and higher MDA concentration than control rats (P < 0.001 for all). Comparing with the HFD group, BCX in combination with HFD inhibited liver NF-κB and TNF-α expression by 22% and 14% and enhanced liver Nrf2, HO-1, PPAR-α, and p-IRS-1 by 1.43, 1.41, 3.53, and 1.33 fold, respectively (P < 0.001). Furthermore, in adipose tissue, BCX up-regulated Nrf2, HO-1, PPAR-α, and p-IRS-1 expression, whereas, down-regulated NF-κB and TNF-α expression. In conclusion, BCX decreased visceral fat and cardiometabolic health risk factors through modulating expressions of nuclear transcription factors.

Salidroside pretreatment attenuates apoptosis and autophagy during hepatic ischemia-reperfusion injury by inhibiting the mitogen-activated protein kinase pathway in mice.

Ischemia–reperfusion injury (IRI) contributes to liver damage in many clinical situations, such as liver resection and liver transplantation. In the present study, we investigated the effects of the antioxidant, anti-inflammatory, and anticancer agent salidroside (Sal) on hepatic IRI in mice. The mice were randomly divided into six groups: normal control, Sham, Sal (20 mg/kg), IRI, IRI + Sal (10 mg/kg), and IRI + Sal (20 mg/kg). We measured liver enzymes, proinflammatory cytokines, TNF-α and interleukin-6, and apoptosis- and autophagy-related marker proteins at 2, 8, and 24 hours after reperfusion. Components of mitogen-activated protein kinase (MAPK) signaling, including P-38, jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK), were also measured using an MAPK activator anisomycin to deduce their roles in hepatic IRI. Our results show that Sal safely protects hepatocytes from IRI by reducing levels of liver enzymes in the serum. These findings were confirmed by histopathology. We concluded that Sal protects hepatocytes from IRI partly by inhibiting the activation of MAPK signaling, including the phosphorylation of P38, JNK, and ERK. This ameliorates inflammatory reactions, apoptosis, and autophagy in the mouse liver.

Effects of N-acetyl cysteine on oxidative stress and TNF-α gene expression in diclofenac-induced hepatotoxicity in rats

The consumption of non-steroidal anti-inflammatory drug, such as diclofenac, can lead to hepatotoxicity. In the present study, protective effect of N-acetyl cysteine (NAC) on diclofenac-induced hepatotoxicity was investigated. Thirty-two male rats were divided into four groups. Group 1 (control group) was treated with normal saline (1 ml/kg, i.p.) for 4 d. Group 2 (test without treatment) received diclofenac only (50 mg/kg, i.p.) for 4 d. Groups 3 and 4 received diclofenac (50 mg/kg, i.p.) plus NAC (150 mg/kg, p.o) and silymarin (100 mg/kg, p.o) for 4 d, respectively. At the end of experiment, serum glutamate pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT), alkaline phosphatase (ALP), lipid profile, uric acid, protein carbonyl content, MDA, liver TNF-α, ferric-reducing antioxidant power, liver catalase, superoxide dismutase, vitamin C, and histopathological examination were done. In group 2, diclofenac caused a significant increase (p < .05) in the levels of serum ALP, GOT, GPT, TNF-α, uric acid, protein carbonyl content, MDA, and liver TNF-α gene expression as opposed to group 1. In treated groups with NAC and silymarin, a significant reduction (p < .05) was seen in all above mentioned parameters as well as improved liver histopathological changes compared with group 2. This study confirmed the protective effect of NAC on diclofenac-induced hepatotoxicity in rats due to not only reduces liver inflammatory cells, TNF-α, serum MDA, and PC but also through increases liver vitamin C, catalase, and superoxide dismutase activities.

Identification and expression analysis of two pro-inflammatory cytokines, TNF-α and IL-8, in cobia (Rachycentron canadum L.) in response to Streptococcus dysgalactiae infection

Tumor necrosis factor-alpha (TNF-α) and interleukin-8 (IL-8/CXCL8) play pivotal roles in mediating inflammatory responses to invading pathogens. In this study, we identified and analyzed expressions of cobia TNF-α and IL-8 during Streptococcus dysgalactiae infection. The cloned cDNA transcript of cobia TNF-α comprised of 1281 base pairs (bp), with a 774 bp open reading frame (ORF) encoding 257 amino acids. The deduced amino acid sequence of cobia TNF-α showed a close relationship (84% similarity) with TNF-α of yellowtail amberjack. The cloned IL-8 cDNA sequence was 828 bp long, including a 300-bp ORF encoding 99 amino acids. The deduced amino acid sequence of cobia IL-8 shared 90% identity with IL-8 of striped trumpeter. Cobia challenged with a virulent S. dysgalactiae strain displayed an early significant up-regulation of TNF-α and IL-8 in head kidney, liver, and spleen. Notably, IL-8 expression level increased dramatically in the liver at the severe stage of infection (72 h). In conclusion, a better understanding of TNF-α and IL-8 allows more detailed investigation of immune responses in cobia and furthers study on controlling the infectious disease caused by S. dysgalactiae.

Curcumin attenuates lipopolysaccharide/d-galactosamine-induced acute liver injury by activating Nrf2 nuclear translocation and inhibiting NF-kB activation.

Curcumin, a polyphenol in curry spice isolated from the rhizome of turmeric, has been reported to possess versatile biological properties including anti-inflammatory, anti-oxidant, antifibrotic, and anticancer activities. In this study, the hepatoprotective effect of curcumin was investigated in lipopolysaccharide (LPS)/d-galactosamine (d-GalN)-induced acute liver injury (ALI) in rats. Experimental ALI was induced with an intraperitoneal (ip) injection of sterile 0.9% sodium chloride (NaCl) solution containing 8μg LPS and 800mg/kg d-GalN. Curcumin was administered once daily starting three days prior to LPS/d-GalN treatment. Results indicated that curcumin could attenuate hepatic pathological damage, decrease serum ALT and AST levels, and reduce malondialdehyde (MDA) content in experimental ALI rats. Moreover, higher dosages of curcumin pretreatment inhibited NF-κB activation and reduced serum TNF-α and liver TNF-α levels induced by LPS/d-GalN ip injection. Furthermore, we found that curcumin up-regulated the expression of nuclear Nrf2 and Nrf2-dependent antioxidant defense genes including heme oxygenase-1 (HO-1), glutamate-cysteine ligase (GCLC), NAD(P)H dehydrogenase, and quinone (NQO-1) in a dose-dependent manner. Our results showed that curcumin protected experimental animals against LPS/d-GalN-induced ALI through activation of Nrf2 nuclear translocation and inhibition of NF-κB activation.

Saccharin induced liver inflammation in mice by altering the gut microbiota and its metabolic functions

Maintaining the balance of the gut microbiota and its metabolic functions is vital for human health, however, this balance can be disrupted by various external factors including food additives. A range of food and beverages are sweetened by saccharin, which is generally considered to be safe despite controversial debates. However, recent studies indicated that saccharin perturbed the gut microbiota. Inflammation is frequently associated with disruptions of the gut microbiota. The aim of this study is to investigate the relationship between host inflammation and perturbed gut microbiome by saccharin. C57BL/6J male mice were treated with saccharin in drinking water for six months. Q-PCR was used to detect inflammatory markers in mouse liver, while 16S rRNA gene sequencing and metabolomics were used to reveal changes of the gut microbiota and its metabolomic profiles. Elevated expression of pro-inflammatory iNOS and TNF-α in liver indicated that saccharin induced inflammation in mice. The altered gut bacterial genera, enriched orthologs of pathogen-associated molecular patterns, such as LPS and bacterial toxins, in concert with increased pro-inflammatory metabolites suggested that the saccharin-induced liver inflammation could be associated with the perturbation of the gut microbiota and its metabolic functions.

Immunosuppressive effects and associated compensatory responses in zebrafish after full life-cycle exposure to environmentally relevant concentrations of cadmium

In natural environments, fish survive in polluted water by cadmium (Cd) throughout their whole life cycle. However, little information is available on Cd toxicity considering a life cycle assessment. The present study investigated effects of environmental levels of cadmium (0, 2.5, and 5μg/L) on immune responses in liver and spleen of zebrafish for 15 weeks, from embryos to sexually maturity. Nitric oxide (NO) levels and iNOS activity declined in liver and spleen of zebrafish exposed to 5μg/L Cd, suggesting an immunosuppressive effect. The result was further supported by the decreased transcriptional levels of proinflammatory cytokines by Cd, such as interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-1β (IL-1β), and tumour necrosis factor-α (TNF-α) in liver. However, a sharp increase in the mRNA levels of these cytokines was observed in spleen of zebrafish exposed to Cd. The increased mRNA expression of these proinflammatory cytokines may be the secondary effect following immunosuppression and just reflect a compensatory mechanism for coping with the decreased immunity, which may explain an increase in mRNA levels and a decrease in iNOS activity in spleen of zebrafish exposed to Cd. In liver, the down-regulated mRNA levels of iNOS paralleled with the decreased iNOS activity, suggesting a synchronous response from a molecular level to a biochemical level. Positive correlations between mRNA expression levels of nuclear transcription factor κB (NF-κB) and proinflammatory cytokines were also observed, suggesting that NF-κB might be required for the protracted induction of inflammatory genes. The corresponding changes in the mRNA levels of the inhibitor of κBα (IκBαa and IκBαb) may form a feedback loop to restore transcriptional activity of NF-κB. Furthermore, splenic ROS levels were increased by 5μg/L Cd, possibly activating NF-κB pathway. Taken together, immunosuppressive effects and tissue-dependent compensatory responses were demonstrated in zebrafish after full life-cycle exposure to environmental levels of Cd, indicating a compromise between survival and immunity.

Anti-inflammatory and ameliorative effects of gallic acid on fluoxetine-induced oxidative stress and liver damage in rats.

Fluoxetine-induced liver damage is a cause of chronic liver disease. In the present study the hepatoprotective effects of gallic acid against fluoxetine-induced liver damage were examined. Forty-eight male rats were divided into six groups as follow: group 1, the control group; group 2, rats receiving fluoxetine (24mg/kg bw daily, po) without treatment; group 3, rats receiving 24mg/kg bw fluoxetine, treated with 50mg/kg bw silymarin and groups 4, 5, and 6 in which gallic acid (50, 100, and 200mg/kg bw, po, respectively) was prescribed after the consumption of fluoxetine. The histopathological changes of hepatic tissues were checked out. Fluoxetine caused a significant increase in the levels of serum glutamate oxaloacetate transaminase (GOT), serum glutamate pyruvate transaminase (GPT), lipid profiles, urea, fasting blood sugar (FBS), creatinine (Cr), protein carbonyl (PC) content, malondialdehyde (MDA), and liver TNF-α as an inflammatory element. Also, the obtained results of group 2 revealed a significant decline in ferric reducing ability of plasma (FRAP), liver catalase (CAT), superoxide dismutase (SOD), and vitamin C levels. The treatment with gallic acid showed significant ameliorations in abnormalities of fluoxetine-induced liver injury as represented by the improvement of hepatic CAT, SOD activities, vitamin C levels, serum biochemical parameters, and histopathological changes, in addition to the recovery of antioxidant defense system status. Gallic acid has inhibitory effects on fluoxetine-induced liver damage. The effect of gallic acid is derived from free radical scavenging properties and the anti-inflammatory effect related to TNF-α.

Liver Regeneration Is Impaired in Mice with Acute Exposure to a Very Low Carbohydrate Diet.

The metabolic response to hepatic insufficiency has been implicated in the regulators of normal liver regeneration. Modulation of nutritional factors has been demonstrated to affect liver regeneration. Diets containing very low carbohydrate and high fat levels cause a unique metabolic state, the effect of which on liver regeneration is unknown. Mice were placed on standard mice chow (ND) or a very low carbohydrate diet (VLCD) after 70% partial hepatectomy (PH). After 48h, mice on VLCD were placed back to ND. The serum metabolic profiles, hepatic lipid content, and gene expression profile were examined. The dynamics of liver regeneration were detected at timed points. Activation of signaling pathways was examined. VLCD feeding caused hypoglycemia and elevation of serum β-hydroxybutyrate and free fatty acids in mice after PH. It increased hepatic triglyceride contents, enhanced fatty acid oxidation, and reduced lipid synthesis. Mice on VLCD exhibited diminished hepatocellular mitotic frequency, a reduced BrdU incorporation and liver mass regeneration ratio, and delayed expression of PCNA. Expressions of IL-6 and TNFα in liver and serum were downregulated. Meanwhile, phosphorylation of STAT3, Erk, and AKT was delayed compared with controls. VLCD feeding delayed liver regeneration, probably because of the suppression of TNFα-IL-6-STAT3 signaling and delayed activation of Erk and AKT induced by the unique metabolic effects of this diet.

The protective effects of probiotic-fermented soymilk on high-fat diet-induced hyperlipidemia and liver injury

The effects of probiotic-fermented soymilk (fermented by mixture of Bifidobacterium bifidum, Lactobacillus casei, and L. plantarum) on high-fat diet (HFD)-induced hyperlipidemia and liver injury were examined. C57BL/6N mice were randomly assigned into four groups that were treated with different diets: normal chow (NC), HFD, HFD with probiotic-fermented soymilk and HFD with non-fermented soymilk. After treatment for 6weeks, probiotic-fermented soymilk treatment significantly reduced HFD-induced body weight gain, hyperlipidemia, liver fat accumulation and reactive oxygen species (ROS) production. In addition, probiotic-fermented soymilk consumption significantly reduced the levels of serum alanine aminotransferase (ALT), lipopolysaccharide (LPS), and liver tumor necrosis factor-α (TNF-α) compared with the HFD treatment. Further, probiotic-fermented soymilk significantly increased the serum leptin level. In conclusion, probiotic-fermented soymilk reduced hyperlipidemia and liver injury induced by HFD. The role of probiotic-fermented soymilk may decrease the production of liver LPS, TNF-α, and oxidative stress and induce adipose leptin and triacylglycerol hydrolase (TGH) production.

Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier.

To investigate whether gut microbiota metabolite sodium butyrate (NaB) is an effective substance for attenuating non-alcoholic fatty liver disease (NAFLD) and the internal mechanisms. Male C57BL/6J mice were divided into three groups, normal control were fed standard chow and model group were fed a high-fat diet (HFD) for 16 wk, the intervention group were fed HFD for 16 wk and treated with NaB for 8 wk. Gut microbiota from each group were detected at baseline and at 16 wk, liver histology were evaluated and gastrointestinal barrier indicator such as zonula occluden-1 (ZO-1) were detected by immunohistochemistry and realtime-PCR, further serum or liver endotoxin were determined by ELISA and inflammation- or metabolism-associated genes were quantified by real-time PCR. NaB corrected the HFD-induced gut microbiota imbalance in mice, while it considerably elevated the abundances of the beneficial bacteria Christensenellaceae, Blautia and Lactobacillus. These bacteria can produce butyric acid in what seems like a virtuous circle. And butyrate restored HFD induced intestinal mucosa damage, increased the expression of ZO-1 in small intestine, further decreased the levels of gut endotoxin in serum and liver compared with HF group. Endotoxin-associated genes such as TLR4 and Myd88, pro-inflammation genes such as MCP-1, TNF-α, IL-1, IL-2, IL-6 and IFN-γ in liver or epididymal fat were obviously downregulated after NaB intervention. Liver inflammation and fat accumulation were ameliorated, the levels of TG and cholesterol in liver were decreased after NaB intervention, NAS score was significantly decreased, metabolic indices such as FBG and HOMA-IR and liver function indicators ALT and AST were improved compared with HF group. NaB may restore the dysbiosis of gut microbiota to attenuate steatohepatitis, which is suggested to be a potential gut microbiota modulator and therapeutic substance for NAFLD.

Effect of Rifaximin on Hepatic Fibrosis in Bile Duct-ligated Rat Model.

The translocation of bacteria and their lipopolysaccharides from the gut can promote fibrosis in cirrhotic patients. The aim of this study was to investigate the effects of rifaximin on hepatic fibrosis in a bile duct-ligated rat model. The bile duct ligation (BDL) was carried out for eight days (acute injury model: sham-operated rats [G1], BDL rats [G2], and BDL rats treated with rifaximin [G3]) or 22 days (chronic injury model: sham-operated rats [G4], BDL rats [G5], and BDL rats treated with rifaximin [G6]). Rifaximin (50 mg/kg/day) was administered daily via gavage after BDL. Liver function, serum tumor necrosis factor-alpha (TNF-α), and hepatic hydroxyproline levels were measured. Moreover, a histological analysis of fibrosis contents was performed using sirius red stain. In the acute injury model, the liver function and TNF-α level were not improved after the rifaximin treatment. The hydroxyproline levels (µg/g liver tissue) in G1, G2, and G3 were 236.4±103.1, 444.8±114.4, and 312.5±131.6, respectively; and fibrosis contents (%) were 0.22±0.04, 1.64±0.53, and 1.66±0.44, respectively. The rifaximin treatment did not ameliorate acute BDL-induced fibrosis. In the chronic injury model, the hydroxyproline levels in G4, G5, and G6 were 311.5±72.9, 1,110.3±357.9, and 944.3±209.3, respectively; and fibrosis contents (%) were 0.19±0.03, 5.04±0.18, and 4.42±0.68, respectively (G5 vs. G6, p=0.059). The rifaximin treatment marginally ameliorated chronic BDL-induced fibrosis. Rifaximin did not reduce inflammation and fibrosis in bile duct-ligated rat model.

ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF-α levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF-α levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D.

Puerarin exerts the protective effect against chemical induced dysmetabolism in rats

In this study, we aim to explore the potential benefits of puerarin on metabolic function of liver fibrosis (LF) rat induced by carbon tetrachloride (CCl4), and to investigate with the underlying molecular mechanism targeted on liver and pancreas tissues. In methodology, The LF rats were prepared through intragastrically giving CCl4 twice each week (2ml/kg, v/w) for 8weeks, and dosed puerarin (20, 40mg/kg) were given three times each week via intraperitoneal injection. After being conducted with oral glucose tolerance test (OGTT), the blood samples of rat were harvested for biochemical tests, as well as the liver and pancreas were isolated for histological examination and biochemical assays. The findings showed that puerarin-administered rats resulted in reduced glucose tolerance, blood insulin level, sero-enzymes of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and increased plasma level of high-density lipoprotein cholesterol (HDL-C) and reduced low-density lipoprotein cholesterol (LDL-C) content in serum. Further, the intrahepatic collagen deposits were lessened and positive cell of alpha smooth muscle actin (α-SMA) was lessened in puerarin treatment, while the pro-apoptotic cell numbers of Caspase 3, Bax in pancreatic islets were reduced dose-dependently. Moreover, the mRNA expressions of toll-like receptor 4 (TLR4) and tumor necrosis factor (TNF-α) in liver and pancreas were downregulated. In addition, TNF-α protein in the CCl4-lesioned liver and pancreas was reduced. Our findings demonstrate that puerarin contributes to attenuating the metabolic dysfunctions of CCl4-damaged liver and pancreas, in which the possible mechanisms may be linked to inhibition of inflammatory stress and normalization of metabolic homoeostasis in the liver and pancreas.

The chloroform extract of Cyclocarya paliurus attenuates high-fat diet induced non-alcoholic hepatic steatosis in Sprague Dawley rats

BackgroundHepatic steatosis (HS) is the early stage of nonalcoholic fatty liver disease which is caused by impaired hepatic lipid homeostasis. Cyclocarya paliurus, an herbal tea consumed in China, has been demonstrated to ameliorate abnormal lipid metabolism for the treatment of metabolic diseases. PurposeWe aimed to investigate the regulative effect of chloroform extract from Cyclocarya paliurus (ChE) on treatment of HS, as well as key factors involved in hepatic lipid metabolism. Study designSprague Dawley rats were fed with high-fat diet (HFD) for 6 weeks to induce HS and treated with or without ChE by gavage for 4 weeks. MethodsThe body weight, relative liver weight and liver fat content were measured. Serum and liver total cholesterol, triglyceride and non-esterified fatty acids, as well as hepatic malonaldehyde levels were accessed by biochemical methods. Serum and liver TNF-α levels were quantified by ELISA kit. Histologic analysis and 1H-MRS study were performed to evaluate HS level. RT-PCR and Western blot were also applied to observe the expression changes of key factors involved in hepatic lipid intake, synthesis, utilization and export. ResultsChE significantly decreased the rats’ body weight, serum lipid and TNF-α level. ChE also reduced their relative liver weight, liver fat content, hepatic oxidative products and TNF-α level. Hepatic steatosis in HFD-fed rats was effectively regressed after 2-weeks administration of ChE. Moreover, ChE treatment remarkably reduced HFD-induced high expression level of fatty acid synthesis genes (including sterol-regulatory element-binding protein 1, acetyl-CoA carboxylase 1 and fatty acid synthase). However, it had no effect on mRNA expression of some genes involved in lipid uptake, β-oxidation and lipid outflow. ConclusionChE exerted a promising regression effect on HS due to a reduced level of serum non-esterified fatty acids which might lead to a decrease in the amount of lipid taken in by the liver, as well as owing to the inhibition of hepatic lipid de novo synthesis to reduce liver lipid production.

Protective effects of thymoquinone and avenanthramides on titanium dioxide nanoparticles induced toxicity in Sprague-Dawley rats

The protective effect of thymoquinone (TQ), the major active ingredient of Nigella sativa seeds, and avenanthramides (AVA) enriched extract of oats on titanium dioxide naonparticles (TiO2 NPs) induced toxicity and oxidative stress in Sprague-Dawley (SD) rats was investigated. Sixty rats were divided into 6 equal groups. The first, second, third, fourth and fifth groups received TiO2 NPs, TiO2 NPs and TQ, TiO2 NPs and AVA, TQ only, or AVA only for 6 weeks. The sixth group served as the control. Exposure to TiO2 NPs resulted in increased liver enzyme markers, oxidative stress indices, tumor necrosis factor alpha (TNF-α) and DNA damage. Histopathological alterations were also observed in the liver, brain, lung, kidney, heart and testes. Co-administration of TQ and AVA with TiO2 NPs decreased the level of liver enzymes, oxidative stress, TNF-α and DNA damage. Furthermore, TQ and AVA increased the total antioxidant and glutathione (GSH) levels. In conclusion, TiO2 NPs induce hazardous effects in different organs and are closely related to oxidative stress. TQ and AVA have antioxidative and anti-inflammatory effect against the detrimental effect of TiO2 NPs.

Clock gene Per2 as a controller of liver carcinogenesis.

Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We assessed liver histopathology, and determined molecular and physiology circadian patterns in mice on chronic diethylnitrosamine (DEN) exposure according to constitutive Per2 mutation. First, we found that Per2m/m liver displayed profound alterations in proliferation gene expression, including c-Myc derepression, phase-advanced Wee1, and arrhythmic Ccnb1 and K-ras mRNA expressions, as well as deregulated inflammation, through arrhythmic liver IL-6 protein concentration, in the absence of any DEN exposure. These changes could then make Per2m/m mice more prone to subsequently develop liver cancers on DEN. Indeed, primary liver cancers were nearly fourfold as frequent in Per2m/m mice as compared to wild-type (WT), 4 months after DEN exposure. The liver molecular clock was severely disrupted throughout the whole carcinogenesis process, including the initiation stage, i.e. within the initial 17 days on DEN. Per2m/m further exhibited increased c-Myc and Ccnb1 mean 24h expressions, lack of P53 response, and arrhythmic ATM, Wee1 and Ccnb1 expressions. DEN-induced tumor related inflammation was further promoted through increased protein concentrations of liver IL-6 and TNF-α as compared to WT during carcinogenesis initiation. Per2 mutation severely deregulated liver gene or protein expressions related to three cancer hallmarks, including uncontrolled proliferation, genomic instability, and tumor promoting inflammation, and accelerated liver carcinogenesis several-fold. Clock gene Per2 acted here as a liver tumor suppressor from initiation to progression.

Anthocyanin Improving Metabolic Disorders in Obese Mice from Aornia melanocarpa

Abstract: The aim of this study was to investigate the effects of Aornia melanocarpa anthocyanin (AMA) on symptoms of metabolic syndrome in obese mouse. AMA can reduce weight. Blood glucose and lipid metabolism were significantly improved, and so as hepatic lipid metabolism. This suggesting AMA is a strong indication of improved glucoselipid metabolism and weight. Moreover, both morphologic and histological detections indicated that AMA significantly reversed obsity induced hepatic steatosis and liver injury. Furthermore, AMA significantly ameliorated inflammatory cytokines including both IL-6 and TNF-α in liver and fatty tissue. Moreover, insulin receptor (IR), p-IRS and p-AKT that associated proteins about glucose-lipid metabolism signaling pathway were markedly up-regulated at protein levels by AMA. Our results demonstrate that Aornia melanocarpa anthocyanin treatment can alleviate obsity and metabolic syndrome. The beneficial effects of AMA are associated with improved glucose-lipid metabolism and reduced levels of inflammatory cytokines. Key words: Metabolic disorders, Obese, Aornia melanocarpa, Anthocyanin, Mechnism.

Protective effect of Yiguanjian decoction against DNA damage on concanavalin A-induced liver injury mice model

ObjectiveTo investigate the inhibitory effect of Yiguanjian decoction (YD) on DNA damage in Concanavalin A (Con A)-induced liver injury mice model and to explain the possible mechanism. MethodsTotally 120 male BALB/c mice were randomly divided into 6 groups, 20 mice each: normal group, model group, Bifendate group, YD low dose group, YD middle dose group and YD high dose group. Except normal group, liver injury model induced by Con A was established. While modeling, each mouse in YD group was given YD (0.4 mL/20 g per day) by intragastric administration (0.13 g YD for YD low dose group; 0.26 g for YD middle dose group; 0.52 g for YD high dose group). Bifendate group was given Bifendate (0.2 g·kg−1·d−1) by gavage. Normal group and model group were fed with same volume of physiological saline daily. After 8 weeks, the serum alanine transaminase (ALT) and aspartate transaminase (AST) were tested. The hematoxylin-eosin staining was used to evaluate the grade of liver inflammation and liver fibrosis stage. Hepatocellular DNA damage was detected by single cell gel electrophoresis technology. The protein expression of tumor necrosis factor-α (TNF-α), Bax and MutT Homolog 1 (MTH1) was detected by western blotting and enzyme linked immunosorbent assay. Bax mRNA and MTH1 mRNA were detected by Real-time Polymerase Chain Reaction (PCR). ResultsYD can improve the degree of liver inflammation and fibrosis in the liver of chronic hepatitis mice, the dose effect relationship is remarkable (P < 0.05). YD can reduce liver cell DNA damage. The difference between YD middle dose group and model group was statistically significant (P < 0.05). YD middle dose group had decreased the protein expression of TNF-α in the mice liver of immunological liver injury (P < 0.05). YD can increase the protein expression of Bax (P < 0.05). Compared with normal group, the protein expression of MTH1 was decreased (P < 0.05), but there was no statistical significance between YD group and model group (P > 0.05). YD can increase the mRNA expression of Bax and MTH1 (both P < 0.05). ConclusionYD can effectively inhibit the DNA damage in immunological liver injury mice, the mechanism may be that it can decrease the TNF-α and increase the Bax and MTH1 expression.

The complement component C5 promotes liver steatosis and inflammation in murine non-alcoholic liver disease model

Non-Alcoholic Fatty Liver Disease (NALD) is considering a hepatic manifestation of metabolic syndrome. Although the pathogenesis of NALD is not completely understood, insulin resistance and inflammatory cytokines are implicated. Considering that component C5 is a central mediator of inflammation, we investigated the role of C5 in the establishment of NALD. Eight to ten-week old B6 C5+ and A/J C5− male mice were fed a high fat diet containing glucose (HFDG) for 6 and 10 weeks. We observed that B6 C5+ mice HFDG-fed for 10 weeks developed hepatomegaly, triglycerides (TG) accumulation, steatosis and enhanced liver TNF-α, IL-6, IL-12p70 and IL-17 levels when compared to A/J C5− mice. Next, B6 C5+ mice were compared with congenic B6 C5− mice. Again, B6 C5+ HFDG-fed mice developed more steatosis, liver centro-lobular inflammation and presented higher levels of liver IL-1β, IL-12p70, IL-17 and TFG-β than B6 C5− mice under the same conditions. B6 C5+ mice HFDG-fed also presented lower concentrations of serum albumin, serum cholesterol, blood leukocytes and liver NO production when compared with B6 C5− mice. We concluded that murine C5 contributes effectively to liver steatosis and inflammation in NALD pathogenesis. In addition, C5 is also important to control serum cholesterol and albumin levels in the C57BL/6 genetic background.