Protective action of glutamine in rats with severe acute liver failure

BACKGROUND Severe acute liver failure(SALF) is a rare, but high-mortality, rapidly evolving syndrome that leads to hepatocyte degeneration with impaired liver function.Thioacetamide(TAA) is a known xenobiotic, which promotes the increase of the formation of reactive oxygen species. Erythroid 2-related factor 2(Nrf2) activates the antioxidant protection of cells. Studies have evidenced the involvement of inflammatory mediators in conditions of oxidative stress.AIM To evaluate the antioxidant effects of glutamine on Nrf2 activation and NFκBmediated inflammation in rats with TAA-induced IHAG.METHODS Male Wistar rats(n = 28) were divided into four groups: control,control+glutamine, TAA, and TAA + glutamine. Two TAA doses(400 mg/kg)were administered intraperitoneally, 8 h apart. Glutamine(25 mg/kg) was administered at 30 min, 24 h, and 36 h. At 48 h, blood was collected for liver integrity analysis [aspartate aminotransferase(AST), alanine aminotransferase(ALT), and alkaline phosphatase(ALP)]. The liver was harvested for histology and assessment of oxidative stress [thiobarbituric acid-reactive substances(TBARS), catalase(CAT), glutathione peroxidase(GPx), glutathione S-transferase(GST), glutathione(GSH), Nrf2, Kelch-like ECH-associated protein 1(Keap1),NADPH quinone oxidoreductase1(NQO1), superoxide dismutase(SOD)] and inflammatory process.RESULTS TAA caused disruption of the hepatic parenchyma, with inflammatoryinfiltration, massive necrosis, and ballooning degeneration. Glutamine mitigated this tissue damage, with visible regeneration of hepatic parenchyma; decreased TBARS(P < 0.001), GSH(P < 0.01), IL-1β, IL6, and TNFα levels(P <0.01) in hepatic tissue; and decreased blood levels of AST, ALT, and ALP(P <0.05). In addition, CAT, GPx, and GST activities were restored in the glutamine group(P<0.01, P <0.01, and P <0.001, respectively vs TAA alone). Glutamine increased expression of Nrf2(P < 0.05), NQO1, and SOD(P < 0.01), as well as levels of IL-10(P <0.001), while decreasing expression of Keap1, TLR4, NFκB(P < 0.001), COX-2 and iNOS,(P < 0.01), and reducing NO_2 and NO_3 levels(P < 0.05).CONCLUSION In the TAA experimental model of IHAG, glutamine activated the Nrf2 pathway,thus promoting antioxidant protection, and blunted the NFκB-mediated pathway, reducing inflammation.

Study on the sensitivity to cadmium of marine fish Salaria basilisca(Pisces: Blennidae)

The present study tested the sensitivity of Salaria basilisca to water-cadmium （Cd） contamination. For this purpose, liver somatic index （LSI）, Cd concentrations and the activities of antioxidant enzymes such as catalase （CAT）, superoxide dismutase （SOD） and glutathione peroxidase （GSH-Px） were measured in the liver of S. basilisca exposed to Cd-contaminated water （2 mg Cd/L as CdCl2） for 14 and 28 d. The results showed that the LSI decreased significantly after 14 and 28 d of Cd-exposure. Cd bioaccumulation in the liver resulted in an increasing uptake up to 42 μg/g dry weight after 28 d of exposure. Activities of CAT and SOD were significantly increased with increasing exposure time. A significant increase in GSH-Px activity, under Cd influence, was observed during 14-day exposure period （p 〈 0.0001）. However, a significant decrease （p 〈 0.05） in this activity with respect to control fish was registered after 28 d of Cd-exposure. These results showed that Cd accumulation in the liver of S. basilisca could induce oxidative stress as demonstrated by changes in the antioxidant enzyme activities. Results also emphasized that S. basilisca may considered as a sensitive species to Cd exposure.

Cadmium bioaccumulation in three benthic fish species, Salaria basilisca, Zosterisessor ophiocephalus and Solea vulgaris collected from the Gulf of Gabes in Tunisia

To select a marine teleost fish which can be used as a bioindicator of cadmium （Cd） pollution in the Gulf of Gabes in Tunisia, Cd concentrations in liver and gill were compared in three benthic fish species including Salaria basilisca, Zosterisessor ophiocephalus and Solea vulgaris. Fish samples were collected from three selected sites in the Gulf of Gabes, with different degrees of Cd contamination： the industrialized coast of Sfax （S 1）, the coast of Douar Chatt （S2） and the coast of Luza （S3）. The results shows that Cd concentrations in both sediment and water collected from S1 were significantly higher （t9 〈 0.0001） than those from S2 and S3. For each species, Cd concentrations, in both liver and gill, showed the decreasing order： S 1 〉 S2 〉 S3. The highest concentration of Cd was detected in the liver of S. basilisca, and only S. basilisca showed bioaccumulation factors （BAF） greater than 1 in all studied sites. In S 1 and S2, BAF values respect the following order： S. basilisca 〉 Z. ophiocephalus 〉 S. vulgaris. These results of significant bioaccumulation of Cd, in terms of hepatic concentrations and bioaccumulation factors, indicated that S. basilisca can be used as bioindicator to evaluate the evolution of Cd pollution in the Gulf of Gabes.

Antioxidant and anti-inflammatory action of melatonin in an experimental model of secondary biliary cirrhosis induced by bile duct ligation

AIM To evaluate the effects of melatonin(Mel) on oxidative stress in an experimental model of bile duct ligation(BDL).METHODS Male Wistar rats(n = 32, weight ± 300 g) were allocated across four groups: CO(sham BDL), BDL(BDL surgery), CO + Mel(sham BDL and Mel administration) and BDL + Mel(BDL surgery and Mel administration). Mel was administered intraperitoneally for 2 wk, starting on postoperative day 15, at a dose of 20 mg/kg.RESULTS Mel was effective at the different standards, reestablishing normal liver enzyme levels, reducing the hepatosomatic and splenosomatic indices, restoring lipoperoxidation and antioxidant enzyme concentrations, reducing fibrosis and inflammation, and thereby reducing liver tissue injury in the treated animals.CONCLUSION The results of this study suggest a protective effect of Mel when administered to rats with secondary biliary cirrhosis induced by BDL.

Nitric oxide and hydrogen sulfide share regulatory functions in higher plant events

Nitric oxide(NO)and hydrogen sulfide(HS)are two molecules that share signaling properties in plant and animal cells NO and H2S originate two farmilies of de rived mol ecules designated reactive nitrogen and sulfur species(RNS and RSS,respectively).These molecules are responsible for certain protein regulatory processes through posttranslational modifications(PTMs),being the most remarkable S nitrosation and persufidation,which afect the thiol group of cysteine residues.NO and H2S can also exert regulatory functions due to their interaction through the iron present in proteins that contain heme groups or iron-sulfur dlusters,as reported mainly in animal cells.Howewer,the available information in plant cells is still very limited thus far.In higher plants,NO and H2S are involved in a myriad of physiological events from seed germination to fruit ripening,but also the mec hanism of response to biotic and abiotic stress conditions.This vie wpoint manuscript highlights the functional regulatory parllelism of these two molecules which also interact with the metabolism of reactive oxygen species(ROS)in plant cells.

Polyphenolic extract of Sorghum bicolor grains enhances reactive oxygen species detoxification in N-nitrosodiethylamine-treated rats

Reactive oxygen species detoxification potentials of Sorghum bicolor polyphenolic extract was investigated in the liver of N-nitrosodiethylaminetreated rats.Male rats,weighing(135±5.5)g were completely randomized into 7 groups(A–G)of five rats each.Rats in C,D,E and F were administered orally once daily at 24-h interval for 7 d with 500,125,250 and 500 mg/kg body weight of polyphenolic extract of S.bicolor,respectively.Group G was given 100 mg/kg body weight of vitamin C.On the sixth day,groups B,D,E,F and G were administered with 100 mg/kg body weight N-nitrosodiethylamine(NDEA).Group A,which served as the control was treated like the test groups except,that the animals received distilled water only.Reactive oxygen species detoxifying enzymes(superoxide dismutase,catalase,glutathione peroxidase,glutathione reductase and glucose 6-phosphate dehydrogenase)activities were significantly(P<0.05)induced by S.bicolor.These inductions significantly(P<0.05)attenuated the NDEA-mediated decrease in reactive oxygen species detoxifying enzymes and compared favourably with vitamin C.NDEA-mediated elevation in the concentrations of oxidative stress biomarkers;malondialdehyde,conjugated dienes,lipid hydroperoxides,protein carbonyl and percentage DNA fragmentation were significantly(P<0.05)lowered by S.bicolor polyphenolic extract.Overall,the results obtained from this study revealed that the polyphenolic extract of S.bicolor grains enhanced the detoxification of reactive oxygen species in NDEA-treated rats.The polyphenols also prevented the peroxidation of lipid,oxidation of proteins as well as fragmentation of DNA component in the liver of rats and hence gave the evidence of possible prophylactic potentials of S.bicolor grains.©2013 Beijing Academy of Food Sciences.Production and hosting by Elsevier B.V.All rights reserved.

炎症调节能量平衡的生理及病理基础

肥胖症中，白色脂肪组织和其他一些组织存在轻度慢性炎症[1]。早期的小鼠实验提示，慢性炎症导致胰岛素抵抗。因此，很多临床试验使用抗炎药物治疗2型糖尿病。然而多数临床结果证明：抗炎治疗不能提高胰岛素敏感性[2-3]。目前，对于抗炎治疗失败的原因尚有争议。争议的主要原因是对炎症调节能量代谢的认识不足。笔者认为，炎症因子是维持能量消耗的必要因素，称之为炎症在调节代谢中的“有益作用”[4]。本文将从肥胖、节食、运动方向进一步来论证这一观点。

Anti-ulcerogenic activity of aqueous extract of Carica papaya seed on indomethacin-induced peptic ulcer in male albino rats

OBJECTIVE： Carica papaya is an important fruit with its seeds used in the treatment of ulcer in Nigeria This study investigated the anti-ulcerogenic and antioxidant activities of aqueous extract of Carica papaya seed against indomethacin-induced peptic ulcer in male rats. METHODS： Thirty male rats were separated into 6 groups （A-F） of five rats each. For 14 d before ulcer induction with indomethacin, groups received once daily oral doses of vehicle （distilled water）, cimetidine 200 mg/kg body weight （BW）, or aqueous extract of C. papaya seed at doses of 100, 150 or 200 mg/kg BW （groups A, B, C, D, E and F, respectively）. Twenty-four hours after the last treatment, groups B, C, D, E and F were treated with 100 mg/kg BW of indomethacin to induce ulcer formation. RESULTS： Carica papaya seed extract significantly （P〈0.05） increased gastric pH and percentage of ulcer inhibition relative to indomethacin-induced ulcer rats. The extract significantly （P〈0.05） decreased gastric acidity, gastric acid output, gastric pepsin secretion, ulcer index and gastric secretion volume relative to group B. These results were similar to that achieved by pretreatment with cimetidine. Specific activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase in the extract-treated groups （D, E and F） were increased significantly over the group B （P〈0.05）. Pretreatment with the seed extract protected rats from the indomethacin-mediated decrease in enzyme function experienced by the group B. Similarly, indomethacin-mediated decrease in reduced glutathione level and indomethacin-mediated increase in malondialdehyde were reversed by Carica papaya extract. CONCLUSION： In this study, pretreatment with aqueous extract of Carica papaya seed exhibited anti- ulcerogenic and antioxidant effects, which may be due to the enhanced antioxidant enzymes.

Mechanisms of insulin resistance in obesity

Obesity increases the risk for type 2 diabetes through induction of insulin resistance.Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance.In those hypotheses,inflammation,mitochondrial dysfunction,hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention.Oxidative stress,endoplasmic reticulum(ER)stress,genetic background,aging,fatty liver,hypoxia and lipodystrophy are active subjects in the study of these concepts.However,none of those concepts or views has led to an effective therapy for type 2 diabetes.The reason is that there has been no consensus for a unifying mechanism of insulin resistance.In this review article,literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance,in which insulin resistance is a result of energy surplus in cells.The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase(AMPK)signaling pathway.Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance.In support,many of existing insulin sensitizing medicines inhibit ATP production in mitochondria.The effective therapies such as weight loss,exercise,and caloric restriction all reduce ATP in insulin sensitive cells.This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity,which may apply to insulin resistance in aging and lipodystrophy.

Mitochondrial inhibitor as a new class of insulin sensitizer

Insulin resistance is a major risk factor for type 2 diabetes.AMP-activated protein kinase(AMPK)is a drug target in the improvement of insulin sensitivity.Several insulin-sensitizing medicines are able to activate AMPK through inhibition of mitochondrial functions.These drugs,such as metformin and STZ,inhibit ATP synthesis in mitochondria to raise AMP/ATP ratio in the.process of A MPK activation.However,chemicals that activate AMPK directly or by activating its upstream kinases have not been approved for treatment of type 2 diabetes in humans.In an early study,we reported that berberine inhibited oxygen consumption in mitochondria,and increased AMP/ATP ratio in cells.The observation suggests an indirect mechanism for AMPK activation by berberine.Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition.The study suggests that mitochondrial inhibition is an approach for AMPK activation.In this review article,literature is critically reviewed to interpret the role of mitochondria function in the mechanism of insulin resistance,which supports that mitochondria inhibitors represent a new class of AMPK activator.The inhibitors are promising candidates for insulin sensitizers.This review provides a guideline in search for small molecule AMPK activators in the drug discovery for type 2 diabetes.

Challenges in drug discovery for thiazolidinedione substitute

Thiazolidinedione(TZD)is a powerful insulin sensitizer in the treatment of type 2 diabetes.It acts as a ligand to the nuclear receptor PPARγ(peroxisome proliferator-activated receptor-gamma)and induces transcription of PPARγ-responsive genes.TZD controls lipid synthesis and storage in adipose tissue,liver and many other tissues through PPARg.Derivatives of TZD,such as rosiglitazone(Avandia)and pioglitazone(Actos),are more powerful than metformin or berberine in insulin sensitization.Although they have common side effects such as weight gain and edema,these did not influence their clinical application in general.However,recent findings of risk for congestive heart failure and bladder cancer have significantly impaired their future in many countries.European countries have prohibited those drugs,and US will terminate application of rosiglitazone in clinics and hospitals.The multiple country actions may mark the end of TZD era.As a result,there is a strong demand for identification of TZD substitute in the treatment of type 2 diabetes.In this regard,literature about PPARγ ligands and potential TZD substitute are reviewed in this article.Histone deacetylase(HDAC)inhibitor is emphasized as a new class of insulin sensitizer here.Regulators of SIRT1,CREB,NO,p38,ERK and Cdk5 are discussed in the activation of PPARγ.

Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes

In obesity, chronic inflammation is believed to induce insulin resistance and impairs adipose tissue function. Although this view is supported by a large body of literature, it has been challenged by growing evidence that pro-inflammatory cytokines may favor insulin sensitivity through induction of energy expenditure. In this review article, interleukin 15 （IL-15） is used as a new example to explain the beneficial effects of the pro- inflammatory cytokines. IL-15 is secreted by multiple types of cells including macrophages, neutrophils and skeletal muscle cells. IL-15 expression is induced in immune cells by endotoxin and in muscle cells by physical exercise. Its transcription is induced by transcription factor NF-KB. IL-15 binds to its receptor that contains three different subunits （~, [5 and 1,） to activate JAK/STAT, PI3K/Akt, IKK/NF-KB and JNK/API pathways in cells. In the regulation of metabolism, IL-15 reduces weight gain without inhibiting food intake in rodents. IL-15 suppresses lipogenesis, stimulates brown fat function, improves insulin sensitivity through weight loss and energy expenditure. In human, circulating IL-15 is negatively associated with body weight. In the immune system, IL-15 stimulates proliferation and differentiation of T cells, NK cells, monocytes and neutrophils. In the anti-obesity effects of IL-15, T cells and NK cells are not required, but leptin receptor is required. In summary, evidence from human and rodents supports that the pro-inflammatory cytokine IL-15 may enhance energy expenditure to protect the body from obesity and type 2 diabetes. The mechanism of IL-15 action remains to be fully uncovered in the regulation of energy expenditure.

Hydrogen sulfide:A novel component in Arabidopsis peroxisomes which triggers catalase inhibition

Plant peroxisomes have the capacity to gen erate different reactive oxygen and nitrogen species(ROS and RNS),such as H2O2,superoxide radical(O2^·-),nitric oxide and peroxynitrite(ONOO^-).These organelles have an active nitrooxidative metabolism which can be exacerbated by adverse stress conditions.Hydrogen sulfide(H2S)is a new signaling gasotransmitter which can mediate the posttranslational modification(PTM)persulfidation.We used Arabidopsis thaliana transgenic seedlings expressing cyan fluorescent protein(CFP)fused to a canonical peroxisome targeting signal 1(PTS1)to visualize peroxisomes in living cells,as well as a specific fluorescent probe which showed that peroxisomes contain H2S.H2S was also detected in chloroplasts under glyphosate-induced oxidative stress conditions.Peroxisomal enzyme activities,including catalase,photorespiratory H2O2-generating glycolate oxidase(GOX)and hydroxypyruvate reductase(HPR),were assayed in vitro with a H2S donor.In line with the persulfidation of this enzyme,catalase activity declined significantly in the presence of the H2S donor.To corroborate the inhibitory effect of H2S on catalase activity,we also assayed pure catalase from bovine liver and pepper fruit-enriched samples,in which catalase activity was inhibited.Taken together,these data provide evidenee of the presence of H2S in plant peroxisomes which appears to regulate catalase activity and,consequently,the peroxisomal H2O2 metabolism.

Plant peroxisomes at the crossroad of NO and H2O2 metabolism

Plant peroxisomes are subcellular compartments involved in many biochemical pathways during the life cycle of a plant but also in the mechanism of response against adverse environmental conditions.These organelles have an active nitro-oxidative metabolism under physiological conditions but this could be exacerbated under stress situations.Furthermore,peroxisomes have the capacity to proliferateand also undergo biochemical adaptations depending on the surrounding cellular status.An important characteristic of peroxisomes is that they have a dynamic metabolism of reactive nitrogen and oxygen species(RNS and ROS)which generates two key molecules,nitric oxide(NO)and hydrogen peroxide(H2O2).These molecules can exert signaling functions by means of post-translational modifications that affect the functionality of target molecules like proteins,peptides or fatty acids.This review provides an overview of the endogenous metabolism of ROS and RNS in peroxisomes with special emphasis on polyamine and uric acid metabolism as well as the possibility that these organelles could be a source of signal molecules involved in the functional interconnection with other subcellular compartments.

NF-κB/HDAC1/SREBP1c pathway mediates the inflammation signal in progression of hepatic steatosis

The transcription factor nuclear factor kappa B(NF-κB)is activated in hepatoctes in the pathogenesis of hepatic steatosis.However,the action mechanism of NF-κB remains to be established in the hepatic steatosis.In this study,the P50 subunit of NF-κB was found to promote the hepatic steatosis through regulation of histone deacetylase 1(HDAC1)in hepatocytes.The activity was supported by the phenotypes of P50 knockout(P50-KO)mice and P65 knockout(P65-KO)mice.Hepatic steatosis was reduced in the P50-KO mice,but not in the P65-KO mice.The reduction was a result of inhibition of HDAC1 activity in the P50-KO cells.Knockdown of Hdac1 gene led to suppression of hepatocyte steatosis in HepG2 cells.A decrease in sterol-regulatory element binding protein lc(SREBP1 c)protein was observed in the liver of P50-KO mice and in cell with Hdac1 knockdown.The decrease was associated with an increase in succinylation of SREBP1 c protein.The study suggests that P50 stabilizes HDAC1 to support the SREBP1 c activity in hepatic steatosis in the pathophysiological condition.Interruption of this novel pathway in the P50-KO,but not the P65-KO mice,may account for the difference in hepatic phenotypes in the two lines of transgenic mice.

Regulation of microbiota–GLP1 axis by sennoside A in diet-induced obese mice

Sennoside A(SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative, which is often used in the treatment of constipation and obesity. However, its activity remains unknown in the regulation of insulin sensitivity. In this study, the impact of SA on insulin sensitivity was tested in high fat diet(HFD)-induced obese mice through dietary supplementation. At a dosage of 30 mg/kg/day, SA improved insulin sensitivity in the mice after 8-week treatment as indicated by HOMA-IR(homeostatic model assessment for insulin resistance) and glucose tolerance test(GTT). SA restored plasma level of glucagon-like peptide 1(GLP1) by 90% and mRNA expression of Glp1 by 80% in the large intestine of HFD mice. In the mechanism, SA restored the gut microbiota profile, short chain fatty acids(SCFAs), and mucosal structure in the colon. A mitochondrial stress was observed in the enterocytes of HFD mice with ATP elevation, structural damage, and complex dysfunction. The mitochondrial response was induced in enterocytes by the dietary fat as the same responses were induced by palmitic acid in the cell culture. The mitochondrial response was inhibited in HFD mice by SA treatment. These data suggest that SA may restore the function of microbiota–GLP1 axis to improve glucose metabolism in the obese mice.

OXIDATION BEHAVIOURS OF POLYPROPYLENE IN PRESENCE OF HYDROGEN CHLORIDE

Ⅰ. INTRODUCTION It is well known that polypropylene (PP) produced by the Zeigler-Natla catalyst contains a small amount of hydrogen chloride (HCI). We have shown that hydrogen chloride at such a low concentration could accelerate the oxidation of PP and destroy the antioxidants and light stabilizers in the commercial product with the decrease of the ageing-resistance prokpertiew. Furthermore, HCI could catalyze and inhibit the thermal oxidation of PP. This duality is known to the hydrogen bromide-polyethylene system, but has not hitherto been reported for the hydrogen chloride-PP system.

METHOD FOR IMPROVING THE THERMAL STABILITY OF SILICONE RUBBER

Silicone rubber is well known for its thermal stability but many attempts to further improve this heat resistant property have so far produced no satisfactory result. The use of antioxidant additives does increase its resistance toward oxidation, yet the problem of weight loss caused by the liberation of low momlecular weight cyclic organosiloxanes due to siloxane degradation remains unsolved. High temperature-resistant silicone rubbers containing carborane are both expensive and poor in mechanical prop-