Science.gov

Sample records for quercetin attenuates hepatitis

  1. Quercetin Attenuates Chronic Ethanol-Induced Hepatic Mitochondrial Damage through Enhanced Mitophagy

    PubMed Central

    Yu, Xiao; Xu, Yanyan; Zhang, Shanshan; Sun, Jian; Liu, Peiyi; Xiao, Lin; Tang, Yuhan; Liu, Liegang; Yao, Ping

    2016-01-01

    Emerging evidence suggested mitophagy activation mitigates ethanol-induced liver injury. However, the effect of ethanol on mitophagy is inconsistent. Importantly, the understanding of mitophagy status after chronic ethanol consumption is limited. This study evaluated the effect of quercetin, a naturally-occurring flavonoid, on chronic ethanol-induced mitochondrial damage focused on mitophagy. An ethanol regime to mice for 15 weeks (accounting for 30% of total calories) led to significant mitochondrial damage as evidenced by changes of the mitochondrial ultrastructure, loss of mitochondrial membrane potential and remodeling of membrane lipid composition, which was greatly attenuated by quercetin (100 mg/kg.bw). Moreover, quercetin blocked chronic ethanol-induced mitophagy suppression as denoted by mitophagosomes-lysosome fusion and mitophagy-related regulator elements, including LC3II, Parkin, p62 and voltage-dependent anion channel 1 (VDAC1), paralleling with increased FoxO3a nuclear translocation. AMP-activated protein kinase (AMPK) and extracellular signal regulated kinase 2 (ERK2), instead of AKT and Sirtuin 1, were involved in quercetin-mediated mitophagy activation. Quercetin alleviated ethanol-elicited mitochondrial damage through enhancing mitophagy, highlighting a promising preventive strategy for alcoholic liver disease. PMID:26742072

  2. Quercetin Attenuates Chronic Ethanol-Induced Hepatic Mitochondrial Damage through Enhanced Mitophagy.

    PubMed

    Yu, Xiao; Xu, Yanyan; Zhang, Shanshan; Sun, Jian; Liu, Peiyi; Xiao, Lin; Tang, Yuhan; Liu, Liegang; Yao, Ping

    2016-01-05

    Emerging evidence suggested mitophagy activation mitigates ethanol-induced liver injury. However, the effect of ethanol on mitophagy is inconsistent. Importantly, the understanding of mitophagy status after chronic ethanol consumption is limited. This study evaluated the effect of quercetin, a naturally-occurring flavonoid, on chronic ethanol-induced mitochondrial damage focused on mitophagy. An ethanol regime to mice for 15 weeks (accounting for 30% of total calories) led to significant mitochondrial damage as evidenced by changes of the mitochondrial ultrastructure, loss of mitochondrial membrane potential and remodeling of membrane lipid composition, which was greatly attenuated by quercetin (100 mg/kg.bw). Moreover, quercetin blocked chronic ethanol-induced mitophagy suppression as denoted by mitophagosomes-lysosome fusion and mitophagy-related regulator elements, including LC3II, Parkin, p62 and voltage-dependent anion channel 1 (VDAC1), paralleling with increased FoxO3a nuclear translocation. AMP-activated protein kinase (AMPK) and extracellular signal regulated kinase 2 (ERK2), instead of AKT and Sirtuin 1, were involved in quercetin-mediated mitophagy activation. Quercetin alleviated ethanol-elicited mitochondrial damage through enhancing mitophagy, highlighting a promising preventive strategy for alcoholic liver disease.

  3. Quercetin attenuates the activation of hepatic stellate cells and liver fibrosis in mice through modulation of HMGB1-TLR2/4-NF-κB signaling pathways.

    PubMed

    Li, Xi; Jin, Qianwen; Yao, Qunyan; Xu, Beili; Li, Zheng; Tu, Chuantao

    2016-11-02

    This study aimed to investigate the effects of quercetin on liver fibrogenesis in mice and to elucidate the underlying molecular mechanisms. Mice were administered with carbon tetrachloride (CCl4) for eight weeks to induce liver fibrosis and concomitantly orally treated with quercetin (50mgkg(-1)day(-1)). Here, we demonstrated that quercetin dramatically ameliorated liver injury, inflammation, and hepatic fibrogenesis induced by CCl4. Quercetin also inhibited the activation of hepatic stellate cells (HSC) in vivo and in vitro, as evaluated by α-smooth muscle actin (α-SMA) expression, which is a specific marker of HSC activation. Moreover, reduced fibrosis was associated with decreased high-mobility group box 1 (HMGB1), toll like receptor (TLR) 2 and TLR4 genes, and protein expression. Quercetin also inhibited the cytoplasmic translocation of HMGB1 in hepatocytes of fibrotic livers. Further investigation demonstrated that quercetin treatment significantly attenuated CCl4-induced nuclear translocation of the nuclear factor-κB (NF-κB) p65 and inhibited degradation of IκBα (an inhibitor of NF-κB) expression in the liver compared with vehicle-treated fibrotic mice. Considered together, our data indicate that quercetin has hepatoprotective and anti-fibrotic effects in animal models of liver fibrosis, the mechanism of which may be involved in modulating the HMGB1-TLR2/4-NF-κB signaling pathways.

  4. Quercetin attenuates TNF-induced inflammation in hepatic cells by inhibiting the NF-κB pathway.

    PubMed

    Granado-Serrano, Ana Belén; Martín, María Ángeles; Bravo, Laura; Goya, Luis; Ramos, Sonia

    2012-01-01

    The dietary flavonoid quercetin is an antioxidant that possesses antiinflammatory and anticarcinogenic properties and may modulate signaling pathways. Inflammation is considered to play a pivotal role in carcinogenesis by triggering activation of transcription factors such as nuclear factor kappa B (NF-κB), functionally dependent on cellular redox status. This study aims to investigate the antiinflammatory effect of quercetin and its role on the NF-κB pathway, and cyclooxygenase-2 (COX-2) and mitogen-activated protein kinases modulation in a human hepatoma cell line (HepG2). Quercetin alone did not modify any of the parameters analyzed but protected cells against activation of the NF-κB route induced by tumor necrosis factor-α. This inhibitory effect of quercetin was mediated, at least in part, by extracellular regulated kinase, c-jun amino-terminal kinase, and reactive oxygen species, and it was accompanied by reduced COX-2 levels. These observations suggest that quercetin may contribute as an antiinflammatory agent in the liver and provide evidences about its role in the prevention of diseases associated with inflammation, including cancer.

  5. Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression

    PubMed Central

    Dong, Qinghua; Chen, Long; Lu, Qunwei; Sharma, Sherven; Li, Lei; Morimoto, Sachio; Wang, Guanyu

    2014-01-01

    Background and Purpose Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity. Experimental Approach Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment. Key Results In H9c2 cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl-2 and Bmi-1. Bmi-1 siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1 and anti-oxidative superoxide dismutase. Conclusions and Implications Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1 expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy. PMID:24902966

  6. Quercetin Attenuates Lactate Production and Extracellular Matrix Secretion in Keratoconus

    PubMed Central

    McKay, T. B.; Lyon, D.; Sarker-Nag, A.; Priyadarsini, S.; Asara, J. M.; Karamichos, D.

    2015-01-01

    Keratoconus(KC) is an ecstatic corneal disease leading to corneal-thinning and the formation of a cone-like cornea. Elevated lactate levels, increased oxidative stress, and myofibroblast formation have all been previously reported. In the current study, we assess the role of Quercetin on collagen secretion and myofibroblast formation in KC in vitro. Human corneal fibroblasts(HCFs) and human keratoconus cells(HKCs) were treated with a stable Vitamin C derivative and cultured for 4 weeks, stimulating formation of a self-assembled extracellular matrix. All samples were analyzed using Western blots and targeted tandem mass spectrometry. Our data showed that Quercetin significantly down regulates myofibroblast differentiation and fibrotic markers, such as α-smooth muscle actin (α-SMA) and Collagen III (Col III), in both HCFs and HKCs. Collagen III secretion was reduced 80% in both HCFs and HKCs following Quercetin treatment. Furthermore, Quercetin reduced lactate production by HKCs to normal HCF levels. Quercetin down regulated TGF-βR2 and TGF-β2 expression in HKCs suggesting a significant link to the TGF-β pathway. These results assert that Quercetin is a key regulator of fibrotic markers and ECM assembly by modulating cellular metabolism and TGF-β signaling. Our study suggests that Quercetin is a potential therapeutic for treatment of corneal dystrophies, such as KC. PMID:25758533

  7. Quercetin Protects Mice from ConA-Induced Hepatitis by Inhibiting HMGB1-TLR Expression and Down-Regulating the Nuclear Factor Kappa B Pathway.

    PubMed

    Li, Xi; Liu, Hong-chun; Yao, Qun-yan; Xu, Bei-li; Zhang, Shun-cai; Tu, Chuan-tao

    2016-02-01

    The dietary flavonoid quercetin has hepatoprotective effects. We analyzed the effects of quercetin on concanavalin A (ConA)-induced hepatitis in mice and its underlying molecular mechanisms of action. Mice were administered quercetin (50 mg/kg body weight, i.p.) or vehicle 30 min before intravenous administration of ConA. Quercetin pretreatment significantly reduced the ConA-induced elevations in plasma aminotransferase concentrations and liver necrosis, as well as reducing serum concentrations of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interferon-γ, and interleukin-4. Quercetin pretreatment also reduced expression of high-mobility group box 1 protein (HMGB1) and toll-like receptor (TLR)-2 and TLR-4 messenger RNA (mRNA) and protein in liver tissues. Quercetin pretreatment significantly inhibited degradation of inhibitory kappa B alpha and modulated ConA-induced nuclear translocation in the liver of nuclear factor kappa B (NF-κB) p65. These results demonstrate that quercetin protects against ConA-mediated hepatitis in mice by attenuating the HMGB1-TLRs-NF-κB signaling pathway.

  8. Dietary quercetin supplementation increases serum antioxidant capacity and alters hepatic gene expression profile in rats.

    PubMed

    Zhao, Liting; Wu, Jianquan; Yang, Jijun; Wei, Jingyu; Gao, Weina; Guo, Changjiang

    2011-06-01

    The aim of this study was to determine the effect of quercetin on hepatic gene expression profile in rats. Twenty male Wistar rats were divided into the control group and the quercetin-treated group, in which a diet containing 0.5% quercetin was provided. After two weeks of feeding, serum and liver samples were collected. Biomarkers of oxidative stress, including serum ferric reducing antioxidant power (FRAP) values and levels of ascorbic acid, vitamin E (VE), glutathione (GSH) and malondialdehyde (MDA) were measured. The hepatic gene expression profile was examined using a microarray technique. The results showed that serum FRAP value, levels of ascorbic acid and VE were increased significantly, whereas serum levels of GSH and MDA were not changed significantly after quercetin supplementation. The microarray analysis revealed that some hepatic genes involved in phase 2 reaction, metabolism of cholesterol and homocysteine, and energy production were expressed differentially in response to quercetin administration. These findings provide a molecular basis for the elucidation of the actions played by quercetin in vivo.

  9. Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus.

    PubMed

    Sharma, D R; Wani, W Y; Sunkaria, A; Kandimalla, R J; Sharma, R K; Verma, D; Bal, A; Gill, K D

    2016-06-02

    Aluminum is a light weight and toxic metal present ubiquitously on earth, which has gained considerable attention due to its neurotoxic effects. It also has been linked ecologically and epidemiologically to several neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Guamanian-Parkinsonian complex and Amyotrophic lateral sclerosis (ALS). The mechanism of aluminum neurotoxicity is poorly understood, but it is well documented that aluminum generates reactive oxygen species (ROS). Enhanced ROS production leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt-c) from mitochondria to cytosol resulting in apoptotic cell death. Quercetin (a natural flavonoid) protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in aluminum-induced neurodegeneration, and then quercetin should ameliorate neuronal apoptosis. Administration of quercetin (10 mg/kg body wt/day) reduced aluminum (10 mg/kg body wt/day)-induced oxidative stress (decreased ROS production, increased mitochondrial superoxide dismutase (MnSOD) activity). In addition, quercetin also prevents aluminum-induced translocation of cyt-c, and up-regulates Bcl-2, down-regulates Bax, p53, caspase-3 activation and reduces DNA fragmentation. Quercetin also obstructs aluminum-induced neurodegenerative changes in aluminum-treated rats as seen by Hematoxylin and Eosin (H&E) staining. Further electron microscopic studies revealed that quercetin attenuates aluminum-induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that treatment with quercetin may represent a therapeutic strategy to attenuate the neuronal death against aluminum-induced neurodegeneration.

  10. Quercetin Induces Hepatic Lipid Omega-Oxidation and Lowers Serum Lipid Levels in Mice

    PubMed Central

    Hoek-van den Hil, Elise F.; Keijer, Jaap; Bunschoten, Annelies; Vervoort, Jacques J. M.; Stankova, Barbora; Bekkenkamp, Melissa; Herreman, Laure; Venema, Dini; Hollman, Peter C. H.; Tvrzicka, Eva; Rietjens, Ivonne M. C. M.; van Schothorst, Evert M.

    2013-01-01

    Elevated circulating lipid levels are known risk factors for cardiovascular diseases (CVD). In order to examine the effects of quercetin on lipid metabolism, mice received a mild-high-fat diet without (control) or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and 1H nuclear magnetic resonance were used to quantitatively measure serum lipid profiles. Whole genome microarray analysis of liver tissue was used to identify possible mechanisms underlying altered circulating lipid levels. Body weight, energy intake and hepatic lipid accumulation did not differ significantly between the quercetin and the control group. In serum of quercetin-fed mice, triglycerides (TG) were decreased with 14% (p<0.001) and total poly unsaturated fatty acids (PUFA) were increased with 13% (p<0.01). Palmitic acid, oleic acid, and linoleic acid were all decreased by 9–15% (p<0.05) in quercetin-fed mice. Both palmitic acid and oleic acid can be oxidized by omega (ω)-oxidation. Gene expression profiling showed that quercetin increased hepatic lipid metabolism, especially ω-oxidation. At the gene level, this was reflected by the up-regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450s) and the transcription factor constitutive androstane receptor (Car; official symbol Nr1i3) were also up-regulated in the quercetin-fed mice. We conclude that quercetin intake increased hepatic lipid ω-oxidation and lowered corresponding circulating lipid levels, which may contribute to potential beneficial effects on CVD. PMID:23359794

  11. Quercetin induces hepatic lipid omega-oxidation and lowers serum lipid levels in mice.

    PubMed

    Hoek-van den Hil, Elise F; Keijer, Jaap; Bunschoten, Annelies; Vervoort, Jacques J M; Stankova, Barbora; Bekkenkamp, Melissa; Herreman, Laure; Venema, Dini; Hollman, Peter C H; Tvrzicka, Eva; Rietjens, Ivonne M C M; van Schothorst, Evert M

    2013-01-01

    Elevated circulating lipid levels are known risk factors for cardiovascular diseases (CVD). In order to examine the effects of quercetin on lipid metabolism, mice received a mild-high-fat diet without (control) or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and (1)H nuclear magnetic resonance were used to quantitatively measure serum lipid profiles. Whole genome microarray analysis of liver tissue was used to identify possible mechanisms underlying altered circulating lipid levels. Body weight, energy intake and hepatic lipid accumulation did not differ significantly between the quercetin and the control group. In serum of quercetin-fed mice, triglycerides (TG) were decreased with 14% (p<0.001) and total poly unsaturated fatty acids (PUFA) were increased with 13% (p<0.01). Palmitic acid, oleic acid, and linoleic acid were all decreased by 9-15% (p<0.05) in quercetin-fed mice. Both palmitic acid and oleic acid can be oxidized by omega (ω)-oxidation. Gene expression profiling showed that quercetin increased hepatic lipid metabolism, especially ω-oxidation. At the gene level, this was reflected by the up-regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450s) and the transcription factor constitutive androstane receptor (Car; official symbol Nr1i3) were also up-regulated in the quercetin-fed mice. We conclude that quercetin intake increased hepatic lipid ω-oxidation and lowered corresponding circulating lipid levels, which may contribute to potential beneficial effects on CVD.

  12. Quercetin regulates hepatic cholesterol metabolism by promoting cholesterol-to-bile acid conversion and cholesterol efflux in rats.

    PubMed

    Zhang, Min; Xie, Zongkai; Gao, Weina; Pu, Lingling; Wei, Jingyu; Guo, Changjiang

    2016-03-01

    Quercetin, a common member of the flavonoid family, is widely present in plant kingdom. Despite that quercetin is implicated in regulating cholesterol metabolism, the molecular mechanism is poorly understood. We hypothesized that quercetin regulates cholesterol homeostasis through regulating the key enzymes involved in hepatic cholesterol metabolism. To test this hypothesis, we compared the profile of key enzymes and transcription factors involved in the hepatic cholesterol metabolism in rats with or without quercetin supplementation. Twenty male Wistar rats were randomly divided into control and quercetin-supplemented groups. Serum total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total bile acids in feces and bile were measured. Hepatic enzymatic activities were determined by activity assay kit and high-performance liquid chromatography-based analyses. The messenger RNA (mRNA) and protein expressions were determined by reverse transcriptase polymerase chain reaction and Western blot analyses, respectively. The results showed that the activity of hepatic cholesterol 7α-hydroxylase, a critical enzyme in the conversion of cholesterol to bile acids, was significantly elevated by quercetin. The expression of cholesterol 7α-hydroxylase, as well as liver X receptor α, an important transcription factor, was also increased at both mRNA and protein levels by quercetin. However, quercetin exposure had no impact on the activity of hepatic HMG-CoA reductase, a rate-limiting enzyme in the biosynthesis of cholesterol. We also found that quercetin treatment significantly increased ATP binding cassette transporter G1 mRNA and protein expression in the liver, suggesting that quercetin may increase hepatic cholesterol efflux. Collectively, the results presented here indicate that quercetin regulates hepatic cholesterol metabolism mainly through the pathways that promote cholesterol-to-bile acid conversion and

  13. Induction of heme oxygenase-1 with dietary quercetin reduces obesity-induced hepatic inflammation through macrophage phenotype switching

    PubMed Central

    Kim, Chu-Sook; Choi, Hye-Seon; Joe, Yeonsoo; Chung, Hun Taeg

    2016-01-01

    BACKGROUND/OBJECTIVES Obesity-induced steatohepatitis accompanied by activated hepatic macrophages/Kupffer cells facilitates the progression of hepatic fibrinogenesis and exacerbates metabolic derangements such as insulin resistance. Heme oxyganase-1 (HO-1) modulates tissue macrophage phenotypes and thus is implicated in protection against inflammatory diseases. Here, we show that the flavonoid quercetin reduces obesity-induced hepatic inflammation by inducing HO-1, which promotes hepatic macrophage polarization in favor of the M2 phenotype. MATERIALS/METHODS Male C57BL/6 mice were fed a regular diet (RD), high-fat diet (HFD), or HFD supplemented with quercetin (HF+Que, 0.5g/kg diet) for nine weeks. Inflammatory cytokines and macrophage markers were measured by ELISA and RT-PCR, respectively. HO-1 protein was measured by Western blotting. RESULTS Quercetin supplementation decreased levels of inflammatory cytokines (TNFα, IL-6) and increased that of the anti-inflammatory cytokine (IL-10) in the livers of HFD-fed mice. This was accompanied by upregulation of M2 macrophage marker genes (Arg-1, Mrc1) and downregulation of M1 macrophage marker genes (TNFα, NOS2). In co-cultures of lipid-laden hepatocytes and macrophages, treatment with quercetin induced HO-1 in the macrophages, markedly suppressed expression of M1 macrophage marker genes, and reduced release of MCP-1. Moreover, these effects of quercetin were blunted by an HO-1 inhibitor and deficiency of nuclear factor E2-related factor 2 (Nrf2) in macrophages. CONCLUSIONS Quercetin reduces obesity-induced hepatic inflammation by promoting macrophage phenotype switching. The beneficial effect of quercetin is associated with Nrf2-mediated HO-1 induction. Quercetin may be a useful dietary factor for protecting against obesity-induced steatohepatitis. PMID:27909560

  14. Quercetin Attenuates Cell Survival, Inflammation, and Angiogenesis via Modulation of AKT Signaling in Murine T-Cell Lymphoma.

    PubMed

    Maurya, Akhilendra Kumar; Vinayak, Manjula

    2017-04-01

    AKT signaling is important to maintaining normal physiology. Hyperactivation of AKT signaling is frequent in cancer, which maintains a high oxidative state in a tumor microenvironment that is needed for tumor adaptation. Therefore, antioxidants are proposed to exhibit anticancer properties by interfering with the tumor microenvironment. Quercetin is an ubiquitous bioactive antioxidant rich in vegetables and beverages. The present study aimed to analyze cancer preventive property of quercetin in ascite cells of Dalton's lymphoma-bearing mice. Protein level was determined by Western blotting. Nitric oxide (NO) level was estimated spectrophotometrically using Griess reagent. Results show downregulation in phosphorylation of AKT and PDK1 by quercetin, which was consistent with decreased phosphorylation of downstream survival factors such as BAD, GSK-3β, mTOR, and IkBα. Further, quercetin attenuated the levels of angiogenic factor VEGF-A and inflammatory enzymes COX-2 and iNOS as well as NO levels, whereas it increased the levels of phosphatase PTEN. Overall results suggest that quercetin modulates AKT signaling leading to attenuation of cell survival, inflammation, and angiogenesis in lymphoma-bearing mice.

  15. Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats.

    PubMed

    Panchal, Sunil K; Poudyal, Hemant; Brown, Lindsay

    2012-06-01

    Metabolic syndrome is a risk factor for cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). We investigated the responses to the flavonol, quercetin, in male Wistar rats (8-9 wk old) divided into 4 groups. Two groups were given either a corn starch-rich (C) or high-carbohydrate, high-fat (H) diet for 16 wk; the remaining 2 groups were given either a C or H diet for 8 wk followed by supplementation with 0.8 g/kg quercetin in the food for the following 8 wk (CQ and HQ, respectively). The H diet contained ~68% carbohydrates, mainly as fructose and sucrose, and ~24% fat from beef tallow; the C diet contained ~68% carbohydrates as polysaccharides and ~0.7% fat. Compared with the C rats, the H rats had greater body weight and abdominal obesity, dyslipidemia, higher systolic blood pressure, impaired glucose tolerance, cardiovascular remodeling, and NAFLD. The H rats had lower protein expressions of nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and carnitine palmitoyltransferase 1 (CPT1) with greater expression of NF-κB in both the heart and the liver and less expression of caspase-3 in the liver than in C rats. HQ rats had higher expression of Nrf2, HO-1, and CPT1 and lower expression of NF-κB than H rats in both the heart and the liver. HQ rats had less abdominal fat and lower systolic blood pressure along with attenuation of changes in structure and function of the heart and the liver compared with H rats, although body weight and dyslipidemia did not differ between the H and HQ rats. Thus, quercetin treatment attenuated most of the symptoms of metabolic syndrome, including abdominal obesity, cardiovascular remodeling, and NAFLD, with the most likely mechanisms being decreases in oxidative stress and inflammation.

  16. The berry constituents quercetin, kaempferol, and pterostilbene synergistically attenuate reactive oxygen species: involvement of the Nrf2-ARE signaling pathway.

    PubMed

    Saw, Constance Lay Lay; Guo, Yue; Yang, Anne Yuqing; Paredes-Gonzalez, Ximena; Ramirez, Christina; Pung, Douglas; Kong, Ah-Ng Tony

    2014-10-01

    Quercetin, kaempferol, and pterostilbene are abundant in berries. The anti-oxidative properties of these constituents may contribute to cancer chemoprevention. However, their precise mechanisms of action and their combinatorial effects are not completely understood. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates anti-oxidative stress enzymes and Phase II drug metabolizing/detoxifying enzymes by binding to antioxidant response element (ARE). This study aimed to investigate the anti-oxidative stress activities of quercetin, kaempferol, and pterostilbene individually and in combination, as well as the involvement of the Nrf2-ARE signaling pathway. Quercetin, kaempferol, and pterostilbene all exhibited strong free-radical scavenging activity in the DPPH assay. The MTS assay revealed that low concentration combinations we tested were relatively non-toxic to HepG2-C8 cells. The results of the DCFH-DA assay and combination index (CI) indicated that quercetin, kaempferol, and pterostilbene attenuated intracellular reactive oxygen species (ROS) levels when pretreated individually and had synergistic effects when used in combination. In addition, the combination treatment significantly induced ARE and increased the mRNA and protein expression of Nrf2-regulated genes. Collectively, our study demonstrated that the berry constituents quercetin, kaempferol, and pterostilbene activated the Nrf2-ARE signaling pathway and exhibited synergistic anti-oxidative stress activity at appropriate concentrations.

  17. Attenuation of Chondrogenic Transformation in Vascular Smooth Muscle by Dietary Quercetin in the MGP-Deficient Mouse Model

    PubMed Central

    Borras, Teresa; Nurminskaya, Maria

    2013-01-01

    Rationale Cartilaginous metaplasia of vascular smooth muscle (VSM) is characteristic for arterial calcification in diabetes and uremia and in the background of genetic alterations in matrix Gla protein (MGP). A better understanding of the molecular details of this process is critical for the development of novel therapeutic approaches to VSM transformation and arterial calcification. Objective This study aimed to identify the effects of bioflavonoid quercetin on chondrogenic transformation and calcification of VSM in the MGP-null mouse model and upon TGF-β3 stimulation in vitro, and to characterize the associated alterations in cell signaling. Methods and Results Molecular analysis revealed activation of β-catenin signaling in cartilaginous metaplasia in Mgp-/- aortae in vivo and during chondrogenic transformation of VSMCs in vitro. Quercetin intercepted chondrogenic transformation of VSM and blocked activation of β-catenin both in vivo and in vitro. Although dietary quercetin drastically attenuated calcifying cartilaginous metaplasia in Mgp-/- animals, approximately one-half of total vascular calcium mineral remained as depositions along elastic lamellae. Conclusion Quercetin is potent in preventing VSM chondrogenic transformation caused by diverse stimuli. Combined with the demonstrated efficiency of dietary quercetin in preventing ectopic chondrogenesis in the MGP-null vasculature, these findings indicate a potentially broad therapeutic applicability of this safe for human consumption bioflavonoid in the therapy of cardiovascular conditions linked to cartilaginous metaplasia of VSM. Elastocalcinosis is a major component of MGP-null vascular disease and is controlled by a mechanism different from chondrogenic transformation of VSM and not sensitive to quercetin. PMID:24098781

  18. Quercetin induces hepatic γ-glutamyl hydrolase expression in rats by suppressing hepatic microRNA rno-miR-125b-3p.

    PubMed

    Wein, Silvia Anette; Laviano, Alessandro; Wolffram, Siegfried

    2015-12-01

    Exogenous factors such as food components including the flavonoid quercetin are suspected to influence micro RNA (miRNA) concentrations and thus possibly target enzymes involved in xenobiotic metabolism. This study therefore investigates the influence of orally administered quercetin on hepatic miRNA and the identification of enzyme target mRNAs relevant in drug metabolism. Male Wistar rats (n=16) were fed either a diet without (C) or with (Q) the addition of 100-ppm quercetin for 7 weeks and subsequently euthanized at the end of the dark phase. To avoid strong effects of food deprivation on hepatic metabolism, food was not removed until 5 h prior to the procedure. Liver was immediately dissected and snap-frozen in liquid nitrogen. Concentrations of 352 hepatic miRNA were measured in pool samples of each dietary group (n=8) using the RT(2) miRNA PCR Array System. Differential expression of miRNAs was assumed with fold changes ≥3. Target genes of differentially expressed miRNAs were identified using the database TargetScan. Because rno-miR-125b-3p showed the most prominent fold-change (-9) we further analyzed the expression of its top predicted target gene gamma-glutamyl hydrolase (GGH) by quantitative real-time PCR using hypoxanthine phosphoribosyltransferase 1 (hprt1) as endogenous control. Compared to controls, 23 miRNAs were differentially expressed in rats fed quercetin. A ninefold reduction in hepatic miRNA rno-miR-125b-3p was paralleled by significant induction of GGH mRNA in liver of quercetin fed rats. Because increased GGH expressions were repeatedly associated with resistance to methotrexate, concomitant intake with quercetin should be monitored carefully.

  19. PI-103 and Quercetin Attenuate PI3K-AKT Signaling Pathway in T- Cell Lymphoma Exposed to Hydrogen Peroxide

    PubMed Central

    Maurya, Akhilendra Kumar; Vinayak, Manjula

    2016-01-01

    Phosphatidylinositol 3 kinase—protein kinase B (PI3K-AKT) pathway has been considered as major drug target site due to its frequent activation in cancer. AKT regulates the activity of various targets to promote tumorigenesis and metastasis. Accumulation of reactive oxygen species (ROS) has been linked to oxidative stress and regulation of signaling pathways for metabolic adaptation of tumor microenvironment. Hydrogen peroxide (H2O2) in this context is used as ROS source for oxidative stress preconditioning. Antioxidants are commonly considered to be beneficial to reduce detrimental effects of ROS and are recommended as dietary supplements. Quercetin, a ubiquitous bioactive flavonoid is a dietary component which has attracted much of interest due to its potential health-promoting effects. Present study is aimed to analyze PI3K-AKT signaling pathway in H2O2 exposed Dalton’s lymphoma ascite (DLA) cells. Further, regulation of PI3K-AKT pathway by quercetin as well as PI-103, an inhibitor of PI3K was analyzed. Exposure of H2O2 (1mM H2O2 for 30min) to DLA cells caused ROS accumulation and resulted in increased phosphorylation of PI3K and downstream proteins PDK1 and AKT (Ser-473 and Thr-308), cell survival factors BAD and ERK1/2, as well as TNFR1. However, level of tumor suppressor PTEN was declined. Both PI-103 & quercetin suppressed the enhanced level of ROS and significantly down-regulated phosphorylation of AKT, PDK1, BAD and level of TNFR1 as well as increased the level of PTEN in H2O2 induced lymphoma cells. The overall result suggests that quercetin and PI3K inhibitor PI-103 attenuate PI3K-AKT pathway in a similar mechanism. PMID:27494022

  20. PI-103 and Quercetin Attenuate PI3K-AKT Signaling Pathway in T- Cell Lymphoma Exposed to Hydrogen Peroxide.

    PubMed

    Maurya, Akhilendra Kumar; Vinayak, Manjula

    2016-01-01

    Phosphatidylinositol 3 kinase-protein kinase B (PI3K-AKT) pathway has been considered as major drug target site due to its frequent activation in cancer. AKT regulates the activity of various targets to promote tumorigenesis and metastasis. Accumulation of reactive oxygen species (ROS) has been linked to oxidative stress and regulation of signaling pathways for metabolic adaptation of tumor microenvironment. Hydrogen peroxide (H2O2) in this context is used as ROS source for oxidative stress preconditioning. Antioxidants are commonly considered to be beneficial to reduce detrimental effects of ROS and are recommended as dietary supplements. Quercetin, a ubiquitous bioactive flavonoid is a dietary component which has attracted much of interest due to its potential health-promoting effects. Present study is aimed to analyze PI3K-AKT signaling pathway in H2O2 exposed Dalton's lymphoma ascite (DLA) cells. Further, regulation of PI3K-AKT pathway by quercetin as well as PI-103, an inhibitor of PI3K was analyzed. Exposure of H2O2 (1mM H2O2 for 30min) to DLA cells caused ROS accumulation and resulted in increased phosphorylation of PI3K and downstream proteins PDK1 and AKT (Ser-473 and Thr-308), cell survival factors BAD and ERK1/2, as well as TNFR1. However, level of tumor suppressor PTEN was declined. Both PI-103 & quercetin suppressed the enhanced level of ROS and significantly down-regulated phosphorylation of AKT, PDK1, BAD and level of TNFR1 as well as increased the level of PTEN in H2O2 induced lymphoma cells. The overall result suggests that quercetin and PI3K inhibitor PI-103 attenuate PI3K-AKT pathway in a similar mechanism.

  1. Iron-Mediated Lysosomal Membrane Permeabilization in Ethanol-Induced Hepatic Oxidative Damage and Apoptosis: Protective Effects of Quercetin.

    PubMed

    Li, Yanyan; Chen, Man; Xu, Yanyan; Yu, Xiao; Xiong, Ting; Du, Min; Sun, Jian; Liu, Liegang; Tang, Yuhan; Yao, Ping

    2016-01-01

    Iron, in its free ferrous states, can catalyze Fenton reaction to produce OH∙, which is recognized as a crucial role in the pathogenesis of alcoholic liver diseases (ALD). As a result of continuous decomposition of iron-containing compounds, lysosomes contain a pool of redox-active iron. To investigate the important role of intralysosomal iron in alcoholic liver injury and the potential protection of quercetin, male C57BL/6J mice fed by Lieber De Carli diets containing ethanol (30% of total calories) were cotreated by quercetin or deferoxamine (DFO) for 15 weeks and ethanol-incubated mice primary hepatocytes were pretreated with FeCl3, DFO, and bafilomycin A1 at their optimal concentrations and exposure times. Chronic ethanol consumption caused an evident increase in lysosomal redox-active iron accompanying sustained oxidative damage. Iron-mediated ROS could trigger lysosomal membrane permeabilization (LMP) and subsequent mitochondria apoptosis. The hepatotoxicity was attenuated by reducing lysosomal iron while being exacerbated by escalating lysosomal iron. Quercetin substantially alleviated the alcoholic liver oxidative damage and apoptosis by decreasing lysosome iron and ameliorating iron-mediated LMP, which provided a new prospective of the use of quercetin against ALD.

  2. Myricetin and quercetin attenuate ischemic injury in glial cultures by different mechanisms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have demonstrated that polyphenols from cinnamon and green tea reduce cell swelling and mitochondrial dysfunction in C6 glial cultures following ischemic injury. We tested the protective effects of the flavonoid polyphenols, myricetin and quercetin, on key features of ischemic injury. C6 cultures...

  3. Quercetin attenuates di-(2-ethylhexyl) phthalate-induced testicular toxicity in adult rats.

    PubMed

    Abd-Ellah, M F; Aly, H A A; Mokhlis, H A M; Abdel-Aziz, A H

    2016-03-01

    The aim of the present study was to investigate the potential oxidative damage of di-(2-ethylhexyl) phthalate (DEHP) in the rat testis and to further elucidate the potential modulatory effect of quercetin. DEHP was diluted in corn oil and given to rats by oral gavage at doses 0, 300, 600, and 900 mg/kg/day (groups I, III, IV, or V, respectively) for 15 consecutive days. Group VI was pretreated with quercetin (90 mg/kg), 24 h before starting the experiment and then treated with DEHP (900 mg/kg/day) for 15 consecutive days. Group II was treated with quercetin (90 mg/kg/day). The relative testes weight and sperm motility were significantly decreased by treatment with 900 mg/kg of DEHP. Both sperm count and daily sperm production were significantly decreased by DEHP treatment at doses of 600 and 900 mg/kg. Serum testosterone level and prostatic acid phosphatase (ACP) activity and testicular lactate dehydrogenase-X (LDH-X) activity were significantly decreased in animals treated with 900 mg/kg. Serum total ACP activity was significantly increased in animals treated with 600 and 900 mg/kg of DEHP. DEHP treatment induced oxidative stress and histopathological abnormality. These abnormalities were effectively normalized by pretreatment with quercetin except for LDH-X near normalcy. In conclusion, the findings of this study demonstrate that DEHP impairs testicular function at least, in part, by inducing oxidative stress and quercetin has a potent protective effect against DEHP-induced testicular toxicity in rats.

  4. A Phase I Dose Escalation Study Demonstrates Quercetin Safety and Explores Potential for Bioflavonoid Antivirals in Patients with Chronic Hepatitis C.

    PubMed

    Lu, Nu T; Crespi, Catherine M; Liu, Natalie M; Vu, James Q; Ahmadieh, Yasaman; Wu, Sheng; Lin, Sherry; McClune, Amy; Durazo, Francisco; Saab, Sammy; Han, Steven; Neiman, David C; Beaven, Simon; French, Samuel W

    2016-01-01

    The hepatitis C virus (HCV) infects more than 180 million people worldwide, with long-term consequences including liver failure and hepatocellular carcinoma. Quercetin bioflavonoids can decrease HCV production in tissue culture, in part through inhibition of heat shock proteins. If quercetin demonstrates safety and antiviral activity in patients, then it could be developed into an inexpensive HCV treatment for third world countries or other affected populations that lack financial means to cover the cost of mainstream antivirals. A phase 1 dose escalation study was performed to evaluate the safety of quercetin in 30 untreated patients with chronic HCV infection and to preliminarily characterize quercetin's potential in suppressing viral load and/or liver injury. Quercetin displayed safety in all trial participants. Additionally, 8 patients showed a "clinically meaningful" 0.41-log viral load decrease. There was a positive correlation (r = 0.41, p = 0.03) indicating a tendency for HCV decrease in patients with a lower ratio of plasma quercetin relative to dose. No significant changes in aspartate transaminase and alanine transaminase were detected. In conclusion, quercetin exhibited safety (up to 5 g daily) and there was a potential for antiviral activity in some hepatitis C patients.

  5. (+)-Catechin attenuates activation of hepatic stellate cells.

    PubMed

    Bragança de Moraes, Cristina Machado; Bitencourt, Shanna; de Mesquita, Fernanda Cristina; Mello, Denizar; de Oliveira, Leticia Paranhos; da Silva, Gabriela Viegas; Lorini, Vinicius; Caberlon, Eduardo; de Souza Basso, Bruno; Schmid, Julia; Ferreira, Gabriela Acevedo; de Oliveira, Jarbas Rodrigues

    2014-04-01

    (+)-Catechin is a type of catechin present in large amounts in açaí fruits and cocoa seeds. Besides its antioxidant and anti-inflammatory activities, little is known about its effects in the liver, especially during hepatic fibrosis. We report here the effects of (+)-catechin on hepatic stellate cells. (+)-Catechin induced quiescent phenotype in GRX cells, along with an increase in lipid droplets. Proliferator-activated receptor γ mRNA expression was upregulated, whereas type I collagen mRNA expression was downregulated. Pro-inflammatory cytokines were not influenced by (+)-catechin, whereas the levels of interleukin 10 were significantly increased. The data provide evidence that (+)-catechin can reduce hepatic stellate cell activation.

  6. Quercetin, Inflammation and Immunity

    PubMed Central

    Li, Yao; Yao, Jiaying; Han, Chunyan; Yang, Jiaxin; Chaudhry, Maria Tabassum; Wang, Shengnan; Liu, Hongnan; Yin, Yulong

    2016-01-01

    In vitro and some animal models have shown that quercetin, a polyphenol derived from plants, has a wide range of biological actions including anti-carcinogenic, anti-inflammatory and antiviral activities; as well as attenuating lipid peroxidation, platelet aggregation and capillary permeability. This review focuses on the physicochemical properties, dietary sources, absorption, bioavailability and metabolism of quercetin, especially main effects of quercetin on inflammation and immune function. According to the results obtained both in vitro and in vivo, good perspectives have been opened for quercetin. Nevertheless, further studies are needed to better characterize the mechanisms of action underlying the beneficial effects of quercetin on inflammation and immunity. PMID:26999194

  7. Quercetin, Inflammation and Immunity.

    PubMed

    Li, Yao; Yao, Jiaying; Han, Chunyan; Yang, Jiaxin; Chaudhry, Maria Tabassum; Wang, Shengnan; Liu, Hongnan; Yin, Yulong

    2016-03-15

    In vitro and some animal models have shown that quercetin, a polyphenol derived from plants, has a wide range of biological actions including anti-carcinogenic, anti-inflammatory and antiviral activities; as well as attenuating lipid peroxidation, platelet aggregation and capillary permeability. This review focuses on the physicochemical properties, dietary sources, absorption, bioavailability and metabolism of quercetin, especially main effects of quercetin on inflammation and immune function. According to the results obtained both in vitro and in vivo, good perspectives have been opened for quercetin. Nevertheless, further studies are needed to better characterize the mechanisms of action underlying the beneficial effects of quercetin on inflammation and immunity.

  8. Melatonin, quercetin and resveratrol attenuates oxidative hepatocellular injury in streptozotocin-induced diabetic rats.

    PubMed

    Elbe, H; Esrefoglu, M; Vardi, N; Taslidere, E; Ozerol, E; Tanbek, K

    2015-09-01

    In this study, effects of melatonin, quercetin and resveratrol on hepatocellular injury in streptozotocin (STZ)-induced experimental diabetes were aimed to be investigated by histological and biochemical methods. Thirty-five male Wistar albino rats were divided into five groups, namely, control, diabetes (STZ 45 mg/kg/single dose/intraperitoneally (ip)), diabetes + melatonin (10 mg/kg/30 days/ip), diabetes + quercetin (25 mg/kg/30 days/ip) and diabetes + resveratrol (10 mg/kg/30 days/ip). Initial and final blood glucose levels and body weights (BWs) were measured. At the end of the experimentation, following routine tissue processing procedure, sections were stained with haematoxylin-eosin (H-E), periodic acid Schiff and Masson's trichrome. Tissue malondialdehyde (MDA) and glutathione (GSH) levels and superoxide dismutase (SOD) and catalase (CAT) activities were examined. The diabetic rats had significantly higher blood glucose levels than those of control rats (p = 0.0001). Mean BWs of diabetic rats were significantly decreased when compared with the control rats (p = 0.0013). Histopathological alterations including cellular glycogen depletion, congestion, sinusoidal dilatation, inflammation and fibrosis were detected in diabetes group. On the other hand, histopathological changes markedly reduced in all of the treatment groups (p = 0.001). Mean tissue MDA level was increased but mean tissue CAT and SOD activities and GSH levels were decreased in the diabetes group. Melatonin, quercetin and resveratrol administered diabetic rats showed an increase in CAT activities and GSH levels and a decrease in MDA levels (p < 0.05, for all). Melatonin, quercetin and resveratrol administrations markedly reduced hepatocellular injury in STZ-induced experimental diabetes.

  9. Genotoxicity and apoptosis in Drosophila melanogaster exposed to benzene, toluene and xylene: Attenuation by quercetin and curcumin

    SciTech Connect

    Singh, Mahendra P.; Mishra, M.; Sharma, A.; Shukla, A.K.; Mudiam, M.K.R.; Patel, D.K.; Ram, K. Ravi; Chowdhuri, D. Kar

    2011-05-15

    Monocyclic aromatic hydrocarbons (MAHs) such as benzene, toluene and xylene are being extensively used for various industrial and household purposes. Exposure to these hydrocarbons, occupationally or non-occupationally, is harmful to organisms including human. Several studies tested for toxicity of benzene, toluene and xylene, and interestingly, only a few studies looked into the attenuation. We used Drosophila model to test the genotoxic and apoptotic potential of these compounds and subsequently evaluated the efficiency of two phytochemicals, namely, quercetin and curcumin in attenuating test chemical induced toxicity. We exposed third instar larvae of wild type Drosophila melanogaster (Oregon R{sup +}) to 1.0-100.0 mM benzene, toluene or xylene, individually, for 12, 24 and 48 h and examined their apoptotic and genotoxic potential. We observed significantly (P < 0.001) increased apoptotic markers and genotoxicity in a concentration- and time-dependent manner in organisms exposed to benzene, toluene or xylene. We also observed significantly (P < 0.001) increased cytochrome P450 activity in larvae exposed to test chemicals and this was significantly reduced in the presence of 3',4'-dimethoxyflavone, a known Aryl hydrocarbon receptor (AhR) blocker. Interestingly, we observed a significant reduction in cytochrome P450 activity, GST levels, oxidative stress parameters, genotoxic and apoptotic endpoints when organisms were exposed simultaneously to test chemical along with quercetin or curcumin. The study further suggests the suitability of D. melanogaster as an alternate animal model for toxicological studies involving benzene, toluene and xylene and its potential in studying the protective role(s) of phytochemicals.

  10. Catechin and quercetin attenuate adipose inflammation in fructose-fed rats and in 3T3-L1 adipocytes

    PubMed Central

    Vazquez Prieto, Marcela A.; Bettaieb, Ahmed; Rodriguez Lanzi, Cecilia; Soto, Verónica C.; Perdicaro, Diahann J.; Galmarini, Claudio R.; Haj, Fawaz G.; Miatello, Roberto M.; Oteiza, Patricia I.

    2015-01-01

    Scope This study evaluated the capacity of dietary catechin (C), quercetin (Q) and the combination of both (CQ), to attenuate adipose inflammation triggered by high fructose (HFr) consumption in rats and by tumor necrosis factor alpha (TNFα) in 3T3-L1 adipocytes. Methods and results In rats, HFr consumption for 6 wk caused dyslipidemia, insulin resistance, reduced plasma adiponectin, adiposity, and adipose tissue inflammation. Dietary supplementation with 20 mg/kg/d of C, Q and CQ improved all these parameters. In 3T3-L1 adipocytes, C and Q attenuated TNFα-induced elevated protein carbonyls, increased pro-inflammatory cytokine expression (MCP-1, resistin), and decreased adiponectin. The protective effects of C and Q on adipose inflammation are in part associated with their capacity to: i) decrease the activation of the mitogen activated kinases (MAPKs) JNK and p38; and ii) prevent the downregulation of PPARγ. In summary, C and Q, and to a larger extent the combination of both, attenuated adipose pro-inflammatory signaling cascades and regulated the balance of molecules that improve (adiponectin) or impair (TNFα, MCP-1, resistin) insulin sensitivity. Conclusion Together, these findings suggest that dietary Q and C may have potential benefits in mitigating MetS associated adipose inflammation, oxidative stress, and insulin resistance. PMID:25620282

  11. Targeting oxidative stress attenuates trinitrobenzene sulphonic acid induced inflammatory bowel disease like symptoms in rats: Role of quercetin

    PubMed Central

    Dodda, Dilip; Chhajed, Ruchi; Mishra, Jitendriya; Padhy, Monalisa

    2014-01-01

    Objective: This study was aimed to investigate the beneficial effects of quercetin (QCT) against trinitrobenzene sulfonic acid (TNBS) induced clinical, morphological, and biochemical alterations in rats. Materials and Methods: Colitis in rats was induced by administration of TNBS (25 mg dissolved in 0.25 ml of 30% ethanol) 8 cm into the rectum of the rat using a catheter. The animals were divided into six experimental groups (n = 6); naive (saline only without TNBS administration), control (saline + TNBS), standard (sulfasalazine 25 mg/kg + TNBS), QCT (25) (QCT 25 mg/kg + TNBS), QCT (50) (QCT 50 mg/kg + TNBS), QCT (100) (QCT 100 mg/kg + TNBS). Sulfasalazine (25 mg/kg) and QCT (25, 50 and 100 mg/kg) were administered per oral for 11 days and the colonic damage was evaluated in terms of macroscopical (body weight, stool consistency, rectal bleeding, and ulcer index) and biochemical parameters (myeloperoxidase activity, lipid peroxidation, nitrite, and glutathione). Results: Treatment with QCT (50, 100 mg/kg) for 10 days following TNBS administration significantly attenuated the clinical, morphological, and biochemical alterations induced by TNBS, whereas it was found to be not effective at its lower dose (25 mg/kg) throughout the experimental protocol. Conclusion: QCT attenuates the clinical, morphological and biochemical alterations induced by TNBS possibly via its antioxidant mechanism. PMID:24987175

  12. Quercetin attenuates the effects of H2O2 on endoplasmic reticulum morphology and tyrosinase export from the endoplasmic reticulum in melanocytes.

    PubMed

    Guan, Cuiping; Xu, Wen; Hong, Weisong; Zhou, Miaoni; Lin, Fuquan; Fu, Lifang; Liu, Dongyin; Xu, Aie

    2015-06-01

    Swollen endoplasmic reticulum (ER) is commonly observed in the melanocytes of vitiligo patients; however, the cause and proteins involved in this remain to be elucidated. Oxidative stress has been reported to be involved in the pathogenesis of vitiligo and previous studies have demonstrated that hydrogen peroxide (H2O2) induced melanocyte apoptosis, whereas quercetin exhibited cytoprotective activities against the effects of H2O2. The aim of the present study was to further investigate the role of H2O2 in the ER of melanocytes as well as its role in the export of tyrosinase from ER; in addition, the present study aimed to determine the mechanism by which quercetin protects against the effects of H2O2. The results demonstrated that melanocyte cells treated with H2O2 presented with swollen ER; however, a normal ER configuration was observed in untreated cells as well as quercetin/H2O2‑treated cells. Furthermore, H2O2 inhibited tyrosinase export from the ER and decreased expression levels of tyrosinase; however, quercetin was found to attenuate the effects induced by H2O2. In conclusion, the results of the present study confirmed the hypothesis that H2O2 induced ER dilation and hindered functional tyrosinase export from the ER of melanocytes. It was also found that quercetin significantly weakened these effects mediated by H2O2, therefore it may have the potential for use in the treatment of vitiligo.

  13. Live attenuated hepatitis A vaccines developed in China.

    PubMed

    Xu, Zhi-Yi; Wang, Xuan-Yi

    2014-01-01

    Two live, attenuated hepatitis A vaccines, H 2 and LA-1 virus strains, were developed through serial passages of the viruses in cell cultures at 32 °C and 35 °C respectively. Both vaccines were safe and immunogenic, providing protection against clinical hepatitis A in 95% of the vaccinees, with a single dose by subcutaneous injection. The vaccine recipients were not protected from asymptomatic, subclinical hepatitis A virus (HAV) infection, which induced a similar antibody response as for unvaccinated subjects. A second dose caused anamnestic response and can be used for boosting. Oral immunization of human with H 2 vaccine or of marmoset with LA-1 vaccine failed, and no evidence was found for person-to-person transmission of the H 2 strain or for marmoset-to-marmoset transmission of LA-1 strain, by close contact. H 2 strain was genetically stable when passaged in marmosets, humans or cell cultures at 37 °C; 3 consecutive passages of the virus in marmosets did not cause virulence mutation. The live vaccines offer the benefits of low cost, single dose injection, long- term protection, and increased duration of immunity through subclinical infection. Improved sanitation and administration of 150 million doses of the live vaccines to children had led to a 90% reduction in the annual national incidence rate of hepatitis A in China during the 16-year period, from 1991 to 2006. Hepatitis A immunization with both live and inactivated HA vaccines was implemented in the national routine childhood immunization program in 2008 and around 92% of the 16 million annual births received the affordable live, attenuated vaccines at 18 months of age. Near elimination of the disease was achieved in China for 14 years following introduction of the H 2 live vaccine into the Expanded Immunization Program (EPI) in 1992.

  14. Quercetin attenuates oxidative stress in the blood plasma of rats bearing DMBA-induced mammary cancer and treated with a combination of doxorubicin and docetaxel.

    PubMed

    Tabaczar, Sabina; Pieniążek, Anna; Czepas, Jan; Piasecka-Zelga, Joanna; Gwoździński, Krzysztof; Koceva-Chyła, Aneta

    2013-12-01

    The development of side-effects during doxorubicin-docetaxel (DOX-DTX) chemotherapy is considered as related to generation of oxidative stress by DOX. The addition of docetaxel potentiates this effect. Thus, antioxidants are assumed as a promising remedy for neutralizing deteriorating effects of reactive oxygen species (ROS) in pathological conditions and polyphenolic antioxidants are suitable candidates for such a therapeutic approach. We evaluated the ability of quercetin to attenuate oxidative stress developed during the process of DMBA carcinogenesis and DOX-DTX chemotherapy in the blood plasma of rats bearing mammary tumors. We have found that quercetin significantly improved the plasma nonenzymatic antioxidant capacity (NEAC) and reduced lipid peroxidation, which suggest the beneficial effect of flavonoid. The inclusion of quercetin to the DOX-DTX chemotherapy was also advantageous. A considerable decrease of carbonyls and lipid peroxidation products (TBARS) and improvement of the endogenous antioxidant defense system (an increase of NEAC, thiols and SOD activity) were observed compared to rats treated with DOX-DTX chemotherapy. These results suggest that quercetin could protect blood plasma constituents against oxidative damage evoked by DOX and DTX.

  15. In vitro inhibition of human CYP2E1 and CYP3A by quercetin and myricetin in hepatic microsomes is not gender dependent.

    PubMed

    Östlund, Johanna; Zlabek, Vladimir; Zamaratskaia, Galia

    2017-04-15

    This is the first in vitro study to investigate gender-related differences in the regulation of human cytochrome P450 by the flavonoids. Activities of CYP2E1 and CYP3A were measured in the presence of quercetin, myricetin, or isorhamnetin in hepatic microsomal pools from male and female donors. Hydroxylation of p-nitrophenol (PNPH) was measured to determine CYP2E1 activity, and O-dealkylation of 7-benzyloxy-4-trifluoromethylcoumarin (BFC) was measured to determine CYP3A activity. Quercetin, but not myricetin or isorhamnetin, competitively inhibited PNPH activity in human recombinant cDNA-expressed CYP2E1 with the Ki=52.1±6.31μM. In the human microsomes, slight inhibition of PNPH activity by quercetin was not considered as physiologically relevant. Quercetin inhibited BFC activity in human recombinant cDNA-expressed CYP3A4 competitively with the Ki=15.4±1.52μM, and myricetin - noncompetitively with the Ki=74.6±7.99μM. The degree of inhibition by quercetin was similar between genders. Myricetin showed somewhat stronger inhibition in female pools, but the Ki values were higher than physiologically relevant concentrations. Isorhamnetin did not affect either PNPH or BFC activity. We concluded that observed inhibition of CYP2E1 and CYP3A by some flavonols were not gender-dependent.

  16. Quercetin attenuates high fat diet-induced atherosclerosis in apolipoprotein E knockout mice: A critical role of NADPH oxidase.

    PubMed

    Xiao, Lin; Liu, Liang; Guo, Xiaoping; Zhang, Shanshan; Wang, Jing; Zhou, Feng; Liu, Liegang; Tang, Yuhan; Yao, Ping

    2017-03-27

    Reactive oxygen species (ROS) have emerged as important molecules in cardiovascular function. Nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase is the major source of ROS in phagocytic and vascular cells. Several lines of evidence indicate that quercetin contributes to protecting against atherosclerosis. Herein, we investigated the effect of quercetin on alleviating atherosclerosis by regulating NADPH oxidase subunits expression in vivo, and explored the mechanism of quercetin suppressing the ROS overproduction stimulated by ox-LDL in mouse peritoneal macrophages (MPMs). Model ApoE KO mice were fed with either a normal chow diet or a high fat diet (HFD) supplemented with or without dosed quercetin for 24 weeks. Quercetin significantly reduced the atherosclerotic plaque area, alleviated the systemic oxidative stress, and suppressed aortic p47phox, p67phox expressions but partially reversed the NOX4 expression as compared to those in the HFD group. In vitro, quercetin effectively inhibited the ox-LDL induced ROS formation in MPMs, and blocked the vital step in activation of NADPH oxidase - membrane translocation of p47phox. Our findings suggest that regular consumption of dietary quercetin plays a role in preventing atherosclerosis giving its evident regulatory effect on subunits of NADPH oxidase.

  17. Effect of quercetin against lindane induced alterations in the serum and hepatic tissue lipids in wistar rats

    PubMed Central

    Padma, Viswanadha Vijaya; Lalitha, Gurusamy; Shirony, Nicholson Puthanveedu; Baskaran, Rathinasamy

    2012-01-01

    Objective To assess the effect of quercetin (flavonoid) against lindane induced alterations in lipid profile of wistar rats. Methods Rats were administered orally with lindane (100 mg/kg body weight) and quercetin (10 mg/kg body weight) for 30 days. After the end of treatment period lipid profile was estimated in serum and tissue. Results Elevated levels of serum cholesterol, triglycerides, low density lipoprotein (LDL), very Low Density Lipoprotein (VLDL) and tissue triglycerides, cholesterol with concomitant decrease in serum HDL and tissue phospholipids were decreased in lindane treated rats were found to be significantly decreased in the quercetin and lindane co-treated rats. Conclusions Our study suggests that quercetin has hypolipidemic effect and offers protection against lindane induced toxicity in liver by restoring the altered levels of lipids. The quercetin cotreatment along with lindane for 30 days reversed these biochemical alterations in lipids induced by lindane. PMID:23569870

  18. Surgical attenuation of spontaneous congenital portosystemic shunts in dogs resolves hepatic encephalopathy but not hypermanganesemia.

    PubMed

    Gow, Adam G; Frowde, Polly E; Elwood, Clive M; Burton, Carolyn A; Powell, Roger M; Tappin, Simon W; Foale, Rob D; Duncan, Andrew; Mellanby, Richard J

    2015-10-01

    Hypermanganesemia is commonly recognized in human patients with hepatic insufficiency and portosystemic shunting. Since manganese is neurotoxic, increases in brain manganese concentrations have been implicated in the development of hepatic encephalopathy although a direct causative role has yet to be demonstrated. Evaluate manganese concentrations in dogs with a naturally occurring congenital shunt before and after attenuation as well as longitudinally following the changes in hepatic encephalopathy grade. Our study demonstrated that attenuation of the shunt resolved encephalopathy, significantly reduced postprandial bile acids, yet a hypermanganasemic state persisted. This study demonstrates that resolution of hepatic encephalopathy can occur without the correction of hypermanganesemia, indicating that increased manganese concentrations alone do not play a causative role in encephalopathy. Our study further demonstrates the value of the canine congenital portosystemic shunt as a naturally occurring spontaneous model of human hepatic encephalopathy.

  19. Quercetin ameliorates chronic unpredicted stress-mediated memory dysfunction in male Swiss albino mice by attenuating insulin resistance and elevating hippocampal GLUT4 levels independent of insulin receptor expression.

    PubMed

    Mehta, Vineet; Parashar, Arun; Sharma, Arun; Singh, Tiratha Raj; Udayabanu, Malairaman

    2017-03-01

    Chronic stress is associated with impaired neuronal functioning, altered insulin signaling, and behavioral dysfunction. Quercetin has shown neuroprotective and antidiabetic effects, besides modulating cognition and insulin signaling. Therefore, in the present study, we explored whether or not quercetin ameliorates stress-mediated cognitive dysfunction and explored the underlying mechanism. Swiss albino male mice were subjected to an array of unpredicted stressors for 21days, during which 30mg/kg quercetin treatment was given orally. The effect of chronic unpredicted stress (CUS) and quercetin treatment on cognition were evaluated using novel object recognition (NOR) and Morris water maze (MWM) tests. Hippocampal neuronal integrity was observed by histopathological examination. Blood glucose, serum corticosterone, and insulin levels were measured by commercial kits and insulin resistance was evaluated in terms of HOMA-IR index. Hippocampal insulin signaling was determined by immunofluorescence staining. CUS induced significant cognitive dysfunction (NOR and MWM) and severely damaged hippocampal neurons, especially in the CA3 region. Quercetin treatment alleviated memory dysfunction and rescued neurons from CUS-mediated damage. Fasting blood glucose, serum corticosterone, and serum insulin were significantly elevated in stressed animals, besides, having significantly higher HOMA-IR index, suggesting the development of insulin resistance. Quercetin treatment alleviated insulin resistance and attenuated altered biochemical parameters. CUS markedly down-regulated insulin signaling in CA3 region and quercetin treatment improved neuronal GLUT4 expression, which seemed to be independent of insulin and insulin receptor levels. These results suggest that intact insulin functioning in the hippocampus is essential for cognitive functions and quercetin improves CUS-mediated cognitive dysfunction by modulating hippocampal insulin signaling.

  20. Quercetin Isolated from Toona sinensis Leaves Attenuates Hyperglycemia and Protects Hepatocytes in High-Carbohydrate/High-Fat Diet and Alloxan Induced Experimental Diabetic Mice

    PubMed Central

    Zhang, Yali; Dong, Huanhuan; Wang, Mimi

    2016-01-01

    The development of diabetes mellitus is related to oxidant stress induced by a high carbohydrate/high-fat diet (HFD). Quercetin, as a major bioactive component in Toona sinensis leaves (QTL), is a natural antioxidant. However, the exact mechanism by which QTL ameliorate diabetes mellitus is still unknown. In this study, we investigated the hypoglycemic effects and hepatocytes protection of QTL on HFD and alloxan induced diabetic mice. Intragastric administration of QTL significantly reduced body weight gain, serum glucose, insulin, total cholesterol, triglyceride, low density lipoprotein-cholesterol, alanine aminotransferase, and aspartate aminotransferase serum levels compared to those of diabetic mice. Furthermore, it significantly attenuated oxidative stress, as determined by lipid peroxidation, nitric oxide content, and inducible nitric oxide synthase activity and as a result attenuated liver injury. QTL also significantly suppressed the diabetes-induced activation of the p65/NF-κB and ERK1/2/MAPK pathways, as well as caspase-9 and caspase-3 levels in liver tissues of diabetic mice. Finally, micrograph analysis of liver samples showed decreased cellular organelle injury in hepatocytes of QTL treated mice. Taken together, QTL can be viewed as a promising dietary agent that can be used to reduce the risk of diabetes mellitus and its secondary complications by ameliorating oxidative stress in the liver. PMID:27975068

  1. Quercetin Blocks Airway Epithelial Cell Chemokine Expression

    PubMed Central

    Nanua, Suparna; Zick, Suzanna M.; Andrade, Juan E.; Sajjan, Umadevi S.; Burgess, John R.; Lukacs, Nicholas W.; Hershenson, Marc B.

    2006-01-01

    Quercetin (3,3′,4′,5,7-pentahydroxyflavone), a dietary flavonoid, is an inhibitor of phosphatidylinositol (PI) 3-kinase and potent antioxidant. We hypothesized that quercetin blocks airway epithelial cell chemokine expression via PI 3-kinase–dependent mechanisms. Pretreatment with quercetin and the PI 3–kinase inhibitor LY294002 each reduced TNF-α–induced IL-8 and monocyte chemoattractant protein (MCP)-1 (also called CCL2) expression in cultured human airway epithelial cells. Quercetin also inhibited TNF-α–induced PI 3-kinase activity, Akt phosphorylation, intracellular H2O2 production, NF-κB transactivation, IL-8 promoter activity, and steady-state mRNA levels, consistent with the notion that quercetin inhibits chemokine expression by attenuating NF-κB transactivation via a PI 3-kinase/Akt-dependent pathway. Quercetin also reduced TNF-α–induced chemokine secretion in the presence of the transcriptional inhibitor actinomycin D, while inducing phosphorylation of eukaryotic translation initiation factor (eIF)-2α, suggesting that quercetin attenuates chemokine expression by post-transcriptional as well as transcriptional mechanisms. Finally, we tested the effects of quercetin in cockroach antigen–sensitized and –challenged mice. These mice show MCP-1–dependent airways hyperresponsiveness and inflammation. Quercetin significantly reduced lung MCP-1 and methacholine responsiveness. We conclude that quercetin blocks airway cell chemokine expression via transcriptional and post-transcriptional pathways. PMID:16794257

  2. Differential Effects of Quercetin and Quercetin Glycosides on Human α7 Nicotinic Acetylcholine Receptor-Mediated Ion Currents

    PubMed Central

    Lee, Byung-Hwan; Choi, Sun-Hye; Kim, Hyeon-Joong; Jung, Seok-Won; Hwang, Sung-Hee; Pyo, Mi-Kyung; Rhim, Hyewhon; Kim, Hyoung-Chun; Kim, Ho-Kyoung; Lee, Sang-Mok; Nah, Seung-Yeol

    2016-01-01

    Quercetin is a flavonoid usually found in fruits and vegetables. Aside from its antioxidative effects, quercetin, like other flavonoids, has a various neuropharmacological actions. Quercetin-3-O-rhamnoside (Rham1), quercetin-3-O-rutinoside (Rutin), and quercetin-3-(2(G)-rhamnosylrutinoside (Rham2) are mono-, di-, and tri-glycosylated forms of quercetin, respectively. In a previous study, we showed that quercetin can enhance α7 nicotinic acetylcholine receptor (α7 nAChR)-mediated ion currents. However, the role of the carbohydrates attached to quercetin in the regulation of α7 nAChR channel activity has not been determined. In the present study, we investigated the effects of quercetin glycosides on the acetylcholine induced peak inward current (IACh) in Xenopus oocytes expressing the α7 nAChR. IACh was measured with a two-electrode voltage clamp technique. In oocytes injected with α7 nAChR copy RNA, quercetin enhanced IACh, whereas quercetin glycosides inhibited IACh. Quercetin glycosides mediated an inhibition of IACh, which increased when they were pre-applied and the inhibitory effects were concentration dependent. The order of IACh inhibition by quercetin glycosides was Rutin≥Rham1>Rham2. Quercetin glycosides-mediated IACh enhancement was not affected by ACh concentration and appeared voltage-independent. Furthermore, quercetin-mediated IACh inhibition can be attenuated when quercetin is co-applied with Rham1 and Rutin, indicating that quercetin glycosides could interfere with quercetin-mediated α7 nAChR regulation and that the number of carbohydrates in the quercetin glycoside plays a key role in the interruption of quercetin action. These results show that quercetin and quercetin glycosides regulate the α7 nAChR in a differential manner. PMID:27098860

  3. Ibuprofen administration attenuates serum TNF-{alpha} levels, hepatic glutathione depletion, hepatic apoptosis and mouse mortality after Fas stimulation

    SciTech Connect

    Cazanave, Sophie; Vadrot, Nathalie; Tinel, Marina; Berson, Alain; Letteron, Philippe; Larosche, Isabelle; Descatoire, Veronique; Feldmann, Gerard; Robin, Marie-Anne |; Pessayre, Dominique |

    2008-09-15

    Fas stimulation recruits neutrophils and activates macrophages that secrete tumor necrosis factor-{alpha} (TNF-{alpha}), which aggravates Fas-mediated liver injury. To determine whether nonsteroidal anti-inflammatory drugs modify these processes, we challenged 24-hour-fasted mice with the agonistic Jo2 anti-Fas antibody (4 {mu}g/mouse), and treated the animals 1 h later with saline or ibuprofen (250 mg/kg), a dual cyclooxygenase (COX)-1 and COX-2 inhibitor. Ibuprofen attenuated the Jo2-mediated recruitment/activation of myeloperoxidase-secreting neutrophils/macrophages in the liver, and attenuated the surge in serum TNF-{alpha}. Ibuprofen also minimized hepatic glutathione depletion, Bid truncation, caspase activation, outer mitochondrial membrane rupture, hepatocyte apoptosis and the increase in serum alanine aminotransferase (ALT) activity 5 h after Jo2 administration, to finally decrease mouse mortality at later times. The concomitant administration of pentoxifylline (decreasing TNF-{alpha} secretion) and infliximab (trapping TNF-{alpha}) likewise attenuated the Jo2-mediated increase in TNF-{alpha}, the decrease in hepatic glutathione, and the increase in serum ALT activity 5 h after Jo2 administration. The concomitant administration of the COX-1 inhibitor, SC-560 (10 mg/kg) and the COX-2 inhibitor, celecoxib (40 mg/kg) 1 h after Jo2 administration, also decreased liver injury 5 h after Jo2 administration. In contrast, SC-560 (10 mg/kg) or celecoxib (40 or 160 mg/kg) given alone had no significant protective effects. In conclusion, secondary TNF-{alpha} secretion plays an important role in Jo2-mediated glutathione depletion and liver injury. The combined inhibition of COX-1 and COX-2 by ibuprofen attenuates TNF-{alpha} secretion, glutathione depletion, mitochondrial alterations, hepatic apoptosis and mortality in Jo2-treated fasted mice.

  4. Progress toward the development of a genetically engineered attenuated hepatitis A virus vaccine.

    PubMed Central

    Funkhouser, A W; Raychaudhuri, G; Purcell, R H; Govindarajan, S; Elkins, R; Emerson, S U

    1996-01-01

    Mutations which positively affect growth of hepatitis A virus in cell culture may negatively affect growth in vivo. Therefore, development of an attenuated vaccine for hepatitis A may require a careful balancing of mutations to produce a virus that will grow efficiently in cells suitable for vaccine production and still maintain a satisfactory level of attenuation in vivo. Since such a balance could be achieved most directly by genetic engineering, we are analyzing mutations that accumulated during serial passage of the HM-175 strain of hepatitis A virus in MRC-5 cell cultures in order to determine the relative importance of the mutations for growth in MRC-5 cells and for attenuation in susceptible primates. Chimeric viral genomes of the HM-175 strain were constructed from cDNA clones derived from a virulent virus and from two attenuated viruses adapted to growth in African green monkey kidney (AGMK) and MRC-5 cells, respectively. Viruses encoded by these chimeric genomes were recovered by in vitro or in vivo transfection and assessed for their ability to grow in cultured MRC-5 cells or to cause hepatitis in primates (tamarins). The only MRC-5-specific mutations that substantially increased the efficiency of growth in MRC-5 cells were a group of four mutations in the 5' noncoding (NC) region. These 5' NC mutations and a separate group of 5' NC mutations that accumulated during earlier passages of the HM-175 virus in primary AGMK cells appeared, independently and additively, to result in decreased biochemical evidence of hepatitis in tamarins. However, neither group of 5' NC mutations had a demonstrable effect on the extent of virus excretion or liver pathology in these animals. PMID:8892918

  5. Progress toward the development of a genetically engineered attenuated hepatitis A virus vaccine.

    PubMed

    Funkhouser, A W; Raychaudhuri, G; Purcell, R H; Govindarajan, S; Elkins, R; Emerson, S U

    1996-11-01

    Mutations which positively affect growth of hepatitis A virus in cell culture may negatively affect growth in vivo. Therefore, development of an attenuated vaccine for hepatitis A may require a careful balancing of mutations to produce a virus that will grow efficiently in cells suitable for vaccine production and still maintain a satisfactory level of attenuation in vivo. Since such a balance could be achieved most directly by genetic engineering, we are analyzing mutations that accumulated during serial passage of the HM-175 strain of hepatitis A virus in MRC-5 cell cultures in order to determine the relative importance of the mutations for growth in MRC-5 cells and for attenuation in susceptible primates. Chimeric viral genomes of the HM-175 strain were constructed from cDNA clones derived from a virulent virus and from two attenuated viruses adapted to growth in African green monkey kidney (AGMK) and MRC-5 cells, respectively. Viruses encoded by these chimeric genomes were recovered by in vitro or in vivo transfection and assessed for their ability to grow in cultured MRC-5 cells or to cause hepatitis in primates (tamarins). The only MRC-5-specific mutations that substantially increased the efficiency of growth in MRC-5 cells were a group of four mutations in the 5' noncoding (NC) region. These 5' NC mutations and a separate group of 5' NC mutations that accumulated during earlier passages of the HM-175 virus in primary AGMK cells appeared, independently and additively, to result in decreased biochemical evidence of hepatitis in tamarins. However, neither group of 5' NC mutations had a demonstrable effect on the extent of virus excretion or liver pathology in these animals.

  6. Carvedilol Attenuates the Progression of Hepatic Fibrosis Induced by Bile Duct Ligation

    PubMed Central

    Tian, Xiaopeng; Zhao, Chunhong; Guo, Jinbo; Xie, Shurui; Yin, Fengrong; Huo, Xiaoxia

    2017-01-01

    Background. The sympathetic nervous system (SNS) is responsible for hepatic stellate cells (HSCs) activation and the accumulation of collagen that occurs in hepatic fibrogenesis. Carvedilol has been widely used for the complication of hepatic cirrhosis in the clinic. Furthermore, it has powerful antioxidant properties. We assessed the potential antifibrotic effects of carvedilol and the underlying mechanisms that may further enhance its clinical benefits. Methods. Using a bile duct ligation rat model of hepatic fibrosis, we studied the effects of carvedilol on the fibrosis, collagen deposition, and oxidative stress based on histology, immunohistochemistry, western blot, and RT-PCR analyses. Results. Carvedilol attenuated liver fibrosis, as evidenced by reduced hydroxyproline content and the accumulation of collagen, downregulated TIMP-1 and TIMP-2, and upregulated MMP-13. MMP-2 was an exception, which was decreased after carvedilol treatment for 2 weeks and upregulated after carvedilol treatment for 4 weeks. Carvedilol reduced the activation of HSCs, decreased the induction of collagen, transforming growth factor-β1, and MDA content, and strengthened the SOD activity. The antifibrotic effects were augmented as dosages increased. Conclusions. The study indicates that carvedilol attenuated hepatic fibrosis in a dose-dependent manner. It can decrease collagen accumulation and HSCs activation by the amelioration of oxidative stress.

  7. A review of immunogenicity and tolerability of live attenuated Hepatitis A vaccine in children

    PubMed Central

    Rao, Sameer; Mao, J. S.; Motlekar, Salman; Fangcheng, Zhuang; Kadhe, Ganesh

    2016-01-01

    ABSTRACT Changing epidemiology of Hepatitis A virus (HAV) has led to an increased susceptibility of adolescents and adults to the infection. Vaccination can remarkably reduce the incidence and associated morbidity of HAV infection. This review is focused on the safety and efficacy of H2 strain derived live attenuated Hepatitis A vaccine. We found the vaccine to be highly immunogenic with minimal or negligible safety issues. Moreover, a single dose of live attenuated vaccine persists a long term immune response and can be a preferred option for developing countries. In 2014, Indian Academy of Paediatrics (IAP) also updated their recommendations for H2 vaccine as a single dose as against the previous 2 dose schedule. A focused approach to include the vaccine in national immunization program should be explored. PMID:27532370

  8. Naltrexone attenuates endoplasmic reticulum stress induced hepatic injury in mice.

    PubMed

    Moslehi, A; Nabavizadeh, F; Nabavizadeh, Fatemeh; Dehpour, A R; Dehpou, A R; Tavanga, S M; Hassanzadeh, G; Zekri, A; Nahrevanian, H; Sohanaki, H

    2014-09-01

    Endoplasmic reticulum (ER) stress provides abnormalities in insulin action, inflammatory responses, lipoprotein B100 degradation and hepatic lipogenesis. Excess accumulation of triglyceride in hepatocytes may also lead to disorders such as non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Opioid peptides are involved in triglyceride and cholesterol dysregulation, inflammation and cell death. In this study, we evaluated Naltrexone effects on ER stress induced liver injury. To do so, C57/BL6 mice received saline, DMSO and Naltrexone, as control groups. ER stress was induced by tunicamycin (TM) injection. Naltrexone was given before TM administration. Liver blood flow and biochemical serum analysis were measured. Histopathological evaluations, TNF-α measurement and Real-time RT-PCR were also performed. TM challenge provokes steatosis, cellular ballooning and lobular inflammation which significantly reduced in Naltrexone treated animals. ALT, AST and TNF-α increased in the TM group and improved in the Naltrexone plus TM group. Triglyceride and cholesterol levels decreased in TM treated mice with no increase in Naltrexone treated animals. In the Naltrexone plus TM group, gene expression of Bax/Bcl-2 ratio and caspase3 significantly lowered compared with the TM group. In this study, we found that Naltrexone had a notable alleviating role in ER stress induced steatosis and liver injury.

  9. Tamoxifen Attenuates Lipopolysaccharide/Galactosamine-induced Acute Liver Failure by Antagonizing Hepatic Inflammation and Apoptosis.

    PubMed

    Zhang, Peng; Zhang, Meisheng; Wan, Mengqi; Huang, Xiaoliu; Jiang, Yan; Xu, Siying; Luo, Mansheng

    2017-04-01

    Bacterial lipopolysaccharide (LPS)-induced acute liver failure (ALF) is a common severe clinical syndrome in intensive care unit. No other methods are available for its prevention apart from supportive treatment and liver transplantation. Tamoxifen (TAM) was reported to attenuate ALF induced by excessive acetaminophen, while its effect on LPS-induced ALF remained unknown. For this, in the present study, we comprehensively assessed whether TAM can attenuate ALF induced by LPS/galactosamine (GaIN). Mice were given TAM once a day for three times. Twelve hours after the last treatment, mice were given LPS/GaIN (intraperitoneally [i.p.]). Survival, plasma transaminases, and histopathology were examined. Serum TNF-α and IL-1β were analyzed by ELISA. Hepatic apoptosis was analyzed by TUNEL and caspase-3 Western blotting, respectively. Compared to the model group, ALF induced by LPS/GaIN was alleviated remarkably following TAM administration, as evidenced by the improvement of survival (87.5% vs. 37.5%), hepatic swell, moderate transaminases, slightly increased serum TNF-α, IL-1β (P < 0.05), and moderate histopathology. In respect of apoptosis, severe hepatocellular apoptosis was reduced notably by TAM treatment confirmed by less TUNEL-positive hepatocytes and decreased caspase-3 cleavage. The results demonstrated that TAM could attenuate LPS/GaIN-induced ALF effectively, probably due to hepatic inflammation and apoptosis antagonism. Furthermore, it was the first report about the effect of TAM on LPS/GaIN-induced ALF.

  10. Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF-TrkB-PI3K/Akt signaling pathway.

    PubMed

    Yao, Rui-Qin; Qi, Da-Shi; Yu, Hong-Li; Liu, Jing; Yang, Li-Hua; Wu, Xiu-Xiang

    2012-12-01

    Many studies have demonstrated that apoptosis play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Neuroprotective effect of quercetin has been shown in a variety of brain injury models including ischemia/reperfusion. It is not clear whether BDNF-TrkB-PI3K/Akt signaling pathway mediates the neuroprotection of quercetin, though there has been some reports on the quercetin increased brain-derived neurotrophic factor (BDNF) level in brain injury models. We therefore first examined the neurological function, infarct volume and cell apoptosis in quercetin treated middle cerebral artery occlusion (MCAO) rats. Then the protein expression of BDNF, cleaved caspase-3 and p-Akt were evaluated in either the absence or presence of PI3K inhibitor (LY294002) or tropomyosin receptor kinase B (TrkB) receptor antagonist (K252a) by immunohistochemistry staining and western blotting. Quercetin significantly improved neurological function, while it decreased the infarct volume and the number of TdT mediated dUTP nick end labeling positive cells in MCAO rats. The protein expression of BDNF, TrkB and p-Akt also increased in the quercetin treated rats. However, treatment with LY294002 or K252a reversed the quercetin-induced increase of BDNF and p-Akt proteins and decrease of cleaved caspase-3 protein in focal cerebral ischemia rats. These results demonstrate that quercetin can decrease cell apoptosis in the focal cerebral ischemia rat brain and the mechanism may be related to the activation of BDNF-TrkB-PI3K/Akt signaling pathway.

  11. Quercetin attenuates oxidative damage induced by treatment of embryonic chicken spermatogonial cells with 4-nitro-3-phenylphenol in diesel exhaust particles.

    PubMed

    Mi, Yuling; Zhang, Caiqiao; Li, ChunMei; Taneda, Shinji; Watanabe, Gen; Suzuki, Akira K; Taya, Kazuyoshi

    2010-01-01

    Quercetin, an antioxidant flavonoid, is considered beneficial for human and animal health. In this study, the protective effect of quercetin on oxidative damage to testicular cells was studied in embryonic chickens after treatment with 4-nitro-3-phenylphenol (PNMPP) derived from diesel exhaust particles. Testicular cells were challenged with PNMPP (10(-8)-10(-6) M) alone and in combination with quercetin for 48 h. The results showed that quercetin manifested no deleterious effect on spermatogonial cells up to 1.0 microg/ml. Exposure to PNMPP (10(-6) M) induced condensed nuclei and vacuolated cytoplasm and reductions in testicular cell viability and spermatogonial cell numbers (p<0.05). It also induced lipid peroxidation by an elevation of thiobarbituric acid reactive substances and decreased glutathione peroxidase activity and superoxide dismutase activity (p<0.05). Simultaneous supplementation with quercetin restored these parameters to the same levels as in the control. These data indicate that quercetin protects spermatogonial cells from oxidative damage in embryonic chickens intoxicated with PNMPP.

  12. Petroselinum crispum extract attenuates hepatic steatosis in rats fed with fructose enriched diet.

    PubMed

    Nair, V Yuneesha; Balakrishanan, N; Antony Santiago, J Victor

    2015-01-01

    Non alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and ongoing research efforts are focused on understanding the underlying pathophysiology of hepatic steatosis with the anticipation that these efforts will identify novel therapeutic targets. This study investigated the Petroselinum crispum extract in hepatic steatosis in rats fed with fructose enriched diet. Rats were divided into the 4 groups: Group 1 rats received standard pellet diet with corn starch for the entire experimental period of 8 weeks. Group 2 rats received standard pellet diet and 2 gm/kg body weight crude Parsley leaf ethanol extract for the entire experimental period of 8 weeks. Group 3 rats received modified fructose diet. Group 4 rats received modified fructose diet and 2gm/kg crude Parsley leaf ethanol extract. Hepatic function and structure was evaluated in these rats. Modified fructose diet produced dyslipidemia, hepatic steatosis and infiltration of inflammatory cells in the liver and higher plasma hepatic markers. Petroselinum crispum extract reversed metabolic changes such as abnormal crispum extract attenuated chronic changes in modified fructose diet induced NAFLD (Tab. 2, Fig. 3, Ref. 43).

  13. Quercetin attenuates high fructose feeding-induced atherosclerosis by suppressing inflammation and apoptosis via ROS-regulated PI3K/AKT signaling pathway.

    PubMed

    Lu, Xue-Li; Zhao, Cui-Hua; Yao, Xin-Liang; Zhang, Han

    2017-01-01

    Quercetin is a dietary flavonoid compound extracted from various plants, such as apple and onions. Previous studies have revealed its anti-inflammatory, anti-cancer, antioxidant and anti-apoptotic activities. This study investigated the ability of quercetin to inhibit high fructose feeding- or LPS-induced atherosclerosis through regulating oxidative stress, apoptosis and inflammation response in vivo and in vitro experiments. 50 and 100mg/kg quercetin were used in our study, showing significant inhibitory role in high fructose-induced atherosclerosis via reducing reactive oxygen species (ROS) levels, Caspase-3 activation, inflammatory cytokines releasing, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells and collagen contents as well as modulating apoptosis- and inflammation-related proteins expression. We also explored the protective effects of quercetin on atherosclerosis by phosphatidylinositide 3-kinases (PI3K)/Protein kinase B (AKT)-associated Bcl-2/Caspase-3 and nuclear factor kappa B (NF-κB) signal pathways activation, promoting AKT and Bcl-2 expression and reducing Caspase-3 and NF-κB activation. Quercetin reduced the atherosclerotic plaque size in vivo in high fructose feeding-induced mice assessed by oil red O. Also, in vitro experiments, quercetin displayed inhibitory role in LPS-induced ROS production, inflammatory response and apoptosis, which were linked with PI3K/AKT-regulated Caspase-3 and NF-κB activation. In conclusion, our results showed that quercetin inhibited atherosclerotic plaque development in high fructose feeding mice via PI3K/AKT activation regulated by ROS.

  14. Tangshen formula attenuates hepatic steatosis by inhibiting hepatic lipogenesis and augmenting fatty acid oxidation in db/db mice

    PubMed Central

    Kong, Qin; Zhang, Haojun; Zhao, Tingting; Zhang, Weiku; Yan, Meihua; Dong, Xi; Li, Ping

    2016-01-01

    Tangshen formula (TSF), a well-prescribed traditional Chinese formula, has been used in the treatment of diabetic nephropathy. However, whether TSF ameliorates dyslipidemia and liver injury associated with diabetes remains unclear. In this study, we examined the effects of TSF on lipid profiles and hepatic steatosis in db/db mice. For this purpose, 8-week-old db/db mice were treated with TSF or saline for 12 weeks via gavage and db/m mice were used as controls. Body weight and blood glucose levels were monitored weekly and bi-weekly, respectively. Blood samples were obtained for the analysis of lipids and enzymes related to hepatic function, and liver tissues were analyzed by histology, immunohistochemistry and molecular examination. The results revealed that TSF markedly reduced body weight, liver index [liver/body weight (LW/BW)] and improved lipid profiles, hepatic function and steatosis in db/db mice. TSF induced the phosphoralation of AMP-activated protein kinase and inhibited the activity of sterol regulatory element-binding protein 1 together with the inhibition of the expression of genes involved in de novo lipogenesis (DNL) and gluconeogenesis, such as fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), stearoyl CoA desaturase 1 (SCD1), glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase 1 (Pck1). Additionally, the silent mating type information regulation 2 homolog 1 (Sirt1)/peroxisome proliferator-activated receptor α (PPARα)/malonyl-CoA decarboxylase (MLYCD) cascade was potently activated by TSF in the liver and skeletal muscle of db/db mice, which led to enhanced fatty acid oxidation. These findings demonstrated that TSF attenuated hepatic fat accumulation and steatosis in db/db mice by inhibiting lipogenesis and augmenting fatty acid oxidation. PMID:27840945

  15. The role of excessive versus acute administration of erythropoietin in attenuating hepatic ischemia-reperfusion injury.

    PubMed

    Pappo, Orit; Ben-Ari, Ziv; Shevtsov, Evgeni; Avlas, Orna; Gassmann, Max; Ravid, Amiram; Cheporko, Yelena; Hochhauser, Edith

    2010-12-01

    Ischemia-reperfusion injury (I/R) is the main cause of primary graft nonfunction. Our aim was to evaluate the effect of excessive versus acute administration of erythropoietin (EPO) in attenuating the hepatic injury induced by I/R in mice. The effect of segmental (70%) hepatic ischemia was evaluated in a transgenic mouse line with constitutive overexpression of human EPO cDNA and in wild-type (WT) mice. Mice were randomly allocated to 5 main experimental groups: (i) WT-sham, (ii) WT ischemia, (iii) WT ischemia + recombinant human erythropoietin (rhEPO), (iv) transgenic-sham, and (v) transgenic ischemia. The EPO-pretreated mice showed a significant reduction in liver enzyme levels and intrahepatic caspase-3 activity and fewer apoptotic hepatocytes (p < 0.05 for all) compared with the WT untreated I/R group. EPO decreased c-Jun N-terminal kinase (JNK) phosphorylation and nuclear factor-κB (NF-κB) expression during I/R. In transgenic I/R livers, baseline histology showed diffused hepatic injury, and no significant beneficial effect was noted between the WT untreated and the transgenic I/R mice. In conclusion, acute pretreatment with EPO in WT mice attenuated in vivo I/R liver injury. However, in excessive EPO overexpression, the initial liver injury abolished the beneficial effect of EPO. These findings have important implications for the potential use of acute EPO in I/R injury during liver transplantation.

  16. Endogenous n-3 Polyunsaturated Fatty Acids Attenuate T Cell-Mediated Hepatitis via Autophagy Activation

    PubMed Central

    Li, Yanli; Tang, Yuan; Wang, Shoujie; Zhou, Jing; Zhou, Jia; Lu, Xiao; Bai, Xiaochun; Wang, Xiang-Yang; Chen, Zhengliang; Zuo, Daming

    2016-01-01

    Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert anti-inflammatory effects in several liver disorders, including cirrhosis, acute liver failure, and fatty liver disease. To date, little is known about their role in immune-mediated liver diseases. In this study, we used fat-1 transgenic mice rich in endogenous n-3 PUFAs to examine the role of n-3 PUFAs in immune-mediated liver injury. Concanavalin A (Con A) was administered intravenously to wild-type (WT) and fat-1 transgenic mice to induce T cell-mediated hepatitis. Reduced liver damage was shown in Con A-administrated fat-1 transgenic mice, as evidenced by decreased mortality, attenuated hepatic necrosis, lessened serum alanine aminotransferase activity, and inhibited production of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-17A, and IFN-γ). In vivo and in vitro studies demonstrated that n-3 PUFAs significantly inhibited the activation of hepatic T cells and the differentiation of Th1 cells after Con A challenge. Further studies showed that n-3 PUFAs markedly increased autophagy level in Con A-treated fat-1 T cells compared with the WT counterparts. Blocking hepatic autophagy activity with chloroquine diminished the differences in T cell activation and liver injury between Con A-injected WT and fat-1 transgenic mice. We conclude that n-3 PUFAs limit Con A-induced hepatitis via an autophagy-dependent mechanism and could be exploited as a new therapeutic approach for autoimmune hepatitis. PMID:27679638

  17. X-ray attenuation of the liver and kidney in cats considered at varying risk of hepatic lipidosis.

    PubMed

    Lam, Richard; Niessen, Stijn J; Lamb, Christopher R

    2014-01-01

    X-ray attenuation of the liver has been measured using computed tomography (CT) and reported to decrease in cats with experimentally induced hepatic lipidosis. To assess the clinical utility of this technique, medical records and noncontrast CT scans of a series of cats were retrospectively reviewed. A total of 112 cats met inclusion criteria and were stratified into three hepatic lipidosis risk groups. Group 1 cats were considered low-risk based on no history of inappetence or weight loss, and normal serum chemistry values; Group 2 cats were considered intermediate risk based on weight loss, serum hepatic enzymes above normal limits, or reasonably controlled diabetes mellitus; and Group 3 cats were considered high risk based on poorly controlled diabetes mellitus due to hypersomatotropism. Mean CT attenuation values (Hounsfield units, HU) were measured using regions of interest placed within the liver and cranial pole of the right kidney. Hepatic and renal attenuation were weakly positively correlated with each other (r = 0.2, P = 0.03) and weakly negatively correlated with body weight (r = -0.21, P = 0.05, and r = -0.34, P = 0.001, respectively). Mean (SD) hepatic and renal cortical attenuation values were 70.7 (8.7) HU and 49.6 (9.2) HU for Group 1 cats, 71.4 (7.9) HU and 48.6 (9.1) HU for Group 2, and 68.9 (7.6) HU and 47.6 (7.2) HU for Group 3. There were no significant differences in hepatic or renal attenuation among groups. Findings indicated that CT measures of X-ray attenuation in the liver and kidney may not be accurate predictors of naturally occurring hepatic lipidosis in cats.

  18. ELF-MF attenuates quercetin-induced apoptosis in K562 cells through modulating the expression of Bcl-2 family proteins.

    PubMed

    Brisdelli, Fabrizia; Bennato, Francesca; Bozzi, Argante; Cinque, Benedetta; Mancini, Fabrizio; Iorio, Roberto

    2014-12-01

    This study investigated the effects of sinusoidal ELF-MF (1 mT; 50 Hz) on the apoptosis induced by four different compounds, namely vinblastine, etoposide, quercetin, and resveratrol, in human K562 chronic myeloid leukemia cells. The exposure to ELF-MF did not affect growth and viability of untreated K562 cells and did not influence the anti-proliferative effects of resveratrol, vinblastine, and etoposide. On the contrary, in quercetin-treated cells, exposure to ELF-MF significantly reduced the percentage of apoptotic cells and the caspase-3 activity and modified the cell cycle profile especially after 48 h of exposure. In addition, the simultaneous treatments for 24 h with quercetin plus ELF-MF increased Bcl-2 protein expression and prevented quercetin-induced downregulation of Mcl-1 and Bcl-xL. Finally, an increase of HSP70 expression was also observed after prolonged ELF-MF treatment. The ELF-MF-dependent modulation of the expression of anti-apoptotic Bcl-2 family and Hsp70 proteins could act as a pro-survival mechanism in K562 cells.

  19. Standardized ultrasound hepatic/renal ratio and hepatic attenuation rate to quantify liver fat content: an improvement method.

    PubMed

    Xia, Ming-Feng; Yan, Hong-Mei; He, Wan-Yuan; Li, Xiao-Ming; Li, Chao-Lun; Yao, Xiu-Zhong; Li, Ruo-Kun; Zeng, Meng-Su; Gao, Xin

    2012-02-01

    Accurate measures of liver fat content are essential for investigating the role of hepatic steatosis in the pathophysiology of multiple metabolic disorders. No traditional imaging methods can accurately quantify liver fat content. [(1)H]-magnetic resonance spectroscopy (MRS) is restricted in large-scale studies because of the practical and technological issues. Previous attempts on computer-aided ultrasound quantification of liver fat content varied in method, and the ultrasound quantitative parameters measured from different ultrasound machines were hardly comparable. We aimed to establish and validate a simple and propagable method for quantitative assessment of liver fat content based on the combination of standardized ultrasound quantitative parameters, using [(1)H]-MRS as gold standard. Totally 127 participants were examined with both ultrasonography (US) and [(1)H]-MRS. Ultrasound hepatic/renal echo-intensity ratio (H/R) and ultrasound hepatic echo-intensity attenuation rate (HA) were obtained from ordinary ultrasound images using computer program. Both parameters were standardized using a tissue-mimicking phantom before analysis. Standardized ultrasound H/R and HA were positively correlated with the liver fat content by [(1)H]-MRS (r = 0.884, P < 0.001 and r = 0.711, P < 0.001, respectively). Linear regression analysis showed ultrasound H/R could modestly predict the amount of liver fat (adjusted explained variance 78.0%, P < 0.001). The addition of ultrasound HA slightly improved the adjusted explained variance to 79.8%. Difference of estimated liver fat contents between different ultrasound machines and operators was reasonably well. Thus, computer-aided US is a valid method to estimate liver fat content and can be applied extensively after standardization of ultrasound quantitative parameters.

  20. Quercetin and vitamin E attenuate Bonny Light crude oil-induced alterations in testicular apoptosis, stress proteins and steroidogenic acute regulatory protein in Wistar rats.

    PubMed

    Ebokaiwe, Azubuike P; Mathur, Premendu P; Farombi, Ebenezer O

    2016-10-01

    Studies have shown the reproductive effects of Bonny Light crude oil (BLCO) via the mechanism of oxidative stress and testicular apoptosis. We investigated the protective role of quercetin and vitamin E on BLCO-induced testicular apoptosis. Experimental rats were divided into four groups of four each. Animals were orally administered 2 ml/kg corn oil (control: group 1), BLCO-800 mg/kg body weight + 10 mg/kg quercetin (group 2), BLCO-800 mg/kg body weight + 50 mg/kg vitamin E (group 3) and BLCO-800 mg/kg body weight only (group 4) for 7 d. Protein levels of caspase 3, FasL, NF-kB, steroidogenic acute regulatory protein and stress response proteins were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Immunofluorescence staining was used to quantify the expression of caspase 3, FasL and NF-kB. Apoptosis was quantified by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. Administration of BLCO resulted in a significant increase in the levels of stress response proteins and apoptosis-related proteins by 50% and above after 7 d following BLCO exposure and a concomitant increase in expression of caspase 3, FasL and NF-kB expression by immunofluorescence staining. Apoptosis showed a significant increase in TUNEL positive cells. Co-administration with quercetin or vitamin E reversed BLCO-induced apoptosis and levels of stress protein, relative to control. These findings suggest that quercetin and vitamin E may confer protection against BLCO-induced testicular oxidative stress-related apoptosis.

  1. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    SciTech Connect

    Wu, Weibin; Zhu, Bo; Peng, Xiaomin; Zhou, Meiling; Jia, Dongwei; Gu, Jianxin

    2014-01-03

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients.

  2. Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis

    PubMed Central

    2014-01-01

    that Aloe vera attenuate APAP-induced hepatitis through the improvement of liver histopathology by decreased oxidative stress, reduced liver injury, and restored hepatic GSH. PMID:25005608

  3. Dietary medium-chain triglycerides attenuate hepatic lipid deposition in growing rats with protein malnutrition.

    PubMed

    Kuwahata, Masashi; Kubota, Hiroyo; Amano, Saki; Yokoyama, Meiko; Shimamura, Yasuhiro; Ito, Shunsuke; Ogawa, Aki; Kobayashi, Yukiko; Miyamoto, Ken-ichi; Kido, Yasuhiro

    2011-01-01

    The objective of this study was to investigate the effects of dietary medium-chain triglycerides (MCT) on hepatic lipid accumulation in growing rats with protein malnutrition. Weaning rats were fed either a low-protein diet (3%, LP) or control protein diet (20%, CP), in combination with or without MCT. The four groups were as follows: CP-MCT, CP+MCT, LP-MCT, and LP+MCT. Rats in the CP-MCT, CP+MCT and LP+MCT groups were pair-fed their respective diets based on the amount of diet consumed by the LP-MCT group. Rats were fed each experimental diet for 30 d. Four weeks later, the respiratory quotient was higher in the LP-MCT group than those in the other groups during the fasting period. Hepatic triglyceride content increased in the LP groups compared with the CP groups. Hepatic triglyceride content in the LP+MCT group, however, was significantly decreased compared with that in the LP-MCT group. Levels of carnitine palmitoyltransferase (CPT) 1a mRNA and CPT2 mRNA were significantly decreased in the livers of the LP-MCT group, as compared with corresponding mRNA levels of the other groups. These results suggest that ingestion of a low-protein diet caused fatty liver in growing rats. However, when rats were fed the low-protein diet with MCT, hepatic triglyceride deposition was attenuated, and mRNA levels encoding CPT1a and CPT2 were preserved at the levels of rats fed control protein diets.

  4. Partial Portal Vein Arterialization Attenuates Acute Bile Duct Injury Induced by Hepatic Dearterialization in a Rat Model

    PubMed Central

    Wei, Jishu; Wu, Junli; Gao, Wentao; Li, Qiang; Jiang, Kuirong

    2016-01-01

    Hepatic infarcts or abscesses occur after hepatic artery interruption. We explored the mechanisms of hepatic deprivation-induced acute liver injury and determine whether partial portal vein arterialization attenuated this injury in rats. Male Sprague-Dawley rats underwent either complete hepatic arterial deprivation or partial portal vein arterialization, or both. Hepatic ischemia was evaluated using biochemical analysis, light microscopy, and transmission electron microscopy. Hepatic ATP levels, the expression of hypoxia- and inflammation-associated genes and proteins, and the expression of bile transporter genes were assessed. Complete dearterialization of the liver induced acute liver injury, as evidenced by the histological changes, significantly increased serum biochemical markers, decreased ATP content, increased expression of hypoxia- and inflammation-associated genes and proteins, and decreased expression of bile transporter genes. These detrimental changes were extenuated but not fully reversed by partial portal vein arterialization, which also attenuated ductular reaction and fibrosis in completely dearterialized rat livers. Collectively, complete hepatic deprivation causes severe liver injury, including bile infarcts and biloma formation. Partial portal vein arterialization seems to protect against acute ischemia-hypoxia-induced liver injury. PMID:27872855

  5. An ω-3-enriched diet alone does not attenuate CCl4-induced hepatic fibrosis.

    PubMed

    Harris, Todd R; Kodani, Sean; Yang, Jun; Imai, Denise M; Hammock, Bruce D

    2016-12-01

    Exposure to the halogenated hydrocarbon carbon tetrachloride (CCl4) leads to hepatic lipid peroxidation, inflammation and fibrosis. Dietary supplementation of ω-3 fatty acids has been increasingly advocated as being generally anti-inflammatory, though its effect in models of liver fibrosis is mixed. This raises the question of whether diets high in ω-3 fatty acids will result in a greater sensitivity or resistance to liver fibrosis as a result of environmental toxicants like CCl4. In this study, we fed CCl4-treated mice a high ω-3 diet (using a mix of docosahexaenoic acid and eicosapentaenoic acid ethyl esters). We also co-administered an inhibitor of soluble epoxide hydrolase, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which has been shown to boost anti-inflammatory epoxy fatty acids that are produced from both ω-3 and ω-6 dietary lipids. We showed that soluble epoxide inhibitors reduced CCl4-induced liver fibrosis. Three major results were obtained. First, the ω-3-enriched diet did not attenuate CCl4-induced liver fibrosis as judged by collagen deposition and collagen mRNA expression. Second, the ω-3-enriched diet raised hepatic tissue levels of several inflammatory lipoxygenase metabolites and prostaglandins, including PGE2. Third, treatment with TPPU in drinking water in conjunction with the ω-3-enriched diet resulted in a reduction in liver fibrosis compared to all other groups. Taken together, these results indicate that dietary ω-3 supplementation alone did not attenuate CCl4-induced liver fibrosis. Additionally, oxylipin signaling molecules may play role in the CCl4-induced liver fibrosis in the high ω-3 diet groups.

  6. Five-year antibody persistence in children after one dose of inactivated or live attenuated hepatitis A vaccine.

    PubMed

    Zhang, Zhilun; Zhu, Xiangjun; Hu, Yuansheng; Liang, Miao; Sun, Jin; Song, Yufei; Yang, Qi; Ji, Haiquan; Zeng, Gang; Song, Lifei; Chen, Jiangting

    2017-02-14

    In China, both inactivated hepatitis A (HA) vaccine and live attenuated HA vaccine are available. We conducted a trial to evaluate 5-year immune persistence induced by one dose of inactivated or live attenuated HA vaccines in children. Subjects with no HA vaccination history had randomly received one dose of inactivated or live attenuated HA vaccine at 18-60 months of age. Anti-HAV antibody concentrations were measured before vaccination and at the first, second, and fifth year after vaccination. Suspected cases of hepatitis A were monitored during the study period. A total of 332 subjects were enrolled and 182 provided evaluable serum samples at all planned time points. seropositive rate at 5 y was 85.9% in the inactivated HA vaccine group and 90.7% in the live attenuated HA vaccine group. GMCs were 76.3% mIU/ml (95% CI: 61.7 - 94.4) and 66.8mIU/ml (95% CI: 57.8 - 77.3), respectively. No significant difference in antibody persistence between 2 groups was found. No clinical hepatitis A case was reported. A single dose of an inactivated or live attenuated HA vaccine at 18-60 months of age resulted in high HAV seropositive rate and anti-HAV antibody concentrations that lasted for at least 5 y.

  7. Quercetin-3-O-(2″-galloyl)-α-L-rhamnopyranoside attenuates cholesterol oxidation product-induced apoptosis by suppressing NF-κB-mediated cell death process in differentiated PC12 cells.

    PubMed

    Lee, Da Hee; Nam, Yoon Jeong; Lee, Chung Soo

    2015-08-01

    Cholesterol oxidation products are suggested to be involved in neuronal cell degeneration. We examined the preventive effect of quercetin-3-O-(2″-galloyl)-α-L-rhamnopyranoside (QGR), a quercetin derivative, on the cholesterol oxidation product-induced neuronal cell death using differentiated PC12 cells in relation to nuclear factor (NF)-κB-mediated apoptotic process. 7-Ketocholesterol and 25-hydroxycholesterol induced a decrease in the levels of BH3 interacting-domain death agonist (Bid) and B cell lymphoma 2 (Bcl-2), increase in the levels of Bcl-2-associated X protein (Bax) and p53, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases, and cleavage of poly(ADP-ribose) polymerase 1 (PARP-1). 7-Ketocholesterol induced increase in cytosolic and nuclear NF-κB p65, nuclear phospho-NF-κB p65, cytosolic NF-κB p50, and cytosolic phospho-IκB-α levels. The addition of QGR, N-acetyl cysteine, or Bay 11-7085 attenuated the cholesterol oxidation product-induced changes in the apoptosis-related protein levels, activation of NF-κB, formation of reactive oxygen species, depletion of glutathione (GSH), nuclear damage, and cell death. The results show that QGR may attenuate the cholesterol oxidation product-induced apoptosis in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways that is mediated by NF-κB activation. The preventive effect appears to be associated with the inhibitory effect on the formation of reactive oxygen species and depletion of GSH.

  8. A Low Dose of Dietary Quercetin Fails to Protect against the Development of an Obese Phenotype in Mice

    PubMed Central

    Enos, Reilly T.; Velázquez, Kandy T.; Carson, Meredith S.; McClellan, Jamie L.; Nagarkatti, Prakash; Nagarkatti, Mitzi; Davis, J. Mark; Murphy, E. Angela

    2016-01-01

    The purpose of this study was to examine the effect of a 40% high-fat diet (HFD) supplemented with a dietary attainable level of quercetin (0.02%) on body composition, adipose tissue (AT) inflammation, Non-Alcoholic Fatty-Liver Disease (NAFLD), and metabolic outcomes. Diets were administered for 16 weeks to C57BL/6J mice (n = 10/group) beginning at 4 weeks of age. Body composition and fasting blood glucose, insulin, and total cholesterol concentrations were examined intermittently. AT and liver mRNA expression (RT-PCR) of inflammatory mediators (F4/80, CD206 (AT only), CD11c (AT only) TLR-2 (AT only), TLR-4 (AT only), MCP-1, TNF-α, IL-6 (AT only), and IL-10 (AT only)) were measured along with activation of NFκB-p65, and JNK (western blot). Hepatic lipid accumulation, gene expression (RT-PCR) of hepatic metabolic markers (ACAC1, SREBP-1, PPAR-γ), protein content of Endoplasmic Reticulum (ER) Stress markers (BiP, phosphorylated and total EIF2α, phosphorylated and total IRE1α, CHOP), and hepatic oxidative capacity were assessed (western blot). Quercetin administration had no effect at mitigating increases in visceral AT, AT inflammation, hepatic steatosis, ER Stress, decrements in hepatic oxidative capacity, or the development of insulin resistance and hypercholesterolemia. In conclusion, 0.02% quercetin supplementation is not an effective therapy for attenuating HFD-induced obesity development. It is likely that a higher dose of quercetin supplementation is needed to elicit favorable outcomes in obesity. PMID:27959936

  9. Activation of α2 adrenoceptor attenuates lipopolysaccharide-induced hepatic injury.

    PubMed

    Chen, Jing-Hui; Yu, Gao-Feng; Jin, Shang-Yi; Zhang, Wen-Hua; Lei, Dong-Xu; Zhou, Shao-Li; Song, Xing-Rong

    2015-01-01

    Sepsis induces hepatic injury but whether alpha-2 adrenoceptor (α2-AR) modulates the severity of sepsis-induced liver damage remains unclear. The present study used lipopolysaccharide (LPS) to induce hepatic injury and applied α2-AR agonist dexmedetomidine (DEX) and/or antagonist yohimbine to investigate the contribution of α2-AR in LPS-induced liver injury. Our results showed that LPS resulted in histological and functional abnormality of liver tissue (ALT and AST transaminases, lactate), higher mortality, an increase in proinflammatory cytokines (IL-1β, IL-6 & TNF-α), as well as a change in oxidative stress (MDA, SOD). Activation of α2-AR by dexmedetomidine (DEX) attenuated LPS-induced deleterious effects on the liver and block of α2-AR by yohimbine aggravated LPS-induced liver damage. Our data suggest that α2-AR plays an important role in sepsis-induced liver damage and activation of α2-AR with DEX could be a novel therapeutic avenue to protect the liver against sepsis-induced injury.

  10. Quercetin prevents ethanol-induced iron overload by regulating hepcidin through the BMP6/SMAD4 signaling pathway.

    PubMed

    Tang, Yuhan; Li, Yanyan; Yu, Haiyan; Gao, Chao; Liu, Liang; Chen, Shaodan; Xing, Mingyou; Liu, Liegang; Yao, Ping

    2014-06-01

    Emerging evidence has demonstrated that chronic ethanol exposure induces iron overload, enhancing ethanol-mediated liver damage. The purpose of this study was to explore the effects of the naturally occurring compound quercetin on ethanol-induced iron overload and liver damage, focusing on the signaling pathway of the iron regulatory hormone hepcidin. Adult male C57BL/6J mice were pair-fed with isocaloric-Lieber De Carli diets containing ethanol (accounting for 30% of total calories) and/or carbonyl iron (0.2%) and treated with quecertin (100 mg/kg body weight) for 15 weeks. Mouse primary hepatocytes were incubated with ethanol (100 mM) and quercetin (100 μM) for 24 h. Mice exposed to either ethanol or iron presented significant fatty infiltration and iron deposition in the liver; these symptoms were exacerbated in mice cotreated with ethanol and iron. Quercetin attenuated the abnormity induced by ethanol and/or iron. Ethanol suppressed BMP6 and intranuclear SMAD4 as well as decreased hepcidin expression. These effects were partially alleviated by quercetin supplementation in mice and hepatocytes. Importantly, ethanol caused suppression of SMAD4 binding to the HAMP promoter and of hepcidin messenger RNA expression. These effects were exacerbated by anti-BMP6 antibody and partially alleviated by quercetin or human recombinant BMP6 in cultured hepatocytes. In contrast, co-treatment with iron and ethanol, especially exposure of iron alone, activated BMP6/SMAD4 pathway and up-regulated hepcidin expression, which was also normalized by quercetin in vivo. Quercetin prevented ethanol-induced hepatic iron overload different from what carbonyl iron diet elicited in the mechanism, by regulating hepcidin expression via the BMP6/SMAD4 signaling pathway.

  11. Grape Seed Extract Attenuates Hepatitis C Virus Replication and Virus-Induced Inflammation

    PubMed Central

    Chen, Wei-Chun; Tseng, Chin-Kai; Chen, Bing-Hung; Lin, Chun-Kuang; Lee, Jin-Ching

    2016-01-01

    Hepatitis C virus (HCV) infection is a causative factor leading to hepatocellular carcinoma due to chronic inflammation and cirrhosis. The aim of the study was first to explore the effects of grape seed extract (GSE) in HCV replication, and then to study mechanisms. The results indicated that a GSE treatment showed significant anti-HCV activity and suppressed HCV-elevated cyclooxygenase-2 (COX-2) expression. In contrast, exogenous COX-2 expression gradually attenuated antiviral effects of GSE, suggesting that GSE inhibited HCV replication by suppressing an aberrant COX-2 expression caused by HCV, which was correlated with the inactivation of IKK-regulated NF-κB and MAPK/ERK/JNK signaling pathways. In addition, GSE also attenuated HCV-induced inflammatory cytokine gene expression. Notably, a combined administration of GSE with interferon or other FDA-approved antiviral drugs revealed a synergistic anti-HCV effect. Collectively, these findings demonstrate the possibility of developing GSE as a dietary supplement to treat patients with a chronic HCV infection. PMID:28066241

  12. Hepatoprotective Effect of Quercetin on Endoplasmic Reticulum Stress and Inflammation after Intense Exercise in Mice through Phosphoinositide 3-Kinase and Nuclear Factor-Kappa B

    PubMed Central

    Tang, Yuhan; Li, Juan; Gao, Chao; Xu, Yanyan; Li, Yanyan; Yu, Xiao; Wang, Jing; Liu, Liegang

    2016-01-01

    The mechanisms underlying intense exercise-induced liver damage and its potential treatments remain unclear. We explored the hepatoprotection and mechanisms of quercetin, a naturally occurring flavonoid, in strenuous exercise-derived endoplasmic reticulum stress (ERS) and inflammation. Intense exercise (28 m/min at a 5° slope for 90 min) resulted in the leakage of aminotransferases in the BALB/C mice. The hepatic ultrastructural malformations and oxidative stress levels were attenuated by quercetin (100 mg/kg·bw). Intense exercise and thapsigargin- (Tg-) induced ERS (glucose-regulated protein 78, GRP78) and inflammatory cytokines levels (IL-6 and TNF-α) were decreased with quercetin. Furthermore, quercetin resulted in phosphoinositide 3-kinase (PI3K) induction, Ca2+ restoration, and blockade of the activities of Jun N-terminal kinase (JNK), activating transcription factor 6 (ATF6) and especially NF-κB (p65 and p50 nuclear translocation). A PI3K inhibitor abrogated the protection of quercetin on ERS and inflammation of mouse hepatocytes. SP600125 (JNK inhibitor), AEBSF (ATF6 inhibitor), and especially PDTC (NF-κB inhibitor) enhanced the quercetin-induced protection against Tg stimulation. Collectively, intense exercise-induced ERS and inflammation were attenuated by quercetin. PI3K/Akt activation and JNK, ATF6, and especially NF-κB suppression were involved in the protection. Our results highlight a novel preventive strategy for treating ERS and inflammation-mediated liver damage induced by intense exercise using natural phytochemicals. PMID:27504150

  13. The quercetin paradox

    SciTech Connect

    Boots, Agnes W. . E-mail: a.boots@farmaco.unimaas.nl; Li, Hui; Schins, Roel P.F.; Duffin, Rodger; Heemskerk, Johan W.M.; Bast, Aalt; Haenen, Guido R.M.M.

    2007-07-01

    Free radical scavenging antioxidants, such as quercetin, are chemically converted into oxidation products when they protect against free radicals. The main oxidation product of quercetin, however, displays a high reactivity towards thiols, which can lead to the loss of protein function. The quercetin paradox is that in the process of offering protection, quercetin is converted into a potential toxic product. In the present study, this paradox is evaluated using rat lung epithelial (RLE) cells. It was found that quercetin efficiently protects against H{sub 2}O{sub 2}-induced DNA damage in RLE cells, but this damage is swapped for a reduction in GSH level, an increase in LDH leakage as well as an increase of the cytosolic free calcium concentration. To our knowledge, this is the first study that indicates that the quercetin paradox, i.e. the exchange of damage caused by quercetin and its metabolites, also occurs in living lung cells. Following depletion of GSH in the cells by BSO pre-treatment, this quercetin paradox becomes more pronounced, confirming that the formation of thiol reactive quercetin metabolites is involved in the quercetin paradox. The quercetin paradox in living cells implies that the anti-oxidant directs oxidative damage selectively to thiol arylation. Apparently, the potential toxicity of metabolites formed during the actual antioxidant activity of free radical scavengers should be considered in antioxidant supplementation.

  14. Opuntia ficus indica (nopal) attenuates hepatic steatosis and oxidative stress in obese Zucker (fa/fa) rats.

    PubMed

    Morán-Ramos, Sofía; Avila-Nava, Azalia; Tovar, Armando R; Pedraza-Chaverri, José; López-Romero, Patricia; Torres, Nimbe

    2012-11-01

    Nonalcoholic fatty liver disease (NAFLD) is associated with multiple factors such as obesity, insulin resistance, and oxidative stress. Nopal, a cactus plant widely consumed in the Mexican diet, is considered a functional food because of its antioxidant activity and ability to improve biomarkers of metabolic syndrome. The aim of this study was to assess the effect of nopal consumption on the development of hepatic steatosis and hepatic oxidative stress and on the regulation of genes involved in hepatic lipid metabolism. Obese Zucker (fa/fa) rats were fed a control diet or a diet containing 4% nopal for 7 wk. Rats fed the nopal-containing diet had ∼50% lower hepatic TG than the control group as well as a reduction in hepatomegaly and biomarkers of hepatocyte injury such as alanine and aspartate aminotransferases. Attenuation of hepatic steatosis by nopal consumption was accompanied by a higher serum concentration of adiponectin and a greater abundance of mRNA for genes involved in lipid oxidation and lipid export and production of carnitine palmitoyltransferase-1 and microsomal TG transfer proteins in liver. Hepatic reactive oxygen species and lipid peroxidation biomarkers were significantly lower in rats fed nopal compared with the control rats. Furthermore, rats fed the nopal diet had a lower postprandial serum insulin concentration and a greater liver phosphorylated protein kinase B (pAKT):AKT ratio in the postprandial state. This study suggests that nopal consumption attenuates hepatic steatosis by increasing fatty acid oxidation and VLDL synthesis, decreasing oxidative stress, and improving liver insulin signaling in obese Zucker (fa/fa) rats.

  15. Bicyclol attenuates tetracycline-induced fatty liver associated with inhibition of hepatic ER stress and apoptosis in mice.

    PubMed

    Yao, Xiao-Min; Li, Yue; Li, Hong-Wei; Cheng, Xiao-Yan; Lin, Ai-Bin; Qu, Jun-Ge

    2016-01-01

    Endoplasmic reticulum (ER) stress is known to be involved in the development of several metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). Tetracycline can cause hepatic steatosis, and ER stress may be involved in tetracycline-induced fatty liver. Our previous study showed that bicyclol has been proven to protect against tetracycline-induced fatty liver in mice, and ER stress may also be involved in bicyclol's hepatoprotective effect. Therefore, this study was performed to investigate the underlying mechanisms associated with ER stress and apoptosis, by which bicyclol attenuated tetracycline-induced fatty liver in mice. Bicyclol (300 mg/kg) was given to mice by gavage 3 times. Tetracycline (200 mg/kg, intraperitoneally) was injected at 1 h after the last dose of bicyclol. At 6 h and 24 h after single dose of tetracycline injection, serum ALT, AST, TG, CHO and hepatic histopathological examinations were performed to evaluate liver injuries. Hepatic steatosis was assessed by the accumulation of hepatic TG and CHO. Moreover, hepatic apoptosis and ER stress related markers were determined by TUNEL, real-time PCR, and western blot. As a result, bicyclol significantly protected against tetracycline-induced fatty liver as evidenced by the decrease of elevated serum transaminases and hepatic triglyceride, and the attenuation of histopathological changes in mice. In addition, bicyclol remarkably alleviated hepatic apoptosis and the gene expression of caspase-3, and increased the gene expression of XIAP. The gene expressions of ER stress-related markers, including CHOP, GRP78, IRE-1α, and ATF6, which were downregulated by bicyclol pretreatment in tetracycline-injected mice. These results suggested that bicyclol protected tetracycline-induced fatty liver partly due to its ability of anti-apoptosis associated with ER stress.

  16. Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance.

    PubMed

    Remington, Gary J; Teo, Celine; Wilson, Virginia; Chintoh, Araba; Guenette, Melanie; Ahsan, Zohra; Giacca, Adria; Hahn, Margaret K

    2015-11-01

    Antipsychotics (APs) are linked to diabetes, even without weight gain. Whether anti-diabetic drugs are efficacious in reversing the direct effects of APs on glucose pathways is largely undetermined. We tested two metformin (Met) doses to prevent impairments seen following a dose of olanzapine (Ola) (3 mg/kg); glucokinetics were measured using the hyperinsulinemic-euglycemic clamp (HIEC). Met (150 mg/kg; n=13, or 400 mg/kg; n=11) or vehicle (Veh) (n=11) was administered through gavage preceding an overnight fast, followed by a second dose prior to the HIEC. Eleven additional animals were gavaged with Veh and received a Veh injection during the HIEC (Veh/Veh); all others received Ola. Basal glucose was similar across treatment groups. The Met 400 group had significantly greater glucose appearance (Ra) in the basal period (i.e., before Ola, or hyperinsulinemia) vs other groups. During hyperinsulinemia, glucose infusion rate (GINF) to maintain euglycemia (reflective of whole-body insulin sensitivity) was higher in Veh/Veh vs other groups. Met 150/Ola animals demonstrated increased GINF relative to Veh/Ola during early time points of the HIEC. Glucose utilization during hyperinsulinemia, relative to basal conditions, was significantly higher in Veh/Veh vs other groups. The change in hepatic glucose production (HGP) from basal to hyperinsulinemia demonstrated significantly greater decreases in Veh/Veh and Met 150/Ola groups vs Veh/Ola. Given the increase in basal Ra with Met 400, we measured serum lactate (substrate for HGP), finding increased levels in Met 400 vs Veh and Met 150. In conclusion, Met attenuates hepatic insulin resistance observed with acute Ola administration, but fails to improve peripheral insulin resistance. Use of supra-therapeutic doses of Met may mask metabolic benefits by increasing lactate.

  17. Ablation of cytochrome P450 omega-hydroxylase 4A14 gene attenuates hepatic steatosis and fibrosis.

    PubMed

    Zhang, Xiaoyan; Li, Sha; Zhou, Yunfeng; Su, Wen; Ruan, Xiongzhong; Wang, Bing; Zheng, Feng; Warner, Margaret; Gustafsson, Jan-Åke; Guan, Youfei

    2017-03-21

    Nonalcoholic fatty liver disease (NAFLD) is characterized by simple hepatic steatosis (SS), nonalcoholic steatohepatitis (NASH), hepatic fibrosis, and cirrhosis. Dysregulated fatty acid metabolism in the liver plays a critical role in the pathogenesis of NAFLD. Cytochrome P450 omega-hydroxylase 4A14 (CYP4A14) is a homolog of human CYP4A hydroxylase that catalyzes omega-hydroxylation of medium-chain fatty acids and arachidonic acid in mice. The goal of this study was to determine the role of CYP4A14 in the development and the progression of NAFLD. Here, we showed that hepatic CYP4A expression was up-regulated in the livers of patients and three murine models of NAFLD. Adenovirus-mediated overexpression of CYP4A14 in the livers of C57BL/6 mice resulted in a fatty liver phenotype with a significant increase in hepatic fatty acid translocase (FAT/CD36) expression. In contrast, CYP4A14 gene-deficient mice fed a high-fat diet or a methionine and choline-deficient (MCD) diet exhibited attenuated liver lipid accumulation and reduced hepatic FAT/CD36 expression. In addition, hepatic inflammation and fibrosis was markedly ameliorated in MCD diet-fed CYP4A14-deficient mice. Collectively, CYP4A14 plays an important role in the pathogenesis of both SS and NASH and may represent a potential therapeutic target for the treatment of NAFLD.

  18. Artemisia annua Leaf Extract Attenuates Hepatic Steatosis and Inflammation in High-Fat Diet-Fed Mice

    PubMed Central

    Kim, Kyung Eun; Ko, Keon-Hee; Heo, Rok Won; Yi, Chin-ok; Shin, Hyun Joo; Kim, Jun Young; Park, Jae-Ho; Nam, Sanghae; Kim, Hwajin

    2016-01-01

    Abstract Artemisia annua L. (AA) is a well-known source of the antimalarial drug artemisinin. AA also has an antibacterial and antioxidant activity. However, the effect of AA extract on hepatic steatosis induced by obesity is unclear. We investigated whether AA extract prevents obesity-induced insulin resistance and hepatic steatosis in high-fat diet (HFD)-fed mice. Mice were randomly divided into groups that received a normal chow diet or HFD with or without AA for 12 weeks. We found that AA extract reduced insulin resistance and hepatic steatosis in HFD-fed mice. Western blot analysis showed that HFD-induced expression of nuclear sterol regulatory element-binding protein 1 and carbohydrate-responsive element-binding protein in the livers was decreased by AA extract. In particular, dietary administration of AA extract decreased hepatic high-mobility group box 1 and cyclooxygenase-2 expression in HFD-fed mice. AA extract also attenuated HFD-induced collagen deposition and fibrosis-related transforming growth factor-β1 and connective tissue growth factor. These data indicate that dietary AA extract has beneficial effects on hepatic steatosis and inflammation in HFD-fed mice. PMID:26741655

  19. A diet high in α-linolenic acid and monounsaturated fatty acids attenuates hepatic steatosis and alters hepatic phospholipid fatty acid profile in diet-induced obese rats.

    PubMed

    Hanke, Danielle; Zahradka, Peter; Mohankumar, Suresh K; Clark, Jaime L; Taylor, Carla G

    2013-01-01

    This study investigated the efficacy of the plant-based n-3 fatty acid, α-linolenic acid (ALA), a dietary precursor of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for modulating hepatic steatosis. Rats were fed high fat (55% energy) diets containing high oleic canola oil, canola oil, a canola/flax oil blend (C/F, 3:1), safflower oil, soybean oil, or lard. After 12 weeks, C/F and weight-matched (WM) groups had 20% less liver lipid. Body mass, liver weight, glucose and lipid metabolism, inflammation and molecular markers of fatty acid oxidation, synthesis, desaturation and elongation did not account for this effect. The C/F group had the highest total n-3 and EPA in hepatic phospholipids (PL), as well as one of the highest DHA and lowest arachidonic acid (n-6) concentrations. In conclusion, the C/F diet with the highest content of the plant-based n-3 ALA attenuated hepatic steatosis and altered the hepatic PL fatty acid profile.

  20. Hepatitis

    MedlinePlus

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Hepatitis KidsHealth > For Teens > Hepatitis Print A A A ... to a liver condition called hepatitis . What Is Hepatitis? The liver is one of the body's powerhouses. ...

  1. Hepatitis

    MedlinePlus

    ... de los dientes Video: Getting an X-ray Hepatitis KidsHealth > For Kids > Hepatitis Print A A A ... an important digestive liquid called bile . What Is Hepatitis? Hepatitis is an inflammation (say: in-fluh-MAY- ...

  2. Attenuation of insulin resistance, metabolic syndrome and hepatic oxidative stress by resveratrol in fructose-fed rats.

    PubMed

    Bagul, Pankaj K; Middela, Harish; Matapally, Saidulu; Padiya, Raju; Bastia, Tanmay; Madhusudana, K; Reddy, B Raghunath; Chakravarty, Sumana; Banerjee, Sanjay K

    2012-09-01

    Metabolic syndrome and oxidative stress are common complications of type 2 diabetes mellitus. The present study was designed to determine whether resveratrol, a widely used nutritional supplement, can improve insulin sensitivity, metabolic complication as well as hepatic oxidative stress in fructose-fed rats. Male Sprague Dawley rats (180-200 g) were divided into four groups with 8 animals each. Fructose-fed insulin resistant group (Dia) animals were fed 65% fructose (Research diet, USA) for a period of 8 weeks, whereas control group (Con) animals were fed 65% cornstarch (Research Diet, USA). Resveratrol, 10 mg/kg/day (Dia+Resv) or metformin 300 mg/kg/day (Dia+Met) were administered orally to the 65% fructose-fed rats for 8 weeks. At the end of the feeding schedule, Dia group had insulin resistance along with increased blood glucose, triglyceride, uric acid and nitric oxide (NO) levels. Significant (p<0.05) increase in hepatic TBARS and conjugated dienes, and significant (p<0.05) decrease in hepatic SOD and vitamin C was observed in Dia group compared to Con group. Administration of metformin or resveratrol significantly (p<0.05) normalized all the altered metabolic parameters. However, a marked insulin sensitizing action was only observed in the Dia+Resv group. Similarly, while metformin administration failed to normalize the increased TBARS levels and decreased SOD activity, resveratrol showed a more promising effect of all oxidative stress parameters measured in the present study. Attenuation of hepatic oxidative stress in fructose-fed rat liver after resveratrol administration was associated with significant (p<0.05) increase in nuclear level of NRF2 compared with other groups. The present study demonstrates that resveratrol is more effective than metformin in improving insulin sensitivity, and attenuating metabolic syndrome and hepatic oxidative stress in fructose-fed rats.

  3. Virulent and attenuated strains of duck hepatitis A virus elicit discordant innate immune responses in vivo.

    PubMed

    Song, Cuiping; Liao, Ying; Gao, Wei; Yu, Shengqing; Sun, Yingjie; Qiu, Xvsheng; Tan, Lei; Cheng, Anchun; Wang, Mingshu; Ma, Zhiyong; Ding, Chan

    2014-12-01

    Previous studies of duck hepatitis A virus infection have focused only on the pathogenicity and host response of one strain. Here, we show that the virulent SH strain and the attenuated FC64 strain induced varied pathogenicity, apoptosis and immune responses in the livers of 1-day-old ducklings. SH infection caused apoptosis and visible lesions in the liver; serum aspartate aminotransferase, alanine transaminase, alkaline phosphatase, γ-glutamyltransferase and total bilirubin activities were markedly upregulated; and ducklings died at 36 h post-infection (p.i.). However, FC64 infection did not induce significant symptoms or impair liver function, and all of the infected ducklings remained healthy. In addition, both virus strains replicated well in the liver, spleen and intestine, whilst the SH strain replicated more efficiently than FC64. IFN-γ, IL-2, inducible nitric oxide synthase and nitric oxide were strongly induced by SH infection, and may be associated with the pathogenicity of the SH strain. IFN-α, IFN-β, IFN-stimulated transmembrane protein 1, IFN-stimulated gene 12, 2',5'-oligoadenylate synthetase-like and IL-6 were moderately induced by SH infection at 24 h p.i., and dramatically induced by FC64 infection at 36 h p.i. The intensive induction of cytokines by FC64 may be involved in restriction of virus replication and stimulation of adaptive immune responses. Ducklings inoculated with FC64 produced high levels of antiviral antibodies within 45 days p.i. The low virulence and strong immune response of FC64 rendered this strain a good vaccine candidate, as confirmed by a protective assay in this study.

  4. Prolyl oligopeptidase attenuates hepatic stellate cell activation through induction of Smad7 and PPAR-γ

    PubMed Central

    Zhou, Da; Wang, Jing; He, Ling-Nan; Li, Bing-Hang; Ding, Yong-Nian; Chen, Yuan-Wen; Fan, Jian-Gao

    2017-01-01

    Prolyl oligopeptidase (POP) is a serine endopeptidase widely distributed in vivo with high activity in the liver. However, its biological functions in the liver have remained largely elusive. A previous study by our group has shown that POP produced N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) and thereby exerted an anti-fibrogenic effect on hepatic stellate cells (HSCs) in vitro. It was therefore hypothesized that POP may affect the activation state of HSCs and has an important role in liver fibrosis. The HSC-T6 immortalized rat liver stellate cell line was treated with the POP inhibitor S17092 or transfected with recombinant lentivirus to overexpress POP. Cell proliferation and apoptosis were determined using a Cell Counting Kit-8 and flow cytometry, respectively. The activation status of HSCs was determined by examination of the expression of α-smooth muscle actin (α-SMA), collagen I, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGF)-β-Smad signaling and peroxisome proliferator activated receptor-γ (PPAR-γ). Inhibition by S17092 decreased, whereas lentiviral expression increased the activity of POP and cell proliferation, while neither of the treatments affected cell apoptosis. Of note, S17092 significantly increased, whereas POP overexpression decreased the expression of α-SMA and MCP-1 without affecting the expression of collagen I and TGF-β1. Furthermore, S17092 caused a reduction, whereas POP overexpression caused an upregulation of Smad7 protein and PPAR-γ, but not phosphorylated-Smad2/3 expression. In conclusion, POP attenuated the activation of HSCs through inhibition of TGF-β signaling and induction of PPAR-γ, which may have therapeutic potential in liver fibrosis. PMID:28352366

  5. Attenuated viral hepatitis in Trem1−/− mice is associated with reduced inflammatory activity of neutrophils

    PubMed Central

    Kozik, Jan-Hendrik; Trautmann, Tanja; Carambia, Antonella; Preti, Max; Lütgehetmann, Marc; Krech, Till; Wiegard, Christiane; Heeren, Joerg; Herkel, Johannes

    2016-01-01

    TREM1 (Triggering Receptor Expressed on Myeloid Cells 1) is a pro-inflammatory receptor expressed by phagocytes, which can also be released as a soluble molecule (sTREM1). The roles of TREM1 and sTREM1 in liver infection and inflammation are not clear. Here we show that patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection manifest elevated serum levels of sTREM1. In mice, experimental viral hepatitis induced by infection with Lymphocytic Choriomeningitis Virus (LCMV)-WE was likewise associated with increased sTREM1 in serum and urine, and with increased TREM1 and its associated adapter molecule DAP12 in the liver. Trem1−/− mice showed accelerated clearance of LCMV-WE and manifested attenuated liver inflammation and injury. TREM1 expression in the liver of wild-type mice was mostly confined to infiltrating neutrophils, which responded to LCMV by secretion of CCL2 and TNF-α, and release of sTREM1. Accordingly, the production of CCL2 and TNF-α was decreased in the livers of LCMV-infected Trem1−/− mice, as compared to LCMV-infected wildtype mice. These findings indicate that TREM1 plays a role in viral hepatitis, in which it seems to aggravate the immunopathology associated with viral clearance, mainly by increasing the inflammatory activity of neutrophils. PMID:27328755

  6. Quercetin protection against ciprofloxacin induced liver damage in rats.

    PubMed

    Taslidere, E; Dogan, Z; Elbe, H; Vardi, N; Cetin, A; Turkoz, Y

    2016-01-01

    Ciprofloxacin is a common, broad spectrum antibacterial agent; however, evidence is accumulating that ciprofloxacin may cause liver damage. Quercetin is a free radical scavenger and antioxidant. We investigated histological changes in hepatic tissue of rats caused by ciprofloxacin and the effects of quercetin on these changes using histochemical and biochemical methods. We divided 28 adult female Wistar albino rats into four equal groups: control, quercetin treated, ciprofloxacin treated, and ciprofloxacin + quercetin treated. At the end of the experiment, liver samples were processed for light microscopic examination and biochemical measurements. Sections were prepared and stained with hematoxylin and eosin, and a histopathologic damage score was calculated. The sections from the control group appeared normal. Hemorrhage, inflammatory cell infiltration and intracellular vacuolization were observed in the ciprofloxacin group. The histopathological findings were reduced in the group treated with quercetin. Significant differences were found between the control and ciprofloxacin groups, and between the ciprofloxacin and ciprofloxacin + quercetin groups. Quercetin administration reduced liver injury caused by ciprofloxacin in rats. We suggest that quercetin may be useful for preventing ciprofloxacin induced liver damage.

  7. The flavonoid quercetin inhibits dimethylnitrosamine-induced liver damage in rats.

    PubMed

    Lee, Eun-Sil; Lee, Hye-Eun; Shin, Ji-Young; Yoon, Sik; Moon, Jeon-Ok

    2003-08-01

    Quercetin, one of the most abundant flavonoids in human diet has been reported to exhibit a wide range of pharmacological properties. In this study, we investigated the protective effect of quercetin on hepatic injury induced by dimethylnitrosamine (DMN) in rats. Treatment with DMN caused a significant decrease in body and liver weight. Oral administration of quercetin (10 mg kg(-1) daily for 4 weeks) remarkably prevented this DMN-induced loss in body and liver weight and inhibited the elevation of serum alanine transaminase, aspartate transaminase and bilirubin levels. Quercetin also increased serum albumin and hepatic glutathione levels and reduced the hepatic level of malondialdehyde. Furthermore, DMN-induced elevation of hydroxyproline content was reduced in the quercetin treated rats, the result of which was consistent with a reduction in type I collagen mRNA production and histological analysis of liver tissue stained with Sirius red. A reduction in hepatic stellate cell activation, as assessed by alpha-smooth muscle actin staining, was associated with quercetin treatment as well as a reduction in transforming growth factor-beta1 expression. In conclusion, these results demonstrate that quercetin exhibited in-vivo hepatoprotective and anti-fibrogenic effects against DMN-induced liver injury and suggest that quercetin may be useful in the preventing the development of hepatic fibrosis.

  8. Lophirones B and C Attenuate Acetaminophen-Induced Liver Damage in Mice: Studies on Hepatic, Oxidative Stress and Inflammatory Biomarkers.

    PubMed

    Ajiboye, Taofeek O

    2016-10-01

    Lophirones B and C are chalcone dimers with proven chemopreventive activity. This study evaluates the hepatoprotective effect lophirones B and C in acetaminophen-induced hepatic damage in mice using biomarkers of hepatocellular indices, oxidative stress, proinflammatory factors and lipid peroxidation. Oral administrations of lophirones B and C significantly (p < 0.05) attenuated acetaminophen-mediated alterations in serum alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, albumin and total bilirubin. Similarly, acetaminophen-mediated decrease in activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose 6- phosphate dehydrogenase were significantly attenuated in the liver of mice. Increased levels of conjugated dienes, lipid hydroperoxides, malondialdehyde, protein carbonyl and fragmented DNA were significantly lowered by lophirones B and C. Levels of tumour necrosis factor-α, interleukin-6 and 8 were significantly lowered in serum of acetaminophen treated mice by the chalcone dimers. Overall, results of this study show that lophirones B and C halted acetaminophen-mediated hepatotoxicity.

  9. Paeoniflorin attenuates hepatic ischemia/reperfusion injury via anti-oxidative, anti-inflammatory and anti-apoptotic pathways

    PubMed Central

    TAO, YE; WEN, ZHIHONG; SONG, YINGQIAN; WANG, HUI

    2016-01-01

    During liver surgery, hepatic blood flow needs to be blocked in order to reduce bleeding, which inevitably results in hepatic ischemia/reperfusion injury (HI/R). Paeoniflorin (PF) is the main active ingredient of the traditional Chinese herbal medicine peony, which has been shown to exert anti-oxidative and anti-apoptotic properties. In the present study, a mouse model of HI/R was generated by clamping the hepatoportal vein, hepatic artery, and hepatic duct of BALB/c mice with a vascular clamp for 30 min, followed by reperfusion for 6 h under anesthesia. Six mice in the three PF treatment groups (5, 10 and 20 mg/kg) were then injected with PF, via the tail vein. A sham group, consisting of six mice that did not undergo the procedure, and a vehicle group, consisting of 6 mice that underwent the procedure but subsequently received injections of physiological saline only, were used as controls. Liver injury was indicated by serum levels of the enzymes alanine transaminase (ALT) and aspartate transaminase (AST). The activities of oxidative stress biomarkers, including superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-PX) and malondialdehyde (MDA), were also measured. Furthermore, the activity of caspase-3 was analyzed in hepatic tissue using a commercial kit. Treatment with PF significantly attenuated HI/R injury histologically, as compared with the vehicle group. In addition, significant reductions in the serum levels of ALT and AST were observed in the PF-treated ischemic mice. Furthermore, treatment with PF enhanced the activities of hepatic tissue SOD, GSH and GSH-PX, but decreased the MDA content. Treatment of ischemic mice with PF markedly reduced the expression levels of inflammatory mediators, including nuclear factor-κB, tumor necrosis factor-α, interleukin (IL)-6, and IL-1β, and decreased the HI/R injury-induced expression of caspase-3. The results of the present study suggest that PF attenuates the HI/R injury of mice via anti

  10. Hepatitis

    MedlinePlus

    ... clotting problems or chronic liver disease. previous continue Hepatitis B and Hepatitis C Although hep A is a ... does — through direct contact with infected body fluids. Hepatitis B and C are even more easily passed in ...

  11. Hepatitis

    MedlinePlus

    ... A if they've been vaccinated against it. Hepatitis B Hepatitis B is a more serious infection. It may lead ... of which cause severe illness and even death. Hepatitis B virus (HBV) is transmitted from person to person ...

  12. Hepatitis

    MedlinePlus

    ... Issues Listen Español Text Size Email Print Share Hepatitis Page Content Article Body Hepatitis means “inflammation of ... it has been associated with drinking contaminated water. Hepatitis Viruses Type Transmission Prognosis A Fecal-oral (stool ...

  13. Coumarin attenuates hepatic steatosis by down-regulating lipogenic gene expression in mice fed a high-fat diet.

    PubMed

    Um, Min Young; Moon, Mi Kyeong; Ahn, Jiyun; Youl Ha, Tae

    2013-05-01

    Coumarin is a natural compound abundant in plant-based foods such as citrus fruits, tomatoes, vegetables and green tea. Although coumarin has been reported to exhibit anti-coagulant, anti-inflammation and cholesterol-lowering properties, the effect of coumarin on hepatic lipid metabolism remains unclear. In the present study, we evaluated the ability of coumarin to protect against hepatic steatosis associated with a high-fat diet (HFD) and investigated potential mechanisms underlying this effect. C57BL/6J mice were fed a normal diet, HFD and HFD containing 0·05 % courmarin for 8 weeks. The present results showed that coumarin reduced weight gain and abdominal fat mass in mice fed the HFD for 8 weeks (P< 0·05). Coumarin also significantly reduced the HFD-induced elevation in total cholesterol, apoB, leptin and insulin (P< 0·05). In the liver of HFD-fed mice, coumarin significantly reduced total lipids, TAG and cholesterol (38, 22 and 9 % reductions, respectively; P< 0·05), as well as lipid droplet number and size. Additionally, thiobarbituric acid-reactive substance levels, as an indicator of hepatic steatosis, were attenuated by coumarin (P< 0·05). Finally, coumarin suppressed the HFD-induced up-regulation in fatty acid synthase (FAS) activity, and the expression of sterol regulatory element-binding protein-1, FAS, acetyl-CoA carboxylase 1, PPARγ and CCAAT/enhancer-binding protein-α in the liver. Taken together, these results demonstrate that coumarin could prevent HFD-induced hepatic steatosis by regulating lipogenic gene expression, suggesting potential targets for preventing hepatic steatosis.

  14. Short-Term Hypocaloric High-Fiber and High-Protein Diet Improves Hepatic Steatosis Assessed by Controlled Attenuation Parameter

    PubMed Central

    Arslanow, Anita; Teutsch, Melanie; Walle, Hardy; Grünhage, Frank; Lammert, Frank; Stokes, Caroline S

    2016-01-01

    OBJECTIVES: Non-alcoholic fatty liver disease is one of the most prevalent liver diseases and increases the risk of fibrosis and cirrhosis. Current standard treatment focuses on lifestyle interventions. The primary aim of this study was to assess the effects of a short-term low-calorie diet on hepatic steatosis, using the controlled attenuation parameter (CAP) as quantitative tool. METHODS: In this prospective observational study, 60 patients with hepatic steatosis were monitored during a hypocaloric high-fiber, high-protein diet containing 1,000 kcal/day. At baseline and after 14 days, we measured hepatic fat contents using CAP during transient elastography, body composition with bioelectrical impedance analysis, and serum liver function tests and lipid profiles using standard clinical–chemical assays. RESULTS: The median age was 56 years (25–78 years); 51.7% were women and median body mass index was 31.9 kg/m2 (22.4–44.8 kg/m2). After 14 days, a significant CAP reduction (14.0% P<0.001) was observed from 295 dB/m (216–400 dB/m) to 266 dB/m (100–353 dB/m). In parallel, body weight decreased by 4.6% (P<0.001), of which 61.9% was body fat. In addition, liver stiffness (P=0.002), γ-GT activities, and serum lipid concentrations decreased (all P<0.001). CONCLUSIONS: This study shows for the first time that non-invasive elastography can be used to monitor rapid effects of dietary treatment for hepatic steatosis. CAP improvements occur after only 14 days on short-term low-calorie diet, together with reductions of body composition parameters, serum lipids, and liver enzymes, pointing to the dynamics of hepatic lipid turnover. PMID:27311064

  15. D-chiro-inositol attenuates epinephrine-stimulated hepatic glucose output in the isolated perfused liver independently of insulin.

    PubMed

    Whiting, L; Danaher, R N; Ruggiero, K; Lee, C-C; Chaussade, C; Mulvey, T; Phillips, A; Loomes, K M

    2013-05-01

    D-chiro-Inositol (DCI) is a cyclic sugar alcohol that evokes both antidiabetic and insulin sensitizing effects. Pharmacological administration of DCI has been shown to lower blood glucose in rat models of diabetes mellitus and enhance insulin sensitivity in humans with polycystic ovary syndrome (PCOS). We hypothesised that the antidiabetic effects of DCI could be due to inhibition of hepatic glucose output (HGO). To test this hypothesis, we perfused isolated rat livers either with buffer, myo-inositol, DCI, or insulin, and investigated their respective effects on the stimulation of HGO by epinephrine. We found that perfusion with 200 μM DCI attenuated epinephrine-stimulated HGO by 35% over 30 min as compared to the buffer control perfusion (p=0.05). By comparison, perfusion with 1 nM insulin attenuated epinephrine-stimulated HGO by 57% (p<0.0001). The glucose-lowering effects by DCI occurred independently of insulin and were specific to the DCI stereoisomer as 200 μM myo-inositol had no effect. These findings suggest that DCI could evoke its antidiabetic effects in vivo by inhibition of HGO. Further identification of the protein targets involved could open up new avenues to regulate hyperglycaemia with wider implications for the treatment of hepatic insulin resistance in PCOS.

  16. Lactobacillus fermentum ZYL0401 Attenuates Lipopolysaccharide-Induced Hepatic TNF-α Expression and Liver Injury via an IL-10- and PGE2-EP4-Dependent Mechanism

    PubMed Central

    Lv, Longxian; Yang, Jianzhuan; Lu, Haifeng; Li, Lanjuan

    2015-01-01

    Lipopolysaccharide (LPS) has essential role in the pathogenesis of D-galactosamine-sensitized animal models and alcoholic liver diseases of humans, by stimulating release of pro-inflammatory mediators that cause hepatic damage and intestinal barrier impairment. Oral pretreatment of probiotics has been shown to attenuate LPS-induced hepatic injury, but it is unclear whether the effect is direct or due to improvement in the intestinal barrier. The present study tested the hypothesis that pretreatment with probiotics enables the liver to withstand directly LPS-induced hepatic injury and inflammation. In a mouse model of LPS-induced hepatic injury, the levels of hepatic tumor necrosis factor-alpha (TNF-α) and serum alanine aminotransferase (ALT) of mice with depleted intestinal commensal bacteria were not significantly different from that of the control models. Pre-feeding mice for 10 days with Lactobacillus fermentum ZYL0401 (LF41), significantly alleviated LPS-induced hepatic TNF-α expression and liver damage. After LF41 pretreatment, mice had dramatically more L.fermentum-specific DNA in the ileum, significantly higher levels of ileal cyclooxygenase (COX)-2 and interleukin 10 (IL-10) and hepatic prostaglandin E2 (PGE2). However, hepatic COX-1, COX-2, and IL-10 protein levels were not changed after the pretreatment. There were also higher hepatic IL-10 protein levels after LPS challenge in LF41-pretreaed mice than in the control mice. Attenuation of hepatic TNF-α was mediated via the PGE2/E prostanoid 4 (EP4) pathway, and serum ALT levels were attenuated in an IL-10-dependent manner. A COX-2 blockade abolished the increase in hepatic PGE2 and IL-10 associated with LF41. In LF41-pretreated mice, a blockade of IL-10 caused COX-2-dependent promotion of hepatic PGE2, without affecting hepatic COX-2levels. In LF41-pretreated mice, COX2 prevented enhancing TNF-α expression in both hepatic mononuclear cells and the ileum, and averted TNF-α-mediated increase in

  17. Lactobacillus fermentum ZYL0401 Attenuates Lipopolysaccharide-Induced Hepatic TNF-α Expression and Liver Injury via an IL-10- and PGE2-EP4-Dependent Mechanism.

    PubMed

    Jin, Pengfeng; Chen, Yunbo; Lv, Longxian; Yang, Jianzhuan; Lu, Haifeng; Li, Lanjuan

    2015-01-01

    Lipopolysaccharide (LPS) has essential role in the pathogenesis of D-galactosamine-sensitized animal models and alcoholic liver diseases of humans, by stimulating release of pro-inflammatory mediators that cause hepatic damage and intestinal barrier impairment. Oral pretreatment of probiotics has been shown to attenuate LPS-induced hepatic injury, but it is unclear whether the effect is direct or due to improvement in the intestinal barrier. The present study tested the hypothesis that pretreatment with probiotics enables the liver to withstand directly LPS-induced hepatic injury and inflammation. In a mouse model of LPS-induced hepatic injury, the levels of hepatic tumor necrosis factor-alpha (TNF-α) and serum alanine aminotransferase (ALT) of mice with depleted intestinal commensal bacteria were not significantly different from that of the control models. Pre-feeding mice for 10 days with Lactobacillus fermentum ZYL0401 (LF41), significantly alleviated LPS-induced hepatic TNF-α expression and liver damage. After LF41 pretreatment, mice had dramatically more L.fermentum-specific DNA in the ileum, significantly higher levels of ileal cyclooxygenase (COX)-2 and interleukin 10 (IL-10) and hepatic prostaglandin E2 (PGE2). However, hepatic COX-1, COX-2, and IL-10 protein levels were not changed after the pretreatment. There were also higher hepatic IL-10 protein levels after LPS challenge in LF41-pretreated mice than in the control mice. Attenuation of hepatic TNF-α was mediated via the PGE2/E prostanoid 4 (EP4) pathway, and serum ALT levels were attenuated in an IL-10-dependent manner. A COX-2 blockade abolished the increase in hepatic PGE2 and IL-10 associated with LF41. In LF41-pretreated mice, a blockade of IL-10 caused COX-2-dependent promotion of hepatic PGE2, without affecting hepatic COX-2 levels. In LF41-pretreated mice, COX2 prevented enhancing TNF-α expression in both hepatic mononuclear cells and the ileum, and averted TNF-α-mediated increase in

  18. Steroidogenic acute regulatory protein (StAR) overexpression attenuates HFD-induced hepatic steatosis and insulin resistance.

    PubMed

    Qiu, Yanyan; Sui, Xianxian; Zhan, Yongkun; Xu, Chen; Li, Xiaobo; Ning, Yanxia; Zhi, Xiuling; Yin, Lianhua

    2017-04-01

    Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology. Intracellular lipid accumulation is the first step in the development and progression of NAFLD. Steroidogenic acute regulatory protein (StAR) plays an important role in the synthesis of bile acid and intracellular lipid homeostasis and cholesterol metabolism. We hypothesize that StAR is involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. The hypothesis was identified using free fatty acid (FFA)-overloaded NAFLD in vitro model and high-fat diet (HFD)-induced NAFLD mouse model transfected by recombinant adenovirus encoding StAR (StAR). StAR expression was also examined in pathology samples of patients with fatty liver by immunohistochemical staining. We found that the expression level of StAR was reduced in the livers obtained from fatty liver patients and NAFLD mice. Additionally, StAR overexpression decreased the levels of hepatic lipids and maintained the hepatic glucose homeostasis due to the activation of farnesoid x receptor (FXR). StAR overexpression attenuated the impairment of insulin signaling in fatty liver. This protective role of StAR was owing to a reduction of intracellular diacylglycerol levels and the phosphorylation of PKCε. Furthermore, FXR inactivation reversed the observed beneficial effects of StAR. The present study revealed that StAR overexpression can reduce hepatic lipid accumulation, regulate glucose metabolism and attenuate insulin resistance through a mechanism involving the activation of FXR. Our study suggests that StAR may be a potential therapeutic target for NAFLD.

  19. β-aminoisobutyric acid attenuates hepatic endoplasmic reticulum stress and glucose/lipid metabolic disturbance in mice with type 2 diabetes

    PubMed Central

    Shi, Chang-Xiang; Zhao, Ming-Xia; Shu, Xiao-Dong; Xiong, Xiao-Qing; Wang, Jue-Jin; Gao, Xing-Ya; Chen, Qi; Li, Yue-Hua; Kang, Yu-Ming; Zhu, Guo-Qing

    2016-01-01

    β-aminoisobutyric acid (BAIBA) is a nature thymine catabolite, and contributes to exercise-induced protection from metabolic diseases. Here we show the therapeutical effects of BAIBA on hepatic endoplasmic reticulum (ER) stress and glucose/lipid metabolic disturbance in diabetes. Type 2 diabetes was induced by combined streptozotocin (STZ) and high-fat diet (HFD) in mice. Oral administration of BAIBA for 4 weeks reduced blood glucose and lipids levels, hepatic key enzymes of gluconeogenesis and lipogenesis expressions, attenuated hepatic insulin resistance and lipid accumulation, and improved insulin signaling in type 2 diabetic mice. BAIBA reduced hepatic ER stress and apoptosis in type 2 diabetic mice. Furthermore, BAIBA alleviated ER stress in human hepatocellular carcinoma (HepG2) cells with glucosamine-induced insulin resistance. Hepatic AMPK phosphorylation was reduced in STZ/HFD mice and glucosamine-treated HepG2 cells, which were restored by BAIBA treatment. The suppressive effects of BAIBA on glucosamine-induced ER stress were reversed by knockdown of AMPK with siRNA. In addition, BAIBA prevented thapsigargin- or tunicamycin-induced ER stress, and tunicamycin–induced apoptosis in HepG2 cells. These results indicate that BAIBA attenuates hepatic ER stress, apoptosis and glucose/lipid metabolic disturbance in mice with type 2 diabetes. AMPK signaling is involved to the role of BAIBA in attenuating ER stress. PMID:26907958

  20. β-aminoisobutyric acid attenuates hepatic endoplasmic reticulum stress and glucose/lipid metabolic disturbance in mice with type 2 diabetes.

    PubMed

    Shi, Chang-Xiang; Zhao, Ming-Xia; Shu, Xiao-Dong; Xiong, Xiao-Qing; Wang, Jue-Jin; Gao, Xing-Ya; Chen, Qi; Li, Yue-Hua; Kang, Yu-Ming; Zhu, Guo-Qing

    2016-02-24

    β-aminoisobutyric acid (BAIBA) is a nature thymine catabolite, and contributes to exercise-induced protection from metabolic diseases. Here we show the therapeutical effects of BAIBA on hepatic endoplasmic reticulum (ER) stress and glucose/lipid metabolic disturbance in diabetes. Type 2 diabetes was induced by combined streptozotocin (STZ) and high-fat diet (HFD) in mice. Oral administration of BAIBA for 4 weeks reduced blood glucose and lipids levels, hepatic key enzymes of gluconeogenesis and lipogenesis expressions, attenuated hepatic insulin resistance and lipid accumulation, and improved insulin signaling in type 2 diabetic mice. BAIBA reduced hepatic ER stress and apoptosis in type 2 diabetic mice. Furthermore, BAIBA alleviated ER stress in human hepatocellular carcinoma (HepG2) cells with glucosamine-induced insulin resistance. Hepatic AMPK phosphorylation was reduced in STZ/HFD mice and glucosamine-treated HepG2 cells, which were restored by BAIBA treatment. The suppressive effects of BAIBA on glucosamine-induced ER stress were reversed by knockdown of AMPK with siRNA. In addition, BAIBA prevented thapsigargin- or tunicamycin-induced ER stress, and tunicamycin-induced apoptosis in HepG2 cells. These results indicate that BAIBA attenuates hepatic ER stress, apoptosis and glucose/lipid metabolic disturbance in mice with type 2 diabetes. AMPK signaling is involved to the role of BAIBA in attenuating ER stress.

  1. Cytochrome P450-mediated metabolism of triclosan attenuates its cytotoxicity in hepatic cells.

    PubMed

    Wu, Yuanfeng; Chitranshi, Priyanka; Loukotková, Lucie; Gamboa da Costa, Gonçalo; Beland, Frederick A; Zhang, Jie; Fang, Jia-Long

    2016-11-28

    Triclosan is a widely used broad-spectrum anti-bacterial agent. The objectives of this study were to identify which cytochrome P450 (CYP) isoforms metabolize triclosan and to examine the effects of CYP-mediated metabolism on triclosan-induced cytotoxicity. A panel of HepG2-derived cell lines was established, each of which overexpressed a single CYP isoform, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, and CYP4B1. The extent of triclosan metabolism by each CYP was assessed by reversed-phase high-performance liquid chromatography with online radiochemical detection. Seven isoforms were capable of metabolizing triclosan, with the order of activity being CYP1A2 > CYP2B6 > CYP2C19 > CYP2D6 ≈ CYP1B1 > CYP2C18 ≈ CYP1A1. The remaining 11 isoforms (CYP2A6, CYP2A7, CYP2A13, CYP2C8, CYP2C9, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, and CYP4B1) had little or no activity toward triclosan. Three metabolites were detected: 2,4-dichlorophenol, 4-chlorocatechol, and 5'-hydroxytriclosan. Consistent with the in vitro screening data, triclosan was extensively metabolized in HepG2 cells overexpressing CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP2C18, and these cells were much more resistant to triclosan-induced cytotoxicity compared to vector cells, suggesting that CYP-mediated metabolism of triclosan attenuated its cytotoxicity. In addition, 2,4-dichlorophenol and 4-chlorocatechol were less toxic than triclosan to HepG2/vector cells. Conjugation of triclosan, catalyzed by human glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), also occurred in HepG2/CYP-overexpressing cells and primary human hepatocytes, with a greater extent of conjugation being associated with higher cell viability. Co-administration of triclosan with UGT or SULT inhibitors led to greater cytotoxicity in HepG2 cells and primary human hepatocytes, indicating that glucuronidation and

  2. Inhibition of hepatic cells pyroptosis attenuates CLP-induced acute liver injury

    PubMed Central

    Chen, Yuan-Li; Xu, Guo; Liang, Xiao; Wei, Juan; Luo, Jing; Chen, Guan-Nan; Yan, Xiao-Di; Wen, Xue-Ping; Zhong, Ming; Lv, Xin

    2016-01-01

    Pyroptosis is a programmed cell death associated with caspase-1 and accompanied by the secretion of a large number of pro-inflammatory cytokines. In the acute stage of sepsis, the release of several pro-inflammatory cytokines aggravates hepatic cell death, and acute liver injury is aggravated with the progress of the disease, resulting in acute liver failure with a very high mortality rate. The present study investigated the effect of inhibiting hepatic cell pyroptosis on the septic acute liver injury. Septic acute liver injury mice model was established by cecal ligation and puncture (CLP model). The liver tissues were assessed for inflammatory infiltration by HE, serum concentrations of ALT, AST, IL-1β, and IL-18 were examined by ELISA, hepatic cell pyroptosis was determined by flow cytometry, and expressions of caspase-1 and NLRP3 were assessed by Western blot. CLP-induced acute liver injury was distinct at 24 h post-operation, with the highest hepatic cell pyroptosis rate. The pyroptosis rate and liver injury indexes were positively correlated. Western blot showed that the expressions of pyroptosis-related proteins, caspase-1, and NLRP3, were increased. Normal mouse hepatic cells were cultured in vitro and LPS+ATP introduced to establish the cell model of septic acute liver injury. The expressions of caspase-1, NLRP3, IL-1β, and IL-18 in LPS+ATP group were significantly higher than the control group by Western blot and ELISA. The inhibitors of NLRP3 (Glyburide) and caspase-1 (AC-YVAD-CMK) alone or in combination were used to pre-treat the hepatic cells, which revealed that the pyroptosis rate was decreased and the cell damage alleviated. The in vivo assay in rats showed that post inhibitor treatment, the 10-days survival was significantly improved and the liver damage reduced. Therefore, inhibiting the hepatic cell pyroptosis could alleviate CLP-induced acute liver injury, providing a novel treatment target for septic acute liver injury. PMID:28078039

  3. Comparison of the bioavailability of quercetin and catechin in rats.

    PubMed

    Manach, C; Texier, O; Morand, C; Crespy, V; Régérat, F; Demigné, C; Rémésy, C

    1999-12-01

    Quercetin and catechin are present in noticeable amounts in human diet and these polyphenolic compounds are supposed to exert beneficial effects on human health. However, their metabolic fates in the organism have never been compared. In the present study, rats were fed a 0.25% quercetin or a 0.25% catechin diet. Quercetin and catechin metabolites were analyzed in plasma and liver samples by high-performance liquid chromatography coupled to an ultraviolet or a multielectrode coulometric detection. All plasma metabolites were present as conjugated forms, but catechin metabolites were mainly constituted by glucuronidated derivatives, whereas quercetin metabolites were sulfo- and glucurono-sulfo conjugates. Quercetin was more intensively methylated than catechin in plasma. The plasma quercetin metabolites are well maintained during the postabsorptive period (approximately 50 microM), whereas the concentration of catechin metabolites dropped dramatically between 12- and 24-h after an experimental meal (from 38.0 to 4.5 microM). In the liver, the concentrations of quercetin and catechin derivatives were lower than in plasma, and no accumulation was observed when the rats were adapted for 14 d to the supplemented diets. The hepatic metabolites were intensively methylated (90-95%), but in contrast to plasma, some free aglycones could be detected. Thus, it clearly appears that studies dealing with the biological impact of these polyphenols should take into account the feature of their bioavailability, particularly the fact that their circulating metabolites are conjugated derivatives.

  4. A novel cystine based antioxidant attenuates oxidative stress and hepatic steatosis in diet-induced obese mice

    PubMed Central

    Sinha-Hikim, Indrani; Sinha-Hikim, Amiya P.; Shen, Ruoqing; Kim, H.; French, Samuel W.; Vazari, Nostrola D.; Crum, Albert; Rajavashisth, Tripathi B.; Norris, Keith C.

    2011-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver pathologies and is associated with obesity and the metabolic syndrome. Here, we investigated the molecular mechanisms by which a novel cystine based glutathione precursor with added selenomethionine (F1) prevents hepatic steatosis in a moderate high fat dietary model of NAFLD. Adult (8 weeks old), male apolipoprotein E (ApoE)−/− mice were fed with a normal diet (ND) or high fat diet (HFD), consisting of 21% fat and 0.21% cholesterol, with or without dietary supplementation of F1 (3 g/kg food) for 16 weeks. Compared with ApoE−/− mice fed with ND with or without F1, ApoE−/− mice fed with HFD exhibited significant weight gain, hepatomegaly, and increased serum cholesterol and triglycerides levels with no change in serum albumin levels. High resolution light and electron microscopy revealed micro-and macro-vesicular steatosis in ApoE−/− mice fed on a HFD. HFD- induced obesity also led to increased lipogenesis, oxidative stress, activation of c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), perturbation of the BAX/BCL-2 rheostat, hepatocyte apoptosis, and activation of caspases 9 and 3. F1 fully prevented the adverse effects of HFD on serum triglyceride levels, body and liver weights, and hepatic steatosis and substantially attenuated HFD-induced increase in lipogenesis, oxidative stress, kinase activation, apoptotic signaling, and hepatocyte ultrastructural abnormalities. These results demonstrate that administration of F1, a glutathione precursor, ameliorates HFD-induced hepatic steatosis in ApoE−/− mice and emphasizes the role of oxidative stress in diet-induced obesity and hepatic steatosis. PMID:21570964

  5. NHERF-1 knockout mice have an attenuated hepatic inflammatory response and are protected from cholestatic liver injury

    PubMed Central

    Li, Man; Mennone, Albert; Soroka, Carol J.; Hagey, Lee R.; Ouyang, Xinshou; Weinman, Edward J.; Boyer, James L.

    2015-01-01

    The intercellular adhesion molecule-1 (ICAM-1) is induced in mouse liver after bile duct ligation (BDL) and plays a key role in neutrophil-mediated liver injury in BDL mice. ICAM-1 has been shown to interact with the cytoskeletal ezrin-radixin-moesin (ERM) proteins that also interact with the PDZ protein, Na+/H+ exchanger regulatory factor 1 (NHERF-1/EBP50). In NHERF-1−/− mice, ERM proteins are significantly reduced in brush border membranes from kidney and small intestine. ERM knockdown reduces ICAM-1 expression in response to TNF-α. Here we show that NHERF-1 assembles ERM proteins, ICAM-1 and F-actin into a macromolecule complex that is increased in mouse liver after BDL. Compared with wild-type (WT) mice, both sham-operated and BDL NHERF-1−/− mice have lower levels of activated ERM and ICAM-1 protein in the liver accompanied by significantly reduced hepatic neutrophil accumulation, serum ALT, and attenuated liver injury after BDL. However, total bile acid concentrations in the serum and liver of sham and BDL NHERF-1−/− mice were not significantly different from the WT controls, although hepatic tetrahydroxylated bile acids and Cyp3a11 mRNA levels were higher in NHERF-1−/− BDL mice. Conclusion NHERF-1 participates in the inflammatory response that is associated with BDL induced liver injury. Deletion of NHERF-1 in mice leads to disruption of the formation of ICAM-1-ERM-NHERF-1 complex and reduction of hepatic ERM proteins and ICAM-1, molecules that are up-regulated and are essential for neutrophil-mediated liver injury in cholestasis. Further study of the role of NHERF-1 in the inflammatory response in cholestasis and other forms of liver injury should lead to discovery of new therapeutic targets in hepatic inflammatory diseases. PMID:26108984

  6. Olive leaf extract attenuates cardiac, hepatic, and metabolic changes in high carbohydrate-, high fat-fed rats.

    PubMed

    Poudyal, Hemant; Campbell, Fiona; Brown, Lindsay

    2010-05-01

    Olive oil, an important component of the Mediterranean diet, produces cardioprotective effects, probably due to both oleic acid and the polyphenols such as oleuropein and hydroxytyrosol. Our aim in this study was to assess whether a polyphenol-enriched extract from the leaves of Olea europaea L. with oleuropein as the major component attenuated the cardiovascular, hepatic, and metabolic signs of a high-carbohydrate, high-fat (HCHF) diet (carbohydrate, 52%; fat, 24%, 25% fructose in drinking water) in rats. Male Wistar rats were fed either a cornstarch diet (CS) or a HCHF diet for a total of 16 wk. Diets of the treatment groups [CS+olive leaf extract (OLE) and HCHF+OLE] were supplemented with 3% OLE after 8 wk of being fed their respective CS or HCHF diets for a further 8 wk. After 16 wk, HCHF rats developed signs of metabolic syndrome, including elevated abdominal and hepatic fat deposition, collagen deposition in heart and liver, cardiac stiffness, and oxidative stress markers (plasma malondialdehyde and uric acid concentrations), with diminished aortic ring reactivity, abnormal plasma lipid profile, impaired glucose tolerance, and hypertension. Compared with HCHF rats, those in the HCHF+OLE group had improved or normalized cardiovascular, hepatic, and metabolic signs with the exception of elevated blood pressure. These results strongly suggest that an OLE containing polyphenols such as oleuropein and hydroxytyrosol reverses the chronic inflammation and oxidative stress that induces the cardiovascular, hepatic, and metabolic symptoms in this rat model of diet-induced obesity and diabetes without changing blood pressure.

  7. Aqueous garlic extract attenuates hepatitis and oxidative stress induced by galactosamine/lipoploysaccharide in rats.

    PubMed

    El-Beshbishy, Hesham A

    2008-10-01

    Injection of D-galactosamine and lipopolysaccharide (DGaIN/LPS) is useful as an experimental model of acute hepatic damage. Juvenile rats were used for investigation. The hepatoprotective activity of aqueous garlic (Allium sativum) extract (AGE) at a dose of 300 mg/kg body weight for 14 days, intraperitoneal (i.p.) prior to the induction of DGalN/LPS, was investigated against DGalN/LPS-induced hepatitis in rats. DGalN/LPS (300 mg/kg body weight/30 microg/kg body weight, i.p.), induced hepatic damage that was manifested by a significant increase in the activities of marker enzymes [alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma glutamyl transferase (gamma GT)], bilirubin, lipid peroxides (LPO), tumor necrosis factor (TNF-alpha) and myeloperoxidase (MPO) activity level in serum. Also, the lipid profile in serum and liver homogenate including total cholesterol, triglycerides, free fatty acids and phospholipids were significantly deteriorated. The antioxidant enzyme activities (superoxide dismutase, SOD; reduced glutathione, GSH; catalase, CAT and glutathione peroxidase, GPX) in liver homogenate were significantly decreased in the DGalN/LPS. Pretreatment of rats with AGE reversed these altered parameters near to normal control values. Results of this study revealed that AGE could afford a significant protection in the alleviation of DGalN/LPS-induced hepatic damage.

  8. Salvianolic Acid B Attenuates Rat Hepatic Fibrosis via Downregulating Angiotensin II Signaling

    PubMed Central

    Li, Shu; Wang, Lina; Yan, Xiuchuan; Wang, Qinglan; Tao, Yanyan; Li, Junxia; Peng, Yuan; Liu, Ping; Liu, Chenghai

    2012-01-01

    The renin-angiotensin system (RAS) plays an important role in hepatic fibrosis. Salvianolic acid B (Sal B), one of the water-soluble components from Radix Salviae miltiorrhizae, has been used to treat hepatic fibrosis, but it is still not clear whether the effect of Sal B is related to angiotensin II (Ang II) signaling pathway. In the present study, we studied Sal B effect on rat liver fibrosis and Ang-II related signaling mediators in dimethylnitrosamine-(DMN-) induced rat fibrotic model in vivo and Ang-II stimulated hepatic stellate cells (HSCs) in vitro, with perindopril or losartan as control drug, respectively. The results showed that Sal B and perindopril inhibited rat hepatic fibrosis and reduced expression of Ang II receptor type 1 (AT1R) and ERK activation in fibrotic liver. Sal B and losartan also inhibited Ang II-stimulated HSC activation including cell proliferation and expression of type I collagen I (Col-I) and α-smooth muscle actin (α-SMA) production in vitro, reduced the gene expression of transforming growth factor beta (TGF-β), and downregulated AT1R expression and ERK and c-Jun phosphorylation. In conclusion, our results indicate that Sal B may exert an antihepatic fibrosis effect via downregulating Ang II signaling in HSC activation. PMID:23243430

  9. Hydrogen-Rich Saline Attenuates Cardiac and Hepatic Injury in Doxorubicin Rat Model by Inhibiting Inflammation and Apoptosis

    PubMed Central

    2016-01-01

    Doxorubicin (DOX) remains the most effective anticancer agent which is widely used in several adult and pediatric cancers, but its application is limited for its cardiotoxicity and hepatotoxicity. Hydrogen, as a selective antioxidant, is a promising potential therapeutic option for many diseases. In this study, we found that intraperitoneal injection of hydrogen-rich saline (H2 saline) ameliorated the mortality, cardiac dysfunction, and histopathological changes caused by DOX in rats. Meanwhile, serum brain natriuretic peptide (BNP), aspartate transaminase (AST), alanine transaminase (ALT), albumin (ALB), tissue reactive oxygen species (ROS), and malondialdehyde (MDA) levels were also attenuated after H2 saline treatment. What is more, we further demonstrated that H2 saline treatment could inhibit cardiac and hepatic inflammation and apoptosis relative proteins expressions by western blotting test. In conclusion, our results revealed a protective effect of H2 saline on DOX-induced cardiotoxicity and hepatotoxicity in rats by inhibiting inflammation and apoptosis. PMID:28104928

  10. Glutathione peroxidase 1 deficiency attenuates concanavalin A-induced hepatic injury by modulation of T-cell activation

    PubMed Central

    Lee, D H; Son, D J; Park, M H; Yoon, D Y; Han, S B; Hong, J T

    2016-01-01

    Concanavalin A (Con A)-induced hepatitis model is well-established experimental T cell-mediated liver disease. Reactive oxygen species (ROS) is associated with T-cell activation and proliferation, but continued ROS exposure induces T-cell hyporesponsiveness. Because glutathione peroxidase 1 (Gpx1) is an antioxidant enzyme and is involved in T-cell development, we investigated the role of Gpx1 during Con A-induced liver injury in Gpx1 knockout (KO) mice. Male wild-type (WT) mice and Gpx1 KO mice were intravenously injected with Con A (10 mg/kg), and then killed after 8 h after Con A injection. Serum levels of aspartate transaminase and alanine transaminase were measured to assess hepatic injury. To identify that Gpx1 affects T cell-mediated inflammation, we pretreated Gpx1 inhibitor to Human Jurkat T cells then treated Con A. Con A-induced massive liver damage in WT mice but its damage was attenuated in Gpx1 KO mice. Con A-induced Th1 cytokines such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin (IL)-2 were also decreased in the liver and spleen of Gpx1 KO mice compared with WT mice. In Jurkat T cells, Con A-induced mRNA levels of IL-2, IFN-γ and TNF-α were downregulated by pretreatment of Gpx inhibitor, mercaptosuccinic acid. We also observed that Gpx1 KO mice showed increasing oxidative stress in the liver and spleen compared with WT mice. These results suggest that Gpx1 deficiency attenuates Con A-induced liver injury by induction of T-cell hyporesponsiveness through chronic ROS exposure. PMID:27124582

  11. Conditional Ablation of Mediator Subunit MED1 (MED1/PPARBP) Gene in Mouse Liver Attenuates Glucocorticoid Receptor Agonist Dexamethasone-Induced Hepatic Steatosis

    PubMed Central

    JIA, YUZHI; VISWAKARMA, NAVIN; FU, TAO; YU, SONGTAO; RAO, M. SAMBASIVA; BORENSZTAJN, JAYME; REDDY, JANARDAN K.

    2009-01-01

    Glucocorticoid receptor (GR) agonist dexamethasone (Dex) induces hepatic steatosis and enhances constitutive androstane receptor (CAR) expression in the liver. CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis. Because transcription coactivator MED1/PPARBP gene is required for GR- and CAR-mediated transcriptional activation, we hypothesized that disruption of MED1/PPARBP gene in liver cells would result in the attenuation of Dex-induced hepatic steatosis. Here we show that liver-specific disruption of MED1 gene (MED1ΔLiv) improves Dex-induced steatotic phenotype in the liver. In wild-type mice Dex induced severe hepatic steatosis and caused reduction in medium- and short-chain acyl-CoA dehydrogenases that are responsible for mitochondrial β-oxidation. In contrast, Dex did not induce hepatic steatosis in mice conditionally null for hepatic MED1, as it failed to inhibit fatty acid oxidation enzymes in the liver. MED1ΔLiv livers had lower levels of GR-regulated CAR mRNA compared to wild-type mouse livers. Microarray gene expression profiling showed that absence of MED1 affects the expression of the GR-regulated genes responsible for energy metabolism in the liver. These results establish that absence of MED1 in the liver diminishes Dex-induced hepatic steatosis by altering the GR- and CAR-dependent gene functions. PMID:19630272

  12. Attenuation of Hepatic Graft-versus-host Disease in Allogeneic Recipients of MyD88-deficient Donor Bone Marrow.

    PubMed

    Lim, Ji-Young; Lee, Young-Kwan; Lee, Sung-Eun; Ju, Ji-Min; Park, Gyeongsin; Choi, Eun Young; Min, Chang-Ki

    2015-06-01

    Acute graft-versus-host-disease (GVHD) is characterized by selective damage to the liver, the skin, and the gastrointestinal tract. Following allogeneic hematopoietic stem cell transplantation, donor bone marrow (BM) cells repopulate the immune system of the recipient. We previously demonstrated that the acute intestinal GVHD (iGVHD) mortality rate was higher in MyD88-deficient BM recipients than that in the control BM recipients. In the present study, the role of MyD88 (expressed by donor BM) in the pathophysiology of hepatic GVHD (hGVHD) was examined. Unlike iGVHD, transplantation with MyD88-deficient T-cell depleted (TCD) BM attenuated hGVHD severity and was associated with low infiltration of T cells into the liver of the recipients. Moreover, GVHD hosts, transplanted with MyD88-deficient TCD BM, exhibited markedly reduced expansion of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSC) in the liver. Adoptive injection of the MDSC from wild type mice, but not MyD88-deficient mice, enhanced hepatic T cell infiltration in the MyD88-deficient TCD BM recipients. Pre-treatment of BM donors with LPS increased MDSC levels in the liver of allogeneic wild type BM recipients. In conclusion, hGVHD and iGVHD may occur through various mechanisms based on the presence of MyD88 in the non-T cell compartment of the allograft.

  13. Helenalin attenuates alcohol-induced hepatic fibrosis by enhancing ethanol metabolism, inhibiting oxidative stress and suppressing HSC activation.

    PubMed

    Lin, Xing; Zhang, Shijun; Huang, Renbin; Wei, Ling; Tan, Shimei; Liang, Shuang; Tian, Yuanchun; Wu, Xiaoyan; Lu, Zhongpeng; Huang, Quanfang

    2014-06-01

    A compound was isolated from Centipeda minima using bioassay-guided screening. The structure of this compound was elucidated based on its spectral data, and it was identified as helenalin. The hepatoprotective effect of helenalin was evaluated using a liver fibrosis model induced by intragastric administration with alcohol within 24 weeks in rats. The results revealed that helenalin significantly prevented alcohol-induced hepatic injury and fibrogenesis, as evidenced by the decrease in serum aminotransferase, the attenuation of histopathological changes, and the inhibition of the hepatic fibrosis indicators, such as hyaluronic acid, type III precollagen, laminin, hydroxyproline and collagen α type I. Mechanistically, studies showed that helenalin expedited ethanol metabolism by enhancing the alcohol and aldehyde dehydrogenase activities. Furthermore, helenalin alleviated lipid peroxidation, recruited the antioxidative defense system, inhibited CYP2E1 activity, and reduced the inflammatory mediators, including TGF-β1, TNF-α, IL-6 and IL-1β and myeloperoxidase, via down-regulation of NF-κB. Helenalin significantly decreased collagen deposition by reducing the profibrotic cytokines like transforming growth factor-β, platelet-derived growth factor-β and connective tissue growth factor, and promoted extracellular matrix degradation by modulating the levels of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9. In addition, helenalin inhibited HSC activation as evidenced by the down-regulation of α-SMA and TGF-β levels. In conclusion, helenalin had a significant protective effect on chronic ethanol-induced hepatic fibrosis and may be a major bioactive ingredient of C. minima.

  14. Proatherogenic macrophage activities are targeted by the flavonoid quercetin.

    PubMed

    Lara-Guzman, Oscar J; Tabares-Guevara, Jorge H; Leon-Varela, Yudy M; Álvarez, Rafael M; Roldan, Miguel; Sierra, Jelver A; Londoño-Londoño, Julian A; Ramirez-Pineda, Jose R

    2012-11-01

    Many studies have demonstrated that the flavonoid quercetin protects against cardiovascular disease (CVD) and related risk factors. Atherosclerosis, the underlying cause of CVD, is also attenuated by oral quercetin administration in animal models. Although macrophages are key players during fatty streak formation and plaque progression and aggravation, little is known about the effects of quercetin on atherogenic macrophages. Here, we report that primary bone marrow-derived macrophages internalized less oxidized low-density lipoprotein (oxLDL) and accumulated less intracellular cholesterol in the presence of quercetin. This reduction of foam cell formation correlated with reduced surface expression of the oxLDL receptor CD36. Quercetin also targeted the lipopolysaccharide-dependent, oxLDL-independent pathway of lipid droplet formation in macrophages. In oxLDL-stimulated macrophages, quercetin inhibited reactive oxygen species production and interleukin (IL)-6 secretion. In a system that evaluated cholesterol crystal-induced IL-1β secretion via nucleotide-binding domain and leucine-rich repeat containing protein 3 inflammasome activation, quercetin also exhibited an inhibitory effect. Dyslipidemic apolipoprotein E-deficient mice chronically treated with intraperitoneal quercetin injections had smaller atheromatous lesions, reduced lipid deposition, and less macrophage and T cell inflammatory infiltrate in the aortic roots than vehicle-treated animals. Serum levels of total cholesterol and the lipid peroxidation product malondialdehyde were also reduced in these mice. Our results demonstrate that quercetin interferes with both key proatherogenic activities of macrophages, namely foam cell formation and pro-oxidant/proinflammatory responses, and these effects may explain the atheroprotective properties of this common flavonoid.

  15. Hepatic FTO expression is increased in NASH and its silencing attenuates palmitic acid-induced lipotoxicity.

    PubMed

    Lim, Andrea; Zhou, Jin; Sinha, Rohit A; Singh, Brijesh K; Ghosh, Sujoy; Lim, Kiat-Hon; Chow, Pierce Kah-Hoe; Woon, Esther C Y; Yen, Paul M

    2016-10-21

    Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver failure worldwide. It is characterized by excess fat accumulation, inflammation, and increased lipotoxicity in hepatocytes. Currently, there are limited treatment options for NASH due to lack of understanding of its molecular etiology. In the present study, we demonstrate that the expression of fat mass and obesity associated gene (FTO) is significantly increased in the livers of NASH patients and in a rodent model of NASH. Furthermore, using human hepatic cells, we show that genetic silencing of FTO protects against palmitate-induced oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis in vitro. Taken together, our results show that FTO may have a deleterious role in hepatic cells during lipotoxic conditions, and strongly suggest that up-regulation of FTO may contribute to the increased liver damage in NASH.

  16. Bamboo salt attenuates CCl4-induced hepatic damage in Sprague-Dawley rats.

    PubMed

    Zhao, Xin; Song, Jia-Le; Kil, Jeung-Ha; Park, Kun-Young

    2013-08-01

    Bamboo salt, a Korean folk medicine, is prepared with solar salt (sea salt) and baked several times at high temperatures in a bamboo case. In this study, we compared the preventive effects of bamboo salt and purified and solar salts on hepatic damage induced by carbon tetrachloride in Sprague-Dawley rats. Compared with purified and solar salts, bamboo salts prevented hepatic damage in rats, as evidenced by significantly reduced serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase (P < 0.05). Bamboo salt (baked 9×) triggered the greatest reduction in these enzyme levels. In addition, it also reduced the levels of the proinflammatory cytokines interleukin (IL)-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. Histopathological sections of liver tissue demonstrated the protective effect of bamboo salt, whereas sections from animals treated with the other salt groups showed a greater degree of necrosis. We also performed reverse transcription-polymerase chain reaction and western blot analyses of the inflammation-related genes iNOS, COX-2, TNF-α, and IL-1β in rat liver tissues. Bamboo salt induced a significant decrease (~80%) in mRNA and protein expression levels of COX-2, iNOS, TNF-α, and IL-1β, compared with the other salts. Thus, we found that baked bamboo salt preparations could prevent CCl4-induced hepatic damage in vivo.

  17. Ginsenoside Rc from Korean Red Ginseng (Panax ginseng C.A. Meyer) Attenuates Inflammatory Symptoms of Gastritis, Hepatitis and Arthritis.

    PubMed

    Yu, Tao; Rhee, Man Hee; Lee, Jongsung; Kim, Seung Hyung; Yang, Yanyan; Kim, Han Gyung; Kim, Yong; Kim, Chaekyun; Kwak, Yi-Seong; Kim, Jong-Hoon; Cho, Jae Youl

    2016-01-01

    Korean Red Ginseng (KRG) is an herbal medicine prescribed worldwide that is prepared from Panax ginseng C.A. Meyer (Araliaceae). Out of ginseng's various components, ginsenosides are regarded as the major ingredients, exhibiting anticancer and anti-inflammatory activities. Although recent studies have focused on understanding the anti-inflammatory activities of KRG, compounds that are major anti-inflammatory components, precisely how these can suppress various inflammatory processes has not been fully elucidated yet. In this study, we aimed to identify inhibitory saponins, to evaluate the in vivo efficacy of the saponins, and to understand the inhibitory mechanisms. To do this, we employed in vitro lipopolysaccharide-treated macrophages and in vivo inflammatory mouse conditions, such as collagen (type II)-induced arthritis (CIA), EtOH/HCl-induced gastritis, and lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-triggered hepatitis. Molecular mechanisms were also verified by real-time PCR, immunoblotting analysis, and reporter gene assays. Out of all the ginsenosides, ginsenoside Rc (G-Rc) showed the highest inhibitory activity against the expression of tumor necrosis factor (TNF)-[Formula: see text], interleukin (IL)-1[Formula: see text], and interferons (IFNs). Similarly, this compound attenuated inflammatory symptoms in CIA, EtOH/HCl-mediated gastritis, and LPS/D-galactosamine (D-GalN)-triggered hepatitis without altering toxicological parameters, and without inducing gastric irritation. These anti-inflammatory effects were accompanied by the suppression of TNF-[Formula: see text] and IL-6 production and the induction of anti-inflammatory cytokine IL-10 in mice with CIA. G-Rc also attenuated the increased levels of luciferase activity by IRF-3 and AP-1 but not NF-[Formula: see text]B. In support of this phenomenon, G-Rc reduced TBK1, IRF-3, and ATF2 phosphorylation in the joint and liver tissues of mice with hepatitis. Therefore, our results strongly suggest that

  18. Interleukin-22 ameliorates liver fibrogenesis by attenuating hepatic stellate cell activation and downregulating the levels of inflammatory cytokines

    PubMed Central

    Lu, Dong-Hong; Guo, Xiao-Yun; Qin, Shan-Yu; Luo, Wei; Huang, Xiao-Li; Chen, Mei; Wang, Jia-Xu; Ma, Shi-Jia; Yang, Xian-Wen; Jiang, Hai-Xing

    2015-01-01

    AIM: To investigate the effect of interleukin (IL)-22 on hepatic fibrosis in mice and the possible mechanism involved. METHODS: Liver fibrosis was induced in male BALB/c mice by CCl4. Recombinant IL-22 (rmIL-22) was administered intraperitoneally in CCl4-treated mice. Fibrosis was assessed by histology and Masson staining. The activation of hepatic stellate cells (HSCs) was investigated by analysis of α-smooth muscle actin expression. The frequencies of T helper (Th) 22 cells, Th17 cells and Th1 cells, the expression of inflammatory cytokines [IL-22, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, IL-1β] and transcription factors [aryl hydrocarbon receptor (AHR), RAR-related orphan receptor (RORγt), T-bet] mRNA in the liver were investigated. In addition, the plasma levels of IL-22, IL-17A, IFN-γ, TNF-α, IL-6 and IL-1β were evaluated. RESULTS: Significant elevations in circulating Th22 cells, Th17 cells, Th1 cells, IL-22, IL-17A, and IFN-γ were observed in the hepatic fibrosis group compared with the control group (P < 0.01). Treatment with rmIL-22 in mice with hepatic fibrosis ameliorated the severity of hepatic fibrosis, which was confirmed by lower hepatic fibrosis pathological scores (P < 0.01). RmIL-22 decreased the frequencies of Th22 cells (6.71% ± 0.97% vs 8.09% ± 0.74%, P < 0.01), Th17 cells (4.34% ± 0.37% vs 5.71% ± 0.24%, P < 0.01), Th1 cells (3.09% ± 0.49% vs 4.91% ± 0.73%, P < 0.01), and the levels of IL-22 (56.23 ± 3.08 vs 70.29 ± 3.01, P < 0.01), IL-17A (30.74 ± 2.77 vs 45.68 ± 2.71, P < 0.01), and IFN-γ (74.78 ± 2.61 vs 124.89 ± 2.82, P < 0.01). Down-regulation of IL-22, IL-17A, IFN-γ, TNF-α, IL-6, IL-1β, AHR RORγt, and T-bet gene expression in the liver was observed in the rmIL-22 group (P < 0.01). CONCLUSION: The frequencies of Th22, Th17 and Th1 cells are elevated in hepatic fibrosis. RmIL-22 can attenuate HSC activation and down-regulate the levels of inflammatory cytokines, thereby ameliorating

  19. Different profiles of quercetin metabolites in rat plasma: comparison of two administration methods.

    PubMed

    Kawai, Yoshichika; Saito, Satomi; Nishikawa, Tomomi; Ishisaka, Akari; Murota, Kaeko; Terao, Junji

    2009-03-23

    The bioavailability of polyphenols in human and rodents has been discussed regarding their biological activity. We found different metabolite profiles of quercetin in rat plasma between two administration procedures. A single intragastric administration (50 mg/kg) resulted in the appearance of a variety of metabolites in the plasma, whereas only a major fraction was detected by free access (1% quercetin). The methylated/non-methylated metabolites ratio was much higher in the free access group. Mass spectrometric analyses showed that the fraction from free access contained highly conjugated quercetin metabolites such as sulfo-glucuronides of quercetin and methylquercetin. The metabolite profile of human plasma after an intake of onion was similar to that with intragastric administration in rats. In vitro oxidation of human low-density lipoprotein showed that methylation of the catechol moiety of quercetin significantly attenuated the antioxidative activity. These results might provide information about the bioavailability of quercetin when conducting animal experiments.

  20. Antagonism of quercetin against tremor induced by unilateral striatal lesion of 6-OHDA in rats.

    PubMed

    Mu, Xin; Yuan, Xia; Du, Li-Da; He, Guo-Rong; Du, Guan-Hua

    2016-01-01

    Quercetin, a flavonoid present in many plants, is reported to be effective in models of neurodegenerative diseases. The aim of the present study was to evaluate the anti-tremor effects of quercetin in 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. In rats, quercetin had no effect on apomorphine-induced rotations, but it could significantly attenuate muscle tremor of 6-OHDA lesioned rats. Interestingly, quercetin could decrease the burst frequency in a dose- and time-dependent manner. These results suggest that quercetin may have a protective effect on models to mimic muscle tremors of Parkinson's disease. This effect of quercetin may be associated with serotonergic system, but further study is needed.

  1. Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice

    SciTech Connect

    Harris, Todd R.; Bettaieb, Ahmed; Kodani, Sean; Dong, Hua; Myers, Richard; Chiamvimonvat, Nipavan; Haj, Fawaz G.; Hammock, Bruce D.

    2015-07-15

    Liver fibrosis is a pathological condition in which chronic inflammation and changes to the extracellular matrix lead to alterations in hepatic tissue architecture and functional degradation of the liver. Inhibitors of the enzyme soluble epoxide hydrolase (sEH) reduce fibrosis in the heart, pancreas and kidney in several disease models. In this study, we assess the effect of sEH inhibition on the development of fibrosis in a carbon tetrachloride (CCl{sub 4})-induced mouse model by monitoring changes in the inflammatory response, matrix remolding and endoplasmic reticulum stress. The sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was administered in drinking water. Collagen deposition in the liver was increased five-fold in the CCl{sub 4}-treated group, and this was returned to control levels by TPPU treatment. Hepatic expression of Col1a2 and 3a1 mRNA was increased over fifteen-fold in the CCl{sub 4}-treated group relative to the Control group, and this increase was reduced by 50% by TPPU treatment. Endoplasmic reticulum (ER) stress observed in the livers of CCl{sub 4}-treated animals was attenuated by TPPU treatment. In order to support the hypothesis that TPPU is acting to reduce the hepatic fibrosis and ER stress through its action as a sEH inhibitor we used a second sEH inhibitor, trans-4-(4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy)-benzoic acid (t-TUCB), and sEH null mice. Taken together, these data indicate that the sEH may play an important role in the development of hepatic fibrosis induced by CCl{sub 4}, presumably by reducing endogenous fatty acid epoxide chemical mediators acting to reduce ER stress. - Highlights: • We administer an inhibitor of sEH in a CCl4 murine model. • sEH inhibition reduces liver collagen deposition and pro-fibrotic gene expression. • sEH inhibition induces MMP-1a activity.

  2. Garcinia Cambogia attenuates diet-induced adiposity but exacerbates hepatic collagen accumulation and inflammation

    PubMed Central

    Kim, Young-Je; Choi, Myung-Sook; Park, Yong Bok; Kim, Sang Ryong; Lee, Mi-Kyung; Jung, Un Ju

    2013-01-01

    AIM: To investigate long-term effects of Garcinia Cambogia (GC), weight-loss supplement, on adiposity and non-alcoholic fatty liver disease in obese mice. METHODS: Obesity-prone C57BL/6J mice were fed a high-fat diet (HFD, 45 kcal% fat) with or without GC (1%, w/w) for 16 wk. The HFD contained 45 kcal% fat, 20 kcal% protein and 35 kcal% carbohydrate. They were given free access to food and distilled water, and food consumption and body weight were measured daily and weekly, respectively. Data were expressed as the mean ± SE. Statistical analyses were performed using the statistical package for the social science software program. Student’s t test was used to assess the differences between the groups. Statistical significance was considered at P < 0.05. RESULTS: There were no significant changes in body weight and food intake between the groups. However, the supplementation of GC significantly lowered visceral fat accumulation and adipocyte size via inhibition of fatty acid synthase activity and its mRNA expression in visceral adipose tissue, along with enhanced enzymatic activity and gene expression involved in adipose fatty acid β-oxidation. Moreover, GC supplementation resulted in significant reductions in glucose intolerance and the plasma resistin level in the HFD-fed mice. However, we first demonstrated that it increased hepatic collagen accumulation, lipid peroxidation and mRNA levels of genes related to oxidative stress (superoxide dismutase and glutathione peroxidase) and inflammatory responses (tumor necrosis factor-α and monocyte chemoattractant protein-1) as well as plasma alanine transaminase and aspartate transaminase levels, although HFD-induced hepatic steatosis was not altered. CONCLUSION: GC protects against HFD-induced obesity by modulating adipose fatty acid synthesis and β-oxidation but induces hepatic fibrosis, inflammation and oxidative stress. PMID:23922466

  3. Protective effects of branched-chain amino acids on hepatic ischemia-reperfusion-induced liver injury in rats: a direct attenuation of Kupffer cell activation.

    PubMed

    Kitagawa, Tomomi; Yokoyama, Yukihiro; Kokuryo, Toshio; Nagino, Masato

    2013-02-15

    We determined whether there is a protective effect of branched-chain amino acid (BCAA) on hepatic ischemia-reperfusion (I/R)-induced acute liver injury. Wister rats were divided into the following four groups: simple laparotomy with vehicle; simple laparotomy with BCAA (1 g/kg body wt orally); I/R (30 min clamp) with vehicle; and I/R with BCAA. Serum liver function tests and the gene expression of adhesion molecules (intercellular adhesion molecule and vascular cell adhesion molecule) and vasoconstrictor-related genes (endothelin-1) in the liver were examined. In the in vivo study, portal venous pressure, leukocyte adhesion, and hepatic microcirculation were evaluated. Furthermore, Kupffer cells were isolated and cultured with various concentrations of BCAA in the presence or absence of lipopolysaccharide (LPS). Increased levels of liver function tests following I/R were significantly attenuated by BCAA treatment. The increased expression of adhesion molecules and endothelin-1 was also significantly attenuated by BCAA treatment. Moreover, increased portal venous pressure, enhanced leukocyte adhesion, and deteriorated hepatic microcirculation following I/R were all improved by BCAA treatment. In the experiment using isolated Kupffer cells, the expression of interleukin-6, interleukin-1β, and endothelin-1 in response to LPS stimulation was attenuated by BCAA in a dose-dependent fashion. These results indicate that perioperative oral administration of BCAA has excellent therapeutic potential to reduce I/R-induced liver injury. These beneficial effects may result from the direct attenuation of Kupffer cell activation under stressful conditions.

  4. Opuntia ficus-indica seed attenuates hepatic steatosis and promotes M2 macrophage polarization in high-fat diet-fed mice.

    PubMed

    Kang, Jung-Woo; Shin, Jun-Kyu; Koh, Eun-Ji; Ryu, Hyojeong; Kim, Hyoung Ja; Lee, Sun-Mee

    2016-04-01

    Opuntia ficus-indica (L.) is a popular edible plant that possesses considerable nutritional value and exhibits diverse biological actions including anti-inflammatory and antidiabetic activities. In this study, we hypothesized that DWJ504, an extract of O ficus-indica seed, would ameliorate hepatic steatosis and inflammation by regulating hepatic de novo lipogenesis and macrophage polarization against experimental nonalcoholic steatohepatitis. Mice were fed a normal diet or a high-fat diet (HFD) for 10 weeks. DWJ504 (250, 500, and 1000 mg/kg) or vehicle (0.5% carboxymethyl cellulose) were orally administered for the last 4 weeks of the 10-week HFD feeding period. DWJ504 treatment remarkably attenuated HFD-induced increases in hepatic lipid content and hepatocellular damage. DWJ504 attenuated increases in sterol regulatory element-binding protein 1 and carbohydrate-responsive element-binding protein expression and a decrease in carnitine palmitoyltransferase 1A. Although DWJ504 augmented peroxisome proliferator-activated receptor α protein expression, it attenuated peroxisome proliferator-activated receptor γ expression. Moreover, DWJ504 promoted hepatic M2 macrophage polarization as indicated by attenuation of the M1 marker genes and enhancement of M2 marker genes. Finally, DWJ504 attenuated expression of toll-like receptor 4, nuclear factor κB, tumor necrosis factor α, interleukin 6, TIR-domain-containing adapter-inducing interferon β, and interferon β levels. Our results demonstrate that DWJ504 prevented intrahepatic lipid accumulation, induced M2 macrophage polarization, and suppressed the toll-like receptor 4-mediated inflammatory signaling pathway. Thus, DWJ504 has therapeutic potential in the prevention of nonalcoholic fatty liver disease.

  5. Theaflavins attenuate hepatic lipid accumulation through activating AMPK in human HepG2 cells.

    PubMed

    Lin, Chih-Li; Huang, Hsiu-Chen; Lin, Jen-Kun

    2007-11-01

    Black tea is one of the world's most popular beverages, and its health-promoting effects have been intensively investigated. The antiobesity and hypolipidemic effects of black tea have attracted increasing interest, but the mechanisms underlying these phenomena remain unclear. In the present study, the black tea major component theaflavins were assessed for their hepatic lipid-lowering potential when administered in fatty acid overload conditions both in cell culture and in an animal experimental model. We found that theaflavins significantly reduced lipid accumulation, suppressed fatty acid synthesis, and stimulated fatty acid oxidation. Furthermore, theaflavins also inhibited acetyl-coenzyme A carboxylase activities by stimulating AMP-activated protein kinase (AMPK) through the LKB1 and reactive oxygen species pathways. These observations support the idea that AMPK is a critical component of decreased hepatic lipid accumulation by theaflavin treatments. Our results show that theaflavins are bioavailable both in vitro and in vivo and may be active in the prevention of fatty liver and obesity.

  6. Agaricoglycerides Protect against Hepatic Ischemia/Reperfusion Injury by Attenuating Inflammatory Response, Oxidative Stress, and Expression of NF-κB

    PubMed Central

    Zhao, Xiang-qian; Liang, Bin; Liu, Yang; Huang, Xiao-qiang

    2015-01-01

    We have investigated the effects of agaricoglycerides (AG) in a mouse model of hepatic I/R injury. I/R triggered increases/changes in markers of liver injury, hepatic oxidative stress, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and nuclear factor κB (NF-κB). AG significantly reduced the extent of liver inflammation and oxidative stress and also attenuated the NF-κB activation as well as TNF-α and IL-1β production. Our results indicate that AG may represent a novel protective strategy against I/R-induced injury and inflammatory diseases. PMID:25960746

  7. Cerebrolysin attenuates cerebral and hepatic injury due to lipopolysaccharide in rats.

    PubMed

    Abdel-Salam, O M E; Omara, E A; Mohammed, N A; Youness, E R; Khadrawy, Y A; Sleem, A A

    2013-12-01

    This study aimed to investigate the effect of cerebrolysin on oxidative stress in the brain and liver during systemic inflammation. Rats were intraperitoneally challenged with a single subseptic dose of lipopolysaccharide (LPS; 300 μg/kg) without or with cerebrolysin at doses of 21.5, 43 or 86 mg/kg. After 4 h, rats were euthanized and the brain and liver tissues were subjected to biochemical and histopathological analyses. Cerebrolysin revealed inhibitory effects on the elevation of lipid peroxidation and nitric oxide induced by LPS. In contrast, the decrease in reduced glutathione level and paraoxonase activity induced by LPS was attenuated by an injection of cerebrolysin in a dose-dependent manner. Moreover, cerebrolysin reduced LPS-induced activation of brain NF-κB and reversed LPS-induced decline of brain butyrylcholinesterase and acetylcholinesterase activities in a dose-dependent manner. Histopathological analyses revealed that neuronal damage and liver necrosis induced by LPS were ameliorated by cerebrolysin dose-dependently. Cerebrolysin treatment dose-dependently attenuated LPS-induced expressions in cyclooxygenase 2, inducible nitric oxide synthase, and caspase-3 in the cortex or striatum as well as the liver. These results suggest that cerebrolysin treatment might have beneficial therapeutic effects in cerebral inflammation. Cerebrolysin might also prove of value in liver disease and this possibility requires further exploration.

  8. Role of p38 MAPK pathway in 17β-estradiol-mediated attenuation of hemorrhagic shock-induced hepatic injury.

    PubMed

    Hsu, Jun-Te; Chen, Tsung-Hsing; Chiang, Kun-Chun; Kuo, Chia-Jung; Lin, Chun-Jung; Yeh, Ta-Sen

    2015-01-15

    Although 17β-estradiol (E2) treatment following hemorrhagic shock or ischemic reperfusion prevents organs from dysfunction and injury, the precise mechanism remains unknown. We hypothesize that the E2-mediated attenuation of liver injury following hemorrhagic shock and fluid resuscitation occurs via the p38 mitogen-activated protein kinase (MAPK)-dependent heme oxygenase (HO)-1 pathway. After a 5-cm midline laparotomy, male rats underwent hemorrhagic shock (mean blood pressure ∼40 mmHg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, E2 (1 mg/kg) alone, or E2 plus p38 MAPK inhibitor SB-203580 (2 mg/kg), HO-1 inhibitor chromium mesoporphyrin-IX chloride (2.5 mg/kg) or estrogen receptor antagonist ICI 182,780 (3 mg/kg). At 2 h after hemorrhagic shock and fluid resuscitation, the liver injury markers were significantly increased compared with sham-operated control. Hemorrhagic shock resulted in a significant decrease in p38 MAPK phosphorylation compared with the shams. Administration of E2 following hemorrhagic shock normalized liver p38 MAPK phosphorylation, further increased HO-1 expression, and reduced cleaved caspase-3 levels. Coadministration of SB-203580 abolished the E2-mediated attenuation of the shock-induced liver injury markers. In addition, administration of chromium mesoporphyrin-IX chloride or ICI 182,780 abolished E2-mediated increases in liver HO-1 expression or p38 MAPK activation following hemorrhagic shock. Our results collectively suggest that the salutary effects of E2 on hepatic injury following hemorrhagic shock and resuscitation are in part mediated through an estrogen-receptor-related p38 MAPK-dependent HO-1 upregulation.

  9. Chrysin attenuates liver fibrosis and hepatic stellate cell activation through TGF-β/Smad signaling pathway.

    PubMed

    Balta, Cornel; Herman, Hildegard; Boldura, Oana Maria; Gasca, Ionela; Rosu, Marcel; Ardelean, Aurel; Hermenean, Anca

    2015-10-05

    We investigated the protective effect of chrysin on chronic liver fibrosis in mice and the potential mechanism underlying TGF-β1-mediated hepatic stellate cells (HSCs) activation on fibrogenesis. Experimental fibrosis was established by intraperitoneal injection of mice with 20% v/v, 2 ml/kg CCl4 twice a week, for 7 weeks. Mice were orally treated with 3 doses of chrysin (50, 100 and 200 mg/kg) or with vehicle as control. For the assessment of the spontaneous reversion of fibrosis, CCl4 treated animals were investigated after two weeks of recovery time. Silymarin was used as standard hepatoprotective flavonoid. Histopathological investigations showed that hepatic fibrosis grade was markedly reduced in the chrysin groups compared to the fibrotic one. Moreover, CCl4 activated HSCs induced an upregulation of smooth muscle actin (α-SMA), an increased number of TGF-β1 immunopositive cells and marked up-regulation of TGF-β1. α-SMA and TGF-β1 levels were significantly reduced in all chrysin treated groups in a dose-dependent manner, whereas the level of spontaneous reversal of fibrosis was lower compared to all flavonoid treated groups. Liver mRNA levels of Smad 2 in the 50, 100 and 200 mg/kg chrysin treated groups were significantly reduced by about 88.54%, 92.15% and 95.56% of the corresponding levels in the fibrosis mice group. The results were similar for mRNA levels of Smad 3. The protective response to silymarin was almost similar to that seen with the highest doses of chrysin. In this study, we have shown that chrysin has the efficacy to reverse CCl4-stimulated liver fibrosis by inhibition of HSCs activation and proliferation through TGF-β1/Smad pathway. These results suggest that chrysin may be useful in stopping or reversing the progression of liver fibrosis and might offer the possibility to develop a new therapeutic drug, useful in treatment of chronic liver diseases.

  10. Octreotide Attenuates Acute Kidney Injury after Hepatic Ischemia and Reperfusion by Enhancing Autophagy

    PubMed Central

    Sun, Huiping; Zou, Shuangfa; Candiotti, Keith A.; Peng, Yanhua; Zhang, Qinya; Xiao, Weiqiang; Wen, Yiyun; wu, Jiao; Yang, Jinfeng

    2017-01-01

    Octreotide exerts a protective effect in hepatic ischemia-reperfusion (HIR) injury. However, whether octreotide preconditioning could also reduce acute kidney injury (AKI) after HIR is unknown. This study was designed to investigate the role of octreotide in AKI after HIR. Male Sprague-Dawley rats were pretreated with octreotide or octreotide combined with 3-methyladenine (autophagy inhibitor, 3MA). Plasma creatinine, inflammation markers (e.g., TNF-α and IL-6 etc.), apoptosis, autophagy and phosphorylation of protein kinase B/mammalian target of rapamycin/p70 ribosomal S6 kinase (Akt/mTOR/p70S6K) in the kidney were measured after 60 minutes of liver ischemia and 24 hours of reperfusion for each rat. Octreotide pretreatment significantly preserved renal function and reduced the severity of renal injury. Moreover, octreotide alleviated inflammation and apoptosis in the kidney after HIR. Additionally, octreotide induced autophagy and autophagy inhibition with 3MA markedly reversed the renoprotective, anti-inflammatory and anti-apoptotic effects of octreotide after HIR. Finally, octreotide abrogated the activation of phosphorylation of Akt, mTOR and p70S6K in the kidney after HIR. Our results indicate that octreotide reduced renal injury after HIR due to its induction of autophagy. The enhancement of autophagy may be potentially linked to the octreotide mediated Akt/mTOR/p70S6K pathway deactivation and reduction of kidney inflammation and apoptosis after HIR. PMID:28205545

  11. Hesperidin upregulates heme oxygenase-1 to attenuate hydrogen peroxide-induced cell damage in hepatic L02 cells.

    PubMed

    Chen, Ming-Cang; Ye, Yi-Yi; Ji, Guang; Liu, Jian-Wen

    2010-03-24

    Hesperidin, a naturally occurring flavonoid presents in fruits and vegetables, has been reported to exert a wide range of pharmacological effects that include antioxidant, anti-inflammatory, antihypercholesterolemic, and anticarcinogenic actions. However, the cytoprotection and mechanism of hesperidin to neutralize oxidative stress in human hepatic L02 cells remain unclear. In this work, we assessed the capability of hesperidin to attenuate hydrogen peroxide (H(2)O(2))-induced cell damage by augmenting the cellular antioxidant defense. Real-time quantitative polymerase chain reaction, Western blot, and enzyme activity assay demonstrated that hesperidin upregulated heme oxygenase-1 (HO-1) expression to protect hepatocytes against oxidative stress. In addition, hesperidin also promoted nuclear translocation of nuclear factor erythroid 2-related factor (Nrf2). What's more, hesperidin exhibited activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). Besides, ERK1/2 inhibitor significantly inhibited hesperidin-mediated HO-1 upregulation and Nrf2 nuclear translocation. Taken together, the above findings suggested that hesperidin augmented cellular antioxidant defense capacity through the induction of HO-1 via ERK/Nrf2 signaling. Therefore, hesperidin has potential as a therapeutic agent in the treatment of oxidative stress-related hepatocyte injury and liver dysfunctions.

  12. Microbial Transformation of Quercetin by Bacillus cereus

    PubMed Central

    Rao, Koppaka V.; Weisner, Nghe T.

    1981-01-01

    Biotransformation of quercetin was examined with a number of bacterial cultures. In the presence of a bacterial culture (Bacillus cereus), quercetin was transformed into two crystalline products, identified as protocatechuic acid and quercetin-3-glucoside (isoquercitrin). PMID:16345844

  13. Mechanism of estrogen-mediated attenuation of hepatic injury following trauma-hemorrhage: Akt-dependent HO-1 up-regulation.

    PubMed

    Hsu, Jun-Te; Kan, Wen-Hong; Hsieh, Chi-Hsun; Choudhry, Mashkoor A; Schwacha, Martin G; Bland, Kirby I; Chaudry, Irshad H

    2007-10-01

    Protein kinase B (Akt) is known to be involved in proinflammatory and chemotactic events in response to injury. Akt activation also leads to the induction of heme oxygenase (HO)-1. Up-regulation of HO-1 mediates potent, anti-inflammatory effects and attenuates organ injury. Although studies have shown that 17beta-estradiol (E2) prevents organ damage following trauma-hemorrhage, it remains unknown whether Akt/HO-1 plays any role in E2-mediated attenuation of hepatic injury following trauma-hemorrhage. To study this, male rats underwent trauma-hemorrhage (mean blood pressure, approximately 40 mmHg for 90 min), followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, E2 (1 mg/kg body weight), E2 plus the PI-3K inhibitor (Wortmannin), or the estrogen receptor (ER) antagonist (ICI 182,780). At 2 h after sham operation or trauma-hemorrhage, plasma alpha-GST and hepatic tissue myeloperoxidase (MPO) activity, IL-6, TNF-alpha, ICAM-1, cytokine-induced neutrophil chemoattractant-1, and MIP-2 levels were measured. Hepatic Akt and HO-1 protein levels were also determined. Trauma-hemorrhage increased hepatic injury markers (alpha-GST and MPO activity), cytokines, ICAM-1, and chemokine levels. These parameters were markedly improved in the E2-treated rats following trauma-hemorrhage. E2 treatment also increased hepatic Akt activation and HO-1 expression compared with vehicle-treated, trauma-hemorrhage rats, which were abolished by coadministration of Wortmannin or ICI 182,780. These results suggest that the salutary effects of E2 on hepatic injury following trauma-hemorrhage are in part mediated via an ER-related, Akt-dependent up-regulation of HO-1.

  14. Connective tissue growth factor hammerhead ribozyme attenuates human hepatic stellate cell function

    PubMed Central

    Gao, Run-Ping; Brigstock, David R

    2009-01-01

    AIM: To determine the effect of hammerhead ribozyme targeting connective tissue growth factor (CCN2) on human hepatic stellate cell (HSC) function. METHODS: CCN2 hammerhead ribozyme cDNA plus two self-cleaving sequences were inserted into pTriEx2 to produce pTriCCN2-Rz. Each vector was individually transfected into cultured LX-2 human HSCs, which were then stimulated by addition of transforming growth factor (TGF)-β1 to the culture medium. Semi-quantitative RT-PCR was used to determine mRNA levels for CCN2 or collagen I, while protein levels of each molecule in cell lysates and conditioned medium were measured by ELISA. Cell-cycle progression of the transfected cells was assessed by flow cytometry. RESULTS: In pTriEx2-transfected LX-2 cells, TGF-β1 treatment caused an increase in the mRNA level for CCN2 or collagen I, and an increase in produced and secreted CCN2 or extracellular collagen I protein levels. pTriCCN2-Rz-transfected LX-2 cells showed decreased basal CCN2 or collagen mRNA levels, as well as produced and secreted CCN2 or collagen I protein. Furthermore, the TGF-β1-induced increase in mRNA or protein for CCN2 or collagen I was inhibited partially in pTriCCN2-Rz-transfected LX-2 cells. Inhibition of CCN2 using hammerhead ribozyme cDNA resulted in fewer of the cells transitioning into S phase. CONCLUSION: Endogenous CCN2 is a mediator of basal or TGF-β1-induced collagen I production in human HSCs and regulates entry of the cells into S phase. PMID:19673024

  15. Osthol attenuates hepatic steatosis via decreased triglyceride synthesis not by insulin resistance

    PubMed Central

    Nam, Ho Hyun; Jun, Dae Won; Jeon, Hye Joon; Lee, Jai Sun; Saeed, Waqar Khalid; Kim, Eun Kyung

    2014-01-01

    AIM: To evaluate the effects of osthol on intrahepatic fat synthesis, β-oxidation, inflammation, and insulin resistance by multifaceted analysis. METHODS: Sprague-Dawley rats (n = 30) were randomly divided into control, non-alcoholic fatty liver disease (NAFLD), and osthol groups. NAFLD and osthol groups were fed with a high-fat diet for 14 wk. After 8 wk of the high-fat diet, the osthol group also received osthol 20 mg/kg orally 5 times/wk. To assess the insulin resistance, oral glucose tolerance was performed at the end of 14 wk. Immunohistochemical (4-HNE, F4/80) and hematoxylin and eosin (HE) staining were performed on liver tissue extracts after animal sacrifice at 14 wk. SREBP1c, FAS, SCD-1, PPAR-α, CROT, MCP-1, IRS-1, and IRS-2 mRNA expressions were assessed with reverse transcription-polymerase chain reaction. RESULTS: HE staining revealed that, compared with the NAFLD group, the osthol group showed significantly decreased intrahepatic fat content (39.4% vs 21.0%; P = 0.021). SREBP1c expression in the NAFLD group increased compared to controls (P = 0.0001), while osthol treatment decreased SREBP1c expression compared with the NAFLD group (P = 0.0059). In the osthol group, intrahepatic FAS and SCD-1, which act downstream of SREBP1c, decreased significantly compared with the NAFLD group. Moreover, PPAR-α expression in the osthol group was also significantly higher than in the NAFLD group (P = 0.0147). CONCLUSION: Osthol treatment attenuated liver steatosis by decreasing de novo liver triglyceride synthesis and had nominal effects on insulin resistance and liver inflammation. PMID:25206279

  16. Tetramethylpyrazine attenuates carbon tetrachloride-caused liver injury and fibrogenesis and reduces hepatic angiogenesis in rats.

    PubMed

    Zhao, Shifeng; Zhang, Zili; Qian, Linnan; Lin, Qiuyi; Zhang, Chenxi; Shao, Jiangjuan; Zhang, Feng; Zheng, Shizhong

    2017-02-01

    Liver fibrosis represents a frequent event following chronic insult to trigger wound healing reactions with abnormalities of angiogenesis in the liver. Capillarization of liver sinusoidal endothelial cell (LSEC) is the pivotal event during liver angiogenesis. In the current study, we sought to investigate the effect of tetramethylpyrazine (TMP) on carbon tetrachloride (CCl4)-induced liver injury and fibrosis in rats, and to further examine the molecular mechanisms of TMP-induced anti-angiogenic effect. We found that TMP significantly ameliorated histopathological feature of liver fibrosis characterized by decreased collagen deposition, hepatocyte apoptosis, and expression of biochemical indicators, such as aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Moreover, TMP appeared to play an essential role in controlling pathological angiogenesis. In addition, TMP attenuated angiogenesis by downregulation of vascular endothelial growth factor-A (VEGF-A), vascular endothelial growth factor receptor 2 (VEGF-R2), platelet-derived growth factor-BB (PDGF-BB), and platelet-derived growth factor-β receptor (PDGF-βR), four important factors transmitting pro-angiogenic pathways. Besides, TMP inhibited LSEC capillarization in CCl4-induced liver fibrotic model with the morphological features of increasing sinusoidal fenestrae. Importantly, we found that disruption of angiogenesis is required for TMP to inhibit hepatocyte apoptosis in rats. Treatment with TMP significantly inhibited the expression of Bax, and up-regulated Bcl-2 expression. Interestingly, treatment with angiogenesis-inducer AngII dramatically eliminated the effect of TMP on Bax/Bcl-2 axis. Overall, these results provide novel perspectives to reveal the protective effect of TMP on liver, opening up the possibility of using TMP based anti-angiogenic drugs for the liver diseases.

  17. Rosiglitazone, a PPAR-γ agonist, fails to attenuate CLA-induced milk fat depression and hepatic lipid accumulation in lactating mice.

    PubMed

    Vyas, Diwakar; Teter, Beverly B; Delmonte, Pierluigi; Erdman, Richard A

    2014-07-01

    Our objective was to investigate the combination of rosiglitazone (ROSI) and conjugated linoleic acid (CLA) on mammary and hepatic lipogenesis in lactating C57Bl/6 J mice. Twenty-four lactating mice were randomly assigned to one of four treatments applied from postpartum day 6 to day 10. Treatments included: (1) control diet, (2) control plus 1.5 % dietary CLA (CLA) substituted for soybean oil, (3) control plus daily intra-peritoneal (IP) rosiglitazone injections (10 mg/kg body weight) (ROSI), and (4) CLA plus ROSI (CLA-ROSI). Dam food intake and milk fat concentration were depressed with CLA. However, no effects were observed with ROSI. The CLA-induced milk fat depression was due to reduced expression for mammary lipogenic genes involved in de-novo fatty acid (FA) synthesis, FA uptake and desaturation, and triacyglycerol synthesis. Liver weight (g/100 g body weight) was increased by CLA due to an increase in lipid accumulation triggering a compensatory reduction in mRNA abundance of hepatic lipogenic enzymes, including acetyl-CoA carboxylase I and stearoyl-CoA desaturase I. On the contrary, no effects were observed with ROSI on hepatic and mammary lipogenic gene and enzyme expression. Overall, feeding CLA to lactating mice induced milk fat depression and increased hepatic lipid accumulation, probably due to the presence of trans-10, cis-12 CLA isomer, while ROSI failed to significantly attenuate both hepatic steatosis and reduction in milk fat content.

  18. Hepatic arterial administration of sorafenib and iodized oil effectively attenuates tumor growth and intrahepatic metastasis in rabbit VX2 hepatocellular carcinoma model

    PubMed Central

    Zhang, Lin; Liu, Feng-Yong; Fu, Jin-Xin; Duan, Feng; Fan, Qing-Sheng; Wang, Mao-Qiang

    2014-01-01

    Aim: To investigate the therapeutic effect of the hepatic arterial administration of sorafenib in rabbit VX-2 hepatocellular carcinoma (HCC) model. Methods: Rabbit VX-2 HCC models were established via implanting VX-2 tumors into the livers, and randomly divided into four groups, respectively treated with (1) The hepatic arterial administration of iodized oil alone (TACE-i), (2) The hepatic arterial administration of iodized oil and pharmorubicin (TACE-ip), (3) The hepatic arterial administration of iodized and cis-DDP (TACE-ic), (4) The hepatic arterial administration of iodized and sorafenib (TACE-is). The growth rate and intrahepatic metastasis of implanted VX-2 tumor in each rabbit were measured. Microvessel density (MVD) in the adjacent tissues of implanted VX-2 tumor were estimated by detecting the expression of CD34 and VEGF level in tumor adjacent tissues were also examined by Immunohistochemistry. Results: Compared with other groups, TACE-is treatment group presented a better effect on inhibiting tumor growth rate and intrahepatic metastasis in rabbit VX-2 HCC model. The angiogenesis (assessed by MVD) in the adjacent tissues were suppressed more dramatically in TACE-is treated group. Moreover, TACE-is treatment did not significantly increase the levels of alanine transaminase and creatinine compared to the group with TACE-i treatment. Conclusion: The hepatic arterial administration of sorafenib and iodized oil (TACE-is) effectively attenuates tumor growth and intrahepatic metastasis in rabbit VX-2 HCC model without obvious hepatic and renal toxicity. One of the related mechanisms may be due to the inhibition of angiogenesis in the adjacent tissues. Our data indicated that TACE-is may be a secure and effective treatment for HCC. PMID:25550815

  19. Adenoviral overexpression of Lhx2 attenuates cell viability but does not preserve the stem cell like phenotype of hepatic stellate cells

    SciTech Connect

    Genz, Berit; Thomas, Maria; Pützer, Brigitte M.; Siatkowski, Marcin; Fuellen, Georg; Vollmar, Brigitte; Abshagen, Kerstin

    2014-11-01

    Hepatic stellate cells (HSC) are well known initiators of hepatic fibrosis. After liver cell damage, HSC transdifferentiate into proliferative myofibroblasts, representing the major source of extracellular matrix in the fibrotic organ. Recent studies also demonstrate a role of HSC as progenitor or stem cell like cells in liver regeneration. Lhx2 is described as stem cell maintaining factor in different organs and as an inhibitory transcription factor in HSC activation. Here we examined whether a continuous expression of Lhx2 in HSC could attenuate their activation and whether Lhx2 could serve as a potential target for antifibrotic gene therapy. Therefore, we evaluated an adenoviral mediated overexpression of Lhx2 in primary HSC and investigated mRNA expression patterns by qRT-PCR as well as the activation status by different in vitro assays. HSC revealed a marked increase in activation markers like smooth muscle actin alpha (αSMA) and collagen 1α independent from adenoviral transduction. Lhx2 overexpression resulted in attenuated cell viability as shown by a slightly hampered migratory and contractile phenotype of HSC. Expression of stem cell factors or signaling components was also unaffected by Lhx2. Summarizing these results, we found no antifibrotic or stem cell maintaining effect of Lhx2 overexpression in primary HSC. - Highlights: • We performed adenoviral overexpression of Lhx2 in primary hepatic stellate cells. • Hepatic stellate cells expressed stem cell markers during cultivation. • Cell migration and contractility was slightly hampered upon Lhx2 overexpression. • Lhx2 overexpression did not affect stem cell character of hepatic stellate cells.

  20. Docosahexaenoic acid attenuates Western diet-induced hepatic fibrosis in Ldlr−/− mice by targeting the TGFβ-Smad3 pathway[S

    PubMed Central

    Lytle, Kelli A.; Depner, Christopher M.; Wong, Carmen P.; Jump, Donald B.

    2015-01-01

    DHA (22:6,ω3), but not EPA (20:5,ω3), attenuates Western diet (WD)-induced hepatic fibrosis in a Ldlr−/− mouse model of nonalcoholic steatohepatitis. We examined the molecular basis for the differential effect of dietary EPA and DHA on WD-induced hepatic fibrosis. DHA was more effective than EPA at preventing WD-induced effects on hepatic transcripts linked to fibrosis, including collagen 1A1 (Col1A1), transforming growth factor-β (TGFβ) signaling and proteins involved in remodeling the extracellular matrix, including metalloproteases, tissue inhibitors of metalloproteases, and lysyl oxidase subtypes. Examination of the TGFβ pathway showed that mice fed the WD supplemented with either olive oil or EPA had a significant (≥2.5-fold) increase in hepatic nuclear abundance of phospho-mothers against decapentaplegic homolog (Smad)3 when compared with mice fed the reference diet (RD); Smad3 is a key regulator of Col1A1 expression in stellate cells. In contrast, mice fed the WD supplemented with DHA had no increase in phospho-Smad3 when compared with mice fed the RD. Changes in hepatic phospho-Smad3 nuclear content correlated with proCol1A1 mRNA and protein abundance. Pretreatment of human LX2 stellate cells with DHA, but not other unsaturated fatty acids, blocked TGFβ1-mediated induction of Col1A1. In conclusion, DHA attenuates WD-induced fibrosis by targeting the TGFβ-Smad3-Col1A1 pathway in stellate cells. PMID:26315048

  1. Protective Effect of Quercetin on Posttraumatic Cardiac Injury

    PubMed Central

    Jing, Zehao; Wang, Zhuorun; Li, Xiujie; Li, Xintao; Cao, Tingting; Bi, Yue; Zhou, Jicheng; Chen, Xu; Yu, Deqin; Zhu, Liang; Li, Shuzhuang

    2016-01-01

    Quercetin is an important dietary flavonoid present in fruits and vegetables and has attracted attention because of its anti-inflammatory and anti-oxidative properties. Inflammation and oxidative stress play important roles in posttraumatic cardiomyocyte apoptosis, which contributes to secondary cardiac dysfunction. This study investigates the protective effect of quercetin on trauma-induced secondary cardiac injury and the mechanisms involved. Widely accepted nonlethal mechanical trauma models were established. In vivo, cardiomyocyte apoptosis and cardiac dysfunction in rats were assessed using TUNEL staining and a biological mechanic experiment system. In vitro, cell viability, tumour necrosis factor-α (TNF-α), reactive oxygen species (ROS) and [Ca2+]i of H9c2 cells were detected using an MTT assay, ELISA, and 2′,7′-dichlorofluorescin diacetate and fluo-4 acetoxymethyl ester assays respectively. Quercetin pretreatment (20 mg/kg i.p.; 0.5 h before trauma) significantly improved posttraumatic cardiomyocyte apoptosis and cardiac dysfunction. Pretreatment with quercetin (20 μM; 24 h before trauma plasma addition) significantly attenuated trauma-induced viability decreases, TNF-α increases, ROS overproduction and [Ca2+]i overload in H9c2 cells. In conclusion, quercetin may reverse posttraumatic cardiac dysfunction by reducing cardiomyocyte apoptosis through the suppression of TNF-α increases, ROS overproduction and Ca2+ overload in cardiomyocytes, representing a potential preventive approach for the treatment of secondary cardiac injury after mechanical trauma. PMID:27470932

  2. Modulation of BV-2 microglia functions by novel quercetin pivaloyl ester.

    PubMed

    Mrvová, Nataša; Škandík, Martin; Kuniaková, Marcela; Račková, Lucia

    2015-11-01

    Chronic inflammation in brain plays a critical role in major neurodegenerative diseases such as Alzheimer's, Parkinson's disease, stroke or multiple sclerosis. Microglia, resident macrophages and intristinc components of CNS, appear to be main effectors in this pathological process. Quercetin, a naturally occurring flavonoid, was proven to downregulate inflammatory genes in microglia. Synthetically modified quercetin, 3'-O-(3-chloropivaloyl) quercetin (CPQ), is assumed to possess better biological availability and enhanced antioxidant properties. In the present study, antineuroinflammatory capability of the novel compound CPQ was assessed in BV-2 microglial cells. Our data show that treatment with CPQ attenuated the production of the inflammatory mediators, nitric oxide (NO) and tumour necrosis factor-α (TNF-α), in LPS-stimulated microglia somewhat more efficiently than did quercetin (p > 0.05 for CPQ vs. quercetin-treated group). Also, protein level of inducible NO synthase (iNOS) in LPS-activated BV-2 microglia was to some extent more effectively supressed by CPQ than by unmodified flavonoid. In consistence with the extent of their effects on pro-inflammatory markers, CPQ and quercetin showed down-regulation of NFκB activation. This quercetin analogue caused also a decline in BV-2 microglia proliferation with interfering with cell cycle progression (p < 0.001 for CPQ vs. quercetin-treated group). However, CPQ did not remarkably affect cell viability. In addition, CPQ showed a minor better suppression of PMA-induced generation of superoxide than did quercetin. Neither CPQ nor quercetin influenced phagocytosis of BV-2 cells. These results point to the therapeutic potential of 3'-O-(3-chloropivaloyl)quercetin (CPQ) as a novel antiinflammatory drug in neurodegenerative diseases, mediating favourable modulation of pro-inflammatory functions of microglia.

  3. Aberrantly elevated microRNA-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor β-Klotho.

    PubMed

    Fu, Ting; Choi, Sung-E; Kim, Dong-Hyun; Seok, Sunmi; Suino-Powell, Kelly M; Xu, H Eric; Kemper, Jongsook Kim

    2012-10-02

    MicroRNA-34a (miR-34a) is the most highly elevated hepatic miR in obese mice and is also substantially elevated in patients who have steatosis, but its role in obesity and metabolic dysfunction remains unclear. After a meal, FGF19 is secreted from the ileum; binds to a hepatic membrane receptor complex, FGF19 receptor 4 and coreceptor β-Klotho (βKL); and mediates postprandial responses under physiological conditions, but hepatic responses to FGF19 signaling were shown to be impaired in patients with steatosis. Here, we show an unexpected functional link between aberrantly elevated miR-34a and impaired βKL/FGF19 signaling in obesity. In vitro studies show that miR-34a down-regulates βKL by binding to the 3' UTR of βKL mRNA. Adenoviral-mediated overexpression of miR-34a in mice decreased hepatic βKL levels, impaired FGF19-activated ERK and glycogen synthase kinase signaling, and altered expression of FGF19 metabolic target genes. Consistent with these results, βKL levels were decreased and hepatic responses to FGF19 were severely impaired in dietary obese mice that have elevated miR-34a. Remarkably, in vivo antisense inhibition of miR-34a in obese mice partially restored βKL levels and improved FGF19 target gene expression and metabolic outcomes, including decreased liver fat. Further, anti-miR-34a treatment in primary hepatocytes of obese mice restored FGF19-activated ERK and glycogen synthase kinase signaling in a βKL-dependent manner. These results indicate that aberrantly elevated miR-34a in obesity attenuates hepatic FGF19 signaling by directly targeting βKL. The miR-34a/βKL/FGF19 axis may present unique therapeutic targets for FGF19-related human diseases, including metabolic disorders and cancer.

  4. Bioactive effects of quercetin in the central nervous system: Focusing on the mechanisms of actions.

    PubMed

    Suganthy, Natarajan; Devi, Kasi Pandima; Nabavi, Seyed Fazel; Braidy, Nady; Nabavi, Seyed Mohammad

    2016-12-01

    Quercetin, a ubiquitous flavonoid that is widely distributed in plants is classified as a cognitive enhancer in traditional and oriental medicine. The protective effects of quercetin for the treatment of neurodegenerative disorders and cerebrovascular diseases have been demonstrated in both in vitro and in vivo studies. The free radical scavenging activity of quercetin has been well-documented, wherein quercetin has been observed to exhibit protective effects against oxidative stress mediated neuronal damage by modulating the expression of NRF-2 dependent antioxidant responsive elements, and attenuation of neuroinflammation by suppressing NF-κB signal transducer and activator of transcription-1 (STAT-1). Several in vitro and in vivo studies have also shown that quercetin destabilizes and enhances the clearance of abnormal protein such as beta- amyloid peptide and hyperphosphorlyated tau, the key pathological hallmarks of Alzheimer's disease. Quercetin enhances neurogenesis and neuronal longevity by modulating a broad number of kinase signaling cascades such as phophoinositide 3- kinase (P13-kinase), AKT/PKB tyrosine kinase and Protein kinase C (PKC). Quercetin has also been well reported for its ability to reverse cognitive impairment and memory enhancement during aging. The current review focuses on summarizing the recent findings on the neuroprotective effect of quercetin, its mechanism of action and its possible roles in the prevention of neurological disorders.

  5. Troxerutin Attenuates Enhancement of Hepatic Gluconeogenesis by Inhibiting NOD Activation-Mediated Inflammation in High-Fat Diet-Treated Mice

    PubMed Central

    Zhang, Zifeng; Wang, Xin; Zheng, Guihong; Shan, Qun; Lu, Jun; Fan, Shaohua; Sun, Chunhui; Wu, Dongmei; Zhang, Cheng; Su, Weitong; Sui, Junwen; Zheng, Yuanlin

    2016-01-01

    Recent evidence suggests that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, exhibits beneficial effects on diabetes-related symptoms. Here we investigated the effects of troxerutin on the enhancement of hepatic gluconeogenesis in high-fat diet (HFD)-treated mice and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + Troxerutin group, and Troxerutin group. Troxerutin was treated by daily oral administration at doses of 150 mg/kg/day for 20 weeks. Tauroursodeoxycholic acid (TUDCA) was used to inhibit endoplasmic reticulum stress (ER stress). Our results showed that troxerutin effectively improved obesity and related metabolic parameters, and liver injuries in HFD-treated mouse. Furthermore, troxerutin significantly attenuated enhancement of hepatic gluconeogenesis in HFD-fed mouse. Moreover, troxerutin notably suppressed nuclear factor-κB (NF-κB) p65 transcriptional activation and release of inflammatory cytokines in HFD-treated mouse livers. Mechanismly, troxerutin dramatically decreased Nucleotide oligomerization domain (NOD) expression, as well as interaction between NOD1/2 with interacting protein-2 (RIP2), by abating oxidative stress-induced ER stress in HFD-treated mouse livers, which was confirmed by TUDCA treatment. These improvement effects of troxerutin on hepatic glucose disorders might be mediated by its anti-obesity effect. In conclusion, troxerutin markedly diminished HFD-induced enhancement of hepatic gluconeogenesis via its inhibitory effects on ER stress-mediated NOD activation and consequent inflammation, which might be mediated by its anti-obesity effect. PMID:28029143

  6. The Dipeptidyl Peptidase-4 Inhibitor Teneligliptin Attenuates Hepatic Lipogenesis via AMPK Activation in Non-Alcoholic Fatty Liver Disease Model Mice.

    PubMed

    Ideta, Takayasu; Shirakami, Yohei; Miyazaki, Tsuneyuki; Kochi, Takahiro; Sakai, Hiroyasu; Moriwaki, Hisataka; Shimizu, Masahito

    2015-12-08

    Non-alcoholic fatty liver disease (NAFLD), which is strongly associated with metabolic syndrome, is increasingly a major cause of hepatic disorder. Dipeptidyl peptidase (DPP)-4 inhibitors, anti-diabetic agents, are expected to be effective for the treatment of NAFLD. In the present study, we established a novel NAFLD model mouse using monosodium glutamate (MSG) and a high-fat diet (HFD) and investigated the effects of a DPP-4 inhibitor, teneligliptin, on the progression of NAFLD. Male MSG/HFD-treated mice were divided into two groups, one of which received teneligliptin in drinking water. Administration of MSG and HFD caused mice to develop severe fatty changes in the liver, but teneligliptin treatment improved hepatic steatosis and inflammation, as evaluated by the NAFLD activity score. Serum alanine aminotransferase and intrahepatic triglyceride levels were significantly decreased in teneligliptin-treated mice (p < 0.05). Hepatic mRNA levels of the genes involved in de novo lipogenesis were significantly downregulated by teneligliptin (p < 0.05). Moreover, teneligliptin increased hepatic expression levels of phosphorylated AMP-activated protein kinase (AMPK) protein. These findings suggest that teneligliptin attenuates lipogenesis in the liver by activating AMPK and downregulating the expression of genes involved in lipogenesis. DPP-4 inhibitors may be effective for the treatment of NAFLD and may be able to prevent its progression to non-alcoholic steatohepatitis.

  7. Genetic diversity of the VP1 gene of duck hepatitis virus type I (DHV-I) isolates from southeast China is related to isolate attenuation.

    PubMed

    Liu, Guangqing; Wang, Fei; Ni, Zheng; Yun, Tao; Yu, Bin; Huang, Jionggang; Chen, Jianping

    2008-10-01

    The complete sequence of an isolate (ZJ-V) of Duck hepatitis virus I (DHV-I), originally taken from the field in southeast China was determined. It was 7691 nucleotides long and had 5'- and 3'-terminal non-coding regions of 626 and 315 nucleotides, respectively. The poly(A) tail contained at least 22 residues and the single open reading frame encoded a polypeptide of 2249 amino acids. The VP1 gene was also sequenced from nine southeast China field isolates and three attenuated DHV-I vaccine strains. In phylogenetic analysis of the isolates and other published sequences, attenuated and tissue-adapted isolates (including ZJ-V) clustered as genotypes significantly different from the field isolates that had not been passaged in chicken/duck embryos. There were two consistent amino acid substitutions (E(129)-->V(129) and A(142)-->S(142)) between all the field isolates and all the tissue-adapted ones. The carboxyl terminal region was generally the most variable and here the four attenuated Chinese isolates showed six consistent differences from the field isolates (S(181)-->L(181), H(183)K(184)-->R(183)G(1841), N(193)-->D(193), E(205)-->K(205), R(217)-->K(217), N(235)-->D(235)). It seems likely that at least some of these differences result from mutations leading to isolate attenuation.

  8. C1q/TNF-Related Protein 9 (CTRP9) attenuates hepatic steatosis via the autophagy-mediated inhibition of endoplasmic reticulum stress.

    PubMed

    Jung, Tae Woo; Hong, Ho Cheol; Hwang, Hwan-Jin; Yoo, Hye Jin; Baik, Sei Hyun; Choi, Kyung Mook

    2015-12-05

    C1q/TNF-Related Protein (CTRP) 9, the closest paralog of adiponectin, has been reported to protect against diet-induced obesity and non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. We explored the protective effect of CTRP9 against hepatic steatosis and apoptosis, and identified the mechanisms through autophagy and endoplasmic reticulum (ER) stress using in vitro and in vivo experiments. Treating HepG2 cells with human recombinant CTRP9 significantly ameliorated palmitate- or tunicamycin-induced dysregulation of lipid metabolism, caspase 3 activity and chromatin condensation, which lead to reduction of hepatic triglyceride (TG) accumulation. CTRP9 treatment induced autophagy markers including LC3 conversion, P62 degradation, Beclin1 and ATG7 through AMPK phosphorylation in human primary hepatocytes. Furthermore, CTRP9 decreased palmitate- or tunicamycin-induced ER stress markers, such as eIF2α, CHOP and IRE-1, in HepG2 cells. Compound C, an AMPK inhibitor, and 3 methyladenine (3 MA), an autophagy inhibitor, canceled the effects of CTRP9 on ER stress, apoptosis and hepatic steatosis. In the livers of HFD-fed mice, adenovirus-mediated CTRP9 overexpression significantly induced AMPK phosphorylation and autophagy, whereas suppressed ER stress markers. In addition, both SREBP1-mediated lipogenic gene expression and apoptosis were significantly attenuated, which result in improvement in hepatic steatosis by overexpression of CTRP9. These results demonstrate that CTRP9 alleviates hepatic steatosis through relief of ER stress via the AMPK-mediated induction of autophagy.

  9. Long term dietary quercetin enrichment as a cardioprotective countermeasure in mdx mice.

    PubMed

    Ballmann, Christopher; Denney, Thomas; Beyers, Ronald J; Quindry, Tiffany; Romero, Matthew; Selsby, Joshua T; Quindry, John C

    2017-02-13

    Duchenne Muscular Dystrophy (DMD) causes declines in cardiac health resulting in premature mortality. As a potential countermeasure, quercetin is a polyphenol possessing inherent anti-inflammatory and antioxidant effects that activate proliferator-activated γ coactivator 1α (PGC-1α) increasing mitochondrial biogenesis protein abundance. We investigated the extent to which lifelong 0.2% dietary quercetin enrichment attenuates dystrophic cardiopathology in mdx mice. Dystrophic animals were fed quercetin or control diet for 12 months while control C57 mice were fed a control diet. Cardiac function was assessed via 7T MRI at 2, 10, and 14 months. At 14 months hearts were collected for histology and western blotting. Results indicate mdx strain dependent declines in cardiac performance at 14 months and that dietary quercetin enrichment did not attenuate functional losses. In contrast, histological analyses provide evidence that quercetin feeding was associated with decreased fibronectin, and indirect damage indices (Hematoxylin & Eosin) as compared to mdx. Dietary quercetin enrichment increased cardiac protein abundance of PGC-1α, cytochrome-c, ETC complexes I-V, citrate synthase, SOD2, and GPX versus untreated mdx. Protein abundance of inflammatory markers NFκB, P-NFκB, and P-IKBα were decreased by quercetin compared to untreated mdx, while preserving IKBα compared to mdx. Furthermore, quercetin decreased TGF-β1, COX2, and F4/80 versus untreated mdx mice. Data suggest that long term quercetin enrichment does not impact physiologic parameters of cardiac function but improves indices of mitochondrial biogenesis and antioxidant enzymes, facilitated DGC assembly, and decreased inflammation in dystrophic hearts. This article is protected by copyright. All rights reserved.

  10. Aguamiel concentrate from Agave salmiana and its extracted saponins attenuated obesity and hepatic steatosis and increased Akkermansia muciniphila in C57BL6 mice

    PubMed Central

    Leal-Díaz, Ana María; Noriega, Lilia G.; Torre-Villalvazo, Ivan; Torres, Nimbe; Alemán-Escondrillas, Gabriela; López-Romero, Patricia; Sánchez-Tapia, Mónica; Aguilar-López, Miriam; Furuzawa-Carballeda, Janette; Velázquez-Villegas, Laura A.; Avila-Nava, Azalia; Ordáz, Guillermo; Gutiérrez-Uribe, Janet A.; Serna-Saldivar, Sergio O.; Tovar, Armando R.

    2016-01-01

    Obesity and its comorbidities are a severe public health problem worldwide. The use of bioactive compounds found in some foods has been demonstrated to ameliorate the metabolic abnormalities associated with obesity. The purpose of this study was to assess whether the bioactive compounds present in aguamiel concentrate (AC) from Agave salmiana could attenuate glucose intolerance and hepatic steatosis in mice fed a high fat (HF) diet. HPLC-ELSD analysis showed that AC contained several saponins. The consumption of an AC extract rich in saponins reduced weight gain and fat mass and lowered serum glucose, insulin and LDL-cholesterol levels in mice fed a HF diet. Additionally, mice fed the saponin extract exhibited a reduced HOMA index and hepatic lipid levels and increased expression of genes involved in fatty acid oxidation. Saponins increased white adipose tissue browning, AMPK phosphorylation, fatty acid oxidation, and mitochondrial activity in skeletal muscle and energy expenditure in mice fed the HF diet. These metabolic changes were accompanied by an increase in the abundance of Akkermansia muciniphila in the gut microbiota. Therefore, Agave salmiana saponins can be an alternative to attenuate the metabolic changes that accompany obesity. PMID:27678062

  11. Aguamiel concentrate from Agave salmiana and its extracted saponins attenuated obesity and hepatic steatosis and increased Akkermansia muciniphila in C57BL6 mice.

    PubMed

    Leal-Díaz, Ana María; Noriega, Lilia G; Torre-Villalvazo, Ivan; Torres, Nimbe; Alemán-Escondrillas, Gabriela; López-Romero, Patricia; Sánchez-Tapia, Mónica; Aguilar-López, Miriam; Furuzawa-Carballeda, Janette; Velázquez-Villegas, Laura A; Avila-Nava, Azalia; Ordáz, Guillermo; Gutiérrez-Uribe, Janet A; Serna-Saldivar, Sergio O; Tovar, Armando R

    2016-09-28

    Obesity and its comorbidities are a severe public health problem worldwide. The use of bioactive compounds found in some foods has been demonstrated to ameliorate the metabolic abnormalities associated with obesity. The purpose of this study was to assess whether the bioactive compounds present in aguamiel concentrate (AC) from Agave salmiana could attenuate glucose intolerance and hepatic steatosis in mice fed a high fat (HF) diet. HPLC-ELSD analysis showed that AC contained several saponins. The consumption of an AC extract rich in saponins reduced weight gain and fat mass and lowered serum glucose, insulin and LDL-cholesterol levels in mice fed a HF diet. Additionally, mice fed the saponin extract exhibited a reduced HOMA index and hepatic lipid levels and increased expression of genes involved in fatty acid oxidation. Saponins increased white adipose tissue browning, AMPK phosphorylation, fatty acid oxidation, and mitochondrial activity in skeletal muscle and energy expenditure in mice fed the HF diet. These metabolic changes were accompanied by an increase in the abundance of Akkermansia muciniphila in the gut microbiota. Therefore, Agave salmiana saponins can be an alternative to attenuate the metabolic changes that accompany obesity.

  12. Water-soluble polysaccharide from Eleutherococcus senticosus stems attenuates fulminant hepatic failure induced by D-galactosamine and lipopolysaccharide in mice.

    PubMed

    Park, Eun-Jeon; Nan, Ji-Xing; Zhao, Yu-Zhe; Lee, Sung Hee; Kim, Young Ho; Nam, Jeong Bum; Lee, Jung Joon; Sohn, Dong Hwan

    2004-06-01

    The aim of this study was to investigate whether Eleutherococcus senticosus stems could attenuate D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure in mice. E. senticosus, known as Siberian ginseng, is a popular folk medicine used as a tonic in Asia. Preparations of E. senticosus used in this study were as follows; (i) 70% ethanol extract (ii) water extract (iii) ethanol-soluble part of the water extract (iv) polysaccharide obtained as an 80% ethanol insoluble of the water extract. Preparations were given by intraperitoneal (300 mg/kg and 50 mg/kg) or oral (300 mg/kg) injection at 12 hr and 1 hr before a D-galactosamine/lipopolysaccharide injection. The intraperitoneal injection of water extract and polysaccharide significantly lowered serum levels of tumour necrosis factor-alpha, aspartate transaminase and alanine transaminase, improved the histologic changes in liver, inhibited hepatocyte apoptosis confirmed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling method and DNA fragmentation assay, and suppressed the lethality induced by D-galactosamine/lipopolysaccharide. The oral administration of water extract and polysaccharide also reduced serum aspartate transaminase, alanine transaminase and tumour necrosis factor-alpha levels. In contrast 70% ethanol extract and ethanol-soluble part of the water extract had no protective effect when treated intraperitoneally or orally. These results indicate E. senticosus stems attenuate fulminant hepatic failure induced by D-galactosamine/lipopolysaccharide in mice and the protective effect is due to water-soluble polysaccharides in E. senticosus stems.

  13. A new cannabinoid CB2 receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury

    PubMed Central

    Horváth, Bėla; Magid, Lital; Mukhopadhyay, Partha; Bátkai, Sándor; Rajesh, Mohanraj; Park, Ogyi; Tanchian, Galin; Gao, Rachel Y; Goodfellow, Catherine E; Glass, Michelle; Mechoulam, Raphael; Pacher, Pál

    2012-01-01

    BACKGROUND AND PURPOSE Cannabinoid CB2 receptor activation has been reported to attenuate myocardial, cerebral and hepatic ischaemia-reperfusion (I/R) injury. EXPERIMENTAL APPROACH We have investigated the effects of a novel CB2 receptor agonist ((1S,4R)-2-(2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl)-7,7-dimethylbicyclo[2.2.1]hept-2-en-1-yl)methanol (HU-910) on liver injury induced by 1 h of ischaemia followed by 2, 6 or 24 h of reperfusion, using a well-established mouse model of segmental hepatic I/R. KEY RESULTS Displacement of [3H]CP55940 by HU-910 from specific binding sites in CHO cell membranes transfected with human CB2 or CB1 receptors (hCB1/2) yielded Ki values of 6 nM and 1.4 µM respectively. HU-910 inhibited forskolin-stimulated cyclic AMP production by hCB2 CHO cells (EC50= 162 nM) and yielded EC50 of 26.4 nM in [35S]GTPγS binding assays using hCB2 expressing CHO membranes. HU-910 given before ischaemia significantly attenuated levels of I/R-induced hepatic pro-inflammatory chemokines (CCL3 and CXCL2), TNF-α, inter-cellular adhesion molecule-1, neutrophil infiltration, oxidative stress and cell death. Some of the beneficial effect of HU-910 also persisted when given at the beginning of the reperfusion or 1 h after the ischaemic episode. Furthermore, HU-910 attenuated the bacterial endotoxin-triggered TNF-α production in isolated Kupffer cells and expression of adhesion molecules in primary human liver sinusoidal endothelial cells stimulated with TNF-α. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of HU-910, while pretreatment with a CB1 antagonist tended to enhance them. CONCLUSION AND IMPLICATIONS HU-910 is a potent CB2 receptor agonist which may exert protective effects in various diseases associated with inflammation and tissue injury. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph

  14. Pequi (Caryocar brasiliense Camb.) almond oil attenuates carbon tetrachloride-induced acute hepatic injury in rats: Antioxidant and anti-inflammatory effects.

    PubMed

    Torres, Lucillia R de O; Santana, Fernanda C de; Torres-Leal, Francisco L; Melo, Illana L P de; Yoshime, Luciana T; Matos-Neto, Emidio M; Seelaender, Marília C L; Araújo, Cintia M M; Cogliati, Bruno; Mancini-Filho, Jorge

    2016-11-01

    Carbon tetrachloride (CCl4) is a potent hepatotoxin, capable of generating free radicals that lead to oxidative stress and the inflammation process. Pequi almond oil (PAO) has been reported to possess unsaturated fatty acid and antioxidant compounds related to beneficial effects on oxidation and inflammatory conditions. The present study was undertaken to evaluate the hepatoprotective effects of handmade and coldpressed PAO on CCl4-induced acute liver injury. The possible mechanisms underlying the effect on liver injury enzymes, histopathological parameters, lipid profile, lipid peroxidation, and antioxidant and detoxification defense systems, as well as inflammatory parameters, were determined. Rats treated with PAO (3 or 6 mL/kg) for 21 days before CCl4 induction (3 mL/kg, 70%) showed significantly decreased levels of alanine aminotransferase and aspartate aminotransferase, milder hepatic lesions and higher levels of serum high-density lipoprotein compared to CCl4 group. Moreover, PAO enhanced antioxidant capacity by increasing hepatic glutathione peroxidase and glutathione reductase enzyme activities, as well as reducing circulating concentrations of leptin and inflammatory mediators such as interleukin-6, leukotrienes -4 and -5 and the tumor necrosis factor receptor. In summary, PAO, especially cold-pressed oil, attenuated the CCl4-induced alterations in serum and hepatic tissue in rats due to its antioxidant and anti-inflammatory properties.

  15. Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death

    PubMed Central

    Mukhopadhyay, Partha; Rajesh, Mohanraj; Horváth, Béla; Bátkai, Sándor; Park, Ogyi; Tanashian, Galin; Gao, Rachel Y; Patel, Vivek; Wink, David A.; Liaudet, Lucas; Haskó, György; Mechoulam, Raphael; Pacher, Pál

    2011-01-01

    Ischemia-reperfusion (I/R) is a pivotal mechanism of liver damage following liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol(CBD), the non-psychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor alpha (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, inter-cellular adhesion molecule 1 mRNA levels, tissue neutrophil infiltration, nuclear factor kappa B (NF-KB) activation), stress signaling (p38MAPK and JNK) and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress and cell death, and also attenuated the bacterial endotoxin-triggered NF-KB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecules expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α, and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent from classical CB1/2 receptors. PMID:21362471

  16. The Combination of Resveratrol and Quercetin Attenuates Metabolic Syndrome in Rats by Modifying the Serum Fatty Acid Composition and by Upregulating SIRT 1 and SIRT 2 Expression in White Adipose Tissue.

    PubMed

    Peredo-Escárcega, Ana Elena; Guarner-Lans, Verónica; Pérez-Torres, Israel; Ortega-Ocampo, Sergio; Carreón-Torres, Elizabeth; Castrejón-Tellez, Vicente; Díaz-Díaz, Eulises; Rubio-Ruiz, María Esther

    2015-01-01

    Resveratrol (RSV) and quercetin (QRC) modify energy metabolism and reduce cardiovascular risk factors included in the metabolic syndrome (MetS). These natural compounds upregulate and activate sirtuins (SIRTs), a family of NAD-dependent histone deacetylases. We analyzed the effect of two doses of a commercial combination of RSV and QRC on serum fatty acid composition and their regulation of SIRTs 1-3 and PPAR-γ expression in white adipose tissue. MetS was induced in Wistar rats by adding 30% sucrose to drinking water for five months. Rats were divided into control and two groups receiving the two different doses of RSV and QRC in drinking water daily for 4 weeks following the 5 months of sucrose treatment. Commercial kits were used to determine serum parameters and the expressions of SIRTs in WAT were analysed by western blot. In MetS rats body mass, central adiposity, insulin, triglycerides, non-HDL-C, leptin, adiponectin, monounsaturated fatty acids (MUFAs), and nonesterified fatty acids (NEFAs) were increased, while polyunsaturated fatty acids (PUFAs) and HDL-C were decreased. SIRT 1 and SIRT 2 were downregulated, while PPAR-γ was increased. RSV + QRC administration improved the serum health parameters modified by MetS and upregulate SIRT 1 and SIRT 2 expression in white abdominal tissue in MetS animals.

  17. The Combination of Resveratrol and Quercetin Attenuates Metabolic Syndrome in Rats by Modifying the Serum Fatty Acid Composition and by Upregulating SIRT 1 and SIRT 2 Expression in White Adipose Tissue

    PubMed Central

    Peredo-Escárcega, Ana Elena; Guarner-Lans, Verónica; Pérez-Torres, Israel; Ortega-Ocampo, Sergio; Carreón-Torres, Elizabeth; Castrejón-Tellez, Vicente; Díaz-Díaz, Eulises; Rubio-Ruiz, María Esther

    2015-01-01

    Resveratrol (RSV) and quercetin (QRC) modify energy metabolism and reduce cardiovascular risk factors included in the metabolic syndrome (MetS). These natural compounds upregulate and activate sirtuins (SIRTs), a family of NAD-dependent histone deacetylases. We analyzed the effect of two doses of a commercial combination of RSV and QRC on serum fatty acid composition and their regulation of SIRTs 1–3 and PPAR-γ expression in white adipose tissue. MetS was induced in Wistar rats by adding 30% sucrose to drinking water for five months. Rats were divided into control and two groups receiving the two different doses of RSV and QRC in drinking water daily for 4 weeks following the 5 months of sucrose treatment. Commercial kits were used to determine serum parameters and the expressions of SIRTs in WAT were analysed by western blot. In MetS rats body mass, central adiposity, insulin, triglycerides, non-HDL-C, leptin, adiponectin, monounsaturated fatty acids (MUFAs), and nonesterified fatty acids (NEFAs) were increased, while polyunsaturated fatty acids (PUFAs) and HDL-C were decreased. SIRT 1 and SIRT 2 were downregulated, while PPAR-γ was increased. RSV + QRC administration improved the serum health parameters modified by MetS and upregulate SIRT 1 and SIRT 2 expression in white abdominal tissue in MetS animals. PMID:26609312

  18. Tyrosol Attenuates High Fat Diet-Induced Hepatic Oxidative Stress: Potential Involvement of Cystathionine β-Synthase and Cystathionine γ-Lyase.

    PubMed

    Sarna, Lindsei K; Sid, Victoria; Wang, Pengqi; Siow, Yaw L; House, James D; O, Karmin

    2016-05-01

    The Mediterranean diet is known for its cardioprotective effects. Recently, its protective qualities have also been reported in patients with non-alcoholic fatty liver disease (NAFLD). Oxidative stress is one of the important factors responsible for the development and progression of NAFLD. Hydrogen sulfide (H2S), a multifaceted gasotransmitter, has emerged as a potential therapeutic target in NAFLD. Cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are major enzymes responsible for endogenous H2S synthesis. Since oxidative stress contributes to NAFLD pathogenesis, the objective of this study was to investigate the effect of tyrosol, a major compound in olive oil and white wine, on high fat diet-induced hepatic oxidative stress and the mechanisms involved. Mice (C57BL/6) were fed for 5 weeks with a control diet (10 % kcal fat), a high fat diet (60 % kcal fat, HFD) or a HFD supplemented with tyrosol. High fat diet feeding induced hepatic oxidative stress, as indicated by the significant increase in lipid peroxidation and NADPH oxidase activity. Tyrosol supplementation significantly increased hepatic CBS and CSE expression and H2S synthesis in high fat diet-fed mice. Such effects were associated with the attenuation of high fat diet-induced hepatic lipid peroxidation and the restoration of the redox equilibrium of the antioxidant glutathione. Tyrosol also inhibited palmitic acid-induced oxidative stress in hepatocytes (HepG2 cells). These results suggest that the antioxidant properties of tyrosol may be mediated through functional changes in CBS and CSE activity, which might contribute to the hepatoprotective effect of the Mediterranean diet.

  19. Medium-chain TAG attenuate hepatic oxidative damage in intra-uterine growth-retarded weanling piglets by improving the metabolic efficiency of the glutathione redox cycle.

    PubMed

    Zhang, Hao; Chen, Yueping; Li, Yue; Yang, Li; Wang, Jianjun; Wang, Tian

    2014-09-28

    The present study investigated the effects of medium-chain TAG (MCT) on hepatic oxidative damage in weanling piglets with intra-uterine growth retardation (IUGR). At weaning (mean 21 (SD 1·06) d of age), twenty-four IUGR piglets and twenty-four normal-birth weight (NBW) piglets were selected according to their birth weight (BW; IUGR: mean 0·95 (SD 0·04) kg; NBW: mean 1·58 (SD 0·04) kg) and weight at the time of weaning (IUGR: mean 5·26 (SD 0·15) kg; NBW: mean 6·98 (SD 0·19) kg) and fed either a soyabean oil (SO) diet (containing 5% SO) or a MCT diet (containing 1% SO and 4% MCT) for 28 d. IUGR piglets exhibited poor (P<0·05) growth performance, lower (P<0·05) metabolic efficiency of hepatic glutathione (GSH) redox cycle, and increased (P<0·05) levels of reactive oxygen species, apoptosis and necrosis in hepatocytes compared with NBW piglets. The MCT diet increased (P<0·05) the average daily gain and feed efficiency of piglets during the first 4 weeks after weaning. Furthermore, MCT diet-fed piglets had a higher (P<0·05) GSH:oxidised glutathione ratio and increased (P<0·05) activities of glucose-6-phosphate dehydrogenase (G6PD) and GSH reductase. The expression of G6PD was up-regulated (P<0·05) by the MCT diet irrespective of BW. Moreover, malondialdehyde concentrations in the liver and apoptosis and necrosis levels in hepatocytes were decreased (P<0·05) by the MCT diet irrespective of BW. These results indicate that MCT might have auxiliary therapeutic potential to attenuate hepatic oxidative damage in IUGR offspring during early life, thus leading to an improvement in the metabolic efficiency of the hepatic GSH redox cycle.

  20. Korean Pine Nut Oil Attenuated Hepatic Triacylglycerol Accumulation in High-Fat Diet-Induced Obese Mice.

    PubMed

    Park, Soyoung; Shin, Sunhye; Lim, Yeseo; Shin, Jae Hoon; Seong, Je Kyung; Han, Sung Nim

    2016-01-21

    Korean pine nut oil (PNO) has been reported to influence weight gain and lipid metabolism. We examined whether PNO replacement in a high-fat diet (HFD) can ameliorate HFD-induced hepatic steatosis. Five-week-old male C57BL mice were fed control diets containing 10% of the energy from fat from PNO or soybean oil (SBO) (PC, SC) or HFDs with 45% of the energy from fat, with 10% from PNO or SBO and 35% from lard (PHFD, SHFD), for 12 weeks. Body weight gain and amount of white adipose tissue were lower in PHFD (10% and 18% lower, respectively) compared with SHFD. Hepatic triacylglycerol (TG) level was significantly lower in PHFD than the SHFD (26% lower). PNO consumption upregulated hepatic ACADL mRNA levels. The hepatic PPARG mRNA level was lower in the PC than in the SC. Expression of the sirtuin (SIRT) 3 protein in white adipose tissue was down-regulated in the SHFD and restored in the PHFD to the level in the lean control mice. SIRT 3 was reported to be upregulated under conditions of caloric restriction (CR) and plays a role in regulating mitochondrial function. PNO consumption resulted in lower body fat and hepatic TG accumulation in HFD-induced obesity, which seemed to be associated with the CR-mimetic response.

  1. Korean Pine Nut Oil Attenuated Hepatic Triacylglycerol Accumulation in High-Fat Diet-Induced Obese Mice

    PubMed Central

    Park, Soyoung; Shin, Sunhye; Lim, Yeseo; Shin, Jae Hoon; Seong, Je Kyung; Han, Sung Nim

    2016-01-01

    Korean pine nut oil (PNO) has been reported to influence weight gain and lipid metabolism. We examined whether PNO replacement in a high-fat diet (HFD) can ameliorate HFD-induced hepatic steatosis. Five-week-old male C57BL mice were fed control diets containing 10% of the energy from fat from PNO or soybean oil (SBO) (PC, SC) or HFDs with 45% of the energy from fat, with 10% from PNO or SBO and 35% from lard (PHFD, SHFD), for 12 weeks. Body weight gain and amount of white adipose tissue were lower in PHFD (10% and 18% lower, respectively) compared with SHFD. Hepatic triacylglycerol (TG) level was significantly lower in PHFD than the SHFD (26% lower). PNO consumption upregulated hepatic ACADL mRNA levels. The hepatic PPARG mRNA level was lower in the PC than in the SC. Expression of the sirtuin (SIRT) 3 protein in white adipose tissue was down-regulated in the SHFD and restored in the PHFD to the level in the lean control mice. SIRT 3 was reported to be upregulated under conditions of caloric restriction (CR) and plays a role in regulating mitochondrial function. PNO consumption resulted in lower body fat and hepatic TG accumulation in HFD-induced obesity, which seemed to be associated with the CR-mimetic response. PMID:26805879

  2. White Pitaya (Hylocereus undatus) Juice Attenuates Insulin Resistance and Hepatic Steatosis in Diet-Induced Obese Mice.

    PubMed

    Song, Haizhao; Zheng, Zihuan; Wu, Jianan; Lai, Jia; Chu, Qiang; Zheng, Xiaodong

    2016-01-01

    Insulin resistance and hepatic steatosis are the most common complications of obesity. Pitaya is an important source of phytochemicals such as polyphenols, flavonoid and vitamin C which are related to its antioxidant activity. The present study was conducted to evaluate the influence of white pitaya juice (WPJ) on obesity-related metabolic disorders (e.g. insulin resistance and hepatic steatosis) in high-fat diet-fed mice. Forty-eight male C57BL/6J mice were assigned into four groups and fed low-fat diet with free access to water or WPJ, or fed high-fat diet with free access to water or WPJ for 14 weeks. Our results showed that administration of WPJ improved high-fat diet-induced insulin resistance, hepatic steatosis and adipose hypertrophy, but it exerted no influence on body weight gain in mice. Hepatic gene expression analysis indicated that WPJ supplement not only changed the expression profile of genes involved in lipid and cholesterol metabolism (Srebp1, HMGCoR, Cpt1b, HL, Insig1 and Insig2) but also significantly increased the expression levels of FGF21-related genes (Klb, FGFR2, Egr1 and cFos). In conclusion, WPJ protected from diet-induced hepatic steatosis and insulin resistance, which was associated with the improved FGF21 resistance and lipid metabolism.

  3. White Pitaya (Hylocereus undatus) Juice Attenuates Insulin Resistance and Hepatic Steatosis in Diet-Induced Obese Mice

    PubMed Central

    Song, Haizhao; Zheng, Zihuan; Wu, Jianan; Lai, Jia; Chu, Qiang; Zheng, Xiaodong

    2016-01-01

    Insulin resistance and hepatic steatosis are the most common complications of obesity. Pitaya is an important source of phytochemicals such as polyphenols, flavonoid and vitamin C which are related to its antioxidant activity. The present study was conducted to evaluate the influence of white pitaya juice (WPJ) on obesity-related metabolic disorders (e.g. insulin resistance and hepatic steatosis) in high-fat diet-fed mice. Forty-eight male C57BL/6J mice were assigned into four groups and fed low-fat diet with free access to water or WPJ, or fed high-fat diet with free access to water or WPJ for 14 weeks. Our results showed that administration of WPJ improved high-fat diet-induced insulin resistance, hepatic steatosis and adipose hypertrophy, but it exerted no influence on body weight gain in mice. Hepatic gene expression analysis indicated that WPJ supplement not only changed the expression profile of genes involved in lipid and cholesterol metabolism (Srebp1, HMGCoR, Cpt1b, HL, Insig1 and Insig2) but also significantly increased the expression levels of FGF21-related genes (Klb, FGFR2, Egr1 and cFos). In conclusion, WPJ protected from diet-induced hepatic steatosis and insulin resistance, which was associated with the improved FGF21 resistance and lipid metabolism. PMID:26914024

  4. iPLA2β deficiency attenuates obesity and hepatic steatosis in ob/ob mice through hepatic fatty-acyl phospholipid remodeling.

    PubMed

    Deng, Xiuling; Wang, Jiliang; Jiao, Li; Utaipan, Tanyarath; Tuma-Kellner, Sabine; Schmitz, Gerd; Liebisch, Gerhard; Stremmel, Wolfgang; Chamulitrat, Walee

    2016-05-01

    PLA2G6 or GVIA calcium-independent PLA2 (iPLA2β) is identified as one of the NAFLD modifier genes in humans, and thought to be a target for NAFLD therapy. iPLA2β is known to play a house-keeping role in phospholipid metabolism and remodeling. However, its role in NAFLD pathogenesis has not been supported by results obtained from high-fat feeding of iPLA2β-null (PKO) mice. Unlike livers of human NAFLD and genetically obese rodents, fatty liver induced by high-fat diet is not associated with depletion of hepatic phospholipids. We therefore tested whether iPLA2β could regulate obesity and hepatic steatosis in leptin-deficient mice by cross-breeding PKO with ob/ob mice to generate ob/ob-PKO mice. Here we observed an improvement in ob/ob-PKO mice with significant reduction in serum enzymes, lipids, glucose, insulin as well as improved glucose tolerance, and reduction in islet hyperplasia. The improvement in hepatic steatosis measured by liver triglycerides, fatty acids and cholesterol esters was associated with decreased expression of PPARγ and de novo lipogenesis genes, and the reversal of β-oxidation gene expression. Notably, ob/ob livers contained depleted levels of lysophospholipids and phospholipids, and iPLA2β deficiency in ob/ob-PKO livers lowers the former, but replenished the latter particularly phosphatidylethanolamine (PE) and phosphatidylcholine (PC) that contained arachidonic (AA) and docosahexaenoic (DHA) acids. Compared with WT livers, PKO livers also contained increased PE and PC containing AA and DHA. Thus, iPLA2β deficiency protected against obesity and ob/ob fatty liver which was associated with hepatic fatty-acyl phospholipid remodeling. Our results support the deleterious role of iPLA2β in severe obesity associated NAFLD.

  5. Immune-driven adaptation of hepatitis B virus genotype D involves preferential alteration in B-cell epitopes and replicative attenuation--an insight from human immunodeficiency virus/hepatitis B virus coinfection.

    PubMed

    Mondal, R K; Khatun, M; Ghosh, S; Banerjee, P; Datta, S; Sarkar, S; Saha, B; Santra, A; Banerjee, S; Chowdhury, A; Datta, S

    2015-07-01

    An important driving force behind the sequence diversity of hepatitis B virus (HBV) is viral adaptation to host immune responses. To gain an insight into the impact of host immunity on genetic diversification and properties of HBV, we characterized HBV of genotype D from treatment-naive hepatitis B e antigen-positive (EP) and hepatitis B e antigen-negative (EN) patients with chronic hepatitis B (CHB), where HBV is under stronger immune pressure, with that of HBV derived from human immunodeficiency virus (HIV)/HBV-coinfected individuals, where HIV infection has significantly weakened the immune system. Full-length sequence analysis showed that HBV heterogeneity was most extensive in EN-CHB followed by EP-CHB and HIV/HBV coinfection. The relative magnitude of non-synonymous changes within B-cell epitopes was greater than that in T-cell epitopes of HBV open reading frames (ORFs) in both EP-CHB and EN-CHB. Nine amino acid substitutions were identified in B-cell epitopes and one in a T-cell epitope of HBV in EN-CHB, most of which resulted in altered hydrophobicities, as determined using the Kyte and Doolittle method, relative to wild-type residues found in HBV from the HIV-positive group. Additionally, 19 substitutions occurred at significantly higher frequencies in non-epitope regions of HBV ORF-P in EN-CHB than HIV/HBV-coinfected patients. In vitro replication assay demonstrated that the substitutions, particularly in reverse transcriptase and RNaseH domains of ORF-P, resulted in a decline in replication capacity of HBV. Hence, our results indicate that HBV adapts to increasing immune pressure through preferential mutations in B-cell epitopes and by replicative attenuation. The viral epitopes linked to immune response identified in this study bear important implications for future HBV vaccine studies.

  6. Ameliorative Effect of Quercetin on Neurochemical and Behavioral Deficits in Rotenone Rat Model of Parkinson's Disease: Modulating Autophagy (Quercetin on Experimental Parkinson's Disease).

    PubMed

    El-Horany, Hemat E; El-Latif, Rania N Abd; ElBatsh, Maha M; Emam, Marwa N

    2016-07-01

    Autophagy is necessary for neuronal homeostasis and its dysfunction has been implicated in Parkinson's disease (PD) as it can exacerbate endoplasmic reticulum (ER) stress and ER stress-induced apoptosis. Quercetin is a flavonoid known for its neuroprotective and antioxidant effects. The present study investigated the protective, autophagy-modulating effects of quercetin in the rotenone rat model of PD. Rotenone was intraperitoneally injected at dose of 2 ml/kg/day for 4 weeks. Simultaneous intraperitoneal injection of quercetin was given at a dose of 50 mg/kg/day also for 4 weeks. Neurobehavioral changes were studied. Oxidative/antioxidant status, C/EBP homologous protein (CHOP), Beclin-1, and dopamine levels were assessed. DNA fragmentation and histopathological changes were evaluated. This research work revealed that quercetin significantly attenuated rotenone-induced behavioral impairment, augmented autophagy, ameliorated ER stress- induced apoptosis with attenuated oxidative stress. From the current study, quercetin can act as an autophagy enhancer in PD rat model and modulates the microenvironment that leads to neuronal death.

  7. Exogenous heat shock cognate protein 70 pretreatment attenuates cardiac and hepatic dysfunction with associated anti-inflammatory responses in experimental septic shock.

    PubMed

    Hsu, Jong-Hau; Yang, Rei-Cheng; Lin, Shih-Jen; Liou, Shu-Fen; Dai, Zen-Kong; Yeh, Jwu-Lai; Wu, Jiunn-Ren

    2014-12-01

    It has been recently demonstrated that intracellular heat shock cognate protein 70 (HSC70) can be released into extracellular space with physiologic effects. However, its extracellular function in sepsis is not clear. In this study, we hypothesize that extracellular HSC70 can protect against lipopolysaccharide (LPS)-induced myocardial and hepatic dysfunction because of its anti-inflammatory actions. In Wistar rats, septic shock developed with hypotension, tachycardia, and myocardial and hepatic dysfunction at 4 h following LPS administration (10 mg/kg, i.v.). Pretreatment with recombinant bovine HSC70 (20 μg/kg, i.v.) attenuated LPS-induced hypotension and tachycardia by 21% and 23%, respectively (P < 0.05), improved myocardial dysfunction (left ventricular systolic pressure: 33%; max dP/dt: 20%; min dP/dt: 33%, P < 0.05), and prevented hepatic dysfunction (glutamic-oxaloacetic transaminase: 81 vs. 593 IU/L; glutamic-pyruvic transaminase: 15 vs. 136 IU/L, P < 0.05) compared with LPS-treated rats at 4 h. Heat shock cognate protein 70 also prevented LPS-induced hypoglycemia (217 vs. 59 mg/dL, P < 0.05) and elevated lactate dehydrogenase (1,312 vs. 6,301 IU/L, P < 0.05). Furthermore, HSC70 decreased LPS-induced elevation of circulating tumor necrosis factor α and nitrite/nitrate, and tissue expression of inducible nitric oxide synthase, cyclooxygenase 2, and matrix metalloproteinase 9 in the heart and liver. To investigate underlying mechanisms, we found that HSC70 attenuated LPS-induced nuclear translocation of nuclear factor κB subunit p65 by blocking the phosphorylation of inhibitor of nuclear factor κB. Finally, we showed that HSC70 repressed the activation of MAPKs caused by LPS. These results demonstrate that in LPS-induced septic shock, extracellular HSC70 conveys pleiotropic protection on myocardial, hepatic, and systemic derangements, with associated inhibition of proinflammatory mediators including tumor necrosis factor α, nitric oxide, cyclooxygenase 2

  8. Melatonin attenuates (-)-epigallocatehin-3-gallate-triggered hepatotoxicity without compromising its downregulation of hepatic gluconeogenic and lipogenic genes in mice.

    PubMed

    Wang, Dongxu; Wei, Yaqing; Wang, Taotao; Wan, Xiaochun; Yang, Chung S; Reiter, Russel J; Zhang, Jinsong

    2015-11-01

    (-)-Epigallocatehin-3-gallate (EGCG), a major constituent of green tea, can ameliorate metabolic syndrome at least in part through reducing gluconeogenesis and lipogenesis. Green tea extracts, of which EGCG is a key constituent, have been used for weight loss in humans. A potential adverse effect of high-dose EGCG or green tea extracts is hepatotoxicity. Melatonin, an endogenous antioxidant with a high safety profile, is effective in preventing various types of tissue damage. The current study investigated the influence of melatonin on EGCG-triggered hepatotoxicity and EGCG-downregulated hepatic genes responsible for gluconeogenesis and lipogenesis in mice. We found that (i) melatonin extended survival time of mice intoxicated with lethal doses of EGCG; (ii) melatonin ameliorated acute liver damage and associated hepatic Nrf2 suppression caused by a nonlethal toxic dose of EGCG; (iii) melatonin reduced subacute liver injury and hepatic Nrf2 activation caused by lower toxic doses of EGCG; and (iv) melatonin did not compromise the action of pharmacological doses of EGCG in downregulating a battery of hepatic genes responsible for gluconeogenesis and lipogenesis, including G6Pc, PEPCK, FOXO1α, SCD1, Fasn, leptin, ACCα, ACCβ, GAPT, and Srebp-1. Taken together, these results suggest that the combination of EGCG and melatonin is an effective approach for preventing potential adverse effects of EGCG as a dietary supplement for metabolic syndrome alleviation and body weight reduction.

  9. Hepatitis B Virus-Induced Parkin-Dependent Recruitment of Linear Ubiquitin Assembly Complex (LUBAC) to Mitochondria and Attenuation of Innate Immunity

    PubMed Central

    Khan, Mohsin; Syed, Gulam Hussain; Kim, Seong-Jun; Siddiqui, Aleem

    2016-01-01

    Hepatitis B virus (HBV) suppresses innate immune signaling to establish persistent infection. Although HBV is a DNA virus, its pre-genomic RNA (pgRNA) can be sensed by RIG-I and activates MAVS to mediate interferon (IFN) λ synthesis. Despite of the activation of RIG-I-MAVS axis by pgRNA, the underlying mechanism explaining how HBV infection fails to induce interferon-αβ (IFN) synthesis remained uncharacterized. We demonstrate that HBV induced parkin is able to recruit the linear ubiquitin assembly complex (LUBAC) to mitochondria and abrogates IFN β synthesis. Parkin interacts with MAVS, accumulates unanchored linear polyubiquitin chains on MAVS via LUBAC, to disrupt MAVS signalosome and attenuate IRF3 activation. This study highlights the novel role of parkin in antiviral signaling which involves LUBAC being recruited to the mitochondria. These results provide avenues of investigations on the role of mitochondrial dynamics in innate immunity. PMID:27348524

  10. Neuroprotective effects of pretreatment with quercetin as assessed by acetylcholinesterase assay and behavioral testing in poloxamer-407 induced hyperlipidemic rats.

    PubMed

    Braun, Josiane B S; Ruchel, Jader B; Adefegha, Stephen A; Coelho, Ana Paula V; Trelles, Kelly B; Signor, Cristiane; Rubin, Maribel A; Oliveira, Juliana S; Dornelles, Guilherme L; de Andrade, Cinthia M; Castilhos, Lívia G; Leal, Daniela B R

    2017-04-01

    Hyperlipidemia is a group of disorders characterized by excessive lipids in the bloodstream. It is associated with the incidence of cardiovascular diseases and recognized as the most important factor underlying the occurrence of atherosclerosis. This study was conducted to investigate whether pretreatment with quercetin can protect against possible memory impairment and deterioration of the cholinergic system in hyperlipidemic rats. Animals were divided into ten groups (n=7): saline/control, saline/quercetin 5mg/kg, saline/quercetin 25mg/kg, saline/quercetin 50mg/kg, saline/simvastatin (0.04mg/kg), hyperlipidemia, hyperlipidemia/quercetin 5mg/kg, hyperlipidemia/quercetin 25mg/kg, hyperlipidemia/quercetin 50mg/kg and hyperlipidemia/simvastatin. The animals were pretreated with quercetin by oral gavage for a period of 30days and hyperlipidemia was subsequently induced by intraperitoneal administration of a single dose of 500mg/kg of poloxamer-407. Simvastatin was administered after the induction of hyperlipidemia. The results demonstrated that hyperlipidemic rats had memory impairment compared with the saline control group (P<0.001). However, pretreatment with quercetin and simvastatin treatment attenuated the damage caused by hyperlipidemia compared with the hyperlipidemic group (P<0.05). Acetylcholinesterase (AChE) activity in the cerebral hippocampus was significantly (P<0.001) reduced in the hyperlipidemic group compared with the control saline group. Pretreatment with quercetin and simvastatin treatment in the hyperlipidemic groups significantly (P<0.05) increased AChE activity compared with the hyperlipidemic group. Our results thus suggest that quercetin may prevent memory impairment, alter lipid metabolism, and modulate AChE activity in an experimental model of hyperlipidemia.

  11. Cx3cr1 deficiency in mice attenuates hepatic granuloma formation during acute schistosomiasis by enhancing the M2-type polarization of macrophages.

    PubMed

    Ran, Lin; Yu, Qilin; Zhang, Shu; Xiong, Fei; Cheng, Jia; Yang, Ping; Xu, Jun-Fa; Nie, Hao; Zhong, Qin; Yang, Xueli; Yang, Fei; Gong, Quan; Kuczma, Michal; Kraj, Piotr; Gu, Weikuan; Ren, Bo-Xu; Wang, Cong-Yi

    2015-07-01

    Acute schistosomiasis is characterized by pro-inflammatory responses against tissue- or organ-trapped parasite eggs along with granuloma formation. Here, we describe studies in Cx3cr1(-/-) mice and demonstrate the role of Cx3cr1 in the pathoetiology of granuloma formation during acute schistosomiasis. Mice deficient in Cx3cr1 were protected from granuloma formation and hepatic injury induced by Schistosoma japonicum eggs, as manifested by reduced body weight loss and attenuated hepatomegaly along with preserved liver function. Notably, S. japonicum infection induced high levels of hepatic Cx3cr1 expression, which was predominantly expressed by infiltrating macrophages. Loss of Cx3cr1 rendered macrophages preferentially towards M2 polarization, which then led to a characteristic switch of the host immune defense from a conventional Th1 to a typical Th2 response during acute schistosomiasis. This immune switch caused by Cx3cr1 deficiency was probably associated with enhanced STAT6/PPAR-γ signaling and increased expression of indoleamine 2,3-dioxygenase (IDO), an enzyme that promotes M2 polarization of macrophages. Taken together, our data provide evidence suggesting that CX3CR1 could be a viable therapeutic target for treatment of acute schistosomiasis.

  12. Treatment with oligonol, a low-molecular polyphenol derived from lychee fruit, attenuates diabetes-induced hepatic damage through regulation of oxidative stress and lipid metabolism.

    PubMed

    Noh, Jeong Sook; Park, Chan Hum; Yokozawa, Takako

    2011-10-01

    We have identified the effects of oligonol, a low-molecular polyphenol derived from lychee fruit, on oxidative stress and lipid metabolism in a type 2 diabetic model. Oligonol was orally administered at 10 or 20 mg per kg body weight per d for 8 weeks to db/db mice, and its effects were compared with those of the vehicle in db/db and m/m mice. Serum and hepatic biochemical factors, and protein and mRNA expression related to lipid metabolism were measured. In the oligonol-administered group, there were significant reductions of reactive oxygen species (ROS), lipid peroxidation, and the TAG and total cholesterol concentrations in both the serum and liver. Additionally, oligonol attenuated oxidative stress through the inhibition of advanced glycation endproduct formation and its receptor expression. Furthermore, augmented expressions of NF-κBp65 and inducible NO synthase were down-regulated to the levels of m/m mice in the group treated with oligonol at 20 mg/kg. Regarding lipid metabolism, lower hepatic lipid resulted from the down-regulation of sterol regulatory element-binding protein-1 and its target gene of lipogenic enzymes in the liver of db/db mice. The present results suggest that oligonol has protective effects against ROS-related inflammation and excess lipid deposition in the type 2 diabetic liver.

  13. Cx3cr1 deficiency in mice attenuates hepatic granuloma formation during acute schistosomiasis by enhancing the M2-type polarization of macrophages

    PubMed Central

    Ran, Lin; Yu, Qilin; Zhang, Shu; Xiong, Fei; Cheng, Jia; Yang, Ping; Xu, Jun-Fa; Nie, Hao; Zhong, Qin; Yang, Xueli; Yang, Fei; Gong, Quan; Kuczma, Michal; Kraj, Piotr; Gu, Weikuan; Ren, Bo-Xu; Wang, Cong-Yi

    2015-01-01

    ABSTRACT Acute schistosomiasis is characterized by pro-inflammatory responses against tissue- or organ-trapped parasite eggs along with granuloma formation. Here, we describe studies in Cx3cr1−/− mice and demonstrate the role of Cx3cr1 in the pathoetiology of granuloma formation during acute schistosomiasis. Mice deficient in Cx3cr1 were protected from granuloma formation and hepatic injury induced by Schistosoma japonicum eggs, as manifested by reduced body weight loss and attenuated hepatomegaly along with preserved liver function. Notably, S. japonicum infection induced high levels of hepatic Cx3cr1 expression, which was predominantly expressed by infiltrating macrophages. Loss of Cx3cr1 rendered macrophages preferentially towards M2 polarization, which then led to a characteristic switch of the host immune defense from a conventional Th1 to a typical Th2 response during acute schistosomiasis. This immune switch caused by Cx3cr1 deficiency was probably associated with enhanced STAT6/PPAR-γ signaling and increased expression of indoleamine 2,3-dioxygenase (IDO), an enzyme that promotes M2 polarization of macrophages. Taken together, our data provide evidence suggesting that CX3CR1 could be a viable therapeutic target for treatment of acute schistosomiasis. PMID:26035381

  14. Benznidazole, the trypanocidal drug used for Chagas disease, induces hepatic NRF2 activation and attenuates the inflammatory response in a murine model of sepsis.

    PubMed

    Lambertucci, Flavia; Motiño, Omar; Villar, Silvina; Rigalli, Juan Pablo; de Luján Alvarez, María; Catania, Viviana A; Martín-Sanz, Paloma; Carnovale, Cristina Ester; Quiroga, Ariel Darío; Francés, Daniel Eleazar; Ronco, María Teresa

    2017-01-15

    Molecular mechanisms on sepsis progression are linked to the imbalance between reactive oxygen species (ROS) production and cellular antioxidant capacity. Previous studies demonstrated that benznidazole (BZL), known for its antiparasitic action on Trypanosoma cruzi, has immunomodulatory effects, increasing survival in C57BL/6 mice in a model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). The mechanism by which BZL inhibits inflammatory response in sepsis is poorly understood. Also, our group recently reported that BZL is able to activate the nuclear factor erytroide-derived 2-Like 2 (NRF2) in vitro. The aim of the present work was to delineate the beneficial role of BZL during sepsis, analyzing its effects on the cellular redox status and the possible link to the innate immunity receptor TLR4. Specifically, we analyzed the effect of BZL on Nrf2 regulation and TLR4 expression in liver of mice 24hours post-CLP. BZL was able to induce NRF2 nuclear protein localization in CLP mice. Also, we found that protein kinase C (PKC) is involved in the NRF2 nuclear accumulation and induction of its target genes. In addition, BZL prompted a reduction in hepatic CLP-induced TLR4 protein membrane localization, evidencing its immunomodulatory effects. Together, our results demonstrate that BZL induces hepatic NRF2 activation with the concomitant increase in the antioxidant defenses, and the attenuation of inflammatory response, in part, by inhibiting TLR4 expression in a murine model of sepsis.

  15. Swertiamarin ameliorates oleic acid induced lipid accumulation and oxidative stress by attenuating gluconeogenesis and lipogenesis in hepatic steatosis.

    PubMed

    Patel, Tushar P; Rawal, Komal; Soni, Sanket; Gupta, Sarita

    2016-10-01

    Swertiamarin, a bitter secoiridoid glycoside, is an antidiabetic drug with lipid lowering activity meliorates insulin resistance in Type 2 Diabetes condition. Therefore, the study was designed to explore the antioxidant and hypolipidemic activity of swertiamarin in ameliorating NAFLD caused due to hepatic lipid accumulation, inflammation and insulin resistance. Steatosis was induced in HepG2 cells by supplementing 1mM oleic acid (OA) for 24h which was marked by significant accumulation of lipid droplets. This was determined by Oil Red O (ORO) staining and triglyceride accumulation. Swertiamarin (25μg/ml) decreased triglyceride content by 2 folds and effectively reduced LDH release (50%) activity by protecting membrane integrity thus, preventing apoptosis evidenced by reduced cleavage of Caspase 3 and PARP1. We observed that swertiamarin significantly increased the expressions of major insulin signaling proteins like Insulin receptor (IR), PI(3)K, pAkt with concomitant reduction in p307 IRS-1. AMPK was activated by swertiamarin action, thus restoring insulin sensitivity in hepatocytes. In addition, qPCR results confirmed OA up-regulated Sterol Regulatory Element Binding Protein (SREBP)-1c and fatty acid synthase (FAS), resulting in increased fatty acid synthesis. Swertiamarin effectively modulated PPAR-α, a major potential regulator of carbohydrate metabolism which, in turn, decreased the levels of the gluconeogenic enzyme PEPCK, further restricting hepatic glucose production and fatty acid synthesis. Cumulatively, swertiamarin targets potential metabolic regulators AMPK and PPAR-α, through which it regulates hepatic glycemic burden, fat accumulation, insulin resistance and ROS in hepatic steatosis which emphasizes clinical significance of swertiamarin in regulating metabolism and as a suitable candidate for treating NAFLD.

  16. Deferoxamine attenuates lipid peroxidation, blocks interleukin-6 production, ameliorates sepsis inflammatory response syndrome, and confers renoprotection after acute hepatic ischemia in pigs.

    PubMed

    Vlahakos, Demetrios; Arkadopoulos, Nikolaos; Kostopanagiotou, Georgia; Siasiakou, Sofia; Kaklamanis, Loukas; Degiannis, Dimitrios; Demonakou, Maria; Smyrniotis, Vassilios

    2012-04-01

    We have previously shown that deferoxamine (DFO) infusion protected myocardium against reperfusion injury in patients undergoing open heart surgery, and reduced brain edema, intracranial pressure, and lung injury in pigs with acute hepatic ischemia (AHI). The purpose of this research was to study if DFO could attenuate sepsis inflammatory response syndrome (SIRS) and confer renoprotection in the same model of AHI in anesthetized pigs. Fourteen animals were randomly allocated to two groups. In the Group DFO (n=7), 150mg/kg of DFO dissolved in normal saline was continuously infused in animals undergoing hepatic devascularization and portacaval anastomosis. The control group (Group C, n=7) underwent the same surgical procedure and received the same volume of normal saline infusion. Animals were euthanized after 24h. Hematological, biochemical parameters, malondialdehyde (MDA), and cytokines (interleukin [IL]-1β, IL-6, IL-8, IL-10, and tumor necrosis factor-α) were determined from sera obtained at baseline, at 12h, and after euthanasia. Hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling were used to evaluate necrosis and apoptosis, respectively, in kidney sections obtained after euthanasia. A rapid and substantial elevation (more than 100-fold) of serum IL-6 levels was observed in Group C reaching peak at the end of the experiment, associated with increased production of oxygen free radicals and lipid peroxidation (MDA 3.2±0.1nmol/mL at baseline and 5.5±0.9nmol/mL at the end of the experiment, P<0.05) and various manifestations of SIRS and multiple organ dysfunction (MOD), including elevation of high-sensitivity C-reactive protein, severe hypotension, leukocytosis, thrombocytopenia, hypoproteinemia, and increased serum levels of lactate dehydrogenase (fourfold), alkaline phosphatase (fourfold), alanine aminotransferase (14-fold), and ammonia (sevenfold). In sharp contrast, IL-6 production and lipid

  17. Ligustrazine attenuates oxidative stress-induced activation of hepatic stellate cells by interrupting platelet-derived growth factor-β receptor-mediated ERK and p38 pathways

    SciTech Connect

    Zhang, Feng; Ni, Chunyan; Kong, Desong; Zhang, Xiaoping; Zhu, Xiaojing; Chen, Li; Lu, Yin; Zheng, Shizhong

    2012-11-15

    Hepatic fibrosis represents a frequent event following chronic insult to trigger wound healing reactions with accumulation of extracellular matrix (ECM) in the liver. Activation of hepatic stellate cells (HSCs) is the pivotal event during liver fibrogenesis. Compelling evidence indicates that oxidative stress is concomitant with liver fibrosis irrespective of the underlying etiology. Natural antioxidant ligustrazine exhibits potent antifibrotic activities, but the mechanisms are poorly understood. Our studies were to investigate the ligustrazine effects on HSC activation stimulated by hydrogen peroxide (H{sub 2}O{sub 2}), an in vitro model mimicking the oxidative stress in liver fibrogenesis, and to elucidate the possible mechanisms. Our results demonstrated that H{sub 2}O{sub 2} at 5 μM significantly stimulated HSC proliferation and expression of marker genes of HSC activation; whereas ligustrazine dose-dependently suppressed proliferation and induced apoptosis in H{sub 2}O{sub 2}-activated HSCs, and attenuated expression of fibrotic marker genes. Mechanistic investigations revealed that ligustrazine reduced platelet-derived growth factor-β receptor (PDGF-βR) expression and blocked the phosphorylation of extracellular regulated protein kinase (ERK) and p38 kinase, two downstream effectors of PDGF-βR. Further molecular evidence suggested that ligustrazine interruption of ERK and p38 pathways was dependent on the blockade of PDGF-βR and might be involved in ligustrazine reduction of fibrotic marker gene expression under H{sub 2}O{sub 2} stimulation. Furthermore, ligustrazine modulated some proteins critical for HSC activation and ECM homeostasis in H{sub 2}O{sub 2}-stimulated HSCs. These data collectively indicated that ligustrazine could attenuate HSC activation caused by oxidative stress, providing novel insights into ligustrazine as a therapeutic option for hepatic fibrosis. Highlights: ► Ligustrazine inhibits oxidative stress-induced HSC activation.

  18. Toyocamycin attenuates free fatty acid-induced hepatic steatosis and apoptosis in cultured hepatocytes and ameliorates nonalcoholic fatty liver disease in mice

    PubMed Central

    Takahara, Ikuko; Akazawa, Yuko; Tabuchi, Maiko; Matsuda, Katsuya; Miyaaki, Hisamitsu; Kido, Youko; Kanda, Yasuko; Taura, Naota; Ohnita, Ken; Takeshima, Fuminao; Sakai, Yusuke; Eguchi, Susumu; Nakashima, Masahiro; Nakao, Kazuhiko

    2017-01-01

    Background and aims A high serum level of saturated free fatty acids (FFAs) is associated with the development of nonalcoholic fatty liver disease (NAFLD). X-box binding protein-1 (XBP-1) is activated by FFA treatment upon splicing. XBP-1 is a transcription factor induced by the endoplasmic reticulum (ER) stress sensor endoribonuclease inositol-requiring enzyme 1 alpha (IRE1α). However, the role of XBP-1 in NAFLD remains relatively unexplored. Toyocamycin was recently reported to attenuate the activation of XBP-1, possibly by inducing a conformational change in IRE1α. In this study, we examined the effect of toyocamycin on hepatocyte lipoapoptosis and steatosis. We also explored the effects of toyocamycin in a mouse model of NAFLD. Methods Huh-7 cells and isolated rat primary hepatocytes were treated with palmitic acid (PA), which is a saturated FFA, in the presence or absence of toyocamycin. In addition, male C57BL/6J mice were fed a diet rich in saturated fat, fructose, and cholesterol (FFC) for 4 months, after which the effect of toyocamycin was assessed. Results Toyocamycin attenuated FFA-induced steatosis. It also significantly reduced PA-induced hepatocyte lipoapoptosis. In addition, toyocamycin reduced the expression of cytosine-cytosine-adenosine-adenosine-thymidine enhancer-binding protein homologous protein (CHOP), which is a key player in ER stress-mediated apoptosis, as well as its downstream cell death modulator, death receptor 5. In the in vivo study, toyocamycin ameliorated the liver injury caused by FFC-induced NAFLD. It also reduced hepatic steatosis and the expression of lipogenic genes. Conclusions The data we obtained suggest that toyocamycin attenuates hepatocyte lipogenesis and ameliorates NAFLD in vivo and may therefore be beneficial in the treatment of NAFLD in humans. PMID:28278289

  19. Pharmacology in health food: metabolism of quercetin in vivo and its protective effect against arteriosclerosis.

    PubMed

    Ishizawa, Keisuke; Yoshizumi, Masanori; Kawai, Yoshichika; Terao, Junji; Kihira, Yoshitaka; Ikeda, Yasumasa; Tomita, Shuhei; Minakuchi, Kazuo; Tsuchiya, Koichiro; Tamaki, Toshiaki

    2011-01-01

    Quercetin, a member of the bioflavonoids family, has been proposed to have anti-atherogenic, anti-inflammatory, and anti-hypertensive properties leading to the beneficial effects against cardiovascular diseases. It was recently demonstrated that quercetin 3-O-β-D-glucuronide (Q3GA) is one of the major quercetin conjugates in human plasma, in which the aglycone could not be detected. Although most of the in vitro pharmacological studies have been carried out using only the quercetin aglycone form, experiments using Q3GA would be important to discover the preventive mechanisms of cardiovascular diseases by quercetin in vivo. Therefore we examined the effects of the chemically synthesized Q3GA, as an in vivo form, on vascular smooth muscle cell (VSMC) disorders related to the progression of arteriosclerosis. Platelet-derived growth factor-induced cell migration and proliferation were inhibited by Q3GA in VSMCs. Q3GA attenuated angiotensin II-induced VSMC hypertrophy via its inhibitory effect on JNK and the AP-1 signaling pathway. Q3GA scavenged 1,1-diphenyl-2-picrylhydrazyl radical measured by the electron paramagnetic resonance method. In addition, immunohistochemical studies with monoclonal antibody 14A2 targeting the Q3GA demonstrated that the positive staining specifically accumulates in human atherosclerotic lesions, but not in the normal aorta. These findings suggest Q3GA would be an active metabolite of quercetin in plasma and may have preventative effects on arteriosclerosis relevant to VSMC disorders.

  20. New Approaches to Attenuated Hepatitis a Vaccine Development: Cloning and Sequencing of Cell-Culture Adapted Viral cDNA.

    DTIC Science & Technology

    1987-10-13

    reverse if necessary and identify by block number) FIELD GROUP SUB-GROUP Hepatitis A Vaccine, Molecular Cloning and Hybridization, 06 13 Strain Differences...cells. Molecular cloning of p16 HM175 virus cDNA. cDNA clones were derived from p16 HM175 virus RNA by cloning cDNA-RNA hybrid molecules into the Pstl... molecular cloning . Clones derived from cDNA synthesized with oligo-dT_12 18 as primer were nearly always restricted to the 3’ terminus of the genome, while

  1. Live Attenuated Vaccine Based on Duck Enteritis Virus against Duck Hepatitis A Virus Types 1 and 3

    PubMed Central

    Zou, Zhong; Ma, Ji; Huang, Kun; Chen, Huanchun; Liu, Ziduo; Jin, Meilin

    2016-01-01

    As causative agents of duck viral hepatitis, duck hepatitis A virus type 1 (DHAV-1) and type 3 (DHAV-3) causes significant economic losses in the duck industry. However, a licensed commercial vaccine that simultaneously controls both pathogens is currently unavailable. Here, we generated duck enteritis virus recombinants (rC-KCE-2VP1) containing both VP1 from DHAV-1 (VP1/DHAV-1) and VP1 from DHAV-3 (VP1/DHAV-3) between UL27 and UL26. A self-cleaving 2A-element of FMDV was inserted between the two different types of VP1, allowing production of both proteins from a single open reading frame. Immunofluorescence and Western blot analysis results demonstrated that both VP1 proteins were robustly expressed in rC-KCE-2VP1-infected chicken embryo fibroblasts. Ducks that received a single dose of rC-KCE-2VP1 showed potent humoral and cellular immune responses and were completely protected against challenges of both pathogenic DHAV-1 and DHAV-3 strains. The protection was rapid, achieved as early as 3 days after vaccination. Moreover, viral replication was fully blocked in vaccinated ducks as early as 1 week post-vaccination. These results demonstrated, for the first time, that recombinant rC-KCE-2VP1 is potential fast-acting vaccine against DHAV-1 and DHAV-3. PMID:27777571

  2. Aucubin and its hydrolytic derivative attenuate activation of hepatic stellate cells via modulation of TGF-β stimulation.

    PubMed

    Lv, Pei-Yu; Feng, Han; Huang, Wei-Hua; Tian, Ying-Ying; Wang, Ya-Qin; Qin, Yu-Hua; Li, Xiao-Hui; Hu, Kai; Zhou, Hong-Hao; Ouyang, Dong-Sheng

    2017-03-01

    Eucommia ulmoides is an important traditional Chinese medicine and has been used as a tonic with a long history. Aucubin is an active component extracted from Eucommia ulmoides, which has liver-protection effects. However the mechanisms are still unclear. To investigate the inhibitory effects and the underlying mechanisms of aucubin on TGF-β1-induced activation of hepatic stellate cells and ECM deposition, Human hepatic stellate cells (LX-2 cells) were incubated with TGF-β1 to evaluate the anti-fibrotic effect of aucubin. Western blot was used to investigate the expression of α-SMA, Col I, Col III, MMP-2 and TIMP-1. ROS production was monitored using DCFH-DA probe, and NOX4 expression was detected by Real-time PCR. Results indicated that TGF-β1 stimulated the activation and ECM deposition of LX-2 cells. Compared with the control group, aucubin and aucubigenin both reduced the protein expression of α-SMA, Col I, Col III and MMP-2 in LX-2 cells. Aucubin and aucubigenin also suppressed the generation of ROS and down-regulated the NOX4 mRNA expression. Taken together, aucubin and aucubigenin both inhibit the activation and ECM deposition of LX-2 cells activated by TGF-β1. Aucubin and aucubigenin are potential therapeutic candidate drugs for liver fibrosis.

  3. A method to determine quercetin by enhanced luminol electrogenerated chemiluminescence (ECL) and quercetin autoxidation.

    PubMed

    Lei, Rong; Xu, Xiao; Yu, Fei; Li, Na; Liu, Hu-Wei; Li, Kèan

    2008-05-30

    Quercetin greatly enhanced luminol electrochemiluminescence of quercetin in alkaline solution. When the concentration of luminol was 0.1 mol L(-1), the detection limit for quercetin was 2.0x10(-8) mol L(-1) with a linear range from 1.0x10(-7) to 2x10(-5) mol L(-1). The pH and buffer substantially affected ECL intensity. Quercetin was autoxidized in alkaline aqueous solution. The rate of autoxidation of quercetin in various pH buffers and borate concentrations were measured. Borate was found to inhibit quercetin autoxidation and compromise quercetin enhancement effect on luminol ECL to some extent. Two final autoxidation products were identified with LC-MS methods. Autoxidation process was associated with enhancement of ECL intensity. The ROS generated during quercetin autoxidation enhanced the ECL intensity.

  4. Quercetin, not caffeine, is a major neuroprotective component in coffee.

    PubMed

    Lee, Moonhee; McGeer, Edith G; McGeer, Patrick L

    2016-10-01

    Epidemiologic studies indicate that coffee consumption reduces the risk of Parkinson's disease and Alzheimer's disease. To determine the factors involved, we examined the protective effects of coffee components. The test involved prevention of neurotoxicity to SH-SY5Y cells that was induced by lipopolysaccharide plus interferon-γ or interferon-γ released from activated microglia and astrocytes. We found that quercetin, flavones, chlorogenic acid, and caffeine protected SH-SY5Y cells from these toxins. They also reduced the release of tumor necrosis factor-α and interleukin-6 from the activated microglia and astrocytes and attenuated the activation of proteins from P38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa light chain enhancer of activated B cells (NFκB). After exposure to toxin containing glial-stimulated conditioned medium, we also found that quercetin reduced oxidative/nitrative damage to DNA, as well as to the lipids and proteins of SH-SY5Y cells. There was a resultant increase in [GSH]i in SH-SY5Y cells. The data indicate that quercetin is the major neuroprotective component in coffee against Parkinson's disease and Alzheimer's disease.

  5. Mood and Vigilance Following Quercetin Supplementation

    DTIC Science & Technology

    2007-11-02

    controlled study was undertaken to test whether quercetin aglycone affects mood and vigilance in humans. Block randomization was used to assign 57...2,000 mg quercetin or 2,000 mg placebo 1 hour prior to completing a 45-minute scanning visual vigilance task. Profile of Mood States (POMS... quercetin concentrations were measured in plasma samples collected 2-hours after treatment. The caffeine group significantly outperformed the placebo group

  6. Intake of a Western diet containing cod instead of pork alters fatty acid composition in tissue phospholipids and attenuates obesity and hepatic lipid accumulation in mice.

    PubMed

    Liisberg, Ulrike; Fauske, Kristin Røen; Kuda, Ondrej; Fjære, Even; Myrmel, Lene Secher; Norberg, Nina; Frøyland, Livar; Graff, Ingvild Eide; Liaset, Bjørn; Kristiansen, Karsten; Kopecky, Jan; Madsen, Lise

    2016-07-01

    The content of the marine n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is far lower in lean than in fatty seafood. Cod filets contain less than 2g fat per kg, whereof approximately 50% is EPA and DHA. However, a large fraction of these n-3 PUFAs is present in the phospholipid (PL) fraction and may have high bioavailability and capacity to change the endocannabinoid profile. Here we investigated whether exchanging meat from a lean terrestrial animal with cod in a background Western diet would alter the endocannabinoid tone in mice and thereby attenuate obesity development and hepatic lipid accumulation. Accordingly, we prepared iso-caloric diets with 15.1 energy (e) % protein, 39.1 e% fat and 45.8 e% carbohydrates using freeze-dried meat from cod filets or pork sirloins, and using a combination of soybean oil, corn oil, margarine, milk fat, and lard as the fat source. Compared with mice receiving diets containing pork, mice fed cod gained less adipose tissue mass and had a lower content of hepatic lipids. This was accompanied by a lower n-6 to n-3 ratio in liver PLs and in red blood cells (RBCs) in the mice. Furthermore, mice receiving the cod-containing diet had lower circulating levels of the two major endocannabinoids, N-arachidonoylethanolamine and 2-arachidonoylglycerol. Together, our data demonstrate that despite the relatively low content of n-3 PUFAs in cod fillets, the cod-containing diet could exert beneficial metabolic effects.

  7. Controlled attenuation parameter using the FibroScan® XL probe for quantification of hepatic steatosis for non-alcoholic fatty liver disease in an Asian population

    PubMed Central

    Nik Mustapha, Nik Raihan; Wong, Grace Lai-Hung; Wong, Vincent Wai-Sun; Mahadeva, Sanjiv

    2016-01-01

    Background The FibroScan® XL probe reduces failure of liver stiffness measurement (LSM) and unreliable results in obese patients. Objective The objective of this article is to evaluate the accuracy of controlled attenuation parameter (CAP) obtained using the XL probe for the estimation of hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD). Methods Adult NAFLD patients with a liver biopsy within six months were included and were examined with the FibroScan® M and XL probes. Histopathological findings were reported according to the Non-Alcoholic Steatohepatitis Clinical Research Network Scoring System. Participants who did not have fatty liver on ultrasonography were recruited as controls. Results A total of 57 NAFLD patients and 22 controls were included. The mean age of the NAFLD patients and controls was 50.1 ± 10.4 years and 20.2 ± 1.3 years, respectively (p = 0.000). The mean body mass index was 30.2 ± 5.0 kg per m2 and 20.5 ± 2.4 kg per m2, respectively (p = 0.000). The distribution of steatosis grades were: S0, 29%; S1, 17%; S2, 35%; S3, 19%. The AUROC for estimation of steatosis grade ≥ S1, S2 and S3 was 0.94, 0.80 and 0.69, respectively, using the M probe, and 0.97, 0.81 and 0.67, respectively, using the XL probe. Conclusion CAP obtained using the XL probe had similar accuracy as the M probe for the estimation of hepatic steatosis in NAFLD patients.

  8. Methane Attenuates Hepatic Ischemia/Reperfusion Injury in Rats Through Antiapoptotic, Anti-Inflammatory, and Antioxidative Actions.

    PubMed

    Ye, Zhouheng; Chen, Ouyang; Zhang, Rongjia; Nakao, Atsunori; Fan, Danfeng; Zhang, Ting; Gu, Zhengyong; Tao, Hengyi; Sun, Xuejun

    2015-08-01

    Hepatic ischemia/reperfusion (I/R) injury, which occurs in various diseases, introduces severe tissue damage and liver dysfunction. However, no promising therapies for such a significant condition currently exist. Methane has been suggested to exert a protective effect against intestinal I/R injury. In this study, we introduced methane to treat hepatic I/R injury to show its promising protective effect. Also, intraperitoneal injection with methane-rich saline, which could have potential clinical applications, was applied as a new method. Partial liver warm ischemia was applied in Sprague-Dawley rats for 60 min followed by succedent reperfusion. In the test for effective dosage, methane-rich saline was administrated intraperitoneally to the rats at doses of 1, 5, 20, or 40 mL/kg at onset of reperfusion. In the test for protective effect, rats received methane-rich saline intraperitoneally at a dose of 10 mL/kg before the initiation of reperfusion. We found that methane-rich saline significantly decreased serum alanine aminotransferase, aspartate aminotransferase activity, and the occurrence of necrosis. Moreover, methane-rich saline reduced the amount of caspase-3 and the number of apoptotic cells. In addition, methane-rich saline increased the level of superoxide dismutase and decreased the level of malondialdehyde and 8-hydroxyguanosine. Furthermore, research indicated that methane-rich saline markedly decreased gene expression and content of tumor necrosis factor-α and interleukin-6. Also, reduced CD68-positive cells showed decreased inflammatory cells in the liver. Our results suggest that methane protects the liver against I/R injury through antiapoptotic, antioxidative, and anti-inflammatory actions.

  9. Hydrodynamics-based transfection of rat interleukin-10 gene attenuates porcine serum-induced liver fibrosis in rats by inhibiting the activation of hepatic stellate cells.

    PubMed

    Huang, Yue-Hong; Chen, Yun-Xin; Zhang, Li-Juan; Chen, Zhi-Xin; Wang, Xiao-Zhong

    2014-09-01

    Liver fibrosis is the common pathological outcome for the majority of chronic liver diseases. Interleukin-10 (IL-10) is a cytokine that downregulates proinflammatory responses and has a modulatory effect on liver fibrogenesis. However, little is known regarding the effect of rat interleukin‑10 (rIL‑10) gene by hydrodynamics-based transfection (HBT) on liver fibrosis in rats. The aim of this study was to investigate the effect of the rIL-10 gene by HBT on the progression of liver fibrosis induced by porcine serum (PS) in rats and explore its possible mechanism. Plasmid‑expressing rIL-10 was transferred into rats by HBT and immunohistochemistry and RT-PCR were used to detect the major organ expressing rIL-10. Liver fibrosis was induced in rats by intraperitoneal administration of PS for 8 weeks. Plasmid pcDNA3-rIL-10 solution was administered weekly by HBT starting at the 5th week. Liver function and hepatic histology were examined. The possible molecular mechanisms of rIL-10 gene therapy were assessed in liver tissue and hepatic stellate cells (HSCs) co-cultured with BRL cells (a hepatocyte line) in vitro. The results showed rIL-10 expression occurred mainly in the liver following rIL-10 gene transfer by HBT. Maintaining a stable expression of rIL-10 in serum was assessed by repeated administration. The rIL-10 gene treatment attenuated liver inflammation and fibrosis in PS-induced fibrotic rats, reduced the deposition of collagen and the expression of α-smooth muscle actin (α-SMA) in fibrotic rats. The in vitro experiment showed that the expression of a-SMA and procollagen type I in HSCs co-cultured with the BRL‑transfected rIL-10 gene were significantly decreased. These findings indicate that rIL-10 gene therapy by HBT attenuates PS-induced liver fibrosis in rats and that its mechanism is associated with rIL-10 inhibiting the activation of HSCs and promoting the degeneration of collagen.

  10. Enriched cereal bars are more effective in increasing plasma quercetin compared with quercetin from powder-filled hard capsules.

    PubMed

    Egert, Sarah; Wolffram, Siegfried; Schulze, Beate; Langguth, Peter; Hubbermann, Eva Maria; Schwarz, Karin; Adolphi, Berit; Bosy-Westphal, Anja; Rimbach, Gerald; Müller, Manfred James

    2012-02-01

    The flavonol quercetin, is one of the major flavonoids found in edible plants. The bioavailability of quercetin in humans may be influenced by the food matrix in which it is consumed as well as by its chemical and physical form. The objective of the present study was to investigate the biokinetics of quercetin from quercetin-enriched cereal bars and quercetin powder-filled hard capsules. In a randomised, single-blinded, diet-controlled cross-over study, six healthy women aged 22-28 years took a single oral dose of approximately 130 mg quercetin equivalents from either quercetin-enriched cereal bars (containing 93·3 % quercetin aglycone plus 6·7 % quercetin-4'-glucoside) or quercetin powder-filled hard capsules (100 % quercetin aglycone). Blood samples were drawn before and after quercetin administration over a 24 h period. The concentrations of quercetin and its monomethylated derivatives, isorhamnetin (3'-O-methyl quercetin) and tamarixetin (4'-O-methyl quercetin), were measured by HPLC with fluorescence detection after plasma enzymatic treatment. The systemic availability as determined by comparing the plasma concentration-time curves of quercetin was found to be five times and the cmax values six times higher after ingestion of 130 mg quercetin by quercetin-enriched cereal bars than after ingestion by quercetin capsules. In contrast, tmax did not differ significantly between the two treatments. The cmax values for isorhamnetin and tamarixetin were four and nine times higher after ingestion of quercetin by quercetin-enriched cereal bars than after ingestion by quercetin capsules. In conclusion, quercetin from quercetin-enriched cereal bars is significantly more bioavailable than from quercetin powder-filled hard capsules.

  11. Long term follow-up study to evaluate immunogenicity and safety of a single dose of live attenuated hepatitis a vaccine in children.

    PubMed

    Mitra, Monjori; Shah, Nitin; Faridi, Mma; Ghosh, Apurba; Sankaranarayanan, V S; Aggarwal, Anju; Chatterjee, Suparna; Bhattacharyya, Nisha; Kadhe, Ganesh; Vishnoi, Gaurav; Mane, Amey

    2015-01-01

    Worldwide, viral hepatitis continues to be a cause of considerable morbidity and mortality. Mass immunization with a single dose of live attenuated HAV has been shown to significantly reduce disease burden in the community. This was a phase IV, 5-year follow up study carried out at 4 centers (Kolkata, Delhi, Mumbai and Chennai) across India. The subjects with antibody titer <20 mIU/mL at baseline were evaluated for long term immunogenicity. Of the 503 subjects enrolled, 349 subjects were baseline seronegative with an anti-HAV antibody titer <20 mIU/mL. Overall, 343 subjects could be followed up at some point of time during this 5 y post vaccination period. In the last year (60 months) of follow-up, 108 subjects (97.3%) of 111 subjects (who came for follow-up at the end of 5 y) had a protective antibody titer (anti-HAV antibody titer >20 mIU/mL). The seroconversion rates considering seroprotection levels of anti-HAV antibody titer >20 mIU/mL, following vaccination starting from 6 weeks, 6 months, 12 months, 24 months, 36 months, 48 months and 60 months were 95.1%, 97.9%, 98.3%, 96.2%, 97.8%, 92.6% and 97.3%, respectively. The geometric mean concentration (GMC) over the years increased from 64.9 mIU/mL at 6 weeks to 38.1 mIU/mL and 135.2 mIU/mL at 6 months and 12 months, respectively and was maintained at 127.1 mIU/mL at 60 months. In conclusion, the result of this 5-year follow up study showed that the single dose of live attenuated vaccine is well tolerated and provides long-term immunogenicity in healthy Indian children.

  12. Dioscin alleviates alcoholic liver fibrosis by attenuating hepatic stellate cell activation via the TLR4/MyD88/NF-κB signaling pathway

    PubMed Central

    Liu, Min; Xu, Youwei; Han, Xu; Yin, Lianhong; Xu, Lina; Qi, Yan; Zhao, Yanyan; Liu, Kexin; Peng, Jinyong

    2015-01-01

    The present work aimed to investigate the activities and underlying mechanisms of dioscin against alcoholic liver fibrosis (ALF). In vivo liver fibrosis in mice was induced by an alcoholic liquid diet, and in vitro studies were performed on activated HSC-T6 and LX2 cells treated with lipopolysaccharide. Our results showed that dioscin significantly attenuated hepatic stellate cells (HSCs) activation, improved collagen accumulation, and attenuated inflammation through down-regulating the levels of myeloid differentiation factor 88 (MyD88), nuclear factor κB (NF-κB), interleukin (IL)-1, IL-6 and tumour necrosis factor-α by decreasing Toll-like receptor (TLR)4 expression both in vivo and in vitro. TLR4 overexpression was also decreased by dioscin, leading to the markedly down-regulated levels of MyD88, NF-κB, transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA) and type I collagen (COL1A1) in cultured HSCs. Suppression of cellular MyD88 by ST2825 or abrogation of NF-κB by pyrrolidine dithiocarbamate eliminated the inhibitory effects of dioscin on the levels of TGF-β1, α-SMA and COL1A1. In a word, dioscin exhibited potent effects against ALF via altering TLR4/MyD88/NF-κB signaling pathway, which provided novel insights into the mechanisms of this compound as an antifibrogenic candidate for the treatment of ALF in the future. PMID:26655640

  13. Herbal compound “Songyou Yin” attenuates hepatoma cell invasiveness and metastasis through downregulation of cytokines secreted by activated hepatic stellate cells

    PubMed Central

    2013-01-01

    Background Activated hepatic stellate cells (aHSCs) play an important role in the progression of hepatocellular carcinoma (HCC). Here, we determined if cytokines secreted in response to the herbal compound “Songyou Yin” (SYY) treatment of aHSCs could influence invasiveness and metastatic capabilities of hepatoma cells. Methods Primary rat hepatic stellate cells (HSCs) were isolated, activated, divided into SYY treated and untreated (nSYY) groups, and conditioned media (CM-SYY and CM-nSYY, respectively) were collected. The hepatoma cell line, McA-RH7777 was cultured for 4 weeks with SYY, CM-SYY, and CM-nSYY, designated McA-SYY, McA-SYYCM and McA-nSYYCM. The invasiveness and metastatic capabilities were evaluated using Matrigel invasion assay in vitro and pulmonary metastasis in vivo. Matrix metalloproteinase-2 (MMP-2), MMP-9, E-cadherin, N-cadherin, and vimentin protein levels in McA-SYYCM and McA-nSYYCM were evaluated by Western blot. Cytokine levels in conditioned media were tested using enzyme-linked immunosorbent assay (ELISA). Results Matrigel invasion assay indicated that the number of McA-SYYCM cells passing through the basement membrane was less than in McA-nSYYCM cells (P < 0.01). Similar results were also observed in vivo for lung metastasis. McA-SYYCM cells showed less pulmonary metastasis capabilities than McA-nSYYCM cells (P < 0.001). The reduced expression of MMP-2 and reversed epithelial to mesenchymal transition with E-cadherin upregulation, and N-cadherin and vimentin downregulation were also found in McA-SYYCM compared to McA-nSYYCM. Metastasis-promoting cytokines hepatocyte growth factor, interleukin-6, transforming growth factor-β1, and vascular endothelial growth factor were markedly decreased in CM-SYY compared to CM-nSYY. Conclusions SYY attenuates hepatoma cell invasiveness and metastasis capabilities through downregulating cytokines secreted by activated hepatic stellate cells. PMID:23622143

  14. Magnolol Attenuates Concanavalin A-induced Hepatic Fibrosis, Inhibits CD4(+) T Helper 17 (Th17) Cell Differentiation and Suppresses Hepatic Stellate Cell Activation: Blockade of Smad3/Smad4 Signalling.

    PubMed

    Zhang, Hongjun; Ju, Baoling; Zhang, Xiaoli; Zhu, Yanfei; Nie, Ying; Xu, Yuanhong; Lei, Qiuxia

    2016-12-29

    Magnolol is a pharmacological biphenolic compound extracted from Chinese herb Magnolia officinalis, which displays anti-inflammatory and antioxidant effects. This study was aimed at exploring the potential effect of magnolol on immune-related liver fibrosis. Herein, BALB/c mice were injected with concanavalin A (ConA, 8 mg/kg/week) up to 6 weeks to establish hepatic fibrosis, and magnolol (10, 20, 30 mg/kg/day) was given to these mice orally throughout the whole experiment. We found that magnolol preserved liver function and attenuated liver fibrotic injury in vivo. In response to ConA stimulation, the CD4(+) T cells preferred to polarizing towards CD4(+) T helper 17 (Th17) cells in liver. Magnolol was observed to inhibit Th17 cell differentiation in ConA-treated liver in addition to suppressing interleukin (IL)-17A generation. Hepatic stellate cells were activated in fibrotic liver as demonstrated by increased alpha smooth muscle actin (α-SMA) and desmin. More transforming growth factor (TGF)-β1 and activin A were secreted into the serum. Magnolol suppressed this abnormal HSC activation. Furthermore, the phosphorylation of Smad3 in its linker area (Thr179, Ser 204/208/213) was inhibited by magnolol. In vitro, the recombinant IL-17A plus TGF-β1 or activin A induced activation of human LX2 HSCs and promoted their collagen production. Smad3/Smad4 signalling pathway was activated in LX2 cells exposed to the fibrotic stimuli, as illustrated by the up-regulated phospho-Smad3 and the enhanced interaction between Smad3 and Smad4. These alterations were suppressed by magnolol. Collectively, our study reveals a novel antifibrotic effect of magnolol on Th17 cell-mediated fibrosis.

  15. Flavonoid quercetin protects against swimming stress-induced changes in oxidative biomarkers in the hypothalamus of rats.

    PubMed

    Haleagrahara, Nagaraja; Radhakrishnan, Ammu; Lee, Nagarajah; Kumar, Ponnusamy

    2009-10-25

    Quercetin is a bioflavonoid abundant in onions, apples, tea and red wine and one of the most studied flavonoids. Dietary quercetin intake is suggested to be health promoting, but this assumption is mainly based on mechanistic studies performed in vitro. The objective of this study was to investigate the effect of quercetin on stress-induced changes in oxidative biomarkers in the hypothalamus of rats. Adult male Sprague Dawley rats were subjected to forced swimming stress for 45 min daily for 14 days. Effect of quercetin at three different doses (10, 20 and 30 mg/kg body weight) on serum corticosterone and oxidative biomarkers (lipid hydroperoxides, antioxidant enzymes and total antioxidants) was estimated. Swimming stress significantly increased the serum corticosterone and lipid hydroperoxide levels. A significant decrease in total antioxidant levels and super oxide dismutase, glutathione peroxidase and catalase levels was seen in the hypothalamus after stress and treatment with quercetin significantly increased these oxidative parameters and there was a significant decrease in lipid hydroperoxide levels. These data demonstrate that forced swimming stress produced a severe oxidative damage in the hypothalamus and treatment with quercetin markedly attenuated these stress-induced changes. Antioxidant action of quercetin may be beneficial for the prevention and treatment of stress-induced oxidative damage in the brain.

  16. Effect of different exposed lights on quercetin and quercetin glucoside content in onion (Allium cepa L.)

    PubMed Central

    Ko, Eun Young; Nile, Shivraj Hariram; Sharma, Kavita; Li, Guan Hao; Park, Se Won

    2014-01-01

    Quercetin and quercetin glucosides are the major flavonols present in onion (Allium cepa L.) and are predominantly present as quercetin, quercetin-3,4′-diglucoside and quercetin-4′-glucoside. Effect of different light wavelengths on onion after harvest and storage, with fluorescent, blue, red and ultra violet light influenced the quercetin and quercetin glucosides profile. In a peeled onion, all the light treatments elevated quercetin content in bulb. Among them, particularly fluorescent light effect was more eminent which stimulates the maximum synthesis of quercetin in onion. In case of whole onion bulb, skin and pulp showed different responses to light treatment, respectively. The pulp had the highest quercetin glucosides under blue light, whereas the lowest under fluorescent light. Onion skin showed nearly opposite pattern as compared to the pulp. In particular, light treatment proved to be a better way to increase the level of quercetin content in onions which might be utilized for industrial production of bioactive compounds from onion and onion waste products. PMID:26150744

  17. Effect of different exposed lights on quercetin and quercetin glucoside content in onion (Allium cepa L.).

    PubMed

    Ko, Eun Young; Nile, Shivraj Hariram; Sharma, Kavita; Li, Guan Hao; Park, Se Won

    2015-07-01

    Quercetin and quercetin glucosides are the major flavonols present in onion (Allium cepa L.) and are predominantly present as quercetin, quercetin-3,4'-diglucoside and quercetin-4'-glucoside. Effect of different light wavelengths on onion after harvest and storage, with fluorescent, blue, red and ultra violet light influenced the quercetin and quercetin glucosides profile. In a peeled onion, all the light treatments elevated quercetin content in bulb. Among them, particularly fluorescent light effect was more eminent which stimulates the maximum synthesis of quercetin in onion. In case of whole onion bulb, skin and pulp showed different responses to light treatment, respectively. The pulp had the highest quercetin glucosides under blue light, whereas the lowest under fluorescent light. Onion skin showed nearly opposite pattern as compared to the pulp. In particular, light treatment proved to be a better way to increase the level of quercetin content in onions which might be utilized for industrial production of bioactive compounds from onion and onion waste products.

  18. Taurine Attenuates Hepatic Inflammation in Chronic Alcohol-Fed Rats Through Inhibition of TLR4/MyD88 Signaling

    PubMed Central

    Lin, Chao-Jen; Chiu, Chun-Ching; Chen, Yi-Chen; Chen, Mu-Lin

    2015-01-01

    Abstract Accumulating evidence indicates that overconsumption of ethanol contributes in many ways to the pathogenesis of hepatic injury. Although studies indicate that taurine decreases lipogenesis, oxidative stress, and inflammatory cytokines, the protective effect of taurine against alcohol-induced liver injury is still unclear. To clarify the precise signaling involved in the beneficial effect of taurine on alcohol-induced liver injury, rats were randomly divided into four treatment groups: (1) control (Ctl), (2) alcohol (Alc), (3) Alc+taurine (Tau), and (4) Alc+silymarin (Sil). The Tau and Sil groups had lower lymphocyte infiltration and significantly lower TLR-4/MyD88 and IκB/NFκB compared to the Alc group. The inducible nitric oxide synthase (iNOS), C-reactive protein (CRP), tumor necrosis factors (TNF)-α, interleukin (IL)-6, and IL-1β were also significantly lower in the Tau and Sil groups than in the Alc group. The experimental results indicated that hepatoprotection against alcohol-induced inflammation may be mediated by decreased TLR-4/MyD88 signaling. PMID:26090712

  19. Aloe vera gel extract attenuates ethanol-induced hepatic lipid accumulation by suppressing the expression of lipogenic genes in mice.

    PubMed

    Saito, Marie; Tanaka, Miyuki; Misawa, Eriko; Yamada, Muneo; Yamauchi, Kouji; Iwatsuki, Keiji

    2012-01-01

    We have previously reported that Aloe vera gel had hypoglycemic activity and anti-obesity effects, although the effect on alcoholic fatty liver was unclear. We examined in this present study the effect of an Aloe vera gel extract (AVGE) on hepatic lipid metabolism by using an ethanol-induced transient fatty liver mouse model. Ethanol (3 g/kg of mouse weight) was orally administered to induce an accumulation of triglyceride (TG) and increase the mRNA expression of such lipogenic genes as sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FASN) in the liver. Although ethanol ingestion caused a 5.4-fold increase in liver TG, pre-treating with AVGE (1 mg/kg/d) for 1 week significantly suppressed this elevation of the ethanol-induced liver TG level. The expression of lipogenic genes was also lower in the AVGE pre-treatment group than in the control group. This inhibitory effect on the ethanol-induced accumulation of TG was attributed to a reduction in the expression of lipogenic genes that were increased by ethanol.

  20. Adenovirus-mediated expression of orphan nuclear receptor NR4A2 targeting hepatic stellate cell attenuates liver fibrosis in rats

    PubMed Central

    Chen, Pengguo; Li, Jie; Huo, Yan; Lu, Jin; Wan, Lili; Yang, Quanjun; Huang, Jinlu; Gan, Run; Guo, Cheng

    2016-01-01

    Liver fibrosis is a wound-healing response characterized with the accumulation of extracellular matrix (ECM). And hepatic stellate cells (HSCs) are the principal cell source of ECM. NR4A2 (Nurr1) is a member of orphan nuclear receptor NR4A family and acts as transcription factor. It participates in regulating cell differentiation, proliferation and apoptosis. We previously demonstrated that NR4A2 expression in fibrotic liver reduced significantly compared with normal liver and NR4A2 knockout in HSCs promoted ECM production. In the present study we explored the role of NR4A2 on liver fibrosis. Studies in cultured HSCs demonstrated that NR4A2 over-expression suppressed the activation of HSCs, such as ECM production and invasion ability. Moreover cell cycle was arrested, cell apoptosis was promoted and cell signaling pathway was influenced. Adenovirus-mediated delivery of NR4A2 in rats ameliorated significantly dimethylnitrosamine (DMN) induced liver fibrosis. The In vivo experiments produced results consistent with in vitro experiments. Taken together these results demonstrate NR4A2 enhancement attenuates liver fibrosis via suppressing the activation of HSCs and NR4A2 may be an ideal target for anti-fibrotic therapy. PMID:27646469

  1. Molecular and biochemical evidence on the protective effects of quercetin in isoproterenol-induced acute myocardial injury in rats.

    PubMed

    Kumar, Mukesh; Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Kumar, Vikas; Lahkar, Mangala

    2017-01-01

    Cardioprotection represents one of the most important and realistic aspects of preventive therapy today. Quercetin, a naturally occurring dietary flavone, has been studied extensively for its antioxidant properties. The objective of present study is to find out the cardioprotective activity and to explore the underlying mechanisms of quercetin pretreatment (50 mg/kg body weight, orally) for 14 days against isoproterenol (ISO; 100 mg/kg body weight, subcutaneously) induced myocardial infarction in Wistar rats. Cardiac diagnostic markers, oxidative stress, inflammatory cytokines, histopathology along with gene expression analysis of calpain 1 and 2 were carried out in experimental rats. Quercetin pretreatment showed protective effects on heart by significantly attenuating the ISO-induced oxidative stress, inflammation, protecting heart architecture, and by downregulation of the expression of calpain. Overall, these findings revealed the cardio-protective potential of quercetin and its mechanism of action against ISO-induced MI in rats.

  2. Inhibitory effects of quercetin on the progression of liver fibrosis through the regulation of NF-кB/IкBα, p38 MAPK, and Bcl-2/Bax signaling.

    PubMed

    Wang, Rong; Zhang, Hai; Wang, Yuanyuan; Song, Fuxing; Yuan, Yongfang

    2017-04-06

    Quercetin, a natural flavonoid, has been used as a nutritional supplement for its anti-inflammatory and antioxidative properties. Quercetin was reported to exhibit a wide range of pharmacological properties, including its effect on anti-hepatic fibrosis. However, the anti-fibrotic mechanisms of quercetin have not been well-characterized to date. This study aimed to investigate the protective effects of quercetin on carbon tetrachloride (CCl4)-induced liver fibrosis in rats and to clarify its anti-hepatofibrotic mechanisms. We demonstrated that quercetin exhibited in-vivo hepatoprotective and anti-fibrogenic effects against CCl4-induced liver injury by improving the pathological manifestations, thereby reducing the activities of serum total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and decreasing the serum levels of hyaluronic acid (HA), laminin (LN), type IV collagen (IV-C) and procollagen III peptide (PIIIP). Furthermore, treatment with quercetin 5-15mg/kg inhibited the activation of NF-κB in a dose-dependent manner via inhibition of IкBα degradation and decreased the expression of p38 MAPK by inhibiting its phosphorylation. Additionally, in a dose-dependent manner, quercetin down-regulated Bax, up-regulated Bcl-2, and subsequently inhibited caspase-3 activation. Moreover, quercetin regulated inflammation factors and hepatic stellate cells (HSCs)-activation markers, such as TNF-α, IL-6, IL-1β, Cox-2, TGF-β, α-SMA, Colla1, Colla2, TIMP-1, MMP-1, and desmin. Taken together, quercetin prevented the progression of liver fibrosis in SD rats. The anti-fibrotic mechanisms of quercetin might be associated with its ability to regulate NF-кB/IкBα, p38 MAPK anti-inflammation signaling pathways to inhibit inflammation, and regulate Bcl-2/Bax anti-apoptosis signaling pathway to prevent liver cell apoptosis.

  3. Therapeutic Effects of Quercetin on Inflammation, Obesity, and Type 2 Diabetes

    PubMed Central

    Chen, Shuang; Wu, Xiaosong

    2016-01-01

    In previous studies, abdominal obesity has been related to total low-grade inflammation and in some cases has resulted in insulin resistance and other metabolism related disorders such as diabetes. Quercetin is a polyphenol, which is a derivative of plants, and has been shown in vitro as well as in a few animal models to have several potential anti-inflammatory as well as anticarcinogenic applications. The substance has also been shown to aid in the attenuation of lipid peroxidation, platelet aggregation, and capillary permeability. However, further research is called for to gain a better understanding of how quercetin is able to provide these beneficial effects. This manuscript reviewed quercetin's anti-inflammatory properties in relation to obesity and type 2 diabetes. PMID:28003714

  4. Essential role of Nrf2 in keratinocyte protection from UVA by quercetin

    SciTech Connect

    Kimura, Shintarou; Warabi, Eiji; Yanagawa, Toru; Ma, Dongmei; Itoh, Ken; Ishii, Yoshiyuki; Kawachi, Yasuhiro; Ishii, Tetsuro

    2009-09-11

    Much of the cell injury caused by ultraviolet A (UVA) irradiation is associated with oxidative stress. Quercetin is a major natural polyphenol that is known to protect cells from UVA-induced damage. Here, we investigated the molecular mechanism of this protection. Quercetin pretreatment strongly suppressed UVA-induced apoptosis in human keratinocyte HaCaT cells, markedly increased protein levels of the transcription factor Nrf2, induced the expression of antioxidative genes, and dramatically reduced the production of reactive oxygen species following UVA irradiation. Importantly, these beneficial effects were greatly attenuated by downregulating Nrf2 expression. Thus, quercetin protects cells from UVA damage mainly by elevating intracellular antioxidative activity via the enhanced accumulation of a transcription factor for antioxidant genes, Nrf2.

  5. Gardenia jasminoides attenuates hepatocellular injury and fibrosis in bile duct-ligated rats and human hepatic stellate cells

    PubMed Central

    Chen, Ying-Hua; Lan, Tian; Li, Jing; Qiu, Chun-Hui; Wu, Teng; Gou, Hong-Ju; Lu, Min-Qiang

    2012-01-01

    AIM: To investigate the anti-hepatofibrotic effects of Gardenia jasminoides in liver fibrosis. METHODS: Male Sprague-Dawley rats underwent common bile duct ligation (BDL) for 14 d and were treated with Gardenia jasminoides by gavage. The effects of Gardenia jasminoides on liver fibrosis and the detailed molecular mechanisms were also assessed in human hepatic stellate cells (LX-2) in vitro. RESULTS: Treatment with Gardenia jasminoides decreased serum alanine aminotransferase (BDL vs BDL + 100 mg/kg Gardenia jasminoides, 146.6 ± 15 U/L vs 77 ± 6.5 U/L, P = 0.0007) and aspartate aminotransferase (BDL vs BDL + 100 mg/kg Gardenia jasminoides, 188 ± 35.2 U/L vs 128 ± 19 U/L, P = 0.005) as well as hydroxyproline (BDL vs BDL + 100 mg/kg Gardenia jasminoides, 438 ± 40.2 μg/g vs 228 ± 10.3 μg/g liver tissue, P = 0.004) after BDL. Furthermore, Gardenia jasminoides significantly reduced liver mRNA and/or protein expression of transforming growth factor β1 (TGF-β1), collagen type I (Col I) and α-smooth muscle actin (α-SMA). Gardenia jasminoides significantly suppressed the upregulation of TGF-β1, Col I and α-SMA in LX-2 exposed to recombinant TGF-β1. Moreover, Gardenia jasminoides inhibited TGF-β1-induced Smad2 phosphorylation in LX-2 cells. CONCLUSION: Gardenia jasminoides exerts antifibrotic effects in the liver fibrosis and may represent a novel antifibrotic agent. PMID:23326120

  6. Hepatitis A virus-encoded miRNAs attenuate the accumulation of viral genomic RNAs in infected cells.

    PubMed

    Shi, Jiandong; Sun, Jing; Wu, Meini; Hu, Ningzhu; Hu, Yunzhang

    2016-06-01

    The establishment of persistent infection with hepatitis A virus (HAV) is the common result of most HAV/cell culture systems. Previous observations show that the synthesis of viral RNAs is reduced during infection. However, the underlying mechanism is poorly understood. We characterized three HAV-encoded miRNAs in our previous study. In this study, we aim to investigate the impact of these miRNAs on the accumulation of viral RNAs. The results indicated that the synthesis of viral genomic RNAs was dramatically reduced (more than 75 % reduction, P < 0.05) when transfected with one or two viral miRNA mimics. Conversely, they were significantly increased (more than 3.3-fold addition, P < 0.05) when transfected with one or two viral miRNA inhibitors. The luciferase reporter assay of miRNA targets showed that viral miRNAs were fully complementary to specific sites of the viral plus or minus strand RNA and strongly inhibited their expressions. Further data showed that the relative abundance of viral genomic RNA fragments that contain miRNA targets was also dramatically reduced (more than 80 % reduction, P < 0.05) when viral miRNAs were overexpressed with miRNA mimics. In contrast, they were significantly increased (approximately 2-fold addition, P < 0.05) when viral miRNAs were inhibited with miRNA inhibitors. In conclusion, these data suggest a possible mechanism for the reduction of viral RNA synthesis during HAV infection. Thus, we propose that it is likely that RNA virus-derived miRNA could serve as a self-mediated feedback regulator during infection.

  7. Quercetin prevents chronic unpredictable stress induced behavioral dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress.

    PubMed

    Mehta, Vineet; Parashar, Arun; Udayabanu, Malairaman

    2017-03-15

    It is now evident that chronic stress is associated with anxiety, depression and cognitive dysfunction and very few studies have focused on identifying possible methods to prevent these stress-induced disorders. Previously, we identified abundance of quercetin in Urtica dioica extract, which efficiently attenuated stress related complications. Therefore, current study was designed to investigate the effect of quercetin on chronic unpredicted stress (CUS) induced behavioral dysfunction, oxidative stress and neuroinflammation in the mouse hippocampus. Animals were subjected to unpredicted stress for 21days, during which 30mg/kg quercetin was orally administered to them. Effect of CUS and quercetin treatment on animal behavior was assessed between day 22-26. Afterward, the hippocampus was processed to evaluate neuronal damage, oxidative and inflammatory stress. Results revealed that stressed animals were highly anxious (Elevated Plus Maze and Open Field), showed depressive-like behavior (sucrose preference task), performed poorly in short-term and long-term associative memory task (passive avoidance step-through task) and displayed reduced locomotion (open field). Quercetin alleviated behavioral dysfunction in chronically stressed animals. Compared to CUS, quercetin treatment significantly reduced anxiety, attenuated depression, improved cognitive dysfunction and normalized locomotor activity. Further, CUS elevated the levels of oxidative stress markers (TBARS, nitric oxide), lowered antioxidants (total thiol, catalase), enhanced expression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β and COX-2) in the hippocampus and damaged hippocampal neurons. Quercetin treatment significantly lowered oxidative and inflammatory stress and prevented neural damage. In conclusion, quercetin can efficiently prevent stress induced neurological complications by rescuing brain from oxidative and inflammatory stress.

  8. Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle

    SciTech Connect

    Khachatoorian, Ronik; Arumugaswami, Vaithilingaraja; Raychaudhuri, Santanu; Yeh, George K.; Maloney, Eden M.; Wang, Julie; and others

    2012-11-25

    We have previously demonstrated that quercetin, a bioflavonoid, blocks hepatitis C virus (HCV) proliferation by inhibiting NS5A-driven internal ribosomal entry site (IRES)-mediated translation of the viral genome. Here, we investigate the mechanisms of antiviral activity of quercetin and six additional bioflavonoids. We demonstrate that catechin, naringenin, and quercetin possess significant antiviral activity, with no associated cytotoxicity. Infectious virion secretion was not significantly altered by these bioflavonoids. Catechin and naringenin demonstrated stronger inhibition of infectious virion assembly compared to quercetin. Quercetin markedly blocked viral translation whereas catechin and naringenin demonstrated mild activity. Similarly quercetin completely blocked NS5A-augmented IRES-mediated translation in an IRES reporter assay, whereas catechin and naringenin had only a mild effect. Moreover, quercetin differentially inhibited HSP70 induction compared to catechin and naringenin. Thus, the antiviral activity of these bioflavonoids is mediated through different mechanisms. Therefore combination of these bioflavonoids may act synergistically against HCV.

  9. Quercetin protects against heat stroke-induced myocardial injury in male rats: Antioxidative and antiinflammatory mechanisms.

    PubMed

    Lin, Xiaojing; Lin, Cheng-Hsien; Zhao, Tingbao; Zuo, Dan; Ye, Zhujun; Liu, Lin; Lin, Mao-Tsun

    2017-03-01

    Heat stroke is characterized by hyperthermia, systemic inflammation, and multiple organ failure including arterial hypotension. This definition can be fulfilled by a rat model of heat stroke used in the present study. Anesthetized animals were exposed to heat exposure (43 °C for 70 min) and then returned to room temperature (26 °C) for recovery. One hour before heat exposure, an intraperitoneal dose of quercetin (30 mg/kg) or vehicle (normal saline 1 ml/kg) was administered to the experimental groups of rats. Additional injection was administered immediately after the onset of heat stroke. Immediately after the onset of heat stroke. Vehicle-treated rats displayed (i) hyperthermia; (ii) suppressed left ventricular function; (iii) decreased contents of cardiac total antioxiant capacity (e.g., superoxide dismutase, glutathione peroxidase, catalase); (iv) increased contents of cardiac oxidative capacity malondialdehyde and thiobarbituric acid reactive substances; (v) increased cardiac levels of pro-inflammatory cytokines tumor necrosis factor-α and interleukin-6; and (vi) decreased cardiac levels of an anti-inflammatory cytokine interleukin 10. Histopathologic and survival observation provided supportive evidence for biochemical analyses. These heat stroke reactions all can be significantly attenuated by quercetin therapy. Our data suggest that quercetin therapy might improve outcomes of heat stroke in rats by attenuating excessive hyperthermia as well as myocardial injury. The protective effects of quercetin could be attributed to anti-lipid peroxidative, anti-oxidant, and anti-inflammatory properties.

  10. Quercetin, luteolin, and epigallocatechin gallate promote glucose disposal in adipocytes with regulation of AMP-activated kinase and/or sirtuin 1 activity.

    PubMed

    Xiao, Na; Mei, Fan; Sun, Yan; Pan, Guojun; Liu, Baolin; Liu, Kang

    2014-08-01

    Quercetin, luteolin, and epigallocatechin gallate are flavonoids abundant in edible and medicinal plants with beneficial effects on glucose homeostasis. This study explored the action of these flavonoids on glucose disposal in adipocytes. Quercetin, luteolin, and epigallocatechin gallate enhanced glucose consumption with the positive regulation of AMP-activated kinase phosphorylation, and the AMP-activated kinase inhibitor compound C abolished their effects on glucose consumption. Luteolin and epigallocatechin gallate, but not quercetin, increased sirtuin 1 abundance, and their regulation of glucose consumption was also attenuated by co-treatment with sirtuin 1 inhibitor nicotinamide. Quercetin, luteolin, and epigallocatechin gallate suppressed nuclear factor-κB activation by inhibition of p65 phosphorylation with beneficial regulation of adipokine expression, whereas these actions were diminished by coincubation with compound C. The sirtuin 1 inhibitor nicotinamide attenuated the effects of luteolin and EGCG on p65 phosphorylation and adipokine expression without any influence on the activity of quercetin. Results of Western blot and fluorescence microscopy also showed that quercetin, luteolin, and epigallocatechin gallate increased Akt substrate of 160 kDa phosphorylation and promoted 2-deoxy-D-glucose uptake by adipocytes under basal and inflammatory conditions. These findings suggested that quercetin, luteolin, and epigallocatechin gallate inhibited inflammation and promoted glucose disposal in adipocytes with the regulation of AMP-activated kinase and/or sirtuin 1.

  11. Quercetin-induced apoptosis prevents EBV infection.

    PubMed

    Lee, Minjung; Son, Myoungki; Ryu, Eunhyun; Shin, Yu Su; Kim, Jong Gwang; Kang, Byung Woog; Cho, Hyosun; Kang, Hyojeung

    2015-05-20

    Epstein-Barr virus (EBV) is a human gamma-1 herpesvirus that establishes a lifelong latency in over 90% of the world's population. During latency, virus exists predominantly as a chromatin-associated, multicopy episome in the nuclei of a variety of tumor cells derived from B cells, T cells, natural killer (NK) cells, and epithelial cells. Licorice is the root of Glycyrrhiza uralensis or G. glabra that has traditionally cultivated in eastern part of Asia. Licorice was reported to have anti-viral, anti-inflammatory, anti-atopic, hepatoprotective, anti-neurodegenerative, anti-tumor, anti-diabetic effects and so forth. Quercetin and isoliquiritigenin are produced from licorice and highly similar in molecular structure. They have diverse bioactive effects such as antiviral activity, anti-asthmatic activity, anti-cancer activity, anti-inflammation activity, monoamine-oxidase inhibitor, and etc. To determine anti-EBV and anti-EBVaGC (Epstein-Barr virus associated gastric carcinoma) effects of licorice, we investigated antitumor and antiviral effects of quercetin and isoliquiritigenin against EBVaGC. Although both quercetin and isoliquiritigenin are cytotoxic to SNU719 cells, quercetin induced more apoptosis in SNU719 cells than isoliquiritigenin, more completely eliminated DNMT1 and DNMT3A expressions than isoliquiritigenin, and more strongly affects the cell cycle progression of SNU719 than isoliquiritigenin. Both quercetin and isoliquiritigenin induce signal transductions to stimulate apoptosis, and induce EBV gene transcription. Quercetin enhances frequency of F promoter use, whereas isoliquiritigenin enhances frequency of Q promoter use. Quercetin reduces EBV latency, whereas isoliquiritigenin increases the latency. Quercetin increases more the EBV progeny production, and inhibits more EBV infection than isoliquiritigenin. These results indicate that quercetin could be a promising candidate for antiviral and antitumor agents against EBV and human gastric carcinoma.

  12. Quercetin-induced apoptosis prevents EBV infection

    PubMed Central

    Lee, Minjung; Son, Myoungki; Ryu, Eunhyun; Shin, Yu Su; Kim, Jong Gwang; Kang, Byung Woog; Sung, Gi-Ho; Cho, Hyosun; Kang, Hyojeung

    2015-01-01

    Epstein-Barr virus (EBV) is a human gamma-1 herpesvirus that establishes a lifelong latency in over 90% of the world's population. During latency, virus exists predominantly as a chromatin-associated, multicopy episome in the nuclei of a variety of tumor cells derived from B cells, T cells, natural killer (NK) cells, and epithelial cells. Licorice is the root of Glycyrrhiza uralensis or G. glabra that has traditionally cultivated in eastern part of Asia. Licorice was reported to have anti-viral, anti-inflammatory, anti-atopic, hepatoprotective, anti-neurodegenerative, anti-tumor, anti-diabetic effects and so forth. Quercetin and isoliquiritigenin are produced from licorice and highly similar in molecular structure. They have diverse bioactive effects such as antiviral activity, anti-asthmatic activity, anti-cancer activity, anti-inflammation activity, monoamine-oxidase inhibitor, and etc. To determine anti-EBV and anti-EBVaGC (Epstein-Barr virus associated gastric carcinoma) effects of licorice, we investigated antitumor and antiviral effects of quercetin and isoliquiritigenin against EBVaGC. Although both quercetin and isoliquiritigenin are cytotoxic to SNU719 cells, quercetin induced more apoptosis in SNU719 cells than isoliquiritigenin, more completely eliminated DNMT1 and DNMT3A expressions than isoliquiritigenin, and more strongly affects the cell cycle progression of SNU719 than isoliquiritigenin. Both quercetin and isoliquiritigenin induce signal transductions to stimulate apoptosis, and induce EBV gene transcription. Quercetin enhances frequency of F promoter use, whereas isoliquiritigenin enhances frequency of Q promoter use. Quercetin reduces EBV latency, whereas isoliquiritigenin increases the latency. Quercetin increases more the EBV progeny production, and inhibits more EBV infection than isoliquiritigenin. These results indicate that quercetin could be a promising candidate for antiviral and antitumor agents against EBV and human gastric carcinoma

  13. Quercetin-6-C-β-D-glucopyranoside, natural analog of quercetin exhibits anti-prostate cancer activity by inhibiting Akt-mTOR pathway via aryl hydrocarbon receptor.

    PubMed

    Hamidullah; Kumar, Rajeev; Saini, Karan Singh; Kumar, Amit; Kumar, Sudhir; Ramakrishna, E; Maurya, Rakesh; Konwar, Rituraj; Chattopadhyay, Naibedya

    2015-12-01

    Pre-clinical studies suggest mitigating effect of dietary flavonoid quercetin against cancer and other diseases. However, quercetin suffers from poor metabolic stability, which appears to offset its pharmacological efficacy. Recently, we isolated quercetin-6-C-β-D-glucopyranoside (QCG) from Ulmus wallichiana planchon that has greater stability profile over quercetin. In the present study, the cytotoxic and apoptotic effects of QCG on prostate cancer cells were assessed. QCG inhibited prostate cancer cell proliferation by arresting cells at G0/G1 phase of cell cycle and induces apoptosis as evident from cytochrome c release, cleavage of caspase 3 and poly (ADP-ribose) polymerase. Mechanistic studies revealed that QCG inhibited reactive oxygen species (ROS) generation and Akt/mTOR cell survival pathways. Aryl hydrocarbon receptor (AhR) was a critical mediator of QCG action as knockdown of AhR attenuated QCG-induced cell cycle arrest, apoptosis and inhibition of Akt/mTOR pathway in prostate cancer cells. Taken together, our results suggest that QCG exhibits anti-cancer activity against prostate cancer cells via AhR-mediated down regulation of Akt/mTOR pathway in PC-3 cells.

  14. Uptake of quercetin and quercetin 3-glucoside from whole onion and apple peel extracts by Caco-2 cell monolayers.

    PubMed

    Boyer, Jeanelle; Brown, Dan; Liu, Rui Hai

    2004-11-17

    Evidence suggests that regular consumption of fruits and vegetables may reduce the risk of chronic diseases, and phytochemicals from fruits and vegetables may be responsible for this health benefit. However, there is limited knowledge on the bioavailability of specific phytochemicals from whole fruits and vegetables. This study used Caco-2 cells to examine uptake of quercetin aglycon and quercetin 3-glucoside as purified compounds and from whole onion and apple peel extracts. Pure quercetin aglycon was absorbed by the Caco-2 cells in higher concentrations than quercetin 3-glucoside (p < 0.05). Caco-2 cells treated with quercetin 3-glucoside accumulated both quercetin 3-glucoside and quercetin. Caco-2 cells absorbed more onion quercetin aglycon than onion quercetin 3-glucoside (p < 0.05), and the percentage of onion quercetin absorbed was greater than that of pure quercetin, most likely due to enzymatic hydrolysis of quercetin 3-glucoside and other quercetin glucosides found in the onion by the Caco-2 cells. Caco-2 cells absorbed low levels of quercetin 3-glucoside from apple peel extracts, but quercetin aglycon absorption was not detected. Caco-2 cell homogenates demonstrated both lactase and glucosidase activities when incubated with lactose and quercetin 3-glucoside, respectively. This use of the Caco2 cell model appears to be a simple and useful system for studying bioavailability of whole food phytochemicals and may be used to assess differences in bioavailability between foods.

  15. Quercetin as a shuttle for labile iron.

    PubMed

    Baccan, Mayara Marinovic; Chiarelli-Neto, Orlando; Pereira, Regina Mara Silva; Espósito, Breno Pannia

    2012-02-01

    The antioxidant activity of flavonoids may involve their ability to complex body iron in non-redox-active forms. In this study, it was found that the catechol flavonoids rutin and quercetin are able to suppress redox-active labile plasma iron (LPI) in both buffered solution and in iron-overloaded sera. Both flavonoids are effective in loading the metal into the iron-transport protein transferrin. Iron derivatives of quercetin and rutin are able to permeate cell membranes, however, only free quercetin is able to gain access to the cytosol and decrease intracellular labile iron pools. These results suggest that the antioxidant activity of quercetin may be dependent on its ability to shuttle labile iron from cell compartments followed by its transfer to transferrin.

  16. Acetonic and Methanolic Extracts of Heterotheca inuloides, and Quercetin, Decrease CCl4-Oxidative Stress in Several Rat Tissues

    PubMed Central

    Coballase-Urrutia, Elvia; Pedraza-Chaverri, José; Cárdenas-Rodríguez, Noemí; Huerta-Gertrudis, Bernardino; García-Cruz, Mercedes Edna; Montesinos-Correa, Hortencia; Sánchez-González, Dolores Javier; Camacho-Carranza, Rafael; Espinosa-Aguirre, Jesús Javier

    2013-01-01

    The present study was designed to test the hypothesis that the acetonic and methanolic extracts of H. inuloides prevent carbon tetrachloride-(CCl4) induced oxidative stress in vital tissues. Pretreatment with both H. inuloides extracts or quercetin attenuated the increase in serum activity of alkaline phosphatase (ALP), total bilirubin (BB), creatinine (CRE), and creatine kinase (CK), and impeded the decrease of γ-globulin (γ-GLOB) and albumin (ALB) observed in CCl4-induced tissue injury. The protective effect was confirmed by histological analysis with hematoxylin-eosin and periodic acid/Schiff's reagent. Level of lipid peroxidation was higher in the organs of rats exposed to CCl4 than in those of the animals treated with Heterohteca extracts or quercetin, and these showed levels similar to the untreated group. Pretreatment of animals with either of the extracts or quercetin also prevented the increase of 4-hydroxynonenal and 3-nitrotyrosine. Pretreatment with the plant extracts or quercetin attenuated CCl4 toxic effects on the activity of several antioxidant enzymes. The present results strongly suggest that the chemopreventive effect of the extracts used and quercetin, against CCl4 toxicity, is associated with their antioxidant properties and corroborated previous results obtained in liver tissue. PMID:23365610

  17. Acetonic and Methanolic Extracts of Heterotheca inuloides, and Quercetin, Decrease CCl(4)-Oxidative Stress in Several Rat Tissues.

    PubMed

    Coballase-Urrutia, Elvia; Pedraza-Chaverri, José; Cárdenas-Rodríguez, Noemí; Huerta-Gertrudis, Bernardino; García-Cruz, Mercedes Edna; Montesinos-Correa, Hortencia; Sánchez-González, Dolores Javier; Camacho-Carranza, Rafael; Espinosa-Aguirre, Jesús Javier

    2013-01-01

    The present study was designed to test the hypothesis that the acetonic and methanolic extracts of H. inuloides prevent carbon tetrachloride-(CCl(4)) induced oxidative stress in vital tissues. Pretreatment with both H. inuloides extracts or quercetin attenuated the increase in serum activity of alkaline phosphatase (ALP), total bilirubin (BB), creatinine (CRE), and creatine kinase (CK), and impeded the decrease of γ-globulin (γ-GLOB) and albumin (ALB) observed in CCl(4)-induced tissue injury. The protective effect was confirmed by histological analysis with hematoxylin-eosin and periodic acid/Schiff's reagent. Level of lipid peroxidation was higher in the organs of rats exposed to CCl(4) than in those of the animals treated with Heterohteca extracts or quercetin, and these showed levels similar to the untreated group. Pretreatment of animals with either of the extracts or quercetin also prevented the increase of 4-hydroxynonenal and 3-nitrotyrosine. Pretreatment with the plant extracts or quercetin attenuated CCl(4) toxic effects on the activity of several antioxidant enzymes. The present results strongly suggest that the chemopreventive effect of the extracts used and quercetin, against CCl(4) toxicity, is associated with their antioxidant properties and corroborated previous results obtained in liver tissue.

  18. Neuroprotective effects of quercetin, rutin and okra (Abelmoschus esculentus Linn.) in dexamethasone-treated mice.

    PubMed

    Tongjaroenbuangam, Walaiporn; Ruksee, Nootchanart; Chantiratikul, Piyanete; Pakdeenarong, Noppakun; Kongbuntad, Watee; Govitrapong, Piyarat

    2011-10-01

    The administration of dexamethasone, a synthetic glucocorticoid receptor agonist, causes neuronal death in the CA3 layer of the hippocampus, which has been associated with learning and memory impairments. This study aimed to examine the ability of okra (Abelmoschus esculentus Linn.) extract and its derivatives (quercetin and rutin) to protect neuronal function and improve learning and memory deficits in mice subjected to dexamethasone treatment. Learning and memory functions in mice were examined using the Morris water maze test. The results showed that the mice treated with dexamethasone had prolonged water maze performance latencies and shorter time spent in the target quadrant while mice pretreated with quercetin, rutin or okra extract prior to dexamethasone treatment showed shorter latencies and longer time spent in target quadrant. Morphological changes in pyramidal neurons were observed in the dexamethasone treated group. The number of CA3 hippocampal neurons was significantly lower while pretreated with quercetin, rutin or okra attenuated this change. Prolonged treatment with dexamethasone altered NMDA receptor expression in the hippocampus. Pretreatment with quercetin, rutin or okra extract prevented the reduction in NMDA receptor expression. Dentate gyrus (DG) cell proliferation was examined using the 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry technique. The number of BrdU-immunopositive cells was significantly reduced in dexamethasone-treated mice compared to control mice. Pretreatment with okra extract, either quercetin or rutin was found to restore BrdU-immunoreactivity in the dentate gyrus. These findings suggest that quercetin, rutin and okra extract treatments reversed cognitive deficits, including impaired dentate gyrus (DG) cell proliferation, and protected against morphological changes in the CA3 region in dexamethasone-treated mice. The precise mechanism of the neuroprotective effect of these plant extracts should be further investigated.

  19. Different cardiovascular protective effects of quercetin administered orally or intraperitoneally in spontaneously hypertensive rats.

    PubMed

    Galindo, P; González-Manzano, S; Zarzuelo, M J; Gómez-Guzmán, M; Quintela, A M; González-Paramás, A; Santos-Buelga, C; Pérez-Vizcaíno, F; Duarte, J; Jiménez, R

    2012-06-01

    We tested whether the administration procedure of quercetin affects its metabolite profile and antihypertensive activity. Spontaneously hypertensive rats (SHR) were randomly assigned to four experimental treatments: (1) 1 mL of 1% methylcellulose by oral gavage and 2% DMSO i.p. (control group); (2) 10 mg kg⁻¹ quercetin by oral gavage once daily and 2% DMSO i.p.; (3) 10 mg kg⁻¹ quercetin by oral gavage divided in two daily doses (5 + 5 at 12 h intervals) and 2% DMSO i.p.; (4) 1 mL of 1% methylcellulose by oral gavage and 10 mg kg⁻¹ quercetin i.p. injection. Rats were treated daily for 5 weeks. Single dose and two daily doses, in a long-term oral treatment were equally efficient, both restoring the impaired aortic endothelium-dependent vasodilatation and reducing mesenteric contractile response to phenylephrine, systolic blood pressure, heart rate, and heart and kidney hypertrophy. Attenuation of vascular NADPH oxidase-driven O₂⁻ production was also found in orally treated rats. Intraperitoneal administration reduced, to lesser extent than oral administration, the increased systolic blood pressure, being without effect to the endothelial dysfunction and vascular oxidative stress. In contrast, greater levels of metabolites were quantified following intraperitoneal compared to oral administration at any time point, except for higher plasma methylated quercetin aglycone in oral as compared to intraperitoneal administration at 2 but not at 8 h. In conclusion, oral quercetin was superior to intraperitoneal administration for the protection from cardiovascular complications in SHR. No differences were found between the oral administration as a single daily dose or divided into two daily doses.

  20. The therapeutic potential and mechanisms of action of quercetin in relation to lipopolysaccharide-induced sepsis in vitro and in vivo.

    PubMed

    Chang, Yu-Cheng; Tsai, Ming-Han; Sheu, Wayne Huey-Herng; Hsieh, Shu-Chen; Chiang, An-Na

    2013-01-01

    Sepsis caused by Gram-negative bacterial infection is characterized by extensive inflammatory cytokine production, which leads to multiple organ failure and a high lethality rate. Therefore, compounds that are able to alleviate profound inflammatory responses may have therapeutic potential in relation to sepsis. Quercetin, one of the flavonoids found widely in the human diet, has been reported to have many health benefits, but the mechanisms underlying its biological effects remain obscure. In the present study, our aim was to investigate the molecular mechanisms by which quercetin inhibits lipopolysaccharide (LPS)-induced pro-inflammatory cytokine production and to evaluate the capacity of quercetin to attenuate the mortality rate in a mice model of lethal sepsis. Our results show that quercetin significantly attenuates LPS-induced production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in RAW264.7 macrophages. The LPS-stimulated phosphorylations of the inhibitors of κB kinase (IKKs), Akt, and c-Jun N-terminal kinase (JNK) are also inhibited by quercetin. Quercetin causes a significant reduction in the phosphorylation and degradation of inhibitor of κBα (IκBα) and in the nuclear level of nuclear factor-κB (NF-κB), the latter being associated with decreased NF-κB binding activity. Most importantly, acute administration of quercetin reduces the lethality rate and circulating levels of TNF-α and IL-1β in C57BL/6J mice with endotoxemia induced by LPS, whereas chronic dietary supplementation with quercetin shows no inhibitory effect on serum TNF-α and IL-1β levels. These findings provide clues that quercetin may be a promising agent for the prevention of systemic inflammatory diseases such as sepsis.

  1. Biotinylated Quercetin as an Intrinsic Photoaffinity Proteomics Probe for the Identification of Quercetin Target Proteins

    PubMed Central

    Wang, Rongsheng E.; Hunt, Clayton R.; Chen, Jiawei; Taylor, John-Stephen

    2012-01-01

    Quercetin is a flavonoid natural product that is found in many foods and has been found to have a wide range of medicinal effects. Though a number of quercetin binding proteins have been identified, there has been no systematic approach to identifying all potential targets of quercetin. We describe an O7- biotinylated derivative of quercetin (BioQ) that can act as a photoaffinity proteomics reagent for capturing quercetin binding proteins, which can then be identified by LC MS/MS. BioQ was shown to inhibit heat induction of HSP70 with almost the same efficiency as quercetin, and to both inhibit and photocrosslink to CK2 kinase, a known target of quercetin involved in activation of the heat shock transcription factor. BioQ was also able to pull down a number of proteins from unheated and heated Jurkat cells following UV-irradiation that could be detected by both silver staining and Western blot analysis with an anti-biotin antibody. Analysis of the protein bands by trypsinization and LC MS/MS led to the identification of heat shock proteins HSP70 and HSP90 as possible quercetin target proteins, along with ubiquitin-activating enzyme, a spliceosomal protein, RuvB-like 2 ATPases, and eukaryotic translation initiation factor 3. In addition, a mitochondrial ATPase was identified that has been previously shown to be a target of quercetin. Most of the proteins identified have also been previously suggested to be potential anticancer targets, suggesting that quercetin's antitumor activity may be due to its ability to inhibit multiple target proteins. PMID:21798748

  2. Novel quercetin derivatives: From redox properties to promising treatment of oxidative stress related diseases.

    PubMed

    Zizkova, Petronela; Stefek, Milan; Rackova, Lucia; Prnova, Marta; Horakova, Lubica

    2017-03-01

    A set of O-substituted quercetin derivatives was prepared with the aim to optimize bioavailability and redox properties of quercetin, a known agent with multiple health beneficial effects. Electron-acceptor/-donor properties of the agents were evaluated theoretically by quantum chemical calculations and by experimental methods in cell-free model systems (2,2-diphenyl-1-picrylhydrazyl (DPPH) test, the ferric reducing ability of plasma (FRAP), peroxynitrite scavenging, protein-thiol oxidation) and in cellular systems of fibroblasts, microglials and cancer lines. The order of individual antioxidant effects varied dependently on the system used. In cellular systems, quercetin derivatives were shown to be better antioxidants compared to quercetin. Monochloropivaloylquercetin (CPQ), monoacetylferuloylquercetin (MAFQ) and chloronaphthoquinonequercetin (CHNQ) showed a prominent inhibitory effect on the key enzymes involved in diabetic complications, aldose reductase and α-glucosidase, suggesting their promising therapeutic application. In the cellular models of BHNF-3 fibroblasts, microglial cell line BV-2, colorectal cancer cell lines HCT-116 and HT-29, CHNQ and CPQ were studied for their cytotoxic, antiproliferative and antiinflammatory properties. In the rat model, CHNQ attenuated colon inflammation induced by acetic acid. In summary, our studies revealed CPQ and CHNQ as potential remedies of chronic age-related metabolic or inflammatory diseases, including diabetes and neurodegenerations. Furthermore, CHNQ represents a novel promising agent exerting its anticancer effect through induction of oxidative stress-dependent cell death.

  3. Quercetin Feeding in Newborn Dairy Calves Cannot Compensate Colostrum Deprivation: Study on Metabolic, Antioxidative and Inflammatory Traits.

    PubMed

    Gruse, Jeannine; Kanitz, Ellen; Weitzel, Joachim M; Tuchscherer, Armin; Stefaniak, Tadeusz; Jawor, Paulina; Wolffram, Siegfried; Hammon, Harald M

    2016-01-01

    formula- than in colostrum-fed groups. Hepatic mRNA expression of tumor necrosis factor was higher after quercetin feeding and expression of C-reactive protein was higher after formula feeding. Data confirm that colostrum improves neonatal health and indicate that quercetin feeding cannot compensate for insufficient colostrum supply.

  4. Quercetin Feeding in Newborn Dairy Calves Cannot Compensate Colostrum Deprivation: Study on Metabolic, Antioxidative and Inflammatory Traits

    PubMed Central

    Gruse, Jeannine; Kanitz, Ellen; Weitzel, Joachim M.; Tuchscherer, Armin; Stefaniak, Tadeusz; Jawor, Paulina; Wolffram, Siegfried; Hammon, Harald M.

    2016-01-01

    formula- than in colostrum-fed groups. Hepatic mRNA expression of tumor necrosis factor was higher after quercetin feeding and expression of C-reactive protein was higher after formula feeding. Data confirm that colostrum improves neonatal health and indicate that quercetin feeding cannot compensate for insufficient colostrum supply. PMID:26752173

  5. Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats

    PubMed Central

    Wang, Wei; Wang, Chuang; Ding, Xiao-Qin; Pan, Ying; Gu, Ting-Ting; Wang, Ming-Xing; Liu, Yang-Liu; Wang, Fu-Meng; Wang, Shui-Juan; Kong, Ling-Dong

    2013-01-01

    Background and Purpose Thioredoxin-interacting protein (TXNIP), a regulator of cellular oxidative stress, has been associated with activation of NOD-like receptor 3 (NLRP3) inflammasome, inflammation and lipid metabolism, suggesting it has a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in diabetes. In this study we investigated whether TXNIP is involved in type 1 diabetes-associated NAFLD and whether antioxidants, quercetin and allopurinol, alleviate NAFLD by targeting TXNIP. Experimental Approach Diabetes was induced in male Sprague-Dawley rats by a single i.p. injection of 55 mg·kg−1 streptozotocin. Quercetin and allopurinol were given p.o. to diabetic rats for 7 weeks. Hepatic function, oxidative stress, inflammation and lipid levels were determined. Rat BRL-3A and human HepG2 cells were exposed to high glucose (30 mM) in the presence and absence of antioxidants, TXNIP siRNA transfection or caspase-1 inhibitor, Ac-YVAD-CMK. Key Results Quercetin and allopurinol significantly inhibited the TXNIP overexpression, activation of NLRP3 inflammasome, down-regulation of PPARα and up-regulation of sterol regulatory element binding protein-1c (SREBP-1c), SREBP-2, fatty acid synthase and liver X receptor α, as well as elevation of ROS and IL-1β in diabetic rat liver. These effects were confirmed in hepatocytes in vitro and it was further shown that TXNIP down-regulation contributed to the suppression of NLRP3 inflammasome activation, inflammation and changes in PPARα and SREBPs. Conclusions and Implications Inhibition of hepatic TXNIP by quercetin and allopurinol contributes to the reduction in liver inflammation and lipid accumulation under hyperglycaemic conditions. The targeting of hepatic TXNIP by quercetin and allopurinol may have therapeutic implications for prevention of type 1 diabetes-associated NAFLD. PMID:23647015

  6. Beneficial effects of quercetin on oxidative stress in liver and kidney induced by titanium dioxide (TiO2) nanoparticles in rats.

    PubMed

    González-Esquivel, Aarón Emmanuel; Charles-Niño, Claudia Lisset; Pacheco-Moisés, Fermín Paul; Ortiz, Genaro Gabriel; Jaramillo-Juárez, Fernando; Rincón-Sánchez, Ana Rosa

    2015-03-01

    TiO2 nanoparticles used as vectors for the delivery of drugs have shown greater effectiveness. However, TiO2 nanoparticles can cause oxidative stress in liver and kidney, so we analyzed if a previous or simultaneous quercetin treatment could counteract this in rats. Five groups of male Wistar rats (200-250 g) were included: (1) healthy controls, (2) TiO2 group, (3) quercetin group, (4) preventive group: quercetin for 5 days prior to exposure of TiO2, and (5) therapeutic group: TiO2 (5 mg/kg, i.v.) plus quercetin single dose for 5 days (5 mg/kg/day, i.p.). Hepatic and renal function tests were made. Five animals from each group were sacrificed (0, 14 and 28 days), and liver and kidney tissue were obtained. Malondialdehyde (MDA), reduced/oxidized glutathione, and activity of glutathione peroxidase/reductase were measured, as well as the level of gene expression by q-PCR. There were no significant changes in serum ALT and AST activities. More damage was observed at 14 versus 28 days, because TiO2 was excreted in urine. Quercetin indeed showed a renal protective effect by increasing glutathione reductase and peroxidase levels and reducing MDA levels. On the other hand, TiO2 liver damage was less pronounced with quercetin as therapeutic treatment. TiO2 induces significantly the glutathione reductase expression and it can be down-regulated by quercetin. Biochemical tests in serum and urine showed a better effect of quercetin administered in the therapeutic group. Care should be taken with the dose and time of administration of quercetin, because this antioxidant could also have a pro-oxidant effect.

  7. Differential effects of quercetin glycosides on GABAC receptor channel activity.

    PubMed

    Kim, Hyeon-Joong; Lee, Byung-Hwan; Choi, Sun-Hye; Jung, Seok-Won; Kim, Hyun-Sook; Lee, Joon-Hee; Hwang, Sung-Hee; Pyo, Mi-Kyung; Kim, Hyoung-Chun; Nah, Seung-Yeol

    2015-01-01

    Quercetin, a representative flavonoid, is a compound of low molecular weight found in various colored plants and vegetables. Quercetin shows a wide range of neuropharmacological activities. In fact, quercetin naturally exists as monomer-(quercetin-3-O-rhamnoside) (Rham1), dimer-(Rutin), or trimer-glycosides [quercetin-3-(2(G)-rhamnosylrutinoside)] (Rham2) at carbon-3 in fruits and vegetables. The carbohydrate components are removed after ingestion into gastrointestinal systems. The role of the glycosides attached to quercetin in the regulation of γ-aminobutyric acid class C (GABAC) receptor channel activity has not been determined. In the present study, we examined the effects of quercetin glycosides on GABAC receptor channel activity by expressing human GABAC alone in Xenopus oocytes using a two-electrode voltage clamp technique and also compared the effects of quercetin glycosides with quercetin. We found that GABA-induced inward current (I GABA ) was inhibited by quercetin or quercetin glycosides. The inhibitory effects of quercetin and its glycosides on I GABA were concentration-dependent and reversible in the order of Rutin ≈ quercetin ≈ Rham 1 > Rham 2. The inhibitory effects of quercetin and its glycosides on I GABA were noncompetitive and membrane voltage-insensitive. These results indicate that quercetin and its glycosides regulate GABAC receptor channel activity through interaction with a different site from that of GABA, and that the number of carbohydrate attached to quercetin might play an important role in the regulation of GABAC receptor channel activity.

  8. Characterization of sulfated quercetin and epicatechin metabolites.

    PubMed

    Dueñas, Montserrat; González-Manzano, Susana; Surco-Laos, Felipe; González-Paramas, Ana; Santos-Buelga, Celestino

    2012-04-11

    Different monosulfates of quercetin and epicatechin with metabolic interest were obtained by hemisynthesis and characterized regarding their chromatographic behavior and absorption and mass spectra. Three of these compounds were further isolated, and their structures were elucidated by mass spectrometry and (1)H and (13)C nuclear magnetic resonance using one- and two-dimensional techniques (heteronuclear single-quantum coherence and heteronuclear multiple-bond correlation). The calculation of the proton and carbon shifts caused by sulfation allowed for the assignment of the position of the sulfate group in the flavonoids, so that the compounds were identified as quercetin-3'-O-sulfate, quercetin 4'-O-sulfate, and epicatechin 4'-O-sulfate. It was found that sulfation at position 3' induced a large upfield shift in the carbon bearing the sulfate group and downfield displacements of the adjacent carbons, whereas no significant upfield or downfield shifts were observed with respect to the parent flavonoid when sulfation was produced at position 4'.

  9. Berberine Attenuates Development of the Hepatic Gluconeogenesis and Lipid Metabolism Disorder in Type 2 Diabetic Mice and in Palmitate-Incubated HepG2 Cells through Suppression of the HNF-4α miR122 Pathway.

    PubMed

    Wei, Shengnan; Zhang, Ming; Yu, Yang; Lan, Xiaoxin; Yao, Fan; Yan, Xin; Chen, Li; Hatch, Grant M

    2016-01-01

    Berberine (BBR) has been shown to exhibit protective effects against diabetes and dyslipidemia. Previous studies have indicated that BBR modulates lipid metabolism and inhibits hepatic gluconeogensis by decreasing expression of Hepatocyte Nuclear Factor-4α (HNF-4α). However, the mechanism involved in this process was unknown. In the current study, we examined the mechanism of how BBR attenuates hepatic gluconeogenesis and the lipid metabolism alterations observed in type 2 diabetic (T2D) mice and in palmitate (PA)-incubated HepG2 cells. Treatment with BBR for 4 weeks improve all biochemical parameters compared to T2D mice. Treatment of T2D mice for 4 weeks or treatment of PA-incubated HepG2 cells for 24 h with BBR decreased expression of HNF-4α and the microRNA miR122, the key gluconeogenesis enzymes Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) and the key lipid metabolism proteins Sterol response element binding protein-1 (SREBP-1), Fatty acid synthase-1 (FAS-1) and Acetyl-Coenzyme A carboxylase (ACCα) and increased Carnitine palmitoyltransferase-1(CPT-1) compared to T2D mice or PA-incubated HepG2 cells. Expression of HNF-4α in HepG2 cells increased expression of gluconeogenic and lipid metabolism enzymes and BBR treatment or knock down of miR122 attenuated the effect of HNF-4α expression. In contrast, BBR treatment did not alter expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. In addition, miR122 mimic increased expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. These data indicate that miR122 is a critical regulator in the downstream pathway of HNF-4α in the regulation of hepatic gluconeogenesis and lipid metabolism in HepG2 cells. The effect of BBR on hepatic gluconeogenesis and lipid metabolism is mediated through HNF-4α and is regulated downstream of miR122. Our data provide new evidence to support HNF-4α and miR122

  10. Berberine Attenuates Development of the Hepatic Gluconeogenesis and Lipid Metabolism Disorder in Type 2 Diabetic Mice and in Palmitate-Incubated HepG2 Cells through Suppression of the HNF-4α miR122 Pathway

    PubMed Central

    Yu, Yang; Lan, Xiaoxin; Yao, Fan; Yan, Xin; Chen, Li; Hatch, Grant M.

    2016-01-01

    Berberine (BBR) has been shown to exhibit protective effects against diabetes and dyslipidemia. Previous studies have indicated that BBR modulates lipid metabolism and inhibits hepatic gluconeogensis by decreasing expression of Hepatocyte Nuclear Factor-4α (HNF-4α). However, the mechanism involved in this process was unknown. In the current study, we examined the mechanism of how BBR attenuates hepatic gluconeogenesis and the lipid metabolism alterations observed in type 2 diabetic (T2D) mice and in palmitate (PA)-incubated HepG2 cells. Treatment with BBR for 4 weeks improve all biochemical parameters compared to T2D mice. Treatment of T2D mice for 4 weeks or treatment of PA-incubated HepG2 cells for 24 h with BBR decreased expression of HNF-4α and the microRNA miR122, the key gluconeogenesis enzymes Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) and the key lipid metabolism proteins Sterol response element binding protein-1 (SREBP-1), Fatty acid synthase-1 (FAS-1) and Acetyl-Coenzyme A carboxylase (ACCα) and increased Carnitine palmitoyltransferase-1(CPT-1) compared to T2D mice or PA-incubated HepG2 cells. Expression of HNF-4α in HepG2 cells increased expression of gluconeogenic and lipid metabolism enzymes and BBR treatment or knock down of miR122 attenuated the effect of HNF-4α expression. In contrast, BBR treatment did not alter expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. In addition, miR122 mimic increased expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. These data indicate that miR122 is a critical regulator in the downstream pathway of HNF-4α in the regulation of hepatic gluconeogenesis and lipid metabolism in HepG2 cells. The effect of BBR on hepatic gluconeogenesis and lipid metabolism is mediated through HNF-4α and is regulated downstream of miR122. Our data provide new evidence to support HNF-4α and miR122

  11. Trigonelline attenuates hepatic complications and molecular alterations in high-fat high-fructose diet-induced insulin resistance in rats.

    PubMed

    Afifi, Nehal A; Ramadan, Amer; Erian, Emad Y; Saleh, Dalia O; Sedik, Ahmed A; Badawi, Manal; El Hotaby, Walid

    2017-04-01

    The present study aimed to evaluate the effect of trigonelline (TRG) on the hepatic complications associated with high-fat high-fructose (HFHF) diet-induced insulin resistance (IR) in rats. IR was induced by giving a saturated fat diet and 10% fructose in drinking water to rats for 8 weeks. Insulin-resistant rats were orally treated with TRG (50 and 100 mg/kg), sitagliptin (SIT; 5 mg/kg), or a combination of TRG (50 mg/kg) and SIT (5 mg/kg) for 14 days. Liver homogenates were used for assessment of hepatic lipids, oxidative stress biomarkers, and inflammatory cytokines. Histopathological and DNA cytometry examinations were carried out for hepatic and pancreatic tissues. Hepatic tissues were examined using Fourier-transform infrared spectroscopy for assessment of any molecular changes. Results of the present study revealed that oral treatment of insulin-resistant rats with TRG or TRG in combination with SIT significantly decreased homeostatic model assessment of IR, hepatic lipids, oxidative stress biomarkers, and the inflammatory cytokines. TRG or TRG in combination with SIT ameliorated the histopathological, DNA cytometry, and molecular alterations induced by a HFHF diet. Finally, it can be concluded that TRG has beneficial effects on the hepatic complications associated with IR due to its hypoglycemic effect and antioxidant potential.

  12. Modulation of mammalian sperm motility by quercetin.

    PubMed

    Nass-Arden, L; Breitbart, H

    1990-04-01

    The flavonoid quercetin inhibits collective motility of ejaculated ram spermatozoa in the first 2 hr of incubation; during the next 3-4 hr motility is stimulated. To explain this interesting effect, we followed the influence of quercetin on sperm glycolysis, extracellular pH, ATP content, mitochondrial respiration, and lipid peroxidation. The collective motility of untreated cells is decreased to about 40% of the original motility during two hours of incubation. During this time, the rate of glycolysis is constant, respiration rate is increasing, there is no change in ATP content, the rate of lipid peroxidation is very slow, and the extracellular pH became very acidic (pH 5.5). It is concluded that motility is decreased due to this acidification. This acidification is prevented to some extent by quercetin, which indirectly inhibits glycolysis. Quercetin inhibits motility due to the inhibition of the plasma membrane calcium pump, as we showed previously (Breitbart et al., J Biol Chem 260:11548-11553, 1985). The motility of untreated cells is arrested after 3.5 hr of incubation, whereas quercetin-treated cells show high motility, which continues for additional 2-3 hr. After 3.5 hr, the control cells show no glycolytic activity, ATP content and respiration rates are decreased, and rate of lipid peroxidation is highly increased. At this time, quercetin-treated cells show no glycolytic activity, only a small decrease in ATP content and respiratory rate, and a very low rate of lipid peroxidation. Based on these data it is concluded that sperm motility after 3.5 hr of incubation is dependent mainly on mitochondrial respiration.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Isorhamnetin attenuates liver fibrosis by inhibiting TGF-β/Smad signaling and relieving oxidative stress.

    PubMed

    Yang, Ji Hye; Kim, Sang Chan; Kim, Kyu Min; Jang, Chang Ho; Cho, Sam Seok; Kim, Seung Jung; Ku, Sae Kwang; Cho, Il Je; Ki, Sung Hwan

    2016-07-15

    Hepatic fibrosis is considered integral to the progression of chronic liver diseases, leading to the development of cirrhosis and hepatocellular carcinoma. Activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. We investigated the ability of isorhamnetin, the 3'-O-methylated metabolite of quercetin, to protect against hepatic fibrosis in vitro and in vivo. Isorhamnetin inhibited transforming growth factor (TGF)-β1-induced expression of α-smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), and collagen in primary murine HSCs and LX-2 cells. The TGF-β1- or Smad-induced luciferase reporter activity of Smad binding elements was significantly decreased by isorhamnetin with a concomitant decrease in Smad2/3 phosphorylation. Isorhamnetin increased the nuclear translocation of Nrf2 in HSCs and increased antioxidant response element reporter gene activity. Furthermore, isorhamnetin blocked TGF-β1-induced reactive oxygen species production. The specific role of Nrf2 in isorhamnetin-mediated suppression of PAI-1 and phosphorylated Smad3 was verified using a siRNA against Nrf2. To examine the anti-fibrotic effect of isorhamnetin in vivo, liver fibrosis was induced by CCl4 in mice. Isorhamnetin significantly prevented CCl4-induced increases in serum alanine transaminase and aspartate transaminase levels, and caused histopathological changes characterized by decreases in hepatic degeneration, inflammatory cell infiltration, and collagen accumulation. Moreover, isorhamnetin markedly decreased the expression of phosphorylated Smad3, TGF-β1, α-SMA, and PAI-1. Isorhamnetin attenuated the CCl4-induced increase in the number of 4-hydroxynonenal and nitrotyrosine-positive cells, and prevented glutathione depletion. We propose that isorhamnetin inhibits the TGF-β/Smad signaling pathway and relieves oxidative stress, thus inhibiting HSC activation and preventing liver fibrosis.

  14. Bioavailability of the flavonol quercetin in neonatal calves after oral administration of quercetin aglycone or rutin.

    PubMed

    Maciej, J; Schäff, C T; Kanitz, E; Tuchscherer, A; Bruckmaier, R M; Wolffram, S; Hammon, H M

    2015-06-01

    Polyphenols, such as flavonoids, are secondary plant metabolites with potentially health-promoting properties. In newborn calves flavonoids may improve health status, but little is known about the systemically availability of flavonoids in calves to exert biological effects. The aim of this study was to investigate the oral bioavailability of the flavonol quercetin, applied either as quercetin aglycone (QA) or as its glucorhamnoside rutin (RU), in newborn dairy calves. Twenty-one male newborn German Holstein calves were fed equal amounts of colostrum and milk replacer according to body weight. On d 2 and 29 of life, 9 mg of quercetin equivalents/kg of body weight, either fed as QA or as RU, or no quercetin (control group) were fed together with the morning meal. Blood samples were taken before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 24, and 48 h after feed intake. Quercetin and quercetin metabolites with an intact flavonol structure (isorhamnetin, tamarixetin, and kaempferol) were analyzed in blood plasma after treatment with glucuronidase or sulfatase by HPLC with fluorescence detection. Maximum individual plasma concentration was depicted from the concentration-time-curve on d 2 and 29, respectively. Additional blood samples were taken to measure basal plasma concentrations of total protein, albumin, urea, and lactate as well as pre- and postprandial plasma concentrations of glucose, nonesterified fatty acids, insulin, and cortisol. Plasma concentrations of quercetin and its metabolites were significantly higher on d 2 than on d 29 of life, and administration of QA resulted in higher plasma concentrations of quercetin and its metabolites than RU. The relative bioavailability of total flavonols (sum of quercetin and its metabolites isorhamnetin, tamarixetin, and kaempferol) from RU was 72.5% on d 2 and 49.6% on d 29 when compared with QA (100%). Calves fed QA reached maximum plasma concentrations of total flavonols much earlier than did RU-fed calves. Plasma

  15. Intracellular ROS protection efficiency and free radical-scavenging activity of quercetin and quercetin-encapsulated liposomes.

    PubMed

    Rezaei-Sadabady, Rogaie; Eidi, Akram; Zarghami, Nosratollah; Barzegar, Abolfazl

    2016-01-01

    Quercetin (3,5,7,3',4'-pentahydroxyflavone) is a natural bio-flavonoid originating from fruits, vegetables, seeds, berries, and tea. The antioxidant activity of quercetin and its protective effects against cardiovascular disorders, anti-cancer, anti-inflammatory, and anti-viral activities have been extensively documented; however, the clinical request of quercetin in cancer treatment is significantly limited due to its very poor delivery features. In order to increase the hydrophilicity and drug delivery capability, we encapsulated quercetin into liposomes. Our data indicated that liposomal quercetin can significantly improve the solubility and bioavailability of quercetin and can be used as an effective antioxidant for ROS protection within the polar cytoplasm, and the nano-sized quercetin encapsulated by liposomes enhanced the cellular uptake (cancer cell human MCF_7). Quercetin has many pharmaceutical applications, many of which arise from its potent antioxidant properties. The present research examined the antioxidant activities of quercetin in polar solvents by a comparative study using reduction of ferric iron in aqueous medium, intracellular ROS/toxicity assays, and reducing DPPH assays. Cell viability and ROS assays demonstrated that quercetin was able to penetrate into the polar medium inside the cells and to protect them against the highly toxic and deadly belongings of cumene hydroperoxide. The purpose of this study was to determine whether a liposomal formulation of quercetin can suggestively improve its solubility and bioavailability and can be a possible request in the treatment of tumor. The authors encapsulated quercetin in a liposomal delivery system. They studied the in vitro effects of this compound on proliferation using human MCF-7 carcinoma cells. The activity of liposomal quercetin was equal to or better than that of free quercetin at equimolar concentrations. Our data indicated that liposomal quercetin can significantly improve the

  16. In vitro digestion and lactase treatment influence uptake of quercetin and quercetin glucoside by the Caco-2 cell monolayer

    PubMed Central

    Boyer, Jeanelle; Brown, Dan; Liu, Rui Hai

    2005-01-01

    Background Quercetin and quercetin glycosides are widely consumed flavonoids found in many fruits and vegetables. These compounds have a wide range of potential health benefits, and understanding the bioavailability of flavonoids from foods is becoming increasingly important. Methods This study combined an in vitro digestion, a lactase treatment and the Caco-2 cell model to examine quercetin and quercetin glucoside uptake from shallot and apple homogenates. Results The in vitro digestion alone significantly decreased quercetin aglycone recovery from the shallot digestate (p < 0.05), but had no significant effect on quercetin-3-glucoside recovery (p > 0.05). Digestion increased the Caco-2 cell uptake of shallot quercetin-4'-glucoside by 2-fold when compared to the non-digested shallot. Despite the loss of quercetin from the digested shallot, the bioavailability of quercetin aglycone to the Caco-2 cells was the same in both the digested and non-digested shallot. Treatment with lactase increased quercetin recovery from the shallot digestate nearly 10-fold and decreased quercetin-4'-glucoside recovery by more than 100-fold (p < 0.05), but had no effect on quercetin recovery from apple digestates. Lactase treatment also increased shallot quercetin bioavailability to the Caco-2 cells approximately 14-fold, and decreased shallot quercetin-4'-glucoside bioavailability 23-fold (p < 0.05). These Caco-2 cells had lactase activity similar to that expressed by a lactose intolerant human. Conclusions The increase in quercetin uptake following treatment with lactase suggests that dietary supplementation with lactase may increase quercetin bioavailability in lactose intolerant humans. Combining the digestion, the lactase treatment and the Caco-2 cell culture model may provide a reliable in vitro model for examining flavonoid glucoside bioavailability from foods. PMID:15644141

  17. Hepatitis B

    MedlinePlus

    ... Home » Hepatitis B » Hepatitis B Entire Lesson Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... Enter ZIP code here Enter ZIP code here Hepatitis B Entire Lesson for Veterans and the Public ...

  18. Peroxisome proliferator-activated receptor γ (PPARγ) mediates the protective effect of quercetin against myocardial ischemia-reperfusion injury via suppressing the NF-κB pathway

    PubMed Central

    Liu, Xinyu; Yu, Zhangjie; Huang, Xian; Gao, Yi; Wang, Xiuzhi; Gu, Jianmin; Xue, Song

    2016-01-01

    Quercetin plays an important role in myocardial ischemia and reperfusion injury (IRI). However, the underlying mechanism for the protective effect of quercetin is largely unclear. In this study, we explored the protected effects of quercetin against myocardial IRI and its molecular mechanisms. Quercetin, GW9962 (PPARγ antagonist) or PPARγ-siRNA was administered alone or in combination prior to myocardial IRI in mice or to hypoxia and reoxygenation (H/R) treatment in H9C2 cells. Infarct size was evaluated by TTC staining after reperfusion. Myocardial injury was assessed by the serum levels of AST, CK-MB, cardiac troponin T (cTnT) and LDH. Cardiac function was measured by echocardiography. Oxidative stress injury was evaluated by analyses of inducible nitric oxide synthase (iNOS), MDA, SOD and glutathione peroxidase (GSH-PX) levels and by reactive oxygen species (ROS) detection. Myocardium apoptosis was evaluated by TUNEL staining, cleaved caspase-3 and Annexin V/PI detection. Moreover, activation of the NF-κB pathway was reflected by phosphorylation of IκB (p-IκB) and nuclear translocation of NF-κB p65. We reported that pretreatment of quercetin significantly improved cardiac function, diminished myocardial injury and reduced the infarct size. Myocardium oxidative damage and apoptosis were remarkably improved by quercetin treatment in vivo and in vitro. Quercetin also suppressed the activation of the NF-κB pathway induced by myocardial IRI. GW9662 or PPARγ knockdown partially attenuated these cardioprotective effects of quercetin during myocardial IRI. In conclusion, our findings suggest that quercetin ameliorated IRI-induced heart damage via PPARγ activation and the underlying mechanism might involve the inhibition of NF-κB pathway by PPARγ activation. PMID:28077993

  19. Clonorchis sinensis lysophospholipase inhibits TGF-β1-induced expression of pro-fibrogenic genes through attenuating the activations of Smad3, JNK2, and ERK1/2 in hepatic stellate cell line LX-2.

    PubMed

    Zhou, Lina; Shang, Mei; Shi, Mengchen; Zhao, Lu; Lin, Zhipeng; Chen, Tingjin; Wu, Yinjuan; Tang, Zeli; Sun, Hengchang; Yu, Jinyun; Huang, Yan; Yu, Xinbing

    2016-02-01

    Liver fibrosis is a wound healing response associated with chronic liver injury. Hepatic stellate cells (HSCs) activation is a key event in the development of liver fibrosis. Since helminths have the ability to live for decades in the host by establishing an adaptive relationship in the interplay with its hosts, we hypothesize that whether Clonochis sinensis LysophospholipaseA (CsLysoPLA), a component of excretory/secretory proteins, can attenuate the fibrogenic response by inhibiting activation of LX-2 cells, thereby balancing the pro-fibrotic and anti-fibrotic response during the Clonochis sinensis (C. sinensis) infection. In the present study, LX-2 cells were stimulated with CsLysoPLA in the presence of TGF-β1, and the expressions of collagen type I (COL1A1), α-smooth muscle actin (α-SMA), and matrix metalloproteinase 2 (MMP2) were decreased. In addition, CsLysoPLA significantly inhibited the proliferation and migration of LX-2 cells stimulated by TGF-β1. Pretreatment of LX-2 cells with CsLysoPLA attenuated the phosphorylation of Smad3 as well as JNK2 and ERK1/2 in response to the stimulation of TGF-β1. For the first time, our results showed an anti-fibrogenic effect of CsLysoPLA by attenuating the response of LX-2 cells to TGF-β1 through inhibiting the activations of Smad3, ERK1/2, and JNK2.

  20. Inhibition of autophagy induced by quercetin at a late stage enhances cytotoxic effects on glioma cells.

    PubMed

    Bi, Yunke; Shen, Chen; Li, Chenguang; Liu, Yaohua; Gao, Dandan; Shi, Chen; Peng, Fei; Liu, Zhendong; Zhao, Boxian; Zheng, Zhixing; Wang, Xiaoxiong; Hou, Xu; Liu, Huailei; Wu, Jianing; Zou, Huichao; Wang, Kaikai; Zhong, Chen; Zhang, Jiakang; Shi, Changbin; Zhao, Shiguang

    2016-03-01

    Glioma is the most common primary brain tumor in the central nervous system (CNS) with high morbidity and mortality in adults. Although standardized comprehensive therapy has been adapted, the prognosis of glioma patients is still frustrating and thus novel therapeutic strategies are urgently in need. Quercetin (Quer), an important flavonoid compound found in many herbs, is shown to be effective in some tumor models including glioma. Recently, it is reported that adequate regulation of autophagy can strengthen cytotoxic effect of anticancer drugs. However, it is not yet fully clear how we should modulate autophagy to achieve a satisfactory therapeutic effect. 3-Methyladenine (3-MA) and Beclin1 short hairpin RNA (shRNA) were used to inhibit the early stage of autophage while chloroquine (CQ) to inhibit the late stage. MTT assay was implemented to determine cell viability. Transmission electron microscopy, western blot, and immunohistochemistry were adopted to evaluate autophagy. Western blot, flow cytometry, and immunohistochemistry were used to detect apoptosis. C6 glioma xenograft models were established to assess the therapeutic effect (the body weight change, the median survival time, and tumor volume) in vivo. Quercetin can inhibit cell viability and induce autophagy of U87 and U251 glioma cells in a dose-dependent manner. Inhibition of early-stage autophagy by 3-MA or shRNA against Beclin1 attenuated the quercetin-induced cytotoxicity. In contrast, suppression of autophagy at a late stage by CQ enhanced the anti-glioma efficiency of quercetin. Therapeutic effect of quercetin for malignant glioma can be strengthened by inhibition of autophagy at a late stage, not initial stage, which may provide a novel opportunity for glioma therapy.

  1. Preparation and characterization of quercetin/dietary fiber nanoformulations.

    PubMed

    Khor, Chia Miang; Ng, Wai Kiong; Chan, Kok Ping; Dong, Yuancai

    2017-04-01

    Quercetin is well known for its beneficial health effects on the human body. However, the slow dissolution rate leading to poor bioavailability constitutes a barrier to being further developed for nutritional products. In this work, quercetin was co-precipitated with dietary fibers into a fast-dissolving nanoformulation via antisolvent precipitation, followed by spray drying. With the help of cellulose fiber, resistant starch or resistant maltodextrin, a high dissolution rate and good storage stability was achieved for quercetin nanoformulations. In addition, nanoformulations exhibited higher level of antioxidant activities in contrast to raw quercetin. The developed quercetin/dietary fiber nanoformulations could be used as supplements or functional ingredients for food development.

  2. Quercetin modulates keratoconus metabolism in vitro

    PubMed Central

    McKay, Tina B; Sarker-Nag, Akhee; Lyon, Desiree’; Asara, John M; Karamichos, Dimitrios

    2016-01-01

    Corneal scarring is the result of a disease, infection or injury. The resulting scars cause significant loss of vision or even blindness. To-date, the most successful treatment is corneal transplantation, but it does not come without side effects. One of the corneal dystrophies that are correlated with corneal scarring is keratoconus (KC). The onset of the disease is still unknown; however, altered cellular metabolism has been linked to promoting the fibrotic phenotype and therefore scarring. We have previously shown that human keratoconus cells (HKCs) have altered metabolic activity when compared to normal human corneal fibroblasts (HCFs). In our current study, we present evidence that quercetin, a natural flavonoid, is a strong candidate for regulating metabolic activity of both HCFs and HKCs in vitro and therefore a potential therapeutic to target the altered cellular metabolism characteristic of HKCs. Targeted mass spectrometry-based metabolomics was performed on HCFs and HKCs with and without quercetin treatment in order to identify variations in metabolite flux. Overall, our study reveals a novel therapeutic target OF Quercetin on corneal stromal cell metabolism in both healthy and diseased states. Clearly, further studies are necessary in order to dissect the mechanism of action of quercetin. PMID:26173740

  3. Therapeutic effect of quercetin in collagen-induced arthritis.

    PubMed

    Haleagrahara, Nagaraja; Miranda-Hernandez, Socorro; Alim, Md Abdul; Hayes, Linda; Bird, Guy; Ketheesan, Natkunam

    2017-03-22

    Quercetin, a bioactive flavonoid with anti-inflammatory, immunosuppressive, and protective properties, is a potential agent for the treatment of rheumatoid arthritis (RA). Collagen-induced arthritis (CIA) is the most commonly used animal model for studying the pathogenesis of RA. This study analysed the therapeutic role of quercetin in collagen-induced arthritis in C57BL/6 mice. The animals were allocated into five groups that were subjected to the following treatments: negative (untreated) control, positive control (arthritis-induced), arthritis+methotrexate, arthritis+quercetin, and arthritis+methotrexate+quercetin. Assessments of weight, oedema, joint damage, and cytokine production were used to determine the therapeutic effect of quercetin. This study demonstrated for the first time the anti-inflammatory and protective effects of quercetin in vivo in CIA. The results also showed that the concurrent administration of quercetin and methotrexate did not offer greater protection than the administration of a single agent. The use of quercetin as a monotherapeutic agent resulted in the lowest degree of joint inflammation and the highest protection. The reduced severity of the disease in animals treated with quercetin was associated with decreased levels of TNF-α, IL-1β, IL-17, and MCP-1. In conclusion, this study determined that quercetin, which was non-toxic, produced better results than methotrexate for the protection of joints from arthritic inflammation in mice. Quercetin may be an alternative treatment for RA because it modulates the main pathogenic pathways of RA.

  4. The Flavonoid Quercetin Reverses Pulmonary Hypertension in Rats

    PubMed Central

    Moreno, Enrique; Moral-Sanz, Javier; Barreira, Bianca; Galindo, Pilar; Pandolfi, Rachele; Jimenez, Rosario; Moreno, Laura; Cogolludo, Angel; Duarte, Juan; Perez-Vizcaino, Francisco

    2014-01-01

    Quercetin is a dietary flavonoid which exerts vasodilator, antiplatelet and antiproliferative effects and reduces blood pressure, oxidative status and end-organ damage in humans and animal models of systemic hypertension. We hypothesized that oral quercetin treatment might be protective in a rat model of pulmonary arterial hypertension. Three weeks after injection of monocrotaline, quercetin (10 mg/kg/d per os) or vehicle was administered for 10 days to adult Wistar rats. Quercetin significantly reduced mortality. In surviving animals, quercetin decreased pulmonary arterial pressure, right ventricular hypertrophy and muscularization of small pulmonary arteries. Classic biomarkers of pulmonary arterial hypertension such as the downregulated expression of lung BMPR2, Kv1.5, Kv2.1, upregulated survivin, endothelial dysfunction and hyperresponsiveness to 5-HT were unaffected by quercetin. Quercetin significantly restored the decrease in Kv currents, the upregulation of 5-HT2A receptors and reduced the Akt and S6 phosphorylation. In vitro, quercetin induced pulmonary artery vasodilator effects, inhibited pulmonary artery smooth muscle cell proliferation and induced apoptosis. In conclusion, quercetin is partially protective in this rat model of PAH. It delayed mortality by lowering PAP, RVH and vascular remodeling. Quercetin exerted effective vasodilator effects in isolated PA, inhibited cell proliferation and induced apoptosis in PASMCs. These effects were associated with decreased 5-HT2A receptor expression and Akt and S6 phosphorylation and partially restored Kv currents. Therefore, quercetin could be useful in the treatment of PAH. PMID:25460361

  5. Quercetin suppresses lung cancer growth by targeting Aurora B kinase.

    PubMed

    Xingyu, Zhu; Peijie, Ma; Dan, Peng; Youg, Wang; Daojun, Wang; Xinzheng, Chen; Xijun, Zhang; Yangrong, Song

    2016-11-01

    aurora B kinase is highly expressed in several cancer cells and promotes tumorigenesis and progression, and therefore, it is an important target for drug to treat tumors. Quercetin was identified to be an antitumor agent. Herein, we report for the first time that quercetin inhibited aurora B activities by directly binding with aurora B in vitro and in vivo. Ex vivo studies showed that quercetin inhibited aurora B activities in JB6 Cl41 cells and A549 lung cancer cells. Moreover, knockdown of aurora B in A549 cells decreased their sensitivities to quercetin. In vivo study demonstrated that injection of quercetin in A549 tumor-bearing mice effectively suppressed cancer growth. The phosphorylation of histone 3 in tumor tissues was also decreased after quercetin treatment. In short, quercetin can suppress growth of lung cancer cells as an aurora B inhibitor both in vitro and in vivo.

  6. Polyploidy Analysis and Attenuation of Oxidative Stress in Hepatic Tissue of STZ-Induced Diabetic Rats Treated with an Aqueous Extract of Vochysia rufa

    PubMed Central

    Moraes, Izabela Barbosa; Manzan-Martins, Camilla; de Gouveia, Neire Moura; Calábria, Luciana Karen; Hiraki, Karen Renata Nakamura; Moraes, Alberto da Silva; Espindola, Foued Salmen

    2015-01-01

    Diabetes mellitus (DM) is characterized by hyperglycemia and alterations in the metabolism of lipids, carbohydrates, and proteins. Due to its hypoglycemic effect Vochysia rufa is frequently used in Uberlandia, Brazil, to treat DM. Despite its popularity, there is little information about its effect on hepatic tissue. Therefore, we evaluated the histoarchitecture, oxidative stress parameters, and polyploidy of liver tissue from streptozotocin- (STZ-) induced diabetic rats treated with aqueous extract of Vochysia rufa (AEV). Histology was determined by fixing the livers, processing, and staining with HE. Oxidative stress was determined by evaluating CAT, GPx, and SOD activity in liver homogenates and hepatic mitochondria fraction and by measuring GST, GSH levels and lipid peroxidation (MDA). Polyploidy was determined by subjecting isolated hepatocyte nuclei to flow cytometry. In the diabetic group, GST activity and GSH rates decreased whereas liver homogenate analysis showed that GPx, SOD activity and MDA increased. AEV treatment restored all parameters to normal levels. The oxidative stress analysis of hepatic mitochondria fraction showed similar results. Lower polyploid cell populations were found in the diabetic rat livers, even after glibenclamide treatment. Thus, AEV treatment efficiently reduced hepatic oxidative stress caused by STZ-induced diabetes and produced no morphological changes in the histological analysis. PMID:25763088

  7. The high antioxidative power of quercetin (aglycone flavonoid) and its glycone (rutin) avert high cholesterol diet induced hepatotoxicity and inflammation in Swiss albino mice.

    PubMed

    Sikder, Kunal; Kesh, Swaraj Bandhu; Das, Nilanjan; Manna, Krishnendu; Dey, Sanjit

    2014-06-01

    The present study demonstrates for the first time the protective role of two common flavonoids, quercetin and its glycone rutin, against high cholesterol diet (2%) induced hepatotoxicity and inflammation. Swiss albino mice were given either a standard laboratory diet (control), high cholesterol diet (HCD) or high cholesterol diet along with quercetin or rutin (100 mg kg(-1) body weight) in their respective groups. The HCD mice exhibited a gain in body weight, significant rise in serum and hepatic level of total cholesterol, triglyceride, liver function enzymes, lipid peroxidation, and pro-inflammatory cytokines (P < 0.05). Histopathological studies showed hepatic fat accumulation and tissue disintegration. There was significant depletion of major hepatic antioxidants (P < 0.05). Immunoblot studies revealed a high expression of redox sensitive transcription factors NF-κB and TNF-α. A subsequent rise in the mRNA expression of inflammatory markers like C reactive protein and inducible nitric oxide synthase 2 were also found from the RT-PCR study. Simultaneous treatment with quercetin or rutin along with HCD significantly prevented the gains in body weight, lipid level, liver function enzymes, lipid peroxidation level and expression of inflammatory markers. The restoration of hepatic antioxidant homeostasis and hepatic morphology has also been observed. Hence, the present study illustrates the hypolipidemic, hepatoprotective and anti-inflammatory effects of two similar flavonoids.

  8. Lymphatic absorption of quercetin and rutin in rat and their pharmacokinetics in systemic plasma.

    PubMed

    Chen, I-Lin; Tsai, Yung-Jen; Huang, Chih-Min; Tsai, Tung-Hu

    2010-01-13

    Substances and macromolecules absorbed by the lymphatic system avoid hepatic first-pass effect and directly enter the blood circulation system. In this study, an anesthetized, mesenteric lymphatic/duodenum-cannulated rat model was used to investigate the role of lymphatic absorption with intraduodenally administered drugs. Quercetin and rutin were administered, respectively, at dosages of 30 and 300 mg/kg intraduodenally. Lymph and plasma samples were collected every 30 min. These samples were prepared by protein precipitation and then analyzed by high-performance liquid chromatography with a photodiode array detector (HPLC-PDA) and verified by LC tandem mass spectrometry (LC-MS/MS). Quercetin was separated by a C18 reversed-phase column, and rutin was separated by a phenyl reverse-phase column. Pharmacokinetic parameters were calculated using the software WinNonlin Standard Edition Version. The maximum concentration (Cmax) of quercetin recovered in lymph, 1.97+/-0.96 microg/mL, was about 5-fold higher than that in plasma, 0.41+/-0.08 microg/mL. The time to reach the highest concentration (Tmax) of quercetin in lymph was 30 min longer than that in plasma. The maximum concentration (Cmax) of rutin recovered in lymph, 0.86+/-0.13 microg/mL, was slightly lower than that in plasma, 1.35+/-0.37 microg/mL. The area under curve (AUC) of rutin recovered in lymph, 359+/-41 min microg/mL, was about 2-fold higher than the AUC of rutin in plasma, 150+/-22 min microg/mL. This phenomenon was due to the milder concentration decline of rutin in the lymphatic system. These results demonstrate the pharmacokinetic data of lymphatic and systemic absorption after intraduodenally administered quercetin and rutin. It is also the first report revealing the lymphatic absorption of rutin. Although both quercetin and rutin are absorbed and transported mainly via the blood circulation system, the AUC of these two drugs in lymph fluid appeared higher than their respective AUC in plasma.

  9. Hepatitis A

    MedlinePlus

    Hepatitis A Hepatitis A Hepatitis A is a contagious viral infection that can easily affect children and adults. It is one of the most common types of hepatitis virus. Often when you hear about hepatitis A ...

  10. 17β-estradiol attenuates reduced-size hepatic ischemia/reperfusion injury by inhibition apoptosis via mitochondrial pathway in rats.

    PubMed

    Lin, Fu Sheng; Shen, Shi Qiang; Chen, Zu Bing; Yan, Rui Chen

    2012-02-01

    The aim of this study was to investigate the effect of 17β-estradiol (E2) on hepatocyte apoptosis after reduced-size hepatic ischemia/reperfusion (I/R) injury and its mechanism. A rat model of reduced-size hepatic I/R injury was established. Sprague-Dawley rats were randomly allocated into sham, I/R, and E2 + I/R group. 17β-Estradiol (4 mg/kg) or the vehicle was administered i.p. 1 h before ischemia and immediately after operation. For each group, 10 rats were used to investigate the survival during a week after reperfusion. Blood samples and liver tissues were obtained in the remaining animals after 3, 6, 12, and 24 h of reperfusion to assess serum aspartate aminotransferase and alanine aminotransferase levels, liver tissue malondialdehyde concentration, superoxide dismutase activity, and histopathologic changes. Apoptosis ratio; expression of cytochrome c, Bcl-2, and Bax proteins; and enzymatic activities of caspase 9 and caspase 3 were performed in the samples at 12 h after reperfusion. The serum aspartate aminotransferase and alanine aminotransferase levels and tissue malondialdehyde concentration were increased in the I/R group, whereas the increase was significantly reduced by E2. The superoxide dismutase activity, depressed by I/R injury, was elevated back to normal levels by treatment with E2. Severe hepatic damage was observed by light microscopy in the I/R group, whereas administration of E2 resulted in tissue and cellular preservation. Furthermore, E2 inhibited hepatocellular apoptosis by upregulating the ratio of Bcl-2 and Bax expression, reduced cytosolic cytochrome c level, and decreased caspase 9 and caspase 3 activities. The 7-day survival rate was significantly higher in the E2 + I/R group than in the I/R group. These results indicated that E2 protects liver tissues from reduced-size hepatic I/R injury by suppressing mitochondrial apoptotic pathways.

  11. Differential effects of quercetin on hippocampus-dependent learning and memory in mice fed with different diets related with oxidative stress.

    PubMed

    Xia, Shu-Fang; Xie, Zhen-Xing; Qiao, Yi; Li, Li-Rong; Cheng, Xiang-Rong; Tang, Xue; Shi, Yong-Hui; Le, Guo-Wei

    2015-01-01

    High fat diets induce oxidative stress which may be involved in neurodegenerative diseases. Quercetin is a kind of antioxidant that has neuroprotective effects and potent7ial pro-oxidant effects as well. In this study, we evaluated cognitive function in mice fed with high fat diets and basic diets with or without quercetin. Male Chinese Kunming (KM) mice were randomly assigned to five groups fed with basic diet (Control), basic diet with 0.005% (w/w) quercetin (CQ1), high fat diet (HFD), HFD with 0.005% (w/w) quercetin (HFDQ1) and 0.01% (w/w) quercetin (HFDQ2) for 13weeks. At the end of the study period, fasting blood glucose (FBG), plasma and hippocampal markers of oxidative stress, plasma lipid status, Morris water maze as well as hippocampal relative mRNA expression of akt, bdnf, camkII, creb, gsk-3β, nrf2 and pi3k were examined. The results suggested that in comparison to the control group, the escape latency was increased and percent time spent in the target quadrant was decreased, with increased reactive carbonyls, malondialdehyde (MDA) and declined expression of pi3k, akt, nrf2, creb and bdnf in the hippocampus of HFD and CQ1 groups. Conversely, higher quercetin supplemented to HFD improved antioxidant capacity and reversed cognitive decline completely. Significant correlations between the redox status and cognition-related gene expression were observed as well (P<0.05). Thus, in the case of oxidative stress, an appropriate dose of quercetin can attenuate oxidative stress to improve hippocampus dependent cognition. But under a balanced situation, quercetin exerts pro-oxidant effects to impair cognition.

  12. Platycodon grandiflorus Root Extract Attenuates Body Fat Mass, Hepatic Steatosis and Insulin Resistance through the Interplay between the Liver and Adipose Tissue

    PubMed Central

    Kim, Ye Jin; Choi, Ji-Young; Ryu, Ri; Lee, Jeonghyeon; Cho, Su-Jung; Kwon, Eun-Young; Lee, Mi-Kyung; Liu, Kwang-Hyeon; Rina, Yu; Sung, Mi-Kyung; Choi, Myung-Sook

    2016-01-01

    The Platycodon grandiflorus root, a Korean medicinal food, is well known to have beneficial effects on obesity and diabetes. In this study, we demonstrated the metabolic effects of P. grandiflorus root ethanol extract (PGE), which is rich in platycodins, on diet-induced obesity. C57BL/6J mice (four-week-old males) were fed a normal diet (16.58% of kilocalories from fat), high-fat diet (HFD, 60% of kilocalories from fat), and HFD supplemented with 5% (w/w) PGE. In the HFD-fed mice, PGE markedly suppressed the body weight gain and white fat mass to normal control level, with simultaneous increase in the expression of thermogenic genes (such as SIRT1, PPARα, PGC1α, and UCP1), that accompanied changes in fatty acid oxidation (FAO) and energy expenditure. In addition, PGE improved insulin sensitivity through activation of the PPARγ expression, which upregulates adiponectin while decreasing leptin gene expression in adipocytes. Furthermore, PGE improved hepatic steatosis by suppressing hepatic lipogenesis while increasing expression of FAO-associated genes such as PGC1α. PGE normalized body fat and body weight, which is likely associated with the increased energy expenditure and thermogenic gene expression. PGE can protect from HFD-induced insulin resistance, and hepatic steatosis by controlling lipid and glucose metabolism. PMID:27589792

  13. Phytosterol esters attenuate hepatic steatosis in rats with non-alcoholic fatty liver disease rats fed a high-fat diet

    PubMed Central

    Song, Lihua; Qu, Dan; Zhang, Qing; jiang, Jing; Zhou, Haiyue; Jiang, Rui; Li, Yating; Zhang, Yao; Yan, Hongli

    2017-01-01

    Given the adverse effects of drugs used for NAFLD treatment, identifying novel and effective natural compound to prevent NAFLD is urgently needed. In the present study, the effects of phytosterol esters (PSEs) on NAFLD were explored. Adult SD rats were randomized into five groups: normal chow diet (NC), high-fat diet (HF), low-, medium- and high-dose PSE treatment plus high-fat diet groups (PSEL, PSEM, and PSEH). Our results showed that the levels of LDL-C in the PSEL group and hepatic TG, TC, and FFA in the three PSEs groups were significantly decreased. Notably, the uric acid (UA) level was significantly decreased by PSEs intervention. The hepatic inflammatory stress was ameliorated via the inhibition of the cytokines, including TGF-β, IL-6, IL-10 and CRP in the PSEs intervention groups. Further, the oxidative status was improved by PSE treatment through adjusting the enzyme activity (SOD and XOD) and decreasing the MDA level. These beneficial effects of PSE may have been partly due to its regulation on the expression of TGF-β1, TGF-β2, TNF-α, UCP-2, PPAR-α and PPAR-γ in hepatic tissue at both mRNA and protein level. The results of this study suggest that PSEs may be used as therapeutic agents for the prevention and progression of NAFLD and that hyperuricemia is induced by high-fat diet consumption. PMID:28169366

  14. TOP1 and 2, polysaccharides from Taraxacum officinale, attenuate CCl(4)-induced hepatic damage through the modulation of NF-kappaB and its regulatory mediators.

    PubMed

    Park, Chung Mu; Youn, Hyun Joo; Chang, Hee Kyung; Song, Young Sun

    2010-05-01

    In this work, we estimate the inhibitory effect of two polysaccharides from Taraxacum officinale (TOP) on CCl(4)-induced oxidative stress and inflammation in Sprague-Dawley rats. TOP1 and 2 (304, 92 mg/kg bw) were administered for 7 days via a stomach sonde, and hepatitis was induced by a single dose of CCl(4) (50% CCl(4)/olive oil; 0.5 mL/kg bw) administration. CCl(4) significantly elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. Histopathological observation further revealed that CCl(4)-induced moderate levels of inflammatory cell infiltration, centrilobular fatty change, apoptosis, and necrosis. However, TOPs pretreatment markedly decreased AST and ALT activities as well as hepatic lesions. TOPs also increased free radical scavenging activity, as exhibited by a lowered TBARS concentration. TOPs pretreatment also reversed other hepatitis-associated symptoms, including GSH depletion, inhibited anti-oxidative enzyme activities, up-regulation of NF-kappaB and increased expression of its regulatory inflammatory mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta. These results suggest that TOPs have a hepatoprotective effect by modulating inflammatory responses and ameliorating oxidative stress.

  15. Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia.

    PubMed

    He, Yuanzhou; Cao, Xiaopei; Guo, Pujian; Li, Xiaochen; Shang, Huihui; Liu, Jin; Xie, Min; Xu, Yongjian; Liu, Xiansheng

    2017-02-01

    Quercetin, an important dietary flavonoid has been demonstrated to potentially reverse or even prevent pulmonary arterial hypertension (PAH) progression. However, the effects of quercetin on apoptosis and autophagy in pulmonary arterial smooth muscle cells (PASMCs) have not yet been clearly elucidated. The current study found that quercetin significantly induce the apoptotic and autophagic capacities of PASMCs in vitro and in vivo in hypoxia. In addition, we found that quercetin increases FOXO1 (a major mediator in autophagy regulation) expression and transcriptional activity. Moreover, FOXO1 knockdown by siRNAs inhibited the phosphorylation of mTOR and 4E-BPI, which is downstream of P70-S6K, and markedly blocked quercetin-induced autophagy. We also observed that FOXO1-mediated autophagy was achieved via SESN3 not Rictor upregulation and after mTOR suppression. Furthermore, Treatment with autophagy-specific inhibitors could markedly enhance quercetin-induced apoptosis in PASMCs under hypoxia. Finally, quercetin in combination with autophagy inhibition treatment could enhance the therapeutic effects of quercetin in hypoxia-associated PAH in vivo. Taken together, quercetin could enhance hypoxia-induced autophagy through the FOXO1-SENS3-mTOR pathway in PASMCs. Combining quercetin and autophagy inhibitors may be a novel therapeutic strategy for treating hypoxia-associated PAH.

  16. Safety and immunogenicity in humans of an attenuated Salmonella typhi vaccine vector strain expressing plasmid-encoded hepatitis B antigens stabilized by the Asd-balanced lethal vector system.

    PubMed Central

    Tacket, C O; Kelly, S M; Schödel, F; Losonsky, G; Nataro, J P; Edelman, R; Levine, M M; Curtiss, R

    1997-01-01

    Attenuated Salmonella typhi organisms which express genes encoding protective antigens of other pathogens have been developed for use as experimental oral vaccines. A delta asd S. typhi strain attenuated by deletions in cya, crp, and cdt which contains hepatitis B core (HBc) and pre-S genes encoded on an Asd+ pBR-based plasmid vector was constructed. Healthy adult volunteers ingested a single dose of 5 x 10(5) to 5 x 10(8) CFU of strain chi4073 (delta cya delta crp delta cdt S. typhi Ty2), 6 x 10(7) or 1 x 10(9) CFU of strain chi4632(pYA3149), a further derivative of chi4073 deleted in asd and containing the Asd+ vector without the HBc-pre-S fusion, or 3 x 10(7) or 7 x 10(8) CFU of strain X4632(pYA3167), a derivative containing the vector with the HBc-pre-S fusion. Chi4073 was generally well tolerated by 22 volunteers. No volunteer had fever or positive blood cultures; 4 of 22 volunteers shed vaccine organisms in the stool in the first 48 h only. Two of 18 volunteers who received one of the plasmid-containing derivatives of chi4073 developed low-grade fevers on day 10 or 12 after ingestion. One of these volunteers had positive blood cultures on days 7 and 8. Seven of these 18 volunteers had vaccine organisms detected in their stools in the first 48 h only. Most volunteers developed S. typhi-specific serum responses and developed S. typhi-specific antibody-secreting cells. However, no volunteer developed serum antibody to hepatitis pre-S or pre-S-specific antibody-secreting cells. Although the parent strain chi4073 was well tolerated, induced immunoglobulin G seroconversion to S. typhi lipopolysaccharide in 80 to 100% of vaccinees and stimulated specific IgA-secreting lymphocytes in 80 to 100% of vaccinees given a single oral dose of 2 x 10(7) and 5 x 10(8) CFU, chi4073 derivatives containing the Asd+ vector with and without sequences encoding the HBc-pre-S fusion caused occasional febrile reactions at high doses and did not stimulate detectable immune responses to

  17. Reduced ATM kinase activity and an attenuated p53 response to DNA damage in carcinogen-induced preneoplastic hepatic lesions in the rat.

    PubMed

    Silins, I; Finnberg, N; Ståhl, A; Högberg, J; Stenius, U

    2001-12-01

    In previous studies we have demonstrated that the p53 response to DNA damage in preneoplastic liver lesions, referred to as enzyme-altered foci (EAF), is attenuated. In the present investigation comparative quantitative RT-PCR revealed no major difference in the p53 mRNA levels in EAF and non-EAF tissue. When CoCl(2) was employed to induce hypoxia-inducible factor (HIF-1alpha), both non-EAF and EAF hepatocytes readily accumulated p53, whereas EAF hepatocytes did not accumulate p53 upon treatment with diethylnitrosamine (DEN). The p53 response was also induced in EAF hepatocytes by the inhibitor of nuclear export, leptomycin B. An inhibitor of DNA-dependent protein kinase (DNA-PK) and ataxia telangiectasia mutated (ATM), wortmannin, blocked the DEN-induced p53 response in non-EAF hepatocytes. Assay of kinase activity in immunoprecipitated material from EAF and non-EAF tissue revealed attenuated ATM activity in EAF. Immunohistological and western blot analysis of the level of ATM protein was in agreement with the activity measurements and no phosphorylation of Ser15 in p53 was detected in EAF tissue 24 h after a challenging dose of DEN. Taken together with previously published data, these data indicate selective attenuation of the DNA damage pathway in EAF hepatocytes. Down-regulation of DNA damage-induced and ATM-mediated phosphorylation of p53 may confer a growth advantage on EAF hepatocytes.

  18. Application of Bioactive Quercetin in Oncotherapy: From Nutrition to Nanomedicine.

    PubMed

    Nam, Ju-Suk; Sharma, Ashish Ranjan; Nguyen, Lich Thi; Chakraborty, Chiranjib; Sharma, Garima; Lee, Sang-Soo

    2016-01-19

    Phytochemicals as dietary constituents are being explored for their cancer preventive properties. Quercetin is a major constituent of various dietary products and recently its anti-cancer potential has been extensively explored, revealing its anti-proliferative effect on different cancer cell lines, both in vitro and in vivo. Quercetin is known to have modulatory effects on cell apoptosis, migration and growth via various signaling pathways. Though, quercetin possesses great medicinal value, its applications as a therapeutic drug are limited. Problems like low oral bioavailability and poor aqueous solubility make quercetin an unreliable candidate for therapeutic purposes. Additionally, the rapid gastrointestinal digestion of quercetin is also a major barrier for its clinical translation. Hence, to overcome these disadvantages quercetin-based nanoformulations are being considered in recent times. Nanoformulations of quercetin have shown promising results in its uptake by the epithelial system as well as enhanced delivery to the target site. Herein we have tried to summarize various methods utilized for nanofabrication of quercetin formulations and for stable and sustained delivery of quercetin. We have also highlighted the various desirable measures for its use as a promising onco-therapeutic agent.

  19. Hepatitis C

    MedlinePlus

    ... Châu và vùng Thái Bình Dương Hepatitis C Hepatitis C What is hepatitis C? Hepatitis C is a viral infection that ... can cure most cases of hepatitis C. Acute hepatitis C Acute hepatitis C is a short-term ...

  20. Hepatitis A

    MedlinePlus

    ... Châu và vùng Thái Bình Dương Hepatitis C Hepatitis A What is hepatitis A? Hepatitis A is a viral infection that ... spreading hepatitis A to others . How common is hepatitis A? In the United States, hepatitis A has ...

  1. Hepatitis B

    MedlinePlus

    ... Châu và vùng Thái Bình Dương Hepatitis C Hepatitis B What is hepatitis B? Hepatitis B is a viral infection that ... to prevent spreading hepatitis B to others . Acute hepatitis B Acute hepatitis B is a short-term ...

  2. Garlic and Resveratrol Attenuate Diabetic Complications, Loss of β-Cells, Pancreatic and Hepatic Oxidative Stress in Streptozotocin-Induced Diabetic Rats

    PubMed Central

    Kaur, Gagandeep; Padiya, Raju; Adela, Ramu; Putcha, Uday K.; Reddy, G. S.; Reddy, B. R.; Kumar, K. P.; Chakravarty, Sumana; Banerjee, Sanjay K.

    2016-01-01

    The study was aimed at finding the effect of garlic and resveratrol on loss of β-cells and diabetic complication in streptozotocin (STZ)-induced Type-I diabetic rats. Rats were injected with single dose STZ (50 mg/kg, i.p.) for induction of type 1 diabetes (Dia) and compared with control group. Rats from third (Dia+Gar), fourth (Dia+Resv), and fifth (Dia+Met) groups were fed raw garlic homogenate (250 mg/kg/day), resveratrol (25 mg/kg/day), and metformin (500 mg/kg/day) orally, respectively, for a period of 4 weeks. Diabetic group had decreased serum insulin and hydrogen sulfide levels along with increased blood glucose and glycated hemoglobin, triglyceride, uric acid, and nitric oxide levels. Significant (p < 0.05) increase in pancreatic and hepatic TBARS, conjugated dienes, nitric oxide, and AGE level and significant (p < 0.05) decrease in SOD, catalase, H2S, GSH level were observed in diabetic group. Administration of garlic, resveratrol, and metformin significantly (p < 0.05) normalized most of the altered metabolic and oxidative stress parameters as well as histopathological changes. Administration of garlic, resveratrol, and metformin in diabetic rat decreases pancreatic β-cell damage and hepatic injury. Our data concluded that administration of garlic showed more promising effect in terms of reducing oxidative stress and pathological changes when compared to resveratrol and metformin groups. PMID:27790139

  3. The reversibility of the glutathionyl-quercetin adduct spreads oxidized quercetin-induced toxicity

    SciTech Connect

    Boots, Agnes W. . E-mail: a.boots@farmaco.unimaas.nl; Balk, Jiska M.; Bast, Aalt; Haenen, Guido R.M.M.

    2005-12-16

    Quercetin is one of the most prominent dietary antioxidants. During its antioxidant activity, quercetin becomes oxidized into its o-quinone/quinone methide QQ. QQ is toxic since it instantaneously reacts with thiols of, e.g., proteins. In cells, QQ will initially form an adduct with glutathione (GSH), giving GSQ. We have found that GSQ is not stable; it dissociates continuously into GSH and QQ with a half life of 2 min. Surprisingly, GSQ incubated with 2-mercapto-ethanol (MSH), a far less reactive thiol, results in the conversion of GSQ into the MSH-adduct MSQ. A similar conversion of GSQ into relatively stable protein thiol-quercetin adducts is expected. With the dithiol dihydrolipoic acid (L(SH){sub 2}), quercetin is formed out of GSQ. These results indicate that GSQ acts as transport and storage of QQ. In that way, the initially highly focussed toxicity of QQ is dispersed by the formation of GSQ that finally spreads QQ-induced toxicity, probably even over cells.

  4. Quercetin Alleviates High-Fat Diet-Induced Oxidized Low-Density Lipoprotein Accumulation in the Liver: Implication for Autophagy Regulation.

    PubMed

    Liu, Liang; Gao, Chao; Yao, Ping; Gong, Zhiyong

    2015-01-01

    A growing body of evidence has indicated that high-fat diet-induced nonalcoholic fatty liver disease is usually accompanied by oxidized low-density lipoprotein (ox-LDL) deposited in the liver. The current study aimed to investigate the effect of quercetin on high-fat diet-induced ox-LDL accumulation in the liver and to explore the potential underlying mechanisms. The results demonstrate that quercetin supplementation for 24 weeks significantly alleviated high-fat diet-induced liver damage and reduced hepatic cholesterol and ox-LDL level. Quercetin notably inhibited both mRNA and protein expression of CD36 (reduced by 53% and 71%, resp.) and MSR1 (reduced by 25% and 45%, resp.), which were upregulated by high-fat diet. The expression of LC3II was upregulated by 2.4 times whereas that of p62 and mTOR was downregulated by 57% and 63% by quercetin treatment. Therefore, the significantly improved autophagy lysosomal degradation capacity for ox-LDL may be implicated in the hepatoprotective effect of quercetin; scavenger receptors mediated ox-LDL uptake might also be involved.

  5. A Novel Matrine Derivative WM130 Inhibits Activation of Hepatic Stellate Cells and Attenuates Dimethylnitrosamine-Induced Liver Fibrosis in Rats.

    PubMed

    Xu, Yang; Peng, Zhangxiao; Ji, Weidan; Li, Xiang; Lin, Xuejing; Qian, Liqiang; Li, Xiaoya; Chai, Xiaoyun; Wu, Qiuye; Gao, Quangen; Su, Changqing

    2015-01-01

    Activation of hepatic stellate cells (HSCs) is a critical event in process of hepatic fibrogenesis and cirrhosis. Matrine, the active ingredient of Sophora, had been used for clinical treatment of acute/chronic liver disease. However, its potency was low. We prepared a high potency and low toxicity matrine derivate, WM130 (C30N4H40SO5F), which exhibited better pharmacological activities on antihepatic fibrosis. This study demonstrated that WM130 results in a decreased proliferative activity of HSC-T6 cells, with the half inhibitory concentration (IC50) of 68 μM. WM130 can inhibit the migration and induce apoptosis in HSC-T6 cells at both concentrations of 68 μM (IC50) and 34 μM (half IC50). The expression of α-SMA, Collagen I, Collagen III, and TGF-β1 could be downregulated, and the protein phosphorylation levels of EGFR, AKT, ERK, Smad, and Raf (p-EGFR, p-AKT, p-ERK, p-Smad, and p-Raf) were also decreased by WM130. On the DMN-induced rat liver fibrosis model, WM130 can effectively reduce the TGF-β1, AKT, α-SMA, and p-ERK levels, decrease the extracellular matrix (ECM) formation, and inhibit rat liver fibrosis progression. In conclusion, this study demonstrated that WM130 can significantly inhibit the activation of HSC-T6 cells and block the rat liver fibrosis progression by inducing apoptosis, suppressing the deposition of ECM, and inhibiting TGF-β/Smad and Ras/ERK pathways.

  6. Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high-fat diet.

    PubMed

    Wang, Li-jun; Zhang, Hong-wei; Zhou, Jing-ya; Liu, Yan; Yang, Yang; Chen, Xiao-ling; Zhu, Cui-hong; Zheng, Rui-dan; Ling, Wen-hua; Zhu, Hui-lian

    2014-03-01

    Aberrant DNA methylation contributes to the abnormality of hepatic gene expression, one of the main factors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Betaine is a methyl donor and has been considered to be a lipotropic agent. However, whether betaine supplementation improves NAFLD via its effect on the DNA methylation of specific genes and the genome has not been explored. Male C57BL/6 mice were fed either a control diet or high-fat diet (HFD) supplemented with 0%, 1% and 2% betaine in water (wt/vol) for 12 weeks. Betaine supplementation ameliorated HFD-induced hepatic steatosis in a dose-dependent manner. HFD up-regulated FAS and ACOX messenger RNA (mRNA) expression and down-regulated PPARα, ApoB and MTTP mRNA expression; however, these alterations were reversed by betaine supplementation, except ApoB. MTTP mRNA expression was negatively correlated with the DNA methylation of its CpG sites at -184, -156, -63 and -60. Methylation of these CpG sites was lower in both the 1% and 2% betaine-supplemented groups than in the HFD group (averages; 25.55% and 14.33% vs. 30.13%). In addition, both 1% and 2% betaine supplementation significantly restored the methylation capacity [S-adenosylmethionine (SAM) concentration and SAM/S-adenosylhomocysteine ratios] and genomic methylation level, which had been decreased by HFD (0.37% and 0.47% vs. 0.25%). These results suggest that the regulation of aberrant DNA methylation by betaine might be a possible mechanism of the improvements in NAFLD upon betaine supplementation.

  7. Quercetin Reduces Ehrlich Tumor-Induced Cancer Pain in Mice

    PubMed Central

    Calixto-Campos, Cassia; Corrêa, Mab P.; Carvalho, Thacyana T.; Zarpelon, Ana C.; Hohmann, Miriam S. N.; Rossaneis, Ana C.; Coelho-Silva, Leticia; Pavanelli, Wander R.; Pinge-Filho, Phileno; Crespigio, Jefferson; Bernardy, Catia C. F.; Casagrande, Rubia; Verri, Waldiceu A.

    2015-01-01

    Cancer pain directly affects the patient's quality of life. We have previously demonstrated that the subcutaneous administration of the mammary adenocarcinoma known as Ehrlich tumor induces pain in mice. Several studies have shown that the flavonoid quercetin presents important biological effects, including anti-inflammatory, antioxidant, analgesic, and antitumor activity. Therefore, the analgesic effect and mechanisms of quercetin were evaluated in Ehrlich tumor-induced cancer pain in mice. Intraperitoneal (i.p.) treatments with quercetin reduced Ehrlich tumor-induced mechanical and thermal hyperalgesia, but not paw thickness or histological alterations, indicating an analgesic effect without affecting tumor growth. Regarding the analgesic mechanisms of quercetin, it inhibited the production of hyperalgesic cytokines IL-1β and TNFα and decreased neutrophil recruitment (myeloperoxidase activity) and oxidative stress. Naloxone (opioid receptor antagonist) inhibited quercetin analgesia without interfering with neutrophil recruitment, cytokine production, and oxidative stress. Importantly, cotreatment with morphine and quercetin at doses that were ineffective as single treatment reduced the nociceptive responses. Concluding, quercetin reduces the Ehrlich tumor-induced cancer pain by reducing the production of hyperalgesic cytokines, neutrophil recruitment, and oxidative stress as well as by activating an opioid-dependent analgesic pathway and potentiation of morphine analgesia. Thus, quercetin treatment seems a suitable therapeutic approach for cancer pain that merits further investigation. PMID:26351625

  8. Viral Hepatitis

    MedlinePlus

    ... Public Home » For Veterans and the Public Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... the Public Veterans and Public Home How is Hepatitis C Treated? Find the facts about the newest ...

  9. Autoimmune Hepatitis

    MedlinePlus

    ... Cholangitis Wilson Disease Liver Disease A-Z Autoimmune Hepatitis What is autoimmune hepatitis? Autoimmune hepatitis is a chronic—or long lasting— ... bacteria, viruses, toxins, and medications. What causes autoimmune hepatitis? A combination of autoimmunity, environmental triggers, and a ...

  10. Reshaping faecal gut microbiota composition by the intake of trans-resveratrol and quercetin in high-fat sucrose diet-fed rats.

    PubMed

    Etxeberria, U; Arias, N; Boqué, N; Macarulla, M T; Portillo, M P; Martínez, J A; Milagro, F I

    2015-06-01

    Diet-induced obesity is associated to an imbalance in the normal gut microbiota composition. Resveratrol and quercetin, widely known for their health beneficial properties, have low bioavailability, and when they reach the colon, they are targets of the gut microbial ecosystem. Hence, the use of these molecules in obesity might be considered as a potential strategy to modulate intestinal bacterial composition. The purpose of this study was to determine whether trans-resveratrol and quercetin administration could counteract gut microbiota dysbiosis produced by high-fat sucrose diet (HFS) and, in turn, improve gut health. Wistar rats were randomised into four groups fed an HFS diet supplemented or not with trans-resveratrol [15 mg/kg body weight (BW)/day], quercetin (30 mg/kg BW/day) or a combination of both polyphenols at those doses. Administration of both polyphenols together prevented body weight gain and reduced serum insulin levels. Moreover, individual supplementation of trans-resveratrol and quercetin effectively reduced serum insulin levels and insulin resistance. Quercetin supplementation generated a great impact on gut microbiota composition at different taxonomic levels, attenuating Firmicutes/Bacteroidetes ratio and inhibiting the growth of bacterial species previously associated to diet-induced obesity (Erysipelotrichaceae, Bacillus, Eubacterium cylindroides). Overall, the administration of quercetin was found to be effective in lessening HFS-diet-induced gut microbiota dysbiosis. In contrast, trans-resveratrol supplementation alone or in combination with quercetin scarcely modified the profile of gut bacteria but acted at the intestinal level, altering the mRNA expression of tight-junction proteins and inflammation-associated genes.

  11. Viral Hepatitis

    MedlinePlus

    ... with hepatitis? How does a pregnant woman pass hepatitis B virus to her baby? If I have hepatitis B, what does my baby need so that she ... Can I breastfeed my baby if I have hepatitis B? More information on viral hepatitis What is hepatitis? ...

  12. Comparative Effect of Quercetin and Quercetin-3-O-β-d-Glucoside on Fibrin Polymers, Blood Clots, and in Rodent Models.

    PubMed

    Choi, Jun-Hui; Kim, Kyung-Je; Kim, Seung

    2016-11-01

    The present study evaluates the in vitro, in vivo, and ex vivo antithrombotic and anticoagulant effect of two flavonoids: quercetin and quercetin-3-O-β-d-glucoside (isoquercetin). The present results have shown that quercetin and isoquercetin inhibit the enzymatic activity of thrombin and FXa and suppress fibrin clot formation and blood clotting. The prolongation effect of quercetin and isoquercetin against epinephrine and collagen-induced platelet activation may have been caused by intervention in intracellular signaling pathways including coagulation cascade and aggregation response on platelets and blood. The in vivo and ex vivo anticoagulant efficacy of quercetin and isoquercetin was evaluated in thrombin-induced acute thromboembolism model and in ICR mice. Our findings showed that in vitro and in vivo inhibitory effects of quercetin were slightly higher than that of quercetin glucoside, whereas in vitro and ex vivo anticoagulant effects of quercetin were weaker than that of quercetin glucoside because of their structural characteristics.

  13. Ezetimibe markedly attenuates hepatic cholesterol accumulation and improves liver function in the lysosomal acid lipase-deficient mouse, a model for cholesteryl ester storage disease.

    PubMed

    Chuang, Jen-Chieh; Lopez, Adam M; Posey, Kenneth S; Turley, Stephen D

    2014-01-17

    Lysosomal acid lipase (LAL) plays a critical role in the intracellular handling of lipids by hydrolyzing cholesteryl esters (CE) and triacylglycerols (TAG) contained in newly internalized lipoproteins. In humans, mutations in the LAL gene result in cholesteryl ester storage disease (CESD), or in Wolman disease (WD) when the mutations cause complete loss of LAL activity. A rat model for WD and a mouse model for CESD have been described. In these studies we used LAL-deficient mice to investigate how modulating the amount of intestinally-derived cholesterol reaching the liver might impact its mass, cholesterol content, and function in this model. The main experiment tested if ezetimibe, a potent cholesterol absorption inhibitor, had any effect on CE accumulation in mice lacking LAL. In male Lal(-/-) mice given ezetimibe in their diet (20 mg/day/kg bw) for 4 weeks starting at 21 days of age, both liver mass and hepatic cholesterol concentration (mg/g) were reduced to the extent that whole-liver cholesterol content (mg/organ) in the treated mice (74.3±3.4) was only 56% of that in those not given ezetimibe (133.5±6.7). There was also a marked improvement in plasma alanine aminotransferase (ALT) activity. Thus, minimizing cholesterol absorption has a favorable impact on the liver in CESD.

  14. Lycium barbarum polysaccharide attenuates high-fat diet-induced hepatic steatosis by up-regulating SIRT1 expression and deacetylase activity

    PubMed Central

    Jia, Li; Li, Wang; Li, Jianning; Li, Yan; Song, Hui; Luan, Yansong; Qi, Hui; Ma, Lirong; Lu, Xiaohong; Yang, Yi

    2016-01-01

    In this study, we aimed to investigate the protective effects and underlying mechanism of Lycium barbarum polysaccharide (LBP) on high-fat-induced nonalcoholic fatty liver disease (NAFLD). Recently, sirtuin 1 (SIRT1) has been shown to play an important role in the regulation of hepatocellular lipid metabolism. Here, we demonstrated that LBP up-regulates SIRT1 deacetylase activity and protein expression by enhancing the NAD+/NADH ratio. Subsequently, LBP promoted LKB1 deacetylation and AMPK phosphorylation via SIRT1-dependent signalling. We also found that LBP increases acetyl-CoA carboxylase (ACC) phosphorylation and adipose triglyceride lipase (ATGL) protein expression and decreases fatty acid synthase (FAS) by activating the SIRT1/LKB1/AMPK pathway in vitro and in vivo. However, SIRT1 small interfering RNA (siRNA)-mediated knockdown reversed the LBP-mediated effects on ACC, FAS and ATGL. Moreover, LBP elevated carnitine palmitoyltransferase-1 alpha (CPT-1α) expression by suppressing malonyl-CoA accumulation. Taken together, our data indicate that LBP plays a vital role in the regulation of hepatic lipid metabolism and that pharmacological activation of SIRT1 by LBP may be a strategy for the prevention of NAFLD. PMID:27824080

  15. Aqueous Date Flesh or Pits Extract Attenuates Liver Fibrosis via Suppression of Hepatic Stellate Cell Activation and Reduction of Inflammatory Cytokines, Transforming Growth Factor-β1 and Angiogenic Markers in Carbon Tetrachloride-Intoxicated Rats

    PubMed Central

    Al-Rasheed, Nouf M.; Attia, Hala A.; Mohamad, Raeesa A.; Al-Rasheed, Nawal M.; Al-Amin, Maha A.; AL-Onazi, Asma

    2015-01-01

    Previous data indicated the protective effect of date fruit extract on oxidative damage in rat liver. However, the hepatoprotective effects via other mechanisms have not been investigated. This study was performed to evaluate the antifibrotic effect of date flesh extract (DFE) or date pits extract (DPE) via inactivation of hepatic stellate cells (HSCs), reducing the levels of inflammatory, fibrotic and angiogenic markers. Coffee was used as reference hepatoprotective agent. Liver fibrosis was induced by injection of CCl4 (0.4 mL/kg) three times weekly for 8 weeks. DFE, DPE (6 mL/kg), coffee (300 mg/kg), and combination of coffee + DFE and coffee + DPE were given to CCl4-intoxicated rats daily for 8 weeks. DFE, DPE, and their combination with coffee attenuated the elevated levels of inflammatory cytokines including tumor necrosis factor-α, interleukin-6, and interleukin-1β. The increased levels of transforming growth factor-β1 and collagen deposition in injured liver were alleviated by both extracts. CCl4-induced expression of α-smooth muscle actin was suppressed indicating HSCs inactivation. Increased angiogenesis was ameliorated as revealed by reduced levels and expression of vascular endothelial growth factor and CD31. We concluded that DFE or DPE could protect liver via different mechanisms. The combination of coffee with DFE or DPE may enhance its antifibrotic effects. PMID:25945106

  16. Standardized Salvia miltiorrhiza extract suppresses hepatic stellate cell activation and attenuates steatohepatitis induced by a methionine-choline deficient diet in mice.

    PubMed

    Lee, Hak Sung; Son, Woo-Chan; Ryu, Jae-Eun; Koo, Bon Am; Kim, Yeong Shik

    2014-06-17

    The aim of this study was to examine the effect of standardized extract of Salvia miltiorrhiza (SME) on gene and protein expression of non-alcoholic steatohepatitis (NASH)-related factors in activated human hepatic stellate cells (HSC), and in mice with steatohepatitis induced by a methionine-choline deficient (MCD) diet. Male C57BL/6J mice were placed on an MCD or control diet for 8 weeks and SME (0, 0.1, 0.5 and 1 mg/kg body weight) was administered orally every other day for 4 or 6 weeks. HSCs from the LX-2 cell line were treated with transforming growth factor β-1 (TGF-β1) or TGF-β1 plus SME (0.1-10 μg/mL). To investigate the effect of SME on reactive oxygen species (ROS)-induced condition, LX-2 cells were treated with hydrogen peroxide (H2O2) or H2O2 plus SME (0.1-100 μg/mL). MCD administration for 12 weeks increased mRNA expression of tumor necrosis factor (TNF-α), TGF-β1, interleukin-1β (IL-1β), C-reactive protein (CRP), α-smooth muscle actin (α-SMA), type I collagen, matrix metalloproteinase-2 (MMP-2) and MMP-9. TGF-β1-induced LX-2 cells exhibited similar gene expression patterns. SME treatment significantly reduced the mRNA and protein expression of NASH-related factors in the mouse model and HSCs. Histopathological liver analysis showed improved non-alcoholic fatty liver disease (NAFLD) activity and fibrosis score in SME-treated mice. The in vivo studies showed that SME had a significant effect at low doses. These results suggest that SME might be a potential therapeutic candidate for NAFLD treatment.

  17. Enhancing oral bioavailability of quercetin using novel soluplus polymeric micelles

    NASA Astrophysics Data System (ADS)

    Dian, Linghui; Yu, Enjiang; Chen, Xiaona; Wen, Xinguo; Zhang, Zhengzan; Qin, Lingzhen; Wang, Qingqing; Li, Ge; Wu, Chuanbin

    2014-12-01

    To improve its poor aqueous solubility and stability, the potential chemotherapeutic drug quercetin was encapsulated in soluplus polymeric micelles by a modified film dispersion method. With the encapsulation efficiency over 90%, the quercetin-loaded polymeric micelles (Qu-PMs) with drug loading of 6.7% had a narrow size distribution around mean size of 79.00 ± 2.24 nm, suggesting the complete dispersibility of quercetin in water. X-ray diffraction (XRD) patterns illustrated that quercetin was in amorphous or molecular form within PMs. Fourier transform infrared spectroscopy (FTIR) indicated that quercetin formed intermolecular hydrogen bonding with carriers. An in vitro dialysis test showed the Qu-PMs possessed significant sustained-release property, and the formulation was stable for at least 6 months under accelerated conditions. The pharmacokinetic study in beagle dogs showed that absorption of quercetin after oral administration of Qu-PMs was improved significantly, with a half-life 2.19-fold longer and a relative oral bioavailability of 286% as compared to free quercetin. Therefore, these novel soluplus polymeric micelles can be applied to encapsulate various poorly water-soluble drugs towards a development of more applicable therapeutic formulations.

  18. Antioxidative and antiinflammatory activities of quercetin-loaded silica nanoparticles.

    PubMed

    Lee, Ga Hyun; Lee, Sung June; Jeong, Sang Won; Kim, Hyun-Chul; Park, Ga Young; Lee, Se Geun; Choi, Jin Hyun

    2016-07-01

    Utilizing the biological activities of compounds by encapsulating natural components in stable nanoparticles is an important strategy for a variety of biomedical and healthcare applications. In this study, quercetin-loaded silica nanoparticles were synthesized using an oil-in-water microemulsion method, which is a suitable system for producing functional nanoparticles of controlled size and shape. The resulting quercetin-loaded silica nanoparticles were spherical, highly monodispersed, and stable in an aqueous system. Superoxide radical scavenging effects were found for the quercetin-loaded silica nanoparticles as well as free quercetin. The quercetin-loaded silica nanoparticles showed cell viability comparable to that of the controls. The amounts of proinflammatory cytokines produced by macrophages, such as interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha, were reduced significantly for the quercetin-loaded silica nanoparticles. These results suggest that the antioxidative and antiinflammatory activities of quercetin are maintained after encapsulation in silica. Silica nanoparticles can be used for the effective and stable incorporation of biologically active natural components into composite biomaterials.

  19. Role of Quercetin in Modulating Chloride Transport in the Intestine

    PubMed Central

    Yu, Bo; Jiang, Yu; Jin, Lingling; Ma, Tonghui; Yang, Hong

    2016-01-01

    Epithelial chloride channels provide the pathways for fluid secretion in the intestine. Cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channels (CaCCs) are the main chloride channels in the luminal membrane of enterocytes. These transmembrane proteins play important roles in many physiological processes. In this study, we have identified a flavonoid quercetin as a modulator of CaCC chloride channel activity. Fluorescence quenching assay showed that quercetin activated Cl− transport in a dose-dependent manner, with EC50 ~37 μM. Short-circuit current analysis confirmed that quercetin activated CaCC-mediated Cl− currents in HT-29 cells that can be abolished by CaCCinh-A01. Ex vivo studies indicated that application of quercetin to mouse ileum and colon on serosal side resulted in activation of CFTR and CaCC-mediated Cl− currents. Notably, we found that quercetin exhibited inhibitory effect against ANO1 chloride channel activity in ANO1-expressing FRT cells and decreased mouse intestinal motility. Quercetin-stimulated short-circuit currents in mouse ileum was multi-component, which included elevation of Ca2+ concentration through L-type calcium channel and activation of basolateral NKCC, Na+/K+-ATPase, and K+ channels. In vivo studies further revealed that quercetin promoted fluid secretion in mouse ileum. The modulatory effect of quercetin on CaCC chloirde channels may therefore represent a potential therapeutic strategy for treating CaCC-related diseases like constipation, secretory diarrhea and hypertension. The inverse effects of quercetin on CaCCs provided evidence that ANO1 and intestinal epithelial CaCCs are different calcium-activated chloride channels. PMID:27932986

  20. [Study of quantum-pharmacological chemical characteristics of quercetin].

    PubMed

    Zahorodnyĭ, M I

    2007-01-01

    It was established in the previous studies that quercetin prevented the development and caused faster regression of ulcers, petechia and anabroses in rats, which were induced by diclofenac taking. In the group of patients taking diclofenac together with quercetin, the ulcers and dyspeptic events were less found. The application of quercetin normalizes the function and metabolism of cartilage tissue of rabbits with an experimental osteoarthrosis and in patients with osteoartrosis. Quantum-chemical properties of molecule quercetin were studied using the methods of molecular mechanics MM+ and ab initio 6-31G*, and also semiempirical method. The following indices were investigated: distance between atoms (A), the distribution of electronic density of only external valency electrons, distribution of electrostatic potential; common energy of the exertion of molecule (kkal/mmol); binding energy (kkal/mmol); electron energy (kkal/mmol); energy of nucleus-nucleus interaction (kkal/mmol); formation heat (kkal/mmol); atomic charge (eB); value of the dipole moment of molecule (D); localization and energy of highest occupied orbital (HOMO) and the lowest unoccupied (LUMO) molecular orbital (eB) of quercetin miolecule; the value of absolute rigidity of chemical structure of bioflavonoid. It was shown, that bioflavonoid quercetin belongs to mild reagents, has nucleophilic properties, can react with alkaline, unsaturated and aromatic compounds,. Polar substitutes in the quercetine molecule influence on the distribution of superficial valency electrons and localization of HOMO and LUMO. The energy value of quercetin LUMO enables us to refer quercetine to the reducing agent and it is illustrated by antioxidant properties of this medicine.

  1. Pharmacologic modulation of acute ocular inflammation with quercetin.

    PubMed

    Romero, J; Marak, G E; Rao, N A

    1989-01-01

    Anti-inflammatory potentials of a safe, common dietary component, quercetin, were investigated in suppression of intraocular inflammation induced by retinal S antigen. Lewis rats sensitized to S antigen were treated daily with intraperitoneal injections of quercetin. Control rats with S-antigen-induced uveitis were similarly treated with diluent. When compared with controls the treated group showed marked reduction in uveal and retinal inflammation and in vasculitis and perivasculitis. Morphometric analysis revealed a significant reduction (p less than 0.005) in choroidal thickness when compared with that of control animals. These results clearly show the antiphlogistic effects of quercetin in experimental uveitis.

  2. Hepatoprotective activity of quercetin against acrylonitrile-induced hepatotoxicity in rats.

    PubMed

    Abo-Salem, Osama M; Abd-Ellah, Mohamed F; Ghonaim, Mabrouk M

    2011-01-01

    Acrylonitrile is a potent hepatotoxic, mutagen, and carcinogen. A role for free radical-mediated lipid peroxidation in the toxicity of acrylonitrile has been suggested. The present study was designed to assess the hepatoprotective effect of quercetin against acrylonitrile-induced hepatotoxicity in rats. Liver damage was induced by oral administration of acrylonitrile (50 mg/kg/day/5 weeks). Acrylonitrile produced a significant elevation of malondialdehyde (138.9%) with a marked decrease in reduced glutathione (72.4%), and enzymatic antioxidants; superoxide dismutase (81%), and glutathione peroxidase (53.2%) in the liver. Serum aspartate aminotransferase, alanine aminotransferases, direct bilirubin, and total bilirubin showed a significant increase in acrylonitrile alone treated rats (115.5%, 110.8%, 1006.8%, and 1000.8%, respectively). Pretreatment with quercetin (70 mg/kg/day/6 weeks) and its coadministration with acrylonitrile prevented acrylonitrile-induced alterations in hepatic lipid peroxides and enzymatic antioxidants as well as serum aminotransferases and bilirubin. Histopathological findings supported the biochemical results. We suggest that querectin possess hepatoprotective effect against acrylonitrile-induced hepatotoxicity through its antioxidant activity.

  3. Hepatitis C

    MedlinePlus

    ... your doctor may want you to get the hepatitis B vaccine (and maybe the hepatitis A vaccine, too), if you don't already have these viruses. If you have hepatitis C, you are more likely to catch hepatitis A or hepatitis B, which would cause more damage to your liver. ...

  4. Naringenin and quercetin--potential anti-HCV agents for NS2 protease targets.

    PubMed

    Lulu, S Sajitha; Thabitha, A; Vino, S; Priya, A Mohana; Rout, Madhusmita

    2016-01-01

    Nonstructural proteins of hepatitis C virus had drawn much attention for the scientific fraternity in drug discovery due to its important role in the disease. 3D structure of the protein was predicted using molecular modelling protocol. Docking studies of 10 medicinal plant compounds and three drugs available in the market (control) with NS2 protease were employed by using rigid docking approach of AutoDock 4.2. Among the molecules tested for docking study, naringenin and quercetin revealed minimum binding energy of - 7.97 and - 7.95 kcal/mol with NS2 protease. All the ligands were docked deeply within the binding pocket region of the protein. The docking study results showed that these compounds are potential inhibitors of the target; and also all these docked compounds have good inhibition constant, vdW+Hbond+desolv energy with best RMSD value.

  5. Comparison of the safety and immunogenicity of live attenuated and inactivated hepatitis A vaccine in healthy Chinese children aged 18 months to 16 years: results from a randomized, parallel controlled, phase IV study.

    PubMed

    Ma, F; Yang, J; Kang, G; Sun, Q; Lu, P; Zhao, Y; Wang, Z; Luo, J; Wang, Z

    2016-09-01

    For large-scale immunization of children with hepatitis A (HA) vaccines in China, accurately designed studies comparing the safety and immunogenicity of the live attenuated HA vaccine (HA-L) and inactivated HA vaccine (HA-I) are necessary. A randomized, parallel controlled, phase IV clinical trial was conducted with 6000 healthy children aged 18 months to 16 years. HA-L or HA-I was administered at a ratio of 1: 1 to randomized selected participants. The safety and immunogenicity were evaluated. Both HA-L and HA-I were well tolerated by all participants. The immunogenicity results showed that the seroconversion rates (HA-L versus HA-I: 98.0% versus 100%, respectively, p >0.05), and geometric mean concentrations in participants negative for antibodies against HA virus IgG (anti-HAV IgG) before vaccination did not differ significantly between the two types of vaccines (HA-L versus HA-I first dose: 898.9 versus 886.2 mIU/mL, respectively, p >0.05). After administration of the booster dose of HA-I, the geometric mean concentrations of anti-HAV IgG (HA-I booster dose: 2591.2 mIU/mL) was higher than that after the first dose (p <0.05) and that reported in participants administered HA-L (p <0.05). Additionally, 12 (25%) of the 48 randomized selected participants who received HA-L tested positive for HA antigen in stool samples. Hence, both HA-L and HA-I could provide acceptable immunogenicity in children. The effects of long-term immunogenicity after natural exposure to wild-type HA virus and the possibility of mutational shifts of the live vaccine virus in the field need to be studied in more detail.

  6. Hepatitis C

    MedlinePlus

    Hepatitis C Overview By Mayo Clinic Staff Hepatitis C is a viral infection that causes liver inflammation, sometimes leading to serious liver damage. The hepatitis C virus (HCV) spreads through contaminated ...

  7. Toxic Hepatitis

    MedlinePlus

    Toxic hepatitis Overview By Mayo Clinic Staff Toxic hepatitis is an inflammation of your liver in reaction to certain substances to which you're exposed. Toxic hepatitis can be caused by alcohol, chemicals, drugs or ...

  8. Molecular Targets Underlying the Anticancer Effects of Quercetin: An Update

    PubMed Central

    Khan, Fazlullah; Niaz, Kamal; Maqbool, Faheem; Ismail Hassan, Fatima; Abdollahi, Mohammad; Nagulapalli Venkata, Kalyan C.; Nabavi, Seyed Mohammad; Bishayee, Anupam

    2016-01-01

    Quercetin, a medicinally important member of the flavonoid family, is one of the most prominent dietary antioxidants. It is present in a variety of foods—including fruits, vegetables, tea, wine, as well as other dietary supplements—and is responsible for various health benefits. Numerous pharmacological effects of quercetin include protection against diseases, such as osteoporosis, certain forms of malignant tumors, and pulmonary and cardiovascular disorders. Quercetin has the special ability of scavenging highly reactive species, such as hydrogen peroxide, superoxide anion, and hydroxyl radicals. These oxygen radicals are called reactive oxygen species, which can cause oxidative damage to cellular components, such as proteins, lipids, and deoxyribonucleic acid. Various oxygen radicals play important roles in pathophysiological and degenerative processes, such as aging. Subsequently, several studies have been performed to evaluate possible advantageous health effects of quercetin and to collect scientific evidence for these beneficial health claims. These studies also gather data in order to evaluate the exact mechanism(s) of action and toxicological effects of quercetin. The purpose of this review is to present and critically analyze molecular pathways underlying the anticancer effects of quercetin. Current limitations and future directions of research on this bioactive dietary polyphenol are also critically discussed. PMID:27589790

  9. The immunostimulating activity of quercetin 3-O-xyloside in murine macrophages via activation of the ASK1/MAPK/NF-κB signaling pathway.

    PubMed

    Lee, Jisun; Choi, Ji Won; Sohng, Jae Kyung; Pandey, Ramesh Prasad; Park, Yong Il

    2016-02-01

    Quercetin is a natural plant flavonoid that has been reported to possess a wide range of beneficial health effects, including anti-cancer and anti-inflammatory activities. Glycosylation of natural flavonoids with various sugar moieties can affect their physical, chemical, and biological properties. In this study, quercetin 3-O-xyloside (Quer-xyl) was enzymatically synthesized, and the immunomodulatory activities of quercetin and Quer-xyl were evaluated and compared. The results showed that Quer-xyl more effectively induced the secretion of TNF-α and IL-6 than quercetin by 2.5 and 1.5-fold, respectively. Quer-xyl dose-dependently induced the inducible nitric oxide synthase (iNOS) expression and increased the production of nitric oxide (NO) 1.3-fold more than quercetin. Quer-xyl also increased the phosphorylation of ASK1 and MAPKs (JNK and p38). Treatment with NQDI-1 (an inhibitor of ASK1) significantly attenuated the Quer-xyl-induced up-regulation of TNF-α secretion. The activation and subsequent nuclear translocation of NF-κB were substantially enhanced upon treatment with Quer-xyl (2.5-20 μM), while NQDI-1 treatment blocked the nuclear translocation of NF-κB. These results demonstrated that Quer-xyl can enhance the early innate immunity more effectively than quercetin by activating macrophages to secrete TNF-α and IL-6 through up-regulation of the redox-dependent ASK1/MAPK/NF-κB signaling pathway, suggesting for the first time that Quer-xyl may represent a new immunostimulator.

  10. Report: quantitative estimation of beta-sitosterol, lupeol, quercetin and quercetin glycosides from leaflets of Soymida febrifuga using HPTLC technique.

    PubMed

    Attarde, D L; Aurangabadkar, V M; Belsare, D P; Pal, S C

    2008-07-01

    Soymida febrifuga (Meliaceae) dried leaflets (10 gm) were extracted with petroleum ether. Unsaponifiable matter quantitatively used for sample preparation, labeled as SF-U. Another 10 gm leaflet powder was extracted with methanol and quantitatively used for sample preparation labeled as SF-A. Sample and standard solution were dosage on three different plates and developed in its respective mobile phase plates were scanned using TLC scanner III and estimated using integration software CATs 4.05. Calculations for percentage were done considering standard and sample R(f), AUC and dilution factor. Estimation of beta Sitosterol, Lupeol, Quercetin, Quercetin-3-O-galactoside, Quercetin-3-O-xyloside and Quercetin-3-O-rutinoside were determined as 0.02146% w/w, 0.0377% w/w, 0.4079% w/w, 0.6197% w/w, 2.974% w/w and 3.235% w/w respectively with the help of HPLC techniques.

  11. Pharmacokinetics and bioavailability of the bioflavonoid biochanin A: effects of quercetin and EGCG on biochanin A disposition in rats.

    PubMed

    Moon, Young Jin; Morris, Marilyn E

    2007-01-01

    Little is known regarding pharmacokinetic (PK) or pharmacodynamic interactions of flavonoids with each other: this is of significance since multiple flavonoids are present in the diet and in dietary supplements. Our objective was to determine the effect of quercetin and (-)-epigallocatechin-3-gallate (EGCG), major flavonoids present in the diet, on the PK and bioavailability of biochanin A, a flavonoid with chemopreventive properties. BCA was administered to rats intravenously (5 mg/kg) or orally (16.67 or 50 mg/kg) with or without concomitant EGCG and quercetin. In vitro studies with the human intestinal Caco-2 and human hepatic HepG2 cell lines were performed to evaluate the effects of quercetin and EGCG on the cellular metabolism of BCA, and studies with human breast cancer MCF-7 cells that overexpress P-glycoprotein or BCRP (MCF-7/ADR and MCF-7/MX100 cells, respectively) or MDCK cells that express MRP2 (MDCK-MRP2) were performed to evaluate the effects of cellular efflux. An HPLC assay was used to determine plasma, urine, and cellular concentrations of BCA and the conjugated metabolites of BCA (following enzymatic hydrolysis). The coadministration of quercetin and EGCG significantly increased the BCA area under the plasma concentration vs time curve (AUC) in rats, after both iv and oral administration of BCA. The AUC of total BCA (unchanged + conjugated) was also increased. The increases in BCA AUC reflected predominantly increased bioavailability; this was true even after iv administration due to an apparent increase in the enterohepatic cycling of BCA. Our findings demonstrate for the first time that the administration of multiple flavonoids results in increased flavonoid bioavailability, as well as a decrease in clearance, potentially due to increased enterohepatic cycling.

  12. Quercetin solubilisation in bile salts: A comparison with sodium dodecyl sulphate.

    PubMed

    Buchweitz, Maria; Kroon, Paul A; Rich, Gillian T; Wilde, Peter J

    2016-11-15

    To understand the bioaccessibility of the flavonoid quercetin we studied its interaction with bile salt micelles. The environmental sensitivity of quercetin's UV-visible absorption spectrum gave information about quercetin partitioning. Two quercetin absorption peaks gave complementary information: Peak A (240-280nm) on the intermicellar phase and Peak B (340-440nm) on the micellar phase. Thus, by altering pH, we showed that only non-ionised quercetin partitions into micelles. We validated our interpretation by studying quercetin's interaction with SDS micelles. Pyrene fluorescence and the quercetin UV-visible spectra show that the adsorption site for pyrene and quercetin in bile salt micelles is more hydrophobic than that for SDS micelles. Also, both quercetin and pyrene reported a higher critical micelle concentration for bile salts than for SDS. Our method of using a flavonoid as an intrinsic probe, is generally applicable to other lipophilic bioactives, whenever they have observable environmental dependent properties.

  13. Antioxidant and Prophylactic Effects of Delonix elata L., Stem Bark Extracts, and Flavonoid Isolated Quercetin against Carbon Tetrachloride-Induced Hepatotoxicity in Rats

    PubMed Central

    Venkatarangaiah, Krishna; Venkatesh; Shivamogga Rajanna, Santosh Kumar; Kashi Prakash Gupta, Rajesh

    2014-01-01

    Delonix elata L. (Ceasalpinaceae), is widely used by the traditional medical practitioners of Karnataka, India, to cure jaundice, and bronchial and rheumatic problems. The objective of this study was to screen the in vitro antioxidant and hepatoprotective activity of the stem bark extracts against CCl4-induced liver damage in rats. Among different stem bark extracts tested, the ethanol extract (DSE) has shown significant in vitro antioxidant property in radicals scavenging, metal chelating, and lipid peroxidation inhibition assays. HPLC analysis of the DSE revealed the presence of known antioxidant molecules, namely, gallic acid, ellagic acid, coumaric acid, quercetin, and rutin. Bioassay-guided fractionation of DSE has resulted in the isolation and characterization of quercetin. DSE and quercetin have shown significant prophylactic effects by restoring the liver function markers (AST, ALT, ALP, serum bilirubin, and total protein) and antioxidant enzymes (SOD, CAT, GPx, and GST). These results were proved to be hepatoprotective at par with silymarin and well supported by the histological observations of liver sections with distinct hepatic cells, and mild degree of fatty change and necrosis. The results indicated that the DSE and quercetin were significant for prophylactic activity against CCl4-induced liver damage in rats. This activity could be attributed to the antioxidant constituents in the DSE and hence justified the ethnomedicinal claims. PMID:24987689

  14. Potential protective effects of quercetin and curcumin on paracetamol-induced histological changes, oxidative stress, impaired liver and kidney functions and haematotoxicity in rat.

    PubMed

    Yousef, Mokhtar I; Omar, Sahar A M; El-Guendi, Marwa I; Abdelmegid, Laila A

    2010-11-01

    The present study was carried out to evaluate the potential protective role of quercetin and curcumin against paracetamol-induced oxidative injury, liver damage and impairment of kidney function, as well as haematotoxicity in rats. Also, N-acetylcysteine was used to evaluate the potency of quercetin and curcumin. Paracetamol caused an elevation in thiobarbituric acid-reactive substances (TBARS) paralleled with significant decline in glutathione peroxidase, glutathione S-transferase, superoxide dismutase and catalase activities (in plasma, brain, lung, heart, liver, kidney and testes) and glutathione content (in lung, liver and kidney). The apparent oxidative injury was associated with evident hepatic necrosis confirmed in histological examination, elevated plasma transmainases, alkaline phosphatase and lactate dehydrogenase. Paracetamol reduced plasma total protein, albumin and globulin, while increased bilirubin, urea and creatinine, and induced haematotoxicity. The presence of quercetin or curcumin with paracetamol successfully mitigated the rise in TBARS and restored the activities of antioxidant enzymes compared to the group treated with both paracetamol and N-acetylcysteine. They also protected liver histology, normalized liver and kidney functions, which was more pronounced with curcumin. Therefore, it can be concluded that concomitant administration of quercetin or curcumin with paracetamol may be useful in reversing the toxicity of the drug compared to N-acetylcysteine.

  15. Effects of quercetin and quercetin-3-O-glycosides on oxidative damage in rat C6 glioma cells.

    PubMed

    Zielińska, Małgorzata; Gülden, Michael; Seibert, Hasso

    2003-01-01

    Flavonoids are reported to be powerful antioxidants in cell free systems. They naturally occur as glycosides rather than as aglycon. In this study the ability of the flavonoid quercetin and its glycosides, quercetin-3-O-rutinoside (rutin), quercetin-3-O-glucoside and quercetin-3-O-(6″-O-acetyl)-glucoside, to protect in vitro rat C6 glioma cells from oxidative damage induced by cumene hydroperoxide was investigated. Cumene hydroperoxide induced cell death and lipid peroxidation. The cytotoxicity of cumene hydroperoxide could be prevented by the radical scavenger dimethyl thiourea and the ferric iron chelator deferoxamine, indicating that its cytotoxic activity is related to the generation of reactive oxygen radicals in the ferrous iron dependent Fenton reaction. Quercetin, in a concentration range of 10-100 μM, but neither rutin nor the other two glycosides, were able to protect C6 cells from cytotoxicity and lipid peroxidation. Furthermore, cytoprotective concentrations of quercetin proved to be cytotoxic itself. These results call in question potential beneficial effects of dietary intake or therapeutic use of naturally occurring flavonoids.

  16. Hepatitis B and HIV

    MedlinePlus

    ... Problems : Hepatitis B Subscribe Translate Text Size Print Hepatitis B What is Hepatitis? Hepatitis means inflammation of the liver. This condition ... our related pages, Hepatitis A and Hepatitis C . Hepatitis B and HIV About 10% of people living ...

  17. Pharmacokinetic comparison between quercetin and quercetin 3-O-β-glucuronide in rats by UHPLC-MS/MS

    NASA Astrophysics Data System (ADS)

    Yang, Le-Le; Xiao, Na; Li, Xiao-Wei; Fan, Yong; Alolga, Raphael N.; Sun, Xiao-Yue; Wang, Shi-Lei; Li, Ping; Qi, Lian-Wen

    2016-10-01

    Quercetin is a natural flavonoid widely distributed in human diet and functional foods. Quercetin 3-O-β-glucuronide (Q3G) is present in wine and some medicinal plants. Quercetin and Q3G may be metabolized from each other in vivo. While quercetin has been the subject of many studies, the pharmacokinetic profiles of quercetin and Q3G (in animals) have not yet been compared. Herein, we prepared a column-based method for rapid isolation of Q3G from Nelumbo nucifera. Then, we developed an UHPLC-MS/MS method to compare the pharmacokinetics of quercetin and Q3G. Our results showed that the plasma concentration-time curves of quercetin and Q3G show two maxima (Tmax1 ≈ 0.75 h, Tmax2 ≈ 5 h). After oral administration of 100 mg/kg quercetin or 100 mg/kg Q3G in rats, predominantly Q3G was detected in plasma with AUC at 39529.2 ± 6108.2 mg·h·L‑1 or 24625.1 ± 1563.8 mg·h·L‑1, 18-fold higher than quercetin with AUC at 1583.9 ± 583.3 mg·h·L‑1 or 1394.6 ± 868.1 mg·h·L‑1, respectively. After intravenous injection of 10 mg/kg in rats, Q3G showed extensive tissue uptake in kidney (409.2 ± 118.4 ng/g), liver (166.1 ± 52.9 ng/g), heart (97.7 ± 22.6 ng/g), and brain (5.8 ± 1.2 ng/g). In conclusion, we have shown that Q3G is a major active component in plasma and tissue for oral administration of quercetin or Q3G.

  18. Pharmacokinetic comparison between quercetin and quercetin 3-O-β-glucuronide in rats by UHPLC-MS/MS

    PubMed Central

    Yang, Le-Le; Xiao, Na; Li, Xiao-Wei; Fan, Yong; Alolga, Raphael N.; Sun, Xiao-Yue; Wang, Shi-Lei; Li, Ping; Qi, Lian-Wen

    2016-01-01

    Quercetin is a natural flavonoid widely distributed in human diet and functional foods. Quercetin 3-O-β-glucuronide (Q3G) is present in wine and some medicinal plants. Quercetin and Q3G may be metabolized from each other in vivo. While quercetin has been the subject of many studies, the pharmacokinetic profiles of quercetin and Q3G (in animals) have not yet been compared. Herein, we prepared a column-based method for rapid isolation of Q3G from Nelumbo nucifera. Then, we developed an UHPLC-MS/MS method to compare the pharmacokinetics of quercetin and Q3G. Our results showed that the plasma concentration-time curves of quercetin and Q3G show two maxima (Tmax1 ≈ 0.75 h, Tmax2 ≈ 5 h). After oral administration of 100 mg/kg quercetin or 100 mg/kg Q3G in rats, predominantly Q3G was detected in plasma with AUC at 39529.2 ± 6108.2 mg·h·L−1 or 24625.1 ± 1563.8 mg·h·L−1, 18-fold higher than quercetin with AUC at 1583.9 ± 583.3 mg·h·L−1 or 1394.6 ± 868.1 mg·h·L−1, respectively. After intravenous injection of 10 mg/kg in rats, Q3G showed extensive tissue uptake in kidney (409.2 ± 118.4 ng/g), liver (166.1 ± 52.9 ng/g), heart (97.7 ± 22.6 ng/g), and brain (5.8 ± 1.2 ng/g). In conclusion, we have shown that Q3G is a major active component in plasma and tissue for oral administration of quercetin or Q3G. PMID:27775094

  19. Hepatitis A

    MedlinePlus

    ... transaminase enzyme levels Treatment There is no specific treatment for hepatitis A. You should rest when the symptoms are ... and have not had hepatitis A or the hepatitis A vaccine. Common reasons for getting one or both of these treatments include: You live with someone who has hepatitis ...

  20. Quercetin-3-O-β-D-Glucuronide Suppresses Lipopolysaccharide-Induced JNK and ERK Phosphorylation in LPS-Challenged RAW264.7 Cells

    PubMed Central

    Park, Jin-Young; Lim, Man-Sup; Kim, Song-In; Lee, Hee Jae; Kim, Sung-Soo; Kwon, Yong-Soo; Chun, Wanjoo

    2016-01-01

    Quercetin, a flavonol, has been reported to exhibit a wide range of biological properties including anti-oxidant and anti-inflammatory activities. However, pharmacological properties of quercetin-3-O-β-D-glucuronide (QG), a glycoside derivative of quercetin, have not been extensively examined. The objective of this study is to elucidate the anti-inflammatory property and underlying mechanism of QG in lipopolysaccharide (LPS)-challenged RAW264.7 macrophage cells in comparison with quercetin. QG significantly suppressed LPS-induced extracellular secretion of pro-inflammatory mediators such as nitric oxide (NO) and PGE2, and pro-inflammatory protein expressions of iNOS and COX-2. To elucidate the underlying mechanism of the anti-inflammatory property of QG, involvement of MAPK signaling pathways was examined. QG significantly attenuated LPS-induced activation of JNK and ERK in concentration-dependent manners with a negligible effect on p38. In conclusion, the present study demonstrates QG exerts anti-inflammatory activity through the suppression of JNK and ERK signaling pathways in LPS-challenged RAW264.7 macrophage cells. PMID:27257013

  1. Suppressive Activity of Quercetin on Periostin Functions In Vitro.

    PubMed

    Irie, Shinji; Kashiwabara, Misako; Yamada, Asako; Asano, Kazuhito

    2016-01-01

    Periostin, a 90-kDa extracellular matrix protein, has been attracting attention as a novel biomarker of airway inflammatory diseases such as allergic rhinitis (AR) and asthma. Although oral administration of quercetin to patients with AR can favorably modify the clinical condition of this disease, the influence of quercetin on periostin functions is not well understood. The present study was, therefore, undertaken to examine the influence of quercetin on the production of both periostin and periostin-induced eosinophil chemoattractants from human nasal epithelial cells (HNEpC) in vitro. HNEpC were stimulated with 15.0 ng/ml interleukin (IL)-4 in the absence or presence of quercetin for 72 h. Periostin levels in the culture supernatants were measured using enzyme-linked immunosorbent assay (ELISA). Addition of 4.0 μM quercetin into cell cultures suppressed periostin production from HNEpC that was induced by IL-4 stimulation through inhibitation of signal transducer and activator of transcription 6 (STAT6) activation. We then examined whether quercetin could inhibit production of the periostin-induced eosinophil chemoattractants, regulated on activation, normal T-cell expressed and secreted (RANTES) and eotaxin, from HNEpC. HNEpC were stimulated with 2.0 ng/ml periostin in the absence or presence of quercetin for 72 h. RANTES and eotaxin levels in culture supernatants were examined using ELISA. Treatment of HNEpC with quercetin at a concentration of 4.0 μM suppressed the ability of cells to produce RANTES and eotaxin. This suppression was mediated through suppression of activation of the transcription factor nuclear factor-kappa B (NF-κB) p65, as measured using ELISA, and of chemokine mRNA expression, as measured using reverse transcriptase-polymerase chain reaction (RT-PCR). These results strongly suggest that quercetin suppresses the production of both periostin and periostin-induced eosinophil chemoattractants from HNEpC and results in improvement of the

  2. Quercetin and quercetin 3-O-glycosides from Bauhinia longifolia (Bong.) Steud. show anti-Mayaro virus activity

    PubMed Central

    2014-01-01

    Background The arthropod-borne Mayaro virus (MAYV) causes ‘Mayaro fever’, a disease of medical significance, primarily affecting individuals in permanent contact with forested areas in tropical South America. Recently, MAYV has attracted attention due to its likely urbanization. Currently, there are no licensed drugs against most mosquito-transmitted viruses. Here, we investigated the in vitro anti-MAYV activity of the flavonoids quercetin and its derivatives from the Brazilian shrub Bauhinia longifolia (Bong.) Steud. Methods Flavonoids were purified by chromatographic fractionation from leaf extracts of B. longifolia and chemically identified as quercetin and quercetin glycosides using spectroscopic techniques. Cytotoxicity of purified flavonoids and of EtOAc- and n-BuOH-containing flavonoid mixtures was measured by the dye-uptake assay while their antiviral activity was evaluated by a virus yield inhibition assay. Results The following flavonoids were purified from B. longifolia leaves: non-glycosylated quercetin and its glycosides guaijaverin, quercitrin, isoquercitrin, and hyperin. EtOAc and n-BuOH fractions containing these flavonoids demonstrated the highest antiviral activity of all tested substances, while quercetin had the highest antiviral activity amongst purified flavonoids. Quercetin, EtOAc, or n-BuOH fractions inhibited MAYV production by more than 90% at 25 μg/mL, displaying a stronger antiviral effect than the licensed antiviral ribavirin. A mixture of the isomers isoquercitrin and hyperin had a modest antiviral effect (IC90 = 104.9), while guaijaverin and quercitrin did not show significant antiviral activity. Conclusions B. longifolia is a good source of flavonoids with anti-Mayaro virus activity. This is the first report of the activity of quercetin and its derivatives against an alphavirus. PMID:24678592

  3. The Phototoxic Potential of the Flavonoids, Taxifolin and Quercetin.

    PubMed

    Svobodová, Alena Rajnochová; Ryšavá, Alena; Psotová, Michaela; Kosina, Pavel; Zálešák, Bohumil; Ulrichová, Jitka; Vostálová, Jitka

    2017-03-16

    Quercetin, one of the most abundant polyphenols in the plant kingdom has been shown to be photodegraded on exposure to UV light. Despite the fact, it is a component of several dermatological preparations. Its phototoxic potential has not been evaluated to date. The aim of this study was to assess whether photo-induced degradation of quercetin is linked to phototoxic effects on living cells. Its dihydro derivative, taxifolin was included in the study. For evaluation, the 3T3 Neutral Red Uptake Phototoxicity Test according to OECD TG 432, was used. To better approximate human skin, HaCaT keratinocytes, normal human epidermal keratinocytes and dermal fibroblasts were used, apart from the Balb/c 3T3 cell line. Quercetin showed a dose-dependent photodegradation in aqueous and organic environments and a phototoxic effect on all used cells. Quercetin pre-treatment and following UVA exposure resulted in increased reactive oxygen species production and intracellular GSH level depletion in human dermal fibroblasts. Taxifolin was found completely non-phototoxic and photostable. As only in vitro methodology was used further studies using 3D skin models and/or human volunteers are needed to confirm whether exposure to sunlight, tanning sunbeds and/or phototherapy in people using cosmetics containing quercetin, is a health risk. This article is protected by copyright. All rights reserved.

  4. DIETARY FLAVONOID QUERCETIN STIMULATES VASORELAXATION IN AORTIC VESSELS

    PubMed Central

    Khoo, Nicholas K.H.; White, C. Roger; Pozzo-Miller, Lucas; Zhou, Fen; Constance, Chad; Inoue, Takafumi; Patel, Rakesh P.; Parks, Dale A.

    2010-01-01

    Considerable epidemiological evidence indicates that dietary consumption of moderate levels of polyphenols decreases both the incidence of cardiovascular disease and the mortality associated with myocardial infarction. Molecular mechanisms of this cardiovascular protection remain uncertain but can involve changes in rates of nitric oxide (NO) generation by endothelial nitric oxide synthase (eNOS). We examined the vascular responses to quercetin using a combination of biochemical and vessel function criteria. Quercetin treatment for 30 min enhanced relaxation of rat aortic ring segments. Moreover, the addition of L-NAME (100 μM) or charybdotoxin (ChTx) blocked quercetin-mediated vasorelaxation thus demonstrating the effect was partially dependent on NOS and endothelium-derived hyperpolarizing factor (EDHF). Additionally, bovine aortic endothelial cells (BAEC) treated with quercetin showed a rapid increase of intracellular Ca2+ concentrations as well as a dose- and time-dependent stimulation of eNOS phosphorylation with a concomitant increase in NO production. These results demonstrate that quercetin-mediated stimulation of eNOS phosphorylation increases NO bioavailability in endothelial cells and can thus play a role in the vascular protective effects associated with improved endothelial cell function. PMID:20423726

  5. Dietary flavonoid quercetin stimulates vasorelaxation in aortic vessels.

    PubMed

    Khoo, Nicholas K H; White, C Roger; Pozzo-Miller, Lucas; Zhou, Fen; Constance, Chad; Inoue, Takafumi; Patel, Rakesh P; Parks, Dale A

    2010-08-01

    Considerable epidemiological evidence indicates that dietary consumption of moderate levels of polyphenols decreases both the incidence of cardiovascular disease and the mortality associated with myocardial infarction. Molecular mechanisms of this cardiovascular protection remain uncertain but can involve changes in rates of nitric oxide (NO) generation by endothelial nitric oxide synthase (eNOS). We examined the vascular responses to quercetin using a combination of biochemical and vessel function criteria. Quercetin treatment for 30min enhanced relaxation of rat aortic ring segments. Moreover, the addition of L-NAME (100muM) or charybdotoxin (ChTx) blocked quercetin-mediated vasorelaxation thus demonstrating the effect was partially dependent on NOS and endothelium-derived hyperpolarizing factor (EDHF). Additionally, bovine aortic endothelial cells (BAEC) treated with quercetin showed a rapid increase of intracellular Ca(2+) concentrations as well as a dose- and time-dependent stimulation of eNOS phosphorylation with a concomitant increase in NO production. These results demonstrate that quercetin-mediated stimulation of eNOS phosphorylation increases NO bioavailability in endothelial cells and can thus play a role in the vascular protective effects associated with improved endothelial cell function.

  6. Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More

    PubMed Central

    Costa, Lucio G.; Garrick, Jacqueline M.; Roquè, Pamela J.; Pellacani, Claudia

    2016-01-01

    Increasing interest has recently focused on determining whether several natural compounds, collectively referred to as nutraceuticals, may exert neuroprotective actions in the developing, adult, and aging nervous system. Quercetin, a polyphenol widely present in nature, has received the most attention in this regard. Several studies in vitro, in experimental animals and in humans, have provided supportive evidence for neuroprotective effects of quercetin, either against neurotoxic chemicals or in various models of neuronal injury and neurodegenerative diseases. The exact mechanisms of such protective effects remain elusive, though many hypotheses have been formulated. In addition to a possible direct antioxidant effect, quercetin may also act by stimulating cellular defenses against oxidative stress. Two such pathways include the induction of Nrf2-ARE and induction of the antioxidant/anti-inflammatory enzyme paraoxonase 2 (PON2). In addition, quercetin has been shown to activate sirtuins (SIRT1), to induce autophagy, and to act as a phytoestrogen, all mechanisms by which quercetin may provide its neuroprotection. PMID:26904161

  7. The effect of quercetin and galangin on glutathione reductase.

    PubMed

    Paulíková, Helena; Berczeliová, Elena

    2005-12-01

    Quercetin and galangin can change the activity of glutathione reductase. Quercetin (a catechol structure in the B-ring) and galangin (any hydroxyl group in the B-ring) have different biological activities but, both possess high antioxidant abilities. Quercetin during the antioxidative action, is converted into an oxidized products (o-semiquinone and o-quinone), and subsequently glutathionyl adducts may be formed or SH-enzyme can be inhibited. We have tried to see whether inhibition of glutathione reductase (GR) can be influenced by preincubation of enzyme with NADPH (a creation of reduced form of enzyme, GRH(2)) and whether diaphorase activity of the enzyme is decreased by these flavonoids. The results confirmed that quercetin inhibits GRH(2) and inhibition is reduced by addition of EDTA or N-acetylcysteine. Both of flavonoids have no effect on diaphorase activity of glutathione reductase and this enzyme could increase the production of free radicals by catalysis of reduction of o-quinone during action of quercetin in vivo.

  8. Pharmacokinetics of quercetin-loaded nanodroplets with ultrasound activation and their use for bioimaging

    PubMed Central

    Chang, Li-Wen; Hou, Mei-Ling; Hung, Shuo-Hui; Lin, Lie-Chwen; Tsai, Tung-Hu

    2015-01-01

    Bubble formulations have both diagnostic and therapeutic applications. However, research on nanobubbles/nanodroplets remains in the initial stages. In this study, a nanodroplet formulation was prepared and loaded with a novel class of chemotherapeutic drug, ie, quercetin, to observe its pharmacokinetic properties and ultrasonic bioimaging of specific sites, namely the abdominal vein and bladder. Four parallel groups were designed to investigate the effects of ultrasound and nanodroplets on the pharmacokinetics of quercetin. These groups were quercetin alone, quercetin triggered with ultrasound, quercetin-encapsulated in nanodroplets, and quercetin encapsulated in nanodroplets triggered with ultrasound. Spherical vesicles with a mean diameter of 280 nm were formed, and quercetin was completely encapsulated within. In vivo ultrasonic imaging confirmed that the nanodroplets could be treated by ultrasound. The results indicate that the initial 5-minute serum concentration, area under the concentration–time curve, elimination half-life, and clearance of quercetin were significantly enhanced by nanodroplets with or without ultrasound. PMID:25945049

  9. [Hypoglycemic and hypolipidemic effects of quercetin and its glycosides].

    PubMed

    Yan, Shu-xia; Li, Xian; Sun, Chong-de; Chen, Kun-song

    2015-12-01

    Quercetin and its glycosides are important flavonols in traditional herbal drugs and plant-derived food, and they have diverse hiological activities such as antioxidant, anticarcinogenic, anti-inflammatory, hypoglycemic and hypolipidemic activities. Numerous studies have demonstrated that quercetin and its glycosides were effective in the prevention and treatment of non-infectious chronic disease such as diabetes, obesity, and hyperlipidemia. They can regulate glucose and lipid metaholism through different mechanisms. They can decrease blood glucose via protecting pancreatic/p cells or/and improving insulin sensitivity. Also, they have lipid-lowering effects, which may be the result of regulation of lipid catabolism or/and anabolism. Their distributions, as well as the hypoglycemic and hypolipidemic effects are reviewed in this paper. In addition, further bioactivities as well as their dose-activity relationship, structure-activity relationship, bioavailability, and future clinical application of quercetin and its glycosides are discussed and proposed.

  10. Synthesis, Characterization and Cytotoxicity of Alkylated Quercetin Derivatives.

    PubMed

    Bao, Xin-Ran; Liao, Han; Qu, Jiao; Sun, Yong; Guo, Xin; Wang, En-Xia; Zhen, Yu-Hong

    2016-01-01

    Quercetin, a ubiquitous flavonol, represents a promising leading drug for development of new chemotherapeutic agents. However, its limited cytotoxicity to cancer cells hampers its clinical use. In order to obtain novel quercetin derivatives with superior cytotoxicity, seven alkylated quercetin derivatives were synthesized. Solubility of these derivatives was determined by turbidimetry. Cytotoxicity of the high-soluble derivatives against MCF-7 cells and caco-2 cells was determined using MTT assay. Among these seven products, 7-O-butylquercetin had the highest solubility in DMEM medium and 7-O-geranylquercetin had the most potent cytotoxicity. Further study on cytotoxicity of 7-O-geranylquercetin on NCI-H446, A549, MGC-803 and SGC-7901 cell lines revealed potential antiproliferative effects. The 7-O-geranylquercetin is a broad spectrum cytotoxic agent and it may be a promising leading drug for cancer chemotherapy.

  11. Quercetin as natural stabilizing agent for bio-polymer

    NASA Astrophysics Data System (ADS)

    Morici, Elisabetta; Arrigo, Rossella; Dintcheva, Nadka Tzankova

    2014-05-01

    The introduction of antioxidants in polymers is the main way to prevent or delay the degradation process. In particular natural antioxidants receive attention in the food industry also because of their presumed safety. In this work bio-polymers, i.e. a commercial starch-based polymer (Mater-Bi®) and a bio-polyester (PLA), and a bio-polyether (PEO) were additivated with quercetin, a natural flavonoid antioxidants, in order to formulate bio-based films for ecosustainable packaging and outdoor applications. The photo-oxidation behavior of unstabilized and quercetin stabilized films was analyzed and compared with the behavior of films additivated with a commercial synthetic light stabilizer. The quercetin is able to slow down the photo-degradation rate of all bio-polymeric films investigated in similar way to the synthetic stabilizer.

  12. Synthesis, Characterization and Cytotoxicity of Alkylated Quercetin Derivatives

    PubMed Central

    Bao, Xin-Ran; Liao, Han; Qu, Jiao; Sun, Yong; Guo, Xin; Wang, En-Xia; Zhen, Yu-Hong

    2016-01-01

    Quercetin, a ubiquitous flavonol, represents a promising leading drug for development of new chemotherapeutic agents. However, its limited cytotoxicity to cancer cells hampers its clinical use. In order to obtain novel quercetin derivatives with superior cytotoxicity, seven alkylated quercetin derivatives were synthesized. Solubility of these derivatives was determined by turbidimetry. Cytotoxicity of the high-soluble derivatives against MCF-7 cells and caco-2 cells was determined using MTT assay. Among these seven products, 7-O-butylquercetin had the highest solubility in DMEM medium and 7-O-geranylquercetin had the most potent cytotoxicity. Further study on cytotoxicity of 7-O-geranylquercetin on NCI-H446, A549, MGC-803 and SGC-7901 cell lines revealed potential antiproliferative effects. The 7-O-geranylquercetin is a broad spectrum cytotoxic agent and it may be a promising leading drug for cancer chemotherapy. PMID:27980567

  13. Quercetin as natural stabilizing agent for bio-polymer

    SciTech Connect

    Morici, Elisabetta; Arrigo, Rossella; Dintcheva, Nadka Tzankova

    2014-05-15

    The introduction of antioxidants in polymers is the main way to prevent or delay the degradation process. In particular natural antioxidants receive attention in the food industry also because of their presumed safety. In this work bio-polymers, i.e. a commercial starch-based polymer (Mater-Bi®) and a bio-polyester (PLA), and a bio-polyether (PEO) were additivated with quercetin, a natural flavonoid antioxidants, in order to formulate bio-based films for ecosustainable packaging and outdoor applications. The photo-oxidation behavior of unstabilized and quercetin stabilized films was analyzed and compared with the behavior of films additivated with a commercial synthetic light stabilizer. The quercetin is able to slow down the photo-degradation rate of all bio-polymeric films investigated in similar way to the synthetic stabilizer.

  14. Estimated Daily Intake and Seasonal Food Sources of Quercetin in Japan

    PubMed Central

    Nishimuro, Haruno; Ohnishi, Hirofumi; Sato, Midori; Ohnishi-Kameyama, Mayumi; Matsunaga, Izumi; Naito, Shigehiro; Ippoushi, Katsunari; Oike, Hideaki; Nagata, Tadahiro; Akasaka, Hiroshi; Saitoh, Shigeyuki; Shimamoto, Kazuaki; Kobori, Masuko

    2015-01-01

    Quercetin is a promising food component, which can prevent lifestyle related diseases. To understand the dietary intake of quercetin in the subjects of a population-based cohort study and in the Japanese population, we first determined the quercetin content in foods available in the market during June and July in or near a town in Hokkaido, Japan. Red leaf lettuce, asparagus, and onions contained high amounts of quercetin derivatives. We then estimated the daily quercetin intake by 570 residents aged 20–92 years old in the town using a food frequency questionnaire (FFQ). The average and median quercetin intakes were 16.2 and 15.5 mg day−1, respectively. The quercetin intakes by men were lower than those by women; the quercetin intakes showed a low correlation with age in both men and women. The estimated quercetin intake was similar during summer and winter. Quercetin was mainly ingested from onions and green tea, both in summer and in winter. Vegetables, such as asparagus, green pepper, tomatoes, and red leaf lettuce, were good sources of quercetin in summer. Our results will help to elucidate the association between quercetin intake and risks of lifestyle-related diseases by further prospective cohort study and establish healthy dietary requirements with the consumption of more physiologically useful components from foods. PMID:25849945

  15. Oral quercetin supplementation hampers skeletal muscle adaptations in response to exercise training.

    PubMed

    Casuso, R A; Martínez-López, E J; Nordsborg, N B; Hita-Contreras, F; Martínez-Romero, R; Cañuelo, A; Martínez-Amat, A

    2014-12-01

    We aimed to test exercise-induced adaptations on skeletal muscle when quercetin is supplemented. Four groups of rats were tested: quercetin sedentary, quercetin exercised, placebo sedentary, and placebo exercised. Treadmill exercise training took place 5 days a week for 6 weeks. Quercetin groups were supplemented with quercetin, via gavage, on alternate days throughout the experimental period. Sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α mRNA levels, mitochondrial DNA (mtDNA) content, and citrate synthase (CS) activity were measured on quadriceps muscle. Redox status was also quantified by measuring muscle antioxidant enzymatic activity and oxidative damage product, such as protein carbonyl content (PCC). Quercetin supplementation increased oxidative damage in both exercised and sedentary rats by inducing higher amounts of PCC (P < 0.001). Quercetin supplementation caused higher catalase (P < 0.001) and superoxide dismutase (P < 0.05) activity in the non-exercised animals, but not when quercetin is supplemented during exercise. Quercetin supplementation increased SIRT1 expression, but when quercetin is supplemented during exercise, this effect is abolished (P < 0.001). The combination of exercise and quercetin supplementation caused lower (P < 0.05) mtDNA content and CS activity when compared with exercise alone. Quercetin supplementation during exercise provides a disadvantage to exercise-induced muscle adaptations.

  16. Interactions between (+)-catechin and quercetin during their oxidation by nitrite under the conditions simulating the stomach.

    PubMed

    Veljovic-Jovanovic, Sonja; Morina, Filis; Yamauchi, Ryo; Hirota, Sachiko; Takahama, Umeo

    2014-05-28

    When foods that contain catechins and quercetin glycosides are ingested, quercetin glycosides are hydrolyzed to quercetin during mastication by hydrolytic enzymes derived from oral bacteria and the generated quercetin aglycone is mixed with catechins in saliva. The present study deals with the interactions between (+)-catechin and quercetin during their reactions with nitrous acid under the conditions simulating the gastric lumen. Nitrous acid reacted with (+)-catechin producing 6,8-dinitrosocatechin, and quercetin partially suppressed the dinitrosocatechin formation. Nitric oxide, which was produced by not only (+)-catechin/nitrous acid but also quercetin/nitrous acid systems, was used to produce 6,8-dinitrosocatechin. Furthermore, 6,8-dinitrosocatechin was oxidized by nitrous acid to the quinone form. The quinone formation was significantly suppressed by quercetin. Quercetin-dependent suppression of the above reactions accompanied the oxidation of quercetin, which was observed with the formation of 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone. Taking the above results into account, we proposed a possible mechanism of 6,8-dinitrosocatechin formation and discuss the importance of quercetin to prevent the quinone formation from 6,8-dinitrosocatechin in the gastric lumen, taking the interactions between quercetin and catechins into account.

  17. Production of 3-O-xylosyl quercetin in Escherichia coli.

    PubMed

    Pandey, Ramesh Prasad; Malla, Sailesh; Simkhada, Dinesh; Kim, Byung-Gee; Sohng, Jae Kyung

    2013-03-01

    Quercetin, a flavonol aglycone, is one of the most abundant flavonoids with high medicinal value. The bioavailability and pharmacokinetic properties of quercetin are influenced by the type of sugars attached to the molecule. To efficiently diversify the therapeutic uses of quercetin, Escherichia coli was harnessed as a production factory by the installation of various plant and bacterial UDP-xylose sugar biosynthetic genes. The genes encoding for the UDP-xylose pathway enzymes phosphoglucomutase (nfa44530), glucose-1-phosphate uridylyltransferase (galU), UDP-glucose dehydrogenase (calS8), and UDP-glucuronic acid decarboxylase (calS9) were overexpressed in E. coli BL21 (DE3) along with a glycosyltransferase (arGt-3) from Arabidopsis thaliana. Furthermore, E. coli BL21(DE3)/∆pgi, E. coli BL21(DE3)/∆zwf, E. coli BL21(DE3)/∆pgi∆zwf, and E. coli BL21(DE3)/∆pgi∆zwf∆ushA mutants carrying the aforementioned UDP-xylose sugar biosynthetic genes and glycosyltransferase and the galU-integrated E. coli BL21(DE3)/∆pgi host harboring only calS8, calS9, and arGt-3 were constructed to enhance whole-cell bioconversion of exogeneously supplied quercetin into 3-O-xylosyl quercetin. Here, we report the highest production of 3-O-xylosyl quercetin with E. coli BL21 (DE3)/∆pgi∆zwf∆ushA carrying UDP-xylose sugar biosynthetic genes and glycosyltransferase. The maximum concentration of 3-O-xylosyl quercetin achieved was 23.78 mg/L (54.75 μM), representing 54.75 % bioconversion, which was an ~4.8-fold higher bioconversion than that shown by E. coli BL21 (DE3) with the same set of genes when the reaction was carried out in 5-mL culture tubes with 100 μM quercetin under optimized conditions. Bioconversion was further improved by 98 % when the reaction was scaled up in a 3-L fermentor at 36 h.

  18. Olive leaf extracts protect cardiomyocytes against 4-hydroxynonenal-induced toxicity in vitro: comparison with oleuropein, hydroxytyrosol, and quercetin.

    PubMed

    Bali, Elif Burcu; Ergin, Volkan; Rackova, Lucia; Bayraktar, Oğuz; Küçükboyaci, Nurgün; Karasu, Çimen

    2014-08-01

    Olive (Olea europaea) leaf, an important traditional herbal medicine, displays cardioprotection that may be related to the cellular redox modulating effects of its polyphenolic constituents. This study was undertaken to investigate the protective effect of the ethanolic and methanolic extracts of olive leaves compared to the effects of oleuropein, hydroxytyrosol, and quercetin as a positive standard in a carbonyl compound (4-hydroxynonenal)-induced model of oxidative damage to rat cardiomyocytes (H9c2). Cell viability was detected by the MTT assay; reactive oxygen species production was assessed by the 2',7'-dichlorodihydrofluorescein diacetate method, and the mitochondrial membrane potential was determined using a JC-1 dye kit. Phospho-Hsp27 (Ser82), phospho-MAPKAPK-2 (Thr334), phospho-c-Jun (Ser73), cleaved-caspase-3 (cl-CASP3) (Asp175), and phospho-SAPK/JNK (Thr183/Tyr185) were measured by Western blotting. The ethanolic and methanolic extracts of olive leaves inhibited 4-hydroxynonenal-induced apoptosis, characterized by increased reactive oxygen species production, impaired viability (LD50: 25 µM), mitochondrial dysfunction, and activation of pro-apoptotic cl-CASP3. The ethanolic and methanolic extracts of olive leaves also inhibited 4-hydroxynonenal-induced phosphorylation of stress-activated transcription factors, and the effects of extracts on p-SAPK/JNK, p-Hsp27, and p-MAPKAPK-2 were found to be concentration-dependent and comparable with oleuropein, hydroxytyrosol, and quercetin. While the methanolic extract downregulated 4-hydroxynonenal-induced p-MAPKAPK-2 and p-c-Jun more than the ethanolic extract, it exerted a less inhibitory effect than the ethanolic extract on 4-hydroxynonenal-induced p-SAPK/JNK and p-Hsp27. cl-CASP3 and p-Hsp27 were attenuated, especially by quercetin. Experiments showed a predominant reactive oxygen species inhibitory and mitochondrial protecting ability at a concentration of 1-10 µg/mL of each extract, oleuropein

  19. Hepatitis virus vaccines: present status.

    PubMed Central

    Krugman, S.

    1982-01-01

    During the past decade there has been extraordinary progress toward the development of vaccines for the prevention of type A and type B hepatitis. The successful propagation of hepatitis A virus in cell culture in 1979 was followed by the preparation of experimental live attenuated hepatitis A vaccines that have been shown to induce antibody in marmosets and chimpanzees and protect immunized marmosets against challenge with hepatitis A virus. The first human immunization trials will begin in mid-1982. An inactivated hepatitis B vaccine that was licensed in the United States in November 1981 has been shown to be safe, immunogenic, and effective. When this vaccine becomes available for use in July 1982, it will be recommended for persons who are considered to be at increased risk of contracting hepatitis B infection. Future generations of hepatitis B vaccines may be prepared from hepatitis B surface antigen derived from DNA recombinant technology or by in vitro synthesis of HBs Ag determinants by chemical means. PMID:6295013

  20. Intracellular metabolism and bioactivity of quercetin and its in vivo metabolites.

    PubMed Central

    Spencer, Jeremy P E; Kuhnle, Gunter G C; Williams, Robert J; Rice-Evans, Catherine

    2003-01-01

    Understanding the cellular effects of flavonoid metabolites is important for predicting which dietary flavonoids might be most beneficial in vivo. Here we investigate the bioactivity in dermal fibroblasts of the major reported in vivo metabolites of quercetin, i.e. 3'-O-methyl quercetin, 4'-O-methyl quercetin and quercetin 7-O-beta-D-glucuronide, relative to that of quercetin, in terms of their further metabolism and their resulting cytotoxic and/or cytoprotective effects in the absence and presence of oxidative stress. Uptake experiments indicate that exposure to quercetin led to the generation of two novel cellular metabolites, one characterized as a 2'-glutathionyl quercetin conjugate and another product with similar spectral characteristics but 1 mass unit lower, putatively a quinone/quinone methide. A similar product was identified in cells exposed to 3'-O-methyl quercetin, but not in the lysates of those exposed to its 4'-O-methyl counterpart, suggesting that its formation is related to oxidative metabolism. There was no uptake or metabolism of quercetin 7-O-beta-D-glucuronide by fibroblasts. Formation of oxidative metabolites may explain the observed concentration-dependent toxicity of quercetin and 3'-O-methyl quercetin, whereas the formation of a 2'-glutathionyl quercetin conjugate is interpreted as a detoxification step. Both O -methylated metabolites conferred less protection than quercetin against peroxide-induced damage, and quercetin glucuronide was ineffective. The ability to modulate cellular toxicity paralleled the ability of the compounds to decrease the level of peroxide-induced caspase-3 activation. Our data suggest that the actions of quercetin and its metabolites in vivo are mediated by intracellular metabolites. PMID:12578560

  1. Hepatitis C: Treatment

    MedlinePlus

    ... Public Home » Hepatitis C » Hepatitis C Treatment Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... Enter ZIP code here Enter ZIP code here Hepatitis C Treatment for Veterans and the Public Treatment ...

  2. Hepatitis A

    MedlinePlus

    ... an inflammation of the liver. One type, hepatitis A, is caused by the hepatitis A virus (HAV). The disease spreads through contact with ... washed in untreated water Putting into your mouth a finger or object that came into contact with ...

  3. Hepatitis B

    MedlinePlus

    ... commonly used with viral hepatitis and related conditions. Web Resources American Liver Foundation A national nonprofit organization ... other liver diseases through research, education, and advocacy. Web site features a database directory of hepatitis clinical ...

  4. Hepatitis B

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000279.htm Hepatitis B To use the sharing features on this page, please enable JavaScript. Hepatitis B is irritation and swelling (inflammation) of the ...

  5. Autoimmune hepatitis

    MedlinePlus

    Lupoid hepatitis; Chronic acute liver disease ... This form of hepatitis is an autoimmune disease . The body's immune system cannot tell the difference between healthy body tissue and harmful, outside ...

  6. Hepatitis B

    MedlinePlus

    ... times more infectious than HIV. Which adults need hepatitis B vaccine? Any sexually active adult who is not in ... share needles, syringes, or other drug-injection equipment. Hepatitis B vaccine is available alone or in a combination with ...

  7. Molecular targets of quercetin with anti-inflammatory properties in atopic dermatitis.

    PubMed

    Karuppagounder, Vengadeshprabhu; Arumugam, Somasundaram; Thandavarayan, Rajarajan A; Sreedhar, Remya; Giridharan, Vijayasree V; Watanabe, Kenichi

    2016-04-01

    Atopic dermatitis (AD) is an inflammatory skin disease. Over the past few decades, AD has become more prevalent worldwide. Quercetin, a naturally occurring polyphenol, shows antioxidant, anti-inflammatory, and antiallergic activities. Several recent clinical and preclinical findings suggest quercetin as a promising natural treatment for inflammatory skin diseases. Significant progress in elucidating the molecular mechanisms underlying the anti-AD properties of quercetin has been achieved in the recent years. Here, we discuss the use of quercetin as treatment for AD, with a particular focus on the molecular basis of its effect. We also briefly discuss the approaches to improve the bioavailability of quercetin.

  8. Hepatitis C

    MedlinePlus

    ... an inflammation of the liver. One type, hepatitis C, is caused by the hepatitis C virus (HCV). It usually spreads through contact with ... childbirth. Most people who are infected with hepatitis C don't have any symptoms for years. If ...

  9. DFT study of glycosyl group reactivity in quercetin derivatives

    NASA Astrophysics Data System (ADS)

    Jeevitha, D.; Sadasivam, K.; Praveena, R.; Jayaprakasam, R.

    2016-09-01

    Density functional theory (DFT) is used to compute relevant electronic properties with the purpose of generating precise information which facilitates the best activity given by the positions of glycosyl group attached at all 3 different rings of quercetin such as Q3G (C- ring), Q7G (A-ring) and Q3‧G (B-ring). Computed values of the OH BDE, frontier molecular orbitals (FMOs), molecular electrostatic potential (MEP), Density of states (DOS,PDOS,OPDOS) and electronic properties such as electron affinity (EA), ionization potential (IP), softness (S), hardness (η), electronegativity (χ) and electrophilic index (ω) indicate that the title compounds possess good radical scavenging activity. Charge delocalization and intramolecular hydrogen bonds are characterized using natural bond orbital (NBO) analysis. NBO accurately differentiate the weak and strong intramolecular hydrogen bond of quercetin-O-glycoside compounds. Results available from the computational investigation have proved that A-ring glycoside of quercetin is capable of donating electrons and acts as a good anti-oxidant than B-ring glycoside and C-ring glycoside of quercetin.

  10. Quercetin protects rat skeletal muscle from ischemia reperfusion injury.

    PubMed

    Ekinci Akdemir, Fazile Nur; Gülçin, İlhami; Karagöz, Berna; Soslu, Recep

    2016-01-01

    In this study, we investigated the potential beneficial effects of quercetin on skeletal muscle ischemia reperfusion injury. Twenty-four Sprague-Dawley type rats were randomly divided into four groups. In the sham group, only gastrocnemius muscle were removed and given no quercetin. In ischemia group, all the femoral artery, vein and collaterals were occluded in the left hindlimb by applying tourniquate under general anaesthesia for three hours but reperfusion was not done. In the Quercetin + Ischemia reperfusion group, quercetin (200 mg kg(-1) dose orally) was given during one-week reoperation and later ischemia reperfusion model was done. Finally, gastrocnemius muscle samples were removed to measure biochemical parameters. The biomarkers, MDA levels, SOD, CAT and GPx activities, were evaluated related to skeletal muscle ischemia reperfusion injury. MDA levels reduced and SOD, CAT and GPx activities increased significantly in Quercetin + Ischemia reperfusion group. Results clearly showed that Quercetin have a protective role against oxidative damage induced by ischemia reperfusion in rats.

  11. Quercetin as colorimetric reagent for determination of zirconium

    USGS Publications Warehouse

    Grimaldi, F.S.; White, C.E.

    1953-01-01

    Methods described in the literature for the determination of zirconium are generally designed for relatively large amounts of this element. A good procedure using colorimetric reagent for the determination of trace amounts is desirable. Quercetin has been found to yield a sensitive color reaction with zirconium suitable for the determination of from 0.1 to 50?? of zirconium dioxide. The procedure developed involves the separation of zirconium from interfering elements by precipitation with p-dimethylaminoazophenylarsonic acid prior to its estimation with quercetin. The quercetin reaction is carried out in 0.5N hydrochloric acid solution. Under the operating conditions it is indicated that quercetin forms a 2 to 1 complex with zirconium; however, a 2 to 1 and a 1 to 1 complex can coexist under special conditions. Approximate values for the equilibrium constants of the complexes are K1 = 0.33 ?? 10-5 and K2 = 1.3 ?? 10-9. Seven Bureau of Standards samples of glass sands and refractories were analyzed with excellent results. The method described should find considerable application in the analysis of minerals and other materials for macro as well as micro amounts of zirconium.

  12. Effect of quercetin and its metabolites isorhamnetin and quercetin-3-glucuronide on inflammatory gene expression: role of miR-155.

    PubMed

    Boesch-Saadatmandi, Christine; Loboda, Agnieszka; Wagner, Anika E; Stachurska, Anna; Jozkowicz, Alicja; Dulak, Jozef; Döring, Frank; Wolffram, Siegfried; Rimbach, Gerald

    2011-03-01

    In the present study the effect of quercetin and its major metabolites quercetin-3-glucuronide (Q3G) and isorhamnetin on inflammatory gene expression was determined in murine RAW264.7 macrophages stimulated with lipopolysaccharide. Quercetin and isorhamnetin but not Q3G significantly decreased mRNA and protein levels of tumor necrosis factor alpha. Furthermore a significant decrease in mRNA levels of interleukin 1β, interleukin 6, macrophage inflammatory protein 1α and inducible nitric oxide synthase was evident in response to the quercetin treatment. However Q3G did not affect inflammatory gene expression. Anti-inflammatory properties of quercetin and isorhamnetin were accompanied by an increase in heme oxygenase 1 protein levels, a downstream target of the transcription factor Nrf2, known to antagonize chronic inflammation. Furthermore, proinflammatory microRNA-155 was down-regulated by quercetin and isorhamnetin but not by Q3G. Finally, anti-inflammatory properties of quercetin were confirmed in vivo in mice fed quercetin-enriched diets (0.1 mg quercetin/g diet) over 6 weeks.

  13. Antihyperglycemic Effect of Quercetin in Ovariectomized Rats Treated with Tamoxifen.

    PubMed

    Silva, Fernanda Coleraus; Bramatti, Isabella Calvo; Toledo, Adrieli Gorlin; Salles, Fernando Marques; Itinose, Ana Maria; Marek, Carla Brugin

    2017-03-01

    Tamoxifen is effective in breast cancer therapy in postmenopausal women; however, it causes adverse effects that alter the glycolytic pathway and induce hyperglycemia. Quercetin, a flavonoid with antioxidant potential, inhibits butyrylcholinesterase (BuChE), which is positively associated with hyperglycemia. Therefore, this study investigated the effect of quercetin on tamoxifen-induced hyperglycemia, using BuChE activity as a bioindicator in adult ovariectomized Wistar rats. The ovariectomized rats were treated orally for 14 days with different concentrations of quercetin (2.5, 7.5, 22.5, and 67.5 mg.kg(-1) b.w.) and tamoxifen (5 mg.kg(-1) b.w.). Subsequently, they were euthanized; blood and tissue samples were collected. The following biochemical parameters were analyzed: plasma glucose levels and BuChE activity in the plasma, liver, intestine, and adipose tissue. The most effective dose of quercetin in reducing hyperglycemia was 22.5 mg.kg(-1) b.w. (Que/TAM 4.5/1, P < .00000), although the doses of 2.5 (Que/TAM 0.5/1, P < .05) and 7.5 mg.kg(-1) b.w. (Que/TAM 1.5/1, P < .05) were also effective. The BuChE activity decreased in the intestine at all tested doses of quercetin coadministered with tamoxifen (P < .01); however, in adipose tissue, there was a biphasic activity with a decrease (P < .05) and increase (P < .05) in activity at doses of 7.5 and 22.5 mg.kg(-1) b.w. of quercetin, respectively. However, the correlation between BuChE and glucose levels was not significant (P > .05). In summary, the findings of the present study suggest that quercetin when associated with tamoxifen decreases in plasma glucose levels. Furthermore, in these cases, BuChE should not be used as an indicator of hyperglycemia.

  14. Maltodextrin fast dissolving films for quercetin nanocrystal delivery. A feasibility study.

    PubMed

    Lai, Francesco; Franceschini, Ilaria; Corrias, Francesco; Sala, Maria Chiara; Cilurzo, Francesco; Sinico, Chiara; Pini, Elena

    2015-05-05

    The objective of this study was to evaluate the feasibility to prepare fast dissolving films as quercetin nanocrystal delivery systems, using maltodextrins as film forming material and glycerin as plasticizer, with the goal of enhancing quercetin oral bioavailability. Quercetin nanosuspensions were prepared using a high-pressure homogenizer, and then directly used to prepare the films by a casting method. Spectroscopic and calorimetric analysis evidenced that reduction of quercetin size at nanoscale and incorporation in maltodextrin films do not affect the solid state of the active ingredient. The loading of quercetin nanocrystals into the film determined a slight variation of film elasticity and ductility. Indeed, the elastic modulus of the loaded films resulted about a half of the placebo ones, while the elongation at break increased four folds. Free and film loaded quercetin nanocrystals showed a comparable dissolution rate, much higher than that of bulk quercetin.

  15. Antioxidant study of quercetin and their metal complex and determination of stability constant by spectrophotometry method.

    PubMed

    Ravichandran, R; Rajendran, M; Devapiriam, D

    2014-03-01

    Quercetin found chelate cadmium ions, scavenge free radicals produced by cadmium. Hence new complex, quercetin with cadmium was synthesised, and the synthesised complex structures were determined by UV-vis spectrophotometry, infrared spectroscopy, thermogravimetry and differential thermal analysis techniques (UV-vis, IR, TGA and DTA). The equilibrium stability constants of quercetin-cadmium complex were determined by Job's method. The determined stability constant value of quercetin-cadminum complex at pH 4.4 is 2.27×10(6) and at pH 7.4 is 7.80×10(6). It was found that the quercetin and cadmium ion form 1:1 complex in both pH 4.4 and pH 7.4. The structure of the compounds was elucidated on the basis of obtained results. Furthermore, the antioxidant activity of the free quercetin and quercetin-cadmium complexes were determined by DPPH and ABTS assays.

  16. Characterization of adsorption and electronic excited states of quercetin on titanium dioxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Zdyb, Agata; Krawczyk, Stanisław

    2016-03-01

    Adsorption of quercetin on colloidal titanium dioxide nanoparticles in ethanol and its excited-state electronic structure were investigated by means of electronic and vibrational spectroscopies. The changes in electronic charge redistribution as reflected by the dipole moment difference, ∆μ, between the ground and excited electronic states were measured with electroabsorption spectroscopy and analyzed using results of TD DFT computations. Adsorption of quercetin causes a red shift of its absorption spectrum. Raman spectra of quercetin analyzed with reference to analogous data for morin indicate binding of quercetin through the hydroxy groups of the catechol moiety. The difference dipole moment, which is 5.5 D in free quercetin, increases to 11.8 D in opposite direction in adsorbed quercetin, and is associated with charge-transfer to the Ti atom. The computed transition energy, intensity, vector Δμ and molecular orbitals involved in the electronic transition at different molecular configurations indicate a bidentate chelating mode of binding of quercetin.

  17. Quercetin liposome sensitizes colon carcinoma to thermotherapy and thermochemotherapy in mice models.

    PubMed

    He, Bing; Wang, Xin; Shi, Hua-shan; Xiao, Wen-jing; Zhang, Jing; Mu, Bo; Mao, Yong-qiu; Wang, Wei; Wang, Yong-sheng

    2013-05-01

    Thermotherapy and thermochemotherapy have been used in clinics to treat patients with malignant diseases, including colon cancer, and their efficacy has been well proved. Heat shock proteins (HSPs), especially Hsp70, play important roles in neutralizing their efficacy. It has been reported that quercetin can suppress cancer by inhibiting the intratumoral expression of Hsp70. This study was designed to investigate whether quercetin could enhance sensitivity to thermotherapy and thermochemotherapy. Soluble quercetin liposome was used in this study. The effects of quercetin were investigated in vitro and in mouse colon cancer models of subcutaneous tumor and peritoneal carcinomatosis. The results showed that quercetin liposome inhibited the upregulation of Hsp70 and enhanced apoptosis induced by hyperthermia and thermochemotherapy. Systemic administration of quercetin liposome can sensitize CT26 cells to thermotherapy and chemothermotherapy. This study suggests that quercetin liposome might be potentially applied for clinical cancer therapy.

  18. Protective mechanism of quercetin on acute myocardial infarction in rats.

    PubMed

    Li, B; Yang, M; Liu, J W; Yin, G T

    2016-03-11

    To investigate the protective mechanism of quercetin on acute myocardial infarction (AMI) rats, an AMI rat model was established by ligating the left coronary anterior descending branch. The rats were randomly divided into the model group and low- and high-dose quercetin groups. The control group comprised sham-operated rats. The rats in the low- and high-dose quercetin groups were administered 100 and 400 mg/kg quercetin, respectively, by gavage. The rats in the control and model groups were administered isometric normal saline once daily for one week. The mRNA and protein levels of TNF-α and IL-1β in the myocardial tissue of rats were detected in each group by real time polymerase chain reaction and enzyme-linked immunosorbent assay. Malondialdehyde (MDA) content in the myocardial tissue and superoxide dismutase (SOD) and catalase (CAT) activities were detected using a colorimetric method. The level of apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling. Compared with those in the control group, the mRNA and protein levels of TNF-α, IL-1β and MDA content in the model, low-, and high-dose groups significantly increased. SOD and CAT activities decreased significantly. The cell apoptosis index increased significantly  (P < 0.05). Compared with those in the model group, the mRNA and protein levels of TNF-α and IL-1β and MDA content in myocardial tissue of rats in the low-dose and high-dose groups decreased significantly. SOD and CAT activities increased significantly. The cell apoptosis index significantly reduced (P < 0.05). In conclusion, quercetin has significant anti-inflammatory, antioxidant, and anti-apoptotic effects on AMI rats and can effectively protect against myocardium damage.

  19. Anti-proliferative effects of quercetin and catechin metabolites.

    PubMed

    Delgado, Laura; Fernandes, Iva; González-Manzano, Susana; de Freitas, Victor; Mateus, Nuno; Santos-Buelga, Celestino

    2014-04-01

    Dietary flavonoids have been associated with a lower incidence of some chronic diseases. However, the mechanisms behind the in vivo biological activity of flavonoids are still mostly unknown. Flavonoids are metabolized in the human body to conjugated forms (methylated, sulphated and glucuronidated derivatives) that should play a role in flavonoid activity. In this study, the anti-proliferative effects of conjugated metabolites of quercetin and (epi)catechin, major flavonoids in the diet, have been evaluated against three different cancer cell lines from breast (MCF-7), colon (Caco-2) and pancreas (BxPC-3) and one normal cell line of human foreskin fibroblasts (HFF-1), and compared with the effect of their unconjugated forms. Quercetin showed anti-proliferative activity on the three assayed cell models, whereas catechin and epicatechin were not active. Methylation on ring-B of quercetin decreased the anti-proliferative effects, especially when the methylation occurred in position 3' (isorhamnetin), although methylated metabolites still showed significant anti-proliferative activity. As to catechins, 4'-O-methyl-epicatechin and 3'-O-methyl-epicatechin were the only ones to show some activity on MCF-7 and BxPC-3 cell lines, respectively. Conjugation of quercetin with glucose or glucuronic acid eliminated the anti-proliferative effects of aglycones. Sulphated metabolites were also tested and found to be inactive in most of the explored cell lines, although quercetin-4'-O-sulphate and epicatechin-3'-O-sulphate still showed some anti-proliferative activity on MCF-7 and Caco-2 cells, respectively.

  20. Hepatitis Vaccines

    PubMed Central

    Ogholikhan, Sina; Schwarz, Kathleen B.

    2016-01-01

    Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B globally. Given the lack of a hepatitis C vaccine, the many challenges facing the production of a hepatitis C vaccine will be shown, along with current and former vaccination trials. As there is no current FDA-approved hepatitis E vaccine, we will present vaccination data that is available in the rest of the world. Finally, we will discuss the existing challenges and questions facing future endeavors for each of the hepatitis viruses, with efforts continuing to focus on dramatically reducing the morbidity and mortality associated with these serious infections of the liver. PMID:26978406

  1. Quercetin Prevents Pyrrolizidine Alkaloid Clivorine-Induced Liver Injury in Mice by Elevating Body Defense Capacity

    PubMed Central

    Ji, Lili; Ma, Yibo; Wang, Zaiyong; Cai, Zhunxiu; Pang, Chun; Wang, Zhengtao

    2014-01-01

    Quercetin is a plant-derived flavonoid that is widely distributed in nature. The present study is designed to analyze the underlying mechanism in the protection of quercetin against pyrrolizidine alkaloid clivorine-induced acute liver injury in vivo. Serum transaminases, total bilirubin analysis, and liver histological evaluation demonstrated the protection of quercetin against clivorine-induced liver injury. Terminal dUTP nick end-labeling assay demonstrated that quercetin reduced the increased amount of liver apoptotic cells induced by clivorine. Western-blot analysis of caspase-3 showed that quercetin inhibited the cleaved activation of caspase-3 induced by clivorine. Results also showed that quercetin reduced the increase in liver glutathione and lipid peroxidative product malondialdehyde induced by clivorine. Quercetin reduced the enhanced liver immunohistochemical staining for 4-hydroxynonenal induced by clivorine. Results of the Mouse Stress and Toxicity PathwayFinder RT2 Profiler PCR Array demonstrated that the expression of genes related with oxidative or metabolic stress and heat shock was obviously altered after quercetin treatment. Some of the alterations were confirmed by real-time PCR. Our results demonstrated that quercetin prevents clivorine-induced acute liver injury in vivo by inhibiting apoptotic cell death and ameliorating oxidative stress injury. This protection may be caused by the elevation of the body defense capacity induced by quercetin. PMID:24905073

  2. Quercetin-containing self-nanoemulsifying drug delivery system for improving oral bioavailability.

    PubMed

    Tran, Thanh Huyen; Guo, Yi; Song, Donghui; Bruno, Richard S; Lu, Xiuling

    2014-03-01

    Quercetin is a dietary flavonoid with potential chemoprotective effects, but has low bioavailability because of poor aqueous solubility and low intestinal absorption. A quercetin-containing self-nanoemulsifying drug delivery system (Q-SNEDDS) was developed to form oil-in-water nanoemulsions in situ for improving quercetin oral bioavailability. On the basis of the quercetin solubility, emulsifying ability, and stability after dispersion in an aqueous phase, an optimal SNEDDS consisting of castor oil, Tween® 80, Cremophor® RH 40, and PEG 400 (20:16:34:30, w/w) was identified. Upon mixing with water, Q-SNEDDS formed a nanoemulsion having a droplet size of 208.8 ± 4.5 nm and zeta potential of -26.3 ± 1.2 mV. The presence of Tween® 80 and PEG 400 increased quercetin solubility and maintained supersaturated quercetin concentrations (5 mg/mL) for >1 month. The optimized Q-SNEDDS significantly improved quercetin transport across a human colon carcinoma (Caco-2) cell monolayer. Fluorescence imaging demonstrated rapid absorption of the Q-SNEDDS within 40 min of oral ingestion. Following oral administration of Q-SNEDDS in rats (15 mg/kg), the area under the concentration curve and maximum concentration of plasma quercetin after 24 h increased by approximately twofold and threefold compared with the quercetin control suspension. These data suggest that this Q-SNEDDS formulation can enhance the solubility and oral bioavailability of quercetin for appropriate clinical application.

  3. Feature Hepatitis: Hepatitis Can Strike Anyone

    MedlinePlus

    ... Navigation Bar Home Current Issue Past Issues Feature Hepatitis Hepatitis Can Strike Anyone Past Issues / Spring 2009 Table ... from all walks of life are affected by hepatitis, especially hepatitis C, the most common form of ...

  4. Hepatitis A through E (Viral Hepatitis)

    MedlinePlus

    ... travelers How can hepatitis B be prevented? The hepatitis B vaccine offers the best protection. All infants and unvaccinated ... should receive hepatitis B immune globulin and the hepatitis B vaccine within 12 hours of birth to help prevent ...

  5. New benzophenone and quercetin galloyl glycosides from Psidium guajava L.

    PubMed Central

    Matsuzaki, Keiichi; Ishii, Rie; Kobiyama, Kaori

    2010-01-01

    New benzophenone and flavonol galloyl glycosides were isolated from an 80% MeOH extract of Psidium guajava L. (Myrtaceae) together with five known quercetin glycosides. The structures of the novel glycosides were elucidated to be 2,4,6-trihydroxybenzophenone 4-O-(6″-O-galloyl)-β-d-glucopyranoside (1, guavinoside A), 2,4,6-trihydroxy-3,5-dimethylbenzophenone 4-O-(6″-O-galloyl)-β-d-glucopyranoside (2, guavinoside B), and quercetin 3-O-(5″-O-galloyl)-α-l-arabinofuranoside (3, guavinoside C) by NMR, MS, UV, and IR spectroscopies. Isolated phenolic glycosides showed significant inhibitory activities against histamine release from rat peritoneal mast cells, and nitric oxide production from a murine macrophage-like cell line, RAW 264.7. PMID:20354804

  6. Hepatitis C Test

    MedlinePlus

    ... Hepatitis C Antibody; Anti-HCV; HCV-PCR; HCV-RNA; Hepatitis C Viral Load Formal name: Viral Hepatitis C Antibody Screen; Viral Hepatitis C RNA by PCR; Hepatitis C Virus Genotype Related tests: ...

  7. Alcohol and Hepatitis

    MedlinePlus

    ... Home » Living with Hepatitis » Daily Living: Alcohol Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... Alcohol for Veterans and the Public Alcohol and Hepatitis: Entire Lesson Overview Alcohol is one of the ...

  8. Hepatitis C: Clinical Trials

    MedlinePlus

    ... and Public Home » Hepatitis C » Treatment Decisions Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... can I find out about participating in a hepatitis C clinical trial? Many trials are being conducted ...

  9. Hepatitis (For Parents)

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Hepatitis KidsHealth > For Parents > Hepatitis Print A A A ... to Call the Doctor en español Hepatitis About Hepatitis The word hepatitis simply means an inflammation of ...

  10. Travelers' Health: Hepatitis B

    MedlinePlus

    ... Chapter 3 - Hepatitis A Chapter 3 - Hepatitis C Hepatitis B Francisco Averhoff INFECTIOUS AGENT Hepatitis B is ... their exposures. Map 3-04. Prevalence of chronic hepatitis B virus infection among adults PDF Version (printable) ...

  11. Quercetin and Ascorbic Acid Suppress Fructose-Induced NLRP3 Inflammasome Activation by Blocking Intracellular Shuttling of TXNIP in Human Macrophage Cell Lines.

    PubMed

    Choe, Jung-Yoon; Kim, Seong-Kyu

    2017-03-22

    The aim of this study was to identify the role of thioredoxin-interacting protein (TXNIP) and its interaction with antioxidants in the activation of the fructose-induced NOD-like receptor protein 3 (NLRP3) inflammasome in human macrophages. The study was performed with U937 and THP-1 macrophage cell lines. Total reactive oxygen species (ROS) were measured by flow cytometry. Interleukin-1β (IL-1β), IL-18, NLRP3, TXNIP, and caspase-1 protein expression was detected using western blotting. Quantitative real-time polymerase chain reaction was used to detect IL-1β, IL-18, and caspase-1 gene expression. Intracellular shuttling of TXNIP was assessed by immunofluorescent staining with MitoTracker Red. Increased production of ROS and expression of IL-1β, IL-18, and caspase-1 genes and proteins were observed in U937 and THP-1 cells incubated with fructose and were effectively inhibited by quercetin and ascorbic acid. Intracellular shuttling of TXNIP from the nucleus into the mitochondria was detected under stimulation with fructose, which was also attenuated by antioxidants quercetin and ascorbic acid but not butylated hydroxyanisole. Treatment of macrophages with fructose promoted the association between TXNIP and NLRP3 in the cytosol, sequentially resulting in the activation of the NLRP3 inflammasome. This study revealed that intracellular TXNIP protein is a critical regulator of activation of the fructose-induced NLRP3 inflammasome, which can be effectively blocked by the antioxidants quercetin and ascorbic acid.

  12. Binding, stability, and antioxidant activity of quercetin with soy protein isolate particles.

    PubMed

    Wang, Yufang; Wang, Xiaoyong

    2015-12-01

    This work is to study the potential of particles fabricated from soy protein isolate (SPI) as a protective carrier for quercetin. When the concentration of SPI particles increases from 0 to 0.35 g/L, quercetin gives a gradually increased fluorescence intensity and fluorescence anisotropy. The addition of quercetin can highly quench the intrinsic fluorescence of SPI particles. These results are explained in terms of the binding of quercetin to the hydrophobic pockets of SPI particles mainly through the hydrophobic force together with the hydrogen bonding. The small difference in the binding constants at 25 and 40 °C suggests the structural stability of SPI particles. The relative changes in values of Gibbs energy, enthalpy, and entropy indicate that the binding of quercetin with SPI particles is spontaneous and hydrophobic interaction is the major force. Furthermore, SPI particles are superior to native SPI for improving the stability and radical scavenging activity of quercetin.

  13. Quercetin nanoparticles display antitumor activity via proliferation inhibition and apoptosis induction in liver cancer cells.

    PubMed

    Ren, Ke-Wei; Li, Ya-Hua; Wu, Gang; Ren, Jian-Zhuang; Lu, Hui-Bin; Li, Zong-Ming; Han, Xin-Wei

    2017-04-01

    Quercetin is a potent cancer therapeutic agent and dietary antioxidant present in fruit and vegetables. Quercetin prevents tumor proliferation by inducing cell cycle arrest and is a well known cancer therapeutic agent and autophagy mediator. Recent studies showed that drug delivery by nanoparticles have enhanced efficacy with reduced side effects. In this regard, gold-quercetin into poly(DL-lactide-co-glycolide) nanoparticles was examined. In this study, we explored the role and possible underlying mechanisms of quercetin nanoparticle in regulation of antitumor activity in liver cancer cells. Treatment with quercetin nanoparticle effectively inhibited the liver cancer cell proliferation, cell migration and colony formation, thus suppressing liver cancer progression. Quercetin nanoparticle also upregulated apoptosis markedly. Further study suggested that quercetin nanoparticle accelerated the cleavage of caspase-9, caspase-3, and induced the up-releasing of cytochrome c (Cyto-c), contributing to apoptosis in liver cancer cells. Quercetin nanoparticles also promoted telomerase reverse transcriptase (hTERT) inhibition through reducing AP-2β expression and decreasing its binding to hTERT promoter. In addition, quercetin nanoparticle had an inhibitory role in cyclooxygenase 2 (COX-2) via suppressing the NF-κB nuclear translocation and its binding to COX-2 promoter. Quercetin nanoparticle also inactivated Akt and ERK1/2 signaling pathway. Taken together, our results suggested that quercetin nanoparticle had an antitumor effect by inactivating caspase/Cyto-c pathway, suppressing AP-2β/hTERT, inhibiting NF-κB/COX-2 and impeding Akt/ERK1/2 signaling pathways. Our results provided new mechanistic basis for further investigation of quercetin nanoparticles to find potential therapeutic strategies and possible targets for liver cancer inhibition.

  14. Quercetin from shallots (Allium cepa L. var. aggregatum) is more bioavailable than its glucosides.

    PubMed

    Wiczkowski, Wieslaw; Romaszko, Jerzy; Bucinski, Adam; Szawara-Nowak, Dorota; Honke, Joanna; Zielinski, Henryk; Piskula, Mariusz K

    2008-05-01

    The lipophilic character of quercetin suggests that it can cross enterocyte membranes via simple diffusion. Therefore, it should be more bioavailable than its glucosides, which require preliminary hydrolysis or active transport for absorption. However, the published human studies show that quercetin is less bioavailable than its glucosides. Assuming that low bioavailability of quercetin aglycone provided to humans as a pure substance is the result of its low solubility in the digestive tract, we studied its bioavailability from dietary sources in which quercetin was dispersed in the food matrix. In a randomized crossover study, 9 volunteers took a single dose of either shallot flesh (99.2% quercetin glucosides and 0.8% quercetin aglycone) or dry shallot skin (83.3% quercetin aglycone and 16.7% quercetin glucosides), providing 1.4 mg quercetin per kg of body weight. Blood samples were collected before and after consumption of shallot preparations. Plasma quercetin was measured on HPLC with electrochemical detection after plasma enzymatic treatment. The maximum plasma quercetin concentration of 1.02 +/- 0.13 micromol/L was reached at 2.33 +/- 0.50 h after shallot flesh consumption compared with 3.95 +/- 0.62 micromol/L at 2.78 +/- 0.15 h after dry skin consumption. The area under the concentration-time curve after dry skin consumption was 47.23 +/- 7.53 micromol x h(-1) x L(-1) and was significantly higher than that after shallot flesh intake (22.23 +/- 2.32 micromol x h(-1) x L(-1)). When provided along with dietary sources, quercetin aglycone is more bioavailable than its glucosides in humans. Results point to the food matrix as a key factor.

  15. Structural basis of the anti-inflammatory activity of quercetin: inhibition of the 5-hydroxytryptamine type 2 receptor.

    PubMed

    Rotelli, Alejandra Ester; Aguilar, Carlos Fernando; Pelzer, Lilian Eugenia

    2009-09-01

    The anti-inflammatory activity of quercetin was evaluated through serotonin-induced rat-paw edema. The experiments showed that quercetin had an important effect on acute inflammatory processes. Docking of serotonin and quercetin into the homology model of the 5-Hydroxytryptamine Type 2 Receptor allowed to analyze the structural basis of the anti-inflammatory activity. Results showed that serotonin and quercetin bind in the same region of the active site with a similar binding energy but quercetin has a much bigger inhibition constant. Therefore, it seems possible that quercetin may act as a natural inhibitor of the receptor blocking the acute inflammation generated by serotonin.

  16. Discriminative protection against hydroxyl and superoxide anion radicals by quercetin in human leucocytes in vitro.

    PubMed

    Wilms, Lonneke C; Kleinjans, Jos C S; Moonen, Edwin J C; Briedé, Jacob J

    2008-03-01

    Antioxidants play a vital role in the cellular protection against oxidative damage. Quercetin is a well-investigated antioxidant and known to be able to protect against cellular oxidative DNA damage. In this study, we tried to relate the protection by quercetin pre-treatment against oxidative DNA damage in human leucocytes in vitro to the interaction of quercetin in solution with hydroxyl and superoxide anion radicals as measured by electron spin resonance (ESR) spectrometry, using DMPO as a spin trap. Further, scavenging capacity of quercetin-treated leucocytes in vitro was evaluated by ESR spectrometry. Quercetin appears capable of protecting human leucocytes against oxidative DNA damage caused by hydrogen peroxide in a dose-dependent manner. The protection of leucocytes against superoxides is ambiguous. Incubation concentrations of quercetin (1, 10, and 50 microM) reduced levels of superoxide-induced oxidative DNA damage, while at 100 microM the amount of damage was increased. These results are supported by ESR-findings on quercetin in solution, also showing a prooxidant effect at 100 microM. ESR spectroscopy showed rate constant values for the reaction kinetics of quercetin in lowering iron-dependent hydroxyl radical formation and NADH-dependent superoxide anion formation of respectively 3.2 x 10(12)M(-1)s(-1) and 1.1 x 10(4)M(-1)s(-1). This shows that quercetin is a more potent inhibitor of hydroxyl radical formation than a scavenger of superoxide anions.

  17. Quercetin Potentiates Doxorubicin Mediated Antitumor Effects against Liver Cancer through p53/Bcl-xl

    PubMed Central

    Wang, Guanyu; Sharma, Sherven; Dong, Qinghua

    2012-01-01

    Background The dose-dependent toxicities of doxorubicin (DOX) limit its clinical applications, particularly in drug-resistant cancers, such as liver cancer. In this study, we investigated the role of quercetin on the antitumor effects of DOX on liver cancer cells and its ability to provide protection against DOX-mediated liver damage in mice. Methodology and Results The MTT and Annexin V/PI staining assay demonstrated that quercetin selectively sensitized DOX-induced cytotoxicity against liver cancer cells while protecting normal liver cells. The increase in DOX-mediated apoptosis in hepatoma cells by quercetin was p53-dependent and occurred by downregulating Bcl-xl expression. Z-VAD-fmk (caspase inhibitor), pifithrin-α (p53 inhibitor), or overexpressed Bcl-xl decreased the effects of quercetin on DOX-mediated apoptosis. The combined treatment of quercetin and DOX significantly reduced the growth of liver cancer xenografts in mice. Moreover, quercetin decreased the serum levels of alanine aminotransferase and aspartate aminotransferase that were increased in DOX-treated mice. Quercetin also reversed the DOX-induced pathological changes in mice livers. Conclusion and Significance These results indicate that quercetin potentiated the antitumor effects of DOX on liver cancer cells while protecting normal liver cells. Therefore, the development of quercetin may be beneficial in a combined treatment with DOX for increased therapeutic efficacy against liver cancer. PMID:23240061

  18. A new acylated quercetin glycoside from the leaves of Stevia rebaudiana Bertoni.

    PubMed

    Li, Jun; Jiang, Hua; Shi, Renbing

    2009-01-01

    A new acylated quercetin glycoside quercetin-3-O-(4'''-O-trans-caffeoyl)-alpha-L-rhamnopyranosyl-(1-->6)-beta-D-galacopyranoside (1), along with luteolin (2), quercetin (3), luteolin-7-O-beta-D-glucoside (4), apigenin-7-O-beta-D-glucoside (5), quercitrin (6), quercetin-3-O-beta-D-arabinoside (7) and 4,5-di-O-caffeoyl quinic acid (8) have been isolated from the leaves of Stevia rebaudiana Bertoni. The structures of these compounds were determined by spectroscopic methods (1H- and 13C-NMR, IR and MS) and by 2D-NMR experiments.

  19. Quercetin suppresses HeLa cells by blocking PI3K/Akt pathway.

    PubMed

    Xiang, Tao; Fang, Yong; Wang, Shi-Xuan

    2014-10-01

    To explore the effect of quercetin on the proliferation and apoptosis of HeLa cells, HeLa cells were incubated with quercetin at different concentrations. Cell viability was evaluated by MTT assay, cell apoptosis was detected by Annexin-V/PI double labeled cytometry and DNA ladder assay. Cell cycle was flow cytometrically determined and the morphological changes of the cells were observed under a fluorescence microscope after Hoechst 33258 staining and the apoptosis-related proteins in the HeLa cells were assessed by Western blotting. The results showed that quercetin significantly inhibited the growth of HeLa cells and induced obvious apoptosis in vitro in a time- and dose-dependent manner. Moreover, quercetin induced apoptosis of HeLa cells in cell cycle-dependent manner because quercetin could induce arrest of HeLa cells at G0/G1 phase. Quercetin treatment down-regulated the expression of the PI3K and p-Akt. In addition, quercetin could down-regulate expression of bcl-2, up-regulate Bax, but exerted no effect on the overall expression of Akt. We are led to conclude that quercetin induces apoptosis via PI3k/Akt pathways, and quercetin has potential to be used as an anti-tumor agent against human cervix cancer.

  20. Hepatitis A

    MedlinePlus

    ... inflammation of the liver.” This inflammation can be caused by a wide variety of toxins, drugs, and metabolic diseases, as well as infection. There are at least 5 hepatitis viruses. Hepatitis A is contracted when a child eats food or drinks water that is contaminated with the virus or has ...

  1. Hepatitis B

    MedlinePlus

    ... B to come back?Should I get the hepatitis B vaccine?What are the side effects of antiviral medicines?Will my liver ever be normal again? Last Updated: October 1996 This article ... B, hepatitis virus, Interferon alpha-2b, jaundice, Lamivudine, liver ...

  2. Dietary quercetin exacerbates the development of estrogen-induced breast tumors in female ACI rats.

    PubMed

    Singh, Bhupendra; Mense, Sarah M; Bhat, Nimee K; Putty, Sandeep; Guthiel, William A; Remotti, Fabrizio; Bhat, Hari K

    2010-09-01

    Phytoestrogens are plant compounds that structurally mimic the endogenous estrogen 17beta-estradiol (E(2)). Despite intense investigation, the net effect of phytoestrogen exposure on the breast remains unclear. The objective of the current study was to examine the effects of quercetin on E(2)-induced breast cancer in vivo. Female ACI rats were given quercetin (2.5 g/kg food) for 8 months. Animals were monitored weekly for palpable tumors, and at the end of the experiment, rats were euthanized, breast tumor and different tissues excised so that they could be examined for histopathologic changes, estrogen metabolic activity and oxidant stress. Quercetin alone did not induce mammary tumors in female ACI rats. However, in rats implanted with E(2) pellets, co-exposure to quercetin did not protect rats from E(2)-induced breast tumor development with 100% of the animals developing breast tumors within 8 months of treatment. No changes in serum quercetin levels were observed in quercetin and quercetin+E(2)-treated groups at the end of the experiment. Tumor latency was significantly decreased among rats from the quercetin+E(2) group relative to those in the E(2) group. Catechol-O-methyltransferase (COMT) activity was significantly downregulated in quercetin-exposed mammary tissue. Analysis of 8-isoprostane F(2alpha) (8-iso-PGF(2alpha)) levels as a marker of oxidant stress showed that quercetin did not decrease E(2)-induced oxidant stress. These results indicate that quercetin (2.5 g/kg food) does not confer protection against breast cancer, does not inhibit E(2)-induced oxidant stress and may exacerbate breast carcinogenesis in E(2)-treated ACI rats. Inhibition of COMT activity by quercetin may expose breast cells chronically to E(2) and catechol estrogens. This would permit longer exposure times to the carcinogenic metabolites of E(2) and chronic exposure to oxidant stress as a result of metabolic redox cycling to estrogen metabolites, and thus quercetin may exacerbate E(2

  3. Quercetin-3-O-glucuronide promotes the proliferation and migration of neural stem cells.

    PubMed

    Baral, Samrat; Pariyar, Ramesh; Kim, Jaehyo; Lee, Ho-Sub; Seo, Jungwon

    2017-04-01

    Quercetin is a bioactive compound exerting therapeutic effects on in vivo animal models of neurodegeneration or neurotoxicity. However, the narrow therapeutic dose-range of quercetin has been a point of concern since previous studies have demonstrated that quercetin induces cytotoxicity in vitro. Quercetin is metabolized to quercetin glucuronates such as quercetin-3-O-glucuronide (Q3GA), primarily detected in the plasma and the brain. Here, we examined whether and how quercetin or Q3GA regulates neural stem cells (NSCs) in vivo and in vitro. Immunohistochemistry showed that oral administration of quercetin increased nestin-, DCX-, BrdU/DCX-, and BrdU/NeuN-positive cells in the dentate gyrus of mice. However, quercetin decreased the viability of human embryonic NSCs in culture, accompanied by decreased Akt phosphorylation and increased cleavage of caspase-3 and PARP. In contrast, Q3GA increased BrdU-positive cell proliferation, Akt phosphorylation, and cyclin D1 expression. PI3K/Akt inhibitor LY294002 reversed Q3GA-induced Akt phosphorylation and cyclin D1 expression, thereby reducing Q3GA-induced proliferation. Furthermore, Q3GA increased the protein secretion of BDNF and its blockade using anti-BDNF antibody reversed Q3GA-induced proliferation. Under differentiation state, Q3GA promotes NSC migration, along with increased mRNA expression of CXCR4. Moreover, Q3GA significantly reversed scopolamine-induced reduction of Akt phosphorylation in the mouse hippocampus and ameliorated scopolamine-induced memory impairments. Our results demonstrate that quercetin and its metabolite Q3GA control NSC viability in a converse manner through contrary regulation of Akt, accounting for the conflicting effects of quercetin in vivo and in vitro. This study provides a novel mechanism for the positive effects of Q3GA on neurogenesis and suggests its therapeutic potential in neurodegenerative diseases.

  4. Influence of quercetin and nanohydroxyapatite modifications of decellularized goat-lung scaffold for bone regeneration.

    PubMed

    Gupta, Sweta K; Kumar, Ritesh; Mishra, Narayan C

    2017-02-01

    In the present study, goat-lung scaffold was fabricated by decellularization of lung tissue and verified for complete cell removal by DNA quantification, DAPI and H&E staining. The scaffold was then modified by crosslinking with quercetin and nanohydroxyapatite (nHAp), and characterized to evaluate the suitability of quercetin-crosslinked nHAp-modified scaffold for regeneration of bone tissue. The crosslinking chemistry between quercetin and decellularized scaffold was established theoretically by AutoDock Vina program (in silico docking study), which predicted multiple intermolecular hydrogen bonding interactions between quercetin and decellularized scaffold, and FTIR spectroscopy analysis also proved the same. From MTT assay and SEM studies, it was found that the quercetin-crosslinked nHAp-modified decellularized scaffold encouraged better growth and proliferation of bone-marrow derived mesenchymal stem cells (BMMSCs) in comparison to unmodified decellularized scaffold, quercetin-crosslinked decellularized scaffold and nHAp-modified decellularized scaffold. Alkaline Phosphatase (ALP) assay results showed highest expression of ALP over quercetin-crosslinked nHAp-modified scaffold among all the tested scaffolds (unmodified decellularized scaffold, quercetin-crosslinked decellularized scaffold and nHAp-modified decellularized scaffold) indicating that quercetin and nHAp is very much efficient in stimulating the differentiation of BMMSCs into osteoblast cells. Alizarin red test quantified in vitro mineralization (calcium deposits), and increased expression of alizarin red over quercetin-crosslinked nHAp-modified scaffold indicating better stimulation of osteogenesis in BMMSCs. The above findings suggest that quercetin-crosslinked nHAp-modified decellularized goat-lung scaffold provides biomimetic bone-like microenvironment for BMMSCs to differentiate into osteoblast and could be applied as a potential promising biomaterial for bone regeneration.

  5. Glucuronidated Quercetin Lowers Blood Pressure in Spontaneously Hypertensive Rats via Deconjugation

    PubMed Central

    Galindo, Pilar; Rodriguez-Gómez, Isabel; González-Manzano, Susana; Dueñas, Montserrat; Jiménez, Rosario; Menéndez, Carmen; Vargas, Félix; Tamargo, Juan; Santos-Buelga, Celestino; Pérez-Vizcaíno, Francisco; Duarte, Juan

    2012-01-01

    Background Chronic oral quercetin reduces blood pressure and restores endothelial dysfunction in hypertensive animals. However, quercetin (aglycone) is usually not present in plasma, because it is rapidly metabolized into conjugated, mostly inactive, metabolites. The aim of the study is to analyze whether deconjugation of these metabolites is involved in the blood pressure lowering effect of quercetin. Methodology/Principal Findings We have analyzed the effects on blood pressure and vascular function in vitro of the conjugated metabolites of quercetin (quercetin-3-glucuronide, Q3GA; isorhamnetin-3-glucuronide, I3GA; and quercetin-3′-sulfate, Q3'S) in spontaneously hypertensive rats (SHR). Q3GA and I3GA (1 mg/kg i.v.), but not Q3'S, progressively reduced mean blood pressure (MBP), measured in conscious SHR. The hypotensive effect of Q3GA was abolished in SHR treated with the specific inhibitor of β-glucuronidase, saccharic acid 1,4-lactone (SAL, 10 mg/ml). In mesenteric arteries, unlike quercetin, Q3GA had no inhibitory effect in the contractile response to phenylephrine after 30 min of incubation. However, after 1 hour of incubation Q3GA strongly reduced this contractile response and this effect was prevented by SAL. Oral administration of quercetin (10 mg/Kg) induced a progressive decrease in MBP, which was also suppressed by SAL. Conclusions Conjugated metabolites are involved in the in vivo antihypertensive effect of quercetin, acting as molecules for the plasmatic transport of quercetin to the target tissues. Quercetin released from its glucuronidated metabolites could be responsible for its vasorelaxant and hypotensive effect. PMID:22427863

  6. DC attenuation meter

    DOEpatents

    Hargrove, Douglas L.

    2004-09-14

    A portable, hand-held meter used to measure direct current (DC) attenuation in low impedance electrical signal cables and signal attenuators. A DC voltage is applied to the signal input of the cable and feedback to the control circuit through the signal cable and attenuators. The control circuit adjusts the applied voltage to the cable until the feedback voltage equals the reference voltage. The "units" of applied voltage required at the cable input is the system attenuation value of the cable and attenuators, which makes this meter unique. The meter may be used to calibrate data signal cables, attenuators, and cable-attenuator assemblies.

  7. Anthocyanin indexes, quercetin, kaempferol, and myricetin concentration in leaves and fruit of Abutilon theophrasti Medik. genetic resources

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Anthocyanin indexes, quercetin, kaempferol, and myricetin may provide industry with potential new medicines or nutraceuticals. Velvetleaf (Abutilon theophrasti Medik) leaves from 42 accessions were analyzed for anthocyanin indexes while both leaves and fruit were used for quercetin, kaempferol, and ...

  8. Quercetin, kaempferol, myricetin, and fatty acid content among several Hibiscus sabdariffa accession calyces based on maturity in a greenhouse

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Flavonols including quercetin, kaempferol, myricetin, and fatty acids in plants have many useful health attributes including antioxidants, cholesterol lowering, and cancer prevention. Six accessions of roselle, Hibiscus sabdariffa calyces were evaluated for quercetin, kaempferol, and myricetin conte...

  9. Quercetin suppresses insulin receptor signaling through inhibition of the insulin ligand–receptor binding and therefore impairs cancer cell proliferation

    SciTech Connect

    Wang, Feng; Yang, Yong

    2014-10-03

    Graphical abstract: - Highlights: • Quercetin inhibits insulin ligand–receptor interactions. • Quercetin reduces downstream insulin receptor signaling. • Quercetin blocks insulin induced glucose uptake. • Quercetin suppresses insulin stimulated cancer cell proliferation and tumor growth. - Abstract: Although the flavonoid quercetin is known to inhibit activation of insulin receptor signaling, the inhibitory mechanism is largely unknown. In this study, we demonstrate that quercetin suppresses insulin induced dimerization of the insulin receptor (IR) through interfering with ligand–receptor interactions, which reduces the phosphorylation of IR and Akt. This inhibitory effect further inhibits insulin stimulated glucose uptake due to decreased cell membrane translocation of glucose transporter 4 (GLUT4), resulting in impaired cancer cell proliferation. The effect of quercetin in inhibiting tumor growth was also evident in an in vivo model, indicating a potential future application for quercetin in the treatment of cancers.

  10. Quercetin-3-O-(2″-galloyl)-α-l-rhamnopyranoside inhibits TNF-α-activated NF-κB-induced inflammatory mediator production by suppressing ERK activation.

    PubMed

    Lee, Chung Soo; Jeong, Eun Byul; Kim, Yun Jeong; Lee, Min Sung; Seo, Seong Jun; Park, Kwan Hee; Lee, Min Won

    2013-08-01

    Quercetin and its derivatives have anti-inflammatory and anti-oxidant effects. However, the effect of quercetin-3-O-(2″-galloyl)-α-l-rhamnopyranoside (QGR), a new quercetin derivative, on the tumor necrosis factor (TNF)-α-stimulated production of inflammatory mediators in keratinocytes is unclear. In addition, the effect of QGR on the ERK and NF-κB-mediated inflammatory process has not been studied. In human keratinocyte HaCat cells, we investigated the effect of QGR on the TNF-α-stimulated production of inflammatory mediators in relation to the nuclear factor (NF)-κB, which regulates the transcription genes involved in immune and inflammatory responses. QGR inhibited the TNF-α-stimulated production of cytokines and chemokines in HaCaT cells. QGR, dexamethasone, cyclosporine A, Bay 11-7085 (an inhibitor of NF-κB activation) and cell signaling ERK inhibitor attenuated the TNF-α-induced formation of inflammatory mediators and activation of the NF-κB and ERK. Unlike other compounds, dexamethasone and cyclosporine A did not reduce formation of reactive oxygen species. The results show that QGR may attenuate TNF-α-stimulated inflammatory mediator production in HaCaT cells by suppressing the activation of the ERK-mediated NF-κB pathway that is mediated by reactive oxygen species. Additionally, QGR may exhibit a preventive effect against the proinflammatory mediator-induced skin diseases by inhibiting the activation of the ERK and NF-κB pathways.

  11. Anti-CSC effects in human esophageal squamous cell carcinomas and Eca109/9706 cells induced by nanoliposomal quercetin alone or combined with CD 133 antiserum.

    PubMed

    Zheng, Nai-Gang; Mo, Sai-Jun; Li, Jin-Ping; Wu, Jing-Lan

    2014-01-01

    CD133 was recently reported to be a cancer stem cell and prognostic marker. Quercetin is considered as a potential chemopreventive agent due to its involvement in suppression of oxidative stress, proliferation and metastasis. In this study, the expression of CD133/CD44 in esophageal carcinomas and Eca109/9706 cells was explored. In immunoflurorescence the locations of CD133+ and multidrug resistance 1 (MDR 1)+ in the same E-cancer cells were coincident, mainly in cytomembranes. In esophageal squamous cell carcinomas detected by double/single immunocytochemistry, small CD133+ cells were located in the basal layer of stratified squamous epithelium, determined as CSLC (cancer stem like cells); CD44+ surrounding the cells appeared in diffuse pattern, and the larger CD44+ (hi) cells were mainly located in the prickle cell layer of the epithelium, as progenitor cells. In E-cancer cells exposed to nanoliposomal quercetin (nLQ with cytomembrane permeability), down-regulation of NF-κBp65, histone deacetylase 1 (HDAC1) and cyclin D1 and up-regulation of caspase-3 were shown by immunoblotting, and attenuated HDAC1 with nuclear translocation and promoted E-cadherin expression were demonstrated by immunocytochemistry. In particular, enhanced E-cadherin expression reflected the reversed epithelial mesenchymal transition (EMT) capacity of nLQ, acting as cancer attenuator/preventive agent. nLQ acting as an HDAC inhibitor induced apoptotic cells detected by TUNEL assay mediated via HDAC-NF-κB signaling. Apoptotic effects of liposomal quercetin (LQ, with cytomembrane-philia) combined with CD133 antiserum were also detected by CD133 immunocytochemistry combined with TUNEL assay. The combination could induce greater apoptotic effects than nLQ induced alone, suggesting a novel anti-CSC treatment strategy.

  12. Glycyrrhetinic acid attenuates lipopolysaccharide-induced fulminant hepatic failure in d-galactosamine-sensitized mice by up-regulating expression of interleukin-1 receptor-associated kinase-M.

    PubMed

    Yin, Xinru; Gong, Xia; Zhang, Li; Jiang, Rong; Kuang, Ge; Wang, Bin; Chen, Xinyu; Wan, Jingyuan

    2017-04-01

    Glycyrrhetinic acid (GA), the main active ingredient of licorice, reportedly has anti-inflammatory and hepatoprotective properties, but its molecular mechanisms remain be elusive. In the present study, Balb/c mice were pretreated with GA (10, 30, or 100mg/kg) 1h before lipopolysaccharide (LPS)/d-galactosamine (D-GalN) administration. In other in vitro experiment, RAW264.7 macrophages were pretreated with GA before LPS exposure. The mortality, hepatic tissue histology, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed. Toll like receptor 4 (TLR4), interleukin-1 receptor-associated kinases (IRAKs), activation of mitogen-activated protein kinases (MAPKs) and NF-κB, and production of TNF-α were assessed by flow cytometry, western blotting, and enzyme-linked immunosorbent assay (ELISA), respectively. Our results showed that pretreatment with GA protected mice against LPS/D-GalN-induced fulminant hepatic failure (FHF), including a dose-dependent alleviation of mortality and ALT/AST elevation, ameliorating hepatic pathological damage, and decreasing TNF-α release. Moreover, GA inhibited LPS-induced activation of MAPKs and NF-κB in response to LPS, but the expression of TLR4 was not affected in vivo and in vitro. Notably, GA pretreatment in vivo suppressed IRAK-1 activity while inducing IRAK-M expression. Silencing of IRAK-M expression with siRNA blocked these beneficial effects of GA on the activation of MAPKs and NF-κB as well as TNF-α production in LPS-primed macrophages. Taken together, we conclude that GA could prevent LPS/D-GalN-induced FHF. The underlying mechanisms may be related to up-regulation of IRAK-M, which in turn caused deactivation of IRAK-1 and subsequent MAPKs and NF-κB, resulting in inhibiting TNF-α production.

  13. Designing polymeric microparticulate drug delivery system for hydrophobic drug quercetin

    PubMed Central

    Hazra, Moumita; Dasgupta Mandal, Dalia; Mandal, Tamal; Bhuniya, Saikat; Ghosh, Mallika

    2015-01-01

    The aim of this study was to investigate pharmaceutical potentialities of a polymeric microparticulate drug delivery system for modulating the drug profile of poorly water-soluble quercetin. In this research work two cost effective polymers sodium alginate and chitosan were used for entrapping the model drug quercetin through ionic cross linking method. In vitro drug release, swelling index, drug entrapment efficiency, Fourier Transforms Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), X-ray Diffraction (XRD) and Differential Scanning Calorimetric (DSC) studies were also done for physicochemical characterization of the formulations. Swelling index and drug release study were done at a pH of 1.2, 6.8 and 7.4 to evaluate the GI mimetic action which entails that the swelling and release of the all the Formulation1 (F1), Formulation2 (F2) and Formulation3 (F3) at pH 1.2 were minimal confirming the prevention of drug release in the acidic environment of stomach. Comparatively more sustained release was seen from the formulations F2 & F3 at pH 6.8 and pH 7.4 after 7 h of drug release profiling. Drug entrapment efficiency of the formulations shows in F1 (D:C:A = 2:5:30) was approximately 70% whereas the increase in chitosan concentration in F2 (D:C:A = 2:10:30) has shown an entrapment efficiency of 81%. But the comparative further increase of chitosan concentration in F3 (D:C:A = 2:15:30) has shown a entrapment of 80% which is not having any remarkable difference from F2. The FTIR analysis of drug, polymers and the formulations indicated the compatibility of the drug with the polymers. The smoothness of microspheres in F2 & F3 was confirmed by Scanning Electron Microscopy (SEM). However F1 microsphere has shown more irregular shape comparatively. The DSC studies indicated the absence of drug-polymer interaction in the microspheres. Our XRD studies have revealed that when pure drug exhibits crystalline structure with less dissolution profile

  14. Prediction of human drug clearance by multiple metabolic pathways: integration of hepatic and intestinal microsomal and cytosolic data.

    PubMed

    Cubitt, Helen E; Houston, J Brian; Galetin, Aleksandra

    2011-05-01

    The current study assesses hepatic and intestinal glucuronidation, sulfation, and cytochrome P450 (P450) metabolism of raloxifene, quercetin, salbutamol, and troglitazone using different in vitro systems. The fraction metabolized by conjugation and P450 metabolism was estimated in liver and intestine, and the importance of multiple metabolic pathways on accuracy of clearance prediction was assessed. In vitro intrinsic sulfation clearance (CL(int, SULT)) was determined in human intestinal and hepatic cytosol and compared with hepatic and intestinal microsomal glucuronidation (CL(int, UGT)) and P450 clearance (CL(int, CYP)) expressed per gram of tissue. Hepatic and intestinal cytosolic scaling factors of 80.7 mg/g liver and 18 mg/g intestine were estimated from published data. Scaled CL(int, SULT) ranged between 0.7 and 11.4 ml · min(-1) · g(-1) liver and 0.1 and 3.3 ml · min(-1) · g(-1) intestine (salbutamol and quercetin were the extremes). Salbutamol was the only compound with a high extent of sulfation (51 and 28% of total CL(int) for liver and intestine, respectively) and also significant renal clearance (26-57% of observed plasma clearance). In contrast, the clearance of quercetin was largely accounted for by glucuronidation. Drugs metabolized by multiple pathways (raloxifene and troglitazone) demonstrated improved prediction of intravenous clearance using data from all hepatic pathways (44-86% of observed clearance) compared with predictions based only on the primary pathway (22-36%). The assumption of no intestinal first pass resulted in underprediction of oral clearance for raloxifene, troglitazone, and quercetin (3-22% of observed, respectively). Accounting for the intestinal contribution to oral clearance via estimated intestinal availability improved prediction accuracy for raloxifene and troglitazone (within 2.5-fold of observed). Current findings emphasize the importance of both hepatic and intestinal conjugation for in vitro-in vivo extrapolation

  15. Microsomal quercetin glucuronidation in rat small intestine depends on age and segment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    UDP-glucuronosyltransferase (UGT) activity toward the flavonoid quercetin and UGT protein were characterized in 3 equidistant small intestine (SI) segments from 4, 12, 18, and 28 mo male F344 rats, n=8/age using villin to control for enterocyte content. SI microsomal intrinsic clearance of quercetin...

  16. Genetic expression profile analysis of the temporal inhibition of quercetin and naringenin on Lactobacillus rhamnosus GG

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The plant polyphenols, quercetin and naringenin, are considered healthy dietary compounds; however, little is known of their effects on the probiotic Lactobacillus rhamnosus GG (LGG). In this study, it was discovered that both quercetin and naringenin produced temporary inhibition of LGG growth, par...

  17. The flavonoid quercetin induces apoptosis and inhibits JNK activation in intimal vascular smooth muscle cells

    SciTech Connect

    Perez-Vizcaino, Francisco . E-mail: fperez@med.ucm.es; Bishop-Bailley, David; Lodi, Federica; Duarte, Juan; Cogolludo, Angel; Moreno, Laura; Bosca, Lisardo; Mitchell, Jane A.; Warner, Timothy D.

    2006-08-04

    Quercetin, the most abundant dietary flavonol, exerts vasodilator, anti-hypertensive, and anti-atherogenic effects and reduces the vascular remodelling associated with elevated blood pressure. Here, we have compared the effects of quercetin in intimal- and medial-type rat vascular smooth muscle cells (VSMC) in culture. After 48 h, quercetin reduced the viability of a polyclonal intimal-type cell line derived from neonatal aorta but not of a medial-type cell line derived from adult aorta. These differential effects were similar in both proliferating and quiescent VSMC. Quercetin also preferentially reduced the viability of intimal-type over medial-type VSMC in primary cultures derived from balloon-injured carotid arteries. The effects of quercetin on cell viability were mainly dependent upon induction of apoptosis, as demonstrated by nuclear condensation and fragmentation, and were unrelated to PPAR{gamma}, pro-oxidant effects or nitric oxide. The expression of MAPKs (ERK, p38, and JNK) and ERK phosphorylation were not different between intimal- and medial-type VSMC. p38 phosphorylation was negligible in both cell types. Medial-type showed a weak JNK phosphorylation while this was markedly increased in intimal-type cells. Quercetin reduced JNK phosphorylation but had no consistent effect on ERK phosphorylation. In conclusion, quercetin preferentially produced apoptosis in intimal-type compared to medial-type VSMC. This might play a role in the anti-atherogenic and anti-hypertensive effects of quercetin.

  18. Dermal quercetin smartCrystals®: Formulation development, antioxidant activity and cellular safety.

    PubMed

    Hatahet, T; Morille, M; Hommoss, A; Dorandeu, C; Müller, R H; Bégu, S

    2016-05-01

    Flavonoids are natural plant pigments, which possess high antioxidative and antiradical activities. However, their poor water solubility led to a limited bioavailability. To overcome this major hurdle, quercetin nanocrystals were produced implementing smartCrystals® technology. This process combines bead milling and subsequent high-pressure homogenization at relatively low pressure (300bar). To test the possibility to develop a dermal formulation from quercetin smartCrystals®, quercetin nanosuspensions were admixed to Lutrol® F127 and hydroxythylcellulose nonionic gels. The physicochemical properties (morphology, size and charge), saturation solubility, dissolution velocity and the antioxidant properties (DPPH assay) as well as the cellular interaction of the produced quercetin smartCrystals® were studied and compared to crude quercetin powder. Quercetin smartCrystals® showed a strong increase in the saturation solubility and the dissolution velocity (7.6 fold). SmartCrystals® loaded or not into gels proved to be physically stable over a period of three months at 25°C. Interestingly, in vitro DPPH assay confirmed the preservation of quercetin antioxidative properties after nanonization. In parallel, the nanocrystalline form did not display cellular toxicity, even at high concentration (50μg/ml), as assayed on an epithelial cell line (VERO cells). In addition, the nanocrystalline form confirmed a protective activity for VERO cells against hydrogen peroxide induced toxicity in vitro. This new formulation presents a promising approach to deliver quercetin efficiently to skin in well-tolerated formulations.

  19. Effects of quercetin on pharmacokinetics of cefprozil in Chinese-Han male volunteers.

    PubMed

    Jia, Fei-Fei; Tan, Zhi-Rong; McLeod, Howard L; Chen, Yao; Ou-Yang, Dong-Sheng; Zhou, Hong-Hao

    2016-10-01

    1. The primary objective of this study was to evaluate the effects of quercetin on the pharmacokinetics of cefprozil. The secondary objective was to evaluate the safety of the combined use of cefprozil and quercetin. 2. An open-label, two-period, crossover phase I trial among 24 Han Chinese male subjects was conducted. Participants were given 500 mg of quercetin orally once daily for 15 d followed by single dose of cefprozil (500 mg) on day 15. Serum concentrations of cefprozil were then measured in all participants on day 15. A 15-d washout period was then assigned after which a 500 mg dose of cefprozil was administered and measured in the serum on day 36. 3. All subjects completed the trial, and no serious adverse events were reported. We measured mean serum concentrations of cefprozil in the presence and absence of quercetin in all participants. The maximum serum concentration of cefprozil in the presence of quercetin was 8.18 ug/ml (95% CI: 7.55-8.81) versus a maximum cefprozil concentration of 8.35 ug/ml (95% CI: 7.51-9.19) in the absence of quercetin. We conclude that the concurrent use of quercetin has no substantial effect on serum concentrations of orally administered cefprozil. 4. Co-administration of quercetin showed no statistically significant effects on the pharmacokinetics of cefprozil in healthy Chinese subjects.

  20. Secretory leukoprotease inhibitor is required for efficient quercetin-mediated suppression of TNFα secretion

    PubMed Central

    Serino, Grazia; Galleggiante, Vanessa; Caruso, Maria Lucia; Mastronardi, Mauro; Cavalcanti, Elisabetta; Ranson, Nicole; Pinto, Aldo; Campiglia, Pietro; Santino, Angelo

    2016-01-01

    Dendritic cells (DCs) are professional antigen presenting cells (APCs) that in response to microbial infections generate long-lasting adaptive immune response. Following microbial uptake, DCs undergo a cascade of cellular differentiation that ultimately leads to “mature” DCs. Mature DCs produce a variety of inflammatory cytokines, including tumor necrosis factor-α (TNFα) a key cytokine for the inflammatory cascade. In numerous studies, polyphenols, including quercetin, demonstrated their ability to suppress TNFα secretion and protect from the onset of chronic inflammatory disorders. We show that murine bone marrow derived DCs express Slpi following quercetin exposure. Slpi is known to suppress LPS mediated NFκB activation, thus, it was hypothesized that its expression could be the key step for polyphenol induced inflammatory suppression. Slpi-KO DCs poorly respond to quercetin administration failing to reduce TNFα secretion in response to quercetin exposure. Supernatant from quercetin exposed DCs could also reduce LPS-mediated TNFα secretion by unrelated DCs, but this property is lost using an anti-Slpi antibody. In vivo, oral administration of quercetin is able to induce Slpi expression. Human biopsies from inflamed tract of the intestine reveal the presence of numerous SLPI+ cells and the expression level could be further increased by quercetin administration. We propose that quercetin induces Slpi expression that in turn reduces the inflammatory response. Our data encourages the development of nutritional strategies to improve the efficiency of current therapies for intestinal chronic inflammatory syndrome and reduce the risks of colorectal cancer development. PMID:27716626

  1. Hepatitis A

    MedlinePlus

    ... bowel movements Loss of appetite Low-grade fever Dark urine Joint pain Yellowing of the skin and ... person ingests even tiny amounts of contaminated fecal matter. The hepatitis A virus infects liver cells and ...

  2. Hepatic Encephalopathy

    MedlinePlus Videos and Cool Tools

    ... is a condition that causes temporary worsening of brain function in people with advanced liver disease. When ... travel through your body until they reach your brain, causing mental and physical symptoms of HE. Hepatic ...

  3. Hepatitis E

    MedlinePlus

    ... with a positive-sense, single-stranded ribonucleic acid (RNA) genome. The virus has at least 4 different ... RT-PCR) to detect the hepatitis E virus RNA in blood and/or stool; this assay requires ...

  4. Autoimmune hepatitis.

    PubMed

    Heneghan, Michael A; Yeoman, Andrew D; Verma, Sumita; Smith, Alastair D; Longhi, Maria Serena

    2013-10-26

    Autoimmune hepatitis is a disease of the hepatic parenchyma that can present in acute or chronic forms. In common with many autoimmune diseases, autoimmune hepatitis is associated with non-organ-specific antibodies in the context of hepatic autoimmunity. This dichotomy has made definition of a unifying hypothesis in the pathophysiology of the disease difficult, although data from the past 8 years have drawn attention to the role of regulatory T cells. Several triggers have been identified, and the disease arises in genetically susceptible individuals. Clinical and biochemical remission is achievable in up to 85% of cases. For the remaining patients, alternative immunosuppression strategies are an option. Liver transplantation provides an excellent outcome for patients with acute liver failure or complications of end-stage liver disease, including hepatocellular carcinoma. Variant or overlapping syndromes are worthy of consideration when unexpected disease features arise.

  5. Hepatitis E.

    PubMed

    Krawczynski, K; Aggarwal, R; Kamili, S

    2000-09-01

    Hepatitis E, previously known as enterically transmitted non-A, non-B hepatitis, is an infectious viral disease with clinical and morphologic features of acute hepatitis. Its causative agent, hepatitis E virus, consists of small, 32- to 34-nm diameter, icosahedral, nonenveloped particles with a single-stranded, positive-sense, 7.5-kb RNA. The virus has two main geographically distinct strains, Asian and Mexican; recently, novel isolates from nonendemic areas and a genetically related swine HEV have been described. HEV is responsible for large epidemics of acute hepatitis and a proportion of sporadic hepatitis cases in the Indian subcontinent, southeast and central Asia, the Middle East, parts of Africa, and Mexico. The virus is excreted in feces and is transmitted predominantly by fecal-oral route, usually through contaminated water. Person-to-person transmission is uncommon. Clinical attack rates are the highest among young adults. Recent evidence suggests that humans with subclinical HEV infection and animals may represent reservoirs of HEV; however, further data are needed. Diagnosis of hepatitis E is usually made by detection of specific IgM antibody, which disappears rapidly over a few months; IgG anti-HEV persists for at least a few years. Clinical illness is similar to other forms of acute viral hepatitis except in pregnant women, in whom illness is particularly severe with a high mortality rate. Subclinical and unapparent infections may occur; however, chronic infection is unknown. No specific treatment is yet available. Use of clean drinking water and proper sanitation is currently the most effective method of prevention. Passive immunization has not been proved to be effective, and recombinant vaccines for travelers to disease-endemic areas and for pregnant women currently are being developed.

  6. Ruminal degradation of quercetin and its influence on fermentation in ruminants.

    PubMed

    Berger, L M; Blank, R; Zorn, F; Wein, S; Metges, C C; Wolffram, S

    2015-08-01

    The aim of the present study was to investigate the ruminal degradation of the flavonol quercetin and to determine its potential antimicrobial effects on ruminal fermentation in cows. Ruminal degradation of quercetin (0 or 100μmol/L, respectively) as well as its influence on ruminal gas production (0, 50, or 100μmol of quercetin equivalents/L, respectively, either applied as aglycone or as its glucorhamnoside rutin) using concentrate, grass hay, and straw as substrates were investigated in vitro using the Hohenheim gas test. Additionally, the influence of quercetin on ruminal concentrations of volatile fatty acids and their molar ratio in rumen-fistulated, nonlactating cows (n=5) after intraruminal application of quercetin as aglycone or as rutin (0, 10, or 50mg of quercetin equivalents/kg of BW, respectively) was evaluated. Quercetin was rapidly and extensively degraded, whereby the disappearance of quercetin was accompanied by the simultaneous appearance of 2metabolites 3,4-dihydroxyphenylacetic acid and 4-methylcatechol. In vitro total gas and methane production were not reduced by the addition of quercetin aglycone or rutin, respectively, using concentrate, grass hay, and straw as substrates. As expected, however, effects of the substrates used were detected on total gas and methane production. Highest gas production was found with concentrate, whereas values obtained with grass hay and straw were lower. Relative methane production was highest with grass hay compared with concentrate and straw (27.1 vs. 25.0 and 25.5%). After intraruminal application of the quercetin aglycone or rutin, respectively, neither total concentration nor the molar ratio of volatile fatty acids in the rumen fluid were influenced. Results of the present study show that quercetin underlies rapid ruminal degradation, whereby 3,4-dihydroxyphenylacetic acid and 4-methylcatechol are the main metabolites, whereas the latter one most likely is formed by dehydroxylation from 3

  7. Induction of apoptosis by quercetin is mediated through AMPKalpha1/ASK1/p38 pathway.

    PubMed

    Lee, Yun-Kyoung; Hwang, Jin-Taek; Kwon, Dae Young; Surh, Young-Joon; Park, Ock Jin

    2010-06-28

    Effective strategies for cancer prevention and treatment can be identified by understanding the mechanism of apoptotic pathways. In this study, we investigated the regulatory mechanism of quercetin-induced apoptosis through apoptosis signal-regulating kinase (ASK)-1 and mitogen-activated protein kinase pathways. Our results showed that quercetin increased apoptotic cell death through reactive oxygen species (ROS) generation and was responsible for ASK1 activation. Increasing ASK1 activity was accompanied by p38 activation. Interestingly, AMP-activated protein kinase (AMPK) seemed to be a critical controller of quercetin-regulated ASK1/p38 activation. Blocking AMPKalpha1 activity using Compound C, a synthetic inhibitor or siRNA showed that quercetin-activated ASK1 could not stimulate p38 activity. Thus, we suggested that quercetin-exerted apoptotic effects involve ROS/AMPKalpha1/ASK1/p38 signaling pathway, and AMPKalpha1 is a necessary element for apoptotic event induced by ASK1.

  8. A Molecularly Imprinted Polymer with Incorporated Graphene Oxide for Electrochemical Determination of Quercetin

    PubMed Central

    Sun, Si; Zhang, Mengqi; Li, Yijun; He, Xiwen

    2013-01-01

    The molecularly imprinted polymer based on polypyrrole film with incorporated graphene oxide was fabricated and used for electrochemical determination of quercetin. The electrochemical behavior of quercetin on the modified electrode was studied in detail using differential pulse voltammetry. The oxidation peak current of quercetin in B-R buffer solution (pH = 3.5) at the modified electrode was regressed with the concentration in the range from 6.0 × 10−7 to 1.5 × 10−5 mol/L (r2 = 0.997) with a detection limit of 4.8 × 10−8 mol/L (S/N = 3). This electrode showed good stability and reproducibility. In the above mentioned range, rutin or morin which has similar structures and at the same concentration as quercetin did not interfere with the determination of quercetin. The applicability of the method for complex matrix analysis was also evaluated. PMID:23698263

  9. The effect of quercetin dietary supplementation on meat oxidation processes and texture of fattening lambs.

    PubMed

    Andrés, S; Huerga, L; Mateo, J; Tejido, M L; Bodas, R; Morán, L; Prieto, N; Rotolo, L; Giráldez, F J

    2014-02-01

    Thirty two lambs were fed a total mixed ration (TMR) formulated either with palm oil (CTRL; 34 g palm oil kg(-1) TMR) or whole flaxseed (+FS, 85 g flaxseed kg(-1) TMR) alone or enriched with quercetin (+QCT, 34 g palm oil plus 2 g quercetin kg(-1) TMR; +FS+QCT, 85 g flaxseed plus 2 g quercetin kg(-1) TMR). Dietary flaxseed did not affect, in a significant manner, the lipid peroxidation of meat samples. Quercetin treatment reduced oxysterol content (P<0.05) after 7 days of refrigerated storage of fresh meat, but did not affect significantly (P>0.05) the level of lipid-derived volatiles in the headspace of the light-exposed stored cooked meat. Sensory evaluation showed flaxseed as being responsible for a negative effect on meat flavour, probably associated with a modification of the fatty acid profile whereas, unexpectedly, quercetin seemed to worsen meat tenderisation.

  10. Synthesis, characterization and study of antioxidant activity of quercetin-magnesium complex.

    PubMed

    Ghosh, Nilanjan; Chakraborty, Tania; Mallick, Sougata; Mana, Supriya; Singha, Deepanwita; Ghosh, Balaram; Roy, Souvik

    2015-12-05

    Quercetin (3,3',4',5,7-pentahydroxyflavone) one of the most abundant dietary flavonoids, has been investigated in the presence of magnesium (II) in methanol. The complex formation between quercetin and magnesium (II) was examined under UV-visible, Infra-red and (1)H NMR spectroscopic techniques. The spectroscopic data denoted that quercetin can reacts with magnesium cation (Mg(+2)) through the chelation site in the quercetin molecule. The free radical antioxidant activity of the complex with respect to the parent molecule was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) method. It was observed that the free radical scavenging activity of quercetin was increased after complexation of magnesium (Mg(+2)) cation.

  11. Quercetin induces mitochondrial biogenesis in experimental traumatic brain injury via the PGC-1α signaling pathway

    PubMed Central

    Li, Xiang; Wang, Handong; Gao, Yongyue; Li, Liwen; Tang, Chao; Wen, Guodao; Yang, Youqing; Zhuang, Zong; Zhou, Mengliang; Mao, Lei; Fan, Youwu

    2016-01-01

    Quercetin, a dietary flavonoid used as a food supplement, has been found to have protective effect against mitochondria damage after traumatic brain injury (TBI) in mice. However, the mechanisms underlying these effects are still not well understood. The aim of the present study was to investigate the effect of quercetin on the potential mechanism mediating these effects in the weight-drop model of TBI in male mice that were treated with quercetin or vehicle via intraperitoneal injection administration 30 min after TBI. Brain samples were collected 24 h later for analysis. Quercetin treatment upregulated the expression of PGC-1α and restored the level of cytochrome c, malondialdehyde (MDA) and superoxide dismutase (SOD). These results demonstrate that quercetin improves mitochondrial function in mice by improving the level of PGC-1α following TBI. PMID:27648146

  12. Quercetin induces mitochondrial biogenesis in experimental traumatic brain injury via the PGC-1α signaling pathway.

    PubMed

    Li, Xiang; Wang, Handong; Gao, Yongyue; Li, Liwen; Tang, Chao; Wen, Guodao; Yang, Youqing; Zhuang, Zong; Zhou, Mengliang; Mao, Lei; Fan, Youwu

    2016-01-01

    Quercetin, a dietary flavonoid used as a food supplement, has been found to have protective effect against mitochondria damage after traumatic brain injury (TBI) in mice. However, the mechanisms underlying these effects are still not well understood. The aim of the present study was to investigate the effect of quercetin on the potential mechanism mediating these effects in the weight-drop model of TBI in male mice that were treated with quercetin or vehicle via intraperitoneal injection administration 30 min after TBI. Brain samples were collected 24 h later for analysis. Quercetin treatment upregulated the expression of PGC-1α and restored the level of cytochrome c, malondialdehyde (MDA) and superoxide dismutase (SOD). These results demonstrate that quercetin improves mitochondrial function in mice by improving the level of PGC-1α following TBI.

  13. Quercetin promotes neurite growth through enhancing intracellular cAMP level and GAP-43 expression.

    PubMed

    Chen, Ming-Ming; Yin, Zhi-Qi; Zhang, Lu-Yong; Liao, Hong

    2015-09-01

    The present study was designed to investigate the role of quercetin on neurite growth in N1E-115 cells and the underlying mechanisms. Quercetin was evaluated for its effects on cell numbers of neurites, neurite length, intracellular cAMP content, and Gap-43 expression in N1E-115 cells in vitro by use of microscopy, LANCE(tm) cAMP 384 kit, and Western blot analysis, respectively. Our results showed that quercetin could increase the neurite length in a concentration-dependent manner, but had no effect on the numbers of cells. Quercetin significantly increased the expression of cellular cAMP in a time- and concentration-dependent manner. The Gap-43 expression was up-regulated in a time-dependent manner. In conclusion, quercetin could promote neurite growth through increasing the intracellular cAMP level and Gap-43 expression.

  14. A molecularly imprinted polymer with incorporated graphene oxide for electrochemical determination of quercetin.

    PubMed

    Sun, Si; Zhang, Mengqi; Li, Yijun; He, Xiwen

    2013-04-25

    The molecularly imprinted polymer based on polypyrrole film with incorporated graphene oxide was fabricated and used for electrochemical determination of quercetin. The electrochemical behavior of quercetin on the modified electrode was studied in detail using differential pulse voltammetry. The oxidation peak current of quercetin in B-R buffer solution (pH = 3.5) at the modified electrode was regressed with the concentration in the range from 6.0 × 10(-7) to 1.5 × 10(-5) mol/L (r2 = 0.997) with a detection limit of 4.8 × 10(-8) mol/L (S/N = 3). This electrode showed good stability and reproducibility. In the above mentioned range, rutin or morin which has similar structures and at the same concentration as quercetin did not interfere with the determination of quercetin. The applicability of the method for complex matrix analysis was also evaluated.

  15. Hepatitis A Test

    MedlinePlus

    ... AACC products and services. Advertising & Sponsorship: Policy | Opportunities Hepatitis A Testing Share this page: Was this page ... HAV-Ab total; Anti-HAV Formal name: Viral Hepatitis A Antibody Related tests: Hepatitis B Testing ; Hepatitis ...

  16. Travelers' Health: Hepatitis A

    MedlinePlus

    ... 3 - Helminths, Soil-Transmitted Chapter 3 - Hepatitis B Hepatitis A Noele P. Nelson, Trudy V. Murphy INFECTIOUS ... hepatitis/HAV Table 3-02. Vaccines to prevent hepatitis A VACCINE TRADE NAME (MANUFACTURER) AGE (Y) DOSE ...

  17. Hepatitis B Foundation

    MedlinePlus

    ... worldwide 2 Billion People have been infected with Hepatitis B Worldwide The Hepatitis B Foundation is working ... of people living with hepatitis B. Learn About Hepatitis B in 11 Other Languages . Resource Video See ...

  18. Hepatitis A FAQs

    MedlinePlus

    ... Professional Resources Patient Education Resources Quick Links to Hepatitis … A | B | C | D | E Viral Hepatitis Home ... Grantees Policy and Programs Resource Center Viral Hepatitis Hepatitis A Questions and Answers for the Public Recommend ...

  19. Hepatitis (For Parents)

    MedlinePlus

    ... people at risk for contracting hepatitis. But frequent hand washing and good hygiene practices can reduce this risk. ... After Having Hepatitis B? Hepatitis B (HBV) Hepatitis Hand Washing Blood Transfusions Body Piercing Tattoos Contact Us Print ...

  20. Preparation of efficient quercetin delivery system on Zn-modified mesoporous SBA-15 silica carrier.

    PubMed

    Trendafilova, Ivalina; Szegedi, Agnes; Mihály, Judith; Momekov, Georgi; Lihareva, Nadejda; Popova, Margarita

    2017-04-01

    Mesoporous silica material type SBA-15 was modified with different amounts of Zn (2 and 4wt.%) by incipient wetness impregnation method in ethanol. The parent, Zn-modified and quercetin loaded samples, were characterized by XRD, N2 physisorption, TEM, thermal gravimetric analysis, UV-vis and FT-IR spectroscopies and in vitro release of quercetin at pH5.5 which is typical of dermal formulations. By this loading method anhydrous quercetin was formed on the silica carrier It was found that the different hydrate forms of quercetin (dihydrate, monohydrate, anhydrite) significantly influence the physico-chemical properties of the delivery system. It was found that hydrate forms of quercetin can be differentiated by XRD and by FT-IR spectroscopic methods. Thus, by evaluating the interaction of the drug with the silica carrier the changes due to its hydration state always have to be taken into account. Formation of Zn-quercetin complex was evidenced on zinc modified SBA-15 silica by FT-IR spectroscopy. High quercetin loading capacity (over 40wt.%) could be achieved on the parent and Zn-containing SBA-15 samples. The in-vitro release process at pH=5.5 showed slower quercetin release from Zn-modified SBA-15 samples compared to the parent one. Additionally, the comparative cytotoxic experiments evidenced that quercetin encapsulated in Zn-modified silica carriers has superior antineoplastic potential against HUT-29 cells compared to free drug. Zn-modified SBA-15 silica particles could be promising carriers for dermal delivery of quercetin.

  1. Calcium releasing action of quercetin on sarcoplasmic reticulum from frog skeletal muscle.

    PubMed

    Kurebayashi, N; Ogawa, Y

    1984-10-01

    The release of Ca by quercetin from the sarcoplasmic reticulum has been claimed to be a result of the well-known inhibition of Ca2+-ATPase activity, or to be due to an intrinsic property of quercetin. To get a clearer understanding of the effect of quercetin, we examined it using fragmented sarcoplasmic reticulum (FSR) from bullfrog skeletal muscle. The rapid phase of Ca release (hereafter simply referred to as "Ca release") from loaded FSR was almost completed within 5 s after addition of quercetin in the presence of ATP. It cannot be ascribed to the inhibition of Ca2+-ATPase activity on the basis of following findings. First, when Ca uptake was driven by carbamylphosphate, no or little Ca release was observed in marked contrast to a stronger reduction in the rate of Ca uptake. Secondly, procaine reverses the Ca releasing action of quercetin, whereas it show a synergistic action in the inhibition of Ca2+-ATPase activity. Thirdly, HFSR released more Ca than LFSR, while the Ca2+-ATPase activities of both fractions were inhibited to a similar extent. The Ca release by quercetin is enhanced by ATP or beta, gamma-methylene adenosine triphosphate, and decreased by procaine or a high concentration of Mg2+. In the presence of 2.5 mM caffeine, the amount of Ca2+ released by quercetin was decreased, and the dose-effect relationship was shifted to higher doses of quercetin. This indicates that quercetin and caffeine probably overlap in the site(s) of the action, but that quercetin is dissimilar from halothane in the mode of its Ca-releasing action.

  2. Evaluation of polyamidoamine dendrimers as potential carriers for quercetin, a versatile flavonoid.

    PubMed

    Madaan, Kanika; Lather, Viney; Pandita, Deepti

    2016-01-01

    The aim of the present research work was to investigate the potential of polyamidoamine (PAMAM) dendrimers as oral drug delivery carriers for quercetin, a Biopharmaceutical Classification System (BCS) class II molecule. The aqueous solubility of quercetin was investigated in different generations of dendrimers, i.e. G0, G1, G2 and G3, with varying concentrations (0.1, 0.5, 1, 2 and 4 µM). Then, it was successfully incorporated in PAMAM dendrimers and they were characterized for incorporation efficacy, nature of nanoformulations, size, size distribution, surface morphology and stability. In vitro release characteristics of quercetin from all quercetin-PAMAM complexes were studied at 37 °C in phosphate buffer saline (PBS; pH 7.4). Furthermore, the efficacy of quercetin-loaded PAMAM dendrimer was assessed by pharmacodynamic experiment, namely, a carrageenan-induced paw edema model to evaluate the acute activity of this nanocarrier in response to inflammation. It was observed that both generation and the respective concentrations of PAMAM dendrimers showed potential positive effects on solubility enhancement of quercetin. All the quercetin-PAMAM complexes were found to be in nanometeric range (<100 nm) with narrow polydispersity index. In vitro study revealed a biphasic release pattern of quercetin which was characterized by an initial faster release followed by sustained release phase and pharmacodynamic study provided the preliminary proof of concept about the potential of quercetin-PAMAM complexes. The study concludes that the dendrimer-based drug delivery system for quercetin has enormous potential to resolve the drug delivery issues associated with it.

  3. Feature Hepatitis: Hepatitis Symptoms, Diagnosis, Treatment & Prevention

    MedlinePlus

    ... Navigation Bar Home Current Issue Past Issues Feature Hepatitis Hepatitis: Symptoms, Diagnosis, Treatment & Prevention Past Issues / Spring 2009 ... No appetite Fever Headaches Diagnosis To check for hepatitis viruses, your doctor will test your blood. You ...

  4. Development of nanosuspension formulation for oral delivery of quercetin.

    PubMed

    Sun, Min; Gao, Yan; Pei, Yan; Guo, Chenyu; Li, Houli; Cao, Fengliang; Yu, Aihua; Zhai, Guangxi

    2010-08-01

    With the aim to enhance dissolution rate and oral bioavailability of quercetin, a poorly water-soluble drug, quercetin loaded nanosuspension (QT-NS) was fabricated by a tandem of nano-precipitation (NP) and high pressure homogenization (HPH) method. The formulation of nanosuspension was optimized by screening different stabilizers. Characterization of the original QT powder and QT-NS was carried out by transmission electron microscopy and scanning electron microscopy, X-ray diffraction (XRD) and dissolution tests. QT-NS presented a sphere-like shape under transmission electron microscopy with an average diameter of 393.5 nm and the zeta potential of -35.75 mV. XRD study suggested that QT was maintained in the state of crystalline during the fabrication process. The solubility of QT in nanosuspension was about 70-fold that of crude QT, and the dissolution of QT from QT-NS was increased as compared to that of the original QT powder. In plasma, QT-NS exhibited a significant reduction of clearance rate (2 +/- 0.1 mL/min vs. 15 +/- 4 mL/min) and increase of AUC(0-infinity), (53995 +/- 4126 microg/mL x min versus 3470 +/- 110.1 microg/mL x min) compared with the control suspension. Our results showed that the developed nanosuspension formulation had a great potential as a possible formulation of the poorly water-soluble QT to enhance the bioavailability.

  5. Silk fibroin nanoparticles: Efficient vehicles for the natural antioxidant quercetin.

    PubMed

    Lozano-Pérez, Antonio Abel; Rivero, Héctor Correa; Pérez Hernández, María Del Carmen; Pagán, Ana; Montalbán, Mercedes G; Víllora, Gloria; Cénis, José Luis

    2017-02-25

    This article describes how silk fibroin nanoparticles (SFNs) are capable of adsorbing and releasing quercetin (Q) and how its integrity is highly preserved, as confirmed by antioxidant activity assays. Q loading onto SFNs was optimized in terms of the Q/SFN ratio (w/w), time of adsorption and solvent mixture. Quercetin-loaded silk fibroin nanoparticles (QSFNs) were characterized using the dynamic light scattering technique to measure the diameter (Z-Average) and Z-potential (ζ). Loaded particles were slightly bigger than the SFNs, while their ζ was less negative. The antioxidant activity against DPPH showed that the Q loaded in QSFNs not only retains the antioxidant activity but also has a synergistic scavenging activity due the intrinsic antioxidant activity of the SF. The drug loading content (DLC) and the encapsulation efficiency (EE) varied with the relation between Q and SFN in the loading solution. The sustained release of Q occurred throughout the experiment both in phosphate buffer saline (pH 7.4) and simulated intestinal fluid (pH 6.8). The results point to SFNs as promising candidates for Q loading, transport and gastrointestinal delivery with potential applications in nanomedicine, while retaining their nano-size and their antioxidant properties.

  6. Anti-ageing and rejuvenating effects of quercetin.

    PubMed

    Chondrogianni, Niki; Kapeta, Suzanne; Chinou, Ioanna; Vassilatou, Katerina; Papassideri, Issidora; Gonos, Efstathios S

    2010-10-01

    Homeostasis is a key feature of the cellular lifespan. Its maintenance influences the rate of ageing and it is determined by several factors, including efficient proteolysis. The proteasome is the major cellular proteolytic machinery responsible for the degradation of both normal and damaged proteins. Alterations of proteasome function have been recorded in various biological phenomena including ageing and replicative senescence. Proteasome activities and function are decreased upon replicative senescence, whereas proteasome activation confers enhanced survival against oxidative stress, lifespan extension and maintenance of the young morphology longer in human primary fibroblasts. Several natural compounds possess anti-ageing/anti-oxidant properties. In this study, we have identified quercetin (QUER) and its derivative, namely quercetin caprylate (QU-CAP) as a proteasome activator with anti-oxidant properties that consequently influence cellular lifespan, survival and viability of HFL-1 primary human fibroblasts. Moreover, when these compounds are supplemented to already senescent fibroblasts, a rejuvenating effect is observed. Finally, we show that these compounds promote physiological alterations when applied to cells (i.e. whitening effect). In summary, these data demonstrate the existence of naturally occurring anti-ageing products that can be effectively used through topical application.

  7. The fetal programming of dietary fructose and saturated fat on hepatic quercetin glucuronidation in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective Phase II biotransformation of flavonoids generates bioactive metabolites in vivo. However, data on the effect of environmental and physiological factors and fetal programming on phase II pathways toward flavonoids are limited. We examined the effect of parental exposure to a diet high in s...

  8. Simultaneous ingestion of high-methoxy pectin from apple can enhance absorption of quercetin in human subjects.

    PubMed

    Nishijima, Tomohiko; Takida, Yoshiki; Saito, Yasuo; Ikeda, Takayuki; Iwai, Kunihisa

    2015-05-28

    Chronic ingestion of apple pectin has been shown to increase the absorption of quercetin in rats. The present study was designed to elucidate whether the simultaneous ingestion of quercetin with apple pectin could enhance the absorption of quercetin in humans, and the effects of dose dependency and degree of pectin methylation on quercetin absorption were also investigated. Healthy volunteers (n 19) received 200 ml of 0.5 mg/ml of quercetin drinks with or without 10 mg/ml of pectin each in a randomised cross-over design study with over 1-week intervals; urine samples from all the subjects were collected within 24 h after ingestion of the test drinks, and urinary deconjugated quercetin and its metabolites were determined using HPLC. The sum of urinary quercetin and its metabolites excreted was increased by 2.5-fold by the simultaneous ingestion of pectin. The metabolism of methylated quercetin (isorhamnetin and tamarixetin) was not affected by pectin ingestion. In six volunteers, who received quercetin drinks containing 0, 3 and 10 mg/ml of pectin, the sum of urinary quercetin and its metabolites excreted also increased in a pectin dose-dependent manner. Furthermore, the simultaneous ingestion of quercetin with low-methoxy and high-methoxy pectin, respectively, increased the sum of urinary excretion of quercetin and its metabolites by 1.69-fold and significantly by 2.13-fold compared with the ingestion of quercetin without pectin. These results elucidated that apple pectin immediately enhanced quercetin absorption in human subjects, and that its enhancing effect was dependent on the dose and degree of pectin methylation. The results also suggested that the viscosity of pectin may play a role in the enhancement of quercetin absorption.

  9. Quercetin phospholipid complex significantly protects against oxidative injury in ARPE-19 cells associated with activation of Nrf2 pathway.

    PubMed

    Xu, Xin-Rong; Yu, Hai-Tao; Yang, Yan; Hang, Li; Yang, Xue-Wen; Ding, Shu-Hua

    2016-01-05

    Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Oxidative stress plays a crucial role in the pathogenesis of dry AMD. Quercetin has potent anti-oxidative activities, but poor bioavailability limits its therapeutic application. Herein, we prepared the phospholipid complex of quercetin (quercetin-PC), characterized its structure by differential scanning calorimetry, infrared spectrum and x-ray diffraction. Quercetin-PC had equilibrium solubility of 38.36 and 1351.27μg/ml in water and chloroform, respectively, which was remarkably higher than those of quercetin alone. Then we established hydrogen peroxide (H2O2)-induced oxidative injury model in human ARPE-19 cells to examine the effects of quercetin-PC. Quercetin-PC, stronger than quercetin, promoted cell proliferation, and the proliferation rate was increased to be 78.89% when treated with Quercetin-PC at 400μM. Moreover, quercetin-PC effectively prevented ARPE-19 cells from apoptosis, and the apoptotic rate was reduced to be 3.1% when treated with Quercetin-PC at 200μM. In addition, quercetin-PC at 200μM significantly increased the activities of SOD, CAT and GSH-PX, and reduced the levels of reactive oxygen species and MDA in H2O2-treated ARPE-19 cells, but quercetin at 200μM failed to do so. Molecular examinations revealed that quercetin-PC at 200μM significantly activated Nrf2 nuclear translocation and significantly enhanced the expression of target genes HO-1, NQO-1 and GCL by different folds at both mRNA and protein levels. Our current data collectively indicated that quercetin-PC had stronger protective effects against oxidative-induced damages in ARPE-19 cells, which was associated with activation of Nrf2 pathway and its target genes implicated in antioxidant defense.

  10. Dietary quercetin exacerbates the development of estrogen-induced breast tumors in female ACI rats

    SciTech Connect

    Singh, Bhupendra; Mense, Sarah M.; Bhat, Nimee K.; Putty, Sandeep; Guthiel, William A.; Remotti, Fabrizio; Bhat, Hari K.

    2010-09-01

    Phytoestrogens are plant compounds that structurally mimic the endogenous estrogen 17{beta}-estradiol (E{sub 2}). Despite intense investigation, the net effect of phytoestrogen exposure on the breast remains unclear. The objective of the current study was to examine the effects of quercetin on E{sub 2}-induced breast cancer in vivo. Female ACI rats were given quercetin (2.5 g/kg food) for 8 months. Animals were monitored weekly for palpable tumors, and at the end of the experiment, rats were euthanized, breast tumor and different tissues excised so that they could be examined for histopathologic changes, estrogen metabolic activity and oxidant stress. Quercetin alone did not induce mammary tumors in female ACI rats. However, in rats implanted with E{sub 2} pellets, co-exposure to quercetin did not protect rats from E{sub 2}-induced breast tumor development with 100% of the animals developing breast tumors within 8 months of treatment. No changes in serum quercetin levels were observed in quercetin and quercetin + E{sub 2}-treated groups at the end of the experiment. Tumor latency was significantly decreased among rats from the quercetin + E{sub 2} group relative to those in the E{sub 2} group. Catechol-O-methyltransferase (COMT) activity was significantly downregulated in quercetin-exposed mammary tissue. Analysis of 8-isoprostane F{sub 2{alpha}} (8-iso-PGF{sub 2{alpha}}) levels as a marker of oxidant stress showed that quercetin did not decrease E{sub 2}-induced oxidant stress. These results indicate that quercetin (2.5 g/kg food) does not confer protection against breast cancer, does not inhibit E{sub 2}-induced oxidant stress and may exacerbate breast carcinogenesis in E{sub 2}-treated ACI rats. Inhibition of COMT activity by quercetin may expose breast cells chronically to E{sub 2} and catechol estrogens. This would permit longer exposure times to the carcinogenic metabolites of E{sub 2} and chronic exposure to oxidant stress as a result of metabolic redox

  11. Liver Cancer and Hepatitis B

    MedlinePlus

    ... Our Accomplishments Annual Reports Our Videos What Is Hepatitis B? What Is Hepatitis B? The ABCs of Viral Hepatitis Liver Cancer and Hepatitis B Hepatitis Delta Coinfection Hepatitis C Coinfection HIV/AIDS ...

  12. Hepatitis C: Sex and Sexuality

    MedlinePlus

    ... with Hepatitis » Sex and Sexuality: Entire Lesson Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... hepatitis C virus through sex. Can you pass hepatitis C to a sex partner? Yes, but it ...

  13. Pressure surge attenuator

    DOEpatents

    Christie, Alan M.; Snyder, Kurt I.

    1985-01-01

    A pressure surge attenuation system for pipes having a fluted region opposite crushable metal foam. As adapted for nuclear reactor vessels and heads, crushable metal foam is disposed to attenuate pressure surges.

  14. Rapid dimerization of quercetin through an oxidative mechanism in the presence of serum albumin decreases its ability to induce cytotoxicity in MDA-MB-231 cells

    SciTech Connect

    Pham, Anh; Bortolazzo, Anthony; White, J. Brandon

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer Quercetin cannot be detected intracellularly despite killing MDA-MB-231 cells. Black-Right-Pointing-Pointer Quercetin forms a heterodimer through oxidation in media with serum. Black-Right-Pointing-Pointer The quercetin heterodimer does not kill MDA-MB-231 cells. Black-Right-Pointing-Pointer Ascorbic acid stabilizes quercetin increasing cell death in quercetin treated cells. Black-Right-Pointing-Pointer Quercetin, and not a modified form, is responsible for apoptosis and cell death. -- Abstract: Quercetin is a member of the flavonoid family and has been previously shown to have a variety of anti-cancer activities. We and others have reported anti-proliferation, cell cycle arrest, and induction of apoptosis of cancer cells after treatment with quercetin. Quercetin has also been shown to undergo oxidation. However, it is unclear if quercetin or one of its oxidized forms is responsible for cell death. Here we report that quercetin rapidly oxidized in cell culture media to form a dimer. The quercetin dimer is identical to a dimer that is naturally produced by onions. The quercetin dimer and quercetin-3-O-glucopyranoside are unable to cross the cell membrane and do not kill MDA-MB-231 cells. Finally, supplementing the media with ascorbic acid increases quercetin's ability to induce cell death probably by reduction oxidative dimerization. Our results suggest that an unmodified quercetin is the compound that elicits cell death.

  15. Quercetin exhibits adjuvant activity by enhancing Th2 immune response in ovalbumin immunized mice.

    PubMed

    Singh, Divya; Tanwar, Himanshi; Jayashankar, Bindhya; Sharma, Jyoti; Murthy, Swetha; Chanda, Sudipta; Singh, Shashi Bala; Ganju, Lilly

    2017-04-02

    Quercetin, one of the most abundant of plant flavonoids, has been studied with a great deal of attention over the last several decades mainly for its properties in inflammation and allergy. In this study, we are reporting for the first time the in vivo immunostimulatory activity of quercetin in ovalbumin immunized Balb/c mice. Administration of quercetin (50mg/kg body weight) along with ovalbumin antigen showed increased ovalbumin specific serum IgG antibody titres in comparison to the control group (p<0.05). Quercetin administration not only showed predominance of Th2 immune response by increasing the IgG1 antibody titres, but also increased the infiltration of CD11c(+) dendritic cells in the mouse peritoneum and also increased LPS activated IL-1β and nitric oxide (NO) production by peritoneal macrophages. Expression of Tbx21, GATA-3 and Oct-2 proteins also enhanced in splenocytes of quercetin administered mice. Quercetin also did not cause any hemolysis in human RBCs. Overall, our findings strongly demonstrate the novel in vivo immunostimulatory and adjuvant potentials of quercetin.

  16. Quercetin ameliorates Aβ toxicity in Drosophila AD model by modulating cell cycle-related protein expression

    PubMed Central

    Kong, Yan; Li, Ke; Fu, Tingting; Wan, Chao; Zhang, Dongdong; Song, Hang; Zhang, Yao; Liu, Na; Gan, Zhenji; Yuan, Liudi

    2016-01-01

    Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by β amyloid (Aβ) deposition and neurofibril tangles. It has been reported that a bioflavonoid, quercetin, could ameliorate AD phenotypes in C. elegans and mice. However, the mechanism underlying the ameliorative effect of quercetin is not fully understood yet. Drosophila models could recapitulate AD-like phenotypes, such as shortened lifespan, impaired locomotive ability as well as defects in learning and memory. So in this study, we investigated the effects of quercetin on AD in Drosophila model and explored the underlying mechanisms. We found quercetin could effectively intervene in AD pathogenesis in vivo. Mechanism study showed quercetin could restore the expression of genes perturbed by Aβ accumulation, such as those involved in cell cycle and DNA replication. Cyclin B, an important cell cycle protein, was chosen to test whether it participated in the AD ameliorative effects of quercetin. We found that cyclin B RNAi in the brain could alleviate AD phenotypes. Taken together, the current study suggested that the neuroprotective effects of quercetin were mediated at least partially by targeting cell cycle-related proteins. PMID:27626494

  17. Magnetic nanoparticles for a new drug delivery system to control quercetin releasing for cancer chemotherapy

    NASA Astrophysics Data System (ADS)

    Barreto, A. C. H.; Santiago, V. R.; Mazzetto, S. E.; Denardin, J. C.; Lavín, R.; Mele, Giuseppe; Ribeiro, M. E. N. P.; Vieira, Icaro G. P.; Gonçalves, Tamara; Ricardo, N. M. P. S.; Fechine, P. B. A.

    2011-12-01

    Quercetin belongs to the chemical class of flavonoids and can be found in many common foods, such as apples, nuts, berries, etc. It has been demonstrated that quercetin has a wide array of biological effects that are considered beneficial to health treatment, mainly as anticancer. However, therapeutic applications of quercetin have been restricted to oral administration due to its sparing solubility in water and instability in physiological medium. A drug delivery methodology was proposed in this work to study a new quercetin release system in the form of magnetite-quercetin-copolymer (MQC). These materials were characterized through XRD, TEM, IR, and Thermal analysis. In addition, the magnetization curves and quercetin releasing experiments were performed. It was observed a nanoparticle average diameter of 11.5 and 32.5 nm at Fe3O4 and MQC, respectively. The presence of magnetic nanoparticles in this system offers the promise of targeting specific organs within the body. These results indicate the great potential for future applications of the MQC to be used as a new quercetin release system.

  18. Chlorpyrifos induced hepatotoxic and hematologic changes in rats: the role of quercetin and catechin.

    PubMed

    Uzun, Fatma Gokce; Kalender, Yusuf

    2013-05-01

    Chlorpyrifos is an organophosphorus insecticide which is widely used throughout in the world and it caused toxic effects on nontarget organisms especially mammalian. In the present study, catechin, quercetin, chlorpyrifos, catechin+chlorpyrifos, quercetin+chlorpyrifos were given to male rats through gavage for 4weeks. Serum total protein, albumin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, trigliceride, total cholesterol levels, hematological changes, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase activities and malondialdehyde content in liver tissues and also histopathological changes of liver were investigated in the rats compared to control group. No significant differences in all investigated parameters were observed between control, catechin and quercetin groups. There were statistically significantly changes in liver function tests, some hematological parameters, antioxidant enzyme activities and malondialdehyde levels in chlorpyrifos treated group compared to control group. In catechin+chlorpyrifos treated group and quercetin+chlorpyrifos treated group we observed the protective effects of catechin and quercetin on examining parameters but not completely. While some histopathological changes detected in liver tissues in chlorpyrifos treated group, less histopathological changes were observed in catechin+chlorpyrifos and quercetin+chlorpyrifos treated groups at the end of the 4thweek. As a result, catechin and quercetin significantly reduce chlorpyrifos induced hepatotoxicity in rats.

  19. Onion skin waste as a valorization resource for the by-products quercetin and biosugar.

    PubMed

    Choi, In Seong; Cho, Eun Jin; Moon, Jae-Hak; Bae, Hyeun-Jong

    2015-12-01

    Onion skin waste (OSW), which is produced from processed onions, is a major industrial waste. We evaluated the use of OSW for biosugar and quercetin production. The carbohydrate content of OSW was analyzed, and the optimal conversion conditions were evaluated by varying enzyme mixtures and loading volumes for biosugar production and quercetin extraction. The enzymatic conversion rate of OSW to biosugar was 98.5% at 0.72 mg of cellulase, 0.16 mg of pectinase, and 1.0mg of xylanase per gram of dry OSW. Quercetin extraction also increased by 1.61-fold after complete enzymatic hydrolysis. In addition, the newly developed nano-matrix (terpyridine-immobilized silica-coated magnetic nanoparticles-zinc (TSMNP-Zn matrix) was utilized to separate quercetin from OSW extracts. The nano-matrix facilitated easy separation and purification of quercetin. Using the TSMNP-Zn matrix the quercetin was approximately 90% absorbed. In addition, the recovery yield of quercetin was approximately 75% after treatment with ethylenediaminetetraacetic acid.

  20. Quercetin ameliorates Aβ toxicity in Drosophila AD model by modulating cell cycle-related protein expression.

    PubMed

    Kong, Yan; Li, Ke; Fu, Tingting; Wan, Chao; Zhang, Dongdong; Song, Hang; Zhang, Yao; Liu, Na; Gan, Zhenji; Yuan, Liudi

    2016-10-18

    Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by β amyloid (Aβ) deposition and neurofibril tangles. It has been reported that a bioflavonoid, quercetin, could ameliorate AD phenotypes in C. elegans and mice. However, the mechanism underlying the ameliorative effect of quercetin is not fully understood yet. Drosophila models could recapitulate AD-like phenotypes, such as shortened lifespan, impaired locomotive ability as well as defects in learning and memory. So in this study, we investigated the effects of quercetin on AD in Drosophila model and explored the underlying mechanisms. We found quercetin could effectively intervene in AD pathogenesis in vivo. Mechanism study showed quercetin could restore the expression of genes perturbed by Aβ accumulation, such as those involved in cell cycle and DNA replication. Cyclin B, an important cell cycle protein, was chosen to test whether it participated in the AD ameliorative effects of quercetin. We found that cyclin B RNAi in the brain could alleviate AD phenotypes. Taken together, the current study suggested that the neuroprotective effects of quercetin were mediated at least partially by targeting cell cycle-related proteins.

  1. Protective effects of quercetin against arsenic-induced testicular damage in rats.

    PubMed

    Baltaci, B B; Uygur, R; Caglar, V; Aktas, C; Aydin, M; Ozen, O A

    2016-12-01

    This study investigated the effect of quercetin on changes in testes due to arsenic exposure. Twenty-seven male rats were divided into three groups: control (10 ml kg(-1)  day(-1) saline), arsenic (10 mg kg(-1)  day(-1) sodium arsenite) and arsenic + quercetin (arsenic + 50 mg kg(-1)  day(-1) quercetin). The rats were sacrificed at the end of 15-day experiment. There was no difference between control group and arsenic group in body weight gain, testicular weight and serum total testosterone level. Quercetin treatment did not cause a significant difference in these parameters. In the arsenic group rats, we determined deterioration in the structure of seminiferous tubules, a decrease in the number of spermatogenic cells, an increase in the number of apoptotic cells, a decrease in the number of PCNA-positive cells, a decrease in SOD, CAT and GSH-Px activities, and an increase in the MDA level in testicular tissue. In all these changes, arsenic+quercetin group showed an improved compared to arsenic group. The amount of arsenic increased in the arsenic group was compared to the control group, and there was no difference between arsenic group and arsenic + quercetin group in the amount of arsenic. In conclusion, quercetin prevented arsenic-induced testicular damage with its anti-apoptotic and antioxidant effects.

  2. The critical role of quercetin in autophagy and apoptosis in HeLa cells.

    PubMed

    Wang, Yijun; Zhang, Wei; Lv, Qiongying; Zhang, Juan; Zhu, Dingjun

    2016-01-01

    In recent years, the effects of quercetin on autophagy and apoptosis of cancer cells have been widely reported, while effects on HeLa cells are still unclear. Here, HeLa cells were subjected to quercetin treatment, and then proliferation, apoptosis, and autophagy were evaluated using MTT, flow cytometry, and MDC staining, respectively. The LC3-I/II, Beclin 1, active caspase-3, and S6K1 phosphorylation were detected using Western blot assay. The ultrastructure of HeLa was observed via transmission electron microscope (TEM). Our findings showed that quercetin can dose-dependently inhibit the growth of HeLa cells. The MDC fluorescence was enhanced with increased concentration of quercetin and hit a plateau at 50 μmol/l. Western blot assay revealed that LC3-I/II ratio, Beclin 1, and active caspase-3 protein were enforced in a dose-dependent method. However, the phosphorylation of S6K1 gradually decreased, concomitant with an increase of autophagy. In addition, TEM revealed that the number of autophagic vacuoles was peaked at 50 μmol/l of quercetin. Besides, interference of autophagy with 3-MA led to proliferation inhibition and increased apoptosis in HeLa cells, accompanied by the decreased LC3-I/II conversion and the increased active caspase-3. In conclusion, quercetin can inhibit HeLa cell proliferation and induce protective autophagy at low concentrations; thus, 3-MA plus quercetin would suppress autophagy and effectively increased apoptosis.

  3. Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics?

    PubMed

    Brito, Ana Filipa; Ribeiro, Marina; Abrantes, Ana Margarida; Pires, Ana Salomé; Teixo, Ricardo Jorge; Tralhão, José Guilherme; Botelho, Maria Filomena

    2015-01-01

    Cancer is a problem of global importance, since the incidence is increasing worldwide and therapeutic options are generally limited. Thus, it becomes imperative to find new therapeutic targets as well as new molecules with therapeutic potential for tumors. Flavonoids are polyphenolic compounds that may be potential therapeutic agents. Several studies have shown that these compounds have a higher anticancer potential. Among the flavonoids in the human diet, quercetin is one of the most important. In the last decades, several anticancer properties of quercetin have been described, such as cell signaling, pro-apoptotic, anti-proliferative and anti-oxidant effects, growth suppression. In fact, it is now well known that quercetin has diverse biological effects, inhibiting multiple enzymes involved in cell proliferation, as well as, in signal transduction pathways. On the other hand, there are also studies reporting potential synergistic effects when combined quercetin with chemotherapeutic agents or radiotherapy. In fact, several studies which aim to explore the anticancer potential of these combined treatments have already been published, the majority with promising results. Actually it is well known that quercetin can act on the chemosensitization and radiosensitization but also as chemoprotective and radioprotective, protecting normal cells of the side effects that results from chemotherapy and radiotherapy, which obviously provides notable advantages in their use in anticancer treatment. Thus, all these data indicate that quercetin may have a key role in anticancer treatment. In this context, this review is focused on the relationship between flavonoids and cancer, with special emphasis on the role of quercetin.

  4. Quercetin-3-O-glucuronide induces ABCA1 expression by LXRα activation in murine macrophages

    SciTech Connect

    Ohara, Kazuaki; Wakabayashi, Hideyuki; Taniguchi, Yoshimasa; Shindo, Kazutoshi; Yajima, Hiroaki; Yoshida, Aruto

    2013-11-29

    Highlights: •The major circulating quercetin metabolite (Q3GA) activated LXRα. •Q3GA induced ABCA1 via LXRα activation in macrophages. •Nelumbo nucifera leaf extracts contained quercetin glycosides. •N. nucifera leaf extract feeding elevated HDLC in mice. -- Abstract: Reverse cholesterol transport (RCT) removes excess cholesterol from macrophages to prevent atherosclerosis. ATP-binding cassette, subfamily A, member 1 (ABCA1) is a crucial cholesterol transporter involved in RCT to produce high density lipoprotein-cholesterol (HDLC), and is transcriptionally regulated by liver X receptor alpha (LXRα), a nuclear receptor. Quercetin is a widely distributed flavonoid in edible plants which prevented atherosclerosis in an animal model. We found that quercetin-3-O-glucuronide (Q3GA), a major quercetin metabolite after absorption from the digestive tract, enhanced ABCA1 expression, in vitro, via LXRα in macrophages. In addition, leaf extracts of a traditional Asian edible plant, Nelumbo nucifera (NNE), which contained abundant amounts of quercetin glycosides, significantly elevated plasma HDLC in mice. We are the first to present experimental evidence that Q3GA induced ABCA1 in macrophages, and to provide an alternative explanation to previous studies on arteriosclerosis prevention by quercetin.

  5. Quercetin Influences Quorum Sensing in Food Borne Bacteria: In-Vitro and In-Silico Evidence

    PubMed Central

    Gopu, Venkadesaperumal; Meena, Chetan Kumar; Shetty, Prathapkumar Halady

    2015-01-01

    Quorum sensing (QS) plays a vital role in regulating the virulence factor of many food borne pathogens, which causes severe public health risk. Therefore, interrupting the QS signaling pathway may be an attractive strategy to combat microbial infections. In the current study QS inhibitory activity of quercetin and its anti-biofilm property was assessed against food-borne pathogens using a bio-sensor strain. In addition in-silico techniques like molecular docking and molecular dynamics simulation studies were applied to screen the quercetin’s potentiality as QS inhibitor. Quercetin (80μg/ml) showed the significant reduction in QS-dependent phenotypes like violacein production, biofilm formation, exopolysaccharide (EPS) production, motility and alginate production in a concentration-dependent manner. Synergistic activity of conventional antibiotics with quercetin enhanced the susceptibility of all tested pathogens. Furthermore, Molecular docking analysis revealed that quercetin binds more rigidly with LasR receptor protein than the signaling compound with docking score of -9.17Kcal/mol. Molecular dynamics simulation predicted that QS inhibitory activity of quercetin occurs through the conformational changes between the receptor and quercetin complex. Above findings suggest that quercetin can act as a competitive inhibitor for signaling compound towards LasR receptor pathway and can serve as a novel QS-based antibacterial/anti-biofilm drug to manage food-borne pathogens. PMID:26248208

  6. Quercetin induces HepG2 cell apoptosis by inhibiting fatty acid biosynthesis

    PubMed Central

    ZHAO, PENG; MAO, JUN-MIN; ZHANG, SHU-YUN; ZHOU, ZE-QUAN; TAN, YANG; ZHANG, YU

    2014-01-01

    Quercetin can inhibit the growth of cancer cells with the ability to act as a ‘chemopreventer’. Its cancer-preventive effect has been attributed to various mechanisms, including the induction of cell-cycle arrest and/or apoptosis, as well as its antioxidant functions. Quercetin can also reduce adipogenesis. Previous studies have shown that quercetin has potent inhibitory effects on animal fatty acid synthase (FASN). In the present study, activity of quercetin was evaluated in human liver cancer HepG2 cells. Intracellular FASN activity was calculated by measuring the absorption of NADPH via a spectrophotometer. MTT assay was used to test the cell viability, immunoblot analysis was performed to detect FASN expression levels and the apoptotic effect was detected by Hoechst 33258 staining. In the present study, it was found that quercetin could induce apoptosis in human liver cancer HepG2 cells with overexpression of FASN. This apoptosis was accompanied by the reduction of intracellular FASN activity and could be rescued by 25 or 50 μM exogenous palmitic acids, the final product of FASN-catalyzed synthesis. These results suggested that the apoptosis induced by quercetin was via the inhibition of FASN. These findings suggested that quercetin may be useful for preventing human liver cancer. PMID:25009654

  7. Involvement of P-glycoprotein in regulating cellular levels of Ginkgo flavonols: quercetin, kaempferol, and isorhamnetin.

    PubMed

    Wang, Yi; Cao, Jiang; Zeng, Su

    2005-06-01

    Quercetin, kaempferol, and isorhamnetin were the most important flavonoid constituents in extracts from Ginkgo biloba leaves. Transport studies of Ginkgo flavonols were performed in Caco-2 cell mono-layers. Their apparent permeability in absorptive and secretion directions was determined, and quercetin, kaempferol and isorhamnetin displayed polarized transport, with the Papp,B-A being higher than the Papp,A-B (P<0.01 for quercetin, P<0.001 for kaempferol and isorhamnetin, Student's t-test). Bcap37/MDR1 cells, which were transfected with a P-glycoprotein (P-gp) gene construct, were treated with quercetin, kaempferol or isorhamnetin. The concentrations of Ginkgo flavonol in Bcap37/MDR1 cells were lower than those in parent cells (P<0.05 for quercetin, P<0.01 for isorhamnetin, Mann-Whitney U test). The concentrations of the flavonol in transfected cells increased when incubated with the P-gp inhibitor verapamil (P<0.05 for kaempferol, Mann-WhitneyU test). A colorometric assay for ATPase activity was applied to the detection of interaction of flavonol with P-gp. Quercetin and kaempferol inhibited the ATPase activity, and isorhamnetin stimulated the ATPase activity (P<0.05 for isorhamnetin, Mann Whitney U test). The results indicated that Ginkgo flavonols quercetin, kaempferol and isorhamnetin were substrates of P-gp. The P-gp type efflux pump might limit the bioavailability of Ginkgo flavonols.

  8. Quercetin induces HepG2 cell apoptosis by inhibiting fatty acid biosynthesis.

    PubMed

    Zhao, Peng; Mao, Jun-Min; Zhang, Shu-Yun; Zhou, Ze-Quan; Tan, Yang; Zhang, Yu

    2014-08-01

    Quercetin can inhibit the growth of cancer cells with the ability to act as a 'chemopreventer'. Its cancer-preventive effect has been attributed to various mechanisms, including the induction of cell-cycle arrest and/or apoptosis, as well as its antioxidant functions. Quercetin can also reduce adipogenesis. Previous studies have shown that quercetin has potent inhibitory effects on animal fatty acid synthase (FASN). In the present study, activity of quercetin was evaluated in human liver cancer HepG2 cells. Intracellular FASN activity was calculated by measuring the absorption of NADPH via a spectrophotometer. MTT assay was used to test the cell viability, immunoblot analysis was performed to detect FASN expression levels and the apoptotic effect was detected by Hoechst 33258 staining. In the present study, it was found that quercetin could induce apoptosis in human liver cancer HepG2 cells with overexpression of FASN. This apoptosis was accompanied by the reduction of intracellular FASN activity and could be rescued by 25 or 50 μM exogenous palmitic acids, the final product of FASN-catalyzed synthesis. These results suggested that the apoptosis induced by quercetin was via the inhibition of FASN. These findings suggested that quercetin may be useful for preventing human liver cancer.

  9. Protective Effects of Quercetin against Dimethoate-Induced Cytotoxicity and Genotoxicity in Allium sativum Test.

    PubMed

    Ahmad, Waseem; Shaikh, Sibhghatulla; Nazam, Nazia; Lone, Mohammad Iqbal

    2014-01-01

    The present investigation was directed to study the possible protective activity of quercetin-a natural antioxidant against dimethoate-induced cyto- and genotoxicity in meristematic cells of Allium sativum. So far there is no report on the biological properties of quercetin in plant test systems. Chromosome breaks, multipolar anaphase, stick chromosome, and mitotic activity were undertaken in the current study as markers of cyto- and genotoxicity. Untreated control, quercetin controls (@ 5, 10 and 20 μg/mL for 3 h), and dimethoate exposed groups (@ 100 and 200 μg/mL for 3 h) were maintained. For protection against cytogenotoxicity, the root tip cells treated with dimethoate at 100 and 200 μg/mL for 3 h and quercetin treatment at 5, 10, and 20 μg/mL for 16 h, prior to dimethoate treatment, were undertaken. Quercetin was found to be neither cytotoxic nor genotoxic in Allium sativum control at these doses. A significant increase (P < 0.05) in chromosomal aberrations was noted in dimethoate treated Allium. Pretreatment of Allium sativum with quercetin significantly (P < 0.05) reduced dimethoate-induced genotoxicity and cytotoxicity in meristematic cells, and these effects were dose dependent. In conclusion, quercetin has a protective role in the abatement of dimethoate-induced cyto- and genotoxicity in the meristematic cells of Allium sativum that resides, at least in part, on its antioxidant effects.

  10. Improvement of quercetin protective effect against oxidative stress skin damages by incorporation in nanovesicles.

    PubMed

    Manca, Maria Letizia; Castangia, Ines; Caddeo, Carla; Pando, Daniel; Escribano, Elvira; Valenti, Donatella; Lampis, Sandrina; Zaru, Marco; Fadda, Anna Maria; Manconi, Maria

    2014-11-01

    Quercetin was incorporated in glycerosomes, new phospholipid-glycerol vesicles, and their protective effect against oxidative stress skin damages was extensively evaluated. In particular, the concentration-dependent effect of glycerol (from 10 to 50%) on vesicle suitability as cutaneous carriers of quercetin was carefully assessed. All vesicles were unilamellar and small in size (∼80-110 nm), as confirmed by cryo-TEM observation, with a drug incorporation efficiency ranging between 81 and 91%. SAXS studies, performed to investigate the bilayer arrangement, indicated a strong, dose-dependent interaction of glycerol with the polar portions of the phospholipid molecules, while quercetin did not significantly change the bilayer packing. In vitro studies on newborn pig skin underlined the concentration-dependent ability of glycerosomes to promote quercetin accumulation in the different layers, also confirmed by confocal microscopic observation of skin treated with fluorescent vesicles. Quercetin incorporated into liposomal and glycerosomal nanoformulations showed a strong ability to scavenge free radicals (DPPH test) and protect human keratinocytes in vitro against hydrogen peroxide damage. Moreover, quercetin-loaded vesicles were avidly taken up by keratinocytes in vitro. Overall, results indicate 40 and 50% glycerosomes as promising nanosystems for the improvement of cutaneous quercetin delivery and keratinocyte protection against oxidative stress damage.

  11. The effects of quercetin supplementation on cognitive functioning in a community sample: a randomized, placebo-controlled trial

    PubMed Central

    Canu, Will H.; Trout, Krystal L.; Nieman, David C.

    2012-01-01

    Background: The purpose of the present study was to examine the effects of quercetin supplementation on neurocognitive functioning. Methods: A large community sample (n = 941) completed a 12-week supplementation protocol, and participants were randomly assigned to receive 500 mg/day or 1000 mg/day quercetin, or placebo. Results: Results failed to indicate significant effects of quercetin on memory, psychomotor speed, reaction time, attention, or cognitive flexibility, despite large increases in plasma quercetin levels among the quercetin treatment groups. Discussion: Consistent with recent research, this study raises concerns regarding the generalizability of positive findings of in vitro and animal quercetin research, and provides evidence that quercetin may not have an ergogenic effect on neurocognitive functioning in humans. PMID:23983966

  12. Combined oral supplementation of fish oil and quercetin enhances neuroprotection in a chronic rotenone rat model: relevance to Parkinson's disease.

    PubMed

    Denny Joseph, K M; Muralidhara

    2015-05-01

    While the neuromodulatory efficacy of n-3 polyunsaturated fatty acids present in fish and fish oil (FO) are well known, some evidence in animal models suggests that chronic consumption of FO supplements may predispose the brain to lipid peroxidation. In view of this, recent approaches envisage the use of dietary antioxidants as adjuncts with FO to obtain a better clinical outcome in neurological disorders. In furtherance of our previous work, in the present study, we examined whether enrichment of FO with quercetin (Q) would enhance the neuroprotective outcome employing a chronic rotenone (ROT) model of neurotoxicity in rats. Growing male rats supplemented either with FO (2 mL/kg bw) or Q (25 mg/kg bw) or FO + Q for 28 days were administered with ROT (0.5 mg/kg bw, 21 days). Monitoring the behavioral phenotype by a battery of tests, terminally, oxidative response in brain regions, mitochondrial dysfunctions and striatal dopamine levels were determined. While both FO and Q offered varying degree of protection, the FO + Q combination offered a higher degree of protection. FO + Q combination significantly attenuated behavioral impairments, restored the ROT-induced oxidative markers, depleted dopamine levels in striatum and reduced mitochondrial dysfunction. These salient findings besides corroborating with our previous data suggest that enrichment of FO with Q indeed offers a higher degree of neuroprotection under chronic exposure to a model neurotoxin such as ROT. Hence, we propose that a combination of FO with known antioxidants such as quercetin is more likely to provide a superior therapeutic advantage in the prevention/treatment of oxidative stress-mediated neurodegenerative conditions such as Parkinson's disease.

  13. Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer

    PubMed Central

    Tan, Bee-Jen; Liu, Yuanjie; Chang, Kai-Lun; Lim, Bennie KW; Chiu, Gigi NC

    2012-01-01

    Background Realizing the therapeutic benefits of quercetin is mostly hampered by its low water solubility and poor absorption. In light of the advantages of nanovehicles in the delivery of flavanoids, we aimed to deliver quercetin perorally with nanomicelles made from the diblock copolymer, polyethylene glycol (PEG)-derivatized phosphatidylethanolamine (PE). Methods Quercetin-loaded nanomicelles were prepared by using the film casting method, and were evaluated in terms of drug incorporation efficiency, micelle size, interaction with Caco-2 cells, and anticancer activity in the A549 lung cancer cell line and murine xenograft model. Results The incorporation efficiency into the nanomicelles was ≥88.9% when the content of quercetin was up to 4% w/w, with sizes of 15.4–18.5 nm and polydispersity indices of <0.250. Solubilization of quercetin by the nanomicelles increased its aqueous concentration by 110-fold. The quercetin nanomicelles were stable when tested in simulated gastric (pH 1.2) and intestinal (pH 7.4) fluids, and were non-toxic to the Caco-2 cells as reflected by reversible reduction in transepithelial electrical resistance and ≤25% lactose dehydrogenase release. The anticancer activity of quercetin could be significantly improved over the free drug through the nanomicellar formulation when tested using the A549 cancer cell line and murine xenograft model. The nanomicellar quercetin formulation was well tolerated by the tumor-bearing animals, with no significant weight loss observed at the end of the 10-week study period. Conclusion A stable PEG-PE nanomicellar formulation of quercetin was developed with enhanced peroral anticancer activity and no apparent toxicity to the intestinal epithelium. PMID:22334787

  14. Quercetin inhibits intestinal iron absorption and ferroportin transporter expression in vivo and in vitro.

    PubMed

    Lesjak, Marija; Hoque, Rukshana; Balesaria, Sara; Skinner, Vernon; Debnam, Edward S; Srai, Surjit K S; Sharp, Paul A

    2014-01-01

    Balancing systemic iron levels within narrow limits is critical for maintaining human health. There are no known pathways to eliminate excess iron from the body and therefore iron homeostasis is maintained by modifying dietary absorption so that it matches daily obligatory losses. Several dietary factors can modify iron absorption. Polyphenols are plentiful in human diet and many compounds, including quercetin--the most abundant dietary polyphenol--are potent iron chelators. The aim of this study was to investigate the acute and longer-term effects of quercetin on intestinal iron metabolism. Acute exposure of rat duodenal mucosa to quercetin increased apical iron uptake but decreased subsequent basolateral iron efflux into the circulation. Quercetin binds iron between its 3-hydroxyl and 4-carbonyl groups and methylation of the 3-hydroxyl group negated both the increase in apical uptake and the inhibition of basolateral iron release, suggesting that the acute effects of quercetin on iron transport were due to iron chelation. In longer-term studies, rats were administered quercetin by a single gavage and iron transporter expression measured 18 h later. Duodenal FPN expression was decreased in quercetin-treated rats. This effect was recapitulated in Caco-2 cells exposed to quercetin for 18 h. Reporter assays in Caco-2 cells indicated that repression of FPN by quercetin was not a transcriptional event but might be mediated by miRNA interaction with the FPN 3'UTR. Our study highlights a novel mechanism for the regulation of iron bioavailability by dietary polyphenols. Potentially, diets rich in polyphenols might be beneficial for patients groups at risk of iron loading by limiting the rate of intestinal iron absorption.

  15. [Protective effect of quercetin against immunological liver injury through activating Nrf2/ARE signaling pathway].

    PubMed

    Wei, Caibing; Zhou, Liandi; Zhang, Yuzhen; Zhang, Jiawei; Zhang, Qihui; Tao, Kun

    2017-03-01

    Objective To observe the protective effect of quercetin against immunological liver injury induced by triptolide, and investigate the involvement of Nrf2/ARE signaling pathway in the protection. Methods Fifty C57BL/6J mice were randomly divided into five groups: control group, model group, (20, 50, 80) mg/kg quercetin pre-treatment groups. Each group included 10 mice. The mice were treated with different doses of quercetin once daily for consecutive 10 days. At the end of the experiment, triptolide (500 μg/kg) was given intragastrically to induce immunological liver injury in all groups except for the control group. Twenty-two hours later, the levels of serum ALT , AST were detected. The contents of GSH, SOD and MDA in liver tissue homogenates were measured through commercial kits. HE staining was performed to observe pathologic changes of the liver. The mRNA expressions of heme oxygenase-1 (HO-1), NQO1, glutamate-cysteine ligase catalytic subunit (GCLC) was tested by quantitative real-time PCR, and the protein expression of Nrf2 was detected by Western blotting. Results Compared with the model group, the serum activities of ALT and AST as well as MDA content remarkably decreased by the administration of quercetin (80 mg/kg), while GSH, SOD contents were elevated in liver tissues; pathologic changes of the liver was ameliorated evidently by quercetin; Nrf2 protein expression in the nucleus as well as mRNA expressions of HO-1, NQO1, GCLC increased. Moreover, the protective effect of 50 mg/kg quercetin was not as good as that of 80 mg/kg quercetin, and 20 mg/kg quercetin did little against the immunological liver injury. Conclusion High-dose quercetin can inhibit immunological liver injury induced by triptolide, and the mechanism may be associated with the activation of Nrf2/ARE signaling pathway.

  16. Metabonomic analysis of quercetin against the toxicity of acrylamide in rat urine.

    PubMed

    Bao, Wei; Cao, Can; Li, Siqi; Bo, Lu; Zhang, Meiyan; Zhao, Xiujuan; Liu, Ying; Sun, Changhao

    2017-03-22

    This research aims to determine whether quercetin has protective effects against the toxicity of acrylamide (AA) using metabonomic technology. Randomly, the rats were assigned into a control group, AA treatment group, quercetin treatment group and quercetin plus AA treatment group. Quercetin and AA were administered to rats daily via gavage and drinking water for 16 weeks, respectively. To detect the metabonomic profiles of urine, ultra-performance liquid chromatography/mass spectrometry was used. A total of 15 metabolites, including biomarkers of AA exposure (GAMA, AAMA, and iso-AAMA) and quercetin exposure (quercetin and isorhamnetin), were identified. In comparison with the control group, the intensities of GAMA, AAMA, iso-AAMA, 1-salicylate glucuronide, vinylacetylglycine, PE(20:1(11Z)/14:0), 7-ketodeoxycholic acid, cysteic acid, p-cresol sulfate, and l-cysteine in the AA-treated group were statistically significantly increased (p < 0.01), and the intensities of 2-indolecarboxylic acid, 3-acetamidobutanal, and kynurenic acid in the AA-treated group were statistically significantly decreased (p < 0.01). The above-mentioned metabolites were significantly ameliorated in the quercetin (50 mg per kg bw) plus AA-treated group compared with the AA-treated group (p < 0.01 or p < 0.05). However, the intensities of these metabolites in the quercetin (50 mg per kg bw) plus AA-treated groups were still significantly different from those of the control group (p < 0.01 or p < 0.05). The above results suggest that quercetin has a partial protective effect on AA-induced toxicity. The protective effects include regulation of fatty acid metabolism and amino acid metabolism and enhancing the antioxidant defense system.

  17. Disruption of quercetin metabolism by fungicide affects energy production in honey bees (Apis mellifera).

    PubMed

    Mao, Wenfu; Schuler, Mary A; Berenbaum, May R

    2017-03-07

    Cytochrome P450 monooxygenases (P450) in the honey bee, Apis mellifera, detoxify phytochemicals in honey and pollen. The flavonol quercetin is found ubiquitously and abundantly in pollen and frequently at lower concentrations in honey. Worker jelly consumed during the first 3 d of larval development typically contains flavonols at very low levels, however. RNA-Seq analysis of gene expression in neonates reared for three days on diets with and without quercetin revealed that, in addition to up-regulating multiple detoxifying P450 genes, quercetin is a negative transcriptional regulator of mitochondrion-related nuclear genes and genes encoding subunits of complexes I, III, IV, and V in the oxidative phosphorylation pathway. Thus, a consequence of inefficient metabolism of this phytochemical may be compromised energy production. Several P450s metabolize quercetin in adult workers. Docking in silico of 121 pesticide contaminants of American hives into the active pocket of CYP9Q1, a broadly substrate-specific P450 with high quercetin-metabolizing activity, identified six triazole fungicides, all fungal P450 inhibitors, that dock in the catalytic site. In adults fed combinations of quercetin and the triazole myclobutanil, the expression of five of six mitochondrion-related nuclear genes was down-regulated. Midgut metabolism assays verified that adult bees consuming quercetin with myclobutanil metabolized less quercetin and produced less thoracic ATP, the energy source for flight muscles. Although fungicides lack acute toxicity, they may influence bee health by interfering with quercetin detoxification, thereby compromising mitochondrial regeneration and ATP production. Thus, agricultural use of triazole fungicides may put bees at risk of being unable to extract sufficient energy from their natural food.

  18. Role of Bax in quercetin-induced apoptosis in human prostate cancer cells

    PubMed Central

    Lee, Dae-Hee; Szczepanski, Miroslaw; Lee, Yong J.

    2012-01-01

    The aim of this study was to investigate the effect of quercetin, a flavonoid, on the apoptotic pathway in a human prostate cell line (LNCaP). We observed that treatment of cells for 24 h with quercetin induced cell death in a dose-dependent manner. A sustained inhibition of the major survival signal, Akt, occurred in quercetin-treated cells. Treatment of LNCaP cells with an apoptosis inducing concentration of quercetin (100 μM) resulted in a rapid decrease in the inhibitory Ser(473) phosphorylation of Akt leading to inhibition of its kinase activity. Quercetin treatment (100 μM) also caused a decrease in Ser(136) phosphorylation of Bad, which is a downstream target of Akt. Protein interaction assay revealed that during treatment with quercetin, Bcl-xL dissociated from Bax and then associated with Bad. Our results also show that quercetin decreases the Bcl-xL:Bax ratio and increases translocation and multimerization of Bax to the mitochondrial membrane. The translocation is accompanied by cytochrome c release, and procaspases-3, -8 and -9 cleavage and increased poly (ADP-ribose) polymerase (PARP) cleavage. Similar results were observed in human colon cancer HCT116Bax+/+ cell line, but not HCT116Bax−/− cell line. Interestingly, at similar concentrations (100 μM), quercetin treatment did not affect the viability or rate of apoptosis in normal human prostate epithelial cell line (PrEC) and rat prostate epithelial cell line (YPEN-1). Our results indicate that the apoptotic processes caused by quercetin are mediated by the dissociation of Bax from Bcl-xL and the activation of caspase families in human prostate cancer cells. PMID:18455702

  19. Genistein modulates the expression of NF-κB and MAPK (p-38 and ERK1/2), thereby attenuating D-Galactosamine induced fulminant hepatic failure in Wistar rats

    SciTech Connect

    Ganai, Ajaz A. Khan, Athar A. Malik, Zainul A. Farooqi, Humaira

    2015-03-01

    Genistein is an isoflavanoid abundantly found in soy. It has been found to play an important role in the prevention of various chronic diseases including cancer. In this study, we evaluated potential therapeutic properties of Genistein against D-Galactosamine (D-GalN) induced inflammation and hepatotoxicity in male Wistar rats. Fulminant hepatic failure (FHF) was induced in rats by intraperitoneal injection of D-GalN (700 mg/kgBW). Genistein (5 mg/kgBW/day) was given as pre-treatment for 30 days via intra-gastric route followed by D-GalN (700 mg/kgBW) injection. The hepatoprotective and curative effects of Genistein were evident from a significant decrease in the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels as well as prevention of histological damage by pre-treatment of Genistein. Genistein pre-treatment significantly inhibited the increased protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), thereby reducing nitric oxide (NO) and prostaglandin-E2 (PGE) levels, respectively. In addition Genistein significantly suppressed the production of D-GalN-induced proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β. These inhibitory effects were associated with the suppression of nuclear factor-kappa B (NF-ĸB) activation, IKKα/β and Mitogen activated protein kinase (MAPK) phosphorylation by Genistein in D-GalN-treated animals. In conclusion, our results suggest that Genistein may serve as a potential supplement in the prevention of hepatic and inflammatory diseases. Furthermore Genistein is able to maintain the redox potential and strengthens the antioxidant defense system of a cell. - Highlights: • First study to evaluate hepatoprotective effect of Genistein against D-GalN • Genistein prevents oxidative damage induced by D-GalN. • Genistein blunts iNOS, COX-2, NF-ĸB, IKKα/β and MAPK expression. • Genistein prevents D-GalN induced apoptosis and

  20. Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis

    PubMed Central

    Schon, Hans-Theo; Bartneck, Matthias; Borkham-Kamphorst, Erawan; Nattermann, Jacob; Lammers, Twan; Tacke, Frank; Weiskirchen, Ralf

    2016-01-01

    The activation and transdifferentiation of hepatic stellate cells (HSCs) into contractile, matrix-producing myofibroblasts (MFBs) are central events in hepatic fibrogenesis. These processes are driven by autocrine- and paracrine-acting soluble factors (i.e., cytokines and chemokines). Proof-of-concept studies of the last decades have shown that both the deactivation and removal of hepatic MFBs as well as antagonizing profibrogenic factors are in principle suitable to attenuate ongoing hepatic fibrosis. Although several drugs show potent antifibrotic activities in experimental models of hepatic fibrosis, there is presently no effective pharmaceutical intervention specifically approved for the treatment of liver fibrosis. Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells. Therefore, targeted delivery systems that bind specifically to receptors solely expressed on activated HSCs or transdifferentiated MFBs and delivery systems that can improve drug distribution to the liver in general are urgently needed. In this review, we summarize current strategies for targeted delivery of drugs to the liver and in particular to pro-fibrogenic liver cells. The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed. Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs. PMID:26941644

  1. Tracer attenuation in groundwater

    NASA Astrophysics Data System (ADS)

    Cvetkovic, Vladimir

    2011-12-01

    The self-purifying capacity of aquifers strongly depends on the attenuation of waterborne contaminants, i.e., irreversible loss of contaminant mass on a given scale as a result of coupled transport and transformation processes. A general formulation of tracer attenuation in groundwater is presented. Basic sensitivities of attenuation to macrodispersion and retention are illustrated for a few typical retention mechanisms. Tracer recovery is suggested as an experimental proxy for attenuation. Unique experimental data of tracer recovery in crystalline rock compare favorably with the theoretical model that is based on diffusion-controlled retention. Non-Fickian hydrodynamic transport has potentially a large impact on field-scale attenuation of dissolved contaminants.

  2. Hydrolytic cleavage of DNA by quercetin zinc(II) complex.

    PubMed

    Jun, Tan; Bochu, Wang; Liancai, Zhu

    2007-03-01

    Quercetin zinc(II) complex was investigated focusing on its hydrolytic activity toward DNA. The complex successfully promotes the cleavage of plasmid DNA, producing single and double DNA strand breaks. The amount of conversion of supercoiled form (SC) of plasmid to the nicked circular form (NC) depends on the concentration of the complex as well as the duration of incubation of the complex with DNA. The rate of conversion of SC to NC is 1.68x10(-4) s(-1) at pH 7.2 in the presence of 100 microM of the complex. The hydrolytic cleavage of DNA by the complex is supported by the evidence from free radical quenching, thiobarbituric acid-reactive substances (TBARS) assay, and T4 ligase ligation.

  3. Hydrolytic cleavage of DNA by quercetin manganese(II) complexes.

    PubMed

    Jun, Tan; Bochu, Wang; Liancai, Zhu

    2007-04-01

    Quercetin manganese(II) complexes were investigated focusing on its DNA hydrolytic activity. The complexes successfully promote the cleavage of plasmid DNA, producing single and double DNA strand breaks. The amount of conversion of supercoiled form (SC) of plasmid DNA to the nicked circular form (NC) depends on the concentration of the complex as well as the duration of incubation of the complexes with DNA. The maximum rate of conversion of the supercoiled form to the nicked circular form at pH 7.2 in the presence of 100 microM of the complexes is found to be 1.32 x 10(-4) s(-1). The hydrolytic cleavage of DNA by the complexes was supported by the evidence from free radical quenching, thiobarbituric acid-reactive substances (TBARS) assay and T4 ligase ligation.

  4. Neuroprotective activities of curcumin and quercetin with potential relevance to mitochondrial dysfunction induced by oxaliplatin.

    PubMed

    Waseem, Mohammad; Parvez, Suhel

    2016-03-01

    Peripheral neurotoxicity is one of the serious dose-limiting side effects of oxaliplatin (Oxa) when used in the treatment of malignant conditions. It is documented that it elicits major side effects specifically neurotoxicity due to oxidative stress forcing the patients to limit its clinical use in long-term treatment. Oxidative stress has been proven to be involved in Oxa-induced toxicity including neurotoxicity. The mitochondria have recently emerged as targets for anticancer drugs in various kinds of toxicity including neurotoxicity that can lead to neoplastic disease. However, there is paucity of literature involving the role of the mitochondria in mediating Oxa-induced neurotoxicity and its underlying mechanism is still debatable. The purpose of this study was to investigate the dose-dependent damage caused by Oxa on isolated brain mitochondria under in vitro conditions. The study was also designed to investigate the neuroprotective effects of nutraceuticals, curcumin (CMN), and quercetin (QR) on Oxa-induced mitochondrial oxidative stress and respiratory chain complexes in the brain of rats. Oxidative stress biomarkers, levels of nonenzymatic antioxidants, activities of enzymatic antioxidants, and mitochondrial complexes were evaluated against the neurotoxicity induced by Oxa. Pretreatment with CMN and QR significantly replenished the mitochondrial lipid peroxidation levels and protein carbonyl content induced by Oxa. CMN and QR ameliorated altered nonenzymatic and enzymatic antioxidants and complex enzymes of mitochondria. We conclude that CMN and QR, by attenuating oxidative stress as evident by mitochondrial dysfunction, hold promise as agents that can potentially reduce Oxa-induced adverse effects in the brain.

  5. Quercetin and Quercetin-Rich Red Onion Extract Alter Pgc-1α Promoter Methylation and Splice Variant Expression

    PubMed Central

    Devarshi, Prasad P.; Jones, Aarin D.; Taylor, Erin M.; Stefanska, Barbara

    2017-01-01

    Pgc-1α and its various isoforms may play a role in determining skeletal muscle mitochondrial adaptations in response to diet. 8 wks of dietary supplementation with the flavonoid quercetin (Q) or red onion extract (ROE) in a high fat diet (HFD) ameliorates HFD-induced obesity and insulin resistance in C57BL/J mice while upregulating Pgc-1α and increasing skeletal muscle mitochondrial number and function. Here, mice were fed a low fat (LF), high fat (HF), high fat plus quercetin (HF + Q), or high fat plus red onion extract (HF + RO) diet for 9 wks and skeletal muscle Pgc-1α isoform expression and DNA methylation were determined. Quantification of various Pgc-1α isoforms, including isoforms Pgc-1α-a, Pgc-1α-b, Pgc-1α-c, Pgc-1α4, total NT-Pgc-1α, and FL-Pgc-1α, showed that only total NT-Pgc-1α expression was increased in LF, HF + Q, and HF + RO compared to HF. Furthermore, Q supplementation decreased Pgc-1α-a expression compared to LF and HF, and ROE decreased Pgc-1α-a expression compared to LF. FL-Pgc-1α was decreased in HF + Q and HF + RO compared to LF and HF. HF exhibited hypermethylation at the −260 nucleotide (nt) in the Pgc-1α promoter. Q and ROE prevented HFD-induced hypermethylation. −260 nt methylation levels were associated with NT-Pgc-1α expression only. Pgc-1α isoform expression may be epigenetically regulated by Q and ROE through DNA methylation. PMID:28191013

  6. Interactions between quercetin and warfarin for albumin binding: A new eye on food/drug interference.

    PubMed

    Di Bari, Lorenzo; Ripoli, Silvia; Pradhan, Sanghamitra; Salvadori, Piero

    2010-06-01

    The interaction between quercetin, a popular antioxidant flavonoid, and human serum albumin (HSA) is investigated and characterized by means of induced circular dichroism and saturation transfer difference NMR. These techiques demonstrate the reversible binding of quercetin to the carrier protein, which is responsible for its dissolution in aqueous medium. Competition experiments with two classical probes for HSA binding sites, namely Ibuprofen and Warfarin (a common anticoagulant coumarin), demonstrate that quercetin has a primary binding site located in the subdomain IIA, where coumarins are hosted. The affinity for this site is large and we found that quercetin may effectively displace warfarin from HSA. This may have relevant consequences in rationalizing the interferences of common dietary compounds and food supplements to anticoagulant treatments.

  7. Quercetin does not alter the oral bioavailability of Atorvastatin in rats.

    PubMed

    Koritala, Rekha; Challa, Siva Reddy; Ragam, Satheesh Kumar; Geddam, Lal Babu; Venkatesh Reddy Challa, Venkatesh Reddy; Devi, Renuka; Sattenapalli, Srinu; Babu, Narendra

    2015-09-01

    The study was undertaken to evaluate the effect of Quercetin on the pharmacokinetics of Atorvastatin Calcium. In-vivo Pharmacokinetic studies were performed on rats in a single dose study and multiple dose study. Rats were treated with Quercetin (10 mg/kg) and Atorvastatin Calcium (20 mg/kg) orally and blood samples were collected at (0) pretreatment and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24 hours post treatment. Plasma concentrations of Atorvastatin were estimated by HPLC method. Quercetin treatment did not significantly alter the pharmacokinetic parameters of atorvastatin like AUC(0-24), AUC(0-α) , T(max), C(max) and T(½) in both single dose and multiple dose studies of Atorvastatin Calcium. Quercetin does not alter the oral bioavailability of Atorvastatin Calcium in rats.

  8. Time-course regulation of quercetin on cell survival/proliferation pathways in human hepatoma cells.

    PubMed

    Granado-Serrano, Ana Belén; Angeles Martín, María; Bravo, Laura; Goya, Luis; Ramos, Sonia

    2008-04-01

    Quercetin, a dietary flavonoid, has been shown to possess anticarcinogenic properties, but the precise molecular mechanisms of action are not thoroughly elucidated. This study was aimed at investigating the time-course regulation effect of quercetin on survival/proliferation pathways in a human hepatoma cell line (HepG2). Quercetin induced a significant time-dependent inactivation of the major survival signaling proteins, i. e., phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (AKT), extracellular regulated kinase (ERK), protein kinase C-alpha (PKC-alpha), in concert with a time-dependent activation of key death-related signals: c-jun amino-terminal kinase (JNK) and PKC-delta. These data suggest that quercetin exerts a tight regulation of survival/proliferation pathways that requires the integration of different signals and persists over time, being the balance of these regulatory signals what determines the fate of HepG2 cells.

  9. Ameliorative effect of quercetin against arsenic-induced sperm DNA damage and daily sperm production in adult male rats.

    PubMed

    Jahan, Sarwat; Rehman, Saima; Ullah, Hizb; Munawar, Asma; Ain, Qurat Ul; Iqbal, Tariq

    2016-01-01

    In this study, the protective effect of quercetin was evaluated against arsenic induced reproductive ailments in male rats. For this purpose, male rats (n = 5/group) weighing 180-250 g were used. First group served as control, second group received arsenic (50 ppm) in drinking water. Third group was treated with quercetin (50 mg/kg) alone, while fourth group received arsenic + quercetin. All treatments were carried out for 49 days. After treatment, animals were killed by decapitation; testis and epididymis were dissected out. Right epididymis was minced immediately for comet assay, while left epididymis was processed for histology. Similarly, right testis was homogenized for estimation of daily sperm production (DSP) and detection of metal concentration. The results of our research revealed that arsenic treatment did not cause any significant change in body weight and testicular volume. Quercetin treatment significantly prevented tissue deposition of arsenic within the testis. Arsenic treatment caused a significant reduction in DSP, however, in the arsenic + quercetin-treated group and quercetin alone-treated group, DSP was significantly high as compared to the arsenic-treated group. Histological study of epididymis showed empty lumen in arsenic-treated group while in arsenic + quercetin-treated group and quercetin alone-treated group, lumen were filled with sperm and were comparable to control. Sperm DNA damage, induced by arsenic, was significantly reversed toward control levels by supplementation of quercetin. These results suggest that quercetin not only prevents deposition of arsenic in tissues, but can also protect the sperm DNA damage.

  10. Effects of dietary quercetin on performance and cytochrome P450 expression of the cotton bollworm, Helicoverpa armigera.

    PubMed

    Liu, D; Yuan, Y; Li, M; Qiu, X

    2015-12-01

    Quercetin is ubiquitous in terrestrial plants. The cotton bollworm Helicoverpa armigera as a highly polyphagous insect has caused severe crop losses. Until now, interactions between this pest and quercetin are poorly understood at the biochemical and molecular levels. In this study, we investigated the in vivo effects of quercetin on performance of cotton bollworm and on cytochrome P450 (P450) expression. Deleterious effects of quercetin on the performance of the cotton bollworm, including growth, survival, pupation and adult emergence were observed after oral administration of 3 and 10 mg g(-1) quercetin to larvae since the third instar, whereas no significant toxic effect was found at 0.1 mg g(-1) quercetin treatment. Piperonyl butoxide treatment enhanced the toxicity of quercetin. In vitro metabolism studies showed that quercetin was rapidly transformed by gut enzymes of fifth instar larvae of the cotton bollworm. qRT-PCR results revealed that the effect of quercetin on P450 expression was tissue- and dose-specific. Quercetin regulated P450 expression in a mild manner, and it could serve as P450 inducer (CYP337B1, CYP6B6) or repressor (CYP337B1, CYP6B7, CYP6B27, CYP9A14, CYP6AE11, and CYP4M7). These findings are important for advancing our understanding of the biochemical and molecular response of insects to plant toxins and have implications for a smart pest control.

  11. Quercetin-induced downregulation of phospholipase D1 inhibits proliferation and invasion in U87 glioma cells

    SciTech Connect

    Park, Mi Hee; Min, Do Sik

    2011-09-09

    Highlights: {yields} Quercetin, a bioactive flavonoid, suppresses expression and enzymatic activity of phospholipase D1. {yields} Quercetin abolishes NFkB-induced phospholipase D1 expression via inhibition of NFkB transactivation. {yields} Quercetin-induced suppression of phospholipase D1 inhibits invasion and proliferation of human glioma cells. -- Abstract: Phospholipase D (PLD) has been recognized as a regulator of cell proliferation and tumorigenesis, but little is known about the molecules regulating PLD expression. Thus, the identification of small molecules inhibiting PLD expression would be an important advance in PLD-mediated physiology. Quercetin, a ubiquitous bioactive flavonoid, is known to inhibit proliferation and induce apoptosis in a variety of cancer cells. In the present study, we examined the effect of quercetin on the expression of PLD in U87 glioma cells. Quercetin significantly suppressed the expression of PLD1 at the transcriptional level. Moreover, quercetin abolished the protein expression of PLD1 in a time and dose-dependent manner, as well as inhibited PLD activity. Quercetin suppressed NF{kappa}B-induced PLD1 expression via inhibition of NFkB transactivation. Furthermore, quercetin inhibited activation and invasion of metalloproteinase-2 (MMP-2), a key modulator of glioma cell invasion, induced by phosphatidic acid (PA), a product of PLD activity. Taken together these data demonstrate that quercetin abolishes PLD1 expression and subsequently inhibits invasion and proliferation of glioma cells.

  12. Hepatic regenerating nodules in hereditary tyrosinemia

    SciTech Connect

    Day, D.L.; Letourneau, J.G.; Allan, B.T.; Sharp, H.L.; Ascher, N.; Dehner, L.P.; Thompson, W.M.

    1987-08-01

    Hereditary tyrosinemia is an autosomal recessive, enzymatic disorder that results in micro- and macronodular cirrhosis in early childhood. Hepatocellular carcinoma occurs in approximately one-third of affected children. We evaluated the imaging studies performed in five children with this disorder. Pathologic examination of all five of the livers revealed cirrhosis and multiple regenerating nodules; hepatocellular carcinoma was present in two of the five livers. All five patients had high-attenuation or high- and low-attenuation foci within the liver. These high-attenuation foci were not apparent as focal lesions in three of four hepatic sonograms or in one of two hepatic nuclear scans. Angiography showed tumor vascularity in one patient with a focal hepatocellular carcinoma, but was indeterminate in a second patient with severe cirrhosis and multifocal hepatocellular carcinoma. Children with cirrhosis due to tyrosinemia may develop regenerating nodules that appear as high-attenuation hepatic foci on CT scans. It is difficult to differentiate regenerating nodules from multifocal hepatocellular carcinoma in these patients.

  13. Quercetin-Loaded Solid Lipid Nanoparticle Dispersion with Improved Physicochemical Properties and Cellular Uptake.

    PubMed

    Vijayakumar, Ajay; Baskaran, Rengarajan; Jang, Young Soo; Oh, Seung Hyun; Yoo, Bong Kyu

    2017-04-01

    The objective of this study was to formulate and characterize properties of solid lipid nanoparticle (SLN) dispersion containing quercetin. SLN was prepared by ultrasonication method using tripalmitin and lecithin as lipid core and then the surface was coated with chitosan. Entrapment efficiency was greater than 99%, and mean particle size of SLN was 110.7 ± 1.97 nm with significant increase in the coated SLN (c-SLN). Zeta potential was proportionally increased and reached plateau at 5% of chitosan coating with respect to tripalmitin. Differential scanning calorimetry showed disappearance of endothermic peak of quercetin in SLNs, indicating conversion of crystalline state to amorphous state. FTIR study of SLNs showed no change in the spectrum of quercetin, which indicates that the lipid and chitosan were not incompatible with quercetin. When coating amount was greater than 2.5% of tripalmitin, particle size and zeta potential were very stable even at 40°C up to 90 days. All SLN dispersions showed significantly faster release profile compared to pure quercetin powder. At pH 7.0, the release rate was increased in proportion to the coating amount. Interestingly, at pH 3.0, chitosan coating of 5.0% or greater decreased the rate. Cellular uptake of quercetin was performed using Caco-2 cells and showed that all SLN dispersions were significantly better than quercetin dispersed in distilled water. However, cellular uptake of quercetin from c-SLN was significantly lower than that from uncoated SLN.

  14. Quercetin as an Emerging Anti-Melanoma Agent: A Four-Focus Area Therapeutic Development Strategy

    PubMed Central

    Harris, Zoey; Donovan, Micah G.; Branco, Gisele Morais; Limesand, Kirsten H.; Burd, Randy

    2016-01-01

    Replacing current refractory treatments for melanoma with new prevention and therapeutic approaches is crucial in order to successfully treat this aggressive cancer form. Melanoma develops from neural crest cells, which express tyrosinase – a key enzyme in the pigmentation pathway. The tyrosinase enzyme is highly active in melanoma cells and metabolizes polyphenolic compounds; tyrosinase expression thus makes feasible a target for polyphenol-based therapies. For example, quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a highly ubiquitous and well-classified dietary polyphenol found in various fruits, vegetables, and other plant products including onions, broccoli, kale, oranges, blueberries, apples, and tea. Quercetin has demonstrated antiproliferative and proapoptotic activity in various cancer cell types. Quercetin is readily metabolized by tyrosinase into various compounds that promote anticancer activity; additionally, given that tyrosinase expression increases during tumorigenesis, and its activity is associated with pigmentation changes in both early- and late-stage melanocytic lesions, it suggests that quercetin can be used to target melanoma. In this review, we explore the potential of quercetin as an anti-melanoma agent utilizing and extrapolating on evidence from previous in vitro studies in various human malignant cell lines and propose a “four-focus area strategy” to develop quercetin as a targeted anti-melanoma compound for use as either a preventative or therapeutic agent. The four areas of focus include utilizing quercetin to (i) modulate cellular bioreduction potential and associated signaling cascades, (ii) affect transcription of relevant genes, (iii) regulate epigenetic processes, and (iv) develop effective combination therapies and delivery modalities/protocols. In general, quercetin could be used to exploit tyrosinase activity to prevent, and/or treat, melanoma with minimal additional side effects. PMID:27843913

  15. Long-Term Quercetin Dietary Enrichment Partially Protects Dystrophic Skeletal Muscle

    PubMed Central

    Spaulding, Hannah R.; Ballmann, Christopher G.; Quindry, John C.; Selsby, Joshua T.

    2016-01-01

    Duchenne muscular dystrophy (DMD) results from a genetic lesion in the dystrophin gene and leads to progressive muscle damage. PGC-1α pathway activation improves muscle function and decreases histopathological injury. We hypothesized that mild disease found in the limb muscles of mdx mice may be responsive to quercetin-mediated protection of dystrophic muscle via PGC-1α pathway activation. To test this hypothesis muscle function was measured in the soleus and EDL from 14 month old C57, mdx, and mdx mice treated with quercetin (mdxQ; 0.2% dietary enrichment) for 12 months. Quercetin reversed 50% of disease-related losses in specific tension and partially preserved fatigue resistance in the soleus. Specific tension and resistance to contraction-induced injury in the EDL were not protected by quercetin. Given some functional gain in the soleus it was probed with histological and biochemical approaches, however, in dystrophic muscle histopathological outcomes were not improved by quercetin and suppressed PGC-1α pathway activation was not increased. Similar to results in the diaphragm from these mice, these data suggest that the benefits conferred to dystrophic muscle following 12 months of quercetin enrichment were underwhelming. Spontaneous activity at the end of the treatment period was greater in mdxQ compared to mdx indicating that quercetin fed mice were more active in addition to engaging in more vigorous activity. Hence, modest preservation of muscle function (specific tension) and elevated spontaneous physical activity largely in the absence of tissue damage in mdxQ suggests dietary quercetin may mediate protection. PMID:27977770

  16. Anticancer effect and mechanism of polymer micelle-encapsulated quercetin on ovarian cancer

    NASA Astrophysics Data System (ADS)

    Gao, Xiang; Wang, Bilan; Wei, Xiawei; Men, Ke; Zheng, Fengjin; Zhou, Yingfeng; Zheng, Yu; Gou, Maling; Huang, Meijuan; Guo, Gang; Huang, Ning; Qian, Zhiyong; Wei, Yuquan

    2012-10-01

    Encapsulation of hydrophobic agents in polymer micelles can improve the water solubility of cargos, contributing to develop novel drugs. Quercetin (QU) is a hydrophobic agent with potential anticancer activity. In this work, we encapsulated QU into biodegradable monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles and tried to provide proof-of-principle for treating ovarian cancer with this nano-formulation of quercetin. These QU loaded MPEG-PCL (QU/MPEG-PCL) micelles with drug loading of 6.9% had a mean particle size of 36 nm, rendering the complete dispersion of quercetin in water. QU inhibited the growth of A2780S ovarian cancer cells on a dose dependent manner in vitro. Intravenous administration of QU/MPEG-PCL micelles significantly suppressed the growth of established xenograft A2780S ovarian tumors through causing cancer cell apoptosis and inhibiting angiogenesis in vivo. Furthermore, the anticancer activity of quercetin on ovarian cancer cells was studied in vitro. Quercetin treatment induced the apoptosis of A2780S cells associated with activating caspase-3 and caspase-9. MCL-1 downregulation, Bcl-2 downregulation, Bax upregulation and mitochondrial transmembrane potential change were observed, suggesting that quercetin may induce apoptosis of A2780S cells through the mitochondrial apoptotic pathway. Otherwise, quercetin treatment decreased phosphorylated p44/42 mitogen-activated protein kinase and phosphorylated Akt, contributing to inhibition of A2780S cell proliferation. Our data suggested that QU/MPEG-PCL micelles were a novel nano-formulation of quercetin with a potential clinical application in ovarian cancer therapy.