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1.
Huan Jing Ke Xue ; 43(4): 2030-2038, 2022 Apr 08.
Artigo em Chinês | MEDLINE | ID: mdl-35393826

RESUMO

It has been verified that, as an emerging contaminant, microplastics are capable of adsorbing certain traditional contaminants like the heavy metal Cd. However, the majority of previous studies only focused on certain types of virgin microplastics, especially for PE and PS. In addition, this adsorption process might be affected by microplastics inevitably undergoing aging and consequent changes in the natural environment. Unfortunately, the relevant reports on aging effects were mainly about organic pollutants, rather than heavy metals. By far, there have been few comprehensive and mechanistic studies on the key aging effects on the Cd adsorption by various types of microplastics. In this study, five representative types of microplastics (i.e., PS, ABS, PP, PVC, and PET) were selected for aging by ultraviolet radiation, and the physicochemical properties of virgin and aged microplastics were thoroughly compared, including specific surface area, crystallinity, surface functional groups, and surface elements. Accordingly, the changes in adsorption isotherms of Cd by microplastics were discussed. The results showed that:① aging induced non-significant changes in specific surface area but a significant decrease in crystallinity. Surface functional groups also changed, including the emergence of a C=O functional group on PS and ABS, the decrease in C=C absorption peak intensity on ABS, and the increase in absorption peak intensities of C=O, C-O, and polar ester groups on PET. Regarding surface C content, C=C/C-C decreased, whereas C-O and O-C=O increased. The total O content and O/C significantly increased as well. ② The Langmuir model well-fitted the adsorption isotherms of Cd by virgin and aged microplastics. Aging significantly expanded the adsorption capacity of Cd by microplastics, as the order of saturated adsorption capacity before aging was ABS (0.2284 mg·g-1)>PVC (0.1360 mg·g-1)>PS (0.1286 mg·g-1)>PP (0.1005 mg·g-1)>PET (0.0462 mg·g-1) and then became PS (0.2768 mg·g-1)>ABS (0.2586 mg·g-1)>PVC (0.1776 mg·g-1)>PP (0.1721 mg·g-1)>PET (0.0951 mg·g-1) after aging. ③ Both crystallinity and surface functional groups played key roles in the adsorption of Cd by microplastics. As for virgin microplastics, crystallinity was negatively correlated with the saturated adsorption capacity of Cd, because the amorphous regions contributed most to Cd adsorption. Aging brought about the decrease in crystallinity and the increase in amorphous regions, which further promoted the oxidation reaction on microplastics. Consequently, oxygen-containing functional groups increased on the surface and eventually expanded the adsorption capacity of Cd by microplastics. Note that certain specific functional groups of various microplastics also had impacts on the adsorption process. These results provide valuable information about the environmental behaviors and interactions of microplastics and heavy metals in nature.


Assuntos
Metais Pesados , Poluentes Químicos da Água , Adsorção , Cádmio , Microplásticos , Plásticos/química , Cloreto de Polivinila , Raios Ultravioleta , Poluentes Químicos da Água/análise
2.
Biol Chem ; 402(9): 1073-1085, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34333885

RESUMO

The structural-functional organization of ammonia and glutamine metabolism in the liver acinus involves highly specialized hepatocyte subpopulations like glutamine synthetase (GS) expressing perivenous hepatocytes (scavenger cells). However, this cell population has not yet been characterized extensively regarding expression of other genes and potential subpopulations. This was investigated in the present study by proteome profiling of periportal GS-negative and perivenous GS-expressing hepatocytes from mouse and rat. Apart from established markers of GS+ hepatocytes such as glutamate/aspartate transporter II (GLT1) or ammonium transporter Rh type B (RhBG), we identified novel scavenger cell-specific proteins like basal transcription factor 3 (BTF3) and heat-shock protein 25 (HSP25). Interestingly, BTF3 and HSP25 were heterogeneously distributed among GS+ hepatocytes in mouse liver slices. Feeding experiments showed that RhBG expression was increased in livers from mice fed with high protein diet compared to standard chow. While spatial distributions of GS and carbamoylphosphate synthetase 1 (CPS1) were unaffected, periportal areas constituted by glutaminase 2 (GLS2)-positive hepatocytes were enlarged or reduced in response to high or low protein diet, respectively. The data suggest that the population of perivenous GS+ scavenger cells is heterogeneous and not uniform as previously suggested which may reflect a functional heterogeneity, possibly relevant for liver regeneration.


Assuntos
Fígado , Animais , Glutamato-Amônia Ligase , Regeneração Hepática , Masculino , Camundongos , Ratos
3.
Nutrients ; 13(3)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809593

RESUMO

The addition of plant oils such as soybean oil (S) to a diet rich in saturated fatty acids is discussed as a possible route to prevent or diminish the development of metabolic disease. Here, we assessed whether a butterfat-rich diet fortified with S affects the development of early non-alcoholic steatohepatitis (NASH) and glucose intolerance. Female C57BL/6J mice were fed a standard-control diet (C); a fat-, fructose-, and cholesterol-rich diet (FFC, 25E% butterfat, 50% (wt./wt.) fructose, 0.16% (wt./wt.) cholesterol); or FFC supplemented with S (FFC + S, 21E% butterfat + 4E% S) for 13 weeks. Indicators of liver damage, inflammation, intestinal barrier function, and glucose metabolism were measured. Lipopolysaccharide (LPS)-challenged J774A.1 cells were incubated with linolenic and linoleic acids (ratio 1:7.1, equivalent to S). The development of early NASH and glucose intolerance was significantly attenuated in FFC + S-fed mice compared to FFC-fed mice associated with lower hepatic toll-like receptor-4 mRNA expression, while markers of intestinal barrier function were significantly higher than in C-fed mice. Linolenic and linoleic acid significantly attenuated LPS-induced formation of reactive nitrogen species and interleukin-1 beta mRNA expression in J774A.1 cells. Our results indicate that fortifying butterfat with S may attenuate the development of NASH and glucose intolerance in mice.


Assuntos
Manteiga/efeitos adversos , Alimentos Fortificados , Intolerância à Glucose/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Óleo de Soja/uso terapêutico , Animais , Arginase/metabolismo , Western Blotting , Gorduras na Dieta/efeitos adversos , Endotoxinas/sangue , Ácidos Graxos não Esterificados/sangue , Feminino , Intolerância à Glucose/etiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR gama/sangue , Peroxidase/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Óleo de Soja/administração & dosagem , Fator de Necrose Tumoral alfa/sangue
4.
Redox Biol ; 41: 101879, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33550112

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is by now the most prevalent liver disease worldwide. The non-proteogenic amino acid l-citrulline (L-Cit) has been shown to protect mice from the development of NAFLD. Here, we aimed to further assess if L-Cit also attenuates the progression of a pre-existing diet-induced NAFLD and to determine molecular mechanisms involved. Female C57BL/6J mice were either fed a liquid fat-, fructose- and cholesterol-rich diet (FFC) or control diet (C) for 8 weeks to induce early stages of NASH followed by 5 more weeks with either FFC-feeding +/- 2.5 g L-Cit/kg bw or C-feeding. In addition, female C57BL/6J mice were either pair-fed a FFC +/- 2.5 g L-Cit/kg bw +/- 0.01 g/kg bw i.p. N(ω)-hydroxy-nor-l-arginine (NOHA) or C diet for 8 weeks. The protective effects of supplementing L-Cit on the progression of a pre-existing NAFLD were associated with an attenuation of 1) the increased translocation of bacterial endotoxin and 2) the loss of tight junction proteins as well as 3) arginase activity in small intestinal tissue, while no marked changes in intestinal microbiota composition were prevalent in small intestine. Treatment of mice with the arginase inhibitor NOHA abolished the protective effects of L-Cit on diet-induced NAFLD. Our results suggest that the protective effects of L-Cit on the development and progression of NAFLD are related to alterations of intestinal arginase activity and intestinal permeability.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Arginase , Citrulina , Dieta Hiperlipídica , Suplementos Nutricionais , Feminino , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Receptor 4 Toll-Like
5.
PLoS One ; 15(9): e0237946, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881925

RESUMO

Dietary fat is discussed to be critical in the development of non-alcoholic fatty liver disease. Here, we assess the effect of exchanging dietary fat source from butterfat to extra virgin olive oil on the progression of an already existing diet-induced non-alcoholic fatty liver disease in mice. Female C57BL/6J mice were fed a liquid butterfat-, fructose- and cholesterol-rich diet (BFC, 25E% from butterfat) or control diet (C, 12%E from soybean oil) for 13 weeks. In week 9, fat sources of some BFC- and C-fed mice were switched either to 25E% or 12E% olive oil (OFC and CO). Glucose and insulin tolerance tests were performed, and markers of liver damage and glucose metabolism were assessed. After 6 weeks of feeding, BFC-fed mice had developed marked signs of insulin resistance, which progressed to week 12 being not affected by the exchange of fat sources. Liver damage was similar between BFC- and OFC-fed mice. Markers of lipid metabolism and lipid peroxidation in liver and of insulin signaling in liver and muscle were also similarly altered in BFC- and OFC-fed mice. Taken together, our data suggest that exchanging butterfat with extra virgin olive oil has no effect on the progression of non-alcoholic fatty liver disease and glucose tolerance in mice.


Assuntos
Resistência à Insulina , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/patologia , Azeite de Oliva/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Progressão da Doença , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/veterinária , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Eur J Med Chem ; 203: 112618, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682200

RESUMO

On the basis and continuation of our previous studies on anti-tubulin and anti-gastric cancer agents, novel tertiary amide derivatives incorporating benzothiazole moiety were synthesized and the antiproliferative activity was studied in vitro. Preliminary structure activity relationships (SARs) were explored according to the in vitro antiproliferative activity results. Some of compounds could significantly inhibit the proliferation of three cancer cells (HCT-116, MGC-803 and PC-3 cells) and compound F10 exhibited excellent antiproliferative activity against HCT-116 cells (IC50 = 0.182 µM), MGC-803 cells (IC50 = 0.035 µM), PC-3 cells(IC50 = 2.11 µM) and SGC-7901 cells (IC50 = 0.049 µM). Compound F10 effectively inhibited tubulin polymerization (IC50 = 1.9 µM) and bound to colchicine binding site of tubulin. Molecular docking results suggested compound F10 could bind tightly into the colchicine binding site of ß-tubulin. Moreover, compound F10 could regulate the Hippo/YAP signaling pathway. Compound F10 activated Hippo signaling pathway from its very beginning MST1/2, as the result of Hippo cascade activation YAP were inhibited. And then it led to a decrease of c-Myc and Bcl-2 expression. Further molecular experiments showed that compound F10 arrested at G2/M phase, inhibited cell colony formatting and induced extrinsic and intrinsic apoptosis in MGC-803 and SGC-7901 cells. Collectively, compound F10 was the first to be reported as a new anticancer agent in vitro via inhibiting tubulin polymerization and activating the Hippo signaling pathway.


Assuntos
Amidas/química , Benzotiazóis/química , Benzotiazóis/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/patologia , Tubulina (Proteína)/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Via de Sinalização Hippo , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP
7.
Metabolism ; 109: 154283, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32497536

RESUMO

BACKGROUND: Absolute dietary fat intake but even more so fatty acid pattern is discussed to be critical in the development of non-alcoholic fatty liver disease (NAFLD). Here, we determined if switching a butterfat enriched diet to a rapeseed oil (RO) enriched diet affects progression of an existing NAFLD and glucose intolerance in mice. METHODS: For eight weeks, female C57Bl/6J mice were either fed a liquid control (C) or a butterfat-, fructose- and cholesterol-rich diet (BFC, 25E% butterfat) to induce early signs of steatohepatitis and glucose intolerance in mice. For additional five weeks mice received either BFC or C or a fat-, fructose- and cholesterol-rich and control diet, in which butterfat was replaced with RO (ROFC and CRO). Markers of glucose metabolism, liver damage and intestinal barrier were assessed. RESULTS: Exchanging butterfat with RO attenuated the progression of BFC diet-induced NAFLD and glucose intolerance. Beneficial effects of RO were associated with lower portal endotoxin levels and an attenuation of the induction of the toll-like receptor-4-dependent signaling cascades in liver. Peroxisome proliferator-activated receptor γ activity was induced in small intestine of ROFC-fed mice. CONCLUSION: Taken together, exchanging butterfat with RO attenuated the progression of diet-induced steatohepatitis and glucose intolerance in mice.


Assuntos
Manteiga/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Intolerância à Glucose/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Óleo de Brassica napus/uso terapêutico , Animais , Progressão da Doença , Endotoxinas/metabolismo , Feminino , Rim/química , Camundongos , Camundongos Endogâmicos C57BL , Receptor 4 Toll-Like
8.
Nutrients ; 12(4)2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32235497

RESUMO

Sodium butyrate (SoB) supplementation has been suggested to attenuate the development of non-alcoholic fatty liver disease (NAFLD). Here, we determined the therapeutic potential of SoB on NAFLD progression and molecular mechanism involved. Eight-week old C57BL/6J mice were pair-fed a fat-, fructose- and cholesterol-rich diet (FFC) or control diet (C). After 8 weeks, some mice received 0.6g SoB/kg bw in their respective diets (C+SoB; FFC+SoB) or were maintained on C or FFC for the next 5 weeks of feeding. Liver damage, markers of glucose metabolism, inflammation, intestinal barrier function and melatonin metabolism were determined. FFC-fed mice progressed from simple steatosis to early non-alcoholic steatohepatitis, along with significantly higher TNFα and IL-6 protein levels in the liver and impaired glucose tolerance. In FFC+SoB-fed mice, disease was limited to steatosis associated with protection against the induction of Tlr4 mRNA and iNOS protein levels in livers. SoB supplementation had no effect on FFC-induced loss of tight junction proteins in the small intestine but was associated with protection against alterations in melatonin synthesis and receptor expression in the small intestine and livers of FFC-fed animals. Our results suggest that the oral supplementation of SoB may attenuate the progression of simple steatosis to steatohepatitis.


Assuntos
Ácido Butírico/administração & dosagem , Ácido Butírico/farmacologia , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Colesterol na Dieta/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Glucose/metabolismo , Inflamação , Interleucina-6/metabolismo , Intestino Delgado/metabolismo , Fígado/metabolismo , Melatonina/metabolismo , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
Am J Physiol Gastrointest Liver Physiol ; 318(4): G736-G747, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32090603

RESUMO

Aging is a risk factor in the development of many diseases, including liver-related diseases. The two aims of the present study were 1) to determine how aging affects liver health in mice in the absence of any interventions and 2) if degenerations observed in relation to blood endotoxin levels are critical in aging-associated liver degeneration. Endotoxin levels and markers of liver damage, mitochondrial dysfunction, insulin resistance, and apoptosis as well as the Toll-like receptor 4 (Tlr-4) signaling cascade were studied in liver tissue and blood, respectively, of 3- and 24-mo-old male C57BL/6J mice. In a second set of experiments, 3- to 4-mo-old and 14-mo-old female lipopolysaccharide-binding protein (LBP)-/- mice and littermates fed standard chow, markers of liver damage, insulin resistance, and mitochondrial dysfunction were assessed. Plasma activity of aspartate aminotransferase and histological signs of hepatic inflammation and fibrosis were significantly higher in old C57BL/6J mice than in young animals. The number of neutrophils, CD8α-positive cells, and mRNA expression of markers of apoptosis were also significantly higher in livers of old C57BL/6J mice compared with young animals, being also associated with a significant induction of hepatic Tlr-4 and LBP expression as well as higher endotoxin levels in peripheral blood. Compared with age-matched littermates, LBP-/- mice display less signs of senescence in liver. Taken together, our data suggest that, despite being fed standard chow, old mice developed liver inflammation and beginning fibrosis and that bacterial endotoxin may play a critical role herein.NEW & NOTEWORTHY Old age in mice is associated with marked signs of liver degeneration, hepatic inflammation, and fibrosis. Aging-associated liver degeneration is associated with elevated bacterial endotoxin levels and an induction of lipopolysaccharide-binding protein (LBP) and Toll-like receptor 4-dependent signaling cascades in liver tissue. Furthermore, in old aged LBP-/- mice, markers of senescence seem to be lessened, supporting the hypothesis that bacterial endotoxin levels might be critical in aging-associated decline of liver.


Assuntos
Proteínas de Fase Aguda/metabolismo , Envelhecimento , Proteínas de Transporte/metabolismo , Endotoxinas/sangue , Cirrose Hepática/patologia , Fígado/patologia , Glicoproteínas de Membrana/metabolismo , Proteínas de Fase Aguda/genética , Animais , Apoptose , Biomarcadores , Proteínas de Transporte/genética , Feminino , Regulação da Expressão Gênica , Glucose/metabolismo , Inflamação/patologia , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Fígado/metabolismo , Malato Desidrogenase/genética , Malato Desidrogenase/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
10.
Eur J Nutr ; 59(2): 787-799, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30879098

RESUMO

PURPOSE: Results of some epidemiological studies suggest that moderate alcohol consumption may be associated with a decreased risk to develop NAFLD. Here, the effect of the consumption of moderate beer and diluted ethanol, respectively, on the development of NAFLD were assessed. METHODS: Female C57BL/6J mice were fed a control diet (C-D) or a diet rich in fructose, fat and cholesterol (FFC) enriched isocalorically and isoalcoholically with beer (FFC + B) or plain ethanol (FFC + E) (2.5 g ethanol/kg body weight/day) for 7 weeks. Liver damage was assessed by histology using NAFLD activity score. Markers of inflammation, insulin resistance and adiponectin signaling were measured at mRNA and protein levels. Using J774A.1 cells as a model of Kupffer cells, the effect of alcoholic beverages on adiponectin receptor 1 (Adipor1) was assessed. RESULTS: Hepatic triglyceride concentration, neutrophil granulocytes, iNOS protein concentrations and early signs of insulin resistance found in FFC-fed mice were significantly attenuated in FFC+ B-fed mice (P < 0.05 for all). These findings were associated with a super-induction of Adipor1 mRNA expression (+ ~ 18-fold compared to all other groups) and a decrease of markers of lipid peroxidation in liver tissue of FFC + B-fed mice when compared to FFC-fed animals. Similar differences were not found between FFC- and FFC+ E-fed mice. Expression of Adipor1 was also super-induced (7.5-fold) in J774A.1 cells treated with beer (equivalent to 2 mmol/L ethanol). CONCLUSIONS: These data suggest that moderate intake of fermented alcoholic beverages such as beer at least partially attenuates NAFLD development through mechanisms associated with hepatic AdipoR1 expression.


Assuntos
Adiponectina/metabolismo , Cerveja , Dieta/efeitos adversos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Dieta/métodos , Modelos Animais de Doenças , Etanol/administração & dosagem , Feminino , Alimentos Fermentados , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo
11.
PLoS One ; 14(10): e0223238, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31600256

RESUMO

There is growing awareness within the scientific community of the strong connection between the inflammation in the intestine and the pathogenesis of Parkinson's disease (PD). In previous studies we developed a PD animal model exposing pup rats to permethrin (PERM) pesticide. Here, we intended to explore whether in our animal model there were changes in gut permeability, fecal microbiota and hepatic injury. Moreover, we tested if the co-treatment with an electrolyzed reduced (ERW) was effective to protect against alterations induced by PERM. Rats (from postnatal day 6 to 21) were gavaged daily with PERM, PERM+ERW or vehicle and gut, liver and feces were analyzed in 2-months-old rats. Increased gut permeability, measured by FITC-dextran assay, was detected in PERM group compared to control and PERM+ERW groups. In duodenum and ileum, concentration of occludin was higher in control group than those measured in PERM group, whereas only in duodenum ZO-1 was higher in control than those measured in PERM and PERM+ERW groups. Number of inflammatory focis and neutrophils as well as iNOS protein levels were higher in livers of PERM-treated rats than in those of PERM+ERW and control rats. Fecal microbiota analysis revealed that Lachnospira was less abundant and Defluviitaleaceae more abundant in the PERM group, whereas the co-treatment with ERW was protective against PERM treatment since the abundances in Lachnospira and Defluviitaleaceae were similar to those in the control group. Higher abundances of butyrate- producing bacteria such as Blautia, U.m. of Lachnospiraceae family, U.m. of Ruminococcaceae family, Papillibacter, Roseburia, Intestinimonas, Shuttleworthia together with higher butyric acid levels were detected in PERM+ERW group compared to the other groups. In conclusion, the PD animal model showed increased intestinal permeability together with hepatic inflammation correlated with altered gut microbiota. The positive effects of ERW co-treatment observed in gut, liver and brain of rats were linked to changes on gut microbiota.


Assuntos
Inflamação/tratamento farmacológico , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Água/administração & dosagem , Animais , Eletrólise , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/complicações , Inflamação/microbiologia , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Intestinos/patologia , Fígado/efeitos dos fármacos , Fígado/lesões , Fígado/patologia , Doença de Parkinson/complicações , Doença de Parkinson/microbiologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Doença de Parkinson Secundária/microbiologia , Permeabilidade/efeitos dos fármacos , Permetrina/toxicidade , Ratos , Água/química
12.
Sci Rep ; 9(1): 6668, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31040374

RESUMO

The antidiabetic drug metformin has been proposed to affect non-alcoholic fatty liver disease (NAFLD) through its effects on intestinal microbiota and barrier function. However, so far most studies focused on long-term effects and more progressed disease stages. The aim of this study was to assess in two experimental settings, if the onset of NAFLD is associated with changes of intestinal microbiota and barrier function and to determine effects of metformin herein. C57Bl/6J mice were fed a liquid control diet (C) or fat-, fructose- and cholesterol-rich diet (FFC) for four days or six weeks ±300 mg/kg BW/day metformin (Met). Markers of liver health, intestinal barrier function and microbiota composition were assessed. Metformin treatment markedly attenuated FFC-induced NAFLD in both experiments with markers of inflammation and lipidperoxidation in livers of FFC + Met-fed mice being almost at the level of controls. Metformin treatment attenuated the loss of tight junction proteins in small intestine and the increase of bacterial endotoxin levels in portal plasma. Changes of intestinal microbiota found in FFC-fed mice were also significantly blunted in FFC + Met-fed mice. Taken together, protective effects of metformin on the onset of NAFLD are associated with changes of intestinal microbiota composition and lower translocation of bacterial endotoxins.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Mucosa Intestinal/microbiologia , Metformina/farmacologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos , Lipogênese , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Distúrbios Nutricionais/etiologia , Distúrbios Nutricionais/metabolismo , Receptor 4 Toll-Like/metabolismo
13.
Proc Natl Acad Sci U S A ; 116(13): 6313-6318, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30862735

RESUMO

Hepatic ammonia handling was analyzed in taurine transporter (TauT) KO mice. Surprisingly, hyperammonemia was present at an age of 3 and 12 months despite normal tissue integrity. This was accompanied by cerebral RNA oxidation. As shown in liver perfusion experiments, glutamine production from ammonia was diminished in TauT KO mice, whereas urea production was not affected. In livers from 3-month-old TauT KO mice protein expression and activity of glutamine synthetase (GS) were unaffected, whereas the ammonia-transporting RhBG protein was down-regulated by about 50%. Double reciprocal plot analysis of glutamine synthesis versus perivenous ammonia concentration revealed that TauT KO had no effect on the capacity of glutamine formation in 3-month-old mice, but doubled the ammonia concentration required for half-maximal glutamine synthesis. Since hepatic RhBG expression is restricted to GS-expressing hepatocytes, the findings suggest that an impaired ammonia transport into these cells impairs glutamine synthesis. In livers from 12-, but not 3-month-old TauT KO mice, RhBG expression was not affected, surrogate markers for oxidative stress were strongly up-regulated, and GS activity was decreased by 40% due to an inactivating tyrosine nitration. This was also reflected by kinetic analyses in perfused liver, which showed a decreased glutamine synthesizing capacity by 43% and a largely unaffected ammonia concentration dependence. It is concluded that TauT deficiency triggers hyperammonemia through impaired hepatic glutamine synthesis due to an impaired ammonia transport via RhBG at 3 months and a tyrosine nitration-dependent inactivation of GS in 12-month-old TauT KO mice.


Assuntos
Amônia/metabolismo , Deficiências Nutricionais , Inativação Metabólica , Fígado/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Animais , Deficiências Nutricionais/patologia , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Técnicas de Silenciamento de Genes , Glutamato-Amônia Ligase/metabolismo , Glutamina/metabolismo , Glicoproteínas/metabolismo , Hepatócitos/metabolismo , Hiperamonemia/metabolismo , Cinética , Fígado/patologia , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Knockout , Estresse Oxidativo , Perfusão , Ureia/metabolismo
14.
Redox Biol ; 21: 101092, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30605883

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide lacking universally accepted therapies. Studies suggest that coffee consumption is associated with a reduced risk of NAFLD; however, molecular mechanisms and ingredients involved remain to be fully understood. Here, we determined the effects of regular intake of decaffeinated coffee on the development of NAFLD in mice, and molecular mechanisms involved. METHODS: Female C57BL/6J mice (n = 6-7/ group) were pair-fed either a liquid control diet (C) or fat-, fructose- and cholesterol-rich diet (FFC) +/- decaffeinated coffee (DeCaf, 6 g/kg BW) for 4 days or 6 weeks. Indices of liver damage, hepatic inflammation and parameters of insulin resistance and intestinal permeability as well as nitric oxide system were determined. RESULTS: Early signs of insulin resistance and non-alcoholic steatohepatitis (NASH) found after 6 weeks of FFC feeding were significantly lower in FFC+DeCaf-fed mice when compared to FFC-fed animals. Moreover, elevation of portal endotoxin levels and loss of tight junction proteins in proximal small intestine found in FFC-fed mice were significantly attenuated in FFC+DeCaf-fed animals. These beneficial effects of DeCaf were associated with a protection against the significant induction of inducible NO-synthase protein levels and 3-nitrotyrosine protein adducts found in proximal small intestine of FFC-fed mice. Similar protective effects of DeCaf were also found in mice fed the FFC diet short-term. CONCLUSION: Our results suggest that protective effects of DeCaf on the development of NAFLD are at least in part related to maintaining intestinal barrier function.


Assuntos
Café , Comportamento Alimentar , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Biomarcadores , Estresse do Retículo Endoplasmático , Feminino , Glucose/metabolismo , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Peroxidação de Lipídeos , Fígado/metabolismo , Fígado/patologia , Camundongos , Óxido Nítrico/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Permeabilidade , Receptor 4 Toll-Like/metabolismo
16.
Nutrients ; 9(9)2017 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-28906444

RESUMO

Intestinal microbiota and barrier functions seem to play an important role in the development of non-alcoholic fatty liver disease (NAFLD). However, whether these changes are an early event in the development of NAFLD or are primarily associated with later stages of the disease, has not yet been clarified. Using a pair-feeding model, we determined the effects of a short-term intake of a fat-, fructose- and cholesterol-rich diet (FFC) on the development of early hepatic steatosis and markers of intestinal barrier function in mice treated with and without non-resorbable antibiotics (AB). For four days, C57BL/6J mice were either pair-fed a control diet or a FFC diet ± AB (92 mg/kg body weight (BW) polymyxin B and 216 mg/kg BW neomycin). Hepatic steatosis and markers of inflammation, lipidperoxidation and intestinal barrier function were assessed. Lipid accumulation and early signs of inflammation found in the livers of FFC-fed mice were markedly attenuated in FFC + AB-fed animals. In FFC-fed mice the development of NAFLD was associated with a significant loss of tight junction proteins and an induction of matrix metalloproteinase-13 in the upper parts of the small intestine as well as significantly higher portal endotoxin levels and an induction of dependent signaling cascades in the liver. As expected, portal endotoxin levels and the expression of dependent signaling cascades in liver tissue were almost at the level of controls in FFC + AB-fed mice. However, FFC + AB-fed mice were also protected from the loss of zonula occludens-1 and partially of occludin protein in small intestine. Our data suggest that the development of early diet-induced hepatic steatosis in mice at least in part results from alterations of intestinal barrier function.


Assuntos
Antibacterianos/farmacologia , Colesterol na Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Fígado Gorduroso/tratamento farmacológico , Frutose/efeitos adversos , Animais , Biomarcadores/metabolismo , Colesterol na Dieta/administração & dosagem , Dieta/efeitos adversos , Gorduras na Dieta/administração & dosagem , Modelos Animais de Doenças , Endotoxinas/metabolismo , Fígado Gorduroso/induzido quimicamente , Feminino , Frutose/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Peroxidação de Lipídeos , Lipogênese , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ocludina/genética , Ocludina/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Triglicerídeos/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
17.
J Nutr ; 147(11): 2041-2049, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28931589

RESUMO

Background: Universally accepted therapeutic strategies for the treatment of nonalcoholic steatohepatitis (NASH) are still lacking. Studies suggest a preventive effect of oral Gln supplementation on the development of NASH; however, whether Gln also has therapeutic potential for pre-existing NASH has not yet been clarified.Objective: The aim of the present study was to determine whether Gln prevents the progression of diet-induced NASH in mice.Methods: For 8 wk, female C57BL/6J mice (6-8 wk old) were pair-fed a liquid Western-style diet [WSD, 25% of energy from fat, 50% wt:wt fructose, 0.16% wt:wt cholesterol] or control diet (C diet) to induce liver damage. From week 8 to 13, they were pair-fed the C diet or WSD alone or supplemented with l-Gln to provide 2.1 g/kg body weight (C diet + Gln or WSD + Gln). Energy intake was adjusted to the group with the lowest energy intake. Indexes of liver damage and inflammation, intestinal barrier function, and toll-like receptor 4 (Tlr4) signaling in the liver were determined.Results: The liver histology scores significantly increased from 8 to 13 wk (+31%) in WSD-fed mice and were significantly higher than in controls (P ≤ 0.05 for both time comparisons), whereas scores did not differ between C diet-fed and WSD + Gln-fed mice after 13 wk of feeding. The occludin protein concentrations in the small intestinal tissue were similarly reduced in both WSD-fed groups when compared with controls [WSD compared with C diet (-53%) and C diet + Gln (-42%), P ≤ 0.05; WSD + Gln compared with C diet + Gln (-34%), P ≤ 0.05] after 13 wk, whereas the expression of myeloid differentiation primary response gene 88 mRNA and concentration of inducible nitric oxide synthase and 4-hydroxynonenal protein adducts were significantly higher only in livers of WSD-fed mice (P ≤ 0.05 for the WSD group compared with all other groups; WSD + Gln group compared with the C diet groups: NS).Conclusion: Taken together, our data suggest that oral Gln supplementation protects mice from the progression of pre-existing, WSD-induced NASH.


Assuntos
Suplementos Nutricionais , Progressão da Doença , Glutamina/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Administração Oral , Aldeídos/metabolismo , Animais , Glicemia/metabolismo , Dieta Ocidental , Modelos Animais de Doenças , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ocludina/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
18.
Amino Acids ; 49(7): 1215-1225, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28434046

RESUMO

Dietary arginine (Arg) supplementation has been proposed to have positive effects on the development of liver diseases. In the present study, we investigate if an oral Arg supplementation in diet protects mice fed a fructose, fat and cholesterol enriched Western-style diet (WSD) from the development of non-alcoholic steatohepatitis (NASH). Female C57BL/6J mice were fed a liquid control diet or a liquid WSD ± Arg (2.49 g/kg body weight/day) for 6 weeks. Indices of liver injury, glucose metabolism and intestinal permeability were determined. While Arg supplementation had no effects on body weight gain, fasting blood glucose levels were significantly lower in WSD+Arg-fed mice than in C+Arg-fed animals. WSD-fed mice developed liver steatosis accompanied with inflammation, both being significantly attenuated in WSD+Arg-fed mice. These effects of Arg supplementation went along with a protection against WSD-induced decreased tight junction protein levels in the upper parts of the small intestine, increased levels of bacterial endotoxin in portal plasma as well as increased hepatic toll-like receptor-4 mRNA and 4-hydroxynonenal protein adduct levels. In conclusion, Arg supplementation may protect mice from the development of NASH.


Assuntos
Arginina/farmacologia , Suplementos Nutricionais , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Administração Oral , Animais , Glicemia/metabolismo , Feminino , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Junções Íntimas/patologia , Receptor 4 Toll-Like/sangue
19.
Mol Nutr Food Res ; 61(5)2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28067024

RESUMO

SCOPE: The role of invariant natural killer T cells in the development of nonalcoholic steatohepatitis (NASH) has not yet been fully understood. Here, the effect of the invariant natural killer T-cell activator alpha-galactosylceramide (αGalCer) on the development of nonalcoholic fatty liver disease and intestinal barrier function was assessed in a mouse model of early Western-style diet (WSD) induced NASH. METHODS AND RESULTS: Female C57BL/6J mice were either fed a liquid control diet or a liquid fructose-enriched WSD for 6 wk while being treated three times weekly with αGalCer (2 µg intraperitoneal) or vehicle. Indices of liver damage, glucose metabolism, and intestinal permeability were measured. Treatment with αGalCer markedly suppressed hepatic fat accumulation and inflammation while not affecting fasting glucose. The protective effects of αGalCer were associated with a protection against the increased translocation of bacterial endotoxins and the decreased protein levels of tight junction proteins occludin and zonula occludens 1 found in vehicle-treated mice while being fed a WSD. CONCLUSION: Taken together, our data suggest that the protective effects of αGalCer against the development of a diet-induced NASH in mice are associated with a protection against the increased translocation of intestinal bacterial endotoxins associated with the development of NASH.


Assuntos
Galactosilceramidas/farmacologia , Intestinos/fisiologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Substâncias Protetoras/farmacologia , Actinas/genética , Actinas/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Endotoxinas/toxicidade , Feminino , Interferon gama/metabolismo , Intestinos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais , Hepatopatia Gordurosa não Alcoólica/etiologia , Ocludina/genética , Ocludina/metabolismo , Proteínas de Junções Íntimas/genética , Proteínas de Junções Íntimas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Triglicerídeos/sangue , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
20.
J Gastroenterol Hepatol ; 32(3): 708-715, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27404046

RESUMO

BACKGROUND AND AIM: It has been suggested in several studies that an increased translocation of bacterial lipopolysaccharide (LPS) and, subsequently, an activation of toll-like receptor (TLR)-dependent signaling pathways in the liver may contribute to the development of non-alcoholic fatty liver disease. METHODS: Eight-week-old lipopolysaccharide-binding protein (LBP)-/- and wild-type (WT) mice were pair fed either a liquid diet rich in fat, fructose, and cholesterol (Western-style diet [WSD]) or a control liquid diet for 8 weeks. Parameters of liver injury, markers of TLR-4-dependent signaling pathway, and glucose/lipid metabolism were determined. RESULTS: Despite similar total caloric intake, weight gain, fasting blood glucose levels, and liver-to-bodyweight ratio, indices of liver damage determined by liver histology and transaminases were markedly lower in WSD-fed LBP-/- mice than in WSD-fed WT animals. In line with these findings, number of neutrophils, F4/80 positive cells, and plasminogen activator inhibitor 1 were only found to be significantly increased in livers of WSD-fed WT mice. While mRNA expressions of TLR-4 and myeloid differentiation primary response 88 were similar between WSD-fed groups, concentrations of inducible nitric oxide synthase protein and 4-hydroxynonenal protein adducts were significantly higher in livers of WSD-fed WT mice than in WSD-fed LBP-/- animals. Markers of lipid metabolism, for example, sterol regulatory element-binding protein 1c and fatty acid synthase per se, were significantly lower in livers of LBP-/- mice; however, mRNA expressions did not differ between controls and WSD-fed mice within the respective mouse strain. CONCLUSION: Taken together, our results suggest that LBP is a critical factor in the development of non-alcoholic fatty liver disease in mice.


Assuntos
Proteínas de Fase Aguda/deficiência , Proteínas de Fase Aguda/fisiologia , Proteínas de Transporte/fisiologia , Lipopolissacarídeos/metabolismo , Fígado/metabolismo , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/fisiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Modelos Animais de Doenças , Glucose/metabolismo , Metabolismo dos Lipídeos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Transdução de Sinais/fisiologia , Receptores Toll-Like/metabolismo
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