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1.
BMC Genomics ; 22(1): 428, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107898

RESUMO

BACKGROUND: Estrogen plays an essential role in female development and reproductive function. In chickens, estrogen is critical for lipid metabolism in the liver. The regulatory molecular network of estrogen in chicken liver is poorly understood. To identify estrogen-responsive genes and estrogen functional sites on a genome-wide scale, we determined expression profiles of mRNAs, lncRNAs, and miRNAs in estrogen-treated ((17ß-estradiol)) and control chicken livers using RNA-Sequencing (RNA-Seq) and studied the estrogen receptor α binding sites by ChIP-Sequencing (ChIP-Seq). RESULTS: We identified a total of 990 estrogen-responsive genes, including 962 protein-coding genes, 11 miRNAs, and 17 lncRNAs. Functional enrichment analyses showed that the estrogen-responsive genes were highly enriched in lipid metabolism and biological processes. Integrated analysis of the data of RNA-Seq and ChIP-Seq, identified 191 genes directly targeted by estrogen, including 185 protein-coding genes, 4 miRNAs, and 2 lncRNAs. In vivo and in vitro experiments showed that estrogen decreased the mRNA expression of PPARGC1B, which had been reported to be linked with lipid metabolism, by directly increasing the expression of miR-144-3p. CONCLUSIONS: These results increase our understanding of the functional network of estrogen in chicken liver and also reveal aspects of the molecular mechanism of estrogen-related lipid metabolism.


Assuntos
MicroRNAs , RNA Longo não Codificante , Animais , Galinhas/genética , Galinhas/metabolismo , Estrogênios , Feminino , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo
2.
Biomed Environ Sci ; 34(5): 356-363, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34059172

RESUMO

Objective: This study aimed to investigate the effects of N,N-dimethylglycine (DMG) on the concentration and metabolism of plasma homocysteine (pHcy) in folate-sufficient and folate-deficient rats. Methods: In this study, 0.1% DMG was supplemented in 20% casein diets that were either folate-sufficient (20C) or folate-deficient (20CFD). Blood and liver of rats were subjected to assays of Hcy and its metabolites. Hcy and its related metabolite concentrations were determined using a liquid chromatographic system. Results: Folate deprivation significantly increased pHcy concentration in rats fed 20C diet (from 14.19 ± 0.39 µmol/L to 28.49 ± 0.50 µmol/L; P < 0.05). When supplemented with DMG, pHcy concentration was significantly decreased (12.23 ± 0.18 µmol/L) in rats fed 20C diet but significantly increased (31.56 ± 0.59 µmol/L) in rats fed 20CFD. The hepatic methionine synthase activity in the 20CFD group was significantly lower than that in the 20C group; enzyme activity was unaffected by DMG supplementation regardless of folate sufficiency. The activity of hepatic cystathionine ß-synthase (CBS) in the 20CFD group was decreased but not in the 20C group; DMG supplementation enhanced hepatic CBS activity in both groups, in which the effect was significant in the 20C group but not in the other group. Conclusion: DMG supplementation exhibited hypohomocysteinemic effects under folate-sufficient conditions. By contrast, the combination of folate deficiency and DMG supplementation has deleterious effect on pHcy concentration.


Assuntos
Dieta , Suplementos Nutricionais , Deficiência de Ácido Fólico/metabolismo , Homocisteína/metabolismo , Sarcosina/análogos & derivados , Animais , Biomarcadores/metabolismo , Cromatografia Líquida , Fígado/metabolismo , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Sarcosina/administração & dosagem , Sarcosina/metabolismo
3.
Nat Commun ; 12(1): 3377, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099716

RESUMO

Animal models of human diseases are classically fed purified diets that contain casein as the unique protein source. We show that provision of a mixed protein source mirroring that found in the western diet exacerbates diet-induced obesity and insulin resistance by potentiating hepatic mTORC1/S6K1 signaling as compared to casein alone. These effects involve alterations in gut microbiota as shown by fecal microbiota transplantation studies. The detrimental impact of the mixed protein source is also linked with early changes in microbial production of branched-chain fatty acids (BCFA) and elevated plasma and hepatic acylcarnitines, indicative of aberrant mitochondrial fatty acid oxidation. We further show that the BCFA, isobutyric and isovaleric acid, increase glucose production and activate mTORC1/S6K1 in hepatocytes. Our findings demonstrate that alteration of dietary protein source exerts a rapid and robust impact on gut microbiota and BCFA with significant consequences for the development of obesity and insulin resistance.


Assuntos
Proteínas na Dieta/efeitos adversos , Ácidos Graxos/metabolismo , Microbioma Gastrointestinal/fisiologia , Resistência à Insulina , Obesidade/etiologia , Ração Animal/efeitos adversos , Animais , Linhagem Celular Tumoral , Dieta Hiperlipídica/efeitos adversos , Dieta Ocidental/efeitos adversos , Sacarose na Dieta/efeitos adversos , Modelos Animais de Doenças , Transplante de Microbiota Fecal , Vida Livre de Germes , Gluconeogênese , Hepatócitos , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Obesidade/metabolismo , Obesidade/patologia , Ratos , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Transdução de Sinais
4.
Sci Total Environ ; 784: 147182, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34088068

RESUMO

Cadmium (Cd) is associated with non-alcoholic fatty liver disease (NAFLD). The hepatic activation of p53/miR-43a-induced suppression of SIRT1/FXR axis plays a significant role in the development of NAFLD. In this study, we have investigated CdCl2-induced NAFLD in rats involves activation of miR34a/SIRT1/FXR axis. Adult male rats were divided into 4 groups (n-8/each) as a control, CdCl2 (10 mg/l), CdCl2 + miR-34a antagomir (inhibitor), and CdCl2 + SRT1720 (a SIRT1 activator) for 8 weeks, daily. With no effect on fasting glucose and insulin levels, CdCl2 significantly reduced rats' final body, fat pads, and liver weights, and food intake. Concomitantly, it increased the circulatory levels of liver markers (ALT, AST, and γ-GTT), increased the serum and hepatic levels of total cholesterol and triglycerides coincided with increased hepatic lipid accumulation. Besides, it increased the mRNA and protein levels of SREBP1, SREBP2, FAS, and HMGCOA reductase but reduced mRNA levels of PPARα, CPT1, and CPT2. Interestingly, CdCl2 also increased mRNA levels of miR34 without altering mRNA levels of SIRT1 but with a significant reduction in protein levels of SIRT1. These effects were associated with increased total protein levels of p53 and acetylated protein of p53, and FXR. Of note, suppressing miR-34a with a specific anatomic or activating SIRT1 by SRT1720 completely prevented all these effects and reduced hepatic fat accumulations in the livers of rats. In conclusion, CdCl2 induced NAFLD by increasing the transcription of miR-34a which in turn downregulates SIRT1 at the translational level.


Assuntos
Cloreto de Cádmio/efeitos adversos , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Animais , Fígado/metabolismo , Masculino , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Proteínas de Ligação a RNA , Ratos , Sirtuína 1/genética , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53
5.
Cells ; 10(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064487

RESUMO

Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19.


Assuntos
COVID-19/diagnóstico , Sobrecarga de Ferro/etiologia , Falência Hepática/etiologia , Fígado/patologia , Índice de Gravidade de Doença , Adulto , Idoso , Antivirais , Biópsia , COVID-19/complicações , COVID-19/mortalidade , COVID-19/terapia , Feminino , Ferritinas/análise , Hepatócitos/citologia , Hepatócitos/patologia , Humanos , Ferro/análise , Ferro/metabolismo , Sobrecarga de Ferro/mortalidade , Sobrecarga de Ferro/patologia , Sobrecarga de Ferro/terapia , Fígado/citologia , Fígado/metabolismo , Falência Hepática/mortalidade , Falência Hepática/patologia , Falência Hepática/terapia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Mitocôndrias/patologia , Respiração com Pressão Positiva , SARS-CoV-2/isolamento & purificação
6.
Nat Commun ; 12(1): 3292, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078910

RESUMO

Autophagy regulates primary cilia formation, but the underlying mechanism is not fully understood. In this study, we identify NIMA-related kinase 9 (NEK9) as a GABARAPs-interacting protein and find that NEK9 and its LC3-interacting region (LIR) are required for primary cilia formation. Mutation in the LIR of NEK9 in mice also impairs in vivo cilia formation in the kidneys. Mechanistically, NEK9 interacts with MYH9 (also known as myosin IIA), which has been implicated in inhibiting ciliogenesis through stabilization of the actin network. MYH9 accumulates in NEK9 LIR mutant cells and mice, and depletion of MYH9 restores ciliogenesis in NEK9 LIR mutant cells. These results suggest that NEK9 regulates ciliogenesis by acting as an autophagy adaptor for MYH9. Given that the LIR in NEK9 is conserved only in land vertebrates, the acquisition of the autophagic regulation of the NEK9-MYH9 axis in ciliogenesis may have possible adaptive implications for terrestrial life.


Assuntos
Autofagia/genética , Cílios/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Cadeias Pesadas de Miosina/genética , Quinases Relacionadas a NIMA/genética , Sequência de Aminoácidos , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Linhagem Celular , Cílios/genética , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Rim/citologia , Rim/metabolismo , Fígado/citologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Quinases Relacionadas a NIMA/deficiência , Ligação Proteica , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais
7.
Zhonghua Gan Zang Bing Za Zhi ; 29(5): 462-467, 2021 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-34107585

RESUMO

Objective: To investigate the effect of baicalein in improving non-alcoholic fatty liver disease caused by high fat-induced oxidative damage in mice. Methods: Male C57BL/6J mice weighing 18-20 g were randomly divided into 4 groups: normal control group (C, 10% fat for energy), high-fat group (H, 60% fat for energy), high-fat + scutellaria baicalein group (H+B, baicalein: 400 mg·kg(-1)·bw(-1)), and baicalein control group (B, baicalein: 400 mg·kg(-1)·bw(-1)). After 12 weeks, mice were sacrificed, and the tissue samples were collected. Liver pathological changes were observed by hematoxylin and eosin staining. Mitochondrial morphology was examined by ultramicropathology. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and mitochondrial membrane potential (MMP) changing levels in the liver were determined by kit. Sestrin2 and protein carbonylation (PCOS) levels were detected by Western blotting. Small interfering RNA (siRNA) was used to knock-down the Sestrin2 protein expression in HepG2 cells. Intramyocellular lipid changes in HepG2 cells was detected by fluorescent dye BODIPY493/503. One way ANOVA was used LSD pairwise comparison method was used to test the statistical difference. Results: Compared with the normal control group, high-fat fed caused significant fatty degeneration, decreased GSH and SOD levels (P ​​< 0.05), increased MDA and protein carbonylation levels, and increased Sestrin2 expression (P < 0.05) in mice. Mitochondrial shape changes, swelling, lack of cristae, and MMP was down-regulated by 33.3% (t = 13.456, P ​​< 0.001). Baicalein intervention had effectively inhibited hepatic steatosis and oxidative damage caused by high-fat fed, and further up-regulated Sestrin2 expression, MMP (t = 10.104, P ​​< 0.001), and significantly alleviated liver damage in mice. Sestrin2 expression knock-down had further increased the intracellular lipid deposition and PCOs expression (P ​​< 0.05), and reduced baicalein ability to antagonize lipid deposition and antioxidant capacity in Hep2 cells. Conclusion: Baicalein alleviate non-alcoholic fatty liver by regulating Sestrin2 expression and high-fat fed-induced liver oxidative damage.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica/efeitos adversos , Flavanonas , Hepatócitos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo
8.
Nat Commun ; 12(1): 3059, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031390

RESUMO

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in the world, however, no drug treatment has been approved for this disease. Thus, it is urgent to find effective therapeutic targets for clinical intervention. In this study, we find that liver-specific knockout of PPDPF (PPDPF-LKO) leads to spontaneous fatty liver formation in a mouse model at 32 weeks of age on chow diets, which is enhanced by HFD. Mechanistic study reveals that PPDPF negatively regulates mTORC1-S6K-SREBP1 signaling. PPDPF interferes with the interaction between Raptor and CUL4B-DDB1, an E3 ligase complex, which prevents ubiquitination and activation of Raptor. Accordingly, liver-specific PPDPF overexpression effectively inhibits HFD-induced mTOR signaling activation and hepatic steatosis in mice. These results suggest that PPDPF is a regulator of mTORC1 signaling in lipid metabolism, and may be a potential therapeutic candidate for NAFLD.


Assuntos
Fígado Gorduroso/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Proteínas Culina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Metabolismo dos Lipídeos , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo
9.
Sci Total Environ ; 773: 145078, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33940715

RESUMO

Nanomaterials are increasingly used in food processing, daily necessities and other fields due to their excellent properties, and increase the environmental contamination. Human beings will inevitably come into contact with these nanomaterials through multiple exposure routes especially oral exposure. The intestine is an important organ for nutrient absorption and physiologic barrier, which may be the main target of nanoparticles (NPs) exposure. However, for a long time, research on the toxicity of NPs has mainly focused on organs such as liver, kidney and brain. There are few assessment data over the intestinal safety. Recently, as reported, NPs can be translocated to the intestinal part in mammals and would be distributed in different substructures of intestines, thus causing damage to the structure and function of the intestine, in which the gut microbiota and its metabolites play important roles. In addition, due to the special physiological environment of gut, nanomaterials will undergo complex transformations that may cause different biological effects from their original form. Therefore, this review aims to assess the potential adverse effects of NPs on intestine and its possible mechanisms through the results of in vivo mammalian experiments. In addition, the exposure pathway, biodistribution and biotransformation of NPs in the intestine are also considered. We hope this review will arouse people's attention to the intestinal nanotoxicology and provide basic information for further related studies.


Assuntos
Microbioma Gastrointestinal , Nanopartículas , Animais , Humanos , Fígado/metabolismo , Mamíferos , Nanopartículas/toxicidade , Distribuição Tecidual
10.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(4): 588-592, 2021 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-33963720

RESUMO

OBJECTIVE: To investigate the inhibitory effect of Xinhui citrus fermentation liquor on liver fibrosis in mice. OBJECTIVE: Mouse models of liver fibrosis were established by intraperitoneal injection of CCl4 in 105 male C57BL/6 mice, followed by gavage of 0.1 mL 40% CCl4 olive oil 3 times a week (model group, n=49) or daily gavage of citrus liquor at the dose of 0.26 mL (citrus liquor group, n=56) for 8 weeks. Seven mice receiving only olive oil treatment (0.1 mL, 3 times a week) and another 7 treated with citrus liquor served as the control group. Liver tissues and serum samples were collected from 7 mice in the citrus liquor group and model group each week and from the mice in the two control groups at the 8th week for pathological examination of the liver tissues using HE staining and Sirius red staining and for determination of the biochemical indexes of liver function. OBJECTIVE: The mice in the model group showed progressively worsened liver fibrosis with obvious hepatic steatosis, necrosis and inflammatory cell infiltration. These liver pathologies were much ameliorated in citrus liquor group, which showed significantly reduced vacuolation, inflammatory cell infiltration, collagen deposition and the Ishak score of the liver tissue (P < 0.05). Serum levels of cholyglycine, alanine aminotransferase, transglutaminase and alanine aminotransferase were all significantly lower in citrus liquor group than in the model group (P < 0.05). OBJECTIVE: Xinhui citrus fermentation liquor has protective effect on the liver and can significantly ameliorate liver fibrosis in mice.


Assuntos
Tetracloreto de Carbono , Citrus , Animais , Tetracloreto de Carbono/metabolismo , Fermentação , Fígado/metabolismo , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
Zhonghua Gan Zang Bing Za Zhi ; 29(4): 362-368, 2021 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-33979964

RESUMO

Objective: To investigate the effect of natural hyperoxic environment on liver lipid metabolism and liver function based on the bile acid-farnesoid X receptor pathway in sub-healthy rats. Methods: Forty adult male Wistar rats were randomly divided into control group (n = 10) and sub-healthy model group (n = 30). The control group was fed a normal diet, and the model group was fed a high-fat-sugar diet with limited daily activities for 5 weeks. The sub-healthy model was successfully established and the feeding conditions were restored. The hyperoxic intervention group (healthy group) were placed in a natural hyperoxic environment for 7 days. The rats feeding status in the spontaneous recovery group were unchanged. The appearance and exhaustive swimming time were compared before and after in healthy rats. Peripheral blood was collected for biochemical measurement. The fluorescence intensity of FXR and peroxisome proliferator activated receptor α (PPAR α) in liver tissue was detected by fluorescence double staining. Real-time fluorescent semi-quantitative PCR and Western blot were used to detect the RNA and protein expression condition of bile acid-FXR signaling pathway related indicators (FXR, PPARα, and SREBP-1c) in liver tissues. Results: Compared with the control group, the model group had gained body weight, and the vitality was decreased, while triglycerides [TG, (1.18 ± 0.20) mmol/L vs. (0.65 ± 0.12) mmol/L] and total cholesterol [TC, (1.23 ± 0.29) mmol/L vs. (1.00 ± 0.25) mmol/L] level was increased, (P < 0.05), which suggests the presence of hepatic steatosis. TG and TC level in the healthy group and spontaneous recovery group were lower than the model group, and the differences between the healthy group and the model group were statistically significant (P < 0.05). Compared with the model group, the expression of FXR and PPARα in the liver of the healthy and the spontaneous recovery group was enhanced, while the expression of the sterol regulatory element binding protein 1c (SREBP-1c) was decreased. FXR and PPARα mRNA levels in the healthy group and the model group were (9.27 ± 0.26 vs. 6.77 ± 0.20), and (9.71 ± 0.21 vs. 7.09 ± 0.24), P < 0.01, respectively. Compared with the model group, spontaneous recovery group mRNA levels were 7.99 ± 0.30 and 8.44 ± 0.28, P < 0.05, respectively. FXR and SREBP-1c protein levels between the healthy group and the model group were (1.30 ± 0.19 vs.0.43 ± 0.28), and (1.56 ± 0.22 vs. 2.43 ± 0.19), P < 0.01, respectively. Compared with the model group, the FXR and SREBP-1c protein levels of the spontaneous recovery group were 0.81 ± 0.33 vs. 2.10 ± 0.38, P < 0.05, respectively. In addition, natural hyperoxic environment had enhanced liver lipid metabolism and improved lipid disorders. Conclusion: The natural hyperoxic environment have the ability to regulate liver lipid metabolism and can improve mild hyperlipidemia to a certain extent.


Assuntos
Ácidos e Sais Biliares , Metabolismo dos Lipídeos , Animais , Ácidos e Sais Biliares/metabolismo , Lipídeos , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar
12.
Zhongguo Zhong Yao Za Zhi ; 46(7): 1727-1737, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33982476

RESUMO

Methotrexate(MTX) is a commonly used antimetabolite, which can be used in the treatment of a variety of diseases. However, hepatotoxicity in the use of MTX severely limits its clinical use. Therefore, how to prevent and treat hepatotoxicity of MTX has become an urgent clinical problem. This paper summarizes and analyzes relevant literatures on the prevention and treatment of hepa-totoxicity caused by MTX with traditional Chinese medicines and natural medicines in recent years. MTX-induced hepatotoxicity mechanisms include folate pathway, oxidative stress damage and adenosine pathway, of which oxidative stress theory is the main research direction. A total of 14 kinds of traditional Chinese medicine and natural medicine extracts including white peony root, and 21 kinds of natural monomer compounds, including berberine, play an anti-MTX-induced hepatotoxic effect by resisting oxidative stress, inhibiting inflammation and regulating signal pathways. According to current studies on the prevention and treatment of hepatotoxicity induced by MTX with traditional Chinese medicines and natural medicines, there are insufficiencies, such as partial and superficial mechanism studies, inadequate combination of experimental research and clinical practice, non-standard experimental design and lack of application of advanced technologies and methods. This paper systematically reviewed the effects and mechanisms of traditional Chinese medicines and natural medicines against hepatotoxicity induced by MTX and defined current studies and deficiencies, in the expectation of proposing new study strategies and directions and providing scientific basis for rational clinical use of MTX and development of new drugs against MTX hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Humanos , Fígado/metabolismo , Medicina Tradicional Chinesa , Metotrexato/toxicidade , Estresse Oxidativo
13.
Zhongguo Zhong Yao Za Zhi ; 46(7): 1795-1802, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33982484

RESUMO

This article aims to investigate the ameliorative effect of Linderae Radix ethanol extract on hyperlipidemia rats induced by high-fat diet and to explore its possible mechanism from the perspective of reverse cholesterol transport(RCT). SD rats were divided into normal group, model group, atorvastatin group, Linderae Radix ethanol extract(LREE) of high, medium, low dose groups. Except for the normal group, the other groups were fed with a high-fat diet to establish hyperlipidemia rat models; the normal group and the model group were given pure water, while each administration group was given corresponding drugs by gavage once a day for five weeks. Serum total cholesterol(TC), triglyceride(TG), high density lipoprotein-cholesterol(HDL-c), low density lipoprotein-cholesterol(LDL-c), alanine aminotransferase(ALT), and aspartate aminotransferase(AST) levels were measured by automatic blood biochemistry analyzer; the contents of TC, TG, total bile acid(TBA) in liver and TC and TBA in feces of rats were detected by enzyme colorimetry. HE staining was used to observe the liver tissue lesions; immunohistochemistry was used to detect the expression of ATP-binding cassette G8(ABCG8) in small intestine; Western blot and immunohistochemistry were used to detect the expression of peroxisome proliferator-activated receptor gamma/aerfa(PPARγ/α), liver X receptor-α(LXRα), ATP-binding cassette A1(ABCA1) pathway protein and scavenger receptor class B type Ⅰ(SR-BⅠ) in liver. The results showed that LREE could effectively reduce serum and liver TC, TG levels, serum LDL-c levels and AST activity, and increase HDL-c levels, but did not significant improve ALT activity and liver index; HE staining results showed that LREE could reduce liver lipid deposition and inflammatory cell infiltration. In addition, LREE also increased the contents of fecal TC and TBA, and up-regulated the protein expressions of ABCG8 in small intestine and PPARγ/α, SR-BⅠ, LXRα, and ABCA1 in liver. LREE served as a positive role on hyperlipidemia model rats induced by high-fat diet, which might be related to the regulation of RCT, the promotion of the conversion of cholesterol to the liver and bile acids, and the intestinal excretion of cholesterol and bile acids. RCT regulation might be a potential mechanism of LREE against hyperlipidemia.


Assuntos
Hiperlipidemias , Animais , Transporte Biológico , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Fígado/metabolismo , Ratos , Ratos Sprague-Dawley , Triglicerídeos/metabolismo
14.
Zhongguo Zhong Yao Za Zhi ; 46(7): 1813-1821, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33982486

RESUMO

Prunella vulgaris(PV) is an edible and traditional medicinal herb which has a wide range application in fighting inflammation and oxidative stress, and protecting liver. Now it has been used to treat various types of liver diseases and has significant clinical efficacy. This study aims to investigate the effects of PV on ethanol-induced oxidative stress injury in rats and its metabolic mechanism. The rats were divided into control group, model group, PV group, and VC group. The liver protection of PV was identified by measuring pharmacological indexes such as antioxidant and anti-inflammatory activity. The metabolic mechanism of long-term ethanol exposure and the metabolic regulation mechanism of PV treatment were studied by LS-MS metabonomics. The pharmacological investigation indicated that ethanol could significantly decrease the contents of SOD, GSH-Px, CAT and other antioxidant enzymes in liver and increase the content of MDA. At the same time, PV could significantly reduce the contents of inflammatory factors(TNF-α, IL-6 and IL-1ß) and liver function markers(ALT, AST, ALP) in serum. What's more, long-term ethanol exposure could significantly cause liver injury, while PV could protect liver. Metabolomics based on multiple statistical analyses showed that long-term ethanol exposure could cause significant metabolic disorder, and fatty acids, phospholipids, carnitines and sterols were the main biomarkers. Meanwhile, pathway analysis and enrichment analysis showed that the ß oxidation of branched fatty acids was the main influencing pathway. Also, PV could improve metabolic disorder of liver injury induced by ethanol, and amino acids, fatty acids, and phospholi-pids were the main biomarkers in PV treatment. Metabolic pathway analysis showed that PV mainly regulated metabolic disorder of ethanol-induced liver injury through phenylalanine, tyrosine and tryptophan biosynthetic pathways. This study could provide a new perspective on the hepatoprotective effect of natural medicines, such as PV.


Assuntos
Prunella , Animais , Antioxidantes/metabolismo , Etanol/toxicidade , Fígado/metabolismo , Metabolômica , Estresse Oxidativo , Ratos
15.
Wei Sheng Yan Jiu ; 50(2): 289-300, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33985639

RESUMO

OBJECTIVE: To explore the toxic effect of bisphenol A on the liver, as well as the influence effect on lipid metabolism. METHODS: The toxic effects of bisphenols on human health were studied by using in vivo experiments of bisphenol A exposure in rats and in vitro experiments of human liver cell line HL-7702. Male SD rats were divided into control group(Ctrl), 1 mg/(kg·d) group(low), 5 mg/(kg·d) group(medium) and 25 mg/(kg·d) group(high) for 14 days subacute exposure of bisphenol A, to evaluate the toxic effect of bisphenol A on the liver in terms of body weight, liver organ index, liver pathological tissue sections, serum biochemical indicators. Then HL-7702 was divided into four groups: control group(Ctrl), low concentration treatment group(0. 16 µmol/L), medium concentration treatment group(4 µmol/L) and high concentration treatment group(100 µmol/L). After 24 hours of exposure to bisphenol A, the contents of triglyceride(TG) and total cholesterol(TC) in cells, reactive oxygen species(ROS) levels were detected, and the transcription levels of genes related to lipid metabolism and oxidative stress were detected by fluorescent quantitative PCR. RESULTS: The 14-day subacute exposure had no significant effect on rat body weight and liver body weight ratio, but liver pathological sections clearly showed that bisphenol A exposure can damage liver tissue structure. Serum biochemical indicator of total bile acid(TBA) was significantly reduced in the high-dose group, which was(4. 75±0. 33)µmol/L, creatinine(Cr) was significantly increased in the medium and high-dose group, which were(18. 00±0. 76)µmol/L and(18. 83±0. 75)µmol/L, respectively. TC, high-density lipoprotein(HDL-C) and low-density lipoprotein(LDL-C) were significantly reduced in the middle-and high-dose groups(P<0. 05), which were(1. 44±0. 10), (1. 14±0. 10)mmol/L;(0. 84±0. 04), (0. 63±0. 07)mmol/L and(0. 21±0. 04), (0. 16±0. 05)mmol/L, respectively. Bisphenol A exposure could significantly reduce the content of TC in hepatocytes(P<0. 05). BPA treatment could significantly increase ROS levels in HL-7702 cells. The transcription level of PPARα was significantly increased in the high concentration group, FABP1 was significantly increased in the high concentration group, SOD1 was significantly decreased in the medium and high concentration group(P<0. 05). CONCLUSION: Bisphenol A may cause oxidative stress by inducing excessive ROS production in liver cells, leading to liver damage and disorder of lipid metabolism in the body, thereby showing liver toxicity.


Assuntos
Transtornos do Metabolismo dos Lipídeos , Metabolismo dos Lipídeos , Animais , Compostos Benzidrílicos , Proteínas de Ligação a Ácido Graxo , Transtornos do Metabolismo dos Lipídeos/metabolismo , Fígado/metabolismo , Masculino , Fenóis , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
16.
Nat Commun ; 12(1): 2745, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980856

RESUMO

In mice, time of day strongly influences lethality in response to LPS, with survival greatest at the beginning compared to the end of the light cycle. Here we show that feeding, rather than light, controls time-of-day dependent LPS sensitivity. Mortality following LPS administration is independent of cytokine production and the clock regulator BMAL1 expressed in myeloid cells. In contrast, deletion of BMAL1 in hepatocytes globally disrupts the transcriptional response to the feeding cycle in the liver and results in constitutively high LPS sensitivity. Using RNAseq and functional validation studies we identify hepatic farnesoid X receptor (FXR) signalling as a BMAL1 and feeding-dependent regulator of LPS susceptibility. These results show that hepatocyte-intrinsic BMAL1 and FXR signalling integrate nutritional cues to regulate survival in response to innate immune stimuli. Understanding hepatic molecular programmes operational in response to these cues could identify novel pathways for targeting to enhance endotoxemia resistance.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Comportamento Alimentar/fisiologia , Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Sepse/mortalidade , Fatores de Transcrição ARNTL/genética , Animais , Ritmo Circadiano/genética , Modelos Animais de Doenças , Resistência à Doença , Hepatócitos/metabolismo , Hipoglicemia/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Knockout , Receptores Citoplasmáticos e Nucleares/genética , Sepse/induzido quimicamente , Sepse/genética , Sepse/metabolismo , Transdução de Sinais
17.
BMC Genomics ; 22(1): 380, 2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34030631

RESUMO

BACKGROUND: Artificial selection of modern meat-producing chickens (broilers) for production characteristics has led to dramatic changes in phenotype, yet the impact of this selection on metabolic and molecular mechanisms is poorly understood. The first 3 weeks post-hatch represent a critical period of adjustment, during which the yolk lipid is depleted and the bird transitions to reliance on a carbohydrate-rich diet. As the liver is the major organ involved in macronutrient metabolism and nutrient allocatytion, a combined transcriptomics and metabolomics approach has been used to evaluate hepatic metabolic reprogramming between Day 4 (D4) and Day 20 (D20) post-hatch. RESULTS: Many transcripts and metabolites involved in metabolic pathways differed in their abundance between D4 and D20, representing different stages of metabolism that are enhanced or diminished. For example, at D20 the first stage of glycolysis that utilizes ATP to store or release glucose is enhanced, while at D4, the ATP-generating phase is enhanced to provide energy for rapid cellular proliferation at this time point. This work has also identified several metabolites, including citrate, phosphoenolpyruvate, and glycerol, that appear to play pivotal roles in this reprogramming. CONCLUSIONS: At Day 4, metabolic flexibility allows for efficiency to meet the demands of rapid liver growth under oxygen-limiting conditions. At Day 20, the liver's metabolism has shifted to process a carbohydrate-rich diet that supports the rapid overall growth of the modern broiler. Characterizing these metabolic changes associated with normal post-hatch hepatic development has generated testable hypotheses about the involvement of specific genes and metabolites, clarified the importance of hypoxia to rapid organ growth, and contributed to our understanding of the molecular changes affected by decades of artificial selection.


Assuntos
Galinhas , Transcriptoma , Animais , Galinhas/genética , Lipogênese , Fígado/metabolismo , Metabolômica
18.
Biomed Res Int ; 2021: 5541780, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937393

RESUMO

Objective: This study is aimed at investigating the enriched functions of polymeric immunoglobulin receptor (PIGR) and its correlations with liver fibrosis stage. Methods: PIGR mRNA expression in normal liver, liver fibrosis, hepatic stellate cells (HSCs), and hepatitis virus infection samples was calculated in Gene Expression Omnibus (GEO) and Oncomine databases. Enrichment analysis of PIGR-related genes was conducted in Metascape and Gene Set Enrichment Analysis (GSEA). Logistic model and ROC curve were performed to evaluate the correlations between pIgR and liver fibrosis. Results: PIGR mRNA was upregulated in advanced liver fibrosis, cirrhosis compared to normal liver (all p < 0.05). PIGR mRNA was also overexpressed in activated HSCs compared to senescent HSCs, liver stem/progenitor cells, and reverted HSCs (all p < 0.05). Enrichment analysis revealed that PIGR-related genes involved in the defense response to virus and interferon (IFN) signaling. In GEO series, PIGR mRNA was also upregulated by hepatitis virus B, C, D, and E infection (all p < 0.05). After adjusting age and gender, multivariate logistic regression models revealed that high PIGR in the liver was a risk factor for liver fibrosis (OR = 82.2, p < 0.001). The area under curve (AUC), positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of PIGR for liver fibrosis stage >2 were 0.84, 0.86, 0.7, 0.61, and 0.90. Conclusion: PIGR was correlated with liver fibrosis and might involve in hepatitis virus infection and HSC transdifferentiation.


Assuntos
Biologia Computacional , Progressão da Doença , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Receptores de Imunoglobulina Polimérica/metabolismo , Regulação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/genética , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/genética , Modelos Logísticos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Imunoglobulina Polimérica/genética
19.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946157

RESUMO

The metabolic ratios lactate/pyruvate and ß-hydroxybutyrate/acetoacetate are considered valuable tools to evaluate the in vivo redox cellular state by estimating the free NAD+/NADH in cytoplasm and mitochondria, respectively. The aim of the current study was to validate a gas-chromatography mass spectrometry method for simultaneous determination of the four metabolites in plasma and liver tissue. The procedure included an o-phenylenediamine microwave-assisted derivatization, followed by liquid-liquid extraction with ethyl acetate and silylation with bis(trimethylsilyl)trifluoroacetamide:trimethylchlorosilane 99:1. The calibration curves presented acceptable linearity, with a limit of quantification of 0.001 mM for pyruvate, ß-hydroxybutyrate and acetoacetate and of 0.01 mM for lactate. The intra-day and inter-day accuracy and precision were within the European Medicines Agency's Guideline specifications. No significant differences were observed in the slope coefficient of three-point standard metabolite-spiked curves in plasma or liver and water, and acceptable recoveries were obtained in the metabolite-spiked samples. Applicability of the method was tested in precision-cut liver rat slices and also in HepG2 cells incubated under different experimental conditions challenging the redox state. In conclusion, the validated method presented good sensitivity, specificity and reproducibility in the quantification of lactate/pyruvate and ß-hydroxybutyrate/acetate metabolites and may be useful in the evaluation of in vivo redox states.


Assuntos
Ácido 3-Hidroxibutírico/metabolismo , Acetoacetatos/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Lactatos/metabolismo , Piruvatos/metabolismo , Ácido 3-Hidroxibutírico/análise , Ácido 3-Hidroxibutírico/sangue , Acetoacetatos/análise , Acetoacetatos/sangue , Animais , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Células Hep G2 , Humanos , Lactatos/análise , Lactatos/sangue , Limite de Detecção , Fígado/química , Fígado/metabolismo , Oxirredução , Piruvatos/análise , Piruvatos/sangue , Ratos Wistar
20.
Nat Commun ; 12(1): 2579, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972514

RESUMO

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.


Assuntos
Alanina Transaminase/genética , Fosfatase Alcalina/genética , Doenças Cardiovasculares/genética , Fígado/enzimologia , Doenças Metabólicas/genética , gama-Glutamiltransferase/genética , Idoso , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Doenças Cardiovasculares/enzimologia , Estudos de Coortes , Bases de Dados Genéticas , Grupo com Ancestrais do Continente Europeu , Feminino , Regulação Enzimológica da Expressão Gênica/genética , Predisposição Genética para Doença , Testes Genéticos , Estudo de Associação Genômica Ampla , Humanos , Resistência à Insulina/genética , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Masculino , Análise da Randomização Mendeliana , Doenças Metabólicas/enzimologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , gama-Glutamiltransferase/sangue
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