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1.
Int J Mol Sci ; 22(16)2021 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-34445236

RESUMO

Sepsis-induced liver dysfunction (SILD) is a common event and is strongly associated with mortality. Establishing a causative link between protein post-translational modification and diseases is challenging. We studied the relationship among lysine acetylation (Kac), sirtuin (SIRTs), and the factors involved in SILD, which was induced in LPS-stimulated HepG2 cells. Protein hyperacetylation was observed according to SIRTs reduction after LPS treatment for 24 h. We identified 1449 Kac sites based on comparative acetylome analysis and quantified 1086 Kac sites on 410 proteins for acetylation. Interestingly, the upregulated Kac proteins are enriched in glycolysis/gluconeogenesis pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) category. Among the proteins in the glycolysis pathway, hyperacetylation, a key regulator of lactate level in sepsis, was observed at three pyruvate kinase M2 (PKM2) sites. Hyperacetylation of PKM2 induced an increase in its activity, consequently increasing the lactate concentration. In conclusion, this study is the first to conduct global profiling of Kac, suggesting that the Kac mechanism of PKM2 in glycolysis is associated with sepsis. Moreover, it helps to further understand the systematic information regarding hyperacetylation during the sepsis process.


Assuntos
Proteínas de Transporte/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/enzimologia , Proteínas de Membrana/metabolismo , Sepse/enzimologia , Hormônios Tireóideos/metabolismo , Acetilação/efeitos dos fármacos , Células Hep G2 , Humanos , Lisina/metabolismo , Sepse/induzido quimicamente
2.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443423

RESUMO

Chronic liver inflammation has become a major global health concern. In the absence of clinical surrogate markers to diagnose inflammatory liver disease, the intervention with effective drugs in modern medicine tends to be late. In Sri Lanka, traditional medical practitioners prescribe herbal preparations from Osbeckia octandra for the prevention and treatment of liver disorders. To test the efficacy of such treatments, we have administered thioacetamide (TAA) to male Wistar rats to induce chronic liver damage (disease control; DC) and examined how various leaf extracts: crude leaf suspension (CLS), boiled leaf extract (BLE), sonicated leaf extract (SLE), methanol leaf extract (MLE) and hexane leaf extract (HLE) of O. octandra ameliorate TAA-induced liver disease. The CLS, BLE and SLE treatments in cirrhotic rats significantly attenuated disease-related changes, such as liver weight and hepato-enzymes. The mRNA levels of Tnf-α were significantly decreased by 3.6, 10 and 3.9 times in CLS, BLE and SLE compared to DC. The same treatments resulted in significantly lower (19.5, 4.2 and 2.4 times) α-Sma levels compared to DC. In addition, Tgf-ß1 and Vegf-R2 mRNA expressions were significantly lower with the treatments. Moreover, BLE expressed a strong anti-angiogenic effect. We conclude that CLS, BLE and SLE from O. octandra have potent hepatic anti-fibrotic effects in TAA-induced liver cirrhosis.


Assuntos
Cirrose Hepática Experimental/tratamento farmacológico , Melastomataceae/química , Neovascularização Patológica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática Experimental/sangue , Neovascularização Patológica/sangue , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tioacetamida , Regulação para Cima/efeitos dos fármacos , Água , Perda de Peso/efeitos dos fármacos
3.
Nutrients ; 13(6)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200606

RESUMO

Algae are potential and natural source of long-chain polyunsaturated fatty acids like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The diatom Pinnularia borealis accumulates high levels of EPA and may be considered as a source for commercial production of dietary supplements. In this study we asked the question whether diet supplementation with P. borealis may augment antioxidant defense and ameliorate risk factors for cardiovascular diseases. We fed mice (Mus musculus) with lyophilized diatom solutions of different concentrations (1%, 3%, and 5%) for 7 days. Then we measured glutathione content and the activity of glutathione redox system enzymes, total cholesterol and triacylglycerol concentrations, and malondialdehyde concentration in the liver and kidney. We found that cholesterol and triacylglycerol concentrations in the liver and kidneys were the lowest in mice who were fed with the highest concentration of Pinnularia borealis, suggesting protective properties of algae. Additionally, the lowest concentration of Pinnularia borealis was sufficient to improve antioxidant capacity. Our results suggest that P. borealis may be used as a source for dietary supplements rich in EPA, but the amount supplied to the organism should be limited.


Assuntos
Diatomáceas/química , Suplementos Nutricionais , Glutationa/metabolismo , Rim/enzimologia , Fígado/enzimologia , Animais , Liofilização , Masculino , Camundongos
4.
Nutrients ; 13(6)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201166

RESUMO

Bisphenol A (BPA) is an organic chemical compound widely used for manufacturing plastics. BPA exposure originates principally from the diet, but it can also originate from dermal contact. In over 90% of individuals, including pregnant women, BPA is detectable in several body fluids. The effects of this exposure on the fetus are under active investigation in several research laboratories. The aim of our work was to study the impact of prenatal exposure to BPA in the liver of rat fetuses from a sex-dependent point of view. We particularly investigated the effects of prenatal BPA exposure on hepatic lipids because of their crucial role, not only for the liver, but also for the whole-body functions. Our results demonstrate that the liver of rat fetuses, in utero exposed to a very low dose of BPA (2.5 µg/kg/day), displays significant modulations with regard to proteins involved in cholesterol and fatty acid biosynthesis and trafficking. Moreover, an impact on inflammatory process has been observed. All these effects are dependent on sex, being observable only in female rat fetuses. In conclusion, this work demonstrates that maternal exposure to BPA compromises hepatic lipid metabolism in female offspring, and it also reveals the perspective impact of BPA on human health at doses currently considered safe.


Assuntos
Compostos Benzidrílicos/toxicidade , Feto/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Compostos Benzidrílicos/química , Receptor alfa de Estrogênio/metabolismo , Feminino , Feto/efeitos dos fármacos , Inflamação/patologia , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Fenóis/química , Gravidez , Ratos Sprague-Dawley
5.
Nutrients ; 13(7)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206655

RESUMO

Fish protein consumption exerts beneficial metabolic effects on human health, also correlating with a decreased risk for cardiovascular disease. Fish waste contains high amount of proteins and utilization may offer the opportunity for generating compounds advantageous for human health. Especially, fish waste protein hydrolysates beneficially influence pathways involved in body composition, exerting anti-inflammatory and antioxidant activities, making their potential supplementation in human disorders of increased interest. This study assessed the effect of a 10% (w/w) anchovy waste protein hydrolysate (APH) diet for 12 weeks in reducing atherosclerosis in ApoE-/- mice, through histological and immunohistochemical methods. In addition, monitoring of plaque development was performed, using high-frequency ultrasound and magnetic resonance imaging. Overall, the APH diet attenuated atherosclerotic plaque development, producing a regression of arterial lesions over time (p < 0.05). Twelve weeks on an APH diet had an anti-obesity effect, improving lipid metabolism and reducing hepatic enzyme activity. A significant reduction in plaque size and lipid content was observed in the aortic sinus of APH-fed mice, compared to the control (p < 0.001), whereas no differences in the extracellular matrix and macrophage recruitment were observed. Supplementation of APH significantly attenuates atherosclerosis in ApoE-/- mice, exerting a lipid-lowering activity. The opportunity to use fish waste protein hydrolysates as a nutraceutical in atherosclerosis is worthy of future investigations, representing a low cost, sustainable, and nutritional strategy with minimal environmental impact.


Assuntos
Aterosclerose/terapia , Suplementos Nutricionais , Proteínas de Peixes/farmacologia , Hipolipemiantes/farmacologia , Hidrolisados de Proteína/farmacologia , Animais , Fármacos Antiobesidade/farmacologia , Modelos Animais de Doenças , Fezes/química , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Placa Aterosclerótica/terapia , Alimentos Marinhos
6.
Biomed Pharmacother ; 138: 111532, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311531

RESUMO

Fufang Zhenzhu Tiaozhi formula (FTZ), a preparation of Chinese herbal medicine, has various pharmacological properties, such as hypoglycemic, hypolipidemic, anticoagulant, and anti-inflammatory activities. Hepatocyte apoptosis is a marker of nonalcoholic steatohepatitis (NASH) and contributes to liver injury, fibrosis, and inflammation. Given the multiple effects of FTZ, we investigated whether FTZ can be a therapeutic agent for NASH and its mechanism. In the present study, we observed that FTZ treatment had an obviously favorable influence on hepatic steatosis and fibrosis in the histopathologic features of type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) with NASH minipigs. In addition, immunohistochemical analysis showed increased expression of the fibrotic marker α-smooth muscle actin (α-SMA), and a TUNEL assay revealed increased apoptotic positive hepatic cells in the liver tissues of the model group. Furthermore, FTZ administration reduced the increased expression of α-SMA, and FTZ inhibited apoptosis by affecting Bcl-2/Bax and cleaved caspase-3 expression. Mechanistically, our data suggested that FTZ treatment attenuated hepatic steatosis and fibrosis via the adenosine monophosphate-activated protein kinase (AMPK) pathway. In vitro studies showed that FTZ also attenuated intracellular lipid accumulation in HepG2 cells exposed to palmitic acid (PA) and oleic acid (OA). FTZ upregulated the expression levels of P-AMPK and BCL-2 and downregulated BAX. The changes induced by FTZ were reversed by Compound C, an inhibitor of AMPK. In conclusion, FTZ attenuated NASH by ameliorating steatosis and hepatocyte apoptosis, which is attributable to the regulation of the AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Doença das Coronárias/enzimologia , Doença das Coronárias/etiologia , Doença das Coronárias/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/enzimologia , Células Hep G2 , Humanos , Lipídeos/sangue , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/enzimologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Suínos , Porco Miniatura
7.
Iran J Med Sci ; 46(4): 237-255, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34305236

RESUMO

Background: The outbreak of the coronavirus disease-2019 (COVID-19) has become a global public health challenge. Assessing the effect of COVID-19 on liver injury is of great importance. A systematic review and meta-analysis were conducted to establish the characteristics of liver function tests in COVID-19 patients. Methods: A systematic search of publications from December 2019 up to April 2020 in Web of Science, Scopus, and Medline (via PubMed) databases was performed. Both cross-sectional and case series studies reporting an association between liver injury and COVID-19 infection were included. The data were analyzed using the STATA software (version 11.0) and the random-effects model for I2>50% was used to pool the results. Results: In this meta-analysis, 42 articles comprising a total of 6,557 COVID-19 patients were studied. The prevalence of increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels was 30% and 21% in non-severe patients and 38% and 48% in severe patients, respectively. Patients with severe COVID-19 infection were 4.22, 4.96, and 4.13 times more likely to have elevated AST, ALT, and lactate dehydrogenase (LDH) levels, respectively. Conclusion: Elevation in liver function tests was higher in patients with severe than non-severe COVID-19 infection. Given the widespread use of drugs that increases the risk of hepatotoxicity, healthcare providers should be aware of changes in liver enzymes in COVID-19 patients. The inclusion of other studies from outside China could confirm the pattern of elevation in liver function tests in COVID-19 patients across the globe. Preprint of this article is available on medRxiv, https://www.medrxiv.org/content/10.1101/2020.05.20.20108357v1.


Assuntos
COVID-19/complicações , Hepatopatias/virologia , Testes de Função Hepática , Alanina Transaminase , Aspartato Aminotransferases , Humanos , L-Lactato Desidrogenase , Fígado/enzimologia , Hepatopatias/epidemiologia
8.
J Toxicol Environ Health A ; 84(20): 821-835, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34187333

RESUMO

The aim of this study was to determine pharmacokinetics of α-amanitin, a toxic bicyclic octapeptide isolated from the poisonous mushrooms, following intravenous (iv) or oral (po) administration in mice using a newly developed and validated liquid chromatography-high resolution mass spectrometry. The iv injected α-amanitin disappeared rapidly from the plasma with high a clearance rate (26.9-30.4 ml/min/kg) at 0.1, 0.2, or 0.4 mg/kg doses, which was consistent with a rapid and a major excretion of α-amanitin via the renal route (32.6%). After the po administration of α-amanitin at doses of 2, 5, or 10 mg/kg to mice, the absolute bioavailability of α-amanitin was 3.5-4.8%. Due to this low bioavailability, 72.5% of the po administered α-amanitin was recovered from the feces. When α-amanitin is administered po, the tissue to plasma area under the curve ratio was higher in stomach > large intestine > small intestine > lung ~ kidneys > liver but not detected in brain, heart, and spleen. The high distribution of α-amanitin to intestine, kidneys, and liver is in agreement with the previously reported major intoxicated organs following acute α-amanitin exposure. In addition, α-amanitin weakly or negligibly inhibited cytochrome P450 and 5'-diphospho-glucuronosyltransferase enzymes activity in human liver microsomes as well as major drug transport functions in mammalian cells overexpressing transporters. Data suggested remote drug interaction potential may be associated with α-amanitin exposure.


Assuntos
Alfa-Amanitina/farmacocinética , Venenos/farmacocinética , Animais , Cromatografia Líquida , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Fígado/enzimologia , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos ICR , Microssomos/metabolismo
9.
Ecotoxicol Environ Saf ; 220: 112398, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34116333

RESUMO

Presently, toxicological assessment of multiple veterinary antimicrobials has not been performed on mammals. In this study, we assessed the short-term toxicity of enrofloxacin (E) combined with colistin (C) and quinocetone (Q). Young male rats were orally dosed drug mixtures and single drugs in 14 consecutive days, each at the dose of 20, 80, and 400 mg/(kg·BW) for environmental toxicologic study. The results showed that at the high dose treatment, the combination of E + C+Q significantly decreased body intake, lymphocytes count on rats; significantly increased the values of Alanine aminotransferase (ALT), Glutamic oxaloacetic transaminase (AST) and, cholinesterase (CHE); it also got the severest histopathological changes, where sinusoidal congestion and a large number of black particles in sinusoids were observed. This means E + C+Q in the high dose groups was able to cause significant damage to the liver. Other combinations or doses did not induce significant liver damage. Transcriptome analysis was then performed on rats in high dose group for further research. For E + C and E + Q, an amount of 375 and 480 differently expressed genes were filtered out, revealing their possible underlying effect on genomes. For E + C+Q, a weighted gene co-expression network analysis was performed and 96 hub genes were identified to reveal the specific effect induced by this combination. This study indicates that joint toxicity should be taken into consideration when involving the risk assessment of these antimicrobials.


Assuntos
Anti-Infecciosos/toxicidade , Colistina/toxicidade , Enrofloxacina/toxicidade , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Quinoxalinas/toxicidade , Drogas Veterinárias/toxicidade , Alanina Transaminase/metabolismo , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/farmacologia , Aspartato Aminotransferases/metabolismo , Colistina/administração & dosagem , Combinação de Medicamentos , Resíduos de Drogas , Enrofloxacina/administração & dosagem , Exposição Ambiental , Perfilação da Expressão Gênica , Humanos , Fígado/enzimologia , Fígado/patologia , Masculino , Quinoxalinas/administração & dosagem , Ratos Sprague-Dawley , Fatores de Tempo , Drogas Veterinárias/administração & dosagem
10.
Medicine (Baltimore) ; 100(25): e26243, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160387

RESUMO

RATIONALE: Eszopiclone, sold under the brand name Lunesta, is a new type of non-benzodiazepine hypnotic. Eszopiclone is a zopiclone dextrorotation, which is classified as a cyclopyrrolone. It functions by binding gamma-aminobutyric acid (GABA) receptors. Compared with benzodiazepines hypnotics, eszopiclone has higher selectivity for certain subunits of the GABA(A) receptor. So far, there are no reports about the elevation of serum enzymes or severe liver injury caused by eszopiclone. Here, we present a case report of acute liver injury following eszopiclone treatment in a patient with chronic hepatitis B virus (HBV). PATIENT CONCERNS: The patient was a 53-year-old female with a 36-year history of positive HBV markers. Due to poor sleep, the patient took trazodone hydrochloride orally for 1 year. After hospital admission for positive hepatitis B pathogenic markers, abdominal distension, fatigue, and aggravation, she was treated with eszopiclone under the guidance of the mental health department. DIAGNOSES: Her transaminase levels increased abnormally after eszopiclone treatment and rapidly decreased after drug withdrawal. This was determined to be an acute liver injury event. liver-protecting treatment was maintained. Considering the patient's anxiety and depression, the patient's family members refused a liver biopsy. OUTCOMES: Transaminase levels decreased rapidly within one week, and the patient continued to take trazodone hydrochloride after discharge. No adverse events occurred in the follow-up period. LESSONS: Sleep disorders are more common in patients with chronic diseases, especially patients with chronic liver disease. Recently, it has become common for patients with hepatitis B and C to use antidepressants along with antiviral treatment. Patients with chronic hepatitis B or C may have a threefold risk of liver dysfunction after receiving antituberculosis treatment.[1,2] A proinflammatory environment induced by actively replicating the hepatitis virus may alter the detoxication process and increase drug toxicity.[3] At this time, the safety of other drugs should be reevaluated. Although hepatitis and liver injury are listed as rare adverse reactions of eszopiclone, this case is the first to report the eszopiclone-involved acute liver injury.


Assuntos
Compostos Azabicíclicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Hepatite B Crônica/complicações , Piperazinas/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Vírus da Hepatite B/imunologia , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/imunologia , Testes de Função Hepática , Pessoa de Meia-Idade , Distúrbios do Início e da Manutenção do Sono/etiologia
11.
FASEB J ; 35(7): e21737, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143495

RESUMO

Relaxin is an insulin-like hormone with pleiotropic protective effects in several organs, including the liver. We aimed to characterize its role in the control of hepatic metabolism in healthy rats. Sprague-Dawley rats were treated with human recombinant relaxin-2 for 2 weeks. The hepatic metabolic profile was analyzed using UHPLC-MS platforms. Hepatic gene expression of key enzymes of desaturation (Fads1/Fads2) of n-6 and n-3 polyunsaturated fatty acids (PUFAs), of phosphatidylethanolamine (PE) N-methyltransferase (Pemt), of fatty acid translocase Cd36, and of glucose-6-phosphate isomerase (Gpi) were quantified by Real Time-PCR. Activation of 5'AMP-activated protein kinase (AMPK) was analyzed by Western Blot. Relaxin-2 significantly modified the hepatic levels of 19 glycerophospholipids, 2 saturated (SFA) and 1 monounsaturated (MUFA) fatty acids (FA), 3 diglycerides, 1 sphingomyelin, 2 aminoacids, 5 nucleosides, 2 nucleotides, 1 carboxylic acid, 1 redox electron carrier, and 1 vitamin. The most noteworthy changes corresponded to the substantially decreased lysoglycerophospholipids, and to the clearly increased FA (16:1n-7/16:0) and MUFA + PUFA/SFA ratios, suggesting enhanced desaturase activity. Hepatic gene expression of Fads1, Fads2, and Pemt, which mediates lipid balance and liver health, was increased by relaxin-2, while mRNA levels of the main regulator of hepatic FA uptake Cd36, and of the essential glycolysis enzyme Gpi, were decreased. Relaxin-2 augmented the hepatic activation of the hepatoprotector and master regulator of energy homeostasis AMPK. Relaxin-2 treatment also rised FADS1, FADS2, and PEMT gene expression in cultured Hep G2 cells. Our results bring to light the hepatic metabolic features stimulated by relaxin, a promising hepatoprotective molecule.


Assuntos
Fígado/efeitos dos fármacos , Fígado/enzimologia , Relaxina/farmacologia , Animais , Linhagem Celular Tumoral , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Glicerofosfolipídeos/metabolismo , Células Hep G2 , Homeostase/efeitos dos fármacos , Humanos , Lipidômica/métodos , Fígado/metabolismo , Masculino , Metaboloma/efeitos dos fármacos , Fosfatidiletanolamina N-Metiltransferase/metabolismo , Fosfatidiletanolaminas/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia
12.
Molecules ; 26(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066494

RESUMO

Mango is rich in polyphenols including gallotannins and gallic acid, among others. The bioavailability of mango polyphenols, especially polymeric gallotannins, is largely dependent on the intestinal microbiota, where the generation of absorbable metabolites depends on microbial enzymes. Mango polyphenols can favorably modulate bacteria associated with the production of bioactive gallotannin metabolites including Lactobacillus plantarum, resulting in intestinal health benefits. In several studies, the prebiotic effects of mango polyphenols and dietary fiber, their potential contribution to lower intestinal inflammation and promotion of intestinal integrity have been demonstrated. Additionally, polyphenols occurring in mango have some potential to interact with intestinal and less likely with hepatic enzymes or transporter systems. This review provides an overview of interactions of mango polyphenols with the intestinal microbiome, associated health benefits and underlying mechanisms.


Assuntos
Anti-Inflamatórios/farmacologia , Intestinos/efeitos dos fármacos , Fígado/enzimologia , Polifenóis/química , Animais , Fibras na Dieta/análise , Ácido Gálico/química , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Taninos Hidrolisáveis/metabolismo , Inflamação , Mangifera , Camundongos , Extratos Vegetais/química , Prebióticos , Ratos
13.
Toxicology ; 458: 152831, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34097992

RESUMO

Aryl hydrocarbon receptor (AHR) activation via 2,3,7,8-tetrachlorodibenzofuran (TCDF) induces the accumulation of hepatic lipids. Here we report that AHR activation by TCDF (24  µg/kg body weight given orally for five days) induced significant elevation of hepatic lipids including ceramides in mice, was associated with increased expression of key ceramide biosynthetic genes, and increased activity of their respective enzymes. Results from chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA) and cell-based reporter luciferase assays indicated that AHR directly activated the serine palmitoyltransferase long chain base subunit 2 (Sptlc2, encodes serine palmitoyltransferase 2 (SPT2)) gene whose product catalyzes the initial rate-limiting step in de novo sphingolipid biosynthesis. Hepatic ceramide accumulation was further confirmed by mass spectrometry-based lipidomics. Taken together, our results revealed that AHR activation results in the up-regulation of Sptlc2, leading to ceramide accumulation, thus promoting lipogenesis, which can induce hepatic lipid accumulation.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Ceramidas/biossíntese , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Ativação Metabólica/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Benzofuranos/farmacologia , Ceramidas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipidômica , Fígado/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Hidrocarboneto Arílico/genética , Serina C-Palmitoiltransferase/genética , Serina C-Palmitoiltransferase/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Triglicerídeos/metabolismo
14.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074061

RESUMO

BACKGROUND: Erythritol, a sugar alcohol, is widely used as a substitute for sugar in diets for patients with diabetes or obesity. METHODS: In this study, we aimed to investigate the effects of erythritol on metabolic disorders induced by a high-fat diet in C57BL/6J mice, while focusing on changes in innate immunity. RESULTS: Mice that were fed a high-fat diet and administered water containing 5% erythritol (Ery group) had markedly lower body weight, improved glucose tolerance, and markedly higher energy expenditure than the control mice (Ctrl group) (n = 6). Furthermore, compared with the Ctrl group, the Ery group had lesser fat deposition in the liver, smaller adipocytes, and significantly better inflammatory findings in the small intestine. The concentrations of short-chain fatty acids (SCFAs), such as acetic acid, propanoic acid, and butanoic acid, in the serum, feces, and white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. In flow cytometry experiments, group 3 innate lymphoid cell (ILC3) counts in the lamina propria of the small intestine and ILC2 counts in the white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. Quantitative real-time reverse transcription polymerase chain reaction analyses showed that the Il-22 expression in the small intestine of the Ery group was markedly higher than that in the Ctrl group. CONCLUSIONS: Erythritol markedly decreased metabolic disorders such as diet-induced obesity, glucose intolerance, dyslipidemia, and fat accumulation in the mouse liver by increasing SCFAs and modulating innate immunity.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Eritritol/farmacologia , Intolerância à Glucose/dietoterapia , Imunidade Inata/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Metabolismo Energético/efeitos dos fármacos , Eritritol/administração & dosagem , Ácidos Graxos Voláteis/sangue , Ácidos Graxos Voláteis/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Intolerância à Glucose/metabolismo , Imunidade Inata/genética , Inflamação/dietoterapia , Inflamação/genética , Inflamação/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Obesidade/genética , Obesidade/metabolismo
15.
Toxicol Appl Pharmacol ; 424: 115594, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34044073

RESUMO

Oxidative stress and inflammation in kidney are the main causes for hyperuricemic nephropathy (HN). Baicalin and baicalein, two flavonoids, have anti-inflammatory and anti-oxidative effects and they are interconvertible in the body. In this study, both baicalin and baicalein were administered by intragastric administration (i.g.) or intraperitoneal injection (i.p.) at the dose of 50 mg kg-1, once a day for 15 consecutive days to HN mice, a model established by i.g. of yeast extract combined with i.p. of potassium oxonate. In HN mice, baicalin and baicalein reduced serum uric acid (SUA) levels and protected kidneys by anti-inflammatory and anti-oxidative effects. Mechanistically, the effect of baicalin and baicalein on reducing SUA levels might due to their inhibitory effect on xanthine oxidase (XO) activity in vivo and in vitro. Furthermore, the mechanisms of baicalin and baicalein against HN were analyzed with network pharmacology and molecular docking technology. The network pharmacology indicated that the protective effects of baicalin and baicalein against HN were mainly related to their down-regulating effects on TLRs, NF-κB, MAPK, PI3K/AKT and NOD-like receptor signaling pathways. Molecular docking indicated high binding affinity of baicalin/baicalein to targets such as AKT1 and MAPK1. In summary, baicalin and baicalein are promising drug candidates for the treatment of HN by inhibiting XO activity, reducing inflammation and cell apoptosis through down-regulating TLRs/NLRP3/NF-κB, MAPK, PI3K/AKT/NF-κB pathways.


Assuntos
Flavanonas/farmacologia , Flavonoides/farmacologia , Nefropatias/tratamento farmacológico , Simulação de Acoplamento Molecular , Alopurinol/farmacologia , Animais , Nitrogênio da Ureia Sanguínea , Fígado/enzimologia , Camundongos , Ácido Úrico/sangue , Xantina Oxidase/antagonistas & inibidores
16.
Biomed Pharmacother ; 139: 111627, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33965728

RESUMO

Lipids excess from an uterine environment can increase free radicals production of and thus induce oxidative status imbalance, a key factor for progression of non-alcoholic fatty liver disease (NAFLD) in offspring. Food antioxidant components in maternal diet may play an important role in preventing offspring metabolic disorders. The objective of the study was to evaluate the effects of açaí pulp supplementation on maternal high-fat diet, by assessing activity and expression of antioxidant enzymes and biomarkers of oxidative stress in the liver. Female Fisher rats were divided into four groups and fed a control diet (C), a high-fat diet (HF), a control diet supplemented with açaí (CA) and a high-fat diet supplemented with açaí (HFA) before mating, during gestation and lactation. The effects of açaí supplementation on oxidative stress biomarkers and antioxidant enzymes expression were evaluated in dams and male offspring after weaning. HFA diet increased body weight in dams, however reduced absolute and relative liver weight. There was a reduction in liver biomarkers of oxidative stress, malondialdehyde and carbonyl protein, as well as in catalase, glutathione peroxidase and superoxide dismutase activity. In offspring, HFA diet reduced liver weight and increased Gpx1, Gpx4 and Sod1 mRNA expression. These results suggest that açaí is able to restore redox status, preventing oxidative damage in dams by a direct mechanism and to promote beneficial effects on expression of antioxidant defences related genes in offspring.


Assuntos
Antioxidantes/metabolismo , Euterpe/química , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Suplementos Nutricionais , Feminino , Expressão Gênica/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Lactação , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Hepatopatia Gordurosa não Alcoólica , Tamanho do Órgão/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Gravidez , Ratos , Ratos Endogâmicos F344 , Superóxido Dismutase-1/metabolismo
17.
Biomed Pharmacother ; 139: 111673, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33965729

RESUMO

Zingiber roseum is native to Bangladesh and widely used in folk medicine. This present study was designed to assess the ameliorative potential of Zingiber roseum rhizome extract in carbon tetrachloride (CCl4) induced hepatotoxicity in mice model. Seven phenolic compounds were identified and quantified by HPLC analysis in the plant extract, including quercetin, myricetin, catechin hydrate, trans-ferulic acid, trans-cinnamic acid, (-) epicatechin, and rosmarinic acid. Hepatotoxicity was induced by administrating a single intraperitoneal injection of CCl4 (10 mL/kg) on 7th day of treatment. The results revealed that plant extract at all doses (100, 200 and 400 mg/kg) significantly reduced (p < 0.05) the elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) concentrations, and these effects were comparable to that of standard drug silymarin. Histopathological examination also revealed the evidence of recovery from CCL4 induced cellular damage when pretreated with Z. roseum rhizome extract. The in-vivo hepatoprotective effects were further investigated by the in-silico study of the aforementioned compounds with liver-protective enzymes such as superoxide dismutase (SOD), peroxiredoxin, and catalase. The strong binding affinities (ranging from -7.3359 to -9.111 KCal/mol) between the phenolic compounds (except trans-cinnamic acid) and oxidative stress enzymes inhibit ROS production during metabolism. The compounds were also found non-toxic in computational prediction, and a series of biological activities like antioxidant, anticarcinogen, cardio-protectant, hepato-protectant have been detected.


Assuntos
Intoxicação por Tetracloreto de Carbono/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Polifenóis/química , Polifenóis/farmacologia , Rizoma/química , Zingiberaceae/química , Animais , Intoxicação por Tetracloreto de Carbono/patologia , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cromatografia Líquida de Alta Pressão , Feminino , Fígado/enzimologia , Fígado/patologia , Testes de Função Hepática , Camundongos , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Peroxirredoxinas/metabolismo , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio , Silimarina/uso terapêutico , Superóxido Dismutase/metabolismo
18.
Nat Commun ; 12(1): 2830, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990564

RESUMO

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.


Assuntos
Café/efeitos adversos , Metilação de DNA , Epigenoma , Chá/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Ilhas de CpG , Epigênese Genética , Feminino , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Fosfoglicerato Desidrogenase/genética , Fatores de Risco
19.
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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