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1.
Toxicol Lett ; 318: 74-85, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31654802

RESUMO

Metabolic flexibility defines the capacity of cells to respond to changes in nutrient status. Mitochondria are important mediators of metabolic flexibility and dysfunction is associated with metabolic inflexibility and pathology. Foodborne toxins are often overlooked as potential factors contributing to metabolic toxicity. Fusaric acid (FA), a neglected mycotoxin, is known to disrupt mitochondrial function. The aim of this study was to investigate the molecular mechanisms underlying a metabolic switch in response to FA. This study investigated the effects of FA on energy homeostasis in cultured human liver (HepG2) cells. HepG2 cells poised to undergo oxidative and glycolytic metabolism were exposed to a range of FA concentrations (4, 63 and 250 µg/mL) for 6 h. We determined mitochondrial toxicity, acetyl CoA levels and cell viability using luminometric, fluorometric and spectrophotometric methods. Expression of metabolic proteins (PDK1, PKM2, phosphorylated-PDH E1α and HIF-1α) and mRNAs (HIF-1α, PKM2, LDHa and PDK1) were determined using western blot and qPCR respectively. Our data connects a constitutive expression of HIF-1α in response to FA, to the inhibition of pyruvate decarboxylation through up-regulation of PDK-1 and phosphorylation of Pyruvate Dehydrogenase E1α subunit. Moreover, we highlight the potential of FA to induce a glucose "addiction" and phenotype reminiscent of the Warburg effect. The findings provide novel insights into the impact of this neglected foodborne mycotoxin in the dysregulation of energy metabolism.


Assuntos
Plasticidade Celular/efeitos dos fármacos , Microbiologia de Alimentos , Ácido Fusárico/toxicidade , Glicólise/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Fenótipo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase (Lipoamida)/metabolismo
2.
Toxicol Lett ; 318: 86-91, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669099

RESUMO

Proton pump inhibitors (PPIs) have been used worldwide to treat gastrointestinal disorders. A recent study showed that long-term use of PPIs caused iron deficiency; however, it is unclear whether PPIs affect iron metabolism directly. We investigated the effect of PPIs on the peptide hepcidin, an important iron regulatory hormone. First, we used the FDA Adverse Event Reporting System database and analyzed the influence of PPIs. We found that PPIs, as well as H2 blockers, increased the odds ratio of iron-deficient anemia. Next, HepG2 cells were used to examine the action of PPIs and H2 blockers on hepcidin. PPIs augmented hepcidin expression, while H2 blockers did not. In fact, the PPI omeprazole increased hepcidin secretion, and omeprazole-induced hepcidin upregulation was inhibited by gene silencing or the pharmacological inhibition of the aryl hydrocarbon receptor. In mouse experiments, omeprazole also increased hepatic hepcidin mRNA expression and blood hepcidin levels. In mice treated with omeprazole, protein levels of duodenal and splenic ferroportin decreased. Taken together, PPIs directly affect iron metabolism by suppressing iron absorption through the inhibition of duodenal ferroportin via hepcidin upregulation. These findings provide a new insight into the molecular mechanism of PPI-induced iron deficiency.


Assuntos
Anemia Ferropriva/induzido quimicamente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Duodeno/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepcidinas/metabolismo , Absorção Intestinal/efeitos dos fármacos , Ferro/sangue , Inibidores da Bomba de Prótons/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Anemia Ferropriva/sangue , Anemia Ferropriva/fisiopatologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Transporte de Cátions/metabolismo , Duodeno/metabolismo , Duodeno/fisiopatologia , Células Hep G2 , Hepatócitos/metabolismo , Antagonistas dos Receptores Histamínicos H2/toxicidade , Humanos , Ferro/deficiência , Masculino , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico/genética
3.
Biochemistry (Mosc) ; 84(10): 1197-1203, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31694515

RESUMO

Here, we suggested that the epigenetic mechanism of benzo(a)pyrene (BP) action might be based on the aryl hydrocarbon receptor (AhR)-mediated transcription of the target genes, including miRNAs, that have the dioxin response element (DRE) in their promoters. The effect of BP on the expression of the oncogenic miR-483-3p, its host gene IGF2, and target gene IGF1 in primary hepatocytes and in the liver of Wistar female rats was investigated. The activation of AhR was confirmed using selective AhR inhibitor CH-223191 and by evaluating expression of the target CYP1A1 gene. The lack of coordination between the expression of miR-483-3p and its host gene IGF2 was revealed, which may be due to the presence of the binding site for the estrogen receptor alpha (ERα), which is a negative expression regulator. Our results confirm the existence of the AhR-mediated pathway in the regulation of expression of miR-483-3p, IGF1, and IGF2 under BP exposure, which is of considerable interest for understanding the epigenetic mechanisms of the carcinogenic effect of BP.


Assuntos
Benzo(a)pireno/farmacologia , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , MicroRNAs/antagonistas & inibidores , Animais , Células Cultivadas , Biologia Computacional , Feminino , Hepatócitos/metabolismo , Fígado/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Wistar
4.
J Agric Food Chem ; 67(46): 12844-12853, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31668063

RESUMO

Flazin is a ß-carboline-derived alkaloid found in Japanese fermented foods. Here, the potential of flazin as an antioxidant food was studied with particular reference to its effect on the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) system in human hepatocytes (C3A). Flazin and flazin analogues including the decarboxylated derivative perlolyrine were chemically synthesized and compared with each other and with chlorogenic acid and curcumin. Among these compounds, flazin showed the lowest cytotoxicity (IC50 < 500 µM) and the highest capacity to activate the Keap1-Nrf2 system. It provided the largest (>3-fold of the control) cytoprotection ability against a pro-oxidant, although its radical absorbance capacity was relatively low. Flazin increased the expressions of Nrf2-dependent phase II enzyme genes and their products (NQO1, GSTP, and GSH proteins). The strong cytoprotection ability of flazin associated with low log P (0-3) is shared by sulforaphane and 3,5-dihydroxy-4-methoxybenzyl alcohol, suggesting the potential value of flazin and flazin-rich foods for the prevention of oxidation-related health disorders.


Assuntos
Carbolinas/farmacologia , Furanos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Transdução de Sinais/efeitos dos fármacos
5.
Anticancer Res ; 39(10): 5495-5504, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570443

RESUMO

BACKGROUND/AIM: Most patients with hepatocellular carcinoma (HCC) cannot be treated using traditional therapies. Boron neutron capture therapy (BNCT) may provide a new treatment for HCC. In this study, the therapeutic efficacy and radiobiological effects of boric acid (BA)-mediated BNCT in a VX2 multifocal liver tumor-bearing rabbit model are investigated. MATERIALS AND METHODS: Rabbits were irradiated with neutrons at the Tsing Hua Open Pool Reactor 35 min following an intravenous injection of BA (50 mg 10B/kg BW). The tumor size following BNCT treatment was determined by ultrasonography. The radiobiological effects were identified by histopathological examination. RESULTS: A total of 92.85% of the tumors became undetectable in the rabbits after two fractions of BNCT treatment. The tumor cells were selectively eliminated and the tumor vasculature was collapsed and destroyed after two fractions of BA-mediated BNCT, and no injury to the hepatocytes or blood vessels was observed in the adjacent normal liver regions. CONCLUSION: Liver tumors can be cured by BA-mediated BNCT in the rabbit model of a VX2 multifocal liver tumor. BA-mediated BNCT may be a breakthrough therapy for hepatocellular carcinoma.


Assuntos
Ácidos Bóricos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/efeitos da radiação , Terapia por Captura de Nêutron de Boro/métodos , Hepatócitos/efeitos dos fármacos , Hepatócitos/efeitos da radiação , Fígado/efeitos dos fármacos , Fígado/efeitos da radiação , Masculino , Coelhos
6.
Zhongguo Zhong Yao Za Zhi ; 44(14): 2960-2965, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31602840

RESUMO

The study aimed to investigate the mechanism of hepatoprotective effect of C-21 steroidal glucosides from Cynanchum auriculatum( Baishouwu) on oxidative stress in mice with liver injury. Mice were randomly divided into normal group,model group,positive control group,Baishouwu high group and Baishouwu low group. The liver injury model was induced by intraperitoneal injection of CCl4 peanut oil solution. All mice were sacrificed to collect blood and liver specimens. The activities of serum levels of ALT and AST were detected. The content of MDA and the activity of SOD in liver homogenate were examined by colorimetry method. Tissues were stained with hematoxylin-eosin for histological examination. The hepatic protein expressions of NF-κB p65,p-IκBα,i NOS and COX-2 were detected by Western blot. The mRNA expressions of TNF-α and IL-6 were determined by RT-PCR. It was found that treatment with C-21 steroidal glucosides from Baishouwu successfully attenuated liver injury induced by CCl4,as shown by decreased levels of serum biochemical indicators( AST,ALT)( P<0. 01). Administration of total C-21 steroidal glucosides enhanced the activity of SOD( P<0. 01) and decreased the content of MDA( P<0. 01) in liver homogenate. Microscopic features suggested that treatment with C-21 steroidal glucosides from Baishouwu was effective in inhibiting CCl4-induced hepatocyte edema and degeneration. Further studies showed that NF-κB p65 overexpression induced by CCl4 was decreased by C-21 steroidal glucosides,leading to the markedly down-regulated protein expression levels of p-IκBα,i NOS and COX-2,as well as the depression of TNF-α and IL-6 mRNA expressions. In conclusion,total C-21 steroidal glucosides from Baishouwu exhibited potent effect on oxidative stress pathway in mice with liver injury induced by CCl4,with enhanced activity of SOD,decreased content of MDA,and down-regulated levels of NF-κB p65,p-IκBα,i NOS and COX-2.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Cynanchum/química , Glucosídeos/farmacologia , Estresse Oxidativo , Animais , Tetracloreto de Carbono , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Camundongos , Distribuição Aleatória
7.
Int J Nanomedicine ; 14: 6035-6060, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534335

RESUMO

Background: The clearance of nanomaterials (NMs) from the liver is essential for clinical safety, and their hepatic clearance is primarily determined by the co-disposition process of various types of hepatic cells. Studies of this process and the subsequent clearance routes are urgently needed for organic NMs, which are used as drug carriers more commonly than the inorganic ones. Materials and methods: In this study, the co-disposition of chitosan-based nanoparticles (CsNps) by macrophages and hepatocytes at both the cellular and animal levels as well as their subsequent biological elimination were investigated. RAW264.7 and Hepa1-6 cells were used as models of Kupffer cells and hepatocytes, respectively. Results: The cellular studies showed that CsNps released from RAW264.7 cells could enter Hepa1-6 cells through both clathrin- and caveolin-mediated endocytosis. The transport from Kupffer cells to hepatocytes was also studied in mice, and it was observed that most CsNps localized to the hepatocytes after intravenous injection. Following the distribution in hepatocytes, the hepatobiliary-fecal excretion route was shown to be the primary elimination route for CsNps, besides the kidney-urinary excretion route. The elimination of CsNps in mice was a lengthy process, with a half time of about 2 months. Conclusion: The demonstration in this study of the transport of CsNps from macrophages to hepatocytes and the subsequent hepatobiliary-fecal excretion provides basic information for the future development and clinical application of NMs.


Assuntos
Quitosana/farmacologia , Hepatócitos/citologia , Hepatócitos/metabolismo , Nanopartículas/química , Animais , Transporte Biológico , Linhagem Celular Tumoral , Portadores de Fármacos/metabolismo , Exocitose , Hepatócitos/efeitos dos fármacos , Cinética , Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , Nanopartículas/ultraestrutura , Fótons
8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 606-612, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537245

RESUMO

Objective To investigate the effect of fibroblast growth factor 21 (FGF21) on the lipid accumulation and inflammation induced by palmitate treatment in L02 hepatocytes and the underlying mechanism. Methods L02 cells were infected with lentivirus expressing SIRT1 shRNA to knockdown SIRT1 expression. Wild-type and SIRT1-knockdown L02 cells were treated with 250 mol/L palmitate for 5 days, and then administrated with 1 g/ml FGF21 for 72 hours. Triglycerides in the cells were detected with the infinity triglycerides reagent. Malondialdehyde (MDA) in the cells was assessed by MDA detection assay. Tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) levels in supernatant were measured by ELISA. Reactive oxygen species (ROS) levels were tested by the specific Amplex red ROS detection assay kit from Thermo Fisher Company. The gene expression of SIRT1, peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), superoxide dismutase 2 (SOD2) and catalase (CAT) were measured by real-time quantitative PCR. The protein levels of SIRT1, PGC1α, SOD2 and CAT were detected by Western blot analysis. Mitochondrial membrane potentials were detected by the JC-1staining kit. Mitochondrial oxygen consumption rate (OCR) was detected with the Seahorse XF Mito stress test kit. Results Palmitate increased the triglycerides level, induced the oxidative stress in both the cells and the mitochondria, decreased the gene expression and protein levels of SIRT1, PGC1α, SOD2 and CAT, increased the levels of TNF-α and IL-6, decreased the mitochondrial membrane potential, and impaired the mitochondrial function. FGF21 treatment could attenuate all of these effects caused by palmitate, while SIRT1 knockdown blocked most of the FGF21 effects on the L02 hepatocytes. Conclusion FGF21 activates SIRT1 pathway and inhibites the lipid accumulation, improves the mitochondrial function, and decreases the oxidative stress as well as inflammation in palmitate-treated L02 cells.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Hepatócitos/metabolismo , Inflamação/metabolismo , Sirtuína 1/metabolismo , Catalase/metabolismo , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Estresse Oxidativo , Palmitatos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Superóxido Dismutase-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
Int J Nanomedicine ; 14: 6451-6464, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496697

RESUMO

Background: We recently reported on long-term comprehensive biocompatibility and biodistribution study of fluorescent nanodiamond particles (NV)-Z-average 800nm (FNDP-(NV)) in rats. FNDP-(NV) primary deposition was found in the liver, yet liver function tests remained normal. Purpose: The present study aimed to gain preliminary insights on discrete localization of FNDP-(NV) in liver cells of the hepatic lobule unit and venous micro-vasculature. Kinetics of FDNP-(NV) uptake into liver cells surrogates in culture was conducted along with cell cytokinesis as markers of cells' viability. Methods: Preserved liver specimens from a pilot consisting of two animals which were stained for cytoskeletal elements (fluorescein-isothiocyanate-phalloidin) were examined for distribution of FNDP-(NV) by fluorescent microscopy (FM) and Confocal-FM (CFM) using near infra-red fluorescence (NIR). Hepatocellular carcinoma cells (HepG-2) and human umbilical vein endothelial cells (HUVEC) were cultured with FNDP-(NV) and assayed for particle uptake and location using spectrophotometric technology and microscopy. Results: HepG-2 and HUVEC displayed rapid (<30 mins) onset and concentration-dependent FNDP-(NV) internalization and formation of peri-nuclear corona. FM/CFM of liver sections revealed FNDP-(NV) presence throughout the hepatic lobules structures marked by spatial distribution, venous microvascular spaces and parenchyma and non-parenchyma cells. Conclusion: The robust presence of FNDP-(NV) throughout the hepatic lobules including those internalized within parenchyma cells and agglomerates in the liver venous micro-circulation were not associated with macro or micro histopathological signs nor vascular lesions. Cells cultures indicated normal cytokinesis in cells containing FNDP-(NV) agglomerates. Liver parenchyma cells and the liver microcirculation remain agnostic to presence of FNDP-(NV) in the sinusoids or internalized in the hepatic cells.


Assuntos
Materiais Biocompatíveis/farmacologia , Fígado/metabolismo , Nanodiamantes/química , Animais , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imagem Tridimensional , Cinética , Fígado/efeitos dos fármacos , Microscopia de Fluorescência , Tamanho da Partícula , Ratos Sprague-Dawley , Distribuição Tecidual
10.
Aquat Toxicol ; 215: 105272, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442592

RESUMO

A number of chemicals have been shown to affect epigenetic patterning and functions. Since epigenetic mechanisms regulate transcriptional networks, epigenetic changes induced by chemical exposure can represent early molecular events for long-term adverse physiological effects. Epigenetics has thus appeared as a research field of major interest within (eco)toxicological sciences. The present study aimed at measuring effects on epigenetic-related mechanisms of selected environmental chemicals (bisphenols, perfluorinated chemicals, methoxychlor, permethrin, vinclozolin and coumarin 47) in zebrafish embryos and liver cells (ZFL). Transcription of genes related to DNA methylation and histone modifications was measured and global DNA methylation was assessed in ZFL cells using the LUMA assay. The differences in results gathered from both models suggest that chemicals affect different mechanisms related to epigenetics in embryos and cells. In zebrafish embryos, exposure to bisphenol A, coumarin 47, methoxychlor and permethrin lead to significant transcriptional changes in epigenetic factors suggesting that they can impact early epigenome reprogramming related to embryonic development. In ZFL cells, significant transcriptional changes were observed upon exposure to all chemicals but coumarin 47; however, only perfluorooctane sulfonate induced significant effects on global DNA methylation. Notably, in contrast to the other tested chemicals, perfluorooctane sulfonate affected only the expression of the histone demethylase kdm5ba. In addition, kdm5ba appeared as a sensitive gene in zebrafish embryos as well. Taken together, the present results suggest a role for kdm5ba in regulating epigenetic patterns in response to chemical exposure, even though mechanisms remain unclear. To confirm these findings, further evidence is required regarding changes in site-specific histone marks and DNA methylation together with their long-term effects on physiological outcomes.


Assuntos
Embrião não Mamífero/metabolismo , Epigênese Genética , Fígado/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Animais , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Embrião não Mamífero/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fígado/efeitos dos fármacos , Testes de Toxicidade Aguda , Transcrição Genética/efeitos dos fármacos
11.
Adv Exp Med Biol ; 1155: 567-581, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468432

RESUMO

Here, we investigated the hepatoprotective effect of a hot water extract from Loliolus beka gray meat (LBMH) containing plentiful taurine in H2O2-induced oxidative stress in hepatocytes. LBMH potently scavenged the 2,2-azino-bis(3-ethylbenzthiazoline)-6-sulfonic acid (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and exhibited the good reducing power and the oxygen radical absorbance capacity (ORAC) value. Also, LBMH improved the cell viability against H2O2-induced hepatic damage in cultured hepatocytes by reducing intracellular reactive oxygen species (ROS) production. In addition, LBMH inhibited apoptosis via a reduction in sub-G1 cell population, as well as inhibition of apoptotic body formation from H2O2-induced oxidative damage in hepatocytes. Moreover, LBMH regulated the expression levels of Bax, a pro-apoptotic molecule and Bcl-2, an anti-apoptotic molecule in H2O2-treated hepatocytes. Additionally, pre-treatment with LBMH increased the expression of heme oxygenase 1 (HO-1), which is a hepatoprotective enzyme, by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) in H2O2-treated hepatocytes. Taken together, LBMH may be useful as a food ingredient for treatment of liver disease by regulating the Nrf2/HO-1 signal pathway.


Assuntos
Antioxidantes , Extratos Celulares/farmacologia , Decapodiformes/química , Hepatócitos/efeitos dos fármacos , Estresse Oxidativo , Taurina/farmacologia , Animais , Células Cultivadas , Heme Oxigenase-1/metabolismo , Hepatócitos/citologia , Humanos , Peróxido de Hidrogênio , Carne , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo
12.
Food Chem ; 301: 125281, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31382109

RESUMO

The need for safe and quality food, free from the presence of hazardous contaminants such as mycotoxins is an on-going and complex challenge. Cold atmospheric pressure plasma (CAPP) has the potential to contribute to achieving this goal. Decontamination efficacy of CAPP against six of the most common mycotoxins found in foods and feedstuffs was assessed herein. Concentration reduction of up to 66% was achieved in maize for both aflatoxin B1 and fumonisin B1. Degradation products were detected only in the case of aflatoxin B1 and zearalenone and were tested on human hepatocarcinoma cells with no increase in cytotoxicity observed. Analysis of treated maize revealed substantial changes to small molecular mass components of the matrix. While CAPP shows promise in terms of mycotoxin detoxification important questions concerning potential changes to the nutritional and safety status of the food matrix require further investigations.


Assuntos
Descontaminação/métodos , Contaminação de Alimentos/análise , Micotoxinas/química , Gases em Plasma/química , Aflatoxina B1/análise , Aflatoxina B1/química , Aflatoxina B1/toxicidade , Fumonisinas/análise , Fumonisinas/química , Fumonisinas/toxicidade , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Micotoxinas/análise , Micotoxinas/toxicidade , Zea mays/química , Zearalenona/análise , Zearalenona/química , Zearalenona/toxicidade
13.
Adv Exp Med Biol ; 1155: 597-610, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468434

RESUMO

Octopus ocellatus meat (OM) is well known as a plentiful protein source. In this study, we evaluated the hepatoprotective effect of an aqueous extract of OM (OMA) against H2O2-triggered oxidative stress in human hepatocytes. First of all, taurine rich OMA showed a good ORAC value and reducing power and it was similar with that of ascorbic acid, which is known as a strong antioxidant. Also, OMA significantly improved H2O2-decreased cell viability by reducing the generation of intracellular reactive oxygen species (ROS) in hepatocytes. Interestingly, the stimulation of H2O2-induced the formations of apoptotic bodies and sub-G1 DNA content, whereas they were inhibited by the treatment with OMA. Furthermore, OMA regulated the protein expression levels of apoptotic molecules, such as Bax and Bcl-2. Taken together, this study suggests that OMA, which contains an abundant amount of taurine, protects hepatocytes from H2O2-triggered oxidative stress and might be a functional food material with hepatoprotective effects.


Assuntos
Extratos Celulares/farmacologia , Hepatócitos/efeitos dos fármacos , Octopodiformes/química , Estresse Oxidativo , Animais , Apoptose , Células Cultivadas , Hepatócitos/citologia , Humanos , Peróxido de Hidrogênio/efeitos adversos , Carne , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína X Associada a bcl-2/metabolismo
14.
Adv Exp Med Biol ; 1155: 661-674, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468438

RESUMO

In the present study, we investigated the antioxidant activity of an aqueous extract from Atrina pectinate meat (APW) against H2O2-induced oxidative stress in a human hepatocyte. The extraction yield of APW was 30.01 ± 0.83% and which contained the highest taurine content among free amino acid contents. APW led to the high antioxidant activity showing 2,2-azino-bis(3-ethylbenzthiazoline)-6-sulfonic acid (ABTS) radical scavenging activity, good reducing power and oxygen radical absorbance capacity (ORAC) value. Also, the results showed that APW improved the cell viability decreased by H2O2 stimulation as well as the reduction of intracellular reactive oxygen species (ROS) generation in hepatocytes. Additionally, APW up-regulated the production of antioxidant mechanisms related enzymes such as catalase and superoxide dismutase (SOD), compared to the only H2O2-treated hepatocytes. Moreover, APW increased the expressions of nuclear Nrf2 and cytosolic HO-1 in H2O2-treated hepatocytes. Interestingly, the treatment of ZnPP, a HO-1 inhibitor abolished the cell viability and intracellular ROS generation induced by APW treatment. In conclusion, this study suggests that APW protects H2O2 induced oxidative stress via up-regulating of Nrf2/HO-1 signal pathway in hepatocytes.


Assuntos
Antioxidantes/farmacologia , Bivalves/química , Extratos Celulares/farmacologia , Hepatócitos/efeitos dos fármacos , Estresse Oxidativo , Animais , Heme Oxigenase-1/metabolismo , Humanos , Peróxido de Hidrogênio , Carne , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo
15.
Toxicol Lett ; 316: 183-193, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31437515

RESUMO

Olanzapine, a representative of antipsychotics, is a first-line drug for treatment of schizophrenia. However, olanzapine-induced liver steatosis limits its clinical utilization. This study is to explore the mechanism of liver steatosis induced by olanzapine based on the regulation of transporters involved in uptake and oxidation of fatty acids. Our results revealed that 12-week oral administration of olanzapine increased hepatic triglyceride(TG), caused liver steatosis. Our further studies showed that the expression of fatty acid transporter 2(FATP2) and fatty acid binding protein 1(FABP1) were up-regulated in liver of female mice after 12-week olanzapine exposure, as well as in primary mouse hepatocytes treated with olanzapine. Olanzapine treatment also reduced hepatic ß-hydroxybutyrate level (indicator of fatty acid ß-oxidation), meanwhile, the L-carnitine (L-Car) concentration in liver of olanzapine group was significantly lower than that in control group. Further study demonstrated that both mRNA and protein expression of hepatic OCTN2 (carnitine/organic cation transporter 2) were obviously down-regulated in male mice after 12-week olanzapine treatment. Also, olanzapine markedly inhibited L-Car uptake in MDCK-hOCTN2 cells (1.06 µM of IC50), HepG2 cells and primary mouse hepatocytes. Supplementation of L-Car attenuated hepatic TG rise and improved simple steatosis in olanzapine treatment mice. Taken together, up-regulation of FATP2/FABP1 and down-regulation/inhibition of hepatic OCTN2 probably contribute to olanzapine-induced liver steatosis. Supplementation of L-Car is a promising strategy to attenuate olanzapine-induced simple steatosis.


Assuntos
Antipsicóticos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Coenzima A Ligases/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Fígado Gorduroso/induzido quimicamente , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Olanzapina/toxicidade , Membro 5 da Família 22 de Carreadores de Soluto/antagonistas & inibidores , Adulto , Animais , Carnitina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Coenzima A Ligases/genética , Cães , Proteínas de Ligação a Ácido Graxo/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/prevenção & controle , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos C57BL , Membro 5 da Família 22 de Carreadores de Soluto/genética , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Regulação para Cima
16.
J Agric Food Chem ; 67(36): 10089-10096, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31423784

RESUMO

Circadian rhythms are closely associated with metabolic homeostasis. Metabolic disorders can be alleviated by many bioactive components through controlling of clock gene expressions. Capsaicin has been demonstrated with many beneficial effects including anti-obesity and anti-insulin resistance activities, yet whether the rhythmic expression of circadian clock genes are involved in the regulation of redox imbalance and glucose metabolism disorder by capsaicin remains unclear. In this work, the insulin resistance was induced in HepG2 cells by treatment of glucosamine. Glucose uptake levels, reactive oxygen species, H2O2 production, and mitochondrial membrane potential (MMP) were measured with/without capsaicin cotreatment. The mRNA and protein expressions of core circadian clock genes were evaluated by RT-qPCR and western blot analysis. Our study revealed that circadian misalignment could be ameliorated by capsaicin. The glucosamine-induced cellular redox imbalance and glucose metabolism disorder were ameliorated by capsaicin in a Bmal1-dependent manner.


Assuntos
Capsaicina/administração & dosagem , Relógios Circadianos/efeitos dos fármacos , Transtornos do Metabolismo de Glucose/tratamento farmacológico , Resistência à Insulina , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Glucose/metabolismo , Transtornos do Metabolismo de Glucose/genética , Transtornos do Metabolismo de Glucose/metabolismo , Transtornos do Metabolismo de Glucose/fisiopatologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Insulinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução/efeitos dos fármacos
17.
Ecotoxicol Environ Saf ; 183: 109467, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31374384

RESUMO

Mancozeb (MZ) is a widely used ethylene-bis-dithiocarbamate fungicide in agriculture causing hepatoxic and genotoxic effects in rats. Curcumin (CUR) has various pharmacological effects including antioxidant and anti-inflammatory properties. This study investigated the efficacy of CUR in mitigating MZ-induced hepatotoxicity and genotoxicity in rats. Twenty-four male rats were divided into four equal groups; group I (control) was given carboxymethyl cellulose, group II was orally administered CUR (100 mg/kg b.wt), group III was gavaged with MZ (750 mg/kg b.wt), and group IV was co-treated with MZ and CUR at the same doses daily for 10 weeks. As a result, the concurrent treatment with CUR and MZ minimized the increased levels of liver function markers in serum, lipid peroxidation, pro-inflammatory mediators and DNA damage parameters in liver. In addition, CUR administration improved the depleted markers of hepatic antioxidant status in MZ-treated rats. Moreover, CUR protected the liver against the histological alterations elicited by MZ exposure and also, reduced the immunopositive reactivity of pro-apoptotic p53 in cytoplasm of hepatocytes. The present findings suggest that CUR exerts a significant protective effect against MZ-induced hepatotoxicity and genotoxicity.


Assuntos
Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Curcumina/farmacologia , Dano ao DNA , Hepatócitos/efeitos dos fármacos , Maneb/toxicidade , Zineb/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Dano ao DNA/efeitos dos fármacos , Hepatócitos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/genética , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Ratos
18.
Ecotoxicol Environ Saf ; 183: 109465, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31376806

RESUMO

Our group found that long-term low-dose exposure to hexavalent chromium [Cr(VI)] in L-02 hepatocytes resulted in premature senescence, which accompanied by the increased expression of Clusterin (CLU), but the functional role of CLU in premature senescence has never been explored. In the present study, the CLU overexpressed or silenced L-02 hepatocytes were established by lentiviral vector transfection. Cell viability assay, cell cycle analysis, western blotting, plate clone formation assay, and confocal microcopy were performed. The results indicated that Cr(VI)-induced premature senescence was associated with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway inhibition, and high expression of CLU in the senescent cells exerted its functional role of promoting cell proliferation. CLU could complex with eukaryotic translation initiation factor 3 subunit I (EIF3I) and prevent its degradation, leading to the increase of AKT activity in Cr(VI)-exposed senescent hepatocytes. Blockage of the PI3K/AKT pathway with its inhibitor LY294002 eliminated the inhibitory effect of CLU on Cr(VI)-induced premature senescence. We concluded that high expression of CLU suppressed Cr(VI)-induced premature senescence through activation of PI3K/AKT pathway, which will provide the experimental basis for the study of Cr(VI)-induced liver cancer, especially for the elucidation of the mechanism of liver cancer cells escaping from senescence.


Assuntos
Senescência Celular/efeitos dos fármacos , Cromo/toxicidade , Clusterina/genética , Hepatócitos/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Senescência Celular/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
19.
Nihon Yakurigaku Zasshi ; 154(2): 72-77, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31406046

RESUMO

In drug disposition, the liver and small intestine are very important as tissues involving in drug metabolism, absorption, and excretion. Thus, in drug development studies, it is necessary to evaluate the pharmacokinetics in these tissues accurately including the contributions of drug-metabolizing enzymes and drug transporters. Currently, all kinds of evaluation systems have been used for the pharmacokinetic prediction; however, there are some issues in these systems. Therefore, the researches for the development of human induced pluripotent stem (iPS) cell-derived hepatocytes and enterocytes, as novel systems besides existing ones, are being advanced. Because human iPS cells have abilities of pluripotency and almost infinite proliferation, it is thought to be possible to stably provide the high-quality cells that have similar characteristics to human normal tissue cells by using human iPS cells. In this review, we describe current status of differentiation studies of human iPS cell-derived hepatocytes and enterocytes and the functional characteristics of these cells centered on pharmacokinetic functions.


Assuntos
Enterócitos/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Diferenciação Celular , Avaliação Pré-Clínica de Medicamentos , Enterócitos/citologia , Hepatócitos/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Intestino Delgado , Fígado , Farmacocinética
20.
Acta Cir Bras ; 34(6): e201900607, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31432998

RESUMO

PURPOSE: Coleus forskohlii Briq., a medicinal plant originally from India, has been indicated against heart disease, expiratory disorders, convulsions, and hepatic changes, among others. In view of the broad pharmacological potential of the plant and the scarce information about its effects, the objective of the present study was to investigate the effect of its use for pretreatment of partially hepatectomized rats. METHODS: The animals were divided into two experimental groups: Control (CG) receiving physiological saline for 10 days before partial hepatetctomy, and Treated (TG) receiving 40 mg Coleus forskohlii/kg/day for 10 days before partial hepatectomy. The treatments were performed by gastric gavage. After the surgical procedure, treatment was continued according to the following groups: CG 24 h, CG 48 h, TG 24 h, and TG 48 hs, and liver tissue and intracardiac blood samples were obtained for histological and biochemical analysis, respectively. RESULTS: No significant differences were observed in mitotic or apoptotic index or in the concentrations of the enzymes AST, ALT and alkaline phosphatase, and no areas of fibrosis were detected. CONCLUSION: Treatment with Coleus forskohlii did not interfere with the course of hepatic hyperplasia.


Assuntos
Hepatectomia/métodos , Fígado/patologia , Extratos Vegetais/administração & dosagem , Plectranthus/química , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Hepatócitos/efeitos dos fármacos , Hiperplasia/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/cirurgia , Masculino , Ratos
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