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1.
Ecotoxicol Environ Saf ; 186: 109749, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31622878

RESUMO

Hexavalent chromium [Cr(VI)] is a common heavy metal pollutant widely used in various industrial fields. It is well known that mitochondria are the most vulnerable targets of heavy metals, but the key molecule/event that directly mediated mitochondrial dysfunction after Cr(VI) exposure is still unclear. The present study was aimed to explore whether Cr(VI) exposure could affect the mitochondrial fission/fusion process, and whether the related abnormal mitochondrial dynamics have been implicated in Cr(VI)-induced mitochondrial dysfunction. We found that the mitochondrial dysfunction caused by Cr(VI) exposure was characterized by decreased mitochondrial respiratory chain complex (MRCC) I/II activities and levels, collapsed mitochondrial membrane potential (MMP), depleted ATP, and increased reactive oxygen species (ROS) level. Cr(VI) induced abnormal mitochondrial fission/fusion events, the antioxidant Nacetyl-L-cysteine (NAC) restored the abnormal mitochondrial function as well as the fission/fusion dynamics. ROS was the up-stream regulator of extracellular regulated protein kinases (ERK) signaling, and the application of a specific ERK1/2 inhibitor PD98059 confirmed that activation of ERK1/2 signaling was associated with the abnormal mitochondrial fission/fusion and mitochondrial dysfunction. We also demonstrated that treatment with dynamic-like protein 1 (DLP1)-siRNA rescued mitochondrial dysfunction in Cr(VI)-exposed L02 hepatocytes. We reached the conclusion that blockage of ROS-ERK-DLP1 signaling and mitochondrial fission alleviates Cr(VI)-induced mitochondrial dysfunction in L02 hepatocytes, which may provide the new avenue for developing effective strategies to protect against Cr(VI)-induced hepatotoxicity.


Assuntos
Antioxidantes/farmacologia , Cromo/toxicidade , Dinaminas/farmacologia , Fígado/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Carcinógenos Ambientais , Dinaminas/metabolismo , Flavonoides/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Humanos , Fígado/citologia , Fígado/metabolismo , Fígado/fisiopatologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/fisiologia , Dinâmica Mitocondrial/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais
2.
Immunity ; 51(4): 638-654.e9, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31561945

RESUMO

Macrophages are strongly adapted to their tissue of residence. Yet, little is known about the cell-cell interactions that imprint the tissue-specific identities of macrophages in their respective niches. Using conditional depletion of liver Kupffer cells, we traced the developmental stages of monocytes differentiating into Kupffer cells and mapped the cellular interactions imprinting the Kupffer cell identity. Kupffer cell loss induced tumor necrosis factor (TNF)- and interleukin-1 (IL-1) receptor-dependent activation of stellate cells and endothelial cells, resulting in the transient production of chemokines and adhesion molecules orchestrating monocyte engraftment. Engrafted circulating monocytes transmigrated into the perisinusoidal space and acquired the liver-associated transcription factors inhibitor of DNA 3 (ID3) and liver X receptor-α (LXR-α). Coordinated interactions with hepatocytes induced ID3 expression, whereas endothelial cells and stellate cells induced LXR-α via a synergistic NOTCH-BMP pathway. This study shows that the Kupffer cell niche is composed of stellate cells, hepatocytes, and endothelial cells that together imprint the liver-specific macrophage identity.


Assuntos
Células Endoteliais/fisiologia , Células Estreladas do Fígado/fisiologia , Hepatócitos/fisiologia , Macrófagos do Fígado/fisiologia , Fígado/citologia , Macrófagos/fisiologia , Monócitos/fisiologia , Animais , Comunicação Celular , Diferenciação Celular , Células Cultivadas , Microambiente Celular , Feminino , Regulação da Expressão Gênica , Proteínas Inibidoras de Diferenciação/genética , Proteínas Inibidoras de Diferenciação/metabolismo , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores Notch/metabolismo
3.
Biomed Environ Sci ; 32(8): 592-601, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31488235

RESUMO

OBJECTIVE: To investigate the development and characterizations of the hepatocytes isolated from fetal ovine and to determine the effect of hypoxia on their growth and metabolism. METHODS: Fresh hepatocytes were isolated from the liver of fetal ovine at late gestation, cultured in specific media, and exposed to normoxia (21% O2) or hypoxia (2% O2). The cellular characteristics and population purity were identified by immunocytochemistry and flow cytometry (FCM). The effects of hypoxia on cell cycle and apoptosis of the hepatocytes were evaluated by FCM, whereas the cellular ultrastructure changes were examined with a transmission electron microscope. RESULTS: The cell purity of hepatocytes was over 95%. Under hypoxia exposure, the hepatocytes showed a gradual increase in proportion at the S phase and in proliferative index, followed with a compatible increase in apoptosis and progressively decreased cell viability. Additionally, the organelles of the hepatocytes demonstrated dramatic changes, including swelling of mitochondria, disorder in cristae arrangement, expansion of endoplasmic reticulum, and a large number of circular lipid droplets emerging in the cytoplasm. CONCLUSION: Fetal ovine hepatocytes could be primarily cultured in a short-term culture system with a high purity of over 95% and with their preserved original characteristics. Hypoxia could induce changes in ultrastructural and inhibit the proliferation of cultured fetal ovine hepatocytes through apoptotic mechanisms.


Assuntos
Feto/fisiologia , Hepatócitos/fisiologia , Oxigênio/análise , Ovinos/fisiologia , Anaerobiose , Animais , Técnicas de Cultura de Células
4.
Elife ; 82019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31393263

RESUMO

Hepatocytes are regarded as the only effective cell source for cell transplantation to treat liver diseases; however, their availability is limited due to a donor shortage. Thus, a novel cell source must be developed. We recently reported that mature rodent hepatocytes can be reprogrammed into progenitor-like cells with a repopulative capacity using small molecule inhibitors. Here, we demonstrate that hepatic progenitor cells can be obtained from human infant hepatocytes using the same strategy. These cells, named human chemically induced liver progenitors (hCLiPs), had a significant repopulative capacity in injured mouse livers following transplantation. hCLiPs redifferentiated into mature hepatocytes in vitro upon treatment with hepatic maturation-inducing factors. These redifferentiated cells exhibited cytochrome P450 (CYP) enzymatic activities in response to CYP-inducing molecules and these activities were comparable with those in primary human hepatocytes. These findings will facilitate liver cell transplantation therapy and drug discovery studies.


Assuntos
Técnicas de Cultura de Células/métodos , Hepatócitos/fisiologia , Células-Tronco/fisiologia , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Humanos , Lactente , Fígado/lesões , Regeneração , Transplante de Células-Tronco , Resultado do Tratamento
6.
Dev Cell ; 50(1): 43-56.e6, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31231040

RESUMO

Two major functions of the epigenome are to regulate gene expression and to suppress transposons. It is unclear how these functions are balanced during physiological challenges requiring tissue regeneration, where exquisite coordination of gene expression is essential. Transcriptomic analysis of seven time points following partial hepatectomy identified the epigenetic regulator UHRF1, which is essential for DNA methylation, as dynamically expressed during liver regeneration in mice. UHRF1 deletion in hepatocytes (Uhrf1HepKO) caused genome-wide DNA hypomethylation but, surprisingly, had no measurable effect on gene or transposon expression or liver homeostasis. Partial hepatectomy of Uhrf1HepKO livers resulted in early and sustained activation of proregenerative genes and enhanced liver regeneration. This was attributed to redistribution of H3K27me3 from promoters to transposons, effectively silencing them and, consequently, alleviating repression of liver regeneration genes, priming them for expression in Uhrf1HepKO livers. Thus, epigenetic compensation safeguards the genome against transposon activation, indirectly affecting gene regulation.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/fisiologia , Metilação de DNA , Epigenômica , Regulação da Expressão Gênica , Hepatócitos/citologia , Regeneração Hepática , Ubiquitina-Proteína Ligases/fisiologia , Animais , Perfilação da Expressão Gênica , Hepatócitos/fisiologia , Masculino , Camundongos , Camundongos Knockout
7.
Int J Mol Sci ; 20(12)2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31248114

RESUMO

Sirt1 (Sirtuin 1), AMPK (AMP-activated protein kinase), and eNOS (endothelial nitric oxide synthase) modulate hepatic energy metabolism and inflammation and play a major role in the development of NASH. Cyclic nucleotide phosphodiesterases (PDEs) play an important role in signal transduction by modulating intracellular levels of cyclic nucleotides. We previously found the PDE5 inhibitor sildenafil to synergize with leucine and leucine-metformin combinations in preclinical studies of NASH and obesity. However, efficacy is diminished at higher sildenafil concentrations. Herein, we have successfully modeled the U-shaped sildenafil dose-response in vitro and utilized this model to assess potential mechanisms of this dose-response relationship. Adipocytes and liver cells were treated with leucine (0.5 mM) and different concentrations of sildenafil (1 nM to 100 µM). cAMP, cGMP, and P-AMPK protein expression were used to demonstrate the biphasic response for increasing concentrations of sildenafil. The reversal with higher sildenafil levels was blunted by PDE2 inhibition. These data indicate that sildenafil-mediated increases in cGMP inhibits PDE3 at lower concentrations, which increases cAMP. However, further increases in cGMP from higher sildenafil concentrations activate PDE2 and consequently decrease cAMP, which demonstrates crosstalk between cAMP and cGMP via PDE2, PDE3, and PDE5. These changes in cAMP concentration are further reflected in downstream effects, including AMPK activation.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Transdução de Sinais/efeitos dos fármacos , Citrato de Sildenafila/farmacologia , Animais , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Humanos , Camundongos
8.
Oxid Med Cell Longev ; 2019: 2301903, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214277

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is more sensitive to ischemia and reperfusion injury (IRI), while there are no effective methods to alleviate IRI. Necroptosis, also known as "programmed necrosis," incorporates features of necrosis and apoptosis. However, the role of necroptosis in IRI of the fatty liver remains largely unexplored. In the present study, we aimed to assess whether necroptosis was activated in the fatty liver and whether such activation accelerated IRI in the fatty liver. In this study, we found that the liver IRI was enhanced in HFD-fed mice with more release of TNFα. TNFα and supernatant of macrophages could induce necroptosis of hepatocytes in vitro. Necroptosis was activated in NAFLD, leading to more severe IRI, and such necroptosis could be inhibited by TN3-19.12, the neutralizing monoclonal antibody against TNFα. Pretreatment with Nec-1 and GSK'872, two inhibitors of necroptosis, significantly reduced the liver IRI and ROS production in HFD-fed mice. Moreover, the inhibition of necroptosis could decrease ROS production of hepatocytes in vitro. Inflammatory response was activated during IRI, and necroptosis inhibitors could suppress signaling pathways of inflammation and the soakage of inflammation cells. In conclusion, TNFα-induced necroptosis played an important role during IRI in the fatty liver. Our findings demonstrated that necroptosis might be a potential target to reduce the fatty liver-associated IRI.


Assuntos
Hepatócitos/fisiologia , Inflamação/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Traumatismo por Reperfusão/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Anticorpos Bloqueadores/farmacologia , Apoptose , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Humanos , Imidazóis/farmacologia , Indóis/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Espécies Reativas de Oxigênio/metabolismo
9.
Comput Biol Chem ; 80: 364-373, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31103917

RESUMO

Grouped gene selection is the most important task for analyzing the microarray data of rat liver regeneration. Many existing gene selection methods cannot outstand the interactions among the selected genes. In the process of rat liver regeneration, one of the most important events involved in many biological processes is the proliferation of rat hepatocytes, so it can be used as a measure of the effectiveness of the method. Here we proposed an adaptive sparse group lasso to select genes in groups for rat hepatocyte proliferation. The weighted gene co-expression networks analysis was used to identify modules corresponding to gene pathways, based on which a strategy of dividing genes into groups was proposed. A strategy of adaptive gene selection was also presented by assessing the gene significance and introducing the adaptive lasso penalty. Moreover, an improved blockwise descent algorithm was proposed. Experimental results demonstrated that the proposed method can improve the classification accuracy, and select less number of significant genes which act jointly in groups and have direct or indirect effects on rat hepatocyte proliferation. The effectiveness of the method was verified by the method of rat hepatocyte proliferation.


Assuntos
Proliferação de Células/genética , Perfilação da Expressão Gênica/métodos , Hepatócitos/fisiologia , Regeneração Hepática/genética , Algoritmos , Animais , Expressão Gênica , Redes Reguladoras de Genes , Ratos
10.
Int J Mol Sci ; 20(10)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137617

RESUMO

Liver regeneration plays a significant role in protecting liver function after liver injury or chronic liver disease. Long non-coding RNAs (lncRNAs) are considered to be involved in the proliferation of hepatocytes and liver regeneration. Therefore, this study aimed to explore the effects of LncRNA-Dreh on the regulation of hepatic progenitor cells (HPCs) during liver regeneration in rats. Initially, the rat model of liver injury was established to investigate the effect of LncRNA-Dreh down-regulation on liver tissues of rats with liver injury. Subsequently, HPCs line WB-F344 cells were transfected with interference plasmid of LncRNA-Dreh and the expression of LncRNA-Dreh and Vimentin was detected. The proliferation and migration ability of WB-F344 cells, as well as the content of albumin (ALB) and alpha fetoprotein (AFP) in cell differentiation were then determined. Disorderly arranged structure of liver tissue, a large number of HPCs set portal area as center extended to hepatic lobule and ductular reaction were observed in liver tissues of rats with liver injury. The expression of LncRNA-Dreh decreased while Vimentin increased in liver tissues of rats with liver injury. Moreover, the proliferation and migration ability, expression of Vimentin and AFP in WB-F344 cells were increased after silencing of LncRNA-Dreh and ALB was decreased. Collectively, our findings demonstrate that inhibition of LncRNA-Dreh can enhance the proliferation and migration abilities of HPCs in liver regeneration but cause abnormal differentiation of HPCs.


Assuntos
Movimento Celular , Proliferação de Células , Hepatócitos/metabolismo , Regeneração Hepática , RNA Longo não Codificante/genética , Células-Tronco/metabolismo , Animais , Linhagem Celular , Hepatócitos/fisiologia , Masculino , RNA Longo não Codificante/metabolismo , Ratos , Ratos Sprague-Dawley , Células-Tronco/fisiologia , Vimentina/genética , Vimentina/metabolismo
11.
J Anim Physiol Anim Nutr (Berl) ; 103(4): 1251-1262, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31087708

RESUMO

MicroRNAs (miRNAs) are a class of single-stranded non-coding small RNA molecules, which participate in the regulation of many physiological processes, and play a crucial role in cancer, metabolism and other processes. Rno-miR-425-5p has been shown to play a role in the response to cold stress. To explore the mechanism by which rno-miR-425-5p regulates the response to cold stress, we analysed the candidate target genes of rno-miR-425-5p. After verification in rat hepatocyte BRL cells and in rat liver tissue, we identified several target genes that were altered in expression in response to cold stress. In rat liver tissue, the expression of rno-miR-425-5p was significantly increased and the expression levels of target genes DLST and SLC16A1 were decreased under cold stress. The miRNA and mRNA levels were analysed by quantitative real-time PCR and the protein levels were detected by Western blot analysis. Combined with the results of bioinformatic analysis, we concluded that rno-miR-425-5p reduced the expression of DLST and SLC16A1, inhibiting energy release from the tricarboxylic acid cycle and preventing the liver from being injured by excessive energy mobilization.


Assuntos
Aciltransferases/metabolismo , Temperatura Baixa , MicroRNAs/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Estresse Fisiológico , Simportadores/metabolismo , Aciltransferases/genética , Animais , Linhagem Celular , Resposta ao Choque Frio , Biologia Computacional , Metabolismo Energético , Regulação da Expressão Gênica , Hepatócitos/fisiologia , Ciência dos Animais de Laboratório , Hepatopatias , Masculino , Transportadores de Ácidos Monocarboxílicos/genética , Distribuição Aleatória , Ratos , Organismos Livres de Patógenos Específicos , Simportadores/genética
12.
Science ; 364(6438): 399-402, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31023926

RESUMO

The maintenance of terminally differentiated cells, especially hepatocytes, in vitro has proven challenging. Here we demonstrated the long-term in vitro maintenance of primary human hepatocytes (PHHs) by modulating cell signaling pathways with a combination of five chemicals (5C). 5C-cultured PHHs showed global gene expression profiles and hepatocyte-specific functions resembling those of freshly isolated counterparts. Furthermore, these cells efficiently recapitulated the entire course of hepatitis B virus (HBV) infection over 4 weeks with the production of infectious viral particles and formation of HBV covalently closed circular DNA. Our study demonstrates that, with a chemical approach, functional maintenance of PHHs supports long-term HBV infection in vitro, providing an efficient platform for investigating HBV cell biology and antiviral drug screening.


Assuntos
Vírus da Hepatite B/crescimento & desenvolvimento , Hepatócitos/fisiologia , Hepatócitos/virologia , Cultura Primária de Células/métodos , Cultura de Vírus/métodos , Antivirais/isolamento & purificação , Antivirais/farmacologia , DNA Circular/biossíntese , DNA Circular/isolamento & purificação , DNA Viral/biossíntese , DNA Viral/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos , Vírus da Hepatite B/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Transcriptoma , Vírion/efeitos dos fármacos , Vírion/crescimento & desenvolvimento
13.
Nutrients ; 11(4)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30979078

RESUMO

: Autophagy plays a role in several physiological and pathological processes as it controls the turnover rate of cellular components and influences cellular homeostasis. The liver plays a central role in controlling organisms' metabolism, regulating glucose storage, plasma proteins and bile synthesis and the removal of toxic substances. Liver functions are particularly sensitive to autophagy modulation. In this review we summarize studies investigating how autophagy influences the hepatic metabolism, focusing on fat accumulation and lipids turnover. We also describe how autophagy affects bile production and the scavenger function within the complex homeostasis of the liver. We underline the role of hepatic autophagy in counteracting the metabolic syndrome and the associated cardiovascular risk. Finally, we highlight recent reports demonstrating how the autophagy occurring within the liver may affect skeletal muscle homeostasis as well as different extrahepatic solid tumors, such as melanoma.


Assuntos
Autofagia/fisiologia , Células Epiteliais/fisiologia , Homeostase/fisiologia , Fígado/citologia , Ductos Biliares/citologia , Morte Celular , Dieta , Dislipidemias , Células Endoteliais/fisiologia , Ingestão de Energia , Hepatócitos/fisiologia , Humanos , Macrófagos do Fígado/fisiologia , Metabolismo dos Lipídeos/fisiologia , Lipólise , Melanoma , Músculo Esquelético/metabolismo , Neoplasias , Estresse Oxidativo
14.
Elife ; 82019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30990169

RESUMO

Hepatocellular carcinoma (HCC) is a deadly human cancer associated with chronic inflammation. The cytosolic pathogen sensor NLRP12 has emerged as a negative regulator of inflammation, but its role in HCC is unknown. Here we investigated the role of NLRP12 in HCC using mouse models of HCC induced by carcinogen diethylnitrosamine (DEN). Nlrp12-/- mice were highly susceptible to DEN-induced HCC with increased inflammation, hepatocyte proliferation, and tumor burden. Consistently, Nlrp12-/- tumors showed higher expression of proto-oncogenes cJun and cMyc and downregulation of tumor suppressor p21. Interestingly, antibiotics treatment dramatically diminished tumorigenesis in Nlrp12-/- mouse livers. Signaling analyses demonstrated higher JNK activation in Nlrp12-/- HCC and cultured hepatocytes during stimulation with microbial pattern molecules. JNK inhibition or NLRP12 overexpression reduced proliferative and inflammatory responses of Nlrp12-/- hepatocytes. In summary, NLRP12 negatively regulates HCC pathogenesis via downregulation of JNK-dependent inflammation and proliferation of hepatocytes.


Assuntos
Carcinoma Hepatocelular/fisiopatologia , Regulação para Baixo , Hepatócitos/enzimologia , Hepatócitos/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , Neoplasias Hepáticas/fisiopatologia , Animais , Carcinógenos/administração & dosagem , Carcinoma Hepatocelular/induzido quimicamente , Proliferação de Células , Dietilnitrosamina/administração & dosagem , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Neoplasias Hepáticas/induzido quimicamente , Camundongos Knockout , Proteínas Proto-Oncogênicas c-myc/metabolismo
15.
Phytomedicine ; 61: 152841, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31035043

RESUMO

BACKGROUND: 14-Deoxy-11,12-didehydroandrographolide (deAND) is the second most abundant diterpenoid in Andrographis paniculata (Burm. f.) Nees, a traditional medicine used in Asia. To date, the biological activity of deAND has not been clearly investigated. PURPOSE: In this study, we intended to examine the modulatory effect of deAND on hepatic drug metabolism as well as its bioavailability. STUDY DESIGN: deAND prepared from A. paniculata was orally given to Sprague-Dawley rats and changes in plasma deNAD were determined by HPLC-MS. Modulation of deAND on drug-metabolizing enzyme and drug transporter expression as well as the possible mechanism involved was examined in primary rat hepatocytes. RESULTS: After a single oral administration of 50 mg/kg deAND to rats, the maximum plasma concentration (Cmax), time to reach the Cmax, area under the curve (AUC0-24h), mean retention time, and half-life (t1/2) of deAND were 2.65 ± 0.68 µg/ml, 0.29 ± 0.15 h, 6.30 ± 1.66 µg/ml•h, 5.55 ± 2.52 h, and 3.56 ± 1.05 h, respectively. The oral bioavailability was 3.42%. In primary rat hepatocytes treated with up to 10 µM deAND, a dose-dependent increase was noted in the expression of cytochrome P450 (CYP) 1A1/2, CYP2C6, and CYP3A1/2; UDP-glucuronosyltransferase (UGT) 1A1, NAD(P)H:quinone oxidoreductase (NQO1), π form of GSH S-transferase (GSTP), multidrug resistance-associated protein 2, p-glycoprotein, and organic anion transporter protein 2B1. Immunoblotting assay and EMSA revealed that deAND increases the nuclear translocation and DNA binding activity of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and nuclear factor erythroid-derived 2-related factor 2 (Nrf2). Knockdown of AhR and Nrf2 expression abolished deAND induction of CYP isozymes and UGT1A1, NQO1, and GSTP expression, respectively. CONCLUSION: These results indicate that deAND quickly passes through enterocytes in rats and effectively up-regulates hepatic drug-metabolizing enzyme and drug transporter expression in an AhR-, PXR-, and Nrf2-dependent manner.


Assuntos
Diterpenos/farmacocinética , Enzimas/metabolismo , Hepatócitos/efeitos dos fármacos , Administração Oral , Andrographis/química , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Disponibilidade Biológica , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Diterpenos/administração & dosagem , Diterpenos/sangue , Enzimas/genética , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Hepatócitos/fisiologia , Inativação Metabólica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Ratos Sprague-Dawley , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Regulação para Cima/efeitos dos fármacos
16.
Biotechnol J ; 14(7): e1800347, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30957976

RESUMO

Recent research has shown that the maintenance of relevant liver functions ex vivo requires models in which the cells exhibit an in vivo-like phenotype, often achieved by reconstitution of appropriate cellular interactions. Multiple different models have been presented that differ in the cells utilized, media, and culture conditions. Furthermore, several technologically different approaches have been presented including bioreactors, chips, and plate-based systems in fluidic or static media constituting of chemically diverse materials. Using such models, the ability to predict drug metabolism, drug toxicity, and liver functionality have increased tremendously as compared to conventional in vitro models in which cells are cultured as 2D monolayers. Here, the authors highlight important considerations for microphysiological systems for primary hepatocyte culture, review current culture paradigms, and discuss their opportunities for studies of drug metabolism, hepatotoxicity, liver biology, and disease.


Assuntos
Técnicas de Cultura de Células , Hepatócitos , Modelos Biológicos , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Humanos , Dispositivos Lab-On-A-Chip , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Esferoides Celulares/citologia , Esferoides Celulares/metabolismo , Esferoides Celulares/fisiologia , Testes de Toxicidade
17.
World J Gastroenterol ; 25(9): 1037-1049, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30862993

RESUMO

The liver has a high regenerative capacity after acute liver injury, but this is often impaired during chronic liver injury. The existence of a dedicated liver stem cell population that acts as a source of regeneration during chronic liver injury has been controversial. Recent advances in transgenic models and cellular reprogramming have provided new insights into the plasticity of the liver epithelium and directions for the development of future therapies. This article will highlight recent findings about the cellular source of regeneration during liver injury and the advances in promoting liver regeneration.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Regeneração Hepática/fisiologia , Fígado/fisiologia , Células-Tronco/fisiologia , Animais , Reprogramação Celular/fisiologia , Epitélio/fisiologia , Hepatócitos/fisiologia , Humanos , Fígado/citologia , Modelos Animais
18.
J Immunol Res ; 2019: 7657294, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906791

RESUMO

Macrophages are the master regulator of the dynamic fibrogenesis-fibrosis resolution paradigm. TNF-like ligand 1 aberrance (TL1A) was found to be able to induce intestinal inflammation and fibrosis. Furthermore, significantly increased TL1A had been detected in liver tissues and mononuclear cells of patients with primary biliary cirrhosis (PBC). This study was to investigate the effect of myeloid cells with constitutive TL1A expression on liver fibrogenesis. We found that TL1A expressions in liver tissues and macrophages were significantly increased in mice with liver fibrosis induced by injection of carbon tetrachloride (CCl4). TL1A overexpression in myeloid cells induced liver function injury, accelerated the necrosis and apoptosis of hepatocytes, recruited macrophages, and promoted activation of hepatic stellate cells (HSCs) and fibrosis. In vitro results of our study showed that TL1A overexpression in macrophages promoted secretion of platelet-derived growth factor-BB (PDGF-BB), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß). Culturing macrophages with TL1A overexpression could accelerate the activation and proliferation of primary HSCs. These results indicated that constitutive TL1A expression in myeloid cells exacerbated liver fibrosis, probably through macrophage recruitment and secretion of proinflammatory and profibrotic cytokines.


Assuntos
Hepatócitos/fisiologia , Inflamação/metabolismo , Cirrose Hepática Biliar/metabolismo , Fígado/patologia , Macrófagos/imunologia , Células Mieloides/fisiologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Animais , Apoptose , Becaplermina/metabolismo , Tetracloreto de Carbono/toxicidade , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Humanos , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/metabolismo
19.
Int Immunopharmacol ; 70: 435-445, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30856394

RESUMO

BACKGROUND: Hepatic ischemia/reperfusion (IR) injury is a common medical phenomenon that occurs during a number of clinical conditions, such as liver transplantation, severe injuries, and shock. In our study, we determined the protective functions of levo-tetrahydropalmatine (L-THP) on hepatic IR injury in mice by inhibiting the ERK/NF-κB signaling pathway. METHOD: BALB/c mice were randomly divided into six groups as follows: normal control (NC); sham; L-THP (40 mg/kg); IR; L-THP (20 mg/kg) + IR; and L-THP (40 mg/kg) + IR. Liver tissues and sera were collected at three time points after reperfusion (2, 8, and 24 h). The liver enzyme, inflammatory factor, and other protein levels in the serum and liver tissues were detected. RESULTS: L-THP pretreatment alleviated hepatocyte injury caused by IR and reduced the production of proinflammatory cytokines, such as IL-6 and TNF-α. Furthermore, L-THP could inhibit the ERK/NF-κB signaling pathway to attenuate hepatocyte apoptosis and autophagy. And the protective effect of L-THP is positively correlated with its dose. CONCLUSION: L-THP protects the liver from IR injury by inhibiting the release of inflammatory factors and alleviating liver cell apoptosis and autophagy. The protective functions of L-THP may be partly based on the downregulation of the ERK/NF-κB pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Hepatócitos/efeitos dos fármacos , Fígado/fisiologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Células Cultivadas , Hepatócitos/fisiologia , Humanos , Interleucina-6/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Mycotoxin Res ; 35(2): 197-205, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30806951

RESUMO

This work studied the effect of deoxynivalenol (DON) and two of its acetylated analogs (3-ADON, 15-ADON) on first indicators of oxidative stress status, namely production of reactive oxygen species (ROS) and induction of lipid peroxidation (LPO), in HepG2 cells. HepG2 cells were exposed to different concentrations of the three toxins, either alone or in combinations, for 24, 48, and 72 h. Results of cytotoxicity obtained in HepG2 cells were correlated with the detection of ROS and LPO. This effect was inversely correlated with ROS while directly correlated with LPO for the assayed mycotoxins in individual treatment. Combinations of two toxins containing 15-ADON yielded highest values, while for two-toxin combinations with 3-ADON, the effects were minor. A combination of all three mycotoxins alleviated ROS production and the highest levels in LPO were detected, in association to a final breakdown of adaption of ROS early produced by HepG2. In conclusion, parameters of stress evaluation presented in this study (ROS and LPO), revealed increases in HepG2 cells exposed to DON, 3-ADON, and 15-ADON either individually or combined.


Assuntos
Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Micotoxinas/toxicidade , Estresse Oxidativo , Tricotecenos/toxicidade , Células Hep G2 , Humanos , Peroxidação de Lipídeos , Espécies Reativas de Oxigênio/metabolismo
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