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1.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(3): 471-475, 2021 Mar 25.
Artículo en Chino | MEDLINE | ID: mdl-33849842

RESUMEN

Polysaccharides are a group of compounds composed of multiple monosaccharides of the same or different structures combined by glycosidic bonds, and are widely found in animals and plants and in the cell walls of microorganisms. Polysaccharides possess the advantages of high safety and low toxicity. Recent studies revealed that polysaccharides have a wide range of biological activities including immunoregulation, anti-tumor, antiviral, antioxidant activities, and blood glucose-and lipid- lowering effects. The effects of polysaccharides in improving insulin sensitivity and regulating glucose and lipid metabolism have drawn much attention from researchers. Many polysaccharides can reduce blood glucose and blood lipid by repairing pancreatic islet cells, improving insulin resistance, regulating intestinal flora, enhancing antioxidant capacity, and regulating the activities of key enzymes in glucose and lipid metabolism. This reviews examines the role and mechanism of polysaccharides in regulating glucose and lipid metabolism. The mechanisms of polysaccharide in regulating glucose metabolism include repairing islet cells and increasing insulin content, increasing insulin sensitivity and improving insulin resistance, regulating the activity of key enzymes in glucose metabolism, increasing synthesis of liver glycogen, and regulating intestinal flora. Polysaccharides can also regulate glucose metabolism by improving immune regulation and antagonizing glucagon. Polysaccharide also regulate lipid metabolism by regulating lipid absorption, expression of the related genes such as PPAR-α, enzyme activities in lipid metabolism, improving antioxidant capacity, and modulating intestinal flora and signaling pathways.


Asunto(s)
Glucosa , Resistencia a la Insulina , Animales , Glucemia/metabolismo , Glucosa/metabolismo , Insulina , Metabolismo de los Lípidos , Hígado/metabolismo , Polisacáridos/farmacología
2.
Methods Mol Biol ; 2269: 139-150, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33687677

RESUMEN

The gold standard for organ preservation before transplantation is static cold storage, which is unable to fully protect suboptimal livers from ischemia/reperfusion injury. An emerging alternative is normothermic machine perfusion (NMP), which permits organ reconditioning. The ex vivo NMP hypoxic Rat Liver Perfusion Model represents a feasible approach that allow pharmacological intervention on isolated rat livers by using a combination of NMP and infusion of a number of drugs and/or biological material (cells, microvesicles, etc.). The combination of these two techniques may not only be applied for tissue preservation purposes, but also to investigate the biological effects of molecules and treatment useful in tissue protection. The protocol describes an ex vivo murine model of NMP capable of maintaining liver function despite an ongoing hypoxic injury induced by hemodilution. Furthermore, with this NMP system it is possible to deliver cells treatment or pharmacological intervention to an ex vivo perfused liver and suggests that could represent an innovative approach to recondition organs.


Asunto(s)
Hepatopatías/metabolismo , Hígado/metabolismo , Daño por Reperfusión/metabolismo , Animales , Modelos Animales de Enfermedad , Hígado/patología , Hepatopatías/patología , Masculino , Ratones , Preservación de Órganos , Perfusión , Ratas , Ratas Wistar , Daño por Reperfusión/patología
3.
Methods Mol Biol ; 2269: 151-165, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33687678

RESUMEN

Human mesenchymal stromal cells (MSC) are adult stem cells, which feature hepatotropism by supporting liver regeneration through amelioration of hepatic inflammation and lipid accumulation in a mouse model of non-alcoholic steatohepatitis (NASH), a more advanced stage of fatty liver. It remains open, how MSC impact on hepatocytic lipid metabolism. To study MSC actions on fatty liver mechanistically, we established an in vitro model of co-culture comprising MSC and isolated mouse hepatocytes at a ratio of 1:1. Lipid storage in hepatocytes was induced by the treatment with medium deficiency of methionine and choline (MCD). The protocol can be adapted for the use of other lipid storage-inducing agents such as palmitic acid and linoleic acid. This co-culture model allows to study, e.g., whether MSC act indirectly via MSC-born paracrine mechanisms or through direct physical interactions between cells beside others. The protocol allows us to detect the formation of extensions (filopodia) from MSC to contact the fatty hepatocytes or other MSC within 24 h of co-culture. These structures may represent tunneling nanotubes (TNT), allowing for long-range intercellular communication.


Asunto(s)
Hepatocitos/metabolismo , Hígado/metabolismo , Células Madre Mesenquimatosas/metabolismo , Modelos Biológicos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Comunicación Paracrina , Animales , Técnicas de Cocultivo , Hepatocitos/patología , Humanos , Hígado/patología , Células Madre Mesenquimatosas/patología , Ratones , Enfermedad del Hígado Graso no Alcohólico/patología
4.
Nat Commun ; 12(1): 1658, 2021 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-33712578

RESUMEN

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses.


Asunto(s)
Relojes Biológicos/fisiología , Ritmo Circadiano/fisiología , Virus de la Hepatitis B/fisiología , Replicación Viral/fisiología , Animales , Relojes Biológicos/efectos de los fármacos , Relojes Biológicos/genética , Ritmo Circadiano/genética , ADN Circular , ADN Viral/metabolismo , Regulación de la Expresión Génica , Genoma Viral , Células Hep G2 , Hepatitis B/virología , Virus de la Hepatitis B/genética , Hepatitis B Crónica/genética , Hepatocitos/metabolismo , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/fisiología , Humanos , Hígado/metabolismo , Ratones , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Regiones Promotoras Genéticas , Simportadores/metabolismo , Transcriptoma , Virión/metabolismo , Internalización del Virus
5.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670590

RESUMEN

Weight control based on dietary restriction (DR) alone can cause lipid metabolic failure and progression to fatty liver. This study aimed to investigate the effect of exercise on preventing DR-induced hepatic fat accumulation in Zucker fatty (ZF) rats by focusing on the relationship between adipose tissue lipolysis and hepatic fat uptake. Six-week-old male ZF rats were randomly assigned to obese, DR, or DR with exercise (DR + Ex) groups. The DR and DR + Ex groups were fed a restricted diet, with the latter also undergoing voluntary exercise. After 6 weeks, hepatic fat accumulation was observed in the DR group, whereas intrahepatic fat was markedly reduced in the DR + Ex group. Compared with the obese (Ob) group, the DR group exhibited 2.09-fold expression of hepatic fatty acid translocase (FAT)/CD36 proteins (p < 0.01) and 0.14-fold expression of hepatic fatty acid-binding protein (FABP)1 (p < 0.01). There were no significant differences between the DR + Ex group and the Ob group. FAT/CD36 and hepatic triglyceride (TG) expression levels were strongly positively correlated (r = 0.81, p < 0.001), whereas there was a strong negative correlation between FABP1 and hepatic TG expression levels (r = -0.65, p < 0.001). Our results suggest that hepatic fat accumulation induced by DR in ZF rats might be prevented through exercise-induced modifications in FAT/CD36 and FABP1 expression.


Asunto(s)
Tejido Adiposo/metabolismo , Dietoterapia/métodos , Hígado Graso/metabolismo , Hígado/metabolismo , Condicionamiento Físico Animal/fisiología , Animales , Antígenos CD36/metabolismo , Proteínas de Unión a Ácidos Grasos/metabolismo , Hígado Graso/fisiopatología , Hígado Graso/prevención & control , Obesidad/metabolismo , Factores Protectores , Ratas Zucker , Triglicéridos/metabolismo
6.
Zhonghua Gan Zang Bing Za Zhi ; 29(2): 163-168, 2021 Feb 20.
Artículo en Chino | MEDLINE | ID: mdl-33685086

RESUMEN

Objective: To investigate the role of 1, 25-dihydroxyvitamin D3 [1.25(OH) (2)D(3)] in liver lipid metabolism so as to provide the clues for elucidating the mechanism of non-alcoholic fatty liver. Methods: 26 SD rats were randomly divided into control group (methionine-choline-sufficient diet, MCS), model group (methionine-choline-deficiency diet, MCD) and intervention group [MCD+1.25(OH) (2)D(3)]. The intervention, control, and model group was given 3 ng/100 g 1.25(OH) (2)D(3) peanut oil solution per day by gavage according to body mass. After 4 weeks the experiment was ended up, and the blood was collected from the inferior vena cava to detect alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The liver tissue was collected to observe the liver morphological and pathological changes (oil red O and HE staining). The changes in the level of liver total triglyceride (TG) content and liver lipid metabolism-related genes [fatty acid transfer protein (FAT/CD36), acetyl-coenzyme A carboxylase (ACC1)] mRNA and protein were detected. One-way analysis of variance was used to compare the means between groups. Results: Oil red O staining and HE staining showed that lipid droplet-vacuoles were significantly increased in the liver tissue of the model group than that of the intervention group. The liver TG content (2.23 ± 0.98) µmol/g of the intervention group was significantly lower than that of the model group (3.53 ± 1.06) µmol/g (F = 5.930, P = 0.035). The ALT content of the intervention group (35.99±9.54) U/L was significantly lower than that of the model group (57.65 ± 19.42) U/L (F = 13.790, P = 0.034). The AST content of the intervention group (16.9 ± 3.73) U/L was significantly lower than that of the model group (27.81 ± 13.31) U/L (F = 3.084, P = 0.046). The relative expression levels of mRNA and protein (mRNA: 1.21 ± 0.61, protein: 1.54 ± 0.75) of FAT/CD36 in the intervention group were significantly lower than those of the model group (mRNA: 2.31 ± 0.81, protein: 2.83 ± 1.42) (mRNA: F = 8.370, P = 0.001, protein: F = 7.212, P = 0.043). The relative expression level of mRNA and protein of ACC1 (mRNA: 0.89 ± 0.54, protein: 0.28 ± 0.11) were also significantly lower than those in model group (mRNA: 1.39 ± 0.19, protein: 0.47 ± 0.24) (mRNA: F = 3.948, P = 0.036, protein: F = 10.933, P = 0.048). Conclusion: 1.25(OH) (2)D(3) can reduce liver fat deposition in rats fed with MCD by inhibiting the expression of fat / CD36 and ACC1.


Asunto(s)
Metabolismo de los Lípidos , Enfermedad del Hígado Graso no Alcohólico , Animales , Colina/metabolismo , Dieta , Hígado/metabolismo , Metionina/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ratas , Ratas Sprague-Dawley
7.
Nat Commun ; 12(1): 1518, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750796

RESUMEN

Growing evidences suggest that cancer stem cells exhibit many molecular characteristics and phenotypes similar to their ancestral progenitor cells. In the present study, human embryonic stem cells are induced to differentiate into hepatocytes along hepatic lineages to mimic liver development in vitro. A liver progenitor specific gene, RALY RNA binding protein like (RALYL), is identified. RALYL expression is associated with poor prognosis, poor differentiation, and metastasis in clinical HCC patients. Functional studies reveal that RALYL could promote HCC tumorigenicity, self-renewal, chemoresistance, and metastasis. Moreover, molecular mechanism studies show that RALYL could upregulate TGF-ß2 mRNA stability by decreasing N6-methyladenosine (m6A) modification. TGF-ß signaling and the subsequent PI3K/AKT and STAT3 pathways, upregulated by RALYL, contribute to the enhancement of HCC stemness. Collectively, RALYL is a liver progenitor specific gene and regulates HCC stemness by sustaining TGF-ß2 mRNA stability. These findings may inspire precise therapeutic strategies for HCC.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo C/metabolismo , Neoplasias Hepáticas/metabolismo , Estabilidad del ARN/fisiología , Factor de Crecimiento Transformador beta2/metabolismo , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular , Células Madre Embrionarias , Femenino , Regulación Neoplásica de la Expresión Génica , Ribonucleoproteína Heterogénea-Nuclear Grupo C/genética , Humanos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones , Persona de Mediana Edad , Células Madre Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/genética , Regulación hacia Arriba
8.
Cell Prolif ; 54(4): e13022, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33686740

RESUMEN

OBJECTIVES: This study aimed to investigate the protective effect of SCARF1 on acute rejection (AR), phagocytic clearance of Kupffer cells (KCs), M2 polarization and the exact mechanism underlying these processes. METHODS: AAV was transfected into the portal vein of rats, and AR and immune tolerance (IT) models of liver transplantation were established. Liver tissue and blood samples were collected. The level of SCARF1 was detected via WB and immunohistochemical staining. Pathological changes in liver tissue were detected using HE staining. Apoptotic cells were detected using TUNEL staining. KC polarization was assessed via immunohistochemical staining. Primary KCs were isolated and co-cultured with apoptotic T lymphocytes. Phagocytosis of apoptotic cells and polarization of KCs were both detected using immunofluorescence. Calcium concentration was determined using immunofluorescence and a fluorescence microplate reader. The levels of PI3K, p-AKT and P-STAT3 were assessed via WB and immunofluorescence. RESULTS: Compared to the IT group, the level of SCARF1 was significantly decreased in the AR group. Overexpression of SCARF1 in KCs improved AR and liver function markers. Enhanced phagocytosis mediated by SCARF1 is beneficial for improving the apoptotic clearance of AR and promoting M2 polarization of KCs. SCARF1-mediated enhancement of phagocytosis promotes increased calcium concentration in KCs, thus further activating the PI3K-AKT-STAT3 signalling pathway. CONCLUSIONS: SCARF1 promotes the M2 polarization of KCs by promoting phagocytosis through the calcium-dependent PI3K-AKT-STAT3 signalling pathway.


Asunto(s)
Calcio/metabolismo , Trasplante de Hígado , Receptores Depuradores de Clase F/metabolismo , Transducción de Señal , Animales , Apoptosis , Polaridad Celular , Células Cultivadas , Técnicas de Cocultivo , Macrófagos del Hígado/citología , Macrófagos del Hígado/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Fagocitosis , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Endogámicas Lew , Factor de Transcripción STAT3/metabolismo , Receptores Depuradores de Clase F/genética , Linfocitos T/citología , Linfocitos T/metabolismo
9.
Cell Prolif ; 54(4): e13021, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33751704

RESUMEN

Although the liver is the only organ with regenerative capacity, various injury factors induce irreversible liver dysfunction and end-stage liver disease. Liver resection and liver transplantation (LT) are effective treatments for individuals with liver failure, liver cirrhosis and liver cancers. The remnant or transplanted liver tissues will undergo hepatic ischaemia/reperfusion (IR), which leads to oxidative stress, inflammation, immune injury and liver damage. Moreover, systemic ischaemia induced by trauma, stroke, myocardial ischaemia, haemorrhagic shock and other injury factors also induces liver ischaemia/reperfusion injury (IRI) in individuals. Hepatic IRI can be divided into warm IRI, which is induced by liver surgery and systemic ischaemia, and cold IRI, which is induced by LT. Multiple studies have shown that melatonin (MT) acts as an endogenous free radical scavenger with antioxidant capacity and is also able to attenuate hepatic IRI via its anti-inflammatory and antiapoptotic capacities. In this review, we discuss the potential mechanisms and current strategies of MT administration in liver surgery for protecting against warm or cold hepatic IRI. We highlight strategies to improve the efficacy and safety of MT for attenuating hepatic IRI in different conditions. After the potential mechanisms underlying the interactions between MT and other important cellular processes during hepatic IR are clarified, more opportunities will be available to use MT to treat liver diseases in the future.


Asunto(s)
Melatonina/uso terapéutico , Daño por Reperfusión/prevención & control , Antioxidantes/química , Apoptosis/efectos de los fármacos , Rechazo de Injerto/patología , Rechazo de Injerto/prevención & control , Humanos , Hígado/metabolismo , Hígado/patología , Melatonina/química , Melatonina/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacos
10.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670100

RESUMEN

Silver-based materials are widely used in clinical medicine. Furthermore, the usage of silver containing materials and devices is widely recommended and clinically approved. The impact on human health of the increasing use of silver nanoparticles in medical devices remains understudied, even though Ag-containing dressings are known to release silver into the bloodstream. In this study, we detected a widespread and sometimes significant silver accumulation both in healthy and sick liver biopsies, levels being statistically higher in patients with various hepatic pathologies. 28 healthy and 44 cirrhotic liver samples were investigated. The median amount of 0.049 ppm Ag in livers was measured in cirrhotic livers while the median was 0.0016 ppm for healthy livers (a more than 30-fold difference). The mean tissue concentrations of essential metals, Fe and Zn in cirrhotic livers did not differ substantially from healthy livers, while Cu was positively correlated with Ag. The serum levels of gamma-glutamyl transpeptidase (GGTP) was also positively correlated with Ag in cirrhotic livers. The increased Ag accumulation in cirrhotic livers could be a side effect of wide application of silver in clinical settings. As recent studies indicated a significant toxicity of silver nanoparticles for human cells, the above observation could be of high importance for the public health.


Asunto(s)
Cobre/metabolismo , Cirrosis Hepática/metabolismo , Trasplante de Hígado , Hígado/metabolismo , Plata/metabolismo , Adulto , Femenino , Humanos , Cirrosis Hepática/cirugía , Masculino , Persona de Mediana Edad
11.
Nat Commun ; 12(1): 1745, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741971

RESUMEN

Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation, tissue-specific persulfidome profiles and their associated functions are not well characterized, specifically under conditions and interventions known to modulate H2S production. We hypothesize that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific persulfidomes. Here, we find protein persulfidation enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking cystathionine γ-lyase (CGL) have overall decreased tissue protein persulfidation numbers and fail to functionally augment persulfidomes in response to DR, predominantly in kidney, muscle, and brain. Here, we define tissue- and CGL-dependent persulfidomes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.


Asunto(s)
Cistationina gamma-Liasa/química , Cistationina gamma-Liasa/metabolismo , Dieta , Proteínas/química , Proteínas/metabolismo , Envejecimiento/metabolismo , Animales , Encéfalo/metabolismo , Cistationina gamma-Liasa/genética , Sulfuro de Hidrógeno/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Longevidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculos/metabolismo , Proteínas/genética , Transcriptoma
12.
Nat Commun ; 12(1): 1455, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674593

RESUMEN

T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Metionina/metabolismo , Linfocitos T/metabolismo , Animales , Biomarcadores de Tumor , Linfocitos T CD8-positivos , Sistemas CRISPR-Cas , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Metionina Adenosiltransferasa/sangre , Metionina Adenosiltransferasa/genética , Metionina Adenosiltransferasa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , S-Adenosilmetionina/metabolismo , Transcriptoma
13.
Aquat Toxicol ; 233: 105792, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33662877

RESUMEN

Although anticoagulant rodenticides (ARs) are effectively used for the control of invasive rodents, nontarget species are also frequently exposed to ARs and secondary poisonings occur widely. However, little data is available on the effects of ARs, especially on marine organisms. To evaluate the effects of ARs on marine wildlife, we chose green sea turtles (Chelonia mydas), which are one of the most common marine organisms around the Ogasawara islands, as our primary study species. The sensitivity of these turtles to ARs was assessed using both in vivo and in vitro approaches. We administered 4 mg/kg of warfarin sodium either orally or intravenously to juvenile green sea turtles. The turtles exhibited slow pharmacokinetics, and prolongation of prothrombin time (PT) was observed only with intravenous warfarin administration. We also conducted an in vitro investigation using liver microsomes from green sea turtles, and two other turtle species (softshell turtle and red-eared slider) and rats. The cytochrome P450 metabolic activity in the liver of green sea turtles was lower than in rats. Additionally, vitamin K epoxide reductase (VKOR), which is the target enzyme of ARs, was inhibited by warfarin in the turtles at lower concentration levels than in rats. These data indicate that turtles may be more sensitive to ARs than rats. We expect that these findings will be helpful for sea turtle conservation following accidental AR-broadcast incidents.


Asunto(s)
Anticoagulantes/toxicidad , Errores Innatos del Metabolismo/sangre , Rodenticidas/toxicidad , Tortugas/sangre , Contaminantes Químicos del Agua/toxicidad , Animales , Resistencia a Medicamentos , Islas , Hígado/efectos de los fármacos , Hígado/metabolismo , Tiempo de Protrombina , Ratas , Medición de Riesgo , Tortugas/metabolismo
14.
Aquat Toxicol ; 233: 105788, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33662878

RESUMEN

The gene expression response thought to underlie the negative apical effects resulting from estrogen exposure have been thoroughly described in fish. Although epigenetics are believed to play a critical role translating environmental exposures into the development of adverse apical effects, they remain poorly characterized in fish species. This study investigated alterations of DNA methylation of estrogen receptor alpha (esr1) in brain and liver tissues from 8 to 10 month old male fathead minnows (Pimephales promelas) after a 2d exposure to either 2.5 ng/L or 10 ng/L 17α-ethynylestradiol (EE2). Changes in the patterns of methylation were evaluated using targeted deep sequencing of bisulfite treated DNA in the 5' region of esr1. Methylation and gene expression were assessed at 2d of exposure and after a 7 and 14d depuration period. After 2d EE2 exposure, males exhibited significant demethylation in the 5' upstream region of esr1 in liver tissue, which was inversely correlated to gene expression. This methylation pattern reflected what was seen in females. No gene body methylation (GBM) was observed for liver of exposed males. Differential methylation was observed for a single upstream CpG site in the liver after the 14d depuration. A less pronounced methylation response was observed in the upstream region in brain tissue, however, several CpGs were necessarily excluded from the analysis. In contrast to the liver, a significant GBM response was observed across the entire gene body, which was sustained until at least 7d post-exposure. No differential expression was observed in the brain, limiting functional interpretation of methylation changes. The identification of EE2-dependent changes in methylation levels strongly suggests the importance of epigenetic mechanisms as a mediator of the organismal response to environmental exposures and the need for further characterization of the epigenome. Further, differential methylation following depuration indicates estrogenic effects persist well after the active exposure, which has implications for the risk posed by repeated exposures..


Asunto(s)
Cyprinidae/metabolismo , Metilación de ADN/efectos de los fármacos , Receptor alfa de Estrógeno/genética , Etinilestradiol/toxicidad , Expresión Génica/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cyprinidae/genética , Estrógenos/metabolismo , Femenino , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Vitelogeninas/metabolismo
15.
Molecules ; 26(4)2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33671486

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is among the leading causes of end-stage liver disease. The impaired hepatic lipid metabolism in NAFLD is exhibited by dysregulated PPARα and SREBP-1c signaling pathways, which are central transcription factors associated with lipid degradation and de novo lipogenesis. Despite the growing prevalence of this disease, current pharmacological treatment options are unsatisfactory. Genistein, a soy isoflavone, has beneficial effects on lipid metabolism and may be a candidate for NAFLD treatment. In an in vitro model of hepatic steatosis, primary human hepatocytes (PHHs) were incubated with free fatty acids (FFAs) and different doses of genistein. Lipid accumulation and the cytotoxic effects of FFAs and genistein treatment were evaluated by colorimetric and enzymatic assays. Changes in lipid homeostasis were examined by RT-qPCR and Western blot analyses. PPARα protein expression was induced in steatotic PHHs, accompanied by an increase in CPT1L and ACSL1 mRNA. Genistein treatment increased PPARα protein expression only in control PHHs, while CPTL1 and ACSL1 were unchanged and PPARα mRNA was reduced. In steatotic PHHs, genistein reversed the increase in activated SREBP-1c protein. The model realistically reflected the molecular changes in hepatic steatosis. Genistein suppressed the activation of SREBP-1c in steatotic hepatocytes, but the genistein-mediated effects on PPARα were abolished by high hepatic lipid levels.


Asunto(s)
Hígado Graso/tratamiento farmacológico , Genisteína/farmacología , Hígado/efectos de los fármacos , Modelos Biológicos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Hígado Graso/metabolismo , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/antagonistas & inhibidores , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo
16.
Int J Mol Sci ; 22(4)2021 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668478

RESUMEN

Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation techniques may improve rheological properties of the post-reperfusion hepatic blood flow and target endothelial cells, exerting a potent protection against hepatic IRI. In this review paper we give a comprehensive overview of microcirculatory, rheological and molecular-pathophysiological aspects of hepatic circulation in the context of IRI and hepatoprotective approaches.


Asunto(s)
Hígado/metabolismo , Preservación de Órganos , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Animales , Velocidad del Flujo Sanguíneo , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Humanos , Hígado/patología , Daño por Reperfusión/patología
17.
Int J Mol Sci ; 22(4)2021 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668611

RESUMEN

The maintenance of proteome homeostasis, or proteostasis, is crucial for preserving cellular functions and for cellular adaptation to environmental challenges and changes in physiological conditions. The capacity of cells to maintain proteostasis requires precise control and coordination of protein synthesis, folding, conformational maintenance, and clearance. Thus, protein degradation by the ubiquitin-proteasome system (UPS) or the autophagy-lysosomal system plays an essential role in cellular functions. However, failure of the UPS or the autophagic process can lead to the development of various diseases (aging-associated diseases, cancer), thus both these pathways have become attractive targets in the treatment of protein conformational diseases, such as alpha 1-antitrypsin deficiency (AATD). The Z alpha 1-antitrypsin (Z-AAT) misfolded variant of the serine protease alpha 1-antitrypsin (AAT) is caused by a structural change that predisposes it to protein aggregation and dramatic accumulation in the form of inclusion bodies within liver hepatocytes. This can lead to clinically significant liver disease requiring liver transplantation in childhood or adulthood. Treatment of mice with autophagy enhancers was found to reduce hepatic Z-AAT aggregate levels and protect them from AATD hepatotoxicity. To date, liver transplantation is the only curative therapeutic option for patients with AATD-mediated liver disease. Therefore, the development and discovery of new therapeutic approaches to delay or overcome disease progression is a top priority. Herein, we review AATD-mediated liver disease and the overall process of autophagy. We highlight the role of this system in the regulation of Z-variant degradation and its implication in AATD-medicated liver disease, including some open questions that remain challenges in the field and require further elucidation. Finally, we discuss how manipulation of autophagy could provide multiple routes of therapeutic benefit in AATD-mediated liver disease.


Asunto(s)
Autofagia , Hepatocitos , Hepatopatías , Trasplante de Hígado , Hígado , Agregación Patológica de Proteínas , alfa 1-Antitripsina , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Cuerpos de Inclusión/genética , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/patología , Hígado/metabolismo , Hígado/patología , Hepatopatías/metabolismo , Hepatopatías/patología , Hepatopatías/cirugía , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , Agregación Patológica de Proteínas/cirugía , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo , Deficiencia de alfa 1-Antitripsina/genética , Deficiencia de alfa 1-Antitripsina/metabolismo , Deficiencia de alfa 1-Antitripsina/patología
18.
Zhonghua Gan Zang Bing Za Zhi ; 29(1): 67-71, 2021 Jan 20.
Artículo en Chino | MEDLINE | ID: mdl-33541026

RESUMEN

Objective: To investigate the protective effect of Colgalt2 gene deletion on acute liver injury induced by acetaminophen (APAP) in mice. Methods: Colgalt2(+/+) wild-type control mice and Colgalt2(-/-) mice (all C57BL/6J strains) were selected as the research subject. APAP solution was injected intraperitoneally to establish a mouse model of acute liver injury. The mouse were divided into four groups: Colgalt2(+/+) wild-type control group, Colgalt2(+/+) wild-type drug group (APAP 500 mg/kg), Colgalt2(-/-) control group, and Colgalt2(-/-) drug group (APAP 500 mg/kg). The survival rate was measured to plot survival curve. Liver function was evaluated by detecting serum ALT and AST levels. Liver histopathological changes were observed by HE staining to evaluate the condition of liver injury. Western blot was used to detect protein c-Jun N-terminal kinase (JNK)-related liver injury. Results: Compared with Colgalt2(+/+) mice, the survival rate was significantly increased after giving APAP to Colgalt2(-/-) mice (86.7% vs. 40%), and liver cell necrosis and inflammatory cell infiltrates of Colgalt2(+/+) mice were milder. Serum ALT, and AST level was significantly decreased [ALT: (5 291.9 ± 1 016.34) U/L vs. (1 616.9 ± 330.65) U/L, P = 0.000; AST: (4 978.0 ± 1 028.43) U/L vs. (1 851.0 ± 437.55) U/L, P = 0.000]. The expression level of JNK was significantly decreased in liver tissue. Conclusion: Colgalt2 gene deletion has a protective effect on acute liver injury induced by acetaminophen (APAP) in mice. Therefore, Colgalt2 may be a potential therapeutic option for acetaminophen-induced hepatotoxicity.


Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Enfermedad Hepática Inducida por Sustancias y Drogas , Acetaminofén/efectos adversos , Acetaminofén/metabolismo , Animales , Antioxidantes/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Eliminación de Gen , Glicosiltransferasas/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo
19.
Ecotoxicol Environ Saf ; 212: 111988, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33548571

RESUMEN

OBJECTIVES: This study was conducted to estimate the heavy metal (HM) content of water sources from oil contaminated area, HM and hepato-renal functions of residents and to determine association between consumption of crude oil contaminated water and development of multiple organ toxicities. METHODS: Heavy metals (Pb, Cd, As, Hg) content of 20 surface water sources (SWS) and 20 underground water sources (UWS) from crude oil contaminated area and 40 water sources (20 SWS and 20 UWS) from uncontaminated area (controls) were estimated using AAS. The HM, indices of liver function (aspartate and alanine aminotransferases (AST and ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total protein (TP), albumin, total and conjugated bilirubin (TB and CB)) and renal functions (urea, creatinine, sodium, chloride, potassium, bicarbonate and kidney injury molecule-1 (KIM-1)) were determined in 120 residents each from contaminated and control areas using enzyme-colorimetry and ELISA methods. RESULTS: The HM levels of all water sources studied were above WHO standards. Water sources from contaminated area had higher HM levels compared to control. HM contents of SWS from contaminated area and control were higher than UWS from both areas. Residents of contaminated area had higher levels of HM, urea, bicarbonate, chloride, sodium, KIM-1, ALP, GGT, AST, ALT, TB and CB and lower TP and albumin compared to residents of control area. CONCLUSION: Water contamination with crude oil is associated with elevated HM content with perturbations in HM, liver and renal functions of consumers which may suggest an increased risk of hepato-renal toxicities.


Asunto(s)
Contaminantes Químicos del Agua/toxicidad , Alanina Transaminasa/metabolismo , Fosfatasa Alcalina/metabolismo , Creatinina , Agua Subterránea , Hígado/metabolismo , Metales Pesados/análisis , Nigeria , Agua/análisis , Contaminantes Químicos del Agua/análisis , gamma-Glutamiltransferasa
20.
Ecotoxicol Environ Saf ; 212: 111968, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33550083

RESUMEN

Despite the fact that copper (Cu) is a vital micronutrient to maintain body function, high doses of Cu through environmental exposure damage various organs, especially the liver, which is the main metabolic organ. To investigate the influence of long-term Cu-induced toxicity on mitophagy and apoptosis in rat liver, 96 seven-month-old male Sprague-Dawley rats were fed TBCC for 24 weeks. The results revealed that exposure to high Cu concentrations could promote oxidative stress liver injury by increasing the hepatic function index (ALT, AST and ALP) and MDA content, while reducing the activity of antioxidant enzymes (T-SOD, GSH-Px and CAT) related to oxidative stress. Consistent with histopathological observations, proper dietary Cu (15-60 mg/kg) could improve antioxidant stress levels and induce a dose-dependent increase in the mRNA expression of mitophagy-related genes, whereas a high Cu concentration (120 mg/kg) could cause severe liver impairment and ultrastructural changes and a reduction in mitophagosomes, accompanied by downregulation of Atg5, Beclin1, Pink1, Parkin, NIX, P62 and LC3B. The expression of apoptosis-related genes (Bax, Bax/Bcl-2, Caspase3, Cytc and p53) and proteins (Caspase3 and p53) was upregulated with the addition of dietary Cu. The results demonstrated that an appropriate dose of TBCC could improve liver function by promoting mitophagy and Cu enzymes that play antioxidative roles, while the accumulation of excess Cu could induce liver lesions by enhancing apoptosis and inhibiting mitophagy pathways.


Asunto(s)
Cloruros/toxicidad , Cobre/toxicidad , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Sulfato de Cobre/análisis , Dieta , Hígado/metabolismo , Masculino , Mitofagia/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Pruebas de Toxicidad Crónica
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