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1.
J. physiol. biochem ; 79(4): 731-743, nov. 2023.
Artigo em Inglês | IBECS | ID: ibc-227548

RESUMO

Hepatocellular carcinoma (HCC) markedly enhances liver secretion of fibroblast growth factor 21 (FGF-21), a hepatokine that increases brown and subcutaneous inguinal white adipose tissues (BAT and iWAT, respectively) uncoupling protein 1 (UCP-1) content, thermogenesis and energy expenditure. Herein, we tested the hypothesis that an enhanced BAT and iWAT UCP-1-mediated thermogenesis induced by high levels of FGF-21 is involved in HCC-associated catabolic state and fat mass reduction. For this, we evaluated body weight and composition, liver mass and morphology, serum and tissue levels of FGF-21, BAT and iWAT UCP-1 content, and thermogenic capacity in mice with Pten deletion in hepatocytes that display a well-defined progression from steatosis to steatohepatitis (NASH) and HCC upon aging. Hepatocyte Pten deficiency promoted a progressive increase in liver lipid deposition, mass, and inflammation, culminating with NASH at 24 weeks and hepatomegaly and HCC at 48 weeks of age. NASH and HCC were associated with elevated liver and serum FGF-21 content and iWAT UCP-1 expression (browning), but reduced serum insulin, leptin, and adiponectin levels and BAT UCP-1 content and expression of sympathetically regulated gene glycerol kinase (GyK), lipoprotein lipase (LPL), and fatty acid transporter protein 1 (FATP-1), which altogether resulted in an impaired whole-body thermogenic capacity in response to CL-316,243. In conclusion, FGF-21 pro-thermogenic actions in BAT are context-dependent, not occurring in NASH and HCC, and UCP-1-mediated thermogenesis is not a major energy-expending process involved in the catabolic state associated with HCC induced by Pten deletion in hepatocytes. (AU)


Assuntos
Animais , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Hepatócitos , Termogênese/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
2.
J. physiol. biochem ; 79(4): 771-785, nov. 2023.
Artigo em Inglês | IBECS | ID: ibc-227551

RESUMO

With recent advancements in single-cell sequencing and machine learning methods, new insights into hepatocellular carcinoma (HCC) progression have been provided. Protein kinase–related genes (PKRGs) affect cell growth, differentiation, apoptosis, and signaling during HCC progression, making the predictive relevance of PKRGs in HCC highly necessary for personalized medicine. In this study, we analyzed single-cell data of HCC and used the machine learning method of LASSO regression to construct PKRG prediction models in six major cell types. CDK4 and AURKB were found to be the best PKRG prognostic signature for predicting the overall survival of HCC patients (including TCGA, ICGC, and GEO datasets) in hepatocytes. Independent clinical factors were further screened out using the COX regression method, and a nomogram combining PKRGs and cancer status was created. Treatment with Palbociclib (CDK4 Inhibitor) and Barasertib (AURKB Inhibitor) inhibited HCC cell migration. Patients classified as PKRG high- or low-risk groups showed different tumor mutation burdens, immune infiltrations, and gene enrichment. The PKRG high-risk group showed higher tumor mutation burdens and gene set enrichment analysis indicated that cell cycle, base excision repair, and RNA degradation pathways were more enriched in these patients. Additionally, the PKRG high-risk group demonstrated higher infiltration levels of Naïve CD8+ T cells, Endothelial cells, M2 macrophage, and Tregs than the low-risk group. In summary, this study established the hepatocytes-related PKRG signature for prognostic stratification at the single-cell level by using machine learning algorithms in HCC and identified potential HCC treatment targets based on the PKRG signature. (AU)


Assuntos
Humanos , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/genética , Células Endoteliais , Hepatócitos , Algoritmos
3.
J. physiol. biochem ; 79(4): 833-849, nov. 2023.
Artigo em Inglês | IBECS | ID: ibc-227556

RESUMO

The underlying mechanisms for the development and progression of nonalcoholic fatty liver disease (NAFLD) are complex and multifactorial. Within the last years, experimental and clinical evidences support the role of ghrelin in the development of NAFLD. Ghrelin is a gut hormone that plays a major role in the short-term regulation of appetite and long-term regulation of adiposity. The liver constitutes a target for ghrelin, where this gut-derived peptide triggers intracellular pathways regulating lipid metabolism, inflammation, and fibrosis. Interestingly, circulating ghrelin levels are altered in patients with metabolic diseases, such as obesity, type 2 diabetes, and metabolic syndrome, which, in turn, are well-known risk factors for the pathogenesis of NAFLD. This review summarizes the molecular and cellular mechanisms involved in the hepatoprotective action of ghrelin, including the reduction of hepatocyte lipotoxicity via autophagy and fatty acid β-oxidation, mitochondrial dysfunction, endoplasmic reticulum stress and programmed cell death, the reversibility of the proinflammatory phenotype in Kupffer cells, and the inactivation of hepatic stellate cells. Together, the metabolic and inflammatory pathways regulated by ghrelin in the liver support its potential as a therapeutic target to prevent NAFLD in patients with metabolic disorders. (AU)


Assuntos
Humanos , Diabetes Mellitus Tipo 2/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Grelina , Hepatócitos/metabolismo , Fígado/metabolismo , Obesidade/metabolismo
4.
Nutr. hosp ; 40(4): 746-754, Juli-Agos. 2023. graf
Artigo em Inglês | IBECS | ID: ibc-224198

RESUMO

Objectives: manganese (Mn) is closely related to type 2 diabetes mellitus and insulin resistance (IR), but the exact mechanism is unclear. This study aimed to explore the regulatory effects and mechanism of Mn on IR using hepatocyte IR model induced by high palmitate (PA), high glucose (HG) or insulin. Methods: HepG2 cells were exposed to PA (200 μM), HG (25 mM) or insulin (100 nM) respectively, alone or with 5 μM Mn for 24 hours. The expression of key proteins in insulin signaling pathway, intracellular glycogen content and glucose accumulation, reactive oxygen species (ROS) level and Mn superoxide dismutase (MnSOD) activity were detected. Results: compared with control group, the expression of phosphorylated protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β) and forkhead box O1 (FOXO1) in the three IR groups was declined, and this decrease was reversed by Mn. The reduction of intracellular glycogen content and increase in glucose accumulation in IR groups were also inhibited by Mn. Additionally, the production of ROS was increased in IR models, compared with normal control group, while Mn reduced the excessive production of ROS induced by PA, HG or insulin. However, Mn did not alter the activity of MnSOD in the three IR models. Conclusion: this study demonstrated that Mn treatment can improve IR in hepatocytes. The mechanism is probably by reducing the level of intracellular oxidative stress, enhancing the activity of Akt/GSK-3β/FOXO1 signal pathway, promoting glycogen synthesis, and inhibiting gluconeogenesis.(AU)


Objetivos: el manganeso (Mn) está estrechamente relacionado con la diabetes mellitus tipo 2 y la resistencia a la insulina (RI), pero el mecanismoexacto aún no está claro. Este estudio tuvo como objetivo explorar los efectos reguladores y el mecanismo del Mn sobre la RI utilizando un modelode RI en hepatocitos inducido por palmitato alto (PA), glucosa alta (HG) o insulina.Métodos: las células HepG2 se expusieron a PA (200 μM), HG (25 mM) o insulina (100 nM), solas o junto con 5 μM de Mn durante 24 horas.Se evaluó la expresión de proteínas clave en la vía de señalización de la insulina, el contenido intracelular de glucógeno y la acumulación deglucosa, el nivel de especies reactivas de oxígeno (ROS) y la actividad superóxido dismutasa del manganeso (MnSOD).Resultados: en comparación con el grupo de control, la expresión de proteína quinasa B fosforilada (Akt), la glucógeno sintasa quinasa-3β(GSK-3β) y la proteína forkhead box O1 (FOXO1) en los tres grupos de RI se redujo, y esta disminución fue revertida por el Mn. La reduccióndel contenido de glucógeno intracelular y el aumento de la acumulación de glucosa en los grupos de RI también fueron inhibidos por el Mn.Además, la producción de ROS aumentó en los modelos de RI en comparación con el grupo de control normal. Mientras que el Mn redujo laproducción excesiva de ROS inducida por PA, HG o insulina. Sin embargo, el Mn no alteró la actividad de la MnSOD en los tres modelos de RI.Conclusión: este estudio demostró que el tratamiento con Mn puede mejorar la RI en hepatocitos. El mecanismo probablemente sea mediantela reducción del nivel de estrés oxidativo intracelular, mejorando la actividad de la vía de señalización Akt/GSK-3β/FOXO1, promoviendo la síntesisde glucógeno e inhibiendo la gluconeogénesis.(AU)


Assuntos
Humanos , Masculino , Feminino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Resistência à Insulina , Manganês/uso terapêutico , Hepatócitos , Estudos de Casos e Controles
6.
An. R. Acad. Nac. Farm. (Internet) ; 88(número extraordinario): 277-291, diciembre 2022. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-225698

RESUMO

La enfermedad del hígado graso no alcohólico (EHGNA) es la enfermedad hepática crónica más común del mundo. La EHGNA se considera la manifestación hepática del síndrome metabólico al estar directamente asociada con la obesidad, la resistencia a la insulina, la diabetes mellitus tipo 2 y las complicaciones cardiovasculares. Pese a su prevalencia, los factores que desencadenan la progresión de la EHGNA a la esteatohepatitis no alcohólica, la cirrosis y el carcinoma hepatocelular son poco conocidos. Actualmente, no existe tratamiento eficaz ni hay disponible un método fiable para su diagnóstico y estatificación más allá de la biopsia hepática altamente invasiva.Recientemente, las vesículas extracelulares (VEs) han emergido como posibles biomarcadores para el diagnóstico de la EHGNA. Las VEs son vesículas derivadas de las células que contienen proteínas y ácidos nucleicos, entre otros componentes, que interactúan y desencadenan una gran variedad de respuestas en células diana próximas o distantes. Varios mecanismos implicados en la progresión de la EHGNA, como la inflamación, la fibrosis y la angiogénesis, relacionados con la lipotoxicidad, desencadenan la secreción de VEs por las células hepáticas. En esta revisión nos centraremos en las VEs secretadas por los hepatocitos (Hep-VEs) como mensajeros del interactoma entre las diferentes células hepáticas en la patogénesis de la EHGNA, así como en su papel como biomarcadores no invasivos para su diagnóstico y estratificación. Además, destacaremos las investigaciones disponibles hasta la fecha, las limitaciones actuales y las futuras directrices para su implementación en un entorno clínico como biomarcadores o dianas terapéuticas de la enfermedad hepática. (AU)


Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD, the hepatic manifestation of the metabolic syndrome, closely associates with insulin resistance, type 2 diabetes mellitus, obesity and cardiovascular disease. Until now, the specific factors involved in the progression of NAFLD from fatty liver to non-alcoholic steatohepatitis, cirrhosis and, ultimately hepatocellular carcinoma have not been totally elucidated.Also, patients have to face the lack of efficient or personalized treatments, as well as the absence of reliable diagnosis or staging methods beyond the highly invasive liver biopsy. In the last years, extracellular vesicles (VEs) are considered as potential biomarkers for the diagnosis many diseases including NAFLD. VEs are released by different cells types into the circulation and contain nucleic acids and proteins, among other components of their, that interact with surrounding or distant target cells, thereby triggering a plethora of responses. During NAFLD progression, several processes such as inflammation, fibrosis and angiogenesis, all related to MS-associated lipotoxicity, lead to VEs release by liver cells. In this review we will focus in the role of hepatocyte-derived VEs (Hep-VEs) and their interactions with non-parenchymal liver cells populations during NAFLD pathogenesis, as well as in their role as non-invasive biomarkers for disease diagnosis and progression. We will highlight the recent work currently available on VEs in the context of NAFLD, the current limitations and future directions for the implementation of VEs as biomarkers or targets of liver disease in the clinical setting. (AU)


Assuntos
Hepatócitos , Inflamação , Vesículas Extracelulares , Biomarcadores
7.
An. R. Acad. Nac. Farm. (Internet) ; 88(número extraordinario): 15-26, diciembre 2022. tab, ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-225738

RESUMO

La infección crónica por el virus de la hepatitis C (VHC) está asociada con la resistencia a la insulina y la diabetes tipo 2. El objetivo general de este estudio fue evaluar los efectos del sofosbuvir sobre la resistencia a la insulina inducida por el VHC. Para ello, se realizó un estudio clínico que incluyó 42 pacientes con VHC resistentes a la insulina, que fueron tratados con diferentes regímenes antivirales basados en sofosbuvir. Asimismo, se utilizó una línea de hepatocitos humanos que expresan un replicón del VHC de manera estable para determinar los mecanismos moleculares implicados en la acción de la insulina regulada por sofosbuvir. Todos los pacientes alcanzaron una respuesta virológica sostenida después del tratamiento con sofosbuvir y se observó una reducción significativa en los marcadores de daño hepático, así como en el estadio de fibrosis. El índice de resistencia a la insulina (HOMA) mejoró significativamente a lo largo del estudio. A nivel molecular, el tratamiento con sofosbuvir mejoró la activación de la cascada de señalización de la insulina tras la estimulación con dicha hormona en los hepatocitos con VHC, y, en consecuencia, revirtió la expresión elevada de genes gluconeogénicos, el aumento de la producción de glucosa y la deficiencia de la síntesis de glucógeno en estas células. En conclusión, estos resultados sugieren que el sofosbuvir mejora la respuesta deficiente a la insulina originada por la infección del VHC, proporcionando novedosas evidencias en cuanto a los mecanismos moleculares implicados en la sensibilización a la insulina inducida por este tratamiento. (AU)


Chronic hepatitis C virus (HCV) infection is associated with insulin resistance and type 2 diabetes. The overall aim of this study was to evaluate the effects of sofosbuvir (SOF) on HCV-induced insulin resistance. Clinical parameters were recorded and insulin resistance index (HOMA) calculated from 42 insulin-resistant HCV-patients who underwent SOF-based regimens, at baseline, at the end of treatment (EoT), and at one year after the EoT. Likewise, Huh7 cells expressing full-length HCV replicons were used to elucidate the molecular mechanisms involved in insulin action regulated by SOF. All patients reached a sustained virological response after SOF treatment and, as expected, a significant reduction in liver damage markers and fibrosis stage was observed at the EoT that remained one year later. HOMA significantly improved throughout the study time period. Besides, an increase of total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B levels were maintained over time after the EoT. At the molecular level, SOF treatment improved the activation of the insulin signalling cascade after stimulation with the hormone in HCV-hepatocytes and, accordingly, reversed the elevated expression of gluconeogenic genes, the increased glucose production and the impairment of glycogen synthesis induced by HCV. Furthermore, SOF challenge induced an increase of insulin receptor substrate 1 (IRS1) content parallel to a reduction in its serine phosphorylation in HCV-hepatocytes. These results provide novel evidence about the molecular mechanisms involved in the hepatic insulin sensitization induced by SOF treatment involving the recovery of IRS1 protein levels as a hallmark of SOF effects. (AU)


Assuntos
Humanos , Hepacivirus , Antivirais , Sofosbuvir , Resistência à Insulina , Hepatócitos
8.
J. physiol. biochem ; 78(1): 9–17, feb. 2022. ilus
Artigo em Inglês | IBECS | ID: ibc-215869

RESUMO

As a highly evolutionarily conserved process, autophagy can be found in all types of eukaryotic cells. Such a constitutive process maintains cellular homeostasis in a wide variety of cell types through the encapsulation of damaged proteins or organelles into double-membrane vesicles. Autophagy not only simply eliminates materials but also serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Previous studies have primarily recognized the role of autophagy in the degradation of dysfunctional proteins and unwanted organelles. However, there are findings of autophagy in physiological and pathological processes. In hepatocytes, autophagy is not only essential for homeostatic functions but also implicated in some diseases, such as viral hepatitis, alcoholic hepatitis, and hepatic failure. In the present review, we summarized the molecular mechanisms of autophagy and its role in several liver diseases and put forward several new strategies for the treatment of liver disease. (AU)


Assuntos
Humanos , Autofagia/fisiologia , Hepatopatias/etiologia , Hepatócitos , Homeostase
9.
J. physiol. biochem ; 78(1): 125-137, feb. 2022.
Artigo em Inglês | IBECS | ID: ibc-215878

RESUMO

Hepatic ischemia reperfusion injury (IRI) occurs in liver transplantation, complex liver resection, and hemorrhagic shock, which causes donor organ shortage and hepatic damage. The burst of reactive oxygen species (ROS) during reperfusion leads to cell apoptosis and necroptosis. It has been reported that estrogen could attenuate hepatic IRI. G protein estrogen receptor (GPER) mediates estrogen effects via nonclassic receptor systems. Here, we investigate whether estrogen protecting liver from hepatic IRI depends on GPER and the influence of GPER activation on hepatocyte necroptosis. We proved that estrogen had a protective effect on both hepatocyte hypoxia re-oxygen (H/R) challenge and mouse hepatic ischemia reperfusion model. However, the application of GPER specific antagonist G15 before estrogen inhibited this beneficial effect. The results of mitochondria functional measurement revealed that estrogen improved hepatocyte mitochondria function by activating GPER, which might benefit from the increased expression of connexin 43 (Cx43) in mitochondria. To investigate the relationship between GPER activation and necroptosis, we used caspase-3/7 inhibitor benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-chloromethylketone (Z-DEVD-FMK) to eliminate the interference of apoptosis. Estrogen showed a protective effect on hepatic IRI after using Z-DEVD-FMK, which could be suppressed by G15. GPER activation decreased the level of receptor interacting protein kinase (RIPK) 3, phosphorylated (p-) RIPK1, and p-mixed lineage kinase domain-like (MLKL). The co-immunoprecipitation result indicated that GPER could bind with RIPK3. GPER is indispensable in estrogen protecting liver from IRI. GPER activation attenuates hepatocyte necroptosis by decreasing the level of RIPK3, p-RIPK1, and p-MLKL. (AU)


Assuntos
Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Fígado/metabolismo , Receptores de Estrogênio/metabolismo , Estrogênios , Proteínas de Ligação ao GTP/metabolismo , Hepatócitos/metabolismo
10.
J. physiol. biochem ; 78(1): 185-197, feb. 2022.
Artigo em Inglês | IBECS | ID: ibc-215882

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that is rapidly becoming a public health problem. An imbalance in lipid distribution to the hepatocytes and metabolism causes hepatocyte steatosis. Vaspin is a newly discovered adipokine that has been linked to a variety of metabolic disorders. The effects of vaspin on steatosis and fibrosis pathogenesis and related mechanisms are unclear. Thus, this study investigated the molecular mechanism of vaspin on hepatocyte steatosis and fibrosis. HepG2 cells were treated with 1.2 mM free fatty acid and the intracellular lipid values were measured by flow cytometry and Nile red assay. RT-qPCR was used to assess the effect of vaspin and blocking of the GRP78 receptor on the expression of lipogenesis, oxidation, uptake, and secretion of fatty acid (FA), as well as AMPK activity. In co-cultured HepG2 and LX-2 cell lines, the expression of main proteins of hepatocyte fibrosis was analyzed using Western blot analysis. In the HepG2 cell line, we discovered that vaspin increased oxidation, FA secretion and gene expression, and AMPK activity and decreased lipogenesis and FA uptake and gene expression. Western blot analysis in co-cultured HepG2 and LX-2 cell lines showed that α-SMA and TGF-β1 protein expression decreased. The data demonstrated that vaspin acts as a novel regulator of hepatocyte steatosis through the GRP78 receptor, effectively reducing hepatocyte fibrosis through AMPK activation and decreasing NF-κB gene expression. (AU)


Assuntos
Humanos , Animais , Camundongos , Serpinas , Hepatopatia Gordurosa não Alcoólica , Proteínas Quinases Ativadas por AMP , Adipocinas , Fibrose , Hepatócitos/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL
11.
Gastroenterol. hepatol. (Ed. impr.) ; 43(1): 14-21, ene. 2020. ilus, graf, tab
Artigo em Inglês | IBECS | ID: ibc-188286

RESUMO

Introduction: Diagnosis of severe hepatitis C recurrence is based on analytical and histological criteria but there is little information about their correlation. Aim: To assess the accuracy of laboratory criteria for the diagnosis of fibrosing cholestatic hepatitis (FCH). Patients and methods: Retrospective analysis of prospectively collected data form HCV positive patients who underwent liver transplantation (LT) between 2000 and 2014 in two European university hospitals. Patients were classified according to laboratory criteria such as FCH, cholestatic hepatitis (CH) and non-cholestatic acute hepatitis (NCAH). Histological characteristics were also evaluated. Results: Seventy patients with acute HCV recurrence within the first year after LT with an available liver biopsy were included in the study. Most patients were male (70%) with a median age of 58 years (50-64) and infected with genotype 1b (71.4%). Median time from LT to diagnosis of recurrence was 2.96 months (2.1-5.3). Thirty-nine patients were classified as FCH, 21 as CH and 10 as NCAH. Marked hepatocyte ballooning and ductular reaction were associated with the presence of FCH with an OR of 4.66 (p=0.047) and 20.58 (p=0.025), respectively. Considering liver biopsy as the gold standard, the sensitivity, specificity, positive and negative predictive values of the analytical criteria were 0.8, 0.5, 0.3 and 0.9, respectively. However, correlation between histological and analytical criteria was poor (k=0.033). Discussion: Analytical criteria may be used to rule out the presence of FCH, but a biopsy is mandatory to confirm the diagnosis. Ductular reaction and hepatocyte ballooning were independent predictors of FCH


Introducción: El diagnóstico de la recurrencia grave de la hepatitis C se basa en criterios histológicos y analíticos. Sin embargo, existe poca información respecto su correlación. Objetivo: Evaluar la precisión de los criterios analíticos el diagnóstico de la hepatitis colestásica fibrosante (HCF). Pacientes y métodos: Análisis retrospectivo de pacientes con una recidiva grave precoz del virus de la hepatitis C (VHC) tras el trasplante hepático (TH) en 2 hospitales universitarios europeos entre 2000-2014. Los pacientes se clasificaron según criterios analíticos en HCF, hepatitis colestásica (HC) y hepatitis aguda no colestásica (HANC). Las características histológicas también fueron evaluadas. Resultados: Se incluyeron 70 pacientes que desarrollaron una recurrencia grave del VHC en el primer año tras TH con una biopsia hepática disponible. La mayoría eran varones (70%) con mediana de edad de 58 años (50-64) y genotipo 1b (71,4%). La mediana de tiempo desde el TH hasta el diagnóstico de la recurrencia fue de 2,96 meses (2,1-5,3). Treinta y nueve pacientes fueron clasificados como HCF, 21 como HC y 10 como HANC. La balonización intensa y reacción ductular se asociaron con HCF con una OR de 4,66 (p=0,047) y 20,58 (p=0,025), respectivamente. Considerando la biopsia hepática como gold standard, la sensibilidad, especificidad y valores predictivos positivo y negativo de los criterios analíticos fueron 0,8, 0,5, 0,3 y 0,9, respectivamente. Sin embargo, la correlación entre ambos fue escasa (k=0,033). Discusión: Los criterios analíticos podrían utilizarse para descartar la presencia de HCF, pero la biopsia sigue siendo obligatoria para el diagnóstico. La reacción ductular y la balonización son predictores de HCF


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Hepatite C/patologia , Transplante de Fígado/efeitos adversos , Hepatócitos/patologia , Hepatite C/diagnóstico , Hepatite C/etiologia , Estudos Retrospectivos , Recidiva , Biópsia , Fígado/patologia , Sensibilidade e Especificidade , Análise Multivariada
13.
Eur. j. anat ; 23(4): 267-272, jul. 2019. ilus
Artigo em Inglês | IBECS | ID: ibc-183000

RESUMO

Ayurvedic medicines is known to use heavy metals in their preparation. Nagabhasma is one such form of a lead-based medicine. Even though lead is known to be toxic to several systems of the human body, according to Ayurveda, the metallic toxicity of the lead gets nullified and thereby imbibes medicinal property when it is prepared using many herbs and stringent traditional methods. Therefore, the present study is designed to evaluate the effect of such detoxified lead in various stages of authentically prepared Nagabhasma on the histopathology of liver in comparison with lead acetate and commercially available Nagabhasma-administered animals. Less than the human-equivalent doses of Nagabhasma at four intermittent stages of its preparation were administered orally for 30 days and 60 days (short term and long term exposure) to Wistar rats. In another set of experiment, test-material-administered animals were kept under observation for an additional period of two months to record the residual effect. Immediately after the administration and after the observation period, the animals were sacrificed to collect the liver for histopathological examination. The histopathological results of the immediate and residual effects showed varying alterations in the microarchitecture of the liver as the stages of Nagabhasma preparation advanced. The final product (stage 4 bhasma), showed very less toxic effect in comparison with other stages. In conclusion, the results state that, by following the traditional procedures while preparing Nagabhasma, the metallic lead gets converted into non-toxic organometallic compound


No disponible


Assuntos
Humanos , Animais , Metais Pesados/toxicidade , Ayurveda/efeitos adversos , Fígado/efeitos dos fármacos , Chumbo/toxicidade , Hepatócitos/efeitos dos fármacos , Capilares/efeitos dos fármacos , Fígado/anatomia & histologia , Fígado/patologia , Ratos Wistar , Vasos Sanguíneos/anatomia & histologia , Vasos Sanguíneos/patologia
14.
Clín. investig. arterioscler. (Ed. impr.) ; 31(3): 111-118, mayo-jun. 2019. ilus, graf, tab
Artigo em Inglês | IBECS | ID: ibc-182704

RESUMO

The very low-density lipoprotein receptor (VLDLR) plays an important function in the control of serum triglycerides and in the development of non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the role of peroxisome proliferator-activated receptor (PPAR)ß/δ activation in hepatic VLDLR regulation. Treatment of mice fed a high-fat diet with the PPARß/δ agonist GW501516 increased the hepatic expression of Vldlr. Similarly, exposure of human Huh-7 hepatocytes to GW501516 increased the expression of VLDLR and triglyceride accumulation, the latter being prevented by VLDLR knockdown. Finally, treatment with another PPARß/δ agonist increased VLDLR levels in the liver of wild-type mice, but not PPARß/δ-deficient mice, confirming the regulation of hepatic VLDLR by this nuclear receptor. Our results suggest that upregulation of hepatic VLDLR by PPARß/δ agonists might contribute to the hypolipidemic effect of these drugs by increasing lipoprotein delivery to the liver. Overall, these findings provide new effects by which PPARß/δ regulate VLDLR levels and may influence serum triglyceride levels and NAFLD development


El receptor de las lipoproteínas de muy baja densidad (VLDLR) desempeña una función muy importante en el control de los niveles de triglicéridos séricos y en el desarrollo de la enfermedad del hígado graso no alcohólico (EHGNA). En este estudio hemos investigado el papel de la activación del receptor activado por los proliferadores peroxisómicos (PPAR)ß/δ en la regulación hepática del VLDLR. El tratamiento de ratones alimentados con una dieta rica en grasas con el agonista PPARß/δ GW501516 aumentó la expresión hepática de Vldlr. Asimismo, la exposición de hepatocitos humanos Huh-7 a GW501516 aumentó la expresión de VLDLR y la acumulación de triglicéridos, siendo este ultimo aumento evitado por el knockdown de VLDLR. Finalmente, el tratamiento con otro agonista PPARß/δ incrementó los niveles de VLDLR en el hígado de ratones wild-type, pero no en el de ratones deficientes en PPARß/δ, confirmando la regulación del VLDLR hepático por este receptor. En conjunto, nuestros resultados proporcionan un nuevo efecto por el que PPARß/δ regula los niveles de VLDLR y puede influenciar los niveles de triglicéridos séricos así como el desarrollo de la EHGNA


Assuntos
Animais , Camundongos , PPAR beta/efeitos dos fármacos , PPAR beta/metabolismo , Hepatócitos/metabolismo , Lipoproteínas VLDL/agonistas , Lipoproteínas VLDL/metabolismo , Gorduras na Dieta , Triglicerídeos/metabolismo , Western Blotting , Análise de Variância , PPAR beta/farmacologia
15.
Rev. esp. enferm. dig ; 111(5): 351-357, mayo 2019. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-189987

RESUMO

Background: the shortage of donors of hepatocyte transplantation therapy led to the use of so-called marginal donors. Some donors may have a hepatic illnesses that is associated with hepatic preneoplasia with foci of altered hepatocytes (FAH). Aims: to determine whether recipients developed FAH upon transplantation with hepatocytes from a preneoplastic liver and whether FAH progresses to a preneoplastic hepatocyte-derived tumor (PHDT), up to 60 days after transplantation. Material and methods: male Wistar adult rats were used as donors and recipients. Donors underwent a 2-phase model of liver preneoplasia for hepatocyte isolation. Recipients underwent a partial two thirds hepatectomy and received 150,000 hepatocytes. Recipients were euthanized seven and 60 days after transplantation. The number of FAH per liver area, percentage of liver occupied by FAH, the hepatic enzymatic profile, the percentage of prothrombin time (PT), the proliferative index (PI) and liver morphology were analyzed. Results: recipients developed few and very isolated FAH. No statistical differences were found between hepatic enzyme activities and PT. There were no differences between the groups with regard to the number of FAH per liver area and percentage of liver occupied by FAH after 60 days. The PI decreased on day 60 compared to day seven. No morphological alterations were found. Conclusions: recipients developed few FAH that did not increase in number or size, nor did they progress to PHDT and had normal plasma biochemical features and liver morphology up to 60 days post-transplant. Additional studies are needed to determine whether FAH development constitutes a risk for recipients while waiting for whole organ transplant


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Assuntos
Animais , Ratos , Carcinoma Hepatocelular/patologia , Hepatócitos/transplante , Carcinogênese/patologia , Neoplasias Hepáticas/patologia , Modelos Animais de Doenças , Lesões Pré-Cancerosas/patologia , Testes de Carcinogenicidade/métodos , Hepatócitos/patologia
16.
Gastroenterol. hepatol. (Ed. impr.) ; 42(3): 202-208, mar. 2019. graf, tab
Artigo em Inglês | IBECS | ID: ibc-182143

RESUMO

A severe shortage of suitable allografts is a long-standing and worldwide problem for patients who are waiting for organ transplantation. Hepatocyte transplantation has been proposed as an alternative therapeutic approach for liver disease patients to address this urgent and unmet medical need. The cell replacement approach does not replace orthotopic liver transplantation (OLT), but rather it complements OLT especially for patients who do not require whole liver replacement, such as those with congenital metabolic disorders. This review article summarizes the current knowledge and limitations of clinical hepatocyte transplantation and aims to advance our understanding toward the goal of developing novel cell replacement therapies for patients who are on the OLT waiting list


Un antiguo problema en todo el mundo es la grave escasez de aloinjertos adecuados para pacientes que esperan un trasplante de órganos. El trasplante de hepatocitos se ha propuesto como un enfoque terapéutico alternativo para hacer frente a esta necesidad médica urgente y sin resolver en pacientes con hepatopatía. El enfoque del reemplazo celular no sustituye el trasplante ortotópico de hígado (OLT, por sus siglas en inglés) sino que lo complementa, sobre todo en pacientes que no requieren reemplazo hepático completo como en aquellos con trastornos metabólicos congénitos. Este artículo de revisión resume el conocimiento actual y las limitaciones del trasplante clínico de hepatocitos y tiene como objetivo mejorar nuestro conocimiento, con el objetivo de crear nuevas terapias de reemplazo celular para aquellos pacientes que están en lista de espera de un OLT


Assuntos
Humanos , Hepatócitos/transplante , Aloenxertos , Terapia Baseada em Transplante de Células e Tecidos
17.
J. physiol. biochem ; 74(4): 511-521, nov. 2018. graf
Artigo em Espanhol | IBECS | ID: ibc-179029

RESUMO

The scaffold protein alpha-syntrophin (SNTA) is a component of the dystrophin glycoprotein complex and has been comprehensively studied in skeletal muscle and adipocytes. SNTA is further expressed in the liver where its biological role remains unclear. Unpublished data from our group suggested that SNTA deficiency is associated with altered tubulin alpha 8 (TUBA8) levels in fat. TUBA8 is highly expressed in different cell lines including hepatoma cells, and here we analyzed whether SNTA has a role herein. In Hepa1-6 cells, TUBA8 protein levels were increased upon SNTA knock down and were reduced upon overexpression of SNTA. This regulation was not identified when analyzing mRNA expression. In the liver of SNTA-deficient mice, TUBA8 protein was higher compared to the respective wild-type controls while RNA expression was even suppressed. Using the HaloTag platform, TUBA8 was found to form a complex with SNTA in Hepa1-6 cells. In the hepatic stellate cell line LX-2, the lack or overexpression of SNTA did, however, not change TUBA8 protein expression. SNTA and TUBA8 are described to regulate cell proliferation. Yet, knock down of SNTA did neither affect proliferation nor viability of Hepa1-6 cells. The present study shows that SNTA protein levels are inversely related to TUBA8 protein expression in the hepatocyte cell line Hepa1-6


Assuntos
Humanos , Animais , Masculino , Camundongos , Proteínas de Ligação ao Cálcio/metabolismo , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Musculares/metabolismo , Tubulina (Proteína)/metabolismo , Células 3T3-L1 , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular Tumoral , Proliferação de Células , Hepatócitos/citologia , Imunoprecipitação , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout
18.
Gastroenterol. hepatol. (Ed. impr.) ; 41(8): 490-497, oct. 2018. graf
Artigo em Inglês | IBECS | ID: ibc-178102

RESUMO

Background: The "secondary injury" theory of liver failure indicated that hyperammonaemia due to liver failure causes further deterioration of hepatocytes. Our previous studies have demonstrated that high blood ammonia levels may lead to hepatocyte apoptosis, as NH4Cl loading caused metabolic acidosis and an increase in sodium-hydrogen exchanger isoform 1 (NHE1). In this study, we established a hyperammonia hepatocyte model to determine the role of NHE1 in the regulation of hepatocyte apoptosis induced by NH4Cl. Materials and methods: In current studies, intracellular pH (pHi) and NHE1 activity were analyzed using the pHi-sensitive dye BCECF-AM. The results showed that intracellular pH dropped and NHE1 activity increased in hepatocytes under NH4Cl treatment. As expected, decreased pHi induced by NH4Cl was associated with increased apoptosis, low cell proliferation and ATP depletion, which was exacerbated by exposure to the NHE1 inhibitor cariporide. We also found that NH4Cl treatment stimulated PI3K and Akt phosphorylation and this effect was considerably reduced by NHE1 inhibition. Conclusion: This study highlighted the significant role of NHE1 in the regulation of cell apoptosis induced by hyperammonaemia


Antecedentes: La teoría de la «lesión secundaria» de la insuficiencia hepática mostró que la hiperamoniaquemia provocada por la insuficiencia hepática causa mayor deterioro de los hepatocitos. Nuestros anteriores estudios previos han demostrado que los niveles altos de amoníaco en sangre pueden conducir a la apoptosis de los hepatocitos. Como la carga de NH4Cl provocó acidosis metabólica y un aumento de la isoforma 1 del intercambiador de sodio/hidrógeno (NHE1). En este estudio, establecimos un modelo de hepatocitos de hiperamonia para establecer el papel de NHE1 en la regulación de la apoptosis de hepatocitos inducida por NH4Cl. Materiales y métodos: En los estudios actuales, el pH intracelular (pHi) y la actividad del NHE1 se analizaron con el colorante BCECF-AM, sensible al pHi. Los resultados mostraron que el pH intracelular disminuyó y la actividad del NHE1 aumentó en hepatocitos con tratamiento del NH4Cl. Como se esperaba, la disminución del pHi inducido por NH4Cl se relacionó con un aumento de la apoptosis, baja proliferación celular y reducción del ATP, que se exacerbó por la exposición a cariporide, inhibidor del NHE1. También encontramos que el tratamiento del NH4Cl estimuló la fosforilación de PI3K y Akt, y este efecto se redujo considerablemente por la inhibición del NHE1. Conclusión: Este trabajo ha destacado el importante papel del NHE1 en la regulación de la apoptosis celular inducida por hiperamoniaquemia


Assuntos
Humanos , Cloreto de Amônio/farmacologia , Apoptose , Hepatócitos/metabolismo , Hiperamonemia/metabolismo , /fisiologia , Trifosfato de Adenosina/biossíntese , Células Cultivadas , Guanidinas/farmacologia , Hepatócitos/citologia , Hepatócitos , Líquido Intracelular , Concentração de Íons de Hidrogênio , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sulfonas/farmacologia , /antagonistas & inibidores
19.
J. physiol. biochem ; 74(2): 247-260, mayo 2018. graf, ilus
Artigo em Inglês | IBECS | ID: ibc-178981

RESUMO

Fibroblast growth factor (FGF) has been considered to modulate liver regeneration (LR) after partial hepatectomy (PH) at the tissue level. Previous studies have demonstrated that FGF15 and FGF19 induce the activation of its receptor, FGF receptor 4 (FGFR4), which can promote hepatocellular carcinoma progression and regulate liver lipid metabolism. In this study, we aimed to explore the role of the ileal FGF15/19- hepatic FGFR4 axis in the LR after PH. Male C57BL/6 mice aged 8-12 weeks were partially hepatectomized and assessed for expression of ileal FGF15/19 to hepatic FGFR4 signaling. We used recombinant human FGF19 protein and a small interfering RNA (siRNA) of FGFR4 to regulate expression of the FGF15/19-FGFR4 axis in vitro and in vivo. The proliferation and cell cycle of hepatocytes, the expression levels of FGF15/19-FGFR4 downstream molecules, liver recovery, and lipid metabolism were assessed. We found that both ileal and serum FGF15 expression were upregulated and hepatic FGFR4 was activated after PH in mice. FGF15/19 promoted cell cycle progression, enhanced proliferation, and reduced hepatic lipid accumulation of hepatocytes both in vitro and in vivo. Furthermore, the proliferative effect and lipid regulatory properties of FGF15/19 were dependent on FGFR4 in hepatocytes. In addition, ileal FGF15/19-hepatic FGFR4 transduction during hepatocyte proliferation was regulated by extracellular regulated protein kinase (ERK) 1/2. In conclusion, the ileal FGF15/19 to hepatic FGFR4 axis is activated and promotes LR after PH in mice, supporting the potential of ileal FGF15/19 to hepatic FGFR4 axis-targeted therapy to enhance LR after PH


Assuntos
Humanos , Animais , Masculino , Camundongos , Fatores de Crescimento de Fibroblastos/metabolismo , Íleo/metabolismo , Fígado/fisiologia , Fígado/cirurgia , Regeneração Hepática , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Proliferação de Células , Fatores de Crescimento de Fibroblastos/genética , Hepatectomia , Hepatócitos/citologia , Hepatócitos/metabolismo , Íleo/citologia , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética
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