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1.
Wiad Lek ; 74(2): 321-326, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33813495

RESUMEN

Many researchers and clinicians have taken the value of hepatic venous pressure gradient (HVPG) as an essential prognostic factor in subjects with chronic liver disorders. And HVPG alterations characterize a predictive value in subjects at the beginning of the disease (HVPG 6 - 10 mmHg) as well as in subjects in whom hemodynamically significant portal hypertension has developed (HVPG ≥ 10 mmHg). Our review aims to present the feasibility and applicability of HVPG in modern clinical practice in patients with liver cirrhosis, including invasive and non-invasive methods. HVPG measurement is a feasible method with a favorable safety profile. However, hemodynamically significant portal hypertension also might be determined using non-invasive options as elastography, magnetic resonance imaging, and indices derived from laboratory parameters, e.g., aspartate aminotransferase-to-platelet ratio, platelet count/spleen diameter ratio, or VITRO score. Hepatic vein catheterization with the evaluation of HVPG is the current gold standard for determining portal pressure; however, new non-invasive techniques are nowadays more frequently used.


Asunto(s)
Várices Esofágicas y Gástricas , Hipertensión Portal , Toma de Decisiones , Várices Esofágicas y Gástricas/patología , Humanos , Hipertensión Portal/complicaciones , Hipertensión Portal/diagnóstico , Hipertensión Portal/patología , Hígado/patología , Cirrosis Hepática/complicaciones , Presión Portal
2.
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
3.
Medicine (Baltimore) ; 100(12): e25234, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33761715

RESUMEN

ABSTRACT: This study investigated the expression change, prognostic values, and potential regulatory mechanisms of mortality factor on chromosome 4 (MORF4)-related gene-binding protein (MRGBP) in hepatocellular carcinoma (HCC).MRGBP expression and clinical data from The Cancer Genome Atlas were used to evaluate the associations between MRGBP expression and clinicopathological characteristics. Kaplan-Meier and Cox regression analyses were performed to assess the factors contributing to prognosis. Gene set enrichment analysis (GSEA) was used to identify pathways associated with MRGBP expression. Single-sample gene set enrichment analysis (ssGSEA) was used to comprehensively analyze the relative immune infiltration levels.High MRGBP expression was significantly associated with a higher T stage, pathologic stage, histologic grade, vascular invasion, tumor protein p53 status, and worse overall survival. MRGBP exhibited high diagnostic accuracy with an area under the receiver operating characteristic curve value of 0.980. GSEA revealed the enrichment of pathways related to tumorigenesis in the MRGBP high-expression phenotype, such as cell cycle and DNA replication pathways. ssGSEA revealed that MRGBP expression was significantly correlated with 15 types of immune cell infiltration levels. The Wilcoxon rank sum test revealed significantly high T helper (Th), T follicular helper, CD56 bright natural killer, and Th2 cell enrichment scores in the high MRGBP expression group and significantly low neutrophil, Th17, dendritic cell (DC), gamma delta T, cytotoxic cell, regulatory T cell, plasmacytoid DC, and immature DC enrichment scores.MRGBP may be a novel prognostic biomarker and a therapeutic target correlated with immune infiltrates in HCC.


Asunto(s)
Carcinoma Hepatocelular , Histona Acetiltransferasas , Neoplasias Hepáticas , Hígado , Proteínas Nucleares , Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Biología Computacional/métodos , Femenino , Regulación Neoplásica de la Expresión Génica , Histona Acetiltransferasas/análisis , Histona Acetiltransferasas/genética , Humanos , Estimación de Kaplan-Meier , Hígado/inmunología , Hígado/patología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Proteínas Nucleares/análisis , Proteínas Nucleares/genética , Pronóstico
4.
Life Sci ; 274: 119344, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33716062

RESUMEN

AIMS: Amiodarone (AM) is a highly efficient drug for arrhythmias treatment, but its extra-cardiac adverse effects offset its therapeutic efficacy. Nanoparticles (NPs)-based delivery system could provide a strategy to allow sustained delivery of AM to the myocardium and reduction of adverse effects. The primary purpose was to develop AM-loaded NPs and explore their ameliorative effects versus off-target toxicities. MATERIALS AND METHODS: Polymeric NPs were prepared using poly lactic-co-glycolic acid and their physicochemical properties were characterized. Animal studies were conducted using a rat model to compare exposure to AM versus that of the AM-loaded NPs. Biochemical evaluation of liver enzymes, lipid profile, and thyroid hormones was achieved. Besides, histopathological changes in liver and lung were studied. KEY FINDINGS: Under optimal experimental conditions, the AM-loaded NPs had a size of 186.90 nm and a negative zeta potential (-14.67 mV). Biochemical evaluation of AM-treated animal group showed a significant increase in cholesterol, TG, LDL, T4, and TSH levels (ρ < 0.05). Remarkably, the AM-treated group exhibited a significant increase of liver enzymes (ρ < 0.05) coupled with an obvious change in liver architecture. The AM-loaded NPs displayed a reduction of liver damage and enzyme levels. Lung sections of the AM-treated group demonstrated thickening of interalveolar septa, mononuclear cellular infiltration with congested blood vessels, and heavy collagenous fibers deposition. Conversely, less cellular infiltration and septal thickening were observed in the animal lungs treated with the AM-loaded NPs-treated. SIGNIFICANCE: Our findings demonstrate the competence of the AM-loaded NPs to open several exciting avenues for evading the AM-induced off-target toxicities.


Asunto(s)
Amiodarona/química , Amiodarona/farmacología , Portadores de Fármacos/química , Hígado/patología , Nanopartículas/toxicidad , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Amiodarona/administración & dosificación , Animales , Antiarrítmicos/administración & dosificación , Antiarrítmicos/química , Antiarrítmicos/farmacología , Hígado/efectos de los fármacos , Masculino , Nanopartículas/administración & dosificación , Estudios Prospectivos , Ratas , Ratas Sprague-Dawley , Pruebas de Toxicidad
5.
Anticancer Res ; 41(3): 1451-1458, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788737

RESUMEN

AIM: To compare the diagnostic value of liver perfusion computed tomography (PCT) and biphasic contrast-enhanced CT (bpCECT) for detection and characterization of hepatocellular carcinoma (HCC), and to identify potential causes for inter-modal discrepancies. PATIENTS AND METHODS: In this retrospective study, 162 cases with a total of 325 HCC-typical lesions were evaluated using both PCT and bpCECT (mean time between examinations=15 days, range=0-13 days). HCC diagnosis was performed by multi-modality imaging including lesion growth at follow-up. For PCT, a total acquisition time of 40 s (26 measurements) each 1.5 s using 80 kV and 100 mAs, as well as 50 ml iodine contrast agent (at 5 ml/s) covering the entire liver was used. Mean arterial liver perfusion (ALP), portal venous perfusion (PVP) and hepatic arterial index (HPI) for both tumor and non-involved liver parenchyma; mean blood flow, blood volume and k-trans for tumor were quantified. Tumor localization, and size were registered. bpCECT consisted of unenhanced, arterial (30-33 s delay), and portal-venous (70-75 s) phases performed using 120 kV, 200-250 mAs, thin-slice reformates (<1 mm), 100 ml contrast agent (at 3 ml/s) followed by 50 ml saline flush. Finally, we divided the results according to detection by PCT only (i.e. missed by pbCECT), and by both PCT and pbCECT. RESULTS: PCT detected 272 lesions compared to 217 with bpCECT only. HCCs in liver segments 4 and 5 were significantly better detected by PCT (p<0.005). Furthermore, PCT detected significantly smaller HCCs than did bpCECT (p<0.001). Lesions detected by both methods had significantly higher mean ALP (p=0.03) and HPI (p=0.02), and lower mean PVP (p=0.01). Tumor blood flow, blood volume and k-trans proved not to be significant for lesion detection. The mean ALP, HPI, and PVP in inconspicuous cirrhotic liver were also not significant for lesion detection. The PVP(tumor)/HPI(liver) ratio of detected lesions was significantly higher for PCT alone (p=0.04). Pretreated, still vital lesions were better detected by bpCECT. CONCLUSION: Detection of smaller HCC lesions, lesions located in liver segments 4 and 5, as well as lesions presenting lower ALP and HPI, and higher PVP(tumor)/HPI(liver) ratio was better using both methods, emphasizing the important role of PCT.


Asunto(s)
Carcinoma Hepatocelular/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Hígado/diagnóstico por imagen , Imagen de Perfusión/métodos , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/diagnóstico , Medios de Contraste , Femenino , Humanos , Hígado/patología , Neoplasias Hepáticas/diagnóstico , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y Especificidad
6.
J Vis Exp ; (169)2021 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-33749673

RESUMEN

Orthotopic liver transplantation (OLT) in rats is a tried and proven animal model used for preoperative, intraoperative, and postoperative studies, including ischemia-reperfusion injury (IRI) of extrahepatic organs. This model requires numerous experiments and devices. The duration of anhepatic phase is closely related to the time to develop IRI after transplantation. In this experiment, we used hemodynamic changes to induce extrahepatic organ damage in rats and determined the maximum tolerance time. The time until the most severe organ injury varied for different organs. This method can easily be replicated and can also be used to study IRI of the extrahepatic organs after liver transplantation.


Asunto(s)
Trasplante de Hígado , Daño por Reperfusión/fisiopatología , Alanina Transaminasa/metabolismo , Amilasas/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Creatinina/metabolismo , Modelos Animales de Enfermedad , Hemodinámica , Ligadura , Hígado/patología , Hígado/fisiopatología , Masculino , Especificidad de Órganos , Ratas Sprague-Dawley
7.
Int J Nanomedicine ; 16: 2323-2335, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33776436

RESUMEN

Background: Colon cancer (CRC) was a malignant tumor and there were about 25% of patients with tumor metastasis at diagnosis stage. Chemotherapeutic agents for metastatic CRC patients were with great side effects and the clinical treatment results of advanced CRC were still not satisfactory. Human epidermal growth factor receptor 2 (HER2) is overexpressed in some CRC patients and is an effective target for CRC patient treatment. Anti-HER2 therapy had a beneficial role in the treatment of HER2-positive metastatic CRC with fewer side effects. CRC patients with BRAF mutations were resistant to HER2 antibodies treatment. Therefore, there was an urgent need to develop new therapeutic agents. Methods: HER2 targeted nanoparticles (TPLNP) drug delivery system loading triptolide (TPL) were prepared and identified. The effects of TPLNP and free TPL on cell viability, targeting and cell cycle progression on HT29 (BRAF mutation) with HER2 overexpression, were evaluated by Cell Counting Kit-8 (CCK8), Fluorescence Activating Cell Sorter (FACS) and immunofluorescence methods, respectively. The anti-tumor efficacies of TPLNP were evaluated in subcutaneous xenograft model of colon cancer and the survival rate, tumor volume, liver and kidney indexes of tumor-bearing mice were measured. Results: TPLNP was small in nanosize (73.4±5.2nm) with narrow size distribution (PDI=0.15±0.02) and favorable zeta potential (pH=9.6, zeta potential: -57.3±6.69mV; pH=7.0, zeta potential: -28.7±5.1mV; pH=5.6, zeta potential: -21.1±4.73mV). Comparing with free TPL treatment group, TPLNP developed stranger colon cancer-killing efficiency in a dose- and time-dependent manner detected with CCK8 method; achieved good in vitro colon cancer targeting detected with flow cytometry and immunofluorescence experiments; enhanced more HT29-HER2 apoptosis and induced more cell cycle arrested in G1-S phase detected with FACS in vitro. As for in vivo antitumor response, TPLNP remarkably inhibited the growth of colon cancer in the colon cancer xenograft model, significantly improved the survival rate and did not exhibit significant liver and kidney toxicity in contrast with free TPL in vivo. Conclusion: TPLNP was effectively against colon cancer with HER2 overexpression and BRAF mutation in pre-clinical models. In summary, the TPLNP appeared to be a promising treatment option for CRC in clinical application based on improved efficacy and the favorable safety profile.


Asunto(s)
Diterpenos/farmacología , Sistemas de Liberación de Medicamentos , Mutación/genética , Nanopartículas/química , Fenantrenos/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Receptor ErbB-2/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinogénesis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Diterpenos/toxicidad , Compuestos Epoxi/farmacología , Compuestos Epoxi/toxicidad , Femenino , Células HT29 , Humanos , Concentración 50 Inhibidora , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanomedicina , Fenantrenos/toxicidad , Transducción de Señal/efectos de los fármacos
8.
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
9.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33671269

RESUMEN

Visceral pain frequently produces referred pain at somatic sites due to the convergence of somatic and visceral afferents. In skin overlying the referred pain, neurogenic spots characterized by hyperalgesia, tenderness and neurogenic inflammation are found. We investigated whether neurogenic inflammatory spots function as acupoints in the rat model of bile duct ligation-induced liver injury. The majority of neurogenic spots were found in the dorsal trunk overlying the referred pain and matched with locations of acupoints. The spots, as well as acupoints, showed high electrical conductance and enhanced expression of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP). Electroacupuncture at neurogenic spots reduced serum hepatocellular enzyme activities and histological patterns of acute liver injury in bile duct ligation (BDL) rats. The results suggest that the neurogenic spots have therapeutic effects as acupoints on hepatic injury in bile-duct ligated rats.


Asunto(s)
Conductos Biliares/patología , Electroacupuntura , Hígado/patología , Inflamación Neurogénica/terapia , Dolor Referido/terapia , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Conductividad Eléctrica , Hiperalgesia/complicaciones , Ligadura , Inflamación Neurogénica/complicaciones , Dolor Referido/complicaciones , Ratas Sprague-Dawley , Piel/patología , Sustancia P/metabolismo
10.
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
11.
Zhongguo Zhong Yao Za Zhi ; 46(6): 1474-1479, 2021 Mar.
Artículo en Chino | MEDLINE | ID: mdl-33787146

RESUMEN

To study the effect and mechanism of extract of Quzhou Aurantii Fructus(QAF) on liver inflammation in CCl_4-induced liver fibrosis mice. Totally 60 C57 BL/6 male mice were randomly divided into control group(distilled water, oral), model group(distilled water, oral), colchicines group(Col, colchicines 2 mg·kg~(-1)·d~(-1), oral), low-dose QAF group(QAF-L, QAF 100 mg·kg~(-1)·d~(-1), oral) and high-dose QAF group(QAF-H, QAF 300 mg·kg~(-1)·d~(-1), oral) by random number table method. The model group and each administration group were injected with carbon tetrachloride(CCl_4) 1 mL·kg~(-1)(CCl_4-olive oil 1∶4), twice a week, totally 6 weeks. After the last administration, the mice were sacrificed, and serum and liver tissue were collected. Serum ALT and AST levels were measured in each group to observe the liver function of mice. The pathological changes and inflammatory cell infiltration in liver were observed by HE staining and F4/80 immunohistochemical staining. The mRNA expressions of TNF-α, IL-18 and IL-1ß were detected by RT-PCR. The protein expressions of IκBα, p-IKKα/ß, p-p65, NLRP3, caspase-1 and cleaved caspase-1 were analyzed by Western blot. The results showed that QAF significantly reduced serum ALT and AST levels, and alleviated the degree of liver damage.The results of immunohistochemistry showed that QAF significantly reduced liver inflammatory cell infiltration in liver fibrosis mice. The results of RT-PCR and Western blot showed that QAF significantly inhibited mRNA expressions of TNF-α, IL-18 and IL-1ß in liver of fibrosis mice. QAF also suppressed the degradation of IκBα protein and reduced p-IKKα/ß, p-p65, NLRP3 and cleaved caspase-1 protein expressions. In conclusion, QAF improves CCl_4-induced liver fibrosis in mice. The mechanism may be related to the inhibition of NF-κB/NLRP3 inflammasome-mediated inflammation signaling pathway.


Asunto(s)
Inflamasomas , FN-kappa B , Animales , Inflamasomas/genética , Inflamación , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/genética , Masculino , Ratones , FN-kappa B/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Extractos Vegetales
12.
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
13.
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
14.
Zhonghua Gan Zang Bing Za Zhi ; 29(2): 121-125, 2021 Feb 20.
Artículo en Chino | MEDLINE | ID: mdl-33685079

RESUMEN

Objective: To investigate the relationship between the expression of hepatocyte nuclear factor-1 α (HNF-1α) and the occurrence and development of liver inflammation and fibrosis in liver tissues of patients with chronic hepatitis B. Methods: Sixty-four patients with chronic hepatitis B who were diagnosed and treated in our hospital from 2011 to 2018 were selected. All patients underwent ultrasound-guided aspiration liver biopsy. The pathological results of liver biopsy were collected for inflammation grading and fibrosis staging. The liver puncture biopsies was collected by paraffin sectioning. The expression of HNF1α in the liver tissue was detected by immunohistochemical staining. Mantel-Haenszel χ(2) test was used for bidirectional ordered grouping data, and Spearman's rank-correlation test was used for rank correlation analysis. Results: There were varying degrees of inflammatory necrosis and fibrosis in the liver tissues of patients with chronic hepatitis B. There was a linear relationship between the expression of HNF1α and the level of inflammation in liver tissues (χ (2)(MH) = 40.70, P < 0.05). The expression of HNF1α in liver tissues of patients with chronic hepatitis B was decreased with the increase of liver inflammation. The expression intensity of HNF1α was negatively correlated with the inflammation grade (r(s) = -0.815, P < 0.05). There was a linear relationship between the expressions of HNF1α and the degree and stage of liver fibrosis (χ (2)(MH) = 31.95, P < 0.05). The expression level of HNF1α in liver tissue was gradually decreased with the aggravation of liver fibrosis. The expression intensity of HNF1α was negatively correlated with fibrosis stage (r(s) = -0.713, P < 0.05). Conclusion: HNF1α is closely related to the occurrence and development of liver tissue inflammation and fibrosis, and is expected to be a sensitive indicator for evaluating the level of liver tissue inflammation and fibrosis in patients with chronic hepatitis B. In addition, its down-regulation may be involved in the process of occurrence and development of liver inflammation and liver fibrosis, and may become a new target for the treatment of chronic hepatitis B.


Asunto(s)
Hepatitis B Crónica , Fibrosis , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/patología , Factor Nuclear 1-alfa del Hepatocito , Humanos , Hígado/patología , Cirrosis Hepática/patología
15.
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
16.
Ter Arkh ; 93(1): 15-19, 2021 Jan 10.
Artículo en Ruso | MEDLINE | ID: mdl-33720620

RESUMEN

AIM: The aim of the study was to evaluate hepatocellular damage and immune inflammation in various forms of alcoholic liver disease (ALD). MATERIALS AND METHODS: 104 patients with ALD were examined: 15 (14.4%) with liver steatosis (LS), 19 (18.3%) with steatohepatitis and 70 (67.3%) with liver cirrhosis (LC); men 50 (48.1%), women 54 (51.9%); age 45.78.4 years. Traditional clinical, laboratory, instrumental studies were performed, the levels of fragments of cytokeratin-18 (FCK-18), cytokines IL-1, TNF-, IL-4, IL-6, IL-8 were determined by ELISA. The control group consisted of 39 healthy individuals: men 20 (51.2%), women 19 (48.7%), age 48.58.3 years. RESULTS: In LS, an increase in the level of FCK-18 was noted with normal aminotransferase activity, the content of TNF-, IL-6, IL-1, IL-8 increased and the level of IL-4 decreased compared to those in healthy individuals. In steatohepatitis, a triple increase in aminotransferases and FCK-18 was observed compared with LS, as well as an increase in the level of inflammatory mediators, to a greater extent IL-6, to a lesser extent IL-8, TNF-, a decrease in IL-4, IL-1 remained at the same level. In LC, there was a further increase in FCK-18, significantly more pronounced than an increase in AST, and the increase in cytokines continued to the same extent, the levels of IL-6 and IL-8, to a lesser extent IL-1 and TNF-, and the level of IL-4. CONCLUSION: With the progression of ALD from LS to steatohepatitis, hepatic cell damage was carried out by equally pronounced processes of hepatocyte necrosis and apoptosis, with the development of cirrhosis of the liver, parenchyma damage occurred mainly due to hepatocyte apoptosis. The immuno-inflammatory process progressively increased from the stage of LS to LC with IL-6 and IL-8 undergoing the greatest dynamics. FCK-18 can serve as a non-invasive marker of hepatic cell damage, and IL-6 and IL-8 markers of immune inflammation in ALD.


Asunto(s)
Carcinoma Hepatocelular , Hepatopatías Alcohólicas , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Femenino , Humanos , Inflamación , Hígado/patología , Cirrosis Hepática/patología , Hepatopatías Alcohólicas/patología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/patología
17.
Toxicol Lett ; 343: 1-10, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33571620

RESUMEN

AIMS: Both gefitinib and afatinib are epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in the treatment of non-small cell lung cancer (NSCLC). It has been reported that gefitinib and afatinib could cause hepatotoxicity during the clinic treatment, therefore it is critical to investigate their hepatotoxicity systematically. In this study, zebrafish (Danio rerio) were used as model animals to compare the hepatotoxicity and their toxic mechanism. MAIN METHODS: The zebrafish transgenic line [Tg (fabp10a: dsRed; ela3l:EGFP) was used in this study. After larvae developed at 3 days post fertilization (dpf), they were put into different concentrations of gefitinib and afatinib. At 6 dpf, the viability, liver area, fluorescence intensity, histopathology, apoptosis, transaminase reflecting liver function, the absorption of yolk sac, and the expression of relative genes were observed and analyzed respectively. KEY FINDINGS: Both gefitinib and afatinib could induce the larvae hepatotoxicity dose-dependently. Based on the liver morphology, histopathology, apoptosis and function assessments, gefitinib showed higher toxicity, causing more serious liver damage. Both gefitinib and afatinib caused abnormal expressions of genes related to endoplasmic reticulum stress (ERS) pathway and apoptosis. For example, jnk, perk, bip, chop, ire1, bid, caspase3 and caspase9 were up-regulated, while xbp1s, grp78, bcl-2/bax, and caspase8 were down-regulated. The hepatotoxicity difference of gefitinib and afatinib might be due to the different expression level of related genes.


Asunto(s)
Afatinib/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Embrión no Mamífero/efectos de los fármacos , Gefitinib/toxicidad , Hígado/efectos de los fármacos , Inhibidores de Proteínas Quinasas/toxicidad , Animales , Animales Modificados Genéticamente , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/patología , Pez Cebra/embriología
18.
Hum Immunol ; 82(3): 177-185, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33597096

RESUMEN

Hepatitis C virus usually produces chronic infection and liver damage. Considering that: i) the human leukocyte antigen-E (HLA-E) molecule may modulate the immune response, and ii) little is known about the role of HLA-E gene variability on chronic hepatitis C, we studied the impact of HLA-E polymorphisms on the magnitude of HLA-E liver expression and severity of hepatitis C. HLA-E variability was evaluated in terms of: i) single nucleotide polymorphism (SNP) alleles and genotypes along the gene (beginning of the promoter region, coding region and 3'UTR), and ii) ensemble of SNPs that defines the coding region alleles, considered individually or as genotypes. The comparisons of the HLA-E variation sites between patients and controls revealed no significant results. The HLA-E + 424 T > C (rs1059510), +756 G > A (rs1264457) and + 3777 G > A (rs1059655) variation sites and the HLA-E*01:01:01:01 and HLA-E*01:03:02:01 alleles, considered at single or double doses, were associated with the magnitude of HLA-E liver expression in Kupfer cell, steatosis, inflammatory activity and liver fibrosis. Although these associations were lost after corrections for multiple comparisons, these variable sites may propitiate biological clues for the understanding of the mechanisms associated with hepatitis C severity.


Asunto(s)
Genotipo , Hepacivirus/fisiología , Hepatitis C Crónica/genética , Antígenos de Histocompatibilidad Clase I/genética , Hígado/metabolismo , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Hígado/patología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Adulto Joven
19.
Life Sci ; 272: 119203, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33577848

RESUMEN

BACKGROUND & AIMS: Splenomegaly is usually taken as a consequence of liver cirrhosis. However, as a risk factor for cirrhosis, the impacts of spleen-liver axis on the development of cirrhosis are largely unknown. This study focused on the impacts of splenomegaly on the development of cirrhosis and assessment of the effects of celecoxib, a selective COX-2 inhibitor, on the splenomegaly and cirrhotic liver. MATERIALS AND METHODS: Liver cirrhosis was induced by thioacetamide (TAA). Sixty rats were randomly divided into control, TAA-16w, TAA + celecoxib groups and normal, TAA + sham, TAA + splenectomy groups. Hepatic stellate cells (HSCs) or hepatocytes were co-cultured with splenocytes from those groups. RESULTS: Splenocytes of cirrhotic rats stimulated the HSCs activation and induced hepatocyte apoptosis via enhancing oxidative stress. The hepatic levels of NOX-4 and the in situ O2- were profoundly reduced in TAA + splenectomy group by 50.6% and 18.5% respectively, p < 0.05. Celecoxib significantly decreased the hepatic fibrotic septa induced with TAA by 50.8%, p < 0.05. Splenic lymphoid tissue proliferation and proinflammatory cytokines of the cirrhotic rats were also obviously suppressed by celecoxib, p < 0.05. Compared with the HSC or hepatocyte cell line co-cultured with the cirrhotic splenocytes, the expression of alpha-SMA, NOX-4, in situ O2- or the levels of cleaved caspase3 and NOX-4 were significantly decreased in those cell lines co-cultured with cirrhotic splenocytes treated by celecoxib, p < 0.05. CONCLUSION: Splenomegaly contributed to the development of liver cirrhosis through enhancing oxidative stress in liver. Celecoxib could effectively ameliorate liver cirrhosis via reducing inflammatory cytokines and immune cells derived from spleen and suppressing oxidative stress.


Asunto(s)
Celecoxib/farmacología , Cirrosis Hepática/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Celecoxib/metabolismo , China , Inhibidores de la Ciclooxigenasa 2/farmacología , Modelos Animales de Enfermedad , Células Estrelladas Hepáticas/metabolismo , Hepatocitos/metabolismo , Inflamación/tratamiento farmacológico , Hígado/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática Experimental/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Bazo/patología , Esplenomegalia/complicaciones , Esplenomegalia/fisiopatología , Tioacetamida/farmacología
20.
Int J Mol Sci ; 22(4)2021 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-33562258

RESUMEN

Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.


Asunto(s)
Envejecimiento , Restricción Calórica/efectos adversos , ADN Mitocondrial/metabolismo , Hígado/patología , Mitocondrias/patología , Biogénesis de Organelos , Estrés Oxidativo , Animales , ADN Mitocondrial/genética , Hígado/metabolismo , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Ratas , Ratas Endogámicas BN , Ratas Endogámicas F344
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