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1.
Life Sci ; 248: 117475, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32119963

RESUMEN

AIMS: Liver fibrosis is a crucial pathological feature which could result in cirrhosis and hepatocarcinoma. But until now, there is no favourable treatment for it. Apigenin (APG) is a flavonoid, which exhibits efficient anti-liver fibrosis activity, but its underlying mechanisms were rarely studied. So this work aims to estimate the potential therapeutic action of APG on liver fibrosis rats and to gain insight into its system-level mechanisms. MAIN METHODS: Hepatic fibrosis was induced by CCl4 in Wistar rats, and APG was given in the light of the regimen. Biochemical indexes, histopathological change and immunohistochemistry of liver were evaluated. The optimal effect group of APG was selected for further transcriptomic and proteomic analysis. KEY FINDINGS: APG ameliorated liver fibrosis via reducing the levels of AST, ALT, ALP, LDH, Hyp, TP, TB, DB, HA, LN, PCIII and IV-C, mitigating fibrosis and inflammation of liver in H&E and Masson staining. Mechanistically, APG elevated the activity of ALB, SOD and GSH-PX with reducing the level of MDA. The results of microarray and TMT revealed that 4919 genes and 4876 proteins were differentially expressed in the APG and model groups. Besides, transcriptomics and proteomics analyses unfolded 120 overlapped proteins, enriched in 111 GO terms containing apoptotic process, angiogenesis, cell migration and proliferation, etc. Meanwhile, KEGG pathway analysis showed that 26 pathways containing HIF-1/MAPK/eNOS/VEGF/PI3K/Akt signaling pathway, regulation of actin cytoskeleton and focal adhesion mostly. SIGNIFICANCE: APG can ameliorate CCl4-induced liver fibrosis via VEGF-mediated FAK phosphorylation through the MAPKs, PI3K/Akt, HIF-1, ROS, and eNOS pathways, which may hopefully become the anti-liver fibrosis activity of natural product.


Asunto(s)
Antiinflamatorios/farmacología , Apigenina/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Cirrosis Hepática/prevención & control , Hígado/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Alanina Transaminasa/genética , Alanina Transaminasa/metabolismo , Albúminas/metabolismo , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Aspartato Aminotransferasas/genética , Aspartato Aminotransferasas/metabolismo , Bilirrubina/sangre , Tetracloruro de Carbono/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Masculino , Malondialdehído/antagonistas & inhibidores , Malondialdehído/metabolismo , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Proteómica/métodos , Ratas , Ratas Wistar , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
2.
Emerg Microbes Infect ; 9(1): 651-663, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32192415

RESUMEN

Equine parvovirus-hepatitis (EqPV-H) has recently been associated with cases of Theiler's disease, a form of fulminant hepatic necrosis in horses. To assess whether EqPV-H is the cause of Theiler's disease, we first demonstrated hepatotropism by PCR on tissues from acutely infected horses. We then experimentally inoculated horses with EqPV-H and 8 of 10 horses developed hepatitis. One horse showed clinical signs of liver failure. The onset of hepatitis was temporally associated with seroconversion and a decline in viremia. Liver histology and in situ hybridization showed lymphocytic infiltrates and necrotic EqPV-H-infected hepatocytes. We next investigated potential modes of transmission. Iatrogenic transmission via allogeneic stem cell therapy for orthopedic injuries was previously suggested in a case series of Theiler's disease, and was demonstrated here for the first time. Vertical transmission and mechanical vectoring by horse fly bites could not be demonstrated in this study, potentially due to limited sample size. We found EqPV-H shedding in oral and nasal secretions, and in feces. Importantly, we could demonstrate EqPV-H transmission via oral inoculation with viremic serum. Together, our findings provide additional information that EqPV-H is the likely cause of Theiler's disease and that transmission of EqPV-H occurs via both iatrogenic and natural routes.


Asunto(s)
Hepatitis Viral Animal/virología , Enfermedades de los Caballos/virología , Hígado/virología , Infecciones por Parvoviridae/veterinaria , Parvovirus/fisiología , Animales , Dípteros/virología , Heces/virología , Femenino , Hepatitis Viral Animal/patología , Hepatitis Viral Animal/transmisión , Hepatocitos/patología , Hepatocitos/virología , Enfermedades de los Caballos/patología , Enfermedades de los Caballos/transmisión , Caballos , Transmisión Vertical de Enfermedad Infecciosa , Insectos Vectores/virología , Hígado/patología , Linfocitos , Masculino , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/virología , Boca/virología , Necrosis , Infecciones por Parvoviridae/patología , Infecciones por Parvoviridae/transmisión , Infecciones por Parvoviridae/virología , Parvovirus/aislamiento & purificación , Parvovirus/patogenicidad , Tropismo Viral , Viremia , Esparcimiento de Virus
3.
JAMA ; 323(12): 1175-1183, 2020 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-32207804

RESUMEN

Importance: Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) and is associated with disease progression, development of cirrhosis, and need for liver transplant. Despite its importance, NASH is underrecognized in clinical practice. Observations: NASH affects an estimated 3% to 6% of the US population and the prevalence is increasing. NASH is strongly associated with obesity, dyslipidemia, type 2 diabetes, and metabolic syndrome. Although a number of noninvasive tests and scoring systems exist to characterize NAFLD and NASH, liver biopsy is the only accepted method for diagnosis of NASH. Currently, no NASH-specific therapies are approved by the US Food and Drug Administration. Lifestyle modification is the mainstay of treatment, including dietary changes and exercise, with the primary goal being weight loss. Substantial improvement in histologic outcomes, including fibrosis, is directly correlated with increasing weight loss. In some cases, bariatric surgery may be indicated to achieve and maintain the necessary degree of weight loss required for therapeutic effect. An estimated 20% of patients with NASH will develop cirrhosis, and NASH is predicted to become the leading indication for liver transplants in the US. The mortality rate among patients with NASH is substantially higher than the general population or patients without this inflammatory subtype of NAFLD, with annual all-cause mortality rate of 25.56 per 1000 person-years and a liver-specific mortality rate of 11.77 per 1000 person-years. Conclusions and Relevance: Nonalcoholic steatohepatitis affects 3% to 6% of the US population, is more prevalent in patients with metabolic disease and obesity, progresses to cirrhosis in approximately 20% of cases, and is associated with increased rates of liver-specific and overall mortality. Early identification and targeted treatment of patients with nonalcoholic steatohepatitis are needed to improve patient outcomes, including directing patients toward intensive lifestyle modification to promote weight loss and referral for bariatric surgery as indicated for management of obesity and metabolic disease.


Asunto(s)
Hígado/patología , Enfermedad del Hígado Graso no Alcohólico , Cirugía Bariátrica , Diagnóstico Diferencial , Progresión de la Enfermedad , Humanos , Estilo de Vida , Cirrosis Hepática/etiología , Cirrosis Hepática/mortalidad , Síndrome Metabólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/terapia , Obesidad/complicaciones , Prevalencia , Estados Unidos/epidemiología
4.
Zhonghua Gan Zang Bing Za Zhi ; 28(2): 135-140, 2020 Feb 20.
Artículo en Chino | MEDLINE | ID: mdl-32164064

RESUMEN

Objective: To investigate the mechanism of occurrence and development of zinc-alpha-2-glycoprotein (AZGP1) in the activated hepatic stellate cells (HSCs) and liver fibrosis. Methods: The activated human hepatic stellate cell line LX2 was induced by the stimulation of transforming growth factor - ß1 to construct carbon tetrachloride liver fibrosis mice model. The situation expression of AZGP1 in liver cells and tissues were observed. Plasmid transfection method was used to detect the activation, proliferation, apoptotic functions and changes in related factors of LX2 cells, respectively, after the overexpression and inhibition of AZGP1expression. Univariate analysis of variance was used for multiple group comparison. Results: The results of immunofluorescence staining showed that AZGP1 protein was decreased and α-smooth muscle actin was increased in the activated LX2 cells, and the two were negatively correlated. AZGP1 gene and protein were significantly under-expressed in activated LX2 cells and liver tissues of mice with carbon tetrachloride liver fibrosis. Collagen I, matrix metalloproteinase-2, and α-smooth muscle actin genes and proteins were significantly down-regulated in LX2 cells after over-expression of AZGP1. Cell fluorescence showed that AZGP1-overexpressing cells were activated and α-smooth muscle actin protein was reduced. In addition, the proliferative activity and G1/S-specific cyclin D1 protein of LX2 cells were significantly reduced after overexpression of AZGP1, while cell cycle experiments showed that the proportion of cells overexpressing AZGP1 was significantly increased in the G0/G1 phase, and the proportion of S phase was significantly reduced. AZGP1 had no significant effect on the apoptosis of LX2 cells. Conclusion: AZGP1 can reverse liver fibrosis by inhibiting the activation and proliferation of hepatic stellate cells, and thereby overexpression of AZGP1 is expected to become a new target for liver fibrosis treatment.


Asunto(s)
Tetracloruro de Carbono/toxicidad , Proliferación Celular/efectos de los fármacos , Glicoproteínas/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Actinas , Animales , Glicoproteínas/genética , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática , Metaloproteinasa 2 de la Matriz , Ratones , Zinc
5.
Zhonghua Gan Zang Bing Za Zhi ; 28(2): 175-178, 2020 Feb 20.
Artículo en Chino | MEDLINE | ID: mdl-32164073

RESUMEN

Although tumor immune checkpoint inhibitors therapy brings survival benefits to cancer patients, it also faces many challenges, such as the occurrence of immune-mediated hepatotoxicity. Therefore, an in-depth understanding of the conditions, possible mechanisms, and risk factors that cause liver injury during the treatment of tumor immune checkpoint inhibitors will facilitate better clinical management.


Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Inmunoterapia/efectos adversos , Hígado/patología , Neoplasias/terapia , Antineoplásicos Inmunológicos/uso terapéutico , Humanos , Factores de Riesgo
6.
J Comput Assist Tomogr ; 44(2): 197-203, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32195798

RESUMEN

INTRODUCTION: Liver segmentation and volumetry have traditionally been performed using computed tomography (CT) attenuation to discriminate liver from other tissues. In this project, we evaluated if spectral detector CT (SDCT) can improve liver segmentation over conventional CT on 2 segmentation methods. MATERIALS AND METHODS: In this Health Insurance Portability and Accountability Act-compliant institutional review board-approved retrospective study, 30 contrast-enhanced SDCT scans with healthy livers were selected. The first segmentation method is based on Gaussian mixture models of the SDCT data. The second method is a convolutional neural network-based technique called U-Net. Both methods were compared against equivalent algorithms, which used conventional CT attenuation, with hand segmentation as the reference standard. Agreement to the reference standard was assessed using Dice similarity coefficient. RESULTS: Dice similarity coefficients to the reference standard are 0.93 ± 0.02 for the Gaussian mixture model method and 0.90 ± 0.04 for the CNN-based method (all 2 methods applied on SDCT). These were significantly higher compared with equivalent algorithms applied on conventional CT, with Dice coefficients of 0.90 ± 0.06 (P = 0.007) and 0.86 ± 0.06 (P < 0.001), respectively. CONCLUSION: On both liver segmentation methods tested, we demonstrated higher segmentation performance when the algorithms are applied on SDCT data compared with equivalent algorithms applied on conventional CT data.


Asunto(s)
Hígado/diagnóstico por imagen , Hígado/patología , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Tomografía Computarizada por Rayos X/métodos , Medios de Contraste , Humanos , Tamaño de los Órganos , Intensificación de Imagen Radiográfica/métodos , Estudios Retrospectivos
7.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(3): 209-214, 2020 Mar 12.
Artículo en Chino | MEDLINE | ID: mdl-32164090

RESUMEN

Objective: To investigate the clinical characteristics of medical staff with novel coronavirus pneumonia(NCP). Methods: 30 patients infected with novel coronavirus referred to jianghan university hospital between January 11, 2020 and January 3, 2020 were studied. The data reviewed included those of clinical manifestations, laboratory investigation and Radiographic features. Results: The patients consisted of 10 men and 20 women, including 22 doctors and 8 nurses,aged 21~59 years(mean 35±8 years).They were divided to 26 common type and 4 severe cases, all of whom had close(within 1m) contact with patients infected of novel coronavirus pneumonia. The average contact times were 12 (7,16) and the average cumulative contact time was 2 (1.5,2.7) h.Clinical symptoms of these patients were fever in 23 patients (76.67%) , headache in 16 petients (53.33%) , fatigue or myalgia in 21patients (70%) , nausea, vomiting or diarrhea in 9 petients (30%) , cough in 25 petients (83.33%) , and dyspnea in 14 petients (46.67%) .Routine blood test revealed WBC<4.0×10(9)/L in 8 petients (26.67%) , (4-10) ×10(9)/L in 22 petients (73.33%) , and WBC>4.0×10(9)/L in 4 petients (13.33%) during the disease.Lymphocyte count<1.0×10(9)/L occurred in 12 petients (40%),abnormal liver function in 7 petients (23.33%) ,myocardial damage in 5 petients(16.67%), elevated D-dimer (>0.5mg/l) in 5 patients (16.67%). Compared with normal patients, the average exposure times, cumulative exposure time, BMI, Fever time, white blood cell count, liver enzyme, LDH, myoenzyme and D-dimer were significantly increased in severe patients, while the lymphocyte count and albumin levels in peripheral blood were significantly decreased.Chest CT mainly showed patchy shadows and interstitial changes.According to imaging examination, 11 patients (36.67%) showed Unilateral pneumonia and 19 patients (63.33%) showed bilateral pneumonia,4 patients (13.33%) showed bilateral multiple mottling and ground-glass opacity.Compared with the patients infected in the protected period, the proportion of severe infection and bilateral pneumonia were both increased in the patients infected in unprotected period. Conclusion: Medical staffs are at higher risk of infection.Infection rates are associated with contact time, the amount of suction virus. Severe patients had BMI increased, heating time prolonged, white blood cell count, lymphocyte count, D-dimer and albumin level significantly changed and were prone to be complicated with liver damage and myocardial damage.Strict protection measures is important to prevent infection for medical workers.


Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus , Fiebre , Personal de Salud , Transmisión de Enfermedad Infecciosa de Paciente a Profesional , Neumonía Viral , Adulto , Índice de Masa Corporal , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/transmisión , Tos/etiología , Disnea/etiología , Femenino , Fiebre/clasificación , Fiebre/etiología , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , Recuento de Leucocitos , Hígado/patología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Miocardio/patología , Neumonía Viral/complicaciones , Neumonía Viral/diagnóstico , Neumonía Viral/transmisión , Estudios Retrospectivos , Factores de Riesgo , Albúmina Sérica , Factores de Tiempo , Adulto Joven
8.
Life Sci ; 246: 117416, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32035927

RESUMEN

AIMS: Diabetes is a common metabolic disease which damages many organs including the liver and causes endoplasmic reticulum (ER) stress, which originates from non-folded proteins. Sonic hedgehog (Shh) pathway plays a role in liver regeneration and repair. To our knowledge, there is no study showing the relation between ER stress and Shh pathway in the liver in diabetes. Thus, the aim of this study was to investigate the interaction between ER stress and Shh pathway in the liver of diabetic mice. MAIN METHODS: Six groups of male mice were formed as control, diabetes (streptozotocine-treated), Shh activator (SAG-treated), Shh inhibitor (SANT1-treated), diabetes + SAG and diabetes + SANT1. At the end of the experiment, mice were weighed, anaesthetized and euthanized. Blood samples were collected, livers were excised and weighed. Thereafter, blood glucose, serum ALT and AST levels, TOS and TAC levels in liver tissue were measured. ER stress marker (GRP78) and Shh pathway molecules (Gli1 and Smo) were evaluated by immunohistochemistry, H-score and western blot analyses. Besides, histopathological examination was performed. KEY FINDINGS: Results showed that GRP78, Gli1 and Smo were increased in liver due to Type 1 diabetes. The SAG agent decreased GRP78 and increased Gli1 and Smo, leading to liver repair, while the inhibitor SANT1 increased GRP78 and decreased Gli1and Smo, causing progression of the liver stress induced by diabetes. SIGNIFICANCE: In conclusion, the Shh pathway is related to ER stress and may provide a new strategy for its treatment, especially liver stress induced by diabetes.


Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Estrés del Retículo Endoplásmico , Proteínas Hedgehog/metabolismo , Hepatopatías/etiología , Transducción de Señal , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Glucemia/análisis , Western Blotting , Diabetes Mellitus Experimental/metabolismo , Hígado/metabolismo , Hígado/patología , Hepatopatías/metabolismo , Hepatopatías/patología , Masculino , Ratones
9.
Mikrobiyol Bul ; 54(1): 95-109, 2020 Jan.
Artículo en Turco | MEDLINE | ID: mdl-32050881

RESUMEN

Chronic hepatitis B (CHB) is an important public health problem in the world and Turkey. The aim of this study was to evaluate the histological, virological, serological and biochemical response rates in CHB patients receiving tenofovir or entecavir therapy. Control liver biopsies were performed on patients who received tenofovir or entecavir therapy for one year or longer. Histopathological grading was scored according to the modified Knodell system. Eighty-seven CHB patients were included in this study, 56 patients were receiving tenofovir and 31 patients were receiving entecavir therapy. Patients in two treatment groups were similar in terms of baseline parameters (p> 0.05). At the end of the treatment, there was a significant decrease in mean values of HBV DNA, alanine aminotransferase and necroinflammatory scores for both groups (p<0.001); however, no statistically significant change was observed in fibrosis scores (p> 0.05). Histological responses were obtained 66.1% from the tenofovir group and 54.8% from the entecavir group. Treatment with tenofovir and entecavir resulted with improvement in Ishak fibrosis scores in 12.5% and 12.9% of the patients, respectively. For 14.3% of the tenofovir-treated patients and for 22.6% of the entecavir-treated patients, the Ishak fibrosis scores worsened. Baseline intermediate/ advanced fibrosis stage (Ishak fibrosis score: 3-6) was found as independent determinant factor on histological response and improvement of fibrosis score (OR= 3.99, p= 0.01; OR= 31.67, p= 0.002; respectively) and treatment duration longer than five years is an independent determinant for improvement of necroinflammatory score (OR= 5.79, p= 0.02). There was no significant difference in the virological, serological, biochemical and, histological responses and improvement of necroinflammatory and fibrosis scores between tenofovir and entecavir groups (p> 0.05). Similar histological, virological, serological and biochemical responses were obtained in patients with CHB receving tenofovir and entecavir treatments. Further studies involving a large number of patients receiving long-term therapy should be done to understand the effects of antiviral treatments on healing of liver histology.


Asunto(s)
Antivirales , Guanina/análogos & derivados , Hepatitis B Crónica , Tenofovir , Antivirales/uso terapéutico , Guanina/uso terapéutico , Virus de la Hepatitis B , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Hígado/patología , Estudios Retrospectivos , Tenofovir/uso terapéutico , Resultado del Tratamiento , Turquia
10.
Toxicol Lett ; 325: 43-50, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32092452

RESUMEN

As a consequence of the detoxification process, drugs and drug related metabolites can accumulate in the liver, resulting in drug induced liver injury (DILI), which is the major cause for dose limitation. Amitriptyline, a commonly used tricyclic anti-depressant, is known to cause DILI. The mechanism of Amitriptyline induced liver injury is not yet completely understood. However, as it undergoes extensive hepatic metabolism, unraveling the molecular changes in the liver upon Amitriptyline treatment can help understand Amitriptyline's mode of toxicity. In this study, Amitriptyline treated male rat liver tissue was analyzed using Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry Imaging (MALDI-MSI) to investigate the spatial abundances of Amitriptyline, lipids, and bile acids. The metabolism of Amitriptyline in liver tissue was successfully demonstrated, as the spatial distribution of Amitriptyline and its metabolites localize throughout treatment group liver samples. Several lipids appear upregulated, from which nine were identified as distinct phosphatidylcholine (PC) species. The detected bile acids were found to be lower in Amitriptyline treatment group. The combined results from histological findings, Oil Red O staining, and lipid zonation by MSI revealed lipid upregulation in the periportal area indicating drug induced macrovesicular steatosis (DIS).


Asunto(s)
Amitriptilina/toxicidad , Antidepresivos Tricíclicos/toxicidad , Ácidos y Sales Biliares/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hígado/química , Hígado/metabolismo , Hígado/patología , Masculino , Espectrometría de Masas , Tamaño de los Órganos/efectos de los fármacos , Fosfatidilcolinas/metabolismo , Ratas , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Regulación hacia Arriba/efectos de los fármacos
11.
Adv Exp Med Biol ; 1234: 43-56, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32040854

RESUMEN

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are the most common types of primary liver cancers. Moreover, the liver is the second most frequently involved organ in cancer metastasis after lymph nodes. The tumor microenvironment is crucial for the development of both primary and secondary liver cancers. The hepatic microenvironment consists of multiple cell types, including liver sinusoidal endothelial cells, Kupffer cells, natural killer cells, liver-associated lymphocytes, and hepatic stellate cells (HSCs). The microenvironment of a normal liver changes to a tumor microenvironment when tumor cells exist or tumor cells migrate to and multiply in the liver. Interactions between tumor cells and non-transformed cells generate a tumor microenvironment that contributes significantly to tumor progression. HSCs play a central role in the tumor microenvironment crosstalk. As this crosstalk is crucial for liver carcinogenesis and liver-tumor development, elucidating the mechanism underlying the interaction of HSCs with the tumor microenvironment could provide potential therapeutic targets for liver cancer.


Asunto(s)
Células Estrelladas Hepáticas , Neoplasias Hepáticas/patología , Microambiente Tumoral , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Humanos , Hígado/patología , Neoplasias Hepáticas/tratamiento farmacológico
12.
Zhonghua Gan Zang Bing Za Zhi ; 28(1): 47-52, 2020 Jan 20.
Artículo en Chino | MEDLINE | ID: mdl-32023699

RESUMEN

Objective: To establish and evaluate diagnostic efficacy and applicability of serum Golgi protein (GP) 73 based non-invasive diagnostic model with other conventional serological indicators for compensated stage hepatitis B cirrhosis. Methods: 666 cases with chronic hepatitis B (CHB) who had visited to the Fifth Medical Center of People's Liberation Army General Hospital from January 2010 to December 2017 were selected as the study subjects, and were classified according to compensated stage cirrhosis into clinical and pathological diagnosis group based on whether or not the liver histological examination was performed. A diagnostic model of compensated stage hepatitis B cirrhosis in the clinical diagnosis group was established. The current clinically used diagnostic model of liver cirrhosis, aspartate aminotransferase/platelet ratio index (APRI), fibrosis index (FIB)-4 and liver stiffness measurement (LSM) were compared. Eventually, the diagnostic model was verified step by step by pathological diagnosis group. Results: The area under the receiver operating characteristic curve (AUC) of GP73 and APRI, FIB-4, and LSM for cirrhosis patients in the clinical diagnosis group were 0.842, 0.857, 0.864, and 0.832, respectively. The diagnostic efficiency of the four indicators were of similar (P value > 0.05). A diagnostic model of compensated stage hepatitis B cirrhosis (GAPA) using logistic regression analysis was established: LogitP = 1/ [1 + exp (1.614-0.054 × GP73-0.045 × Age + 0.030 × PLT-0.015 × ALP)]. The AUC of the model was as high as 0.940 and the optimal cut-off value were 0.41. The corresponding diagnostic sensitivity and specificity were 0.92 and 0.82, respectively. The diagnostic efficiency was better than that of APRI, FIB-4, LSM and GP73 alone (P < 0.05). The AUC of GAPA was 0.877 in the pathological diagnosis group, which was similar to the diagnostic efficacy of LSM (0.891) and FIB-4 (0.847) (P > 0.1), but still superior to that of APRI (0.811) and GP73 alone (0.780) (P < 0.001). Conclusion: GAPA, a diagnostic model for compensated stage hepatitis B cirrhosis established in this study, has a good diagnostic efficacy in both the clinical and pathological diagnosis group, and has certain auxiliary diagnostic value in the areas where resources are relatively scarce or where LSM has not been developed.


Asunto(s)
Biomarcadores/metabolismo , Cirrosis Hepática/diagnóstico , Hígado/metabolismo , Proteínas de la Membrana/metabolismo , Aspartato Aminotransferasas/metabolismo , Biopsia , Fibrosis , Hepatitis B , Humanos , Hígado/patología , Proteínas de la Membrana/sangre , Curva ROC , Índice de Severidad de la Enfermedad
14.
Life Sci ; 245: 117356, 2020 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-31991181

RESUMEN

AIMS: NPY-Y1R plays an important role in dietary regulation. Although germline knockdown of NPY-Y1R in mice alleviates high-fat-diet-induced obesity and increases CPT1α levels in the liver, the role of the Y1 receptor in specific tissues has not been studied. MAIN METHODS: MCD diet is the most widely used method to establish a model of lean NASH in a short time. We therefore evaluated the role of liver NPY-Y1R in NASH progression. KEY FINDINGS: In mice with liver-specific knockout of NPY-Y1R (LivKO) and wild-type control littermates fed MCD diet for 4 weeks, NPY-Y1R deficiency significantly decreased body and liver weight. Moreover, NPY-Y1R deletion protected mice against hepatic steatosis and injury. LivKO decreased TG, TC, and FFA levels in the liver and alanine aminotransferase activity in plasma. To clarify the mechanism, we evaluated the key enzymes involved in triglyceride hydrolase and fatty-acid oxidase. Expression of ATGL, CPT1α, and ACO was significantly increased in LivKO mice, whereas expression of fatty-acid synthase was significantly decreased. mRNA expression analysis revealed a marked reduction of genes involved in de-novo lipogenesis and monosaturated fatty-acid synthesis, including sterol-regulatory element-binding protein 1c and fatty-acid synthase. Moreover, liver injury-related factors were significantly decreased in LivKO mice, such as TNF-α, inducible nitric oxide synthase, and MCP-1. Thus, NPY-Y1R deficiency in the liver alleviates lipid deposition and injury. However, NPY-Y1R did not affect inflammation and fibrosis. SIGNIFICANCE: NPY-Y1R deficiency in the liver directly suppresses not only hepatic steatosis, but also liver injury, and thus provides a treatment option for NASH.


Asunto(s)
Deficiencia de Colina/metabolismo , Hígado/metabolismo , Metionina/deficiencia , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores de Neuropéptido Y/metabolismo , Animales , Western Blotting , Modelos Animales de Enfermedad , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Triglicéridos/metabolismo
15.
Int J Occup Environ Med ; 11(1): 53-58, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31905195

RESUMEN

BACKGROUND: Exposure to numerous chemicals, including industrial ones, may result in liver damage. The body susceptibility to the environmental hazards largely depends on the activity of the enzymes in the xenobiotic detoxification system. Function abnormalities of such enzymes due to genetic variations would increase the risk of developing various diseases. OBJECTIVE: To elucidate the relationship between polymorphism in glutathione S-transferase genes (GSTM1, GSTT1 and GSTP1) and the risk of toxic liver damage in a group of petrochemical workers. METHODS: This study was conducted on 72 workers with toxic liver injury, 156 healthy workers, and 322 healthy individuals without history of occupational exposure to chemicals. Genotyping of the GSTP1 rs1695 gene polymorphism was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Polymerase chain reaction (PCR) was used to perform genotyping of the GSTM1 and GSTT1 genes polymorphism. RESULTS: There was a significant difference in genotype frequencies of the GSTP1 rs1695 gene polymorphism among the groups studied. The distribution of Val/Val genotype of the GSTP1 rs1695 gene polymorphism had a higher incidence in healthy workers compared with patients with toxic liver damage (p=0.036). No significant association was found between the GSTM1 and GSTT1 polymorphisms and toxic liver damage. CONCLUSION: The GSTP1 rs1695 gene polymorphism can play a protective role in the development of toxic liver damage in petrochemical workers.


Asunto(s)
Gutatión-S-Transferasa pi/genética , Glutatión Transferasa/genética , Hígado/patología , Exposición Profesional/efectos adversos , Adulto , Estudios de Casos y Controles , Frecuencia de los Genes/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción
16.
Acta Cir Bras ; 34(11): e201901103, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31939502

RESUMEN

PURPOSE: To evaluate liver regeneration after selective ligation of portal vein and hepatic artery by 3D Computed Tomography in an experimental model. METHODS: Sixteen Wistar rats were randomized into four equal groups: Group I- control (sham), Group II- isolated selective ligation of the hepatic artery, Group III- isolated selective ligation of the portal vein and Group IV- combined ligation of portal vein and hepatic artery. Before procedure and five days after a 3D CT Scan was performed to analyze the hypertrophy, weight and function of the remnant liver. RESULTS: The largest regeneration rate and increase of weight in the hypertrophied lobe was detected in group IV, the first with an average of 3.99 (p=0.006) and the last varying from 6.10g to 9.64g (p=0.01). However, total liver weight and the R1 ratio (Hypertrophied Lobe Weight/Total Liver Weight) was higher in group III (P<0.001) when compared with groups I, II and IV and showed no difference between them. The immunohistochemical examination with PCNA also found higher percentages with statistical significance differences in rats of groups III and IV. It was possible to confirm a strong correlation between hypertrophied lobe weight and its imaging volumetric study. Liver function tests only showed a significant difference in serum gamma-glutamyltransferase and phosphorous. CONCLUSION: There is a largest liver regeneration after combined ligation of portal vein and hepatic artery and this evidence may improve the knowledge of surgical treatment of liver injuries, with a translational impact in anima nobile.


Asunto(s)
Arteria Hepática/cirugía , Regeneración Hepática/fisiología , Hígado/diagnóstico por imagen , Vena Porta/cirugía , Animales , Hepatomegalia/diagnóstico por imagen , Hepatomegalia/fisiopatología , Imagen Tridimensional/métodos , Inmunohistoquímica , Ligadura , Hígado/irrigación sanguínea , Hígado/patología , Masculino , Tamaño de los Órganos/fisiología , Distribución Aleatoria , Ratas Wistar , Reproducibilidad de los Resultados , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento
17.
Life Sci ; 243: 117275, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31926242

RESUMEN

AIMS: Imatinib is an effective tyrosine kinase inhibitor which has different therapeutic actions. The recent work demonstrated the possible beneficial effects of imatinib on the progression of atherosclerosis, endothelial dysfunction, and hypercholesterolemia-associated liver damage in rabbits. MAIN METHODS: Animals had been distributed in 4 groups: group 1 (non-treated): animals fed regular diet; group 2 high cholesterol [HC]: animals fed 1% cholesterol supplemented diet for 30 days; group 3 (HC-Imatinib): animals fed 1% cholesterol supplemented diet+imatinib (0.01 g/kg daily, p.o) for 30 days; group 4 (Imatinib): animals fed regular diet with imatinib (0.01 g/kg daily, p.o). After thirty days, tissue samples and blood were isolated to be detected biochemically, histologically, and for in vitro analysis. KEY FINDINGS: HC exhibited significant elevations in serum lipid parameters, CRP, ALT, AST and ALP. Additionally, HC induced significant increases for aortic and hepatic MDA, aortic NO and hepatic PDGFR-ß, while significantly exhibited reductions in aortic and hepatic GSH, SOD and hepatic PPARγ1. Moreover, HC produced impairment in ACh-enhanced aortic relaxation and aortic pathological changes. Histopathological examination of HC-fed rabbits revealed hepatic steatosis compared with non-treated group. Imatinib administration exhibited significant decreases in serum lipid parameters, CRP, ALT, AST and ALP. Additionally, imatinib induced significant decreases for aortic and hepatic MDA, aortic NO and hepatic PDGFR-ß, while significantly exhibited elevations in aortic and hepatic GSH, SOD and hepatic PPARγ1 compared with HC animals. Furthermore, imatinib significantly protected against HC produced attenuation in ACh-induced aortic relaxation and pathological changes in aortic and hepatic tissues. Interestingly, imatinib could return serum CRP, ALP, hepatic SOD and PDGFR-ß to basal values. SIGNIFICANCE: The recent observation reports that imatinib could have beneficial effect against atherosclerosis progression, vascular malfunction, and liver damage in high cholesterol diet (HCD)-fed rabbits.


Asunto(s)
Aterosclerosis/prevención & control , Endotelio Vascular/efectos de los fármacos , Hipercolesterolemia/complicaciones , Mesilato de Imatinib/uso terapéutico , Hígado/efectos de los fármacos , Hígado/patología , Animales , Aorta/enzimología , Aorta/metabolismo , Aorta/patología , Aterosclerosis/etiología , Peso Corporal , Proteína C-Reactiva/metabolismo , Colesterol en la Dieta/administración & dosificación , Dieta , Endotelio Vascular/fisiopatología , Enzimas/sangre , Enzimas/metabolismo , Mesilato de Imatinib/farmacología , Lípidos/sangre , Masculino , Conejos
18.
J Comput Assist Tomogr ; 44(2): 204-208, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31972750

RESUMEN

PURPOSE: The purpose of this study was to determine whether liver extracellular volume (ECV) measured using equilibrium computed tomography (EQ-CT) can be used to quantitatively assess doxorubicin-induced liver injury (DILI). METHODS: The ethical approval was obtained from the Institutional Animal Care and Use Committee regulations. Thirteen dogs administered with doxorubicin for 0 to 24 weeks were imaged by contrast-enhanced EQ-CT. The dogs were divided into 3 groups: the baseline (13 dogs), 16-week (10 dogs), and 24-week (7 dogs) groups. Pathological analysis of the liver was performed using hematoxylin-eosin and Masson staining. Liver ECV uptake was calculated for each group and correlated with the histopathological and serological findings of hepatic fibrosis (hyaluronic acid and procollagen type III). RESULTS: In the baseline group, the median ECVs of the right and left liver lobes were 21.78% (interquartile range [IQR], 16.78%-26.68%) and 20.91% (IQR, 16.39%-24.07%), respectively. In the 16- and 24-week groups, the median ECVs of these 2 liver lobes were 28.18% (IQR, 20.56%-34.61%) and 25.96% (IQR, 14.07%-41.38%) and 29.71% (IQR, 27.19%-35.25%) and 29.22% (IQR, 22.62%-38.67%), respectively. There were no significant differences in ECV between the left and right lobes in the 3 groups (P < 0.05). Both the 16- and 24-week groups showed significantly higher ECV than did the primary group (P = 0.001-0.0006). However, there were no significant differences in ECV between the 16-week group and 24-week group (P = 0.412). There was a positive correlation between the serum index and edema due to the inflammation and necrosis associated with DILI (R = 0.6534, R = 0.7129). CONCLUSIONS: Extracellular volume measured by EQ-CT imaging can accurately predict the potential DILI through the quantification of ECV changes.


Asunto(s)
Antibióticos Antineoplásicos/efectos adversos , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/diagnóstico por imagen , Doxorrubicina/efectos adversos , Hígado/diagnóstico por imagen , Hígado/patología , Tomografía Computarizada por Rayos X/métodos , Animales , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/patología , Modelos Animales de Enfermedad , Perros , Femenino , Tamaño de los Órganos
19.
J Zoo Wildl Med ; 50(4): 997-999, 2020 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-31926535

RESUMEN

A single incision laparoscopic system (SILS) was used to remove the falciform ligament of an adult male cheetah (Acinonyx jubatus) during routine diagnostic liver biopsy. Adipose tissue isolated from the falciform ligament was used to establish a mesenchymal stem cell culture. The use of a SILS port for liver biopsy and falciform ligament collection allowed for a large amount of fat to be collected from a small surgical incision and rapid postoperative recovery. This case expands the use of the single incision laparoscopy surgical technique beyond reproductive sterilization procedures in large cats.


Asunto(s)
Acinonyx/cirugía , Laparoscopía/veterinaria , Ligamentos/cirugía , Tejido Adiposo/citología , Animales , Biopsia/instrumentación , Biopsia/métodos , Biopsia/veterinaria , Hígado/patología , Masculino , Células Madre Mesenquimatosas
20.
Z Gastroenterol ; 58(1): 68-73, 2020 Jan.
Artículo en Alemán | MEDLINE | ID: mdl-31931543

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is of increasing prevalence globally. While lifestyle modifications are recommended, many patients do not succeed to achieve significant and maintained weight loss from lifestyle and as such there is a high unmet need for pharmacotherapy in this group. Comparable to other metabolic diseases including diabetes and dyslipidaemia, a high proportion of patients will likely benefit from permanent pharmacological therapy. Currently there are many compounds with different mechanisms of action in clinical development including metabolic, anti-inflammatory and anti-fibrotic drugs. A number of phase 3 clinical trials are currently ongoing including Elafibranor, a dual PPAR α/δ agonist, Cenicriviroc, a CCR2/CCR5 chemokine antagonist, the nuclear bile acid receptor FXR agonist obeticholic acid, Aramchol, a fatty acid bile acid conjugate that modulates SCD-1, and Resmetrion, a liver-specific THR-ß agonist. Further studies with promising pathophysiological mechanisms of action, e. g. the ASK-1 inhibitor Selonsertib or the caspase inhibitor Emricasan have shown negative results. However, some are being further evaluated in combination therapies. The complex pathophysiology of the disease, which combines inflammation, metabolism and fibrosis, has led to the fact that even combinations of several substances are investigated with different modes of action. This review summarizes pivotal clinical trials for patients with NASH in the absence of cirrhosis which are recruiting in the fall of 2019.


Asunto(s)
Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Antiinflamatorios , Ensayos Clínicos como Asunto , Humanos , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Resultado del Tratamiento
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