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1.
Nat Commun ; 11(1): 4964, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009394

RESUMO

Thrombosis leads to platelet activation and subsequent degradation; therefore, replenishment of platelets from hematopoietic stem/progenitor cells (HSPCs) is needed to maintain the physiological level of circulating platelets. Platelet-derived microparticles (PMPs) are protein- and RNA-containing vesicles released from activated platelets. We hypothesized that factors carried by PMPs might influence the production of platelets from HSPCs, in a positive feedback fashion. Here we show that, during mouse acute liver injury, the density of megakaryocyte in the bone marrow increases following an increase in circulating PMPs, but without thrombopoietin (TPO) upregulation. In vitro, PMPs are internalized by HSPCs and drive them toward a megakaryocytic fate. Mechanistically, miR-1915-3p, a miRNA highly enriched in PMPs, is transported to target cells and suppresses the expression levels of Rho GTPase family member B, thereby inducing megakaryopoiesis. In addition, direct injection of PMPs into irradiated mice increases the number of megakaryocytes and platelets without affecting TPO levels. In conclusion, our data reveal that PMPs have a role in promoting megakaryocytic differentiation and platelet production.


Assuntos
Plaquetas/metabolismo , Diferenciação Celular , Micropartículas Derivadas de Células/metabolismo , Megacariócitos/citologia , MicroRNAs/metabolismo , Animais , Sequência de Bases , Linhagem Celular , Endocitose , Perfilação da Expressão Gênica , Humanos , Fígado/lesões , Fígado/patologia , Masculino , Megacariócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , Poliploidia , Proteína rhoB de Ligação ao GTP/metabolismo
2.
J Gastrointestin Liver Dis ; 29(3): 473-475, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32919428
4.
Nat Commun ; 11(1): 4383, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873799

RESUMO

Mongolia has the highest incidence of hepatocellular carcinoma (HCC) in the world, but its causative factors and underlying tumor biology remain unknown. Here, we describe molecular characteristics of HCC from 76 Mongolian patients by whole-exome and transcriptome sequencing. We present a comprehensive analysis of mutational signatures, driver genes, and molecular subtypes of Mongolian HCC compared to 373 HCC patients of different races and ethnicities and diverse etiologies. Mongolian HCC consists of prognostic molecular subtypes similar to those found in patients from other areas of Asia, Europe, and North America, as well as other unique subtypes, suggesting the presence of distinct etiologies linked to Mongolian patients. In addition to common driver mutations (TP53, CTNNB1) frequently found in pan-cancer analysis, Mongolian HCC exhibits unique drivers (most notably GTF2IRD2B, PNRC2, and SPTA1), the latter of which is associated with hepatitis D viral infection. These results suggest the existence of new molecular mechanisms at play in Mongolian hepatocarcinogenesis.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Hepatite D/genética , Neoplasias Hepáticas/genética , Idoso , Carcinogênese/genética , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/virologia , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Hepatectomia , Hepatite D/epidemiologia , Hepatite D/cirurgia , Hepatite D/virologia , Vírus Delta da Hepatite/isolamento & purificação , Humanos , Incidência , Fígado/patologia , Fígado/cirurgia , Fígado/virologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Mongólia/epidemiologia , Mutação , Prognóstico , Sequenciamento Completo do Exoma
5.
Clinics (Sao Paulo) ; 75: e1670, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32935822

RESUMO

OBJECTIVES: Acoustic radiation force impulse (ARFI) elastography, the aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), and the fibrosis-4 (FIB-4) index are widely used to assess liver fibrosis. However, efficacies of these methods in the evaluation of hepatic functional reserve remain unclear. In this study, we investigated the relationship between ARFI elastography combined with either AAR, APRI, or FIB-4 index and Child-Pugh (CP) class for the evaluation of hepatic functional reserve in patients with chronic hepatitis B (CHB)-related cirrhosis. METHODS: The shear wave velocities of 104 patients with clinically confirmed CHB-related cirrhosis were determined using the ARFI; and clinical serum markers (e.g. ALT, AST, PLT) were used to calculate the AAR, APRI, and FIB-4 index. Cirrhosis patients were scored according to their CP class. The ARFI, AAR, APRI, and FIB-4 index were compared with the CP class. The efficacy of each indicator in diagnosis was analyzed using the receiver operating characteristic (ROC) curve and the ARFI combined with either the AAR, APRI, or FIB-4 index, which is used to predict decompensated cirrhosis. RESULTS: No significant differences were observed in gender and age among CP classes A, B, and C patients (p>0.05). The ARFI values and the AAR, APRI, and FIB-4 index of patients with CP classes A, B, and C were significantly different (p<0.05). With an increasing CP class, the ARFI, AAR, APRI, and FIB-4 values increased. The correlation between the ARFI and the CP class was stronger than that between the AAR, APRI, and FIB-4 index and the CP class. The area under the ROC curve for the diagnosis of decompensated cirrhosis using the ARFI was 0.841, which was higher than that for the AAR, APRI, and FIB-4 index. According to the area under the curve results, no significant differences were found when the ARFI was combined with either the AAR, APRI, or FIB-4 index and when the ARFI alone was used. CONCLUSIONS: The ARFI value has a strong correlation with the CP class. Therefore, ARFI elastography complements CP class in the assessment of the hepatic functional reserve in patients with CHB-related cirrhosis.


Assuntos
Acústica , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Técnicas de Imagem por Elasticidade , Cirrose Hepática/patologia , Biomarcadores/sangue , Biópsia , Criança , Técnicas de Imagem por Elasticidade/métodos , Feminino , Humanos , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico por imagem , Masculino , Valor Preditivo dos Testes , Curva ROC , Sensibilidade e Especificidade , Índice de Gravidade de Doença
6.
Nat Commun ; 11(1): 4875, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978388

RESUMO

Single-cell whole-exome sequencing (scWES) is a powerful approach for deciphering intratumor heterogeneity and identifying cancer drivers. So far, however, simultaneous analysis of single nucleotide variants (SNVs) and copy number variations (CNVs) of a single cell has been challenging. By analyzing SNVs and CNVs simultaneously in bulk and single cells of premalignant tissues and tumors from mouse and human BRCA1-associated breast cancers, we discover an evolution process through which the tumors initiate from cells with SNVs affecting driver genes in the premalignant stage and malignantly progress later via CNVs acquired in chromosome regions with cancer driver genes. These events occur randomly and hit many putative cancer drivers besides p53 to generate unique genetic and pathological features for each tumor. Upon this, we finally identify a tumor metastasis suppressor Plekha5, whose deficiency promotes cancer metastasis to the liver and/or lung.


Assuntos
Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Predisposição Genética para Doença/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lesões Pré-Cancerosas/genética , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Heterogeneidade Genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fígado/patologia , Pulmão/patologia , Camundongos , Camundongos Knockout , Mutação , Lesões Pré-Cancerosas/patologia , Transcriptoma
7.
Medicine (Baltimore) ; 99(39): e22489, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991488

RESUMO

RATIONALE: Primary sarcomatoid hepatocellular carcinoma (SHC) is a rare subtype of morphologic hepatocellular carcinoma reported on less than 1% of surgical pathology specimens. Herein, we report a rare case of SHC. The case in question was initially misdiagnosed as a liver abscess due to the clinical and radiological similarity between these 2 pathologies. Ultrasound(US)- and contrast-enhanced ultrasound (CEUS)- guided biopsies are helpful in making an accurate diagnosis under the appropriate biopsy area and angle of puncture. PATIENT CONCERNS: A 56-year old male presented to our hospital with a 2-month history of dull, upper abdominal pain without radiation. DIAGNOSES: Upon initial investigation with computed tomography, a cystic mass was found in the hepatic V segment and an infectious etiology was presumed. Further diagnostic examination with CEUS and magnetic resonance imaging suggested a hepatic abscess. However, a diagnosis of atypical intrahepatic cholangiocarcinoma was not excluded. The patient received the standard antibiotic treatment without alleviation of his symptoms. Through 3 diagnostic US-and CEUS-guided biopsies over a 3-month period, the pathological diagnosis of SHC was finally confirmed. INTERVENTIONS: The patient was diagnosed by 3 diagnostic US-and CEUS-guided biopsies, the pathological diagnosis of SHC was finally confirmed. OUTCOMES: Due to the delay in diagnosis, the patient was not a candidate for surgical resection, and showed dissemination of the lesion to the portal vein. Therefore, treatment with chemotherapy was initiated. After 4 courses of this regimen, tumor progression was found on enhanced magnetic resonance imaging. Therefore, the patient received immunotherapy and targeted therapy with limited response. The patient passed away 3 months later due to tumor progression. LESSONS: A hepatic abscess should be considered as a malignant lesion when clinical symptoms do not resolve upon standard treatment. US- and CEUS- guided biopsies are helpful in making an accurate diagnosis under the appropriate biopsy area and angle of puncture.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Abscesso Hepático/diagnóstico , Neoplasias Hepáticas/diagnóstico por imagem , Fígado/patologia , Carcinoma Hepatocelular/patologia , Diagnóstico Diferencial , Evolução Fatal , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Ultrassonografia
8.
Z Gastroenterol ; 58(9): 847-854, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32947630

RESUMO

BACKGROUND: The aim of our study is to analyze viscosity characteristics of focal liver lesions (FLLs) and the diagnostic performance of shear wave dispersion (SWD) in differentiating benign and malignant FLLs. METHODS: Between January 2018 and April 2018, 58 consecutive patients (median age 57, age range 21-74 years, 37 males) with 58 FLLs located on the right lobe of liver were prospectively studied. The Aplio i900 series diagnostic ultrasound system (Canon Medical systems) equipped with a curvilinear PV1-475BX transducer (1-8 MHz) was used. SWD slope and viscosity measurements were expressed as mean ± standard deviation for both liver tumors and background liver parenchyma. Histopathological results after surgery were regarded as the gold standard for diagnosis. RESULTS: Final diagnosis included 40 cases of malignant and 18 cases of benign FLLs. The mean viscosity value were 14.78 ±â€Š1.86 m/s/kHz for hepatocellular carcinoma (n = 30), 14.81 ±â€Š2.35 m/s/kHz for liver metastasis lesions (n = 10), 13.23 ±â€Š1.31 m/s/kHz for hemangioma (n = 13), and 13.67 ± 2.72 m/s/kHz for focal nodular hyperplasia (n = 5). Malignant FLLs showed higher mean viscosity values (14.79 ±â€Š3.15 m/s/KHz) than benign FLLs (13.36 ±â€Š2.76 m/s/KHz) (p < 0.05). The best performing cut-off value of lesion viscosity was 13.15 m/s/kHz (sensitivity 83.3 %; specificity 56.5 %; area under the curve (AUC) 0.71) for malignancy) (p < 0.05). CONCLUSIONS: The analysis of SWD slope and liver viscosity parameters provide additional viscoelastic information about FLLs before operation.


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Fígado/diagnóstico por imagem , Adulto , Idoso , Meios de Contraste , Diagnóstico Diferencial , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Ultrassonografia , Viscosidade , Adulto Jovem
9.
Nat Commun ; 11(1): 4810, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968061

RESUMO

Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3-synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3+CD147+), but not single antigen (GPC3-CD147+) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients.


Assuntos
Basigina/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Antígenos Quiméricos/efeitos dos fármacos , Animais , Basigina/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células Hep G2 , Humanos , Células Matadoras Naturais , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Khirurgiia (Mosk) ; (7): 12-17, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32736458

RESUMO

OBJECTIVE: To determine the value of membrane protective effect in intestine and liver cells for the effectiveness of minimally invasive surgery for acute peritonitis. MATERIAL AND METHODS: Patients with acute peritonitis undergoing laparoscopic (n=60) and open (n=50) surgery are analyzed. Functional characteristics of liver and bowel, disorders of homeostasis were evaluated in early postoperative period. RESULTS: Reduced negative impact of surgical aggression on the state of liver and intestine is essential to improve treatment outcomes in patients with acute peritonitis undergoing minimally invasive surgery. Fast recovery of intestine inevitably results reduced release of endotoxins while restoration of liver function is associated with rapid elimination of these toxins. These processes prevent severe intoxication and facilitate accelerated recovery. Functional restoration of liver and bowel is associated with reduced oxidative stress during laparoscopic operations. It is also important because peritonitis causes activation of free-radical processes per se. Therefore, an additional source of oxidative phenomena is extremely undesirable in these cases. CONCLUSION: Laparoscopic surgery for acute peritonitis minimizes surgical aggression and is associated with more favorable recovery of liver and bowel function. Undoubtedly, these findings should be considered to choose surgical approach in this severe category of patients.


Assuntos
Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Peritonite/cirurgia , Doença Aguda , Membrana Celular/metabolismo , Membrana Celular/patologia , Membrana Celular/fisiologia , Humanos , Mucosa Intestinal/metabolismo , Intestinos/patologia , Intestinos/fisiopatologia , Laparoscopia/efeitos adversos , Laparotomia/efeitos adversos , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Estresse Oxidativo/fisiologia , Peritonite/metabolismo , Peritonite/fisiopatologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Recuperação de Função Fisiológica , Toxinas Biológicas/biossíntese , Toxinas Biológicas/metabolismo
11.
Ecotoxicol Environ Saf ; 202: 110962, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800233

RESUMO

Chronic exposure to fluoride (F) beyond the permissible limit (1.5 ppm) is known to cause detrimental health effects by induction of oxidative stress-mediated DNA damage overpowering the DNA repair machinery. In the present study, we assessed F induced oxidative stress through monitoring biochemical parameters and looked into the effect of chronic F exposure on two crucial DNA repair genes Ogg1 and Rad51 having important role against ROS induced DNA damages. To address this issue, we exposed Swiss albino mice to an environmentally relevant concentration of fluoride (15 ppm NaF) for 8 months. Results revealed histoarchitectural damages in liver, brain, kidney and spleen. Depletion of GSH, increase in lipid peroxidation and catalase activity in liver and brain confirmed the generation of oxidative stress. qRT-PCR result showed that expressions of Ogg1 and Rad51 were altered after F exposure in the affected organs. Promoter hypermethylation was associated with the downregulation of Rad51. F-induced DNA damage and the compromised DNA repair machinery triggered intrinsic pathway of apoptosis in liver and brain. The present study indicates the possible association of epigenetic regulation with F induced neurotoxicity.


Assuntos
Dano ao DNA , DNA Glicosilases/genética , Reparo do DNA , Epigênese Genética/efeitos dos fármacos , Fluoretos/toxicidade , Rad51 Recombinase/genética , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Relação Dose-Resposta a Droga , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos
12.
Rom J Morphol Embryol ; 61(1): 209-218, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32747912

RESUMO

We are reporting a case of natural evolution and pathological data from a young person that was diagnosed with coronavirus disease 2019 (COVID-19). All data has been collected from the autopsy of a 30-year-old female, which was performed by the Department of Forensic Medicine from Emergency County Hospital, Drobeta Turnu Severin, Mehedinti County, Romania. The infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed by reverse transcription polymerase chain reaction (RT-PCR) on the lung tissue which was obtained during autopsy. This case provides the opportunity to study the natural evolution of COVID-19 pneumonia in a young person with clinical signs of pneumonia but without associated comorbidities. The patient had not received any treatment. The histopathological examination of the lung revealed a process of productive proliferation, proteinaceous and fibrin-macrophagic interalveolar spaces exudate, and lesions consistent with vasculitis. In the heart, we identified a cardiac thrombus. These changes are likely to suggest an advanced natural evolution of SARS-CoV-2 virus infection.


Assuntos
Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Pulmão/virologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Adulto , Autopsia , Betacoronavirus , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Feminino , Humanos , Rim/patologia , Fígado/patologia , Pulmão/patologia , Miocárdio/patologia , Pâncreas/patologia , Pandemias , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Romênia , Trombose/patologia , Trombose/virologia
13.
Medicine (Baltimore) ; 99(30): e21357, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791740

RESUMO

INTRODUCTION: Accessory liver lobe (ALL), an autonomous island of normal liver parenchyma, is a rare congenital anomaly that is difficult for preoperative diagnosis and often identified incidentally. It can also be accompanied with benign or malignant diseases, which is extremely rare. There are only 3 cases of focal nodular hyperplasia (FNH) detected on ALL reported by previous literature. PATIENT CONCERNS: A 33-year-old woman was incidentally diagnosed with a mass in left upper quadrant abdomen by a routine ultrasound examination. Doppler ultrasound revealed that the mass was attached to left liver lobe with a vascular pedicle. A spoke-wheel artery with diffuse enhancement during hepatic arterial phase was visualized on contrast-enhanced ultrasound, and the mass was continuously hyper-enhanced with a hypo-enhanced intralesional scar during the portal and delayed phase. And contrast-enhanced computed tomography showed a similar enhancement mode of the mass. DIAGNOSIS: The mass was resected and postoperative histopathologic result of the lesion revealed a nodular hyperplastic parenchyma with a central fibrous scar, without tumor cells. And a final diagnosis of FNH on ALL was determined accordingly. INTERVENTIONS: Mass resection was conducted according to patient's demand. OUTCOME: After general postoperative administration, the patient was discharged. Then, she had been undergoing regular serological tests and imaging examinations in our hospital for 24 months. CONCLUSION: The finding of a mass connecting with liver by a stalk should alert the clinician of the possibility of ALL, as well as benign or malignancies on an ALL. This is the first case of FNH on ALL preoperatively confirmed by contrast-enhanced ultrasound. We suggest that an integrated radiologic approach is crucial to evaluate an incidentally detected, asymptomatic abdominal focal mass.


Assuntos
Hiperplasia Nodular Focal do Fígado/diagnóstico por imagem , Fígado/anormalidades , Adulto , Angiografia por Tomografia Computadorizada , Feminino , Hiperplasia Nodular Focal do Fígado/patologia , Humanos , Achados Incidentais , Fígado/patologia , Ultrassonografia
14.
Orv Hetil ; 161(35): 1449-1455, 2020 08.
Artigo em Húngaro | MEDLINE | ID: mdl-32822323

RESUMO

Autophagy plays an important role in the homeostasis of the cells and it may be upregulated in response to several types of stresses. Deregulation of autophagy is a key mechanism in the pathogenesis and progression of several liver diseases. Deficient autophagy can contribute to liver steatosis, to endoplasmic reticulum stress and to the progression of non-alcoholic fatty liver disease. Chronic alcohol consumption inhibits autophagy. The accumulated mutant protein in the endoplasmic reticulum can be degraded by autophagy in alpha-1-antitrypsin deficiency. Hepatitis C and B viruses may exploit the autophagy pathway to promote the own replication. Hepatitis C virus non-structural protein 5A and 5B have roles in the induction of autophagosomes. MicroRNAs regulate multiple physiological, pathological functions and autophagy through the modulation of gene expression. MicroRNA-122 is involved in HCV replication. In HBV-infected livers, the microRNA pathways related to cell death, DNA damage, recombination and signal transduction were activated. MicroRNA-122 effects multiple important factors which regulate the lipid and carbohydrate metabolisms in human non-alcoholic fatty liver disease. Oxidative stress and free oxygen radicals generation involved in alcoholic liver diseases development are regulated by microRNAs through different pathways. MicroRNAs control autophagy process and autophagy regulates the expression of microRNA-s. The exploration of their interactions contributes to understanding the development of liver diseases. Orv Hetil. 2020; 161(35): 1499-1455.


Assuntos
Autofagia , Carcinoma Hepatocelular/patologia , Hepacivirus/patogenicidade , Hepatite C Crônica/patologia , Hepatite C , Fígado/virologia , MicroRNAs/genética , Carcinoma Hepatocelular/virologia , Estresse do Retículo Endoplasmático , Hepacivirus/fisiologia , Hepatite C Crônica/virologia , Hepatite Viral Humana/fisiopatologia , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Estresse Oxidativo
15.
Orv Hetil ; 161(35): 1456-1465, 2020 08.
Artigo em Húngaro | MEDLINE | ID: mdl-32822324

RESUMO

INTRODUCTION: Fatty liver can develop as a result of diseases, surgical procedures, medicaments, malnutrition or excessive alcohol consumption, however, fat and poor fiber feeding can be attributed as the primary cause. Non-alcoholic fatty liver can be found in 20-30% of the population. Generally, alimentary-induced fatty liver in early state is described as uncomplicated liver injury. AIM: The aim of our research was to study the effect of fat rich nutrition on the gut-liver axis by routine laboratory, analytical and histological methods in rats. METHODS: We also examined the redox parameters of the liver and of the bowel. Fatty acid composition and element content of liver were measured. RESULTS: Significant changes were found in parameters of redox homeostasis as well as alterations in liver enzymes and metabolites. The changes could be detected in the liver, blood and bowel parts. The development of fatty liver is associated with the decrease of transmethylation capacity. Fatty acid composition and metal ion homeostasis were also altered in liver. Histological examinations showed that hepatocytes were swollen in the central part of the liver lobules, showed droplets and pycnotic nuclei, which were characterized by fatty degeneration. Small and large bowel enterocytes were damaged, sometimes pushed from the surface, and sometimes inflammatory reactions in the mucous membrane were observed. CONCLUSION: Our results suggest that alimentary fatty liver in early state is not considered simply as a reversible alteration because it alters the entire body's redox homeostasis and establishes heart and serious metabolic diseases as well as hasten the development of gastrointestinal tumors. Orv Hetil. 2020; 161(35): 1456-1465.


Assuntos
Dieta Hiperlipídica , Inflamação/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica , Animais , Ácidos Graxos , Hepatócitos , Intestinos/patologia , Síndrome Metabólica/complicações , Ratos
16.
BMC Infect Dis ; 20(1): 590, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778058

RESUMO

BACKGROUND: Antiviral therapy is recommended for patients with immune-active chronic hepatitis B (CHB) to decrease the risk of liver-related complications. However, the outcomes of the pegylated IFN-α (PEG-IFN-α) therapy vary among CHB patients. We aimed to identify factors that can influence the outcomes in CHB patients who received antiviral PEG-IFN-α monotherapy. METHODS: Thirty-two CHB patients who received PEG-IFN-α monotherapy were enrolled in this study. All of the patients underwent two liver biopsies at baseline and 6 months after the initiation of the therapy. CD8+ T cells, CD4+ T cells, CD68+ mononuclear cells, and PD-1 levels in the 64 liver biopsy specimens were examined via immunofluorescence. RESULTS: The overall median frequency of CD8+ T cells in the liver tissues of 32 CHB patients significantly decreased at 6 months after the therapy initiation (p < 0.01). In the FIER (fibrosis and inflammation response with HBeAg seroconversion) group, CD8+PD-1+ T cells significantly decreased at 6 months (p < 0.05), while CD8+PD-1- T cells had no significant difference. On the contrary, in the FIENR (no fibrosis and inflammation response and HBeAg seroconversion) group, CD8+PD-1- T cells significantly decreased after 6 months of PEG-IFN-α treatment (p < 0.05), while CD8+PD-1+ T cells had no significant difference. In addition, the levels of CD68+ mononuclear cells in the FIER group showed an overall increasing trend after treatment (p < 0.05). CONCLUSIONS: The changes in the levels of CD8+PD-1+ T cells and CD68+ mononuclear cells may be related to the response to PEG-IFN-α therapy.


Assuntos
Antivirais/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Fígado/patologia , Polietilenoglicóis/uso terapêutico , Adulto , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Antígenos E da Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Fígado/metabolismo , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Recombinantes/uso terapêutico , Adulto Jovem
17.
Gene ; 761: 145036, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32777525

RESUMO

Lupinus albus γ-conglutin is proposed to positively affect glucose metabolism through inhibition of hepatic glucose production and insulin-mimetic activity; however, the action mechanism is not entirely known. Besides, most studies had focused on its effect on molecular targets directly related to glucose metabolism, and few studies have investigated how γ-conglutin may affect the liver gene expression or if it plays a role in other metabolic processes. Therefore, we investigated the influence of γ-conglutin on the liver transcriptome of streptozotocin-induced diabetic rats using DNA microarrays, ontological analyses, and quantitative PCR. Of the 22,000 genes evaluated, 803 and 173 were downregulated and upregulated, respectively. The ontological analyses of the differentially expressed genes revealed that among others, the mitochondria, microtubules, cytoskeleton, and oxidoreductase activity terms were enriched, implying a possible role of γ-conglutin on autophagy. To corroborate the microarray results, we selected and quantified, by PCR, the expression of two genes associated with autophagy (Atg7 and Snx18) and found their expression augmented two and threefold, respectively; indicating a higher autophagy activity in animals treated with γ-conglutin. Although complementary studies are required, our findings indicate for the first time that the hypoglycaemic effects of γ-conglutin may involve an autophagy induction mechanism, a pivotal process for the preservation of cell physiology and glucose homeostasis.


Assuntos
Colectinas/farmacologia , Lupinus/metabolismo , Soroglobulinas/farmacologia , Transcriptoma/genética , Animais , Glicemia/metabolismo , Colectinas/metabolismo , Colectinas/fisiologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Fígado/patologia , Lupinus/genética , Masculino , Proteínas de Plantas/genética , Ratos , Ratos Wistar , Sementes/metabolismo , Soroglobulinas/metabolismo , Soroglobulinas/fisiologia
18.
Aquat Toxicol ; 227: 105583, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32835849

RESUMO

The presence of diclofenac in the aquatic environment and the risks for aquatic wildlife, especially fish, have been raised in several studies. One way to manage risks without enforcing improved wastewater treatment would be to substitute diclofenac (when suitable from a clinical perspective) with another non-steroidal anti-inflammatory drug (NSAID) associated with less environmental risk. While there are many ecotoxicity-studies of different NSAIDs, they vary extensively in set-up, species studied, endpoints and reporting format, making direct comparisons difficult. We previously published a comprehensive study on the effects of diclofenac in the three-spined stickleback (Gasterosteus aculeatus). Our present aim was to generate relevant effect data for another NSAID (naproxen) using a very similar setup, which also allowed direct comparisons with diclofenac regarding hazards and risks. Sticklebacks were therefore exposed to naproxen in flow-through systems for 27 days. Triplicate aquaria with 20 fish per aquarium were used for each concentration (0, 18, 70, 299 or 1232 µg/L). We investigated bioconcentration, hepatic gene expression, jaw lesions, kidney and liver histology. On day 21, mortalities in the highest exposure concentration group unexpectedly reached ≥ 25 % in all three replicate aquaria, leading us to terminate and sample that group the same day. On the last day (day 27), the mortality was also significantly increased in the second highest exposure concentration group. Increased renal hematopoietic hyperplasia was observed in fish exposed to 299 and 1232 µg/L. This represents considerably higher concentrations than those expected in surface waters as a result of naproxen use. Such effects were observed already at 4.6 µg/L in the experiment with diclofenac (lowest tested concentration). Similar to the responses to diclofenac, a concentration-dependent increase in both relative hepatic gene expression of c7 (complement component 7) and jaw lesions were observed, again at concentrations considerably higher than expected in surface waters. Naproxen bioconcentrated less than diclofenac, in line with the observed effect data. An analysis of recent sales data and reported concentrations in treated sewage effluent in Sweden suggest that despite higher dosages used for naproxen, a complete substitution would only be expected to double naproxen emissions. In summary, naproxen and diclofenac produce highly similar effects in fish but the environmental hazards and risks are clearly lower for naproxen. Hence, if there are concerns for environmental risks to fish with diclofenac, a substitution would be advisable when naproxen presents an adequate alternative from a clinical point-of-view.


Assuntos
Bioacumulação , Diclofenaco/toxicidade , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Naproxeno/toxicidade , Smegmamorpha/metabolismo , Poluentes Químicos da Água/toxicidade , Animais , Diclofenaco/metabolismo , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Humanos , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Modelos Teóricos , Naproxeno/metabolismo , Smegmamorpha/genética , Suécia , Poluentes Químicos da Água/metabolismo
19.
PLoS One ; 15(8): e0237430, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841307

RESUMO

BACKGROUND & AIMS: Given ongoing challenges in non-invasive non-alcoholic liver disease (NAFLD) diagnosis, we sought to validate an ALT-based NAFLD phenotype using measures readily available in electronic health records (EHRs) and population-based studies by leveraging the clinical and genetic data in the Million Veteran Program (MVP), a multi-ethnic mega-biobank of US Veterans. METHODS: MVP participants with alanine aminotransferases (ALT) >40 units/L for men and >30 units/L for women without other causes of liver disease were compared to controls with normal ALT. Genetic variants spanning eight NAFLD risk or ALT-associated loci (LYPLAL1, GCKR, HSD17B13, TRIB1, PPP1R3B, ERLIN1, TM6SF2, PNPLA3) were tested for NAFLD associations with sensitivity analyses adjusting for metabolic risk factors and alcohol consumption. A manual EHR review assessed performance characteristics of the NAFLD phenotype with imaging and biopsy data as gold standards. Genetic associations with advanced fibrosis were explored using FIB4, NAFLD Fibrosis Score and platelet counts. RESULTS: Among 322,259 MVP participants, 19% met non-invasive criteria for NAFLD. Trans-ethnic meta-analysis replicated associations with previously reported genetic variants in all but LYPLAL1 and GCKR loci (P<6x10-3), without attenuation when adjusted for metabolic risk factors and alcohol consumption. At the previously reported LYPLAL1 locus, the established genetic variant did not appear to be associated with NAFLD, however the regional association plot showed a significant association with NAFLD 279kb downstream. In the EHR validation, the ALT-based NAFLD phenotype yielded a positive predictive value 0.89 and 0.84 for liver biopsy and abdominal imaging, respectively (inter-rater reliability (Cohen's kappa = 0.98)). HSD17B13 and PNPLA3 loci were associated with advanced fibrosis. CONCLUSIONS: We validate a simple, non-invasive ALT-based NAFLD phenotype using EHR data by leveraging previously established NAFLD risk-associated genetic polymorphisms.


Assuntos
Alanina Transaminase/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , 17-Hidroxiesteroide Desidrogenases/genética , Abdome/diagnóstico por imagem , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Alanina Transaminase/genética , Registros Eletrônicos de Saúde , Feminino , Loci Gênicos , Predisposição Genética para Doença , Variação Genética , Humanos , Lipase/genética , Fígado/patologia , Lisofosfolipase/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etnologia , Hepatopatia Gordurosa não Alcoólica/genética , Fenótipo , Fatores de Risco , Veteranos
20.
PLoS One ; 15(8): e0236104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32776939

RESUMO

There is an increasing emphasis on effects-based monitoring to document responses associated with exposure to complex mixtures of chemicals, climate change, pathogens, parasites and other environmental stressors in fish populations. For decades aquatic monitoring programs have included the collection of tissues preserved for microscopic pathology. Consequently, formalin-fixed, paraffin-embedded (FFPE) tissue can be an important reservoir of nucleic acids as technologies emerge that utilize molecular endpoints. Despite the cross-linking effects of formalin, its impact on nucleic acid quality and concentration, amplification, and sequencing are not well described. While fresh-frozen tissue is optimal for working with nucleic acids, FFPE samples have been shown to be conducive for molecular studies. Laser capture microdissection (LCM) is one technology which allows for collection of specific regions or cell populations from fresh or preserved specimens with pathological alterations, pathogens, or parasites. In this study, smallmouth bass (Micropterus dolomieu) liver was preserved in three different fixatives, including 10% neutral buffered formalin (NBF), Z-Fix® (ZF), and PAXgene® (PG) for four time periods (24 hr, 48 hr, seven days, and 14 days). Controls consisted of pieces of liver preserved in RNALater® or 95% ethanol. Smallmouth bass were chosen as they are an economically important sportfish and have been utilized as indicators of exposure to endocrine disruptors and other environmental stressors. Small liver sections were cut out with laser microdissection and DNA and RNA were purified and analyzed for nucleic acid concentration and quality. Sanger sequencing and the NanoString nCounter® technology were used to assess the suitability of these samples in downstream molecular techniques. The results revealed that of the formalin fixatives, NBF samples fixed for 24 and 48 hr were superior to ZF samples for both Sanger sequencing and the Nanostring nCounter®. The non-formalin PAXgene® samples were equally successful and they showed greater stability in nucleic acid quality and concentration over longer fixation times. This study demonstrated that small quantities of preserved tissue from smallmouth bass can be utilized in downstream molecular techniques; however, future studies will need to optimize the methods presented here for different tissue types, fish species, and pathological conditions.


Assuntos
Bass/genética , DNA/efeitos dos fármacos , Monitoramento Ambiental/métodos , Fixadores/efeitos adversos , RNA/efeitos dos fármacos , Animais , Clivagem do DNA/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Formaldeído/efeitos adversos , Perfilação da Expressão Gênica/métodos , Fígado/efeitos dos fármacos , Fígado/patologia , Microdissecção , Desnaturação de Ácido Nucleico/efeitos dos fármacos , RNA/isolamento & purificação , Estabilidade de RNA/efeitos dos fármacos , Análise de Sequência de DNA , Fatores de Tempo , Fixação de Tecidos/métodos , West Virginia
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