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La trombosis de la vena porta (TVP) en pacientes con o sin cirrosis hepática (CH) se define como una obstrucción de la vena porta debido a la formación de un trombo que puede extenderse a las venas mesentéricas superiores y esplénica. Esta es una complicación común de la enfermedad hepática avanzada. Se creía que la TVP se producía predominantemente debido al potencial protrombótico del paciente con CH, ya que se observaba una mayor incidencia de TVP en CH con una puntuación MELD y Child-Pugh más altas, con una prevalencia informada del 10 % al 25%.
Portal vein thrombosis (PVT) in patients with or without hepatic cirrhosis (CH) is defined as an obstruction of the portal vein due to the formation of a thrombus that may extend to the superior mesenteric and splenic veins. This is a common complication of advanced liver disease. It was believed that PVT predominantly occurred due to the prothrombotic potential of the patient with CH, as a higher incidence of PVT was observed in CH with higher MELD and Child-Pugh scores, with a reported prevalence of 10% to 25%.
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OBJECTIVE: To investigate clinical effects of hepatic artery interventional embolization chemotherapy (TACE) for primary hepatocellular carcinoma (PHC). METHODS: 73 patients with PHC in our hospital from January 2017 to January 2018 were selected and divided into 37 cases in study group and 36 cases in control group by random number table method. The control group received only ultrasound-guided microwave ablation treatment, and the study group received TACE treatment again before surgery based on control group. The expression levels of cancer antigen 125 (CA125), alpha-fetoprotein (AFP), multiple tumor suppressors 1 (P16) proteins, and cancer antigen 19-9 (CA19-9) were compared between the two groups at different time periods after treatment, and the remission rate (ORR), control rate (DCR), complication rate at 3 months after treatment and survival rate at 3 years after treatment were compared. RESULTS: After 1 year of treatment, ORR, DCR, and P16 protein levels in the study group were higher than those in the control group (P < 0.05), and differences were statistically significant; CA125, CA19-9, and AFP levels in study group were lower than those in the control group (P < 0.05), and differences were statistically significant. The regression equation showed that long-term survival rate of both groups showed decreasing trend over time, while long-term survival rate of study group was always higher than that of the control group. CONCLUSION: Comprehensive intervention for hepatic artery interventional chemoembolization in patients with primary hepatocellular carcinoma is more effective, which can effectively reduce incidence of complications and adverse effects in patients and help shorten treatment time of hepatic artery interventional chemoembolization in patients.
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Lifestyle changes, such as poor eating habits and a reduction in physical exercise, have impaired human lipid profiles. Statins are widely used to treat dyslipidemias, of which rosuvastatin shows greater improvement in the lipid profile and may be used since childhood. This study aimed to assess the hepatic effects when male mice were given 0.9% saline solution or doses of rosuvastatin of 1.5 or 5.5 mg/kg/day from postnatal day (PND) 23 until PND 80. Body mass gain and water and food consumption were monitored during the treatment. Mice were euthanized on PND 80 when blood was collected for serum obtainment, and several organs were collected and weighed. Serum was used for evaluating lipid profiles and markers of hepatic injuries. The liver was assessed for histopathological, morphometric, and stereological changes. There was a temporary reduction in body mass gain and water and food consumption in the rosuvastatin-exposed groups. Both rosuvastatin-treated groups exhibited reduced total cholesterol levels and showed signs of hepatic tissue adaptation in response to prolonged exposure, such as sinusoidal dilation, inflammatory infiltrates, and cell death of hepatocytes. These results are considered side effects of the treatment and may indicate a hepatic adaptation to the chronic exposure.
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PURPOSE: This study aimed to evaluate the efficacy of percutaneous microwave ablation (MWA) for treating hepatic malignant tumors and to identify factors influencing tumor recurrence post-treatment. METHODS: A total of 249 patients with hepatic malignant tumors treated at the Shandong Cancer Hospital and Institute were included, and 101 patients were analyzed. Disease-free and overall survival rates were assessed at 1, 2, and 3 years post-MWA. Correlations between tumor recurrence and factors such as Child-Pugh B classification and lesion count were examined, and a meta-analysis was conducted to identify independent risk factors for recurrence. RESULTS: The study found disease-free survival rates of 80.2%, 72.3%, and 70.3% at 1, 2, and 3 years post-MWA, with overall survival rates at 99%, 97%, and 96%. Significant correlations were observed between tumor recurrence, Child-Pugh B classification, and the number of lesions. Meta-analysis confirmed lesion count and Child-Pugh B classification as independent risk factors for recurrence following MWA treatment. CONCLUSION: The study underscores the importance of considering Child-Pugh B classification and lesion count in predicting tumor recurrence after MWA for hepatic malignant tumors. These findings offer valuable insights for clinicians in decision-making and post-treatment monitoring.
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Right superior resection (segments 7 and 8) is an uncommon resection for liver malignancies, with most of the literature limited to case reports and small series. Resection of segments 4, 7, and 8 has been reported in only a few cases. When the right hepatic vein is resected, venous reconstruction or identification of one or more right inferior hepatic veins is considered mandatory, to maintain segmentary function of segments 5 and 6. We present a case of liver resection of segments 4, 7, and 8 including the right and middle hepatic veins for symptomatic benign liver disease with no right hepatic vein reconstruction, nor a prominent right inferior hepatic vein(s). After the resection, there was no change in liver function tests, and the patient made an unremarkable recovery. Three months after the operation, partial atrophy of segments 5 and 6 with hypertrophy of the left lateral section was observed, while two and one half years after resection, the patient is asymptomatic. When right hepatic vein reconstruction would add unnecessary operative time, and there is low likelihood of the need for repeated resection, particularly when the hepatic vein is difficult to dissect, this approach can be safe and useful, while providing an adequate postoperative liver mass in the short-term to recover uneventfully from major liver resection.
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Entamoeba histolytica is the protozoan causative of human amoebiasis. The EhADH adhesin (687 aa) is a protein involved in tissue invasion, phagocytosis and host-cell lysis. EhADH adheres to the prey and follows its arrival to the multivesicular bodies. It is an accessory protein of the endosomal sorting complexes required for transport (ESCRT) machinery. Here, to study the role of different parts of EhADH during virulence events, we produced trophozoites overexpressing the three domains of EhADH, Bro1 (1-400 aa), Linker (246-446 aa) and Adh (444-687 aa) to evaluate their role in virulence. The TrophozBro11-400 slightly increased adherence and phagocytosis, but these trophozoites showed a higher ability to destroy cell monolayers, augment the permeability of cultured epithelial cells and mouse colon, and produce more damage to hamster livers. The TrophozLinker226-446 also increased the virulence properties, but with lower effect than the TrophozBro11-400. In addition, this fragment participates in cholesterol transport and GTPase binding. Interestingly, the TrophozAdh444-687 produced the highest effect on adherence and phagocytosis, but it poorly influenced the monolayers destruction; nevertheless, they augmented the colon and liver damage. To identify the protein partners of each domain, we used recombinant peptides. Pull-down assays and mass spectrometry showed that Bro1 domain interplays with EhADH, Gal/GalNAc lectin, EhCPs, ESCRT machinery components and cytoskeleton proteins. While EhADH, ubiquitin, EhRabB, EhNPC1 and EhHSP70 were associated to the Linker domain, and EhADH, EhHSP70, EhPrx and metabolic enzymes interacted to the Adh domain. The diverse protein association confirms that EhADH is a versatile molecule with multiple functions probably given by its capacity to form distinct molecular complexes.
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Entamoeba histolytica , Proteínas de Protozoários , Entamoeba histolytica/patogenicidade , Entamoeba histolytica/metabolismo , Animais , Camundongos , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Humanos , Virulência , Fagocitose , Domínios Proteicos , Entamebíase/parasitologia , Entamebíase/metabolismo , Cricetinae , Trofozoítos/metabolismoRESUMO
The global prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is increasing, now affecting 25%-30% of the population worldwide. MASLD, characterized by hepatic steatosis, results from an imbalance in lipid metabolism, leading to oxidative stress, lipoperoxidation, and inflammation. The activation of autophagy, particularly lipophagy, alleviates hepatic steatosis by regulating intracellular lipid levels. Lutein, a carotenoid with antioxidant and anti-inflammatory properties, protects against liver damage, and individuals who consume high amounts of lutein have a lower risk of developing MASLD. Evidence suggests that lutein could modulate autophagy-related signaling pathways, such as the transcription factor EB (TFEB). TFEB plays a crucial role in regulating lipid homeostasis by linking autophagy to energy metabolism at the transcriptional level, making TFEB a potential target against MASLD. STARD3, a transmembrane protein that binds and transports cholesterol and sphingosine from lysosomes to the endoplasmic reticulum and mitochondria, has been shown to transport and bind lutein with high affinity. This protein may play a crucial role in the uptake and transport of lutein in the liver, contributing to the decrease in hepatic steatosis and the regulation of oxidative stress and inflammation. This review summarizes current knowledge on the role of lutein in lipophagy, the pathways it is involved in, its relationship with STARD3, and its potential as a pharmacological strategy to treat hepatic steatosis.
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Pancreaticopleural fistula is a rare complication of pancreatitis. We present a rare case of pancreaticopleural fistula in a 43-year-old alcoholic male. He presented with recurrent episodes of left pleural effusion that were managed with aspiration and chest tube placement. An MRI of the chest and upper abdomen revealed a pancreaticopleural fistula. The patient underwent distal pancreatectomy with splenectomy and Roux-en-Y pancreaticojejunostomy. The surgical approach was our first-line management due to the unavailability of octreotide and endoscopic retrograde cholangiopancreatography. His recovery was complicated by an empyema that was managed by tube thoracostomy and IV antibiotics. There was no issue detected at his 3-month follow-up clinic visit.
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BACKGROUND: In traditional descriptions, the upper surface of the liver is smooth and convex, but deep depressions are variants that are present in 5%-40% of patients. We sought to determine the relationship between surface depressions and the diaphragm. AIM: To use exploratory laparoscopy to determine the relationship between surface depressions and the diaphragm. METHODS: An observational study was performed in all patients undergoing laparoscopic upper gastro-intestinal operations between January 1, 2023 and January 20, 2024. A thirty-degree laparoscope was used to inspect the liver and diaphragm. When surface depressions were present, we recorded patient demographics, presence of diaphragmatic bands, rib protrusions and/or any other source of compression during inspection. RESULTS: Of 394 patients, 343 had normal surface anatomy, and 51 (12.9%) had prominent surface depressions on the liver. There was no significant relationship between the presence of surface depressions and gender nor the presence of rib projections. However, there was significant association between the presence of surface depressions and diaphragmatic muscular bands (P < 0.001). CONCLUSION: With these data, the diaphragmatic-band theory has gained increased importance over other theories for surface depressions. Further studies are warranted using cross sectional imaging to confirm relationships with intersectional planes as well as beta-catenin assays in the affected liver parenchyma.
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The aim of this work was to develop a liver tissue function index during the transition period of dairy cows managed in low-tropic conditions. In two farms, twenty crossbred and synthetic native cows during the peripartum period were selected, and blood samples were taken on days -30 and -15 prepartum, the calving day, and 7, 20, 35, 50, 65, 80 and 105 days postpartum for serum metabolic tests. On each measurement day, body condition scores (BCS) and parameters on nitrogen metabolism (total protein-TP, albumin-ALB, globulin-GLOB, urea), adipose tissue metabolism (cholesterol-COL, non-esterified fatty acids-NEFA) and two transaminases (alanine aminotransferase-ALT and aspartate aminotransferase-AST) were evaluated. Data analysis included the Spearman correlation, principal components, multiple linear regression and cluster analysis. Results showed that regarding the days after calving and BCS, a liver tissue function index can be constructed using the TP, urea, COL, ALT and NEFA. The estimated index generated three groupings, both by days after calving and BCS. In the former, the index discriminated the metabolic behavior in the prepartum, parturition and postpartum periods, while in the latter, the index discriminated between extreme (2.25, 2.50 and 4.25), slightly low (2.75 and 3.0) and slightly high (3.25 to 4) conditions. The results allow us to conclude that it is feasible to construct mathematical function indexes for liver function to monitor metabolic changes during highly demanding productive phases in dairy cows under tropical conditions.
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INTRODUCTION AND OBJECTIVES: Although the Psychometric Hepatic Encephalopathy Score (PHES) remains the gold standard in diagnosing minimal hepatic encephalopathy (MHE), its complexity limits its application in clinical practice. While more convenient tests, such as the Stroop test, Quickstroop, and the 1-min animal naming test (ANT-1), have emerged, they haven't been validated in our setting. Our objective was to validate these tests in our population. PATIENTS AND METHODS: This multicenter, observational, descriptive, and cross-sectional study was conducted in three hospitals in northeastern Mexico. MHE was defined as a PHES <-4. We included patients with cirrhosis aged >15 years without a history of overt hepatic encephalopathy. Data regarding sex, age, education, Child-Pugh/MELD-Na scores, etiology of cirrhosis, diabetes, hypertension, obesity, ascites, and clinically significant portal hypertension was collected. Fisher's exact test, Mann-Whitney U test, and receiver operating characteristic (ROC) curves were used for statistical analysis. RESULTS: Of the 121 patients included, 35.5 % were diagnosed with MHE. The presence of MHE was significantly associated with education level, years of study, and scores in the Stroop test, Quickstroop, and ANT-1. The AUROC curves were 77.9 %, 74.6 %, and 72.7 % for the Stroop test, Quickstroop, and ANT-1, respectively. The resulting cut-off points were 218.398 (sensitivity: 74 %; specificity: 74 %), 40.535 (sensitivity: 77 %; specificity: 68 %), and <16 animals (sensitivity: 58 %; specificity: 79 %), respectively. CONCLUSIONS: These tests are valid diagnostic tools for detecting MHE in our population. Their simpler use and applicability could increase the early diagnosis of MHE and prompt primary prophylaxis initiation for overt hepatic encephalopathy.
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The present study aimed to establish zebrafish as an experimental model for investigations into obesity and physical exercise, as well as to assess the effects of these factors on metabolism. The experiment spanned twelve weeks, comprising a feeding trial during which the last four weeks incorporated a physical exercise protocol. This protocol involved placing fifteen animals in a five-liter aquarium, where they were subjected to swimming at an approximate speed of 0.08 m/s for 30 min daily. Throughout the experiment, histological analyses of visceral, subcutaneous, and hepatic adipose tissues were conducted, along with biochemical analyses of total cholesterol and its fractions, triglycerides, glucose, lactate, and alanine aminotransferase (ALT) levels. Additionally, oxidative stress markers, such as reactive oxygen species (ROS) levels, superoxide dismutase (SOD) activity, and catalase activity and the formation of thiobarbituric acid-reactive substances, were investigated. The results revealed that the group fed a high-fat diet exhibited an increase in ROS production and SOD activity. In contrast, the group administered the high-fat diet and subjected to physical exercise demonstrated a notable reduction in visceral adipocyte area, hepatic steatosis levels, ALT levels, and SOD activity. These findings indicate that physical exercise has a positive effect on obesity and oxidative stress in zebrafish, providing promising evidence for future investigations in this field.
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Acute liver failure is a rare but serious syndrome, with an incidence of approximately 2,000 to 3,000 cases per year in North America. Its pathophysiology and clinical course vary, depending on the cause of the primary liver injury, and can lead to high morbidity and mortality or the need for liver transplantation, despite available therapies. This syndrome involves excessive activation of the immune system, with damage in other organs, contributing to its high mortality rate. The most accepted definition includes liver injury with hepatic encephalopathy and coagulopathy within the past 26 weeks in a patient with no previous liver disease. The main causes are paracetamol poisoning, viral hepatitis, and drug-induced liver injury, among others. Identifying the cause is crucial, given that it influences prognosis and treatment. Survival has improved with supportive measures, intensive therapy, complication prevention, and the use of medications, such as N-acetylcysteine. Liver transplantation is a curative option for nonresponders to medical treatment, but adequate evaluation of transplantation timing is vital for improving results. Factors such as patient age, underlying cause, and severity of organ failure influence the post-transplant outcomes and survival.
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Falência Hepática Aguda , Humanos , Falência Hepática Aguda/terapia , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/diagnóstico , Prognóstico , Transplante de FígadoRESUMO
BACKGROUND: Glycogen storage disease type Ia (GSD-Ia) is one of the most common hepatic GSD. Its treatment mainly consists of a diet including a high intake of slow-digestion carbohydrates such as raw cornstarch and the restriction of simple sugars. This enables the maintenance of euglycemia and prevents secondary metabolic disorders. Starch is a glucose polymer formed by amylose and amylopectin, which can be obtained from distinct sources. Although uncooked cornstarch has been successfully used in the treatment of GSD-Ia, it can lead to hyperglycemia and weight gain. in vitro andin vivo tests indicated that sweet manioc starch can be potentially used in the treatment of GSD-Ia. RESULTS: The moisture analysis revealed a variation from 10.3 to 12.8% in the sweet manioc starch samples, whereas the moisture content of uncooked cornstarch ranged from 7.3 to 11.1%. Quantifiable sugar was detected in 3/5 samples of sweet manioc starch and 1/3 samples of uncooked cornstarch. Notably, this uncooked cornstarch brand is widely employed in GSD-Ia treatment in Brazil. Products B and E had higher values of amylopectin and undetectable levels of sugars. A clinical trial is warranted to compare samples F and G and determine the impact of sugar trace in the same dietary source of starch. CONCLUSIONS: Collectively, the results demonstrated possible therapeutic alternatives for GSD-Ia in addition to traditional uncooked cornstarch.
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Doença de Depósito de Glicogênio Tipo I , Amido , Doença de Depósito de Glicogênio Tipo I/metabolismo , Doença de Depósito de Glicogênio Tipo I/dietoterapia , Humanos , Amilopectina , AnimaisRESUMO
Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF6, to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133+ and CD44high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs.
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Apoptose , Morte Celular Autofágica , Neoplasias Hepáticas , Células-Tronco Neoplásicas , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Humanos , Apoptose/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Células Hep G2 , Morte Celular Autofágica/efeitos dos fármacos , Tiazolidinas/farmacologia , Animais , Camundongos , Movimento Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/químicaRESUMO
Introducción: El aneurisma de la arteria hepática es infrecuente, presentándose principalmente en trauma y en pacientes con aterosclerosis. Su manejo es complejo y desafiante aún en manos expertas, siendo el abordaje endovascular de elección. Caso clínico: Se presenta el caso de una paciente de 66 años con poliarteritis nodosa a la que se le diagnostica, incidentalmente, un aneurisma de la arteria hepática común (AHC). Inicialmente, se intenta manejo conservador, sin embargo se evidencia crecimiento significativo en el seguimiento por lo que se decide resolución quirúrgica endovascular. Se realiza embolización selectiva de todo el segmento aneurismático de la AHC, mantiendo la perfusión del lóbulo hepático derecho, con apoyo de ultrasonografía intraoperatoria. Discusión: El método de tratamiento preferido para esta entidad es la embolización percutánea con coils metálicos. Si bien es el de menor morbimortalidad asociada, no está exento de riesgos.
Introduction: Hepatic artery aneurysm is rare. The most common etiologies are atherosclerosis and trauma. Management is difficult and challenging. An endovascular approach is preferred to open surgery. Case report: 66-year-old patient with polyarteritis nodosa who was incidentally diagnosed with a common hepatic artery (CHA) aneurysm. Initially, conservative management was performed, however, during follow-up significant growth was evidenced. Endovascular treatment was decided over surgery. Selective embolization of the entire aneurysmal segment of CHA was performed, maintaining perfusion of the right hepatic lobe. Discussion: Percutaneous embolization with metal coils is the treatment of choice for this entity. Although it is the one with the lowest morbidity and mortality, it is not without risks.
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BACKGROUND: Lipid metabolism factors may play a role in the development of arthritis and hepatic steatosis and fibrosis. The aim of this study was to explore the potential association between arthritis and hepatic steatosis and liver fibrosis. MATERIALS AND METHODS: The nationally representative sample from the National Health and Nutrition Examination Survey was analyzed, with data on arthritis diagnosis, subtype, and liver status obtained. Liver status was assessed using transient elastography. Hepatic steatosis was defined as a Controlled Attenuation Parameter (CAP) score ≥263 dB/m, and liver fibrosis status was defined as F0âF4. Logistic regression models and subgroup analyses stratified by sex were used to evaluate the associations. Smooth curve fitting was used to describe the associations. RESULTS: The present study of 6,840 adults aged 20 years or older found a significant positive correlation between arthritis and CAP in multivariate logistic regression analysis (ß = 0.003, 95 % CI 0.001 to 0.0041, p < 0.001). Participants with arthritis had a higher risk of hepatic steatosis (OR = 1.248, 95 % CI 1.036 to 1.504, p = 0.020), particularly those with osteoarthritis or degenerative arthritis, but not rheumatoid arthritis (p = 0.847). The positive correlation was maintained in females (ß = 0.004, 95 % CI 0.002 to 0.006, p < 0.001), but not in males. There was no significant relationship between arthritis and liver fibrosis (p = 0.508). CONCLUSION: This study indicates that there is a positive correlation between arthritis and hepatic steatosis, particularly in females. Nonetheless, there is no significant relationship between arthritis and the risk of liver fibrosis.
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Artrite , Técnicas de Imagem por Elasticidade , Cirrose Hepática , Inquéritos Nutricionais , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Fatores de Risco , Artrite/epidemiologia , Artrite/complicações , Estados Unidos/epidemiologia , Fígado Gorduroso/complicações , Fígado Gorduroso/epidemiologia , Adulto Jovem , Idoso , Fatores Sexuais , Estudos Transversais , Modelos Logísticos , Distribuição por SexoRESUMO
Introduction: Liver cirrhosis is a condition characterized by the gradual replacement of normal liver tissue with scar tissue, ultimately leading to liver failure. This slow and progressive disease begins with a chronic inflammatory process induced by a noxious agent. In its advanced stages, the disease lacks effective therapies. Research has demonstrated the significant involvement of the endocannabinoid system in the pathogenesis of this disease. This study evaluated the hepatoprotective effect of cannabidiol (CBD) in the progression of experimental hepatic cirrhosis induced by thioacetamide (TAA) in rats. Methods: A randomized experimental design was employed using Holtzman rats. Hepatic cirrhosis was induced by intraperitoneal administration of TAA at a dose of 150 mg/kg for 6 weeks, with treatment initiated additionally. The groups were as follows: Group 1: TAA + vehicle; Group 2: TAA + CBD 2 mg/kg; Group 3: TAA + CBD 9 mg/kg; Group 4: TAA + CBD 18 mg/kg; Group 5: TAA + silymarin 50 mg/kg; and Group 6: Healthy control. Serum biochemical analysis (total bilirubin, direct bilirubin, ALT, AST, alkaline phosphatase, and albumin) and hepatic histopathological study were performed. The Knodell histological activity index (HAI) was determined, considering periportal necrosis, intralobular degeneration, portal inflammation, fibrosis, and focal necrosis. Results: All groups receiving TAA exhibited an elevation in AST levels; however, only those treated with CBD at doses of 2 mg/kg and 18 mg/kg did not experience significant changes compared to their baseline values (152.8 and 135.7 IU/L, respectively). Moreover, ALT levels in animals treated with CBD showed no significant variation compared to baseline. The HAI of hepatic tissue was notably lower in animals treated with CBD at doses of 9 and 18 mg/kg, scoring 3.0 and 3.25, respectively, in contrast to the TAA + vehicle group, which recorded a score of 7.00. Animals treated with CBD at 18 mg/kg showed a reduced degree of fibrosis and necrosis compared to those receiving TAA alone (p ≤ 0.05). Conclusion: Our findings demonstrate that cannabidiol exerts a hepatoprotective effect in the development of experimental hepatic cirrhosis induced in rats.
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INTRODUCTION AND OBJECTIVES: Liver fibrosis remains a complication derived from a chronic Hepatitis C Virus (HCV) infection even when it is resolved, and no liver antifibrotic drug has been approved. Molecular mechanisms on hepatocytes and activation of hepatic stellate cells (HSCs) play a central role in liver fibrogenesis. To elucidate molecular mechanisms, it is important to analyze pathway regulation during HSC activation and HCV infection. MATERIALS AND METHODS: We evaluate the fibrosis-associated molecular mechanisms during a co-culture of human HSCs (LX2), with human hepatocytes (Huh7) that express HCV NS5A or Core protein. We evaluated LX2 activation induced by HCV NS5A or Core expression in Huh7 cells during co-culture. We determined a fibrosis-associated gene expression profile in Huh7 that expresses NS5A or Core proteins during the co-culture with LX2. RESULTS: We observed that NS5A induced 8.3-, 6.7- and 4-fold changes and that Core induced 6.5-, 1.8-, and 6.2-fold changes in the collagen1, TGFß1, and timp1 gene expression, respectively, in LX2 co-cultured with transfected Huh7. In addition, NS5A induced the expression of 30 genes while Core induced 41 genes and reduced the expression of 30 genes related to fibrosis in Huh7 cells during the co-culture with LX2, compared to control. The molecular pathways enriched from the gene expression profile were involved in TGFB signaling and the organization of extracellular matrix. CONCLUSIONS: We demonstrated that HCV NS5A and Core protein expression regulate LX2 activation. NS5A and Core-induced LX2 activation, in turn, regulates diverse fibrosis-related gene expression at different levels in Huh7, which can be further analyzed as potential antifibrotic targets during HCV infection.
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Técnicas de Cocultura , Colágeno Tipo I , Hepacivirus , Células Estreladas do Fígado , Hepatócitos , Cirrose Hepática , Inibidor Tecidual de Metaloproteinase-1 , Fator de Crescimento Transformador beta1 , Proteínas do Core Viral , Proteínas não Estruturais Virais , Humanos , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Hepacivirus/genética , Hepatócitos/metabolismo , Hepatócitos/virologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Proteínas do Core Viral/genética , Proteínas do Core Viral/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Regulação da Expressão Gênica , Transdução de Sinais , Cadeia alfa 1 do Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I/metabolismo , Perfilação da Expressão Gênica/métodos , Linhagem Celular Tumoral , RNA Polimerase Dependente de RNARESUMO
BACKGROUND AND AIM: Although it is well established that hormones like glucagon stimulates gluconeogenesis via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2, the role of neural signals in the regulation of gluconeogenesis remains uncertain. METHODS AND RESULTS: Here, we characterize the noradrenergic bundle architecture in mouse liver; we show that the sympathoexcitation induced by acute cold exposure promotes hyperglycemia and upregulation of gluconeogenesis via triggering of the CREB/CRTC2 pathway. Following its induction by dephosphorylation, CRTC2 translocates to the nucleus and drives the transcription of key gluconeogenic genes. Rodents submitted to different models of sympathectomy or knockout of CRTC2 do not activate gluconeogenesis in response to cold. Norepinephrine directly acts in hepatocytes mainly through a Ca2+-dependent pathway that stimulates CREB/CRTC2, leading to activation of the gluconeogenic program. CONCLUSION: Our data demonstrate the importance of the CREB/CRTC2 pathway in mediating effects of hepatic sympathetic inputs on glucose homeostasis, providing new insights into the role of norepinephrine in health and disease.