RESUMO
Objective: To explore the pathogenic mechanism of the miR-340/high mobility group box 1 (HMGB1) axis in the formation of liver fibrosis. Methods: A rat liver fibrosis model was established by injecting CCl(4) intraperitoneally. miRNAs targeting and validating HMGB1 were selected with gene microarrays after screening the differentially expressed miRNAs in rats with normal and hepatic fibrosis. The effect of miRNA expressional changes on HMGB1 levels was detected by qPCR. Dual luciferase gene reporter assays (LUC) was used to verify the targeting relationship between miR-340 and HMGB1. The proliferative activity of the hepatic stellate cell line HSC-T6 was detected by thiazolyl blue tetrazolium bromide (MTT) assay after co-transfection of miRNA mimics and HMGB1 overexpression vector, and the expression of extracellular matrix (ECM) proteins type I collagen and α-smooth muscle actin (SMA) was detected by western blot. Statistical analysis was performed by analysis of variance and the LSD-t test. Results: Hematoxylin-eosin and Masson staining results showed that the rat model of liver fibrosis was successfully established. Gene microarray analysis and bioinformatics prediction had detected eight miRNAs possibly targeting HMGB1, and animal model validation had detected miR-340. qPCR detection results showed that miR-340 had inhibited the expression of HMGB1, and a luciferase complementation assay suggested that miR-340 had targeted HMGB1. Functional experiments results showed that HMGB1 overexpression had enhanced cell proliferation activity and the expression of type I collagen and α-SMA, while miR-340 mimics had not only inhibited cell proliferation activity and the expression of HMGB1, type I collagen, and α-SMA, but also partially reversed the promoting effect of HMGB1 on cell proliferation and ECM synthesis. Conclusion: miR-340 targets HMGB1 to inhibit the proliferation and ECM deposition in hepatic stellate cells and plays a protective role during the process of liver fibrosis.
Assuntos
Animais , Ratos , Proliferação de Células , Colágeno Tipo I/metabolismo , Fibrose , Células Estreladas do Fígado , Proteína HMGB1/genética , Cirrose Hepática/patologia , MicroRNAs/metabolismoRESUMO
Fontan-associated liver disease (FALD) is one of the main complications after the Fontan procedure, manifesting mostly as liver fibrosis and even cirrhosis, with a high incidence rate and a lack of typical clinical symptoms that seriously affect patient prognosis. The specific cause is unknown, although it is considered to be associated with long-term elevated central venous pressure, impaired hepatic artery blood flow, and other relevant factors. The absence of association between laboratory tests, imaging data, and the severity of liver fibrosis makes clinical diagnosis and monitoring difficult. A liver biopsy is the gold standard for diagnosing and staging liver fibrosis. The most important risk factor for FALD is time following the Fontan procedure; therefore, it is recommended to do a liver biopsy 10 years after the Fontan procedure and to be cautious for the presence of hepatocellular carcinoma. Combined heart-liver transplantation is a recommended choice with favorable outcomes for patients with Fontan circulatory failure and severe hepatic fibrosis.
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Humanos , Hepatopatias/patologia , Cirrose Hepática/patologia , Fígado/patologia , Carcinoma Hepatocelular/patologia , Transplante de Fígado/efeitos adversos , Técnica de Fontan/efeitos adversos , Complicações Pós-Operatórias/patologia , Neoplasias Hepáticas/patologiaRESUMO
An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism. Hepatic fibrosis is characterized by activated hepatic stellate cells (aHSCs) with an excessive production of extracellular matrix. Although promoted activation of HSCs by M2 macrophages has been demonstrated, the molecular mechanism involved remains ambiguous. Herein, we propose that the vitamin D receptor (VDR) involved in macrophage polarization may regulate the communication between macrophages and HSCs by changing the functions of exosomes. We confirm that activating the VDR can inhibit the effect of M2 macrophages on HSC activation. The exosomes derived from M2 macrophages can promote HSC activation, while stimulating VDR alters the protein profiles and reverses their roles in M2 macrophage exosomes. Smooth muscle cell-associated protein 5 (SMAP-5) was found to be the key effector protein in promoting HSC activation by regulating autophagy flux. Building on these results, we show that a combined treatment of a VDR agonist and a macrophage-targeted exosomal secretion inhibitor achieves an excellent anti-hepatic fibrosis effect. In this study, we aim to elucidate the association between VDR and macrophages in HSC activation. The results contribute to our understanding of the pathogenesis mechanism of hepatic fibrosis, and provide potential therapeutic targets for its treatment.
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Humanos , Células Estreladas do Fígado/patologia , Receptores de Calcitriol , Cirrose Hepática/patologia , Macrófagos/metabolismoRESUMO
Objective: To explore the role of transient elastography technology in the assessment of disease staging and treatment in patients with chronic hepatitis B virus (HBV) infection. Methods: Patients who were clinically diagnosed with chronic HBV infection at Beijing Tsinghua Changgung Hospital from January 2018 to December 2021 was collected. Liver stiffness measurement (LSM) examination was performed more than once by transient elastography. The count data were expressed as cases (%) and the χ (2) test was made. Fisher's exact test was used with theoretical frequency less than 5. The measurement data between two groups was compared by t-test. Multiple groups were compared with an analysis of variance. Results: 1 055 patients were included in this study, including 669 (63.4%) males and 386 (36.6%) females. 757 (71.8%) patients were untreated. Among the untreated patients, the LSM value in the immune clearance (10.2 ± 3.8) kPa (187 cases, 40.4%), and the reactivation stages (9.1 ± 3.4) kPa (114 cases, 24.6%) was significantly higher than that in the immune tolerance (8.7 ± 3.6) kPa (78 cases, 16.8%) and immune control stages (8.4 ± 3.5) KPa (84 cases, 18.1%), and the difference between the four groups was statistically significant (F = 5.31 and P = 0.03). With ALT (male: 30 U/L, female: 19 U/L) as defined the normal value, the LSM value in the immune tolerance and the immune control stages were (5.8 ± 0.9) kPa and (7.1 ± 2.5) kPa, respectively, which were significantly lower than those of patients in the immune tolerance and immune control stages, and the difference was statistically significant (P < 0.01). There were 294 (38.8%) patients with uncertain period, excluding patients with fatty liver. Patients with uncertain periods were divided into four gray zone (GZ) groups: immune tolerance stage: LSM (5.1 ± 1.3) kPa was significantly lower than GZ-A (6.5 ± 2.4) kPa, t = 2.06, P = 0.03, and the difference was statistically significant; immune control stage: LSM was (5.6 ± 1.5) kPa, which was also lower than GZ-C (6.8 ± 1.3) kPa, t = 3.08, P = 0.02, and the difference was statistically significant; immune clearance stage: LSM > 8.0 kPa. LSM values showed a year-by-year reduction in patients with expanded indications who started antiviral treatment and were followed up for three years. Conclusion: The LSM value is significantly lower after the decrease of the defined high-normal ALT value in patients with the immune tolerance and immune control stages of chronic HBV infection. The LSM values of GZ-A and GZ-C in the uncertain periods of chronic HBV infection are higher than those of patients in the immune tolerance and immune control stages.
Assuntos
Humanos , Masculino , Feminino , Hepatite B Crônica/tratamento farmacológico , Cirrose Hepática/patologia , Técnicas de Imagem por Elasticidade , Antivirais/uso terapêutico , Fígado/patologiaRESUMO
Objective: To investigate the effects of combined blockade of interleukin-33 (IL-33) and inducible co-stimulatory molecule (ICOS) on carbon tetrachloride-induced chronic liver fibrosis and imbalance of T helper lymphocyte subsets in mice. Methods: There were 40 BALB/c mice in each model and control group. Flow cytometry was used to determine the proportion of Th1/Th2/Th17 cells in the splenic lymphocyte suspension of mice, the expression levels of interferon γ, IL-4, and IL-17 in the splenic lymphocyte suspension of liver fibrosis mice after combined blockade of IL-33 and ICOS, and the pathological changes of liver histopathology in mice with liver fibrosis. Two independent sample t-test was used to compare data between groups. Results: Compared with the non-blocking group, the proportion of Th2 and Th17 cells in the IL-33/ICOS blocking group was significantly down-regulated (Th2: 65.96% ± 6.04% vs. 49.09% ± 7.03%; Th17: 19.17% ± 4.03% vs. 9.56% ± 2.03%), while the proportion of Th1 cells and Th1/Th2 ratio were up-regulated (Th1: 17.14% ± 3.02% vs. 31.93% ± 5.02%; Th1/Th2: 0.28 ± 0.06 vs. 0.62 ± 0.23), and the difference was statistically significant (t = 5.15, 6.03, 7.14, 4.28, respectively, with P < 0.05). After entering the chronic inflammation stage of liver fibrosis in mice (10 weeks), compared with the non-blocking group, the expression levels of IL-4 and IL-17 in the blockade group were significantly down-regulated [IL-4: (84.75 ± 14.35) pg/ ml vs. (77.88 ± 19.61) pg/ml; IL-17: (72.38 ± 15.13) pg/ml vs. (36.38 ± 8.65) pg/ml], while the expression of interferon γ was up-regulated [(37.25 ± 11.51) pg/ml vs. (77.88 ± 19.61) pg/ml], and the difference was statistically significant (t: IL-4: 4.71; IL-17: 5.84; interferon γ: 5.05, respectively, with P < 0.05). Liver histopathological results showed that hepatic necrosis, hepatic lobular structural disorder, and fibrous tissue hyperplasia were significantly lower in the blockade group than those in the non-blocking group at 13 weeks of liver fibrosis. Conclusion: Combined blockade of the ICOS signaling pathway and IL-33 can regulate Th2 and Th17 polarization, down-regulate the inflammatory response, and inhibit or prevent the occurrence and progression of fibrosis.
Assuntos
Camundongos , Animais , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Citocinas/metabolismo , Tetracloreto de Carbono , Células Th2 , Interleucina-4/metabolismo , Cirrose Hepática/patologia , Células Th1 , Células Th17/patologia , ImunidadeRESUMO
Objective: To compare the clinical and pathological features of children with chronic viral hepatitis B combined with metabolic-associated fatty liver disease (CHB-MAFLD) and chronic viral hepatitis B alone (CHB alone), and to further explore the effect of MAFLD on the progression of hepatic fibrosis in CHB. Methods: 701 initially treated CHB children confirmed by liver biopsy admitted to the Fifth Medical Center of the PLA General Hospital from January 2010 to December 2021 were collected continuously. They were divided into CHB-MAFLD and CHB-alone groups according to whether they were combined with MAFLD. A retrospective case-control study was conducted. CHB-MAFLD was used as the case group, and 1:2 propensity score matching was performed with the CHB alone group according to age and gender, including 56 cases in the CHB-MAFLD group and 112 cases in the CHB alone group. The body mass index (BMI), metabolic complications, laboratory indicators, and pathological characteristics of liver tissue were compared between the two groups. The related factors affecting liver disease progression in CHB were analyzed by a binary logistic regression model. The measurement data between groups were compared using the t-test and rank sum test. The χ (2) test was used for the comparison of categorical data between groups. Results: Alanine aminotransferase (ALT, P = 0.032) and aspartate aminotransferase (AST, P = 0.003) levels were lower in the CHB-MAFLD group than those in the CHB alone group, while BMI (P < 0.001), triglyceride (TG, P < 0.001), total cholesterol (P = 0.016) and the incidence of metabolic syndrome (P < 0.001) were higher in the CHB alone group. There were no statistically significant differences in HBsAg quantification or HBV DNA load between the two groups (P > 0.05). Histologically, the proportion of significant liver fibrosis (S2-S4) was higher in the CHB-MAFLD group than that in the CHB alone group (67.9% vs. 49.1%, χ (2) = 5.311, P = 0.021). Multivariate regression results showed that BMI (OR = 1.258, 95% CI: 1.145 ~ 1.381, P = 0.001) and TG (OR = 12.334, 95% CI: 3.973 ~ 38.286, P < 0.001) were the risk factors for hepatic steatosis occurrence in children with CHB. MAFLD (OR = 4.104, 95% CI: 1.703 ~ 9.889, P = 0.002), liver inflammation (OR = 3.557, 95% CI: 1.553 ~ 8.144, P = 0.003), and γ-glutamyl transferase (OR = 1.019, 95% CI: 1.001 to 1.038, P = 0.038) were independent risk factors for significant hepatic fibrosis in children with CH. Conclusion: MAFLD occurrence is related to metabolic factors in children with CHB. Additionally, the combination of MAFLD may promote liver fibrosis progression in CHB patients.
Assuntos
Humanos , Criança , Hepatite B Crônica/patologia , Estudos Retrospectivos , Estudos de Casos e Controles , Vírus da Hepatite B/genética , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Fatores de RiscoRESUMO
Objective: To analyze the safety and efficacy of using novel oral anticoagulants (rivaroxaban and others) in patients with cirrhosis accompanied with portal vein thrombosis (PVT). Methods: Clinical research literature published from the establishment of the database to June 20, 2021, was retrieved from PubMed, Web of Science, CNKI, Wanfang, and Weipu databases by combining subject terms and free words. RevMan software was used for the random group meta-analysis model. Results: In terms of PVT recanalization, the novel oral anticoagulants (such as low molecular weight heparin and others) had a higher recanalization rate than traditional anticoagulants (OR = 13.75, 95%CI 3.58-52.9, P = 0.000 1). In terms of bleeding, the novel oral anticoagulants did not increase the risk of bleeding compared with traditional anticoagulants (OR = 2.42, 95%CI 0.62-9.41, P = 0.20). Conclusion: The novel oral anticoagulant drugs are superior to traditional anticoagulants in terms of the occurrence of PVT recanalization; however, there is no statistically significant difference in terms of the occurrence of bleeding between the two groups.
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Humanos , Veia Porta/patologia , Resultado do Tratamento , Trombose Venosa/complicações , Cirrose Hepática/patologia , Anticoagulantes/uso terapêutico , HemorragiaRESUMO
Liver fibrosis incidence and adverse outcomes are high; however, there are no known chemical drugs or biological agents that are specific and effective for treatment. The paucity of a robust and realistic in vitro model for liver fibrosis is one of the major causes hindering anti-liver fibrosis drug development. This article summarizes the latest progress in the development of in vitro cell models for liver fibrosis, with a focus based on the analysis of induction and activation of hepatic stellate cells, cell co-culture, and 3D model co-construction, as well as concurrent potential methods based on hepatic sinusoidal endothelial cell establishment.
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Humanos , Cirrose Hepática/patologia , Células Estreladas do Fígado , Técnicas de Cultura de Células , Células EndoteliaisRESUMO
A normal liver can develop cirrhosis through long-term and repeated stimulation from various etiologies. Histological manifestations like the collapse of hepatic lobular structure (including microvascular structure) and the formation of pseudolobules can lead to portal hypertension and even decompensated cirrhosis. More and more evidence suggests that effective etiological treatment can not only delay but also reverse the progression of cirrhosis. The mechanism of cirrhosis reversal mainly includes the degradation of extracellular matrix, hepatocyte regeneration, and hepatic lobular remodeling. The "gold standard" for the evaluation of cirrhosis reversal at present is still a liver biopsy. Therefore, the histopathological evaluation of cirrhosis reversal is very important for determining the disease's prognosis, efficacy, and mechanism of exploration.
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Humanos , Cirrose Hepática/patologia , Fígado/patologia , Hipertensão Portal , Hepatócitos/patologia , PrognósticoRESUMO
Primary myelofibrosis (PMF) is easily confused with cirrhosis, due to its main clinical manifestations of splenomegaly and the blood cytopenia. This review focuses on clinical studies to identify primary myelofibrosis and cirrhosis related portal hypertension, to analyze the differences between the two diseases, in order to distinguish PMF and cirrhosis from the pathogenesis, clinical manifestations, laboratory examinations and treatment principles, and simultaneously improve clinicians' understanding of PMF, which is a reference for exploring the early screening or diagnostic indicators of PMF, also provides a clinical basis for the application of new targeted drugs such as ruxolitinib.
Assuntos
Humanos , Mielofibrose Primária/tratamento farmacológico , Hipertensão Portal/complicações , Cirrose Hepática/patologia , Esplenomegalia/patologia , AnemiaRESUMO
Objective: To explore the new mechanism of liver fibrosis through D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced necroptosis as an entry point to inhibit lethal injury. Methods: The carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis was established. At 6 weeks of fibrosis, the mice were challenged with a lethal dose of D-GalN/LPS, and the normal mice treated with the same treatment were used as the control. The experiment was divided into four groups: control group (Control), acute injury group (D-GalN/LPS), liver fibrosis group (Fib), and liver fibrosis + acute challenge group (Fib + D-GalN/LPS). Quantitative PCR and immunofluorescence were used to analyze the expression of necroptosis key signal molecules RIPK1, RIPK3, MLKL and/or P-MLKL in each group. Normal mice were treated with inhibitors targeting key signaling molecules of necroptosis, and then given an acute challenge. The inhibitory effect of D-GalN/LPS-induced-necroptosis on acute liver injury was evaluated according to the changes in transaminase levels and liver histology. Liver fibrosis spontaneous ablation model was established, and then acute challenge was given. Necroptosis key signal molecules expression was analyzed in liver tissue of mice in each group and compared by immunohistochemistry. The differences between groups were compared with t-test or analysis of variance. Results: Quantitative PCR and immunofluorescence assays result showed that D-GalN/LPS-induced significant upregulation of RIPK1, RIPK3, MLKL and/or P-MLKL. Necroptosis key signal molecules inhibition had significantly reduced D-GalN/LPS-induced liver injury, as manifested by markedly reduced serum ALT and AST levels with improvement in liver histology. Necroptosis signaling molecules expression was significantly inhibited in fibrotic livers even under acute challenge conditions. Additionally, liver fibrosis with gradual attenuation of fibrotic ablation had inhibited D-GalN/LPS-induced necroptosis. Conclusion: Liver fibrosis may protect mice from acute lethal challenge injury by inhibiting D-GalN/LPS-induced necroptosis.
Assuntos
Animais , Camundongos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Galactosamina/efeitos adversos , Lipopolissacarídeos/efeitos adversos , Fígado/patologia , Cirrose Hepática/patologia , Falência Hepática Aguda/induzido quimicamente , NecroptoseRESUMO
Artificial intelligence (AI) refers to the use of computer programs to simulate and extend human intelligence, and has application prospects in the diagnosis and treatment of diseases. This review focuses on the research status of the screening and diagnosis of NAFLD and nonalcoholic steatohepatitis using artificial intelligence technology, electronic health record data, multi-omics prediction models, image recognition technology based on liver imaging and pathological biopsy, and new drugs research and development, with a view to provide new ideas for the diagnosis and treatment.
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Humanos , Inteligência Artificial , Biópsia/métodos , Fígado/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
Objective: To evaluate the diagnostic value of transient elastography, aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis index based on 4 factors (FIB-4) for liver fibrosis in children with non-alcoholic fatty liver disease (NAFLD). Methods: A retrospective study was conducted on 100 cases of nonalcoholic fatty liver disease in Hunan Children's Hospital between August 2015 to October 2020 to collect liver tissue pathological and clinical data. The receiver operating characteristic curve (ROC curve) was used to analyze the diagnostic value of liver stiffness measurement (LSM), APRI and FIB-4 in the diagnosis of different stages of liver fibrosis caused by NAFLD in children. Results: The area under the ROC curve (AUC) value of LSM, APRI and FIB-4 for diagnosing liver fibrosis (S≥1) were 0.701 [95% confidence interval (CI): 0.579 ~ 0.822, P = 0.011], 0.606 (95%CI: 0.436 ~ 0.775, P = 0.182), and 0.568 (95%CI: 0.397 ~ 0.740, P = 0.387), respectively. The best cut-off values were 6.65 kPa, 21.20, and 0.18, respectively. The AUCs value of LSM, APRI, and FIB-4 for diagnosing significant liver fibrosis (S≥ 2) were 0.660 (95% CI: 0.552 ~ 0.768, P = 0.006), 0.578 (95% CI: 0.464 ~ 0.691, P = 0.182) and 0.541 (95% CI: 0.427 ~ 0.655, P = 0.482), respectively. The best cut-off values were 7.35kpa, 24.78 and 0.22, respectively. The AUCs value of LSM, APRI and FIB-4 for the diagnosis of advanced liver fibrosis (S≥ 3) were 0.639 (95% CI: 0.446 ~ 0.832, P = 0.134), 0.613 (95% CI: 0.447 ~ 0.779, P = 0.223) and 0.587 (95% CI: 0.411 ~ 0.764, P = 0.346), respectively. The best cut-off values were 8.55kpa, 26.66 and 0.27, respectively. Conclusion: The transient elastography technique has a better diagnostic value than APRI and FIB-4 for liver fibrosis in children with NAFLD.
Assuntos
Criança , Humanos , Aspartato Aminotransferases , Biomarcadores , Técnicas de Imagem por Elasticidade , Fígado/patologia , Cirrose Hepática/patologia , Testes de Função Hepática , Hepatopatia Gordurosa não Alcoólica/patologia , Curva ROC , Estudos RetrospectivosRESUMO
For the detection of steatosis, quantitative ultrasound imaging techniques have achieved great progress in past years. Magnetic resonance imaging proton density fat fraction is currently the most accurate test to detect hepatic steatosis. Some blood biomarkers correlate with non-alcoholic steatohepatitis, but the accuracy is modest. Regarding liver fibrosis, liver stiffness measurement by transient elastography (TE) has high accuracy and is widely used across the world. Magnetic resonance elastography is marginally better than TE but is limited by its cost and availability. Several blood biomarkers of fibrosis have been used in clinical trials and hold promise for selecting patients for treatment and monitoring treatment response. This article reviews new developments in the non-invasive assessment of non-alcoholic fatty liver disease (NAFLD). Accumulating evidence suggests that various non-invasive tests can be used to diagnose NAFLD, assess its severity, and predict the prognosis. Further studies are needed to determine the role of the tests as monitoring tools. We cannot overemphasize the importance of context in selecting appropriate tests.
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Humanos , Técnicas de Imagem por Elasticidade/métodos , Fígado/patologia , Cirrose Hepática/patologia , Imageamento por Ressonância Magnética/métodos , Hepatopatia Gordurosa não AlcoólicaRESUMO
The purpose of this study was to investigate the effect of Geniposide on hepatic fibrosis and activation of hepatic stellate cells (HSCs) and to explore possible underlying mechanism. Human HSCs (LX-2) were treated with 5 ng/mL transforming growth factor-β1 (TGF-β1), followed by co-culture with Geniposide at various concentrations (0, 1, 2.5, 5, 10, 20, 40, 60, 80, 100 μmol/L). Cell viability was determined by MTT assay. Then, LX-2 cells were divided into control, TGF-β1 (5 ng/mL) and TGF-β1 + Geniposide (20 μmol/L) groups, and the gene and protein expression of collagen I, fibronectin, α-smooth muscle actin (α-SMA), p-Smad2 and p-Smad3 was detected by qPCR and Western blot, respectively. BALB/c mice were treated with CCl4 (25%, 1 mL/kg) to generate a model of hepatic fibrosis (CCl4 group), and the control group and CCl4 + Geniposide group were administered with olive oil and CCl4 + 40 mg/kg Geniposide, respectively. After 4 weeks of treatment, the liver function and serum hepatic fibrosis indexes of mice were detected, histological observation was performed by HE and Masson staining, and α-SMA expression in the tissue was analyzed by immunohistochemistry. Western blot was utilized for the determination of the protein expression of α-SMA, TGF-β1, p-Smad2 and p-Smad3. The results showed that Geniposide inhibited LX-2 cell proliferation. In addition, Geniposide significantly downregulated the gene and protein expression of collagen I, fibronectin and α-SMA and the expression of TGF-β1/Smad signaling-related proteins induced by TGF-β1 in vitro. Histological observations showed that Geniposide significantly inhibited CCl4-induced hepatic fibrosis, HSC activation and expression of TGF-β1/Smad signaling-related proteins in mice. In summary, Geniposide prevents the hepatic fibrosis and HSC activation possibly through the inhibition of the TGF-β1/Smad signaling pathway.
Assuntos
Animais , Camundongos , Colágeno Tipo I/metabolismo , Fibronectinas , Células Estreladas do Fígado/patologia , Iridoides , Cirrose Hepática/patologia , Transdução de Sinais , Proteínas Smad/farmacologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
OBJECTIVE@#To investigate the molecular mechanism underlying the anti-hepatic fibrosis activity of ethyl acetate fraction Dicliptera chinensis (L.) Juss. (EDC) in human hepatic stellate cells (HSCs) in vitro and in a carbon tetrachloride (CCl4)-induced hepatic fibrosis mouse model in vivo.@*METHODS@#For in vitro study, HSCs were pre-treated with platelet-derived growth factor (10 ng/mL) for 2 h to ensure activation and treated with EDC for 24 h and 48 h, respectively. The effect of EDC on HSCs was assessed using cell counting kit-8 assay, EdU staining, transmission electron microscopy, immunofluorescence staining, and Western blot, respectively. For in vivo experiments, mice were intraperitoneally injected with CCl4 (2 ° L/g, adjusted to a 25% concentration in olive oil), 3 times per week for 6 weeks, to develop a hepatic fibrosis model. Forty 8-week-old male C57BL/6 mice were divided into 4 groups using a random number table (n=10), including control, model, positive control and EDC treatment groups. Mice in the EDC and colchicine groups were intragastrically administered EDC (0.5 g/kg) or colchicine (0.2 mg/kg) once per day for 6 weeks. Mice in the control and model groups received an equal volume of saline. Biochemical assays and histological examinations were used to assess liver damage. Protein expression levels of α -smooth muscle actin (α -SMA) and microtubule-associated protein light chain 3B (LC3B) were measured by Western blot.@*RESULTS@#EDC reduced pathological damage associated with liver fibrosis, downregulated the expression of α -SMA and upregulated the expression of LC3B (P<0.05), both in HSCs and the CCl4-induced liver fibrosis mouse model. The intervention of bafilomycin A1 and rapamycin in HSCs strongly supported the notion that inhibition of autophagy enhanced α -SMA protein expression levels (P<0.01). The results also found that the levels of phosphoinositide (PI3K), p-PI3K, AKT, p-AKT, mammalian target of rapamycin (mTOR), p-mTOR, and p-p70S6K all decreased after EDC treatment (P<0.05).@*CONCLUSIONS@#EDC has anti-hepatic fibrosis activity by inducing autophagy and might be a potential drug to be further developed for human liver fibrosis therapy.
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Animais , Masculino , Camundongos , Acetatos , Autofagia , Tetracloreto de Carbono , Células Estreladas do Fígado , Fígado/patologia , Cirrose Hepática/patologia , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismoRESUMO
ABSTRACT Objective: Identifying significant fibrosis is crucial to evaluate the prognosis and therapeutic interventions in patients with nonalcoholic fatty liver disease (NAFLD). We assessed the performance of acoustic radiation force impulse (ARFI) elastography, APRI, FIB-4, Forns, NFS and BARD scores in determining liver fibrosis in severe obesity. Subjects and methods: A prospective study included 108 patients undergoing bariatric surgery. Liver biopsy specimens were obtained intraoperatively and classified according to the NAFLD Activity Score. Patients were assessed with serological markers and shear wave velocity of the liver was measured with the Siemens S2000 ultrasound system preoperatively. Optimal cut-off values were determined using the area under the receiver operating characteristic curves (AUROC). Results: In the entire cohort prevalence of NAFLD was 80.6%, steatohepatitis 25.9% and significant fibrosis 19.4%. The best tests for predicting significant fibrosis were FIB-4 and Forns scores (both AUROC 0.78), followed by APRI (AUROC 0.74), NFS (AUROC 0.68), BARD (AUROC 0.64) and ARFI (AUROC 0.62). ARFI elastography was successful in 73% of the patients. Higher body mass index (BMI) correlated with invalid ARFI measurements. In patients with BMI < 42 kg/m2, ARFI showed 92.3% sensitivity and 82,6% specificity for the presence of significant fibrosis, with AUROC 0.86 and cut-off 1.32 m/s. Conclusions: FIB-4 and Forns scores were the most accurate for the prediction of significant fibrosis in bariatric patients. Applicability and accuracy of ARFI was limited in individuals with severe obesity. In patients with BMI < 42 kg/m2, ARFI elastography was capable for predicting significant fibrosis with relevant accuracy.
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Humanos , Obesidade Mórbida/complicações , Obesidade Mórbida/diagnóstico por imagem , Estudos Prospectivos , Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Acústica , Biópsia , Fatores de Risco , Curva ROC , Fígado/patologia , Fígado/diagnóstico por imagem , Cirrose Hepática/patologia , Cirrose Hepática/diagnóstico por imagemRESUMO
SUMMARY: Obesity and fatty liver steatosis are already considered metabolic risk factors which may aggravate the severity of COVID-19. This study aims to investigate the correlation between COVID-19 severity, obesity, and liver steatosis and fibrosis. 230 consecutive patients with laboratory-confirmed COVID-19 aged between 15 and 84? years, admitted to a hospital devoted to COVID-19 patients, were enrolled in the study. COVID-19 severity was classified as severe versus non-severe based on admission to ICU. Obesity was assessed by Body Mass Index (BMI). CT-scan was used to check for the liver steatosis. Fibrosis-4 score was calculated. The study was conducted in March-May 2020. Obesity strongly and positively correlated with severe COVID-19 illness r: 0.760 (P<0.001). Hepatic steatosis had rather less of a correlation with COVID-19 severity r: 0.365 (P<0.001). Multivariable-adjusted association between hepatic steatosis or obesity, or both (as exposure) and COVID-19 severity (as the outcome) revealed increased risk of severe COVID-19 illness with obesity (Adjusted model I OR: 465.3, 95 % CI: 21.9-9873.3, P<0.001), with hepatic steatosis (Adjusted model I OR: 5.1, 95 % CI: 1.2-21.0, P<0.025), and with hepatic steatosis among obese patients (Adjusted model I OR: 132, 95 % CI: 10.3-1691.8, P<0.001). Obesity remained the most noticeable factor that strongly correlated with COVID-19 severity, more than liver steatosis. However, the risk to COVID-19 severity was greater in those with both factors: obesity and liver steatosis.
RESUMEN: La obesidad y la esteatosis del hígado graso ya se consideran factores de riesgo metabólico que pueden empeorar la gravedad de la COVID-19. Este estudio tiene como objetivo investigar la correlación entre la gravedad de COVID- 19, la obesidad y la esteatosis y fibrosis hepática. El estudio se realizó en 230 pacientes consecutivos entre 15 y 84 años con COVID-19 confirmado por laboratorio, ingresados en un hospital dedicado a pacientes con COVID-19. La gravedad de COVID-19 se clasificó como grave, versus no grave según el ingreso a la UCI. La obesidad se evaluó mediante el índice de masa corporal (IMC). Se utilizó una tomografía computarizada para verificar la esteatosis hepática. Se calculó la puntuación de Fibrosis-4. El estudio se realizó entre marzo-mayo de 2020. La obesidad se correlacionó fuerte y positivamente con la enfermedad grave de COVID-19 r: 0,760 (P <0,001). La esteatosis hepática tuvo una correlación bastante menor con la gravedad de COVID-19 r: 0.365 (P <0.001). La asociación ajustada multivariable entre la esteatosis hepática u obesidad, o ambas (como exposición) y la gravedad de COVID-19 (como resul- tado) reveló un mayor riesgo de enfermedad grave por COVID- 19 con obesidad (OR del modelo ajustado I: 465,3, IC del 95%: 21,9 -9873,3, P <0,001), con esteatosis hepática (OR del modelo I ajustado: 5,1, IC del 95 %: 1,2-21,0, P <0,025) y con esteatosis hepática entre los pacientes obesos (OR del modelo I ajustado: 132, IC del 95 % : 10,3-1691,8, P <0,001). La obesidad siguió siendo el factor más notable que se correlacionó significativamente con la gravedad de COVID-19, más que la esteatosis hepática. Sin embargo, el riesgo de gravedad de COVID-19 fue mayor en aquellos con ambos factores: la obesidad y esteatosis hepática.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Fígado Gorduroso/patologia , Fígado Gorduroso/diagnóstico por imagem , COVID-19/patologia , Obesidade/patologia , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Índice de Massa Corporal , Cirrose Hepática/patologia , Cirrose Hepática/diagnóstico por imagemAssuntos
Humanos , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/patologia , Varizes Esofágicas e Gástricas/diagnóstico por imagem , Técnicas de Imagem por Elasticidade , Valor Preditivo dos Testes , Fígado/patologia , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Cirrose Hepática/diagnóstico por imagemRESUMO
SUMMARY OBJECTIVE: Gamma-glutamyl transpeptidase-platelet ratio, system inflammation response index, and systemic immune inflammation index are three systemic immune and inflammation indexes that were investigated for their diagnostic and prognostic proficiencies in cardiovascular diseases and cancers. However, their predictive values for invasive aspergillosis have not yet been studied. The aim of this study was to evaluate Gamma-glutamyl transpeptidase-platelet ratio, system inflammation response index, and systemic immune inflammation index levels and their diagnostic values in invasive aspergillosis. METHODS: A total of 23 patients with invasive aspergillosis and 23 sex- and age-matched healthy participants were included in this study. Complete blood count parameters and liver function tests were studied. Gamma-glutamyl transpeptidase-platelet ratio, system inflammation response index, and systemic immune inflammation index were calculated. RESULTS: Leukocyte, neutrophil, lymphocyte, and monocyte levels were statistically significantly higher in IA group (p=0.031, p=0.027, p=0.033, and p=0.001, respectively). In invasive aspergillosis group, platelets were numerically lower; Aspartate transaminase, alanine aminotransferase, and lactic dehydrogenase levels were numerically higher than those in control group but differences between levels were not statistically significant (p>0.05). The γ-glutamyl transpeptidase levels of patients were statistically significantly higher (p=0.007), and in addition, statistically significant differences were found between groups in terms of gamma-glutamyl transpeptidase-platelet ratio, system inflammation response index, and systemic immune inflammation index (p<0.001, p=0.037, p=0.001, respectively). Receiver operating characteristic analysis was performed, and areas under the curves were evaluated. gamma-glutamyl transpeptidase-platelet ratio had the higher area under the curve than systemic immune inflammation index and system inflammation response index (AUC 0.849, 0.798, 0.693, respectively). The results from receiver operating characteristic analysis of the data suggested that the use of a cutoff value of 0.15 for gamma-glutamyl transpeptidase-platelet ratio would be optimum for clinical use to confirm independent predictors of patients with invasive aspergillosis. CONCLUSIONS: Gamma-glutamyl transpeptidase-platelet ratio is an independent, a useful predictor, and is superior to other evaluated markers in the diagnosis of inflammation in invasive aspergillosis. Gamma-glutamyl transpeptidase-platelet ratio may also be a helpful biomarker for clinicians to follow-up the inflammatory process of these patients.