The deubiquitinating enzyme 13 retards non-alcoholic steatohepatitis via blocking inactive rhomboid protein 2-dependent pathway

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated. Inactive rhomboid protein 2 (IRHOM2), a promising target for treatment of inflammation-related diseases, contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanism underlying Irhom2 regulation is still not completely understood. In this work, we identify the ubiquitin-specific protease 13 (USP13) as a critical and novel endogenous blocker of IRHOM2, and we also indicate that USP13 is an IRHOM2-interacting protein that catalyzes deubiquitination of Irhom2 in hepatocytes. Hepatocyte-specific loss of the Usp13 disrupts liver metabolic homeostasis, followed by glycometabolic disorder, lipid deposition, increased inflammation, and markedly promotes NASH development. Conversely, transgenic mice with Usp13 overexpression, lentivirus (LV)- or adeno-associated virus (AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of rodent. Mechanistically, in response to metabolic stresses, USP13 directly interacts with IRHOM2 and removes its K63-linked ubiquitination induced by ubiquitin-conjugating enzyme E2N (UBC13), a ubiquitin E2 conjugating enzyme, and thus prevents its activation of downstream cascade pathway. USP13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway.

Synergistic activation of AMPK by AdipoR1/2 agonist and inhibitor of EDPs-EBP interaction recover NAFLD through enhancing mitochondrial function in mice

Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), is a common hepatic manifestation of metabolic syndrome. However, there are no effective therapy to treat this devastating disease. Accumulating evidence suggests that the generation of elastin-derived peptides (EDPs) and the inhibition of adiponectin receptors (AdipoR)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis. We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix (ECM) and ameliorated liver fibrosis. However, the degradation of the ECM lead to the generation of EDPs, which could further alter liver homeostasis negatively. Thus, in this study, we successfully combined AdipoR1/2 agonist JT003 with V14, which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation. We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other. These effects are induced by the enhancement of the mitochondrial antioxidant capacity, mitophagy, and mitochondrial biogenesis via AMPK pathway. Furthermore, specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress, increased mitophagy and mitochondrial biogenesis. These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.

Effect of Gegen Qinliantang-medicated Serum on Nonalcoholic Steatohepatitis Based on Nrf2/TXNIP Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the effect of Gegen Qinliantang （GGQLT）-medicated serum on free fatty acid （FFA）-induced nonalcoholic steatohepatitis （NASH） in vitro model of human hepatoma cells HepG2. MethodNASH model of HepG2 cells was established in vitro， and the cells were intervened with different volume fractions of GGQLT-medicated serum and resveratrol. Intracellular lipid deposition in each group was detected by oil red O staining， the level of reactive oxygen species （ROS） in each group were detected by flow cytometry， the levels of glutathione peroxidase （GSH-Px）， superoxide dismutase （SOD）， triglyceride （TG） and malondialdehyde （MDA） in each group were detected by kits. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to measure the mRNA expression levels of nuclear transcription factor （NF）E2-related factor 2 （Nrf2）， heme oxygenase-1 （HO-1）， quinone oxidoreductase 1 （NQO1）， Kelch-like epichlorohydrin-associated protein-1 （Keap1）， NF-κB， thioredoxin interacting protein （TXNIP）， interleukin-1β （IL-1β） in HepG2 cells of each group. The protein expression of Nrf2， TXNIP in cells of each group was detected by Western blot. ResultFFA induced large accumulation of intracellular lipids. Compared with the normal group， the activities of GSH-Px and SOD were significantly decreased （P<0.01） and the contents of TG， ROS and MDA were significantly increased （P<0.05， P<0.01） in the model group. Compared with the model group， all GGQLT groups and resveratrol group could elevate intracellular SOD activity to different degrees （P<0.05， P<0.01） and significantly reduce the levels of intracellular ROS and MDA （P<0.05， P<0.01）， GGQLD high- and medium-dose groups and resveratrol group significantly elevated GSH-Px activity （P<0.01）， GGQLD medium- and low-dose groups and resveratrol group significantly decreased TG content （P<0.05， P<0.01）. Compared with the model group， GGQLT high- and medium-dose groups and resveratrol group could significantly upregulate the mRNA expression levels of Nrf2， HO-1 and NQO1 （P<0.01）， all GGQLT groups and resveratrol group could significantly downregulate the TXNIP protein expression level， as well as significantly downregulate the mRNA expression levels of Keap1， NF-κB （P<0.05， P<0.01）. Nrf2-siRNA transfection of cells revealed that Nrf2 expression was significantly downregulated （P<0.01） in the Nrf2-siRNA group of cells by comparing with NC-siRNA group at the corresponding dose of drugs， and the inhibitory effects of GGQLT and resveratrol on TXNIP， IL-1β were attenuated. ConclusionFFA induces the production of ROS and inflammatory factors in HepG2 cells， and GGQLT can improve the anti-inflammatory and antioxidant capacities of cells， and its mechanism may be related to the regulation of Nrf2/TXNIP signaling pathway， so as to improve NASH.

Mechanism of Tibetan medicine Ershiwuwei Songshi Pills in regulating intestinal flora and improving non-alcoholic steatohepatitis / 中国中药杂志

This study aimed to investigate the effect of Tibetan medicine Ershiwuwei Songshi Pills(ESP) on the intestinal flora of non-alcoholic steatohepatitis(NASH) mice. Forty-eight male C57 BL/6 mice were randomly divided into the control group, model(methionine-choline-deficient, MCD) group, high-(0.8 g·kg~(-1)), medium-(0.4 g·kg~(-1)), and low-dose(0.2 g·kg~(-1)) ESP groups, and pioglitazone(PGZ, 10 mg·kg~(-1)) group, with eight mice in each group. Mice in the control group were fed with normal diet, while those in the remaining five groups with MCD diet for five weeks for inducing NASH. During modeling, they were gavaged with the corresponding drugs. The changes in body mass, daily water intake, and daily food intake were recorded. At the end of the experiment, the liver tissues were collected and stained with hematoxylin-eosin(HE) for observing the pathological changes, followed by oil red O staining for observing fat accumulation in the liver. The levels of serum aspartate aminotransferase(AST) and alanine aminotransferase(ALT) and triglyceride(TG) in liver tissue were measured. The changes in intestinal flora of mice were determined using 16 S rRNA high-throughput sequencing technology. The results showed that compared with the model group, the high-, medium-and low-dose ESP groups and the PGZ group exhibited significantly lowered AST and ALT in serum and TG in liver tissues and alleviated hepatocellular steatosis and fat accumulation in the liver. As demonstrated by 16 S rRNA sequencing, the abundance index and diversity of intestinal flora decreased in the model group, while those increased in the ESP groups. Besides, the Firmicutes to Bacteroidetes ratio decreased at the phylum level. In the alteration of the composition of intestinal flora, ESP reduced the abundance of Erysipelotrichia and Faecalibaculum but increased the abundance of Desulfovibrionaceae, Rikenellaceae, Lachnospiraceae, and Ruminococcaceae. This study has revealed that ESP has a protective effect against NASH induced by MCD diet, which may be related to its regulation of the changes in intestinal flora, alteration of the composition of intestinal flora, and inhibition of the intestinal dysbiosis.

Evaluación de la fibrogénesis hepática en pacientes con esteatohepatitis no alcohólica tratados con propóleos rojo oral cubano / Evaluation of hepatic fibrogenesis in patients with nonalcoholic steatohepatitis treated with cuban oral red propolis

Introducción: La enfermedad por depósito graso no alcohólica constituye una pandemia del mundo contemporáneo. Su espectro silente atraviesa estadios de cronicidad y puede llegar a la cirrosis hepática y sobre esta pudiera desarrollarse un hepatocarcinoma. No existen tratamientos y solo se puede actuar sobre los factores de riesgo. Objetivo: Evaluar el efecto citohepatoprotector y antifibrótico del propóleos rojo cubano oral en pacientes con esteatohepatitis no alcohólica. Métodos: Se realizó un estudio longitudinal prospectivo en pacientes seleccionados de las consultas de Gastroenterología, Endocrinología y Medicina Interna del Hospital Clínico Quirúrgico Hermanos Ameijeiras durante el periodo de abril 2017 a abril 2018. El universo de estudio fue de 120 pacientes con diagnóstico imagenológico de hígado graso. La muestra quedó conformada por 70 pacientes con diagnóstico de hígado graso, y que cumplieron criterios de inclusión y exclusión. Las pruebas estadísticas aplicadas fueron análisis de frecuencia y porcentaje para las variables demográficas. La prueba T para las muestras relacionadas evaluó el comportamiento enzimático al inicio y al final del tratamiento y los cambios elastográficos fueron analizados mediante test de Kappa y porcentaje. Resultados: Las variables bioquímicas estudiadas mostraron una disminución estadísticamente significativa al final del tratamiento. Los cambios elastográficos al final del estudio evidenciaron la efectividad del tratamiento, en el cual el 91,4 por ciento de los pacientes evolucionaron hacia el menor grado de fibrosis. Conclusiones: El propóleos rojo cubano demostró ser un apifármaco con acción citohepatoprotectora y antifibrótica de valor terapéutico(AU)

Introduction: Nonalcoholic fat deposition disease is a pandemic in the contemporary world. Its silent spectrum goes through stages of chronicity and it can reach liver cirrhosis and on this a hepatic carcinoma could develop. There are no treatments and medical handling can act on only risk factors. Objective: To evaluate cytohepatoprotective and antifibrotic effect of oral Cuban red propolis in patients with nonalcoholic steatohepatitis. Methods: A prospective longitudinal study was carried out in selected patients from the Gastroenterology, Endocrinology and Internal Medicine consultations at Hermanos Ameijeiras Clinical Surgical Hospital from April 2017 to April 2018. The study universe was 120 patients with imaging diagnosis of fatty liver. The sample consisted of 70 patients with fatty liver diagnosis, who met the inclusion and exclusion criteria. Frequency and percentage analysis for the demographic variables were the statistical tests applied. The T test for the related samples evaluated the enzymatic behavior at the beginning and at the end of the treatment and the elastography changes were analyzed using Kappa and percentage tests. Results: The biochemical variables studied showed statistically significant decrease at the end of the treatment, which evidenced the effectiveness of the treatment. 91.4 percent of the patients progressed to a lower degree of fibrosis. Conclusions: Cuban red propolis proved to be a therapeutic drug with cytohepathoprotective and antifibrotic action(AU)

Pathogenesis of NASH and Promising Natural Products / 中国天然药物

Nonalcoholic steatohepatitis (NASH) is a common clinical condition that can lead to advanced liver diseases. The mechanism of the diaease progression, which is lacking effective therapy, remains obsure. Therefore, there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies. To accomplish this goal, experimental animal models that recapitulate the human disease are necessary. Currently, an increasing number of studies have focused on natural constituents from medicinal plants which have been emerged as a new hope for NASH. This review summarized the pathogenesis of NASH, animal models commonly used, and the promising targets for therapeutics. We also reviewed the natural constituents as potential NASH therapeutic agents.

Mechanism of catgut embedding at back- points for nonalcoholic steatohepatitis based on IKK/IKB/NF-κB signaling pathway / 中国针灸

OBJECTIVE@#To explore the mechanism of catgut embedding at back- points on nonalcoholic steatohepatitis (NASH) in rats based on IKK/IKB/NF-κB signaling pathway and downstream inflammatory factors.@*METHODS@#Eighty SPF SD rats were selected, among them 10 rats were selected divided into a normal group (group A), and the remaining 70 rats were fed with high-fat diet to establish NASH model. At the end of 12 weeks, 10 rats were randomly selected to verify whether the model establishment was successful. Then the remaining 60 rats were randomly divided into a model group (group B), a catgut embedding at back- points group (group C), a catgut embedding at abdominal points group (group D), an acupuncture at back- points group (group E), a sham catgut embedding group (group F) and a western medication group (group G), 10 rats in each group. The rats in the group C were treated with catgut embedding at "Ganshu" (BL 18), "Pishu" (BL 20), "Weishu" (BL 21) and "Shenshu" (BL 23); the rats in the group D were treated with catgut embedding at "Daheng" (SP 15), "Fujie" (SP 14), "Huaroumen" (ST 24) and "Tianshu" (ST 25); the rats in the group E were treated with acupuncture at the same acupoints as the group C; the rats in the group F were treated with catgut embedding at back- points but the needle did not enter subcutaneous tissue gamma; the rats in the group G were treated with intragastric administration of vitamin E capsule. All the treatment was given for 4 weeks. The rats in the group A were fed with normal diet until the end of 16 weeks without any intervention. The rats in the group B continued to be fed with high-fat diet until the end of 16 weeks. After the intervention, the liver index was calculated; the liver histomorphology was observed by HE staining; the liver function [alanine aminotransferase (ALT), gamma glutamyl transferase (γ-GGT), alkaline phosphatase (ALP)] and blood lipid [serum total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL)] were measured by serum biochemistry. The serum levels of TNF-α, IL-6 and IL-1βwere detected by ELISA, and the expressions of IKK-α, NF-κBp65, IL-6, IL-1β and TNF-α proteins in liver tissue were detected by Western blot. The temperature of the conception vessel and the governor vessel was measured by infrared thermography.@*RESULTS@#Compared with the group A, the obvious steatosis and inflammatory cell infiltration were observed in the group B, and the body weight, liver wet-weight and liver index were all increased (0.05), while the temperature of the governor vessel in the group C was superior to that in the group D (<0.05).@*CONCLUSION@#The catgut embedding at back- points might inhibit the activation of IKK/IKB/NF-κB signaling pathway to interrupt the inflammatory cascade, and reduce the "second hit" of inflammatory factors on liver, which could slow down NASH progress and prevent and treat NASH.

Research status of liver transplantation in the treatment of non-alcoholic fatty liver disease / 器官移植

Liver transplantation is the most effective means to treat the related end-stage liver disease caused by non-alcoholic fatty liver disease (NAFLD). But the recurrence rate of NAFLD after liver transplantation is very high due to the affection of obesity, metabolic syndrome and other adverse factors. In recent years, liver transplantation for NAFLD related end-stage liver disease has made some progress both in China and abroad. This article reviews the research progress of NAFLD and liver transplantation for NAFLD.

Establishment of non-alcoholic steatohepatitis mouse model induced by Western diet combined with low-dose carbon tetrachloride / 上海交通大学学报（医学版）

Objective • To construct a non-alcoholic steatohepatitis (NASH) mouse model by the combination of Western diet (WD) and low-dose carbon tetrachloride (CCl4), and explore the time nodes of typical NASH pathological changes. Methods • Male 8-week C57BL/6 mice were fed WD and intraperitoneally injected with CCl4 at a dose of 2 μL/g of body weight per week to construct NASH models. At different time points, the fasting blood glucose, and the levels of triacylglyceride, glutamic-pyruvic transaminase and glutamic-oxaloacetic transaminase were tested; glucose tolerance was tested at the 24th week. Besides, the liver index was calculated and oil red O staining, Sirius red staining, hematoxylin-eosin staining and TUNEL test were conducted to evaluate liver pathological changes after liver sampling. Results • Between the control group and model group, there was no significant difference in fasting blood glucose and glucose tolerance test result, while the significant differences of liver index were observed at the 8th, 12th and 24th week (P<0.05). And at the 24th week, the levels of triacylglyceride, glutamic-pyruvic transaminase and glutamic-oxaloacetic transaminase were higher in the model group than those in the control group (P<0.05). According to the results of oil red O staining, Sirius red staining, hematoxylin-eosin staining and TUNEL test, in the model group, a large amount of small lipid droplets accumulation in the liver tissues was detected and hepatocytes were mainly in apoptotic state at the 8th week; large lipid droplets, hepatocellular ballooning and spot-like necrosis were observed, and hepatocyte apoptosis persisted at the 16th week; stage 3 fibrosis of liver was observed, and the number of spot-like necrosis increased but lipid droplets decreased, while hepatocytes were mainly in a proliferative state at the 24th week. Conclusion • The mouse model of NASH can be established successfully by WD combined with low-dose CCl4, which can simulate the pathologic features of NASH in a short time.

Hepatic Steatosis, its Complication and Correlation with Risk Factor and Management

Liver detoxifies the various metabolic products inside thebody and converts toxic substance to less toxic by differentphases of detoxification reaction. It play broad-spectrumrole (synthetic, storage, metabolic, protective secretary andExcretory). Sedentary life style, Unhygienic food, adulteratedfood, high dose of alcohol, fatty diet adversely affect the normalfunctioning of liver. Fatty Liver Disease refers to a reversiblecondition in which there is accumulation of triglyceride fatinto intra-cytoplasmic Vacuole. If fatty liver is not treatable attime then it goes to various stages (NAFLD, NASH, Fibrosis,Cirrhosis and Hepatocellular Carcinoma). Diet and aerobicexercise plays an important role in management of Liverdisease. The present article focused on fatty liver disease ismanageable at earlier stage by spreading awareness programamong the individual.

Drug-Induced Fatty Liver

Drug-induced fatty liver disease is defined as the accumulation of fat in the liver due to exposure to some drugs. This condition is callednon-alcoholic fatty liver disease (NAFLD). Fatty liver can be progressed to inflammation called non-alcoholic steatohepatitis or NASH,which can be progressed into fibrosis and eventually liver failure. This condition is frequently associated with long-term intake of thepotentially harmful drug. Differents mechanisms have been postulated to illustrate how these drugs could induce fatty liver. Due to currentlifestyle, the fatty liver rate is increasing, however, some drugs can induce this condition even in non-obese persons. This review focuses ondrug-induced fatty liver and the possible role for some antioxidants in reversing this condition.

Non-alcoholic fatty liver disease associated with hepatocellular carcinoma: An increasing concern

Hepatocellular carcinoma (HCC) is the sixth most common cancer in world and third largest cause of cancer-related deaths. The last few decades have witnessed the emergence of non-viral causes of HCC, the most important being non-alcoholic fatty liver disease (NAFLD). NAFLD ranges from simple steatosis in the absence of excessive alcohol intake to non-alcoholic steatohepatitis (NASH) with or without cirrhosis. About 3-15 per cent of the obese patients with NASH progress to cirrhosis and about 4-27 per cent of NASH with cirrhosis patients transform to HCC. It is also known that HCC can develop de novo in patients with NASH without the presence of cirrhosis. Yearly cumulative incidence of NASH-related HCC is low (2.6%) compared to four per cent of viral-HCC. NAFLD has been associated with risk factors such as metabolic syndrome, insulin resistance, altered gut flora and persistent inflammation. Due to alarming rise in metabolic diseases, both in the developing as well as the developed world, it is expected that the incidence of NAFLD/NASH-HCC would rise manifold in future. No definite guidelines have been drawn for surveillance and management of NAFLD/NASH-associated HCC. It is thus important to discuss the entity of HCC in NAFLD at length with special focus on its epidemiology, risk factors, pathophysiology, diagnosis, clinical presentation and prevention.

Efectos de la cirugia bariátrica en pacientes con esteatohepatitis no alcohólica / Effects of bariatric surgery in patients with nonalcoholic steatohepatitis

La obesidad es el factor que más se asocia a la esteatohepatitis no alcohólica (EHNA). La cirugía bariátrica ha demostrado ser eficaz en la EHNA y junto con el tratamiento de la diabetes mellitus tipo 2 (DMT2) y la dislipidemia, logran una mejoría en las alteraciones de las enzimas hepáticas y de los cambios ecográficos hepáticos. Objetivo: Analizar el efecto de la cirugía bariátrica en pacientes con índice de masa corporal (IMC) ≥ 35 kg/m2 y EHNA. Método: se hizo una investigación retrospectiva de 20 pacientes sometidos a cirugía bariátrica: bypass gástrico en Y de Roux (BPGYR) y gastrectomía vertical (GV) entre 2014 y 2015. Resultados: De los 20 pacientes, 14 fueron intervenidas de BPGYR y 6 de GV; 95% fueron del sexo femenino, con edad promedio de 35,95 ± 8,54 años. Los valores preoperatorios de aspartato aminotransferasa (AST) y alanino aminotransferasa (ALT) de todos los pacientes fue > 30 U/L. Los valores postoperatorios de AST y ALT al año de la cirugía fueron normales en 85% y 80% de los casos respectivamente. No se observaron alteraciones en los niveles pre y postoperatorios de lactato deshidrogenasa (LDH). Todos los pacientes presentaron infiltración grasa hepática moderada la cual se redujo a leve o sin infiltración grasa al año de la cirugía de acuerdo a la evaluación ecográfica. Conclusiones: La cirugía bariátrica demostró tener un impacto favorable en EHNA dado por la mejoría en los niveles de AST, ALT y de la esteatosis hepática corroborada por controles ecográficos(AU)

Obesity is the factor that is most associated with non-alcoholic steatohepatitis (NASH). Bariatric surgery has been shown to be effective in NASH and, along with treatment of type 2 diabetes (T2D) and dyslipidemia, they achieve a significant improvement in liver enzymes and liver ultrasound changes. Objective: To analyze the effect of bariatric surgery in patients with a body mass index (BMI) > 35 kg/m2 and NASH. Method: It was performed a retrospective investigation of 20 patients who underwent bariatric surgery: Roux-en-Y gastric bypass (RYGBP) or sleeve gastrectomy (SG) between 2014 and 2015. Results: Of the 20 patients, 14 underwent BPGYR and 6 GV; 95% were female, with a mean age of 35.95 ± 8.54 years. The preoperative levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) for all patients were >30 U/L. Postoperative levels of AST and ALT one year after surgery were normal in 85% and 80% of cases, respectively. No alterations were observed in pre and postoperative levels of lactate dehydrogenase (LDH). All patients presented moderate hepatic fat infiltration which was reduced to mild or without fat infiltration one year after surgery according to the ultrasonographic evaluation. Conclusions: Bariatric surgery was shown to have a favorable impact on NASH due to the improvement observed in AST and ALT levels, and hepatic steatosis corroborated by ultrasound scans(AU)

Correlation between Non-Alcoholic Fatty Liver Disease and Visceral Adipose Tissue in Non-Obese Chinese Adults: A CT Evaluation

OBJECTIVE: To investigate the correlation between non-alcoholic fatty liver disease and visceral adipose tissue in non-obese Chinese adults using computed tomography (CT). MATERIALS AND METHODS: The study included 454 subjects undergoing abdominal CT scan. Degree of CT attenuation in liver and spleen, and the degree of fat infiltration in liver were evaluated according to three indices: the attenuation value of liver parenchyma (CTLP), the attenuation ratio of liver and spleen (LSratio) and the attenuation difference between liver and spleen (LSdif). Visceral fat area (VFA) and total fat area (TFA) at L2/3 and L4/5 levels were measured, and the abdominal subcutaneous fat area (SFA) was calculated. Bivariate correlation analysis was carried out to determine the correlation among these factors. RESULTS: In men, VFA, SFA and TFA at L2/3 and L4/5 levels showed significant differences in terms of the three indices to distinguish fatty liver from non-fatty liver (all, p < 0.001). In men, all the three indices showed negative correlation with TFA, SFA and VFA (all, p < 0.001). The negative correlation between the three indices and VFA at the L2/3 level was higher than at L4/5 level (r = −0.476 vs. r = −0.340 for CTLP, r = −0.502 vs. r = −0.413 for LSratio, r = −0.543 vs. r = −0.422 for LSdif, p < 0.001, respectively). The negative correlation between LSratio, LSdif and VFA at L2/3 and L4/5 levels was higher than SFA at the corresponding level. In women, all the three indices showed negative correlation with VFA and TFA at L2/3 and L4/5 levels, and the negative correlation between CTLP and VFA was higher at L2/3 level than at L4/5 level (r = −0.294 vs. r = −0.254, p < 0.001). CONCLUSION: In non-obese Chinese adults, the degree of hepatic fatty infiltration showed a strong correlation with abdominal fat on CT. VFA at L2/3 level was more closely related to fatty liver compared with VFA at L4/5 level.

Analysis and Policy Suggestion of Hierarchical Diagnosis and Treatment System Based on Game Theory in China / 中国医院管理

Objective To discuss the dilemma of establishing the hierarchical diagnosis and treatment system in China and the relevant policy recommendations.Method Game theory and Pareto improvement theory can be used to analyze and promote the implementation of the hierarchical diagnosis and treatment system.Results The difficulty of grading diagnosis and treatment lies in the failure to achieve Pareto improvement,that is,patients and the government can save costs in the grading system,but doctors have not been given corresponding incentives,therefore,they are lack of enthusiasm for subsidence.Conclusion The hierarchical diagnosis and treatment system can save the government subsidies for health insurance and medical costs.If the doctor can get part of the costs,they will sink to the grassroots medical institutions,which can realize the Pareto improvement.The order of medical treatment and classification will be formed.

Protective effects of total saponins of Panax japonicas on HepG2 cell apoptosis induced with palmitic acid / 中国中药杂志

This study aimed to investigate the molecular mechanism and protective effect of total saponins of Panax japonicas (TSPJ) on HepG2 cells apoptosis induced by palmitic acid (PA).The HepG2 cells were cultured , and divided into five groups: the control group, the model group, the high-dose group (50 mg·L⁻¹), the middle-dose group (25 mg·L⁻¹) and the low-dose group (12.5 mg·L⁻¹).The cells of the five groups were cultured continuously for 24 hours. The cell viability was measured with MTT. HepG2 cells apoptosis was detected by Hoechest staining and Annexin V-FITC/PI staining. The protein expressions of BCL-2, CHOP and TLR4 were measured with western blotting and flow cytometry analysis. The mRNA expressions of TNF-α, IL-1β, BCL-2, CHOP and GAPDH were measured with RT-PCR. The results suggested that compared with the control group, the number of HepG2 cells of the model group were reduced significantly (<0.01), while the number of apoptotic HepG2 cells were increased. Compared with the model group, the number of HepG2 cells of the high-dose group and the middle-dose group were increased significantly (<0.01), whereas the number of apoptotic HepG2 cells were reduced. Compared with the control group, TNF-α, IL-1β and CHOP mRNA expressions and CHOP and TLR4 protein expressions in the model group were significantly up-regulated (<0.01), while BCL-2 protein and mRNA expressions in the model group were significantly decreased (<0.01). Compared with the model group, TNF-α, IL-1β and CHOP mRNA expressions and CHOP and TLR4 protein expressions in the high-dose group were significantly decreased (<0.01), while BCL-2 protein and mRNA expressions in the high-dose group were significantly up-regulated (<0.01).In conclusion, TSPJ can reduce inflammation and apoptosis induced by palmitic acid, with a certain protective effect on liver cells.

Management Strategies for Liver Fibrosis

Abstract: Liver fibrosis resulting from chronic liver injury are major causes of morbidity and mortality worldwide. Among causes of hepatic fibrosis, viral infection is most common (hepatitis B and C). In addition, obesity rates worldwide have accelerated the risk of liver injury due to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Also liver fibrosis is associated with the consumption of alcohol, or autoimmune hepatitis and chronic cholangiophaties. The response of hepatocytes to inflammation plays a decisive role in the physiopathology of hepatic fibrosis, which involves the recruitment of both pro- and anti-inflammatory cells such as monocytes and macrophages. As well as the production of other cytokines and chemokines, which increase the stimulus of hepatic stellate cells by activating proinflammatory cells. The aim of this review is to identify the therapeutic options available for the treatment of the liver fibrosis, enabling the prevention of progression when is detected in time.

Efecto del extracto purificado rico en antocianinas del fruto del maqui (Aristotelia chilensis) en un modelo experimental de hígado graso no alcohólico / Effect of a purified anthocyanin-rich extract of maqui (Aristotelia chilensis) on experimental model of nonalcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of hepatic lesions, ranging from benign intrahepatic lipid accumulation (steatosis) to progressive non-alcoholic steatohepatitis, in absence of other known secondary causes. Both insulin resistance and oxidative stress have been involved in NAFLD development and progression and, therefore, insulin-sensitizers and/or antioxidants have been targets of different therapeutic agents. Some natural compounds such as Aristotelia chilensis have a high content of polyphenols, which are known for their antioxidant and anti-inflammatory properties. Objective: To assess the effect of a purified anthocyanin-rich extract of maqui (Aristotelia chilensis) on experimental model of NAFLD. Methods: C57BL6 mice were separated in four experimental groups (n = 4-10) and fed a control diet (chow) or a high fat diet (HFD) with or without a purified anthocyanin-rich extract of Aristotelia chilensis (ACnE) (400 mg/kg/day diluted in drinking water). The hepatic effects of HFD were assessed measuring serum levels of glucose and aminotransferases, hepatic histology and triglycerides. Results: HFD diet induced an increase in hepatic triglycerides and histological NAFLD. Administration of ACnE did not affect serum aminotransferases, hepatic triglycerides, liver weight or histological NAFLD. Conclusion: Administration of an ACnE showed no effects on NAFLD in the HFD experimental model.

Introducción: El hígado graso no alcohólico (HGNA) constituye un espectro de lesiones hepáticas, desde la acumulación lipídica intrahepática benigna (esteatosis) hasta la esteatohepatitis no-alcohólica progresiva, en ausencia de causas secundarias conocidas. En el desarrollo y la progresión del HGNA se ha involucrado la resistencia a insulina y el estrés oxidativo y, por lo tanto, insulino-sensibilizantes y antioxidantes han sido blancos de diferentes agentes terapéuticos. Algunos compuestos naturales como la Aristotelia chilensis (maqui) tienen un alto contenido de polifenoles, los que presentan propiedades antiinflamatorias y antioxidantes. Objetivo: Evaluar el efecto de un extracto purificado rico en antocianinas (EACn) del fruto del maqui (Aristotelia chilensis) sobre la esteatosis, en un modelo experimental de HGNA. Métodos: Los ratones fueron distribuidos en 4 grupos (n = 4-10). Dos alimentados con una dieta estándar (grupo control) y dos con una dieta alta en grasa- high fat diet (grupo HFD). Un grupo control y uno HFD recibieron además 400 mg/kg/día de EACn (grupo EACn). Se determinaron los niveles séricos de aminotransferasas y glucosa; se evaluó la histología hepática y el contenido hepático de triglicéridos. Resultados: HFD indujo aumento de triglicéridos hepáticos e HGNA histológico. La administración de EACn no modificó las transaminasas séricas, los triglicéridos hepáticos, el peso del hígado ni el HGNA histológico. Conclusiones: La administración de un EACn no mostró efectos en el modelo experimental de HGNA inducido por una dieta alta en grasa.

Game Analysis of Constraint Mechanism on Excessive Medical Behavior of Doctors in Chinese Medical Market / 中国药房

OBJECTIVE:To investigate the constraint mechanism on excessive medical behavior of doctors in Chinese medical market. METHODS:Under certain assumptions(suppose the hospital and the doctor's demands are consistent,the government and the patient's demands are consistent,etc),mixed game method(game theory)was used to analyze Nash equilibrium between government and doctors,between patients and doctors.The qualitative analysis was performed for these constraints based on the re-ality. RESULTS&CONCLUSIONS:The strict punishing mechanism and the choice right to doctor of patients and public satisfac-tion with the government can achieve the Nash equilibrium of game and effectively inhibit excessive medical behavior. The govern-ment should create a competitive environment to enhance the right of patients to select doctor and improve the relevant legal system on the basis of promoting incentive compatibility among all parties so as to strengthen the implementation of supervision. At the same time,the government should establish credit archives of the doctor to form effective reputation incentive mechanism to doc-tors,and proactively explore the patients participation mechanism based on reducing the cost of patient participation.

Game Analysis of Constraint Mechanism on Excessive Medical Behavior of Doctors in Chinese Medical Market / 中国药房

OBJECTIVE:To investigate the constraint mechanism on excessive medical behavior of doctors in Chinese medical market. METHODS:Under certain assumptions(suppose the hospital and the doctor's demands are consistent,the government and the patient's demands are consistent,etc),mixed game method(game theory)was used to analyze Nash equilibrium between government and doctors,between patients and doctors.The qualitative analysis was performed for these constraints based on the re-ality. RESULTS&CONCLUSIONS:The strict punishing mechanism and the choice right to doctor of patients and public satisfac-tion with the government can achieve the Nash equilibrium of game and effectively inhibit excessive medical behavior. The govern-ment should create a competitive environment to enhance the right of patients to select doctor and improve the relevant legal system on the basis of promoting incentive compatibility among all parties so as to strengthen the implementation of supervision. At the same time,the government should establish credit archives of the doctor to form effective reputation incentive mechanism to doc-tors,and proactively explore the patients participation mechanism based on reducing the cost of patient participation.