Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. This malignancy is associated with poor prognosis and high mortality. Novel approaches for prolonging the overall survival of patients with advanced HCC are urgently needed. The antitumor activities of adoptive cell transfer therapy (ACT), such as strategies based on tumor-infiltrating lymphocytes and cytokine-induced killer cells, are more effective than those of traditional strategies. Currently, chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved numerous breakthroughs in the treatment of hematological malignancies, including relapsed or refractory lymphoblastic leukemia and refractory large B-cell lymphoma. Nevertheless, this approach only provides a modest benefit in the treatment of solid tumors. The clinical results of CAR-T immunotherapy for HCC that could be obtained at present are limited. Some published studies have demonstrated that CAR-T could inhibit tumor growth and cause severe side effects. In this review, we summarized the current application of ACT, the challenges encountered by CAR-T technology in HCC treatment, and some possible strategies for the future direction of immunotherapeutic research.
Adoptive Transfer ; methods ; Carcinoma, Hepatocellular ; immunology ; therapy ; Humans ; Immunotherapy, Adoptive ; methods ; Liver Neoplasms ; immunology ; therapy ; Lymphocytes, Tumor-Infiltrating ; cytology ; Randomized Controlled Trials as Topic ; Receptors, Chimeric Antigen ; T-Lymphocytes ; cytology

The aim of this paper was to investigate the molecular mechanism of Calculus Bovis Sativus( CBS) in alleviating lipid accumulation in vitro by serum pharmacology. The CBS-containing serum of mice was obtained by serum pharmacology method to evaluate its effect on the proliferation of LO2 hepatocytes. The lipid reducing effects of CBS-containing serum through Nrf2 was evaluated by fructose-induced LO2 hepatocyte steatosis model,nuclear factor erythroid 2 related factor 2( Nrf2) agonist oltipraz combined intervention,cell oil red O staining and intracellular triglyceride( TG) content. The effects of CBS-containing serum on lipid peroxidation and hepatocytes apoptosis were evaluated by reactive oxygen species( ROS) and apoptosis assay,respectively. Real-time quantitative polymerase chain reaction( PCR) was used to detect the relative expression of lipid synthesis-related genes and apoptosis-related genes.RESULTS:: showed that CBS drug-containing serum had no significant effect on LO2 hepatocyte proliferation. As compared with the model group,CBS-containing serum could effectively reduce the formation of lipid droplets in fructose-induced LO2 hepatocytes,significantly reduce intracellular TG and ROS levels,and significantly reduce hepatocyte apoptosis rate( P < 0. 05). As compared with the model group,carbohydrate responsive element binding protein( ChREBP),sterol regulatory element binding protein-1 c( SREBP-1 c),fatty acid synthase( FAS),acetyl-CoA carboxylase 1( ACC1),stearoyl-CoA desaturase 1( SCD1),Bax and caspase-3 mRNA levels were significantly reduced in CBS drug-containing serum treatment group( P<0. 05). All of the above effects could be reversed by oltipraz.In conclusion,CBS-containing serum can significantly inhibit the fructose-induced LO2 liver fat deposition,and the mechanism may be related to reducing intracellular ROS level through the Nrf2 pathway and improving intracellular peroxidation state to reduce apoptosis.
Animals ; Apoptosis ; Cattle ; Cells, Cultured ; Fatty Liver ; Fructose ; Gallstones ; chemistry ; Hepatocytes ; cytology ; metabolism ; Lipid Metabolism ; Lipid Peroxidation ; Liver ; Medicine, Chinese Traditional ; Mice ; Reactive Oxygen Species ; metabolism ; Serum ; chemistry ; Sterol Regulatory Element Binding Protein 1 ; metabolism ; Triglycerides

The mechanistic target of rapamycin (mTOR) signaling pathway regulates many metabolic and physiological processes in different organs or tissues. Dysregulation of mTOR signaling has been implicated in many human diseases including obesity, diabetes, cancer, fatty liver diseases, and neuronal disorders. Here we review recent progress in understanding how mTORC1 (mTOR complex 1) signaling regulates lipid metabolism in the liver.
Animals ; Humans ; Lipid Metabolism ; Lipogenesis ; Liver ; cytology ; metabolism ; pathology ; Mechanistic Target of Rapamycin Complex 1 ; metabolism ; Signal Transduction

To investigate the effect of ursolic acid on the invasion and migration of hepatocellular carcinoma (HCC) cells co-cultured with macrophages, and to explore the underlying mechanisms.
 Methods: The migration and invasion ability of HCC cells in the co-culture system with or without ursolic acid intervention were evaluated by transwell assay. The levels of epithelial-mesenchymal transition (EMT) markers E-cadherin, N-cadherin, and vimentin in HCC cells co-cultured with macrophages were detected by Western blot.
 Results: The migration and invasion ability and EMT were significantly enhanced when co-cultured with macrophages, and the expression of E-cadherin was significantly increased while N-cadherin and vimentin levels were significantly decreased. However, after ursolic acid treatment, the migration and invasion ability were significantly reduced, and the expression of E-cadherin was increased while N-cadherin and vimentin levels were decreased.
 Conclusion: Ursolic acid exerts inhibitory effect on the ability of migration, invasion, and EMT for HCC, which are enhanced by co-culturing with macrophages.
Cadherins ; genetics ; Carcinoma, Hepatocellular ; pathology ; Cell Line, Tumor ; Cell Movement ; drug effects ; Coculture Techniques ; Epithelial-Mesenchymal Transition ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Liver Neoplasms ; pathology ; Macrophages ; cytology ; Neoplasm Invasiveness ; pathology ; Triterpenes ; pharmacology

OBJECTIVE: To establish a model for predicting the short-term prognosis of patients with HBV-related acute-onchronic liver failure (HBV-ACLF) based on red blood cell distribution width (RDW) and the model for end-stage liver disease (MELD) scores. METHODS: A total of 245 patients with HBV-ACLF were retrospectively analyzed for their clinical data and results of routine hematological tests, liver function, renal function, coagulation test, HBV-DNA, and other indicators at admission. Univariate analysis and binary logistic regression analysis were used to test the short-term risk factors for death of the patients, and the MELD-RDW model was established. The accuracy of each index and the established model was verified using the ROC curve. RESULTS: The surviving patients with HBV-ACLF had significantly decreased RDW (14.97 ± 1.38) and MELD score (23.54±4.35) compared with those in the patients dead within 90 days (17.05±2.92 and 28.95±5.99, respectively). Multivariate analysis indicated that RDW was a significant independent prognostic factor for mortality in patients with HBVACLF (OR=1.840, 95%CI: 1.47902.289, < 0.005). The risk assessment model was [logisticMELD-RDW]=-9.375+0.582×RDW- 0.091×ALB-0.05×PTA+0.186×MELD. The area under the ROC curve of MELD score combined with RDW was 0.878, which was higher than RDW (0.724) and MELD score (0.780) alone. CONCLUSIONS RDW is an independent prognostic indicator for mortality in patients with HBV-ACLF. Compared with MELD score, the risk assessment model based on MELD and RDW has a greater value in predicting the short-term prognosis of patients with HBV-ACLF.
Acute-On-Chronic Liver Failure ; blood ; mortality ; Cell Size ; End Stage Liver Disease ; blood ; mortality ; Erythrocyte Volume ; Erythrocytes ; cytology ; Hepatitis B ; blood ; complications ; mortality ; Humans ; Prognosis ; ROC Curve ; Retrospective Studies

Objective To identify and verify the distribution of Telocytes derived from heterogeneous interstitial cells in the vital organs of ApoE mice.Methods Heart,kidney,and liver tissues were harvested from ApoE adult mice. Immunohistochemical assays were performed by using different immunobiological markers.Results Telocytes were found in these vital organs. The expressions of immunobiological markers differed among different organs. CD34,CD117,and CD28 were positively expressed in Telocytes in cardiac tissue;CD117 and plateled-derived growth factor-Α were negatively expressed in Telocytes in renal tissue;and CD117 and plateled-derived growth factor receptor-Α had negative expression in Telocytes in hepatic tissue. Furthermore,the distribution of Telocytes also differed in the same organ.Conclusions Telocytes exist in the vital organs of ApoE mice,as demonstrated by immunohistochemisty assay. The expressions of immunobiological markers differ among Telocytes in different organs.
Animals ; Antigens, CD34 ; metabolism ; CD28 Antigens ; metabolism ; Kidney ; cytology ; Liver ; cytology ; Mice ; Mice, Knockout, ApoE ; Myocardium ; cytology ; Proto-Oncogene Proteins c-kit ; metabolism ; Telocytes ; cytology

OBJECTIVETo study the effects of Astragalus polysaccharide (APS), the primary effective component of the Chinese herb medicine Astragalus membranaceus (frequently used for its anti-hepatic fibrosis effects), on nanoscale mechanical properties of liver sinusoidal endothelial cells (SECs).

METHODSUsing endothelial cell medium as the control, 5 experimental groups were established utilizing different concentrations of APS, i.e. 12.5, 25, 50, 100, and 200 μg/mL. By using atomic force microscopy along with a microcantilever modified with a silicon dioxide microsphere as powerful tools, the value of Young's modulus in each group was calculated. SAS 9.1 software was applied to analyze the values of Young's modulus at the pressed depth of 300 nm. Environmental scanning electron microscopy was performed to observe the surface microtopography of the SECs.

RESULTSThe value of Young's modulus in each APS experimental group was significantly greater than that of the control group: as APS concentration increased, the value of Young's modulus presented as an increasing trend. The difference between the low-concentration (12.5 and 25 μg/mL) and high-concentration (200 μg/mL) groups was statistically significant (P<0.05), but no significant differences were observed between moderateconcentration (50 and 100 μg/mL) groups versus low- or high-concentration groups (P>0.05). Surface topography demonstrated that APS was capable of increasing the total area of fenestrae.

CONCLUSIONSThe values of Young's modulus increased along with increasing concentrations of APS, suggesting that the stiffness of SECs increases gradually as a function of APS concentration. The observed changes in SEC mechanical properties may provide a new avenue for mechanistic research of anti-hepatic fibrosis treatments in Chinese medicine.

Animals ; Astragalus Plant ; chemistry ; Biomechanical Phenomena ; drug effects ; Elastic Modulus ; Endothelial Cells ; cytology ; ultrastructure ; Liver ; cytology ; Microscopy, Atomic Force ; Microspheres ; Nanotechnology ; Polysaccharides ; pharmacology ; Rats ; Silicon Dioxide ; chemistry ; Surface Properties

BACKGROUND: The interaction between killer immunoglobulin-like receptors (KIRs) and HLA class I regulates natural killer (NK) cell cytotoxicity and function. The impact of NK cell alloreactivity through KIR in liver transplantation remains unelucidated. Since the frequency of HLA-C and KIR genotypes show ethnic differences, we assessed the impact of HLA-C, KIR genotype, or KIR-ligand mismatch on the allograft outcome of Korean liver allografts. METHODS: One hundred eighty-two living donor liver transplant patients were studied. Thirty-five patients (19.2%) had biopsy-confirmed acute rejection (AR), and eighteen (9.9%) had graft failure. The HLA-C compatibility, KIR genotypes, ligand-ligand, and KIR-ligand matching was retrospectively investigated for association with allograft outcomes. RESULTS: Homozygous C1 ligands were predominant in both patients and donors, and frequency of the HLA-C2 allele in Koreans was lower than that in other ethnic groups. Despite the significantly lower frequency of the HLA-C2 genotype in Koreans, donors with at least one HLA-C2 allele showed higher rates of AR than donors with no HLA-C2 alleles (29.2% vs 15.7%, P=0.0423). Although KIR genotypes also showed ethnic differences, KIR genotypes and the number of activating KIR/inhibitory KIR were not associated with the allograft outcome. KIR-ligand mismatch was expected in 31.6% of Korean liver transplants and had no impact on AR or graft survival. CONCLUSIONS: This study could not confirm the clinical impact of KIR genotypes and KIR-ligand mismatch. However, we demonstrated that the presence of HLA-C2 allele in the donor influenced AR of Korean liver allografts.
Adult ; Alleles ; Asian Continental Ancestry Group/*genetics ; Female ; Genotype ; Graft Rejection ; Graft Survival ; HLA-C Antigens/*genetics ; Homozygote ; Humans ; Killer Cells, Natural/cytology/immunology ; Ligands ; *Liver Transplantation ; Male ; Middle Aged ; Proportional Hazards Models ; Receptors, KIR/chemistry/*genetics/metabolism ; Republic of Korea ; Tissue Donors ; Transplantation, Homologous

OBJECTIVETo study the clinicopathologic features of combined hepatocellular-cholangiocarcinoma (cholangiolocellular type, CLC type) with stem cell features and its relationship to hepatic progenitor cells (HPCs).

METHODSClinical and histologic features of 26 cases of combined hepatocellular-cholangiocarcinoma (CLC type) were reviewed. Histochemistry was performed to confirm the type of mucin and immunohistochemical study was carried out for hepatocytic markers (Hep Par-1 and AFP) and biliary/HPCs markers (CK7, CK9, EMA, EpCAM, NCAM, CKIT).

RESULTSThe age of patients ranged from 51 to 82 years (mean 64 years). All 26 cases contained CLC and hepatocellular carcinoma components. CLC area was composed of mixtures of small monotonous glands with abundant fibrous stroma and lymphocytic infiltrate. Tumor cells were cuboidal, smaller in size than normal hepatocytes, with basophilic cytoplasm and round nuclei. All cases, especially at the tumor boundary, showed HCC-like trabecular areas characterized by mildly atypical tumor cells with abundant eosinophilic cytoplasm and little stroma. Out of 26 cases, 21 showed definite glandular formation with mucin production, representing intrahepatic cholangiocarcinoma areas. The three distinct areas showed transitional zones merging with each other. The surrounding liver tissue showed cirrhosis and chronic hepatitis with varying degrees of fibrosis and periportal ductular reaction. Immunohistochemistry showed that biliary/HPC markers (CK7, CK9, EMA, EpCAM, NCAM and CKIT) were strongly positive in CLC area in almost all cases, similar to the staining pattern of ductular reaction. In HCC-like areas, CK7 and CK19 were positive in all cases and the expression rates of EMA, EpCAM, NCAM, CKIT, AFP, Hep Par-1 were 80.8% (21/26), 88.5% (23/26), 84.6% (22/26), 88.5% (23/26), 46.2% (12/26) and 53.8% (14/26) respectively, similar to the staining pattern of intermediate hepatocytes. In ICC areas, CK7, CK9, EMA and EpCAM were positive in all cases without the expression of NCAM and CKIT.

CONCLUSIONThe clinicopathologic findings and immunohistochemical results in this study highly suggest a hepatic progenitor cell origin of combined hepatocellular-cholangiocarcinoma (CLC type).

Bile Duct Neoplasms ; pathology ; Biomarkers ; metabolism ; Carcinoma, Hepatocellular ; pathology ; Cholangiocarcinoma ; pathology ; Hepatocytes ; cytology ; Humans ; Immunohistochemistry ; Liver Cirrhosis ; pathology ; Liver Neoplasms ; pathology ; Mucins ; metabolism ; Stem Cells ; cytology

Vertical sleeve gastrectomy (VSG) is becoming more and more popular among the world. Despite its dramatic efficacy, however, the mechanism of VSG remains largely undetermined. This study aimed to test interferon (IFN)-γ secretion n of mesenteric lymph nodes in obese mice (ob/ob mice), a model of VSG, and its relationship with farnesoid X receptor (FXR) expression in the liver and small intestine, and to investigate the weight loss mechanism of VSG. The wild type (WT) mice and ob/ob mice were divided into four groups: A (WT+Sham), B (WT+VSG), C (ob/ob+Sham), and D (ob/ob+VSG). Body weight values were monitored. The IFN-γ expression in mesenteric lymph nodes of ob/ob mice pre- and post-operation was detected by flow cytometry (FCM). The FXR expression in the liver and small intestine was detected by Western blotting. The mouse AML-12 liver cells were stimulated with IFN-γ at different concentrations in vitro. The changes of FXR expression were also examined. The results showed that the body weight of ob/ob mice was significantly declined from (40.6±2.7) g to (27.5±3.8) g on the 30th day after VSG (P<0.05). At the same time, VSG induced a higher level secretion of IFN-γ in mesenteric lymph nodes of ob/ob mice than that pre-operation (P<0.05). The FXR expression levels in the liver and small intestine after VSG were respectively 0.97±0.07 and 0.84±0.07 fold of GAPDH, which were significantly higher than pre-operative levels of 0.50±0.06 and 0.48±0.06 respectively (P<0.05). After the stimulation of AML-12 liver cells in vitro by different concentrations of IFN-γ (0, 10, 25, 50, 100, and 200 ng/mL), the relative FXR expression levels were 0.22±0.04, 0.31±0.04, 0.39±0.05, 0.38±0.05, 0.56±0.06, and 0.35±0.05, respectively, suggesting IFN-γ could distinctly promote the FXR expression in a dose-dependent manner in comparison to those cells without IFN-γ stimulation (P<0.05). It was concluded that VSG induces a weight loss in ob/ob mice by increasing IFN-γ secretion of mesenteric lymph nodes, which then increases the FXR expression of the liver and small intestine.
Animals ; Body Weight ; Cell Line ; Gastrectomy ; methods ; Gene Expression ; Hepatocytes ; cytology ; drug effects ; metabolism ; Interferon-gamma ; biosynthesis ; pharmacology ; secretion ; Intestine, Small ; drug effects ; metabolism ; Liver ; drug effects ; metabolism ; Lymph Nodes ; drug effects ; metabolism ; Mesentery ; drug effects ; metabolism ; Mice ; Mice, Obese ; Obesity ; metabolism ; pathology ; surgery ; Receptors, Cytoplasmic and Nuclear ; agonists ; genetics ; metabolism ; Weight Loss