Amelioration of hepatic steatosis is associated with modulation of gut microbiota and suppression of hepatic miR-34a in Gynostemma pentaphylla (Thunb.) Makino treated mice.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a chronic and progressive liver disease with an increased risk of morbidity and mortality. However, so far no specific pharmacotherapy has been approved. Gynostemma pentaphylla (Thunb.) Makino (GP) is a traditional Chinese medicine that is widely used against hyperlipemia as well as hyperglycemia. This study aims to evaluate the effect of GP on NAFLD and explore the possible mechanism. METHODS: High-fat-diet induced NAFLD mice model were orally administrated with GP at dose of 11.7 g/kg or equivalent volume of distilled water once a day for 16 weeks. Body weight, food intake and energy expenditure were assessed to evaluate the general condition of mice. The triglycerides, total cholesterol content in the liver and liver histopathology, serum lipid profile and serum insulin level, fecal microbiome, hepatic microRNAs and relative target genes were analyzed. RESULTS: Mice in GP treatment group displayed improved hepatic triglycerides content with lower lipid droplet in hepatocyte and NAFLD activity score. Besides, GP treatment altered the composition of gut microbiota and the relative abundance of some of the key components that are implicated in metabolic disorders, especially phylum Firmicutes (Eubacterium, Blautia, Clostridium and Lactobacillus). Several hepatic microRNAs were downregulated by GP treatment such as miR-130a, miR-34a, miR-29a, miR-199a, among which the expression miR-34a was altered by more than four-fold compared to that of HFD group (3:14). The correlation analysis showed that miR-34a was strongly related to the change of gut microbiota especially phylum Firmicutes (R = 0.796). Additionally, the target genes of miR-34a (HNF4α, PPARα and PPARα) were restored by GP both in mRNA and protein levels. CONCLUSION: Our results suggested that GP modulated the gut microbiota and suppressed hepatic miR-34a, which was associated with the amelioration of hepatic steatosis.

HCRP1, ID4 and Glypican-3: an optimal panel of biomarkers for diagnosis of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with high morbidity and mortality. The aim of this study was to assess the diagnostic role of HCC related protein 1 (HCRP1) and inhibitor of DNA Binding 4 (ID4) as novel reliable markers for HCC diagnosis. METHODS: Immunohistochemistry for HCRP1, ID4 and Glypican-3 (GPC-3) was performed in 98 cases of HCCs, 15 large regenerative nodules arising in cirrhotic livers, 12 hepatocellular adenomas (HCA), 10 focal nodular hyperplasias (FNH), and 20 specimens of normal liver tissues (NL). RESULTS: HCRP1 immunoactivity was decreased in 64 of 98 (65.3%) HCC cases but present in almost all of the benign liver nodules (56/57, 98.2%, P < 0.001). 68 of 98 (69.4%) and 70 of 98 (71.4%) HCC cases were positive for ID4 and GPC-3, respectively, which were much higher than in benign lesions. Even though HCRP1 is highly specific (98.25%) in differentiating well differentiated HCC (WDHCC) from benign liver nodules, it has only a limited value because of its low sensitivity (37.5%), neither for the ID4, GPC-3 alone or combination (P > 0.05). The expression of HCRP1 alone could efficiently distinguish WDHCC from moderate-poorly differentiated HCC (M-PHCC), and the combination of using either two or three markers could notably increase the diagnosis accuracy (P < 0.05). CONCLUSION: HCRP1 and ID4 represent potentially novel valuable biomarkers for distinguishing HCC from benign liver nodules, and it is recommended to use the combination of HCRP1, ID4 and GPC-3 as a panel in HCC differentiation estimation.

Downregulation of esophageal cancer-related gene 4 promotes proliferation and migration of hepatocellular carcinoma.

Esophageal cancer-related gene 4 (ECRG4) is a candidate tumor suppressor gene, which is involved in cell apoptosis, migration, infection and inflammation responsiveness; however, its expression level and clinical significance in hepatocellular carcinoma (HCC) remains unclear. In the present study, the authors aim to evaluate the clinical significance and potential role of ECRG4 in HCC. Level of ECRG4 protein expression in HCC and peripheral tissues was investigated in tissue specimens obtained from 56 consecutive HCC patients by immunohistochemistry. Cell proliferation, cell migration and invasion regulations were examined by MTT curves, flow cytometry, Transwell assays and western blotting. ECRG4 expression was weak positive in normal liver cells but was downregulated in HCC cells in vivo or in vitro. A decreased expression of ECRG4 was associated with the age of the patients, metastasis and Ki-67 proliferation index. However, decreased ECRG4 expression was not associated with differentiation, tumor size, the presence of portal vein tumor thrombosis, satellite lesions, tumor relapse or mortality. Further investigations revealed that ectopic expression of ECRG4 inhibited cell proliferation, migration and invasion and promoted cell apoptosis in SMMC-7721 cells, which was mediated by the regulation of BAX and B cell lymphoma-2, in addition to the upregulation of epithelial-mesenchymal transition markers. In conclusion, the results of the present study indicated that ECRG4 was downregulated in HCC and served important roles in promoting cell proliferation and migration.

Natural history of mild subclinical hypothyroidism in a middle-aged and elderly Chinese population: a prospective study.

Subclinical hypothyroidism (SCH) has a high global prevalence. Most SCH patients have mild cases (thyrotropin ≤10 mIU/L). Treatment recommendations for mild SCH are controversial, which raises concerns about the natural history of mild SCH. We aimed to clarify the natural history of mild SCH. This is a prospective population-based study. We measured thyroid function in 11,000 participants in the REACTION study and followed 505 newly diagnosed mild SCH patients aged 40-years or older between 2011 and 2014. Logistic regression analysis was used to seek baseline parameters associated with the natural outcomes of mild SCH. Among 505 mild SCH patients, 221 (43.8%) had persistent SCH, 251 (49.7%) reverted to euthyroidism, and 17 (3.4%) progressed to overt hypothyroidism (OH). Patients with higher baseline total cholesterol (TC, between 201.0-240.0 mg/dL or >240.0 mg/dL vs. <201.0 mg/dL, p = 0.048 and 0.006, respectively) or positive thyroid peroxidase antibodies (TPOAb, p = 0.009) had higher risks of progression to OH, while those with higher baseline creatinine (CR, between 0.71-0.80 mg/dL or >0.80 mg/dL vs. ≤0.65 mg/dL, p = 0.031 and 0.004, respectively), higher baseline thyrotropin (≥7 mIU/L, p < 0.001) or older (>60 years vs. ≤50 years, p = 0.012) had lower odds of reverting to euthyroidism. In conclusion, TPOAb and TC seem to be more important predictors of progression to OH than initial thyrotropin, whereas high baseline thyrotropin or CR were negative correlated with reversion to euthyroidism. The prognostic value of TC and CR in mild SCH should be considered.

HCRP1 downregulation promotes hepatocellular carcinoma cell migration and invasion through the induction of EGFR activation and epithelial-mesenchymal transition.

Hepatocellular carcinoma related protein 1 (HCRP1), which is essential for internalization and degradation of ubiquitinated membrane receptors, is downregulated in several tumors and strongly affects the outcomes of cancer patients. It is reported the expression of HCRP1 is inversely related to epidermal growth factor receptor (EGFR) in breast cancer and lead to resistance to cetuximab in ovarian cancer. However, its exact mechanism in the progression of Hepatocellular carcinoma (HCC) remains unknown. Herein, HCRP1 expression and its clinical significance were examined in 101 HCC patients using immunohistochemistry. Cell proliferation, migration and invasion assays were conducted in HCC cell lines. EGFR activation and degradation were then observed after EGF inducing in HCRP1 knockdown HepG2 cells. In addition, we also detected whether epithelial-to-mesenchymal transition (EMT) was involved in the malignancy promoted by HCRP1. The results showed that 59 of the 101 HCC cases exhibited downregulation of HCRP1 expression (P<0.01) as compared to 30 benign liver lesions and 20 normal liver tissues, all of which showed a high level of HCRP1. HCRP1 expression was significantly related to age (P=0.017), pathological grade (P=0.003), tumor encapsulation (P=0.037), recurrence (P=0.039) and death (P=0.015), but unrelated to cirrhosis (P=0.216), tumor size (P=0.273), and distant metastasis (P=0.554). Lower HCRP1 expression was correlated with shorter RFS and OS (P<0.001), and decreased HCRP1 level is an independent prognostic marker in HCC patients (P<0.05). Overexpression of HCRP1 decreased and knockdown increased HCC cell proliferation, migration and invasion. HCRP1 depletion increased EGFR activation and inhibited EGFR degradation. EMT phenotype was promoted after HCRP1 downregulation via increase of Snail and Twist1 and activation of Akt phosphorylation in HepG2 cells. Conversely, upregulation of HCRP1 in SMMC-7721 cells led to the opposite effect. In conclusion, our study indicated that downregulation of HCRP1 is a valuable prognostic factor involved in EGFR regulation and acquisition of the mesenchymal phenotype of HCC cells.

Intercellular adhesion molecule 1 is a sensitive and diagnostically useful immunohistochemical marker of papillary thyroid cancer (PTC) and of PTC-like nuclear alterations in Hashimoto's thyroiditis.

Intercellular adhesion molecule 1 (ICAM-1) is important in the progression of inflammatory responses. Recently, increased levels of ICAM-1 have been reported in a number of types of malignancy. The present study aimed to investigate ICAM-1 expression in papillary thyroid cancer (PTC) and in Hashimoto's thyroiditis (HT) with PTC-like nuclear alterations, and to assess the predictive value of ICAM-1 in thyroid lesions. ICAM-1 expression was retrospectively investigated in 132 consecutive cases of PTC, 72 cases of HT, 10 of follicular cancer, 15 of follicular adenoma, 16 of nodular goiter and 8 samples of normal thyroid tissue using immunohistochemical analyses, and in 42 PTC patients using western blotting. ICAM-1 expression was not detected in normal follicular cells, follicular lesions (adenoma and cancer) and benign nodular hyperplasia, but was frequently overexpressed in PTC cells. ICAM-1 overexpression was associated with extra-thyroidal invasion and lymph node metastasis; no association was found with age, gender, tumor size, multifocality, pathological stage, recurrence or distant metastasis. ICAM-1 expression in HT patients with PTC-like nuclear alterations was significantly higher than that in HT cases with non-PTC-like features. Compared with antibodies against cytokeratin 19, galectin-3 and Hector Battifora mesothelial-1, ICAM-1 was the most sensitive marker for the detection of PTC-like features in HT. These findings demonstrate that ICAM-1 expression is upregulated in PTC and in HT with PTC-like nuclear alterations. This feature may be an important factor in the progression of cancer of the thyroid gland.

Genetic Association Between CDKN1B rs2066827 Polymorphism and Susceptibility to Cancer.

Much attention has been directed to the association between cancer risk and rs2066827 polymorphism of the CDKN1B gene. However, the results are indefinitive and inconclusive. This study was devised to evaluate the hypothesis that rs2066827 polymorphism is associated with the risk of cancer.Computer-based databases (EMBASE, PubMed, and CNKI) were used to seek all case-control studies evaluating rs2066827 polymorphism and susceptibility to cancer. The genetic risk was assessed by calculating pooled odds ratio (OR) with its corresponding 95% confidence interval (CI). Fixed-effects pooled ORs were calculated by the Mantel-Haenszel method (Ph > 0.05), and random-effects pooled ORs were estimated by the DerSimonian-Laird method (Ph < 0.05).Data on rs2066827 polymorphism and cancer risk were available for 9038 cancer cases and 11,596 controls participating in 17 studies. Carriage of a TG genotype was associated with a minor but significant decrease in the risk of cancer (pooled OR 0.92, 95% CI: 0.86-0.99; model, TG vs. TT). We observed a moderately decreased risk of ovarian cancer based on 1829 cases and 2868 controls (pooled OR 0.85, 95% CI: 0.74-0.97; model, TG vs. TT). A slightly deceased risk of cancer was also indicated in Caucasians consisting of 6707 cases and 8279 controls (pooled OR 0.91, 95% CI: 0.85-0.98; model, TG vs. TT).These data suggest that carriage of a TG genotype at rs2066827 polymorphism may be associated with decreased susceptibility to cancer, ovarian cancer in particular.

Role of scavenger receptors in dendritic cell function.

Dendritic cells (DCs), the most potent of the antigen-presenting cells, are crucial in initiating and shaping innate and adaptive immune responses. DCs discriminate unmodified self antigens from non-self and altered/modified self antigens via a large family of receptors called pattern-recognition receptors, which include Toll-like receptors and scavenger receptors (SRs). Recent findings underscore the critical role of SRs on DCs in pathogen clearance, atherosclerosis, apoptotic cell recognition, diesel exhaust particle recognition, etc. These new findings present SRs as an unexplored therapeutic target that warrants further basic and applied research, and have implications for vaccine development. This review highlights recent insights into the emerging role of these receptors in DC-mediated immune responses.