The value of the atherogenic index of plasma in non-obese people with non-alcoholic fatty liver disease: a secondary analysis based on a cross-sectional study.

BACKGROUND AND OBJECTIVES: The atherogenic index of plasma (AIP) is elevated in fatty liver disease, but its value in non-obese people with non-alcoholic fatty liver disease (NAFLD) is unclear. This study aimed to investigate the relationship between AIP and NAFLD as well as to determine whether AIP might be used as an indicator of NAFLD in non-obese individuals. METHODS: The present study involved non-obese Chinese and Japanese participants. Risk factors are evaluated using univariate and multivariate analysis. The performance of risk factors was compared according to the area under the receiver operating characteristic curve. RESULTS: In the unadjusted model, the odds ratio (OR) for every 1 standard deviation (SD) increase in AIP was 52.30. In adjusted models I and II, the OR for every 1 SD increase in AIP was 36.57 and 50.84, respectively. The area under the receiver operating characteristic curve for AIP was 0.803 and 0.802 in the development and validation groups, respectively. The best cut-off value of AIP for discrimination between NAFLD and non-NAFLD was 0.005 in the Chinese group and - 0.220 in the Japanese group. CONCLUSIONS: AIP and NAFLD are positively correlated in Chinese and Japanese populations. Therefore, AIP can be used as a new screening indicator for non-obese people with NAFLD in different nations.

Long non-coding RNAs and hepatocellular carcinoma.

Recent advances in next-generation sequencing technology in transcriptome analysis have helped identify numerous non-coding RNAs. The long non-coding RNA (lncRNA) is commonly defined as an RNA molecule with a length of 200 bp-100 kbp that lacks protein-coding potential. LncRNAs play a critical role in the regulation of gene expression, including chromatin modification, transcription and post-transcriptional processing. It has been confirmed that dysregulation of lncRNAs is associated with a number of human diseases, particularly tumors. In this study, we focused on the most extensively investigated lncRNAs in hepatocellular carcinoma (HCC). The biological functions and molecular mechanisms of the majority of lncRNAs have yet to be investigated. The improved knowledge on lncRNAs in HCC may help identify lncRNAs that may be used as novel prognostic markers and therapeutic targets.

Serum peroxiredoxin3 is a useful biomarker for early diagnosis and assessemnt of prognosis of hepatocellular carcinoma in Chinese patients.

BACKGROUND: Recently, peroxiredoxin3 (PRDX3) was identified as a novel molecular marker for the progression of hepatocellular carcinoma (HCC). However, its potential clinical application as a serum marker for the early diagnosis and prognosis of HCC has not been investigated. METHODS: PRDX3, alpha-fetaprotein (AFP), and other biochemical parameters were measured in serum samples from 297 Chinese patients, including 96 with HCC, 98 with liver cirrhosis (LC), and 103 healthy controls (HCs). Correlations between serum PRDX3 expression and clinicopathological variables and the relationship between serum PRDX3 expression and prognosis were analyzed. RESULTS: Serum PRDX3 was significantly higher in HCC patients than in the LC and HC groups. The sensitivity and specificity of serum PRDX3 for the diagnosis of HCC were 85.9% and 75.3%, respectively, at a cutoff of 153.26 ng/mL, and the area under the curve was 0.865. Moreover, serum PRDX3 expression was strongly associated with AFP level, tumor diameter, TNM stage, and portal vein invasion. Kaplan-Meier curve analysis revealed that HCC patients with high serum PRDX3 expression had a shorter median survival time than those with low PRDX3 expression. Moreover, serum PRDX3 expression was an independent risk factor for overall survival. The inverse correlation between serum PRDX3 and patient survival remained significant in patients with early-stage HCC and in those with normal serum AFP levels. CONCLUSIONS: Serum PRDX3 can be used as a noninvasive biomarker for the diagnosis and/or prognosis of HCC.

[Expression of miRNA-29b and its clinical significances in primary hepatic carcinoma].

OBJECTIVE: To explore the clinical value of miRNA-29b expression and the combined detection of serum miRNA-29b and alpha-fetoprotein (AFP) in the diagnosis of primary hepatic carcinoma(PHC). METHODS: From January 2007 to May 2010, the serum levels of miRNA-29b and AFP from 96 healthy controls and 87 PHC patients were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) respectively. The relationship of miRNA-29b and various clinical parameters was analyzed. RESULTS: Serum levels of miRNA-29b in PHC pre-operative group (0.250 (0.124 - 0.381)) significantly decreased versus the control group [0.860 (0.587 - 1.338)] and the post-operative group (0.890 (0.637 - 1.414)) (P < 0.001). Also, the levels of AFP in PHC pre-operative group (65.4 (20.1 - 212.3)) was obviously higher than that in the control group (13.3 (7.1 - 19.8)) and the post-operative group (23.2 (11.6 - 55.7)) (P < 0.001). A lower expression of miRNA-29b was correlated with lower differentiation and higher TNM stages (P < 0.045, P < 0.001). Kaplan-Meier curve analysis revealed that PHC patients with a low serum expression of miRNA-29b had a significantly shortened overall survival when compared with a high serum expression of miRNA-29b (25.52 vs 36.94 months, P = 0.008). Multivariable Cox regression analysis indicated that the serum expression of miRNA-29b was an independent risk factor for overall survival. Relative risk was 0.482 (95% confidence interval: 0.236 - 0.985). The critical values for miRNA-29b and AFP were determined at 0.38 and 23.1 µg/L through the ROC curves. Under the critical value, the sensitivity of miRNA-29b and AFP were 75.9% and 70.1% and the specificity of miRNA-29b and AFP 89.5% and 92.7% respectively. Combined detection could increase the sensitivity up to 87.3%, and achieve a specificity of 88.5%. CONCLUSION: The combined detection of miRNA-29b and AFP aids the diagnosis of PHC and the prediction of its prognosis.

Histone deacetylases inhibitor sodium butyrate inhibits JAK2/STAT signaling through upregulation of SOCS1 and SOCS3 mediated by HDAC8 inhibition in myeloproliferative neoplasms.

Constitutive activation of Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) signaling has an important role in the oncogenesis of myeloproliferative neoplasms (MPNs) and leukemia. Histone deacetylases (HDACs) inhibitors have been reported to possess anticancer activity through different mechanisms. However, whether HDACs inhibitors suppress JAK2/STAT signaling in MPNs is still unknown. In this study, we show that the HDAC inhibitor sodium butyrate (SB) inhibited JAK2/STAT signaling and increased the expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3, both of which are the potent feedback inhibitors of JAK2/STAT signaling. SB upregulated the expression of SOCS1 and SOCS3 by triggering the promoter-associated histone acetylation of SOCS1 and SOCS3 in K562 and HEL cell lines. Importantly, we found that upon knockdown of each class I HDACs, only knockdown of HDAC8 resulted in the increased expression of SOCS1 and SOCS3. Moreover, overexpression of SOCS1 and SOCS3 significantly inhibited cell growth and suppressed JAK2/STAT signaling in K562 and HEL cells. Furthermore, SB increased the transcript levels of SOCS1 and SOCS3 and inhibited the clonogenic activity of hematopoietic progenitors from patients with MPNs. Taken together, these data establish a new anticancer mechanism that SB inhibits JAK2/STAT signaling through HDAC8-mediated upregulation of SOCS1 and SOCS3. Thus, HDACs inhibitors may have therapeutic potential for the treatment of MPNs.

miR-15a and miR-16-1 inhibit the proliferation of leukemic cells by down-regulating WT1 protein level.

BACKGROUND: miR-15a and miR-16-1(miR-15a/16-1) have been implicated as tumor suppressors in chronic lymphocytic leukemia, multiple myeloma, and acute myeloid leukemic cells. However the mechanism of inhibiting the proliferation of leukemic cells is poorly understood. METHODS: K562 and HL-60 cells were transfected with pRS-15/16 or pRS-E, cell growth were measured by CCK-8 assay and direct cell count. Meanwhile WT1 protein and mRNA level were measured by Western blotting and quantitative real-time PCR. RESULTS: In this study we found that over-expression of miR-15a/16-1 significantly inhibited K562 and HL-60 cells proliferation. Enforced expression of miR-15a/16-1 in K562 and HL-60 cells significantly reduced the protein level of WT1 but not affected the mRNA level. However enforced expression of miR-15a/16-1 can not reduce the activity of a luciferase reporter carrying the 3'-untranslated region(3'UTR) of WT1. Silencing of WT1 by specific siRNA suppressed leukemic cells proliferation resembling that of miR-15a/16-1 over-expression. Anti-miR-15a/16-1 oligonucleotides (AMO) reversed the expression of WT1 in K562 and HL-60 cells. Finally, we found a significant inverse correlation between miR-15a or miR-16-1 expression and WT1 protein levels in primary acute myeloid leukemia (AML) blasts and normal controls. CONCLUSIONS: These data suggest that miR-15a/16-1 may function as a tumor suppressor to regulate leukemic cell proliferation potentially by down-regulating the WT1 oncogene. However WT1 is not directly targeted by miR-15a/16-1 through miRNA-mRNA base pairing, therefore more study are required to understand the mechanism by which miR-15a/16-1 downregulate WT1.

Down-regulation of angiotensin II by shRNA reduces collagen synthesis in hepatic stellate cells.

The angiotensin-converting enzyme 2 (ACE-2), angiotensin II type I receptor (ATIR) antagonists and angiotensin-converting enzyme inhibitors (ACEI) were explored to block the renin-angiotensin-aldosterone system (RAAS). The experimental results were still not satisfactory, mainly due to excessive level of angiotensin II (AngII) in gene expression. RNA interference (RNAi) is a mature gene blocking technique, able to block target gene expression efficiently, specifically and continuously. In this study, we observed the effect of short hairpin RNA (shRNA) expression vectors targeting rat AngII on collagen synthesis in hepatic stellate cells (HSCs). According to rat AngII gene sequences, three AngII targeted shRNA expression vectors were designed and constructed. Using liposomes as transfection reagents, they were transfected into HSC-T6 cells. Enzyme digestion confirmed that the transfected shRNA target gene segment was successfully cloned to the vectors. Compared with the control group, AngII mRNA expression examined in shRNA1, shRNA2 and shRNA3 groups was inhibited by about 37, 30 and 61%, respectively. AngII protein expression in all three groups was also reduced by about 21, 24 and 59%, respectively. Furthermore, we revealed that the inhibitory effect exhibited a dose- and time-dependent relationship. In shRNA3 group, TGF-beta1 mRNA expression was reduced by about 51%. The levels of PIIIP, HA and LN were decreased by about 53, 47 and 58%, respectively. In conclusion, shRNA expression vectors targeting rat AngII can decrease collagen synthesis, which would hopefully serve as a foundation for RNAi study of liver fibrosis in vivo.