Up-regulation of MIC19 promotes growth and metastasis of hepatocellular carcinoma by activating ROS/NF-κB signaling.

BACKGROUND: Mitochondrial malfunction has been well-recognized as a critical step in the pathogenesis of many types of diseases, including cancer. MIC19 is a core a subunit of the MICOS complex that plays a critical role in maintaining the normal function of mitochondria. However, the biological functions of MIC19 in human hepatocellular carcinoma (HCC) remain unclear. METHODS: The expression level of MIC19 in HCC was evaluated by bioinformatics analysis, quantitative real-time PCR and immunohistochemistry staining assays. Cell growth and metastasis experiments were used to assess the biological functions of MIC19 in HCC cells. FINDINGS: MIC19 expression was frequently upregulated in both human HCC specimens and cell lines, and its upregulation is closely associated with patients' survival. Results from loss-of-function and gain-of-function experiments demonstrated that knockdown of MIC19 significantly attenuated, while overexpression of MIC19 enhanced, the proliferation, colony formation, migration and invasion abilities of HCC cells. Mechanistically, we found that MIC19 has no effect on mitochondrial energy production, while activated ROS/NF-κB signaling, which was required for MIC19-promoted HCC growth and metastasis. INTERPRETATION: Our findings suggest that MIC19 play a critical oncogenic role in HCC, implying that MIC19 may serve as a potential therapeutic target in the treatment of HCC.

Activation of peroxymonosulphate using a highly efficient and stable ZnFe2O4 catalyst for tetracycline degradation.

Tetracycline (TC) is a widely used antibiotic that adversely affects ecosystems and, therefore, must be removed from the environment. Owing to their strong ability to oxidise pollutants, including antibiotics, and selectivity for these pollutants, an improved oxidation method based on sulphate radicals (SO4·-) has gained considerable interest. In this study, a novel technique for removing TC was developed by activating peroxymonosulphate (PMS) using a ZnFe2O4 catalyst. Using the co-precipitation method, a ZnFe2O4 catalyst was prepared by doping zinc into iron-based materials, which increased the redox cycle, while PMS was active and facilitated the production of free radicals. According to electron paramagnetic resonance spectroscopy results, a ZnFe2O4 catalyst may activate PMS and generate SO4·-, HO·, O2·-, and 1O2 to eliminate TC. This research offers a new method for creating highly effective heterogeneous catalysts that can activate PMS and destroy antibiotics. The study proposes the following degradation pathways: hydroxylation and ring-opening of TC based on the products identified using ultra-performance liquid chromatography-mass spectrometry. These results illustrated that the prepared ZnFe2O4 catalyst effectively removed TC and exhibited excellent catalytic performance.

Transcriptional investigation of the toxic mechanisms of perfluorooctane sulfonate in rats based on an RNA-Seq approach.

Perfluorooctane sulfonate (PFOS) was widely used in industrial applications before it was listed as a persistent organic pollutant by the Conference of the Parties in the Stockholm Convention in 2009. Although the potential toxicity of PFOS has been studied, its toxic mechanisms remain largely undefined. Here, we investigated novel hub genes and pathways affected by PFOS to gain new conceptions of the toxic mechanisms of PFOS. Reduced body weight gain and abnormal ultra-structures in the liver and kidney tissues were spotted in PFOS-exposed rats, indicating successful establishment of the PFOS-exposed rat model. The transcriptomic alterations of blood samples upon PFOS exposure were analysed using RNA-Seq. GO analysis indicates that the differentially expressed gene-enriched GO terms are related to metabolism, cellular processes, and biological regulation. Kyoto encyclopaedia of gene and genomes (KEGG) and gene set enrichment analysis (GSEA) were conducted to identify six key pathways: spliceosome, B cell receptor signalling pathway, acute myeloid leukaemia, protein processing in the endoplasmic reticulum, NF-kappa B signalling pathway, and Fc gamma R-mediated phagocytosis. The top 10 hub genes were screened from a protein-protein interaction network and verified via quantitative real-time polymerase chain reaction. The overall pathway network and hub genes may provide new insights into the toxic mechanisms of PFOS exposure states.

Intra-tumor heterogeneity and prognostic risk signature for hepatocellular carcinoma based on single-cell analysis.

Intra-tumor heterogeneity poses a serious challenge in the treatment of cancer, including hepatocellular carcinoma (HCC). Recent developments in single-cell RNA sequencing (scRNA-seq) make it possible to examine the heterogeneity of tumor cells. The Gene Expression Omnibus (GEO) database was retrieved to obtain scRNA-seq data of 13 HCC and 8 para cancer samples, and the cells were clustered using FindNeighbors and FindClusters functions. Cell subsets were defined using the "Enricher" function of the clusterProfiler package. Monocle was used to predict cell developmental trajectory. The LIMMA package included in the R program was utilized to detect differentially expressed genes (DEGs) between HCC and paracancerous tissues. Univariate Cox analysis and Least Absolute and Selection Operator (Lasso) Cox regression analysis were conducted to establish a risk assessment model. Thirteen cell subpopulations were identified from the sequencing data of 64,634 single cells. Four cell subgroups (dendritic cells, hepatocytes, liver bud hepatic cells, and liver progenitor cells) in tumor tissues were highly enriched. Between HCC and para cancer tissues, 3024 DEGs were identified, and 641 were specific markers of four cell subgroups. To develop a prognostic risk model, 9 genes among the 641 genes were selected. In the training and validation sets, the model demonstrated a higher 5-year AUC and independently served as a prognostic marker as confirmed by multivariate and univariate Cox analyses. This study revealed the characteristics of different cell subpopulations of immune cells and tumor cells from the HCC microenvironment. We established a novel nine-gene prognostic model to determine the death risk of HCC patients. The discoveries in this research improved the current knowledge of HCC heterogeneity and may inspire future research.

Shift of Glucose Peak Time During Oral Glucose Tolerance Test is Associated with Changes in Insulin Secretion and Insulin Sensitivity After Therapy with Antidiabetic Drugs in Patients with Type 2 Diabetes.

INTRODUCTION: Delay in peak blood glucose during an oral glucose tolerance test (OGTT) predicts declining ß-cell function and poor ability to regulate glucose metabolism. Glucose peak time has not been used as a comparative indicator of the improvement in islet function after treatment with exenatide, insulin, or oral antidiabetic drugs (OADs). We evaluated the efficacy of three types of antidiabetic drugs on the basis of blood glucose peak time in patients with non-newly diagnosed type 2 diabetes. METHODS: The data from 100 patients with diabetes who completed two OGTTs within 6 months were collected. Thirty-seven of them with type 2 diabetes were treated with Humalog Mix25, 28 patients with OADs (metformin, acarbose, and gliclazide), and 35 patients with exenatide. RESULTS: Glycated hemoglobin improved in all three groups after treatment (P < 0.05). Subcutaneous adipose tissue (P < 0.01) and visceral adipose tissue (P < 0.0001) significantly decreased in the exenatide group. The insulinogenic index (IGI) (P = 0.01) and IGI × oral glucose insulin sensitivity (OGIS) (P = 0.01) improved in the exenatide group only. Homeostatic assessment of ß-cell function (HOMA-ß) and OGIS were greater in the exenatide and OAD groups than in the Humalog Mix25 group (all P < 0.05). A shift to an earlier peak was observed in 57.1%, 35.7%, and 27.0% of patients in the exenatide, OAD, and Humalog Mix25 groups, respectively (P = 0.029). OGIS (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.33-0.89, P = 0.026) and IGI × OGIS (OR 1.72, 95% CI 0.44-6.68, P = 0.012) were independently related to shifts in glucose peak time. CONCLUSION: Exenatide, Humalog Mix25, and OADs improved glycemic metabolism. However, exenatide exhibited superior efficacy in shifting blood glucose peak time to an earlier point, while it improved insulin secretion and insulin sensitivity. Hence, the shift of glucose peak time may be considered an indicator for the evaluation of the effect of hypoglycemic drugs.

Serum galectin-3 as a biomarker for screening, early diagnosis, prognosis and therapeutic effect evaluation of pancreatic cancer.

Galectin-3 plays an important role in cell-cell adhesion, macrophage activation, angiogenesis, metastasis and apoptosis and is overexpressed in pancreatic cancer. We explored the importance of galectin-3 in the screening, early diagnosis, prognosis and therapeutic effect evaluation of pancreatic cancer. A time-resolved fluorescence immunoassay was performed to detect serum galectin-3 level. Serum samples were collected from healthy controls and patients with pancreatic cancer before and after different treatments, and the relationships between galectin-3 level and clinical parameters were analysed. Among the healthy controls, one individual with an abnormally high concentration of galectin-3 (9.85 µg/L) was diagnosed with pancreatic cancer. Compared to the pre-operative level, galectin-3 concentration significantly decreased in patients with radical excision 1 month after surgery (P < .05), but showed no obvious change in patients who underwent palliative resection. Additionally, among patients with radical excision, carcinoma recurrence rate was significantly higher in those with increased or unchanged galectin-3 level. Retrospective analysis revealed the extraordinarily high value and high specificity of galectin-3 for predicting 3-year survival (P < .001). Thus, galectin-3 may serve as a potential biomarker for the screening and early diagnosis of pancreatic cancer and as an independent prognostic indicator in patients with pancreatic cancer.

Correlation Between Serum Uric Acid Level and Central Body Fat Distribution in Patients with Type 2 Diabetes.

BACKGROUND: The aim of this study was to investigate the correlation between serum uric acid level and central body fat distribution in patients with type 2 diabetes (T2DM). METHODS: A total of 867 patients with T2DM were enrolled. Measurements of central fat distribution were obtained by dual energy X-ray absorptiometry. Patients were stratified into three groups according to their levels of serum uric acid (SUA). Multiple linear regression analysis was used to determine the association between SUA and central body fat distribution. Logistic regression analysis was used to estimate the risk factors for hyperuricemia (HUA). Mediation analysis was applied to assess the overall, direct, and indirect mediators of SUA levels. RESULTS: Multiple linear regression analysis showed that SUA levels were significantly positively correlated with waist circumference (WC), body mass index (BMI), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), Android fat mass, Gynoid fat mass, fasting c-peptide (F-CP), and area under the curve of C-peptide (P < 0.05 for all). VAT [odds ratio (OR), 2.367; 95% confidence interval (CI), 1.078-5.197; P < 0.001)], WC (OR, 1.041; 95% CI, 1.011-1.072; P < 0.001), high-density lipoprotein (OR, 0.274; 95% CI, 0.104-0.727; P < 0.001), and estimated glomerular filtration rate (OR, 0.966; 95% CI, 0.959-0.973; P < 0.001) were found to be independent risk factors for T2DM patients with HUA. After mediation analysis, BMI and central obesity were found to have different partial effects on the association between SUA and F-CP (P < 0.001). CONCLUSION: In patients with T2DM, HUA was positively correlated with F-CP and central body fat distribution, especially VAT. These results suggest that central obesity may play a role in the positive correlation between HUA and insulin resistance (IR).

Tyrosine hydroxylase expression in CD4(+) T cells is associated with joint inflammatory alleviation in collagen type II-induced arthritis.

We have recently reported that CD4(+) T cells synthesize and secrete catecholamines that facilitate a shift of T helper 1 (Th1)/Th2 balance toward Th2 polarization. In this study, we used an animal model of human rheumatoid arthritis, collagen type II-induced arthritis (CIA), to explore relationship between catecholamine production in CD4(+) T cells and Th1-/Th2-mediated joint inflammation. Histopathological observation of ankle joints of CIA mice displayed an evident inflammatory change on day 35 and a major damage to bones on day 55 post-immunization. Expression of Th1-specific transcription factor, T-bet, and cytokines, IL-2 and IFN-γ, and Th2-specific transcription factor, GATA-3, and cytokines, IL-4 and IL-10, was all upregulated on days 35 and 55 post-immunization, but the elevated Th1 response tended to decrease and the enhanced Th2 response tended to increase with the CIA progression. Expression of tyrosine hydroxylase (TH), a rate-limiting enzyme for synthesis of catecholamines, dramatically increased in ankle joints of CIA mice, although this increase was reduced on day 55 relative to that on day 35 post-immunization. In synovial tissue of CIA ankle joints but not normal joints, CD4-, T-bet-, GATA-3-, and TH-immunoreactive cells were found. Importantly, co-expressed cells with CD4 and TH, T-bet and TH, and GATA-3 and TH were observed in synovial tissue of CIA ankle joints. These results suggest that an increase in catecholamine production occurs in inflamed joints of CIA. The catecholamines are, at least in part, from Th1 and Th2 cells, and they may be related to joint inflammatory alleviation in CIA progression.

The use of vitrification to preserve primary rat hepatocyte monolayer on collagen-coated poly(ethylene-terephthalate) surfaces for a hybrid liver support system.

We developed a scaled-up procedure for vitrifying hepatocytes for hybrid liver support system applications. Hepatocyte monolayer cultured on collagen-coated polyethylene terephthalate (PET) discs constituted the basic module for a hybrid liver support system. Freshly isolated rat hepatocytes were seeded on collagen-coated PET discs with a diameter of 33 mm at a density of 5x10(6) cells per disc, and were cultured for 24 h before cryopreservation. The total duration of procedure starting from exposure to low concentrations of cryoprotectants up to cryostorage is 10 min. Vitrification of the modules was achieved by using two vitrification solutions sequentially with first vitrification solution containing two cryoprotectants, ethylene glycol (EG) and sucrose, while second vitrification solution contained additionally polymer, Ficoll. Direct exposure to liquid nitrogen vapours was followed by immersion into liquid nitrogen. Recovery procedure for vitrified modules included their warming in 1m sucrose at temperature of 38-39 degrees C followed by subsequently washing in sucrose-based solutions of decreased concentration within 15 min at room temperature. Viability, structural characteristics, and functions of cells were preserved by vitrification. Hepatocytes in the post-vitrified and warmed monolayer maintained differentiated hepatocyte characteristics both structurally and functionally. In average, protein synthesis measured as albumin production was 181.00+/-33.46 ng/million cells and 166.10+/-28.11 ng/million cells, for control and vitrified modules respectively. Urea production was, in average, 1.52+/-0.40 ng/million cells and 1.36+/-0.31 ng/million cells for a 7 day culture respectively, with no significant statistical difference between the control and vitrified modules.