Independent markers of nonalcoholic fatty liver disease in a gentrifying population-based Chinese cohort.

BACKGROUND: Prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in developing countries, but its causes are not known. We aimed to ascertain the prevalence and determinants of NAFLD in a new largely unmedicated population-based cohort from the rapidly gentrifying region of Pinggu, China. METHODS: We randomized cluster sampled 4002 Pinggu residents aged 26 to 76 years. Data from 1238 men and 1928 women without significant alcohol drinking or hepatitis virus B or C infection were analysed. NAFLD was defined using a liver-spleen ratio (L/S ratio) ≤1.1 on unenhanced abdominal computed tomography (CT) scanning. RESULTS: Of men and women, 26.5% and 20.1%, respectively, had NAFLD. NAFLD prevalence was highest in younger men and older women. In multivariate logistic regression models, higher body mass index, waist circumference, serum triglyceride, alanine transaminase, and haemoglobin A1c independently increased the odds of NAFLD in both men and women separately. Higher annual household income and systolic blood pressure for men and higher serum uric acid and red meat intake and lower physical activity levels for women also independently associated with higher odds of NAFLD. Individuals with L/S ratio ≤1.1 had linearly increasing rates of obesity, diabetes, and metabolic syndrome that paralleled fatty liver increase. CONCLUSIONS: NAFLD is common in a gentrifying Chinese population particularly in younger men of high socioeconomic status and older women with sedentary behaviour who eat red meat. Demographic factors add independent risk of NAFLD above traditional metabolic risk factors. A CT L/S ratio of ≤1.1 identifies individuals at high risk of metabolic disease.

Determination of chromium(III) in aqueous solution using CePO4 :Tb(3+) nanocrystals in a fluorescence resonance energy transfer system.

Trivalent chromium is an essential element required for normal carbohydrate, lipid and protein metabolism in humans and animals. This article describes an efficient fluorescence resonance energy transfer (FRET) system between CePO4 :Tb(3+) nanocrystals as the donor and chromium(III) as the acceptor. CePO4 :Tb(3+) nanocrystals were synthesized in aqueous solution, and characterized by transmission electron microscopy. Under optimum conditions, a linear calibration graph was obtained (R(2) = 0.996). The linear range and detection limit of chromium(III) were 0.01-2.2 µM, and 9.1 nM, respectively. The proposed method had a wide linear range and proved to be very sensitive, rapid and simple. Moreover, the method was applied successfully to the determination of chromium(III) in synthetic samples and tap water.

Codelivery of HBx-siRNA and Plasmid Encoding IL-12 for Inhibition of Hepatitis B Virus and Reactivation of Antiviral Immunity.

Chronic hepatitis B is a critical cause of many serious liver diseases such as hepatocellular carcinoma (HCC). The main challenges in hepatitis B treatment include the rebound of hepatitis B virus (HBV)-related antigen levels after drug withdrawal and the immunosuppression caused by the virus. Herein, we demonstrate that the HBV-related antigen can be effectively inhibited and antiviral immunity can be successfully reactivated through codelivery of the small interfering RNA (siRNA) targeting HBV X protein (HBx) and the plasmid encoding interleukin 12 (pIL-12) to hepatocytes and immune cells. After being treated by the siRNA/pIL-12 codelivery system, HBx mRNA and hepatitis B surface antigen (HBsAg) are dramatically reduced in HepG2.215 cells. More importantly, the downregulated CD47 and programmed death ligand 1 (PD-L1) and the upregulated interferon-ß promoter stimulator-1 (IPS-1), retinoic acid-inducible gene-1 (RIG-1), CD80, and human leukocyte antigen-1 (HLA-1) in treated HepG2.215 cells indicate that the immunosuppression is reversed by the codelivery system. Furthermore, the codelivery system results in inhibition of extracellular regulated protein kinases (ERK) and phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) pathways, as well as downregulation of B-cell lymphoma-2 (Bcl-2) and upregulation of p53, implying its potential in preventing the progression of HBV-induced HCC. In addition, J774A.1 macrophages treated by the codelivery system were successfully differentiated into the M1 phenotype and expressed enhanced cytokines with anti-hepatitis B effects such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α). Therefore, we believe that codelivery of siRNA and pIL-12 can effectively inhibit hepatitis B virus, reverse virus-induced immunosuppression, reactivate antiviral immunity, and hinder the progression of HBV-induced hepatocellular carcinoma. This investigation provides a promising approach for the synergistic treatment of HBV infection.

Multifunctionalized Protein-Based Drug Delivery System for Inhibition of Tumor Growth and Progression.

To improve the bioavailability of hydrophobic drugs and realize tumor targeting therapeutic actions efficiently, a nanosized multifunctional protein-based drug delivery system was constructed by self-assembly in a facile manner. Negatively charged cRGD-conjugated bovine serum albumin (cRGD-BSA) loaded with a hydrophobic antitumor drug (curcumin, CUR) was complexed with electropositive protamine sulfate (PS) via electroattractive forces to form CUR@cRGD-BSA/PS nanoparticles. Flow cytometry and confocal microscopy show that the multifunctional CUR@cRGD-BSA/PS nanoparticles lead to significantly increased intracellular drug accumulation in tumor cells owing to the tumor specific affinity of cRGD ligands as well as the membrane translocating property of PS. As a result, the multifunctional protein-based delivery system (CUR@cRGD-BSA/PS) exhibits an apparently enhanced inhibitory efficiency on malignant cells as compared with free CUR and the monofunctional delivery system (CUR@cRGD-BSA). More importantly, the expression of proteins (Bcl-2, cyclin D1, ß-catenin, c-Myc, and MMP-9) involved in cancer development in the tumor cells treated by CUR@cRGD-BSA/PS is dramatically downregulated, implying the functional protein-based drug delivery system can effectively prevent tumor progression. Our investigation gives insight into the construction of multifunctional protein-based delivery carriers for tumor targeting delivery of hydrophobic drugs.

Mutations in the P10 region of procaspase-8 lead to chemotherapy resistance in acute myeloid leukemia by impairing procaspase-8 dimerization.

Caspase-8 activation initiates apoptotic signaling cascades, and certain mutations in procasepase-8 have been reported to be associated with the progression and prognosis of different types of tumors. In this study, we have identified four novel mutations, which are highly correlated with chemotherapy resistance and poor prognosis of acute myeloid leukemia (AML) patients, within the P10 subunit of procaspase-8. These newly discovered mutations cause premature termination of translation, resulting in truncated procaspase-8 protein, which is incapable of forming dimer to initiate apoptosis signaling pathway. Further biochemical analysis reveals that the segment of P10 subunit of procaspase-8 consisting of three amino acid residues from L491 to F493 is crucial for the formation of procaspase-8 interdimer, and the aberration of this segment disrupts the dimerization and consequently precludes the activation of caspase-8 and downstream apoptotic signaling pathway. Therefore, the patients with AML who bear these types of P10 mutations were more likely to develop chemotherapy resistance due to impaired apoptotic signaling in cellular system, leading to significantly reduced overall survival (OS) as compared with patients carrying no such types of P10 mutations. Taken together, these newly identified P10 mutations in procaspase-8 could be used as novel biomarkers for predicting response and survival of chemotherapy-treated AML patients, as well as potential therapeutic targets for medical intervention in the future.