Tissue inhibitor of metalloproteinase-3 expression affects clinicopathological features and prognosis of aflatoxin B1-related hepatocellular carcinoma.

BACKGROUND: The dysregulation of tissue inhibitor of metalloproteinase-3 (TIMP3) was positively correlated with the progression of hepatocellular carcinoma (HCC). However, it is not clear whether TIMP3 expression is associated with the clinicopathological features and prognosis of aflatoxin B1 (AFB1)-related HCC (AHCC). AIM: To assess the effects of TIMP3 expression on the clinicopathological features and prognosis of AHCC. METHODS: A retrospective study, including 182 patients with AHCC, was conducted to explore the link between TIMP3 expression in cancerous tissues and the clinicopathological characteristics and prognosis of AHCC. TIMP3 expression was detected by immunohistochemistry and its effects on the clinicopathological features and prognosis of AHCC were evaluated by Kaplan-Meier survival analysis and Cox regression survival analysis. Odds ratio, hazard ratio (HR), median overall survival time (MST), median tumor recurrence-free survival time (MRT), and corresponding 95% confidential interval (CI) was calculated to evaluate the potential of TIMP3 expression in predicting AHCC prognosis. RESULTS: Kaplan-Meier survival analysis showed that compared with high TIMP3 expression, low TIMP3 expression in tumor tissues significantly decreased the MST (36.00 mo vs 18.00 mo) and MRT (32.00 mo vs 16 mo) of patients with AHCC. Multivariate Cox regression survival analysis further proved that decreased expression of TIMP3 increased the risk of death (HR = 2.85, 95%CI: 2.04-4.00) and tumor recurrence (HR = 2.26, 95%CI: 1.57-3.26). Furthermore, decreased expression of TIMP3 protein in tissues with AHCC was significantly correlated with tumor clinicopathological features, such as tumor size, tumor grade and stage, tumor microvessel density, and tumor blood invasion. Additionally, TIMP3 protein expression was also negatively associated with amount of AFB1-DNA adducts in tumor tissues. CONCLUSION: These findings indicate that the dysregulation of TIMP3 expression is related to AHCC biological behaviors and affects tumor outcome, suggesting that TIMP3 may act as a prognostic biomarker for AHCC.

In situ quantitative analysis by ultrasonic extraction and nebulization combined with hydrogen flame ionization mass spectrometry: Diisopropylnaphthalene (DIPN), a marker of recycled paper in packing materials.

Ambient mass spectrometry is used for direct analysis and high-throughput screening in many fields. However, most researches are about qualitative analysis. Quantitative detection based on AMS only performs on standard compounds and the relative standard deviation is so large that the accuracy of the result is low. In this study, a hydrogen flame ion source with ultrasonic nebulizer as sampling unit was established to enable solid samples to extract, nebulize and quantitatively detect in situ, with high sensitivity. This device was used to quantificationally determine the content of diisopropylnaphthalene (DIPN) in food packaging paper to identify recycled paper. Rapid analysis was performed in situ without complex pretreatment and the whole analysis time was less than 10 min. It's environmentally friendly that only 100 mg (or less) of sample and no more than 1 mL of solvent are required for one test. The external standard method was used for quantitative determination. The limit of detection was measured to be as low as 0.01 ng mL-1 and the linear dynamic range was 0.03-0.60 µg mL-1 in positive multiple reactions monitoring mode. It has been successfully applied to detect actual samples and the content of DIPN was 0.020-0.095 mg kg-1.

Chrysene, a four-ring polycyclic aromatic hydrocarbon, induces hepatotoxicity in mice by activation of the aryl hydrocarbon receptor (AhR).

Polycyclic aromatic hydrocarbons (PAHs) are a group of persistent organic global environmental pollutants and cause harmful effects on human health. Here, we evaluated adverse effects of chrysene, which is a four-ring PAH and an important member of 16 priority PAHs, on the liver. Chrysene was detected in some common raw and cooked Chinese food samples. Hepatotoxicity including increased relative liver weight, hepatocyte swelling and degeneration, and elevated serum alanine aminotransferase (ALT) levels were observed in chrysene-exposed C57BL/6 mice. Glutamine treatment effectively ameliorated chrysene-induced mice liver injury by decreasing serum ALT levels. Chrysene induced mice hepatic glutathione depletion and oxidative DNA damage with increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. Hepatic expression levels of the aryl hydrocarbon receptor (AhR), AhR-related target genes including CYP1A1, CYP1A2 and CYP1B1, and AhR nuclear translocator (ARNT) were significantly increased in chrysene-exposed C57BL/6 mice. Chrysene induced mice hepatic mRNA levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-mediated phase II detoxifying and antioxidant enzymes including NQO1, UGT1A1, UGT1A6, SULT1A1, GSTm1, GSTm3, Catalase (CAT), GPx1, and SOD2. We found that chrysene had toxic effects including increased relative liver weight and elevated serum ALT levels on AhR+/+ mice but not AhR-/- mice. Chrysene significantly induced hepatic mRNA levels of CYP1A1 and CYP1A2 in AhR+/+ mice but not AhR-/- mice. To our knowledge, this study is the first to demonstrate that hepatotoxicity causes by chrysene is dependent on AhR, and Nrf2 plays an important regulation role in protection against oxidative liver injury induced by chrysene.

Palladium-Catalyzed Regioselective Olefination of O-Acetyl Cyanohydrins.

A practical palladium-catalyzed ortho-olefination of O-acetyl cyanohydrins assisted by synergetic directing groups has been developed. Thus, a range of olefinated O-acetyl cyanohydrins were synthesized in moderate to good yields. The reaction occurs efficiently with high regioselectivity and with a satisfactory tolerance of functional groups.

Copper-Catalyzed Dehydrogenative Diels-Alder Reaction.

A practical and effective copper-catalyzed dehydrogenative Diels-Alder reaction of gem-diesters and ketone with dienes has been established. The active dienophiles were generated in situ via a radical-based dehydrogenation process, which reacted with a wide variety of dienes to afford various polysubstituted cyclohexene derivatives in good to excellent yields.

Palladium-catalyzed silaborative carbocyclizations of 1,6-diynes.

An addition/cyclization reaction of 1,6-diynes was developed for the synthesis of highly substituted 1,2-dialkylidenecycloalkanes. In this work, 1,6-diynes reacted with (dimethylphenylsilyl)pinacol-borane in the presence of a palladium catalyst to afford 1,2-dialkylidenecycloalkanes bearing silyl and boryl groups with a (Z,Z)-configuration in good to excellent yields. Moreover, the corresponding products could be easily converted into other synthetically useful compounds. This protocol provides an efficient and practical method of heteroelement-element linkage addition to the unsaturated 1,6-diynes.

Chelation versus Non-Chelation Control in the Stereoselective Alkenyl sp2 C-H Bond Functionalization Reaction.

A hydroxy group chelation-assisted stereospecific oxidative cross-coupling reaction between alkenes was developed under mild reaction conditions. In the presence of palladium catalyst, the alkenes tethered with hydroxy functionality can couple efficiently with electron-deficient alkenes to form the corresponding multi-substituted olefin products. The hydroxy group on the substrate could play dual roles in reaction, acting as the directing group for alkenyl C-H bond activation and controlling the stereoselectivity of the products.

Palladium-Catalyzed Direct Intramolecular C-N Bond Formation: Access to Multisubstituted Dihydropyrroles.

A palladium-catalyzed intramolecular amination of alkenes with retention of olefin functionalization was achieved under mild reaction conditions. In the presence of palladium catalyst, the tosyl-protected amine can directly couple with a double bond to provide versatile dihydropyrrole derivatives in moderate to excellent yields.

Palladium-catalyzed difunctionalization of internal alkynes via highly regioselective 6-endo cyclization and alkenylation of enynoates: synthesis of multisubstituted pyrones.

An efficient Pd(II)-catalyzed difunctionalization reaction of internal alkynes is reported. In this reaction, various enynoates and electron-deficient alkenes were used for the syntheses of useful highly substituted pyrone derivatives via a 6-endo cyclization and subsequent alkenylation pathway. The corresponding products could be obtained in moderate to good yields under very mild reaction conditions. The high regioselectivity and wide compatibility with different functional groups found in the desired products demonstrate this method to be a general and useful tool for the synthesis of highly substituted pyrone derivatives.

Addition of optically pure H-phosphinate to ketones: selectivity, stereochemistry and mechanism.

Aromatic methyl ketones and cyclic asymmetric ketones underwent hydrophosphorylation with P-stereogenic H-P species in the presence of potassium carbonate to produce P,C-stereogenic tertiary α-hydroxyl phosphinates in excellent yields with up to 99 : 1 dr. The diastereoselectivity was induced by a reversible conversion of less stable stereomer of product to that of a more stable one via an equilibrium, which was confirmed by aldehyde/ketone exchanging reaction. Toward the exchange, aliphatic or aldehyde carbonyl were more active than aromatic or ketone carbonyls, respectively. The stability difference between the two diastereomers was controlled by the sizes of substituents linking to phosphorus or α-carbon.