Excessive exposure to polycyclic aromatic hydrocarbons (PAHs) often results in lung cancer, a disease with the highest cancer mortality in the United States. After entry into the lung, PAHs induce phase I metabolic enzymes such as cytochrome P450 (CYP) monooxygenases, i.e. CYP1A1/2 and 1B1, and phase II enzymes such as glutathione S-transferases, UDP glucuronyl transferases, NADPH quinone oxidoreductases (NQOs), aldo-keto reductases (AKRs), and epoxide hydrolases (EHs), via the aryl hydrocarbon receptor (AhR)-dependent and independent pathways. Humans can also be exposed to PAHs through diet, via consumption of charcoal broiled foods. Metabolism of PAHs through the CYP1A1/1B1/EH pathway, CYP peroxidase pathway, and AKR pathway leads to the formation of the active carcinogens diol-epoxides, radical cations, and o-quinones. These reactive metabolites produce DNA adducts, resulting in DNA mutations, alteration of gene expression profiles, and tumorigenesis. Mutations in xenobiotic metabolic enzymes, as well as polymorphisms of tumor suppressor genes (e.g. p53) and/or genes involved in gene expression (e.g. X-ray repair cross-complementing proteins), are associated with lung cancer susceptibility in human populations from different ethnicities, gender, and age groups. Although various metabolic activation/inactivation pathways, AhR signaling, and genetic susceptibilities contribute to lung cancer, the precise points at which PAHs induce tumor initiation remain unknown. The goal of this review is to provide a current state-of-the-science of the mechanisms of human lung carcinogenesis mediated by PAHs, the experimental approaches used to study this complex class of compounds, and future directions for research of these compounds.

No abstract

Alkaloids, a category of natural products with ring structures and nitrogen atoms, include most U.S. Food and Drug Administration approved plant derived anti-cancer agents. Evodiamine is an alkaloid with attractive multitargeting antiproliferative activity. Its high content in the natural source ensures its adequate supply on the market and guarantees further medicinal study. To the best of our knowledge, there is no systematic review about the antiproliferative effects of evodiamine derivatives. Therefore, in this article the review of the antiproliferative activities of evodiamine will be updated. More importantly, the antiproliferative activities of structurally modified new analogues of evodiamine will be summarized for the first time.

Coamorphous systems using citric acid as a small molecular excipient were studied for improving physical stability and bioavailability of loratadine, a BCS class II drug with low water solubility and high permeability. Coamorphous loratadine-citric acid systems were prepared by solvent evaporation technique and characterized by differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy. Solid-state analysis proofed that coamorphous loratadine-citric acid system (1:1) was amorphous and homogeneous, had a higher T over amorphous loratadine, and the intermolecular hydrogen bond interactions between loratadine and citric acid exist. The solubility and dissolution of coamorphous loratadine-citric acid system (1:1) were found to be significantly greater than those of crystalline and amorphous form. The pharmacokinetic study in rats proved that coamorphous loratadine-citric acid system (1:1) could significantly improve absorption and bioavailability of loratadine. Coamorphous loratadine-citric acid system (1:1) showed excellently physical stability over a period of 3 months at 25°C under 0% RH and 25°C under 60% RH conditions. The improved stability of coamorphous loratadine-citric acid system (1:1) could be related to an elevated T over amorphous form and the intermolecular hydrogen bond interactions between loratadine and citric acid. These studies demonstrate that the developed coamorphous loratadine-citric acid system might be a promising oral formulation for improving solubility and bioavailability of loratadine.

Cap formation is the first step of pre-mRNA processing in eukaryotic cells. Immediately after transcription initiation, capping enzyme (CE) is recruited to RNA polymerase II (Pol II) by the phosphorylated carboxyl-terminal domain of the Pol II largest subunit (CTD), allowing cotranscriptional capping of the nascent premRNA. Recent studies have indicated that CE affects transcription elongation and have suggested a checkpoint model in which cotranscriptional capping is a necessary step for the early phase of transcription. To investigate further the role of the CTD in linking transcription and processing, we generated a fusion protein of the mouse CTD with T7 RNA polymerase (CTD-T7 RNAP). Unexpectedly, in vitro transcription assays with CTD-T7 RNAP showed that CE promotes formation of DNA⅐RNA hybrids or R loops. Significantly, phosphorylation of the CTD was required for CE-dependent R-loop formation (RLF), consistent with a critical role for the CTD in CE recruitment to the transcription complex. The guanylyltransferase domain was necessary and sufficient for RLF, but catalytic activity was not required. In vitro assays with appropriate synthetic substrates indicate that CE can promote RLF independent of transcription. ASF/SF2, a splicing factor known to prevent RLF, and GTP, which affects CE conformation, antagonized CE-dependent RLF. Our findings suggest that CE can play a direct role in transcription by modulating displacement of nascent RNA during transcription.RNA displacement ͉ RNA polymerase II ͉ RNA processing R NA polymerase II (Pol II) plays a critical role not only in the transcription of mRNA precursors, but also in their subsequent processing. The best characterized example is cotranscriptional cap formation, which is achieved by the physical interaction of capping enzymes (CEs) with the phosphorylated carboxyl-terminal domain of the Pol II largest subunit (CTD) (1-5). The CTD, composed mainly of a repeated heptapeptide motif, YSPTSPS, is extensively phosphorylated, and its regulation is tightly controlled during the transcription cycle (6-8). Phosphorylation of serine-5 in the heptad repeats, by Cdk7 in human and Kin28 in yeast, occurs shortly after transcription initiation and is required for cotranscriptional recruitment of CE (9, 10).The formation of the 5Ј-terminal m7G(5Ј)ppp(5Ј)N cap is the first step of pre-mRNA processing and involves a series of three enzymatic reactions. RNA triphosphatase (RTPase) removes a phosphate from the 5Ј end of the nascent transcript, RNA guanylyltransferase (GTase) transfers GMP from GTP to the diphosphate RNA terminus, and RNA (guanine-N7) methyltransferase (MTase) adds a methyl group (11). In budding yeast, capping is carried out by three polypeptides that are encoded separately (12). Cet1 (RTPase) interacts with Ceg1 (GTase), and this interaction is critical for stimulating Ceg1 activity (13). Abd1 (MTase) and Ceg1 bind directly to the phosphorylated CTD (2, 3). Mammalian CEs consist of two components, a bifunctional CE (with an N-terminal RTPase domain and C-t...

Objective: The aim of this study is to evaluate the liver metastasis risk among colorectal cancer patients with liver cirrhosis. Methods: This was a nationwide population-based cohort study of 2973 newly diagnosed colorectal cancer patients with liver cirrhosis and 11 892 age-sex matched controls enrolled in Taiwan between 2000 and 2010. The cumulative risk by Kaplan-Meier method, hazard ratio by the multivariate Cox proportional model and the incidence density were evaluated. Results: The median time interval from the colorectal cancer diagnosis to the liver metastasis event was 7.42 months for liver cirrhosis group and 7.67 months for non-liver cirrhosis group. The incidence density of liver metastasis was higher in the liver cirrhosis group (61.92/1000 person-years) than in the non-liver cirrhosis group (47.48/1000 person-years), with a significantly adjusted hazard ratio of 1.15 (95% CI = 1.04-1.28, P = 0.007). The 10-year cumulative risk of liver metastasis for the liver cirrhosis and the non-liver cirrhosis group was 27.1 and 23.6%, respectively (P = 0.006). For early cancer stage with locoregional disease patients receiving surgery alone without adjuvant anti-cancer treatments, patients with liver cirrhosis (10-year cumulative risk 23.9 vs. 15.7%, P < 0.001) or cirrhotic symptoms (10-year cumulative risk 25.6 vs. 16.6%, P = 0.009) both still had higher liver metastasis risk compared with their counterparts. For etiologies of liver cirrhosis, the 10-year cumulative risk for hepatitis B virus and hepatitis C virus, hepatitis B virus, hepatitis C virus, other causes and nonliver cirrhosis were 29.5, 28.9, 27.5, 26.7 and 23.4%, respectively, (P = 0.03). Conclusions: Our study found that liver metastasis risk was underestimated and even higher in colorectal cancer patients with liver cirrhosis.

No abstract

A simple and sensitive method based on the combination of solid-phase microextraction (SPME) and high-performance liquid chromatography with ultroviolet detection was developed for the simultaneous determination of clenbuterol, salbutamol and ractopamine in pig samples. Parameters of the SPME procedure affecting extraction efficiency, such as the type of fiber, extraction time, extraction temperature, ion strength, pH of sample and stirring rate, were optimized. The developed method was validated according to the International Conference on Harmonization guidelines. The calibration curves were linear over a range of 0.5-50 µg/L for clenbuterol and ractopamine, and 0.2-20 µg/L for salbutamol. The limits of detection were 0.1 µg/L for clenbuterol, 0.05 µg/L for salbutamol and 0.1 μg/L for ractopamine, respectively. The averages of intra- and inter-day accuracy ranged from 79.8 to 92.4%. The intra-day and inter-day precision were below 9.6% for the three analytes. This method exhibited the advantages of simplicity, rapidity and low solvent consumption, and was suitable for the monitoring of β2 -agonists residue in pig samples.