Search

Although phthalate esters contribute to airway remodeling by increasing bronchial cells’ migration and proliferation, the relationship between human exposure to phthalates and asthma is not understood. We measured phthalate exposure in the human body and evaluated its effect on asthma. Asthma (n = 123) and asthma-free (n = 139) participants were, respectively, recruited from an asthma clinic and the community in Taiwan. The urine levels of six phthalate metabolites were determined by liquid chromatography tandem mass spectrometry. Compared with the controls, male asthma patients had higher means of mono-(2-ethylhexyl) phthalate (MEHP) (116.3 nmol/g), monobutyl phthalate (MBP) (850.3 nmol/g) and monoethyl phthalate (MEP) (965.8 nmol/g), and female patients had greater MBP (2902.4 nmol/g). Each 10-fold increase in the level of these phthalate metabolites was correspondingly associated with a 5.0-, 5.8-, 4.2- and 5.3-fold risk of contracting asthma. Male asthma patients were identified to have a higher proportion of MEHP exposure (32.5%) than the controls (25.3%). In asthma patients, an increase in urine MEHP levels and the total phthalate metabolite concentration were notably linked to increased risks of emergency room visits and being hospitalized. For the occurrence and acute clinical events of adult asthma, phthalate exposures and MEHP retention may contribute to higher risks of contracting this respiratory disorder.

Antrodia cinnamomea (AC) is one of the Far East's treasured medicinal mushrooms and a major ingredient in different nutritional supplements targeting several serious ailments. Developing a sensitive simple quality control protocol for AC and its products is an unmet goal which we target in the current investigation through detecting its biomarkers. Among the AC components, benzenoid derivatives are considered therapeutically attractive due their anti-inflammatory and cytotoxic activities. We proposed a convenient method for concentrating the benzenoid-rich fraction (FNH), from AC wild fruiting bodies ethanolic extract (EEAC). Three benzenoids, 4,7-dimethoxy-5-methyl-1,3-benzodioxole (1), antrocamphin A (2) and 4,7-dimethoxy-5-methyl-6-(3-methylbut-3-en-1-ynyl)-1,3-benzodioxole (3) were purified and their structures were elucidated. Different wild AC samples and the separated benzenoids (1–3) exhibited anti-inflammatory activity through inhibiting superoxide anion generation and elastase release by human neutrophils in response to N-formyl-methionyl-leucyl-phenylalanine (FMLP)/cytochalasin B (CB). Compound 1 exhibited the most potent activity against superoxide anion generation (IC50 5.08 μg/ml) while compounds 2 and 3 were less active (IC50 > 10 μg/ml) implying the advantageous use of 1–3 as biomarkers for AC. HPLC-tandem MS analytical protocol was developed for the quantification of the three major benzenoids from different AC commercial products. The results showed that compound 1 is a unique characteristic biomarker for AC quality control. The concentrations of compounds 2 and 3 were higher in certain sources of AC fruiting bodies and were absent in mycelia, suggesting their usefulness as biomarkers for quality control of fruiting bodies products. The HPLC-tandem MS results were compared to the results obtained by quantitative NMR.

A series of novel enediyne-containing molecules, 1-aryl-6-(3,4,5-trimethoxyphenyl)-3(Z)-hexen-1,5-diynes, were synthesized and displayed significant IC50 values of 10(-7) to 10(-6) M against various cancer cell lines. Of these compounds, 1-(2-pyridinyl)-6-(3,4,5-trimethoxyphenyl)-3(Z)-hexen-1,5-diyne (8) demonstrated the greatest growth inhibition activity. Compound 8 also arrested cancer cells in the G2/M phase and induced apoptosis via activation of Caspase-3. In addition to the G2/M block, compound 8 caused microtubule depolymerization at low concentrations and markedly decreased tumor size in xenographic studies.

Fluoxetine (FT), fluvoxamine (FX), sertraline (ST) and trazodone (TD) are new type of antidepressants acting as selective serotonin reuptake inhibitors (SSRIs). In structures, they all have chromophore and can be easily monitored by UV absorption spectrophotometry. A simple isocratic high-performance liquid chromatographic method with ultraviolet detection (215 nm) was developed for the simultaneous quantification of FT, FX, ST and TD. The determination range of the method is over 10.0–400.0 μM for each drug. The detection limits (S/N = 3, injection 20 μL) are about 0.1 μM for TD, 0.2 μM for FT, FX and ST. The relative standard deviation and relative error of the method for intra- and inter-day analyses of FT, FX, ST and TD were all below 3.7%. Application of the method to the analysis of FT, FX or ST in pharmaceutical product proved feasible. The method could be used for the quality control assay of the analytes in bulk and in formulations.

Compounds 4a-f, 5a-f and 6-9, showed significant growth inhibition activity against human tumor cell lines. Of these compounds, 1-(2-((Z)-6-(2-(trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one (8) displayed the most potent growth inhibition activity. Compound 8 also arrested cancer cells in G2/M phase and induced apoptosis via activation of caspase-3 and -9. According to western-blotting analysis, compound 8 can up-regulate Bax, down-regulate Bcl-2 and XIAP, as well as promote cytochrome c release.

Compounds 2a- h and 6 displayed significant GI 50 values of 10(-7)-10(-6) M against various cancer cell lines. Of these compounds, 2-(6-(2-trifluoromethylphenyl))-3(Z)-hexen-1,5-diynyl)aniline (2c) showed the most potent growth inhibition activity. Compound 2c also arrested cancer cells in the G2/M phase and in low concentration reduced a significant percentage of MDA-MB-231/ATCC breast cancer tetraploid cells. In addition to the G2/M block, compound 2c caused microtubule depolymerization and induced apoptosis via activation of the caspase family.

Treatment of 2-(1-aryl-3-propynoyl) anisoles 1 with N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) gave the 3-halogenated flavones and their related molecules in moderate yields.

In continuing the search for fluorescent reagents for analytical derivatization in chromatography, we found a simple chemical, (2-naphthoxy)acetyl chloride, with potential fluorophore/chromophore characteristics for the highly sensitive detection of analytes with an amino function. The reagent has an auxochrome (a substituted alkoxy moiety) attached to the fluorophoric/chromophoric naphthalene system, resulting in favorable spectrophotometric properties. The reagent can be easily prepared from (2-naphthoxy)acetic acid and has been used in organic synthesis; it is initially introduced as a fluorescent reagent to derivatise amantadine and memantine (amino pharmaceuticals) as model analytes. The resulting naphthoxy derivatives of the drugs can be analyzed at sub-microM levels by HPLC with fluorimetric detection (excitation wavelength 227 nm, emission wavelength 348 nm). Application of the reagent to the fluorimetric derivatization of important biological amines for sensitive detection can be expected.

A novel cytotoxic diterpenoid, chabrolin A (1) (possessing an unprecedented terpenoid skeleton), as well as three new cytotoxic sesquiterpenoids, parathyrsoidins E–G (2–4), were isolated by cytotoxicity-guided fractionation from soft corals Nephthea chabroli and Paralemnalia thyrsoides. The structures of the new compounds were determined by extensive analysis of spectroscopic data.

Transforming growth factor-β (TGF-β) responsiveness in cultured cells can be modulated by TGF-β partitioning between lipid raft/caveolae- and clathrin-mediated endocytosis pathways. Lipid rafts are plasma membrane microdomains with an important role in cell survival signaling, and cholesterol is necessary for the lipid rafts' structure and function. Euphol is a euphane-type triterpene alcohol that is structurally similar to cholesterol and has a wide range of pharmacological properties, including anti-inflammatory and anti-cancer effects. In the present study, euphol suppressed TGF-β signaling by inducing TGF-β receptor movement into lipid-raft microdomains and degrading TGF-β receptors.

National Health Research Institutes National Science Council, Taiwan National Institute for Health Research (NIHR) Biomedical Research Centre and Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust King's College London Background: Betel nut is commonly used in many countries. Despite evidence suggesting an association with asthma, few studies have investigated the connection between betel nut use and asthma; thus, the underlying mechanism for the association with asthma is also unclear. the aim of this study was to investigate the association between betel chewing and asthma as well as the associations of plasma arecoline (a biomarker for exposure) and eotaxin-1 (a potential mediator) with asthma and lung function.Methods: We recruited 600 hospital-based asthmatic patients and 1200 age- and gender-matched community controls in southern Taiwan. To clarify the mechanism of action for eotaxin-1 in the association between betel chewing and asthma, we also designed an in vitro experiment to study the functional associations between arecoline exposure and eotaxin-1 levels.Results: A significant association was found between asthma and current betel chewing (adjusted odds ratio 2.05, 95% CI = 1.12-3.76), which was independent of potential confounders but was attenuated following adjustment for eotaxin-1. Arecoline and eotaxin-1 levels were positively correlated (Spearman r = 0.303, p = 0.02), while arecoline and arecaidine were negatively correlated with lung function. Functionally, arecoline alone does not induce eotaxin-1 release in vitro from dermal and gingival fibroblasts. However, in the presence of IL-4 and TNF-alpha, arecoline at 100 mg/ml induced more eotaxin-1 release than arecoline at 0 mu g/ml (2700 +/- 98 pg/ml vs 1850 +/- 142 pg/ml, p = 0.01 in dermal fibroblast cells, and 1489 +/- 78 pg/ml vs 1044 +/- 95 pg/ml, p = 0.03 in gingival fibroblast cells, respectively).Conclusion: Betel chewing is associated with asthma in this population, with arecoline induction of eotaxin-1 supported as a plausible causal pathway. Kaohsiung Med Univ, Coll Hlth Sci, Dept Publ Hlth, Kaohsiung, Taiwan Kaohsiung Med Univ, Ctr Excellence Environm Med, Kaohsiung, Taiwan Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Coll Med, Dept Internal Med,Div Pulm & Crit Care Med & Geri, Kaohsiung, Taiwan Chang Gung Univ, Chang Gung Mem Hospital, Coll Med, Med Ctr,Dept Med,Div Pulm & Critical Care Med, Kaohsiung, Taiwan Kaohsiung Med Univ, Dept Med & Appl Chem, Kaohsiung, Taiwan Kaohsiung Chang Gung Mem Hosp, Dept Dermatol, Kaohsiung, Taiwan Chang Gung Univ, Coll Med, Kaohsiung, Taiwan Kaohsiung Med Univ, Coll Dent Med, Sch Dent, Kaohsiung, Taiwan China Med Univ Hosp, Environment Omics Dis Res Ctr, Taichung, Taiwan China Med Univ, Grad Inst Clin Med Sci, Taichung, Taiwan Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Coll Med, Fac Med,Dept Internal Med,Div Pulm & Crit Care Me, Kaohsiung, Taiwan Chung Shan Med Univ, Chung Shan Med Univ Hosp, Sch Med, Inst Med,Dept Psychiat, Taichung, Taiwan Universidade Federal de São Paulo, Dept Psychobiol, São Paulo, Brazil Kings Coll London, Inst Psychiat, London, England Universidade Federal de São Paulo, Dept Psychobiol, São Paulo, Brazil National Health Research Institutes: NHRI-CN-PD9611P National Science Council, Taiwan: NSC96-2314-B-037-040-MY3 National Science Council, Taiwan: NSC100-2314-B-037-025-MY3 Web of Science

(Z)-7-Sulfonyl-3-hexen-1,5-diyne containing molecules are stable at room temperature and isomerized to eneyne-allene-sulfones under alkaline conditions. These eneyne-allene-sulfones were not isolable, spontaneously cyclized to form biradical intermediates under mild conditions, and exhibited good DNA-cleaving and human tumor cell line growth inhibition properties. Further studies indicated that compounds bearing on aromatic ring at C(3) and C(4), such as 25, proved to be more active against those tumor cell lines. Removal of acetylene unit at C(1) and C(2), made the resulting compound less active. A related compound, (Z,Z)-12-(2-tetrahydropyranyl)oxy-1-phenylsulfonyldodeca-4,8-diene-2,6,10-triyne (37), was synthesized. Upon treatment of triethylamine at refluxing benzene, this compound undergoes double cycloaromatization to form a naphalene adduct, which possesses excellent DNA-cleaving activity.

Two novel enediynes 1 and 2 and related molecules containing a (Z)-7-sulfonyl-3-hepten-1,5-diyne functionality and quinoline moiety related to dynemicin A were synthesized from quinoline and 4-methoxyquinoline, respectively. The key synthetic features involve (1) magnesium acetylide addition to the 1-acylsalt of the quinolines (2) a Pd(0)Cu(I) catalyzed coupling reaction of vinyl chloride or aryl iodide with acetylenes (3) conversion of the alcohol to a sulfide, followed by oxidation to a sulfone. These molecules proved to be active against the growth of leukemia, colon, epidermoid and melanoma cancer cell lines.

Several α-ketoalcohols of synthetic value were resolved using lipase as a catalyst. Lipoprotein lipase (LPL) provided the best rate of hydrolysis and kinetic differentiation. One of these optically pure α-ketoalcohol was converted to (5)-ibuprofen in good optical purity. The stereospecific inversion of (R)-alcohol to (S)-alcohol is described.

Background Areca nut chewing has been reported to be associated with obesity, metabolic syndrome, hypertension, and cardiovascular mortality in previous studies. The aim of this study was to examine whether chewing areca nut increases the risk of coronary artery disease (CAD) in Taiwanese men. Methods This study is a hospital-based case-control study. The case patients were male patients diagnosed in Taiwan between 1996 and 2009 as having a positive Treadmill exercise test or a positive finding on the Thallium-201 single-photon emission computed tomography myocardial perfusion imaging. The case patients were further evaluated by coronary angiography to confirm their CAD. Obstructive CAD was defined as a ≥ 50% decrease in the luminal diameter of one major coronary artery. The patients who did not fulfill the above criteria of obstructive CAD were excluded. The potential controls were males who visited the same hospital for health check-ups and had a normal electrocardiogram but no history of ischemic heart disease or CAD during the time period that the case patients were diagnosed. The eligible controls were randomly selected and frequency-matched with the case patients based on age. Multiple logistic regression analyses were used to estimate the odds ratio of areca nut chewing and the risk of obstructive CAD. Results A total of 293 obstructive CAD patients and 720 healthy controls, all men, were analyzed. Subjects who chewed areca nut had a 3.5-fold increased risk (95% CI = 2.0-6.2) of having obstructive CAD than those without, after adjusting for other significant covariates. The dose-response relationship of chewing areca nut and the risk of obstructive CAD was also noted. After adjusting for other covariates, the 2-way additive interactions for obstructive CAD risk were also significant between areca nut use and cigarette smoking, hypertension and dyslipidemia. Conclusions Long-term areca nut chewing was an independent risk factor of obstructive CAD in Taiwanese men. Interactive effects between chewing areca nut and cigarette smoking, hypertension, and dyslipidemia were also observed for CAD risk. Further exploration of their underlying mechanisms is necessary.

Two novel enediynes 1 and 2 and related molecules containing a (Z)-7-sulfonyl-3-hepten-1,5-diyne functionality and quinoline moiety related to dynemicin A were synthesized from quinoline and 4-methoxyquinoline, respectively. The key synthetic features involve (1) magnesium acetylide addition to the 1-acylsalt of the quinolines (2) a Pd(0)Cu(I) catalyzed coupling reaction of vinyl chloride or aryl iodide with acetylenes (3) conversion of the alcohol to a sulfide, followed by oxidation to a sulfone. These molecules proved to be active against the growth of leukemia, colon, epidermoid and melanoma cancer cell lines.

Resolution of several α-ketoalcohols of synthetic value using lipase as a catalyst is described.

The optically active naproxen was synthesized in good chemical yield and high optical purity starting from a chiral α-ketoalcohol which was prepared from enzymatic resolution of the corresponding racemic acetate using lipase as a catalyst.

A simple and sensitive liquid chromatographic method is described for the analysis of amantadine and memantine. The method is based on the derivatization of amantadine and memantine extracted from alkalified samples with (2-naphthoxy)acetyl chloride at mild conditions. The resulting derivatives were analyzed by isocratic HPLC with a fluorimetric detector (lambdaex, 227 nm; lambdaem, 348 nm). The linear range for the determination of amantadine or memantine spiked in urine (1.0 ml) was 1.0-10.0 nmol with a detection limit of about 0.2 nmol (S/N = 3; injected sample 20 microl). Only amantadine preparations are available on our local market, and application of the method to the analysis of amantadine in formulation and in the urine of a dosed subject was demonstrated and proved feasible. Quantitation of AT in tablets or capsules is capable in the linear range of 2.0-50.0 microM. Toluene was used as the solvent for extracting amantadine or memantine in samples and the resulting toluene extract was directly subjected to subsequent derivatization without solvent replacement leading to a simpler analytical procedure.

Resolution of several α-ketoalcohols of synthetic value using lipase as a catalyst is described.