[An investigation of trichloroethylene-induced effects on histone methylation in L-02 hepatic cells].

Objective: To further explore TCE-induced hepatotoxicity and its mechanisms by identification of trichloroethylene (TCE) induced abnormal histone methylation in human liver cells. Methods: L-02 cells were treated with 0 and 8 mmol/L TCE for 24 h. Histones were extracted by acid. Liquid chromatography electrospray ionization tandem mass spectrometry (ESI-LC-MS/MS) were used to identify and quantify TCE related histone methylations. TCE induced abnormal methylation of H3K79 me2 and H3K79 me3 were validated by Western blot analysis. The further analysis of the function of histone abnormal methylation modifications were done by single cell gel electrophoresis (SCGE) and Western blot analysis of p53 and ɤH2AX. Results: After treatment with TCE for 24 h in L-02 cells, the 36 TCE related histone methylation sites in 28 peptide segments were identified by MS. After treatment with TCE in concentrations of 0 and 8.0 mmol/L in L-02 cells for 24 h, the relative expression level of histone H3K79 me3 were 1.00±0.06, 0.70±0.09 (t=15.01, P=0.015); the relative expression level of histone H3K79 me2 were 1.00±0.05, 0.74±0.07 (t=16.69, P=0.018); the Olive Tail Moment about DNA damage were 1.46±0.28, 3.12± 0.68 (t=15.22, P=0.018); the relative expression levels of p53 were 1.00±0.04, 1.24±0.04 (t=18.71, P= 0.012); and the relative expression levels of ɤH2AX were 1.00 ± 0.03, 1.56 ± 0.11 (t=8.32, P=0 045). Conclusion: TCE can induce changes in the relative expression level of H3K79 me2 and H3K79 me3 in L-02 cell, and induce DNA damage, suggesting that TCE may induce changes in the relative expression level of H3K79 me2 and H3K79 me3 by DNA damage.

The prevalence of Parkinson's disease continues to rise after 80 years of age: a cross-sectional study of Chinese veterans.

OBJECTIVE: The purpose of this study was to examine whether the prevalence of Parkinson's disease (PD) continues to rise after 80 years of age. METHODS: This is a two-stage, multi-center, cross-sectional study using a stratified cluster sampling approach was employed. Subjects included veterans at ≥ 60 years of age living in veterans' communities for at least one month in 18 major cities across China. In the first step, possible PD was screened using a PD screening scale. Demographic and relevant information were collected. In the second step, PD diagnosis was established using the United Kingdom Parkinson's Disease Society Brain Bank (UKPDSBB) diagnostic criteria. RESULTS: The study was conducted during the period from December 2009 to December 2012. The study included 277 veterans' communities. Among the approached 11,593 subjects, 9676 subjects, (9096 men, 580 women) responded. The response rate was 83.46%.The age was ≥ 80 years in 6722 (69.47%) subjects. A diagnosis of PD was established in 228 subjects (2.36%) in the entire sample. The rate of PD was 2.65% in those with an age of ≥ 80 years. The rate of PD increased with increasing age (0%, 1.84%, 2.60% and 3.68% in the subjects at < 70, 70-79, 80-89 and ≥ 90 years of age, respectively; χ2 = 10.891, p = 0.001 in chi-square test). The rate of PD was higher in men (2.44%) than in women (1.46%) on the surface. However, no significant difference was detected (p = 0.241). CONCLUSIONS: The prevalence of PD continues to increase beyond the age of 80 years. The prevalence of PD in Chinese veterans is not lower than that in other countries and regions.

[Crystal and molecular structure of the antimalarial agent alpha-(dibutylaminomethyl)-2, 7-dichloro-9-(p-chlorobenzylidene)-4- fluorenemethanol(benflumetol)].

The three-dimensional crystal and molecular structure of benflumetol(I), alpha-(dibutylaminomethyl)-2, 7-dichloro-9-(p-chlorobenzylidene)-4-fluorenemethanol, was determined by X-ray crystallography and compared with the crystal structures of the cinchona alkaloids. The aromatic rings of fluorene-phenyl system of benflumetol are twisted from each other by 52.8 degrees. The torsion angle of N-C-C-O of benflumetol is 47.6 degrees. The intramolecular aliphatic N-O distance in benflumetol is 2.709A, which is close to the N-O distance found in antimalarial cinchona alkaloids. Benflumetol contains an intramolecular hydrogen bond between the aliphatic nitrogen and oxygen atoms, no intermolecular hydrogen bond was found, which is different from the known amino alcohol antimalarials.

[Synthesis and antimalarial activities of fluorenemethanols].

For the purpose of improving the oral antimalarial activities of the fluorenemethanols (reported by us in previous articles) which were less effective by oral than by subcutaneous administration, 24 alpha-(alkylaminomethyl)-2, 7-dichloro-9-substituted benzylidene-4-fluorenemethanols (III) were synthesized. The results of preliminary screenings demonstrated that five compounds (No. 1-4, 8) exhibited significant antimalarial activities against Plasmodium berghei NK65 strain in mice by oral administration, at dose of 6.25 mg.kg-1.d-1 x 3 with suppressive rate of 100%. Further evaluation of these 5 compounds showed that 4 of them (No. 1-4) were superior to chloroquine in parallel tests, their ED50 and ED90 were 1.0, 1.6; 0.6, 0.9; 0.7, 1.5 and 0.8, 1.6 mg.kg-1.d-1 x 3 respectively, while the ED50 and ED90 of chloroquine were 1.9 and 2.9 mg.kg-1. d-1 x 3 respectively; one compound (No 8) was equal to chloroquine, its ED50 and ED90 were 1.5 and 3.2 mg.kg-1.d-1 x 3 respectively. Further assessment of these 4 compounds are in progress.

[Synthesis of 4-methyl-5-substituted phenoxy-primaquine analogues and preliminary evaluation on their antimalarial activity].

On basis of our previous work, seven 4-methyl-5-substituted phenoxy-6-methoxy-8-(1-methyl-4-amino-butylamino)-quinolines (II2-8) were synthesized and their antimalarial activities were preliminarily evaluated. The target compounds were prepared from 2-nitro-4-methoxy-5-bromo-acetanilide as previously described. The structures of II2-8 and all of the unknown intermediates were confirmed by elementary and spectral analyses. Preliminary biological evaluation revealed that all of II2-8 exhibited significant blood schizonticidal activity and were 4-8 times as effective as primaquine in causal prophylactic test in mice.

[Synthesis of 2-methyl-5-substituted phenoxy-primaquine and antimalarials activity].

In searching for efficient, safe and radically curative agent and causal prophylactics for malaria, seven 2-methyl-5-substituted phenoxy-6-methoxy-8-(1-methyl-4-aminobutylamino)-quinolines (II1-7) were synthesized and their antimalarial activities were compared with the corresponding 4-methyl substituted derivatives of primaquine. The starting material, 2-nitro-4-methoxy-5-bromo-acetanilide (III), was prepared from p-methoxy aniline through acetylation, bromination and nitration. III was then condensed with substituted phenols in the presence of potassium carbonate. The condensed products were subsequently hydrolyzed with dilute alcoholic hydrochloric acid to yield 2-nitro-4-methoxy-5-substituted phenoxy-aniline (V) which underwent Skraup's reaction with 2-butenal to provide the key intermediates 2-methyl-5-substituted phenoxy-6-methoxy-8-nitroquinolines (VI). These 8-nitroquinoline derivatives were reduced to 8-aminoquinoline derivatives (VII). The latter were condensed with 4-bromo-1-phthalimido-pentane and then hydrolyzed with hydrazine hydrate, the final products were obtained as oxalate or succinate. The structure of the target compounds and unknown intermediates were confirmed by elementary and spectral analysis. Primary biological evaluation showed that all compounds II1-7 were much less active than the 4-methyl substituted derivatives and slightly less active than primaquine in both causal prophylactic test against Plasmodium yoelii and suppressive antimalarial test against P. berhei.