Sesquiterpenoids from Artemisia gilvescens and an anti-MRSA compound

A new secoguaianolide sesquiterpene (1) was isolated along with its three stereoisomers (2-4) from the nonmedicinal plant Artemisia gilvescens. The structure of 1 was elucidated to be (4S,5S)-dihydro-5-[(1R,2S)-2-hydroxy-2-methyl-5-oxo-3-cyclopenten-1-yl]-3-methylene-4-(3-oxobutyl)-2(3H)-furanone on the basis of 2D NMR and other spectroscopic evidence. Five known sesquiterpenoids were also isolated from this plant, and one of them (5) showed activity against methicillin-resistant Staphylococcus aureus (MRSA).     

Induction of apoptosis by mono(2-ethylhexyl)phthalate (MEHP) in U937 cells

Treatment of U937 cells with mono(2-ethylhexyl)phthalate (MEHP) for 20 h led to a dose-dependent loss of cell viability, assessed by propidium iodide (PI) staining with fluorescent activated cell sorting (FACS) analysis. The cytotoxic behavior of MEHP is attributed to the induction of apoptosis. MEHP induced activation of caspase-3, internucleosomal DNA fragmentation and the morphological features of nuclear apoptosis. Analysis with LightCycler quantitative RT-PCR demonstrated the decrease of bcl-2 and increase of bax mRNA levels. Peroxisome proliferator-activated receptor (PPAR) gamma antagonists, bisphenol A diglycidyl ether (BADGE) and GW9662, significantly inhibited the MEHP-induced caspase-3 activity and apoptotic nuclear morphological changes. Furthermore, a PPARgamma ligand, rosiglitazone synergized the MEHP-induced caspase-3 activity. These results suggest that MEHP can induce apoptosis in U937 cells through modulation of the balance of bcl-2/bax in part by PPARgamma activation.     

Alteration of antibacterial activity of tosufloxacin and various antibacterial agents against Streptococcus pneumoniae

The minimum inhibitory concentrations (MICs) of tosufloxacin (TFLX), levofloxacin (LVFX), ciprofloxacin (CPFX), gatifloxacin (GFLX), sparfloxacin (SPFX), azithromycin (AZM), cefteram (CFTM), cefdinir (CFDN) and cefpodoxime (CPDX) against 337 clinical isolates of Streptococcus pneumoniae isolated from Japanese hospital from 1997 to 2002 were investigated by agar plate method. The incidence of penicillin-susceptible S. pneumoniae (PSSP), penicillin-intermediate resistant S. pneumoniae (PISP), and penicillin-resistant S. pneumoniae (PRSP) in each year was studied, and the MICs of antibacterial agents against these strains were determined. As the results, the total incidence of PSSP, PISP, and PRSP was 51.0%, 40.4% and 8.6%, respectively. The incidences of PSSP from 1997 to 2002 were 46.0-55.9%, and were almost definite in each year. In quinolone antibiotics, the differences of antibacterial activity among TFLX, SPFX, and GFLX against PSSP, PISP, and PRSP, were not observed, and these 3 quinolones had potent antibacterial activity. Although CPFX and LVFX showed antibacterial activity as well as other quinolones by 2001, the CPFX-resistant or LVFX-intermediate resistant strains of PSSP were seen with 56.5% and 91.3% in 2002, respectively. Thirty percents of each PSSP, PISP, and PRSP strains were AZM-resistant strains. Such tendency of increase was recognized in PSSP. Against cephem antibiotics, the incidence of intermediate resistant and resistant strains was higher for PISP and PRSP than for PSSP. No difference in the incidence of resistant strains was noted among CFTM, CFDN, and CPDX.     

Aberrant methylation in promoter-associated CpG islands of multiple genes in therapy-related leukemia

Methylation profile was analyzed in eleven cases of therapy-related leukemia (t-leukemia) for p14, p15, p16, Rb, hMLH1, hMSH2, MGMT, APC, RAR beta, DAPK, RIZ1, FHIT, and SOCS-1 genes by using methylation specific polymerase chain reaction (MSP) analysis. Six (55%) of eleven cases showed methylation of at least one gene. The average time to the development of t-leukemia after the treatment of the primary tumor was significantly shorter in patients with methylation than those without methylation (49.3 months vs. 133.2 months, P=0.044). These results suggest that hypermethylation might be involved in the development of t-leukemia.     

H-ras mutations at codon 61 or 13 in tumors initiated with a NO donor in mouse skin

The tumor-initiating activity of nitric oxide (NO) in carcinogenesis was assessed using (+/-)-(E)-4-methyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexenamide (NOR1), a synthetic NO donor. Topical application of NOR1 followed by 12-O-tetradecanoylphorbol 13-acetate (TPA) treatment twice a week for 20 weeks resulted in the development of papillomas in mice. All of the papillomas examined contained H-ras mutations at codons 61 or 13. At codon 61, CAA-CTA and CAA-TTA mutations were seen in 42/46 and 1/46 of the papillomas, respectively. Three papillomas without a mutation at codon 61 were mutated at codon 13. A GGC-CGC mutation was found in two of these samples while the third possessed a GGC-GTC mutation. These results suggest that NO possesses tumor-initiating activity through a process that induces mutation in H-ras.     

The inhibitory effect of local anesthetics on bradykinin-induced phospholipase D activation in rat pheochromocytoma PC12 cells

Bradykinin induces activation of phospholipase D (PLD) via B(2) receptors in neuronal cells. To demonstrate molecular mechanism(s) of local anesthetics, we examined whether and how local anesthetics affect bradykinin-induced PLD activation in PC12 cells. Using [(3)H]Palmitic acid-labeled PC12 cells stimulated with bradykinin, formation of [(3)H]phosphatidylbutanol was measured as a variable of PLD activity. Bradykinin-stimulated PLD activity seemed to peak at 2 min. Procaine, lidocaine, ropivacaine, bupivacaine, and tetracaine suppressed the bradykinin-induced PLD activation. We chose tetracaine, the most potent drug among the local anesthetics tested, to examine how local anesthetics affect phospholipase C, protein tyrosine kinase, and extracellular signal-regulated kinase, which are the molecules upstream of PLD. Tetracaine at clinically relevant concentrations (1 approximately 10 x 10(-4) M) inhibited the bradykinin-induced PLD activation in a dose- and time-dependent manner, but neither tetrodotoxin nor nifedipine affected the PLD activation. Tetracaine (5 x 10(-4) M) slightly potentiated brady-kinin-induced phospholipase C activation. Bradykinin-stimulated protein tyrosine-phosphorylation and extracellular signal-regulated kinase activation were not affected by tetracaine. Tetracaine significantly decreased PLD activity of membrane fraction in PC12 cells. These results indicate that local anesthetics depress bradykinin-induced lipid signaling pathway(s) and may provide some clues to understanding the molecular mechanisms of these drugs for anesthesia or analgesia. IMPLICATIONS: Local anesthetics depressed the bradykinin-induced activation of phospholipase D (PLD) in PC12 cells. The effects of tetracaine, the most potent among the anesthetics tested, on the bradykinin-induced intracellular signaling molecules were examined. The bradykinin-induced PLD activation could be one of the potential intracellular signaling molecular sites of local anesthetic action.     

A correspondence behavioral approach for 6 lifestyle's improvements in a workplace

OBJECTIVE: The purpose of this research was to examine the effect of a mediated minimal behavioral intervention aimed at lifestyle improvement in with reference to physical activity, healthy diet, appropriate alcohol consumption, quitting or decreasing smoking, dental care, and relaxation, coping with stress. Behavioral strategies used in this program were self-checks for these 6 daily habits, with goal setting for behavioral changes, and self-monitoring. The program ran for one month and support was provided for the participants to master behavioral techniques of self-control by explanation in the application format and rewards which were presented post intervention. METHODS: The participants were 435 office workers, 255 males (mean age: 46.6 years) and 180 females (mean age: 34.4 years). One healthcare provider managed the total intervention for all participants. Each selected optionally one of the 6 habits and 3 target behaviors from 10-12 realistic examples of behavior change on an application form. They received a monitoring sheet and a brief educational pamphlet for their selected habits. Next, they monitored and recorded their target behavior every day for one month. The primary outcome measures were behavior changes at the end of the intervention period and at 6 months thereafter. RESULTS: The results showed high compliance of application rates (7.8%) and record's performance ratios (80%). All habits improved significantly for a total of 18 concrete behavior traits: for example daily walking (P < .01), using stairs (P < .01), vegetable intake (P < .01), eating speed (P < .05), alcohol drinking frequency (P < .01), drinking frequency except at home (P < .05), cigarettes per day (P < .01), breathing cigarette smoke by the lungs (P < .01), teeth brushing frequency (P < .01), gum brushing frequency (P < .01), overall sleep time (P < .01), and taking a bath comfortably (P < .01). Two hundred and 72 (62.5%) subjects completed questionnaires after 6 months. Comparing pre, post, follow-up questionnaire, results 17 concrete behavior traits improved over the period studied. CONCLUSION: The intervention appeared to prompt and reinforce starting and practicing improved behavior because of the attractive application format, letter and rewards. Therefore, it was concluded that correspondence behavioral intervention is cost-effective and useful for lifestyle modification in the general population.     

Acute Leukemia with Normal Platelet Count at Diagnosis

Thirty-six (17.8%) of 202 children with acute lymphoblastic leukemia (ALL) and 2 (3.7%) of 54 children with acute nonlymphoblastic leukemia (ANLL) had a platelet count over 150 times 10⁹/1 at diagnosis. Children with ALL and a platelet count over 150 times 10⁹/1 were analysed in detail. The ALL patients without thrombocytopenia tended to be male predominant and had less frequent bleeding manifestations (p < 0.01).These patients without thrombocytopenia had also significantly less marked leukocytosis (p < 0.01), less severe anemia (p < 0.05) and lower percentages of bone marrow blasts (p < 0.05) than those with thrombocytopenia. In addition, ALL patients without thrombocytopenia had a significantly higher probability of continuous complete remission than those with thrombocytopenia (p < 0.01).