Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute pancreatitis induced by cerulein

OBJECTIVE: In the present study, we investigated the effects of rosiglitazone (10 mg/kg, i.p.), a PPAR-gamma agonist, on the development of acute pancreatitis. DESIGN: Intraperitoneal injection of cerulein in mice induced an acute pancreatitis characterized by edema, neutrophil infiltration elevated serum levels of amylase and lipase. This experimental model was performed to test the anti-inflammatory activity of rosiglitazone. SETTING. University research laboratory. INTERVENTIONS: Male CD mice (20-22 g) were allocated into four groups (n=10 for each group): (a) Cerulein+vehicle group. Mice were treated hourly (x 5) with cerulein (50 microg/kg, in saline solution, i.p.); (b) Rosiglitazone group (same as the Cerulein+vehicle group but were administered rosiglitazone, 10 mg/kg bolus, 30 min prior to cerulein); (c) Sham+saline group. Mice were treated with saline instead of cerulein; (d) Sham+Rosiglitazone. Identical to Rosiglitazone group except that the saline was administered instead of cerulein. Mice were killed at 6 h after the induction of pancreatitis. Blood samples, pancreas, and lungs were collected. MEASUREMENTS AND RESULTS: Infiltration of pancreatic and lung tissue with neutrophils was associated with enhanced lipid peroxidation. Immunohistochemical examination demonstrated a marked increase in immunoreactivity for nitrotyrosine and for ICAM-1 in the pancreas of cerulein-treated mice. In contrast, the degree of (a) pancreatic inflammation and tissue injury, (b) upregulation/formation of ICAM-1 and nitrotyrosine, and (c) neutrophils infiltration was markedly reduced in pancreatic tissue obtained from rosiglitazone-treated mice. CONCLUSION: These findings support the view that rosiglitazone and other potent PPAR-gamma agonists may be useful in the therapy of acute pancreatitis.     

Antidepressant-like effect of the extract from leaves of Schinus molle L. in mice: evidence for the involvement of the monoaminergic system

Schinus molle L. (Anacardiaceae), among other uses, is popularly employed for the treatment of depression. In this study, the antidepressant-like effect of the hexanic extract from leaves of S. molle was investigated in the mouse tail suspension test (TST), a predictive model of depression. The immobility time in the TST was significantly reduced by the extract (dose range 30-600 mg/kg, p.o.), without accompanying changes in ambulation when assessed in an open-field test. The efficacy of extract was found to be comparable to that of fluoxetine (10 mg/kg, p.o.). The anti-immobility effect of the extract (100 mg/kg, p.o.) was prevented by pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), NAN-190 (0.5 mg/kg, i.p., a 5-HT(1A) receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), MDL72222 (0.1 mg/kg, i.p., a 5-HT(3) receptor antagonist), prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a D(1) receptor antagonist) or sulpiride (50 mg/kg, i.p., a D(2) receptor antagonist). It may be concluded that the hexanic extract of S. molle produces an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems. These results provide evidence that the extract from S. molle shares with established antidepressants some pharmacological effects, at least at a preclinical level.     

Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFNγ, IL-1α, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1α, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.     

雷公藤的肝毒性研究及ADME/Tox评价思路

雷公藤Triptergium wil fordii为卫矛科植物,具有多种药理作用,作为一种传统常用中药,其临床应用广泛,疗效显著,但使用中引起的肝损伤报道频繁发生。作为一种有毒中药,雷公藤本身所含化学成分多而复杂,且化合物多存在同物异名现象。现就雷公藤所含成分进行总结,并从相关临床病例报道出发,对雷公藤所致肝损害的特点及其可能的作用机制进行综述,提出基于ADME/Tox评价中药肝毒性的研究新思路,在原有的病理表征等传统研究方法的基础上,开展更为细致的中药毒性物质基础的研究。     

Prediction of maximal oxygen uptake from the ratings of perceived exertion and heart rate during a perceptually-regulated sub-maximal exercise test in active and sedentary participants

This study assessed whether the accuracy of predicting maximal oxygen uptake (VO2max) from sub-maximal heart rate (HR) and ratings of perceived exertion (RPE) values was moderated by gender and habitual activity. In total, 27 men and 18 women completed two GXTs to determine VO2max and three perceptually-regulated GXTs, incremented by RPE 9, 11, 13, 15 and 17. The RPE and HR were individually regressed against VO2max (approximately 0.96) to enable predictions of VO2max. The VO2max was predicted from three RPE ranges (9-17, 9-15, 9-13). The RPE ranges were extrapolated to RPE(19), RPE(20) and age-predicted maximal HR (HRmax(pred)). ANOVA revealed no differences between measured and predicted VO2max (P > 0.05) when the RPE range 9-17 was extrapolated to RPE(19) and HRmax(pred). Extrapolation of RPE 9-17 to RPE(20) overestimated VO2max (P < 0.05), but no differences were observed when predicted from the RPE ranges 9-15 and 9-13. The prediction of VO2max was not moderated by gender or activity status. Hierarchical regression analysis revealed that HR explained additional variance in VO2max when added to the RPE (2%). Hierarchical multiple regression analysis also indicated that VO2max was significantly correlated with power output at sub-maximal RPE values of 13 and 15 (P < 0.01) in men and women. The addition of HRmax(pred) improved the accuracy of the prediction equation for men (P = 0.05) but not for women. The study confirmed the validity of estimating VO2max from perceptually-regulated, sub-maximal GXT and indicated the potential utility of regression analysis to gauge appropriate sub-maximal exercise intensities.     

常压缺氧高二氧化碳对大鼠肺组织β肾上腺素受体的影响

将雄性SD大鼠置常压缺氧高二氧化碳舱内饲养,通过放射配体结合试验观察肺组织β受体的变化。对照组肺β受体最大结合容量(Bmax)为330±45fmol/mg蛋白,缺氧高二氧化碳4、8周后分别降至260±38和263±30fmol/mg蛋白(P均<0.05),缺氧高二氧化碳前后肺β受体解离常数(kd)无明显变化(P均>0.05)。缺氧高二氧化碳时肺β受体数目的减少能促进肺血管的收缩,故这一变化在缺氧高二氧化碳导致肺动脉高压中可能起一定作用。     

MKC-242, a novel 5-HT1A receptor agonist, facilitates cortical acetylcholine release by a mechanism different from that of 8-OH-DPAT in awake rats

We have previously reported that 5-{3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole (MKC-242), a potent and selective serotonin (5-HT)_1A receptor agonist, exerts anxiolytic- and antidepressant-like effects in animal models and that the antidepressant-like effect may be mediated by postsynaptic 5-HT_1A receptors. The present study, using a microdialysis technique, was undertaken to characterize in vivo the effect of MKC-242 on cholinergic neurons. Subcutaneous injection of MKC-242 (0.5–1.0 mg/kg), like the typical 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), increased extracellular acetylcholine (ACh) levels in the rat cerebral cortex. The increase in ACh release by MKC-242 was also observed in the hippocampus. The effect of MKC-242 on cortical ACh release was attenuated by pretreatment with the 5-HT_1A receptor antagonists (10 mg/kg, s.c.) propranolol and N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropanamide. The increase in cortical ACh release by MKC-242 was blocked by lesion of serotonergic neurons with 5,7-dihydroxytryptamine, whereas that by 8-OH-DPAT was not. Lesion of noradrenergic neurons with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine did not affect the MKC-242-induced increase in ACh release. These results suggest that systemic injection of MKC-242 facilitates in vivo ACh release via an activation of somadendritic 5-HT_1A autoreceptors, and that MKC-242 and 8-OH-DPAT affect cholinergic neurons in the rat cerebral cortex via different mechanisms.     

A novel indole alkaloid from deep-sea sediment metagenomic clone-derived Escherichia coli fermentation broth

To explore secondary metabolites in deep-sea sediment metagenomic clone-derived Escherichia coli fermentation broth, different kinds of chromatography methods were used in the isolation procedures, while the structures of the isolated compounds were assigned based on the MS analysis and their ¹H and ¹³C NMR spectra including 2D NMR techniques such as COSY, HMQC, and HMBC experiments. As a result, a novel compound was isolated and characterized as N-{1-[4-(acetylamino)phenyl]-3-hydroxy-1-(1H-indol-3-yl)propan-2-yl}-2,2-dichloroacetamide (1). In addition, eight known compounds were also obtained. Fatty acid amide hydrolase and monoacylglycerol lipase were used to screen analgesic activity, and the new compound showed analgesic activity to some extent in pharmacological test.     

Directional $\mathcal{H}^2$ Compression Algorithm: Optimisations and Application to a Discontinuous Galerkin BEM for the Helmholtz Equation

This study aimed to specialise a directional $\mathcal{H}^2 (\mathcal{D}\mathcal{H}^2)$ compression to matrices arising from the discontinuous Galerkin (DG) discretisation of the hypersingular equation in acoustics. The significant finding is an algorithm that takes a DG stiffness matrix and finds a near-optimal $\mathcal{D}\mathcal{H}^2$ approximation for low and high-frequency problems. We introduced the necessary special optimisations to make this algorithm more efficient in the case of a DG stiffness matrix. Moreover, an automatic parameter tuning strategy makes it easy to use and versatile. Numerical comparisons with a classical Boundary Element Method (BEM) show that a DG scheme combined with a $\mathcal{D}\mathcal{H}^2$ gives better computational efficiency than a classical BEM in the case of high-order finite elements and $hp$ heterogeneous meshes. The results indicate that DG is suitable for an auto-adaptive context in integral equations.     

Determinants of dental service utilization among 2 to 11-year-old California children

OBJECTIVE: The 2001 California Health Interview Survey (CHIS) was designed to elicit population-based estimates about health care access and insurance coverage. This study aimed to determine factors associated with dental service utilization among children ages 2 to 11 years in California. METHODS: CHIS was a random digit dialing telephone survey. Interviews were conducted with the adult in the household that was most knowledgeable about the child's care, and information was collected on the child's last dental visit. RESULTS: Data on dental visits were collected on 10,569 children ages 2-11 years. In 2001, 73.5 (+/- 0.6)% of children had a dental visit, 58.2 (+/- 0.6)% a preventive dental visit, while 18.3 (+/- 0.5)% had never visited the dentist. Nearly 1 million children had never visited the dentist, primarily children ages 2-5 years. Overall, 76.3 (+/- 0.6)% of children had dental insurance. Children with a past-year dental visit were likely to be school age, insured and from high-income households. Other predictors of utilization were the responding adult's age and educational attainment. CONCLUSION: Dental service utilization is determined by a mix of parental, child and household factors.