南海软珊瑚Lobophytum sp.中二萜类化合物的研究

目的 对海洋来源软珊瑚Lobophytum sp.中的化学成分结构多样性及生物活性进行研究。方法 利用硅胶、十八烷基硅烷键合硅胶（ODS-C18）、凝胶Sephadex LH-20和半制备高效液相（semi-HPLC）等色谱学方法对软珊瑚乙酸乙酯提取物中的化学成分进行分离;利用紫外（UV）、核磁共振波谱（NMR）、质谱（MS）等波谱学方法,结合与文献的数据对比确定化合物的结构。结果 从软珊瑚的乙酸乙酯提取物中分离鉴定了10个西松烷型二萜类化合物,分别为sarcomililatins B（1）、lobophytins A（2）、isosarcophine（3）、sarcophytoxide（4）、isosarcophytoxide（5）、(+)-11,12-epoxyepoxy-11,12-dihydrocembrene-C（6）、cherbonnolide B（7）、sarcomililatins A（8）、sarcophytonin B（9）和3,4-dihydro-4α-hydroxy-?2-sarcophine（10）。其中化合物7和8为首次从该属软珊瑚中分离得到。化合物1和3在20 μmol/L 浓度下对LPS诱导NO产生的抑制率分别为31.5%和28.6%。结论 从南海软珊瑚Lobophytum sp.中分离得到了化合物1~10,其中化合物1和3对LPS诱导NO产生具有一定的抑制作用。     

Comparative 5-HT4 receptor antagonist activity of LY353433 and its active hydroxylated metabolites

LY353433 is a selective, potent, and orally active 5-HT₄ receptor antagonist with a long duration of pharmacological activity following its oral administration to rats. After oral administration of LY353433 (100 mg/kg) to rats, peak plasma concentration of the parent material was approximately 25 ng/ml and rapidly declined such that 4 h after administration, plasma concentration of the parent material was barely detectable. However, two additional peaks (LY343031 and LY343032) were observed in plasma via HPLC and subsequently identified as hydroxylated metabolites of LY353433. Peak plasma concentrations of LY343031 (approximately 50 ng/ml) and of LY343032 (approximately 150 ng/ml) were achieved within 1 h after the oral administration of LY353433. Furthermore, plasma concentrations of these metabolites were maintained for several hours and declined more slowly than plasma concentrations of the parent material. Both metabolites inhibited esophageal 5-HT₄ receptors in a concentration range similar to that observed with LY353433. In addition, the receptor selectivity profiles for LY343031 and LY343032 were similar to that of LY353433 at α₁, α₂, β, Dopamine D₁, Dopamine D₂, benzodiazapine, histamine H₁, GABA_A, 5-HT₂, and muscarinic receptors. Thus, these hydroxylated derivatives of LY353433 were potent and selective 5-HT₄ receptor antagonists in vitro. Lastly, using ex vivo esophageal relaxation to serotonin to assess 5-HT₄ receptor antagonism, these compounds were less active after oral administration to rats than LY353433. Thus, the long duration of pharmacological activity observed after oral administration of LY353433 is likely related not only to the 5-HT₄ receptor antagonist activity of the parent molecule, but also to the 5-HT₄ receptor antagonist activity associated with its two hydroxylated metabolites. Drug Dev. Res. 43:193–199, 1998. © 1998 Wiley-Liss, Inc.     

Urinary excretion of methylated catecholamine metabolites in a child with neuroblastoma maturing into ganglioneuroma

Neuroblastomas are malignant tumors derived embryonically from the neural crest. Biological diagnosis relies on assay of urinary excretion of homovanillic acid (HVA), vanillylmandelic acid (VMA), and dopamine (DA). Spontaneous regression of these neoplasms has been reported by numerous investigators. The authors report the case of a child with neuroblastoma that illustrates the relationship between catecholamine metabolites and tumor maturation. At 1 month of age, this infant presented an adrenal neuroblastoma with multiple metastases (stage IV); the initial histological diagnosis based on examination of cutaneous metastases was neuroblastoma. At the age of 6 months, after chemotherapy, the primary tumor was resected; hepatic metastases were discovered at laparotomy. The histological diagnosis for all lesions was highly differentiated, mature ganglioneuroma-like tissue. The main biochemical abnormality at the time of diagnosis was an elevation in normetanephrine (NMN). HVA was only slightly increased but rose progressively during chemotherapy; it dropped back to normal levels after the sixth course. This case illustrates the potential benefits of separate assays of urinary methylated catecholamine metabolites for biochemical diagnosis and therapeutic management of neuroblastoma in addition to assays of HVA, VMA, and DA. Case findings suggest existence of a transformation process with maturation of the tumor involving enzymatic regulation and expression of MAO. © 1996 Wiley-Liss, Inc.     

Structure-activity relationships in the mutagenicity and cytotoxicity of putative metabolites and related analogs of benzene derived from the valence tautomers benzene oxide and oxepin

A series of putative metabolites and related analogs of benzene, derived from the valence tautomers benzene oxide and oxepin, was tested for mutagenicity (reversions to histidine prototrophy and forward mutations to resistance to 8-azaguanine) and for cytotoxicity by the Ames Salmonella mutagenicity test. Benzene was not mutagenic in either assay. The benzene oxide-oxepin system and benzene dihydrodiol induced point mutations but not frameshifts. 4,5-sym-Oxepin oxide, which is a putative metabolite of the oxepin valence tautomer; 3,6-diazo-cyclohexane-1,6-3,4-dioxide, a synthetic precursor of sym-oxepin oxide; and transoid-4, 11-diox-atricyclo(5.1 0)undeca-1,6-diene, a stable bridgehead diene analog of sym-oxepin oxide, were toxic but not mutagenic in both assays. 4H-Pyran-4-carboxaldehyde, a stable acid catalyzed rearrangement product of sym-oxepin oxide, was not mutagenic and much less cytotoxic than sym-oxepin oxide. Stable analogs of the valence tautomer benzene oxide, namely syn-indan-3a, 7a-oxide and syn-2-hydroxyindan-3a,7a-oxide, were mutagenic and induced point mutations. All compounds were cytotoxic to Salmonella. Firstly, the apparent decay times of these chemicals, especially that of sym-oxepin oxide, were surprisingly longer than expected, as judged by quantitative plate diffusion assays. Secondly, it is concluded that if benzene oxide is further metabolized in its oxepin tautomeric form, toxic but not mutagenic products are formed. Thirdly, the relatively weak mutagenicity of benzene oxide may be mainly due to its instability and corresponding low probability to reach intracellular polynucleotide targets, whereas stable analogs of benzene oxide are relatively more potent mutagens. © 1996 Wiley-Liss, Inc.     

Elucidating the role of blood metabolites on pancreatic cancer risk using two-sample Mendelian randomization analysis

Pancreatic ductal adenocarcinoma (PDAC) is an uncommon but highly fatal malignancy. Identifying causal metabolite biomarkers offers an opportunity to facilitate effective risk assessment strategies for PDAC. In this study, we performed a two-sample Mendelian randomization (MR) study to characterize the potential causal effects of metabolites in plasma on PDAC risk. Genetic instruments were determined for a total of 506 metabolites from one set of comprehensive genome-wide association studies (GWAS) involving 913 individuals of European ancestry from the INTERVAL/EPIC-Norfolk cohorts. Another set of genetic instruments was developed for 483 metabolites from an independent GWAS conducted with 8299 individuals of European ancestry from the Canadian Longitudinal Study on Aging (CLSA) cohort. We analyzed GWAS data of the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), comprising 8275 PDAC cases and 6723 controls of European ancestry. The association of metabolites with PDAC risk was assessed using the inverse-variance weighted (IVW) method, and complemented with sensitivity analyses of MR-Egger and MR-PRESSO tests. Potential side effects of targeting the identified metabolites for PDAC intervention were further evaluated by a phenome-wide MR (Phe-MR) analysis. Forty-four unique metabolites were identified to be significantly associated with PDAC risk, of which four top-ranking metabolites (X: 12798, X: 11787, X: 11308 and X: 19141) showed replication evidence when using instruments developed from both two cohorts. Our results highlight novel blood metabolites related to PDAC risk, which may help prioritize metabolic features for PDAC mechanistic research and further evaluation of their potential role in PDAC risk assessment.     

Laboratory stress in normotensives,borderline hypertensives and essential hypertensives is associated with priming of phagocytic cells

The present study was designed to investigate the effect of standardized laboratory physical and mental stress on phagocytic generation of reactive oxygen species (ROS) and hormonal responses in normotensives (NT), borderline hypertensives (BH) and essential hypertensives (EH). BH were characterized by increased neurohormonal activation in the prestress situation as indicated by significant higher noradrenaline and ACTH values. Although physical stress resulted in a marked activation of the sympatho-adrenal system in all groups, the BH group revealed a strong tendency of more pronounced sympatho-adrenal response. The intracellular and extracellular production of ROS was quantified using chemiluminescence (CL) assays. Phagocytic cells of NT, BH and EH responded to stress with a significantly enhanced zymosan-stimulated luminol- and lucigenin-amplified CL, predominantly localized intracellularly. In the BH group, but not in NT and EH, significant stress-related increases of extracellularly and intracellularly generated oxidative metabolites of isolated granulocytes after stimulation with the chemotactic peptide FMLP were found. Baseline values of all measured CL parameters did not differ between NT, BH and EH. The results show that stress is followed by priming of phagocytes for enhanced oxygen radical generation. In addition to stress-related activation of intracellular ROS production granulocytes of BH showed enhanced release of oxygen metabolites into the extracellular space.     

PHARMACOKINETICS AND POLYMORPHIC OXIDATION OF DEXTROMETHORPHAN IN A JAPANESE POPULATION

The plasma concentration and cumulative urinary excretion over 34 h of dextromethorphan, free and conjugated dextrorphan, and 3-hydroxymorphinan were determined in seven healthy Japanese subjects after oral administration of 30 mg dextromethorphan hydrobromide. Conjugated metabolites were extensively present, whereas no detectable dextromethorphan or free metabolites were observed in the plasma of any subject. On average, 72% of the dose was excreted in urine within 34 h. This was detected mainly as conjugated metabolites with only slight traces of dextromethorphan and free metabolites. From the time-courses of the metabolic ratio (the ratio of urinary output of dextromethorphan to dextrorphan), the metabolic ratios seemed to become constant 7·5 h after oral administration. Phenotyping was performed using metabolic ratios in 75 unrelated healthy Japanese subjects (43 males and 32 females). The logarithmic metabolic ratio was bimodally distributed and one subject (1·3%) was identified as a poor metabolizer.     

大鼠灌胃毛橘红醇提物血浆中柚皮苷、柚皮素及其代谢产物液质分析

目的:分析大鼠灌胃毛橘红醇提物后血浆中柚皮苷、柚皮素及其代谢产物。方法:健康雄性SD大鼠按50 g.kg-1剂量经口给予毛橘红醇提物,1.0 h后采集眼眶静脉血液制备血浆,采用UPLC-Q-TOF的MSE功能与M etabolynxTM软件联合的方法分析。结果:在大鼠血浆中检测到柚皮苷(M1)、柚皮素(M2)、柚皮苷5-O-葡萄糖醛酸苷(M3)、柚皮苷4′-O-葡萄糖醛酸苷(M4)、柚皮素葡萄糖醛酸苷(M5)、柚皮苷4′-O-硫酸酯(M6)、羟基化柚皮素甲醚(M7)、柚皮素葡萄糖醛酸基和硫酸酯基共价结合物(M8)、羟基化柚皮素葡萄糖醛酸苷(M9)。其中M3,M4,M6为首次报道的柚皮苷代谢物,M7,M9为首次报道的柚皮素代谢物。结论:柚皮苷、柚皮素在大鼠体内以葡萄糖醛酸化、硫酸化的形式被代谢,柚皮素还以氧甲基化、羟化葡萄糖醛酸化的形式被代谢。     

Automatic analytical approach for the determination of 12 illicit drugs and nicotine metabolites in wastewater using on-line SPE-UHPLC-MS/MS

In this study, we developed a novel on-line solid phase extraction (SPE)-ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS)-based analytical method for simultaneously quantifying 12 illicit drugs and metabolites (methamphetamine, amphetamine, morphine, codeine, 6-monoacetylmorphine, benzoylecgonine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, cocaine, ketamine, norketamine, and methcathinone) and cotinine (COT) in wastewater samples. The analysis was performed by loading 2 mL of the sample onto an Oasis hydrophilic-lipophilic balance cartridge and using a cleanup step (5% methanol) to eliminate interference with a total run time of 13 min. The isotope-labeled internal standard method was used to quantify the target substances and correct for unavoidable losses and matrix effects during the on-line SPE process. Typical analytical characteristics used for method validation were sensitivity, linearity, precision, repeatability, recovery, and matrix effects. The limit of detection (LOD) and limit of quantification (LOQ) of each target were set at 0.20 ng/L and 0.50 ng/L, respectively. The linearity was between 0.5 ng/L and 250 ng/L, except for that of COT. The intra- and inter-day precisions were <10.45% and 25.64%, respectively, and the relative recovery ranged from 83.74% to 162.26%. The method was used to analyze various wastewater samples from 33 cities in China, and the results were compared with the experimental results of identical samples analyzed using off-line SPE. The difference rate was between 19.91% and −20.44%, and the error range could be considered acceptable. These findings showed that on-line SPE is a suitable alternative to off-line SPE for the analysis of illicit drugs in samples.     

代谢组学方法分析香烟烟雾暴露对大鼠视网膜的影响

目的 通过构建香烟暴露大鼠模型,并利用代谢组学的方法分析香烟暴露对大鼠视网膜的影响,寻找香烟烟雾中引起视网膜功能下降的潜在毒物.方法 使用代谢组学方法分析大鼠经香烟暴露后血浆、房水和视网膜中的差异代谢物.使用LC-MS明确香烟暴露大鼠视网膜中萘代谢产物的存在.使用细胞衰老β-半乳糖苷酶染色(senescence-ass...