Human biomonitoring of phthalate exposure in Austrian children and adults and cumulative risk assessment

Phthalates are a class of chemicals widely used as plasticisers in a multitude of common consumer products. Through contact with such products, people are regularly exposed to phthalates, which are suspected to contribute to adverse health effects, particularly in the reproductive system.In the present study, 14 urinary phthalate metabolites of 10 parent phthalates were analysed by HPLC–MS/MS among the Austrian population aged 6–15 and 18–81 years in order to assess phthalate exposure. In the total study population, ranges of urinary phthalate metabolite concentrations were n.d.–2,105 μg/l (median 25 μg/l) for monoethyl phthalate (MEP), n.d.–88 μg/l (10 μg/l) for mono-n-butyl phthalate (MnBP), n.d.–248 μg/l (28 μg/l) for mono-isobutyl phthalate (MiBP), n.d.–57 μg/l (1.8 μg/l) for mono-benzyl phthalate (MBzP), n.d.–20 μg/l (n.d.) for mono-(2-ethylhexyl) phthalate (MEHP), n.d.–80 μg/l (2.6 μg/l) for mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), n.d.–57 μg/l (1.9 μg/l) for mono-(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP), n.d.–219 μg/l (11 μg/l) for mono-(5-carboxy-2-ethylpentyl) phthalate (5cx-MEPP), n.d.–188 μg/l (1.6 μg/l) for 3-carboxy-mono-proply phthalate (3cx-MPP), n.d.–5.5 μg/l (n.d.) for mono-cyclohexyl phthalate (MCHP), n.d.–4.5 μg/l (n.d.) for mono-n-pentyl phthalate (MnPeP), n.d.–3.4 μg/l (n.d.) for mono-n-octyl phthalate (MnOP), n.d.–13 μg/l (n.d.) for mono-isononyl phthalate (MiNP), and n.d.–1.1 μg/l (n.d.) for mono-isodecyl phthalate (MiDP). Generally, children exhibited higher levels of exposure to the majority of investigated phthalates, except to MEP, which was found in higher concentrations in adults and senior citizens at a maximum concentration of 2,105 μg/l. Individual daily intakes were estimated based on urinary creatinine and urinary volume excretion and were then compared to acceptable exposure levels, leading to the identification of exceedances of mainly the Tolerable Daily Intakes (TDI), especially among children. The execution of a cumulative risk assessment based on Hazard Indices showed cause for concern mainly for children, as well as in rare cases for adults.Although phthalate exposure seems to have decreased in previous years, the wide distribution and existing exceedances of acceptable levels indicate that phthalate exposure should be further monitored in order to identify exposure sources and enable appropriate minimisation measures.     

代谢产物在检测阿片类物质滥用中的研究进展

目的对近年来检测阿片类物质滥用的代谢产物进行综述,为加强阿片类物质的管理、确证滥用导致的死亡等提供依据,也可以用于区别滥用和正常摄入。方法通过大量检索检测阿片类物质滥用的代谢产物相关资料,总结归纳阿片类物质体内代谢过程、常用代谢产物检测的优缺点及应用。结果海洛因、含可待因的药物和罂粟类物质等均能代谢生成吗啡,导致假阳性结果。目前尚未有明确统一的金标准用于准确判断阿片类物质的滥用,滥用确证时除了检测常用的代谢产物指标6-单乙酰吗啡和吗啡外,乙酰可待因、可待因、吗啡与可待因浓度比值、蒂巴因与罂粟碱及那可汀的代谢物也可附加检测。结论在确证阿片类物质滥用时,需谨慎判断代谢产物检测结果的可靠性,并详细询问被检测者近期的服药史。     

软珊瑚共附生真菌Schizophyllum sp. CGF9-1-2次生代谢产物研究

目的 首次对软珊瑚来源共附生裂褶菌属真菌Schizophyllum sp. CGF9-1-2次生代谢产物的化学成分进行研究,以期获得结构新颖、生理活性好的次生代谢产物。方法 以PDA及真4培养基发酵软珊瑚共附生真菌Schizophyllum CGF9-1-2;采用硅胶、凝胶、ODS等柱层析、高效液相色谱法（HPLC）等方法对其菌丝体的乙酸乙酯部位进行分离纯化;采用核磁共振（NMR）、（高分辨）质谱（（HR）MS）和旋光（ORD）等现代波谱解析手段,并与文献数据对照方法确定化合物结构。结果 从其乙酸乙酯部位共分离鉴定10个化合物,依次为7, 8-二甲基四氧嘧啶（1）、杂色曲霉素（2）、Arugosin C（3）、酒酵母甾醇（4）、（22e,24r）-3β, 5α, 9α-三乙烯基麦角甾-7, 22-二乙烯-6酮（5）、1-亚油酸甘油酯（6）、10-十七烯酸甲酯（7）,2-辛烷烯酸甲酯（8）、十八烷酸（9）和十四烷酸（10）。结论 首次从裂褶菌属真菌CGF9-1-2中分离鉴定10个化合物,结构类型涉及吡嗪类、芳香酚酸类和长链脂肪酸及酯类。丰富了宿主软珊瑚中海洋微生物的种类,确定其次生代谢产物的多样性,为进一步药理活性实验奠定了基础。     

一株红树内生真菌Penicillium sp. JY246次级代谢产物及其活性研究

目的 研究一株红树角果木来源内生真菌Penicillium sp. JY246的次级代谢产物及其生物活性。方法 利用硅胶柱层析、Sephadex LH-20凝胶柱层析、半制备HPLC等方法,对该菌发酵产物的乙酸乙酯浸膏进行分离纯化;利用NMR、MS等波谱解析方法以及与文献数据对照,鉴定化合物的结构;通过抗菌和抗虫活性模型对化合物的生物活性进行评价。结果 从内生真菌Penicillium sp. JY246中分离得到12个化合物,分别为7-hydroxy-2-(2-hydroxypropyl)-5-methylchromone (1),(2′S)-2-(propan-2′-ol)-5-hydroxy-benzopyran-4-one (2),2, 3-dihydro-5-hydroxy-2(S)-methyl-4H-1-benzopyran-4-one (3),(11S)-diaprothin (4),questin (5),4-hydroxy-3-prenylbenzoic acid (6),4-methoxy-6-styryl-pyran-2-one (7),(R) 4-hydroxy-2-oxo-1-pyrrolidineacetamide (8),p-hydroxy-benzaldehyde (9),4-hydroxyacetophenone (10),apocynin (11)和1-(2,6-dihydroxyphenyl) ethan-1-one (12)。结论 从内生真菌Penicillium sp. JY246的次级代谢产物中分离得到12个单体化合物,并对所有化合物进行抗菌和抗虫活性测试。结果表明,化合物1, 2, 4和5显示抗细菌活性;化合物4, 5和8对棉铃虫幼虫显示了生长抑制活性。     

基于OSMAC策略对深海来源真菌Acrostalagmus luteoalbus SCSIO F457化学多样性的初步研究

摘要：目的 采用单菌多次级代谢产物（OSMAC）策略对1株采自南海深海2 801 m沉积环境的白黄笋顶孢霉属真菌Acrostalagmus luteoalbus SCSIO F457进行化学多样性的初步研究。方法 通过在不同培养基、不同pH与不同盐度条件下对菌株进行培养调控并筛选2种适宜发酵条件进行小规模发酵。采用硅胶柱层析、葡聚糖凝胶层析、半制备高效液相等色谱学方法对发酵产物进行化学分离,利用NMR、MS等波谱学技术并结合文献鉴定化合物结构,并对化合物进行初步抗氧化和抗菌活性测试。结果 从菌株SCSIO F457的发酵产物中共新增分离鉴定11个单体化合物,包括paulownin（1）、cyclo(L-Phe-L-Pro)（2）、cyclo(L-Tyr-L-Pro)（3）、cyclo(L-Val-L-Pro)（4）、cyclo(D-Ile-L-Pro)（5）、cyclo(D-Leu-L-Pro)（6）、1-methyoxy-4-(2-hydroxy)ethylbenzene（7）、2-(4-hydroxyphenyl)-ethanol（8）、1-phenylbutane-2,3-diol（9）、3-methoxy-2-methyl-4H-pyran-4-one（10）及3-(hydroxy-acetyl)-1H-indole（11）,化合物7表现出较弱的1,1-二苯基-2-苦基肼（1,1-Diphenyl-2-picryl-hydrazyl, DPPH）自由基清除活性。     

海绵共附生真菌Nigrospora sp.的次级代谢产物及PD-1/PD-L1抑制活性研究

目的 研究海绵Callyspongia sp.共附生真菌Nigrospora sp.中化学成分以及生物活性。 方法 利用正相硅胶柱层析、Sephadex LH-20凝胶柱层析和半制备型反相高效液相色谱(RPLC)等方法对该菌株乙酸乙酯提取物进行分离纯化;通过核磁共振谱(NMR)、质谱(MS)等技术并结合文献报道数据分析鉴定化合物结构;采用均相时间分辨荧光(HTRF)法检测化合物的PD-1/PD-L1结合抑制活性。结果 分离得到7个已知化合物,分别为punctaporonin D (1),punctaporonin E (2),punctaporonin F (3),desuccinoylpunctaporonin C (4),(20S, 22E, 24R)-麦角甾-7, 22-二烯-3β, 5α, 6β-三醇 (5),(22E, 24R)-麦角甾-3β-羟基-5α, 9α-环氧-7, 22-二烯-6-酮 (6),麦角甾-7, 22-二烯-6β-甲氧基-3β, 5α-二醇 (7)。在体外生物活性检测中,化合物6显示出PD-1/PD-L1结合抑制活性,其IC50值为22.5 μmol/L。结论 化合物4为新天然产物,化合物1-3和化合物6为首次从该属真菌中分离得到。化合物6显示PD-1/PD-L1结合抑制活性。     

Experiencia en práctica clínica de optimización de tiopurinas mediante determinación de sus metabolitos en la enfermedad inflamatoria intestinal

Introduction

Thiopurine therapy can be optimised by determining the concentration of the drug's metabolites.

Production of certified reference materials for the sports doping control of the REV‐ERB agonist SR9009

Two human metabolites of the REV‐ERB agonist SR9009, identified by researchers with an interest in sports doping control, have been synthesized and assessed for purity. The synthesis employed was a modification of published procedures for the parent SR9009, careful attention to the purification of intermediates and the final product ensuring materials of the highest purity were available for certification. For each candidate material impurities of related structure were identified and quantified as a relative mass fraction using high performance liquid chromatography–ultraviolet (HPLC–UV) detection and proton nuclear magnetic resonance (¹H NMR) spectroscopy. The quantification of water, occluded solvent, and inorganic residue was assessed using Karl Fischer, ¹H NMR, and thermogravimetric analysis, thereby completing the assessment of all impurities typically characterized by the mass balance approach. Summation and subtraction from 1000 mg/g afforded the mass fraction of the main component, the associated uncertainty ensuring certified reference material status can be applied to the resulting pure substance calibration standards. The availability of these standards to the sports doping control community will facilitate delivery of metrological traceability to the SI unit for mass (kg) to routine testing results and aid method development for the detection and quantification of SR9009 abuse.     

深海真菌Phomopsis tersa的次级代谢产物及其细胞毒活性研究

目的 研究深海真菌Phomopsis tersa FS441的次级代谢产物及其细胞毒活性。方法 采用正、反相硅胶柱、凝胶柱和高效液相等多种色谱技术对菌株FS441的固体发酵产物进行分离纯化,并通过NMR、MS等波谱方法鉴定化合物结构,采用SRB法对得到的单体化合物进行细胞毒活性测试。结果 从发酵物中分离纯化得到11个化合物,分别鉴定为：5α, 8α-表二氧麦角甾-6,22-二烯-3β-醇（1）、麦角甾醇（2）、12-hydroxydehydrobotrydienol（3）、5,6-二羟基-2,3,6-三甲基环己-2-烯酮（4）、1,2-二羟基-3,4-脱氢蒽酮（5）、（1S,2S,3S,4R） -3-氯-4-（2-羟基丙吡啶-2-基）-1-甲基环己烷-1,2-二醇（6）、（-）-5-methylmellein（7）、酪醇（8）、胸腺嘧啶核苷（9）、（R）-（+）-甘油1-9 （Z）,12 （Z）-十八碳二烯酸酯（10）、亚油酸（11）。结论 化合物3～6为首次从Phomopsis属分离得到,化合物1和2对SF-268、MCF-7、HepG-2和A549 4种肿瘤细胞株具有弱的细胞毒活性。