钚促排药物的设计与合成

利用仿生化学的原理，本文设计并合成了两个儿茶酚胺类和两个羟基吡啶酮类八配位的螯合剂，初步动物试验表明，具有较强的钚促排能力。     

3,4-Bis(3′-hydroxyphenyl)hexane — A new mammary tumor-inhibiting compound

Summary The syntheses of the hexestrol derivatives 3,4-bis-(3-hydroxyphenyl)hexane (4a), 3,4-bis(4-fluoro-3-hydroxyphenyl)hexane (4b), 3,4-bis(3, 4dihydroxyphenyl)hexane (4c), and 3,4-bis(3,4-diacetoxyphenyl)hexane (4d) are described. All compounds showed a marked, competitive inhibition of the estradiol receptor interaction (K _a4c>K_a4a>K_a4d>K_a4b). Evaluated in the mouse uterine weight test compounds 4c and 4d almost reached the estrone effect, whereas 4a and 4b did not produce full uterotrophic response. Compounds 4a-d antagonized the estrone stimulated uterine growth of the immature mouse. Compound 4a (NSC-297170) exhibited a specific, dose-related growth inhibition of the estrogen responsive MCF-7 human breast tumor cell line. Tested on the 9,10-dimethyl-1,2-benzanthracene-induced hormonedependent mammary adenocarcinoma of the Sprague-Dawley rat all compounds showed marked inhibition of tumor growth. As in all experiments compounds 4a and 4b, which is resistant to hydroxylation in 4position exhibited an identical pattern of action, which is different from that shown by compound 4c, the effect of compound 4a cannot be explained by its possible catechol metabolite 4c.Supported by grants from the Deutsche Forschungsgemeinschaft and the Verband der Chemischen Industrie-Fonds der Chemischen Industrie     

The application of novel mussel-inspired compounds in dentistry

ObjectiveTo give a current review of the mechanism of mussel adhesion, the application of mussel-inspired compounds in dentistry and the challenges associated with clinical application.MethodsInspired by the wet adhesion property of 3,4-dihydroxyphenol-l-alanine (Dopa) in mussel plaques, various chemical compounds have been synthesized to mimic the mussel as an adhesion model for medical applications. Similar to mussels in the marine environment, dental materials in the oral environment have to endure long-term water hydrolysis, mechanical stress and other chemical challenges. These challenges have influenced an increasing number of studies that are exploring the translation of mussel-inspired adhesion to clinical applications. Therefore, this review discusses the mussel adhesion chemistry and its related application in dentistry.ResultsMussel-inspired compounds have achieved relatively acceptable performances in various dental fields, including surface coating, metal ions chelation, dentin bonding and mucosal adhesion. However, two practical problems remain to be comprehensively addressed, namely the protection of catechol groups from oxidation, and the feasibility for clinical application.SignificanceThe mussel’s wet adhesion ability has attracted much research interest in the dental field because of its properties of moisture-resistant adhesion and surface coating. Despite the emergence of several mussel-inspired compounds in recent years, a comprehensive and timely review of their applications in dentistry is lacking. Therefore, the current review hopes to provide valuable information around the application of mussel-inspired compounds in dentistry with their pros and cons discussed.     

COMTval158met基因多态性对患者术前焦虑和疼痛敏感性的影响

目的 探讨COMTval158met基因多态性对患者术前焦虑和疼痛敏感性的影响.方法 择期手术患者284例,性别不限,年龄20～ 50岁,体重指数在正常范围,ASA分级Ⅰ或Ⅱ级;另取健康志愿者28名,年龄18 ～ 25岁,体重指数在正常范围.采用苯酚-氯仿萃取法提取DNA.采用聚合酶链式反应-限制性片段长度多态性法进行COMTval158met基因多态性检测.根据患者和健康志愿者基因型分组:野生型纯合子组(G/G组)、突变型杂合子组(G/A组)和突变型纯合子组(A/A组).手术或试验前1d进行焦虑状态评分(SAI评分)和焦虑特质评分(TAI评分);患者或健康志愿者入室后平静10 min,采用电刺激仪测定痛阈与耐痛阈.结果 患者G/G组132例,G/A组110例,A/A组42例.健康志愿者G/G组12名,G/A组11名,A/A组5名.COMTval158met等位基因A突变频率为34.5％.健康志愿者3个基因组痛阈、耐痛阈、SAI评分和TAI评分比较差异无统计学意义(P＞0.05);与G/G组比较,患者A/A组痛阈、耐痛阈降低,SAI评分和TAI评分升高(P＜0.05),G/A组上述指标差异无统计学意义(P＞0.05);与健康志愿者比较,患者G/G组和G/A组SAI评分升高,A/A组痛阈、耐痛阈降低,SAI评分升高(P＜0.05).患者COMTval158met等位基因A与耐痛阈、痛阈呈负相关,与术前SAI评分呈正相关(P＜0.05).结论 COMT val158 met基因多态性与患者术前焦虑程度显著相关,以致引起患者疼痛敏感性增强.     

Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes

22q11.2 deletion syndrome (22q11.2DS) is a common genetic risk factor for the development of schizophrenia. We investigated two neurophysiological endophenotypes of schizophrenia – P50 sensory gating and mismatch negativity in 22q11.2DS subject and evaluated their association with catechol O-methyltransferase (COMT) and proline dehydrogenase (PRODH) genetic variants. We also assessed the association of neurophysiological measures with schizophrenia-like symptomatology in 22q11.2DS. Fifty-nine subjects, 41 with 22q11.2DS and 18 typically developing controls, participated in the study. The participants with 22q11.2DS were genotyped for the COMT Val¹⁵⁸Met (rs4680) and PRODH Gln¹⁹Pro (rs2008720) and Arg¹⁸⁵Trp (rs4819756) polymorphisms. Following psychiatric evaluation, all the participants underwent neurophysiological recordings and executive function assessment. The 22q11.2DS group showed poorer sensory gating of the P50 response than the controls. Within the 22q11.2DS group, the COMT Met allele was associated with poorer sensory gating, while both the COMT Met allele and the PRODH Pro-Arg haplotype were associated with smaller mismatch negativity amplitudes. Smaller mismatch negativity amplitudes predicted greater impairment of executive functions and greater severity of schizophrenia-like negative symptoms in 22q11.2DS. The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating and mismatch negativity schizophrenia-like impairments in 22q11.2DS, possibly via dopaminergic/glutamatergic networks. The associations of mismatch negativity impairments with increased severity of schizophrenia-like negative symptoms and poorer executive functions performance in our 22q11.2DS sample suggest that mismatch negativity is a potential endophenotype for schizophrenia in 22q11.2DS.     

COMT基因rs4680位点与中国汉族人群帕金森病遗传易患性关联性分析

目的 探讨儿茶酚胺氧位甲基转移酶(COMT)基因rs4680位点Val158Met多态性与帕金森病遗传易患性的相关性.方法 采用聚合酶链反应-连接酶检测反应(polymerase chain reaction-ligase detection reaction,PCR-LDR)基因多态性测序方法,分析COMT rs4680位点基因型及等位基因频率在帕金森病患者(437例)和健康对照者(530人)间的分布差异.结果 帕金森病患者G等位基因频率为77.2％,A等位基因频率为22.8％,而在健康对照者分别为74.7％、25.3％,两组间COMTrs4680位点Val158Met等位基因频率分布差异没有统计学意义(P =0.199).各基因型频率在帕金森病患者分别为G/G型57.4％、G/A型39.6％、A/A型3.0％,在健康对照者分别为54.9％、39.6％、5.5％,两组间基因型频率分布差异无统计学意义(P=0.156).在校正性别、年龄混杂因素后经二元Logistic回归分析,COMT rs4680位点各基因型与帕金森病发病风险之间仍无相关性.结论 COMT基因r4680位点Val158Met多态性与中国汉族人群帕金森病易患性可能无关,进一步扩大样本量及在其他不同种族中的研究能更好地确定COMT rs4680位点Val158Met多态性在帕金森病发病风险中的作用.     

Dietary catechol causes increased oxidative DNA damage in the livers of mice treated with acetaminophen

We have shown that direct reaction of catechol with nitric oxide (NO) results in generation of reactive oxygen and nitrogen species (RNS) through semiquinone radical formation, leading to oxidative DNA damage in rat forestomach. In the present study, we investigated whether dietary catechol systemically exerts the same effects under NO-rich circumstances, when given before and during induction of inflammatory lesions. Male ICR mice were treated with or without 0.8% catechol in the diet for 2 weeks followed by acetaminophen (APAP) administration at a dose of 300 mg/kg by single i.p. injection. Along with several indicators of APAP-induced hepatitis, 8-hydroxydeoxyguanosine (8-OHdG) levels and immunohistochemistry for 3-nitrotyrosine (NO₂Tyr) in the livers were examined at 1.5, 4 and 24 h after APAP injection. 8-OHdG was significantly increased at 24 h in the co-treatment group, but not with either catechol or APAP alone. Elevation of serum ALT and AST activities, decrease of reduced glutathione levels and histopathological liver changes were observed to the same extents in both APAP-treated groups. In view of the finding of positive hepatocytes for NO₂Tyr prior to generation of 8-OHdG, the process of oxidative DNA damage might involve RNS formation. Precise quantitative analysis of NO₂Tyr by means of liquid chromatography with tandem mass spectrometry (LC-MS/MS) in an additional study with the same experimental protocol confirmed increase of RNS due to the reaction of catechol with NO produced after APAP-induced hepatitis. The overall data imply that antioxidants with a catechol structure can cause oxidative DNA damage under inflammatory conditions.     

Psychopharmacological activity of immune complexes in rat brain is complement dependent

Sprague-Dawley male rats implanted with chronic indwelling cannulae at the perifornical hypothalamus eat excessively during the sixth hour following administration of exogenous immune-complexing reactants to the brain site. Rabbit anti-HSA was injected, followed in 30 min by a 20-fold excess of antigen. Anaphylatoxin C5a has also been shown to induce excessive intake, an effect similar to that of norepinephrine at this brain site. If the anaphylatoxins or other byproducts or consequence of the complement cascade were responsible for the immune complex effect, interference with the initiation of the cascade or with the conversion of C3 to C3a and C3b should abolish the behavioral response. These experiments demonstrate that immune complexes formed with the non-complement-fixing F(ab′)₂ fragment of the rabbit anti-HSA do not induce eating, and that normally active IgG antibody complexes do not induce eating if the site has been pretreated with goat anti-rat C3. This latter treatment had no effect, however, on the ability of the animals to respond to norepinephrine or to C5a. We conclude that the immune complex effect is complement dependent.     

强迫症患者儿茶酚氧位甲基转移酶基因表达的研究

目的 探讨汉族人群中外周血儿茶酚氧位甲基转移酶(COMT)基因表达与强迫症的关系.方法 采用实时定量逆转录-聚合酶链反应技术检测35例强迫症首次发病患者(强迫症组)与31名健康对照(对照组)外周血COMT基因表达水平;使用美国精神障碍诊断与统计手册第4版轴Ⅱ诊断结构式临床访谈问卷(SCID-Ⅱ)评估强迫症与强迫性人格障碍的共病情况.结果 强迫症组COMT基因表达水平明显低于对照组(t=2.56,P＜0.05),下调约32%;无强迫人格患者(15例)与对照组间COMT基因表达水平的差异有统计学意义(t=2.41,P＜0.05),而伴强迫人格患者(20例)与对照组的差异无统计学意义(t=1.50,P＞0.05);伴强迫人格与无强迫人格的强迫症患者COMT基因表达水平分别下调14%和56%;COMT表达水平与症状严重度无显著相关(r＝0.09,P＜0.05).结论 COMT基因表达下调可能与强迫症发病有关;伴或无强迫人格患者的遗传机制可能存在差异.     

双相情感障碍与DRD3、DRD2和COMT基因多态性的关联分析

目的　探索多巴胺D3受体 (DRD3)、多巴胺D2受体 (DRD2 )和儿茶酚氧位甲基转移酶 (COMT)基因多态性与双相情感障碍的关系。方法　使用病例 对照的关联分析方法 ,对 10 5名双相情感障碍患者和 12 8名对照者之DRD3、DRD2和COMT的多态性进行检测 ,并进行关联分析。结果　DRD3等位基因在两组间的分布有显著性差异 (χ2 =5 77,P =0 0 2 ) ,Logistic多元回归分析发现基因型 1/ 1和 2 / 2在两组间分布的有显著性差异 (P =0 0 36 ,OR=5 72 7) ,等位基因分析也有显著性差异 (P =0 0 2 2 ,OR =6 786 ) ;DRD2和COMT基因型和等位基因的分布在两组间无显著性差异 (χ2 =1 983,P =0 37/ χ2 =1 6 7,P =0 4 1;χ2 =0 2 16 ,P >0 0 5 / χ2 =0 14 3,P >0 0 5 ) ;将DRD3和DRD2共同分析时发现OR值升高 (OR =6 6 97)。结论　DRD3基因多态性与双相情感障碍有关联 ,且与DRD2有协同作用。