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1.
Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ12,14PGJ2 a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ12,14PGJ2 production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ2 and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment. 相似文献
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报道新化合物A-失碳-17β-羟基-17α-乙炔基-Δ3(5),9(10)-雌甾二烯-2-酮2的合成。文中探讨了用炔钾粗品对A-失碳-Δ3(5),9(10)-雌甾二烯-2,17-二酮1和A-失碳-6β,19-环氧-Δ3-雄甾-2,17-二酮3的选择性炔化,分别得标题化合物2(44%)及A-失碳-17β-羟基-17α-乙炔基-6β,19-环氧-Δ3雄甾-2-酮4(65%),4经还原性破开环氧、去羟甲基和去醋酰氧基合成了标题化合物2。四步总收率为34%。 相似文献
4.
T. Saarne L. Kaiser H. Grönlund O. Rasool G. Gafvelin M. van Hage-Hamsten 《Clinical and experimental allergy》2005,35(5):657-663
BACKGROUND: Allergen-specific immunotherapy is the only treatment for allergic disease providing long-lasting symptom relief. Currently, it is mainly based on the use of crude allergen extracts. The treatment may be improved by the use of genetically engineered allergens, hypoallergens, aiming at a more effective and safer therapy. OBJECTIVE: The aim of this study was to provide a rational design of hypoallergen candidates for immunotherapy by using structural information and knowledge of B and T cell epitopes of an allergen. METHODS: The three-dimensional structure of the major cat allergen Fel d 1 was systematically altered by duplication of selected T cell epitopes and disruption of disulphide bonds. Seven Fel d 1 derivatives were generated and screened for allergenic reactivity in comparison with recombinant Fel d 1 in competition-ELISA. The allergenicity was further evaluated in basophil activation experiments and T cell reactivity was assessed in a lymphoproliferation assay. RESULTS: Three out of seven Fel d 1 derivatives, with two duplicated T cell epitopes and one or two disulphide bonds disrupted, were carefully evaluated. The three derivatives displayed a strong reduction in allergenicity with 400-900 times lower IgE-binding capacity than recombinant Fel d 1. In addition, they induced a lower degree of basophil activation and similar or stronger T cell proliferation than recombinant Fel d 1. CONCLUSION: By a rational approach, we have constructed three Fel d 1 hypoallergens with reduced IgE-binding capacities and retained T cell reactivities. This strategy may be applied to any well-characterized allergen to improve immunotherapy for allergic patients. 相似文献
5.
AMACR(P504S)、P63、34βE12联合检测在前列腺癌早期诊断中的应用 总被引:3,自引:0,他引:3
目的:探讨AMACR(P504S)、P63、34βE12联合检测在前列腺癌(PCa)早期诊断中的临床应用价值。方法:应用即用型组合式单克隆抗体和双酶标记的免疫组化MaxvisionTM一步法检测42例PCa、12例高级别前列腺上皮内瘤变(HGPIN)和30例良性前列腺增生(BPH)穿刺活检标本中AMACR、P63、34βE12的表达情况。比较Glea-son评分各组中AMACR阳性表达情况。结果:AMACR、P63、34βE12抗原在PCa和BPH穿刺标本中的表达差异均有极显著性(P<0.01),PCa组织中AMACR阳性表达率为100%,无P63和34βE12表达;BPH组织中均无AM-ACR表达,P63和34βE12均高表达。HGPIN中AMACR的阳性表达率(91.67%)与BPH差异有极显著性(P<0.01),与PCa差异无显著性(P>0.05);P63和34βE12阳性表达率HGPIN(100%)与PCa差异有极显著性(P<0.01),而与BPH差异无显著性(P>0.05)。AMACR表达强弱与PCa的Gleason评分无关(P>0.05)。结论:AMACR是PCa高度敏感和特异的标志物,P63和34βE12联合标记基底细胞的特异性高,3者联合检测能增加前列腺穿刺活检标本诊断的准确性,在PCa早期诊断中具有重要的临床应用价值。 相似文献
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p63基因在小细胞肺癌及肺腺癌组织中转录表达水平的研究 总被引:2,自引:0,他引:2
7.
目的 研究血小板激活因子拮抗剂SRI63-441对大鼠缺血再灌注损伤心肌的保护作用。方法 将实验大鼠分成3组,对照组未行缺血及药物治疗,再灌注组及SRI63—441治疗组结扎大鼠左冠状动脉前降支(LAD)缺血30分钟后,行再灌注10小时,其中治疗组结扎前1分钟给予SRI63—441(1mg/kg),观察大鼠再灌注心律失常,再灌注区心肌组织中丙二醛浓度、超氧化物歧化酶活性的变化。结果 SRI63—441能明显降低再灌注时室性心律失常的严重程度,使缺血30分钟再灌注10小时大鼠的心肌梗塞面积从21.6±3.1%降至12.7±2.5%,心肌组织中脂质过氧化最终产物丙二醛(MDA)含量下降,超氧化物歧化酶(SOD)活性升高。结论SRI63—441用于大鼠心肌缺血再灌注可减少心肌损伤,提示PAF为心肌再灌注损伤的重要介质,而PAF拮抗剂有可能用于心肌缺血再灌注损伤的治疗。 相似文献
8.
目的探讨颞叶癫痫的发病机制。方法取健康雄性SD大鼠制成颞叶癫痫模型,用免疫组织化学和原位杂交技术对匹罗卡品致痫后不同时间点CA1区的Sema3C mRNA、Np1 mRNA和蛋白表达进行分析。结果在匹罗卡品致痫后7d,实验组CA1区Sema3C、Np1的表达明显低于对照组(P〈0.01)。结论CA1区Sema3C、Np1的表达下凋可能参与了海马CA1区内的轴突出芽机制。 相似文献
9.
ΔNp63蛋白在膀胱移行上皮癌中的表达及其临床意义 总被引:3,自引:1,他引:2
目的 :探讨 p5 3基因家族新成员截短型p6 3(△Np6 3)在膀胱癌组织中的表达及其意义。 方法 :采用免疫组织化学SP法检测 4 0例膀胱移行上皮癌 (TCC)、6例膀胱内翻性乳头状瘤和 8例正常膀胱移行上皮中△Np6 3的表达 ,并分析△Np6 3表达与膀胱癌病理类型、临床分期的关系。 结果 :正常膀胱移行上皮、膀胱内翻性乳头状瘤、TCC中△Np6 3的阳性表达率分别为 37.5 % (3/ 8)、6 6 .7% (4/ 6 )、10 0 % (40 / 4 0 ) ,组间差异有统计学意义 (P <0 .0 1)。TCCG3 级与G2 级△Np6 3的强阳性、中度阳性表达率显著高于G1级 (P <0 .0 1)。Ta~T1期以△Np6 3弱阳性为主 (6 6 .7% ) ,随TCC浸润程度的增加 ,△Np6 3染色强度逐渐增强。T2 期△Np6 3强阳性表达率为 35 .3% ,T3 ~T4期增至 6 3.6 %。结论 :△Np6 3在TCC中高表达 ,与TCC病理分级、临床分期密切相关 ;△Np6 3可能参与TCC的发生、发展 ,是评估TCC预后的潜在因素之一。 相似文献
10.
R. Gottschalk C. Seidl T. Löffler E. Seifried D. Hoelzer J.P. Kaltwasser 《Tissue antigens》1998,51(3):270-275
Abstract: Genetic hemochromatosis (GH) is closely associated with genes of the major histocompatibility complex (MHC) on chromosome 6. Recently, a candidate gene for GH, with structural similarities to MHC class I genes, designated HLA-H and presently named HFE, has been cloned. The HFE gene is localized telomeric to the MHC and several reports have indicated that the HFE gene is mutated in GH patients. In the present study we have analyzed the relationship of HFE gene variants and disease manifestation in GH patients and family members. Fifty-seven patients with GH, 73 family members and 153 healthy blood donors were studied for the amino acid dimorphism at codon 63 (His63Asp=H63D) and codon 282 (Cys282Tyr= C282Y) of the HFE gene. The codon 63 and 282 dimorphism were defined by PCR amplification of genomic DNA samples and restriction enzyme digestion using RsaI/SnaBI for C282Y and Bcll/Mbo 1 for H63D. Ferritin, transferrin serum levels and total iron-binding capacity were determined prior to therapeutic intervention. The Tyr-282 substitution occurred in 53 (93%) of patients compared with 8 (5.2%) of controls (OR=169, P >0.0001). Fifty-one (90%) patients were Tyr-282 homozygous. In contrast, the Asp-63 substitution was present in 5 (8.8%) of the patients compared with 34 (22%) of controls (OR=0.39, P =NS) with none of the patients being homozygous. In Tyr-282 homozygous GH patients serum ferritin levels, transferrin saturation, liver iron and liver iron index were elevated significantly compared to Tyr-282-negative patients, whereas no difference was observed between Tyr/Cys-282 heterozygous and Tyr-282-negative patients. 相似文献