皮肤黑色素在黑素小体内合成,黑素小体是黑素细胞内合成和储存黑色素的溶酶体相关细胞器。自噬是广泛存在于真核生物的生命现象,近年来研究表明,自噬在包括色素障碍性皮肤病、银屑病、黑素瘤等在内的很多皮肤病中起着重要的作用。黑素细胞自噬水平,尤其是线粒体自噬的改变对黑素小体功能有重要的影响。据文献报道,线粒体外膜转位蛋白18kDa(Translocator protein 18kDa,TSPO)能够参与细胞线粒体自噬过程。本课题组前期研究也发现,TSPO在体内外水平参与调节色素合成。TSPO与多个色素代谢相关的差异表达蛋白存在相互作用。通过微量热泳动技术(MST)、western blot、siRNA基因沉默技术研究发现,药物通过作用于TSPO,一方面启动cAMP/PKA通路,上调MITF和TYR的蛋白表达进而促进黑色素合成;另一方面促进蛋白Rab17,Cdc42的表达进而提升黑色素小体的转运。Tspo基因沉默后可阻断此药效进程。同时通过对多种白癜风动物模型分析,发现在以精神应激诱导的色素脱失和以氢醌涂抹造成的色素脱失模型上均发现皮肤TSPO表达显著下调。运用TSPO激动剂、拮抗剂等多方面的验证,提示TSPO在皮肤色素合成过程中发挥重要作用。
Background:Individual variability in the therapeutic response to an antihypertensive drug could have agenetic *** investigated whether the αlA-adrenergic receptor(alA-AR) Arg347 Cys,angiotensin II type 1 receptor(AT1...
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Background:Individual variability in the therapeutic response to an antihypertensive drug could have agenetic *** investigated whether the αlA-adrenergic receptor(alA-AR) Arg347 Cys,angiotensin II type 1 receptor(AT1 R),potassium inwardly rectifying channel,subfamily J,member 11(KCNJ11) I337 V,and kininogen(KNG1) Ilel97 Met gene polymorphisms are associated with the blood pressure(BP) therapeutic response to irbesartan and whether the association couldbe altered by the plasma irbesartan ***:A total of 1049 hypertensive subjects were treated with a daily oral dose of 150 mg *** BP was measured before the first *** the 28 th day,after 27 consecutive days of treatment andan overnight fast,BPs and blood samples were obtained before the morning dose(0 hours) and 6 hours after the morning dose was *** irbesartan concentrations were measured by use of *** gene polymorphisms were determined using high-throughput TaqMan ***:1) Relative to noncarriers,alA-AR Cys347 allelic carriers had a significantly greater diastolic blood pressure(DBP) response at 0 hours(7.5±8.4 mm Hg versus 5.5±8.4 mm Hg;P=0.016) and at 6 hours(16.2±9.1 mm Hg versus 14.2±8.9 mm Hg,P=0.025).When subjects were stratified into subgroups with high or low plasma irbesartan concentrations,Cys347 allelic carriers in the high-concentration group,relative to noncarriers,had a more pronounced DBP response at 0 hours(adjusted[p±SE],3.0±1.0 mm Hg;P=0.004) and at 6 hours(3.0±1.2 mm Hg;P=0.014),and the same was true for the SBP response at 0 hours(5.6±2.1 mm Hg;P=0.006) and at 6 hours(4.7±2.0 mm Hg;P=0.021).In contrast,in the low-concentration group,there was no significant association between DBP or SBP responses and Arg347 Cys genotypes at 0 hours and 6 hours.2) When stratified by genotypes,patients carrying allele C of AT1 R rs5186 showed positive association between irbesartan concentration and BP response[SBP:p±SE=6.1±2.3 with false disc
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