目的:研究九味楮实方对中枢性性早熟（central precocious puberty，CPP）模型大鼠血清性激素水平及下丘脑Kisspeptin蛋白表达的影响。方法:以SD大鼠配种得到雌性仔鼠60只，按随机数字表法分为正常对照组、模型组、戈那瑞林组及九味楮实方高、中、低剂量组，每组10只。除正常对照组外，其余大鼠均皮下注射N-甲基-DL-天冬氨酸建立CPP模型，戈那瑞林组皮下注射戈那瑞林100 μg/（kg·d），九味楮实方高、中、低剂量组分别灌胃九味楮实方浸膏剂5.75、2.87、1.43 ml/（kg·d）。采用ELISA法检测大鼠血清LH、FSH、雌二醇（E 2）水平，Western blot法检测下丘脑促性腺激素释放激素（GnRH）、Kisspeptin蛋白表达情况。 结果:与模型组比较，九味楮实方低、中、高剂量组LH、E 2水平降低（ P<0.05），FSH水平升高（ P<0.05），九味楮实方中、高剂量组GnRH［（0.657±0.110）、（0.536±0.152）比（0.912±0.219）］、Kisspeptin［（0.508±0.035）、（0.347±0.073）比（0.659±0.030）］蛋白表达降低（ P<0.05）。 结论:九味楮实方可干预CPP模型大鼠下丘脑Kisspeptin蛋白表达，抑制下丘脑GnRH表达，降低血清LH、E 2水平。

Kiss1基因编码的Kisspeptin及其受体在哺乳动物体内分布广泛，目前Kisspeptin已被确认为哺乳动物生殖轴的重要调控因子，通过调控下丘脑促性腺激素释放激素的分泌，进而控制垂体黄体生成素和卵泡刺激素的分泌及性行为的调节。此外，Kisspeptin还参与情感方面的调节，包括恐惧、焦虑和认知等。生殖和情感关系密切，在临床中，生殖功能异常与情感障碍伴随的疾病十分常见，然而关于协调生殖与情感方面的研究还较少。目前的研究表明，Kisspeptin可能是介导生殖及情感协调的控制中心。本文将对Kisspeptin在生殖与情感功能两方面的调控作用进行综述，以期为防治因情感障碍导致的生殖疾病提供新的靶点和思路。

OBJECTIVE:To elucidate the mechanism of the nourishing Yin and purging fire Chinese herbal mixture(NYPF)in delaying light-induced premature puberty in rats.METHODS:Twenty-one days old female Sprague-Dawley rats were randomly assigned to normal group(N),long light exposure group(L),NYPF and normal saline group(NS).Rats in the L,NYPF and NS groups were exposed to 16 h:350 lux light/8 h:dark,while rats in the N group were exposed to 12 h:50 lux light/12 h:dark.NYPF and normal saline was administered to the rats in the NYPF group or NS group,respectively,from day 21.Five rats in every group were sacrificed at 9 p.m.on day 28(P28),on the day when rat's vulva opened in the L group(L-VO),on the day when the first estrous interphase occurred in rats of L group(L-E1),and on the day when the second estrous interphase occurred in rats of L group(L-E2),respectively.RESULITS:On day 34,all rats in the L group,80％of rats in the NS group,40％of rats in the N group,and 20％of rats in the NYPF group showed complete opening of the vulva.At P28,mRNA level of hypothalamic kisspeptin(Kiss-1)in the L group was significantly higher than that in the N group(P＜0.05).The rats in the L and NS groups had significantly lower hypothalamic arginine-phenylalanine-amide(RFamide)-related peptide 3(RFRP-3)mRNA levels than those in the N group(P＜0.05),whereas RFRP-3 mRNA level was significantly higher in the NYPF group than that in the L group(P＜0.05).At L-VO,the ovarian index of the L and NS groups was significantly higher than that of the N group(P＜0.05)and estradiol(E2)level of the NYPF group was significantly lower than that of the N and NS groups(P＜0.05);hypothalamic Kiss-1 mRNA level in the L and NS groups was significantly higher than that in the N and NYPF groups(P＜0.05),whereas hypothalamic RFRP-3 mRNA level in the L,NYPF,and NS groups was significantly lower than that in the N group(P＜0.05).At L-E1,E2 level of the L and NS groups was significantly higher than that of the N group(P＜0.01),whereas it was significantly lower in the NYPF group than that of the N,L,and NS groups(P＜0.01),and serum luteinizing hormone level of the L and NS groups was significantly higher than that of the N group(P＜0.05);levels of serum melatonin and ovarian melatonin receptor 1(MT-1)mRNA in the L,NYPF,and NS groups were significantly lower than those in the N group(P＜0.05).At L-E2,the uterine organ index of the NYPF group was significantly lower than that of the L group(P＜0.05);and ovarian MT-1 mRNA level of the L and NS groups was significantly lower than that in the N group(P＜0.05).CONCLUSIONS:NYPF can delay puberty onset in rats exposed to strong light for a prolonged duration,and regulation of the gene expression of Kiss-1 and RFRP-3 in the hypothalamus has been suggested as one of the mechanisms.

Kiss1基因编码Kisspeptins,是一种细胞间信号肽,其相应的受体为Kiss1R.最初的研究发现Kiss1/Kiss1R系统具有抑制肿瘤转移的作用,越来越多的证据表明,其可作用于下丘脑-垂体-性腺轴,是青春期启动和进展的关键,在生殖的神经内分泌调节中扮演重要角色.本文就Kiss1/Kiss1R系统的发现、诱导的细胞内信号转导通路、对下丘脑-垂体-性腺轴的作用、调节机制及其临床应用进行综述.

目的 探讨亲吻素(kisspeptin 1,Kiss-1)、亲吻素受体(kisspeptin 1 receptor,Kiss-1R)2种蛋白在胃腺癌浸润、转移过程中的作用及其临床意义.方法 收集胃腺癌组织40例,癌旁胃正常黏膜组织28例,采用免疫组织化学 SP方法检测Kiss-1、Kiss-1R 2种蛋白在2组中的表达情况,分析其与临床病理特征之间的关系.结果Kiss-1及Kiss-1R 蛋白在胃腺癌组织的阳性表达率均显著低于癌旁胃正常黏膜组织(P<0.01);低分化、有淋巴结转移、TNMⅢ+Ⅳ期胃腺癌组织Kiss-1蛋白阳性表达率低于中高分化、无淋巴结转移、Ⅰ+Ⅱ期胃腺癌组织,差异有统计学意义(P<0.05);不同性别、年龄、肿瘤大小和肿瘤浸润深度胃腺癌组织 Kiss-1蛋白阳性表达率差异无统计学意义(P>0.05).不同性别、年龄、肿瘤大小、分化程度、浸润深度、淋巴结转移、TNM分期胃腺癌组织中 Kiss-1R蛋白阳性表达率差异无统计学意义(P>0.05).Kiss-1与 Kiss-1R 蛋白在胃腺癌组织中表达呈正相关(P<0.05).结论 Kiss-1在胃腺癌进展过程中发挥抑制肿瘤转移的作用,其有潜力成为判断胃腺癌转移和预后的生物学指标;Kiss-1/Kiss-1R信号通路有望成为胃腺癌治疗的有效干预靶点.

Kiss 1基因是Lee等[1]于1996年在宾夕法尼亚州发现的,该基因可以编码一个含有145个氨基酸的多肽,该多肽可以被整体切割成几种活性相似的同型异构体称为 Kisspeptins[2].Kisspeptin可以激活 G蛋白偶联受体 54[3],并且与细胞膜受体 G 蛋白受体 54 (GPR54)特异性结合后,通过激活磷脂酶 C /蛋白激酶C、有丝分裂蛋白激酶、磷酸化细胞外信号调节激酶或p38等多条细胞内信号转导通路发挥其生物学效应[1].早期研究集中在Kisspeptin 能够抑制黑色素瘤和乳腺癌细胞系的转移潜能上[1,4].

青春期是个体获得生殖功能的重要发育阶段,发生早晚主要由遗传因素决定[1],但也受众多内源性和外源性因素的调控[2-3],其中代谢信号对青春期发育的影响不容忽视[4-5].流行病学证据显示,在过去100年间,女童青春期启动和月经初潮的年龄明显提前[6].有观点认为,肥胖发生率的上升可能在其中发挥了重要作用[7],但潜在的机制尚不清楚.过去十余年开展的研究逐步揭示了中枢神经内分泌通路在青春期代谢调控中的重要作用,特别是kiss1基因编码的Kisspeptins在调节促性腺激素释放激素(gonadotropinreleasing hormone,GnRH)中的突出效应[8].与此同时,释放Kisspeptin、神经激肽B(neurokinin B,NKB)和强啡肽(dynorphin,Dyn)的KNDy神经元、细胞能量传感器包括哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)、腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)和沉默信息调控因子1(silent information regulator 1,SIRT1)等[9]在青春期代谢稳态调控中的作用均是当前研究热点.本文主要对参与青春期代谢调控的中枢神经肽和关键细胞能量传感器的生理作用及作用机制的最新进展进行综述,以提供一个新的视角,更好地预防与控制青春期疾病的发生.

目的:探讨清心滋肾汤治疗绝经综合征(menopausal syndrome,MPS)心肾不交证的临床疗效及对神经-内分泌的影响.方法:选取MPS患者104例,按随机数字表法分为对照组和观察组,每组52例.对照组给予中药安慰剂,观察组给予清心滋肾汤治疗.比较两组临床疗效,症状评分,Kupperman指数(Kupper-man index,KI),生存质量量表(menopause-specific quality of life,MENQOL)评分,外周血中肿瘤转移抑制基因亲吻素1(kisspeptins-1,Kiss-1)、内源性受体G蛋白偶联受体54(G protein-coupled receptor 54,GPR54)、神经激肽B(neurokinin B,NKB)、强啡肽(dynorphin,DYN)mRNA水平,血清促性腺激素释放激素(gonadotropin releasing hormone,GnRH)、雌二醇(estradiol,E2)、卵泡刺激素(follicle stimulating hormone,FSH)、黄体生成素(luteinizing hormone,LH)水平.结果:治疗后,观察组临床疗效总有效率[98.08％(51/52)]高于对照组[84.62％(44/52)](P<0.01).观察组症状评分,KI、MENQOL总分均低于对照组(P<0.01).观察组外周血中Kiss-1、GPR54、NKB、DYN mRNA及血清GnRH、FSH、LH水平低于对照组,E2高于对照组,差异有统计学意义(P<0.01).结论:清心滋肾汤治疗MPS心肾不交证可改善患者临床症状和生活质量,提高疗效,调节神经-内分泌的作用可能是其疗效途径之一.

Cancer metastasis,a process that primary tumor cells disseminate to secondary organs,is the most lethal and least effectively treated characteristic of human cancers.Kisspeptins are proteins encoded by the KISS1 gene that was originally described as a melanoma metastasis suppressor gene.Then,Kisspeptins were discovered as the natural ligands of the G-protein-coupled receptor 54(GPR54)that is also called KISS1R.The KISS1/KISS1R signaling is essential to control GnRH secretion during puberty and to establish mammalian reproductive function through the hypothalamic-pituitary-gonadal(HPG)axis.Although KISS1 primarily plays a suppressive role in the metastasis progression in several cancer types,emerging evidence indicates that the physiological effect of KISS1/KISS1R in cancer metastasis is tissue context-dependent and still controversial.Here,we will discuss the epigenetic mechanism involved in the regulation of KISS1 gene expression,the context-dependent role of KISS1/KISS1R,prometastasis/anti-metastasis signaling pathways of KISS1/KISS1R,and the perspective anticancer therapeutics via targeting KISS1/KISS1R.