“四时五脏阴阳”理论的生物学基础—四时阴阳气化与基因变化调节的观察与研究
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摘要
“四时五脏阴阳”理论,是从时间结构的角度认识人体生命,以解释人体各种生理、病理变化规律所形成的本质和基础,通过对不同时相中人体生理机能变化表现于外的状态进行观察和分析,来认识和探讨内在脏腑的实质。
1目的
采用实验方法,以“褪黑素”为切入点,考察“四时五脏阴阳”理论的生物学基础,掌握四季对机体影响的规律。同时利用四季模拟系统,探讨运用人工模拟的方法来研究气候变化对机体的生理病理影响机制的科学性和可知性,为人工模拟季节的可行性和可信性提供相关数据,以期为“四时五脏阴阳”理论的研究提供新的途经。
2方法
2.1研究概述
以仓鼠为研究对象,以褪黑素为切入口,以白天/黑夜时间变化为依据,选取春分夏至、秋分和冬至的时间点,以褪黑素合成限速酶HIOMT为指标,观察生理状态下,松果腺、下丘脑、垂体中褪黑素合成限速酶HIOMT活性、蛋白质水平及松果腺中mRNA表达的季节变化规律,并分析其相关性。同时利用四季模拟系统,比较上述指标人工模拟四季与自然四季的变化情况。
2.2实验对象
雄性仓鼠(金黄地鼠),二月龄,在春分日、秋分日、冬至日、夏至日前1m购入,按随机数字表法,随机分为自然气候、人工模拟气候两个大组,分别有春分、夏至、秋分、冬至四个节气组,每组各8只。即每个大组共32只。不同组动物分笼饲养,人工模拟组放在人工模拟系统箱中饲养,其余条件相同,给予充足的水和食。饲料为普通鼠全价颗粒饲料,由北京维通利华动物研究中心提供。自然气候组：仓鼠饲养于采光充足室温可控的动物房,自然光照(不加人工照明)；室温：春季和秋季(20±2)叁,冬季(17±2)℃,夏季(25±2)℃。湿度自然。人工模拟气候组：采用四季模拟系统箱,饲养动物,进行反季模拟。四季模拟箱中的模拟季节与时令季节相反(冬季时模拟夏季；夏季时模拟冬季；秋季模拟春季；春季模拟秋季)。人工模拟季节的主要控制参数为光照、温度、湿度,并且以昼夜长短变化为最主要参数。春分日(3月21日)秋分日(9月22日)冬至日(12月22日)和夏至日(6月21日)晚9时进行取材实验。
2.3指标测定
松果腺、下丘脑、垂体中褪黑素合成限速酶HIOMT蛋白质水平和酶活性测定,酶联免疫法；松果腺中褪黑素合成限速酶HIOMT mRNA表达量测定,荧光实时定量PCR(Real-time)PCR法。
2.4统计学方法
数据以均数±标准差(x±S)表示。运用SPSS19.0软件,采用单因素方差分析(ANOVA)进行统计处理,以P<0.05作为差异有统计学意义的界限。
3结果
3.1在自然气候条件下,松果腺中褪黑素合成限速酶HIOMT总蛋白含量在冬季最高,春季最低。冬与春相比,有显著性差异(p<0.05)；垂体中褪黑素合成限速酶HIOMT总蛋白含量亦为冬季最高,其他三组接近,冬季组与其他三组相比,各组间相比,有显著性差异(p<0.05)；下丘脑中褪黑素合成限速酶HIOMT总蛋白含量在秋季最高,与其他三组相比,有显著性差异(p<0.05)；其他组别之间相比,季节性差异不明显(p>0.05)。松果腺、垂体、下丘脑中褪黑素合成限速酶HIOMT酶活性季节性变化不明显,除垂体中HIOMT酶活性春、秋组之间有明显差异外(p<0.05),其他各组间相比,均无显著性差异(p>0.05)。说明HIOMT酶活性可随季节变化发生一定的波动,但其差异无统计学意义。
3.2在自然气候条件下,松果腺中HIOMT酶的mRNA表达的季节性变化规律,为冬季最高,夏季最低。其中冬季组松果腺中HIOMT酶的mRNA表达与其他三个季节相比,夏季组与秋季组相比,均有显著性差异(p<0.05)。
3.3人工模拟条件下,松果腺中褪黑素合成限速酶HIOMT mRNA的表达与自然条件下节律一致,相应的组别之间无显著性差异(p>0.05),提示模拟较为成功。
4结论
季节气候的变化可以使机体相应的整体功能发生改变,而且其内在规律存在与中医五脏功能相吻合的归类性。这为从时间结构角度,以脏应时的研究思路提供了可行性依据人工模拟条件下,气候对机体的影响与自然季节基本一致。提示应用人工模拟系统模拟自然季节较为成功,利用其模拟季节进行科学研究的思路具有可行性。松果腺-褪黑素在气候因素对机体生理病理影响中具有重要作用。同时在研究过程中,一些实验结果如人工模拟条件下,褪黑素合成限速酶HIOMT的蛋白含量等指标等也表现出了与主体结果的不一致性,这一方面表明了机体功能、气候因素的复杂性,同时也反映出该研究继续的必要性。
"Four seasons,five zang-organs and yinyang" understand the human life explain the nature and basis of human physiological and pathological variation from the point of view of the time structure. Through observation and analysis the outside state of physiological functions in the different time structure to know and to explore the essence of the internal organs
1. Objective
The study tends to understand the biological basis of "Four seasons,five zang-organs and yinyang", master the Four Seasons impact on the body of law by using experimental methods, taking melatonin as cut in point. Simultaneously, we introduced four season simulation system and artificially simulated natural season change. It provided a new way to research "Four seasons, five zang-organs and yinyang" theory. Thus, it provides a new idea to contemporary research work of TCM.
2. Methods
2.1Theoretical methods
Using hamsters as the research object, taking melatonin as cut-in point, using day/night time changes as the basis, selecting the point in time of the vernal equinox, summer solstice, autumnal equinox and the winter sol stice,choosing HIOMT as indicator, we observe seasonal changes of IIIOMT,activity of pineal gland HIOMT, protein level and mRNA expression of hamsters inphysiological state and analyzed the associability. Otherwise, we observed the same target in reversing seasonal state which made by the four season simulation system and compared with the natural state.
2.2Experimental animal
Male hamsters,2-month-old, were randomly divided into groups as nature group, Simulation group, nature group:rats were adopted in light adequacy, temperature controllable and Natural light condition (room temperature was17±2degree in winter, it was25±2degree in summer, it was20±2degree in spring and autumn).Simulation group:adopted four season simulation system to reverse season. The main Simulation factors were illumination, temperature and humidity. Illumination was taken as chief variable of season change. Hamsters ate and drank freely. Hamsters decollated at9pm on Winter Solstice.Vernal Equinox, Autumnal Equinox and the Summer Solstice.
2.3Test methods
ELISA for activity HIOMT and protein level, Real-time PCR for HIOMT mRNA expression.
2.4Statistical analyses
Hormone levels were represented by mean±tandard error (SE). Significance (p value) was calculated with Duncan's multiple range test or Student's t test. The difference was significant when p<0.05. We used SPSS19.0statistical package to analyzed difference between difference groups.
3Results
3.1In natural condition, protein level of pineal gland HIOMT, presented a disposition tendency that it was high in winter and low insummer. Difference was significance between winter and spring.(p<0.05) Protein level of pituitary HIOMT, presented a disposition tendency that it was highest in winter. Difference was significance between the four seasons.(p<0.05) Protein level of hypothalamus HIOMT, presented a disposition tendency that it was highest in autumn. Difference was significance between the four seasons.(p<0.05) Activity of pineal gland, pituitary and hypothalamus HIOMT wasn't significance between the four seasons.(p>0.05)
3.2In natural condition, mRNA expression of pineal gland HIOMT, presented a disposition tendency that it was high in winter and low insummer. Difference was significance between autumn and summer.(p<0.05)
3.3In four season simulation system condition, mRNA expression of pineal gland HIOMT content in winter Simulation group was higher than summer Simulation group and was consistent with natural group. Difference was significance.(p<0.05). The difference between summer Simulation group and winter nature groupand between winter Simulation group and summer nature group was statistical significance. But the difference between summer Simulation group and nature group and between winter Simulation group and nature group was not significance.(p>0.05) The data showed that using four season simulation system to do research work could be feasibility.
4Conclusions
Seasonal changes in climate can change the body corresponding to the overall function,and its inherent laws coincide with the Chinese five internal organs function. It is feasible to understand the human life, explain the nature and basis of human physiological and pathological variation from the point of view of the time structure. Four season simulation system could successfully simulate natural climate change approximately. It had feasibility and creditability to investigate "Correspondence between man and nature" theory by using the four seasonsimulation system. Pineal gland-melatonin in the climatic factors play an important role in the body's physiological and pathological impact. Simultaneously, body functions and climatic factors are complex,which need us to Further study.
1目的
采用实验方法,以“褪黑素”为切入点,考察“四时五脏阴阳”理论的生物学基础,掌握四季对机体影响的规律。同时利用四季模拟系统,探讨运用人工模拟的方法来研究气候变化对机体的生理病理影响机制的科学性和可知性,为人工模拟季节的可行性和可信性提供相关数据,以期为“四时五脏阴阳”理论的研究提供新的途经。
2方法
2.1研究概述
以仓鼠为研究对象,以褪黑素为切入口,以白天/黑夜时间变化为依据,选取春分夏至、秋分和冬至的时间点,以褪黑素合成限速酶HIOMT为指标,观察生理状态下,松果腺、下丘脑、垂体中褪黑素合成限速酶HIOMT活性、蛋白质水平及松果腺中mRNA表达的季节变化规律,并分析其相关性。同时利用四季模拟系统,比较上述指标人工模拟四季与自然四季的变化情况。
2.2实验对象
雄性仓鼠(金黄地鼠),二月龄,在春分日、秋分日、冬至日、夏至日前1m购入,按随机数字表法,随机分为自然气候、人工模拟气候两个大组,分别有春分、夏至、秋分、冬至四个节气组,每组各8只。即每个大组共32只。不同组动物分笼饲养,人工模拟组放在人工模拟系统箱中饲养,其余条件相同,给予充足的水和食。饲料为普通鼠全价颗粒饲料,由北京维通利华动物研究中心提供。自然气候组：仓鼠饲养于采光充足室温可控的动物房,自然光照(不加人工照明)；室温：春季和秋季(20±2)叁,冬季(17±2)℃,夏季(25±2)℃。湿度自然。人工模拟气候组：采用四季模拟系统箱,饲养动物,进行反季模拟。四季模拟箱中的模拟季节与时令季节相反(冬季时模拟夏季；夏季时模拟冬季；秋季模拟春季；春季模拟秋季)。人工模拟季节的主要控制参数为光照、温度、湿度,并且以昼夜长短变化为最主要参数。春分日(3月21日)秋分日(9月22日)冬至日(12月22日)和夏至日(6月21日)晚9时进行取材实验。
2.3指标测定
松果腺、下丘脑、垂体中褪黑素合成限速酶HIOMT蛋白质水平和酶活性测定,酶联免疫法；松果腺中褪黑素合成限速酶HIOMT mRNA表达量测定,荧光实时定量PCR(Real-time)PCR法。
2.4统计学方法
数据以均数±标准差(x±S)表示。运用SPSS19.0软件,采用单因素方差分析(ANOVA)进行统计处理,以P<0.05作为差异有统计学意义的界限。
3结果
3.1在自然气候条件下,松果腺中褪黑素合成限速酶HIOMT总蛋白含量在冬季最高,春季最低。冬与春相比,有显著性差异(p<0.05)；垂体中褪黑素合成限速酶HIOMT总蛋白含量亦为冬季最高,其他三组接近,冬季组与其他三组相比,各组间相比,有显著性差异(p<0.05)；下丘脑中褪黑素合成限速酶HIOMT总蛋白含量在秋季最高,与其他三组相比,有显著性差异(p<0.05)；其他组别之间相比,季节性差异不明显(p>0.05)。松果腺、垂体、下丘脑中褪黑素合成限速酶HIOMT酶活性季节性变化不明显,除垂体中HIOMT酶活性春、秋组之间有明显差异外(p<0.05),其他各组间相比,均无显著性差异(p>0.05)。说明HIOMT酶活性可随季节变化发生一定的波动,但其差异无统计学意义。
3.2在自然气候条件下,松果腺中HIOMT酶的mRNA表达的季节性变化规律,为冬季最高,夏季最低。其中冬季组松果腺中HIOMT酶的mRNA表达与其他三个季节相比,夏季组与秋季组相比,均有显著性差异(p<0.05)。
3.3人工模拟条件下,松果腺中褪黑素合成限速酶HIOMT mRNA的表达与自然条件下节律一致,相应的组别之间无显著性差异(p>0.05),提示模拟较为成功。
4结论
季节气候的变化可以使机体相应的整体功能发生改变,而且其内在规律存在与中医五脏功能相吻合的归类性。这为从时间结构角度,以脏应时的研究思路提供了可行性依据人工模拟条件下,气候对机体的影响与自然季节基本一致。提示应用人工模拟系统模拟自然季节较为成功,利用其模拟季节进行科学研究的思路具有可行性。松果腺-褪黑素在气候因素对机体生理病理影响中具有重要作用。同时在研究过程中,一些实验结果如人工模拟条件下,褪黑素合成限速酶HIOMT的蛋白含量等指标等也表现出了与主体结果的不一致性,这一方面表明了机体功能、气候因素的复杂性,同时也反映出该研究继续的必要性。
"Four seasons,five zang-organs and yinyang" understand the human life explain the nature and basis of human physiological and pathological variation from the point of view of the time structure. Through observation and analysis the outside state of physiological functions in the different time structure to know and to explore the essence of the internal organs
1. Objective
The study tends to understand the biological basis of "Four seasons,five zang-organs and yinyang", master the Four Seasons impact on the body of law by using experimental methods, taking melatonin as cut in point. Simultaneously, we introduced four season simulation system and artificially simulated natural season change. It provided a new way to research "Four seasons, five zang-organs and yinyang" theory. Thus, it provides a new idea to contemporary research work of TCM.
2. Methods
2.1Theoretical methods
Using hamsters as the research object, taking melatonin as cut-in point, using day/night time changes as the basis, selecting the point in time of the vernal equinox, summer solstice, autumnal equinox and the winter sol stice,choosing HIOMT as indicator, we observe seasonal changes of IIIOMT,activity of pineal gland HIOMT, protein level and mRNA expression of hamsters inphysiological state and analyzed the associability. Otherwise, we observed the same target in reversing seasonal state which made by the four season simulation system and compared with the natural state.
2.2Experimental animal
Male hamsters,2-month-old, were randomly divided into groups as nature group, Simulation group, nature group:rats were adopted in light adequacy, temperature controllable and Natural light condition (room temperature was17±2degree in winter, it was25±2degree in summer, it was20±2degree in spring and autumn).Simulation group:adopted four season simulation system to reverse season. The main Simulation factors were illumination, temperature and humidity. Illumination was taken as chief variable of season change. Hamsters ate and drank freely. Hamsters decollated at9pm on Winter Solstice.Vernal Equinox, Autumnal Equinox and the Summer Solstice.
2.3Test methods
ELISA for activity HIOMT and protein level, Real-time PCR for HIOMT mRNA expression.
2.4Statistical analyses
Hormone levels were represented by mean±tandard error (SE). Significance (p value) was calculated with Duncan's multiple range test or Student's t test. The difference was significant when p<0.05. We used SPSS19.0statistical package to analyzed difference between difference groups.
3Results
3.1In natural condition, protein level of pineal gland HIOMT, presented a disposition tendency that it was high in winter and low insummer. Difference was significance between winter and spring.(p<0.05) Protein level of pituitary HIOMT, presented a disposition tendency that it was highest in winter. Difference was significance between the four seasons.(p<0.05) Protein level of hypothalamus HIOMT, presented a disposition tendency that it was highest in autumn. Difference was significance between the four seasons.(p<0.05) Activity of pineal gland, pituitary and hypothalamus HIOMT wasn't significance between the four seasons.(p>0.05)
3.2In natural condition, mRNA expression of pineal gland HIOMT, presented a disposition tendency that it was high in winter and low insummer. Difference was significance between autumn and summer.(p<0.05)
3.3In four season simulation system condition, mRNA expression of pineal gland HIOMT content in winter Simulation group was higher than summer Simulation group and was consistent with natural group. Difference was significance.(p<0.05). The difference between summer Simulation group and winter nature groupand between winter Simulation group and summer nature group was statistical significance. But the difference between summer Simulation group and nature group and between winter Simulation group and nature group was not significance.(p>0.05) The data showed that using four season simulation system to do research work could be feasibility.
4Conclusions
Seasonal changes in climate can change the body corresponding to the overall function,and its inherent laws coincide with the Chinese five internal organs function. It is feasible to understand the human life, explain the nature and basis of human physiological and pathological variation from the point of view of the time structure. Four season simulation system could successfully simulate natural climate change approximately. It had feasibility and creditability to investigate "Correspondence between man and nature" theory by using the four seasonsimulation system. Pineal gland-melatonin in the climatic factors play an important role in the body's physiological and pathological impact. Simultaneously, body functions and climatic factors are complex,which need us to Further study.
引文
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[15]卢全生,郭霞珍,徐砚通等.季节与生殖相关性实验研究[J].北京中医药大学学报,2003,26(1)：27-29.
[16]史楠楠、刘晓燕、袁卫玲等,“心应夏”理论与心血管系统疾病现代流行病学研究[J],北京中医药大学学报(中医临床版),2009,16(5)：34-35
[17]徐巍华,“肺应秋”适应性调控机制的理论和实验研究,北京中医药大学硕士研究生学位论文,2008,5
[18]金光亮,梁怡,郭霞珍,等.有关抑郁症季节性发病机理的研究及其启示[J].北京中医药大学学报,1997,20(1)：15-17
[19]苏建民,苏晶,张培琰,等.四时阴阳消长变化对精神分裂症季节性发病的影响[J].中华精神科杂志,1996,29(4)：251
[1]中国象科学观——易、道与兵、医：819
[2]老子,二十五章：169
[3]庄子,大宗师：210、227-228
[4]吕氏春秋,仲夏纪,大乐：30
[5]陈曦,《黄帝内经》气化理论研究,中国中医科学院博士研究生学位论文,2006,5
[6]黄帝内经素问·五常政大论：157
[7]类经·二十六卷·运气类·至有先后行有位次：609
[8]类经·二十六卷·运气类·至有先后行有位次：610
[9]黄帝内经素问·六微旨大论：142
[10]刘燕池,李晓君.试论气化学说的内涵、外延和应用[J].中国中医基础医学杂志,2009,15(6)：401-404
[11]王仰宗.气基因相应—人体气化＆基因代谢&精气神平衡[J].北京扶阳论坛,2008：70-83
[12]林乔,王米渠,吴斌.基因的多效性与中医理论的气化作用考辨[J].中医药学刊,2004,22(8)：1416-1418
[13]林乔,王米渠.《宋史》人物遗传、疾病和环境对寿限的影响[J].遗传学报,2000,27(12)：1049-1056
[1]Reiter RJ.1991. Pineal melatonin:cell biology of its synthesis and its physiological interactions [J]. Endocr Rev,12(2):151-180.
[2]Garfinkel,D,m.Laudon,D.Nof and N.Zisaapel 1995 Improvement of sleep quality in elderly people by controlled-realease melatonin.Lancet 346:541-544
[3]Reiter RJ.1995. Oxidative process and antioxidative defense mechanism in the aging brain.FASEBJ.9:526-533
[4]许筱颖,褪黑素及其合成限速酶在肾藏象调控理论中作用和地位的探讨和研究,北京中医药大学博士研究生学位论文,2007,5
[5]Morgan P J et al.Pineal gland hormone melatonin receptors:localization,molecular pharmacology and physiological significance Neurochem.Int,1994,24:101-146
[6]Gastel JA, Roseboom PH, Rinaldi PA, Weller JL, Klein DC.1998. Melatonin production: proteaosomal proteolysis in serotonin N-acetyltransferase regulation [J]. Science, 279(5355):1358-1360.
[7]Ganguly S, Gastel J A, Weller JL, Schwartz C, Jaffe H, Namboodiri MA, Coon SL, Hickman AB, Rollag M, Obsil T, Beauverger P, Ferry G, Boutin JA, Klein DC.2001. Role of a pineal camp-operated arylalkylamine N-acetyltransferase/14-3-3-binding switch in melatonin synthesis [J]. Proc Natl Acad Sci USA,98(14):8083-8088.
[8]Roseboom PH, Klein DC.1995. "Norepinephrine stimulation of pineal cyclic AMP response element-binding protein phosphorylation:involvement of a beta-adrenergic/cyclic AMP mechanism [J]. Mol Parmacol,47(3):439-449.
[9]Maronde E. Schomerus C, Stehle JH, Korf HW.1997. Control of CREB phosphorylation and its role for induction of melatonin synthesis in rat pinealocytes [J]. Biol Cell,89(8):505-511.
[10]Roseboom PH, Coon SL, Baler R, McCune SK, Weller JL, Klein DC.1996. Melatonin synthesis: analysis of the more than 150-fold nocturnal increase in serotonin N-acetyltransferase mRNA in the rat pineal gland [J]. Endocrinology,137(7):3033-3044.
[1]Simonneux V, Ribelayga C.2003. Generation of the melatonin endocrine message in mammals:a review of the complex regulation of melatonin synthesis by norepinephrine, peptides. and other pineal transmitters [J]. Pharmacol Rev,55(2):325-395.
[12]Klein DC, Roseboom PH, Coon SL.1996. New light is shining on melatonin rhythm enzyme. The first postcloning view [J]. Trends Endocrinol Metab,7(3):106-112.
[13]Ribelayga C, Gauer F, Pevet P, Pevet P, Simonneaux V.1999. Photoneural regulation of rat pineal hydroxyindole-O-methyltransferase (HIOMT) messager ribonucleic acid expression:an analysis of its complex relationship with HIOMT activity [J]. Endocrinology,140(3):1375-1384.
[14]Klein DC.2000. Serotonin N-acetyltransferase. A personal historical perspective [A]. Adv Exp Med Biol,460:5-16.
[15]Drijfhout WJ, van der Linde AG, De Vries JB, Grol CJ, Westerink BH.1996. Microdialysis reveals dynamics of coupling between noradrenaline release and melatonin secretion in conscious rats [J]. Neurosci Lett,202(3):185-188.
[16]Klein DC, Ganguly S, Coon SL, Weller JL, Obsil T, Hickman A, Dyda F.2002.14-3-3 Proteins and photoneuroendocrine transduction:role in controlling the daily rhythm in melatonin [J]. Biochem Soc Trans,30(4):365-373.
[17]Gastel JA, Roseboom PH, Rinaldi PA, Weller JL, Klein DC.1998. Melatonin production: proteaosomal proteolysis in serotonin N-acetyltransferase regulation [J]. Science, 279(5355):1358-1360.
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[14]马淑然,郭霞珍,刘燕池等.肾应冬调控机制的分子生物学实验研究[J].中国中医基础医学杂志,2001,7(12)：16-19.
[15]卢全生,郭霞珍,徐砚通等.季节与生殖相关性实验研究[J].北京中医药大学学报,2003,26(1)：27-29.
[16]史楠楠、刘晓燕、袁卫玲等,“心应夏”理论与心血管系统疾病现代流行病学研究[J],北京中医药大学学报(中医临床版),2009,16(5)：34-35
[17]徐巍华,“肺应秋”适应性调控机制的理论和实验研究,北京中医药大学硕士研究生学位论文,2008,5
[18]金光亮,梁怡,郭霞珍,等.有关抑郁症季节性发病机理的研究及其启示[J].北京中医药大学学报,1997,20(1)：15-17
[19]苏建民,苏晶,张培琰,等.四时阴阳消长变化对精神分裂症季节性发病的影响[J].中华精神科杂志,1996,29(4)：251
[1]中国象科学观——易、道与兵、医：819
[2]老子,二十五章：169
[3]庄子,大宗师：210、227-228
[4]吕氏春秋,仲夏纪,大乐：30
[5]陈曦,《黄帝内经》气化理论研究,中国中医科学院博士研究生学位论文,2006,5
[6]黄帝内经素问·五常政大论：157
[7]类经·二十六卷·运气类·至有先后行有位次：609
[8]类经·二十六卷·运气类·至有先后行有位次：610
[9]黄帝内经素问·六微旨大论：142
[10]刘燕池,李晓君.试论气化学说的内涵、外延和应用[J].中国中医基础医学杂志,2009,15(6)：401-404
[11]王仰宗.气基因相应—人体气化＆基因代谢&精气神平衡[J].北京扶阳论坛,2008：70-83
[12]林乔,王米渠,吴斌.基因的多效性与中医理论的气化作用考辨[J].中医药学刊,2004,22(8)：1416-1418
[13]林乔,王米渠.《宋史》人物遗传、疾病和环境对寿限的影响[J].遗传学报,2000,27(12)：1049-1056
[1]Reiter RJ.1991. Pineal melatonin:cell biology of its synthesis and its physiological interactions [J]. Endocr Rev,12(2):151-180.
[2]Garfinkel,D,m.Laudon,D.Nof and N.Zisaapel 1995 Improvement of sleep quality in elderly people by controlled-realease melatonin.Lancet 346:541-544
[3]Reiter RJ.1995. Oxidative process and antioxidative defense mechanism in the aging brain.FASEBJ.9:526-533
[4]许筱颖,褪黑素及其合成限速酶在肾藏象调控理论中作用和地位的探讨和研究,北京中医药大学博士研究生学位论文,2007,5
[5]Morgan P J et al.Pineal gland hormone melatonin receptors:localization,molecular pharmacology and physiological significance Neurochem.Int,1994,24:101-146
[6]Gastel JA, Roseboom PH, Rinaldi PA, Weller JL, Klein DC.1998. Melatonin production: proteaosomal proteolysis in serotonin N-acetyltransferase regulation [J]. Science, 279(5355):1358-1360.
[7]Ganguly S, Gastel J A, Weller JL, Schwartz C, Jaffe H, Namboodiri MA, Coon SL, Hickman AB, Rollag M, Obsil T, Beauverger P, Ferry G, Boutin JA, Klein DC.2001. Role of a pineal camp-operated arylalkylamine N-acetyltransferase/14-3-3-binding switch in melatonin synthesis [J]. Proc Natl Acad Sci USA,98(14):8083-8088.
[8]Roseboom PH, Klein DC.1995. "Norepinephrine stimulation of pineal cyclic AMP response element-binding protein phosphorylation:involvement of a beta-adrenergic/cyclic AMP mechanism [J]. Mol Parmacol,47(3):439-449.
[9]Maronde E. Schomerus C, Stehle JH, Korf HW.1997. Control of CREB phosphorylation and its role for induction of melatonin synthesis in rat pinealocytes [J]. Biol Cell,89(8):505-511.
[10]Roseboom PH, Coon SL, Baler R, McCune SK, Weller JL, Klein DC.1996. Melatonin synthesis: analysis of the more than 150-fold nocturnal increase in serotonin N-acetyltransferase mRNA in the rat pineal gland [J]. Endocrinology,137(7):3033-3044.
[1]Simonneux V, Ribelayga C.2003. Generation of the melatonin endocrine message in mammals:a review of the complex regulation of melatonin synthesis by norepinephrine, peptides. and other pineal transmitters [J]. Pharmacol Rev,55(2):325-395.
[12]Klein DC, Roseboom PH, Coon SL.1996. New light is shining on melatonin rhythm enzyme. The first postcloning view [J]. Trends Endocrinol Metab,7(3):106-112.
[13]Ribelayga C, Gauer F, Pevet P, Pevet P, Simonneaux V.1999. Photoneural regulation of rat pineal hydroxyindole-O-methyltransferase (HIOMT) messager ribonucleic acid expression:an analysis of its complex relationship with HIOMT activity [J]. Endocrinology,140(3):1375-1384.
[14]Klein DC.2000. Serotonin N-acetyltransferase. A personal historical perspective [A]. Adv Exp Med Biol,460:5-16.
[15]Drijfhout WJ, van der Linde AG, De Vries JB, Grol CJ, Westerink BH.1996. Microdialysis reveals dynamics of coupling between noradrenaline release and melatonin secretion in conscious rats [J]. Neurosci Lett,202(3):185-188.
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