牦牛金属硫蛋白（MTs）-Ⅲ/-Ⅳ分子特性及MT-Ⅲ表达研究
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摘要
牦牛(Bos grunniens)是生存于青藏高原的特有物种,对低氧、强紫外线的高原环境具有很强的适应性,可能形成了保护中枢神经系统免受低氧损伤与氧化损伤的特殊机制。金属硫蛋白(MTs)是一类低分子量、高半胱氨酸含量和富含金属的细胞质蛋白,具有重金属解毒,清除自由基,保护脑细胞免受缺血缺氧性脑损伤,以及促进多种脑病理损伤修复等作用。推测金属硫蛋白可能对牦牛适应低氧、强紫外线的高原环境发挥了重要作用,具有相应的分子遗传基础,然而牦牛MT-Ⅲ和MT-Ⅳ基因的研究尚未见报道。本论文采用RT-PCR、5'RACE等基因克隆技术首次克隆了牦牛MT-Ⅲ转录区序列和MT-Ⅳ基因序列,采用生物信息学方法对牦牛MT-Ⅲ和MT-Ⅳ蛋白质性质和结构进行了预测,并构建了MT-Ⅲ原核表达体系,主要获得以下结论:
1、牦牛MT-Ⅲ基因转录区序列全长1484bp(GenBank Accession No.:DQ492300和EU653285),5'非翻译区、外显子1、内含子1、外显子2、内含子2、外显子3和3'侧翼区长度依次为56bp、31bp、232bp、66bp、817bp、110bp和172bp。
2、牦牛MT-Ⅲ基因编码区长207bp,编码68个氨基酸,其中Cys占27.9%,不含芳香簇氨基酸。与MT-Ⅰ和MT-Ⅱ相比,在N端第四个氨基酸后插入一个苏氨酸,在C端插入了GEGAEA序列。牦牛MT-Ⅲ蛋白质分子量6.94KDa,没有明显的疏水区,没有跨膜结构域,不存在信号肽,是一种细胞内蛋白质。
3、与人和鼠相比,牦牛MT-Ⅲ基因编码区第88位的碱基T突变成A,使氨基酸序列中第30位保守的Cys被Ser代替,这可能对牦牛MT-Ⅲ的结构和功能产生一定的影响,有待深入研究。
4、牦牛MT-Ⅳ基因三个外显子和内含子全长2099bp(GenBank Accession No.:EU665491),三个外显子长度分别为31bp、66bp和92bp,二个内含子长度分别为1392bp和518bp。编码区长189bp,编码62个氨基酸,其中Cys 20个,不含芳香簇氨基酸。与MT-Ⅰ和MT-Ⅱ相比,在N端第四个氨基酸后插入了一个谷氨酸。MT-Ⅳ蛋白质分子量6.25KDa,没有明显的疏水区,没有跨膜结构域,不存在信号肽,是一种细胞内蛋白质。
5、研究表明MT-ⅣmRNA在不存在复层扁平鳞状上皮细胞的器官肝脏、脾脏、脑和脑垂体中也有表达,表明MT-Ⅳ可能不仅限于在复层扁平鳞状上皮细胞中表达,这有待于深入研究。
6、牦牛MT-Ⅲ和MT-Ⅳ编码区序列和氨基酸序列与其它哺乳动物的高度同源,在进化上高度保守,建立的系统进化树与比较形态学和生理学分类结果一致。但非编码区序列同源性很低,这些序列可能存在物种特异性。
7、以鼠MT-Ⅲ三级结构为模板,预测出了牦牛MT-Ⅲα结构域的三级结构,表明牦牛MT-Ⅲ蛋白质在第43-46氨基酸间形成α螺旋;以兔MT-Ⅱ三级结构为模板,预测出了牦牛MT-Ⅳ三级结构,MT-Ⅳ没有规则的二级结构,与其它MTs来型不同,MT-Ⅳ两个结构域连接序列为RKS。
8、采用pET-42a(+)表达载体,BamH I、XHoI酶切,构建了pET-42a(+)-MT-Ⅲ融合表达重组质粒,转化E.Coli BL21(DE3)plysS表达菌,建立了IPTG诱导表达MT-Ⅲ原核表达体系。
The yak species(Bos grunniens) represents a unique bovine species adapted to the Tibetan plateau of China at altitudes of 3,000m above sea level with intense ultraviolet radiation.Consequently,yak adapted to this environment likely have special physiological adaptive mechanisms to protect their central nervous systems against hypoxic and oxidative injury.The metallothionein(MT) family is a class of low molecular, intracellular,and cysteines-rich proteins with a high affinity for metals.Accumulating studies have demonstrated MTs fulfill unique biological roles in scavenger of free radicals,metal detoxication and homeostasis,and homeostasis of the central nervous system and in the etiology of neuropathological disorders. The MTs of yak maybe important for protecting yak from hypoxic and oxidative injury and it is essential to study MTs gene of yak.However,there were no detailed reports concerning MT-Ⅲand MT-Ⅳgene in Yak. In this study,MT-Ⅲand MT-Ⅳgene were cloned by reverse transcriptase-polymerase chain reaction (RT-PCR) and 5'-RACE methods firstly.To analysis the gene structure and the protein characteristics of MT-Ⅲand MT-Ⅳby bioinformatics methods,and established the expression system of MT-Ⅲproteins in E. coli..The main results were got as following:
1.The translated region sequence of MT-Ⅲgene in yak was gotten,the total length was 1484bp,the length of 5' UTR,exonl,intronl,exon2,intron2,exon3 and 3'UTR was 56bp,31bp,66bp,817bp,110bp and 172bp respectively.The sequences had been deposited in the GenBank data base(Accession No.DQ492300 and EU653285 ).
2.The coding regions of Yak MT-Ⅲwere composed by 207 nucleotides,encoded a 68-amino acid protein, and contained 19 cysteine residues,no aromatic AA.Compared to 61 amino acids for MT-Ⅰand MT-Ⅱisoforms,MT-Ⅲcontained 2 inserts,a single threonine in the N terminal region and a glutamic acid rich hexapeptide(GEGAEA) in the C-terminal region.The molecular weight of Yak MT-Ⅲis 6.94 KDa,analysis of hydrophobicity,transmembrane region,and signal peptides suggested that MT-Ⅲof the yak are nonsecretory proteins.
3.The corresponding conservative Cys~(30) of MT-Ⅲin human and mouse was replaced by Ser~(30),due to a mutation at the 88th nucleotide acid where T mutated into A,it may implied some structural/or dynamic and physiological function differences.
4.The sequence length of MT-Ⅳgene in yak is 2099bp,including 3 exons and 2 introns,the length of 3 exons were respectively 31bp,66bp and 92bp,the length of 2 introns were respectively 1392bp and 518bp,the sequences had been deposited in the GenBank data base(Accession No.EU665491).The coding regions were composed by 189 nucleotides,encode a 62-amino acid protein,and contain 20 cysteine residues,no aromatic AA.Compared to MT-Ⅰand MT-Ⅱisoforms,MT-Ⅳcontained a single glutamic inserts in the N terminal region.The molecular weight of Yak MT-Ⅲwas 6.25 KDa.,Analysis of hydrophobicity,transmembrane region,and signal peptides suggested that MT-Ⅳof the yak are nonsecretory proteins.
5.The coding region of MT-Ⅳwas cloned by RT-PCR from liver,spleen,brain and pituitary in yak,yellow cattle,sheep and goat,in which there are no cornified stratified squamous epithelium,it applied the expression of MT-Ⅳnot only limited in stratified squamous epithelium.
6.The coding regions and amino acid sequence of MTs among mammalian are highly identical,and highly conserved in evolution.But the identity of the noncoding regions sequence are very low,these sequence is special for species likely.
7.Modelling on three-dimensional solution structure of mouse MT-Ⅲ,the three-dimensional solution structure ofα-domain of MT-Ⅲin yak was predict,and lainα-helix from the Glu~(43rd) to Ala~(46th).Modelling on three-dimensional solution structure of rabbit MT-Ⅱ,the three-dimensional solution structure of MT-Ⅳin yak was predict,different from other MT isforms,the conserved hinge region between two domain in other MT isoforms were replaced by RKS in MT-Ⅳ.
8.Establishing pET-42a(+)-MT-Ⅲexpression system in E.Coli BL21(DE3)plysS with IPTG.
1、牦牛MT-Ⅲ基因转录区序列全长1484bp(GenBank Accession No.:DQ492300和EU653285),5'非翻译区、外显子1、内含子1、外显子2、内含子2、外显子3和3'侧翼区长度依次为56bp、31bp、232bp、66bp、817bp、110bp和172bp。
2、牦牛MT-Ⅲ基因编码区长207bp,编码68个氨基酸,其中Cys占27.9%,不含芳香簇氨基酸。与MT-Ⅰ和MT-Ⅱ相比,在N端第四个氨基酸后插入一个苏氨酸,在C端插入了GEGAEA序列。牦牛MT-Ⅲ蛋白质分子量6.94KDa,没有明显的疏水区,没有跨膜结构域,不存在信号肽,是一种细胞内蛋白质。
3、与人和鼠相比,牦牛MT-Ⅲ基因编码区第88位的碱基T突变成A,使氨基酸序列中第30位保守的Cys被Ser代替,这可能对牦牛MT-Ⅲ的结构和功能产生一定的影响,有待深入研究。
4、牦牛MT-Ⅳ基因三个外显子和内含子全长2099bp(GenBank Accession No.:EU665491),三个外显子长度分别为31bp、66bp和92bp,二个内含子长度分别为1392bp和518bp。编码区长189bp,编码62个氨基酸,其中Cys 20个,不含芳香簇氨基酸。与MT-Ⅰ和MT-Ⅱ相比,在N端第四个氨基酸后插入了一个谷氨酸。MT-Ⅳ蛋白质分子量6.25KDa,没有明显的疏水区,没有跨膜结构域,不存在信号肽,是一种细胞内蛋白质。
5、研究表明MT-ⅣmRNA在不存在复层扁平鳞状上皮细胞的器官肝脏、脾脏、脑和脑垂体中也有表达,表明MT-Ⅳ可能不仅限于在复层扁平鳞状上皮细胞中表达,这有待于深入研究。
6、牦牛MT-Ⅲ和MT-Ⅳ编码区序列和氨基酸序列与其它哺乳动物的高度同源,在进化上高度保守,建立的系统进化树与比较形态学和生理学分类结果一致。但非编码区序列同源性很低,这些序列可能存在物种特异性。
7、以鼠MT-Ⅲ三级结构为模板,预测出了牦牛MT-Ⅲα结构域的三级结构,表明牦牛MT-Ⅲ蛋白质在第43-46氨基酸间形成α螺旋;以兔MT-Ⅱ三级结构为模板,预测出了牦牛MT-Ⅳ三级结构,MT-Ⅳ没有规则的二级结构,与其它MTs来型不同,MT-Ⅳ两个结构域连接序列为RKS。
8、采用pET-42a(+)表达载体,BamH I、XHoI酶切,构建了pET-42a(+)-MT-Ⅲ融合表达重组质粒,转化E.Coli BL21(DE3)plysS表达菌,建立了IPTG诱导表达MT-Ⅲ原核表达体系。
The yak species(Bos grunniens) represents a unique bovine species adapted to the Tibetan plateau of China at altitudes of 3,000m above sea level with intense ultraviolet radiation.Consequently,yak adapted to this environment likely have special physiological adaptive mechanisms to protect their central nervous systems against hypoxic and oxidative injury.The metallothionein(MT) family is a class of low molecular, intracellular,and cysteines-rich proteins with a high affinity for metals.Accumulating studies have demonstrated MTs fulfill unique biological roles in scavenger of free radicals,metal detoxication and homeostasis,and homeostasis of the central nervous system and in the etiology of neuropathological disorders. The MTs of yak maybe important for protecting yak from hypoxic and oxidative injury and it is essential to study MTs gene of yak.However,there were no detailed reports concerning MT-Ⅲand MT-Ⅳgene in Yak. In this study,MT-Ⅲand MT-Ⅳgene were cloned by reverse transcriptase-polymerase chain reaction (RT-PCR) and 5'-RACE methods firstly.To analysis the gene structure and the protein characteristics of MT-Ⅲand MT-Ⅳby bioinformatics methods,and established the expression system of MT-Ⅲproteins in E. coli..The main results were got as following:
1.The translated region sequence of MT-Ⅲgene in yak was gotten,the total length was 1484bp,the length of 5' UTR,exonl,intronl,exon2,intron2,exon3 and 3'UTR was 56bp,31bp,66bp,817bp,110bp and 172bp respectively.The sequences had been deposited in the GenBank data base(Accession No.DQ492300 and EU653285 ).
2.The coding regions of Yak MT-Ⅲwere composed by 207 nucleotides,encoded a 68-amino acid protein, and contained 19 cysteine residues,no aromatic AA.Compared to 61 amino acids for MT-Ⅰand MT-Ⅱisoforms,MT-Ⅲcontained 2 inserts,a single threonine in the N terminal region and a glutamic acid rich hexapeptide(GEGAEA) in the C-terminal region.The molecular weight of Yak MT-Ⅲis 6.94 KDa,analysis of hydrophobicity,transmembrane region,and signal peptides suggested that MT-Ⅲof the yak are nonsecretory proteins.
3.The corresponding conservative Cys~(30) of MT-Ⅲin human and mouse was replaced by Ser~(30),due to a mutation at the 88th nucleotide acid where T mutated into A,it may implied some structural/or dynamic and physiological function differences.
4.The sequence length of MT-Ⅳgene in yak is 2099bp,including 3 exons and 2 introns,the length of 3 exons were respectively 31bp,66bp and 92bp,the length of 2 introns were respectively 1392bp and 518bp,the sequences had been deposited in the GenBank data base(Accession No.EU665491).The coding regions were composed by 189 nucleotides,encode a 62-amino acid protein,and contain 20 cysteine residues,no aromatic AA.Compared to MT-Ⅰand MT-Ⅱisoforms,MT-Ⅳcontained a single glutamic inserts in the N terminal region.The molecular weight of Yak MT-Ⅲwas 6.25 KDa.,Analysis of hydrophobicity,transmembrane region,and signal peptides suggested that MT-Ⅳof the yak are nonsecretory proteins.
5.The coding region of MT-Ⅳwas cloned by RT-PCR from liver,spleen,brain and pituitary in yak,yellow cattle,sheep and goat,in which there are no cornified stratified squamous epithelium,it applied the expression of MT-Ⅳnot only limited in stratified squamous epithelium.
6.The coding regions and amino acid sequence of MTs among mammalian are highly identical,and highly conserved in evolution.But the identity of the noncoding regions sequence are very low,these sequence is special for species likely.
7.Modelling on three-dimensional solution structure of mouse MT-Ⅲ,the three-dimensional solution structure ofα-domain of MT-Ⅲin yak was predict,and lainα-helix from the Glu~(43rd) to Ala~(46th).Modelling on three-dimensional solution structure of rabbit MT-Ⅱ,the three-dimensional solution structure of MT-Ⅳin yak was predict,different from other MT isforms,the conserved hinge region between two domain in other MT isoforms were replaced by RKS in MT-Ⅳ.
8.Establishing pET-42a(+)-MT-Ⅲexpression system in E.Coli BL21(DE3)plysS with IPTG.
引文
[1] Acarin, L., Carrasco, J., Gonzalez, B., etc.. Expression of growth inhibitory factor (metallothionein-III) mRNA and protein following excitotoxic immature brain injury [J]. J. Neuropathol. Exp. Neurol. 1999, 58:389 -397.
[2] Allan SM & Rothwell NJ., Inflammation in central nervous system injury [J]. Philos Trans R Soc Lond B Biol Sci., 2003, 358, 1669-1677.
[3] Andrews GK & Geiser J., Expression of the mouse metallothionein-I and -II genes provides a reproductive advantage during maternal dietary zinc deficiency [J]. J Nutr. 1999, 129, 1643-1648.
[4] Andrews GK., Regulation of metallothionein gene expression by oxidative stress and metal ions [J]. Biochem. Pharmacol, 2000, 59, 95-104.
[5] Anezaki T, lshiguro H, Hozumi I, etc., Expression of growth inhibitory factor (GIF) in normal and injured rat brains [J]. Neurochem. Int., 1995, 27, 89-94.
[6] Aoki C, Nakanishi T, Sogawa N,etc. Stimulatory effects of 4-methylcatechol, dopamine and levodopa on the expression of metallothionein-Ill (GIF) mRNA in immortalized mouse brain glial cells (VR-2g) [J]. Brain Res., 1998,792,335-339.
[7] Aschner M, Cherian MG, Klaassen CD, etc., Metallothionein in brain: The role in physiology and pathology [J]. Toxicol. Appl. Pharmacol. 1997, 142, 229-242.
[8] Avolio C, F Giuliani, GM Liuzzi, etc., Adhesion molecules and matrix metalloproteinases in multiple sclerosis: effects induced by interferon-beta[J]. Brain Res Bull, 2003, 61, 357-364.
[9] Ayaz M, HA. Celik, HH. Aydin, etc., Sodium selenite protects against diabetes induced alterations in the antioxidant defense system of the liver [J]. Diabetes Metab Res Rev, 2005, 22(4): 295-299.
[10] Baskin F, GM Smith, JA Fosmire etc., Altered apoliopoprotein E secretion in cytokine treated human astrocyte cultures [J]. J Neurol. Sci., 1997,148, 15-18.
[11] Bauman, J. W., McKim, J. M. Jr., etc. Induction of metallothionein by diethyl maleate [J]. Toxicol. Appl. Pharmacol., 1992, 114:188-196.
[12] Beattie JH, AM Wood, AM Newman,etc, Obesity and hyperleptinemia in metallothionein (-I and -II) null mice[J]. Proc Natl. Acad. Sci., USA, 1998, 95, 358-363.
[13] Beattie JH, AM Wood, P Trayhurn, etc., Metallothionein is expressed in adipocytes of brown fat and is induced by catecholamines and zinc[J]. Am J Physiol. Regal. Integer. Comp. Physiol., 2000, 278, R1082-R1089.
[14] Binz P.A., J.H.R. Kagi, Molecular Evolution of Metallothioneins: Contributions from coding and non-coding Regions, http://www.bioc.uzh.ch.
[15] Bronnegard M, S Werner & JA Gustafsson, Regulation of glucocorticoid receptor expression in cultured fibroblasts from a patient with familial glucocorticoid resistance[J]. J Steroid Biochem. Mol. Biol. 1991, 39, 693-701.
[16] Brugnera E., O.Georgiev, F.Radtke,etc, Cloning, chromosomal mapping and characterization of the human metal-regulatory transcription factor MTF-1 [J], Nucleic Acids Res, 1994,22:3167-3173
[17] Bush, A I, W H Pettingell, MD Paradis, etc., Modulation of A beta adhesiveness and secretase site cleavage by zinc [J]. J. Biol. Chem. 1994. 269:12152-12158.
[18] Campbell IL., Cytokine-mediated inflammation and signaling in the intact central nervous system [J]. Prog Brain Res, 2001, 132,481-498.
[19] Canpolat E & Lynes MA., In vivo manipulation of endogenous metallothionein with a monoclonal antibody enhances a T-dependent humoral immune response [J]. Toxicol Sci., 2001,62,61-70
[20] Carol J., SD Findley, JC Erickson, etc., Induction of a New Metallothionein Isoform(MT-IV) Occurs during Differentiation of Stratified Squamous Epithelia [J], Biochemistry, 1994, 33:7250-7259.
[21] Carrasco J, Hernandez J, H Bluethmann, etc., Interleukin-6 and tumor necrosis factor-alpha type 1 receptor deficient mice reveal a role of IL-6 and TNF-alpha on brain metallothionein-I and -III regulation [J]. Brain Res Mol Brain Res, 1998, 57, 221-234.
[22] Carrasco J, J Hernandez, B Gonzalez, etc., Localization of metallothionein-I and -III expression in the CNS of transgenic mice with astrocyte-targeted expression of interleukin 6 [J]. Exp. Neurol., 1998, 153, 184-194.
[23] Carrasco J, M Penkowa, H Hadberg, etc., Enhanced seizures and hippocampal neurodegeneration following kainic acid-induced seizures in metallothionein-I + II-deficient mice [J]. Eur. J. Neurosis., 2000, 12, 2311-2322.
[24] Carrasco J., M.Giralt, M.Penkowa, etc., Metallothioneins are upregulated in symptomatic mice with astrocyte-targeted expression of tumor necrosis factor-alpha [J]. Exp Neurol., 2000, 163, 46-54.
[25] Ceballos D, N Lago, E Verdu, etc., Role of metallothioneins in peripheral nerve function [J]. Regeneration Cell Mol Life Sci., 2003,60,1209-1216.
[26] Chapman GA, Kay J and Kille P: Structural and functional analysis of the rat metallothionein Ill genomic locus. Biochim [J]. Biophys. Acta, 1999, 1445, 32 1-329.
[27] Cherian MG & Apostolova MD., Nuclear localization of metallothionein during cell proliferation and differentiation [J]. Cell Mol Biol., 2000,46, 347-356.
[28] Chiharu, A. S., M Asanuma, N Sogawa, etc., Localization, Regulation, and Function if Metallothionein-III in the brain, Acta Med. Okayama, 2001, 55(1):1-9.
[29] Choudhuri S, McKim JM Jr and Klaassen CD: Differential expression of the metallothionein gene in liver and brain of mice and rats [J]. Toxicol Appl. Pharmacol, 1993, 119: 1-10.
[30] Chung RS and West AK., A role for extracellular metallothioneins in CNS injury and repair [J]. Neuroscience, 2004, 123: 595-599.
[31] Chung RS, PA Adlard, J Dittmann, etc., Neuron-glia communication: metallothionein expression is specifically up-regulated by astrocytes in response to neuronal injury [J]. J. Neurochem., 2004, 88: 454-461.
[32] Chung RS, Vickers JC, Chuah MI, etc., Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury [J]. J. Neurosci., 2003,23: 3336-3342.
[33] Coogan, T. P., RM Bare, EJ Bjornson, etc. Enhanced metallothionein gene expression is associated with protection from cadmium-induced genotoxicity in cultured rat liver cells[J]. J. Toxicol. Environ. Health, 1994, 41:233-245.
[34] Crowthers KC, V Kline, C Giardina, etc., Augmented humoral immune function in metallothionein-null mice [J]. Toxicol Appl. Pharmacol, 2000, 166: 161-172.
[35] Cuajungco, M. P.; Lees, G. J. Zinc metabolism in the brain: Relevance to human neurodegenerative disorders [J]. Neurobiol. Dis. 1997,4:137-169.
[36] Danscher, G., KB Jensen, CJ Frederickson, etc., Increased amount of zinc in the hippocampus and amygdala of Alzheimer's diseased brains: A proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material [J]. J. Neurosci. Methods, 1997, 76:53-59.
[37] Dincer, Z., S Haywood, B.Jasani, Immunocytochemical detection of metallothionein (MT1 and MT2) in copper-enhanced sheep brains [J]. J. Comp. Pathol., 1999, 120:29 -37.
[38] Dunn, M. A., TL Blalock, RJ Cousins, Metallothionein[J]. Proc. Soc. Exp. Biol. Med., 1987, 185:107-119.
[39] Ebadi M, Brown-Borg H, El Refaey H, etc., Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease[J]. Brain Res Mol Brain Res, 2005, 134: 67-75.
[40] Ebadi M, Sharma SK, Ghafourifar P, etc., Peroxynitrite in the pathogenesis of Parkinson's disease and the neuroprotective role of Metallothioneins [J]. Meth Enzymol., 2005, 396: 276-298.
[41] Ebadi, M., PL Iversen, R Hao, etc., Expression and regulation of brain metallothionein[J]. Neurochem. Int. 1995, 27:1-22.
[42] Eileen M. DW., K. L. Gilby, S.E. Howlett, etc., Isolation of total cellular RNA from brain tissue[M], OXFORD Practical Approach Series, Oxford University, 2001.
[43] Elmayan T, Tepfer M: Synthesis of a bifunctional metallothionein/-glucuronidase fusion protein in transgenic tobacco plants as a means of reducing leaf cadmium levels[J]. Plant J., 1994,6:433-440.
[44] Erickson JC, Hollopeter G, Thomas SA, etc., Discruption of the metallothionein-Ill gene in mice: Analysis of brain zinc, behavior and neuron vulnerability to metals, aging, and seizures [J]. J Neurosci., 1997, 17: 1271 -1281 .
[45] Erickson JC, Masters BA, Kelly EJ, etc., Expression of human metallothionein-III in transgenic mice [J]. Neurochem. Int. 1995, 27: 35-4 1.
[46] Erickson JC, Sewell AK, Jensen LT, etc., Enhanced neurotrophic activity in Alzheimer's disease cortex is not associated with down-regulation of metallothionein-III (GIF) [J]. Brain Res., 1994, 649: 297-304.
[47] Erickson, J. C; Hollopeter, G.; Thomas, S. A., etc., Disruption of the metallothionein-III gene in mice: Analysis of brain zinc, behavior, and neuron vulnerability to metals, aging, and seizures [J]. J. Neurosci., 1997, 17:1271-1281.
[48] Espejo C & Martinez-Caceres EM., The role of methallothioneins in experimental autoimmune encephalomyelitis and multiple sclerosis[J]. Ann NY Acad. Sci., 2005, 1051: 88-96.
[49] Espejo C, Penkowa M, Demestre M, etc., Time-course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during experimental autoimmune encephalomyelitis [J]. Neuroscience, 2005, 132: 1135-1149.
[50] Faulkner JR., Herrmann JE, Woo MJ, etc., Reactive astrocytes protect tissue and preserve function after spinal cord injury [J]. J Neurosci., 2004, 24:2143-2155.
[51] Feng W, Cai J, Pierce WM,etc, Metallothionein transfers zinc to mitochondrial aconitase through a direct interaction in mouse hearts[J]. Biochem. Biophys Res Commun, 2005, 332: 853-858.
[52] Floyd, R. A. Neuroinflammatory processes are important in neurodegenerative diseases: A hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development[J]. Free Radic. Biol. Med., 1999,26:1346-1355.
[53] Fowler BA, Hildebrand CE, Kojima Y, Webb M. Nomenclature of metallothionein[J]. Experiential Suppl. 1987, 52:19-22.
[54] Frederickson CJ, Maret W & Cuajungco MP., Zinc and excitotoxic brain injury: a new model. Neuroscientist, 2004, 10: 18-25.
[55] Garrett SH, Sens MA, Shukla D, etc., Metallothionein isoforms 3 expression in the human prostate and cancer-derived cell lines[J]. Prostate, 1999,41: 196-202.
[56] Garrett SH, Sens MA, Todd JH, etc., Expression of MT-3 protein in the human kidney[J]. Toxicol Lett. 1999, 105:207-2 14.
[57] Gasche Y, Soccal PM, Kanemitsu M, etc., Matrix metalloproteinases and diseases of the central nervous system with a special emphasis on ischemic brain[J]. Front Biosci., 2006, 11: 1289-1301.
[58] Ghazi I. EL, B. L. Martin, I. M. Armitage, Metallothionein-3 Is A Component of Mutiprotein Complex in the Mouse Brain[J], Exp. Biol. Med.,2006, 231: 1500-1506
[59] Ghoshal K. and Jacob ST., Regulation of metallothionein gene expression[J]. Prog Nucleic Acid Res Mol Biol, 2001, 66: 357-384.
[60] Giralt M, Carrasco J, Penkowa M, etc., Campbell IL and Hidalgo J., Astrocyte-targeted expression of interleukin-3 and interferon-alpha causes region-specific changes in metallothionein expression in the brain[J]. Exp Neurol, 2001, 168:334-346.
[61] Giralt M, Penkowa M, Hernandez J,etc, Metallothionein-1+2 deficiency increases brain pathology in transgenic mice with astrocyte- targeted expression of interleukin 6[J]. Neurobiol Dis. 2002, 9: 319-338.
[62] Giralt M, Penkowa M, Lago N, etc., Metallothionein-1+2 protect the CNS after a focal brain injury[J]. Exp Neurol, 2002,173:114-128.
[63] Gong YH & Elliott JL., Metallothionein expression is altered in a transgenic murine model of familial amyotrophic lateral sclerosis[J]. Exp Neurol, 2000, 162: 27-36.
[64] Hahn SH, Yoo OJ & Gahl WA . Effect of metal ions on the stability of metallothionein in the degradation by cellular fractions in vitro[J]. Exp Mol Med. 2001, 33:32-36.
[65] Haq F, Mahoney M & Koropatnick J., Signaling events for metallothionein induction[J]. Mutat Res, 2003, 533: 211-226.
[66] Hernandez J, Molinero A, Campbell IL, etc., Transgenic expression of interleukin 6 in the central nervous system regulates brain metallothionein-I and -III expression in mice[J]. Brain Res Mol Brain Res ,1997, 48: 125-131.
[67] Hidalgo J, Aschner M, Zatta P, etc., Roles of the metallothionein family of proteins in the central nervous system[J]. Brain Res Bull, 2001, 55: 133-145.
[68] Hidalgo J, Belloso E, Hernandez J, etc., Role of glucocorticoids on rat brain metallothionein-I and -III response to stress [J]. Stress, 1997, 1: 231-240.
[69] Hidalgo J., Penkowa M., Giralt M., etc., Metallothionein expression and oxidative stress in the brain [J]. Methods Enzymol, 2002, 348:238-249.
[70] Hoey JG, Garrett SH, Sens MA, etc., Expression of MT-3 mRNA in human kidney, proximal tubule cell cultures, and renal cell carcinoma [J]. Toxicol Lett, 1997, 92:149- 160.
[71] Honegger P and Guentert-Lauber B, Epidermal growth factor (EGF) stimulation of cultured brain cells. I. Enhancement of the developmental increase in glial enzymatic activity [J]. Brain Res. 1983,313:245-251.
[72] Hozumi, I.; Inuzuka, T.; Hiraiwa, M.; etc., Changes of growth inhibitory factor after stab wounds in rat brain [J]. Brain Res. 1995, 688:143-148.
[73] Hozumi, I.; Inuzuka, T.; Ishiguro, etc., Immunoreactivity of growth inhibitory factor in normal rat brain and after stab wounds—An immunocytochemical study using confocal laser scan microscope [J]. Brain Res., 1996, 741:197-204.
[74] Huang, X.; Cuajungco, M. P.; Atwood, etc., Alzheimer's disease, beta-amyloid protein and zinc [J]. J. Nutr., 2000, 130:1488-1493;
[75] Hye, G. J., CK Youn, HJ Cho, Metallothionein-III Prevents γ-Ray-induced 8-Oxoguanine Accumulation in Normal and hOGG1-depleted Cells [J], 2004, 33(279): 34138-34149. Chinese hamster ovary cells expressing mouse metallothionein [J]. Mol. Pharmacol., 1993, 44:44-50;
[94] Kramer KK, Liu J, Choudhuri S and Klssen CD: Induction of metallothionein mRNA and protein in murine astrocyte cultures [J]. Toxicol Appl Pharmacol. 1996, 136: 94-100.
[95] Kramer KK, Zoelle JT and Klssen CD: lnduction of metallothionein mRNA and protein in primary murine neuron cultures [J]. Toxicol Appl Pharmacol, 1996, 141: 1-7.
[96] Lefebvre, D. D., Miki, B. L. & Laliberte, J. F., Mammalian metallothionein functions in plants [J]. Biotechnology, 1987, 5:1053-1056.
[97] Leibbrandt ME & Koropatnick J., Activation of human monocytes with lipopolysaccharide induces metallothionein expression and is diminished by zinc [J]. Toxicol Appl Pharmacol, 1994,124:72-81.
[98] Leibbrandt ME, Khokha R & Koropatnick J., Antisense down-regulation of metallothionein in a human monocytic cell line alters adherence, invasion, and the respiratory burst [J]. Cell Growth Differ. 1994,5: 17-25.
[99] Leutz A and Schachner M, Epidermal growth factor stimulates DNAsynthesis of astrocytes in primary cerebellar cultures [J]. Cell Tissue Res., 1981, 220: 393-404.
[100] Liu, J.; Kershaw, W. C; Klaassen, C. D. The protective effect of metallothionein on the toxicity of various metals in rat primary hepatocyte culture [J]. Toxicol. Appl. Pharmacol. 1991, 107: 27-34.
[101] Liu, Y.; Liu, J.; Iszard, M. B., etc., Transgenic mice that overexpress metallothionein-I are protected from cadmium lethality and hepatotoxicity [J]. Toxicol. Appl. Pharmacol. 1995, 135:222-228.
[102] Lovell, M. A.; Robertson, J. D.; Teesdale, W. J., etc., Copper, iron, and zinc in Alzheimer's disease senile plaques [J]. J. Neurol. Sci., 1998, 158:47-52;.
[103] ltano Y, Noji S, Koyama E, etc., Bacterial endotoxin-induced expression of metallothionein genes in rat brain, as revealed by in situ hybridization [J], Neurosci Lett ,1991, 124: 13- 16.
[104] Lynes MA, Borghesi LA, Youn J, etc. Immunomodulatory activities of extracellular metallothionein I: metallothionein effects on antibody production [J]. Toxicology , 1993, 85: 161-177.
[105] Maret W., Optical methods for measuring zinc binding and release, zinc coordination environments in zinc finger proteins, and redox sensitivity and activity of zinc-bound thiols [J]. Methods Enzymol, 2002, 348: 230-237.
[106] Maret W, Heffron G, Hill HA, Djuricic D, etc., The ATP/metallothionein interaction: NMR and STM [J]. Biochem, 2002,41: 1689-1694.
[107] Masatoshi N., S. Kumar, Molecular evolution and phylogenetics[M], Oxford University Press, Inc., 2000.
[108] Masters BA, Kelly EJ, Quaife CJ, etc. Targeted disruption of metallothionein I and II genes increases sensitivity to cadmium [J]. Proc Natl Acad Sci USA , 1994, 91: 584-588.
[109] Masters BA, Quaife CJ, Erickson JC, etc., Metallothionein Ill is expressed in neurons that sequester zinc in synaptic vesicles [J]. J Neurosci., 1994, 14: 5844-5857.
[110] Mehra, R. K.; Bremner, I. Species differences in the occurrence of copper-metallothionein in the particulate fractions of the liver of copper-loaded animals [J]. Biochem. J., 1984, 219:539-546.
[111] Mhatre M, Floyd RA & Hensley K., Oxidative stress and neuroinflammation in Alzheimer's disease and amyotrophic lateral sclerosis: common links and potential therapeutic targets [J]. J Alzheimers Dis., 2004,6: 147-157.
[112] Michalska AE & Choo KH. Targeting and germ-line transmission of a null mutation at the metallothionein I and II loci in mouse [J]. Proc Natl Acad Sci USA., 1993, 90: 8088-8092.
[113] Miesel R & Zuber M., Copper-dependent antioxidase defenses in inflammatory and autoimmune rheumatic diseases [J]. Inflammation, 1993, 17: 283-294.
[114] Milena P., Metallothioneins are multipurpose neuroprotectants during brain pathology [J], FEBS Journal, 2006, 273:1857-1870.
[115] Miles AT, Hawksworth GM, Beattie JH, etc., Induction, regulation, degradation, and biological significance of mammalian metallothioneins [J]. Crit Rev Biochem Mol Biol, 2000, 35:35-70.
[116] Miyazaki I, Sogawa CA, Asanuma M, etc., Expression of metallothionein-Ill mRNA and its regulation by levodopa in the basal ganglial of hemi-parkinsonian rats [J]. Neurosci Lett., 2000, 293: 65-68.
[117] Moffatt P and Seguin C, Expression of the gene encoding metallothionein-3 in organs of the reproductive system [J]. DNA Cell Biol., 1998, 17: 501-510.
[118] Molinero A., Penkowa M., Hernandez J., etc., Metallothionein-I overexpression decreases brain pathology in transgenic mice with astrocyte-targeted expression of interleukin-6 [J]. JNeuropathol Exp Neurol, 2003, 62: 315-328.
[119] Morrison RS, Kornblum HI, Leslie FM, etc., Trophic stimulation of cultured neurons from neonatal rat brain by epidermal growth factor [J]. Science, 1987, 238: 72-75.
[120] Nagano S, Satoh M, Sumi H, etc., Reduction of metallothioneins promotes the disease expression of familial amyotrophic lateral sclerosis mice in a dosedependent manner [J]. Eur J Neurosci, 2001, 13: 1363-1370.
[121] Naruse S, lgarashi S, Furuya T, etc., Structures of the human and mouse growth inhibitory factorencoding genes [J]. Gene, 1994, 144: 283-287.
[122] Natale JE, Knight JB, Cheng Y, etc., Metallothionein I and II mitigate age-dependent secondary brain injury [J]. J Neurosci Res., 2004, 78: 303-314.
[123] Nordberg, M., and Kojima, Y. Metallothionein and other low molecular weight metal binding proteins. In 'Metallothionein'[C]. (Eds J. H. R. Kagi and M. Nordberg.) (Birkhauser-Verlag: Boston.), 1979, 197-204..
[124] Ogawa N: Levodopa and dopamine agonists in the treatment of Parkinson's disease: Advantages and disadvantages [J]. Eur Neurol., 1994, 34:20-28.
[125] Ogra Y & Suzuki KT, Nuclear trafficking of metallothionein: possible mechanisms and current knowledge [J]. Cell Mol Biol. 2000, 46: 357-365.
[126] Oz, G., K. Zangger, and I. M. Armitage. Three-dimensional structure and dynamics of a brain specific growth inhibitory factor: metallothionein-3 [J]. Biochem., 2001,40: 11433-11441.
[127] Palmiter R D, Brinster R L, Hammer R E, etc., Dramatic growth of mice that develop from eggs microinjected with metallothionein growth hormone fusion genes [J], Nature, 1982, 300:611-615
[128] Palmiter RD, Norstedt G, Gelinas RE, etc., Metallothionein human GH fusion genes stimulate growth of mice [J]. Science, 1983,222: 809-814
[129] Penkowa M & Hidalgo J., Metallothionein I+II expression and their role in experimental autoimmune encephalomyelitis [J]. Glia, 2000, 32: 247-263.
[130] Penkowa M & Hidalgo J., Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE) [J]. Exp Neurol., 2001, 170:1-14.
[131] Penkowa M and Hidalgo J., Treatment with metallothionein prevents demyelination and axonal damage and increases oligodendrocyte precursors and tissue repair during experimental autoimmune encephalomyelitis [J]. J Neurosci Res, 2003, 72: 574-586.
[132] Penkowa M, Camats J, Hadberg H,etc, Astrocyte-targeted expression of interleukin-6 protects the central nervous system during neuroglial degeneration induced by 6-aminonicotinamide [J]. J Neurosci Res. 2003, 73: 481-496.
[133] Penkowa M, Carrasco J, Giralt M, etc., Altered central nervous system cytokine-growth factor expression profiles and angiogenesis in metallothionein-I+II deficient mice [J]. J Cereb Blood Flow Metab., 2000, 20: 1174-1189.
[134] Penkowa M, Carrasco J, Giralt M, etc., CNS wound healing is severely depressed in metallothionein I- and II-deficient mice [J]. J Neurosci, 1999, 19: 2535-2545.
[135] Penkowa M, Espejo C, Martinez-Caceres EM, Montalban X & Hidalgo J. Increased demyelination and axonal damage in metallothionein I+II-deficient mice during experimental autoimmune encephalomyelitis [J]. Cell Mol Life Sci., 2003, 60: 185-197.
[136] Penkowa M, Espejo C, Martinez-Caceres EM, etc., Altered inflammatory response and increased neurodegeneration in metallothionein I+II deficient mice during experimental autoimmune encephalomyelitis [J]. J Neuroimmunol, 2001, 119: 248-260.
[137] Penkowa M, Florit S, Giralt M, etc., Metallothionein reduces central nervous system inflammation, neurodegeneration, and cell death following kainic acidinduced epileptic seizures [J]. J Neurosci Res, 2005, 79: 522-534.
[138] Penkowa M, Giralt M, Camats J, etc., Metallothionein 1+2 protect the CNS during neuroglial degeneration induced by 6-aminonicotinamide [J]. J Comp Neurol, 2002, 444: 174-189.
[139] Penkowa M, Giralt M, Moos T, etc. Impaired inflammatory response to glial cell death in genetically metallothionein-I- and -II-deficient mice [J]. Exp Neurol., 1999, 156: 149-164.
[140] Penkowa M, Giralt M, Thomsen PS, etc. Zinc or copper deficiency-induced impaired inflammatory response to brain trauma may be caused by the concomitant metallothionein changes [J]. J Neurotrauma, 2001, 18: 447-463.
[141] Penkowa M, Molinero A, Carrasco J,etc, Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures [J]. Neuroscience, 2001,102: 805-818.
[142] Penkowa M, Moos T, Carrasco J, etc., Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice [J]. Glia, 1999, 25: 343-357.
[143] Penkowa M, Nielsen H, Hidalgo J, etc., Distribution of metallothionein I +II and vesicular zinc in the developing central nervous system:correlative study in the rat [J]. J Comp Neurol, 1999, 412:303-318.
[144] Penkowa M, Poulsen C, Carrasco J, etc., M-CSF deficiency leads to reduced metallothioneins I and II expression and increased tissue damage in the brain stem after 6-aminonicotinamide treatment [J]. Exp Neurol, 2002, 176: 308-321.
[145] Penkowa M, Quintana A, Carrasco J, etc., Metallothionein prevents neurodegeneration and central nervous system cell death after treatment with gliotoxin 6-aminonicotinamide [J]. J Neurosci Res, 2004, 77: 35-53.
[146] Penkowa M, Tio L, Mecedes G, etc., Specificity and divergence in the neurobiological effects of different Metallothioneins after brain injury [J]. J Neurosci Res, 2006, doi: 10.1002/jnr.20790.
[147] Penkowa M. and Hidalgo J., Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE) [J]. Exp Neurol, 2001, 170: 1-14.
[148] Penkowa, M.; Carrasco, J.; Giralt, M., etc. Altered central nervous system cytokinegrowth factor expression profiles and angiogenesis in metallothionein-I/II deficient mice [J]. J. Cereb. Blood Flow Metab., 2000,20:1174-1189;.
[149] Penkowa, M.; Moos, T.; Carrasco, etc. Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice [J]. Glia., 1999, 25:343-357;.
[150] Piscator, M. Om kadmium i normala ma¨nniskonjurar samt redogorelse for isolering av metallothionein ur level fran kadmiumexponerade kaniner [J]. Nord. Hyg. Tidskr., 1964, 45: 76-82.
[151] Poulsen CB, Penkowa M, Borup R, etc., Brain response to traumatic brain injury in wild-type and interleukin-6 knockout mice: a microarray analysis [J]. J Neurochem, 2005, 92: 417-432.
[152] Pulido P, Kagi JHR, Vallee BL: Isolation and some. Properties of human metallothionein [J]. Biochemistry., 1966, 5:1768-1777.
[153] Pursel VG, Pinkert CA, Miller KF, etc. Genetic enginee ring of livestock [J]. Science, 1989,244:1281-1288.
[154] Quaife, C. J., Findley, S. D., Erickson, J. C.,etc, Organization and Assembly of Metal-Thiolate Clusters in Epithelium specific Metallothionein-4 [J], Biochemistry, 1994, 33:7250-7259.
[155] Quintana A, Giralt M, Rojas S, etc., Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury [J]. J Neurosci Res, 2005, 82:701-716.
[156] Richard D. P., S. D. Findley, T. E. Whitmore, etc., MT-III, a brain-special member of the metallothionein gene family [J], Proc. Natl. Acad. Sci. USA, 1992, 89: 6333-6337.
[157] Richard D. P., The elusion function of metallothioneines [J], Pro. Natl. Acad.Sci., UAS, 1998,95:8424-8430.
[158] Sadhu, C.; Gedamu, L. Metal-specific posttranscriptional control of human metallothionein genes [J]. Mol. Cell. Biol., 1989, 9:5738 -5741.
[159] Safieh-Garabedian B, Haddad JJ & Saade NE., Cytokines in the central nervous system: targets for therapeutic intervention [J]. Curr Drug Targets CNS Neurol Disord, 2004, 3: 271-280.
[160] Safieh-Garabedian B, Mouneimne GM, El Jouni W, etc., The effect of endotoxin on functional parameters of mammary CID-9 cells [J]. Reproduction, 2004, 127, 397-406.
[161] Sano T., Glazer A N, Cantor C R, A Strepravidin-metallothionein chimera that allows specific labeling of biological materials with many different heavy metal ions [J], Proc. Natl. Acad. Sci. USA, 1992, 89: 1534-1538
[162] Saremi M. A., S. Mahnaz, T. Mahmood, Rapid Genomic DNA Extraction (RGDE) [Z], Protocol Online, http://www.protocol-online.org.
[163] Sato M, Bremner I. Oxygen free radicals and metallothionein [J].Free Rad Biol 1993,14: 325-37.
[164] Scheede-Bergdahl C, Penkowa M, Hidalgo J, etc. Metallothionein-mediated antioxidant defense system and its response to exercise training are impaired in human type 2 diabetes [J]. Diabetes, 2005, 54: 3089-3094.
[165] Searle PF, Davison BL, Stuart GW, etc., Regulation, linkage, and sequence of mouse metallothionein I and II genes [J]. Mol Cell Biol, 1984,4: 1221-1230.
[166] Sewell AK, Jensen LT, Erickson JC, etc., Bioactivity of metallothionein-3 correlates with its novel domain sequence rather than metal binding properties [J]. Biochemistry, 1995, 34: 4740-4747.
[167] Sharp F. R., RQ. Ran, AG Lu, etc., Hypoxic Preconditioning Protects against Ischemic Brain Injury [J], NeuroRx., 2004, 1(1): 26-35.
[168] Sofroniew MV., Reactive astrocytes in neural repair and protection [J]. Neuroscientist, 2005,11:400-407.
[169] Sogawa CA, Miyazaki I, Sogawa N, etc., Antioxidants protect against dopamine- induced metallothionein-Ill (GIF) mRNA expression in mouse glial cell line (VR-2g) [J]. Brain Res, 2000, 853:310-316.
[170] Stankovic RK, Atrophy of large myelinated axons in metallothionein-I, II knockout mice [J]. Cell Mol Neurobiol, 2005,25:943-953.
[171] Steinebach OM & Wolterbeek BT., Metallothionein biodegradation in rat hepatoma cells: a compartmental analysis aided 35S-radiotracer study [J]. Biochim Biophys Acta. 1992,1116,155-165.
[172] Stuart G. W., Searle P.F. & Palmiter R.D. Identification of multiple metal regulatory elements in mouse metallothionein-I promoter by assaying synthetic sequences [J], Nature, 1985, 317:828-831.
[173] Takahashi Y, Ogra Y & Suzuki KT., Nuclear trafficking of metallothionein requires oxidation of a cytosolic partner [J]. J Cell Physiol, 2005, 202, 563-569.
[174] Tang CM, Westling J & Seto E., Transrepression of the human metallothionein IIA gene promoter by PZ120, a novel 120-kilodalton zinc finger protein [J]. Mol Cell Biol, 1999, 19: 680-689.
[175] Thornalley PJ, Vasa k M. Possible role for metallothionein in protection against radiation induced oxidative stress. Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals [J]. Biochim Biophys Acta, 1985, 827:36-44.
[176] Trayhurn P, Duncan JS, Wood AM & Beattie JH., Metallothionein gene expression and secretion in white adipose tissue [J]. Am J Physiol Regul Integr Comp Physiol, 2000, 279: R2329-R2335.
[177] Trayhurn P, Duncan JS, Wood AM & Beattie JH., Regulation of metallothionein gene expression and secretion in rat adipocytes differentiated from preadipocytes in primary culture [J]. Horm Metab Res, 2000, 32: 542-547.
[178] Trendelenburg G, Prass K, Priller J, et al. Serial analysis of gene expression identifies metallothionein-II as major neuroprotective gene in mouse focal cerebral ischemia [J]. J Neurosci, 2002, 22: 5879-5888.
[179] Tsuji S, Kobayashi H, Uchida Y, etc., Molecular cloning of human growth inhibitory factor cDNA and its down-regulation in Alzheimer's disease [J]. EMBO J., 1992, 11: 4843-4850.
[180] Uchida Y, Masumizu A and lhara Y, Protection of cultured cortical neurons from P-amyloid neurotoxicity [J]. Neurochem Res , 1995,21: 320-32 1.
[181] Uchida Y, Shimizu T and lhara Y, Inhibition of P-amyloid-induced toxicity by GIF (in Japanese) [J]. Bulletin of the Japanese Society for Neurochemistry, 1994, 35: 184-185.
[182] Uchida Y, Growth-inhibitory factor, metallothionein-like protein, and neurodegenerative diseases [J]. Biol Signals, 1994, 3: 211-215.
[183] Uchida Y, Regulation of growth inhibitory factor expression by epidermal growth factor and interleukin-lp in cultured rat asctrocytes [J]. J Neurochem, 1999, 73: 1945- 1953.
[184] Uchida, Y. Growth-inhibitory factor, metallothionein-like protein, and neurodegenerative diseases [J]. Biol. Signals, 1994, 3:211-215.
[185] Uchida, Y. Regulation of growth inhibitory factor expression by epidermal growth factor and interleukin-1b in cultured rat astrocytes [J]. J. Neurochem. 1999,73:1945-1953.
[186] Uchida, Y., K. Takio, K. Titani, etc. The growth inhibitory factor that is deficient in the Alzheimer's diseased brain is a 68 amino acid metallothionein-like protein [J]. J. Neuron. 1991, 7: 337-347.
[187] Uchida, Y.; Takio, K.; Titani, K.; etc. The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein [J]. Neuron, 1991,7:337-347.
[188] Van L. CM., H. Thibodeaux, N.V. Bruggen, etc., Evidence for a protective role of metallothionein-1 in focal cerebral ischemia [J]. Proc Natl Acad Sci USA, 1999, 96: 12870-12875.
[189] Vasak M., Advances in metallothionein structure and functions [J], Journal of Trace Elements in Medicine and Biology, 2005, 19:13-17
[190] Vasconcelos MH, Tarn SC, Beattie JH, etc. Evidence for differences in the post-transcriptional regulation of rat metallothionein isoforms [J]. Biochem J. 1996, 315: 665-671.
[191] Vasconcelos MH, Tam SC, Hesketh JE, etc. Metal- and tissue-dependent relationship between metallothionein mRNA and protein [J]. Toxicol Appl Pharmacol, 2002, 182:91-97.
[192] Villoslada P & Genain CP. Role of nerve growth factor and other trophic factors in brain inflammation [J]. Prog Brain Res, 2004, 146, 403-414.
[193] Waalkes MP and Klaassen CD, Concentration of metallothionein in major organs of rats after administration of various metals [J]. Fundam Appl Toxicol, 1985, 5: 473-477
[194] Wang J, Asensio VC & Campbell IL . Cytokines and chemokines as mediators of protection and injury in the central nervous system assessed in transgenic mice [J]. Curr Top Microbiol Immunol, 2002,265,23-48.
[195] Wang, H., Q. Zhang, B. Cai, etc. Solution structure and dynamics of human metallothionein-3 (MT-3) [J]. FEBS Letters, 2006, 580: 795-800.
[196] West AK, Chuah MI, Vickers JC, etc., Protective role of metallothioneins in the injured mammalian brain [J]. Rev Neurosci., 2004, 15: 157-166.
[197] Wilson, A.; Trombetta, L. D. The protective effects of zinc on diethyldithiocarbamate cytotoxicity on rat astrocytes in vitro [J]. Toxicol. Lett. 1999, 105:129 -140.
[198] Woo ES., Dellapiazza D., Wang AS. and Lazo JS., Energy-dependent nuclear binding dictates metallothionein localization [J]. J Cell Physiol, 2000, 182: 69-76.
[199] Wright J, George S, Martinez-Lara E, etc. Levels of cellular glutathione and metallothionein affect the toxicity of oxidative stressors in an established carp cell line [J]. Mar Environ Res 2000, 50:503-8.
[200] Wu, J. P., B. Y. Ma, H. W. Ren, etc. Characterization of metallothioneins MT-I and MT-II in yak [J]. J. Anim. Sci., 2007, 85:1357-1362.
[201] Wu, J. Y.; Matsuda, T.; Roberts, E. Purification and characterization of glutamate decarboxylase from mouse brain [J]. J. Biol. Chem., 1973, 248:3029-3034;
[202] www.bioc.uzh.ch/mtpage/MT.html
[203] Yamada M, Hayashi S, Hozumi I, etc., Subcellular localization of growth inhibitory factor in rat brain: Light and electron microscopic immunohistochemical studies [J]. Brain Res, 1996, 735: 257-264.
[204] Yanagitani S, Miyazaki H, Nakahashi Y, etc., Ischemia induces metallothionein Ill expression in neurons of rat brain [J]. Life Sci., 1999,64: 707-715.
[205] Yao, C. P.; Allen, J. W.; Conklin, D. R., etc. Transfection and overexpression of metallothionein-I in neonatal rat primary astrocyte cultures and in astrocytoma cells increases their resistance to methylmercury-induced cytotoxicity [J]. Brain Res. 1999., 818:414-420;
[206] Yao, C. P., J. W. Allen, L. A.Mutkus , etc. Foreign metallothionein-I (MT-I) expression by transient transfection in MT-I and -II null astrocytes confers increased protection against acute methylmercury cytotoxicity [J]. Brain Res. 2000, 855: 32-38.
[207] Ye B, Maret W & Vallee BL. Zinc metallothionein imported into liver mitochondria modulates respiration [J]. Proc Natl Acad Sci USA. 2001, 98, 2317-2322.
[208] Yin X, Knecht DA & Lynes MA. Metallothionein mediates leukocyte chemotaxis [J]. BMC Immunol, 2005, 6: 21.
[209] Youn J & Lynes MA. Metallothionein-induced suppression of cytotoxic T lymphocyte function: an important immunoregulatory control [J]. Toxicol Sci., 1999, 52:199-208.
[210] Youn J, Borghesi LA, Olson EA & Lynes MA. Immunomodulatory activities of extracellular metallothionein II: effects on macrophage functions [J]. J Toxicol Environ Health, 1995,45,397-413.
[211] Yuguchi, T., Kohmura, E., Yamada, K., etc. Expression of growth inhibitory factor mRNA following cortical injury [J]. J. Neurotrauma, 1995, 12:299 -306.
[212]Zambenedetti,P.;Giordano,R.;Zatta,P.Metallothioneins are highly expressed in astrocytes and microcapillaries in Alzheimer's disease[J].J.Chem.Neuroanat.,1998,15:21-26.
[213]Zangger K,Oz G,Haslinger E,etc.Nitric oxide selectively releases metals from the aminoterminal domain of metallothioneins:potential role at inflammatory sites[J].FASEB J.,2001,15:1303-10.
[214]Zhang Rongchang,Wu Jianping and Han Jianlin.Yak production in China.Asian livestock:Yak[M],1994,615(10):115-118.
[215]Zheng H,Berman NE and Klaassen CD:Chemical modulation of metallothionein I and Ill mRNA in mouse brain[J].Neurochem lnt,1995,27:43-58.
[216]陈文明,李永森,亓绍玫等,青藏高原有色金属矿产分布特征[J],地球学报,2000,21:26-27
[217]彭克美,张登荣,组织学与胚胎学[M],中国农业出版社,2002.
[218]任宏伟,茹炳根,金属硫蛋白(Metallothionein,MT)基因在转基因领域的应用,生物工程进展[J],2000,20(4):35-39
[219]芮宗瑶,李光明,王龙生,青藏高原的金属矿产资源[J],地质通报,2004,1,VOL23(1):20-23
[220]萨姆布鲁克,J.,D.W.拉塞尔,黄培堂译.分子克隆试验指南(第三版)[M],科学出版社,2002.8
[221]吴建平,马彬云,张利平等,简明基因工程与应用[M],科学出版社,2005。
[222]张容昶,中国的牦牛[M],甘肃科学技术出版社,1988
[2] Allan SM & Rothwell NJ., Inflammation in central nervous system injury [J]. Philos Trans R Soc Lond B Biol Sci., 2003, 358, 1669-1677.
[3] Andrews GK & Geiser J., Expression of the mouse metallothionein-I and -II genes provides a reproductive advantage during maternal dietary zinc deficiency [J]. J Nutr. 1999, 129, 1643-1648.
[4] Andrews GK., Regulation of metallothionein gene expression by oxidative stress and metal ions [J]. Biochem. Pharmacol, 2000, 59, 95-104.
[5] Anezaki T, lshiguro H, Hozumi I, etc., Expression of growth inhibitory factor (GIF) in normal and injured rat brains [J]. Neurochem. Int., 1995, 27, 89-94.
[6] Aoki C, Nakanishi T, Sogawa N,etc. Stimulatory effects of 4-methylcatechol, dopamine and levodopa on the expression of metallothionein-Ill (GIF) mRNA in immortalized mouse brain glial cells (VR-2g) [J]. Brain Res., 1998,792,335-339.
[7] Aschner M, Cherian MG, Klaassen CD, etc., Metallothionein in brain: The role in physiology and pathology [J]. Toxicol. Appl. Pharmacol. 1997, 142, 229-242.
[8] Avolio C, F Giuliani, GM Liuzzi, etc., Adhesion molecules and matrix metalloproteinases in multiple sclerosis: effects induced by interferon-beta[J]. Brain Res Bull, 2003, 61, 357-364.
[9] Ayaz M, HA. Celik, HH. Aydin, etc., Sodium selenite protects against diabetes induced alterations in the antioxidant defense system of the liver [J]. Diabetes Metab Res Rev, 2005, 22(4): 295-299.
[10] Baskin F, GM Smith, JA Fosmire etc., Altered apoliopoprotein E secretion in cytokine treated human astrocyte cultures [J]. J Neurol. Sci., 1997,148, 15-18.
[11] Bauman, J. W., McKim, J. M. Jr., etc. Induction of metallothionein by diethyl maleate [J]. Toxicol. Appl. Pharmacol., 1992, 114:188-196.
[12] Beattie JH, AM Wood, AM Newman,etc, Obesity and hyperleptinemia in metallothionein (-I and -II) null mice[J]. Proc Natl. Acad. Sci., USA, 1998, 95, 358-363.
[13] Beattie JH, AM Wood, P Trayhurn, etc., Metallothionein is expressed in adipocytes of brown fat and is induced by catecholamines and zinc[J]. Am J Physiol. Regal. Integer. Comp. Physiol., 2000, 278, R1082-R1089.
[14] Binz P.A., J.H.R. Kagi, Molecular Evolution of Metallothioneins: Contributions from coding and non-coding Regions, http://www.bioc.uzh.ch.
[15] Bronnegard M, S Werner & JA Gustafsson, Regulation of glucocorticoid receptor expression in cultured fibroblasts from a patient with familial glucocorticoid resistance[J]. J Steroid Biochem. Mol. Biol. 1991, 39, 693-701.
[16] Brugnera E., O.Georgiev, F.Radtke,etc, Cloning, chromosomal mapping and characterization of the human metal-regulatory transcription factor MTF-1 [J], Nucleic Acids Res, 1994,22:3167-3173
[17] Bush, A I, W H Pettingell, MD Paradis, etc., Modulation of A beta adhesiveness and secretase site cleavage by zinc [J]. J. Biol. Chem. 1994. 269:12152-12158.
[18] Campbell IL., Cytokine-mediated inflammation and signaling in the intact central nervous system [J]. Prog Brain Res, 2001, 132,481-498.
[19] Canpolat E & Lynes MA., In vivo manipulation of endogenous metallothionein with a monoclonal antibody enhances a T-dependent humoral immune response [J]. Toxicol Sci., 2001,62,61-70
[20] Carol J., SD Findley, JC Erickson, etc., Induction of a New Metallothionein Isoform(MT-IV) Occurs during Differentiation of Stratified Squamous Epithelia [J], Biochemistry, 1994, 33:7250-7259.
[21] Carrasco J, Hernandez J, H Bluethmann, etc., Interleukin-6 and tumor necrosis factor-alpha type 1 receptor deficient mice reveal a role of IL-6 and TNF-alpha on brain metallothionein-I and -III regulation [J]. Brain Res Mol Brain Res, 1998, 57, 221-234.
[22] Carrasco J, J Hernandez, B Gonzalez, etc., Localization of metallothionein-I and -III expression in the CNS of transgenic mice with astrocyte-targeted expression of interleukin 6 [J]. Exp. Neurol., 1998, 153, 184-194.
[23] Carrasco J, M Penkowa, H Hadberg, etc., Enhanced seizures and hippocampal neurodegeneration following kainic acid-induced seizures in metallothionein-I + II-deficient mice [J]. Eur. J. Neurosis., 2000, 12, 2311-2322.
[24] Carrasco J., M.Giralt, M.Penkowa, etc., Metallothioneins are upregulated in symptomatic mice with astrocyte-targeted expression of tumor necrosis factor-alpha [J]. Exp Neurol., 2000, 163, 46-54.
[25] Ceballos D, N Lago, E Verdu, etc., Role of metallothioneins in peripheral nerve function [J]. Regeneration Cell Mol Life Sci., 2003,60,1209-1216.
[26] Chapman GA, Kay J and Kille P: Structural and functional analysis of the rat metallothionein Ill genomic locus. Biochim [J]. Biophys. Acta, 1999, 1445, 32 1-329.
[27] Cherian MG & Apostolova MD., Nuclear localization of metallothionein during cell proliferation and differentiation [J]. Cell Mol Biol., 2000,46, 347-356.
[28] Chiharu, A. S., M Asanuma, N Sogawa, etc., Localization, Regulation, and Function if Metallothionein-III in the brain, Acta Med. Okayama, 2001, 55(1):1-9.
[29] Choudhuri S, McKim JM Jr and Klaassen CD: Differential expression of the metallothionein gene in liver and brain of mice and rats [J]. Toxicol Appl. Pharmacol, 1993, 119: 1-10.
[30] Chung RS and West AK., A role for extracellular metallothioneins in CNS injury and repair [J]. Neuroscience, 2004, 123: 595-599.
[31] Chung RS, PA Adlard, J Dittmann, etc., Neuron-glia communication: metallothionein expression is specifically up-regulated by astrocytes in response to neuronal injury [J]. J. Neurochem., 2004, 88: 454-461.
[32] Chung RS, Vickers JC, Chuah MI, etc., Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury [J]. J. Neurosci., 2003,23: 3336-3342.
[33] Coogan, T. P., RM Bare, EJ Bjornson, etc. Enhanced metallothionein gene expression is associated with protection from cadmium-induced genotoxicity in cultured rat liver cells[J]. J. Toxicol. Environ. Health, 1994, 41:233-245.
[34] Crowthers KC, V Kline, C Giardina, etc., Augmented humoral immune function in metallothionein-null mice [J]. Toxicol Appl. Pharmacol, 2000, 166: 161-172.
[35] Cuajungco, M. P.; Lees, G. J. Zinc metabolism in the brain: Relevance to human neurodegenerative disorders [J]. Neurobiol. Dis. 1997,4:137-169.
[36] Danscher, G., KB Jensen, CJ Frederickson, etc., Increased amount of zinc in the hippocampus and amygdala of Alzheimer's diseased brains: A proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material [J]. J. Neurosci. Methods, 1997, 76:53-59.
[37] Dincer, Z., S Haywood, B.Jasani, Immunocytochemical detection of metallothionein (MT1 and MT2) in copper-enhanced sheep brains [J]. J. Comp. Pathol., 1999, 120:29 -37.
[38] Dunn, M. A., TL Blalock, RJ Cousins, Metallothionein[J]. Proc. Soc. Exp. Biol. Med., 1987, 185:107-119.
[39] Ebadi M, Brown-Borg H, El Refaey H, etc., Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease[J]. Brain Res Mol Brain Res, 2005, 134: 67-75.
[40] Ebadi M, Sharma SK, Ghafourifar P, etc., Peroxynitrite in the pathogenesis of Parkinson's disease and the neuroprotective role of Metallothioneins [J]. Meth Enzymol., 2005, 396: 276-298.
[41] Ebadi, M., PL Iversen, R Hao, etc., Expression and regulation of brain metallothionein[J]. Neurochem. Int. 1995, 27:1-22.
[42] Eileen M. DW., K. L. Gilby, S.E. Howlett, etc., Isolation of total cellular RNA from brain tissue[M], OXFORD Practical Approach Series, Oxford University, 2001.
[43] Elmayan T, Tepfer M: Synthesis of a bifunctional metallothionein/-glucuronidase fusion protein in transgenic tobacco plants as a means of reducing leaf cadmium levels[J]. Plant J., 1994,6:433-440.
[44] Erickson JC, Hollopeter G, Thomas SA, etc., Discruption of the metallothionein-Ill gene in mice: Analysis of brain zinc, behavior and neuron vulnerability to metals, aging, and seizures [J]. J Neurosci., 1997, 17: 1271 -1281 .
[45] Erickson JC, Masters BA, Kelly EJ, etc., Expression of human metallothionein-III in transgenic mice [J]. Neurochem. Int. 1995, 27: 35-4 1.
[46] Erickson JC, Sewell AK, Jensen LT, etc., Enhanced neurotrophic activity in Alzheimer's disease cortex is not associated with down-regulation of metallothionein-III (GIF) [J]. Brain Res., 1994, 649: 297-304.
[47] Erickson, J. C; Hollopeter, G.; Thomas, S. A., etc., Disruption of the metallothionein-III gene in mice: Analysis of brain zinc, behavior, and neuron vulnerability to metals, aging, and seizures [J]. J. Neurosci., 1997, 17:1271-1281.
[48] Espejo C & Martinez-Caceres EM., The role of methallothioneins in experimental autoimmune encephalomyelitis and multiple sclerosis[J]. Ann NY Acad. Sci., 2005, 1051: 88-96.
[49] Espejo C, Penkowa M, Demestre M, etc., Time-course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during experimental autoimmune encephalomyelitis [J]. Neuroscience, 2005, 132: 1135-1149.
[50] Faulkner JR., Herrmann JE, Woo MJ, etc., Reactive astrocytes protect tissue and preserve function after spinal cord injury [J]. J Neurosci., 2004, 24:2143-2155.
[51] Feng W, Cai J, Pierce WM,etc, Metallothionein transfers zinc to mitochondrial aconitase through a direct interaction in mouse hearts[J]. Biochem. Biophys Res Commun, 2005, 332: 853-858.
[52] Floyd, R. A. Neuroinflammatory processes are important in neurodegenerative diseases: A hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development[J]. Free Radic. Biol. Med., 1999,26:1346-1355.
[53] Fowler BA, Hildebrand CE, Kojima Y, Webb M. Nomenclature of metallothionein[J]. Experiential Suppl. 1987, 52:19-22.
[54] Frederickson CJ, Maret W & Cuajungco MP., Zinc and excitotoxic brain injury: a new model. Neuroscientist, 2004, 10: 18-25.
[55] Garrett SH, Sens MA, Shukla D, etc., Metallothionein isoforms 3 expression in the human prostate and cancer-derived cell lines[J]. Prostate, 1999,41: 196-202.
[56] Garrett SH, Sens MA, Todd JH, etc., Expression of MT-3 protein in the human kidney[J]. Toxicol Lett. 1999, 105:207-2 14.
[57] Gasche Y, Soccal PM, Kanemitsu M, etc., Matrix metalloproteinases and diseases of the central nervous system with a special emphasis on ischemic brain[J]. Front Biosci., 2006, 11: 1289-1301.
[58] Ghazi I. EL, B. L. Martin, I. M. Armitage, Metallothionein-3 Is A Component of Mutiprotein Complex in the Mouse Brain[J], Exp. Biol. Med.,2006, 231: 1500-1506
[59] Ghoshal K. and Jacob ST., Regulation of metallothionein gene expression[J]. Prog Nucleic Acid Res Mol Biol, 2001, 66: 357-384.
[60] Giralt M, Carrasco J, Penkowa M, etc., Campbell IL and Hidalgo J., Astrocyte-targeted expression of interleukin-3 and interferon-alpha causes region-specific changes in metallothionein expression in the brain[J]. Exp Neurol, 2001, 168:334-346.
[61] Giralt M, Penkowa M, Hernandez J,etc, Metallothionein-1+2 deficiency increases brain pathology in transgenic mice with astrocyte- targeted expression of interleukin 6[J]. Neurobiol Dis. 2002, 9: 319-338.
[62] Giralt M, Penkowa M, Lago N, etc., Metallothionein-1+2 protect the CNS after a focal brain injury[J]. Exp Neurol, 2002,173:114-128.
[63] Gong YH & Elliott JL., Metallothionein expression is altered in a transgenic murine model of familial amyotrophic lateral sclerosis[J]. Exp Neurol, 2000, 162: 27-36.
[64] Hahn SH, Yoo OJ & Gahl WA . Effect of metal ions on the stability of metallothionein in the degradation by cellular fractions in vitro[J]. Exp Mol Med. 2001, 33:32-36.
[65] Haq F, Mahoney M & Koropatnick J., Signaling events for metallothionein induction[J]. Mutat Res, 2003, 533: 211-226.
[66] Hernandez J, Molinero A, Campbell IL, etc., Transgenic expression of interleukin 6 in the central nervous system regulates brain metallothionein-I and -III expression in mice[J]. Brain Res Mol Brain Res ,1997, 48: 125-131.
[67] Hidalgo J, Aschner M, Zatta P, etc., Roles of the metallothionein family of proteins in the central nervous system[J]. Brain Res Bull, 2001, 55: 133-145.
[68] Hidalgo J, Belloso E, Hernandez J, etc., Role of glucocorticoids on rat brain metallothionein-I and -III response to stress [J]. Stress, 1997, 1: 231-240.
[69] Hidalgo J., Penkowa M., Giralt M., etc., Metallothionein expression and oxidative stress in the brain [J]. Methods Enzymol, 2002, 348:238-249.
[70] Hoey JG, Garrett SH, Sens MA, etc., Expression of MT-3 mRNA in human kidney, proximal tubule cell cultures, and renal cell carcinoma [J]. Toxicol Lett, 1997, 92:149- 160.
[71] Honegger P and Guentert-Lauber B, Epidermal growth factor (EGF) stimulation of cultured brain cells. I. Enhancement of the developmental increase in glial enzymatic activity [J]. Brain Res. 1983,313:245-251.
[72] Hozumi, I.; Inuzuka, T.; Hiraiwa, M.; etc., Changes of growth inhibitory factor after stab wounds in rat brain [J]. Brain Res. 1995, 688:143-148.
[73] Hozumi, I.; Inuzuka, T.; Ishiguro, etc., Immunoreactivity of growth inhibitory factor in normal rat brain and after stab wounds—An immunocytochemical study using confocal laser scan microscope [J]. Brain Res., 1996, 741:197-204.
[74] Huang, X.; Cuajungco, M. P.; Atwood, etc., Alzheimer's disease, beta-amyloid protein and zinc [J]. J. Nutr., 2000, 130:1488-1493;
[75] Hye, G. J., CK Youn, HJ Cho, Metallothionein-III Prevents γ-Ray-induced 8-Oxoguanine Accumulation in Normal and hOGG1-depleted Cells [J], 2004, 33(279): 34138-34149. Chinese hamster ovary cells expressing mouse metallothionein [J]. Mol. Pharmacol., 1993, 44:44-50;
[94] Kramer KK, Liu J, Choudhuri S and Klssen CD: Induction of metallothionein mRNA and protein in murine astrocyte cultures [J]. Toxicol Appl Pharmacol. 1996, 136: 94-100.
[95] Kramer KK, Zoelle JT and Klssen CD: lnduction of metallothionein mRNA and protein in primary murine neuron cultures [J]. Toxicol Appl Pharmacol, 1996, 141: 1-7.
[96] Lefebvre, D. D., Miki, B. L. & Laliberte, J. F., Mammalian metallothionein functions in plants [J]. Biotechnology, 1987, 5:1053-1056.
[97] Leibbrandt ME & Koropatnick J., Activation of human monocytes with lipopolysaccharide induces metallothionein expression and is diminished by zinc [J]. Toxicol Appl Pharmacol, 1994,124:72-81.
[98] Leibbrandt ME, Khokha R & Koropatnick J., Antisense down-regulation of metallothionein in a human monocytic cell line alters adherence, invasion, and the respiratory burst [J]. Cell Growth Differ. 1994,5: 17-25.
[99] Leutz A and Schachner M, Epidermal growth factor stimulates DNAsynthesis of astrocytes in primary cerebellar cultures [J]. Cell Tissue Res., 1981, 220: 393-404.
[100] Liu, J.; Kershaw, W. C; Klaassen, C. D. The protective effect of metallothionein on the toxicity of various metals in rat primary hepatocyte culture [J]. Toxicol. Appl. Pharmacol. 1991, 107: 27-34.
[101] Liu, Y.; Liu, J.; Iszard, M. B., etc., Transgenic mice that overexpress metallothionein-I are protected from cadmium lethality and hepatotoxicity [J]. Toxicol. Appl. Pharmacol. 1995, 135:222-228.
[102] Lovell, M. A.; Robertson, J. D.; Teesdale, W. J., etc., Copper, iron, and zinc in Alzheimer's disease senile plaques [J]. J. Neurol. Sci., 1998, 158:47-52;.
[103] ltano Y, Noji S, Koyama E, etc., Bacterial endotoxin-induced expression of metallothionein genes in rat brain, as revealed by in situ hybridization [J], Neurosci Lett ,1991, 124: 13- 16.
[104] Lynes MA, Borghesi LA, Youn J, etc. Immunomodulatory activities of extracellular metallothionein I: metallothionein effects on antibody production [J]. Toxicology , 1993, 85: 161-177.
[105] Maret W., Optical methods for measuring zinc binding and release, zinc coordination environments in zinc finger proteins, and redox sensitivity and activity of zinc-bound thiols [J]. Methods Enzymol, 2002, 348: 230-237.
[106] Maret W, Heffron G, Hill HA, Djuricic D, etc., The ATP/metallothionein interaction: NMR and STM [J]. Biochem, 2002,41: 1689-1694.
[107] Masatoshi N., S. Kumar, Molecular evolution and phylogenetics[M], Oxford University Press, Inc., 2000.
[108] Masters BA, Kelly EJ, Quaife CJ, etc. Targeted disruption of metallothionein I and II genes increases sensitivity to cadmium [J]. Proc Natl Acad Sci USA , 1994, 91: 584-588.
[109] Masters BA, Quaife CJ, Erickson JC, etc., Metallothionein Ill is expressed in neurons that sequester zinc in synaptic vesicles [J]. J Neurosci., 1994, 14: 5844-5857.
[110] Mehra, R. K.; Bremner, I. Species differences in the occurrence of copper-metallothionein in the particulate fractions of the liver of copper-loaded animals [J]. Biochem. J., 1984, 219:539-546.
[111] Mhatre M, Floyd RA & Hensley K., Oxidative stress and neuroinflammation in Alzheimer's disease and amyotrophic lateral sclerosis: common links and potential therapeutic targets [J]. J Alzheimers Dis., 2004,6: 147-157.
[112] Michalska AE & Choo KH. Targeting and germ-line transmission of a null mutation at the metallothionein I and II loci in mouse [J]. Proc Natl Acad Sci USA., 1993, 90: 8088-8092.
[113] Miesel R & Zuber M., Copper-dependent antioxidase defenses in inflammatory and autoimmune rheumatic diseases [J]. Inflammation, 1993, 17: 283-294.
[114] Milena P., Metallothioneins are multipurpose neuroprotectants during brain pathology [J], FEBS Journal, 2006, 273:1857-1870.
[115] Miles AT, Hawksworth GM, Beattie JH, etc., Induction, regulation, degradation, and biological significance of mammalian metallothioneins [J]. Crit Rev Biochem Mol Biol, 2000, 35:35-70.
[116] Miyazaki I, Sogawa CA, Asanuma M, etc., Expression of metallothionein-Ill mRNA and its regulation by levodopa in the basal ganglial of hemi-parkinsonian rats [J]. Neurosci Lett., 2000, 293: 65-68.
[117] Moffatt P and Seguin C, Expression of the gene encoding metallothionein-3 in organs of the reproductive system [J]. DNA Cell Biol., 1998, 17: 501-510.
[118] Molinero A., Penkowa M., Hernandez J., etc., Metallothionein-I overexpression decreases brain pathology in transgenic mice with astrocyte-targeted expression of interleukin-6 [J]. JNeuropathol Exp Neurol, 2003, 62: 315-328.
[119] Morrison RS, Kornblum HI, Leslie FM, etc., Trophic stimulation of cultured neurons from neonatal rat brain by epidermal growth factor [J]. Science, 1987, 238: 72-75.
[120] Nagano S, Satoh M, Sumi H, etc., Reduction of metallothioneins promotes the disease expression of familial amyotrophic lateral sclerosis mice in a dosedependent manner [J]. Eur J Neurosci, 2001, 13: 1363-1370.
[121] Naruse S, lgarashi S, Furuya T, etc., Structures of the human and mouse growth inhibitory factorencoding genes [J]. Gene, 1994, 144: 283-287.
[122] Natale JE, Knight JB, Cheng Y, etc., Metallothionein I and II mitigate age-dependent secondary brain injury [J]. J Neurosci Res., 2004, 78: 303-314.
[123] Nordberg, M., and Kojima, Y. Metallothionein and other low molecular weight metal binding proteins. In 'Metallothionein'[C]. (Eds J. H. R. Kagi and M. Nordberg.) (Birkhauser-Verlag: Boston.), 1979, 197-204..
[124] Ogawa N: Levodopa and dopamine agonists in the treatment of Parkinson's disease: Advantages and disadvantages [J]. Eur Neurol., 1994, 34:20-28.
[125] Ogra Y & Suzuki KT, Nuclear trafficking of metallothionein: possible mechanisms and current knowledge [J]. Cell Mol Biol. 2000, 46: 357-365.
[126] Oz, G., K. Zangger, and I. M. Armitage. Three-dimensional structure and dynamics of a brain specific growth inhibitory factor: metallothionein-3 [J]. Biochem., 2001,40: 11433-11441.
[127] Palmiter R D, Brinster R L, Hammer R E, etc., Dramatic growth of mice that develop from eggs microinjected with metallothionein growth hormone fusion genes [J], Nature, 1982, 300:611-615
[128] Palmiter RD, Norstedt G, Gelinas RE, etc., Metallothionein human GH fusion genes stimulate growth of mice [J]. Science, 1983,222: 809-814
[129] Penkowa M & Hidalgo J., Metallothionein I+II expression and their role in experimental autoimmune encephalomyelitis [J]. Glia, 2000, 32: 247-263.
[130] Penkowa M & Hidalgo J., Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE) [J]. Exp Neurol., 2001, 170:1-14.
[131] Penkowa M and Hidalgo J., Treatment with metallothionein prevents demyelination and axonal damage and increases oligodendrocyte precursors and tissue repair during experimental autoimmune encephalomyelitis [J]. J Neurosci Res, 2003, 72: 574-586.
[132] Penkowa M, Camats J, Hadberg H,etc, Astrocyte-targeted expression of interleukin-6 protects the central nervous system during neuroglial degeneration induced by 6-aminonicotinamide [J]. J Neurosci Res. 2003, 73: 481-496.
[133] Penkowa M, Carrasco J, Giralt M, etc., Altered central nervous system cytokine-growth factor expression profiles and angiogenesis in metallothionein-I+II deficient mice [J]. J Cereb Blood Flow Metab., 2000, 20: 1174-1189.
[134] Penkowa M, Carrasco J, Giralt M, etc., CNS wound healing is severely depressed in metallothionein I- and II-deficient mice [J]. J Neurosci, 1999, 19: 2535-2545.
[135] Penkowa M, Espejo C, Martinez-Caceres EM, Montalban X & Hidalgo J. Increased demyelination and axonal damage in metallothionein I+II-deficient mice during experimental autoimmune encephalomyelitis [J]. Cell Mol Life Sci., 2003, 60: 185-197.
[136] Penkowa M, Espejo C, Martinez-Caceres EM, etc., Altered inflammatory response and increased neurodegeneration in metallothionein I+II deficient mice during experimental autoimmune encephalomyelitis [J]. J Neuroimmunol, 2001, 119: 248-260.
[137] Penkowa M, Florit S, Giralt M, etc., Metallothionein reduces central nervous system inflammation, neurodegeneration, and cell death following kainic acidinduced epileptic seizures [J]. J Neurosci Res, 2005, 79: 522-534.
[138] Penkowa M, Giralt M, Camats J, etc., Metallothionein 1+2 protect the CNS during neuroglial degeneration induced by 6-aminonicotinamide [J]. J Comp Neurol, 2002, 444: 174-189.
[139] Penkowa M, Giralt M, Moos T, etc. Impaired inflammatory response to glial cell death in genetically metallothionein-I- and -II-deficient mice [J]. Exp Neurol., 1999, 156: 149-164.
[140] Penkowa M, Giralt M, Thomsen PS, etc. Zinc or copper deficiency-induced impaired inflammatory response to brain trauma may be caused by the concomitant metallothionein changes [J]. J Neurotrauma, 2001, 18: 447-463.
[141] Penkowa M, Molinero A, Carrasco J,etc, Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures [J]. Neuroscience, 2001,102: 805-818.
[142] Penkowa M, Moos T, Carrasco J, etc., Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice [J]. Glia, 1999, 25: 343-357.
[143] Penkowa M, Nielsen H, Hidalgo J, etc., Distribution of metallothionein I +II and vesicular zinc in the developing central nervous system:correlative study in the rat [J]. J Comp Neurol, 1999, 412:303-318.
[144] Penkowa M, Poulsen C, Carrasco J, etc., M-CSF deficiency leads to reduced metallothioneins I and II expression and increased tissue damage in the brain stem after 6-aminonicotinamide treatment [J]. Exp Neurol, 2002, 176: 308-321.
[145] Penkowa M, Quintana A, Carrasco J, etc., Metallothionein prevents neurodegeneration and central nervous system cell death after treatment with gliotoxin 6-aminonicotinamide [J]. J Neurosci Res, 2004, 77: 35-53.
[146] Penkowa M, Tio L, Mecedes G, etc., Specificity and divergence in the neurobiological effects of different Metallothioneins after brain injury [J]. J Neurosci Res, 2006, doi: 10.1002/jnr.20790.
[147] Penkowa M. and Hidalgo J., Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE) [J]. Exp Neurol, 2001, 170: 1-14.
[148] Penkowa, M.; Carrasco, J.; Giralt, M., etc. Altered central nervous system cytokinegrowth factor expression profiles and angiogenesis in metallothionein-I/II deficient mice [J]. J. Cereb. Blood Flow Metab., 2000,20:1174-1189;.
[149] Penkowa, M.; Moos, T.; Carrasco, etc. Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice [J]. Glia., 1999, 25:343-357;.
[150] Piscator, M. Om kadmium i normala ma¨nniskonjurar samt redogorelse for isolering av metallothionein ur level fran kadmiumexponerade kaniner [J]. Nord. Hyg. Tidskr., 1964, 45: 76-82.
[151] Poulsen CB, Penkowa M, Borup R, etc., Brain response to traumatic brain injury in wild-type and interleukin-6 knockout mice: a microarray analysis [J]. J Neurochem, 2005, 92: 417-432.
[152] Pulido P, Kagi JHR, Vallee BL: Isolation and some. Properties of human metallothionein [J]. Biochemistry., 1966, 5:1768-1777.
[153] Pursel VG, Pinkert CA, Miller KF, etc. Genetic enginee ring of livestock [J]. Science, 1989,244:1281-1288.
[154] Quaife, C. J., Findley, S. D., Erickson, J. C.,etc, Organization and Assembly of Metal-Thiolate Clusters in Epithelium specific Metallothionein-4 [J], Biochemistry, 1994, 33:7250-7259.
[155] Quintana A, Giralt M, Rojas S, etc., Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury [J]. J Neurosci Res, 2005, 82:701-716.
[156] Richard D. P., S. D. Findley, T. E. Whitmore, etc., MT-III, a brain-special member of the metallothionein gene family [J], Proc. Natl. Acad. Sci. USA, 1992, 89: 6333-6337.
[157] Richard D. P., The elusion function of metallothioneines [J], Pro. Natl. Acad.Sci., UAS, 1998,95:8424-8430.
[158] Sadhu, C.; Gedamu, L. Metal-specific posttranscriptional control of human metallothionein genes [J]. Mol. Cell. Biol., 1989, 9:5738 -5741.
[159] Safieh-Garabedian B, Haddad JJ & Saade NE., Cytokines in the central nervous system: targets for therapeutic intervention [J]. Curr Drug Targets CNS Neurol Disord, 2004, 3: 271-280.
[160] Safieh-Garabedian B, Mouneimne GM, El Jouni W, etc., The effect of endotoxin on functional parameters of mammary CID-9 cells [J]. Reproduction, 2004, 127, 397-406.
[161] Sano T., Glazer A N, Cantor C R, A Strepravidin-metallothionein chimera that allows specific labeling of biological materials with many different heavy metal ions [J], Proc. Natl. Acad. Sci. USA, 1992, 89: 1534-1538
[162] Saremi M. A., S. Mahnaz, T. Mahmood, Rapid Genomic DNA Extraction (RGDE) [Z], Protocol Online, http://www.protocol-online.org.
[163] Sato M, Bremner I. Oxygen free radicals and metallothionein [J].Free Rad Biol 1993,14: 325-37.
[164] Scheede-Bergdahl C, Penkowa M, Hidalgo J, etc. Metallothionein-mediated antioxidant defense system and its response to exercise training are impaired in human type 2 diabetes [J]. Diabetes, 2005, 54: 3089-3094.
[165] Searle PF, Davison BL, Stuart GW, etc., Regulation, linkage, and sequence of mouse metallothionein I and II genes [J]. Mol Cell Biol, 1984,4: 1221-1230.
[166] Sewell AK, Jensen LT, Erickson JC, etc., Bioactivity of metallothionein-3 correlates with its novel domain sequence rather than metal binding properties [J]. Biochemistry, 1995, 34: 4740-4747.
[167] Sharp F. R., RQ. Ran, AG Lu, etc., Hypoxic Preconditioning Protects against Ischemic Brain Injury [J], NeuroRx., 2004, 1(1): 26-35.
[168] Sofroniew MV., Reactive astrocytes in neural repair and protection [J]. Neuroscientist, 2005,11:400-407.
[169] Sogawa CA, Miyazaki I, Sogawa N, etc., Antioxidants protect against dopamine- induced metallothionein-Ill (GIF) mRNA expression in mouse glial cell line (VR-2g) [J]. Brain Res, 2000, 853:310-316.
[170] Stankovic RK, Atrophy of large myelinated axons in metallothionein-I, II knockout mice [J]. Cell Mol Neurobiol, 2005,25:943-953.
[171] Steinebach OM & Wolterbeek BT., Metallothionein biodegradation in rat hepatoma cells: a compartmental analysis aided 35S-radiotracer study [J]. Biochim Biophys Acta. 1992,1116,155-165.
[172] Stuart G. W., Searle P.F. & Palmiter R.D. Identification of multiple metal regulatory elements in mouse metallothionein-I promoter by assaying synthetic sequences [J], Nature, 1985, 317:828-831.
[173] Takahashi Y, Ogra Y & Suzuki KT., Nuclear trafficking of metallothionein requires oxidation of a cytosolic partner [J]. J Cell Physiol, 2005, 202, 563-569.
[174] Tang CM, Westling J & Seto E., Transrepression of the human metallothionein IIA gene promoter by PZ120, a novel 120-kilodalton zinc finger protein [J]. Mol Cell Biol, 1999, 19: 680-689.
[175] Thornalley PJ, Vasa k M. Possible role for metallothionein in protection against radiation induced oxidative stress. Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals [J]. Biochim Biophys Acta, 1985, 827:36-44.
[176] Trayhurn P, Duncan JS, Wood AM & Beattie JH., Metallothionein gene expression and secretion in white adipose tissue [J]. Am J Physiol Regul Integr Comp Physiol, 2000, 279: R2329-R2335.
[177] Trayhurn P, Duncan JS, Wood AM & Beattie JH., Regulation of metallothionein gene expression and secretion in rat adipocytes differentiated from preadipocytes in primary culture [J]. Horm Metab Res, 2000, 32: 542-547.
[178] Trendelenburg G, Prass K, Priller J, et al. Serial analysis of gene expression identifies metallothionein-II as major neuroprotective gene in mouse focal cerebral ischemia [J]. J Neurosci, 2002, 22: 5879-5888.
[179] Tsuji S, Kobayashi H, Uchida Y, etc., Molecular cloning of human growth inhibitory factor cDNA and its down-regulation in Alzheimer's disease [J]. EMBO J., 1992, 11: 4843-4850.
[180] Uchida Y, Masumizu A and lhara Y, Protection of cultured cortical neurons from P-amyloid neurotoxicity [J]. Neurochem Res , 1995,21: 320-32 1.
[181] Uchida Y, Shimizu T and lhara Y, Inhibition of P-amyloid-induced toxicity by GIF (in Japanese) [J]. Bulletin of the Japanese Society for Neurochemistry, 1994, 35: 184-185.
[182] Uchida Y, Growth-inhibitory factor, metallothionein-like protein, and neurodegenerative diseases [J]. Biol Signals, 1994, 3: 211-215.
[183] Uchida Y, Regulation of growth inhibitory factor expression by epidermal growth factor and interleukin-lp in cultured rat asctrocytes [J]. J Neurochem, 1999, 73: 1945- 1953.
[184] Uchida, Y. Growth-inhibitory factor, metallothionein-like protein, and neurodegenerative diseases [J]. Biol. Signals, 1994, 3:211-215.
[185] Uchida, Y. Regulation of growth inhibitory factor expression by epidermal growth factor and interleukin-1b in cultured rat astrocytes [J]. J. Neurochem. 1999,73:1945-1953.
[186] Uchida, Y., K. Takio, K. Titani, etc. The growth inhibitory factor that is deficient in the Alzheimer's diseased brain is a 68 amino acid metallothionein-like protein [J]. J. Neuron. 1991, 7: 337-347.
[187] Uchida, Y.; Takio, K.; Titani, K.; etc. The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein [J]. Neuron, 1991,7:337-347.
[188] Van L. CM., H. Thibodeaux, N.V. Bruggen, etc., Evidence for a protective role of metallothionein-1 in focal cerebral ischemia [J]. Proc Natl Acad Sci USA, 1999, 96: 12870-12875.
[189] Vasak M., Advances in metallothionein structure and functions [J], Journal of Trace Elements in Medicine and Biology, 2005, 19:13-17
[190] Vasconcelos MH, Tarn SC, Beattie JH, etc. Evidence for differences in the post-transcriptional regulation of rat metallothionein isoforms [J]. Biochem J. 1996, 315: 665-671.
[191] Vasconcelos MH, Tam SC, Hesketh JE, etc. Metal- and tissue-dependent relationship between metallothionein mRNA and protein [J]. Toxicol Appl Pharmacol, 2002, 182:91-97.
[192] Villoslada P & Genain CP. Role of nerve growth factor and other trophic factors in brain inflammation [J]. Prog Brain Res, 2004, 146, 403-414.
[193] Waalkes MP and Klaassen CD, Concentration of metallothionein in major organs of rats after administration of various metals [J]. Fundam Appl Toxicol, 1985, 5: 473-477
[194] Wang J, Asensio VC & Campbell IL . Cytokines and chemokines as mediators of protection and injury in the central nervous system assessed in transgenic mice [J]. Curr Top Microbiol Immunol, 2002,265,23-48.
[195] Wang, H., Q. Zhang, B. Cai, etc. Solution structure and dynamics of human metallothionein-3 (MT-3) [J]. FEBS Letters, 2006, 580: 795-800.
[196] West AK, Chuah MI, Vickers JC, etc., Protective role of metallothioneins in the injured mammalian brain [J]. Rev Neurosci., 2004, 15: 157-166.
[197] Wilson, A.; Trombetta, L. D. The protective effects of zinc on diethyldithiocarbamate cytotoxicity on rat astrocytes in vitro [J]. Toxicol. Lett. 1999, 105:129 -140.
[198] Woo ES., Dellapiazza D., Wang AS. and Lazo JS., Energy-dependent nuclear binding dictates metallothionein localization [J]. J Cell Physiol, 2000, 182: 69-76.
[199] Wright J, George S, Martinez-Lara E, etc. Levels of cellular glutathione and metallothionein affect the toxicity of oxidative stressors in an established carp cell line [J]. Mar Environ Res 2000, 50:503-8.
[200] Wu, J. P., B. Y. Ma, H. W. Ren, etc. Characterization of metallothioneins MT-I and MT-II in yak [J]. J. Anim. Sci., 2007, 85:1357-1362.
[201] Wu, J. Y.; Matsuda, T.; Roberts, E. Purification and characterization of glutamate decarboxylase from mouse brain [J]. J. Biol. Chem., 1973, 248:3029-3034;
[202] www.bioc.uzh.ch/mtpage/MT.html
[203] Yamada M, Hayashi S, Hozumi I, etc., Subcellular localization of growth inhibitory factor in rat brain: Light and electron microscopic immunohistochemical studies [J]. Brain Res, 1996, 735: 257-264.
[204] Yanagitani S, Miyazaki H, Nakahashi Y, etc., Ischemia induces metallothionein Ill expression in neurons of rat brain [J]. Life Sci., 1999,64: 707-715.
[205] Yao, C. P.; Allen, J. W.; Conklin, D. R., etc. Transfection and overexpression of metallothionein-I in neonatal rat primary astrocyte cultures and in astrocytoma cells increases their resistance to methylmercury-induced cytotoxicity [J]. Brain Res. 1999., 818:414-420;
[206] Yao, C. P., J. W. Allen, L. A.Mutkus , etc. Foreign metallothionein-I (MT-I) expression by transient transfection in MT-I and -II null astrocytes confers increased protection against acute methylmercury cytotoxicity [J]. Brain Res. 2000, 855: 32-38.
[207] Ye B, Maret W & Vallee BL. Zinc metallothionein imported into liver mitochondria modulates respiration [J]. Proc Natl Acad Sci USA. 2001, 98, 2317-2322.
[208] Yin X, Knecht DA & Lynes MA. Metallothionein mediates leukocyte chemotaxis [J]. BMC Immunol, 2005, 6: 21.
[209] Youn J & Lynes MA. Metallothionein-induced suppression of cytotoxic T lymphocyte function: an important immunoregulatory control [J]. Toxicol Sci., 1999, 52:199-208.
[210] Youn J, Borghesi LA, Olson EA & Lynes MA. Immunomodulatory activities of extracellular metallothionein II: effects on macrophage functions [J]. J Toxicol Environ Health, 1995,45,397-413.
[211] Yuguchi, T., Kohmura, E., Yamada, K., etc. Expression of growth inhibitory factor mRNA following cortical injury [J]. J. Neurotrauma, 1995, 12:299 -306.
[212]Zambenedetti,P.;Giordano,R.;Zatta,P.Metallothioneins are highly expressed in astrocytes and microcapillaries in Alzheimer's disease[J].J.Chem.Neuroanat.,1998,15:21-26.
[213]Zangger K,Oz G,Haslinger E,etc.Nitric oxide selectively releases metals from the aminoterminal domain of metallothioneins:potential role at inflammatory sites[J].FASEB J.,2001,15:1303-10.
[214]Zhang Rongchang,Wu Jianping and Han Jianlin.Yak production in China.Asian livestock:Yak[M],1994,615(10):115-118.
[215]Zheng H,Berman NE and Klaassen CD:Chemical modulation of metallothionein I and Ill mRNA in mouse brain[J].Neurochem lnt,1995,27:43-58.
[216]陈文明,李永森,亓绍玫等,青藏高原有色金属矿产分布特征[J],地球学报,2000,21:26-27
[217]彭克美,张登荣,组织学与胚胎学[M],中国农业出版社,2002.
[218]任宏伟,茹炳根,金属硫蛋白(Metallothionein,MT)基因在转基因领域的应用,生物工程进展[J],2000,20(4):35-39
[219]芮宗瑶,李光明,王龙生,青藏高原的金属矿产资源[J],地质通报,2004,1,VOL23(1):20-23
[220]萨姆布鲁克,J.,D.W.拉塞尔,黄培堂译.分子克隆试验指南(第三版)[M],科学出版社,2002.8
[221]吴建平,马彬云,张利平等,简明基因工程与应用[M],科学出版社,2005。
[222]张容昶,中国的牦牛[M],甘肃科学技术出版社,1988
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