接上文 Part.2

 

Parkinsonism: The biometals iron, manganese and copper have been associated to Parkinson’s disease and Parkinsonism. In recent work, it was reported for the first time that acute or chronic Fe, Mn and Cu exposure significantly reduced life span and locomotor activity in Drosophila melanogaster. It was shown that the concentration of those biometals dramatically increase in Drosophila’s brain acutely or chronically fed with metal, and that the metal accumulation in the fly’s head is associated with the neurodegeneration of several dopaminergic neuronal clusters. Furthermore, they found that the chelator desferoxamine, ethylenediaminetetraacetic acid, and D-penicillamine were able to protect but not rescue D. melanogaster against metal intoxication. Taken together these data suggest that iron, manganese and copper are capable to destroy dopaminergic neurons in the fly’s brain, thereby impairing their movement capabilities [198].
帕金森病：生物金属铁、锰和铜与帕金森病和帕金森病有关。在最近的工作中，首次报道急性或慢性铁、锰和铜暴露显著降低了黑腹果蝇的寿命和运动活动。结果表明，这些生物金属的浓度在果蝇的大脑中急剧或长期地急剧增加，并且在果蝇头部中的金属积累与几个多巴胺能神经元簇的神经变性有关。此外，他们发现螯合剂去铁胺、乙二胺四乙酸和D-青霉胺能够保护但不能拯救黑腹果蝇免受金属中毒。综合这些数据表明，铁、锰和铜能够破坏果蝇大脑中的多巴胺能神经元，从而削弱它们的运动能力[198]。
 
Malignant glioma: The scientists assessed relevance of mineral trace element and heavy metal levels in patients with malignant gliomas. In the study, erythrocyte catalase, and carbonic anhydrase, serum copper, zinc, lead, iron, cadmium, cobalt, manganese, and magnesium levels were measured in plasma of 22 healthy humans and 22 malignant glioma patients. The Cd, Fe, Mg, Mn, Pb and Zn levels were significantly elevated in the patients as a whole compared to controls (P<0.05), while copper was decreased and cobalt demonstrated no change. Although mean erythrocyte activity were significantly lowered, carbonic anhydrase exhibited significant increase. The results of the current study indicate that antioxidant enzymes may have a role in the genesis of considerable oxidative stress in patients with malignant glioma [199].
恶性神经胶质瘤：科学家评估了矿物质微量元素和重金属水平与恶性神经胶质瘤患者的相关性胶质瘤。在这项研究中，测量了22名健康人和22名恶性胶质瘤患者血浆中的红细胞过氧化氢酶和碳酸酐酶、血清铜、锌、铅、铁、镉、钴、锰和镁的水平。与对照组相比，患者整体镉、铁、镁、锰、铅和锌水平显著升高（P<0.05），而铜降低，钴无变化。虽然平均红细胞活性显著降低，但碳酸酐酶显著增加。目前的研究结果表明，抗氧化酶可能在恶性神经胶质瘤患者的大量氧化应激的发生中起作用[199]。
 
Serum copper and zinc concentrations and copper/zinc ratios have been shown to be increased in several types of human malignancies, including human brain tumors. In this study, copper and zinc levels and copper/zinc ratios were determined by atomic absorption analysis in tissue and serum from 29 primary and metastatic brain tumor patients. Metastatic carcinomas and malignant gliomas revealed significantly higher tissue copper concentrations than control tissues and meningiomas. Malignant gliomas demonstrated significantly higher tissue copper/zinc ratios. Also in serum, both serum copper and copper/zinc ratio were significantly higher in the metastatic carcinoma group than control. There were no differences both in the serum and the tissue concentrations of these trace elements in meningiomas and controls. These data suggested that copper, an important angiogenic factors, is accumulated within the malignant tissues of metastatic carcinoma and malignant glioma, but not meningiomas. These findings may have implications regarding Cu in angiogenesis in these tumors [200].
已显示血清铜和锌浓度以及铜/锌比率在几种类型的人类恶性肿瘤中增加，包括人脑肿瘤。在这项研究中，通过原子吸收分析对29名原发性和转移性脑肿瘤患者的组织和血清中的铜和锌水平以及铜/锌比率进行了测定。转移性癌和恶性神经胶质瘤显示组织铜浓度显著高于对照组织和脑膜瘤。恶性神经胶质瘤表现出显著更高的组织铜/锌比率。同样在血清中，转移癌组的血清铜和铜/锌比率均显著高于对照组。在脑膜瘤和对照组中，这些微量元素的血清和组织浓度没有差异。这些数据表明，铜是一种重要的血管生成因子，在转移癌和恶性胶质瘤的恶性组织中积累，而不是脑膜瘤。这些发现可能对这些肿瘤血管生成中的铜有影响 [200]。
 
Age-related macular degeneration: Some studies have suggested that both zinc and antioxidants delay the progression of age-related macular degeneration (AMD) and vision loss, possibly by preventing cellular damage in the retina [89,90]. In a population-based cohort study in the Netherlands, high dietary intake of zinc as well as beta carotene, vitamin C, and vitamin E was associated with reduced risk of AMD [201]. Participants also received 2 mg of copper to prevent the copper deficiency associated with high zinc intakes. After an average follow-up period of 6.3 years, supplementation with antioxidants plus zinc (but not antioxidants alone) significantly reduced the risk of developing advanced AMD and reduced visual acuity loss. Zinc supplementation alone significantly reduced the risk of developing advanced AMD in subjects at higher risk but not in the total study population [201,202]. However, the authors of a systematic review and meta-analysis published in 2007 concluded that zinc is not effective for the primary prevention of early AMD, although zinc might reduce the risk of progression to advanced AMD [203].
年龄相关性黄斑变性：一些研究表明，锌和抗氧化剂都可以延缓年龄相关性黄斑变性 (AMD) 和视力丧失的进展，可能是通过预防视网膜细胞损伤 [89,90]。在荷兰的一项基于人群的队列研究中，锌以及β胡萝卜素、维生素C和维生素E的高膳食摄入量与AMD风险降低有关 [201]。参与者还接受了2毫克铜，以防止与高锌摄入量相关的铜缺乏症。在平均6.3年的随访期后，补充抗氧化剂加锌（但不是单独的抗氧化剂）显著降低了发展为晚期AMD的风险并减少了视力丧失。仅补充锌可显著降低高风险受试者发生晚期AMD的风险，但在整个研究人群中却没有 [201,202]。然而，2007年发表的一项系统评价和荟萃分析的作者得出结论，尽管锌可能降低进展为晚期AMD的风险，但锌对早期AMD的一级预防无效 [203]。
 
Auditory system disorders: Copper is a trace element known to be critical for normal brain function, and abnormal copper metabolism in rats has been associated with some disorders involving the auditory system. The scientists examined effects of copper deficiency on metabolism in major structures of the auditory system. Cochlea, cochlear nucleus and inferior colliculus of rats, as well as whole brain, were assayed for activities of enzymes of oxidative and glycolytic energy metabolism - malate and lactate dehydrogenase, enzymes of acetylcholine metabolism -choline acetyltransferase and acetylcholinesterase, and concentrations of amino acids. Whole brain was also assayed for activity of superoxide dismutase, and concentrations of minerals. The significant differences between copper-deficient and copper-adequate rats were: decreased copper and magnesium and increased potassium concentrations in whole brain of copper-deficient rats and an elevation of glutamine concentration in inferior colliculus and whole brain of copper-deficient rats. The elevated glutamine could not be related to any change in activity of glutamine synthetase or glutaminase, major enzymes of glutamine metabolism. It is speculated that the increase in glutamine might result from a net increase in ammonia accumulation in the brains of copperdeficient rats [204].
听觉系统疾病：铜是一种已知对正常脑功能至关重要的微量元素，大鼠体内铜代谢异常与一些涉及听觉系统的疾病有关。科学家们检查了铜缺乏对听觉系统主要结构新陈代谢的影响。测定大鼠的耳蜗、耳蜗核和下丘以及全脑的氧化和糖酵解能量代谢酶-苹果酸和乳酸脱氢酶、乙酰胆碱代谢酶-胆碱乙酰转移酶和乙酰胆碱酯酶的活性以及氨基酸浓度。还检测了全脑的超氧化物歧化酶活性和矿物质浓度。铜缺乏和铜充足大鼠之间的显著差异是：铜和镁减少，铜缺乏大鼠全脑钾浓度增加，谷氨酰胺浓度升高。在缺铜大鼠的下丘和全脑中。谷氨酰胺升高与谷氨酰胺合成酶或谷氨酰胺酶（谷氨酰胺代谢的主要酶）活性的任何变化无关。据推测，谷氨酰胺的增加可能是由于缺铜大鼠大脑中氨积累的净增加所致 [204]。

 

Metabolic and endocrinological disorders 代谢和内分泌疾病

Disorders of thyroid gland: The aim of the present study was to investigate the effect of copper deficiency on thyroid hormone metabolism in rats. Therefore, an experiment with growing male rats was carried out, consisting of two groups of rats fed either a copperdeficient (0.06 mg Cu/kg) or a copper-adequate diet (16 mg Cu/kg). Copper deficiency decreased the final body weight of the rats by 5% compared to copper-adequate control rats. A severe copper-deficient state in the rats fed the copper-deficient diet was proved by a large decrease of ceruloplasmin activity in serum (by 97%) and hematological changes. Copper-deficient rats had an increased concentration of T3 in serum, whereas the concentrations of total and free thyroxine were not different compared with copper-adequate control rats [205].
甲状腺疾病：本研究的目的是研究铜缺乏对大鼠甲状腺激素代谢的影响。因此，对生长中的雄性大鼠进行了一项实验，由两组大鼠组成，分别喂食铜缺乏（0.06mg 铜/kg）或铜充足饮食（16mg 铜/kg）。与铜充足的对照大鼠相比，铜缺乏使大鼠的最终体重降低了5%。通过血清中铜蓝蛋白活性的大幅下降（97%）和血液学变化证明了喂食缺铜饮食的大鼠严重缺铜状态。铜缺乏的大鼠血清中T3浓度增加，而总甲状腺素和游离甲状腺素的浓度与铜充足的对照大鼠相比没有差异 [205]。
 
In the subsequent study the intracellular localization of Cu/ Zn- and Mn-superoxide dismutase was studied in the thyroid tissue of various thyroid disorders by an immunohistochemical technique. The concentrations of both SODs in those tissues were measured also by a sandwich enzyme immunoassay technique. Copper/zinc-SOD in thyroid tissues was identified by immunocytochemical staining in most cases of papillary carcinoma and in some cases of other thyroid disorders. In normal follicular cells this enzyme is localized in the perinuclear cytoplasm, whereas in thyroid tumor or hyperplastic follicular cells it exists homogeneously in cytoplasm. ManganeseSOD stained strongly in papillary carcinoma and papillary-growing cells in the thyroid tissue of adenoma and Graves’ disease. The concentrations of Cu/Zn-and Mn-SOD in thyroid tumor tissues and hyperplastic follicular disorders were significantly higher than those in normal thyroid tissue. In conclusion, SOD seems to be related to cell proliferation and differentiation in the thyroid follicular cell because Cu/Zn-SOD changes its localization in tumor and hyperplastic follicular cells and because the Mn-SOD concentration is increased in papillary carcinoma or papillary-growing cells [206].
在随后的研究中，通过免疫组织化学技术在各种甲状腺疾病的甲状腺组织中研究了铜/锌超氧化物歧化酶（Cu/Zn-SOD）和锰超氧化物歧化酶（Mn-SOD）的细胞内定位。还通过夹心酶免疫测定技术测量了这些组织中两种SOD的浓度。在大多数乳头状癌病例和一些其他甲状腺疾病病例中，通过免疫细胞化学染色鉴定甲状腺组织中的Cu/Zn-SOD。在正常滤泡细胞中，这种酶定位于核周细胞质中，而在甲状腺肿瘤或增生性滤泡细胞中，它均匀地存在于细胞质中。Mn-SOD在腺瘤和格雷夫斯病的甲状腺组织中的乳头状癌和乳头状生长细胞中强烈染色。甲状腺肿瘤组织和增生性滤泡病变组织中Cu/Zn-和Mn-SOD的浓度明显高于正常甲状腺组织。总之，SOD似乎与甲状腺滤泡细胞中的细胞增殖和分化有关，因为Cu/Zn-SOD改变了其在肿瘤和增生滤泡细胞中的定位，并且因为Mn-SOD浓度在乳头状癌或乳头状生长细胞中增加 [206]。
 
Diabetes:A laboratory animal study found that copper-deficient rats tend to have elevated blood sugar levels over time, indicating a possible connection between low copper and diabetes [132]. But a clinical study including people with diabetes, however, found very different results. Copper levels were higher in people with diabetes compared to those without. In fact, the higher the copper level, the more likely the person was to have complications from diabetes, including retinopathy, high blood pressure, or vascular disease [207].
糖尿病：一项实验室动物研究发现，随着时间的推移，缺铜大鼠的血糖水平往往会升高，这表明低铜与糖尿病之间可能存在联系 [132]。但是，一项包括糖尿病患者在内的临床研究却发现了截然不同的结果。与没有糖尿病的人相比，糖尿病患者的铜含量更高。事实上，铜水平越高，这个人就越有可能出现糖尿病并发症，包括视网膜病变、高血压或血管疾病 [207]。
 
Digestive system: In the next study, a growing rat model of zinc deficiency was established to investigate the effect of zinc deficiency on intestinal mucosal morphology and digestive enzyme activity. Symptoms of zinc deficiency, such as anorexia, diarrhea, dermatitis, and growth retardation, were observed. Zinc deficiency can cause loss of appetite, weight loss, and decreased activity of peptidase in the jejunal mucosal brush border. Zinc deficiency has little effect on the height ratio of the villus and crypt and lactase activity, thereby indicating that zinc deficiency may first affect protein digestion and absorption [208].
消化系统：在接下来的研究中，建立生长发育的缺锌大鼠模型，研究缺锌对肠黏膜形态和消化酶活性的影响。观察到缺锌症状，如厌食、腹泻、皮炎和生长迟缓。缺锌可导致食欲不振、体重减轻和空肠黏膜刷状缘肽酶活性降低。缺锌对绒毛和隐窝的高度比及乳糖酶活性影响不大，从而表明缺锌可能首先影响蛋白质的消化和吸收 [208]。
 
Osteoporosis: Trace elements are essential for normal growth and development of skeletons in humans and animals. Although they are minor building components in teeth and bone, they play important functional roles in bone metabolism and bone turnover. Zinc regulates secretion of calcitonin from thyroid grand and influences on bone turnover. Copper induces low bone turnover by both suppressions of osteoblastic and osteoclastic functions. Among the trace elements in bone and hair, significant differences were found in the contents of zinc, copper and manganese between normal subjects and osteoporotic patients. However, exact involvements of the trace elements in osteoporosis have not yet been clarified [209].
骨质疏松症：微量元素对于人类和动物骨骼的正常生长和发育至关重要。尽管它们是牙齿和骨骼中的次要组成部分，但它们发挥着重要作用骨代谢和骨转换中的功能作用。锌调节甲状腺分泌降钙素并影响骨转换。铜通过抑制成骨细胞和破骨细胞功能来诱导低骨转换。在骨骼和毛发中的微量元素中，正常人与骨质疏松患者的锌、铜、锰含量存在显著差异。然而，微量元素在骨质疏松症中的确切作用尚未明确[209]。
 
Zinc is implicated as an activator for bone formation. The following study examined how zinc regulates the bone matrix calcification in osteoblasts. The findings suggest that zinc deprivation inhibits extracellular matrix calcification in osteoblasts by decreasing the synthesis and activity of matrix proteins, type I collagen and alkaline phosphatase, and decreasing Ca and P accumulation. Therefore zinc deficiency can be considered as risk factor for poor extracellular matrix calcification [210].
锌被认为是骨形成的激活剂。以下研究检查了锌如何调节成骨细胞中的骨基质钙化。研究结果表明，锌缺乏通过降低基质蛋白、I型胶原蛋白和碱性磷酸酶的合成和活性，以及减少钙和磷的积累来抑制成骨细胞中的细胞外基质钙化。因此，缺锌可以被认为是细胞外基质钙化不良的危险因素 [210]。
 
Testosterone deficiency: Testosterone deficiency is associated with late-onset hypogonadism. Micronutrients including copper and zinc have influence on testosterone synthesis. The association between micronutrient concentrations in hair tissue and serum testosterone was studied in Korean men. Subjects with normal testosterone group had a significantly higher Zn level compared to low testosterone group (P=0.003). Significant negative correlations were evident between total testosterone and Cu level (P=0.022), and the Cu/Zn ratio (P=0.008). Normal testosterone is associated with a higher Zn level. Decreased serum testosterone is significantly associated with a high level of Cu and elevated Cu/Zn ratio in hair tissue [211].
睾酮缺乏症：睾酮缺乏症与迟发性性腺功能减退症有关。包括铜和锌在内的微量营养素对睾酮合成有影响。在韩国男性中研究了头发组织中微量营养素浓度与血清睾酮之间的关系。与低睾酮组相比，睾酮正常组受试者的锌水平显著升高(P=0.003)。总睾酮与铜水平（P=0.022）和铜/锌比（P=0.008）之间存在显著负相关。正常的睾酮与较高的锌水平有关。血清睾酮降低与头发组织中高水平的铜和铜/锌比率升高显著相关 [211]。
 
The role of Zn in fertility: Semen is particularly rich in Zn, which is a key factor in prostate gland function and reproductive organ growth [78]. In the present study on rats, scientists observed changes in the testes after dietary zinc deficiency. Ultrastructural studies revealed several apoptotic features such as wavy basement membrane, displaced nuclei, chromatin condensation, plasma membrane blebbing, nuclear membrane dissolution, loss of inter-Sertoli cell junctional complexes, and intercellular bridges and deformed mitochondria. Increased apoptotic degeneration in testes may cause irreversible changes in the germ cells associated with decreased epididymal sperm concentration, motility, and fertility index which contributes to the low efficiency of spermatogenesis thereby indicating a possible role of zinc in fertility [212].
锌在生育中的作用：精液中特别富含锌，锌是前列腺功能和生殖器官生长的关键因素 [78]。在目前对大鼠的研究中，科学家观察到饮食缺锌后睾丸的变化。超微结构研究揭示了几种凋亡特征，例如波浪状基底膜、移位的细胞核、染色质凝聚、质膜起泡、核膜溶解、支持细胞间连接复合物的丢失以及细胞间桥和变形的线粒体。睾丸凋亡变性增加可能导致生殖细胞发生不可逆转的变化，这与附睾精子浓度、运动性和生育指数降低有关，这导致精子发生效率低，从而表明锌可能在生育能力中发挥作用[212]。
 
 
接下文 Part.4