海洋深层水对代谢综合征预防作用的初步研究
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摘要
近年来,随着世界经济的迅猛发展,陆地资源的有限性与经济发展对资源的需求之间的矛盾日益突出,于是世界各大经济强国对资源探索的目光都不约而同的转向海洋。海洋是一座资源宝库,它不但拥有大量的矿藏、能源,同时还拥有其它众多的宝贵资源,海洋深层水(deep-sea water, DSW)正是其中之一。DSW作为一种新的天然资源正在受到世人的瞩目。
DSW通常是指阳光照射不到,不能进行光合作用,约200m以深的海水。研究表明,DSW具有不少有别于海洋表层水(surface-sea water, SSW)的优良性质,如低温恒定性、矿物元素丰富且稳定及无菌清洁性等特性。药理研究表明,DSW具有多种药理活性,如预防心血管疾病(cardiovascular disease, CVD),预防和治疗肥胖病和糖尿病(diabetes mellitus, DM),治疗皮肤病,调节免疫系统及抗氧化,抗疲劳,抗肿瘤及治疗骨质疏松等,但是其作用机制尚未阐明,而且DSW的取水深度也不确定,在不同文献中DSW的取水深度不尽相同。DSW的开发利用在日本、韩国和美国已经进入商品化阶段,但我国尚无DSW方面的研究开发。
随着人们生活方式和饮食习惯的改变,代谢综合征(metabolic syndrome,MS)及其相关疾病如高脂血症、Ⅱ型糖尿病(type2diabetes mellitus, T2DM)的发病率逐年升高。研究表明,矿物元素与MS及其相关疾病的发生和发展密切相关,通过饮食补充有益矿物元素Ca、V、, Cr、Mn、Zn、Se,同时减少有毒微量元素Pb、Hg等的接触,以维持体内矿物元素含量的相对稳定,对预防MS及其相关疾病的发生具有积极意义。DSW富含92种矿物元素,涵盖了人体新陈代谢所需的元素种类,可以均衡满足机体摄取各种矿物元素的需求,因此理论上,DSW对MS及其相关疾病均具有较好的预防作用。
在我国水资源日益紧缺,水污染日趋严重,MS及其相关疾病发病率逐年攀升的情况下,无论是从经济角度还是人类健康角度出发,开发和利用DSW都具有非常重要的意义及价值。
本论文对我国南海海域DSW的药用价值进行了较为系统的研究,首先确定具有开发利用价值的DSW的取水深度,并在细胞和动物水平对DSW的安全性、其对MS及其相关疾病的预防作用与作用机制进行了深入研究。主要内容如下：
1.具有开发利用价值的DSW取水深度的确定。研究表明,在海洋深层,海水的化学成分是相对恒定的,不随深度、季节和海域的不同而变化；同时,日本学者Miyamura M发现,与SSW相比,DSW对高脂血症的预防作用更显著。即在化学成分和药理活性方面,DSW与SSW是有区别的。因此,采用化学成分和药理活性分析相结合的方法确定具有开发利用价值的DSW的取水深度。分别汲取深度为150m,200m,300m,500m和1000m处海水,选择这5个深度的原因为150m为公认的表层,200m,300m和500m则是不同学者对海洋深层和表层的分界点,而1000m则是公认的海洋深层。首先对这5个不同深度海水的化学成分进行分析对比：采用ICP-MS测定海水中52种无机元素的含量；通过OPA-MPA柱前衍生RP-HPLC法、TPTZ分光光度法、气相色谱法及HPLC、UPLC-MS法对海水中的溶解游离氨基酸(dissolved free aminoacid, DFAA)、碳水化合物、脂肪酸和溶解有机物(dissolved organic matter, DOM)进行测定分析,并采用主成分分析和聚类分析方法对测定结果进行分析,结果表明,500m和1000m海水的化学成分非常相似,而与其他深度差异较大,说明500m及其以深的海水化学成分较为恒定。然后对不同深度的海水进行脱盐处理,制备得到硬度为1000的实验用海水,并以自由饮水的方式给予高脂乳剂造模的高脂血症大鼠,观察它们对高脂血症的预防作用及差异,结果发现,给予28天后,500m和1000m海水能显著降低高脂血症大鼠的血脂水平,提高机体抗氧化酶如SOD及GSH-Px的酶活,抑制脂质过氧化,并显著提高脂蛋白代谢酶LCAT, LPL及HL的活性,从而改善高脂血症大鼠体内的脂质代谢紊乱状态及其并发的脂肪肝和糖尿病,而其它深度海水组的各项指标则与模型对照组没有显著差异,这一结果表明500m及其以深的海水具有较好的生物活性。结合化学成分与药理活性分析结果,我们确定中国南海海域500m及其以深的海水均可用于DSW的开发利用。因为海洋的平均水深为3800m,所以海水的87%都可以用于DSW的研究开发,这一资源的数量是相当巨大的。此外,化学成分分析表明,与SSW相比,DSW富含有益微量元素V、Cr、Mn、Zn、Se等,而有毒微量元素Hg和Pb的含量则很低,而这些元素对MS及其相关疾病的发病和治疗都是有影响的,所以DSW的药理活性应该与这些元素密切相关,而这些元素在DSW和SSW中的含量差异导致了它们药理活性的差异。接下来,以取自1000m的DSW为例,对其安全性及对MS相关疾病如高脂血症及T2DM的预防作用及其作用机制进行了深入研究。
2.DSW的长期毒性研究。小鼠连续饮用硬度为1000的DSW63天,结果发现,与给予自来水的空白对照组相比,其生长指标如体重、饮水量、摄食量及各项血液学指标、血液生化学指标均无差异,主要脏器的组织形态学正常,未见与药物毒性相关的明显病变。这些结果表明DSW是安全无毒的。
3.DSW对脂质代谢的调节作用及机制研究。通过体外培养HepG2细胞,并采用ELISA、Western Blot等方法检测脂质代谢关键蛋白HMGCR、ACC、LDLR、 CYP7Al、Apo AI等的含量及其对AMPK及SREBPs信号通路的影响,对DSW的降脂机制进行研究。结果表明,DSW可以显著降低HepG2细胞胞内的脂质含量,对肝脏脂质代谢具有很好的调节作用。其作用机制为通过激活AMPK,磷酸化并失活胆固醇及脂肪酸合成的关建酶HMGCR和ACC,从而抑制胆固醇和脂肪酸的合成,并促进脂肪酸的氧化,同时抑制SREBP-1c的表达,进一步抑制脂肪酸及TG的合成；通过激活SREBP-2的裂解,上调LDLR的表达,提高机体清除LDL-C的能力；促进CYP7A1的表达,促进胆固醇向胆汁酸的转化；促进Apo AI的分泌,增强胆固醇的逆转运,从而在各个方面对脂质代谢进行调节。
4.DSW对T2DM的预防作用及机制研究。分别在动物和细胞水平探讨了DSW对T2DM的预防作用及其机制。动物实验结果表明硬度为1000的DSW可以显著降低高脂高糖饲料联合STZ诱导的T2DM小鼠的空腹血糖(fasting blood glucose, FBG)和空腹胰岛素(fasting insulin, FIns)含量,并显著提高其胰岛素敏感指数(insulin sensitivity index, ISI),说明DSW可以提高T2DM小鼠的胰岛素敏感性,对T2DM具有较好的预防作用。细胞实验结果表明DSW能够明显对抗高浓度葡萄糖诱导的胰岛素抵抗(insulin resistance, IR)。DSW能够激活IRS-2/PI3K信号途径,促进IRS-2的酪氨酸磷酸化及其与PI3K的p85亚基之间的相互作用,提高下游分子Akt及GSK-3的磷酸化程度,抑制G6Pase的表达,促进糖原合成,抑制糖异生而减少肝糖输出,从而抑制IR的形成。此外,DSW能够激活细胞内的AMPK信号通路,打开AMPK这个代谢“总开关”进而调节糖脂代谢,通过抑制肝脏脂质沉积改善IR。DSW还能够抑制细胞内JNK信号通路的激活,从氧化应激方面改善IR。因为IR被公认为MS的一个重要诱发因素,所以DSW对IR的改善作用表明其对MS具有较好的预防作用。
同时,研究发现,人工配制的只含Mg和Ca的人工矿物质水(artificial mineral water, AMW)对脂质代谢和IR也具有一定的调节作用,而且作用机制和DSW较为相似,只是各方面的作用都较为微弱。这些结果表明DSW中的常量元素Mg和Ca对于DSW改善糖脂代谢和IR发挥了一定作用,而微量元素如V、Cr、 Mn、Zn、Se等则进一步加强了该效应,使得DSW的药理活性更为显著,因此DSW对MS及其相关疾病的预防作用应归因于其中常量元素和微量元素的联合作用,体现了多种矿物元素“协同作战”的效果。
本论文首次对我国南海海域DSW对MS及其相关疾病的预防作用进行了较为系统的研究,为MS及其相关疾病如高脂血症、DM等的预防提供一个新的思路,为DSW的研究开发提供了实验基础和理论依据,并为更加全面而深入的研究开发提供了借鉴意义和启示。
DSW可以通过多途径、多靶点对糖脂代谢进行调节,对MS及其相关疾病具有较好的预防作用,而且DSW具有安全无毒、资源丰富等特性,所以DSW在医药领域具有广阔的开发应用价值及前景。在当前水源污染日趋严重、水资源日益紧缺的情况下,DSW这一新资源的开发和利用必将给社会带来深远的影响,DSW将成为人类新的资源宝库。
Recently, as the development of the world economy, especially the Chinese economy, the contradiction between the limited land resources and the demand for resources has become increasingly prominent. Many countries pay more attention to the ocean for resources exploring. The ocean is rich in natural resources. It not only has a large number of minerals resources, energy, but also has many other valuable resources, such as DSW. Currently, DSW is attracting much attention as a new natural resource.
DSW generally refers to sea water from a depth of more than200m. Water at those depths is free of the pollutants and pathogen that can taint SSW. Moreover, depth of more than200m is free of sunlight, so there is no photosynthesis, and the mineral component is more wealthy and stable. For these reasons, DSW exerts many properties that SSW does not have, such as purity, low temperature stability, and wealth of mineral components. DSW has been demonstrated to exert diverse beneficial health effects such as inhibition of atherosclerosis, hypertension, obesity, osteoporosis, and cancer. However, the underlying mechanisms remained totally undefined. Moreover, the pumping depth of DSW is not very precise, and is different in every literature.The development and utilization of DSW in Japan, Korea and the United States has entered into the commercialization stage, but in our country, there is no related research and development.
Previous studies found relationship between minerals intake and MS. Supplement of mineral elements through diet is of positive significance to the prevention of MS. DSW contains abundant major elements such as Mg, Ca, along with minute amounts of many beneficial trace elements such as V, Cr, Mn, Zn and Se. Therefore, in theory, DSW should have preventative effect on MS. In our country, water resource shortage and water pollution is becoming more serious. Thus, from the perspectives of economy and treatment of disease, study on DSW has both scientific significance and application values.
This paper conducted a systematic study on the pharmaceutical value of DSW pumped up from the South China Sea. Firstly, the pumping depth of DSW was determined, then, the safty, preventative effect on MS and the mechanism of DSW were investigated in cells and animals. The main results of this paper were listed below:
1. The pumping depth of DSW was determined. Researchers found that in the deep ocean, the chemical composition is relatively stable and will not change along with the depth, sea area and season. Besides, investigators found that DSW was useful for the prevention of hyperlipidemia and arteriosclerosis compared with SSW in animal model studies, that is to say, DSW is distinct from SSW in chemical constituent and pharmacological effect, so in this study, The pumping depth of DSW was determined using the combination method of chemical composition and pharmacological effect analysis. Seawater was pumped up from150m,200m,300m,500m and1000m respectively, the reason why these5depths are chosen is that150m is acknowledged as SSW,1000m is accepted as DSW, while200m,300m and500m are considered as boundary between SSW and DSW by different researchers. The analyses of mineral elements, dissolved fatty amino aicds, carbohydrates, fatty acids and dissolved organic matter were performed by ICP-MS, RP-HPLC, TPTZ-spectrophotometric method, gas chromatography and UPLC-MS respectively. Results suggested that seawater from500m and1000m was similar in their chemical constituents, distinguishing from seawater from other depths. Thereafter, seawater was desalinated to prepare water with hardness1000, and given to rats administrated with high fat emulsion for28days. Lipid parameters were determined and results indicated that seawater from500m and1000m were useful for the prevention of hyperlipidemia compared to seawater from other depths. The results of chemical composition and pharmacological effect analysis suggested that seawater from more than500m could be used in the research and exploitation of DSW. Because the average water depth of seawater was3800m, so87%of the seawater could be used as DSW. DSW is a resource with large quantity. Besides, compared with SSW, DSW is rich in beneficial microelement, such as V, Cr, Mn, Zn and Se, while contents of poisonous element, such as Hg and Pb in DSW are lower. These elements have influence on the prevention and development of MS and related diseases, so the activity of DSW must be related to thses trace elemtents, The difference between DSW and SSW in the content of trace minerals was considered to cause the difference in the hypolipidemia effects.Thereafter, the subacute effect, preventative effect on MS and the action mechanism of DSW were studied deeply.
2. DSW was safe as drinking water. To confirm the safety of DSW, the chronic toxicity of DSW was investigated in mice. None of the mice showed any clear abnormal growth or behavior, neither did any show signs of illness nor a single case of death during the9weeks of study. In terms of body weight gain, food and water intake, hematological parameters, blood biochemical parameters and morphological changes of the main internal organs, no significance difference was found between the DSW group and the control group who received tap water. This finding suggested that DSW showed no acute or subacute effects and was safe as drinking water.
3. The modulation and action mechanism of DSW on lipid metabolism were investigated in HepG2cells. It has been found that DSW was associated with lower serum lipid in animal model studies. Herein we further elucidated how DSW modulated lipid metabolism in HepG2cells. When DSW was added to HepG2cells, it decreased the lipid contents of hepatocyte through the activation of AMPK, thus inhibiting the synthesis of cholesterol and fatty acid. Besides, LDLR was upregulated by activation of SREBP-2. In addition, the levels of ApoAI and CYP7Alwere also increased. That was to say, DSW could modulate lipid metabolism in many aspects.
4. The preventive effects of DSW on T2DM were evaluated in mice and HepG2cells, with the investigation of its mechanism. Compared with the control group administrated with distilled water, treatment with DSW significantly decreased the fasting blood glucose and fasting insulin in mice, raised the insulin sensitive index at the same time. These results indicated that DSW exerted good hyperglycemic activity. Insulin resistance is recognized as an important causative factor for pathogenesis of MS, and many study suggested that the defect of insulin signaling was the main reason for insulin resistance, and IRS-2/PI3K pathway is mainly involved in the control of metabolic actions by insulin in liver. Therefore, in the present study, the investigations of DSW on insulin signaling are performed in insulin-responsive human HepG2cells cotreated with high glucose. Result suggested that treatment of DSW activated IRS-2/PI3K pathway, depressed glucose production, protected hepatocytes from oxidative stress, and inhibited lipogenesis in insulin resistant HepG2cells. Our data demonstrate that DSW may attenuate insulin signaling blockade via AMPK and JNK pathways, establishing a new mechanism for DSW preventing insulin resistance. Insulin resistance is recognized as an important causative factor for pathogenesis of metabolic syndrome, so DSW must have good preventive effect on metabolic syndrome.
Interestingly, we found that AMW which contained Mg and Ca only also had similar effects to DSW on prevention of MS, moreover, both action mechanisms were similar, but AMW exerted weaker activities in all aspects than DSW. These results demonstrated that among minerals in DSW, Mg and Ca might play important roles in the regulatory effect of DSW in glcose and lipid metabolism, at the same time, trace elements such as V, Cr, Mn, Zn and Se enhanced these effects. So, the pharmacological activities of DSW must be attributed to the combined action of mineral ions contained in DSW.
A systematic investigation of the pharmaceutical value of DSW has been performed in this paper for the first time, the present findings open up new avenues into the prevention and treatment of MS, providing experimental basis for the medicinal exploitation of DSW and reference meaning and inspiration in the further study.
DSW can regulate glucose and lipid metabolism via multi-ruotes and multi-targets, and it possesses good prevention and protection effect on MS. DSW is natural, pure water resources with large quantity and is of benefit to people in many aspects. Under the condition of water pollution and water resources shortage, exploitation of DSW is of profound and lasting significance. DSW is a new resource treasury for China and the world.
DSW通常是指阳光照射不到,不能进行光合作用,约200m以深的海水。研究表明,DSW具有不少有别于海洋表层水(surface-sea water, SSW)的优良性质,如低温恒定性、矿物元素丰富且稳定及无菌清洁性等特性。药理研究表明,DSW具有多种药理活性,如预防心血管疾病(cardiovascular disease, CVD),预防和治疗肥胖病和糖尿病(diabetes mellitus, DM),治疗皮肤病,调节免疫系统及抗氧化,抗疲劳,抗肿瘤及治疗骨质疏松等,但是其作用机制尚未阐明,而且DSW的取水深度也不确定,在不同文献中DSW的取水深度不尽相同。DSW的开发利用在日本、韩国和美国已经进入商品化阶段,但我国尚无DSW方面的研究开发。
随着人们生活方式和饮食习惯的改变,代谢综合征(metabolic syndrome,MS)及其相关疾病如高脂血症、Ⅱ型糖尿病(type2diabetes mellitus, T2DM)的发病率逐年升高。研究表明,矿物元素与MS及其相关疾病的发生和发展密切相关,通过饮食补充有益矿物元素Ca、V、, Cr、Mn、Zn、Se,同时减少有毒微量元素Pb、Hg等的接触,以维持体内矿物元素含量的相对稳定,对预防MS及其相关疾病的发生具有积极意义。DSW富含92种矿物元素,涵盖了人体新陈代谢所需的元素种类,可以均衡满足机体摄取各种矿物元素的需求,因此理论上,DSW对MS及其相关疾病均具有较好的预防作用。
在我国水资源日益紧缺,水污染日趋严重,MS及其相关疾病发病率逐年攀升的情况下,无论是从经济角度还是人类健康角度出发,开发和利用DSW都具有非常重要的意义及价值。
本论文对我国南海海域DSW的药用价值进行了较为系统的研究,首先确定具有开发利用价值的DSW的取水深度,并在细胞和动物水平对DSW的安全性、其对MS及其相关疾病的预防作用与作用机制进行了深入研究。主要内容如下：
1.具有开发利用价值的DSW取水深度的确定。研究表明,在海洋深层,海水的化学成分是相对恒定的,不随深度、季节和海域的不同而变化；同时,日本学者Miyamura M发现,与SSW相比,DSW对高脂血症的预防作用更显著。即在化学成分和药理活性方面,DSW与SSW是有区别的。因此,采用化学成分和药理活性分析相结合的方法确定具有开发利用价值的DSW的取水深度。分别汲取深度为150m,200m,300m,500m和1000m处海水,选择这5个深度的原因为150m为公认的表层,200m,300m和500m则是不同学者对海洋深层和表层的分界点,而1000m则是公认的海洋深层。首先对这5个不同深度海水的化学成分进行分析对比：采用ICP-MS测定海水中52种无机元素的含量；通过OPA-MPA柱前衍生RP-HPLC法、TPTZ分光光度法、气相色谱法及HPLC、UPLC-MS法对海水中的溶解游离氨基酸(dissolved free aminoacid, DFAA)、碳水化合物、脂肪酸和溶解有机物(dissolved organic matter, DOM)进行测定分析,并采用主成分分析和聚类分析方法对测定结果进行分析,结果表明,500m和1000m海水的化学成分非常相似,而与其他深度差异较大,说明500m及其以深的海水化学成分较为恒定。然后对不同深度的海水进行脱盐处理,制备得到硬度为1000的实验用海水,并以自由饮水的方式给予高脂乳剂造模的高脂血症大鼠,观察它们对高脂血症的预防作用及差异,结果发现,给予28天后,500m和1000m海水能显著降低高脂血症大鼠的血脂水平,提高机体抗氧化酶如SOD及GSH-Px的酶活,抑制脂质过氧化,并显著提高脂蛋白代谢酶LCAT, LPL及HL的活性,从而改善高脂血症大鼠体内的脂质代谢紊乱状态及其并发的脂肪肝和糖尿病,而其它深度海水组的各项指标则与模型对照组没有显著差异,这一结果表明500m及其以深的海水具有较好的生物活性。结合化学成分与药理活性分析结果,我们确定中国南海海域500m及其以深的海水均可用于DSW的开发利用。因为海洋的平均水深为3800m,所以海水的87%都可以用于DSW的研究开发,这一资源的数量是相当巨大的。此外,化学成分分析表明,与SSW相比,DSW富含有益微量元素V、Cr、Mn、Zn、Se等,而有毒微量元素Hg和Pb的含量则很低,而这些元素对MS及其相关疾病的发病和治疗都是有影响的,所以DSW的药理活性应该与这些元素密切相关,而这些元素在DSW和SSW中的含量差异导致了它们药理活性的差异。接下来,以取自1000m的DSW为例,对其安全性及对MS相关疾病如高脂血症及T2DM的预防作用及其作用机制进行了深入研究。
2.DSW的长期毒性研究。小鼠连续饮用硬度为1000的DSW63天,结果发现,与给予自来水的空白对照组相比,其生长指标如体重、饮水量、摄食量及各项血液学指标、血液生化学指标均无差异,主要脏器的组织形态学正常,未见与药物毒性相关的明显病变。这些结果表明DSW是安全无毒的。
3.DSW对脂质代谢的调节作用及机制研究。通过体外培养HepG2细胞,并采用ELISA、Western Blot等方法检测脂质代谢关键蛋白HMGCR、ACC、LDLR、 CYP7Al、Apo AI等的含量及其对AMPK及SREBPs信号通路的影响,对DSW的降脂机制进行研究。结果表明,DSW可以显著降低HepG2细胞胞内的脂质含量,对肝脏脂质代谢具有很好的调节作用。其作用机制为通过激活AMPK,磷酸化并失活胆固醇及脂肪酸合成的关建酶HMGCR和ACC,从而抑制胆固醇和脂肪酸的合成,并促进脂肪酸的氧化,同时抑制SREBP-1c的表达,进一步抑制脂肪酸及TG的合成；通过激活SREBP-2的裂解,上调LDLR的表达,提高机体清除LDL-C的能力；促进CYP7A1的表达,促进胆固醇向胆汁酸的转化；促进Apo AI的分泌,增强胆固醇的逆转运,从而在各个方面对脂质代谢进行调节。
4.DSW对T2DM的预防作用及机制研究。分别在动物和细胞水平探讨了DSW对T2DM的预防作用及其机制。动物实验结果表明硬度为1000的DSW可以显著降低高脂高糖饲料联合STZ诱导的T2DM小鼠的空腹血糖(fasting blood glucose, FBG)和空腹胰岛素(fasting insulin, FIns)含量,并显著提高其胰岛素敏感指数(insulin sensitivity index, ISI),说明DSW可以提高T2DM小鼠的胰岛素敏感性,对T2DM具有较好的预防作用。细胞实验结果表明DSW能够明显对抗高浓度葡萄糖诱导的胰岛素抵抗(insulin resistance, IR)。DSW能够激活IRS-2/PI3K信号途径,促进IRS-2的酪氨酸磷酸化及其与PI3K的p85亚基之间的相互作用,提高下游分子Akt及GSK-3的磷酸化程度,抑制G6Pase的表达,促进糖原合成,抑制糖异生而减少肝糖输出,从而抑制IR的形成。此外,DSW能够激活细胞内的AMPK信号通路,打开AMPK这个代谢“总开关”进而调节糖脂代谢,通过抑制肝脏脂质沉积改善IR。DSW还能够抑制细胞内JNK信号通路的激活,从氧化应激方面改善IR。因为IR被公认为MS的一个重要诱发因素,所以DSW对IR的改善作用表明其对MS具有较好的预防作用。
同时,研究发现,人工配制的只含Mg和Ca的人工矿物质水(artificial mineral water, AMW)对脂质代谢和IR也具有一定的调节作用,而且作用机制和DSW较为相似,只是各方面的作用都较为微弱。这些结果表明DSW中的常量元素Mg和Ca对于DSW改善糖脂代谢和IR发挥了一定作用,而微量元素如V、Cr、 Mn、Zn、Se等则进一步加强了该效应,使得DSW的药理活性更为显著,因此DSW对MS及其相关疾病的预防作用应归因于其中常量元素和微量元素的联合作用,体现了多种矿物元素“协同作战”的效果。
本论文首次对我国南海海域DSW对MS及其相关疾病的预防作用进行了较为系统的研究,为MS及其相关疾病如高脂血症、DM等的预防提供一个新的思路,为DSW的研究开发提供了实验基础和理论依据,并为更加全面而深入的研究开发提供了借鉴意义和启示。
DSW可以通过多途径、多靶点对糖脂代谢进行调节,对MS及其相关疾病具有较好的预防作用,而且DSW具有安全无毒、资源丰富等特性,所以DSW在医药领域具有广阔的开发应用价值及前景。在当前水源污染日趋严重、水资源日益紧缺的情况下,DSW这一新资源的开发和利用必将给社会带来深远的影响,DSW将成为人类新的资源宝库。
Recently, as the development of the world economy, especially the Chinese economy, the contradiction between the limited land resources and the demand for resources has become increasingly prominent. Many countries pay more attention to the ocean for resources exploring. The ocean is rich in natural resources. It not only has a large number of minerals resources, energy, but also has many other valuable resources, such as DSW. Currently, DSW is attracting much attention as a new natural resource.
DSW generally refers to sea water from a depth of more than200m. Water at those depths is free of the pollutants and pathogen that can taint SSW. Moreover, depth of more than200m is free of sunlight, so there is no photosynthesis, and the mineral component is more wealthy and stable. For these reasons, DSW exerts many properties that SSW does not have, such as purity, low temperature stability, and wealth of mineral components. DSW has been demonstrated to exert diverse beneficial health effects such as inhibition of atherosclerosis, hypertension, obesity, osteoporosis, and cancer. However, the underlying mechanisms remained totally undefined. Moreover, the pumping depth of DSW is not very precise, and is different in every literature.The development and utilization of DSW in Japan, Korea and the United States has entered into the commercialization stage, but in our country, there is no related research and development.
Previous studies found relationship between minerals intake and MS. Supplement of mineral elements through diet is of positive significance to the prevention of MS. DSW contains abundant major elements such as Mg, Ca, along with minute amounts of many beneficial trace elements such as V, Cr, Mn, Zn and Se. Therefore, in theory, DSW should have preventative effect on MS. In our country, water resource shortage and water pollution is becoming more serious. Thus, from the perspectives of economy and treatment of disease, study on DSW has both scientific significance and application values.
This paper conducted a systematic study on the pharmaceutical value of DSW pumped up from the South China Sea. Firstly, the pumping depth of DSW was determined, then, the safty, preventative effect on MS and the mechanism of DSW were investigated in cells and animals. The main results of this paper were listed below:
1. The pumping depth of DSW was determined. Researchers found that in the deep ocean, the chemical composition is relatively stable and will not change along with the depth, sea area and season. Besides, investigators found that DSW was useful for the prevention of hyperlipidemia and arteriosclerosis compared with SSW in animal model studies, that is to say, DSW is distinct from SSW in chemical constituent and pharmacological effect, so in this study, The pumping depth of DSW was determined using the combination method of chemical composition and pharmacological effect analysis. Seawater was pumped up from150m,200m,300m,500m and1000m respectively, the reason why these5depths are chosen is that150m is acknowledged as SSW,1000m is accepted as DSW, while200m,300m and500m are considered as boundary between SSW and DSW by different researchers. The analyses of mineral elements, dissolved fatty amino aicds, carbohydrates, fatty acids and dissolved organic matter were performed by ICP-MS, RP-HPLC, TPTZ-spectrophotometric method, gas chromatography and UPLC-MS respectively. Results suggested that seawater from500m and1000m was similar in their chemical constituents, distinguishing from seawater from other depths. Thereafter, seawater was desalinated to prepare water with hardness1000, and given to rats administrated with high fat emulsion for28days. Lipid parameters were determined and results indicated that seawater from500m and1000m were useful for the prevention of hyperlipidemia compared to seawater from other depths. The results of chemical composition and pharmacological effect analysis suggested that seawater from more than500m could be used in the research and exploitation of DSW. Because the average water depth of seawater was3800m, so87%of the seawater could be used as DSW. DSW is a resource with large quantity. Besides, compared with SSW, DSW is rich in beneficial microelement, such as V, Cr, Mn, Zn and Se, while contents of poisonous element, such as Hg and Pb in DSW are lower. These elements have influence on the prevention and development of MS and related diseases, so the activity of DSW must be related to thses trace elemtents, The difference between DSW and SSW in the content of trace minerals was considered to cause the difference in the hypolipidemia effects.Thereafter, the subacute effect, preventative effect on MS and the action mechanism of DSW were studied deeply.
2. DSW was safe as drinking water. To confirm the safety of DSW, the chronic toxicity of DSW was investigated in mice. None of the mice showed any clear abnormal growth or behavior, neither did any show signs of illness nor a single case of death during the9weeks of study. In terms of body weight gain, food and water intake, hematological parameters, blood biochemical parameters and morphological changes of the main internal organs, no significance difference was found between the DSW group and the control group who received tap water. This finding suggested that DSW showed no acute or subacute effects and was safe as drinking water.
3. The modulation and action mechanism of DSW on lipid metabolism were investigated in HepG2cells. It has been found that DSW was associated with lower serum lipid in animal model studies. Herein we further elucidated how DSW modulated lipid metabolism in HepG2cells. When DSW was added to HepG2cells, it decreased the lipid contents of hepatocyte through the activation of AMPK, thus inhibiting the synthesis of cholesterol and fatty acid. Besides, LDLR was upregulated by activation of SREBP-2. In addition, the levels of ApoAI and CYP7Alwere also increased. That was to say, DSW could modulate lipid metabolism in many aspects.
4. The preventive effects of DSW on T2DM were evaluated in mice and HepG2cells, with the investigation of its mechanism. Compared with the control group administrated with distilled water, treatment with DSW significantly decreased the fasting blood glucose and fasting insulin in mice, raised the insulin sensitive index at the same time. These results indicated that DSW exerted good hyperglycemic activity. Insulin resistance is recognized as an important causative factor for pathogenesis of MS, and many study suggested that the defect of insulin signaling was the main reason for insulin resistance, and IRS-2/PI3K pathway is mainly involved in the control of metabolic actions by insulin in liver. Therefore, in the present study, the investigations of DSW on insulin signaling are performed in insulin-responsive human HepG2cells cotreated with high glucose. Result suggested that treatment of DSW activated IRS-2/PI3K pathway, depressed glucose production, protected hepatocytes from oxidative stress, and inhibited lipogenesis in insulin resistant HepG2cells. Our data demonstrate that DSW may attenuate insulin signaling blockade via AMPK and JNK pathways, establishing a new mechanism for DSW preventing insulin resistance. Insulin resistance is recognized as an important causative factor for pathogenesis of metabolic syndrome, so DSW must have good preventive effect on metabolic syndrome.
Interestingly, we found that AMW which contained Mg and Ca only also had similar effects to DSW on prevention of MS, moreover, both action mechanisms were similar, but AMW exerted weaker activities in all aspects than DSW. These results demonstrated that among minerals in DSW, Mg and Ca might play important roles in the regulatory effect of DSW in glcose and lipid metabolism, at the same time, trace elements such as V, Cr, Mn, Zn and Se enhanced these effects. So, the pharmacological activities of DSW must be attributed to the combined action of mineral ions contained in DSW.
A systematic investigation of the pharmaceutical value of DSW has been performed in this paper for the first time, the present findings open up new avenues into the prevention and treatment of MS, providing experimental basis for the medicinal exploitation of DSW and reference meaning and inspiration in the further study.
DSW can regulate glucose and lipid metabolism via multi-ruotes and multi-targets, and it possesses good prevention and protection effect on MS. DSW is natural, pure water resources with large quantity and is of benefit to people in many aspects. Under the condition of water pollution and water resources shortage, exploitation of DSW is of profound and lasting significance. DSW is a new resource treasury for China and the world.
引文
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