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Potential Health Benefits of Deep Sea Water: A Review.

1. Introduction

Water is generally defined as a liquid which is shaped by the container that it is filled in and is able to have many variants of colours. It is the crucial component for all living things. For instance, humans need water for many functions such as to regulate body temperature, enhance body metabolism, and provide minerals that are essential to the body. There are many sources of water, such as surface water, aquifer, spring, and seawater. Meanwhile, deep sea water (DSW) can also be a good water source. It is beneficial as it could supply minerals that are essential to health. DSW commonly refers to seawater that is pumped up from a depth of over 200 m. It is usually associated with the following characteristics: low temperature, high purity, and being rich in nutrients, namely, beneficial elements [1]. Its location being far from solar radiation results in it having minimal to no bacteria activities. Less photosynthesis of plant plankton, consumption of nutrients, and lots of organic decomposition causes abundant nutrients to remain there. The abundance of inorganic material becomes higher when the depth of the seawater is increased. These characteristics have derived attention for research regarding DSW especially for its numerous beneficial minerals, which include magnesium (Mg), calcium (Ca), potassium (K), chromium (Cr), selenium (Se), zinc (Zn), and vanadium (V) [1, 2]. DSW is claimed to be high in minerals compared to other sources of water [2].

People usually consume drinking water that is in the form of bottled drinking water (such as mineral water), filtered tap water, or boiled tap water. Drinking water sold by suppliers is expected to contain good nutrient content and be safe to be consumed, because the suppliers possess a production license from the authorities. Surprisingly, some drinking water that is available in the market has been reported to have low mineral content [3]. This is possibly due to the common process drinking water undergo such as reverse osmosis and filtration, which removes the mineral contents inside it. Mineral water, which does not undergo the extensive process needed, is completely taken from groundwater and gains mineral ions from its sources such as rocks. It is also reported to contain low minerals [3]. However, the mineral contents in the water may vary with the geographical locations and the treatment process that it has gone through. Promisingly, DSW can offer plenty of minerals for the production of drinking water, and other DSW by-products. The production of refined DSW usually involves a desalination process, followed by a mineralization process. A high concentration of mineral salts in DSW though will commonly be processed through means such as reverse osmosis, electrodialysis, or low vacuum temperature in order to produce a safe concentration of water for consumption [1, 4, 5].

DSW has been acquired from many countries with sources of it that are accessible to land. This include Korea, Japan, Taiwan, China, and the USA [1, 2, 6, 7]. Most of those countries conducted researches regarding the health effects that can be attained from the consumption of DSW. As a result, the production of products such as deep sea drinking water (DSDW) became available from those countries. DSDW is claimed as a drinking water which can promote health, since it does not contain carbohydrate, fat, protein, and other bioactive materials which potentially cause adverse health effects, instead of providing valuable minerals to health. Despite being produced for drinking water, it is also used for a variety of purposes such as for food products, cosmetics, aquaculture, and agriculture [8]. Thus, due to the availability of numerous minerals, many researches have been conducted regarding it, in order to discover its benefits to health. By conducting literature reviews, the findings regarding the potential health benefits of DSW applications have been compiled and discussed in this paper.

2. Minerals in Deep Sea Water

DSW contains many types of minerals, such as Mg, Ca, Cl, Na, K, Se, and V, as shown in Table 1 [8]. In fact, DSW is more abundant in minerals compared to surface seawater [6]. The example of the difference between the amount of minerals among surface seawater and DSW is shown in Table 2. DSW is a good nutrient source and could be claimed as a nutrients provider, since the minerals contained inside it provide many benefits to health. For instance, Mg is significant for many physiological processes in the body such as for energy metabolism and enzyme functions [9]. Mg is able to reduce lipids accumulation in the aorta of subjects that has high cholesterol intake [10]. Besides that, Mg is beneficial to people who have cardiovascular disease as it can reduce the potential of a heart attack by dilating the blood vessels and stopping spasms in the heart muscles and vessel walls [11]. It is also able to reduce the risk of obesity, diabetes, and asthma [1,12]. Drinking water, which has high Mg content, has shown higher inhibitory effects in the adipocyte differentiation, which means that the synthesis of fat cells is able to be slowed down by Mg [13]. Ca is one of the major minerals for humans. It has many benefits to health such as for bone development and density and acts as the pivotal cofactor for several enzymes needed for energy metabolism. Adequate intake of Ca can help reduce the risks of cardiovascular disease, obesity, and some forms of cancers [1, 9,12]. A high Ca diet is able to increase lipolysis and preserve thermogenesis during caloric restriction, in away that markedly accelerates weight loss [14]. Cr is an essential nutrient that is required for carbohydrates and lipids metabolism [15, 16]. It has antioxidant properties which are useful for expanding cell life [17]. V has the potential for reducing lipids and has shown effectiveness in inhibiting adipocyte differentiation of the fat cells [18]. There are lots of benefits of other elements in DSW to health, which remain to be elucidated, particularly for the trace elements. The total amount of each element contained in DSW has been estimated [8], based upon the average concentration of each element in DSW. The total volume of DSW of 1.35 x [10.sup.18] [m.sup.3] is shown in Table 1.

3. Potential Benefits of Deep Sea Water to Health

Many researchers and scientists have done studies about DSW, particularly about refined or balanced DSW. The minerals in it have been proven to improve many health problems. The potential health benefits of DSW are described below by providing some of the mechanisms involved. The findings that have been reviewed in this paper are significant, and comparisons have been made between the treated group and the control group.

3.1. Improvement of the Cholesterol Profiles. The most promising benefits that can be attained from DSW intake are that it is able to improve the cholesterol profiles in the serum and liver, respectively. Its applications have reduced the levels of triglyceride (TG), non-high-density lipoprotein cholesterol (non-HDL-C) levels, and total cholesterol (TC) in the serum and liver of animal models, respectively [4-6, 19-22, 24]. Drinking water produced from DSW which contains Mg of 600 and 1000 ppm, is able to decrease cholesterol levels by 18% and 15%, respectively [22]. Interestingly, a study of DSW consumption by hypercholesterolemic individuals proved that it could reduce TC and low density lipoproteins (LDL) and decreased lipid peroxidation in those subjects. The mechanisms for the improvement of cholesterol profiles are associated with the upregulation of hepatic low density lipoprotein receptor and cholesterol-7a-hydroxylase (CYP7A1) gene expressions, which are involved in cholesterol catabolism. A DSW intake resulted in a higher faecal cholesterol and bile acid excretions, thus decreasing the TC levels [5]. DSW decreases the lipid contents of hepatocytes through the activation of AMP-activated protein kinase, inhibiting the synthesis of cholesterol and fatty acid [19]. The details of respective studies are described in Table 3.

3.2. Protection from Cardiovascular Problems. DSW provides protection from cardiovascular diseases by decreasing the TC, TG, atherogenic index, and malondialdehyde (MDA) levels, while increasing the serum trolox equivalent antioxidant capacity (TEAC). The molecular mechanism of its cardiovascular protection is via upregulation of hepatic low density lipoprotein receptors (LDL receptors) and CYP7A1 gene expressions [5]. The cardioprotective effects of it were further proven, when its application can reduce abnormal cardiac architecture and apoptosis and enhance insulin-like growth factor-1 receptor (IGF-1R) cardiac survival signalling [25]. DSW can also improve cardiovascular hemodynamics in the study conducted by Katsuda et al. [2]. More details about the protective effects of DSW on the cardiovascular system are described in Table 4.

3.3. Prevention from Atherogenesis. Atherogenesis is the formation of plaque in the inner lining of an artery, which deposits fatty substances, cholesterol, cellular waste products, calcium, and other substances. Treatment with DSW was able to prevent the atherogenesis process [6, 21]. DSW with the hardness of 300, 900, and 1500 had significantly decreased the atherogenic index [(TC - HDL-C)/HDL-C] [5]. Antiatherogenic effects of DSW are associated with 5adenosine monophosphate-activated protein kinase (AMPK) stimulation and the consequent inhibition of phosphorylation of acetyl-CoA carboxylase (ACC) [6]. AMPK plays an important role in lipid metabolism via the inhibition of 3-Hydroxy-3-methyl- glutaryl-CoA reductase (HMGCR) and ACC and then inhibits the production of cholesterol. The details of these studies are described in Table 5. Prevention of atherogenesis may avoid severe health problems, including coronary heart disease and stroke. DSW has antiatherogenic properties due to the existence of many beneficial mineral ions such as Mg and Ca in it. Hence, it could be widely promoted to enhance cardiovascular protection.

3.4. Reduction of Blood Pressure. DSW could improve cardiovascular hemodynamics and reduce blood pressure [2, 6, 20]. Hypertensive rats that were treated with DSW for eight weeks had lower blood pressure than the control group [20]. Reduced fats and blood lipids, such as in the artery, may be associated with the reduced blood pressure. Although DSW used in the study contains pretty much salt, the blood pressure did not increase. In another study [5], DSW application did not affect the blood pressure. Moreover, DSW can also prevent thrombotic disorder by suppressing the release of type-1 plasminogen activator inhibitor from the human vascular endothelial cells [7]. Lots of minerals combination in the DSW, such as Mg, Ca, and Na are associated with a reduced blood pressure. Na content may induce hypertension, though Mg supplement might lower the blood pressure by suppressing the adrenergic activity and, likely, natriuresis [46]. It is interesting that high Mg content can lower blood pressure in the presence of sodium. The details of these respective studies are described in Table 6.

3.5. Protection from Obesity. DSW has antiobesity properties and has been proven to reduce fat and body weight [1, 27, 29, 45]. It has been recognized as possible antiobesity therapeutics from nature [47]. The research has reported that DSW was significantly able to reduce lipids accumulation in the in vitro and in vivo models. Study with obese mice elucidated that DSW with hardness of 1000 was able to reduce body weight by 7%. It also increased the plasma protein levels of adiponectin and decreased plasma protein levels of resistin, RBP4, and fatty acid binding protein [1, 29]. The results suggest that the antiobesity activities were mediated by modulating the expression of obesity-specific molecules. The expression of key adipogenic genes such as peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]), CCAAT/enhancer-binding protein-[alpha] (C/EBP[alpha]), and adipocyte protein-2 (aP2) was suppressed, and the expression of glucose transporter 4 (GLUT4) was increased by its application [1, 27]. The magnificent effects of DSW on obesity were further proven when it stimulated mitochondrial biogenesis, the component which controls the release of energy associated with lipid metabolism [26]. Mg and Ca ions play a role as the main active components to reduce fats. However, DSW that has the same hardness of 1000 with drinking water which only contains Mg and Ca ions has showed small different effects in the obesity finding [13]. Thus, this hypothesized that Mg and Ca are not the main factors to reduce fats, as the roles of many elements in DSW remain to be elucidated. However the available findings on the clinical study showed that there is no significant difference of TG level and body weight, between treated subjects and controls [4]. More clinical studies are warranted. The detailed mechanisms involved regarding the effects of DSW on obesity-specific molecules are described in Table 7.

3.6. Treatment for Diabetes. DSW was able to improve glucose intolerance and suppress hyperglycaemia which indicated its ability to treat diabetes [26, 27, 29]. Its application had recovered the size of the pancreatic islets of Langerhans and increased the secretion of glucagon and insulin. Through quantitative reverse transcription polymerase chain reaction, DSW showed improvement results regarding the expression of hepatic genes involved in glycogenolysis and glucose oxidation. Whereas in muscles, glucose uptake, [beta]-oxidation, and glucose oxidation were increased by its supplementation [29]. DSW increased the phosphorylation of IRS-1, LKB1, AMPK, and mTOR, which are signalling molecules related to lipid and glucose metabolism [27]. Moreover, blood glucose in treated mice was reduced by its application [27, 29]. The plasma glucose levels in DSW-fed mice were substantially reduced by 35.4%, compared to the control mice group [1]. The antidiabetic properties of it were associated with the existence of mineral ions such as Mg and Ca. The details of these studies are described in Table 8.

3.7. Treatment for Skin Problems. DSW is also capable of treating skin problems. In a study involving patients with atopic eczema/dermatitis syndrome (AEDS) treated with DSW, the improvement of skin symptoms such as inflammation, lichenification, and cracking of the skin was observed [31]. AEDS patients typically exhibit an imbalance of various essential minerals in hair, and some have toxic minerals present. From that study, DSW intake has restored the essential minerals such as Se and reduces the levels of toxic minerals such as mercury and lead in the treated patients. In another study, the intake of DSW has reduced allergic skin responses and serum levels of total IgE, Japanese cedar pollen-specific IgE, interleukin-4 (IL-4), IL-6, IL-13, and IL-18 in the patients with allergic rhinitis, compared to the distilled water intake which fails to give those effects [32].

In vivo study revealed that DSW can recover the atopic skin lesion by improving the skin symptoms such as edema, erythema, dryness, itching, transepidermal water loss (TEWL), decreased epidermal thickness, and infiltration of inflammatory cells. Its application can reduce allergic responses when reduction of total IgE levels and histamine released were recorded. It also inhibited upregulation of IgE, histamine, and proinflammatory cytokines (tumor necrosis factor a (TNF-[alpha]), IL-1[beta], and IL-6) in the serum. Downregulated CD4+/CD8+ ratio in spleen lymphocyte by 10% CDSW was also observed. Its application can reduce the expression of IL-4 and IL-10 from Th2 cells in the 10% CDSW-treated group [30]. The details of these studies are described in Table 9.

3.8. Protection from Hepatic Problems. High fat diets may cause problems to hepatic systems. DSW is able to give protection for hepatic problems. In a study by Chen et al. [33], it has decreased the lipid accumulation in livers, which are associated with the increase in daily faecal lipid and bile acid outputs. The hepatic antioxidative levels were also improved by its application, which were proven by the high capacity levels of liver glutathione and trolox equivalent antioxidant. DSW was able to regulate hepatic fatty acid homeostasis by upregulating genes related to b-oxidation of fatty acids, which are hepatic peroxisome proliferator-activated receptor-alpha, retinoid X receptor-alpha, and uncoupling protein-2 gene expression. Its application can attenuate hepatic damage, which is proven by reduced lipid peroxidation status in livers, which might be related to reducing hepatic malondialdehyde (MDA) content [33]. The liver damage indices which are aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are also reduced by its application. The details of these studies are described in Table 10.

3.9. Treatment for Fatigue. DSW can restore fatigue and improve exercise workload. Its application has promoted the endurance and reduced exhaustive period of rats in an exercise test [34]. The ratios of lactic acid elimination to lactic acid increment were improved in DSW treated rats. The study showed low blood urea nitrogen (BUN) level of rats fed with D100 in a dosage of 30 mL/kg-d and D600 in dosages of 6,12, and 30 mL/kg-d, respectively. As a result, the liver glycogen content had increased in the rats fed with D100 in a dosage of 6 mL/kg-d. Study regarding effects of DSW on human shows significant findings as well. DSW is able to accelerate recovery from physical fatigue of people, following an exhaustive physical challenge [35]. The findings suggested that DSW which has enriched contents of boron, magnesium, lithium, and rubidium may complement and enhance the molecular and cellular complexity of human during exercise, eradicate exercise-induced muscle damage, and strengthen antioxidant capability against oxidative stress. The details of these studies are described in Table 11.

3.10. Treatment for Stomach Ulcer. DSW can reduce ulcer area as well as apoptotic signalling in acetic acid-induced duodenal ulcers. It had upregulated antioxidant and enhanced Bcl-2 and thioredoxin reductase 1 expression in a study that used rats [36]. In that study, DSW ingestion provides intestinal protection via the antioxidant and antiapoptotic mechanisms of selenium. The details of this study are described in Table 12.

3.11. Prevention of Cancer. DSW is potential to prevent cancer. Its application can inhibit human breast cancer cell lines' migratory ability in a wound-healing assay. The inhibitory effects of DSW on breast cancer invasion/metastasis that uses MDA-MB-231 cells appears to be mediated through TGF-[beta] and Wnt5a signalling, resulting in attenuated expression of CD44 [37]. In a study that uses the noninvasive MCF-7 cells, DSW treatment resulted in the inhibition of TPA-induced migration and MMP-9 activity with a concomitant decrease in mRNA levels of MMP-9, TGF-[beta], Wnt5a, and Wnt3a [37]. DSW also improves the quality of green tea prepared with it, in which it enhanced the production of epigallocatechin gallate (EGCG), which could potentially act as an inhibitor for N-nitrosation, which can induce mutagenic and cell damaging reactions [38]. The details of the studies regarding effects of DSW on cancer are described in Table 13.

3.12. Improvement in Antibacterial Activity. DSW has promising effects on antibacterial activity. The findings of its antibacterial activities were proven in the studies using the in vitro, in vivo, and clinical model as described in Table 14.

3.13. Treatment for Cataract. DSW application can delay cataract development [40, 41]. This effect is associated with the presence of Mg and Ca content in DSW. The details of these studies are described in Table 15.

3.14. Recovery from Osteoporosis. DSW has therapeutic potential on osteoporosis. DSW at hardness 1000 showed significant increase in proliferation of osteoblastic cell (MC3T3). In the in vivo study that uses DSW for 4 months, bone mineral density (BMD) was strongly enhanced followed by the significantly increased trabecular numbers through micro-CT examination. Biochemistry analysis showed that serum alkaline phosphatase (ALP) activity was decreased. BMSCs treated with DSW showed increase of osteogenic differentiation markers such as BMP2, RUNX2, OPN, and OCN and enhanced colony forming abilities, compared to the control group. The results demonstrated the regenerative potentials of DSW on osteogenesis, showing that it could potentially be applied in osteoporosis therapy as a complementary and alternative medicine (CAM). The details of these studies are described in Table 16.

4. Effects of Deep Sea Water in the Liver and Kidney Status

From the available studies, DSW hardness which ranges from 0 to 1500 had caused no damage to liver and kidneys. In a study, through in vivo and clinical subjects, ALT, AST, and BUN levels showed that there is no significant difference between treated subjects and the controls. The details of these respective studies are described in Table 17.

5. Functional Deep Sea Water with Other Substances

DSW is very beneficial to health. Its uses are applied to many DSW by-products. For example, it can enhance the antibacterial activity of yogurt [44]. The green tea leaves that were soaked in DSW had an increase in the antioxidant and catechin properties [38]. These findings increase the value of DSW as a health-promoting water. Combination of DSW with Sesamum indicum leaf extract (SIE) had prevented high fat diet-induced obesity, through AMPK activation in the visceral adipose tissue [45]. Furthermore, DSW has advantages for the development of functional fermentation food. The main factors of its increased health properties are due to it being able to increase functional metabolite production, intrinsic health functions of DSW, and the microbial use of mechanisms of converting the absorbed inorganic ions into highly bioavailable organic ions for the human body [48]. The detailed reviews regarding effects of DSW applications for the development of functional fermentation food are explained by Lee [48]. The detailed studies of functional deep sea water with other substances are described in Table 18.

6. Discussion and Conclusion

DSW originates from deep levels of the sea, which are far from contamination except for the natural occurrence of hazardous chemicals such as arsenic and mercury. It will usually undergo a process such as desalination to make it suitable for a particular purpose such as drinking water. The hardness of DSW of up to 1500 caused no cytotoxicity effects in the in vitro study [13]. However, the maximum hardness of it for human consumption should be remarked. The hardness values of water were estimated according to the following equation:

Hardness = Mg (mg/L) x 4.1 + Ca (mg/L) x 2.5; (1) see [49].

The probability of physical, chemical, or bacteriological contaminants present in the drinking water has triggered compulsory actions by most authorities to ensure that the water is subjected to appropriate treatments prior to being supplied. This includes the step of adding chlorine into the drinking water as a treatment. However, chlorine causes an unpleasant taste and raises health concerns such as cancer due to its ability to accumulate within the body [50-52]. Nowadays, it is becoming a trend to supply drinking water, through a vending machine that has the reverse osmosis system, from the treated wastewater and from the treated water pipeline. The process of water treatment will commonly cause reduction or loss of minerals. The increase in the availability of treated drinking water through processes such as reverse osmosis and chlorination should be put in high concern. Chlorine is not good for health. Furthermore, low nutrient in the drinking water can pose as a health threat to people that have nutrient deficiency. The desalinated DSW is usually added or concentrated with minerals, by the process of dilution, blending, or mixing it with concentrated minerals from the DSW [2, 4, 19, 53]. These mineralized methods of desalinated seawater have been a popular method. Therefore, the desalinated DSW will normally regain its minerals that might have been lost through the desalination process again, compared to the packaged drinking water, which has lost most of its minerals through water treatments. Thus, DSDW is able to have numerous minerals constituents in the water compared to the common mineral water sources such as aquifer, which only contain minerals that originated readily from the source. It can be claimed that the mineral contents in the DSW are greater than in the groundwater sources.

Through the impressive findings of DSW benefits to health, it is suggested that its utilization should be promoted widely. The nutrients deficiency of population in a region could be provided with DSW. Adequate nutrient contents in the drinking water supply can contribute to a healthy population status in the area of supply. Areas which have lack of nutrient contents in the water supply are linked with the deficiency of nutrients among their populations. Nutritious water supply is crucial for the people. Prevalence of cardiovascular mortality and sudden death is 10% to 30% greater in the soft water areas, which has low Mg or Ca ions, compared to the hard water areas that have high Mg or Ca ions in the water supply [54]. Intake of hard water has potential to decrease the risks of cardiovascular disease [55]. The importance of mineral contents in the drinking water is proven, when its intake is able to reduce calcium oxalate stone in the kidney of people that consume drinking water rich in minerals such as Mg, Ca, and bicarbonate [5658]. In contrast, consumption of low calcium content in the drinking water has resulted in the hip fracture incident in the Norwegian population [59]. Instead of epidemiological studies, researchers have identified the importance of mineral water content in the experimental studies. According to the study, the rabbits and men which consumed water with low mineral contents have higher risks of cardiovascular disease, compared to the group that consumed water with high mineral content [60]. The miracle of water to cure diseases has progressively been discussed. One of the mechanisms of mineral water to treat diseases is through the existence of minerals which are capable of activating the aquaporin genes, which are responsible for transporting water within the cells [61]. Lack of aquaporin gene activation has been linked to many disease occurrences [62]. Minerals in the DSW are plenty and thus could be a major factor in curing diseases.

Some areas may have lack of nutrients in the soil and crops, which may pose as health threats to its consumers. The soil provides minerals to the plants, and through the plants the minerals go to the animals and humans [63]. Referring to the chain, it is a health threat to people that usually rely on the crops and animals as their main nutrients provider. For instance, nutrient deficiency in the land of South Africa was associated with many diseases occurrences such as thyroid, iodine deficiency disorders (IDD), Mseleni Joint Disease (MJD), HIV-AIDS, and Mg insufficiency [64]. Besides that, the groundwater could be contaminated with man-made activities including the industries, agriculture, and logging. These could pose as a threat to the residents that use groundwater as a source for drinking water. For instance, agricultural activities have caused an increase in the nitrate concentration of groundwater in the area of Machang, Malaysia, resulting from the fertilizer application [65]. DSW which is far from man-made contamination could provide a safe water source. DSW is rarely polluted, has no or slight bacteria existence, and is very pure [2, 8, 66].

Furthermore, nutrients deficiency among the people was also associated with the types of daily food intake. For instance, the regular consumption of phytate content foods had caused the zinc deficiency among Korean people [67]. Phytate impairs the zinc bioavailability. Thus, choosing the right foods is crucial for nutrient intake. Dynamic activities in today's life had caused the tendency for people to choose fast, instant, and easy prepared foods. These kinds of foods usually contain a small amount of nutrients, which is not the most promising source of nutrients intake. Minerals in food may also be lost during cooking [68-70]. In a nutshell, nutrients intake should not solely rely on food intake. DSW has lots of minerals to supply, and could be provided in the form of health drinks or water supply, as an alternative to maintain nutrients source. The roles of minerals in the water to heal disease and maintain health has already been recognized. Water can be classified into a few categories based on its total salt content, its mineral biological activity, and its ion mineral composition [71]. The effort to put DSW as a water source that is beneficial for health should be enhanced. The studies regarding types of mineral water have also been progressively carried out. Examples of these studies can be referred to Astel et al. [72], included in the discussion about the types of minerals available in the water, types of available water treatments, associated regulations, and therapeutic potentials of mineral water. The study to classify DSW into particular types of water based on the types of production should be established, as there is a great therapeutic potential about it yet to be discovered.

Ideally, countries with the accessibility to pump up water from DSW should consider maximizing the use of it. Perhaps, the only limitations are the technology provider and cost of production, rather than reachable sources to the DSW itself. Technologies that are involved may include desalination, low vacuum temperature, and ocean thermal energy conversion (OTEC). OTEC is a kind of technology which could produce water as a by-product from its process, without the extensive cost [73]. There are many great findings from the studies regarding DSW applications in the in vitro models such as using 3T3L-1 cells, and in the in vivo models such as using mice, and rabbits. However, the potential health benefits of its applications in the clinical studies are not widely established. Hence, the study of its applications especially to the human health should be conducted more. DSW is worthy of further investigations and could be developed as medicated water in the prevention and treatment of many health problems, especially lifestyle-related diseases.

http://dx.doi.org/10.1155/2016/6520475

Competing Interests

The authors declare that there are no competing interests.

Acknowledgments

The authors would like to acknowledge the UTM Ocean Thermal Energy Centre (Universiti Teknologi Malaysia), the Malaysian-Japan International Institute of Technology (Universiti Teknologi Malaysia), and the Institute Marine Biotechnology (Universiti Malaysia Terengganu) for the support of this study.

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Samihah Zura Mohd Nani, (1,2,3) F. A. A. Majid, (2,3,4) A. B. Jaafar, (2,5) A. Mahdzir, (1,2) and M. N. Musa (2)

(1) Malaysian-Japan International Institute of Technology, Universiti Teknologi Malaysia, 54100 Kuala Lumpur, Malaysia

(2) UTM Ocean Thermal Energy Centre (OTEC), Universiti Teknologi Malaysia, 54100 Kuala Lumpur, Malaysia

(3) Tissue Culture Engineering Research Laboratory, Faculty of Chemical Engineering, Universiti Teknologi Malaysia, 81310 Skudai, Johor, Malaysia

(4) Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 23000 Kuala Terengganu, Terengganu, Malaysia

(5) Perdana School of Science, Technology, Innovation and Policy, Universiti Teknologi Malaysia, 54100 Kuala Lumpur, Malaysia

Correspondence should be addressed to Samihah Zura Mohd Nani; samihahzura@gmail.com

Received 8 June 2016; Accepted 27 October 2016

Academic Editor: Norman Temple
Table 1: Total amount of elements in deep sea water [8].

Element      Total ([10.sup.6] ton)

CI               26,120,000,000
Na               14,550,000,000
Mg               1,728,000,000
S                1,312,000,000
Ca                556,000,000
K                 538,000,000
Br                 90,000,000
C                  36,000,000
N                  11,700,000
Sr                 10,500,000
B                  6,100,000
O                  3,800,000
Si                 3,800,000
                   1,900,000
Ar                  840,000
Li                  240,000
Rb                  160,000
                     84,000
I                    78,000
Ba                   20,000
Mo                   14,000
U                    4,300
V                    2,700
As                   1,600
Ni                    650
Zn                    470
Kr                    420
Cs                    413
Cr                    271
Sb                    270
Ne                    216
Se                    209
Cu                    202
Cd                     94
Xe                     89
Fe                     40
Al                     40
Mg                     27
Y                      22
Zr                     20
TI                     17
W                      13
Re                     11
He                     10
Ti                    8.8
La                    7.6
Ge                    2.4
Nb                     <7
Hf                    4.6
Nd                    4.4
Ta                     <3
Ag                    2.7
Co                    1.6
Ga                    1.6
Er                    1.6
Yb                    1.6
Dy                    1.5
Gd                    1.2
Pr                    0.9
Ce                    0.9
Se                    0.9
Sm                    0.8
Sn                    0.7
Ho                    0.5
Lu                    0.3
Be                    0.3
Tm                    0.3
Eu                    0.2
Hg                    0.2
Rh                    0.1
Te                    0.1
Pd                   0.008
Pt                    0.07
Bi                    0.04
Au                    0.03
Th                    0.02
In                    0.01
Ru                   <0.006
Os                   0.003
Ir                   0.0002

Table 2: Amount of elements in the surface seawater and deep sea water
[6].

Type of element      Surface seawater      Deep sea water
                          (mg/L)               (mg/L)

Na                        10800                 7240
K                          392                 10400
Ca                         411                   39
Mg                         1290                96100
Sr                         8.1                  0.17
B                          4.45                 320
Fe                        0.003                 0.25
Li                         0.17                 11.7
Cu                        0.0009                0.22
Co                        0.0004                0.26
Mo                         0.01                 0.62
Ni                        0.0066                0.11
Cr                        0.0002               0.087
Rb                         0.12                 1.2
Si                         2.9                  0.5
V                         0.002                 1.2
F                           13                  21.8
Br                         67.3                 5400
I                         0.064                 5.5

Table 3: Effects of deep sea water on cholesterol levels.

Type of study     Experimental method         Major activity
model             [subject (age/weight),
                  treatment dosage,
                  duration of treatment]

In vivo study     High fat diet (HFD) male    Increased the level of
                  Wistar rats (200-220 g),    HDL-C.
                  DSW 1,000 hardness, ad
                  libitum, 4 weeks

In vivo study     Cholesterol/fed diet        Improved plasma total
                  (CFD) male New Zealand      cholesterol (TC),
                  white rabbits (1500/2000    triglyceride (TG), and
                  g) fed diet containing      LDL-C levels.
                  3.75, 37.5, and 75 mg/kg
                  of Mg, DSW 1410 hardness,
                  8 weeks

In vivo study     High cholesterol diet       Reduced the level of TG,
                  (HCD) ICR mice (7 weeks),   TC, and non-high-
                  reverse osmosis (RO DSW)    density lipoprotein
                  (44.6 hardness),            cholesterol (non-HDL-C)
                  electrodialysis (ED DSW)    levels in the serum and
                  (4685.9 hardness) and 10%   liver of animal models,
                  (v/v) dilution with         respectively.
                  dd[H.sub.2]O 10% DSW
                  (544.2 hardness), ad
                  libitum, 8 weeks

                  HFD Hamster (5 weeks),
                  DSW 300, 900, 1500
                  hardness, ad libitum, 6
                  weeks

Type of study     Male hyperlipidemia         Reduced plasma TC and
model             rabbits (1.8/2.0 g), DSW    plasma LDL cholesterol
                  1200 hardness, 150 ml/d,    level. Increased plasma
                  ad libitum, 12 weeks        HDL cholesterol.

In vivo study     Male Wistar rats (90 g),    Attenuated plasma TC.
                  DSW containing 200, 600,
                  and 1000 mg/L of Mg, ad
                  libitum, 4 weeks

Clinical study    Hypercholesterolemic        Decreased serum TC and
                  individuals (23 men and     low-density lipoprotein
                  19 women), DSW (1410        cholesterol (LDL-C).
                  hardness), supplemented
                  1050 mL daily, 6 weeks

Clinical study    CFD and hyperlipemia male   Reduced TC and LDL-C
                  Japanese rabbits, DSW       levels in hyperlipemia
                  hardness of28, 300, and     rabbits. Prevented
                  1200,150 ml/d, ad           increase of TC and LDL-C
                  libitum, 4 weeks            levels in CFD rabbits.

Type of study     Experimental method         Mechanism of action
model             [subject (age/weight),
                  treatment dosage,
                  duration of treatment]

In vivo study     High fat diet (HFD) male    ND.
                  Wistar rats (200-220 g),
                  DSW 1,000 hardness, ad
                  libitum, 4 weeks

In vivo study     Cholesterol/fed diet        Improved the protein
                  (CFD) male New Zealand      expression of AMPK
                  white rabbits (1500/2000    phosphorylation, ACC
                  g) fed diet containing      phosphorylation, and
                  3.75, 37.5, and 75 mg/kg    HMGCR.
                  of Mg, DSW 1410 hardness,
                  8 weeks

In vivo study     High cholesterol diet       Increase in daily faecal
                  (HCD) ICR mice (7 weeks),   lipid of TG and TC and
                  reverse osmosis (RO DSW)    bile acid outputs.
                  (44.6 hardness),
                  electrodialysis (ED DSW)
                  (4685.9 hardness) and 10%   Increase in daily faecal
                  (v/v) dilution with         lipid of TG and TC and
                  dd[H.sub.2]O 10% DSW        bile acid outputs.
                  (544.2 hardness), ad        Upregulated hepatic
                  libitum, 8 weeks            low-density-lipoprotein
                                              receptor (LDL receptor)
                  HFD Hamster (5 weeks),      and cholesterol-7a-
                  DSW 300, 900, 1500          hydroxylase (CYP7A1)
                  hardness, ad libitum, 6     gene expressions.
                  weeks

Type of study     Male hyperlipidemia         ND.
model             rabbits (1.8/2.0 g), DSW
                  1200 hardness, 150 ml/d,
                  ad libitum, 12 weeks

In vivo study     Male Wistar rats (90 g),    ND.
                  DSW containing 200, 600,
                  and 1000 mg/L of Mg, ad
                  libitum, 4 weeks

Clinical study    Hypercholesterolemic        Decreased lipid
                  individuals (23 men and     peroxidation in
                  19 women), DSW (1410        hypercholesterolemic
                  hardness), supplemented     subjects.
                  1050 mL daily, 6 weeks

Clinical study    CFD and hyperlipemia male   ND.
                  Japanese rabbits, DSW
                  hardness of28, 300, and
                  1200,150 ml/d, ad
                  libitum, 4 weeks

Type of study     Experimental method         Reference
model             [subject (age/weight),
                  treatment dosage,
                  duration of treatment]

In vivo study     High fat diet (HFD) male       [19]
                  Wistar rats (200-220 g),
                  DSW 1,000 hardness, ad
                  libitum, 4 weeks

In vivo study     Cholesterol/fed diet           [6]
                  (CFD) male New Zealand
                  white rabbits (1500/2000
                  g) fed diet containing
                  3.75, 37.5, and 75 mg/kg
                  of Mg, DSW 1410 hardness,
                  8 weeks

In vivo study     High cholesterol diet          [20]
                  (HCD) ICR mice (7 weeks),
                  reverse osmosis (RO DSW)
                  (44.6 hardness),
                  electrodialysis (ED DSW)
                  (4685.9 hardness) and 10%      [5]
                  (v/v) dilution with
                  dd[H.sub.2]O 10% DSW
                  (544.2 hardness), ad
                  libitum, 8 weeks

                  HFD Hamster (5 weeks),
                  DSW 300, 900, 1500
                  hardness, ad libitum, 6
                  weeks

Type of study     Male hyperlipidemia            [21]
model             rabbits (1.8/2.0 g), DSW
                  1200 hardness, 150 ml/d,
                  ad libitum, 12 weeks

In vivo study     Male Wistar rats (90 g),     [22, 23]
                  DSW containing 200, 600,
                  and 1000 mg/L of Mg, ad
                  libitum, 4 weeks

Clinical study    Hypercholesterolemic           [4]
                  individuals (23 men and
                  19 women), DSW (1410
                  hardness), supplemented
                  1050 mL daily, 6 weeks

Clinical study    CFD and hyperlipemia male      [24]
                  Japanese rabbits, DSW
                  hardness of28, 300, and
                  1200,150 ml/d, ad
                  libitum, 4 weeks

ND: not described.

Table 4: Effects of deep seawater on cardiovascular protection.

Type of study     Experimental method
model             [subject (age/weight),      Major activity
                  treatment dosage,
                  duration of treatment]

In vivo study     HCD ICR mice (7 weeks),     Reduced abnormal cardiac
                  reverse osmosis-DSW 44.6    architecture, apoptosis
                  hardness,                   in left ventricle (LV).
                  Electrodialysis-DSW         Increased cardiac
                  4685.9 hardness, 10% DSW    survival signalling
                  544.2 hardness, 8 weeks     components in LV of mice.

                                              Change in Fas and
                                              mitochondrial-dependent
                                              apoptotic components in
                                              LV of mice.

                                              Change in apoptosis
                                              related proteins and
                                              cardiac apoptotic cells
                                              in LV of mice.

In vivo study     High fat/cholesterol-fed    Decreased levels of serum
                  (HFCD) male Syrian Golden   TC, TG, atherogenic
                  hamster (5 weeks), DSW      index, and
                  300, 900, and 1500          malondialdehyde.
                  hardness, ad libitum, 6
                  weeks

In vivo study     Kurosawa and                Improved cardiovascular
                  Kusanagi/                   hemodynamics.
                  Hypercholesterolemic
                  (KHC) rabbits (4 months),
                  DSW 1000 hardness, 500

Type of study
model             Mechanism of action          Reference

In vivo study     Decreased LV diameter, LV      [25]
                  thickness, and ratio of
                  thickness to diameter in
                  hearts.

                  Increased insulin/like
                  growth factor/1 receptor,
                  phosphoinositide/3/
                  kinases, and p-AKT/AKT
                  ratio.

                  Decreased the protein
                  products of TNF-[alpha]
                  in LV of mice.

                  Decreased levels of Fas,
                  cytochrome c, cleaved
                  caspase-9, t-Bid, and
                  cleaved caspase-3.

                  Decreased Bak and
                  increased antiapoptotic
                  proteins, including Bcl-
                  XL and ratio of p-Bad to
                  Bad. Decreased TUNEL-
                  positive cardiac cells.

In vivo study     Increase in daily faecal
                  lipid of TG and TC and
                  bile acid outputs.

                  Upregulated hepatic
                  low-density-lipoprotein
                  receptor (LDL receptor)         [5]
                  and cholesterol-7a-
                  hydroxylase (CYP7A1) gene
                  expressions. Increase of
                  serum trolox equivalent
                  antioxidant capacity
                  (TEAC).

In vivo study     Lowered systolic,               [2]
                  diastolic pulse, mean
                  arterial pressures, and
                  total peripheral
                  resistance.
                  ml/d, 6 months

Table 5: Effects of deep sea water on atherosclerosis.

Type of study     Experimental method
model             [subject (age/weight),      Major activity
                  treatment dosage,
                  duration of treatment]

In vivo study     CFD male New Zealand        Reduced serum lipids,
                  white rabbits (1500/2000    prevented atherogenesis,
                  g) fed diet contain 3.75,   and suppressed serum
                  37.5, and 75 mg/kg of Mg,   cholesterol levels.
                  DSW 1410 hardness, 8        Reduced lipids
                  weeks                       accumulation in liver
                                              tissues, and limited
                                              aortic fatty streaks.

In vivo study     Male hyperlipidemia         Suppressed lipid
                  rabbits (1.8/2.0 g), DSW    deposition on the inner
                  1200 hardness, 150 ml/d,    wall of the aorta.
                  ad libitum, 12 weeks        Suppressed foam cell
                                              formation.

In vivo study     CFD and hyperlipemia male   Reduced TC and LDL-C
                  Japanese rabbits, DSW       levels in hyperlipemia
                  hardness of28, 300, and     rabbits. Prevented
                  1200, 150 ml/d, 4 weeks     increase of TC and LDL-C
                                              levels in CFD rabbits.
                                              Reduced lipid
                                              accumulation in liver and
                                              permeation of macrophages
                                              in CFD rabbits.
Type of study
model             Mechanism of action         Reference

In vivo study     Improved protein               [6]
                  expression of AMPK
                  phosphorylation, ACC
                  phosphorylation, and
                  HMGCR.

In vivo study     Reduced plasma TC, plasma      [21]
                  LDL cholesterol, and LPO.
                  Increased plasma HDL
                  cholesterol. Increased
                  glutathione peroxidase
                  (GPx) activity.
                  Decreased plasma lipid
                  peroxide (TBARS) value.

In vivo study     ND.                            [24]

ND: not described.

Table 6: Effects of deep sea water on blood pressure.

                  Experimental method
Type of study     [subject (age/weight),      Major activity
model             treatment dosage,
                  duration of treatment]

In vivo study     Spontaneous hypertensive    Decreased blood
                  rats (250/300 g) fed diet   pressure.
                  containing 3.75, 37.5,
                  and 75 mg/kg of Mg, DSW
                  1410 hardness, ad
                  libitum, 8 weeks

In vivo study     Kurosawa and Kusanagi/      Decreased blood
                  Hypercholesterolemic        pressure.
                  (KHC) rabbits (4 months),
                  DSW 1000 hardness, 500ml/
                  d, 6 months

Type of study     Mechanism of action          Reference
model

In vivo study     Decreased systolic and          [6]
                  diastolic pressure.

In vivo study     Lowered systolic,               [2]
                  diastolic pulse, and mean
                  arterial pressure and
                  total peripheral
                  resistance.

Table 7: Effects of deep sea water on obesity.

                  Experimental method
Type of study     [subject (age/weight),      Major activity
model             treatment dosage,
                  duration of treatment]

In vitro study    C2C12 cells, DSW 100,       Increased mitochondrial
                  500, 1000, 1500, and 2000   biogenesis and function.
                  hardness, indicated time
                  of0, 1, 2, and 3 days

In vitro study    3T3-L1 cells, DSW 100,      Decreased lipid
                  500, and 1000 hardness, 3   accumulation.
                  days

In vivo study     HFD C57BL/6J mice (6        Enhanced mitochondrial
                  weeks), DSW 500, 1000,      biogenesis in muscles.
                  and 2000 hardness, ad
                  libitum, 20 weeks

In vivo           HFD C57BL-6J mice (6-26     Suppressed body weight
study             weeks), DSW 500, 1000,      gain.
                  and 2000 hardness, ad       Inhibited increase
                  libitum, 20 weeks           in adipocyte size.
                                              Suppressed the expression
                                              of adipogenic, lipogenic,
                                              lipolytic, and
                                              proinflammatory cytokine
                                              genes.
                                              Increased the expression
                                              of adipokines and b-
                                              oxidation genes in fat.

In vivo study     Male C57BL/6J ob/ob mice,   Decreased body weight
                  DSW 1000 hardness, ad       gain by 7%.
                  libitum, 84 days
                                              Reduced plasma glucose
                                              levels by 35.4%.

Type of study     Mechanism of action          Reference
model

In vitro study    Enhanced gene expression       [26]
                  of peroxisome
                  proliferator-activated
                  receptor gamma
                  coactivator 1 [alpha]
                  (PGC-1a), nuclear
                  respiratory factor-1
                  (NRF-1), and
                  mitochondrial
                  transcription factor A
                  (TFAM); mitofusin-1-2
                  (MFN1-2) and dynamin-
                  related protein 1 (DRP1)
                  for mitochondrial fusion;
                  optic atrophy 1 (OPA1)
                  for mitochondrial
                  fission; translocase of
                  outer mitochondrial
                  membrane 40 (TOMM40) and
                  translocase of inner
                  mitochondrial membrane 44
                  (TIMM44) for
                  mitochondrial protein
                  import; carnitine
                  palmitoyltransferase 1a
                  (CPT1a) and medium-chain
                  acyl-CoA dehydrogenase
                  (MCAD) for fatty acid
                  oxidation; and cytochrome
                  c (CytC) for oxidative
                  phosphorylation.
                  Increased mitochondria
                  staining, citrate
                  synthase (CS) activity,
                  CytC oxidase activity,
                  NAD+ to NADH ratio, and
                  the phosphorylation of
                  signalling molecules such
                  as AMPK and sirtuin 1
                  (SIRT1).

In vitro study    Reduced expression mRNA        [13]
                  levels of PPAR[gamma] and
                  C/EBP[alpha] and protein
                  levels of fatty acid
                  binding protein and
                  adiponectin.

In vivo study     Improved mitochondrial         [26]
                  DNA (mtDNA) content in
                  the muscles of HFD-
                  induced obese mice.
                  Enhanced expression of
                  PGC-1[alpha], NRF1, and
                  mtTFA.
                  Enhanced estrogen-
                  related receptor a
                  (ERR[alpha]),
                  PPAR[alpha], and
                  PPAR[alpha].

In vivo           Suppressed mRNA              [27] [27]
study             expression of key
                  adipogenic genes such as
                  PPAR[gamma], C/
                  EBP[alpha], and aP2.
                  Increased the expression
                  of GLUT4, adiponectin,
                  and leptin.
                  Decreased the expressions
                  of IL-6 and TNF-a.
                  Decreased the expressions
                  of sterol regulatory
                  element-binding protein
                  1c (SREBP1c) and fatty
                  acid synthase (Fas),
                  which are involved in
                  lipogenesis; adipose
                  triglyceride lipase
                  (ATGL) and hormone-
                  sensitive lipase (HSL),
                  which are involved in
                  lipolysis.
                  Increased the expression
                  of MCAD and CPT1a, which
                  are involved in b-
                  oxidation.
                  Increased phosphorylation
                  ofIRS-1, LKB1, AMPK, and
                  mTOR in fat.

In vivo study     Increased glucose               [1]
                  disposal.
                  Increased plasma protein
                  levels of adiponectin.
                  Decreased plasma protein
                  levels of resistin, RBP4,
                  and fatty acid binding
                  protein.
                  Increased GLUT4 and AMP-
                  activated protein kinase
                  levels in skeletal muscle
                  tissue.
                  Decreased PPAR[gamma] and
                  adiponectin in adipose
                  tissue.

Table 8: Effects of deep sea water on diabetes.

                  Experimental method
Type of study     [subject (age/weight),      Major activity
model             treatment dosage,
                  duration of treatment]

In vitro study    Differentiated C2C12        Increased glucose uptake.
                  cells, DSW 100, 500,
                  1000, 1500, and 2000
                  hardness, 1 hr

In vitro study    Matured 3T3-L1 cells, DSW   Increased glucose uptake.
                  500, 1000, and 2000
                  hardness, 1 hr

In vivo study     Streptozotocin-(STZ-)       Improved impaired glucose
                  induced diabetic male ICR   tolerance.
                  mice (4-9 weeks), DSW       Regulated blood glucose
                  1000, 2000, and 4000        levels by inhibited
                  hardness, ad libitum, 4     glucose production and
                  weeks                       enhanced glucose uptake
                                              via regulation of gene
                                              expression.

In vivo study     HFD-induced diabetic male   Improved impaired glucose
                  C57BL-6J mice (6-25         tolerance.
                  weeks), DSW 500, 1000,      Suppressed the expression
                  and 2000 hardness, ad       of hepatic genes involved
                  libitum, 20 weeks           in glucogenesis,
                                              glycogenolysis, and
                                              glucose oxidation.
                                              Increased glucose uptake,
                                              [beta]-oxidation, and
                                              glucose oxidation in
                                              muscle.
                                              Improved impaired AMPK
                                              phosphorylation in the
                                              muscles and livers.

In vivo study     Male C57BL/6J ob/ob mice,   Reduced glucose levels in
                  DSW 1000 hardness, ad       plasma by 35.4%.
                  libitum, 84 days

Type of study     Mechanism of action         Reference
model

In vitro study    Stimulated the                 [28]
                  phosphorylation ofIRS-1,
                  LKB1, AMPK, and mTOR and
                  improved impaired
                  phosphorylation of these
                  molecules.

In vitro study    Increased AMPK                 [29]
                  phosphorylation in 3T3-
                  L1 pre-and mature
                  adipocytes.
                  Stimulated
                  phosphoinositol-3-kinase
                  and AMPK pathway-
                  mediated glucose uptake.
                  Increased adiponectin and
                  leptin levels and reduced
                  the levels of the
                  proinflammatory cytokines
                  IL-6 and TNF-[alpha].
                  Improved architecture of
                  pancreatic islets of
                  Langerhans and enhanced
                  insulin secretion from
                  [beta]-cells.
                  Stimulated the
                  phosphorylation ofIRS-1,
                  LKB1, AMPK, and mTOR and
                  improved impaired
                  phosphorylation of these
                  molecules in muscle.

In vivo study     Downregulated the              [28]
                  expression of
                  phosphoenolpyruvate
                  carboxykinase (PEPCK) and
                  glucose 6-phosphatase
                  (G6Pase), both of which
                  are required for
                  gluconeogenesis;
                  glucokinase (GK) and
                  citrate synthase (CS),
                  both of which are
                  required for glucose
                  oxidation; and liver
                  glycogen phosphorylase
                  (LGP), which is required
                  for glycogenolysis.
                  Upregulated glycogen
                  synthase (GS) expression.

                  Upregulated the
                  expression of GLUT1 and
                  GLUT4 in skeletal muscle,
                  which are required for
                  glucose transport;
                  glucokinase and citrate
                  synthase, which are
                  required for glucose
                  oxidation; and acyl-CoA
                  oxidase (ACO),
                  CPT1[alpha], and MCAD,
                  which are required for
                  [beta]-oxidation.

In vivo study     Recovered size of the          [29]
                  pancreatic islets of
                  Langerhans and increased
                  the secretion of insulin
                  and glucagon.
                  Increased adiponectin
                  levels. Decreased IL-6
                  and TNF-[alpha] levels.
                  Downregulated the
                  expression of PEPCK and
                  G6Pase for
                  gluconeogenesis; GK and
                  CS for glucose oxidation;
                  and LGP for
                  glycogenolysis.
                  Upregulated the
                  expression of GS for
                  glycogenesis.
                  Upregulated the GLUT1 and
                  GLUT4 for glucose
                  transport, GK and CS for
                  glucose ACO, CPT1a, and
                  MCAD for [beta]-
                  oxidation in skeletal
                  muscle.
                  Increased the expression
                  of SIRT family proteins
                  such as SIRT1, SIRT4, and
                  SIRT6.

In vivo study     Increased glucose              [1]
                  disposal.
                  Increased adiponectin
                  levels in plasma.
                  Decreased plasma protein
                  levels of resistin, RBP4,
                  and fatty acid binding
                  protein.
                  Increased GLUT4 and AMP-
                  activated protein kinase
                  levels in skeletal muscle
                  tissue.

Table 9: Effects of deep sea water on skin diseases.

                  Experimental method
Type of study     [subject (age/weight),      Major activity
model             treatment dosage,
                  duration of treatment]

In vivo study     Male NC/Nga mice (6         Reduced severity of
                  weeks), 2% concentrated     symptoms in the skin
                  DSW (CDSW) (7958.6          lesions, such as edema,
                  hardness), 10% CDSW         erythema, dryness,
                  (39793 hardness), 200       itching, and
                  [micro]L of test samples,   transepidermal water loss
                  five times per week, six    (TEWL).
                  weeks                       Decreased epidermal
                                              thickness and
                                              infiltration of
                                              inflammatory cells.

Clinical study    33 patients (mean age 26    Improved skin symptoms.
                  years, range 1/50 years,    Balanced certain minerals
                  13 male and 20 female       in the body.
                  subjects), DSW 1000
                  hardness, 500 ml/day, 6
                  months

Clinical study    50 patients with allergic   Improved skin symptoms.
                  rhinitis (age 22/50
                  years), DSW 1000
                  hardness, 500 ml/day, 3
                  weeks

Type of study     Mechanism of action         Reference
model

In vivo study     Inhibited upregulation of      [30]
                  IgE, histamine, and
                  proinflammatory cytokines
                  (TNF-[alpha], IL-
                  1[beta], and IL-6) in the
                  serum.
                  Downregulated CD4+/CD8+
                  ratio in spleen
                  lymphocyte by 10% CDSW.
                  Reduced the expression of
                  IL-4 and IL-10 from Th2
                  cells in the 10% CDSW-
                  treated group.

Clinical study    Improved skin symptoms         [31]
                  such as inflammation,
                  lichenification, and
                  cracking in skin.
                  Restored essential
                  minerals such as Se and
                  reduced the level of
                  toxic minerals such as
                  mercury and lead.

Clinical study    Reduced allergic skin          [32]
                  responses and serum
                  levels of total IgE,
                  Japanese cedar pollen-
                  specific IgE, IL-4,
                  IL-6, IL-13, and IL-18.

Table 10: Effects of Deep Sea Water on Hepatic Protection.

Type of study     Experimental method         Major activity
model             [subject (age/weight),
                  treatment dosage,
                  duration of treatment]

In vitro study    HepG2 cells, DSW 200,       Decreased lipids
                  400, 600, 800, and 1000     accumulation.
                  hardness, 24 hr

In vivo study     HFD male Wistar rats        Decreased levels of TC
                  (200-220 g), DSW 1,000      and TG in liver.
                  hardness, ad libitum, 4     Improved liver function.
                  weeks

In vivo study     HFD C57BL-6J mice (6-26     Suppressed the expression
                  weeks), DSW 500, 1000,      of genes involved in
                  and 2000 hardness, ad       lipogenesis and
                  libitum, 20 weeks           cholesterol synthesis;
                                              and increased the
                                              expression of genes
                                              related to b-oxidation in
                                              liver.
                                              Improved severe liver
                                              steatosis.
                                              Regulated mitochondrial
                                              biogenesis and function
                                              in liver.

In vivo study     HFD male Golden Syrian      Decreased lipids
                  hamsters (5 weeks), DSW     accumulation in liver.
                  300, 900, and 1500          Regulated hepatic fatty
                  hardness, ad libitum, 6     acid homeostasis.
                  weeks                       Improved hepatic
                                              antioxidative levels.
                                              Attenuated hepatic
                                              damage.

Type of study     Mechanism of action         Reference
model

In vitro study    Inhibited the activity of     [19]
                  HMGCR by 30.2%. Increased
                  the phosphorylation level
                  of AMPK by 15.2%.
                  Reduced p68 of SREBP-1
                  levels by 55%.
                  DSW of hardness 600, 800,
                  and 1,000 increased p68
                  levels of SREBP-2 by 12,
                  42, and 80%,
                  respectively.
                  DSW of hardness 600, 800,
                  and 1,000 increased level
                  of CYP7A1 by 41,115, and
                  162%, respectively.
                  DSW of hardness 1,000
                  increased Apo AI content
                  by 20.3%.

In vivo study     Decreased serum levels of     [19]
                  AST and ALT.

In vivo study     Decreased the expression
                  of Fas and acetyl-CoA
                  carboxylase 1 (ACC1),
                  which are involved in
                  lipogenesis, and liver X
                  receptor a (LXR a), and
                  5-hydroxy-3-                  [27]
                  methylglutaryl-coenzyme A
                  reductase (HMG-CoAR),
                  which are involved in
                  cholesterol metabolism.
                  Increased the expression
                  of MCAD and CPT1[alpha],
                  which are involved in b-
                  oxidation.
                  Increased the
                  phosphorylation of IRS-
                  1, LKB1, AMPK, and mTOR
                  in liver.
                  Increased expression of
                  PGC1a, NRF1, Tfam, and
                  mtDNA content in liver.

In vivo study     Increased daily faecal        [33]
                  lipid and bile acid
                  outputs.
                  Upregulated genes
                  Of hepatic PPAR[alpha],
                  retinoid X receptor-
                  alpha, and uncoupling
                  protein-2 (UCP-2) gene
                  expression. Maintained
                  higher liver glutathione
                  and TEAC levels.
                  Reduced lipid
                  peroxidation status (MDA
                  content) in liver.

Table 11: Effects of deep sea water on fatigue.

                  Experimental method
Type of study     [subject (age/weight),      Major activity
model             treatment dosage,
                  duration of treatment]

In vivo study     Exercise/induced fatigue    Promoted the
                  male Wistar rats, DSW       endurance of rats
                  100, and 600 hardness,      in exercise test.
                  dosages (6,12, and 30 mL/   Reduced
                  kg x d)                     exhaustive period.

Clinical study    12 healthy male             Accelerated
                  volunteers (age 24 [+ or    recovery from
                  -] 0.8 years; height        physical fatigue.
                  171.8 [+ or -] 1.5 cm;
                  weight 68.2 [+ or -] 2.3
                  kg; VO2max 49.7 [+ or -
                  ]2.2 ml x [kg.sup.-1 x
                  [min.sup.-1]),
                  randomized, double-
                  blind, placebo-
                  controlled, DSW 710
                  hardness, fatiguing
                  exercise conducted for
                  4hr at 30[degrees]C

Type of study     Mechanism of action         Reference
model

In vivo study     Improved the ratio of          [34]
                  lactic acid elimination
                  to lactic acid increment.
                  Reduced BUN level of rats
                  fed with D100 in a dosage
                  of 30 mL/kg x d and D600
                  in dosages of 6, 12, and
                  30 mL/kg x d.
                  Increased liver glycogen
                  content in rats group fed
                  with D100 in a dosage of
                  6 mL/kg x d.

Clinical study    Complete recovery of           [35]
                  aerobic power within 4
                  hr. Elevated muscle power
                  above placebo levels
                  within 24 hr.
                  Increased circulating
                  creatine kinase (CK) and
                  myoglobin; indicatives of
                  exercise-induced muscle
                  damage, were completely
                  eliminated, in parallel
                  with attenuated oxidative
                  damage.

Table 12: Effects of deep sea water on stomach ulcer.

                  Experimental method
Type of study     [subject (age/weight),      Major activity
model             treatment dosage,
                  duration of treatment]

In vivo study     Female Wistar rats (220/    Reduced ulcer area as
                  250 g weight), DSW 600      well as apoptotic
                  (41 mL/day), DSW 1200 (39   signalling in acetic
                  mL/day), 1 week             acid-induced duodenal
                                              ulcers. DSW influenced
                                              oxidative stress genes
                                              expression.
                                              Upregulated antioxidant
                                              and antiapoptotic genes
                                              and downregulated
                                              proapoptotic gene
                                              expression by DSW of
                                              hardness 600 and 1200,
                                              respectively.

Type of study     Mechanism of action         Reference
model

In vivo study     Increased pH value,            [36]
                  scavenging
                  [H.sub.2][O.sub.2], and
                  HOCl activity and reduced
                  ORP value. Enhanced
                  Bcl-2 and thioredoxin
                  reductase 1 expression.
                  DSW1200 activated the
                  expression of flavin-
                  containing monooxygenase
                  2 (Fmo2), Gpx1, Gpx5,
                  Gpx6, glutathione
                  reductase (Gsr), nitric
                  oxide synthase 2,
                  inducible (Nos2),
                  thioredoxin reductase 1
                  (Txnrd1), superoxide
                  dismutase 1 (Sod1), some
                  antioxidant-related
                  genes, peroxiredoxin 4
                  (Prdx4), and
                  selenoprotein P plasma 1
                  (Sepp1).
                  DSW600 and DSW1200
                  upregulated Txnrd1 and
                  Bcl-2 and downregulated
                  Bax, caspase 3, and PARP
                  in duodenal cells.
                  DSW 600 upregulated
                  expression of apoptosis-
                  inducing factor,
                  mitochondrion-associated
                  1 (Aifm1), DNA-damage-
                  inducible, alpha
                  (Gadd45a), myeloid cell
                  leukemia sequence 1 (Mcl
                  1), and X-linked
                  inhibitor of apoptosis
                  (Xiap).
                  DSW 600 downregulated
                  expression of apoptosis
                  inhibitor 5 BCL2-
                  associated athanogene
                  (Api5), cell death-
                  inducing DFFA-like
                  effector b (Ciedb),
                  cytochrome c, and somatic
                  (Cycs), Fas (TNF receptor
                  superfamily, member 6),
                  growth arrest and mitogen
                  activated protein kinase
                  1 (Mapk1), PYD and CARD
                  domain containing
                  (Pycard).
                  DSW 1200 upregulated
                  expression of Fas,
                  Gadd45a, and Mcl1.
                  DSW 1200 downregulated
                  expression of Aifm1,
                  Api5, Bag1, Cideb, Cycs,
                  and Pycard.

Table 13: Effects of deep sea water on cancer.

                Experimental method
Type of study   [subject (age/        Major activity        Reference
model           weight), treatment
                dosage, duration of
                treatment]

In vitro study  MDA-MB-231 cells,     Inhibited cells'
                DSW 200, 400, 800,    migratory ability in  [37] [37]
                and 1500 hardness,    a wound-healing
                2-3 days              assay, mediated
                                      through TGF-[beta]
                                      and Wnt5a
                                      signalling,
                                      resulting in
                                      attenuated
                                      expression of CD44.

In vitro study  Noninvasive MCF-7     Inhibited TPA-
                cells, DSW 200, 400,  induced migration        [37]
                800, and 1500         and MMP-9 activity
                hardness, 2-3 days    with a concomitant
                                      decrease in mRNA
                                      levels of MMP-9,
                                      TGF-[beta], Wnt5a,
                                      and Wnt3a.

                Green tea leaves      Increased nitrite        [38]
                were soaked in        scavenging activity
                desalinated DSW at    from 31.33 [+ or -]
                75[degrees]C for 10   0.05 to 37.12 [+ or
                min                   -] 0.42%. Increased
                                      overall amounts of
                                      catechins.

                Salmonella            71.4% inhibitory      [39] [39]
                Typhimurium TA98 and  effect on the
                TA100, Ames test,     mutagenesis induced
                methanol extract of   by 4NQO against TA98
                kochujang added with  strain. 56.1% and
                sea tangle and deep   83.6% inhibitions on
                sea water salts       the mutagenesis
                (SDK), 200 [micro]g/  induced by 4NQO and
                plate                 MNNG against TA100
                                      strain.

Table 14: Effects of deep sea water on cataract.

                  Experimental method
Type of study     [subject (age/weight),      Major activity
model             treatment dosage,
                  duration of treatment]

In vivo study     Male Shumiya cataract rat   Delayed cataract
                  (5-15 weeks), DSW           development.
                  ([Mg.sup.2+], 200 mg-L,
                  [Ca.sup.2+]; 71 mg-L), 9-
                  10 weeks

In vivo study     Male Shumiya cataract rat   Delayed cataract onset.
                  (5-15 weeks), DSW
                  containing Mg of 50, 200,
                  and 1000 mg-L,
                  respectively, 9-10 weeks

Type of study     Mechanism of action         Reference
model

In vivo study     Reduced less opaque and        [40]
                  nitric oxide (NO) levels.

In vivo study     Mg suppressed Ca influx        [41]
                  into the lens.

Table 15: Effects of deep sea water on antibacterial activity.

                Experimental method
Type of study   [subject (age/        Major activity        Reference
model           weight), treatment
                dosage, duration of
                treatment]

In vitro study  Five types ratio of   Inhibited bacterial      [42]
                DSW containing        growth and mobility.
                magnesium : calcium
                (Mg : Ca) ratios of
                1: 2 (A), 1: 1 (B),
                3 : 1 (C), 1: 0 (D),
                and0 : 1 (E) at
                different
                concentrations to
                give levels of
                hardness of 100,
                250, 500, and 1000;
                produced 20 types of
                samples Sixteen H.
                pylori strains,
                clinical isolates
                were obtained from
                patients with
                gastric cancer,
                gastric ulcer, and
                normal gastric
                mucosa

In vitro study  Sheep blood, H.       DSW hardness of 1200     [36]
                pylori obtained from  and 2400 inhibited
                gastric biopsy        growth of H. pylori
                specimens of peptic   strains by 20% and
                ulcer patients, 3 to  60%, respectively.
                5 days

In vivo study   Male Mongolian        Decreased amount of      [42]
                gerbils (4 weeks),    H. pylori colonized
                DSW at 5 different    in stomach by
                Mg/Ca ratios          treatment with 2
                (hardness of 1000)    types of DSW ratio
                were administered     which are C and D.
                for 2 weeks           Anti-H. pylori
                                      effects were
                                      observed in [greater
                                      than or equal to]
                                      90% of subjects.

Clinical study  Healthy subjects      Reduced [DELTA]13 C      [42]
                infected with H.      values.
                pylori, DSW at 5
                different Mg/Ca
                ratios (hardness:
                1000), 1 L/daily,

Table 16: Effects of deep sea water on osteoporosis.

                Experimental method
Type of study   [subject (age/        Major activity        Reference
model           weight), treatment
                dosage, duration of
                treatment]

In vitro study  Osteoblastic cell     Increased cells          [43]
                (MC3T3), DSW          proliferation.
                50,1000, and 2000
                hardness, 3 days

In vitro study  Bone marrow stromal   Enhanced colony          [43]
                cells (BMSCs), DSW    forming abilities.
                1000 hardness, 3
                days

In vivo study   Ovariectomized (OVX)  Enhanced bone            [43]
                SAMP8 mice (4         mineral density.
                months), DSW 1000     Increased trabecular
                hardness, 5.2 mL/     numbers through
                day, 4 months         micro-CT
                                      examination.
                                      Decreased serum
                                      alkaline phosphatase
                                      (ALP).
                                      Increased osteogenic
                                      differentiation
                                      markers such as
                                      BMP2, RUNX2, OPN,
                                      and OCN.

Table 17: Effects of deep sea water in the liver and kidney status.

                Experimental method
Type of study   [subject (age/        Major activity        Reference
model           weight), treatment
                dosage, duration of
                treatment]

In vivo study   HFD male Wistar rats  Improved liver           [19]
                (200-220 g), DSW      function by the
                1,000 hardness, ad    decrease of serum
                libitum, 4 weeks      levels of AST and
                                      ALT.

In vivo study   HFD male Golden       Attenuated serum AST     [33]
                Syrian hamsters (5    values in hamsters
                weeks), DSW 300,      drinking DSW 300,
                900, and 1500         900, and 1500. Lower
                hardness, ad          serum ALT values in
                libitum, 6 weeks      hamsters drinking
                                      DSW 900 and DSW
                                      1500.

In vivo study   CFD male New Zealand  No differences were      [6]
                white rabbits (1500/  observed in values
                2000 g) fed diet      of AST and ALT.
                containing 3.75,
                37.5, and 75 mg/kg
                of Mg, DSW 1410
                hardness, 8 weeks

In vivo study   Male hyperlipidemia   No differences were      [21]
                rabbits (1.8/2.0 g),  observed in values
                DSW 1200 hardness,    of AST and ALT.
                150 ml/d, ad
                libitum, 12 weeks

Clinical study  Hypercholesterolemic  No significant
                individuals (23 men   difference of ALT,       [4]
                and 19 women), DSW    AST, and BUN levels
                (1410 hardness),      between treated
                supplemented 1050 mL  subjects and
                daily, 6 weeks        controls.

Table 18: Effects of functional deep sea water with other substances.

                  Experimental method
Type of study     [subject (age/weight),      Major activity
model             treatment dosage,
                  duration of treatment]

In vivo study     Outbred albino female ICR   Increased populations of
                  mice (20/26 g), yogurt      intestinal lactic acid
                  containing DSW, 10.3 g      bacteria.
                  hardness of CaC[O.sub.3]/   Decreased the activity of
                  L, 8 weeks                  serum AST and ALT.
                                              Reduced TC, TC to HDL-C
                                              ratio, TAG, and HDL-C in
                                              serum.

In vivo study     HFD/induced obesity ICR     Reduced body weights in
                  (4 weeks), DSW, and DSW +   the DSW group by 3.95%
                  125 mg/kg SIE (DSS), ad     and in the DSS group by
                  libitum, treated with SIE   8.42%, respectively.
                  once per day for 8 weeks    Decreased plasma glucose
                                              levels in the DSW group
                                              by 14.9% and in the DSS
                                              group by 36.4%,
                                              respectively.
                                              Decreased serum levels of
                                              glucose, TAG, and leptin.
                                              Decreased insulin
                                              resistance index (HOMA-
                                              IR) values for the DSS-
                                              treated group by 38.2%.

In vivo study     Green tea leaves were       Increased antioxidant
                  soaked in desalinated DSW   activity.
                  at 75[degrees]C for 10
                  min

Type of study     Mechanism of action         Reference
model

In vivo study     ND.                            [44]

In vivo study     Decreased size of the          [45]
                  epididymal white,
                  retroperitoneal white,
                  and scapular brown
                  adipose tissue.
                  Increased levels of
                  phosphorylated AMPK and
                  its substrate and ACC in
                  mice epididymal adipose
                  tissues.
                  Upregulated the
                  expression levels of
                  lipolysis-associated
                  mRNA, PPAR-[alpha],
                  cluster of
                  differentiation 36
                  (CD36), and energy
                  expenditure-associated
                  mRNA and UCP2 and CPT1
                  epididymal adipose
                  tissues.
                  Suppressed the expression
                  of SREBP1 at the mRNA
                  level.

In vivo study     Increased 2, 2-diphenyl-       [38]
                  1-picrylhydrazyl (DPPH)
                  radical scavenging
                  activities by 83.98% and
                  increased reducing power
                  by 15%.
                  Increased nitrite
                  scavenging activity from
                  31.33 [+ or -] 0.05 to
                  37.12 [+ or -] 0.42%.
                  Increased amounts of
                  catechins and caffeine.

ND: not described.
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Author:Nani, Samihah Zura Mohd; Majid, F.A.A.; Jaafar, A.B.; Mahdzir, A.; Musa, M.N.
Publication:Evidence - Based Complementary and Alternative Medicine
Article Type:Report
Date:Jan 1, 2017
Words:12625
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