WO2018066676A1 - 有機セレン化合物含有組成物 - Google Patents
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- WO2018066676A1 WO2018066676A1 PCT/JP2017/036390 JP2017036390W WO2018066676A1 WO 2018066676 A1 WO2018066676 A1 WO 2018066676A1 JP 2017036390 W JP2017036390 W JP 2017036390W WO 2018066676 A1 WO2018066676 A1 WO 2018066676A1
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Definitions
- the present invention relates to a composition containing an organic selenium compound as an active ingredient. More specifically, the present invention relates to reduction of oxidative stress and prevention of ischemic disease, improvement of fatty liver, improvement of glucose tolerance, improvement of metabolic syndrome including abnormal lipid metabolism, improvement of protection against disorders associated with metabolic syndrome, suppression of carcinogenesis, whole body
- the present invention relates to a composition, food, food composition, and pharmaceutical composition for suppressing immunoreactivity, inhibiting arteriosclerosis, preventing dementia and improving brain function, protecting corneal epithelial cells and improving dry eye, and / or suppressing inflammation.
- Selenonein an organic selenium compound, has been found to have a strong antioxidant ability (radical scavenging activity) and to exhibit a biological antioxidant action on human cells (Patent Document 1).
- a substance having an antioxidant action removes reactive oxygen species in the living body and exhibits various physiological activities. Since selenium is an essential trace element for the human body, intake of selenium, which is organic selenium derived from seafood, can compensate for insufficient intake of selenium from the diet. Therefore, application to functional foods containing selenonein as an active ingredient is expected.
- selenonein may contribute to the prevention of such lifestyle-related diseases and anti-aging.
- the effect of selenonein on preventing lifestyle-related diseases, its molecular mechanism, and the interaction between selenonein and other biomolecules have not been verified.
- the effect of improving the health function by improving the antioxidant ability such as radical scavenging activity by ingesting selenonein into the human body and animal cells has not been investigated so far. Therefore, it was necessary to verify the biological activity of selenonein against biomolecules, model cells, and living bodies, and to verify the effectiveness of selenonein for the development and commercialization of new applications.
- the present invention as a health functional study of selenonein, an organic selenium compound, analyzes its effectiveness on the actual living body using mammalian cells and rodents, antimetabolic syndrome, carcinogenesis prevention, ischemic disease protection, cognition
- the purpose of this study is to demonstrate the effects of improving oxidative stress disorders and reducing stress in vivo such as prevention of infectious diseases, improvement of dry eye, and suppression of inflammation.
- the selenium compound containing composition which has novel food functionality, such as an antimetabolic syndrome effect
- Oxidative stress is defined as an unfavorable condition for the living body because the balance between the oxidation and antioxidant reactions of the living body caused by active oxygen, active nitrogen species and free radicals is lost.
- Oxidative stress are involved in various diseases such as inflammation, arteriosclerosis, cancer, aging, cranial nerve disease, respiratory disease, cataract, skin disease, gastrointestinal disease, heart disease, high blood pressure, It is known to play a central role in pathogenesis.
- Selenonein which has strong radical scavenging activity, reduces active oxygen, free radicals, and oxidative stress generated in the body, and verifies the preventive effect of diseases caused by these oxidative stress. New foods can be developed.
- the present inventors have found that the intake of a selenium compound-containing composition has the effect of reducing stress that protects against brain damage caused by cerebral ischemia and the prevention effect of stress-induced damage. As a result, the present invention has been completed.
- R is hydrogen, an ergothionyl group, a glutathionyl group, or a cysteinyl group
- the organic selenium compound has the formula II:
- composition according to [1] above which is 3- (2-hydroseleno-1H-imidazol-5-yl) -2- (trimethylammonio) propanoate represented by the formula:
- a metabolic comprising the composition according to any one of [1] to [4] above, including reduction of oxidative stress, suppression of lipid oxidation, prevention of ischemic disease, improvement of metabolic syndrome, improvement of glucose tolerance, and abnormal lipid metabolism Food for improving protection of disorders associated with syndrome, suppressing carcinogenesis, suppressing systemic immunity reduction, suppressing vascular endothelial damage, suppressing arteriosclerosis, preventing dementia, improving brain function, protecting corneal epithelial cells, improving dry eye, or suppressing inflammation Composition.
- R is hydrogen, an ergothionyl group, a glutathionyl group, or a cysteinyl group
- the organic selenium compound has the formula II:
- composition according to claim 7 which is 3- (2-hydroseleno-1H-imidazol-5-yl) -2- (trimethylammonio) propanoate represented by the formula:
- an organic selenium compound represented by the following formula: reducing oxidative stress, suppressing oxidized lipid, preventing ischemic disease, improving metabolic syndrome, improving glucose tolerance, improving protection of disorders associated with metabolic syndrome including abnormal lipid metabolism,
- an organic selenium compound represented by the following formula: reducing oxidative stress, suppressing oxidized lipid, preventing ischemic disease, improving metabolic syndrome, improving glucose tolerance, improving protection of disorders associated with metabolic syndrome including abnormal lipid metabolism,
- the organic selenium compound of the present invention has hitherto been known as an antioxidant based on radical scavenging activity and an antioxidant ability to suppress the generation of radicals. No proof of gender has been published.
- Anti-cancer, anti-arteriosclerosis, etc. are being demonstrated by efficacy tests by administration to human cells and living bodies, and can be used for new applications such as prevention and improvement of lifestyle-related diseases and diseases due to aging.
- the chromatogram (A) of selenium 82, a standard product of selenonein, and the chromatogram (B) of the selenonein-containing fish extract obtained in Example 1 are shown.
- ischemic stress we measured spontaneous momentum, examined the effects of cerebral ischemia and reperfusion, and evaluated the effect of the selenium-containing composition of the test substance (selenonein-containing fish extract) in this model .
- a Y-maze test was conducted to examine the effects of cerebral ischemia / reperfusion (day 7), and the selenium-containing composition of the test substance in this model (fish extract containing selenonein) It is the figure which evaluated the effect of.
- a Y-maze test was conducted to examine the effects of cerebral ischemia reperfusion (day 14), and the test substance in this model (selenium-containing composition selenonein-containing fish extract) It is the figure which evaluated the effect of. It is the figure which examined the improvement effect of the metabolic syndrome by ingestion of the selenium containing composition in the mouse
- the present invention relates to a selenium-containing composition for improving metabolic syndrome and the like containing an organic selenium compound as an active ingredient.
- Organic selenium compound The selenium-containing composition of the present invention can be obtained, for example, according to the method described in Japanese Patent No. 5666956.
- an “organic selenium compound” means a selenonein monomer represented by Formula II and its tautomer represented by Formula III, a selenonein dioxide represented by Formula IV. It is contemplated that the selenonene chemical modifications represented by the formula and formula I are shown and may include “selenium-containing compositions” containing these compounds.
- the organic selenium compound can be obtained by obtaining a selenium concentrate by extracting a sample derived from an organism such as fish with an aqueous solvent or an organic solvent, and then separating and purifying it by chromatography.
- the “selenium concentrate” refers to a selenium concentrate containing an organic selenium compound (described later) represented by the chemical formulas I to IV of the present invention. After extracting a sample with an organic solvent or water, a rotary evaporator or the like And the like obtained by concentrating with the above.
- the selenium concentrate is in the form of a solution, the selenium concentrate preferably contains 5 ⁇ g / mL or more of the organic selenium compound of the present invention, and more preferably a dry powder obtained by drying under reduced pressure.
- a metal or a polymer material in which an “organic selenium compound” is bonded via a selenol group is also included.
- the organic selenium compound of the present invention includes a compound of formula II:
- the organic selenium compounds represented by the formulas II and III are both monomers of the organic selenium compound.
- the organic selenium compound of formula II has a molecular structure in which a selenol group is bonded to the carbon atom at the 2-position of the imidazole ring, and the selenol group forms a tautomer in equilibrium with the selenoketone group.
- organic selenium compound of the present invention includes the formula IV:
- oxidized dimer represented by (3,3 ′-(2,2′-diselanediylbis (1H-imidazole-5,2-diyl)) bis (2- (trimethylammonio) propanoate))
- a dimer in which a compound having a molecular structure in which a selenol group and a trimethylammonium group are bonded to an imidazole ring as a basic unit and this compound forms a diselenide via a selenol group is also included.
- the selenium content contained in the selenium-containing composition is determined by a fluorescence method using 2,3-diaminonaphthalene (DAN) (for example, J. H. Watkinson, Anal. Chem., 38, 92-97 ( 1966)) or an HPLC-ICP-MS analysis method using a GPC column (for example, see H. Ge, et al., Anal. Commun., 33, 279-281 (1996)).
- DAN 2,3-diaminonaphthalene
- HPLC-ICP-MS analysis method using a GPC column for example, see H. Ge, et al., Anal. Commun., 33, 279-281 (1996).
- the selenium-containing composition of the present invention may be provided in the form of a composition containing, for example, a compound represented by Formula II (“selenonein”).
- the composition containing selenonein of the present invention is not limited, but may be in the form of a tablet, paste or beverage containing 0.1-100 ⁇ g of selenium as a selenium concentrate, a dried product thereof, or a purified selenone product. .
- Examples of the raw material of selenonein as a typical example of the organic selenium compound of the present invention include tuna (bluefin tuna, southern bluefin tuna, yellowfin, bigeye, albacore), swordfish (swordfish, marlin, sailfish, blackfish), bonito ( Bonito, Marsoda bonito, Hiraso bonito, Hagatsuo, suma), mackerel (massaba, sesame mackerel, norwegian mackerel) And other microorganisms such as marine mammals including whales, yeasts (Schizosaccharomyces pombe) ("Methylmercury and selenium in marine products" Chemistry and Biology 50 (11), 807-817, 2012-11-01; Genetic .
- the present invention provides a selenium-containing composition containing the organic selenium compound as an active ingredient.
- the content of the organic selenium compound contained in the composition of the present invention may be 0.000001 to 99% by weight with respect to the total weight of the composition.
- the content of the selenium compound can be adjusted as appropriate.
- a selenium-containing composition When a selenium-containing composition is used as an active ingredient, it can take a form containing 0.1 to 100 ⁇ g of selenium as described above.
- the raw material of the composition is not particularly limited as long as it contains selenonein.
- microorganisms such as fish, marine mammals and yeast, mycelium, plants, seaweeds, algae, chemical synthesis Goods can also be a raw material.
- the organic selenium compound of the present invention may also contain other components depending on the purpose in addition to the organic selenium compound which is an active ingredient.
- Other ingredients that can be included in the selenium-containing composition of the present invention include, but are not limited to, water; alcohol; processed meat products; rice, wheat, corn, potatoes, sweet potatoes, soy, kombu, wakame, tengusa, etc.
- composition of the present invention may further contain other drugs as necessary.
- the content of such other components and / or other drugs is not particularly limited and can be appropriately selected by those skilled in the art.
- a food, food composition and pharmaceutical composition comprising the composition of the present invention are provided.
- the composition of the present invention may contain a carrier acceptable as a food according to a desired product form and other additives.
- carriers and additives include excipients, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, disintegrating agents, lubricants. And preservatives.
- the pharmaceutical composition of the present invention is, for example, a solid preparation such as a food, a food additive, a tablet, a powder, a fine granule, a granule, a capsule, a pill, a sustained-release agent, a solution, Examples thereof include liquid preparations such as suspensions and emulsions. These can be formulated or commercialized, together with carriers and additives as necessary, by techniques commonly used in the art.
- the selenium-containing composition containing the selenium compound formulas I to IV of the present invention as an active ingredient, and foods and food compositions containing the composition are used for reducing oxidative stress, suppressing oxidative lipids, preventing ischemic diseases, and metabolic. Improvement of syndrome, improvement of glucose tolerance, improvement of protection of disorders associated with metabolic syndrome including abnormal lipid metabolism, suppression of carcinogenesis, suppression of systemic immunity, suppression of vascular endothelial damage, suppression of arteriosclerosis, prevention of dementia, improvement of brain function, corneal epithelium Expected to protect cells, improve dry eye, and suppress inflammation.
- amelioration refers to improvement or alleviation of a disease, symptom or condition, prevention or delay of a disease, symptom or condition, or reversal, prevention or delay of progression of a disease, symptom or condition.
- Reduction refers to delay in appearance of disease, symptom or condition, decrease in frequency, decrease in severity, and may be used synonymously with “improvement”.
- inhibitor refers to the complete or partial suppression of a disease, symptom, or condition.
- prevention refers to preventing or delaying the onset of a disease or symptom in an individual or reducing the risk of developing an individual's disease or symptom.
- Protection means not causing the onset of various clinical symptoms, and may be understood to include “prevention”.
- the organic selenium compound that is an active ingredient is 0.1 ng to 10 mg, more preferably 1 ng to 5 mg, more preferably 1 kg per adult body weight. Is preferably 2 ng to 3 mg, more preferably 3 ng to 1 mg, still more preferably 5 ng to 500 ⁇ g, even more preferably 5 ng to 100 ⁇ g, and most preferably 10 ng to 50 ⁇ g. More specifically, it is preferably administered or ingested 2 ng to 2550 ⁇ g per day, more preferably 5 ng to 47 ⁇ g, still more preferably 10 ng to 14.5 ⁇ g. In the present invention, this amount of the active ingredient is divided into 1 to several times a day, and the compound is used as it is or in a desired form such as food, composition, medicine, food and drink, It can be administered or ingested.
- ischemic disease is prevented and oxidative stress is reduced.
- ischemia a large amount of active oxygen is produced during reperfusion of blood, causing damage.
- the selenium-containing composition of the present invention By ingesting the selenium-containing composition of the present invention, the biological antioxidant effect is enhanced, the oxidative stress in the brain is reduced, and ischemic brain disease can be prevented.
- Such an ischemic disease prevention effect and oxidative stress reduction effect are confirmed by, for example, cerebral ischemia / reperfusion model tests using gerbils after administration of a selenium-containing composition to confirm the effect of reducing ischemia / reperfusion injury. be able to.
- a selenium-containing composition for example, selenonein-containing fish extract
- gerbils for 2 weeks
- blood flow in the bilateral common carotid artery is stopped for 5 minutes, followed by reperfusion.
- the administration of the organic selenium compound can be continued for 2 weeks, and the spontaneous exercise amount and working memory ability can be examined and evaluated (see Example 2 described later).
- the brain and heart may be removed after sacrifice and the ischemic site may be confirmed biochemically.
- the selenium-containing composition of the present invention can be used as a food ingredient that protects against oxidative stress due to oxygen deficiency, ischemic heart disease, cerebral infarction and the like, and an active ingredient of the composition.
- patients with nonalcoholic hepatitis have increased in addition to hepatitis due to alcohol intake and viruses.
- Ingestion of the selenium-containing composition of the present invention can prevent lipid peroxide (oxidized LDL) suppression, nonalcoholic hepatitis, fatty liver, impaired glucose tolerance, metabolic syndrome, and diabetes associated therewith.
- non-alcoholic hepatitis model mice against diabetes were produced by administering streptozotocin and a high fat diet, and the selenium-containing composition of the present invention was mixed with the diet to administer non-alcoholic hepatitis It is possible to confirm the preventive effect against oxidative stress and liver damage in the liver.
- the selenium-containing composition of the present invention is ingested with a selenonein-containing fish extract and a high fat diet, the liver is removed after 4 weeks, and the hepatitis score and the like are measured. It is possible to evaluate the effects of reducing the amount of fat accumulated in the liver, the onset of hepatitis and metabolic syndrome, and the effect of improving the protection from the accompanying disorders (see Example 3 described later).
- Carcinogenicity prevention effect and suppression effect of systemic immunity decline By ingesting the selenium-containing composition of the present invention, the suppression effect on cancer growth, metastasis and carcinogenesis and the reduction suppression effect on systemic immunity can be enhanced.
- an animal model By using an animal model, it is possible to confirm a carcinogenesis-preventing effect and a systemic immunity reduction effect.
- the cancer cell growth inhibitory effect was measured by measuring the decrease in tumor area when a cancer cell was transplanted into a mouse and a feed containing the selenium-containing composition of the present invention (for example, selenium concentration 3 mg / kg) was administered. It can be confirmed by doing.
- the effect of suppressing mutagenicity by the selenium-containing composition of the present invention can be confirmed by a reverse mutation test using bacteria. Further, under conditions closer to a living body, the transformation inhibitory effect of the selenium-containing composition of the present invention can be confirmed using mammalian-derived cells (for example, Bhas42 cells).
- mammalian-derived cells for example, Bhas42 cells. This method is a test method used for the detection of carcinogens established by the Food and Drug Center, and can also detect carcinogenic initiation activity and promotion activity separately.
- the transformation inducer 3-methylcholanthrene is added to the medium and treated for 3 days.
- the medium is replaced with a selenonein-containing fish extract-added medium and cultured until day 21 after cell seeding, and then the number of transformed foci is counted. Since the effect can be confirmed for each stage of cancer initiation, promotion, and progression, it can be evaluated whether or not it can be used as a food ingredient having a cancer prevention effect (see Example 4 described later). ).
- the selenium-containing composition of the present invention may be administered to a gall cancer mouse to confirm the systemic immunity improving effect.
- the carcinogenesis-suppressing effect of the selenium-containing composition can be verified by analyzing regulatory T (Treg) cells that have an immunosuppressive function and promote tumor growth (described later). See Example 4).
- Oxidized LDL is considered as a part of the mechanism of arteriosclerosis progression, and it has been reported that smooth muscle cells are migrated by oxidized LDL. It has been found that the selenium-containing composition of the present invention has an arteriosclerosis-preventing effect that inhibits smooth muscle cell dedifferentiation and migration into the blood vessel lumen, which cause stenosis during the progression of arteriosclerosis.
- the selenium-containing composition of the present invention can be administered to smooth muscle cells to confirm the action of inhibiting smooth muscle cell migration and inhibiting arteriosclerosis.
- human aortic smooth muscle cells can be cultured in a medium supplemented with a selenium-containing composition, and the number of migrated cells can be measured to evaluate whether it can be used as a food material having an arteriosclerosis-preventing effect. Yes (see Example 5 below).
- the migration of smooth muscle cells can be suppressed, and for example, the promotion of atherosclerosis can be suppressed.
- vascular endothelial damage related to arteriosclerosis can be improved.
- the selenium-containing composition of the present invention has an effect of improving brain function by reducing the generation of reactive oxygen species due to aging, diabetes and the like, and preventing the onset of dementia.
- “dementia” means Alzheimer-type dementia, Lewy body dementia, cerebrovascular dementia, frontotemporal dementia, and the like.
- the “brain function” means a memory function (for example, working memory, short-term memory), emotion, language function, cognitive function, motor function, learning function, attention function, and the like.
- the brain function is diverse, and the function deterioration can be suppressed by protecting the ischemia / reperfusion injury and the cranial nerve.
- the risk of depression is increased due to diabetes, and it is possible to prevent depression as well as dementia by protecting against brain function deterioration due to diabetic disorder.
- the brain function improvement effect as described above is, for example, that Alzheimer's disease state model mice are produced by administration of streptozotocin, and the Alzheimer progression reduction effect by administration of the selenium-containing composition of the present invention (for example, selenonein-containing fish extract) is confirmed Can do.
- streptozotocin is administered after ingesting the selenium-containing composition of the present invention for one week. Thereafter, the selenium-containing composition can be ingested for 2 weeks and evaluated by examining working memory and brain tissue. Furthermore, amyloid ⁇ accumulation inhibitory action can be confirmed biochemically by a test using cells. Ingestion of a selenium-containing composition having an effect of preventing and improving brain function deterioration and foods made from the same can be expected to have a brain function protecting effect not only for the sick but also for healthy elderly people (see below) (See Example 6).
- dry eye is not a major disease, it tends to be overlooked, but dry eye improvement is very important for improving patients' QOL, and it can be evaluated whether it can be used as a dry eye improving food ingredient (see below). See Example 7).
- dry stress of corneal cells can be protected and dry eye can be prevented and improved.
- Inflammation-suppressing effect Ingestion of the selenium-containing composition of the present invention suppresses redness, swelling, fever, pain and dysfunction associated with inflammation, and prevents rheumatoid arthritis, hemolytic anemia and myasthenia gravis due to inflammation Can do. In normal people, the immune regulation mechanism functions in a balanced manner. However, if an abnormality occurs in the immune regulation mechanism of the host for some reason, autoantibodies that recognize their own biological components as antigens are produced, resulting in various immune responses. Causing fibrosis and dysfunction. Examples of such autoimmune diseases include rheumatoid arthritis, hemolytic anemia, myasthenia gravis and the like.
- Immunosuppressive agents such as azathioprine, cyclophosphamide, pinklistin and the like are used as therapeutic agents for such autoimmune diseases, but it is known that side effects associated with administration of these drugs are various. However, most of the external inflammatory therapeutic agents applied directly to the affected area are steroids and their use is limited due to their side effects.
- the organic selenium compound of the present invention can be used as food, has no side effects, and is expected to suppress various inflammatory reactions.
- the subject of the anti-inflammatory effect by ingestion of the selenium-containing composition of the present invention is particularly caused by NF ⁇ -B activation, such as allergic diseases, anti-cancer, arthritis, autoimmune diseases, inflammatory bowel diseases, It is effective against systemic lupus erythematosus, ankylosing spondylitis, and celiac disease (see Example 8 described later).
- Example 1 Preparation of organic selenium compound An organic selenium compound was prepared by obtaining an extract containing selenonein from tuna blood exposed water according to the method described in Japanese Patent No. 5669056 (Patent Document 1). To obtain a selenonein-containing fish extract.
- the selenonein content of the selenonein-containing fish extract (Brix55) obtained in Example 1 was calculated as selenium equivalent ( ⁇ g Se / g) based on the measurement value obtained by the following LC-ICPMS.
- cysteine hydrochloride (Wako Pure Chemical Industries, Ltd.) 0.1 g cysteine hydrochloride (Wako Pure Chemical Industries, Ltd.) is added to 100 g of blood muscle and polytron homogenizer (PT MR 6000, KINEMATICA) at 6800 rpm in 10 volumes of acetonitrile (Wako Pure Chemical Industries, Ltd.). For 15 seconds while cooling with ice water.
- Fraction 2 was passed through an Ultrahydrogel® 120 column (7.8 ⁇ 300 mm Japan Waters) equilibrated with 0.1% acetic acid, and fractions containing selenonein were collected and a rotary evaporator under reduced pressure. Concentrated with selenoneine to obtain a standard product.
- the total selenium content in the selenonein standard product was 0.476 ⁇ g / mL as measured by the fluorescence method described later.
- the selenonein standard products obtained in the above (5-1) to (5-9) include compounds represented by the formulas (1) to (4), and the compounds represented by the formula (2) Is known to be the main component (Doctor of Agriculture, University of Tokyo pp17-19 (Yumiko Yamashita, 2012)).
- (6-1) Selenonein standard product shows a peak at an elution time of around 10.3 minutes.
- the standard selenonein product in which a signal of an unidentified selenium compound is detected measures the integrated value of all selenium signals for 6-11 minutes, and the peak area corresponding to the total selenium injection amount quantified by the fluorescence method described later Considered.
- FIG. 1 shows a chromatogram (A) of selenium 82, a standard product of selenonein, and a chromatogram (B) of a selenonein-containing fish extract obtained in Example 1.
- the total selenium content of the selenonein-containing fish extract obtained in Example 1 was 95.3 mg / kg.
- Example 2 Examination of the effect of reducing ischemia-reperfusion injury After loading gerbils with cerebral ischemia-reperfusion, spontaneous momentum measurement and Y-maze test were conducted to examine the effects of cerebral ischemia-reperfusion, and in this model The effect of the test substance (selenonein-containing fish extract) was evaluated.
- Test system Seven-week-old gerbils (MON / Jms / Gbs Slc, male) were purchased from Japan SLC Co., Ltd., acclimated for 5 days, then weighed and divided into groups. During the test period, normal feed (CRF-1, Oriental Yeast Co., Ltd.) and water were ad libitum. The test group was divided into the following 6 groups.
- the administration start date of the test substance was Day 0, and the incision was sutured on Day 14 under isoflurane anesthesia and threaded on the common carotid artery the day before ischemia.
- the next day in order to maintain the body temperature at 37 ° C., they were laid on a hot plate set at 40 ° C. ⁇ 3 ° C., the thread at the incision was cut, the bilateral common carotid arteries were pulled, and the arteries were hemostatic with a clamp. Thereafter, the clamp was removed and reperfusion was performed, and the incision was sutured.
- the bilateral common carotid artery was exposed under isoflurane anesthesia, and the skin incision was sutured without treatment.
- test substance administration group was forcibly administered 6.2 mL / kg of the test substance every day during the test period using a disposable syringe and a stomach tube made of polypropylene. Water was administered to the normal group and the control group in the same manner as 6.2 mL / Kg. Forcible administration was performed once a day for 22 or 29 days. When ischemia-reperfusion is performed, behavioral abnormalities (increased locomotor activity), learning memory impairment, and the like occur due to hippocampal cell death. Spontaneous momentum measurement and Y-maze test were performed as evaluation of the protective effect of brain damage caused by ischemia-reperfusion of the test substance.
- the test substance administration start date is set to Day 0, and each day's spontaneous exercise amount measurement is performed on Day 6, 13, 15, 17, 19, 21, and 27 (Day 27 is the second course only). It was.
- a multi-channel spontaneous momentum measurement system Supermex (Muromachi Kikai Co., Ltd.) was used.
- Y-maze test Y-shaped maze test is to place animals in Day 21 (1st cool) and Day 28 (2nd cool), let them move freely for 6 minutes, and measure the rate of selecting a new arm. The memory learning behavior was evaluated.
- the selenium protein content in the blood clot was not significantly different between groups 1, 2, and 3, but the selenonein content was less than the detection limit (0.01 ⁇ g / g) in groups 1 and 2. In contrast, in group 3, 0.95 ⁇ 0.24 ⁇ g / g per selenium was detected, and the selenonein content was significantly increased (p ⁇ 0.05). From this result, it was shown that selenonein accumulated in the blood cells of gerbils by administration of the test substance for 22 days.
- Example 3 Examination of effect of improving protection from metabolic syndrome and associated disorders (1) Improvement effect of metabolic syndrome By administration of streptozotocin, mice having abnormal glucose metabolism as in type I diabetes were ingested. It was. After a predetermined period, the non-alcoholic hepatitis inhibitory effect by administration of a selenonein-containing fish extract was verified using NAFLD activity score, which is a method that can be comprehensively evaluated for liver fat accumulation and the like.
- mice 10 females of SPF mice (C57BL / 6J, Japan SLC) were purchased on the 14th day of pregnancy and acclimated. All animals were delivered naturally and born male mice were used for model animal production. The weaning was 4 weeks old.
- mice whose birth was observed at the 8:00 parturition observation the day before the observation day was the birth day, and for mice whose birth was observed at the 20:00 parturition observation, the day of observation was the birth date , Counted from day 0 after birth.
- Streptozotocin Sigma Aldrich Japan Co., Ltd.
- mice at the age of 2 days is adjusted to a concentration of 10 mg / mL with physiological saline (Japanese Pharmacopoeia, Otsuka Pharmaceutical Factory, Inc.) and back at 20 ⁇ L / head (200 ⁇ g / head). It was administered once subcutaneously. After that, the mother animals were raised until weaning. The animals were weaned at the age of 28 ⁇ 2 days after birth, and thereafter were raised on a high fat diet [High Fat Diet 32 (radiation sterilized, Claire Japan, Inc.)].
- the dose per administration was 15 mg / kg body weight of selenonein-containing fish extract.
- the administration volume was 10 mL / kg body weight, and oral gavage was performed using an oral sonde.
- the control group was similarly administered at 10 mL / kg body weight.
- the liquid dose for each individual was calculated based on the body weight in the morning of the day (unit: 0.01 mL). The period was 28 days, once a day from 5 weeks of age. After the administration was completed, exsanguination was caused by abdominal aortic amputation, the liver was removed, the outer left lobe was divided into 6 equal parts, two pieces were stained with hematoxylin eosin, and NAFLD activity score was calculated.
- NAFLD activity score is a score of the degree of liver fattening, liver parenchymal inflammation, and hepatocyte damage (balloon-like degeneration), and is used for pathological diagnosis of nonalcoholic hepatitis.
- balloon-like degeneration of hepatocytes, deposition of large and small droplets, inflammatory cell infiltration including lymphocytes and neutrophils were observed.
- NAFLD Activity score was significantly lower in the selenonein-containing fish extract administration group than in the control group.
- Selenonein was suggested to prevent and improve fat accumulation and the like due to metabolic abnormalities caused by metabolic syndrome, and the effect of preventing and improving metabolic syndrome was considered (FIG. 5, Table 3).
- the icv-STZ-induced Alzheimer-type dementia model is a model animal of Alzheimer-type dementia with a diabetes-like background caused by impaired brain insulin signal. This model does not use genetic factors as the primary factor. Therefore, this model is useful for studying therapeutic effects on sporadic Alzheimer-type dementia.
- model induction was started in icv-STZ-induced Alzheimer-type dementia model mice 7 days before the start of model induction. Forced oral administration was carried out for 21 days up to 14 days after the start.
- Streptozotocin (Sigma Aldrich Japan Co., Ltd.) is added to mice (C57BL / 6J, 6-week-old male at the time of arrival, Japan SLC Co., Ltd.) in physiological saline (Japanese Pharmacopoeia, Otsuka Pharmaceutical Factory Co., Ltd.) at 20 mg / mL concentration And administered into the lateral ventricle. 3 ⁇ L is administered once to the left ventricle on the day of model induction, and 3 ⁇ L is administered once to the right ventricle on the second day after the start of model induction, thereby producing an icv-STZ-induced Alzheimer-type dementia model animal did.
- Alternate action rate (%) was used as an index of SAB.
- Example 4 Examination of anticancer effect or suppression effect on systemic immunity decrease (1) Verification of anticancer effect and suppression effect on systemic immunity decrease using colorectal cancer primary tumor model The effects on tumor growth and systemic immunity of patients were investigated using cancer model animals. In each group, there was a change in feeding between 1.73 and 2.65 g per day. The intake of selenonein-containing fish extract obtained from the selenonein-containing fish extract feed varied from 81.48 to 125.82 mg per day. As a result of using the colorectal cancer primary tumor model, the growth of the primary tumor tends to be suppressed, and a marked decrease in IL-10 production ability observed in gall cancer animals was not observed in the selenonein administration group. The possibility of enhanced immunity was shown.
- Treg regulatory T
- mice-derived colon cancer cell Colon Tumor 26 (CT-26) strain ATCC No. CRL-2638
- RPMI-1640 medium R8758, Sigma-Aldrich
- mouse spleen cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 50 ⁇ M 2-mercaptoethanol (21417-52, Nacalai Tesque).
- APC-30D water jacket incubator
- mice (BALB / c female, Charles River) were fed selenonein-containing feed or control feed from 5 weeks of age to 8 weeks of age (see Table 5 below). After acclimatization for 1 week (6 weeks old), 500,000 cells of CT26 strain per mouse were transplanted subcutaneously. Mice 14 days after transplantation (8 weeks old) were euthanized, tumors were removed, and tumor volumes were measured. Tumor volume (mm 3 ) was calculated by the formula of square of width (mm) ⁇ length (mm) ⁇ 0.5.
- spleen was removed, and a subset of CD4-positive Foxp3-positive regulatory T cells (Treg) in the spleen cells was analyzed using a fluorescence staining cell analyzer (Accuri C6, BD bioscience) and FlowJo software (TreeStar). It was measured by. IL-10 concentration in the culture supernatant of splenocytes was measured by ELISA.
- Raw materials other than AIN-93M and selenonein-containing feed fish extract were purchased from Oriental Yeast.
- Treg cells Although regulatory T (Treg) cells have an immunosuppressive function and promote tumor growth, it was strongly suggested that Treg cells of gall cancer mice could be suppressed by ingestion of selenonein-containing food. In addition, IL-10 production ability responsible for regulation of antitumor activity by regulatory immunity was significantly attenuated in the gall cancer mice, but not in the selenonein-containing food intake group. It was suggested that tumor growth was also suppressed. This suggested that selenonein improves systemic immunity and suppresses cancer growth. The effect of preventing cancer recurrence was also considered by suppressing Treg cells (FIG. 9).
- B After detaching Bhas 42 cells (cells derived from whole mouse fetus-derived BALB / c 3T3, A31-1-1, v-Ha-ras gene, Food and Drug Safety Center, Japan) using 0.25% trypsin,
- the suspension was a cell concentration of 2000 cells / mL. 2 mL (4000 cells) of this cell suspension was dispensed onto a plate (6 wells / group) and cultured for 1 day. One day after sowing, the MCA preparation was added and treated for 3 days.
- Selenonein purified product and RA retinoic acid, Sigma-Aldrich
- the medium was replaced with a fresh medium (treated for 10 days), and further cultured for 7 days.
- the plate for the transformation test was fixed with methanol 21 days after sowing and stained with 5 vol% Giemsa solution to count the number of transformation foci per well.
- Example 5 Examination of arteriosclerosis inhibitory effect The effect of a test substance on cell migration was examined using human aortic smooth muscle cells. As a result, 2 mg / ml selenonein-containing fish extract and 100 nM purified selenonein suppressed migration in the presence of collagen.
- AoSMC cells (aortic smooth muscle cells) (LONZA, CC-2571) were adjusted to the required number of cells with a dedicated medium (SmGM-2 Bullet Kit (LONZA, CC-3182)).
- a test medium containing a test substance fish extract containing 2 mg / ml selenonein or 100 nM purified selenonein
- 300 ⁇ g / mL collagen peptide was added to the lower chamber, followed by culturing for 48 hours. Thereafter, the cells migrated by detaching and lysing the cells from the transwell membrane were measured with CyQuant GR Dye attached to the cell migration assay kit.
- Example 6 Examination of brain function improvement effect Amyloid ⁇ protein, which is considered to be one of the causes of Alzheimer's, has neurotoxicity. The effect of preventing dementia is expected by protecting cells from the toxicity of amyloid ⁇ . In this example, it was verified whether the toxicity of amyloid ⁇ can be protected by a test substance using PC-12 cells.
- PC-12 cells (RIKEN BioResource Center, RCB0009, Lot No. 52, 53, 54) were penicillin in 395 ml of DMEM medium (DMEM medium (Nacalai Tesque, Cat. No. 08456-65)) supplemented with 10% FBS and Horse Serum.
- DMEM medium Nacalai Tesque, Cat. No. 08456-65
- FBS FBS
- Horse Serum GIBCO, 16050-122
- Nerve cells are seeded at 2 ⁇ 10 3 cells / 100 ⁇ L / well in a 96-well plate (collagen coat) in the above DMEM medium and cultured in a CO 2 incubator (5% CO 2 , 37 ° C.). On the next day, the medium was replaced with a medium containing the test substance (containing 1% FBS, 10 ng / mL NGF (Alomon Labs, PRODUCT # N-100)). A final concentration of 1 mM in amyloid ⁇ (1-40) (SIGMA, Cat. No. A1075-1.MG) (PBS (Nissui Pharmaceutical Co., Ltd., Code 05913)) to a final concentration of 2 ⁇ M after 24 hours of culture.
- a medium containing the test substance containing 1% FBS, 10 ng / mL NGF (Alomon Labs, PRODUCT # N-100)
- a final concentration of 1 mM in amyloid ⁇ (1-40) SIGMA, Cat
- a lysate 50 ⁇ L / well
- the culture supernatant is replaced with 100 ⁇ L (per well) of a test medium containing 10% viable cell count measuring reagent (WST-8) (Nacalai Tesque, Cat. No. 07553-44). Incubated for 30 minutes and 90 minutes.
- WST-8 10% viable cell count measuring reagent
- the absorbance (absorption wavelength: 450 nm, reference wavelength: 630 nm) of each well is measured with a microplate reader (Precision microplate reader) (Molecular Devices), and the amount of change in absorbance per hour is calculated from both values, and living cells Cell viability was determined as a number.
- a test substance final concentration
- selenonein-containing fish extract 2 mg / mL
- selenonein 100 nM were used as a test substance (final concentration)
- the number of viable cells was about 70% in the non-added group with the addition of amyloid ⁇ .
- cell viability was significantly improved in the selenolein-containing fish extract as compared with the amyloid ⁇ -added control (FIG. 11).
- Example 7 Examination of dry eye improvement effect HCE-T cells (human immortalized corneal epithelial cells) (RIKEN BioResource Center, RCB2280) were tested in a test medium (DMEM / F12 (ThermoFisher, Cat. No. 11330-032) (1 1) 10% FBS (Biowest, Cat. No. S1820, Lot No. 516536), 1% NEAA (Gibco, Cat. No. 11140-050), 1% antibiotic (Nacalai Tesque, Cat. No. 26253) -84)), the cells were pre-cultured in a T75 flask in a CO 2 incubator (5% CO 2 , 37 ° C.) until the required number of cells was reached.
- DMEM / F12 ThermoFisher, Cat. No. 11330-032
- 10% FBS Biowest, Cat. No. S1820, Lot No. 516536
- NEAA Gibco, Cat. No. 11140-050
- antibiotic Nacalai
- the cells were detached from the flask using a trypsin / EDTA solution (Nacalai Tesque, Cat. No. 32777-44), neutralized with trypsin in the test medium, and centrifuged to collect the cells. Thereafter, the cells were resuspended again in the test medium and used as a cell suspension.
- trypsin / EDTA solution Nacalai Tesque, Cat. No. 32777-44
- Selenonein-containing fish extract is water-soluble and was directly dissolved in a medium to prepare a stock solution.
- the selenium-containing composition of the present invention protects the corneal cells from drought stress, The effect of preventing and improving eye was shown (FIGS. 12 and 13).
- Example 8 Anti-inflammatory effect Various inflammatory responses involve a transcription factor called “NF ⁇ B”.
- NF ⁇ B transcription factor
- cytokines such as TNF- ⁇
- inactive NF ⁇ B is activated.
- Inflammatory response is induced. It has been reported that the expression of NF ⁇ -B is increased in many diseases including allergic diseases and cancer (Chemistry and Biology, Vol. 47, No. 9, P.602-604 (2009)).
- the test substance was confirmed to have an inflammation suppressing effect by suppressing the activity of NF ⁇ -B induced by TNF- ⁇ .
- a reporter gene was introduced into a target cell, and the NF ⁇ B transcriptional activity by TNF ⁇ stimulation was measured by luciferase activity.
- the final concentration of the test substance was selenonein (crude purification): 0.4 mg / mL (HEK293 cells), selenonein (purification): 100 nM.
- HEK293 cells (RIKEN BioResource Center, RBC1637, Lot. 20) were prepared using basal medium (MEM, 10% FBS, 1% NEAA, antibiotics) ((MEM NEAA: Gibco, Cat. No. 11140-050, FBS: Biowest, Cat. No. S1820, Lot No. 516536, Antibiotic: Nacalai Tesque, Cat. No. 26253-84), required number of cells in a CO 2 incubator (5% CO 2 , 37 ° C.) in a T75 flask The cells were detached from the flask using a trypsin / EDTA solution (Nacalai Tesque, Cat. No. 32777-44), and neutralized with trypsin in the test medium, followed by centrifugation. Cells were collected and then again The test medium was resuspended cells were used as cell suspensions.
- basal medium MEM, 10% FBS, 1% NEAA, antibiotics
- MEM NEAA Gibco, Cat
- HEK293 cells were seeded in a 96-well plate at 1.5 ⁇ 10 4 cells / 0.1 mL / well and cultured for 1 day in a CO 2 incubator (5% CO 2 , 37 ° C.). Thereafter, a DNA vector (pGL4.32 [luc2P / NF-kB-RE / Hygro] vector (Promega, Cat. No. E8491)) was introduced into the cells using a transfection reagent (Roche, Cat. No. 06362440001).
- NF- ⁇ B was activated by TNF- ⁇ stimulation to promote induction of the luciferase gene.
- 30 ⁇ L of the culture supernatant was extracted from each well.
- 70 ⁇ L of luciferase assay reagent (Promega, Cat. No. E2610) was added to each well (total 150 ⁇ L of culture supernatant), mixed gently, and allowed to stand for 2 minutes. Thereafter, the relative luminous intensity (RLU) of each well was measured with a plate reader for luminescence measurement (luminometer: Thermo Fisher Scientific, Varioscan Flash, model number 5250040). 200 mM ammonium pyrrolidine dithiocarbamate (APDC) (SIGMA, Cat. No. P8765-1G) was used as a positive control.
- APDC ammonium pyrrolidine dithiocarbamate
- Both selenonein and selenonein-containing fish extract significantly suppressed NF ⁇ -B activation by addition of TNF- ⁇ . It suppressed inflammatory reactions involved in various diseases such as allergies, arthritis, rheumatism, cancer and chronic inflammatory conditions (FIG. 14).
- Example 9 Examination of Glucose Tolerance Improvement Effect
- SELENOP selenoprotein P
- SELENOP selenoprotein P
- Impairing and inducing abnormal glucose metabolism, as opposed to knocking out the SELENOP gene and knocking down with RNAi has been reported to improve systemic insulin sensitivity and glucose tolerance in mice (Misu H. et al. , Et al., Cell Metabolism, 12, 483-495 (2010)).
- PFKFB3 6-phosphofructo-2-kinase / fructose-2,6-biphosphatase 3
- Akt signaling system When PFKFB3 is inhibited by an inhibitor, it is stimulated by insulin. Uptake of glucose, translocation of glucose transporter (GLUT4) to the cell membrane, Akt signaling system is inhibited, and conversely, in cells overexpressing PFKFB3 gene, Akt signaling system may be activated Have been reported (Treferry S., et al., J. Biol. Chem., 290, 25834-25846 (2015)).
- the selenium-containing composition of the present invention Since the selenonein-containing fish extract suppresses the SELENOP gene expression level to 1/3 or less and conversely increases the expression level of the PFKFB3 gene more than twice as compared with the case of no addition (control), the selenium-containing composition of the present invention was shown to have an effect of improving glucose tolerance abnormality (Table 7).
- Example 10 Examination of lipid metabolism abnormality improvement effect 27-Hydroxycholesterol (27HC) is a metabolite of cholesterol that is abundant in blood, promotes the progression of arteriosclerosis, and causes inflammation in blood vessels.
- 27HC in the body is catabolized by cytochrome P450 family 7 subfamily B member 1 (CYP7B1) (Umetani M. et al., Cell Metabolism, 20, 172-182 (2014)).
- CYP7B1 cytochrome P450 family 7 subfamily B member 1
- mice knocked out of the CYP7B1 gene the 27HC concentration in blood and tissue is increased 4 to 5 times compared to the wild type (Umetani M., supra).
- the effect of the selenonein-containing fish extract on the expression level of the CYP7B1 gene was examined.
- the selenium-containing composition of the present invention can be used as a new agent for reducing ischemia-reperfusion injury, anti-metabolic syndrome, and the like.
- a new application of selenonein concentrate extracted from fishery processing residue is found, which can contribute to high added value of low unused marine products.
- New foods and functional ingredients that respond to consumer health can be commercialized.
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Abstract
Description
[1]式I:
Rは、水素、エルゴチオニル基、グルタチオニル基、またはシステイニル基である]
で表される有機セレン化合物を有効成分として含有する、酸化ストレス低減、酸化脂質抑制、虚血性疾患予防、メタボリックシンドローム改善、耐糖能異常改善、脂質代謝異常を含むメタボリックシンドロームに伴う障害の保護改善、発がん抑制、全身免疫能低下抑制、血管内皮障害抑制、動脈硬化抑制、認知症予防、脳機能改善、角膜上皮細胞保護、ドライアイ改善、または炎症抑制のための組成物。
[6]上記[1]~[4]のいずれかに記載の組成物を含む食品。
Rは、水素、エルゴチオニル基、グルタチオニル基、又はシステイニル基である]
で表される有機セレン化合物を有効成分として含有する、酸化ストレス低減、酸化脂質抑制、虚血性疾患予防、メタボリックシンドローム改善、耐糖能異常改善、脂質代謝異常を含むメタボリックシンドロームに伴う障害の保護改善、発がん抑制、全身免疫能低下抑制、血管内皮障害抑制、動脈硬化抑制、認知症予防、脳機能改善、角膜上皮細胞保護、ドライアイ改善、または炎症抑制のための医薬組成物。
本発明のセレン含有組成物は、例えば、特許第5669056号公報に記載の方法に従って得ることができる。本明細書において別段の指示がない限り、「有機セレン化合物」は、化学式IIに表されるセレノネイン単量体および化学式IIIに表されるその互変異性体、化学式IVに表されるセレノネイン酸化二量体および化学式Iに表されるセレノネイン化学修飾物を示し、これら化合物を含有する「セレン含有組成物」を含み得ることが意図される。ここで、有機セレン化合物は、魚類等の生物由来の試料を水系溶媒または有機溶媒で抽出することによりセレン濃縮物を得た後、クロマトグラフィーによって分離・精製することによって得ることができる。ここで、「セレン濃縮物」とは、本発明の化学式I~IVに表される有機セレン化合物(後述)を含むセレン濃縮物を指し、試料を有機溶媒または水で抽出した後、ロータリーエバポレーター等で濃縮して得られるもの等が挙げられる。セレン濃縮物は、溶液状である場合には、本発明の有機セレン化合物を5μg/mL以上を含有しているものであることが好ましく、減圧濃縮によって乾固した乾燥粉末がより好ましい。
本発明は、上記の有機セレン化合物を有効成分として含有するセレン含有組成物を提供するものである。本発明の組成物に含まれる有機セレン化合物の含有量は、組成物全重量に対して、0.000001~99重量%であってよく、当業者であれば、所望の効果を得るために有機セレン化合物の含有量を適宜調整することができる。また、セレン含有組成物を有効成分とする場合は、上記の通り、セレンとして0.1~100μgを含有する形態をとることができる。また、該組成物の原料については、セレノネインを含有するものであれば特に限定されず、例えば、上記魚類、海洋性哺乳類、酵母等の微生物の他、菌糸類、植物、海藻、藻類、化学合成品も原料となり得る。
本発明によれば、上記本発明の組成物を含む食品、食品組成物および医薬組成物が提供される。本発明の組成物を食品および食品組成物として使用する場合、所望の製品形態に応じた食品として許容され得る担体や、他の添加剤を含んでもよい。このような担体および添加剤としては、例えば、賦形剤、結合剤、香料、緩衝剤、増粘剤、着色剤、安定剤、乳化剤、分散剤、懸濁化剤、崩壊剤、滑沢剤、防腐剤等が挙げられる。本発明の医薬組成物は、経口用の形態としては、例えば、食品、食品添加剤、錠剤、散剤、細粒剤、顆粒剤、カプセル剤、丸剤、徐放剤などの固形製剤、溶液、懸濁液、乳濁液などの液状製剤の形態が挙げられる。これらは、当該技術分野で通常行われている手法により、必要に応じて担体や添加剤とともに、製剤化もしくは製品化することができる。
本発明のセレン化合物式I~IVを有効成分とするセレン含有組成物、並びに該組成物を含む食品および食品組成物は、酸化ストレス低減、酸化脂質抑制、虚血性疾患予防、メタボリックシンドローム改善、耐糖能異常改善、脂質代謝異常を含むメタボリックシンドロームに伴う障害の保護改善、発がん抑制、全身免疫能低下抑制、血管内皮障害抑制、動脈硬化抑制、認知症予防、脳機能改善、角膜上皮細胞保護、ドライアイ改善の効果および炎症抑制が期待される。なお、食品としての使用における態様では、限定されないが、健康食品、機能性食品、特定保健用食品、栄養機能食品、栄養補助食品、機能性表示食品、飲料等の形態であってもよい。本明細書において使用するとき、「改善」とは、疾患、症状若しくは状態の好転若しくは緩和、疾患、症状若しくは状態悪化の防止、もしくは遅延、又は疾患、症状若しくは状態の進行の逆転、防止若しくは遅延をいう。「低減」とは、疾患、症状又は状態の出現の遅延、頻度の減少、重症度の低下をいい、「改善」と同義に使用されてもよい。また、「阻害」とは、疾患、症状又は状態を完全に又は部分的に抑制することをいう。本明細書において、上記の「改善」、「低減」、及び「阻害」は、互いに同義として使用され得る。一方、「予防」とは、個体における疾患若しくは症状の発症の防止若しくは遅延、又は個体の疾患若しくは症状の発症の危険性を低下させることをいう。「保護」とは、各種臨床症状の発症を引き起こさないことをいい、「予防」を含むものと理解してよい。
虚血では血液の再灌流の際に活性酸素が多量に生成され、障害が生じることが知られている。本発明のセレン含有組成物の摂取によって、生体抗酸化作用が強化され、脳での酸化ストレスが軽減され、虚血性脳疾患を予防することができる。このような虚血性疾患の予防効果および酸化ストレス低減効果は、例えば、セレン含有組成物を投与後、スナネズミを用いた脳虚血再灌流モデル試験により、虚血再灌流障害の軽減効果を確認することができる。より具体的には、スナネズミにセレン含有組成物(例えば、セレノネイン含有魚エキス)を2週間投与し、両側総頸動脈の血流を5分間止めた後に再灌流を行う。その後、有機セレン化合物の投与を2週間継続し、自発運動量と作業記憶能力を検査して評価することができる(後述する実施例2参照)。さらに、屠殺後脳および心臓を摘出し、虚血部位を生化学的に確認してもよい。本発明のセレン含有組成物は、酸欠による酸化ストレスの軽減、虚血性心疾患、脳梗塞等による障害から防御する食品原料および組成物の有効成分などに利用可能である。
アルコール多量摂取、ウイルス等による肝炎だけでなく、非アルコール性肝炎の患者が近年増加している。本発明のセレン含有組成物の摂取によって過酸化脂質(酸化LDL)の抑制、非アルコール性肝炎、脂肪肝、耐糖能異常、メタボリックシンドロームおよびそれらに伴う糖尿病の発症を予防することができる。動物モデルとして、ストレプトゾトシンと高脂肪食を投与することにより糖尿病を背景とした非アルコール性肝炎モデルマウスを作製し、本発明のセレン含有組成物を食餌に混合して投与することによって非アルコール性肝炎に伴う肝臓における酸化ストレスおよび肝臓障害に対する予防効果を確認することができる。例えば、本発明のセレン含有組成物であるセレノネイン含有魚エキスと高脂肪食を摂取させ、4週間後に肝臓を摘出し、肝炎スコア等を測定することにより、本発明のセレン含有組成物による酸化ストレスの軽減効果、肝臓中の脂肪蓄積量の減少、肝炎およびメタボリックシンドロームの発症、それに伴う障害からの保護改善効果を評価することができる(後述する実施例3参照)。
本発明のセレン含有組成物の摂取によって、がん増殖、転移および発がんに対する抑制効果および全身免疫能の低下抑制効果を増強することができる。動物モデルを用いることによって発がん予防効果および全身免疫能低下の抑制効果を確認することができる。がん細胞の増殖抑制効果は、マウスにがん細胞を移植し、例えば、本発明のセレン含有組成物を含む飼料(例えば、セレン濃度3mg/kg)を投与した時の腫瘍部の減少を測定することによって確認することができる。
酸化LDLは動脈硬化進展の機序の一部として考えられており、酸化LDLにより平滑筋細胞が遊走されることが報告されている。本発明のセレン含有組成物は、動脈硬化の進展時に狭窄が生じる原因となる平滑筋細胞の脱分化と血管内腔への遊走を阻止する動脈硬化予防効果を有することが見出された。本発明のセレン含有組成物を平滑筋細胞に投与して、平滑筋細胞の遊走を阻止し、動脈硬化を抑制する作用を確認することができる。例えば、ヒト大動脈平滑筋細胞をセレン含有組成物を添加した培地で培養し、遊走した細胞数を測定することにより、動脈硬化予防効果をもつ食品原料として利用可能であるかどうかを評価することができる(後述する実施例5参照)。本発明によれば、平滑筋細胞の遊走性を抑制することができ、例えば、アテローム性動脈硬化の促進を抑制することができる。また、動脈硬化に関連した血管内皮障害を改善することができる。
アルツハイマーのリスク要因として、加齢、遺伝的素因、生活習慣病(糖尿病など)が知られている。本発明のセレン含有組成物は、加齢や糖尿病等による活性酸素種の発生を軽減し、認知症の発症を予防する脳機能改善効果を有することが見出された。なお、本明細書において、「認知症」とは、アルツハイマー型認知症、レビー小体型認知症、脳血管性認知症、前頭側頭型認知症などを意味する。また、「脳機能」とは、記憶機能(例えば、作業記憶、短期記憶)、情動、言語機能、認知機能、運動機能、学習機能、注意機能などを意味する。このように脳機能は多岐に亘り、虚血再灌流障害や脳神経を保護することで機能低下を抑制することができる。また、糖尿病に起因してうつ病リスクが高まるということが知られており、糖尿病性障害による脳機能低下から保護することにより認知症のみならずうつ病も予防することができる。上記のような脳機能改善効果は、例えば、ストレプトゾトシン投与によりアルツハイマーの病態モデルマウスを作製し、本発明のセレン含有組成物(例えば、セレノネイン含有魚エキス)の投与によるアルツハイマー進展低減効果を確認することができる。脳内にストレプトゾトシンを直接投与することにより脳内酸化ストレスが増大し、アミロイドβ、タウタンパク質の蓄積が起こり、アルツハイマー病と同様の病態になることが知られている。モデル作製には、本発明のセレン含有組成物を1週間摂取させた後にストレプトゾトシン投与する。その後、2週間、セレン含有組成物を摂取させ、作業記憶および脳組織を検査することにより評価することができる。さらに、細胞を用いた試験によりアミロイドβ蓄積抑制作用を生化学的に確認することができる。脳機能低下予防改善効果を有するセレン含有組成物およびそれを原料とする食品の摂取は、病者だけでなく健康な高齢者に対しても脳機能保護効果をもつことが期待できる(後述する実施例6参照)。
セレン含有組成物を摂取することよって、角膜上皮細胞の乾燥および酸化ストレスが軽減および保護され、ドライアイの予防効果を得ることができる。ドライアイ患者は日本に約800万~2200万人いると言われている。炎症や持続的な酸化ストレスはドライアイを悪化させ、ムチンの低下や、ドライアイモデルマウスではミトコンドリアの形成異常が見られることが報告されている(Kawai, M., et al., Sci. Rep., vol.3, 2455 (2013))。ヒト不死化角膜上皮細胞を用いて、有機セレン化合物(例えば、セレノネイン含有魚エキス)を添加した培地で培養し、ムチンの産生等を測定することにより評価することができる。ドライアイは大きな疾患ではないため見過ごされがちであるが、ドライアイ改善は患者のQOL改善に非常に重要であり、ドライアイ改善食品原料として利用可能であるかどうかを評価することができる(後述する実施例7参照)。本発明のセレン含有組成物を用いることによって、角膜細胞の乾燥ストレスを保護し、ドライアイを予防および改善することができる。
本発明のセレン含有組成物の摂取によって、炎症に伴う発赤、腫脹、発熱、疼痛および機能障害を抑制し、炎症に起因する関節リウマチ、溶血性貧血および重症筋無力症を予防することができる。正常人においては免疫調節機構がバランスよく機能しているが、何らかの原因により宿主の免疫調節機構に異常が発生した場合、自己の生体成分を抗原として認識する自己抗体が産生され、種々の免疫反応を引き起こし、線維障害、機能障害が生じている。このような自己免疫疾患としては、関節リウマチ、溶血性貧血、重症筋無力症等が挙げられる。このような自己免疫疾患の治療薬としてアザチオプリン、サイクロフォスファマイド、ピンクリスチン等の免疫抑制剤が用いられるが、これら薬剤投与に伴う副作用も多岐にわたることが知られている。しかしながら、直接患部に塗布する外用性炎症治療剤はステロイド系のものがほとんどでその副作用のため、服用が限られていた。本発明の有機セレン化合物は食品としても使用することができ、副作用もなく、各種炎症反応の抑制に期待される。本発明のセレン含有組成物の摂取による炎症抑制効果の対象は、特にNFκ-B活性化に起因するものであり、例えば、アレルギー疾患、抗がん、関節炎、自己免疫疾患、炎症性腸疾患、全身性エリテマトーデス、強直性脊椎炎、セリアック病に対して有効である(後述する実施例8参照)。
有機セレン化合物は、既報の特許第5669056号公報(特許文献1)に記載の方法に準じて、マグロ血合肉さらし水からセレノネインを含む抽出液を得て、Brix55まで濃縮し、セレノネイン含有魚エキスを得た。
実施例1で得られたセレノネイン含有魚エキス(Brix55)のセレノネインの含有量は、以下のLC-ICPMSで得た測定値に基づきセレン当量(μgSe/g)として算出した。
分離用カラム :Ultrahydrogel 120 (Waters)
LCポンプ :Pu712(GLサイエンス株式会社)
サンプルインジェクター:9725i(Rheodyne)
ICPMS :ELAN DRC II(Perkin-Elmer)
移動層:0.1%IGEPAL-CA63、0.1M酢酸アンモニウム(pH5.3)
流速 :1.0mL/min
サンプル注入量:0.01mL
測定元素 :Se
質量数 :82
RF出力(W) :1200
ネブライザーガス(Ar,L/min):1.0
補助ガス(Ar,L/min) :1.3
プラズマガス(Ar,L/min) :17
メイクアップガス(Ar,L/min):0
反応ガス(Ar,L/min) :0
パルスステージ電圧(eV) :1050
RPq :2.5
滞在時間(sec/amu) :0.4
実施例1で得られたセレノネイン含有魚エキスを20μLに対し19倍容(380μL)の超純水(Milli-Q Element、ミリポア社)を加えて混和し、12000rpmで10分間遠心した上清をHPLC-ICPMS分析に使用した。
セレノネイン標準品は以下の方法でメカジキ血合筋から精製して得たものを使用した:
(5-1)冷凍メカジキフィレーを5℃で一晩解凍して血合筋を切り取って集めたものを用いた。
(4)の試料およびセレノネイン標準品について、(1)~(3)で述べたLC-ICPMS装置でセレン82を測定してクロマトグラムを得、これらを用いてセレノネインの同定および含有量を決定した。
X=(A/B)×(1000/C)×D/1000 式(5)
(ここで、
X:試料中のセレノネイン含有量(μgSe/g)
A:試料の10.3分のピーク面積。
B:セレノネイン標準品の注入セレン重量あたりの検出面積(/ngSe)
C:LC-ICPMSにおいて注入した試料のマイクロL量(今回はC=5)
D:試料を調製した際の超純水による希釈倍率(今回はD=20)。
図1に、セレノネイン標準品のセレン82のクロマトグラム(A)及び実施例1で得られたセレノネイン含有魚エキスのクロマトグラム(B)を示す。
従って、実施例1で得られたセレノネイン含有魚エキスに含まれるセレン化合物の多くは式IVで表される化合物が主成分であることがわかった。実施例1で得られたセレノネイン含有魚エキスについて、算出されたセレノネイン含有量は32.5mgSe/Lであった。
実施例1で得られたセレノネイン含有魚エキス、(5-1)~(5-9)で得られたセレノネイン標準品を文献(Fluorometric determination of selenium in nanogram amounts in biological materials using 2, 3-diaminonaphthalene. R. Hasunuma, T. Ogawa, Y. Kawanishi, Analytical biochemistry (1982),126:242-245)記載の方法で湿式分解し、セレン化合物をすべて無機態とした後、2,3-ジアミノナフタレン(DAN)と反応させ、Se(IV)との錯体形成反応により生じる4,5-ベンゾピアセレノール(Se-DAN)の蛍光を測定することによって定量した。得られた測定値に基づき試料重量あたりのセレン重量(mg/kg)として算出した。具体的には、以下の条件で測定した。
スナネズミに脳虚血再灌流を負荷後、自発運動量測定およびY字迷路試験を行い、脳虚血再灌流の影響を検討するとともに、このモデルにおける被験物質(セレノネイン含有魚エキス)の効果を評価した。
7週齢スナネズミ(MON/Jms/Gbs Slc、雄)を日本エスエルシー株式会社より購入し、5日間馴化した後、体重測定を行い、群分けした。試験期間中は通常飼料(CRF-1、オリエンタル酵母工業株式会社)と水を自由摂取させた。試験群として以下の6群に分けた。
被験物質投与開始日をDay 0として、Day 6、13、15、17、19、21および27(Day 27は第2クールのみ)に、各1時間の自発運動量測定を行った。測定には、マルチチャンネル型自発運動量測定システム・スーパーメックス(室町機械株式会社)を使用した。
(2)Y迷路試験
Y字型の迷路試験はDay 21(第1クール)およびDay 28(第2クール)に動物を入れて6分間自由に行動させ、新しいアームを選択した割合を測定することで記憶学習行動の評価を行った。
(3)セレノネイン測定
第一クール終了時、1群、2群、および3群の生残した試験体から2.5%イソフルラン吸入麻酔下で動物の腹部大動脈からヘパリン入りシリンジで全採血することで放血安楽死させた。採血した血液を遠心分離(3000rpm、10分、4℃)して血漿と血餅を分けて採取した。血餅中のセレノネイン含量を実施例1の方法に準じて分析した。
虚血再灌流処置から1日後では、コントロール群の2群(図2中、「コントロール22日群」)と5群(図2中、「コントロール29日群」)では自発運動量が増加していたが、被験物質投与群である3群(図2中、「セレノネイン含有魚エキス投与22日群」)と6群(図2中、「セレノネイン含有魚エキス投与29日群」)では有意に抑制されていた(図2)。一方、Y迷路試験を処置から7日後および14日後に行った結果、それぞれコントロール群では正答率が低下するが、セレノネイン含有魚エキス投与群では有意に低下が抑制され、これは「正常群」(無処置)と同程度であり、被験物質は虚血再灌流による脳障害から保護する効果があることが確認された(図3と4)。
(1)メタボリックシンドロームの改善効果
ストレプトゾトシン投与により、I型糖尿病と同様に糖代謝異常を起こしているマウスに高脂肪食を摂取させた。所定期間後、肝臓の脂肪蓄積等について総合して評価可能な方法であるNAFLD activity scoreを用いて、セレノネイン含有魚エキス投与による非アルコール性肝炎抑制効果を検証した。
icv-STZ誘導性アルツハイマー型認知症モデルは、脳内インスリンシグナルを障害することで生じる、糖尿病様背景をもったアルツハイマー型認知症のモデル動物であり、遺伝要因を第一要因としないモデルである。したがって、本モデルは孤発性アルツハイマー型認知症に対する治療効果の検討に有用である。本実施例においては、被験物質であるセレノネイン含有魚エキスのアルツハイマー型認知症に対する効果を検討することを目的として、icv-STZ誘導性アルツハイマー型認知症モデルマウスにモデル誘導開始の7日前からモデル誘導開始後14日までの21日間強制経口投与を行った。モデル誘導開始後13日目に行動解析を行い、モデル誘導開始後14日目に屠殺し、解析を行った。溶媒投与群(RO水、コントロール投与群)とセレノネイン含有魚エキス投与群との比較により、セレノネイン含有魚エキスのicv-STZ誘導性アルツハイマー型認知症モデルにおけるアルツハイマー型認知症に対する効果を検討した。
交替行動率=100×(3回続けて異なるアームへ進入した回数)/(アームへ進入した全回数-2)
結果、コントロールと比較してセレノネイン含有魚エキス群は有意に交替行動率が高かった(P<0.05)。セレノネイン摂取により糖尿病による脳機能低下から保護されることが示唆された。
(1)大腸がん原発巣モデルを用いた抗がん効果および全身免疫能低下抑制効果の検証
セレノネイン含有魚エキスが、がん患者の腫瘍成長や全身免疫能に及ぼす影響をがんモデル動物を用いて検討した。各群とも1日あたり、1.73~2.65gの間の摂餌で推移した。セレノネイン含有魚エキス飼料から得られるセレノネイン含有魚エキス摂取量は、1日あたり81.48~125.82mgで推移した。大腸がん原発巣モデルを用いた結果、原発巣腫瘍成長が抑制される傾向があり、胆がん動物でみられるIL-10産生能の顕著な減弱がセレノネイン投与群では観察されず、調節性免疫能が増強される可能性が示された。また、調節性T(Treg)細胞がセレノネイン投与によって減少しており、Treg細胞による抗腫瘍免疫能調節は改善される可能性が示唆された。すなわち、セレノネインはがん患者の全身免疫能の改善および腫瘍の成長を抑制する効果があることが示唆された(図7と8)。
Bhas 42細胞を用いた形質転換試験を実施することにより、セレノネイン精製品の主成分であるセレノネインについて、インビトロでの発がん抑制作用の有無を検討した。用量設定試験において、Bhas 42細胞をセレノネイン精製品(0.31、0.63、1.3、2.5、5.0、10μM)で処理したところ、細胞毒性作用は見られなかった(データ示さず)。そこで、この結果および他の実験でのデータを元に、形質転換試験における濃度を1μMに設定した。形質転換試験では、1μg/mLの3-メチルコラントレン(MCA)(Sigma-Aldrich)により誘発される形質転換巣の数が、1μMのセレノネイン精製品により低下するか調べた。すなわち、MCA+超純水群とMCA+セレノネイン精製品群における形質転換率(形質転換巣数/ウェル)を比較した。その結果、それぞれの形質転換率は15.8および10.2となり、形質転換巣数の有意な低下が認められた。以上の結果から、セレノネインはインビトロで発がん抑制作用を有することが示唆された。
ヒト大動脈平滑筋細胞を用いて被験物質の細胞遊走性に及ぼす影響を検討した。その結果、コラーゲン存在下において2mg/mlセレノネイン含有魚エキスおよび100nM精製セレノネインは遊走性を抑制した。
アルツハイマーの原因の一つと考えられているアミロイドβタンパクは神経細胞毒性を有する。アミロイドβの毒性から細胞を防御することで認知症を予防する効果が期待される。本実施例では、PC-12細胞を用いてアミロイドβの毒性を被験物質によって保護できるのかを検証した。
HCE-T細胞(ヒト不死化角膜上皮細胞)(理研バイオリソースセンター、RCB2280)は、試験培地(DMEM/F12(ThermoFisher,Cat.No.11330-032)(1:1)、10%FBS(Biowest,Cat.No.S1820,Lot No.516536)、1%NEAA(Gibco,Cat.No.11140-050)、1%抗生物質(Nacalai Tesque,Cat.No.26253-84))を用いて、T75フラスコにてCO2インキュベーター(5%CO2、37℃)内で必要細胞数に達するまで前培養した。細胞の継代にはトリプシン/EDTA溶液(Nacalai Tesque,Cat.No.32777-44)を用いて細胞をフラスコから剥離し、試験培地でトリプシンを中和後、遠心分離して細胞を回収した。その後、再び試験培地に細胞を再懸濁し、細胞懸濁液として使用した。
HCE-Tを2.5×104細胞/0.1mL/ウェルで、96ウェルプレートに播種し、CO2インキュベーター内(5%CO2、37℃)で5時間培養後、細胞がプレート底面に接着したことを確認し、被験物質を含む試験培地に交換した。その後、1日間培養した。続いて、培養上清を除去し、乾燥状態に細胞を曝した(乾燥ストレス処理時間:10分間)。その後、専用培地を添加し、再び、CO2インキュベーター内(5%CO2、37℃)で3時間培養した。細胞の増殖性を生細胞数測定試薬SF(Nacalai Tesque,Cat.No.07553-44)(WST-8)を用いて測定した。
HCE-Tを6×104細胞/0.5mL/ウェルで、48ウェルプレートに播種し、CO2インキュベーター内(5%CO2、37℃)で1日間培養後、被験物質を含む試験培地に交換した。被験物質を添加してから5時間後、細胞から総RNAを回収し、cDNA化後にリアルタイムPCR(Light Cycler 96 System(Roche))によりムチン遺伝子発現解析を行った。解析対象遺伝子:膜結合型ムチン遺伝子MUC1、内部標準遺伝子:GAPDHとした。
様々な炎症応答には「NFκB」と呼ばれる転写因子が関与しており、TNF-α等のサイトカインによって細胞が刺激を受けると、不活性型のNFκBは活性化されて炎症反応が誘導される。NFκ-Bの発現は、アレルギー性疾患やがんを始め多くの疾患で亢進していることが報告されている(化学と生物、Vol.47、No.9、P.602-604(2009))。被験物質は、TNF-αで誘導されるNFκ-Bの活性を抑制することで炎症抑制効果を確認した。NFκ-B活性測定系は、目的細胞にレポーター遺伝子を導入し、TNFα刺激によるNFκB転写活性をルシフェラーゼ活性にて測定した。被験物質の終濃度は、セレノネイン(粗精製):0.4mg/mL(HEK293細胞)、セレノネイン(精製):100nMとした。
従来、ヒト肝臓においてセレノプロテインP(SELENOP)遺伝子の発現量がインスリン抵抗性と相関すること、精製したSELENOPで肝細胞と筋細胞を処理するとインスリンシグナルを障害し、糖代謝の異常を誘導すること、それとは反対に、SELENOP遺伝子のノックアウトおよびRNAiによるノックダウンにより、マウスにおいて全身のインスリン感受性と耐糖能を改善することが報告されている(Misu H.,et al.,Cell Metabolism,12,483-495(2010))。また、6-ホスホフルクト-2-キナーゼ/フルクトース-2,6-ビホスファターゼ3(PFKFB3)は解糖系とインスリンシグナル伝達系の正の調節因子であり、PFKFB3を阻害剤で阻害すると、インスリンで刺激されるグルコースの取込みとグルコーストランスポーター(GLUT4)の細胞膜へのトランスロケーション、Aktシグナル伝達系が阻害されること、反対にPFKFB3遺伝子を過剰発現した細胞では、Aktシグナル伝達系が活性化することが報告されている(Trefely S.,et al.,J.Biol.Chem.,290,25834-25846(2015))。
27-ヒドロキシコレステロール(27HC)は血中に豊富に存在するコレステロールの代謝産物であり、動脈硬化の進展を促進し、血管における炎症を惹起する。体内の27HCは、シトクロームP450ファミリー7 サブファミリーBメンバー1(CYP7B1)によって異化される(Umetani M.et al.,Cell Metabolism,20,172-182(2014))。実際に、CYP7B1遺伝子をノックアウトしたマウスでは、野生型と比べると、血中および組織中の27HC濃度は4~5倍上昇する(Umetani M.,前掲)。本実施例では、セレノネイン含有魚エキスのCYP7B1遺伝子の発現量に及ぼす影響を検証した。実施例9と同じ方法で細胞およびサンプルを調整し、データを収集および解析した。セレノネイン含有魚エキスは、無添加(コントロール)と比べて、CYP7B1遺伝子の発現量を8倍以上に増やしたため、本発明のセレン含有組成物には脂質代謝異常改善効果があることが示された(表8)。
Claims (10)
- 請求項1~4のいずれか1項に記載の組成物を含む、酸化ストレス低減、酸化脂質抑制、虚血性疾患予防、メタボリックシンドローム改善、耐糖能異常改善、脂質代謝異常を含むメタボリックシンドロームに伴う障害の保護改善、発がん抑制、全身免疫能低下抑制、血管内皮障害抑制、動脈硬化抑制、認知症予防、脳機能改善、角膜上皮細胞保護、ドライアイ改善、または炎症抑制のための食品組成物。
- 請求項1~4のいずれか1項に記載の組成物を含む食品。
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