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WO2009005329A2 - Composition comprenant de l'amidon ou une fibre alimentaire provenant de graminées, destinée à la prévention et au traitement de maladies ischémiques et de maladies cérébrales dégénératives - Google Patents

Composition comprenant de l'amidon ou une fibre alimentaire provenant de graminées, destinée à la prévention et au traitement de maladies ischémiques et de maladies cérébrales dégénératives Download PDF

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Publication number
WO2009005329A2
WO2009005329A2 PCT/KR2008/003975 KR2008003975W WO2009005329A2 WO 2009005329 A2 WO2009005329 A2 WO 2009005329A2 KR 2008003975 W KR2008003975 W KR 2008003975W WO 2009005329 A2 WO2009005329 A2 WO 2009005329A2
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Prior art keywords
starch
ischemic
dietary fiber
diseases
total dietary
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PCT/KR2008/003975
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WO2009005329A3 (fr
Inventor
Jong Won Lee
Yae Sil Kim
Kyung Sik Song
Hyung Soo Han
Jung Hee Jang
Chae Ha Yang
Sun Ha Lim
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SUN MOK INSTITUTE EDUCATION FOUNDATION
Hypoxi Co Ltd
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SUN MOK INSTITUTE EDUCATION FOUNDATION
Hypoxi Co Ltd
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Priority claimed from KR1020080064291A external-priority patent/KR101121543B1/ko
Application filed by SUN MOK INSTITUTE EDUCATION FOUNDATION, Hypoxi Co Ltd filed Critical SUN MOK INSTITUTE EDUCATION FOUNDATION
Priority to US12/666,969 priority Critical patent/US8211483B2/en
Priority to JP2010514647A priority patent/JP5700243B2/ja
Publication of WO2009005329A2 publication Critical patent/WO2009005329A2/fr
Publication of WO2009005329A3 publication Critical patent/WO2009005329A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • the present invention relates to a composition comprising starch or total dietary fiber for preventing and treating ischemic diseases and degenerative brain diseases and the use thereof.
  • the present invention relates to a composition comprising at least one component selected from the group consisting of arabinoxylan, beta-glucan, arabinose and xylose for preventing and treating ischemic diseases and degenerative brain diseases.
  • Cerebral infarction and myocardial infarction are caused by necrosis of the surrounding tissues that is also caused by clogging of cerebral or coronary arteries by thrombus, which was already narrowed by various factors such as hypertension, hyperlipidemia, diabetes, or smoking etc.
  • Cardiovascular disease the leading cause of death worldwide each year, comprises approximately 30% of the total death, of which cerebral and myocardial infarction occupies 75%. Therefore, those two diseases and cancer are representative three diseases with the highest morbidity.
  • the methods to decrease the morbidity caused by myocardial infarction and cerebral infarction are classified into two groups: one is to prevent vascular occlusion by treating hypertension and hyperlipidemia, and the other is to reduce necrosis of surrounding tissues when vascular occlusion occurs.
  • the myocardiac injury can occur where the amount of oxygen required is more excessive than that of oxygen supplied by a pump- oxygenator, or subsequent cerebral injury can also occur by hypotension when a surgery is performed with cardiac arrest.
  • the heart failure caused by myocardial injury and the hemiplegia caused by brain damage may occur when the operations accompany with the occlusion of the part of blood vessels, for example, coronary artery bypass graft performed in case of the obstruction of coronary artery, and aneurysm surgery performed where the aneurysm occurs in cerebral arteries and aorta, etc.
  • apoptotic neuronal cell death is caused by decrease of ATP concentration and occurrence of edema, which occurs in case that transient ischemia following the blockage of oxygen and glucose supply to the brain is generated. It has been reported that apoptotic neuronal cell death in cerebral ischemia is induced by two mechanisms: one is excitatory neuronal cell death mechanism, whereby cerebral ischemia induces excessive accumulation of glutamate outside cells, influx of the glutamate into the cells, and excessive accumulation of calcium ion inside the cells (Kang TC et al . , J. Neurocytol .
  • minocycline a tetracycline antibiotic which inhibits apoptosis under ischemic condition
  • ischemic diseases such as cerebral infarction (Yrjanheikki J et al . , Proc. Natl. Acad. Sci. USA, 96(23), ppl3496-13500, 1999), myocardial infarction (Scarabelli TM et al . , J. Am. Coll. Cardiol., 43(5), pp865-874, 2004), ischemic acute renal failure (Wang J et al . , J. Biol.
  • neuronal cell apoptosis such as Alzheimer's disease (Hunter CL, Eur. J. Neurosci., 19(12), pp3305-3316, 2004), Parkinson's disease (Wu DC et al . , J. Neurosci., 22(5), ppl763-1771, 2002), amyotrophic lateral sclerosis (Zhu S et al., Nature, 417(6884), pp74-78, 2002), Huntington's disease (Chen. M. et al., Nat.
  • G418 inhibited apoptosis under ischemic conditions and showed efficacy in treating cerebral infarction as well. Based on these results, it has been expected that any samples showing the same cell survival effect under ischemic condition as that of G418 may have efficacy in treating ischemic diseases such as myocardial infarction, and also have efficacy in preventing and treating degenerative brain diseases that are caused by apoptosis.
  • the present inventors finally found that the crude extract of Gramineae plant, including Triticum aestivum L., improved cell viability under hypoxic conditions, and subsequently showed that the crude extract had efficacy in treating ischemic diseases such as cerebral and myocardial infarction, and degenerative brain diseases such as Alzheimer's disease, which was proven using ischemic and degenerative brain diseases animal models (Korea Patent Registration No. 10-0723950; and PCT/RR2006/000027).
  • ischemic diseases such as cerebral and myocardial infarction
  • degenerative brain diseases such as Alzheimer's disease
  • ⁇ ii> The seeds of representative plants belonging to family Gramineae have been reported to contain about 10% moisture, carbohydrate component including 50-60% starch (25% in case of barley), 10-20% protein, 2-8% lipid, and 10-20% total dietary fiber (40% in case of barley) including 1-3% soluble dietary fiber (9% in case of barley) (Ranhotra GS et al., Cereal Chemistry 68(5), pp556-558, 1991); or to contain 50-60% starch, 10-20% protein, 1-5% lipid, and 10-20% total dietary fiber (Grausgruber H et al . , In Genetic variation for plant breeding (Vollmann J et al. (Eds.)), pp23-26, Eucarpia & Boku, Vienna, 2004).
  • Arabinoxylan and beta-glucan are two major dietary fibers consisting of the cell wall of endosperm cell (Izydorczyk MS et al . , Carbohydrate Polymers, 28, pp33-48, 1995; Zekovic DB et al . , Crit. Rev. Biotech., 25, pp205-230, 2005), whereby the cell wall of wheat (Triticum aestivum L.) (Philippe S et al., Planta, 224(2), pp449-461, 2006) and rye (Secale cereale L.) (Vinkx CJA et al . , J.
  • Cereal Sci., 24, ppl-14, 1996) has been reported to contain more arabinoxylan than beta-glucan while that of oat (Avena sativa L.) (Miller SS et al., Cereal Chem. , 72(5), pp421-427, 1995) and barley (Hordeum vulgare L.) (Kanauchi M and Bamforth CW, Cereal Chem., 78(2), ppl21-124, 2001) has been reported to contain more beta-glucan than arabinoxylan.
  • arabinoxylan is composed of arabinose and xylose
  • beta-glucan is composed of glucose (Izydorczyk MS et al., Carbohydr. Polym., 28, pp33-48, 1995).
  • the cell wall also comprises compounds showing high antioxidative effect, i.e., ferulic acid participating in crosslinking arabinoxylan molecules (Adams EL et al., Carbohydr. Res., 340, ppl841-1845, 2005), coumaric acid, vanillic acid, p-OH benzoic acid and syringic acid etc (Zhou K et al . , J. Agric. Food Chem., 52, pp6108-6114, 2004; Clifford MN, J. Sci. Food Agric, 79, pp362- 372, 1999).
  • ferulic acid participating in crosslinking arabinoxylan molecules
  • coumaric acid vanillic acid
  • p-OH benzoic acid p-OH benzoic acid
  • syringic acid etc Zhou K et al . , J. Agric. Food Chem., 52, pp6108-6114, 2004; Clifford MN, J. Sci. Food Agric,
  • Starch a main reserve substance in the seed, root, stem, bulb, fruit etc of the green plants having abundant chlorophyll, is important as a carbohydrate source to higher animals. It is a colorless and odorless white powder having molecular weight ranging from 1,000,000 to 10,000,000, and having specific gravity of 1.65; exists as a granular form with different sizes and morphologies, depending on plants; and is a mixture of amylose and amylopectin with almost constant ratio in several kinds of starch, generally, 20-30% amylose and 70-80% amylopectin (Yoo et al . , Carbohydr. Polymers, 49, pp297-305, 2002). However, glutinous rice, waxy maize and etc., comprise little amylose and mainly amylopectin.
  • ⁇ i6> Accordingly, the inventors of the present invention have completed the present inventions by investigating and confirming that starch or total dietary fiber isolated from Gramineae plants improved cell survival under hypoxic conditions, as well as in the presence of beta-amyloid or 6- hydroxydopamine, and that the starch or total dietary fiber also had an efficacy in improving and treating the ischemic diseases and degenerative brain diseases, using animal disease models.
  • the object of the present invention is to provide a pharmaceutical composition comprising a starch or total dietary fiber, and the use thereof to prevent and treat ischemic diseases and degenerative brain diseases induced by apoptosis under ischemic condition.
  • ⁇ 20> Accordingly, it is an object of the present invention to provide a pharmaceutical composition comprising a starch or total dietary fiber as an active ingredient for the prevention and treatment of ischemic diseases and degenerative brain diseases.
  • ⁇ 2i> Also, it is an object of the present invention to provide a health care food comprising a starch or total dietary fiber as an active ingredient for the prevention and improvement of ischemic diseases and degenerative brain diseases.
  • the present invention also provides a use of starch or total dietary fiber for the manufacture of pharmaceutical composition to prevent and treat ischemic diseases and degenerative brain diseases caused by apoptosis in mammal or human in need thereof.
  • the present invention provides a method of preventing and treating ischemic diseases and degenerative brain diseases in a human or mammal suffering from ischemic diseases and degenerative brain diseases by administering an effective amount of starch or total dietary fiber, together with a pharmaceutically acceptable carriers or adjuvants thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one component selected from the group consisting of arabinoxylan, beta-glucan, arabinose and xylose as active ingredients for the prevention and treatment of ischemic diseases and degenerative brain diseases.
  • the present invention provides a health care food comprising at least one component selected from the group consisting of arabinoxylan, beta- glucan, arabinose and xylose as active ingredients for the prevention and treatment of ischemic diseases and degenerative brain diseases.
  • the present invention also provides a use of at least one component selected from the group consisting of arabinoxylan, beta-glucan, arabinose and xylose for the manufacture of pharmaceutical composition to prevent and treat ischemic diseases and degenerative brain diseases caused by apoptosis in a mammal or human in need thereof.
  • the present invention provides a method of preventing and treating ischemic diseases and degenerative brain diseases in a human or mammal suffering from ischemic diseases and degenerative brain diseases by administering an effective amount of at least one component selected from the group consisting of arabinoxylan, beta-glucan, arabinose and xylose, together with a pharmaceutically acceptable carriers or adjuvants thereof.
  • ischemic diseases comprises various ischemic diseases such as myocardial infarction, cerebral infarction, ischemic acute renal failure, ischemic acute hepatic failure, diabetic foot ulcer, diabetic nephropathy, and ischemic diseases resulting from the side effect of surgical operation or organ-tissue injury, preferably, myocardial infarction, cerebral infarction etc.
  • the ischemic disease resulting from the side effect of surgical operation comprises an ischemic heart failure, ischemic renal failure, ischemic hepatic failure or ischemic stroke, preferably, ischemic heart failure, ischemic stroke etc.
  • organ-tissue injury disclosed herein is the ischemia- reperfusion injury occurring when organ surgery or transplantation, or reconnection of parts of body severed by an accident is performed.
  • organ comprises internal organs, for example, kidney, liver, pancreas, lung, heart etc.
  • degenerative brain diseases comprises various degenerative brain diseases such as Alzheimer's disease, vascular dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease or spinal cord injury, preferably, Alzheimer's disease, vascular dementia, Parkinson's disease etc.
  • starch include various starch purified from Gramineae plants such as Triticum aestivum L., Tritici levis semen, Secale cereale L., Oryza sativa L. (rice), Horde ⁇ m vulgare var. hexastichon ASCH., malt, Avena sativa, Zea mays L., Sorghum bicolor MOENCH, Coix lacryma-jobi var. mayuen STAPF, Panicum miliaceum L. or Setaria italica Beauv. or potato, preferably, starch purified from Triticum aestivum L., Zea mays L., Hordeum vulgare var.
  • hexastichon ASCH. rice or potato, more preferably, starch purified from Triticum aestivum L., starch purified from Zea mays L., starch purified from rice or soluble starch purified from potato, furthermore preferably, starch purified from Triticum aestivum L., starch purified from Zea mays L., starch purified from rice or soluble starch purified from potato, all with the molecular weight ranging from 1,000,000 to 10,000,000.
  • total dietary fiber include total dietary fiber purified from Gramineae plants such as Triticum aestivum L., Tritici levis semen, Secale cereale L., Oryza sativa L., Hordeum vulgare var. hexastichon ASCH., malt, Avena sativa, Zea mays L., Sorghum bicolor MOENCH, Coix lacryma-jobi var. mayuen STAPF, Panicum miliace ⁇ m L., Setaria italica Beauv. or potato, preferably, total dietary fiber purified from Triticum aestivum L., Secale cereale L., Hordeum vulgare var.
  • hexastichon ASCH. Zea mays L. or Oryza sativa L., more preferably, total dietary fiber purified from Triticum aestivum L. consisting of arabinoxylan, beta-glucan and arabinogalactan with the ratio of 5 ⁇ 20: 1: 1-10 by relative weight%, furthermore preferably, total dietary fiber purified from Triticum aestivum L. consisting of arabinoxylan and beta-glucan with the molecular weight ranging from 50,000 to 400,000 dalton.
  • arabinose and xylose disclosed herein comprise both L- and D-form, preferably, the forms produced in nature, namely arabinose comprises L-form, and xylose comprises D-form.
  • inventive starch can be prepared in detail by the following procedures;
  • Gramineae plants preferably Triticum aestivum L., Tritici levis semen, Secale cereale L., brown rice, Hordeum vulgare var. hexastichon ASCH., malt, Avena sativa, Zea mays L., Sorghum bicolor MOENCH, Coix lacryma-jobi var. mayuen STAPF, Panicum miliaceum L.
  • Triticum aestivum L. to powder; mixing the powder with 10 to 100%, preferably, approximately 50 to 70% volume of distilled water to make dough; wrapping the dough with nylon bolting cloth, pressing the dough under running water for the starch to be eluted, and centrifuging the eluant to collect the precipitates; finally, purifying the inventive starch by suspending the precipitates in distilled water, and centrifuging altogether to collect the inventive starch of the present invention.
  • inventive total dietary fiber can be prepared in detail by the following procedures;
  • Triticum aestivum L. Tritici levis semen, Secale cereale L., brown rice, Hordeum vulgare var. hexastichon ASCH., malt, Avena sativa, Zea mays L., Sorghum bicolor MOENCH, Coix lacryma-jobi var. mayuen STAPF, Panicum miliaceum L. or Setaria italica Beauv, more preferably, Triticum aestivum L., brown rice or Zea mays L.
  • the present invention provides a pharmaceutical composition comprising the starch or total dietary fiber as an active ingredient prepared by the above-described preparation method for the prevention and treatment of ischemic and degenerative brain diseases.
  • the starch, total dietary fiber, arabinoxylan, beta-glucan, arabinose and xylose of the present invention can be obtained by the well-known isolation or purification method in the art or from commercial market or companies.
  • the inventive starch or total dietary fiber can be used safely for a long term because of almost no side effects and no toxicity.
  • composition comprising inventive starch or total dietary fiber can also comprise proper carriers, adjuvants and diluents, which are conventionally used in manufacturing the pharmaceutical composition.
  • the pharmaceutically acceptable carriers, adjuvants or diluents that can be included in the pharmaceutical composition containing the inventive starch or total dietary fiber are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrol idone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil.
  • the formulations may additionally include fillers, anti-agglutinating agents, lubricating agents, wetting agents, flavoring agents, emulsifiers, preservatives and the like.
  • the compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after their administration to a patient by employing any of the procedures well known in the art.
  • compositions of the present invention can be dissolved in oils, propylene glycol or other solvents that are commonly used to produce an injection.
  • suitable examples of the carriers include physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc., but are not limited to them.
  • the extract of the present invention can be formulated in the form of ointments and creams.
  • compositions containing present composition may be prepared in any form, such as oral dosage form (powder, tablet, capsule, soft capsule, aqueous medicine, syrup, elixir, pill, powder, sachet, granule), or topical preparation (cream, ointment, lotion, gel, balm, patch, paste, spray solution, aerosol and the like), or injectable preparation (solution, suspension, emulsion).
  • composition of the present invention in pharmaceutical dosage forms may be used in the form of their pharmaceutically acceptable salts, and also may be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.
  • the desirable dose of the inventive extract or composition varies depending on the condition and the weight of the subject, severity, drug form, route and period of administration, and may be chosen by those skilled in the art. However, in order to obtain desirable effects, it is generally recommended to administer at the amount ranging 10 mg/kg, preferably, 0.1 to 1000 mg/kg by weight/day of the inventive extract or composition of the present invention. The dose may be administered in single or divided into several times per day.
  • composition of present invention can be administered to a subject animal such as mammals (rat, mouse, domestic animals or human) via various routes. All modes of administration are contemplated, for example, administration can be made orally, rectal Iy or by intravenous, intramuscular, subcutaneous, intracutaneous, intrathecal, epidural or intracerebroventricular injection.
  • the present invention provides a health care food comprising the starch or total dietary fiber as an active ingredient for the prevention and improvement of ischemic diseases and degenerative brain diseases.
  • health care food means the manufactured and processed food containing the active ingredients or components showing useful functions to human health, whereby “functions to human health” means the beneficial effect or advantageous effect on human health through its physiological action or regulation on human according to the structure and function of human body.
  • the health care food of the present invention for the prevention and improvement of ischemic diseases and degenerative brain diseases comprises the above starch or total dietary fiber as 0.01 to 95% by weight, preferably 1 to 80% by weight based on the total weight of the composition.
  • pharmaceutically administrative form such as powder, granule, capsule, tablet, suspension, emulsion, syrup etc, or health care food such as health beverage etc for the prevention and improvement of ischemic diseases and degenerative brain diseases may be manufactured and processed.
  • the health beverage composition of the present invention contains the above-described ingredient as an essential component in the indicated ratio
  • the other component can be various deodorant or natural carbohydrate etc.
  • aforementioned natural carbohydrate are monosaccharide such as glucose, fructose etc; disaccharide such as maltose, sucrose etc; conventional sugar such as dextrin, cyclodextrin; and sugar alcohol such as xylitol, and erythritol etc.
  • natural deodorant such as taumatin, stevia extract such as levaudioside A, glycyrrhizin et al .
  • synthetic deodorant such as saccharin, aspartam et al .
  • the amount of the above-described natural carbohydrate generally ranges from about 1 to 20 g, preferably 5 to 12 g in 100 ml of the present beverage composition.
  • ⁇ 62> Other components than aforementioned components are various nutrients, a vitamin, a mineral or an electrolyte, synthetic flavoring agent, a coloring agent and improving agent in case of cheese chocolate et al . , pectic acid and the salt thereof, alginic acid and the salt thereof, organic acid, protective colloidal adhesive, pH controlling agent, stabilizer, a preservative, glycerin, alcohol, carbonizing agent used in carbonate beverage et al .
  • Other components beside the aforementioned ones may be fruit for preparing natural fruit juice, fruit juice beverage and vegetable beverage, wherein the components can be used independently or in combination.
  • the ratio of the components is not so important but has ranges generally from about 0 to 20 w/w% per 100 w/w% present composition.
  • the inventive starch and total dietary fiber can be added to food, additive or beverage for the prevention of ischemic diseases and degenerative brain diseases, wherein the amount of the above-described extract in food or beverage may generally range from about 0.01 to 15 w/w% of total weight of health care food, and from 0.02 to 5 g, preferably 0.3 to 1 g in 100 ml of the health beverage.
  • the starch or total dietary fiber of the present invention improved the cell viability when respective cells were cultured under hypoxic condition, or in the presence of beta-amyloid and 6-hydroxydopamine, as well as prevented and treated myocardiac infarction, cerebral infarction and vascular dementia, or alleviated memory loss, all of which were proven using rats as the repective animal models. Therefore, the starch or total dietary fiber of the present invention can be used as therapeutics or health care food for preventing and treating ischemic diseases or degenerative brain diseases.
  • Fig. 1 shows the analysis data of the sugar composition of the arabinoxylan and beta-glucan etc comprising inventive TDF; ⁇ 68> Fig.2a shows the improving effect of addition of various concentrations of the crude extract and inventive starch isolated from Gramineae plants
  • Fig. 2b shows the effect of addition of various concentrations of inventive TDF purified from the crude extract of Triticum aestivum L. on
  • Fig. 3a shows the improving effect of addition of various concentrations of the inventive starch purified from Triticum aestivum L. on
  • Fig. 3b shows the improving effect of addition of various concentrations of the soluble starch on SH-SY5Y cell viability cultured with various concentrations of beta-amyloid; ⁇ 72> Fig. 3c shows the improving effect of addition of various concentrations of the crude extract of Triticum aestivum L. (HY6228) and inventive starches purified from Gramineae plants (SC: corn; SR: rice; SS: soluble starch; SW: Triticum aestivum L.) on SH-SY5Y cell viability cultured with 25 microM of beta-amyloid; ⁇ 73> Fig.
  • FIG. 3d shows the improving effect of addition of various concentrations of the inventive total dietary fiber including ash component on SH-SY5Y cell viability cultured with 10 microM of beta-amyloid; ⁇ 74> Fig. 3e shows the improving effect of addition of arabinoxylan and beta-glucan comprising total dietary fiber, and arabinose and xylose comprising arabinoxylan on SH-SY5Y cell viability cultured with 15 microM of beta-amyloid; ⁇ 75> Fig. 4 shows the improving effect of addition of various concentrations of the crude extract of Triticum aestivum L. (HY6228) on SH-SY5Y cell viability cultured with 250 microM 6-hydroxydopamine; ⁇ 76> Fig.
  • Fig. 6 presents the inhibitory effect of the orally administered inventive starch purified from Triticum aestivum L. on the cerebral infarction in cerebral-infraction animal model; ⁇ 80> Fig. 7a presents the inhibitory effect of the orally administered inventive starch purified from Triticum aestivum L. on memory loss, measured by water-maze test in dementia-induced animal model; ⁇ 8i> Fig. 7b presents the inhibitory effect of the orally administered inventive TDF purified from Triticum aestivum L. on memory loss, measured by water-maze test in dementia-induced animal model; ⁇ 82> Fig.
  • Fig. 8a presents the inhibitory effect of the orally administered inventive crude extract (HY6228) on dementia, measured by water-maze test in vascular-dementia animal model; ⁇ 83> Fig. 8b presents the inhibitory effect of the orally administered inventive starch and TDF on dementia, measured by water-maze test in vascular-dementia animal model; ⁇ 84> Fig. 8c presents the inhibitory effect of the orally administered arabinoxylan on dementia, measured by water-maze test in vascular-dementia animal model .
  • HY6228 inventive crude extract
  • P-BGBM from barley, viscosity: 28 cSt, MW: 260,000 daltons
  • Xylose Catalog No. 95729: D(+) form, MW 150.13
  • Fluka Germany
  • Example 1 The preparation of crude extracts of the Gramineae plants ⁇ %> 100 g of Triticum aestivum L. purchased from the market was washed, mixed with 2 1 of water and extracted two times using oriental herb medicine electric brewing pot (Daewoong oriental herb medicine electric brewing pot DWP-2000, Daewoong). The solution was filtered and 2 1 of the filtered extract obtained was lyophilized to get 22 g of dried crude extract of Triticum aestivum L. (designated as "HY6228" hereinafter).
  • Example 2 The preparation of inventive total dietary fiber of the Gramineae plants ⁇ ioo> The total dietary fiber containing ash component has been isolated from the crude extract of Triticum aestivum L. prepared in Example 1 (HY6228) according to procedure disclosed in the literature (Lee S. C. et al . , J.
  • ⁇ ioi> 10 g of HY6228 prepared in Example 1 was poured in 500 ml bottle, and 400 ml of MES/TRIS buffer solution (each of 0.05 M, pH 8.0, 24°C) was added thereto. The solution was mixed thoroughly, and then 70 microliter of alpha- amylase (23 mg/ml Termamyl , 930 U/mg, 24"C) was added thereto to react at 80 °C for 35 mins in water bath. After the reaction, the solution was cooled to 60°C and 1000 microliter of protease (-350 U/ml Megazyme Cat. No. E-BSPRT) was added thereto to react at 60°C for 30 mins in water bath.
  • MES/TRIS buffer solution each of 0.05 M, pH 8.0, 24°C
  • the solution was adjusted to pH 4.3 with 3 M acetic acid and 2000 microliter of amyloglucosidase (3300 U/ml, Megazyme Cat. No. E-AMGDF) was added thereto to react at 60°C for 30 mins in water bath.
  • the solution was mixed with 1600 ml of 95% EtOH preheated to 60°C, and left at room temperature for 60 mins, without stirring.
  • the solution was centrifuged to collect the precipitate, and the precipitates were dried to obtain 2.3 g of total dietary fiber (TDF).
  • ⁇ iO5> 2 mg/ml of TDF was subjected to acid hydrolysis for 4 hours at 100°C with trifluoroacetic acid.
  • 10 microliter (total 0.2 microgram) of hydrolyzed solution was injected into CarboPacTMPAl column (HPAEC-PAD system, Dionex, USA), and eluted with 18 mM NaOH at the flow rate of 1.0 ml/min (Houben R et al., J. Cereal ScL, 26, pp37-46, 1997).
  • the amount of beta-glucan in TDF was determined using mixed-linkage beta-glucan assay procedure (McCleary method), for which mixed-linkage beta-glucan assay kit (Megazyme K-BGLU 04/06) was used.
  • McCleary method mixed-linkage beta-glucan assay kit
  • lichenase hydrolyzes beta- glucan partially, and then beta-glucosidase hydrolyzes the partially hydrolyzed beta-glucan completely to glucose.
  • the amount of glucose produced was determined by measuring absorbance at 510 nm after the glucose was reacted with glucose oxidase and peroxidase. From the experiment, the beta- glucan within the TDF was measured to be approximately 1.1% (w/w%).
  • Example 4 The preparation of inventive starch from the Gramineae plants.
  • HepG2 cells human hepatoma cell line, ATCC HB 8065, 2X10 5 cells/800 ⁇ i
  • EMEM Eagle's minimum essential medium; Invitrogen, USA
  • penicillin G sodium 100 Units/L, Invitrogen, USA
  • streptomycin sulfate 100 mg/L, Invitrogen, USA
  • 10% w/v fetal bovine serum
  • the media were changed with fresh medium, the media were added with various concentrations of inventive crude extract, starch and total dietary fiber dissolved in 100% DMSO to the final concentrations of crude extract, and starch: 100, 200, 400 and 800 microgram/ml ; TDF: 100 and 1000 microgram/ml as a test group, or with none as a negative control group.
  • the cells were further incubated under hypoxic condition (oxygen cone.: 1%) for another 2 days. Finally, the result of the MTT assay was obtained as shown in Fig.2a and 2b.
  • HY6228 at the concentration of 1000 microgram/ml showed strong improving effect of cell viability.
  • SH-SY5Y cells human neuroblastoma cell line, ATCC CRL-2266, 4X10* cells/300 microliter/well
  • SH-SY5Y cells human neuroblastoma cell line, ATCC CRL-2266, 4X10* cells/300 microliter/well
  • the cells were treated with beta-amyloid to the final concentrations of 0, 2.5, 7.5 and 25 microM for 24 hours in the absence (designated as A ⁇ 2 s-35 alone group hereinafter) or presence with inventive starch isolated from Triticum aestivum L. (final concentration: 125 microgram/ml ; designated as A 25-35 + SW group hereinafter) or soluble starch (final concentration: 125 microgram/m1 ; designated as A 25-35 + SS group hereinafter) which were made from 50 microgram/ml stock solutions in DMSO (See Fig. 3a & 3b). After incubation, cells were treated with MTT solution (final concentration of 1 mg/ml) for 2 hours. The dark blue formazan in viable cells was dissolved in DMSO and absorbance at 540 nm was measured by a microplate reader (FLUOstar OPTIMA, BMG LABTECH, GERMANY).
  • arabinoxylan AX; 500 microgram/ml
  • arabinose Ara; 250 microgram/ml
  • xylose XyI; 250 microgram/ml
  • beta-glucan b-glu; 20 microgram/ml
  • inventive starch and total dietary fiber of the present invention showed improving effect on cell viability by decreasing cytotoxicity caused by beta-amyloid, similarly to the crude extract of Triticum aestivum L. (HY6228). Accordingly, the inventive starch and total dietary fiber of the present invention can be useful in treating Alzheimer's disease occurring by the accumulation of beta- amyloid.
  • SH-SY5Y cells human neuroblastoma cell line, ATCC CRL-2266, 6X10 4 cells/300 microliter/well
  • SH-SY5Y cells human neuroblastoma cell line, ATCC CRL-2266, 6X10 4 cells/300 microliter/well
  • Dulbecco's modified Eagle Medium/F12 90% medium Invitrogen, USA
  • penicillin G sodium 100 Units/L, Invitrogen, USA
  • streptomycin sulfate 100 mg/L, Invitrogen, USA
  • 10% (w/v) fetal bovine serum Invitrogen, USA
  • ⁇ i39> SD rats prepared in Reference Example 1 were anesthetized with 10 mg/kg ketamine (Yuhan Corp., KOREA) and 5 mg/kg xylazine (Sigma, USA) and intubated endotracheal Iy.
  • the rats were connected to a respirator through a tracheotomy, and the heart was rapidly exteriorized through a left thoracotomy and pericardial incision.
  • the upper region of left coronary artery (LAD) was ligated by passing a 5-0 prolene thread under LAD and tightening polyethylene tubing 50 (PE 50), resulting in ischemia. After 30 min of ischemia, 3 hours of reperfusion followed, after the tightened PE 50 was loosened.
  • LAD left coronary artery
  • the PE 50 was tightened again to induce ischemia, and then 2 ml of 1% Evans blue dye solution was infused intravenously to circulate whole body. Then the heart was isolated, cut into the width of 2-3 mm after the right atrium and right ventricle of the heart were removed. Then the stained (LV-AAR) and unstained area (AAR) of cross sectioned tissue was measured by using image analysis system (Quantity One 4.2, Bio-Rad, USA) to calculate the area at risk (AAR/LV, %). Then, the tissue was stained with 1% TTC (2,3,5-triphenyltetrazolium chloride, Sigma, USA) at 37°C for 15 mins, fixed with 10% formalin solution. The infarcted area (IA/LV, %) was determined by measuring necrotic white area (IA) and total left ventricle area (LV). The ratio of IA to AAR of test samples and control group was compared to test efficacy.
  • TTC 2,3,5-triphenylte
  • ⁇ i4i> Three days before the induction of ischemia, 400 mg/kg/day of HY6228 or inventive starch, or 10 mg/kg/day of inventive total dietary fiber, or 10 mg/kg/day of its components, such as arabinoxylan, beta-glucan, arabinose and xylose, was fed with 20 g of food with free access. After induction of myocardial infarction with 3 hours of reperfusion, the infarcted area was measured, the value of IA (%AAR) was calculated, and then efficacy of the inventive starch and total dietary fiber was compared with each other.
  • ⁇ i48> The SD rats prepared in Reference Example 1 were anesthetized by inhalation using enflurane (Choongwae Pharm. Corp., KOREA). The neck of rats was incised, carotid artery was exposed, and carotid artery and the external carotid artery were ligated. And then 3-0 nylon thread was inserted into the internal carotid artery to occlude the middle cerebral artery (MCA), resulting in ischemia.
  • MCA middle cerebral artery
  • Ischemic index (%) A/B x 100
  • inventive starch and total dietary fiber prepared in Examples were orally administered to the rats prepared in Reference Example 1 for 12 consecutive days as test groups.
  • Physiological saline was treated as negative control group.
  • 0.5 mg/kg of scopolamine was started to be injected intraperitoneal Iy into the rats for another 5 days.
  • water-maze test was also performed everyday to measure degree of memory loss for another 5 days.
  • escape latency is the time(s) taken for the rats to find and escape onto the submerged platform, and, out of escape latencies measured, those that the rats stayed on the platform over 30 sec were counted effective.
  • “Mean escape latency” is the average time(s) of three trials per day per rat. Therefore, fifteen trials per rat was performed for the five day's period of water-maze test. The same cut-off time of 90 sec was set in a case that the mean escape latency exceeds over 90 sec.
  • ⁇ i6i> Before induction of dementia, 200 mg/kg of the inventive HY6228 prepared in Example 1 and the inventive starch prepared in Example 4, and 50 mg/kg of the inventive total dietary fiber prepared in Example 2 (Test group) or saline (Sham group) were administered orally. From the 8 day of administration of the inventive starch and the fiber, 0.5 mg/kg of scopolamine was started to be injected intraperitoneal Iy into the rats and water-maze test was also performed everyday, both for another 5 days.
  • HY6228 200 mg/kg
  • inventive starch SW; 200 mg/kg
  • TDF 50 mg/kg
  • arabinoxlyan 50 mg/kg
  • VD negative control
  • Powder preparation was prepared by mixing the above components and filling sealed package.
  • ⁇ i88> Tablet preparation was prepared by mixing the above components and entabletting.
  • Capsule preparation was prepared by mixing the above components and filling gelatin capsule by conventional gelatin preparation method.
  • Injection preparation was prepared by dissolving active component, controlling pH to about 7.5 and then filling all the components in 2 ml ample and sterilizing by conventional injection preparation method.
  • Liquid preparation was prepared by dissolving active component, filling all the components and sterilizing by conventional liquid preparation method.
  • Health beverage preparation was prepared by dissolving active component, mixing, stirred at 85 ° C for 1 hour, filtered and then filling all the components in 1000 ml ample and sterilizing by conventional health beverage preparation method.

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  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
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  • Medicinal Chemistry (AREA)
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Abstract

La présente invention concerne une composition comprenant de l'amidon ou une fibre alimentaire totale, qui améliore la viabilité des cellules. Plus particulièrement, l'amidon et la fibre alimentaire totale de l'invention, isolés de l'extrait de graminées et de ses composés, ont amélioré la viabilité des cellules lorsque celles-ci ont été incubées dans des conditions hypoxiques ou lors d'un traitement par la bêta-amyloïde et la 6-hydroxydopamine. Ils ont également empêché ou traité l'infarctus du myocarde, l'infarctus cérébral et la démence vasculaire, ou ont atténué la perte de mémoire, toutes ces expériences positives ayant été menées sur des rats servant de modèles animaux dans chaque cas. Ils peuvent par conséquent être utilisés comme médicaments thérapeutiques ou aliments diététiques pour prévenir et traiter des maladies ischémiques ou des maladies cérébrales dégénératives.
PCT/KR2008/003975 2007-07-04 2008-07-04 Composition comprenant de l'amidon ou une fibre alimentaire provenant de graminées, destinée à la prévention et au traitement de maladies ischémiques et de maladies cérébrales dégénératives Ceased WO2009005329A2 (fr)

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US12/666,969 US8211483B2 (en) 2007-07-04 2008-07-04 Composition comprising starch or dietary fiber from gramineae plant for prevention and treatment of ischemic diseases and degenerative brain disease
JP2010514647A JP5700243B2 (ja) 2007-07-04 2008-07-04 虚血性疾患および脳変性疾患の予防および治療のためのイネ科植物（Ｇｒａｍｉｎｅａｅｐｌａｎｔ）からのでんぷんまたは食物繊維を含む組成物

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KR20070066887 2007-07-04
KR10-2007-0066887 2007-07-04
KR1020080064291A KR101121543B1 (ko) 2007-07-04 2008-07-03 벼과식물로부터 수득되는 전분 또는 식이섬유를 포함하는허혈성 질환 및 퇴행성 뇌질환의 예방 및 치료를 위한조성물
KR10-2008-0064291 2008-07-03

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011057642A (ja) * 2009-09-14 2011-03-24 National Agriculture & Food Research Organization 神経突起伸展促進剤
US9649328B2 (en) 2012-04-23 2017-05-16 Generale Biscuit Association of beta-glucans and arabinoxylans
CN119097636A (zh) * 2023-06-07 2024-12-10 上海赛普瑞特生物科技有限公司 阿拉伯木聚糖的用途及其组合物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6797705B2 (en) * 2002-12-16 2004-09-28 Endomatrix, Inc. Rhamnan sulphate composition for treatment of endothelial dysfunction
KR100723950B1 (ko) * 2005-01-04 2007-05-31 주식회사 하이폭시 벼과 식물 추출물을 포함하는 허혈성 질환 및 퇴행성뇌질환의 예방 및 치료를 위한 조성물

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011057642A (ja) * 2009-09-14 2011-03-24 National Agriculture & Food Research Organization 神経突起伸展促進剤
US9649328B2 (en) 2012-04-23 2017-05-16 Generale Biscuit Association of beta-glucans and arabinoxylans
US10335429B2 (en) 2012-04-23 2019-07-02 Generale Biscuit Association of beta-glucans and arabinoxylans
CN119097636A (zh) * 2023-06-07 2024-12-10 上海赛普瑞特生物科技有限公司 阿拉伯木聚糖的用途及其组合物

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