WO2013162126A1 - Anti-inflammatory composition for the intestine comprising glutinous rice water-extracts - Google Patents

Anti-inflammatory composition for the intestine comprising glutinous rice water-extracts Download PDF

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WO2013162126A1
WO2013162126A1 PCT/KR2012/005993 KR2012005993W WO2013162126A1 WO 2013162126 A1 WO2013162126 A1 WO 2013162126A1 KR 2012005993 W KR2012005993 W KR 2012005993W WO 2013162126 A1 WO2013162126 A1 WO 2013162126A1
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Prior art keywords
glutinous rice
extract
rice water
water
precipitate
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PCT/KR2012/005993
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French (fr)
Inventor
Bong Whan Ahn
Young-Eun JOO
Sung Yeul Yang
Kee-oh CHAY
Dong-Up Song
Mi Sun Jang
Young-Lan PARK
Hyun-Joong Yoon
Hyun-Woo Kim
Eugene Kim
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Dasan M&F, Inc.
Industry Foundation Of Chonnam National University
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Publication of WO2013162126A1 publication Critical patent/WO2013162126A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/02—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of powders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine

Definitions

  • Anti-inflammatory composition for the intestine comprising glutinous rice water-extracts
  • the present invention relates to an anti-inflammatory composition for the intestine comprising the water-extract of glutinous rice as an effective ingredient.
  • the present inventors have reported that glutinous rice water-extract shows excellent effects in inhibiting the occurrence of the gastric ulcer and healing the occurred ulcer(Ahn et. al., Korean Patent No. 0208969, No. 0253740 and No. 10- 0627820). Furthermore, DongUiBoGam (Treasured Paragon of Eastern Medicine) mentions about the anti-diarrheal action of glutinous rice. However, no scientific research indicating that the glutinous rice can inhibit the inflammatory processes occurring in the intestine has been reported.
  • the present inventors have conducted a research to scientifically clarify that the glutinous rice has an anti-inflammatory effect on intestinal tissues, and to provide a composition with anti-inflammatory effects on the intestine comprising glutinous rice water-extract as a main ingredient.
  • the present inventors prepared a water-extract from glutinous rice powder and specific fractions therefrom, and examined their anti-inflammatory actions in cultured cells such as rat intestinal cells and mouse bone marrow-derived macrophages.
  • the inventors examined the anti-inflammatory effects of dietary glutinous rice water-extract in an animal model in which colitis was induced experimentally. As a result, the inventors have found that various forms of glutinous rice water extract show anti-inflammatory actions both in the above mentioned cells and animals, and accomplished this invention.
  • the present invention is related to an anti-inflammatory composition for the intestine comprising glutinous rice water-extract as an effective ingredient, and a process for producing the extract.
  • the glutinous rice water-extract is obtained by adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation.
  • the glutinous rice water-extract is a precipitate fraction of glutinous rice water-extract obtained by the steps of: a) adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation to obtain extract; b) standing the extract obtained by step a) at room temperature for 12-24 hours.
  • the glutinous rice water-extract is a precipitate fraction of glutinous rice water-extract obtained by the steps of: a) adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation to obtain extract; b) adding 0.1 - 1.0% by weight of citric acid, acetic acid or malic acid to the extract obtained by step a) to obtain a precipitate.
  • the glutinous rice water-extract is a solubilized subtraction of precipitate fraction of glutinous rice water- extract as a clear liquid obtained by the steps of: a) adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation to obtain extract; b) standing the extract obtained by step a) at room temperature to obtain a precipitate; c) suspending the precipatate obtained by step b) in distilled water of the same weight used in step a); d) incubating the mixture of step c) at 40-65 ° C for 1-24 hours; and, e) separating by centrifugation or filtration.
  • the glutinous rice water-extract is a solubilized subtraction of precipitate fraction of glutinous rice water- extract as a clear liquid obtained by the steps of: a) adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation to obtain extract; b) adding 0.1 - 1.0% by weight of citric acid, acetic acid or malic acid to the extract obtained by step a) to obtain a precipitate; c) suspending the precipitate obtained by step b) in distilled water of the same weight used in step a); d) incubating the mixture of step c) at 40-65 ° C for 1-24 hours; and, e) separating by centrifugation or filtration.
  • the present invention is related with the anti-inflammatory composition for the intestine comprising glutinous rice water-extract as an effective ingredient characterized in that the composition is formulated in a form for oral administration.
  • the present invention is related with a food composition comprising glutinous rice water-extract as an effective ingredient.
  • the anti-inflammatory composition for the intestine in accordance with the present invention can be formulated in the forms for oral administration.
  • Preferred forms for oral administration are liquids, tablets, capsules, and these forms may contain: binders such as gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch or glycine; lubricants such as polyethylene glycol or silica; disintegrating agents such as starch; conventional exipients containing wetting agent.
  • Tablets can be transformed to sugar coating tablets using pharmaceutical additives that are commonly used for controlling the decomposition and absorption in gastrointestinal tract, for example, protective agents, cordials and/or colorants such as sugar, cellulose or derivatives thereof, polyvinylpyrrolidone, food colorants, dying lacquers, aromatization agent or pigments.
  • pharmaceutical additives that are commonly used for controlling the decomposition and absorption in gastrointestinal tract, for example, protective agents, cordials and/or colorants such as sugar, cellulose or derivatives thereof, polyvinylpyrrolidone, food colorants, dying lacquers, aromatization agent or pigments.
  • beverage compositions in accordance with the present invention can be manufactured by adding and mixing 7-10% by weight of liquid fructose and 0.1-0.2% by weight of citric acid to the preparations according to the present invention.
  • sugar and glucose can be used instead of liquid fructose
  • acetic acid or malic acid can be used instead of citric acid, or mixtures thereof can be used.
  • 10-30% by weight of juices of apple, orange, pineapple, grape, grapefruit, or mixtures thereof can be added.
  • compositions of the present invention show excellent anti-inflammatory effects not only in the cultured intestinal cells and macrophages, but also in mice subjected to induction of colitis. And the compositions of the present invention can be used widely since they comprise glutinous rice water- extracts as an active ingredient which can be obtained by simple procedures from a very common and safe food material.
  • Fig. 1 shows that glutinous rice water-extract and the precipitate fraction of glutinous rice water-extract inhibit the LPS-induced activation of pro-inflammatory mediator NFKB in the rat intestinal epithelial (RIE) cells, while the liquid fraction of glutinous rice water-extract does not.
  • Fig. 2 shows that the solubilized subtraction of precipitate fraction of glutinous rice water-extract (here-in-after "solubilized subtraction of precipitate fraction”) inhibits the LPS-induced activation of NFKB in the rat intestinal epithelial (RIE) cells.
  • * p ⁇ 0.05, ** p ⁇ 0.01 significantly different in comparison with the LPS-treated control group (analyzed by ANOVA))
  • Fig. 3 shows that the solubilized subtraction of precipitate fraction inhibits the LPS-induced expression of pro-inflammatory mediator IL-12p40, IL-23pl9 and IL- ⁇ genes in RIE cells.
  • GRE means the solubilized subtraction of precipitate fraction of glutinous rice water-extract.
  • Fig. 4 shows that the solubilized subtraction of precipitate fraction inhibits the
  • GRE LPS-induced degradation of ⁇ in bone marrow-derived macrophages
  • Fig. 5 shows that the solubilized subtraction of precipitate fraction inhibits the LPS-induced DNA binding of NFi ⁇ B-p65 in bone marrow-derived macrophages (BMMs).
  • GRE means the solubilized subfraction of precipitate fraction of glutinous rice water-extract.
  • Fig. 6 shows that solubilized subfraction of precipitate fraction inhibits the LPS-induced expression of pro-inflammatory mediator TNF-a, IL-6, and MCP-1 genes in bone marrow-derived macrophages (BMMs).
  • GRE means the solubilized subfraction of precipitate fraction of glutinous rice water-extract.
  • Fig. 7 shows that dietary precipitate fraction of glutinous rice water-extract inhibits the decrease of colon length in mice with colitis induced by DSS.
  • GR means the precipitate fraction of glutinous rice water-extract.
  • Fig. 8 shows that dietary precipitate fraction of glutinous rice water-extract inhibits the increase of serum cytokine levels in mice with colitis induced by DSS.
  • Fig. 9 shows the structure of PNFKB-LUC.
  • Example 1 Preparation of glutinous rice water-extract Two hundred grams of glutinous rice powder were added to 5 times weight of distilled water and agitated vigorously for 30 sec. with a vortex mixer 3 times. After agitation, the mixture was centrifuged at l ,000xg for 10 min to obtain a supernatant. The protein concentration of the supernatant, as determined with a BCA kit (Pierce, USA), was 1.56mg/ml. The supernatant was diluted with distilled water to 1 mg/ml of protein concentration and the resulting preparation was used as a glutinous rice water- extract.
  • Example 2 Preparation of the precipitate and liquid fractions of glutinous rice water- extract
  • Example 2 Four hundred milliliters of glutinous rice water-extract prepared in Example 1 were stood at room temperature for 15hrs to form a precipitate and separated into a precipitate and a clear supernatant by centrifugation at 2,000*g for lOmin. The resultant precipitate was used as a precipitate fraction of glutinous rice water-extract, and the clear supernatant was used as a liquid fraction of glutinous rice water-extract. When applied to culture cells, the precipitate thus obtained was suspended in 400ml of distilled water before use.
  • Example 3 Preparation of the solubilized subtraction of precipitate fraction of glutinous rice water-extract
  • the precipitate fraction of glutinous rice water-extract prepared as in Example 2 was suspended in 400ml of distilled water and incubated at 55 ° C for 5hr with shaking, and then centrifuged at 2,000xg for lOmin to get a clear supernatant.
  • the resultant supernatant was used as a solubilized subfraction of precipitate fraction of glutinous rice water-extract (here-in-after "solubilized subfraction of precipitate fraction").
  • 200ml of the solubilized subfraction was freeze-dried to obtain 145mg of solid which was used in the cell experiments.
  • Example 4 Preparation of animal chow comprising precipitate fraction of glutinous rice water-extract
  • the precipitate fraction of glutinous rice water-extract prepared by treating lKg of glutinous rice powder as in Example 1 and 2 was freeze-dried to get about 10.4g powder.
  • Standard chows AIN-76 comprising the freeze-dried powder at 0.5 and 1.0% by weight, respectively, were prepared by a laboratory chow manufacturing company (Dae Han Biolink Co., Chungbuk, Korea).
  • NFKB is a typical pro-inflammatory transcription factor in the cell.
  • the pNFi B-Luc plasmid (Clontech, CA, USA, see Fig. 9) was transfected to the RIE cells which are a rat intestinal epithelial cell-derived cell line.
  • PNFKB-LUC has a structure in which the expression of luciferase gene, a reporter gene, is controlled by ⁇ 4 sequence which can react to NFKB activation.
  • the RIE cells were treated with lipopolysaccharide(LPS) to induce NFKB activation.
  • the RIE cells were pre- treated with the extracts before LPS treatment. More detailed procedures are as follows:
  • RIE cells 10 5 RIE cells were seeded in a 6-well plate and cultured for 1 day. Plasmid DNA of l ⁇ g was mixed with 3 ⁇ 1 Fugene HD (Roche, France) and transfected to the prepared cells. Next day, the cells in the 6-well plate were allocated and transferred to the 24-well plate, and cultured for 1 day. The cultured cells were pretreated with 0-100 ⁇ 1 or 0-2mg/ml (total reaction volume, 500 ⁇ 1) of glutinous rice water extracts for 30min, and l( ⁇ g/ml LPS (Sigma, MO, USA) was added to the cells to induce the activation of NFKB for 2 hrs.
  • 0-100 ⁇ 1 or 0-2mg/ml total reaction volume, 500 ⁇ 1
  • l( ⁇ g/ml LPS Sigma, MO, USA
  • the activity of luciferase was increased by LPS in the RIE cells that had been transfected with PNFKB-LUC.
  • the cells were pretreated with 0-100 ⁇ 1 glutinous rice water-extract, 0-100 ⁇ 1 precipitate fraction of glutinous rice water-extract, or 0-2mg/ml solubilized subtraction of precipitate fraction of glutinous rice water-extract, the LPS-induced increase in the luciferase activity was markedly suppressed, indicating that the above glutinous rice extracts inhibited the LPS-induced NFKB activation.
  • the glutinous rice extracts inhibited the LPS-induced NFKB activation in dose-dependent manners.
  • the liquid fraction of glutinous rice water-extract did not show any significant effect on LPS-induced activation of NFKB.
  • the first strand of cDNA was synthesized from ⁇ g RNA using MMLV reverse transcriptase (Invitrogen) and RNAsin (Takara, Shiga, Japan), and cDNAs were amplified using specific primers of respective genes and GO taq. Polymerase (Promega, WI, USA).
  • the sequences of the primers are as follows:
  • the gene expressions of the above pro-inflammatory mediators were induced by LPS in the RIE cells, and their expressions were inhibited to various extents by pre-treatment of the cells with the solubilized subtraction of precipitate fraction.
  • the macrophages used in this experiment are bone marrow-derived macrophages (BMMs), which were isolated from C57/B1/6 mice (Chambers TJ et. al., Proc Natl Acad Sci USA 1993, 90:5578-5582).
  • the amount of ⁇ was decreased by LPS treatment.
  • the decrease in the amount of ⁇ was completely inhibited, and the amount was even significantly more than the basal value before the LPS treatment.
  • NFKB On activation of NFKB, p65, the active subunit of NFKB, is transferred to necleus and binds to DNA.
  • BMM cells were pretreated for lhr with 10C ⁇ g/ml of solubilized subfraction of precipitate fraction and ⁇ BAY11- 7082 which is an inhibitor used for a positive control, and stimulated with 1 ⁇ g/ml of LPS for 30min. After the cells were separated, nuclear extract was prepared and binding of NFi B-p65 with DNA was measured by EMSA (Song Y-A et. al., BMC Complementary & Alternative Medicine 2011, 11:91-99).
  • the amount of NFKB-p65-DNA complex was increased by the LPS treatment, but the increase in the amount of NFKB-p65-DNA complex by LPS was completely inhibited by the pretreatment with solubilized subfraction of precipitate fraction or BAY 1 1-7082.
  • BMM cells were pretreated with 100 ⁇ g/ml of solubilized subfraction of precipitate fraction for lhr and stimulated with 1 ig/m ⁇ of LPS for 1 and 4hr. Then total RNA was extracted from the cells, and RT-PCR was performed using specific primers for the above pro-inflammatory mediator genes.
  • the sequences of the primers used are as follows:
  • Colitis was induced by adding 3% DSS(MP Biomedicals, Aurora, OH) to drinking water from the 4th chow feeding day. After 5 days of DSS treatment, the animals were sacrificed by cervical dislocation and carbon dioxide suffocation. Blood was collected by cardiac puncture and used for serum cytokine measurement. The concentration of serum IL-6 and TNF-a was measured using ELISA kits(BD Bioscience). And the entire colons were dissected and their lengths were measured.
  • the serum concentration of cytokines such as IL-6 and TNF-a increased markedly. If the mice had been fed on the chow comprising precipitate fraction of glutinous rice water- extract, the increase in the serum IL-6 and TNF-a levels due to DSS treatment was inhibited noticeably.
  • freeze-dried powder of the precipitate fraction of glutinous rice water- extract was prepared as in the pharmaceutical formulation Example 1.

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Abstract

The present invention relates to an anti-inflammatory composition for the intestine comprising water-extract of glutinous rice as an effective ingredient. The compositions of the present invention show excellent anti-inflammatory effects not only in the cultured intestinal cells and macrophages, but also in mice subjected to induction of colitis. And the compositions can be used widely since they comprise glutinous rice water-extracts as an active ingredient which can be obtained by simple procedures from a very common and safe food material.

Description

Anti-inflammatory composition for the intestine comprising glutinous rice water-extracts
Technical Field
The present invention relates to an anti-inflammatory composition for the intestine comprising the water-extract of glutinous rice as an effective ingredient.
Background Art
The present inventors have reported that glutinous rice water-extract shows excellent effects in inhibiting the occurrence of the gastric ulcer and healing the occurred ulcer(Ahn et. al., Korean Patent No. 0208969, No. 0253740 and No. 10- 0627820). Furthermore, DongUiBoGam (Treasured Paragon of Eastern Medicine) mentions about the anti-diarrheal action of glutinous rice. However, no scientific research indicating that the glutinous rice can inhibit the inflammatory processes occurring in the intestine has been reported.
Disclosure of the Invention
Technical problem
The present inventors have conducted a research to scientifically clarify that the glutinous rice has an anti-inflammatory effect on intestinal tissues, and to provide a composition with anti-inflammatory effects on the intestine comprising glutinous rice water-extract as a main ingredient.
To this end, the present inventors prepared a water-extract from glutinous rice powder and specific fractions therefrom, and examined their anti-inflammatory actions in cultured cells such as rat intestinal cells and mouse bone marrow-derived macrophages.
Also, the inventors examined the anti-inflammatory effects of dietary glutinous rice water-extract in an animal model in which colitis was induced experimentally. As a result, the inventors have found that various forms of glutinous rice water extract show anti-inflammatory actions both in the above mentioned cells and animals, and accomplished this invention.
Technical Solution
The present invention is related to an anti-inflammatory composition for the intestine comprising glutinous rice water-extract as an effective ingredient, and a process for producing the extract.
According to one embodiment of the present invention, the glutinous rice water-extract is obtained by adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation.
According to one embodiment of the present invention, the glutinous rice water-extract is a precipitate fraction of glutinous rice water-extract obtained by the steps of: a) adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation to obtain extract; b) standing the extract obtained by step a) at room temperature for 12-24 hours.
According to one embodiment of the present invention, the glutinous rice water-extract is a precipitate fraction of glutinous rice water-extract obtained by the steps of: a) adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation to obtain extract; b) adding 0.1 - 1.0% by weight of citric acid, acetic acid or malic acid to the extract obtained by step a) to obtain a precipitate.
According to one embodiment of the present invention, the glutinous rice water-extract is a solubilized subtraction of precipitate fraction of glutinous rice water- extract as a clear liquid obtained by the steps of: a) adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation to obtain extract; b) standing the extract obtained by step a) at room temperature to obtain a precipitate; c) suspending the precipatate obtained by step b) in distilled water of the same weight used in step a); d) incubating the mixture of step c) at 40-65 °C for 1-24 hours; and, e) separating by centrifugation or filtration.
According to one embodiment of the present invention, the glutinous rice water-extract is a solubilized subtraction of precipitate fraction of glutinous rice water- extract as a clear liquid obtained by the steps of: a) adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation to obtain extract; b) adding 0.1 - 1.0% by weight of citric acid, acetic acid or malic acid to the extract obtained by step a) to obtain a precipitate; c) suspending the precipitate obtained by step b) in distilled water of the same weight used in step a); d) incubating the mixture of step c) at 40-65 °C for 1-24 hours; and, e) separating by centrifugation or filtration.
Furthermore, the present invention is related with the anti-inflammatory composition for the intestine comprising glutinous rice water-extract as an effective ingredient characterized in that the composition is formulated in a form for oral administration.
Furthermore, the present invention is related with a food composition comprising glutinous rice water-extract as an effective ingredient.
The anti-inflammatory composition for the intestine in accordance with the present invention can be formulated in the forms for oral administration. Preferred forms for oral administration are liquids, tablets, capsules, and these forms may contain: binders such as gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch or glycine; lubricants such as polyethylene glycol or silica; disintegrating agents such as starch; conventional exipients containing wetting agent. Tablets can be transformed to sugar coating tablets using pharmaceutical additives that are commonly used for controlling the decomposition and absorption in gastrointestinal tract, for example, protective agents, cordials and/or colorants such as sugar, cellulose or derivatives thereof, polyvinylpyrrolidone, food colorants, dying lacquers, aromatization agent or pigments.
Furthermore, the beverage compositions in accordance with the present invention can be manufactured by adding and mixing 7-10% by weight of liquid fructose and 0.1-0.2% by weight of citric acid to the preparations according to the present invention.
And, sugar and glucose can be used instead of liquid fructose, acetic acid or malic acid can be used instead of citric acid, or mixtures thereof can be used. Furthermore, 10-30% by weight of juices of apple, orange, pineapple, grape, grapefruit, or mixtures thereof can be added.
Advantageous Effects
The compositions of the present invention show excellent anti-inflammatory effects not only in the cultured intestinal cells and macrophages, but also in mice subjected to induction of colitis. And the compositions of the present invention can be used widely since they comprise glutinous rice water- extracts as an active ingredient which can be obtained by simple procedures from a very common and safe food material.
Description of Drawings
Fig. 1 shows that glutinous rice water-extract and the precipitate fraction of glutinous rice water-extract inhibit the LPS-induced activation of pro-inflammatory mediator NFKB in the rat intestinal epithelial (RIE) cells, while the liquid fraction of glutinous rice water-extract does not. The shown values are mean+standard deviation (N=3). (*p<0.05, **p<0.01 : significantly different in comparison with the LPS-treated control group (analyzed by ANOVA))
Fig. 2 shows that the solubilized subtraction of precipitate fraction of glutinous rice water-extract (here-in-after "solubilized subtraction of precipitate fraction") inhibits the LPS-induced activation of NFKB in the rat intestinal epithelial (RIE) cells. The shown values are mean+standard deviation (N=3). (*p<0.05, **p<0.01 : significantly different in comparison with the LPS-treated control group (analyzed by ANOVA))
Fig. 3 shows that the solubilized subtraction of precipitate fraction inhibits the LPS-induced expression of pro-inflammatory mediator IL-12p40, IL-23pl9 and IL-Ιβ genes in RIE cells. GRE means the solubilized subtraction of precipitate fraction of glutinous rice water-extract.
Fig. 4 shows that the solubilized subtraction of precipitate fraction inhibits the
LPS-induced degradation of ΙκΒα in bone marrow-derived macrophages (BMMs). GRE means the solubilized subtraction of precipitate fraction of glutinous rice water-extract.
Fig. 5 shows that the solubilized subtraction of precipitate fraction inhibits the LPS-induced DNA binding of NFi<B-p65 in bone marrow-derived macrophages (BMMs). GRE means the solubilized subfraction of precipitate fraction of glutinous rice water-extract.
Fig. 6 shows that solubilized subfraction of precipitate fraction inhibits the LPS-induced expression of pro-inflammatory mediator TNF-a, IL-6, and MCP-1 genes in bone marrow-derived macrophages (BMMs). GRE means the solubilized subfraction of precipitate fraction of glutinous rice water-extract.
Fig. 7 shows that dietary precipitate fraction of glutinous rice water-extract inhibits the decrease of colon length in mice with colitis induced by DSS. GR means the precipitate fraction of glutinous rice water-extract. The shown values are mean+standard deviation (N=6). (*p<0.05: significantly different in comparison with the DSS-treated control group (analyzed by ANOVA)).
Fig. 8 shows that dietary precipitate fraction of glutinous rice water-extract inhibits the increase of serum cytokine levels in mice with colitis induced by DSS. The shown values are mean+standard deviation (N=6). (*p<0.05: significantly different in comparison with the DSS-treated control group (analyzed by ANOVA)).
Fig. 9 shows the structure of PNFKB-LUC.
Best mode for the invention
Hereinafter, the present invention will be described in detail with reference to the following examples and experiments, which are intended only to exemplify the present invention, and the scope of the present invention is not limited thereto.
Example 1 : Preparation of glutinous rice water-extract Two hundred grams of glutinous rice powder were added to 5 times weight of distilled water and agitated vigorously for 30 sec. with a vortex mixer 3 times. After agitation, the mixture was centrifuged at l ,000xg for 10 min to obtain a supernatant. The protein concentration of the supernatant, as determined with a BCA kit (Pierce, USA), was 1.56mg/ml. The supernatant was diluted with distilled water to 1 mg/ml of protein concentration and the resulting preparation was used as a glutinous rice water- extract. Example 2: Preparation of the precipitate and liquid fractions of glutinous rice water- extract
Four hundred milliliters of glutinous rice water-extract prepared in Example 1 were stood at room temperature for 15hrs to form a precipitate and separated into a precipitate and a clear supernatant by centrifugation at 2,000*g for lOmin. The resultant precipitate was used as a precipitate fraction of glutinous rice water-extract, and the clear supernatant was used as a liquid fraction of glutinous rice water-extract. When applied to culture cells, the precipitate thus obtained was suspended in 400ml of distilled water before use.
Example 3 : Preparation of the solubilized subtraction of precipitate fraction of glutinous rice water-extract The precipitate fraction of glutinous rice water-extract prepared as in Example 2 was suspended in 400ml of distilled water and incubated at 55 °C for 5hr with shaking, and then centrifuged at 2,000xg for lOmin to get a clear supernatant. The resultant supernatant was used as a solubilized subfraction of precipitate fraction of glutinous rice water-extract (here-in-after "solubilized subfraction of precipitate fraction"). And 200ml of the solubilized subfraction was freeze-dried to obtain 145mg of solid which was used in the cell experiments.
Example 4: Preparation of animal chow comprising precipitate fraction of glutinous rice water-extract
The precipitate fraction of glutinous rice water-extract prepared by treating lKg of glutinous rice powder as in Example 1 and 2 was freeze-dried to get about 10.4g powder. Standard chows AIN-76 comprising the freeze-dried powder at 0.5 and 1.0% by weight, respectively, were prepared by a laboratory chow manufacturing company (Dae Han Biolink Co., Chungbuk, Korea).
Experiment 1 : Anti-inflammatory action of glutinous rice water extract in rat intestinal epithelial (RIE) cells
1 ) Inhibition of LPS-induced activation of NFKB
(1) Measurement using pNFi B-Luc plasmid
NFKB is a typical pro-inflammatory transcription factor in the cell. In this experiment, first, the pNFi B-Luc plasmid (Clontech, CA, USA, see Fig. 9) was transfected to the RIE cells which are a rat intestinal epithelial cell-derived cell line. PNFKB-LUC has a structure in which the expression of luciferase gene, a reporter gene, is controlled by κΒ4 sequence which can react to NFKB activation. After transfection, the RIE cells were treated with lipopolysaccharide(LPS) to induce NFKB activation. And to examine the anti-inflammatory effects of glutinous rice water-extracts, the RIE cells were pre- treated with the extracts before LPS treatment. More detailed procedures are as follows:
First, 105 RIE cells were seeded in a 6-well plate and cultured for 1 day. Plasmid DNA of l^g was mixed with 3μ1 Fugene HD (Roche, France) and transfected to the prepared cells. Next day, the cells in the 6-well plate were allocated and transferred to the 24-well plate, and cultured for 1 day. The cultured cells were pretreated with 0-100μ1 or 0-2mg/ml (total reaction volume, 500μ1) of glutinous rice water extracts for 30min, and l(^g/ml LPS (Sigma, MO, USA) was added to the cells to induce the activation of NFKB for 2 hrs.
The LPS-treated cells were washed with PBS and measured for the luciferase activity using the assay system of Promega(WI, USA) according to the manufacturer's instruction. (2) Effect of glutinous rice water extract on LPS-induced activation of NFKB
As shown in Fig. 1 and 2, the activity of luciferase was increased by LPS in the RIE cells that had been transfected with PNFKB-LUC. When the cells were pretreated with 0-100μ1 glutinous rice water-extract, 0-100μ1 precipitate fraction of glutinous rice water-extract, or 0-2mg/ml solubilized subtraction of precipitate fraction of glutinous rice water-extract, the LPS-induced increase in the luciferase activity was markedly suppressed, indicating that the above glutinous rice extracts inhibited the LPS-induced NFKB activation. The glutinous rice extracts inhibited the LPS-induced NFKB activation in dose-dependent manners. However, the liquid fraction of glutinous rice water-extract did not show any significant effect on LPS-induced activation of NFKB.
2) Inhibition of LPS-induced expression of other pro-inflammatory mediators
(1) Determination of IL-12p40 and IL-23pl9 and IL-Ιβ gene expression using RT-PCR The RIE cells were pretreated with 10C^g/ml of solubilized subtraction of precipitate fraction for lhr and stimulated with IC^g/ml LPS for 1 and 4hr. Then total RNA was extracted from the cells by using TRIzol reagent (Invitrogen, CA, USA), and the quantity and purity of the RNA were measured using a Nanodrop reader. The first strand of cDNA was synthesized from ^g RNA using MMLV reverse transcriptase (Invitrogen) and RNAsin (Takara, Shiga, Japan), and cDNAs were amplified using specific primers of respective genes and GO taq. Polymerase (Promega, WI, USA). The sequences of the primers are as follows:
Table 1
Figure imgf000012_0001
(2) Inhibition of IL-12p40, IL-23pl9 and IL-Ιβ gene expression by glutinous rice water- extract
As shown in Fig. 3, the gene expressions of the above pro-inflammatory mediators were induced by LPS in the RIE cells, and their expressions were inhibited to various extents by pre-treatment of the cells with the solubilized subtraction of precipitate fraction.
In case of IL-Ιβ, the expression was completely inhibited for 4hr. And the expressions of IL-12p40 and IL-23pl9 were inhibited markedly at the initial stage, and then recovered gradually thereafter.
The above results indicate that the glutinous rice water-extract can inhibit not only the activation of NFKB, but also the expression of IL-12p40, IL-23pl9, and IL-Ιβ in the RIE cells. Experiment 2: Anti-inflammatory action of glutinous rice water-extract in macrophages
Since macrophages can participate in inflammatory processes in many tissues including the intestine, the effect of glutinous rice water-extract on the inflammatory reaction of macrophages was examined in this experiment.
The macrophages used in this experiment are bone marrow-derived macrophages (BMMs), which were isolated from C57/B1/6 mice (Chambers TJ et. al., Proc Natl Acad Sci USA 1993, 90:5578-5582).
1) Inhibition of LPS-induced activation of NFKB (1) The effect on ΙκΒα degradation
The degradation of ΙκΒα, the inhibitory subunit of NFKB, is required for the activation of NFKB. Therefore, in this experiment, the effect of solubilized subfraction of precipitate fraction on the degradation of ΙκΒα induced by LPS in the BMM cells was examined. To this end, BMM cells were pretreated with 10(^g/ml of solubilized subfraction of precipitate fraction for 1 hr, and then stimulated with ^g/ml LPS for 30min. After the cells were separated and lysed, the quantity of ΙκΒα was measured by western blotting(Song Y-A et. al., BMC Complementary & Alternative Medicine 2011, 11:91-99).
As shown in Fig. 4, the amount of ΙκΒα was decreased by LPS treatment. When the cells had been pretreated with solubilized subfraction of precipitate fraction, the decrease in the amount of ΙκΒα was completely inhibited, and the amount was even significantly more than the basal value before the LPS treatment.
(2) The effect on DNA binding of NFi<B-p65
On activation of NFKB, p65, the active subunit of NFKB, is transferred to necleus and binds to DNA. In this experiment, BMM cells were pretreated for lhr with 10C^g/ml of solubilized subfraction of precipitate fraction and ΙΟμΜ BAY11- 7082 which is an inhibitor used for a positive control, and stimulated with 1 μg/ml of LPS for 30min. After the cells were separated, nuclear extract was prepared and binding of NFi B-p65 with DNA was measured by EMSA (Song Y-A et. al., BMC Complementary & Alternative Medicine 2011, 11:91-99).
As shown in Fig. 5, the amount of NFKB-p65-DNA complex was increased by the LPS treatment, but the increase in the amount of NFKB-p65-DNA complex by LPS was completely inhibited by the pretreatment with solubilized subfraction of precipitate fraction or BAY 1 1-7082.
The results of Fig. 4 and 5 indicate that the activation of NFKB in BMM cells was powerfully inhibited by solubilized subfraction of precipitate fraction.
2) Inhibition of LPS-induced expression of TNF-a, IL-6, and MCP-1
As in RIE cells, the effect of solubilized subfraction of precipitate fraction on LPS-induced TNF-a, IL-6, and MCP-1 gene expressions in BMM cells was investigated by RT-PCT.
To this end, BMM cells were pretreated with 100 μg/ml of solubilized subfraction of precipitate fraction for lhr and stimulated with 1 ig/m\ of LPS for 1 and 4hr. Then total RNA was extracted from the cells, and RT-PCR was performed using specific primers for the above pro-inflammatory mediator genes. The sequences of the primers used are as follows:
Table 2
Gene Sequence of PCR Primers
TNF-a Forward 5'- GCA CAG AAA GCA TGA TCC GCG -3'
TNF-a Reverse 5'- GGA GCA CGT AGT CGG GGC AG -3'
IL-6 Forward 5'- GGA TAC CAC CCA CAA CAG ACC-3'
IL-6 Reverse 5'- GGT CCT TAG CCA CTC CTT CTG -3'
MCP-1 Forward 5'- CTG TCA TGC TTC TGG GCC TG-3'
MCP-1 Reverse 5'- GAA GAC CTT AGG GCA GAT GCA G -3' As shown in Fig. 6, LPS induced the expression of TNF-a, IL-6, and MCP-1 in the BMM cells to various extents, and the solubilized subfraction of precipitate fraction inhibited almost completely the LPS-induced expressions of pro- inflammatory mediators.
The above results indicate that the solubilized subfraction of precipitate fractions can inhibit not only the activation of NFKB but also the expression of other pro-inflammatory mediators in the BMM cells. Experiment 3: Inhibitory effect of dietary glutinous rice water-extract on dextran sulfate sodium(DSS)-induced colitis in mice
1) Induction of colitis by DSS Mice(C57BL/6NCRjOri SPF/VAF) weighing 20+ lg were used for the experiment and allowed free access to water and chow in a specific pathogen free (SPF) environment. Animals (6 mice in each group) were fed on AIN-76 chow comprising precipitate fraction of glutinous rice water-extract in 0.5% and 1.0%, respectively as prepared in the Example 4. And the AIN-76 chow that does not comprise the precipitate fraction of glutinous rice extract was given for the control group. There was no significant difference in the consumption of chow and drinking water between the experimental groups. Colitis was induced by adding 3% DSS(MP Biomedicals, Aurora, OH) to drinking water from the 4th chow feeding day. After 5 days of DSS treatment, the animals were sacrificed by cervical dislocation and carbon dioxide suffocation. Blood was collected by cardiac puncture and used for serum cytokine measurement. The concentration of serum IL-6 and TNF-a was measured using ELISA kits(BD Bioscience). And the entire colons were dissected and their lengths were measured.
2) Effect of dietary precipitate fraction of glutinous rice water-extract on DSS- induced decrease in the length of colon.
On induction of colitis by DSS in mice, the length of colon decreases (Song Y-A et. al., BMC Complementary & Alternative Medicine 2011, 11:91-99). However, as shown in Fig. 7, if the mice had been fed on the chow comprising the precipitate fraction of glutinous rice water-extract, decrease in colon length due to the DSS treatment was inhibited partially.
3) Effect of dietary precipitate fraction of glutinous rice water-extract on DSS- induced increase in the serum cytokine level.
As shown in Fig. 8, on DSS treatment of mice, the serum concentration of cytokines such as IL-6 and TNF-a increased markedly. If the mice had been fed on the chow comprising precipitate fraction of glutinous rice water- extract, the increase in the serum IL-6 and TNF-a levels due to DSS treatment was inhibited noticeably.
Taken together, the above results indicate that the glutinous rice water-extracts show an anti-inflammatory action not only in the cultured cells such as intestinal cells and macrophages but also in animals with experimental colitis. Pharmaceutical formulation Example 1 : Tablets
Twenty-five grams of glutinous rice powder were processed as in the Examples 1 and 2. The resultant precipitate fraction of glutinous rice water-extract was freeze-dried giving about 250mg powder. Tablets comprising the freeze-dried powder as its major ingredient were prepared by the conventional tablet manufacturing processes.
Table 3
Figure imgf000018_0001
Pharmaceutical formulation Example 2: Capsules
After the following ingredients had been mixed thoroughly, hard gelatin capsules were filled with the mixtures to obtain capsules containing 250mg freeze- dried powder of the precipitate fraction of glutinous rice water-extract. In this example, freeze-dried powder of the precipitate fraction of glutinous rice water- extract was prepared as in the pharmaceutical formulation Example 1.
Table 4
Figure imgf000018_0002
Pharmaceutical preparation Example 3: Beverages
Twenty-five grams of glutinous rice powder were processed as in the Example 1. The resultant glutinous rice water-extract was mixed with 7-10% by weight of liquid fructose and 0.1-0.2% by weight of citric acid to prepare 140ml of mixed beverage.
Pharmaceutical preparation Example 4: Beverages
Twenty- five grams of glutinous rice powder were processed as in the Example 3. The resultant clear solution was mixed with 7-10% by weight of liquid fructose and 0.1-0.2% by weight of citric acid to prepare 140ml of mixed beverage.

Claims

1. An anti-inflammatory composition for the intestine comprising glutinous rice water-extract as an effective ingredient.
2. The anti-inflammatory composition for the intestine according to claim 1 , characterized in that the glutinous rice water-extract is obtained by adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation. v
3. The anti-inflammatory composition for the intestine according to claim 1 , characterized in that the glutinous rice water-extract is a precipitate fraction of glutinous rice water-extract obtained by the steps of:
a) adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation to obtain extract; and
b) standing the extract obtained by step a) at room temperature for 12-24 hours.
4. The anti-inflammatory composition for the intestine according to claim 1 , characterized in that the glutinous rice water-extract is a precipitate fraction of glutinous rice water-extract obtained by the steps of:
a) adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation to obtain extract; and
b) adding 0.1 - 1.0% by weight of citric acid, acetic acid or malic acid to the extract obtained by step a) to obtain a precipitate. ,
5. The anti-inflammatory composition for the intestine according to claim 1, characterized in that the glutinous rice water-extract is a solubilized subfraction of precipitate fraction of glutinous rice water-extract as a clear liquid obtained by the steps of:
a) adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation to obtain extract;
b) standing the extract obtained by step a) at room temperature to obtain a precipitate;
c) suspending the precipatate obtained by step b) in distilled water of the same weight used in step a);
d) incubating the mixture of step c) at 40-65 °C for 1-24 hours; and,
e) separating by centrifugation or filtration.
6. The anti-inflammatory composition for the intestine according to claim 1 , characterized in that the glutinous rice water-extract is a solublized subfraction of precipitate fraction of glutinous rice water-extract as a clear liquid obtained by the steps of:
a) adding 2-20 times weight of distilled water to glutinous rice powder, mixing and centrifugation to obtain extract;
b) adding 0.1 - 1.0% by weight of citric acid, acetic acid or malic acid to the extract obtained by step a) to obtain a precipitate;
c) suspending the precipitate obtained by step b) in distilled water of the same weight used in step a);
d) incubating the mixture of step c) at 40-65 °C for 1 -24 hours; and, e) separating by centrifugation or filtration.
7. The anti-inflammatory composition for the intestine according to claim 1, characterized in that the composition is formulated in a form for the oral administration.
8. A food composition comprising glutinous rice water-extract of claim 1 as an effective ingredient.
PCT/KR2012/005993 2012-04-24 2012-07-27 Anti-inflammatory composition for the intestine comprising glutinous rice water-extracts WO2013162126A1 (en)

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