WO2005042508A1 - 植物由来β3アドレナリン受容体作動性物質およびその利用 - Google Patents
植物由来β3アドレナリン受容体作動性物質およびその利用 Download PDFInfo
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- WO2005042508A1 WO2005042508A1 PCT/JP2004/016330 JP2004016330W WO2005042508A1 WO 2005042508 A1 WO2005042508 A1 WO 2005042508A1 JP 2004016330 W JP2004016330 W JP 2004016330W WO 2005042508 A1 WO2005042508 A1 WO 2005042508A1
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- quercetin
- leaf extract
- lotus leaf
- fat
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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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/62—Nymphaeaceae (Water-lily family)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
Definitions
- Plant-derived adrenergic receptor agonist and use thereof
- the present invention relates to a novel adrenergic ⁇ agonist prepared with lotus leaf strength.
- Obesity is a condition in which excess triglycerides are accumulated in fat cells.
- Fat cells have white and brown fats.
- White fat cells are relatively large cells that are widely distributed throughout the body, such as under the skin and around the visceral organs. Most of the cell body is occupied by huge lipid droplets.
- brown adipocytes are located only in the interscapular area, axillary area, etc., and the fat has a multilocular structure in which many small droplets are separated, and a large number of mitochondria are present close to it. I do.
- Physiological functions of white fat and brown fat are greatly different, and white fat is a place for storing excess energy, whereas brown fat is a place for releasing energy as heat by oxidative decomposition of fat.
- Fat accumulated in white cells is decomposed into fatty acids in an energy-deficient state, released into the blood and consumed throughout the body, but when brown fat is decomposed into fatty acids by stimulation, it is immediately stored in brown fat cells. It is oxidized to heat (non-patent literature lZSaito M., Sasaki N. Experimental Medicine Vol. 14 NO. 16, 1996).
- Receptors are divided into j8, ⁇ , and 13 subtypes. In each case, from about 400 amino acids
- Amino acid homology with force ⁇ , ⁇ , a seven-pass receptor is only about 50%
- Receptor is present mainly in the heart, etc.
- 2 Receptor is mainly present in bronchial smooth muscle, etc.
- Receptors are mainly found in adipose tissue, and also in tissues such as the intestinal tract and brain.
- j8 Adrenergic receptor agonists (agonists) accumulate cAMP in adipocytes
- Beta-adrenergic receptor agonists induce lipolysis in white adipocytes
- anti-obesity drugs that are being developed as anti-diabetic drugs.
- lotus which is a perennial plant of the Lotus family, is widely used for herbal medicine prescriptions and health foods in addition to its roots being used for food, as well as seeds and leaves.
- lotus leaves are known to have an obesity-improving effect (Patent Document 1Z, JP-A-8-198769), there has been no detailed report on an active ingredient exhibiting the obesity effect of lotus or its action.
- Patent document 1 JP-A-8-198769
- Non-patent literature l Saito M., Sasaki N. Experimental Medicine Vol.14 NO.16, 1996
- Non-Patent Document 2 History of Medicine Vol.192 N0.5 2001.1.29
- Non-Patent Document 3 J Clin Invest. 1996 Jun 15; 97 (12): 2898-904., Life
- Non-patent document 4 Biochemical Pharmacology, Vol. 47, No. 3, pp521-529
- the present invention has been made in view of such a situation, and the purpose thereof is firstly to clarify the active ingredient of a plant of the family Rosaceae, and secondly, to identify this active ingredient.
- the inventors of the present invention to achieve the above object have produced lotus leaf extracts, and have conducted intensive research to find an effective ingredient for improving obesity. As a result, one of the effective ingredients was found. Quercetin was found. Although quercetin is one of the flavonoids widely present in plants, the present inventors have newly revealed that quercetin is contained in lotus. Previous findings on quercetin indicate that quercetin acted on rat adipocytes, resulting in the accumulation of cAMP, suggesting that quercetin has rat / 3 adrenergic receptor agonist activity ( Biochemical Pharmacology, Vol.47, No.3, pp521-529), and its activity against human j8 adrenergic receptor (j83AR).
- quercetin be converted to human
- the quercetin acted as a ⁇ -adrenergic receptor agonist to improve obesity and anti-diabetic activity.
- the present inventors administered a lotus leaf extract containing quercetin to a human subject with borderline human diabetes, and actually confirmed the body fat reducing effect on humans. In other words, they have found that the formulation of a lotus leaf preparation makes it possible to develop pharmaceuticals and foods that are effective in improving obesity and diabetes, thereby completing the present invention.
- the present invention relates to a novel ⁇ -adrenergic receptor agonist which also controls lotus leaf power.
- the present invention relates to the following invention.
- Quercetin 13 is an adrenergic receptor agonist.
- quercetin is derived from a plant.
- An agent for treating or preventing diabetes comprising the substance described in (1) to (3).
- a medicament for treating or preventing obesity comprising the substance according to (1) to (3) and having an effect of improving fat metabolism.
- composition for treating or preventing diabetes comprising the substance described in (1) to (3) above.
- a diet for treating or preventing obesity comprising the substance described in (1) to (3) above.
- FIG. 7 is a diagram showing the results of a glucose tolerance test of a lotus leaf extract administration group (human) and a control group (human).
- the blood glucose level after each elapsed time with respect to the blood glucose level before glucose load was defined as a relative glucose value ( 0/0 ).
- the present invention provides a 13-adrenergic receptor agonist comprising quercetin. Departure
- quercetin was contained as an active ingredient in the lotus leaf extract, as described above, and further found that this quercetin had j8 adrenergic receptor agonistic activity.
- Quercetin is formally known as 3,3 ', 4', 5,7-pentahydroxyflavone (
- 3,3 ', 4', 5,7-pentahydoroxyflavone a CAS number 117-39-5
- flavonols widely present in the plant world. Its properties include fine yellow needles, melting point 316-317 ° C, and two molecules of water of crystallization. Insoluble in cold water, slightly soluble in boiling water, easily soluble in hot alcohol 'glacial acetic acid, poorly soluble in cold alcohol' ether. Many glycosides are found due to the binding of various sugars at position 3, 7 or both, and quercetin is mainly glycoside in plants (Dictionary of Biochemistry (3rd edition) Tokyo Chemical Doujinshi, Dictionary of Chemical Chemistry Tokyo Chemical Dojin). As described above, quercetin generally refers to an unglycosylated state (aglycone), but “quercetin” in the present specification functions as a 13-adrenergic receptor agonist.
- quercetin glycoside examples include quercetin 3-dalcuronide, quercetin 3-darcoside (isoquercitrin), quercitrin, quersimeritrin and rutin.
- quercetin 3-dalcuronide is also designated as quercetin 3-0-j8-D-glucuronide and Q3GA, and has a molecular weight of 478, a melting point of 182-195 ° C, and a CAS NO.22688-79-5.
- Q3GA a quercetin glycoside, has
- ⁇ -adrenergic receptor agonizing activity can stimulate ⁇ -adrenergic receptor
- the activity as a 13-adrenergic receptor agonist is determined by
- cAMP activity can be measured by an EIA method, an ELISA method, an RIA method, or other well-known Imnoassays. ⁇ ⁇ ⁇ It is also possible to use a kit sold.
- quercetin it is not limited to the plant species and plant parts from which it is derived, and it can be an i8 adrenergic receptor agonist composed of quercetin of the present invention.
- Ming is the power of the lotus leaf extract, but ⁇ -adrenergic receptor agonistic activity
- plant powers other than lotus can also include prepared quercetin.
- quercetin onions and broccoli, tea, green leaves, spinach, kale, parsley, celery, brussels sprouts, asparagus, apples, pears, guava leaves, beans, peppers, moloheiya, oranges, strawberries Etc.
- rutin is present in buckwheat and tomato. Therefore, quercetin as a 13 adrenergic receptor agonist is
- quercetin a vegetable power
- An example of extracting quercetin also from the leaf mosquitoes shown in the examples can be given.
- a leaf can be mentioned, but if it is a part containing quercetin, a flower, a root, a stem, a fruit, a pericarp, a pericarp, a rhizome It can also be used in other parts such as, tubers, seeds, stigmas, semen, essential oils. Different sites may be used depending on the plant.
- the quercetin can be effectively purified with plant power by a method well known to those skilled in the art.
- a plant may be directly or crushed and shredded, and the plant (or a processed plant product) may be extracted by adding a solvent such as water or ethanol, and based on the known properties of quercetin, such as liquid chromatography. It can be purified from the extract according to the common general knowledge of those skilled in the art. Isolation of plant power [as a column, the isolation of quercetin from Rhododendron cinnabarinum hook, Ericaceae power is reported in Rangaswami et al., Proc. Indian Acad. Sci. 56A, 239 (1962).
- the quercetin of the present invention can be used for purified natural products other than plants, chemically synthesized products, and biologically synthesized products using microorganisms. Powerful ⁇ -ad
- ⁇ -adrenergic receptor agonists promote lipolysis in white adipocytes
- the quercetin of the present invention can be used, inter alia, as an agent for treating or preventing obesity or an agent for treating or preventing diabetes.
- adrenergic receptor agonism Based on adrenergic receptor agonism, it may be used to treat diseases.
- quercetin is used as the j8 adrenergic receptor antagonist,
- Cetine can be used as it is, and its activity as 13 adrenergic receptor agonist
- quercetin does not need to be purified. If quercetin is contained, quercetin can be used to extract plant extracts and other extracts, dried extracts, and plant preparations such as powdered plants and the like. Consisting of 13 adrenergic receptor agonism
- the present invention relates to human quercetin, which is also effective in treating diabetes mellitus containing an adrenergic agonist.
- Diabetes is a group of diseases characterized by persistent hyperglycemia due to insufficient insulin action and the onset of which is linked to genetic and environmental factors. Diabetes is not solely associated with its etiology or pathology. Diabetes is classified by its onset or insulin action deficiency. The etiology is divided into type 1 diabetes, type 2 diabetes, other specific types and gestational diabetes. Type 1 diabetes is characterized by the destruction of ⁇ cells of the spleen islets of Langerhans. Type 2 diabetes is associated with both reduced insulin secretion and reduced insulin sensitivity (insulin resistance). Other specific types are those associated with other diseases. The classification based on the degree of insulin action deficiency is classified into an insulin-dependent state and an insulin-independent state.
- Certain drugs containing quercetin can be used to treat or prevent diabetes.
- examples of diabetes in which the drug of the present invention is effective include type 2 diabetes, and a drug containing a 13-adrenergic receptor agonist composed of quercetin,
- the ability of a drug or food to be effective for diabetes can be determined, for example, by administering the drug to a test animal that has developed diabetes and measuring the blood glucose level of the test animal as in the example of the present invention. You can know by. If the blood glucose level or the fasting blood glucose level before and after drug administration is compared between the drug administration group and the control group and the blood glucose level of the drug administration group is lower than that of the control group, the drug is effective for diabetes .
- a model animal of spontaneous type II diabetes eg, KK- Ay mouse
- a high-fat diet-loaded obesity model animal can be used.
- a model animal with an artificial onset caused by administration of streptozotocin and a model animal with a spontaneous type I diabetes can be used.
- the present invention provides a fat containing a quercetin-active 13-adrenergic receptor agonist.
- ⁇ -adrenaline As mentioned earlier, ⁇ -adrenaline
- Quercetin a 3-adrenergic receptor agonist
- a dried lotus leaf extract containing quercetin has an effect of improving fat metabolism in humans and mice.
- the dried lotus leaf extract containing quercetin is useful not only for humans but also for mammals including rodents such as mice and the like as drugs and foods for treating or preventing obesity.
- the dried lotus leaf extract containing quercetin is used for treating or preventing obesity, there is no limitation on the amount of intake as long as it can be safely and effectively taken.
- the intake of 0.01 g / day-100 g / day preferably O.lgZday-lOgZday.
- an intake of 0.88 mg / day-8.82 g / day, preferably 8.82 mg Zday-0.88 gZday is an example of a preferred range.
- the effect of improving fat metabolism in vitro can be evaluated, for example, by adding a test substance to fat cells and measuring the amount of glycerol, which is a lipolysis product.
- the amount of glycerol can be obtained by decomposing with glycerol kinase or the like and finally measuring the absorbance.
- test substance increases the amount of glycerol in the cells, it can be evaluated that the test substance has an effect of improving fat metabolism.
- in vivo effects a high-fat diet and After receiving the test substance and the other group receiving only the high-fat diet without the test substance, and keeping the other groups for a certain period under the same other conditions, the amount of visceral fat in the animal group was determined. Can be evaluated by comparing. If the amount of visceral fat in the group receiving the test substance is lower than that in the group receiving only the high-fat diet, it can be evaluated that the test substance has an effect of improving fat metabolism.
- the dosage form can be selected depending on the purpose of treatment, administration route, etc., for example, tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, injections, suppositories Elixir, syrup, dipstick, decoction, tincture and the like.
- diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, and lubricants can be used as necessary.
- a coloring agent, a preservative, a flavor, a flavoring agent, a sweetener, and other pharmaceuticals may be contained in the pharmaceutical preparation.
- the form of a food containing a 13-adrenergic receptor agonist composed of quercetin includes:
- Beta-adrenaline consisting of quercetin
- a sanitary acceptable composition for example, a stabilizer, preservative, coloring agent, flavor, vitamin, etc. is appropriately added and mixed, and tablets and granules are prepared in the usual manner.
- Foods such as granules, powders, capsules, liquids, creams, and beverages can be obtained.
- Quercetin-containing plants, such as lotus, are used in the manufacture of these drugs and foods.
- J8 consisting of quercetin
- Example 1 Method for producing lotus leaf extract Add 10L of water to 1kg of dried leaves. Adjust the pH to 6.0 and leave at room temperature for 30 minutes. Then, extract by boiling at 90 ° C under reduced pressure for 1 hour. The filtrate (separated into 0 and the residue, 10 times the amount of water was added to the residue, and the mixture was extracted by boiling under reduced pressure at 90 ° C for 1 hour. The filtrate (ii) was separated into the residue and the filtrate ( The filtrate (ii) was combined with 0. The mixture was concentrated by heating under reduced pressure to a specific gravity of about 1. Then, about 100 g of dry powder was obtained with a spray dryer.
- Lotus leaf extract was analyzed by LC / MS.
- the column used was Capcell Pak C18 UG120 ⁇ 2.0 X 150 mm (Shiseido).
- solution A 5% aqueous acetonitrile containing 1% acetic acid
- liquid B acetonitrile containing 1% acetic acid
- Reverse phase HPLC conditions were as follows: column temperature: 40 ° C., injection volume: 5 L, elution rate: L / min.
- Ion-Dai was performed by the ESI method (Negative). Quercetin (Wako Pure Chemical Industries, Ltd.
- quercetin dihydrate commercially available quercitrin (quercetin 3-rhamnoside) (Tokyo Kasei Kogyo Co., Ltd.) and commercially available isoquercitrin (quercetin 3- Darcoside) (EXTRASYNTHESE) and analyzed in the same manner.
- lotus leaf extract lg was dissolved in 500 mL of ultrapure water (Milli-Q water) and adjusted to pH 3 with 6N hydrochloric acid. The mixture was extracted three times with 500 mL of ethyl acetate and dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure to obtain an acidic fraction (147 mg, yield 14.7%). Next, the above-mentioned acidic fraction was purified by HPLC using 5 mg aliquots of 30 times each. The conditions for purification by HPLC are as follows. As a purification column, Capcell Pak C18 UG120 ⁇ 20 X 250 mm (Shiseido) was used.
- H-HCOSY, HMQC and HMBC were measured and compared with literature values (J. Agric. Food Chem., 46, pp. 4898-4903 (1998)).
- Human ⁇ -adrenergic receptor cDNA is derived from a human small intestine-derived cDNA library (Takara Shuzo).
- the PCR-synthesized cDNA is desalted with Cefacryl S-300 to remove unreacted primers, and then digested with the restriction enzyme sites Nhel and EcoRI, which were inserted at the end when designing the primers, and further digested.
- a ligation reaction was performed using pTracer-EFA (Invitrogen), an animal expression vector digested with Spel and EcoRI restriction enzymes, and a ligation kit (Takara Shuzo).
- the DNA after ligation was precipitated with ethanol and suspended in an appropriate amount of a 10% aqueous glycerol solution. Using the DNA solution, Escherichia coli DH5 ⁇ strain was transformed by electoporation. The cells after the operation were plated on an LB agar plate medium containing ampicillin, and cultured at 37 ° C overnight to obtain colonies of the transformant. Human in 10 transformants
- the resulting composite plasmid was selected.
- the above-mentioned complex plasmid for expressing human ⁇ -adrenergic receptor is alkaline-soluble from E. coli cells.
- DMEM Dulbecco's modified Eagle's medium
- FCS 10% fetal calf serum
- FCS fetal calf serum
- the obtained recombinant cells were cultured in a 96-well microphone plate to a 100% cell density.
- the medium is removed, and the cells are washed once with Dulbecco's modified phosphate buffer (hereinafter abbreviated as PBS) (Takara Shuzo), and the buffer for Atsey containing 10 M isoproterenol (DMEM, 10% FCS, 20 mM HEPES (pH 7.2), O.lmM isobutylmethylxanthine] was added to 100 L.
- PBS Dulbecco's modified phosphate buffer
- DMEM 10 M isoproterenol
- FCS 10 M isoproterenol
- 20 mM HEPES pH 7.2
- recombinant cells with significantly increased intracellular cAMP levels were selected by isoproterenol-added ketone, a ⁇ -adrenergic receptor antagonist.
- the selected recombinant cells were further cultured, detached with trypsin, diluted with a culture medium, and dispensed into a 96-well microplate such that one cell per well was filled.
- Recombinant 6H4-2d3 expressing human ⁇ -adrenergic receptor was prepared in a 96-well microphone plate.
- the cells were cultured in a DMEM medium containing 10% FCS and 500 / z g / mL zeocin at 37 ° C and 5% C02. After culturing for 2-3 days to grow to a cell density of about 100%, remove the medium, wash the cells once with PBS, and wash the sample to be measured in an assay buffer (DMEM, 10% FCS,
- the above measurement was performed using the dried leaf extract as a sample. That is, the dried lotus leaf extract was added to the test medium at a concentration of 0.5 mg / mL, 1 mg / mL, and 2 mg / mL, and human adrenaline was added.
- the cells were expressed with CHO-K1 cells expressing the receptor, and the response to the original CHO-K1 cells was observed.
- 1 mg of isoproterenol was used as a positive control.
- the human) 8 adrenergic receptor was expressed by the dried mulberry with lotus leaf extract.
- Quercetin the main component of the dried lotus leaf extract, was added to the test medium at a concentration of 15 M, 30 M, and 60 ⁇ .
- the cells were expressed with CHO-K1 cells expressing the receptor for CHO-K1 and the reaction on the original CHO-K1 cells was observed. In addition, 2 mg of isoproterenol was used as a positive control. As a result, CHO-K1 cells expressing human j8 adrenergic receptor
- 3T3-L1 cells (purchased from Human Science Research Resources Bank), which are preadipocytes derived from mice, are added to a 96-well plate at lxl04 / well, and 10% fetal calf serum (FCS) -supplemented Dulbecco's modified Eagle
- FCS fetal calf serum
- FCS fetal calf serum
- the medium was replaced with D-MEM supplemented with 10% FCS supplemented with 0.8 M insulin only. Thereafter, the culture solution was replaced every 2-3 days, and the culture was continued to separate the cells into adipocytes. Then, it was replaced with D-MEM containing 10% FCS and cultured for 2 days. Aspirate the culture medium of these cells cultured in a 96-well plate, add 100 ⁇ L / well of D-MEM containing 10% FCS containing the test substance, incubate for 3 days, and collect 80 L of the culture medium in each well Then, the amount of glycerol in the culture solution was measured using "F-kit glycerol" (manufactured by Boehringer Mannheim). The significance test of the mean value was performed by Student's t-test, and was considered significant when p ⁇ 0.05.
- Female Wistar rats were 5 weeks old and preliminarily reared for 4 days, and then divided into groups so that the average body weight of the rats was almost the same. Groups are divided into 8 groups per group.
- Food group, high-fat diet + lotus leaf extract 0.01 g / g intake group (high-fat diet + lg lotus leaf extract 0.01 g / g, high-fat diet + lotus leaf extract 0.05 g / g intake) Divided into 4 groups.
- the diet of the high fat diet group was supplemented with starch, sucrose, lard oil (10%), corn oil (5%), and cholesterol (1%). Each group was reared for 2 weeks and then dissected. Six hours before the start of dissection, food was withdrawn and fasted.
- Intraperitoneal fat was excised and weighed.
- the intraperitoneal fat per 100 g of body weight was 2.2340 ⁇ 0.6427 g in the normal diet group, 3.9071 ⁇ 1.2562 g in the high fat diet group, 3.5564 ⁇ 0.8805 in the 0.01 g / g lotus leaf extract group.
- high fat diet + lotus leaf extract 0.05745 g / g intake group was 2.7745 ⁇ 0.9099 g. All of the above measured values are averagers SD.
- Type 2 diabetes model mice Male KK- Ay mice, 4 weeks old, were preliminarily reared for 3 days and then divided into 2 groups of 10 mice per group according to body weight. After grouping, blood glucose levels were measured. The solvent control group was allowed to drink tap water, and the lotus leaf extract water-supplying group was allowed to drink water-soluble leaf extract water dissolved at 10 mg / ml of the dried lotus leaf extract. Drinking water was freely available. Food (CRF-1) was also freely available. Blood glucose levels were measured every week. Blood glucose measurements were taken after a 6 hour fast. The blood glucose level under non-fasting on day 25 after the start of administration was also measured. The results are shown in Figs.
- Dried lotus leaf extract was administered as a test substance to high-fat diet-loaded mice, and the effect was examined.
- quarantine ⁇ 40 animals that gained weight during the habituation period and showed no abnormalities in the general condition were used for the study, and were grouped according to the stratified random sampling method according to body weight.
- the test group consisted of group A: basic feed intake group, group B: high fat diet intake group, group C: high fat diet intake group containing 2% lotus leaf extract dry matter, Group D: lotus leaf extract dry matter 5 % High-fat diet intake group, 4 groups, 10 animals per group.
- mice in the same group were divided into 5 cages, each group being housed in 2 cages.
- Powder feed CE-2 (CLEA Japan) was used as the basic feed.
- Other feeds high fat diet, lotus leaf extraction
- Table 1 shows the high fat diet containing dry matter. The numerical values in the table indicate the amount of each mixture when the total amount of the feed mixture is 1 kg.
- the feeding method was that the feed was placed in a powder feeder and the animals were allowed free access.
- For water supply tap water was placed in a water bottle and fed freely through a nozzle.
- the administration of the test substance to the mice was continued for 10 weeks, and the mice were observed for general condition, measured for body weight, measured for food consumption, and examined anatomically, and the following results were obtained.
- body weight, food consumption and organ weight were expressed as mean standard deviation (mean S.D.).
- the significant difference test between the basic feed intake group and the high-fat diet intake group and the significant difference test between the high-fat diet intake group and the test substance intake group were performed using Student's t-test or multiple comparison test (Dunnett's test). Seven.
- Body weight was measured using an electronic precision balance immediately before and once a week after administration of the test substance. The results are shown in Table 2 for each group.
- Food consumption was measured twice a week after administration of the test substance, ie, every 3 or 4 days. Each cage was measured as a weight including the feeder using an electronic precision balance, and calculated by subtracting the amount of remaining food from the serving amount.
- Average daily consumption per group A 5.2-7.9 g / day
- average daily consumption per group B 3.0-6.8 g / day
- group C daily The average food consumption was 2.7-6.1 g / day
- the average daily food consumption per group D was 3.1-5.6 g / day.
- Group A clearly showed higher food consumption than the other groups.
- the B-D group there was a tendency that the amount of food consumed in the first half of the test (per 2 weeks) was large and the amount of food consumed in the second half (after 6 weeks) was small, There was no noticeable change.
- the 2% lotus leaf extract dry matter intake group showed a tendency to suppress weight gain, but no significant effect was observed.
- the 5% lotus leaf extract dry matter intake group significantly inhibited weight gain. Admitted.
- weight loss is the effect of food consumption and the effect of dried lotus leaf extract. Therefore, the amount of food required to increase body weight lg from the weight gain at the end of the test and the total food consumption during the test was calculated for each group.
- Leaf extract dry matter intake group (high fat diet + 2% lotus leaf extract dry matter) 20.2g
- 5% lotus leaf extract dry matter intake group high fat diet + 5% lotus leaf extract dry matter
- the fat weight at the time of dissection tended to decrease in the 2% lotus leaf extract dry matter intake group, and a significant fat weight decrease was confirmed in the 5% lotus leaf extract dry matter intake group, confirming the above conclusions. Can be.
- the purpose of this example was to examine the effects of dried lotus leaf extract on human glucose and lipid metabolism.
- human subjects were limited to those meeting certain conditions.
- the conditions to be satisfied as a subject in this example were as follows.
- border type that is, a fasting blood glucose level of 110-126 mg / dl or a 2-hour blood glucose level of 140-200 mg / dl in a 75 g glucose tolerance test (OGTT).
- OGTT 75 g glucose tolerance test
- a fasting blood glucose level of 126 mg / dl or more or 75 g OGTT 2 hour value of 200 mg / dl or more is a diabetic type.
- the subject power in the examples was excluded.
- BMI Body Mass Index
- questionnaires were conducted to select subjects.
- questions were asked about A. daily calorie intake, B. dietary preferences, C. medical history, family history, work and living environment, exercise habits, smoking and drinking.
- T group dry lotus leaf extract group
- R group placebo group
- S group placebo group
- T group dry lotus leaf extract group
- S group placebo group
- a control group a group consuming a lotus leaf extract-free! / ⁇ -based tea drink (200 ml Z) was used as a group S
- a test substance intake group a tea drink containing 0.5 gZ200 ml of lotus leaf extract dry powder was used.
- the ingesting group was designated as T group
- R group the group ingesting a tea beverage containing 1.0 g Z200 ml of lotus leaf extract dry powder
- Anthropometric measurements were performed on each subject before, 6 weeks after, and 12 weeks after ingestion.
- the measurement items were height, weight, waist circumference, BMI, hip circumference, body fat percentage, and visceral fat level.
- the measurement of the body fat percentage and the visceral fat level was performed using an Omron body weight composition meter HBF-352.
- a visceral fat level of 10 corresponds to a visceral fat area of 100 cm 2 .
- a glucose tolerance test (75 g glucose / body) was performed twice before and 12 weeks after ingestion. Subjects were asked to avoid eating and drinking after 21:00 on the night before blood collection. On the test day, blood was first collected on an empty stomach and used as blood before glucose loading. Subsequently, 75 g of glucose was loaded, and blood samples 30, 60 and 90 minutes after loading were collected with time. The trial was completed by 11am. The blood glucose level in plasma was measured using Hitachi automatic analyzer 7075.
- Fig. 7 shows the results.
- the blood glucose level after each elapsed time with respect to the blood glucose level before the glucose load was represented as a relative glucose value (%).
- the AUC (Area Under Curve) for 0 to 120 minutes was calculated based on the relative value of glucose ⁇ at each elapsed time.
- the body fat reducing effect of the dried lotus leaf extract was observed in humans as in the animal test.
- the intake of 2 g / day of dry extract of lotus leaf for 6 weeks suggests that the reduction in body fat mass was reflected in the decrease in body weight.
- lg / day a similar effect was observed after ingestion for 12 weeks. From these effects and the results of the glucose tolerance test, it is considered that there is an effect of reducing body fat mass and reducing insulin resistance.
- quercetin as a j8 adrenergic receptor agonist.
- the substance of the present invention can be used as a new option for improving obesity and treating diabetes.
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Abstract
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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AU2004285803A AU2004285803A1 (en) | 2003-11-04 | 2004-11-04 | Plant-origin beta3-adrenoceptor agonist and use of the same |
EP04817426A EP1681289A1 (en) | 2003-11-04 | 2004-11-04 | Plant-origin beta3-adrenoceptor agonist and use of the same |
CA002544781A CA2544781A1 (en) | 2003-11-04 | 2004-11-04 | Plant-derived .beta.3-adrenergic receptor agonist substances and uses thereof |
US10/578,015 US20080146657A1 (en) | 2003-11-04 | 2004-11-04 | Plant-Origin Alpha3-Adrenoceptor Agonist and Use of the Same |
JP2005515206A JPWO2005042508A1 (ja) | 2003-11-04 | 2004-11-04 | 植物由来β3アドレナリン受容体作動性物質およびその利用 |
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JP2003374836 | 2003-11-04 | ||
JP2003-374836 | 2003-11-04 |
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PCT/JP2004/016330 WO2005042508A1 (ja) | 2003-11-04 | 2004-11-04 | 植物由来β3アドレナリン受容体作動性物質およびその利用 |
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US (1) | US20080146657A1 (ja) |
EP (1) | EP1681289A1 (ja) |
JP (1) | JPWO2005042508A1 (ja) |
CN (1) | CN1902189A (ja) |
AU (1) | AU2004285803A1 (ja) |
CA (1) | CA2544781A1 (ja) |
WO (1) | WO2005042508A1 (ja) |
Cited By (9)
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WO2005082391A1 (ja) * | 2004-03-01 | 2005-09-09 | Kaneka Corporation | ヒトβ3アドレナリン受容体アゴニスト剤 |
JP2007145751A (ja) * | 2005-11-28 | 2007-06-14 | Maruzen Pharmaceut Co Ltd | 抗老化剤、スリミング剤、及び保湿剤、並びに皮膚化粧料 |
JP2009137913A (ja) * | 2007-12-10 | 2009-06-25 | S Net:Kk | 脂質代謝改善剤 |
JP2010070501A (ja) * | 2008-09-19 | 2010-04-02 | Noevir Co Ltd | 保湿剤、抗老化剤、抗酸化剤、中性脂肪蓄積抑制剤、美白剤、抗炎症剤、皮膚外用剤、経口用剤 |
JP2011140457A (ja) * | 2010-01-06 | 2011-07-21 | Kobe Univ | 筋肉の糖取り込み促進剤 |
US20140072659A1 (en) * | 2009-02-10 | 2014-03-13 | Fhg Corporation D/B/A Integrity Nutraceuticals | Dietary supplements containing extracts of nelumbo and methods of using same |
JP2017514913A (ja) * | 2014-05-05 | 2017-06-08 | 南京睿▲鷹▼▲潤▼▲澤▼生物医▲薬▼科技有限公司Nanjing Ruiying Runze Biopharmaceutical Technology Co., Inc. | 漢方薬毛チコリの脂肪降下有効成分を配合した組成物 |
US10888574B2 (en) | 2017-10-02 | 2021-01-12 | Kinjirushi Co.. Ltd. | Method for suppressing obesity, method for treating obesity, and method for promoting gene expression |
JP7180854B2 (ja) | 2017-12-08 | 2022-11-30 | 日本メナード化粧品株式会社 | 亜鉛トランスポーター発現促進剤 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8017634B2 (en) | 2003-12-29 | 2011-09-13 | President And Fellows Of Harvard College | Compositions for treating obesity and insulin resistance disorders |
KR101274543B1 (ko) * | 2008-06-11 | 2013-06-17 | 리콤 코포레이션 | 인간 아드레날린 β3 수용체 리간드, 이를 포함하는 식품 및 의약품 |
WO2010134085A1 (en) * | 2009-05-20 | 2010-11-25 | Institute Of Life Sciences | Pharmaceutical co-crystals of quercetin |
CN114948929A (zh) * | 2022-04-08 | 2022-08-30 | 上海市中医医院 | 一种槲皮素的用途 |
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- 2004-11-04 JP JP2005515206A patent/JPWO2005042508A1/ja active Pending
- 2004-11-04 EP EP04817426A patent/EP1681289A1/en not_active Withdrawn
- 2004-11-04 CA CA002544781A patent/CA2544781A1/en not_active Abandoned
- 2004-11-04 AU AU2004285803A patent/AU2004285803A1/en not_active Abandoned
- 2004-11-04 US US10/578,015 patent/US20080146657A1/en not_active Abandoned
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005082391A1 (ja) * | 2004-03-01 | 2005-09-09 | Kaneka Corporation | ヒトβ3アドレナリン受容体アゴニスト剤 |
JP2007145751A (ja) * | 2005-11-28 | 2007-06-14 | Maruzen Pharmaceut Co Ltd | 抗老化剤、スリミング剤、及び保湿剤、並びに皮膚化粧料 |
JP2009137913A (ja) * | 2007-12-10 | 2009-06-25 | S Net:Kk | 脂質代謝改善剤 |
JP2010070501A (ja) * | 2008-09-19 | 2010-04-02 | Noevir Co Ltd | 保湿剤、抗老化剤、抗酸化剤、中性脂肪蓄積抑制剤、美白剤、抗炎症剤、皮膚外用剤、経口用剤 |
US20140072659A1 (en) * | 2009-02-10 | 2014-03-13 | Fhg Corporation D/B/A Integrity Nutraceuticals | Dietary supplements containing extracts of nelumbo and methods of using same |
JP2011140457A (ja) * | 2010-01-06 | 2011-07-21 | Kobe Univ | 筋肉の糖取り込み促進剤 |
JP2017514913A (ja) * | 2014-05-05 | 2017-06-08 | 南京睿▲鷹▼▲潤▼▲澤▼生物医▲薬▼科技有限公司Nanjing Ruiying Runze Biopharmaceutical Technology Co., Inc. | 漢方薬毛チコリの脂肪降下有効成分を配合した組成物 |
US10888574B2 (en) | 2017-10-02 | 2021-01-12 | Kinjirushi Co.. Ltd. | Method for suppressing obesity, method for treating obesity, and method for promoting gene expression |
JP7180854B2 (ja) | 2017-12-08 | 2022-11-30 | 日本メナード化粧品株式会社 | 亜鉛トランスポーター発現促進剤 |
Also Published As
Publication number | Publication date |
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CA2544781A1 (en) | 2005-05-12 |
CN1902189A (zh) | 2007-01-24 |
JPWO2005042508A1 (ja) | 2007-05-24 |
EP1681289A1 (en) | 2006-07-19 |
AU2004285803A1 (en) | 2005-05-12 |
US20080146657A1 (en) | 2008-06-19 |
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