KR20160134925A - Compositions Comprising Extract from Artemisia Princeps Pamp. and Ulmi cortex for Preventing or Treating Osteoarthritis - Google Patents
Compositions Comprising Extract from Artemisia Princeps Pamp. and Ulmi cortex for Preventing or Treating Osteoarthritis Download PDFInfo
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- KR20160134925A KR20160134925A KR1020150066797A KR20150066797A KR20160134925A KR 20160134925 A KR20160134925 A KR 20160134925A KR 1020150066797 A KR1020150066797 A KR 1020150066797A KR 20150066797 A KR20150066797 A KR 20150066797A KR 20160134925 A KR20160134925 A KR 20160134925A
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- A—HUMAN NECESSITIES
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- 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)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
- A61K36/282—Artemisia, e.g. wormwood or sagebrush
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- 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
- 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)
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
The present invention relates to a composition for the prevention or treatment of osteoarthritis, which comprises lysozyme moxa and a milk extract as an active ingredient.
Osteoarthritis is a disease caused by degenerative changes of articular cartilage, and there is no known method that can completely eliminate it. Therefore, the current goal of osteoarthritis treatment is to reduce the pain and to prevent the destruction and deformation of the joints to maintain the normal joints are just enough. Conventional therapeutic methods for alleviating the pain of osteoarthritis include oral administration methods such as COX-1 or COX-2 inhibitors, narcotic analgesics, glucosamine and chondroitin, topical application agents, steroids Hyaluronic acid, and the like are being administered. Drugs such as acetaminophen are used when the pain is relatively mild. However, despite the administration of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) are mainly used in the treatment of arthritis in patients with pain, patients with severe pain, and patients with inflammation. However, the use of NSAIDs is limited because of the high risk of serious gastrointestinal complications in elderly people over 65 years of age, people who have had previous ulcerations, people with gastrointestinal complications such as gastrointestinal bleeding, and those who are receiving steroids or anticoagulants . Glucosamine and chondroitin have also been recommended by the European Rheumatology Society for the treatment of pain in osteoarthritis patients, but there is still much controversy about its safety. As the conventional chemotherapeutic drugs are showing limitations, there have been various kinds of therapeutic agents for osteoarthritis which are based on various herbal ingredients in Korea.
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
The present inventors have sought to develop a human-safe substance, particularly a plant-derived natural substance, capable of preventing or treating osteoarthritis-related diseases. As a result, the inventors of the present invention found that a natural herbal composition comprising an extract of Lepidoptera sp. Mucilaginus and Milkweed as an active ingredient exhibits suppression of swelling, improvement of behavioral activity, anti-inflammation, anti-inflammatory analgesic action and inhibition of joint tissue degradation, The present invention has been completed.
Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating osteoarthritis.
It is another object of the present invention to provide a food composition for preventing or ameliorating osteoarthritis.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention and claims.
According to one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating osteoarthritis comprising, as an active ingredient, Artemisia princeps Pamp. And Ulmi cortex extract.
According to another aspect of the present invention, there is provided a food composition for preventing or ameliorating osteoarthritis comprising, as an active ingredient, loser mugwort and whey protein extract.
The present inventors have sought to develop a human-safe substance, particularly a plant-derived natural substance, capable of preventing or treating osteoarthritis-related diseases. As a result, the inventors of the present invention found that a natural herbal composition comprising an extract of Lepidoptera sp. Mucilaginus and Milkweed as an active ingredient exhibits suppression of swelling, improvement of behavioral activity, anti-inflammation, anti-inflammatory analgesic action and inhibition of joint tissue degradation, .
The present invention includes, as an active ingredient, an extract of Lepidoptera mugwort and whey bark or the above solvent fraction.
Artemisia Princeps Pamp., Which is used as an active ingredient in the composition of the present invention, is also called fortified wormwood, fortified lion wormwood, wormwood wormwood, wormwood wormwood, wormwood wormwood, and ladybug. Lepidoptera is known to contain calcium, fiber, vitamins A, B1 and C, and exhibits antimicrobial and antioxidant effects.
The milky white blood which is used as an active ingredient in the composition of the present invention is a medicinal herb that has been used as a folk medicine for a long time in Korea and other Northeast Asian countries as a bark of the elm tree or bark cork layer which is a deciduous tree belonging to the elm family. It is reported that it is also applied to urine, constipation, relieving, masturbation, solitary mastitis, and mastitis.
The term " extract " used herein to refer to the composition as used herein includes not only extraction results obtained by treating extract media with lysozyme moxa and whey protein, but also by formulating (e.g., pulverizing) And the like.
In the composition of the present invention, the method for obtaining the active ingredient includes an extraction method. The extraction method in the composition of the present invention includes any extraction method known in the art. The extraction method is preferably selected from a cold precipitation method, a hot precipitation method, a hot water extraction method, a fermentation extraction method, a filtration leaching method, a steam distillation method, an extraction method using a microwave process, a supercritical fluid extraction method or a combination thereof. More preferably, it is cold precipitation method, hot precipitation method, hot water extraction method or a combination thereof, and most preferred is hot water extraction method.
When the extract used in the composition of the present invention is obtained by treating an extraction solvent, various extraction solvents may be used. Preferably, a polar solvent or a non-polar solvent can be used. Suitable polar solvents are (i) water, (ii) alcohols (preferably methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, n-butanol, 1-pentanol, Or ethylene glycol), (iii) acetic acid, (iv) dimethyl-formamide (DMFO) and (v) dimethyl sulfoxide (DMSO). Suitable nonpolar solvents are acetone, acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, hexane, 2,2,4-trimethylpentane, decane, cyclohexane, cyclopentane, diisobutylene, 1- But are not limited to, pentane, 1-chlorobutane, 1-chloropentane, o-xylene, diisopropyl ether, 2- chloropropane, toluene, 1- chloropropane, chlorobenzene, benzene, diethyl ether, diethylsulfide, Methane, 1,2-dichloroethane, aniline, diethylamine, ether, carbon tetrachloride, and THF.
More preferably, the extraction solvent used in the present invention is (a) water, (b) anhydrous or hydrated lower alcohol having 1 to 4 carbon atoms (methanol, ethanol, propanol, butanol, etc.) (E) ethyl acetate, (f) chloroform, (g) butyl acetate, (h) 1,3-butylene glycol, (i) hexane and (j) diethyl ether. . Most preferably, the extract of the present invention is obtained by treating water, methanol, ethanol, or a mixture thereof, with lysozyme and whey protein.
As used herein, the term " extract " means that it is used in the art as a crude extract as described above, but broadly includes fractions obtained by further fractionating the extract. That is, the lysozyme moxa and the milky skin extract include not only those obtained by using the above-mentioned extraction solvent but also those obtained by additionally applying a purification process thereto. For example, a fraction obtained by passing the above extract through an ultrafiltration membrane having a constant molecular weight cut-off value, and a separation by various chromatography (manufactured for separation according to size, charge, hydrophobicity or affinity) The fraction obtained by the purification method is also included in the extract of the spider mosquito and whey of the present invention.
The extract of Lepidoptera and Milkweed, used in the present invention, can be prepared in powder form by an additional process such as re-extraction, vacuum distillation, freeze-drying, spray-drying or a combination thereof.
According to one embodiment of the present invention, the extract of lepidoptera and whey bark is prepared by adding water to lepidoptera and whey powder, extracting the active ingredient, and centrifuging to obtain a supernatant, followed by lyophilization.
According to an embodiment of the present invention, in the composition of the present invention, the mixing ratio of the lysozyme moxa and the whey extract is 1: 3 by weight.
The composition for the prevention or treatment of osteoarthritis of the present invention is useful for inhibiting reduction of bone mineral density (BMD) and lean body mass, inhibition of degradation of proteoglycan in cartilage, inhibition of expression of MMP-3 and MMP-13, Thereby inhibiting osteoarthritis and preventing or treating osteoarthritis.
In the case of osteoarthritis, decrease in BMD and fat-free body weight is observed, and osteoarthritis can be prevented by increasing BMD and fat-free weight in joints.
Proteoglycans are composed of proteins and sugars. They are complex molecules that give elasticity to the cartilage so that the collagen fibers are clumped together to form dense or dense structures within the cartilage to allow the body to bend and stretch. In addition, proteoglycans act as a sponge in the cartilage tissue, allowing cartilage to continue the joint movement. When osteoarthritis progresses, the cartilage is destroyed along with the inflammatory reaction, and proteoglycans in cartilage are degraded.
In addition, the osteoarthritic cartilage tissue is destroyed by MMP synthesis and activation, and the expression and activity of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13 are increased. Thus, decreased expression of MMP-3 and MMP-13 is an important marker for measuring the degree of improvement of osteoarthritis.
On the other hand, the overproduction of the inflammatory cytokines TNF-α, IL-1β and IL-6 affects progression of inflammation, differentiation of cells, destruction of joints, and thereby causes arthritis.
The composition of the present invention inhibits degradation of proteoglycan in cartilage to improve bone degradation, inhibits the expression of MMP-3 and MMP-13, which induce bone degradation, and inhibits the expression of inflammatory cytokines, which are the inventors of arthritis Thereby preventing the progress of osteoarthritis.
As demonstrated in the following examples, the extract of Leek mugwort and mugwort extract of the present invention showed a superior osteoarthritis treatment effect as compared with 17β-estradiol, which is known to be effective for treating osteoarthritis, Compared with the control group, showing an increased therapeutic effect on osteoarthritis.
The composition of the present invention comprises: (a) a pharmaceutically effective amount of the above-mentioned lysolecithrine and milky lotus extract of the present invention; And (b) a pharmaceutically acceptable carrier. As used herein, the term " pharmaceutically effective amount " means an amount sufficient to achieve efficacy or activity of the above-mentioned lanolin waxy and milky blood extracts.
When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995). The pharmaceutical composition of the present invention can be administered orally or parenterally, and is preferably administered orally.
The pharmaceutical composition of the present invention may be formulated into various oral or parenteral dosage forms described below, but the present invention is not limited thereto.
Formulations for oral administration include, for example, tablets, pills, light / soft capsules. Liquid. Suspensions, emulsifiers, syrups. Granules, and elixirs. These formulations may contain one or more diluents or excipients such as fillers, extenders, wetting agents, disintegrants, lubricants, binders, surfactants and the like which are commonly used in addition to the above-mentioned effective ingredients. As the disintegrant, agar, starch, alginic acid or its sodium salt, anhydrous calcium monohydrogenphosphate, etc. may be used. As the lubricant, silica, talc, stearic acid or its magnesium or calcium salt, polyethylene glycol and the like may be used , Magnesium aluminum silicate as the binder. Starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, and low-substituted hydroxypropylcellulose. In addition, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose. Glycine, etc. may be used as a diluent. In some cases, a generally known boiling mixture, an absorbent, a colorant, a flavoring agent, a sweetening agent, etc. may be used together.
In addition, the pharmaceutical composition may be administered parenterally, and parenteral administration may be performed by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intra-thoracic injection. At this time, in order to formulate the formulation for parenteral administration, lecithin waxy mucilaginous and whey protein extract or its fractions may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, which may be prepared into a unit dosage form of ampoule or vial .
The composition may be sterilized or contain adjuvants such as preservatives, stabilizers, wettable or emulsifying accelerators, salts for controlling osmotic pressure, buffering agents and other therapeutically useful substances and may be prepared by conventional methods such as mixing, granulating or coating . ≪ / RTI >
The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . Typical dosages of the pharmaceutical compositions of the present invention are in the range of 0.001-1000 mg / kg on an adult basis.
The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
According to one embodiment of the present invention, the composition of the present invention comprises (a) a pharmacologically effective amount of leishmania sp. And (b) a pharmaceutically acceptable carrier.
When the composition of the present invention is prepared with a food composition, it includes not only the above extract as an active ingredient but also components that are ordinarily added at the time of food production, for example, proteins, carbohydrates, fats, nutrients, . Examples of the above-mentioned carbohydrates are monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavorings such as tau martin and stevia extract (e.g., rebaudioside A and glycyrrhizin) and synthetic flavorings (saccharine, aspartame, etc.) can be used as flavorings.
For example, when the food composition of the present invention is prepared as a drink, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice, jujube extract or licorice extract may be further added in addition to the above- have.
The features and advantages of the present invention are summarized as follows:
(i) The present invention provides a composition for the prevention, treatment or amelioration of osteoarthritis, which comprises lysozyme moxa and a milk-and-fat extract as an active ingredient.
(Ii) The composition of the present invention exhibits an edema-suppressing action, an improvement in behavioral activity, an anti-inflammatory action, an anti-inflammatory analgesic action and an inhibition of joint tissue degradation, and is thus very effective for preventing or treating osteoarthritis.
(Iii) The extract of Leek mugwort and mallow extract of the present invention exhibits a superior effect as compared with a drug known to have therapeutic effect on osteoarthritis, and exhibits a remarkably increased therapeutic effect on osteoarthritis even when compared with each single extract.
(Iv) Furthermore, since the composition of the present invention is composed of natural materials, it has little side effects and is safe for human body.
FIG. 1 shows the results of analysis of (+) - catechin and (-) - epicatechin of milky blood.
FIG. 2 is a result of measuring the change in skin temperature of the tail in an osteoarthritic animal model.
FIG. 3 shows the result of measuring the limping score in an osteoarthritic animal model.
Figure 4 shows the results of an evaluation of pain-related behaviors for osteoarthritis in an osteoarthritic animal model.
FIG. 5 shows the results of measurement of BMD and fat-free body weights in an animal model of osteoarthritis.
FIG. 6 shows mRNA expression of MMP-3, MMP-13 and inflammatory cytokines in the knee articular cartilage of an osteoarthritic animal model.
FIG. 7 is a result of pathological analysis of knee articular cartilage in an animal model of osteoarthritis.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
Example
Materials and methods
Leafy mugwort and milky water extract
Dried Lepidoptera ( Artemisia princeps Pamp.) And Ulmi cortex were purchased from Kyungdong Medicines Market (Seoul, Korea). After washing the medicinal material, it was dried at room temperature and lyophilized to give a powder. Distilled water was added to the powder, and the mixture was heat-treated at 100 ° C for 12 hours, centrifuged at 4 ° C and 10,000g for 20 minutes, and the supernatant was lyophilized.
The content of total phenolic compounds was measured using FolinCiocalteu reagent. The content of total phenolic compounds was calculated using gallic acid as a standard substance, and the content of total phenolic compounds was in mg / g of glacial equivalent (AOAC, 1995. Official Methods of Analysis. 16th ed. Method 952.03 Association of Official Analytical Communities, Arlington, Va, USA. Chapter 26, pp 16-17). The powder was dissolved in ethanol and the total flavonoid content was measured by a known method (Saleh ES, Hameed A. 2008. Food Chem , 114, 1271-1277). The routine was used as a standard.
The catechin and epicatechin contents of the whey extract were analyzed by HPLC equipment (Agilent Technologies, USA) using a Luna C18 column (4.6 x 250 mm, 5; Phenomenex, USA). The mobile phase consists of a solvent, distilled water (A) and acetonitrile (B) containing 0.1% ascic acid. The concentration gradient was as follows: 0 min, A: B 9: 1 (v / v); 30 minutes, A: B 75:25. The mobile phase flow rate was 0.8 mL / min, the column temperature was 30 占 폚, the injection volume was 10 占 및 and the UV detection was 230 nm. Catechin and epicatechin contents were quantified using (+) - catechin and (-) - epicatechin (1-250 μg / mL; Sigma, St. Loise,
After lysozyme powder was dissolved in methanol, pyridine was added at a ratio of 1:10, and 20 μl of the powder was injected into the HPLC. At this time, 70% methanol + 0.1% TFA was used as the eluting solvent, and the elution rate was 1.5 mL / min. Next, the contents of eupatilin and jaceosidin, which are known to be major components of lepidoptera, were determined.
Experimental animal
Magnetic SpragueDawley rats (weight 231 ± 20 g) were used as experimental animals. Experimental animals were placed in a stainless steel cage and fed under the conditions of 23 ° C and 12 hours / cancer cycle. All surgical and experimental procedures were carried out in accordance with Hoseo University Guidelines for Animal Experimental Ethics Committee. An ovariectomy (OVX) or sham operation was performed by subcutaneous injection of a ketamine and xylazine mixture (100 and 10 mg / kg body weight, respectively) in rats (Choi SB, et al. , Endocrinology 2005; 146: 4786-4794). An incision was made in the middle of the abdomen, and the most part of the oviduct was tied up to isolate each ovary. Both ovaries were removed with scissors. In the sham group, the same surgery was performed except for tubal ligation and ovariectomy.
After OVX or most surgery, the rats were allowed to move freely in water, and high fat diet was provided to worsen osteoarthritis and menopausal symptoms. A high-fat diet for animal experiments was prepared using a semi-purified method comprising a modified AIN-93 formulation (Reeves PG. J Nutri 1997; 127: 838S-8341S). The high fat diet consisted of 40% energy (En%) of carbohydrate, 20 En% of protein and 45 En% of fat. The main sources of carbohydrates, proteins and fats are starchy sugar, casein (milk protein) and lard (CJ Co., Seoul, Korea). The high-fat diet was supplemented with 2% of freeze-dried Lepidoptera (APP) water extract, 2% of lyophilized milky white (UCE) water extract or 2% of dextrose (control). In APP + UCE experimental group, APP and UCE were mixed at a mixing ratio of 5:15 (w / w) and added 2% in high fat diet.
Experimental design
In a preliminary experiment of the present inventors, when treated with a small amount (0.5-2 μg / mL) of lyophilized leishmanial extract of APP (water), RAW 264.7 cells activated by LPS (lipopolysaccharide) -α) expression. In addition, TNF-α was reduced in RAW 264.7 cells stimulated by LPS when treated with relatively large amounts (2-10 μg / mL) of lyophilized milky blood (UCE) Based on preliminary and conventional experimental results, a diet containing an additional 2% of APP and UCE was provided in OVX rats (Kim MJ, et al., Exp Biol Med 2014; pii: 1535370214551693.).
40 OVX rats were randomly divided into 4 groups as follows: 1) 2% dextrose (placebo; OVX-control), 2) 2% APP, 3) 2% UCE, 1.5% UCE + 0.5% APP,
MIA-induced osteoarthritis animal model
Ketamine and xylazine mixtures (100 and 10 mg / kg body weight, respectively) were anesthetized by intramuscular injection of the rats. Then, MIA (4 mg / 50 μL saline; Sigma Co.) was injected into the joint using a 26-gauge needle through the right knee patellofemoral ligament of OVX rats. In addition, most experimental rats injected saline into the right knee as in the normal control group. Saline was injected into the left knee of all rats. MIA injection, and the next day, the right knee edema was observed.
Tail skin temperature measurement
Tail skin temperature was monitored for 4 weeks and 8 weeks of sleep using an infrared thermometer (BIO-152-IRB, Bioseb, Chaville, France) for salting. Three measurements were taken at 10 minute intervals, and the mean value for the animals was used as a single data point.
BMD (bone mineral density) measurement
A dual-energy X-ray extinometer (DEXA; Norland Medical Systems Inc., Fort Atkinson, Wis., USA) was calibrated using phantoms provided by the manufacturer prior to use. The rats were anesthetized with ketamine and xylazine (100 and 10 mg / kg body weight, respectively), and allowed to remain on an external rotation state using a tape after being prone. The hip, knee, and ankle joints were bent 90 °. BMD was measured in the right femur and knee using DEXA equipped with software suitable for measuring bone density in small animals (Ko BS, et al., J Ethnopharmacol 2014; 155: 267-276). In a similar manner, abdominal fat and lean mass were measured via DEXA.
Osteoarthritis progression
Knee diameter was measured using a digital caliper (Mitotoyo, Japan) at 3, 7, 14, and 21 days after MIA injection. All experimental animals were weighed, and weekly knee joint edema and gait disturbances on freely moving cages were carefully observed. Edema and gait disturbances were classified as no change (0), slight presence (1), moderate presence (2), and severe (3) (Kobayashi K, et al., J Vet Med Sci 2003; 65: 1195-1199). The evaluation according to the classification was carried out by an investigator who did not know the contents of the experiment overall.
Pain-related behavior test
Pain-related behaviors were assessed by incapacitance testing at maximum running speed on a treadmill (Linton incapacitance tester, UK) on
Motor activity
The locomotor activity was determined using a Linton AM1053 Activity Monitor (Linton Instruments, UK) consisting of a three-dimensional array of infrared beams placed around a transparent perceptive cage containing AmLogger software. Exercise activity was measured for 1 hour in the dark cycle of the light / dark cycle when the rat was allowed to adapt for 30 minutes in a clear Puckspecs cage and then moved most actively.
From articular cartilage Total RNA isolation and real time PCR
Articular cartilage samples were obtained from 5 rats in each experimental group after 28 days of administration of MIA. Each cartilage sample was made into powder using a cold steel mortar and pestle, then phenol and guanidine isothiocyanate (Life Technologies, Rockville, Md., USA) to extract total RNA according to the manufacturer's instructions. Lt; / RTI > solution. RNA concentration was measured using a Lamda 850 spectrophotometer (Perkin Elmer, Waltham, MA, USA) and cDNA was synthesized from 1 μg RNA using Superscript III reverse transcriptase kit (Life Science Technology). Real-time PCR was performed using the cDNA of each experimental group. Primers specific for the same amount of cDNA and gene were mixed with SYBR Greenmix (Bio-Rad, Richmond, Calif.) And amplified using real-time PCR instrument (Bio-Rad). The PCR conditions were as follows: 40 cycles at 55 ° C for 2 minutes, 95 ° C for 10 minutes, 94 ° C for 20 seconds, 30 seconds at 65 ° C, and 20 seconds at 72 ° C. IL-1β, IL-6, MMP (matrix metalloproteinase) -3 and MMP-13 in order to evaluate the degree of expression of genes involved in inflammation and arthritic cartilage degradation. Specific primers were used (Park S, et al., J Korean Soc Appl Biol Chem 2014; 57: 143-151, Kobayashi K, et al., J Vet Med Sci 2003; 65: 1195-1199). The Cycle of Threshold (CT) value of each sample was determined. Gene expression levels of unknown samples were quantified using a comparative CT method (ΔΔCT method; Livak & Schmittgen, 2001). ΔCT was calculated using the following equation: ΔCT = CT (target gene) - CT (standard expression gene, β-actin). Relative fold-change in expression was calculated by the following equation: ΔΔCt = ΔCt treated group ΔCt control group. The result is shown as 2-ΔΔCT.
Pathological Analysis of Knee
After 21 days of MIA administration, the rats were sacrificed and chronic morphological changes of the knee joint bones, reduction of joints, cartilage erosion and bone formation were evaluated by histological methods (Park S, et al., J Korean Soc Appl Biol Chem Pomonis JD, et al., Pain 2005; 114: 339-346, Bar-Yehuda S, et al., Arthritis Rheum 2009; 60: 3061-3071). For histological analysis, the knee joints were separated, fixed with formalin, and then calcined with 10% nitric acid for 72 hours and embedded in paraffin. The 5 μm sections were stained with hematoxylin and eosin (HE) and sapranin-fast green, and morphological changes were observed. Pathological changes in each experimental animal were expressed quantitatively using the following scoring system (Kobayashi K, et al., J Vet Med Sci 2003; 65: 1195-1199). Cartilage damage was assessed by depth and degree of injury. Damage depth was scored on a scale of 0-5: 0 is normal; 1 affects minimal, surface only; 2 is weak, only penetrates to upper middle part; 3 penetrates into middle and middle parts; 4 is pronounced, penetrating to deep but not to the tide mark; And 5 are severe, and the whole is decomposed to the tide mark. The degree of tibial plateau and proteoglycan loss were scored as 1 (minimal), 2 (weak), 3 (moderate) and 4 (severe).
Statistical analysis
Statistical analysis was performed using SAS, version 7.0. All results were expressed as mean ± SD. The metabolic effects of OVX-control, APP, UCE, UCE + APP and 17 [beta] -estradiol (positive control) were evaluated by one-way ANOVA. Significant differences between the experimental groups were analyzed by Tukey's test (p <0.05). Differences between OVX-control rats and normal control rats were determined by this table t-test.
Experiment result
Polyphenol and flavonoid content
APP contains 7.45 and 3.31 mg / g dry weight of total polyphenols and flavonoids, respectively, and UCE contains 21.5 and 16.4 mg / g dry weight, respectively (Table 1). UCE (1 g dry weight) contains 6.20 mg (+) - catechin and 7.80 mg (-) - epicatechin (Fig. 1), and lysozyme mugwort contains 1.34 ± 0.11 mg / g, 0.88 0.09 mg / g.
Measured values are expressed as mean ± standard deviation.
Metabolism associated with menopausal symptoms
Experimental 8 week-old and tail skin temperatures were higher in OVX-control rats than in positive control rats by 2.4 ° C, and the skin temperature increased in OVX-control rats over time, but not in positive control rats 2). Experimental treatments at 4 and 8 weeks, UCE, APP + UCE and 17β-estradiol inhibited the increase of tail skin temperature in OVX rats and their tail skin temperature was similar to that of positive control rats. On the other hand, APP decreased tail skin temperature at the 8th week of the experiment but was still higher than the positive control.
Osteoarthritis symptoms
Edema began to appear in the right knee injected with MIA, and the rat began to wake up the next day after MIA injection regardless of treatment. The score for edema and lame was measured from the third day after MIA injection. On the third day of experiment, APP rats underwent less legs than OVX control rats. In OVX control group and APP group, the legs continued to deteriorate until the seventh day of experiment, but in other experimental groups, the lap score decreased slightly from the third day of experiment. There was no significant difference between the experimental groups on the 7th day of the experiment. The experimental 14 day limping score was decreased in the order of control> APP> UCE> APP + UCE. The 21st-day and lame scores of the experiment were almost the same as those of the 14th day, but the score of APP-UCE was the lowest (Fig. 3a).
In addition, the right knee edema score was higher in the OVX control rats from the 7th day of the experiment. On the 14th day of experiment, the edema score was significantly decreased in the order of OVX control> APP and positive control = UCE> APP + UCE. On the 21st day of the experiment, the edema score was almost the same as the 14th day result, but the APP-UCE score was significantly lower on day 21 (FIG. 3B).
Pain-related behavioral assessment of osteoarthritis
Pain-related behaviors were measured through asymmetric weight distribution, maximum running speed and behavioral activity in Tremill. The weight distribution of the right hind leg in normal rats is 50%, while the weight distribution of MIA-injected rats is not the same in both legs. The right leg weight distribution of the control group was 43.5% on the 3rd day of the experiment due to the pain, and the difference in the weight distribution of the right leg gradually decreased until the 21st day of experiment (Fig. 4A). The body weight distribution of the APP, UCE, APP + UCE and 17β-estradiol test groups was similar to that of the OVX control group on the third day of experiment. Unlike the OVX control group, the right legs of APP, UCE, APP + UCE and 17β- Body weight distribution was increased on the 14th and 21st days of the experiment (Fig. 4A). In the APP + UCE group, the weight distribution of the legs was almost uniform and no edema was observed.
The maximum treadmill running speed decreased in rats induced osteoarthritis in the knee by pain. The maximal rate was about 75.5 m / hr before injection of MIA in the right knee and was significantly decreased in the third day of experiment in all rats injected with MIA, while in APP, UCE, APP + UCE and positive control gradually decreased until
In addition, behavioral activity indicative of spontaneous behavior represents pain in the legs. The migration distance of OVX rats injected with MIA was significantly lower (76.3 ± 5.5 m / hr) compared with the positive control rats. The migration distance of the rats was increased in the order of the control <APP <UCE and the positive control <APP + UCE group (FIG. 4C). Pain-related behaviors in the MIA injected legs were significantly improved in the APP-UCE treated group, which was superior to the positive control group.
In the right femur and knee BMD And lean body mass.
When osteoarthritis occurs, BMD and fat-free weight are reduced. Osteoarthritis can be prevented if the body weight of the knee and femur is increased without BMD and fat. The BMD of the right femur measured by DEXA was lower in the OVX rats compared with the positive control rats at the 4th and 7th weeks of experiment, and the BMD of the right knee was significantly decreased at 7th week of the experiment (Fig. 5A). APP and UCE did not affect the BMD of the right femur and knee in OVX rats during the experiment whereas APP + UCE and 17 [beta] -estradiol overcome the negative effects of OVX in the 7th BMD of the experiment (Figure 5a). On the other hand, MIA injection reduced BMD of right femur and knee in all experimental groups (P <0.05).
Experiments on the femur and knee of the right leg were not significantly different in the OVX control rats and in the positive control rats except for the 4th test. However, in the 7th week of OVX rats, fat-free weight was significantly reduced, and 17β-estradiol also did not prevent weight loss of the right femur except fat. This fat-free weight loss of
Right knee From articular cartilage Cytokine mRNA Manifestation of
MRNA expression of MMP-3 and MMP-13 was increased in the knee articular cartilage of OVX rats to which MIA was administered, and 17? -Estradiol suppressed the expression of the mRNA in the right femoral articular cartilage. In addition, APP + UCE inhibited the increased expression of MMP-3 and MMP-13 in the right knee to the positive control level. APP and UCE did not alone decrease the expression of MMP-3 and MMP-13 by APP + UCE (Fig. 6A).
Expression of TNF-α, IL-1β and IL-6 mRNA mediating inflammatory responses was increased in the articular cartilage of MIA-treated OVX rat knees. The expression of the mRNA was the highest in the control group, and the expression level was decreased in descending order of APP>UCE> APP + UCE = 17β-estradiol test group (FIG. 6b). That is, APP + UCE has a beneficial effect in reducing the expression of inflammatory cytokines in articular cartilage of the right knee of OVX rats administered with MIA (Fig. 5B).
Pathological analysis
In pathological evaluations via HE staining, MIA treatment injured the articular cartilage and cartilaginous bone of OVX control rat knees compared to normal control rats. Normal control rats were found to have a smooth joint surface, normal chondrocytes with columnar orientation, and intact tide marks and cartilaginous bone. However, the administration of MIA induces the degradation of the circumferential orientation, the degradation of the tide mark, and the penetration of the cartilaginous bone. Damage due to joint degradation is prevented by UCE and APP + UCE, and APP + UCE effectively suppresses the depth and degree of articular cartilage damage (FIG. 7A). APP + UCE improved osteolysis more effectively than the 17? -Estradiol experimental group. The positive control prevented penetration of the cartilage, but did not prevent decomposition of the tide mark. A decrease in proteoglycans in the saprinin-Ospast green stain was found in the OVX control rats and the degree of proteoglycan reduction and tibial plateau in the articular cartilage was significantly reduced in the control <APP <UCE = positive control <APP + UCE (Fig. 7B). These results indicate that 0.5% APP + 1.5% UCE treatment effectively prevents degradation of joint surfaces.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
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| CN107929432A (en) * | 2017-11-30 | 2018-04-20 | 柳州市妇幼保健院 | One kind disappears numbness pain liniment |
| US10434128B2 (en) | 2017-07-03 | 2019-10-08 | Dongguk University Gyeongju Campus Industry-Academy Cooperation Foundation | Composition comprising Ulmi cortex extracts for inhibiting ovotoxicity |
| KR20190137317A (en) | 2018-06-01 | 2019-12-11 | 제주대학교 산학협력단 | Composition comprising carpomitra costata(stackhouse) batters extract for preventing or treating osteoarthritis |
| KR20210000685A (en) * | 2019-06-25 | 2021-01-05 | 아주대학교산학협력단 | Composition for preventing or treating bone disease comprising a extract mixture of ulmus bark and cornus officinalis |
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| US10434128B2 (en) | 2017-07-03 | 2019-10-08 | Dongguk University Gyeongju Campus Industry-Academy Cooperation Foundation | Composition comprising Ulmi cortex extracts for inhibiting ovotoxicity |
| CN107929432A (en) * | 2017-11-30 | 2018-04-20 | 柳州市妇幼保健院 | One kind disappears numbness pain liniment |
| KR20190137317A (en) | 2018-06-01 | 2019-12-11 | 제주대학교 산학협력단 | Composition comprising carpomitra costata(stackhouse) batters extract for preventing or treating osteoarthritis |
| KR20210000685A (en) * | 2019-06-25 | 2021-01-05 | 아주대학교산학협력단 | Composition for preventing or treating bone disease comprising a extract mixture of ulmus bark and cornus officinalis |
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