KR101789392B1 - Pharmaceutical composition having extract of rhei rhizoma and glycyrrhizae rhizoma for prevention or treatment of reflux esophagitis - Google Patents
Pharmaceutical composition having extract of rhei rhizoma and glycyrrhizae rhizoma for prevention or treatment of reflux esophagitis Download PDFInfo
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- KR101789392B1 KR101789392B1 KR1020150190835A KR20150190835A KR101789392B1 KR 101789392 B1 KR101789392 B1 KR 101789392B1 KR 1020150190835 A KR1020150190835 A KR 1020150190835A KR 20150190835 A KR20150190835 A KR 20150190835A KR 101789392 B1 KR101789392 B1 KR 101789392B1
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- licorice
- extract
- reflux esophagitis
- rhubarb
- expression
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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)
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- A61K36/708—Rheum (rhubarb)
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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
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- 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)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/484—Glycyrrhiza (licorice)
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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
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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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
- 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
- A23V2300/00—Processes
- A23V2300/14—Extraction
Abstract
The present invention provides a pharmaceutical composition containing an extract of rhubarb and licorice as an active ingredient and exhibiting an excellent effect for preventing or treating reflux esophagitis, and a functional food exhibiting an effect for preventing or improving reflux esophagitis.
Description
The present invention relates to a pharmaceutical composition for preventing or treating reflux esophagitis, and more particularly, to a pharmaceutical composition for preventing or treating reflux esophagitis containing a rhubarb and licorice complex extract.
Gastroesophageal reflux disease is a disease manifesting various clinical symptoms such as heartburn, bulging, nausea, nausea, chest pain, and swallowing pain. It is an increase in westernized eating habits such as high calorie diet and high fat diet, obesity, (Jung, SG, Rhee, PL, Prevalence, Clinical Manifestations, and Treatment of Gastroesophageal Reflux Disease in Korea.) Korean J Gastroenterol 2008 Jun; 51 (6): 331-7). According to statistics of the National Health Insurance Corporation, the number of patients treated with gastroesophageal reflux disease increased by 37% from 3.56 million in 2009 to 3.51 million in 2013. Reflux esophagitis (gastroesophageal reflux disease) is defined as reflux esophagitis when gastric acid or stomach contents reflux into the esophagus and cause mucosal damage such as erythema, erosion or ulceration in the esophageal mucosa.
Treatment of reflux esophagitis is generally the most basic treatment of lifestyle habits. Medications such as antacids, H 2 receptor blockers, and proton pump inhibitors (PPI) are used to minimize the effects of gastric acid (Jung HY Pharmacological treatment for reflux esophagitis J Korean Med Assoc 2011; 54 (1): 88-91). However, in 40-60% of patients, complications such as high recurrence rate, incomplete mucosal recovery, persistent symptoms, esophageal stricture, pulmonary disease, Barrett's esophagus and esophageal cancer occur despite adequate duration of acid secretion inhibitors (Badillo R , Francis D. Diagnosis and treatment of gastroesophageal reflux disease. World J Gastrointest Pharmacol Ther. 2014; 5 (3): 105-12).
Recently, it has been reported that oxidative stress plays an important role in esophageal mucosal injury rather than acid reflux (Lee JS, Oh TY, Ahn BO, Cho H, Kim WB, Kim YB, Sur YJ, Kim HJ and Hahm KB. Involvement of oxidative stress in experimentally induced reflux esophagitis and Barrett's esophagus: clue for the chemoprevention of esophageal carcinoma by antioxidants. Mutat Res 2001; 480-481: 189-200). Oxidative stress caused by excessive free radical formation activates leukocytes and forms Reactive oxygen species such as superoxide anions (O 2 - ), hydrogen peroxide (H 2 O 2 ), hydroxyl radicals (OH - Increased damage to the tissue (Oh TY, Lee JS, Ahn BO, Cho H, Kim WB, Kim YB, Surh YJ, Cho SW, Lee KM, Hahm KB. Oxidative stress is more important than acid pathogenesis of reflux oesophagitis in rats Gut 2001; 49 (3): 364-71). On the other hand, administration of antioxidants and free radical scavengers has been reported to reduce mucosal damage due to excessive reactive oxygen species (Lee JS et al.).
Rhei Rhizoma is the root of the perennial plant Rheum palmatum L., R. tanguticum Maxim. Et Balf. Or R. officinale Baill. In the Polygonaceae, (Kim BH, et al.) Rheumatoid arthritis (Gastric Ulcer in Sprague-Dawley rheumatoid arthritis), which is a dry form of rhabdomyosarcoma, can be used for abdominal pain, hemorrhagic fever, Dawley Rats, Korean J Orient Physiol Pathol, 2011; 5 (1): 71-7; Lee SN, Kim HK, Seo BL. A Philological Study on Poisoning of Rhei Radix et Rhizoma Medicine, 2012; 37 (3): 13-24; Herbalogy. Seoul: younglimsa. Pp 242-243, 1995). Antimicrobial activities of rhubarb and its anthraquinone derivatives have been investigated in vitro and in vivo using an anti-thrombotic agent (He ZH, He MF, Ma SC, But PP). Anti-angiogenic effects of rhubarb and its anthraquinone derivatives J Ethnopharmacol. 2009; 121 (2): 313-7) Huang Q, Lu G, Shen HM, Chung MC, Ong CN, Anti-cancer properties of anthraquinones from rhubarb.Med Res Rev. 2007; 27 (5): 609-30), neuroprotective effect (Myung SH, Kim YS. 2005; 19 (3): 647-55), hyperlipidemia (Son YJ, Kim YS, and Lee YJ, The Effects of Rheumatoid Arthritis in Rheumatoid Arthritis, (1): 61-8), gastric mucosal protective effect (Kim BH), antioxidant effect (Yokozawa T. et al., J. Biol. , Chen CP, Tanaka T. Direct scavenging of nitric oxide by traditional crude drugs. Phytomedicine. 2000; 6 (6): 453-63).
Licorice (Glycyrrhiza uralensis) is a perennial herbaceous plant belonging to the soybean family. It is a traditional medicinal herb that is used to dry roots. It is a chronic hepatitis, antidiabetic (Mae T, Kishida H, Nishiyama T, Tsukagawa M, Konishi E, Kuroda M, Mimaki Y, Sashida Y, Takahashi K, Kawada T, Nakagawa K, Kitahara M.A. licorice ethanolic extract with peroxisome proliferator-activated receptor-gamma ligand-binding activity affects diabetes mellitus in KK-Ay mice, 2003), anti-ulcer effects of anti-inflammatory effects (JS, Kang BG, Jang YS, Kim SH, Wang Z, Park JH, YH, Park, JH and Lim, SS Studies on Standardization of Licorice Based on its Active Components with On-line HPLC Bioassay System, J. Plant Res. 2014, 27 (5): 401-14, Park BH, Pharmacological and Physiologicol activities of Glycyrrhizae Radix. College of Pharmacy. Ewha Womans University. 1983), ulcerative for Salt inhibitory effects (Lee KH, KH Rhee. Anti-Inflammatory Effects of Glycyrrhiza glabra Linne Extract in a Dextran Sulfate Sodium-Induced Mouse Colitis Model. Korean J. Food & Nutr. 2010; 23 (4): 435-9), and antioxidant effect (Woo KS, Hwang IG, Noh YH, Jeong HS. Antioxidant Activity of Heated Licorice ( Glycyrrhiza uralensis Fisch) Extracts in Korea. J Korean Soc Food Sci Nutr. 6): 689-95).
Thus, the protection of gastric mucosa and antioxidative effects of rhubarb and licorice have been reported. However, the effect of these complexes on reflux esophagitis is unknown.
Accordingly, the present invention provides a pharmaceutical composition having anti-reflux esophagitis preventive or therapeutic effect by using a combination of rhubarb and licorice.
The present invention also provides a functional food having anti-reflux esophagitis prevention or improving effect by using a combination of rhubarb and licorice.
The present invention provides a pharmaceutical composition for preventing or treating reflux esophagitis, which comprises an extract of rhubarb and licorice as an active ingredient.
Also, the present invention provides a pharmaceutical composition for preventing or treating reflux esophagitis, wherein the combined extract is a hot-water extract.
In order to solve the above-mentioned problems, the present invention provides a functional food for preventing or improving reflux esophagitis, which comprises an extract of rhubarb and licorice as an active ingredient.
Also, the present invention provides a functional food for preventing or improving reflux esophagitis, wherein the complex extract is a hot-water extract.
According to the present invention, it is possible to provide a pharmaceutical composition containing an extract of rhubarb and licorice as an active ingredient, exhibiting an excellent efficacy in the prevention or treatment of reflux esophagitis, and a functional food exhibiting an effect for preventing or improving reflux esophagitis.
1 is a graph showing the measurement results of DPPH radical scavenging activity and ABTS radical scavenging activity,
FIG. 2 is a graph (D) showing comparative photographs (A to C) for explaining the effect of the complex extract on the esophageal mucosal injury,
FIG. 3 is a graph showing the results of measurement of oxidative stress biomarker changes in blood,
Figure 4 shows electrophoresis photographs and graphs comparing the effects of complex extracts on Nrf-2 and HO-1 expression,
5 and 6 are electrophoresis photographs and graphs showing the effect of the complex extract on inflammation-related protein expression, respectively,
FIG. 7 is a schematic view showing the action mechanism of the extract of Rhododendron and Licorice complex according to the present invention to exert the effect on reflux esophagitis. FIG.
Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in detail with reference to the accompanying drawings.
The inventors of the present invention found that the anti-inflammatory effect of arginate and licorice (RGE), which is a combination of rhubarb and liquorice, on the antioxidant effect of reflux esophagitis, In rats fed with rhubarb and licorice complex extracts, it was surprisingly found that the extracts of rhubarb and licorice complex showed excellent efficacy in the prevention and treatment of reflux esophagitis due to the esophageal mucosal defense effect and antioxidant effect And arrived at the present invention.
Accordingly, the present invention discloses a pharmaceutical composition for preventing or treating reflux esophagitis containing rhubarb and licorice complex extract as an active ingredient, and a functional food for preventing or improving reflux esophagitis, which comprises rhubarb and licorice complex extract as an active ingredient.
Although the ratio of the content of rhubarb and licorice is not particularly limited, in order to realize a synergistic effect on reflux esophagitis without deteriorating function of each component in hot water extraction, rhizome: licorice weight ratio More preferably from 1: 2 to 2: 1, most preferably from 1: 1.5 to 1.5: 1, most preferably from 1:10 to 10: 1, Do.
Example
After adding 300 ml of distilled water to 15 g of rhubarb (Onggi Herbal Medicine, Daegu, Korea) and 15 g of licorice (Onggi Herbal Medicine, Daegu, Korea), the resulting solution was extracted with a hot water extractor for 2 hours and then concentrated with a vacuum extractor (5.93 g) was obtained. The yield was 19.8%. This was diluted in distilled water immediately before the experiment while being frozen (-80 ° C). The rhubarb and licorice used in this example were subjected to sensory evaluation after purchasing according to the catalog of herbal medicines, and only those that passed the pharmacopoeial specification were selected and used.
Experimental Example
Animal experiments were conducted to confirm the efficacy of the Rhodiola and Licorice complex extract prepared according to the above examples to prevent or treat reflux esophagitis. All experiments were approved by the Daegu Han University Ethics Committee (DHU2013-037) and were complied with animal care regulations.
18 male Sprague-Dawley rats (Samtaco, Osan, Korea) were used as experimental animals. The conditions of the animal breeding room were controlled by a conventional system at a temperature of 22 ± 2 ° C, a humidity of 50 ± 5% and a light (dark) cycle of 12 hours. Diet feeds (crude protein 22.1% or higher, crude fat 8.0% or less, crude fiber 5.0% or less, crude protein 8.0% or less, calcium 0.6% or more, phosphorus 0.4% or more, and samyangsa or no antibiotics) were used. The experimental group consisted of three groups: normal (normative), reflux esophagitis, reflux esophagitis control (Vehicle) treated with distilled water, drug induced reflux esophagitis, drug treated with rhizome and licorice complex extract at 350 mg / kg (RGE) were divided into 6 groups.
The reflux esophagitis induction was performed as follows. The animals were fed an adequate amount of solid diet and water until the day before the experiment. After 24 hours of operation, they were anesthetized with a 25 mg / kg intraperitoneal injection of Zoletile mixture (Vibrac, France). After anesthesia, the anesthesia was opened about 2 cm, the Taiwan area was bound to the silk thread, the adjacent nail site was bound to the other silk thread, and the peritoneal membrane and the skin were sealed.
The analytical methods for the normal group, the control group and the drug administration group are as follows.
[Measurement of DPPH radical scavenging activity]
DPPH (1,1-diphenyl-2-picrylhydrazyl) is a very stable free radical, a deep violet compound that exhibits specific absorption at 517 nm. However, the antioxidant activity can be easily measured since it is decolorized quantitatively by an antioxidant having a radical scavenging activity. This radical scavenging activity is correlated with antioxidant activity including lipid peroxidation inhibitory activity and is widely used for antioxidant search. Add 0.1 ml of 60 μM DPPH to 0.1 ml of each sample solution, stir and incubate at room temperature for 30 minutes, and then measure the absorbance at 540 nm.
[Measurement of ABTS radical scavenging activity]
The antioxidative effect of ABTS (2,2'-azinobis (ethylbenzthiazoline-6-sulfonate)) radical scavenging activity was measured. 7 mM ABTS and 2.45 mM potassium persulfate were dissolved in distilled water for 16 hours and reacted to form an ABTS radical to prepare a stock solution. The absorbance of this solution was measured at 735 nm using distilled water to prepare an ABTS working solution. 95 ㎕ of working solution and 5 ㎕ of sample were added and reacted for 15 minutes in the dark room, and the absorbance was measured at 734 nm to confirm the antioxidative effect by ABTS radical scavenging activity.
[Measurement of esophageal mucosal damage]
After 6 hours of operation, the esophagus was removed and the esophagus was cut longitudinally using surgical scissors. The cut esophagus was washed with an appropriate amount of 0.9% sodium chloride (NaCl), developed on a clean nonwoven fabric, and photographed using an optical digital camera (Sony, Tokyo, Japan). Damaged esophageal mucosa was measured using an I-Solution lite (Innerview Co., Korea) program to measure the area of the actual lesion area.
[Measurement of oxidative stress biomarker in serum and esophageal tissue]
Blood collected from the heart was centrifuged at 4,000 rpm for 10 minutes to obtain serum. The esophagus tissue was pulverized using a buffer (1 mM EDTA-50 mM sodium phosphate buffer, pH 7.4). To measure the reactive oxygen species (ROS), 25 mM DCFH-DA was added, and the mixture was incubated for 30 minutes using a 530 nm emission wavelength and 486 nm excitation wavelength for 10 minutes starting from 0 minutes using a fluorescence spectrophotometer The measured values were calculated. In order to measure ONOO - and TBARS (thiobarbituric acid reactive substances) in esophageal tissues, Kooy NW, Royall JA, Ischiropoulos H, Beckman JS, Peroxynitrite-mediated oxidation of dihydrorhodamine 123. Free Radic Biol Med. 1994; (2): 149-56) and Mitsurue et al. (Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978; 86 (1): 271-8).
[Western blot]
To obtain the cytoplasm of the esophagus, a buffer A (buffer A: 100 mM Tris-HCl (pH 7.4), 5 mM Tris-HCl (pH 7.5), 2 mM MgCl 2 , 15 mM CaCl 2 , 1.5 M sucrose and 0.1 M DTT, ) Was added, followed by pulverization with a tissue grinder (Bio Spec Product, USA) and 10% NP-40 solution was added. The mixture was allowed to stand on ice for 20 minutes and then centrifuged at 12,000 rpm for 2 minutes to separate the supernatant containing cytoplasm. To obtain nuclei, rinse twice in buffer A supplemented with 10% NP-40 and add 100 μl of buffer C (buffer C; 50 mM HEPES, 50 mM KCl, 0.3 mM NaCl, 0.1 mM EDTA, 1 mM DTT, 0.1 mM PMSF and 10% glycerol ) Was added and resuspended, followed by 3 times of voltex every 10 minutes. After centrifugation at 12,000 rpm for 10 min at 4 ° C, the supernatant containing the nuclei was obtained and stored frozen at 80 ° C. In order to measure the expression of HO-1, IκBα, iNOS, COX-2, TNF-α, IL-6, β-actin and NF-kBp65, Nrf2, Histone and protein in the cytoplasm of esophageal tissue, Was electrophoresed using 8 to 15% SDS-polyacrylamide gel, and the acrylamide gel was transferred to a nitrocellulose membrane. Each of the prepared membranes was treated with each primary antibody and then overnight at 4 ° C. Then, the washed membrane was washed 5 times with PBS-T every 6 minutes, and the secondary antibody (PBS -T at 1: 3000) for 1 hour at room temperature and then washed 5 times with PBS-T every 6 minutes. After exposing ECL (enhanced chemiluminescence) solution to GE Healthcare (Arlington Heights, IL, USA), sensitization was performed on Sensi-Q2000 Chemidoc (Lugen Sci Co., Ltd., Seoul, Korea) Bands were quantified using the ATTO Densitograph Software (ATTO Corporation, Tokyo, Japan) program.
[Statistical processing]
All data were expressed as mean ± SE and the statistical significance of each data was verified by one-way analysis of variance (ANOVA) using SPSS (18.0 for Windows program) A p-value <0.05 between the control and the treatment groups was determined to be significant.
[reagent]
The sources of the reagents used in the above experiments are as follows.
Nitrocellulose membranes were purchased from Amersham GE Healthcare (Little Chalfont, UK) and were purchased from PfEM, NF-κB inhibitor alpha (IkBa), nuclear factor-kappa B (NF-κBp65) (IL-1), Inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α), interleukin-6 The protease inhibitor mixture and solution ethylenediaminetetraacetic acid (EDTA) were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan), and the Histone, β-actin and secondary antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, ). In addition, 2 ', 7'-Dichlorofluorescein diacetate (DCF-DA) and Dihydrorhodamine 123 were purchased from Molecular Probes (Eugene, OR, USA) and ECL Western Blotting Detection Reagents from GE Healthcare. BCA protein assay kit for protein determination was purchased from Thermo Scientific (Rockford, IL, USA).
DPPH radical scavenging activity and ABTS radical scavenging activity
1 is a graph showing the measurement results of DPPH radical scavenging activity and ABTS radical scavenging activity.
DPPH radical scavenging activity was measured to confirm the antioxidative activity of RGE used in the experiment. The DPPH scavenging activity is 4.88 + - 0.23 g / ml when expressed as IC 50 values. In order to confirm the antioxidant activity of RGE used in the experiment, ABTS scavenging ability was increased and concentration - dependent ABTS scavenging ability was increased. The ABTS scavenging activity was 45.55 ± 2.10 μg / ml when expressed as the IC 50 value.
In other words, the activities of DPPH and ABTS radical scavenging activity were measured to determine the antioxidative effect of Rhododendron and Licorice complex extracts. The IC 50 values were 4.88 ± 0.23 μg / ㎖ and 45.55 ± 2.10 μg / ㎖, respectively From these results, it can be confirmed that RGE has excellent antioxidative activity through DPPH and ABTS radical scavenging, and antioxidant activity can be expected to help suppress tissue damage due to reflux esophagitis (Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C. Antioxidant activity using an improved ABTS radical cation decolorization assay. Free Radic Biol Med 1999; 26 (9-10): 1231-7; DudonnS, Vitrac X, (5): 1768-8. [CrossRef], [Web of Science ®]). In this study, we investigated the effects of antioxidant properties and antioxidant properties of plant extracts, 74).
Changes in esophageal mucosal damage
Fig. 2 is a comparative photograph (A to C) explaining the effect of the complex extract on the esophageal mucosal injury and a graph (D) showing the measurement result of the damage rate of the esophagus mucosa.
The mucosal damage was not detected in the esophagus in the normal group (A) without reflux esophagitis, but in the control group (B) treated with distilled water before surgery, the esophageal mucosa was damaged by gastric acid Fever, redness, and inflammation occurred, and the area ratio of damaged area was analyzed as 47.8 ± 0.03%. In contrast, 26.3 ± 0.07% ( p <0.01) of RGE in the experimental group (C) was significantly decreased compared to the control group.
Oxidative stress biomarker changes in blood
FIG. 3 is a graph showing the results of measurement of changes in oxidative stress biomarkers of blood. FIG.
The blood collected from the heart at the time of autopsy was centrifuged and the serum was separated. Using the separated serum were measured for markers of ROS in oxidative stress control (8032 ± 217 fluorescence / min / ㎖) the value is increased compared to the control group (3693 ± 344 fluorescence / min / ㎖, p <0.01) And in the RGE - treated group (5652 ± 525 fluorescence / min / ㎖, p <0.05).
Oxidative stress biomarker changes in esophageal tissue
In the esophageal tissue after autopsy, oxidative stress biomarkers, ROS and ONOO - , TBARS (Vincent HK, Taylor AG, Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans. Int J Obes (Lond). 2006; 30 (3): 400-18) .
The ROS values were increased in the control group (8032 ± 217 fluorescence / min / mg protein) compared with the normal group (3693 ± 344 fluorescence / min / mg protein, p < / min / mg protein, p <0.01) compared to the control group. The ONOO - values in the tissues were also significantly increased in the control group (234.2 ± 8.8 fluorescence / mg protein) compared to the normal group (189.8 ± 6.5 fluorescence / mg protein, p <0.01) In the RGE - treated group (209.1 ± 4.4 fluorescence / mg protein, p <0.05), the ONOO - level was significantly decreased compared to the control group. TBARS is the normal group (0.65 ± 0.03 nmol / mg protein , p <0.001) the control group (2.03 ± 0.09 nmol / mg protein ) in the increased significantly, group of the RGE (1.08 ± 0.04 nmol / mg protein, p <0.001 , compared in ).
This suggests that oxidative stress in the reflux esophagus causes damage to the esophagus tissue, but oxidative stress, which is significantly reduced by the administration of RGE, is effective in improving the esophageal damage.
Antioxidant protein expression in esophageal tissue
Figure 4 is an electrophoresis photograph and graph comparing the effects of the combined extract on Nrf-2 and HO-1 expression.
The expression of Nrf-2 was decreased in the control group (0.25 ± 0.03) compared to the normal group (0.42 ± 0.07, p <0.05) by Western blotting in the esophagus tissues and the antioxidant enzymes Nrf-2 and HO- , And RGE group (0.48 ± 0.06, p <0.01), respectively. The expression of HO-1 was also decreased in the control group (0.39 ± 0.05) compared to the normal group (0.93 ± 0.05, p <0.001) but increased significantly in the RGE group (1.15 ± 0.09, p <0.001).
Nrf-2 is activated in the body via the pathway to HO-1 and reduces oxidative stress by synthesizing glutathione, SOD (superoxide dimutase) and catalase (Dreger H, Westphal K, Weller A , Baumann G, Stangl V, Meiners S, Stangl K. Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitor-mediated cardioprotection. Cardiovasc Res. 2009; 83 (2): 354-61; Qiu L, Song Z , Setaluri V. Oxidative stress and vitiligo: the Nrf2-ARE signaling connection, J Invest Dermatol, 2014; 134 (8): 2074-6). Increased expression of ROS in the cell plays a major role in the development of various inflammatory factors by promoting the transcription of NF-κB or AP-2. When the expression of Nrf-2 increases, (Nrf-2) in inflammatory disorders. Mutat Res. 2010; 690 (6) (1999). 1-2): 12-23). It has been reported that the antioxidant effect in the esophagus inhibits the expression of inflammatory cytokines by inhibiting the transcription of inflammatory factors such as NF-κB (Lee JS, Oh TY, Ahn BO, Cho H, Kim WB, Kim YB, Kim HJ, Hahm KB, et al. Involvement of oxidative stress in experimentally induced reflux esophagitis and Barrett's esophagus: a clue for the chemoprevention of esophageal carcinoma by antioxidants.Mutat Res 2001; 480-481: 189-200; Yoshida N. Inflammation and oxidative stress in gastroesophageal reflux disease. J Clin Biochem Nutr 2007; 40 (1): 13-23).
In this experiment, expression of Nrf-2 protein in the esophageal tissue was significantly decreased in the reflux esophagitis control group compared with that of the normal group, but was significantly increased in the RGE-treated group. HO-1 protein was also significantly decreased in the RGE-treated group compared to the control group of the reflux esophagus. The results showed that the administration of RGE effectively reduced oxidative stress, increased Nrf-2 and HO-1, and significantly inhibited mucosal injury in esophageal tissue.
Expression of inflammatory cytokines and mediators in esophageal tissue
5 and 6 are electrophoresis photographs and graphs respectively showing the effect of the complex extract on inflammation-related protein expression.
The expression of IκB and NF-κBp65 in the esophageal tissues were significantly lower in the control group (0.13 ± 0.00) than in the normal group (0.36 ± 0.02, p <0.001) (0.26 ± 0.04, p <0.01), respectively. Expression of NF-κBp65 was increased in the control group (0.70 ± 0.03) compared to the normal group (0.33 ± 0.04, p <0.001) but decreased in the RGE-treated group (0.36 ± 0.07, p <0.001)
Expression of COX-2, iNOS, TNF-α and IL-6 in the esophageal tissue of the control group was found to be 0.20 ± 0.02, p <0.001 in the control group (0.38 ± 0.03) (0.26 ± 0.00, p <0.001) in the RGE - treated group. The expression of iNOS was significantly increased in the control group (0.63 ± 0.01) compared to the normal group (0.42 ± 0.02, p <0.001) and decreased significantly in the RGE group (0.47 ± 0.04, p <0.001). The expression of TNF-α was significantly increased in the control group (0.43 ± 0.02) compared to the normal group (0.24 ± 0.03, p <0.001) but decreased significantly in the RGE-treated group (0.34 ± 0.02, p <0.01). IL-6 was significantly increased in the control group (1.30 ± 0.08) compared to the normal group (0.84 ± 0.06, p <0.001), but decreased only in the RGE group (1.20 ± 0.12).
NF-κB has been implicated in the immune function (Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994; 12: 141-79) and cell death (Van Antwerp DJ, Martin SJ, Verma IM , Green DR. Inhibition of TNF-a-induced apoptosis by NF-kappa B. Trends Cell Biol 1998; 8 (3): 107-11). Expression of NF-κB plays an important role in the development of inflammatory diseases and cancer. IκB binds to NF-κB and inhibits NF-κB migration into the nucleus (O'Neill LA, Kaltschmidt C. NF -kappa B: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci., 1997; 20 (6): 252-8).
In this experiment, the expression of IκB and NF-κBp65 was measured by western blot. As a result, the expression of IκB was significantly increased in the RGE-treated group compared to the control group, and the expression of NF-kB was significantly decreased in the RGE treated group compared to the control group. These results suggest that RGE inhibits inflammation through inhibition of NF-κBp65 activity by inhibiting the decrease of IκB expression in esophageal tissues.
NF-κBp65 promotes the transcription of factors such as TNF-a and IL-6 (Beg AA, Finco TS, Nantermet PV, Baldwin AS Jr. Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha : a mechanism for NF-kappa B activation, Mol Cell Biol. 1993; 13 (6): 3301-10), and regulates the expression of inflammatory cytokines such as COX-2 and iNOS (Lee S, Shin S, (NF-κB pathways). J Inflamm (Lond). Infectious Diseases of the Gastrointestinal Tract in Korea. J Inflamm (Lond). ; 8 (1): 16). When the human body is exposed to inflammatory stimuli, expression of TNF-a appears, and TNF-a exhibits various inflammation and cytotoxicity (Van Antwerp DJ, Martin SJ, Verma IM, Green DR. Inhibition of TNF-a-induced apoptosis by NF -Kappa B. Trends Cell Biol 1998; 8 (3): 107-11). IL-6 is known to be a cytokine that stimulates the differentiation of T cells together with TNF-a and promotes the inflammatory response (Gi Y. Effects on Squalene Secretion of TNF-a and IL-6 by Glycerol- Department of Biology, Chosun university, 2006). COX-2 plays an important role in the inflammatory response and tumorigenesis by forming PGE 2 (Lee, S, Kim, K, Kwon J, Kwak JH, Lee CK, Ha NJ, Yim D, Kim K. Anti-inflammatory function of arctin by inhibiting COX-2 expression via NF-κB pathways J Inflamm (Lond) 2011; 8 (1): 16). In addition, iNOS is expressed by massive production of NO and acts as an inflammatory mediator in cells (Ekmekcioglu S, Ellerhorst J, Smid CM, Prieto VG, Munsell M, Buzaid AC, Grimm EA. Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival.
In the present study, expression of NF-κB-related cytokine by Western blot analysis was significantly decreased in RGE-treated group and expression of TNF-α was significantly decreased in RGE-treated group compared to the control group Respectively. However, the expression of IL-6 tended to decrease. Therefore, the administration of RGE shows improvement of reflux esophagitis through reduction of inflammatory cytokine in esophageal tissue.
Effect of Rhubarb Extract on Reflux Esophagitis
FIG. 7 is a diagram schematically showing the action mechanism of the extract of Rhododendron and Licorice complex according to the present invention for exerting an effect on reflux esophagitis.
7, the effect of the rhubarb and licorice complex extracts using the reflux esophagitis model was summarized. As a result of administration of the rhubarb and licorice complex extracts to the reflux esophagitis induction model, Nrf-2 and HO -1 and NF-κBp65, respectively. In addition, the administration of RGE effectively inhibited the expression of TNF-α, IL-6, COX-2 and iNOS expressed through NF-κBp65, It can be improved.
Hereinafter, examples of the pharmaceutical composition for preventing or treating reflux esophagitis containing the extract of Rhododendron and Licorice root as an active ingredient according to the present invention will be described, but the present invention is not limited thereto.
Formulation Example 1: Powder preparation
Table 2 below shows the powder composition containing the above-described rhododendron and licorice complex extract according to the present invention as an active ingredient. Powders can be prepared by mixing the following ingredients and filling the airtight container.
Formulation Example 2: Preparation of tablets
Table 3 below shows a tablet composition containing the rhubarb and licorice complex extract according to the present invention as an active ingredient. The tablet may be prepared by mixing the following ingredients and then tableting according to a conventional tablet preparation method.
Formulation Example 3: Capsule preparation
Table 4 below shows the composition of the capsule formulation containing the above-described rhubarb and licorice complex extract according to the present invention as an active ingredient. The capsules may be prepared by mixing the following ingredients according to the conventional method for preparing a capsule, and filling the capsules with gelatin.
Formulation Example 4: Injection preparation
In the following Table 5, the composition of injections containing the above-described rhododendron and licorice complex extract according to the present invention as an active ingredient is illustrated. The injectable preparation can be prepared in the following ingredient contents per ampoule (2 ml) according to the usual injection preparation method.
Formulation Example 5: Liquid preparation
Table 6 below shows the composition of the liquid formulation containing the above-described rhododendron and licorice complex extract according to the present invention as an active ingredient. The liquid preparation is prepared by adding and dissolving each of the following ingredients in purified water according to a conventional liquid preparation method, mixing the following components after adding a proper amount of lemon flavor, adding purified water to adjust the total volume to 100 ml, filling and sterilizing in a brown bottle .
Formulation Example 6: Preparation of health food
The following Table 7 shows the composition of the functional health food containing the above-described rhododendron and licorice complex extract according to the present invention as an active ingredient. In the following composition, the composition ratio of the vitamin and mineral mixture shows that a composition suitable for health food is mixed and formulated as a preferable preparation. However, the blending ratio may be arbitrarily changed, and each ingredient may be mixed The granules can then be prepared and used in the manufacture of a health food composition according to conventional methods.
Formulation Example 7: Healthy Beverage Manufacturing
Table 8 below shows the functional health beverage composition containing the above-described rhubarb and licorice complex extract according to the present invention as an active ingredient. For example, the following ingredients are mixed in accordance with a conventional health drink manufacturing method, and the mixture is heated at 85 DEG C for about 1 hour under stirring, and the solution thus obtained is filtered to obtain a sterilized 2 liter container. After sealing sterilization, It can be stored and used. Although the following composition ratio is mixed with the ingredients suitable for the preferred beverage as a preferred embodiment, the blending ratio may be arbitrarily varied according to the regional and national preference such as the demand class, the demanding country, and the use purpose.
The preferred embodiments of the present invention have been described in detail with reference to the drawings. It will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present invention as defined by the appended claims.
Accordingly, the scope of the present invention is defined by the appended claims rather than the foregoing detailed description, and all changes or modifications derived from the meaning, range, and equivalence of the claims are included in the scope of the present invention Should be interpreted.
Claims (4)
Wherein the complex extract is a hot-water extract, and the ratio of the rhubarb and licorice contents is 1: 2 to 2: 1 in terms of rhizome: licorice weight ratio based on the content of the hot-water extraction subject ingredient.
Wherein the complex extract is a hot-water extract, and the ratio of the rhubarb and licorice contents is 1: 2 to 2: 1 in terms of rhizome: licorice weight ratio based on the content of the hot-water extraction subject ingredient.
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