KR20200092119A - Composition of the extract of combined herb CGE for preventing and treating respiratory inflammation - Google Patents
Composition of the extract of combined herb CGE for preventing and treating respiratory inflammation Download PDFInfo
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- KR20200092119A KR20200092119A KR1020190009276A KR20190009276A KR20200092119A KR 20200092119 A KR20200092119 A KR 20200092119A KR 1020190009276 A KR1020190009276 A KR 1020190009276A KR 20190009276 A KR20190009276 A KR 20190009276A KR 20200092119 A KR20200092119 A KR 20200092119A
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Abstract
Description
본 발명은 CGE 생약 조합 추출물을 유효성분으로 함유하는 호흡기성 염증 질환 예방 및 치료용 조성물에 관한 것이다.The present invention relates to a composition for the prevention and treatment of respiratory inflammatory diseases containing the CGE herbal extract combination as an active ingredient.
[문헌 1]Rogers DF, Barnes PJ. 2006. Treatment of airway mucus hypersecretion. AnnMed 38:116-125.[Document 1] Rogers DF, Barnes PJ. 2006. Treatment of airway mucus hypersecretion. AnnMed 38: 116-125.
[문헌 2]Voynow JA, Rubin BK. Mucins, mucus and sputum. 2009. Chest 135:505-512.[Document 2] Voynow JA, Rubin BK. Mucins, mucus and sputum. 2009. Chest 135:505-512.
[문헌 3]Li JD, Dohrman AF, Gallup M, Miyata S, Gum JR, Kim YS, Nadel JA, Prince A, Basbaum CB. 1997. Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc Natl Acad Sci USA 94: 967-972.Literature 3 Li JD, Dohrman AF, Gallup M, Miyata S, Gum JR, Kim YS, Nadel JA, Prince A, Basbaum CB. 1997. Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc Natl Acad Sci USA 94: 967-972.
[문헌 4]Takeyama K, Dabbagh K, Lee HM, Agusti C, Lausier JA, Ueki IF, Grattan KM, Nadel JA. 1999. Epidermal growth factor system regulates mucin production in airways. Proc Natl Acad Sci USA 96: 3081-3086.[Document 4] Takeyama K, Dabbagh K, Lee HM, Agusti C, Lausier JA, Ueki IF, Grattan KM, Nadel JA. 1999. Epidermal growth factor system regulates mucin production in airways. Proc Natl Acad Sci USA 96: 3081-3086.
[문헌 5]Shao MX, Ueki IF, Nadel JA. 2003. Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci USA 100:11618-11623.[Document 5] Shao MX, Ueki IF, Nadel JA. 2003. Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci USA 100:11618-11623.
[문헌 6]Cohn L, Whittaker L, Niu N, Homer RJ. 2002. Cytokine regulation of mucus production in a model of allergic asthma. Novartis Found Symp 248:201-213. [Document 6] Cohn L, Whittaker L, Niu N, Homer RJ. 2002. Cytokine regulation of mucus production in a model of allergic asthma. Novartis Found Symp 248:201-213.
[문헌 7]Evans CM, Koo JS. 2009. Airway mucus: the good, the bad, the sticky. Pharmacol Ther 121(3): 332-348.[Document 7] Evans CM, Koo JS. 2009. Airway mucus: the good, the bad, the sticky. Pharmacol Ther 121(3): 332-348.
[문헌 8]Hewson CA, Edbrooke MR, Johnston SL. 2004. PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells via PKC, EGF/TGF-alpha, Ras/Raf, MEK, REK and Sp1-dependent mechanisms. J Mol Biol 344:683-695.[Document 8] Hewson CA, Edbrooke MR, Johnston SL. 2004. PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells via PKC, EGF/TGF-alpha, Ras/Raf, MEK, REK and Sp1-dependent mechanisms. J Mol Biol 344:683-695.
[문헌 9]Hong DH, Petrovics G, Anderson WB, Forstner J, Forstner G. 1999. Induction of mucin gene expression in human colonic cell lines by PMA is dependent on PKC-epsilon. Am J Physiol 277:G1041-G1047.[Document 9] Hong DH, Petrovics G, Anderson WB, Forstner J, Forstner G. 1999.Induction of mucin gene expression in human colonic cell lines by PMA is dependent on PKC-epsilon. Am J Physiol 277: G1041-G1047.
[문헌 10]Pon DJ, van Staden CJ, Boulet L, Rodger IW. 1994. Hyperplastic effects of aerosolized sodium metabisulfite on rat airway mucus-secretory epithelial cells. Can J Physiol Pharmacol 72(9): 1025-1030.[Document 10]Pon DJ, van Staden CJ, Boulet L, Rodger IW. 1994. Hyperplastic effects of aerosolized sodium metabisulfite on rat airway mucus-secretory epithelial cells. Can J Physiol Pharmacol 72(9): 1025-1030.
호흡기에 존재하는 점액(mucus)의 생리적 기능은 주로 점액성 당단백질 (mucous glycoprotein)인 뮤신(mucin)의 물리화학적 성질 때문인데 뮤신은 분자량 수백만 dalton의 당단백질(glycoprotein)로 그 탄수화물의 구조에 있어 상당한 다양성을 나타낸다(Rogers DF, Barnes PJ. 2006. Treatment of airway mucus hypersecretion. AnnMed 38:116-125). 뮤신은 정상 생리상태에서는 적정한 점도(viscosity)가 유지되어 섬모세포의 운반작용에 의해 배출이 용이하게 되어 있어 기도 및 폐내 이물질 제거, 폐의 윤활작용 등의 중요한 기능을 담당하고 있다(Voynow JA, Rubin BK. Mucins, mucus and sputum. 2009. Chest 135:505-512). 섬모는 미세먼지, 화석연료의 연소에 의해 발생되는 대기오염 물질, 자극성 기체의 흡입이나, 감염, 흡연 등의 자극에 의해 그 길이가 단축되기도 하고 섬모운동 자체가 활발하지 못하게 되거나 정지하기도 한다. 배상세포(goblet cell)는 위에 언급한 자극들이나, 천식, 만성 기관지염 등의 질환으로 세포수가 증가하고 분비 점액을 증가시키며 증가된 점액은 객담(sputum)의 형태로 배출된다(Li JD, Dohrman AF, Gallup M, Miyata S, Gum JR, Kim YS, Nadel JA, Prince A, Basbaum CB. 1997. Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc Natl Acad Sci USA 94: 967-972.). The physiological function of mucus present in the respiratory system is mainly due to the physicochemical properties of mucin, a mucous glycoprotein. Mucin is a glycoprotein with a molecular weight of several million daltons, which is in the structure of its carbohydrates. Significant diversity (Rogers DF, Barnes PJ. 2006. Treatment of airway mucus hypersecretion. AnnMed 38: 116-125). In normal physiological state, mucin maintains an appropriate viscosity and is easily discharged by the transport of ciliated cells, and thus plays an important role in removing foreign substances in the airways and lungs, and lubricating the lungs (Voynow JA, Rubin) BK. Mucins, mucus and sputum. 2009. Chest 135:505-512). Cilia may be shortened in length due to stimulation of fine dust, air pollutants generated by the combustion of fossil fuels, inhalation of irritating gases, or infection, smoking, and cilia movement itself may become inactive or stop. Goblet cells are the above-mentioned stimuli, but diseases such as asthma and chronic bronchitis increase the number of cells, increase secretory mucus, and the increased mucus is discharged in the form of sputum (Li JD, Dohrman AF, Gallup M, Miyata S, Gum JR, Kim YS, Nadel JA, Prince A, Basbaum CB. 1997.Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease.Proc Natl Acad Sci USA 94: 967-972 .).
이와 같이, 정상 생리상태 혹은 호흡기 임상에서 일반적으로 가벼운 질환의 발생 시에는 기도점액의 생체방어적 역할이 요긴하지만 기도 뮤신의 양 혹은 질의 이상, 예를 들어, 천식, 낭포성 섬유증, 만성 폐쇄성 폐질환(chronic obstructive pulmonary disease)과 같은 질환 발생 시 수반되는 극심한 점액의 점도 증가 및 점액의 물리화학적 특성 변화에 기인한 점액전(mucus plug)의 형성은 기도 분비물의 배출을 오히려 방해하며 침착된 분비물에 의한 기관지 폐쇄, 감염 발생 시 배농 장애 등을 유발한다(Takeyama K, Dabbagh K, Lee HM, Agusti C, Lausier JA, Ueki IF, Grattan KM, Nadel JA. 1999. Epidermal growth factor system regulates mucin production in airways. Proc Natl Acad Sci USA 96: 3081-3086., Shao MX, Ueki IF, Nadel JA. 2003. Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci USA 100:11618-11623). As such, in normal physiological or respiratory clinical cases, in the event of mild disease, a biodefensive role of airway mucus is required, but the amount or quality of airway mucin is abnormal, for example, asthma, cystic fibrosis, chronic obstructive pulmonary disease When a disease such as (chronic obstructive pulmonary disease) occurs, the formation of a mucus plug due to an increase in viscosity of the mucus and a change in the physicochemical properties of the mucus rather interferes with the discharge of airway secretions and is caused by the deposited secretions. Causes bronchial obstruction and drainage disorders when infection occurs (Takeyama K, Dabbagh K, Lee HM, Agusti C, Lausier JA, Ueki IF, Grattan KM, Nadel JA. 1999. Epidermal growth factor system regulates mucin production in airways.Proc Natl Acad Sci USA 96: 3081-3086., Shao MX, Ueki IF, Nadel JA. 2003. Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells.Proc Natl Acad Sci USA 100:11618-11623 ).
따라서, 기도점액의 과다분비 혹은 점도의 변화로 큰 고통을 겪게되는 호흡기 질환 환자에 있어서는 기도점액 분비의 조절이 질환으로 인한 고통의 경감과 질환의 치료에 있어 대단히 중요하다(Cohn L, Whittaker L, Niu N, Homer RJ. 2002. Cytokine regulation of mucus production in a model of allergic asthma. Novartis Found Symp 248:201-213.). Therefore, in patients with respiratory diseases who suffer from great pain due to excessive secretion or changes in viscosity of the airway mucus, control of airway mucus secretion is very important in alleviating pain caused by the disease and treating the disease (Cohn L, Whittaker L, Niu N, Homer RJ. 2002. Cytokine regulation of mucus production in a model of allergic asthma.Novartis Found Symp 248:201-213.).
지금까지, 호흡기 질환의 임상에서 점액분비 및 조절 이상의 치료에는, (1) 점액성 분비물의 점도를 낮추어 분비물의 배출을 용이하게 하는 방법, (2) 분비물의 배출을 더욱 자극하여 분비물을 용이하게 다량 배출시키려는 방법 등이 시도되어 왔으며 점액성 분비물의 점도를 낮추기 위해서는 점액용해제 (mucolytics) 를 사용해 왔으나, 이같은 약물의 사용으로 점액의 점도 감소가 지나칠 경우에는 오히려 점액이 원위 기관지로 흘러 들어가, 기관지 경축(bronchospasm)등으로 기관지 폐쇄가 더욱 악화된다(Evans CM, Koo JS. 2009. Airway mucus: the good, the bad, the sticky. Pharmacol Ther 121(3): 332-348.). So far, in the clinical treatment of respiratory diseases, for the treatment of mucus secretion and control abnormalities, (1) a method of lowering the viscosity of mucous secretions to facilitate the discharge of secretions, (2) stimulating the discharge of secretions to facilitate secretion of large amounts Methods have been tried to discharge, and mucolytics have been used to lower the viscosity of mucus secretions.However, if the viscosity of the mucus is excessively reduced due to the use of such drugs, the mucus flows into the distal bronchus, thereby preventing bronchospasm ( bronchospasm, etc., worsening bronchial obstruction (Evans CM, Koo JS. 2009.Airway mucus: the good, the bad, the sticky.Pharmacol Ther 121(3): 332-348.)
또한, 점도 저하 후의 기도점액의 물리적 흡인법은 기도 벽의 자극을 유발하고, 반사기전에 의해 점액 분비를 오히려 자극하게 되며 마취 하에서 그런 방법이 시도된다고 해도 점액의 제거는 피드백 기전(feedback mechanism)을 통해 점액의 생성과 분비를 더욱더 자극하므로 물리적 방법은 점액 과다분비로 고생하는 환자의 치료에 큰 도움이 되지 못했다. 따라서, 현재 호흡기 질환의 임상에서 원칙적으로 권장되는 방법은, 충분한 수분의 섭취를 통해 환자 본인이 기침을 하여 점액(객담)이 잘 배출될 정도로 점도를 조절하는 방법인데 아직 기존 의약품으로는 불가능하다고 보고 있다(Rogers DF, Barnes PJ. 2006. Treatment of airway mucus hypersecretion. AnnMed 38:116-125.).In addition, the physical aspiration method of airway mucus after viscosity decrease causes irritation of the airway wall, and rather stimulates mucus secretion by a reflex mechanism, and even if such a method is attempted under anesthesia, the removal of mucus is via a feedback mechanism. Physical methods have not been of great help in the treatment of patients suffering from mucus hypersecretion, as it stimulates the production and secretion of mucus more and more. Therefore, currently, the recommended method in clinical practice of respiratory diseases is a method of adjusting the viscosity so that the patient himself coughs and discharges mucus (sputum) well through intake of sufficient moisture. (Rogers DF, Barnes PJ. 2006. Treatment of airway mucus hypersecretion. AnnMed 38: 116-125.).
그러나 상기 문헌의 어디에도 금은화, 맥문동, 사삼, 길경 및 지실로 구성된 조합생약 추출물의 호흡기성 염증 질환 치료제로서의 효능이 교시되거나 개시된 바는 없다.However, none of the above documents teaches or discloses the efficacy of a combination herbal extract composed of gold, silver, and green leaves, Ginseng, Gilkyung, and Jisil as a therapeutic agent for respiratory inflammatory diseases.
인동덩굴 꽃(금은화)은 인동과(Caprifoliaceae)에 속하는 인동덩굴(Lonicera japonica Thunberg)의 꽃봉오리로서, 꽃에는 루테올린 (luteolin), 이노시톨(inositol), 이소클로로겐산 (isochlrorogenic acid), 클로로겐산 (chlorogenic acid) 등을 함유하며, 항균작용 등이 알려져 있다(정보섭외, 도해 향약대사전, 영림사, p939-940, 1998년).The honeysuckle flower (Gold and Silver) is a bud of the honeysuckle (Lonicera japonica Thunberg) belonging to the family Caprifoliaceae, and luteolin, inositol, isochlrorogenic acid, and chlorogenic acid are in the flower. ), and its antibacterial action is known (information submission, Dohae Hyangyak Daejeon, Yeonglimsa, p939-940, 1998).
맥문동은 백합과(liliaceae)에 속하는 맥문동 (iriope platyphylla Wang et Tang)의 괴경으로서, 시토스테롤(sitosterol), 스티그마스테롤(stigmasterol), 스테로이드 사포닌(steroid saponin) 등을 함유하며, 혈당강하작용, 항균작용 등이 알려져 있다(정보섭외, 도해 향약대사전, 영림사, p177-178, 1998년).Macmundong is a tuber of the iriope platyphylla Wang et Tang belonging to the Liliaceae family, and contains citosterol, stigmasterol, and steroid saponin, and has hypoglycemic and antibacterial effects. This is known (Information Submission, Dohae Hyangyakdae Dictionary, Yeonglimsa, p177-178, 1998).
사삼은 초롱꽃과 (Campanulaceae)에 속하는 사삼 (Adenophora tryphilla var. japonica Hara)의 뿌리로서, 트리테르페노이드 사포닌 (triterpenoid saponin) 등을 함유하며, 강심작용, 항진경작용, 등이 알려져 있다(정보섭외, 도해 향약대사전, 영림사, p1086-1087, 1998년).Ginseng is the root of Adenophora tryphilla var. japonica Hara belonging to the Campanulaceae family, contains triterpenoid saponin, etc., and is known for its strong, antispasmodic, etc. , Dohae Hyangyak Daejeon, Yeonglimsa, p1086-1087, 1998).
길경은 초롱꽃과 (Campanulaceae)에 속하는 도라지 (Platycodum grandiflorum A. DC)의 뿌리로서, 폴리갈라식산(polygalacic acid), 플라티코디게닌(platycodigenin), 플라티코도닌(platycodonin), 이눌린(inulin) 등을 함유하며, 거담작용, 배농작용, 등이 알려져 있다(정보섭외, 도해 향약대사전, 영림사, p1089-1090, 1998년).Gilgyeong is the root of the bellflower (Platycodum grandiflorum A. DC) belonging to the Campanulaceae family, polygalacic acid, platicodigenin, platycodonin, inulin, etc. It contains, and is known for the expectorant action, drainage action, etc. (information submission, Dohae Hyangyakdae, Yeonglimsa, p1089-1090, 1998).
지실(Ponciri Fructus)은 탱자나무(Poncirius trifoliata)의 익지 않은 열매를 말린 것으로, 대부분 반구형이고, 바깥 면은 진한 녹색에서 갈색을 띠며 거칠고 유실(油室)에 의한 오목한 작은 점이 많다. 특이한 냄새가 있고 맛은 쓰며, 방향성 고미건위약에 쓰인다 (한약 규격집 주해서, 한국메디칼인덱스사, p.604, 1988). The branch (Ponciri Fructus) is a dried fruit of the primrose ( Poncirius trifoliata ), mostly hemispherical, dark green to brown on the outside, rough, with many concave small spots due to loss. It has a peculiar smell, a bitter taste, and is used in aromatic gomi placebo (Korean Medicine Standards Collection, Korea Medical Index, p.604, 1988).
본원 발명자들은 본 발명의 조합 추출물을 대상으로 호흡기성 염증 질환 치료 효과 평가실험을 시행한 결과, 호흡기 염증 발생 시 과다하게 생성 및 분비되는 뮤신(점액, 객담의 가장 주된 생화학적 구성요소)의 유전자 발현 및 생성 (production)을 억제하였고, 그람음성세균이 함유하는 내독소(endotoxin)에 의해 유발된 호흡기 염증의 지표인 TNF-α의 과다 생성 및 분비를 억제하였고, in vivo 점액 과다분비를 억제하였으며, 이산화황(SO2)의 흡입으로 유발된 호흡기 염증에 기인한 in vivo 점액 과다분비도 억제하는 강력한 호흡기성 염증 질환 치료효과를 나타냄을 확인함으로써, 본 발명을 완성하게 되었다.The inventors of the present invention conducted the experiment for evaluating the effect of treating respiratory inflammatory diseases on the combination extract of the present invention, and as a result, gene expression of mucin (mucus, the most important biochemical component of sputum) that is excessively produced and secreted when respiratory inflammation occurs And suppressed production, inhibited overproduction and secretion of TNF-α, an indicator of respiratory inflammation caused by endotoxins contained in Gram-negative bacteria, and inhibited hypersecretion in mucus in vivo. The present invention has been completed by confirming that it exhibits a potent respiratory inflammatory disease treatment effect that also suppresses in vivo mucus hypersecretion due to respiratory inflammation caused by inhalation of sulfur dioxide (SO 2 ).
따라서 본 발명의 목적은 금은화, 맥문동, 사삼, 길경 및 지실로 구성된 조합생약 추출물을 유효성분으로 포함하는 호흡기성 염증 질환 예방 및 치료용 약학조성물, 건강기능식품 및 식품첨가제를 제공하는데 있다.Accordingly, an object of the present invention is to provide a pharmaceutical composition, health functional food and food additives for the prevention and treatment of respiratory inflammatory diseases comprising a combination herbal extract composed of gold, silver, and green leaves, and ginseng, and ginseng as active ingredients.
상기와 같은 목적을 달성하기 위하여 본 발명은 금은화, 맥문동, 사삼, 길경 및 지실로 구성된 조합생약 추출물을 유효성분으로 함유하는 호흡기성 염증 질환의 예방 및 치료용 약학 조성물을 제공한다. In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention and treatment of respiratory inflammatory disease, which contains as an active ingredient a combination herbal extract consisting of gold, silver, pulmonary, sasam, gilkyung and gissil.
본원에서 정의되는 생약 조합은 금은화, 맥문동, 사삼, 길경 및 지실로 구성된 조합생약의 중량 배합 조합비가 바람직하게는 0.1 내지 20 중량부 (w/w): 0.1 내지 20 중량부 (w/w); 0.1 내지 20 중량부 (w/w); 0.1 내지 20 중량부 (w/w); 1 중량부 (w/w)인 조합, 보다 바람직하게는, 0.5 내지 10 중량부 (w/w): 0.5 내지 10 중량부 (w/w); 0.1 내지 10 중량부 (w/w); 0.1 내지 10 중량부 (w/w); 1 중량부 (w/w), 보다 더 바람직하게는, 1 내지 8 중량부 (w/w): 1 내지 8 중량부 (w/w); 1 내지 8 중량부 (w/w); 1 내지 8 중량부 (w/w); 1 중량부 (w/w)로 배합된 생약 조합을 포함한다. Herbal medicine combinations as defined herein, the weight ratio of the combination of herbal medicines consisting of gold, silver, pulmonary ginseng, ginseng, gilkyung and jisil is preferably 0.1 to 20 parts by weight (w/w): 0.1 to 20 parts by weight (w/w); 0.1 to 20 parts by weight (w/w); 0.1 to 20 parts by weight (w/w); 1 part by weight (w/w) in combination, more preferably 0.5 to 10 parts by weight (w/w): 0.5 to 10 parts by weight (w/w); 0.1 to 10 parts by weight (w/w); 0.1 to 10 parts by weight (w/w); 1 part by weight (w/w), even more preferably, 1 to 8 parts by weight (w/w): 1 to 8 parts by weight (w/w); 1 to 8 parts by weight (w/w); 1 to 8 parts by weight (w/w); Includes herbal combinations formulated in 1 part by weight (w/w).
본원에서 정의되는 추출물은 물, 주정, 탄소수 1 내지 4의 저급 알콜 또는 이들의 혼합용매, 바람직하게는 물, 주정, 에탄올 또는 이들의 혼합용매, 바람직하게는 물 또는 10 내지 90% 에탄올 또는 주정, 보다 바람직하게는 물 또는 10 내지 50% 에탄올 또는 주정에 가용한 추출물을 포함한다.The extract as defined herein is water, spirits, lower alcohols having 1 to 4 carbon atoms or mixed solvents thereof, preferably water, spirits, ethanol or mixed solvents thereof, preferably water or 10 to 90% ethanol or spirits, More preferably, it contains water or 10-50% ethanol or an extract soluble in alcohol.
본원에서 정의되는 “호흡기성 염증 질환”은 천식, 급성 기관지염, 폐렴, 만성 기관지염, 기관지 확장증, 편도선염, 인후염, 만성 폐쇄성 폐질환(chronic obstructive pulmonary disease), 낭포성 섬유증, 폐섬유화증, 바람직하게는, 천식, 낭포성 섬유증, 만성 폐쇄성 폐질환(chronic obstructive pulmonary disease), 보다 바람직하게는, 미세먼지로 기인한 천식, 만성 폐쇄성 폐질환(chronic obstructive pulmonary disease)을 포함한다.“Respiratory inflammatory disease” as defined herein is asthma, acute bronchitis, pneumonia, chronic bronchitis, bronchiectasis, tonsillitis, sore throat, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary fibrosis, preferably , Asthma, cystic fibrosis, chronic obstructive pulmonary disease, more preferably asthma caused by fine dust, chronic obstructive pulmonary disease .
이하, 본 발명의 생약 추출물을 수득하는 방법을 상세히 설명한다.Hereinafter, a method for obtaining the herbal extract of the present invention will be described in detail.
먼저, 건조 상태의 금은화, 맥문동, 사삼, 길경 및 지실로 배합된 생약 조합에 추출용매로서 정제수를 포함한 물, C1 내지 C4의 저급 알콜 또는 이들의 혼합용매, 바람직하게는 물, 에탄올 또는 이들의 혼합용매, 바람직하게는 물 또는 10 내지 90% 에탄올, 보다 바람직하게는 물 또는 10 내지 50% 에탄올을 시료 중량의 약 1 내지 20배, 바람직하게는 10 내지 14배 부피 양(w/v)을 넣어, 20 내지 160℃, 바람직하게는 80 내지 120℃에서 약 1시간 내지 48시간, 바람직하게는 2시간 내지 24시간 동안 냉침추출, 열수추출, 초음파 추출, 환류냉각 추출, 가열추출 등, 바람직하게는 환류냉각 추출법으로 추출하고, 동결건조 및 분쇄하여 본 발명의 조합 추출물을 얻을 수 있다. First, water containing purified water as an extraction solvent in a combination of herbal medicines composed of dried gold and silver coins, McMun-dong, Ginseng, Gilkyung and Jisil, lower alcohols of C 1 to C 4 or mixed solvents thereof, preferably water, ethanol or these A mixed solvent of, preferably water or 10 to 90% ethanol, more preferably water or 10 to 50% ethanol, about 1 to 20 times the sample weight, preferably 10 to 14 times the volume amount (w/v) Put, 20 to 160 ℃, preferably 80 to 120 ℃ for about 1 hour to 48 hours, preferably 2 hours to 24 hours for cold immersion extraction, hot water extraction, ultrasonic extraction, reflux cooling extraction, heating extraction, etc., preferably It can be extracted by reflux cooling extraction method, lyophilized and pulverized to obtain a combination extract of the present invention.
따라서 본 발명은 상기 제조방법으로 얻어진 금은화, 맥문동, 사삼, 길경 및 지실로 구성된 조합생약 추출물을 유효성분으로 함유하는 호흡기성 염증 질환 예방 및 치료용 약학 조성물을 제공한다. Therefore, the present invention provides a pharmaceutical composition for the prevention and treatment of respiratory inflammatory diseases, which contains as an active ingredient a combination herbal extract composed of gold, silver, macmundong, ginseng, gilkyung and gisil obtained by the above manufacturing method.
본 발명에 따른 추출물을 포함하는 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 추출물을 포함하는 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무,알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화 할 경우에는 보통 사용하는 충진제, 중량제, 결합제, 습윤제, 봉해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물 및 분획물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. The pharmaceutical composition comprising the extract according to the present invention is formulated in the form of external preparations, suppositories and sterile injectable solutions for oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc. Can be used interchangeably. Carriers, excipients and diluents that may be included in the composition comprising the extract include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate , Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared using diluents or excipients such as fillers, weights, binders, wetting agents, sealants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in the extract and fraction, for example, starch, calcium carbonate, sucrose It is prepared by mixing (sucrose) or lactose, gelatin, etc. In addition, lubricants such as magnesium stearate and talc are used in addition to simple excipients. Liquid preparations for oral use include suspensions, intravenous solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, can be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.
상기한 제제에는 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤젤라틴 등이 사용될 수 있다.Non-aqueous solvents, suspending agents such as propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as the above-described preparation. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin butter, and glycerol gelatin may be used.
본 발명의 추출물을 포함하는 약학 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나 바람직한 효과를 위해서, 본 발명의 정제물을 포함하는 약학조성물은 1일 0.0001 내지 100 mg/kg으로, 바람직하게는 0.001 내지 100 mg/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. The preferred dosage of the pharmaceutical composition comprising the extract of the present invention depends on the patient's condition and body weight, the degree of disease, the drug form, the route of administration and the duration, but can be appropriately selected by those skilled in the art. However, for the desired effect, the pharmaceutical composition containing the tablet of the present invention is preferably administered at 0.0001 to 100 mg/kg per day, preferably 0.001 to 100 mg/kg per day. Administration may be administered once a day, or may be divided into several times. The above dosage does not limit the scope of the invention in any aspect.
본 발명의 추출물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내(Intracerebroventricular) 주사에 의해 투여될 수 있다. The extract of the present invention can be administered by various routes to mammals such as rats, mice, livestock, and humans. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dura mater or intracerebroventricular injection.
또한, 본 발명은 금은화, 맥문동, 사삼, 길경 및 지실로 구성된 조합생약 추출물을 유효성분으로 함유하는 호흡기성 염증 질환의 예방 또는 개선용 건강기능식품을 제공한다. In addition, the present invention provides a health functional food for the prevention or improvement of respiratory inflammatory diseases, which contains a combination herbal extract composed of gold, silver, and green leaves, ginseng, ginseng, and ginseng as an active ingredient.
본원에서 정의되는 "건강기능식품"은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다."Health functional food" as defined herein refers to food manufactured and processed using raw materials or ingredients having useful functionality for the human body according to the Act No. 6727 on the Health Functional Food, and "functional" means It means to ingest for the purpose of obtaining useful effects for health purposes such as adjusting nutrients for structure and function or physiological action.
본 발명의 목적 질환의 예방 또는 개선을 위한 건강기능식품은, 조성물 총 중량에 대하여 상기 정제물을 0.01 내지 95%, 바람직하게는 1 내지 80% 중량백분율로 포함한다.Health functional food for the prevention or improvement of the target disease of the present invention, the tablets in an amount of 0.01 to 95%, preferably 1 to 80% by weight, based on the total weight of the composition.
또한, 목적 질환의 예방 또는 개선을 위한 목적으로 산제, 과립제, 정제, 캡슐제, 환제, 현탁액, 에멀젼, 시럽 등의 약학 투여형태 또는 티백제, 침출차, 건강 음료 등의 형태인 건강기능식품으로 제조 및 가공이 가능하다.In addition, for the purpose of preventing or improving the target disease, it is manufactured as a pharmaceutical functional form such as powder, granule, tablet, capsule, pill, suspension, emulsion, syrup, or health functional food in the form of tea bag, leach tea, health drink, etc. And processing is possible.
또한, 본 발명은 금은화, 맥문동, 사삼, 길경 및 지실로 구성된 조합생약 추출물을 유효성분으로 함유하는 호흡기성 염증 질환의 예방 또는 개선용 건강보조식품을 제공한다.In addition, the present invention provides a health supplement for the prevention or improvement of respiratory inflammatory diseases, which contains a combination herbal extract consisting of gold, silver, and green leaves, ginseng, and ginseng as an active ingredient.
또한, 본 발명은 금은화, 맥문동, 사삼, 길경 및 지실로 구성된 조합생약 추출물을 유효성분으로 함유하는 호흡기성 염증 질환의 예방 또는 개선용 식품 또는 식품첨가물을 제공한다.In addition, the present invention provides a food or food additive for the prevention or improvement of respiratory inflammatory diseases, which contains a combination herbal extract composed of gold, silver, and green leaves, ginseng, and ginseng as an active ingredient.
또한 상기 건강기능식품은 식품첨가물을 추가로 포함할 수 있으며, "식품첨가물"로서의 적합여부는 다른 규정이 없는 한 식품의약품안정청에 승인된 식품첨가물공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다. In addition, the health functional foods may additionally include food additives, and whether or not they are suitable as "food additives" is related to the product according to the General Regulations and General Test Methods of the Food Additives Code approved by the Korea Food and Drug Administration unless otherwise specified. Judging by standards and standards.
상기 "식품첨가물공전"에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀롤로오스, 구아검 등의 천연첨가물, L-글루타민산나트륨제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합 제제류들을 들 수 있다.Items listed in the "Food Additives Fair" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamon acid, natural additives such as chromosomes, licorice extract, crystalline cellulose, and guar gum, L- And mixed preparations such as sodium glutamate, noodle-added alkalis, preservatives, and tar colorants.
본 발명의 추출물이 포함된 기능성 식품으로는 빵, 떡류, 건과류, 캔디류, 초콜릿류, 츄잉껌, 쨈류와 같은 과자류 아이스크림류, 빙과류, 아이스크림 분말류와 같은 아이스크림 제품류 우유류, 저지방 우유류, 유당분해우유, 가공유류, 산양유, 발효유류, 버터유류, 농축유류, 유크림류, 버터유, 자연치즈, 가공치즈, 분유류, 유청류와 같은 유가공품류 식육가공품, 알가공품, 햄버거와 같은 식육제품류 어묵, 햄, 소세지, 베이컨 등의 어육가공품과 같은 어육제품류 라면류, 건면류, 생면류, 유탕면류, 호화건먼류, 개량숙면류, 냉동면류, 파스타류와 같은 면류 과실음료, 채소류음료, 탄산음료, 두유류, 요구르트 등의 유산균음료, 혼합음료와 같은 음료 간장, 된장, 고추장, 춘장, 청국장, 혼합장, 식초, 소스류, 토마토케첩, 카레, 드레싱과 같은 조미식품 마가린, 쇼트닝 및 피자를 들 수 있으나, 이에 제한되는 것은 아니다.Functional foods containing the extract of the present invention include bread, rice cake, dried fruits, candy, chocolates, chewing gum, confectionary ice creams, such as ice cream, ice cream powders, milk products, low fat milk, lactose-degraded milk , Processed oil, goat oil, fermented milk, butter oil, condensed milk, milk cream, butter oil, natural cheese, processed cheese, milk powder, dairy products such as whey, meat processed products, egg processed products, meat products such as hamburger fish cake, ham Fish products such as fish meat products such as sausage, bacon, ramen, dried noodles, raw noodles, fried noodles, luxurious dried noodles, improved noodles, frozen noodles, pasta, etc. Fruit fruits, vegetable drinks, carbonated drinks, soy milk , Lactic acid bacteria beverages such as yogurt, beverages such as mixed beverages, soy sauce, miso, red pepper paste, chunjang, cheonggukjang, mixed vinegar, sauces, tomato ketchup, curry, seasoning foods such as curry, dressing, margarine, shortening and pizza. It is not limited.
본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 정제물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, (예를 들어, 포도당, 과당 등); 디사카라이드, (예를 들어 말토스, 슈크로스 등); 및 폴리사카라이드, (예를 들어 덱스트린, 시클로덱스트린 등)과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등)) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100㎖ 당 일반적으로 약 1~20g, 바람직하게는 약 5~12g 이다.The health functional beverage composition of the present invention is an essential component in the indicated proportions, and there is no particular limitation on other components except for containing the above-mentioned tablets, and may contain various flavoring agents or natural carbohydrates, etc., as additional components, as in conventional beverages. . Examples of the natural carbohydrates described above include monosaccharides (eg, glucose, fructose, etc.); Disaccharides (eg maltose, sucrose, etc.); And polysaccharides, common sugars such as (eg, dextrin, cyclodextrin, etc.), and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatine, stevia extract (for example, rebaudioside A, glycyrrhizine, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. have. The ratio of the natural carbohydrate is generally about 1 to 20 g per 100 ml of the composition of the present invention, preferably about 5 to 12 g.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 조성물들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다. In addition to the above, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and neutralizing agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and the like. It may contain salts, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonic acid used in carbonated beverages, and the like. In addition, the compositions of the present invention may contain flesh for the preparation of natural fruit juice and fruit juice beverages and vegetable beverages. These ingredients can be used independently or in combination. The proportion of these additives is not so critical, but is generally selected from 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
또한, 본 발명의 추출물은 목적 질환의 예방 효과를 목적으로 식품 또는 음료에 첨가될 수 있다. 이 때, 식품 또는 음료 중의 상기 추출 정제물의 양은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100㎖ 을 기준으로 0.02 내지 5g, 바람직하게는 0.3 내지 1g 의 비율로 가할 수 있다.In addition, the extract of the present invention may be added to a food or beverage for the purpose of preventing a target disease. In this case, the amount of the purified extract in food or beverage may be added at 0.01 to 15% by weight of the total food weight, and the healthy beverage composition may be added at a rate of 0.02 to 5g, preferably 0.3 to 1g, based on 100ml. have.
상기 건강기능식품을 제조하는 과정에서 음료를 포함한 식품에 첨가되는 본 발명에 따른 정제물은 필요에 따라 그 함량을 적절히 가감할 수 있다. In the process of manufacturing the health functional food, the purified product according to the present invention, which is added to foods including beverages, may appropriately adjust its content as necessary.
본 발명에 따른 조합 추출물은 호흡기성 염증 질환 치료 효과 평가실험에서 호흡기 염증 발생 시 과다하게 생성 및 분비되는 뮤신(점액, 객담의 가장 주된 생화학적 구성요소)의 유전자 발현 및 생성 (production)을 억제하였고, 그람음성세균이 함유하는 내독소(endotoxin)에 의해 유발된 호흡기 염증의 지표인 TNF-α의 과다 생성 및 분비를 억제하였고, in vivo 점액 과다분비를 억제하였으며, 이산화황(SO2)의 흡입으로 유발된 호흡기 염증에 기인한 in vivo 점액 과다분비도 억제하는 강력한 호흡기성 염증 질환 치료효과를 나타냄을 확인함으로써, 호흡기성 염증 질환의 예방 및 치료용 약학조성물, 건강기능식품 및 식품첨가제로 유용하게 이용될 수 있다. The combination extract according to the present invention inhibited gene expression and production of mucin (mucus, the most important biochemical component of sputum) that is excessively produced and secreted when respiratory inflammation occurs in an evaluation experiment for the treatment of respiratory inflammatory diseases. , Inhibits overproduction and secretion of TNF-α, an indicator of respiratory inflammation caused by endotoxins contained in Gram-negative bacteria, inhibited hypersecretion in mucus in vivo, and was inhaled by sulfur dioxide (SO 2 ) Effectively used as a pharmaceutical composition, health functional food and food additive for prevention and treatment of respiratory inflammatory diseases by confirming that it exhibits a powerful respiratory inflammatory disease treatment effect that also suppresses hypersecretion of mucus caused in vivo due to induced respiratory inflammation Can be.
도 1은 시료의 NCI-H292 세포에서의 PMA-유도 MUC5AC 유전자 발현에 미치는 영향을 나타낸 도이며 (NCI-H292 세포에 다양한 농도의 시료를 30분간 처치하고 24시간 동안 PMA (10ng/㎖)로 자극시켰으며 MUC5AC 유전자 발현을 RT-PCR로 측정하고 정량적 대조군으로서 구조적으로 발현되는 housekeeping gene 중 하나로 small ribosomal subunit protein을 코딩하는 Rig/S15 rRNA를 이용하였고, 3개의 독립적 실험을 수행하고 대표적인 데이터를 표기함; 여기에서 cont: control, concentration unit은 mg/㎖임);
도 2는 시료의 NCI-H292 세포에서의 PMA-유도 MUC5AC 뮤신 생성에 미치는 영향을 나타낸 도이며 (NCI-H292 세포에 다양한 농도의 시료를 30분간 처치하고 24시간 동안 PMA (10ng/㎖)로 자극시켰으며 ELISA로 MUC5AC 뮤신 생성 정도의 측정을 위하여 세포 용해물을 회수하였고 3개의 독립적 실험을 수행하고 대표적인 데이터를 표기하였고 개개 바(bar)는 대조군을 100 %로 환산했을 때 3개 배양 웰의 평균과 평균의 표준오차 (mean ±S.E.M.)로 표기하였음. * 는 대조군 대비 유의적으로 상이함 (p<0.05); + 는 PMA 단독군과 유의적으로 상이함 (p<0.05)을 의미함. 여기에서 cont: control, concentration unit은 mg/㎖임);
도 3은 그람음성세균 유래 엔도톡신(lipopolysaccharides, LPS)에 노출된 흰쥐에서 in vivo TNF-alpha의 생성 및 분비에 미치는 영향을 나타낸 도이며 (흰쥐를 lipopolysaccharides에 노출시키고 흰쥐로부터 in vivo TNF-alpha의 생성 및 분비량을 측정하였으며, 개개 바(bar)는 5마리의 흰쥐에서의 평균과 평균의 표준오차 (mean ±S.E.M.)로 표기하였음. * 는 대조군 대비 유의적으로 상이함 (p<0.05); + 는 LPS 단독군과 유의적으로 상이함 (p<0.05)을 의미함. 여기에서 cont: control, Dexa: dexamethasone, LPS: lipopolysaccharides, concentration unit은 mg/kg임)
도 4는 그람음성세균 유래 엔도톡신(lipopolysaccharides, LPS)에 노출된 흰쥐에서 in vivo 기도 뮤신의 생성 및 분비에 미치는 영향을 나타낸 도이며 (흰쥐를 lipopolysaccharides에 노출시키고 흰쥐로부터 in vivo 뮤신의 생성 및 분비량을 측정하였으며, 개개 바(bar)는 5마리의 흰쥐에서의 평균과 평균의 표준오차 (mean ±S.E.M.)로 표기하였음. * 는 대조군 대비 유의적으로 상이함 (p<0.05); + 는 LPS 단독군과 유의적으로 상이함 (p<0.05)을 의미함. 여기에서 cont: control, Dexa: dexamethasone, LPS: lipopolysaccharides, concentration unit은 mg/kg임);
도 5는 이산화황에 노출된 흰쥐에서 in vivo 기도 뮤신의 생성 및 분비에 미치는 영향을 나타낸 도이며 (흰쥐를 이산화황에 노출시키고 흰쥐로부터 in vivo 기도 뮤신의 생성 및 분비량을 측정하였으며, 개개 바(bar)는 5마리의 흰쥐에서의 평균과 평균의 표준오차 (mean ±S.E.M.)로 표기하였음. * 는 대조군 대비 유의적으로 상이함 (p<0.05); + 는 이산화황(SO2) 단독군과 유의적으로 상이함 (p<0.05)을 의미함. 여기에서 cont: control, Dexa: dexamethasone, SO2: sulfur dioxide, concentration unit은 mg/kg임)
도 6은 이산화황에 노출된 흰쥐에서 in vivo 기도 상피 배상세포 내의 점액 함유량 증가 및 배상세포 과다증식에 미치는 영향을 나타낸 도이며 (흰쥐를 이산화황에 노출시키고 흰쥐에서 기도 상피 배상세포 내의 점액 함유량 증가 및 배상세포 과다증식 정도를 조직병리학적으로 검증하였으며, Hematoxylin-eosin 및 Periodic Acid Schiff (PAS)-Alcian Blue staining을 실시한 후 200 X배 배율로 관찰, 사진 촬영한 결과임. Dark purple - black 으로 나타난 부분이 뮤신을 의미함)
도 7은 시료의 경구 투여후 흰쥐의 체중 증가에 미치는 영향을 나타낸 도이다 (시료를 2주간 투여하고 대조군 및 시료 투여군의 체중을 측정하고 개개 바(bar)는 5마리 흰쥐에서의 평균과 평균의 표준오차 (mean ±S.E.M.)로 표기하였음.
도 8은 시료의 경구 투여후 흰쥐의 혈중 GOT 및 GPT 활성에 미치는 영향을 나타낸 도이다 (시료를 2주간 투여하고 대조군 및 시료 투여군의 혈중 GOT 및 GPT 활성을 측정하고 개개 바(bar)는 5마리 흰쥐에서의 평균과 평균의 표준오차 (mean ±S.E.M.)로 표기하였음.
도 9는 시료의 경구투여후 흰쥐의 혈중 BUN 및 creatinine 농도에 미치는 영향을 나타낸 도이다 (시료를 2주간 투여하고 대조군 및 시료 투여군의 혈중 BUN 및 creatinine 농도를 측정하고 개개 바(bar)는 5마리 흰쥐에서의 평균과 평균의 표준오차 (mean ±S.E.M.)로 표기하였음.1 is a view showing the effect on the expression of PMA-induced MUC5AC gene in NCI-H292 cells of a sample (treated with samples of various concentrations in NCI-H292 cells for 30 minutes and stimulated with PMA (10 ng/ml) for 24 hours. The MUC5AC gene expression was measured by RT-PCR, and Rig/S15 rRNA encoding a small ribosomal subunit protein was used as one of the structurally expressed housekeeping genes as a quantitative control, and 3 independent experiments were performed and representative data were indicated. ; Where cont: control, concentration unit is mg/ml);
2 is a view showing the effect of the sample on the production of PMA-induced MUC5AC mucin in NCI-H292 cells (treated with samples of various concentrations in NCI-H292 cells for 30 minutes and stimulated with PMA (10 ng/ml) for 24 hours. The cell lysate was recovered for the measurement of MUC5AC mucin production by ELISA, and 3 independent experiments were performed and representative data were expressed, and each bar averaged 3 culture wells when the control was converted to 100%. And the standard error of the mean (mean ±SEM) * is significantly different from the control group (p<0.05); + is significantly different from the PMA alone group (p<0.05). In cont: control, concentration unit is mg/ml);
3 is a diagram showing the effect on the production and secretion of TNF-alpha in vivo in rats exposed to gram-negative bacteria-derived endotoxins (lipopolysaccharides, LPS) (production of TNF-alpha in vivo from rats exposed to lipopolysaccharides) And the amount of secretion was measured, and the individual bars were expressed as the mean and the standard error of the mean (mean ±SEM) in 5 rats * is significantly different from the control group (p<0.05); + is Means significantly different from LPS alone group (p<0.05), where cont: control, Dexa: dexamethasone, LPS: lipopolysaccharides, concentration unit is mg/kg)
Figure 4 is a diagram showing the effect on the production and secretion of airway mucin in vivo in rats exposed to gram-negative bacteria-derived endotoxin (lipopolysaccharides, LPS) (exposed rats to lipopolysaccharides and in vivo mucin production and secretion from rats) The individual bars were measured and expressed as the mean and the standard error of the mean (mean ±SEM) in 5 rats * is significantly different from the control group (p<0.05); + is the LPS alone group And significantly different (p<0.05), where cont: control, Dexa: dexamethasone, LPS: lipopolysaccharides, concentration unit is mg/kg);
5 is a view showing the effect on the production and secretion of airway mucins in vivo in rats exposed to sulfur dioxide (the rats were exposed to sulfur dioxide and the production and secretion of airway mucins in vivo from rats was measured, and individual bars) Is denoted as the mean of 5 rats and the standard error of the mean (mean ±SEM) * is significantly different from the control group (p<0.05); + is significantly different from the sulfur dioxide (SO 2 ) alone group Means different (p<0.05), where cont: control, Dexa: dexamethasone, SO 2 : sulfur dioxide, concentration unit is mg/kg)
FIG. 6 is a diagram showing the effect of increasing mucus content in airway epithelial goblet cells in vivo in sulfur dioxide-exposed mice and affecting goblet cell hyperproliferation (increasing mucus content in airway epithelial goblet cells in rats exposed to sulfur dioxide) The degree of cell hyperproliferation was confirmed histopathologically, and hematoxylin-eosin and Periodic Acid Schiff (PAS)-Alcian Blue staining were performed and observed at 200 X magnification and photographed. Musin)
7 is a view showing the effect on the weight gain of the rats after oral administration of the sample (samples are administered for 2 weeks, the weights of the control and sample administration groups are measured, and the individual bars are the average and average of the 5 rats) Standard error (mean ±SEM).
8 is a view showing the effect on the blood GOT and GPT activity in rats after oral administration of the sample (sample administered for 2 weeks, blood GOT and GPT activity in the control and sample administration groups was measured, and the individual bars were 5) The mean and standard error of the mean (mean ±SEM) in the rats are indicated.
9 is a view showing the effect on the blood BUN and creatinine concentrations in rats after oral administration of the sample (samples are administered for 2 weeks, blood and BUN and creatinine concentrations in the control and sample administration groups are measured, and each bar is 5) The mean and standard error of the mean (mean ±SEM) in the rats are indicated.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 더욱 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예에 의하여 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred embodiments are provided to help understanding of the present invention. However, the following examples are only provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.
실시예 1. 조합 추출물 (CGE) 의 제조Example 1 Preparation of Combination Extract (CGE)
경동 한약방(대한민국 대전)에서 구매하여 경희대학교 약학대학 표본실에 보관중인 건조된 (1) 맥문동 (Liriope platyphylla Wang et Tang, Liliaceae, KHU- OPS 2017-21) 10g (2) 사삼 (Adenophora tryphilla var. japonica Hara, Campanulaceae, KHU-OPS 2017-22) 40g (3) 길경 (Platycodum grandiflorum A. DC), Campanulaceae,, KHUOPS 2017-23) 40g (4) 지실 (Poncirius trifoliata, KHUOPS 2017-24) 60g (5) 금은화 (Lonicera japonica Thunberg, Caprifoliaceae, KHUOPS 2017-25) 10g로 배합한 조합 생약 160g을 두 번 증류한 탈이온수에 1,600㎖로 100 ℃에서 3시간 동안 추출하고 여과하여 여과액을 얻었다. 이 여과액을 회전식 진공 증발건조기(Eyela, Freeze Dryer FDU-540)에서 감압 농축하여 동결건조하여 건조상태의 조합예 추출물 32g을 얻어 -70 ℃에서 보관하였다(수율: 20%). 이를 하기 실험예에 시료로 사용하였다 (이하, “CGE”라 함, 수득율: 20%).Dried (1) Macmun-dong (Liriope platyphylla Wang et Tang, Liliaceae, KHU- OPS 2017-21) 10 g (2) Sasam (Adenophora tryphilla var. japonica) purchased from Kyung-Dong Oriental Medicine (Daejeon, Korea) and stored in a specimen room at Kyung Hee University Hara, Campanulaceae, KHU-OPS 2017-22) 40 g (3) Gilty (Platycodum grandiflorum A. DC), Campanulaceae,, KHUOPS 2017-23) 40 g (4) Gisil ( Poncirius trifoliata , KHUOPS 2017-24) 60 g (5) Gold and silver coins (Lonicera japonica Thunberg, Caprifoliaceae, KHUOPS 2017-25) 160 g of the combined herbal medicines formulated with 10 g were extracted with distilled deionized water twice at 1,600 mL for 3 hours at 100° C. and filtered to obtain a filtrate. The filtrate was concentrated under reduced pressure in a rotary vacuum evaporator (Eyela, Freeze Dryer FDU-540) and freeze-dried to obtain 32 g of a combination extract in a dry state and stored at -70°C (yield: 20%). This was used as a sample in the following experimental examples (hereinafter referred to as "CGE", yield: 20%).
실험예 1: 세포주 실험을 이용한 기도점액(뮤신) 생성 및 유전자 발현 억제 활성실험Experimental Example 1: Production of airway mucus (mucin) and inhibition of gene expression using cell line experiment
상기 실시예에서 수득한 시료들의 세포주 실험을 이용한 기도점액(뮤신) 생성 및 유전자 발현 억제 활성을 확인하기 위하여 문헌에 기재된 방법을 응용하여 하기와 같이 실험을 수행하였다 (Hewson CA, Edbrooke MR, Johnston SL. 2004. PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells via PKC, EGF/TGF-alpha, Ras/Raf, MEK, REK and Sp1-dependent mechanisms. J Mol Biol 344:683-695; Hong DH, Petrovics G, Anderson WB, Forstner J, Forstner G. 1999. Induction of mucin gene expression in human colonic cell lines by PMA is dependent on PKC-epsilon. Am J Physiol 277:G1041-G1047).In order to confirm the airway mucus (mucin) production and gene expression inhibitory activity using the cell line experiments of the samples obtained in the above examples, experiments were performed as follows (Hewson CA, Edbrooke MR, Johnston SL) 2004.PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells via PKC, EGF/TGF-alpha, Ras/Raf, MEK, REK and Sp1-dependent mechanisms.J Mol Biol 344:683-695; Hong DH, Petrovics G , Anderson WB, Forstner J, Forstner G. 1999.Induction of mucin gene expression in human colonic cell lines by PMA is dependent on PKC-epsilon.Am J Physiol 277:G1041-G1047).
1-1. NCI-H292 세포 배양 및 CGE의 처리 1-1. NCI-H292 cell culture and treatment of CGE
24시간의 CGE 처리(투여) 기간 동안, CGE가 인간 기도 상피세포인 NCI-H292 세포 내에 존재하는 MUC5AC 뮤신의 생성 및 유전자(mRNA)의 발현에 미치는 영향을 관찰하기 위하여 NCI-H292 세포를 문헌에 기재된 방법으로 하기와 같이 배양하였다. During the 24-hour CGE treatment (administration) period, NCI-H292 cells were reviewed in the literature to observe the effect of CGE on the production of MUC5AC mucins present in human airway epithelial cells NCI-H292 cells and expression of genes (mRNA). The culture was performed as described below.
인간 기도 상피세포인 NCI-H292 세포(ATCC, Manassas, VA, U.S.A.)는 습도가 충분히 유지되며 95% 공기, 5% CO2를 함유하는 37℃ 조건에서 HEPES (25mM), penicillin G (100U/㎖), streptomycin (100㎍/㎖), FBS (10%, V/V) 등이 첨가된 RPMI 1640 배양액(Sigma-Aldrich, St. Louis, MO, U.S.A., 이하 배양액으로 약칭) 에서 배양되었는데, 1주에 2회의 빈도로 계대배양(subculture) 하였다. NCI-H292 cells (ATCC, Manassas, VA, USA), human airway epithelial cells, are sufficiently maintained in humidity and contain HEPES (25 mM), penicillin G (100 U/mL) at 37° C. containing 95% air and 5% CO 2 . ), streptomycin (100㎍ / ㎖), FBS (10%, V / V), RPMI 1640 culture medium (Sigma-Aldrich, St. Louis, MO, USA, abbreviated as culture medium) was added, cultured for 1 week Subculture was performed at a frequency of 2 times.
뮤신 생성 및 그 유전자 발현에 대한 약물의 작용을 검증하기 위하여, 뮤신 생성량 검증을 위해서는 24 웰 배양 플레이트(well culture plate)를 기준으로 웰(well) 당 2.0 x 104 cells/well 의 밀도로, 뮤신 유전자 발현 정도의 검증을 위해서는 6 웰 배양 플레이트(well culture plate)를 기준으로 웰(well) 당 5.0 x 104 cells/well 의 밀도로 각각 세포를 도포하고 배양하였다. 세포가 다 자라면, FBS의 농도를 0.2%로 감소시킨 배양액을 주고 24 시간 동안 배양하고, 이후, 혈청(serum)을 첨가하지 않은 배양액 (serum-free medium)으로 세포를 세척하였다. 이렇게 준비된 세포에 다양한 농도의 CGE를 함유하는 배양액 200㎕를 웰(well) (24 well plate 기준) 마다 가하고, 30분이 지난 시점에 PMA (phorbol 12-myristate 13-acetate) (Sigma-Aldrich, St. Louis, MO, U.S.A.) 10 ng/ml을 각 웰(well)마다 투여한 후 37℃에서 24 시간동안 배양하였다.In order to verify the action of the drug on mucin production and its gene expression, to verify the amount of mucin production, the mucin gene at a density of 2.0 x 104 cells/well per well based on a 24 well culture plate For verification of expression level, cells were applied and cultured at a density of 5.0 x 104 cells/well per well based on a 6 well culture plate. When the cells are grown, the culture medium is reduced to a concentration of 0.2% FBS, cultured for 24 hours, and then, the cells are washed with a serum-free medium (serum-free medium). To the prepared cells, 200 μl of a culture solution containing various concentrations of CGE was added to each well (based on a 24 well plate), and after 30 minutes, PMA (phorbol 12-myristate 13-acetate) (Sigma-Aldrich, St. Louis, MO, USA) 10 ng/ml was administered for each well, and then cultured at 37°C for 24 hours.
1-2. NCI-H292 세포에서의 MUC5AC 뮤신 생성량 측정 1-2. Measurement of MUC5AC mucin production in NCI-H292 cells
24 시간의 배양이 종료된 시점에 세포 용해용 완충액(20mM Tris, 0.5% NP-40, 250mM NaCl, 3mM EDTA, 3mM EGTA, protease inhibitor cocktail (Sigma-Aldrich, St. Louis, MO, U.S.A.) 을 가하여 세포 내에 존재하는 MUC5AC 뮤신을 추출한 후 이후의 실험에 사용하였다. 즉, 수거된 세포 용해 추출액 (cell lysate) 을 PBS로 1/10 배 희석하고 희석된 각 시료(sample)를 ELISA 전용의 96-well plate 에 각각 100㎕ 씩 분포시킨 후, 42℃ 에서 완전히 건조될 때까지 배양(incubation)하였다. 그 후 PBS-Tween 20 (0.05%, PBS-T) 용액 200㎕/well 을 이용, 각 웰(well) 당 3회씩 세척하였다. 세척 후 PBS-T 에 용해된 2% BSA 용액 200㎕ 를 각 well 당 가하고, 다시 1시간 동안 배양하였다. 1시간 후 PBS-T 200㎕ 로 3회 세척하고 MUC5AC에 대한 단일클론 항체(monoclonal antibody)인 mouse anti-MUC5AC clone 45M1 (NeoMarkers, CA, U.S.A.)를 2% BSA에 1: 200 의 비율로 희석한 후에 각 웰(well)당 100㎕ 씩 첨가하고 1시간 동안 배양(incubation)하였다. 1시간 후 PBS-T 로 3회 세척하고, 2차 항체인 Horse radish peroxidase (HRP)-Goat Anti-Mouse IgG Conjugate (Calbiochem, Carlsbad, CA, U.S.A.) 를 2% BSA에 1: 3,000의 비율로 희석한 후, 각 웰(well)당 100㎕씩 첨가하고 1시간 동안 배양(incubation) 하였다. Cell lysis buffer (20mM Tris, 0.5% NP-40, 250mM NaCl, 3mM EDTA, 3mM EGTA, protease inhibitor cocktail (Sigma-Aldrich, St. Louis, MO, USA)) was added at the end of the 24 hour culture. After extracting the MUC5AC mucin present in the cells, it was used in subsequent experiments, that is, the collected cell lysate was diluted 1/10-fold with PBS and each diluted sample was 96-well dedicated to ELISA. After 100 μl of each was distributed on the plate, the cells were incubated until completely dried at 42° C. Then, 200 μl/well of PBS-Tween 20 (0.05%, PBS-T) solution was used for each well. ) After washing, 200 µl of 2% BSA solution dissolved in PBS-T was added to each well, followed by incubation for 1 hour.After 1 hour, washing 3 times with 200 µl of PBS-T and washing for MUC5AC After diluting monoclonal antibody mouse anti-MUC5AC clone 45M1 (NeoMarkers, CA, USA) in 2% BSA at a ratio of 1:200, add 100 µl per well and incubate for 1 hour. (Incubation) After 1 hour, washed 3 times with PBS-T, and the secondary antibody, Horse radish peroxidase (HRP)-Goat Anti-Mouse IgG Conjugate (Calbiochem, Carlsbad, CA, USA) was added to 2% BSA 1: After diluting at a rate of 3,000, 100 µl was added for each well and incubated for 1 hour.
PBS-T로 다시 3회 세척 후, 3,3',5,5'- tetramethyl-benzidine peroxide (TMB) 용액 (Sigma-Aldrich, St. Louis, MO, U.S.A.) 100㎕ 를 각 well 에 첨가하고, 5분 후 1N H2SO4 50㎕ 를 첨가, 반응을 정지시켰다. 450nm 에서 각 well 의 흡광도를 측정함으로써 대조군과 약물 처리군 간의 MUC5AC 를 정량, 비교하였다.After washing three times with PBS-T, 100 µl of 3,3',5,5'-tetramethyl-benzidine peroxide (TMB) solution (Sigma-Aldrich, St. Louis, MO, USA) was added to each well, After 5 minutes, 50 µl of 1N H 2 SO 4 was added to stop the reaction. By measuring the absorbance of each well at 450 nm, MUC5AC between the control and drug treatment groups was quantified and compared.
통계처리Statistics processing
모든 측정 결과는 Mean±으로 환산한 후, 약물 처리군의 측정치는 대조군 측정치의 백분율로 나타내었다. 통계처리는 One-way ANOVA로 하고 post-hoc test는 Holm-Sidak test로 하며, p<0.05인 경우 통계적으로 유의성이 있는 것으로 판정하였다. After all measurement results were converted to Mean±, the measurement value of the drug treatment group was expressed as a percentage of the control measurement value. Statistical processing was performed by one-way ANOVA, post-hoc test was performed by Holm-Sidak test, and p<0.05 was determined to be statistically significant.
1-3.실험 결과 1-3.Results of experiment
1-3-1. NCI-H292 세포에서 PMA로 유도된 MUC5AC 유전자 발현 증가에 미치는 CGE의 영향1-3-1. Effect of CGE on PMA-induced MUC5AC gene expression increase in NCI-H292 cells
CGE는 24 시간의 처리 기간 동안 PMA로 유도된 MUC5AC mRNA의 발현 수준을 감소시키는 경향을 보여주었다 (도 1).CGE showed a tendency to decrease the expression level of MUC5AC mRNA induced by PMA over a 24 hour treatment period (FIG. 1 ).
1-3-2. CGE가 인간 호흡기 상피세포 (NCI-H292세포)에서 PMA로 자극된 MUC5AC 뮤신 과다생성에 미치는 영향1-3-2. Effect of CGE on PUC-stimulated MUC5AC mucin overproduction in human respiratory epithelial cells (NCI-H292 cells)
상기 실험 결과, CGE는 PMA로 자극된 뮤신 과다생성을 152 % 저해율 (최고 처리농도 기준)로 억제하였다 (도 2 및 표 1 참조). As a result of the above experiment, CGE inhibited PMA-stimulated mucin overproduction at a 152% inhibition rate (based on the highest treatment concentration) (see FIG. 2 and Table 1).
1-4. NCI-H292 세포 내에 존재하는 total RNA의 분리1-4. Isolation of total RNA present in NCI-H292 cells
24 시간 동안 약물 처리한 세포를 냉각된 PBS 로 2회 세척하였다. 세포에 trypsin-EDTA 용액(Sigma-Aldrich, St. Louis, MO, U.S.A.)을 처리하여 배양 용기 바닥으로부터 분리하고, 세포들의 혼합물을 1.5㎖ 용량의 microtube 에 옮겨 원심 분리함으로써 세포들만 수거하였다. 이어서, total RNA를 분리하고자 INTRON biotechnology 사의 Easy-Blue RNA extraction kit (total RNA isolation reagent (INTRON biotechnology, Inc. Kyung-gi-do, Korea) 를 이용해 (0.5㎖/4x105 cells) 세포를 lysis 시키고, 상온에서 5분간 방치하였다. 5분 후 즉시, microtube 에 chloroform 을 첨가, 15초간 볼텍싱(vortexing) 하고 상온에 2-3분간 방치한 후 4℃, 13,000 rpm (Hanil centrifuge, MICRO 17 R) 에서 10분간 원심 분리하여 얻은 상층 액 400㎕ 를 새 microtube 에 옮겼다. 상층 액에 동량의 isopropanol 을 첨가하여 잘 혼합한 후 상온에서 10분간 방치하고 다시 4℃, 13,000 rpm 에서 10분간 원심 분리하여 RNA 침전물을 얻었다. The cells treated with the drug for 24 hours were washed twice with cooled PBS. Cells were treated with trypsin-EDTA solution (Sigma-Aldrich, St. Louis, MO, USA) to separate from the bottom of the culture vessel, and the mixture of cells was transferred to a 1.5 ml microtube and centrifuged to collect only cells. Subsequently, to isolate total RNA, cells were lysed (0.5 mL/4x10 5 cells) using INTRON biotechnology's Easy-Blue RNA extraction kit (total RNA isolation reagent (INTRON biotechnology, Inc. Kyung-gi-do, Korea)), It was left at room temperature for 5 minutes Immediately after 5 minutes, chloroform was added to the microtube, vortexed for 15 seconds, left at room temperature for 2-3 minutes, and then at 4°C and 13,000 rpm (Hanil centrifuge, MICRO 17 R) 10 The 400 µl of the supernatant obtained by centrifugation for a minute was transferred to a new microtube, the same amount of isopropanol was added to the supernatant, mixed well, left at room temperature for 10 minutes, and centrifuged again at 4°C and 13,000 rpm for 10 minutes to obtain RNA precipitate. .
이 침전물에 diethylpyrocarbonate (DEPC) (Sigma-Aldrich, St. Louis, MO, U.S.A.) 가 함유된 75% ethanol 을 가하고 4℃, 10,000 rpm 에서 10분간 원심 분리함으로써 세척하였다. 수거된 RNA 침전물을 5분간 대기 중에서 건조시킨 후, 20㎕ 의 RNase-free water (Sigma-Aldrich, St. Louis, MO, U.S.A.) 로 부유시키고, spectrophotometer (Beckman, DU-650) 를 사용하여 260 nm 파장에서 흡광도를 측정함으로써 RNA 의 농도를 측정한 후 실험에 사용하였다 (1.0A260=single strand RNA 40 ㎍/㎖).To this precipitate, 75% ethanol containing diethylpyrocarbonate (DEPC) (Sigma-Aldrich, St. Louis, MO, U.S.A.) was added and washed by centrifugation at 4°C and 10,000 rpm for 10 minutes. The collected RNA precipitate was dried in the air for 5 minutes, and then suspended with 20 μl of RNase-free water (Sigma-Aldrich, St. Louis, MO, USA) and 260 nm using a spectrophotometer (Beckman, DU-650). The concentration of RNA was measured by measuring absorbance at a wavelength, and then used in the experiment (1.0A260=single strand RNA 40 µg/ml).
1-5. PCR (Polymerase Chain Reaction) 을 위한 primer 제조1-5. Primer preparation for PCR (Polymerase Chain Reaction)
PCR에 사용된 primer 는 전문 제조회사인 Genotec (주)(Daejeon, Korea) 에 주문, 합성하였다. NCI-H292 세포에서의 human MUC5AC 유전자 합성을 위해 사용한 sense primer 의 염기서열은 5'-TGA TCA TCC AGC AGC AGG GCT-3', antisense primer의 염기서열은 5'-CCG AGC TCA GAG GAC ATA TGG G-3' 이었다. 정량적 대조 유전자로 사용된 Rig/S15 유전자 primer의 염기서열은 (sense primer) 5'-TTC CGC AAG TTC ACC TAC C-3' 및 (antisense primer) 5'-CGG GCC GGC CAT GCT TTA CG-3'이었다.(표 2 참조)The primers used for PCR were ordered and synthesized by Genotec (Daejeon, Korea), a professional manufacturer. The base sequence of sense primer used for human MUC5AC gene synthesis in NCI-H292 cells is 5'-TGA TCA TCC AGC AGC AGG GCT-3', and the base sequence of antisense primer is 5'-CCG AGC TCA GAG GAC ATA TGG G It was -3'. The nucleotide sequence of the Rig/S15 gene primer used as a quantitative control gene is (sense primer) 5'-TTC CGC AAG TTC ACC TAC C-3' and (antisense primer) 5'-CGG GCC GGC CAT GCT TTA CG-3' (See Table 2)
1-6. RNA의 역전사 반응 및 중합효소 연쇄반응 (RT-PCR)1-6. RNA reverse transcription reaction and polymerase chain reaction (RT-PCR)
수거된 total RNA를 이용, 역전사 반응 (Reverse Transcription) 으로 cDNA 를 만들고, 이를 중합효소 연쇄반응 (PCR) 으로 증폭시켰다. 즉, 얻어진 total RNA 1㎍ 을 75℃ 에서 5분간 가열함으로써 변성(denaturation) 시키고, 이를 얼음에 담가 급냉 시킨 후 RT premix kit (BIONEER Corporation, Daejeon, Korea) 의 사용자 설명서에 따라 역전사 반응을 진행시켰다. MUC5AC 유전자에 대한 PCR 은, 각각의 역전사 반응에서 얻은 cDNA 산물 2㎕ 를 PCR premix kit 의 사용자 설명서에 따라 진행시켰다. 증폭반응을 위하여, PCR을 40회 실시하였으며, 변성(denaturation)은 94℃ 에서 30초, 아닐링(annealing)은 60℃ 에서 30초, 연장(extension)은 72℃ 에서 30초간 각각 시행하였다. Using the collected total RNA, cDNA was prepared by reverse transcription, and amplified by polymerase chain reaction (PCR). That is, 1 µg of the total RNA obtained was denatured by heating at 75° C. for 5 minutes, quenched in ice, and then reverse-transcribed according to the user manual of the RT premix kit (BIONEER Corporation, Daejeon, Korea). PCR for the MUC5AC gene was performed according to the user manual of the PCR premix kit with 2 μl of the cDNA product obtained in each reverse transcription reaction. For the amplification reaction, PCR was performed 40 times, denaturation was performed at 94°C for 30 seconds, annealing was performed at 60°C for 30 seconds, and extension was performed at 72°C for 30 seconds, respectively.
1-7. 전기영동에 의한 중합효소 연쇄반응 산물의 확인1-7. Identification of polymerase chain reaction products by electrophoresis
RNA의 역전사 반응 및 중합효소 연쇄반응으로 증폭된 cDNA 산물들을 전기영동으로 분리함으로써 MUC5AC 유전자 발현 변동 여부를 관찰하였다. 즉, 증폭된 PCR 산물 10㎕ 를 10×loading buffer (0.25% bromphenol blue, 0.25% xylene cyanol FF, 50% glycerol) 와 잘 혼합한 다음, Tris-acetate-EDTA buffer (40 mM Tris-acetate, 1 mM EDTA (Sigma-Aldrich, St. Louis, MO, U.S.A.) 용액 및 1㎍/㎖ 의 ethidium bromide 가 포함된 1.0% agarose gel (Sigma-Aldrich, St. Louis, MO, U.S.A.) 에서 전기 영동하였다. Gel 상에서 이동된 각각의 DNA band 는 자외선 투사기 (ultraviolet transilluminator (Bio-Rad, Hercules, CA, U.S.A.) 를 이용하여 관찰하고, 사진 촬영하였다. It was observed whether the MUC5AC gene expression fluctuated by separating cDNA products amplified by RNA reverse transcription reaction and polymerase chain reaction by electrophoresis. That is, 10 μl of the amplified PCR product was well mixed with 10×loading buffer (0.25% bromphenol blue, 0.25% xylene cyanol FF, 50% glycerol), and then Tris-acetate-EDTA buffer (40 mM Tris-acetate, 1 mM Electrophoresis was performed on a 1.0% agarose gel (Sigma-Aldrich, St. Louis, MO, USA) containing EDTA (Sigma-Aldrich, St. Louis, MO, USA) solution and 1 μg/ml of ethidium bromide. Each DNA band that was moved was observed using an ultraviolet projector (ultraviolet transilluminator (Bio-Rad, Hercules, CA, USA)), and photographed.
1-8. 실험결과1-8. Experiment result
CGE는 인간 호흡기 상피세포인 NCI-H292 세포에서, 호흡기 염증 발생 시 과다하게 생성 및 분비되는 뮤신(점액, 객담의 가장 주된 생화학적 구성요소)의 유전자 발현 및 생성 (production)을 억제하였다.CGE inhibited gene expression and production of mucin (mucus, the most important biochemical component of sputum), which is excessively produced and secreted when respiratory inflammation occurs in human respiratory epithelial cells, NCI-H292 cells.
실험예 2: 기관지 염 유도 동물모델을 이용한 호흡기 염증인자 및 기도점액 과다 분비에 대한 억제 활성Experimental Example 2: Inhibitory activity against respiratory inflammatory factors and excessive airway mucus secretion using bronchitis-induced animal models
상기 실시예에서 수득한 시료들의 흰쥐 기관지염 모델에서 호흡기 염증인자 및 기도점액 과다 분비에 대한 억제 활성을 확인하기 위하여 문헌에 기재된 방법을 응용하여 하기와 같이 실험을 수행하였다 (Pon DJ, van Staden CJ, Boulet L, Rodger IW. 1994. Hyperplastic effects of aerosolized sodium metabisulfite on rat airway mucus-secretory epithelial cells. Can J Physiol Pharmacol 72(9): 1025-1030). In the rat bronchitis model of the samples obtained in the above examples, experiments were carried out as follows by applying the method described in the literature to confirm the inhibitory activity against respiratory inflammatory factors and airway mucus hypersecretion (Pon DJ, van Staden CJ, Boulet L, Rodger IW. 1994. Hyperplastic effects of aerosolized sodium metabisulfite on rat airway mucus-secretory epithelial cells.Can J Physiol Pharmacol 72(9): 1025-1030).
2-1. 실험 동물2-1. Experimental animals
병원체에 감염되지 않은 SD 수컷 흰쥐((Pathogen-free male Sprague-Dawrley, SD rat, 몸무게 200~220g, 5주령, Daehan Biolink, Seoul, Korea)를 케이지에 5마리씩 보관하였으며 정제수와 음식은 무제한으로 제공되었다. 생육 온도는 일정하게 22.5℃, 습도는 55%였으며 낮밤주기는 12시간이었다(빛 쏘이는 시간 08:00-20:00). 실험 동물들은 실험 내내 국립 충남대학교의 실험동물관리 및 이용 규칙에 따라 관리되었다.Five male rats (Pathogen-free male Sprague-Dawrley, SD rat, weight 200-220 g, 5 weeks old, Daehan Biolink, Seoul, Korea) that were not infected with pathogens were stored in cages, and purified water and food were provided for unlimited use. The growth temperature was 22.5℃, the humidity was 55%, and the day and night cycle was 12 hours (lighting time 08:00-20:00).The experimental animals were in accordance with the National Animal Care and Use Rules of Chungnam National University throughout the experiment. It was managed accordingly.
2-2. 실험 설계 2-2. Experimental Design
그람음성 세균의 내독소 흡입에 의한 호흡기 염증성 점액 과다분비 동물모델의 제작 및 CGE의 경구투여Production of animal models of hypersecretion of respiratory inflammatory mucus by inhalation of endotoxins from Gram-negative bacteria and oral administration of CGE
흰쥐 체중 kg 당 내독소(lipopolysaccharides from e-coli O111:B4) (List biological laboratories, INC., Campbell, CA, U.S.A.) 를 5mg 씩 1mg/㎖ 농도로 탈이온 이차증류수에 현탁하여 흡입 투여시켰다. CGE가 생약의 복합추출 조성물임을 고려하여 내독소 투여로 호흡기 염증이 유발되기 7일 전부터 총 10일간 CGE를 경구 투여했는데, 체중 70kg 성인이 복용하는 용량을 기준으로 환산된 체중 350g의 흰쥐에의 투여용량을 적절히 산출하여 경구 투여용 주사바늘을 이용하여 투여하였다. Endotoxins per kg body weight of rats (lipopolysaccharides from e-coli O111:B4) (List biological laboratories, INC., Campbell, CA, U.S.A.) were suspended in deionized secondary distilled water at a concentration of 5 mg at 1 mg/mL for inhalation administration. Considering that CGE is a complex extract composition of herbal medicine, CGE was orally administered for a total of 10 days from the 7th day before respiratory inflammation was induced by the administration of endotoxin. The dose was calculated appropriately and administered using an injection needle for oral administration.
2-3. CGE가 내독소 흡입에 의한 흰쥐 호흡기 in vivo 뮤신 분비에 미치는 영향 측정2-3. Measurement of the effect of CGE on mucin secretion in rat respiratory system by endotoxin inhalation
흡입된 내독소가 호흡기에 염증을 유발하는 데 걸리는 기간인 72 시간(만 3일)이 지난 시점에 대조군, 내독소 흡입 투여군, 내독소 흡입 및 CGE 경구 투여군에 배당된 실험동물을 마취한 후 기관지-폐포 세척술(bronchoalveolar lavage, BAL)을 문헌에 기재된 방법에 따라 하기와 같이 시행하였다 (Pon et al., 1994). Bronchial tubes after anesthetized experimental animals assigned to the control group, endotoxin inhalation group, endotoxin inhalation and CGE oral administration groups after 72 hours (3 days), which is the time period for inhaled endotoxin to inflame the respiratory tract. -Alveolar lavage (bronchoalveolar lavage, BAL) was performed as follows according to the method described in the literature (Pon et al., 1994).
좌폐로 분지되는 부위를 결찰한 후 기관-기관지를 통하여 우폐 내부까지 5㎖의 멸균 인산완충 생리식염수를 주입하고 5회의 세척 조작을 같은 강도와 시간 간격을 두고 실시한 후 4㎖의 최종 세척액을 수거하였다. 수거된 세척액은 -20℃ 조건에 보관해 두고 즉시 혹은 차후에 점액(뮤신)의 함량을 ELISA 방법을 이용하여 측정하였고 (구체적 실험방법은 NCI-H292 세포에서의 MUC5AC 뮤신 생성량 측정 항목과 동일함) 대조군, 내독소 흡입 투여군, 내독소 흡입 및 CGE 경구 투여군 간 점액 함량을 비교, 분석하였다. 각 군당 동물의 수효는 최소한 5마리로 하였으며 대조군은 전 실험 기간 동안 내독소에 노출되는 과정 및 CGE 투여 과정만 제외하고 동일한 조건에서 사육되었다. After ligation of the site branched to the left lung, 5 ml of sterile phosphate buffered physiological saline was injected into the right lung through the trachea-bronchi, and 5 washing operations were performed at the same intensity and time interval, and then 4 ml of the final washing solution was collected. . The collected washing solution was stored at -20°C and the content of mucus (mucin) was measured immediately or later using an ELISA method. , Mucus content between endotoxin inhalation group, endotoxin inhalation and CGE oral administration groups was compared and analyzed. The number of animals in each group was at least 5, and the control group was kept under the same conditions except for the process of exposure to endotoxin and CGE administration during the entire experimental period.
2-4. CGE가 내독소 흡입에 의한 흰쥐 호흡기 염증 지표인 TNF-alpha 생성 및 분비량에 미치는 영향 측정2-4. Measurement of the effect of CGE on the production and secretion of TNF-alpha, an indicator of respiratory inflammation in rats by endotoxin inhalation
수거된 기관지-폐포 세척액 (BALF, bronchoalveolar lavage fluid)을 PBS로 1/10 배 희석하고 희석된 각 시료를 ELISA 전용의 96-well plate 에 각각 100㎕ 씩 분포시켰다. 그 후 PBS-Tween 20 (0.05%, PBS-T (Sigma-Aldrich, St. Louis, MO, U.S.A.) 용액 200㎕/well 을 이용, 각 well 당 3회씩 세척하였다. 세척 후 PBS-T 에 용해된 2% BSA 용액 (Sigma-Aldrich, St. Louis, MO, U.S.A.) 200㎕ 를 각 well 당 가하고, 다시 1시간 동안 배양(incubation) 하였다. 1시간 후, PBS-T 200㎕ 로 3회 세척하고, TNF-alpha에 대한 단일클론 항체(monoclonal antibody) (Santa Cruz Biotechnology, Santa Cruz, CA, U.S.A.) 를 2% BSA에 1: 1,000 의 비율로 희석한 후에, 각 well당 100㎕ 씩 첨가하고, 1시간 동안 배양하였다. 1시간 후 PBS-T 로 3회 세척하고, 2차 항체인 Horse radish peroxidase (HRP)-Goat Anti-Mouse IgG Conjugate (Calbiochem, Carlsbad, CA, U.S.A.) 를 2% BSA에 1: 2,000의 비율로 희석한 후, 각 웰(well) 당 100㎕씩 첨가하고 1시간 동안 배양하였다. PBS-T로 다시 3회 세척 후, 3,3',5,5'- tetramethyl-benzidine peroxide (TMB) 용액 (Sigma-Aldrich, St. Louis, MO, U.S.A.) 100㎕ 를 각 웰(well) 에 첨가하고, 5분 후 1N H2SO4 50㎕ 를 첨가, 반응을 정지시켰다. 450nm 에서 각 well 의 흡광도를 측정함으로써 대조군과 CGE 처리군 간의 TNF-alpha를 정량, 비교하였다. The collected bronchial-alveolar lavage fluid (BALF, bronchoalveolar lavage fluid) was diluted 1/10-fold with PBS, and each diluted sample was distributed in 100 µl each in a 96-well plate dedicated to ELISA. Thereafter, 200-µl/well of PBS-Tween 20 (0.05%, PBS-T (Sigma-Aldrich, St. Louis, MO, USA) solution) was used to wash three times for each well. 200 µl of 2% BSA solution (Sigma-Aldrich, St. Louis, MO, USA) was added to each well and incubated for another hour, after 1 hour, washed 3 times with 200 µl of PBS-T, After monoclonal antibody against TNF-alpha (Santa Cruz Biotechnology, Santa Cruz, CA, USA) was diluted in a ratio of 1: 1,000 in 2% BSA, 100 µl per well was added, and 1 hour. After 1 hour, the cells were washed 3 times with PBS-T, and the secondary antibody Horse radish peroxidase (HRP)-Goat Anti-Mouse IgG Conjugate (Calbiochem, Carlsbad, CA, USA) was 1: 2,000 in 2% BSA. After diluting at the ratio of, 100 µl per well was added and incubated for 1 hour After washing 3 times with PBS-T, 3,3',5,5'-tetramethyl-benzidine peroxide (TMB ) 100 μl of solution (Sigma-Aldrich, St. Louis, MO, USA) was added to each well, and after 5 minutes, 50 μl of 1N H 2 SO 4 was added to stop the reaction. By measuring absorbance, TNF-alpha between control and CGE-treated groups was quantified and compared.
2-5. 이산화황 흡입에 의한 호흡기 염증성 점액 과다분비 동물모델의 제작2-5. Production of animal models of hypersecretion of respiratory inflammatory mucus by inhalation of sulfur dioxide
직육면체 형태의 상자(200cm x 60cm x 30cm, 아크릴 수지 재질)의 한 면에 출입구를 설치하고, 그 면을 기준으로 좌우 양 측면에 각각 구멍을 뚫어 직경 10cm의 경질 폴리에틸렌 튜브를 연결하였다. 한쪽 측면의 폴리에틸렌 튜브는 초음파 가습기에 연결하여 아황산가스(이산화황, SO2)가 공급되도록 하였고 반대쪽은 배기펌프에 연결해 두었다.A door was installed on one side of a rectangular parallelepiped box (200 cm x 60 cm x 30 cm, acrylic resin material), and a hole in each of the left and right sides was drilled based on the side to connect a rigid polyethylene tube having a diameter of 10 cm. The polyethylene tube on one side was connected to an ultrasonic humidifier so that sulfur dioxide (sulfur dioxide, SO 2 ) was supplied and the other side was connected to an exhaust pump.
10% (V/V) 의 Sodium metabisulfite (MBS) 수용액((Sigma-Aldrich, St. Louis, MO, U.S.A.)을 초음파 가습기에 주입하고 스위치를 작동시켰다. 3분 이내에 아크릴 상자의 내부는 이산화황 증기(아황산가스)로 충만하게 되며 아황산가스의 농도는 노출 종료시점까지 130 - 150 ppm 으로 유지되도록 하였다. 무작위로 동물들을 선택하여 대조군, 3주간 아황산가스 노출군, 1주간 아황산가스 노출 후 2주간 CGE 경구 투여 및 아황산가스 노출군으로 구분하고 각 군당 동물의 수효는 최소한 5마리로 하였다. 노출 기간은 1일 3시간, 1주 5일, 총 3주간으로 하였다. 대조군은 전 실험기간 동안 아황산가스에 1일 3시간 노출되는 과정만 제외하고 동일한 조건에서 사육되었다. A 10% (V/V) aqueous solution of sodium metabisulfite (MBS) ((Sigma-Aldrich, St. Louis, MO, USA) was injected into the ultrasonic humidifier and the switch was operated. Sulfur dioxide), and the concentration of sulfur dioxide was maintained at 130-150 ppm until the end of exposure, animals were randomly selected to control, for 3 weeks for sulfur dioxide exposure, for 1 week for 2 weeks after exposure to sulfur dioxide It was divided into administration and sulfur dioxide exposure groups, and the number of animals per group was at least 5. The exposure period was 3 hours a day, 5 days a week, for a total of 3 weeks. It was kept under the same conditions except for the process exposed for 3 hours a day.
2-6.이산화황 흡입에 의한 호흡기 염증성 점액 과다분비 모델 흰쥐에 CGE의 경구투여2-6.Oral administration of CGE to rats with hypersecretory model of respiratory inflammatory mucus by inhalation of sulfur dioxide
이산화황 1주 처리 후 최종 2주간 이산화황 처리 및 CGE 경구 투여 군에 배당된 실험동물을 대상으로, 체중 70kg 성인이 복용하는 용량을 기준으로 환산된 투여용량을 적절히 산출하여 경구 투여용 주사바늘을 이용하여 투여하였다. For experimental animals allocated to the group treated with sulfur dioxide and CGE orally for the final 2 weeks after treatment with sulfur dioxide for 1 week, the calculated dose calculated based on the dose taken by an adult weighing 70 kg is appropriately calculated, and the needle is used for oral administration. Was administered.
즉, 총 3주간의 이산화황 노출 기간 중 마지막 2주간 (총10일) 매일 반복적으로 추출물을 투여하는데 투여는 오전 10시에서 11시 사이에, 이산화황 흡입은 오후 1시에서 4시까지, 각각 실시하였다. That is, the extract was repeatedly administered daily for the last 2 weeks (10 days in total) during the total 3 weeks of exposure to sulfur dioxide. .
2-7.CGE가 이산화황 흡입에 의한 흰쥐 호흡기 in vivo 뮤신 분비 및 배상세포 내 점액 함유량에 미치는 영향 측정Measurement of the effect of 2-7.CGE on mucin secretion and mucus content in rat respiratory system in vivo by inhalation of sulfur dioxide
CGE가 흰쥐 호흡기에서의 in vivo 뮤신 분비 및 배상세포 내 점액 함유량에 미치는 영향을 측정하기 위하여 먼저, 대조군, 이산화황 흡입 투여군, 이산화황 흡입 및 CGE 경구 투여군에 소속된 해당 실험동물을 마취한 후 기관지-폐포 세척술을 시행 하였는데, 좌폐로 분지되는 부위를 결찰한 후 기관-기관지를 통하여 우폐 내부까지 5㎖의 멸균 인산완충 생리식염수를 주입하고 5회의 세척 조작을 같은 강도와 시간 간격을 두고 실시한 후 4㎖의 최종 세척액을 수거하였다. To measure the effect of CGE on mucin secretion and mucus content in intestinal cells in vivo in rat respiratory tract, first, anesthetize the experimental animal belonging to the control group, sulfur dioxide inhalation group, sulfur dioxide inhalation and CGE oral administration group, and then broncho-alveolar Washing was performed. After ligation of the site branched to the left lung, 5 ml of sterile phosphate buffered saline was injected into the right lung through the trachea-bronchi, and 5 washing operations were performed at the same intensity and time interval, and then 4 ml of The final washing liquid was collected.
수거된 세척액은 -20℃ 조건에 보관해 두고 즉시 혹은 차후에 점액(뮤신)의 함량을 ELISA 방법을 이용하여 측정하고(구체적 실험방법은 NCI-H292 세포에서의 MUC5AC 뮤신 생성량 측정 항목과 동일함), 대조군, 이산화황 흡입 투여군, 이산화황 흡입 및 CGE 경구 투여군 간 점액 함량을 비교, 분석하였다. 동시에, 기관을 분리하여 기관내강 상피세포층에 대한 병리조직학적 검사를 실시하였다. The collected washing solution is stored at -20°C and the content of mucus (mucin) is measured immediately or later using an ELISA method (the specific experimental method is the same as that of MUC5AC mucin production in NCI-H292 cells). Mucus content was compared and analyzed between the control group, sulfur dioxide inhalation group, sulfur dioxide inhalation and CGE oral administration group. At the same time, the trachea histological examination of the tracheal epithelial cell layer was performed by separating the trachea.
즉, 기관지-폐포 세척술을 시행한 후 기관을 분리하고 냉각된 10% formalin in PBS (pH 7.2) (Sigma-Aldrich, St. Louis, MO, U.S.A.) 에 넣어 24 시간동안 고정하였다. 고정한 조직을 파라핀으로 포매 (包埋; embedding) 하였다. Microtome (Leica Biosystems Inc., IL, U.S.A.) 을 이용하여 5μm 두께로 잘라 조직절편을 제작하였다. 탈 파라핀 과정을 거치고 Hematoxylin-eosin 염색 (Sigma-Aldrich, St. Louis, MO, U.S.A.) 과 Periodic Acid Schiff (PAS) - Alcian Blue (pH 2.5) 염색 (Sigma-Aldrich, St. Louis, MO, U.S.A.) 을 실시한 후 광학 현미경 하에서 관찰하고 200 배 배율에서 사진기 (Leica Biosystems Inc., IL, U.S.A.) 로 사진 촬영하였다. 대조군, 이산화황 흡입 투여군, 이산화황 흡입 및 CGE 경구 투여군의 배상세포 내 점액 함유량을 비교함으로써 CGE가 배상세포 내 점액 함유 정도에 미치는 영향을 판정하였다. That is, after performing the bronchial-alveolar lavage, the trachea was separated and placed in cooled 10% formalin in PBS (pH 7.2) (Sigma-Aldrich, St. Louis, MO, U.S.A.) and fixed for 24 hours. The fixed tissue was embedded with paraffin (包埋; embedding). Using a Microtome (Leica Biosystems Inc., IL, U.S.A.) was cut to a thickness of 5μm to prepare a tissue section. Hematoxylin-eosin stain (Sigma-Aldrich, St. Louis, MO, USA) and Periodic Acid Schiff (PAS)-Alcian Blue (pH 2.5) stain (Sigma-Aldrich, St. Louis, MO, USA) after deparaffinization After performing the observation under an optical microscope and photographed with a camera (Leica Biosystems Inc., IL, USA) at 200 times magnification. By comparing the mucus content in the goblet cells of the control group, sulfur dioxide inhalation group, sulfur dioxide inhalation and CGE oral administration group, the effect of CGE on the content of mucus in the goblet cells was determined.
통계처리Statistics processing
모든 측정 결과는 Mean±으로 환산한 후, 약물 처리군의 측정치는 대조군 측정치의 백분율로 나타내었다. 통계처리는 One-way ANOVA로 하고 post-hoc test는 Holm-Sidak test로 하며, p<0.05인 경우 통계적으로 유의성이 있는 것으로 판정하였다. After all measurement results were converted to Mean±, the measurement value of the drug treatment group was expressed as a percentage of the control measurement value. Statistical processing was performed by one-way ANOVA, post-hoc test was performed by Holm-Sidak test, and p<0.05 was determined to be statistically significant.
2-8. 실험 결과2-8. Experiment result
CGE가 흰쥐에서 내독소 흡입으로 유발된 호흡기 염증의 지표인 TNF-alpha 생성 및 분비에 미치는 영향Effect of CGE on TNF-alpha production and secretion of respiratory inflammation induced by endotoxin inhalation in rats
CGE는 내독소 흡입으로 유발된 호흡기 염증의 지표인 TNF-alpha 생성을 억제(감소)하였다. 양성 대조약물인 dexamethasone 0.5mg/kg (Sigma-Aldrich, St. Louis, MO, U.S.A.) 투여군 역시 통계적으로 유의한 감소 현상을 나타내었다(도 3 및 표 3).CGE inhibited (reduced) TNF-alpha production, an index of respiratory inflammation caused by endotoxin inhalation. The positive control drug dexamethasone 0.5mg/kg (Sigma-Aldrich, St. Louis, MO, U.S.A.) administration group also showed a statistically significant decrease (Fig. 3 and Table 3).
CGE가 내독소 흡입으로 유발된 염증성 기도 점액 분비에 미치는 영향 Effect of CGE on inflammatory airway mucus secretion induced by endotoxin inhalation
흰쥐에게 경구 투여 시, CGE는 내독소 흡입으로 유발된 염증성 기도 점액의 분비를 억제(감소)하였다 (도 4 및 표 4).When administered orally to rats, CGE inhibited (reduced) the secretion of inflammatory airway mucus caused by endotoxin inhalation (Figure 4 and Table 4).
CGE가 이산화황 흡입으로 유발된 기도 점액분비에 미치는 영향 Effect of CGE on airway mucus secretion induced by inhalation of sulfur dioxide
흰쥐에게 경구 투여 시, CGE는 이산화황 흡입으로 유발된 기도 점액의 분비를 억제(감소)하였다 (도 5 및 표 5).When administered orally to rats, CGE inhibited (reduced) the secretion of airway mucus caused by inhalation of sulfur dioxide (FIG. 5 and Table 5).
CGE가 이산화황 흡입으로 유발된 기도 상피 배상세포 내의 점액 함유량 증가에 미치는 영향The effect of CGE on the increase of mucus content in airway epithelial goblet cells induced by inhalation of sulfur dioxide
CGE는 흰쥐에서 이산화황 흡입으로 유발된 기도 상피 배상세포 내의 점액 함유량 증가 및 배상세포 과다증식을 억제(감소)시키는 경향을 보여주었다. 즉, 기도 상피세포층에 Hematoxylin-eosin 염색과 Periodic Acid Schiff (PAS) - Alcian Blue 염색을 실시한 후 광학 현미경 하에서 관찰해 보면 이산화황에 3주간 노출된 흰쥐의 배상세포 내에 검은 보라색으로 염색된 뮤신(점액)의 양이 증가되어 있음에 비하여, 이산화황 1주 노출 후 2주간 약물 동시 경구 투여군에서는 배상세포 내에 뮤신(점액)의 양이 감소된 것을 알 수 있었다 (도 6).CGE showed a tendency to suppress (decrease) mucus content in the airway epithelial goblet cells induced by inhalation of sulfur dioxide and overproliferation of goblet cells in rats. That is, when hematoxylin-eosin staining and Periodic Acid Schiff (PAS)-Alcian Blue staining were performed on the airway epithelial cell layer and observed under an optical microscope, mucin (mucus) stained in black and purple in rat goblet cells exposed to sulfur dioxide for 3 weeks It was found that the amount of mucin (mucus) in the goblet cells was decreased in the group of simultaneous oral administration of the drug for 2 weeks after 1 week of exposure to sulfur dioxide, compared to the increased amount of (Fig. 6).
실험예 3: 동물모델을 이용한 독성실험Experimental Example 3: Toxicity experiment using animal model
상기 실시예에서 수득한 시료들의 동물모델을 이용한 독성을 확인하기 위하여 문헌에 기재된 방법을 응용하여 하기와 같이 실험을 수행하였다 (Pon DJ, van Staden CJ, Boulet L, Rodger IW. 1994. Hyperplastic effects of aerosolized sodium metabisulfite on rat airway mucus-secretory epithelial cells. Can J Physiol Pharmacol 72(9): 1025-1030). In order to confirm the toxicity using the animal model of the samples obtained in the above examples, the method described in the literature was applied to perform the experiment as follows (Pon DJ, van Staden CJ, Boulet L, Rodger IW. 1994. Hyperplastic effects of aerosolized sodium metabisulfite on rat airway mucus-secretory epithelial cells.Can J Physiol Pharmacol 72(9): 1025-1030).
3-1. 실험 동물3-1. Experimental animals
병원체에 감염되지 않은 SD 수컷 흰쥐((Pathogen-free male Sprague-Dawrley, SD rat, 몸무게 200~220g, 5주령, Daehan Biolink, Seoul, Korea)를 케이지에 5마리씩 보관하였으며 정제수와 음식은 무제한으로 제공되었다. 생육 온도는 일정하게 22.5℃, 습도는 55%였으며 낮밤주기는 12시간이었다(빛 쏘이는 시간 08:00-20:00). 실험 동물들은 실험 내내 국립 충남대학교의 실험동물관리 및 이용 규칙에 따라 관리되었다.Five male rats (Pathogen-free male Sprague-Dawrley, SD rat, weight 200-220 g, 5 weeks old, Daehan Biolink, Seoul, Korea) that were not infected with pathogens were stored in cages, and purified water and food were provided for unlimited use. The growth temperature was 22.5℃, the humidity was 55%, and the day and night cycle was 12 hours (lighting time 08:00-20:00).The experimental animals were in accordance with the National Animal Care and Use Rules of Chungnam National University throughout the experiment. It was managed accordingly.
3-2. 흰쥐에게 CGE의 경구 투여 시 체중 증가 정도에 미치는 영향3-2. Effect of Oral Administration of CGE on Weight Gain in Rats
2주간의 약물 경구 투여 기간을 포함한 전체 3주간의 실험 기간 동안 각 실험동물의 체중 변화를 측정한 결과, 대조군과 약물 투여군 간에 유의한 차이를 보이지 않음으로써 CGE가 실험동물의 영양 섭취 및 대사 상태에 유의한 독성을 유발하지 않을 가능성을 확인하였다 (도 7).As a result of measuring the weight change of each experimental animal during the entire 3-week experimental period including the oral administration period of 2 weeks, the CGE showed no significant difference between the control group and the drug-administered group. The possibility of not causing significant toxicity was confirmed (Fig. 7).
3-3. 흰쥐에게 CGE의 경구 투여 시 간 기능에 미치는 영향 3-3. Effects of CGE Oral Administration on Liver Function in Rats
간독성의 지표로는 트랜스아미나제인 GOT, GPT의 혈청 중 활성을 선정하였으며, 2주간의 CGE 경구 투여 후 GOT, GPT의 혈청 중 활성을 측정한 결과 대조군과 약물 투여군 간에 유의한 차이를 보이지 않음으로써 CGE가 실험동물에서 간독성을 유발하지 않음을 보여주었다 (도 8).As an indicator of hepatotoxicity, the activity in the serum of the transaminases GOT and GPT was selected. As a result of measuring the activity in the serum of GOT and GPT after oral administration of CGE for 2 weeks, CGE by not showing a significant difference between the control group and the drug administration group Showed that it did not induce liver toxicity in experimental animals (Fig. 8).
3-4. 흰쥐에게 CGE의 경구 투여 시 신장 기능에 미치는 영향3-4. Effect of Oral Administration of CGE on Kidney Function in Rats
신장독성의 지표로는 Blood Urea Nitrogen (BUN) 및 creatinine의 혈청 중 농도를 선정하였으며, 2주간의 약물 경구 투여 후 Blood Urea Nitrogen (BUN) 및 creatinine의 혈청 중 농도를 측정한 결과, 대조군과 약물 투여군 간에 유의한 차이를 보이지 않음으로써 CGE가 실험동물에서 신장독성도 유발하지 않음을 보여주었다 (도 9).Serum concentrations of Blood Urea Nitrogen (BUN) and creatinine were selected as indicators of renal toxicity, and serum concentrations of Blood Urea Nitrogen (BUN) and creatinine were measured after oral administration for 2 weeks. It was shown that CGE did not induce renal toxicity in the experimental animals by not showing a significant difference between the liver (FIG. 9).
상기 실험 결과, As a result of the above experiment,
1. CGE는 인간 호흡기 상피세포인 NCI-H292 세포에서, 호흡기 염증 발생 시 과다하게 생성 및 분비되는 뮤신(점액, 객담의 가장 주된 생화학적 구성요소)의 유전자 발현 및 생성 (production)을 억제하였다.1. CGE inhibited gene expression and production of mucin (mucus, the most important biochemical component of sputum), which is excessively produced and secreted when respiratory inflammation occurs in human respiratory epithelial cells, NCI-H292 cells.
2. CGE는 흰쥐에서, 그람음성세균이 함유하는 내독소(endotoxin)에 의해 유발된 호흡기 염증의 지표인 TNF-α의 과다 생성 및 분비를 억제하였다.2. CGE inhibited the overproduction and secretion of TNF-α, an index of respiratory inflammation caused by endotoxins contained in Gram-negative bacteria in rats.
3. CGE는 흰쥐에서, 그람음성세균이 함유하는 내독소(endotoxin)에 의해 유발된 호흡기 염증에 기인한 in vivo 점액 과다분비를 억제하였다.3. CGE suppressed hypersecretion of mucus in vivo due to respiratory inflammation caused by endotoxins contained in Gram-negative bacteria in rats.
4. CGE는 흰쥐에서, 화석 연료의 연소 후 발생되는 대표적 대기오염물질인 이산화황(SO2)의 흡입으로 유발된 호흡기 염증에 기인한 in vivo 점액 과다분비도 억제하였다.4. CGE also inhibited hypersecretion of mucus in vivo due to respiratory inflammation caused by inhalation of sulfur dioxide (SO 2 ), a representative air pollutant generated after combustion of fossil fuels in rats.
5. CGE는 흰쥐에서, 약물투여 전 기간 동안 간독성, 신독성을 유발하지 않았으며, 체중 증가에 대해서도 억제적 영향을 미치지 않음으로써, 영양 및 대사과정에 유해한 영향을 주지 않았다. 5. CGE did not induce hepatotoxicity and nephrotoxicity during the entire period of drug administration in rats, and did not have a detrimental effect on nutrition and metabolic processes by not having an inhibitory effect on weight gain.
본 발명의 추출물을 포함하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.A formulation example of a composition comprising the extract of the present invention will be described, but the present invention is intended to be described in detail rather than to limit it.
제제예 1. 산제의 제조Formulation Example 1. Preparation of powder
CGE 추출물 ------------------------------------------ 20 mgCGE extract ------------------------------------------ 20 mg
유당 ----------------------------------------------- 100 mgLactose ----------------------------------------------- 100 mg
탈크 ------------------------------------------------ 10 mgTalc ------------------------------------------------ 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled in an airtight fabric to prepare a powder.
제제예 2. 정제의 제조Formulation Example 2. Preparation of tablets
CGE 추출물 ----------------------------------------- 10 mgCGE extract ----------------------------------------- 10 mg
옥수수전분 ----------------------------------------- 100 mgCorn starch ----------------------------------------- 100 mg
유당 ----------------------------------------------- 100 mgLactose ----------------------------------------------- 100 mg
스테아린산 마그네슘 -------------------------------- 2 mgMagnesium stearate-------------------------------- 2 mg
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above ingredients, tablets are prepared by tableting according to a conventional tablet manufacturing method.
제제예 3. 캡슐제의 제조Formulation Example 3. Preparation of capsules
CGE 추출물 ------------------------------------------ 10 mgCGE extract ------------------------------------------ 10 mg
결정성 셀룰로오스 ----------------------------------- 3 mgCrystalline cellulose ----------------------------------- 3 mg
락토오스 ------------------------------------------- 14.8 mgLactose ------------------------------------------- 14.8 mg
마그네슘 스테아레이트 ------------------------------- 0.2 mgMagnesium stearate ------------------------------- 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충진하여 캡슐제를 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled in a gelatin capsule to prepare a capsule.
제제예 4. 주사제의 제조Formulation Example 4. Preparation of injection
CGE 추출물 -------------------------------------- 10 mgCGE extract -------------------------------------- 10 mg
만니톨 ----------------------------------------- 180 mgMannitol ----------------------------------------- 180 mg
주사용 멸균 증류수 --------------------------- 2974 mgSterile distilled water for injection --------------------------- 2974 mg
Na2HPO412H2O ---------------------------------- 26 mgNa 2 HPO 4 12H 2 O ---------------------------------- 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당 (2) 상기의 성분 함량으로 제조한다.It is prepared with the above-mentioned ingredient content per ampoule (2) according to the preparation method of a conventional injection.
제제예 5. 액제의 제조Formulation Example 5. Preparation of liquid formulation
CGE 추출물 ------------------------------------------ 10 mgCGE extract ------------------------------------------ 10 mg
이성화당 --------------------------------------------- 10 gIseonghwadang --------------------------------------------- 10 g
만니톨 ----------------------------------------------- 5 gMannitol ----------------------------------------------- 5 g
정제수 ----------------------------------------------- 적량Purified water ----------------------------------------------- suitable amount
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 100 로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.Each component is added to the purified water according to the conventional method for dissolving it, and the lemon flavor is added in an appropriate amount.The above components are mixed, and then purified water is added to adjust the total to 100. do.
제제예 6. 건강 식품의 제조Formulation Example 6. Preparation of healthy food
CGE 추출물 --------------------------------------- 1000 mgCGE extract --------------------------------------- 1000 mg
비타민 혼합물 --------------------------------------- 적량Vitamin mixture --------------------------------------- suitable amount
비타민 A 아세테이트 -------------------------------- 70 ugVitamin A Acetate -------------------------------- 70 ug
비타민 E ------------------------------------------ 1.0 mgVitamin E ------------------------------------------ 1.0 mg
비타민 B1 ---------------------------------------- 0.13 mgVitamin B1 ---------------------------------------- 0.13 mg
비타민 B2 ---------------------------------------- 0.15 mgVitamin B2 ---------------------------------------- 0.15 mg
비타민 B6 ----------------------------------------- 0.5 mgVitamin B6 ----------------------------------------- 0.5 mg
비타민 B12 ---------------------------------------- 0.2 ugVitamin B12 ---------------------------------------- 0.2 ug
비타민 C ------------------------------------------- 10 mgVitamin C ------------------------------------------- 10 mg
비오틴 --------------------------------------------- 10 ugBiotin --------------------------------------------- 10 ug
니코틴산아미드 ------------------------------------ 1.7 mgNicotinamide ------------------------------------ 1.7 mg
엽산 ----------------------------------------------- 50 ugFolic acid ----------------------------------------------- 50 ug
판토텐산 칼슘 ------------------------------------- 0.5 mgCalcium Pantothenate ------------------------------------- 0.5 mg
무기질 혼합물 --------------------------------------- 적량Mineral mixture --------------------------------------- suitable amount
황산제1철 ---------------------------------------- 1.75 mgFerrous sulfate ---------------------------------------- 1.75 mg
산화아연 ----------------------------------------- 0.82 mgZinc oxide ----------------------------------------- 0.82 mg
탄산마그네슘 ------------------------------------- 25.3 mgMagnesium carbonate ------------------------------------- 25.3 mg
제1인산칼륨 ---------------------------------------- 15 mgPotassium phosphate ---------------------------------------- 15 mg
제2인산칼슘 ---------------------------------------- 55 mgDibasic calcium phosphate ---------------------------------------- 55 mg
구연산칼륨 ----------------------------------------- 90 mgPotassium citrate ----------------------------------------- 90 mg
탄산칼슘 ------------------------------------------ 100 mgCalcium carbonate ------------------------------------------ 100 mg
염화마그네슘 ------------------------------------- 24.8 mgMagnesium chloride ------------------------------------- 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.Although the composition ratio of the vitamin and mineral mixture is a composition suitable for a relatively healthy food in a preferred embodiment, the composition ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for preparing a healthy food. , Granules can be prepared and used in the preparation of healthy food compositions according to conventional methods.
제제예 7. 건강 음료의 제조Formulation Example 7. Preparation of healthy beverages
CGE 추출물 -------------------------------------- 1000 mgCGE extract -------------------------------------- 1000 mg
구연산 ------------------------------------------ 1000 mgCitric acid ------------------------------------------ 1000 mg
올리고당 ------------------------------------------ 100 gOligosaccharide ------------------------------------------ 100 g
매실농축액 ------------------------------------------ 2 gPlum concentrate ------------------------------------------ 2 g
타우린 ---------------------------------------------- 1 gTaurine ---------------------------------------------- 1 g
정제수를 가하여 ------------------------------ 전체 900 ㎖Purified water was added ------------------------------ Total 900 ml
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2L용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다.After mixing the above components according to a conventional health drink manufacturing method, and stirring and heating at 85° C. for about 1 hour, the resulting solution is filtered, obtained in a sterilized 2L container, sealed and sterilized, and then refrigerated and stored in the present invention. It is used for the preparation of healthy beverage compositions.
<110> PYUNGANG CORPORATION/ INDUSTRIAL COOPERATION FOUNDATION CHUNGNAM NATIONAL UNIVERSITY. <120> Composition of the extract of combined herb CGE for preventing and treating respiratory inflammation <130> DIFI190102EK <150> <151> <160> 4 <170> KoPatentIn <210> 1 <211> 21 <212> DNA <213> Homo Sapiens <400> TGA TCA TCC AGC AGC AGG GCT 20 <210> 2 <211> 21 <212> DNA <213> Homo Sapiens <400> CCG AGC TCA GAG GAC ATA TGG G 20 <210> 3 <211> 16 <212> DNA <213> Homo Sapiens <400> TTC CGC AAG TTC ACC TAC C 20 <210> 4 <211> 20 <212> DNA <213> Homo Sapiens <400> CGG GCC GGC CAT GCT TTA CG 20 <110> PYUNGANG CORPORATION/ INDUSTRIAL COOPERATION FOUNDATION CHUNGNAM NATIONAL UNIVERSITY. <120> Composition of the extract of combined herb CGE for preventing and treating respiratory inflammation <130> DIFI190102EK <150> <151> <160> 4 <170> KoPatentIn <210> 1 <211> 21 <212> DNA <213> Homo Sapiens <400> TGA TCA TCC AGC AGC AGG GCT 20 <210> 2 <211> 21 <212> DNA <213> Homo Sapiens <400> CCG AGC TCA GAG GAC ATA TGG G 20 <210> 3 <211> 16 <212> DNA <213> Homo Sapiens <400> TTC CGC AAG TTC ACC TAC C 20 <210> 4 <211> 20 <212> DNA <213> Homo Sapiens <400> CGG GCC GGC CAT GCT TTA CG 20
Claims (11)
상기 생약 조합은 금은화, 맥문동, 사삼, 길경 및 지실로 구성된 조합생약의 중량 배합 조합비가 0.1 내지 20 중량부 (w/w): 0.1 내지 20 중량부 (w/w); 0.1 내지 20 중량부 (w/w); 0.1 내지 20 중량부 (w/w); 1 중량부 (w/w)임을 특징으로 하는 약학조성물. According to claim 1,
The herbal combination is gold silver, McMun-dong, Ginseng, Gilkyung, and weight ratio of the combination of herbal medicines is 0.1 to 20 parts by weight (w/w): 0.1 to 20 parts by weight (w/w); 0.1 to 20 parts by weight (w/w); 0.1 to 20 parts by weight (w/w); Pharmaceutical composition characterized by 1 part by weight (w/w).
상기 추출물은 물, 주정, 탄소수 1 내지 4의 저급 알콜 또는 이들의 혼합용매에 가용한 추출물임을 특징으로 하는 약학조성물. According to claim 1,
The extract is a pharmaceutical composition characterized in that the extract is soluble in water, alcohol, lower alcohol having 1 to 4 carbon atoms or a mixed solvent thereof.
상기 호흡기성 염증 질환은 천식, 급성 기관지염, 폐렴, 만성 기관지염, 기관지 확장증, 편도선염, 인후염, 만성 폐쇄성 폐질환(chronic obstructive pulmonary disease), 낭포성 섬유증, 또는 폐섬유화증임을 특징으로 하는 약학조성물. According to claim 1,
The respiratory inflammatory disease is asthma, acute bronchitis, pneumonia, chronic bronchitis, bronchiectasis, tonsillitis, sore throat, chronic obstructive pulmonary disease (chronic obstructive pulmonary disease), cystic fibrosis, or pulmonary fibrosis.
상기 생약 조합은 금은화, 맥문동, 사삼, 길경 및 지실로 구성된 조합생약의 중량 배합 조합비가 0.1 내지 20 중량부 (w/w): 0.1 내지 20 중량부 (w/w); 0.1 내지 20 중량부 (w/w); 0.1 내지 20 중량부 (w/w); 1 중량부 (w/w)임을 특징으로 하는 건강기능식품. The method of claim 5,
The herbal combination is gold silver, McMun-dong, Ginseng, Gilkyung, and weight ratio of the combination of herbal medicines is 0.1 to 20 parts by weight (w/w): 0.1 to 20 parts by weight (w/w); 0.1 to 20 parts by weight (w/w); 0.1 to 20 parts by weight (w/w); Health functional food characterized by 1 part by weight (w/w).
상기 추출물은 물, 주정, 탄소수 1 내지 4의 저급 알콜 또는 이들의 혼합용매에 가용한 추출물임을 특징으로 하는 건강기능식품. The method of claim 5,
The extract is a health functional food, characterized in that the extract is soluble in water, alcohol, lower alcohol having 1 to 4 carbon atoms or a mixed solvent thereof.
상기 호흡기성 염증 질환은 천식, 급성 기관지염, 폐렴, 만성 기관지염, 기관지 확장증, 편도선염, 인후염, 만성 폐쇄성 폐질환(chronic obstructive pulmonary disease), 낭포성 섬유증, 또는 폐섬유화증임을 특징으로 하는 건강기능식품. The method of claim 5,
The respiratory inflammatory disease is asthma, acute bronchitis, pneumonia, chronic bronchitis, bronchiectasis, tonsillitis, sore throat, chronic obstructive pulmonary disease (chronic obstructive pulmonary disease), cystic fibrosis, or pulmonary fibrosis.
상기 건강기능식품은 산제, 과립제, 정제, 캡슐제, 환제, 현탁액, 에멀젼, 시럽, 티백제, 침출차, 건강 음료의 형태인 건강기능식품.The method of claim 5,
The health functional foods are health functional foods in the form of powders, granules, tablets, capsules, pills, suspensions, emulsions, syrups, tea bags, leaching teas, and health drinks.
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KR20060116596A (en) * | 2005-05-10 | 2006-11-15 | (주)토종물산 | Health beverage composition comprising an extract of platycodon grandiflorum, glycyrrhiza uralensis, liriope platyphylla and chaenomeles sinesis koehne for preventing a respiratory disease |
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