KR102020585B1 - Pharmaceutical composition comprising 3-Bromo-4,5-dihydroxybenzaldehyde for prevention or treatment of diabetes mellitus - Google Patents
Pharmaceutical composition comprising 3-Bromo-4,5-dihydroxybenzaldehyde for prevention or treatment of diabetes mellitus Download PDFInfo
- Publication number
- KR102020585B1 KR102020585B1 KR1020180023514A KR20180023514A KR102020585B1 KR 102020585 B1 KR102020585 B1 KR 102020585B1 KR 1020180023514 A KR1020180023514 A KR 1020180023514A KR 20180023514 A KR20180023514 A KR 20180023514A KR 102020585 B1 KR102020585 B1 KR 102020585B1
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- South Korea
- Prior art keywords
- dihydroxybenzaldehyde
- bromo
- compound
- cell
- diabetes
- Prior art date
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Abstract
본 발명은 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 당뇨병 예방 또는 치료용 약학적 조성물에 관한 것으로, 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드는 베타세포(β-cell)의 세포사멸이 유도된 조건에서 베타세포의 세포사멸 및 인슐린 분비 저하를 억제하는 효과를 나타내므로, 상기 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드는 베타세포의 세포사멸 및 인슐린 분비 저하로 인해 발생하는 당뇨병의 예방 또는 치료에 유용하게 사용될 수 있다. The present invention relates to a pharmaceutical composition for preventing or treating diabetes, comprising compound 3-bromo-4,5-dihydroxybenzaldehyde, or a pharmaceutically acceptable salt thereof as an active ingredient. Since mother-4,5-dihydroxybenzaldehyde has an effect of inhibiting beta cell death and decreased insulin secretion under conditions in which beta cell (β-cell) cell death is induced, the compound 3-bromo -4,5-dihydroxybenzaldehyde may be usefully used for the prevention or treatment of diabetes caused by beta cell death and decreased insulin secretion.
Description
본 발명은 3-브로모-4,5-디하이드록시벤즈알데하이드(3-Bromo-4,5-dihydroxybenzaldehyde)를 유효성분으로 포함하는 당뇨병의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating diabetes comprising 3-bromo-4,5-dihydroxybenzaldehyde (3-Bromo-4,5-dihydroxybenzaldehyde) as an active ingredient.
최근 우리나라도 급속한 경제성장과 생활수준의 향상 및 서구화로 신체발달 측면에서는 매우 바람직한 현상을 보이는 반면, 성인들의 경우 과다한 고칼로리 음 식의 섭취, 운동부족 및 산업사회의 고도화에 따른 스트레스로 인하여 질병양상도 점점 성인병 위주로 서구화되고 있다. 대표적인 성인병의 예로는 간질환, 고혈압, 당뇨병, 비만증, 고지혈증 등을 들 수 있다. Recently, Korea also shows a very desirable phenomenon in terms of physical development due to rapid economic growth, improved living standards, and westernization.In the case of adults, the disease pattern is caused by stress caused by excessive high calorie food intake, lack of exercise and industrial society. Increasingly, the disease is becoming more westernized, especially in adult diseases. Representative adult diseases include liver disease, high blood pressure, diabetes, obesity, hyperlipidemia and the like.
대표적인 성인병의 하나인 당뇨병은 비전염성 만성질환으로, 췌장의 β세포에서 분비되는 인슐린이 부족하거나 그 기능을 제대로 발휘하지 못하여 체내에서 포도당이 에너지원으로 이용되지 못하고 혈액 내에 고농도로 남아 있다가 소변으로 배설되는 질환이다. 당뇨병은 그 발병원인 및 증상의 치료방법에 따라 크게 인슐린 의존형 당뇨병(insulin dependent diabetes mellitus, IDDM)과 인슐린 비의존형 당뇨병(non-insulin dependent diabetes mellitus, NIDDM)으로 분류할 수 있다. 우리나라의 경우 당뇨병 환자의 95% 이상이 NIDDM 환자이다. 당뇨병은 그 자체가 큰 질환이라기 보다는 장기간 이 질환에 걸려 있음으로 해서 발병하는 합병증, 예를 들어 당뇨병성 신경병증(neuropathy), 망막병증(retinopathy), 백내장(cataract), 신장병(nephropathy) 등으로 인해 환자들이 정상적인 삶을 영위할 수 없을 뿐 아니라 치명적인 결과까지 초래할 수 있기 때문에 사회적으로 큰 문제가 되는 것이다.Diabetes, one of the typical adult diseases, is a non-communicable chronic disease. Insulin secreted by the pancreatic β cells is insufficient or does not function properly. Therefore, glucose is not used as an energy source in the body and remains high in the blood. It is a disease that is excreted. Diabetes can be broadly classified into insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM) according to its pathogenesis and treatment of symptoms. In Korea, more than 95% of diabetics are NIDDM patients. Diabetes is not a big disease in itself but rather a complication caused by long-term disease, such as diabetic neuropathy, retinopathy, cataract, nephropathy, etc. This is a social problem because patients can not only live a normal life but can have fatal consequences.
현재 흔히 사용되는 당뇨병 치료제는 경구용 혈당강하제와 인슐린 주사제로 크게 구분된다. 일반적으로, 체내에서 인슐린 분비가 없는 인슐린 의존형 당뇨병 환자, 임신성 당뇨병 환자 및 경구용 혈당강하제로 혈당조절이 제대로 안 되는 인슐린 비의존형 당뇨병 환자에게는 인슐린 주사를, 식사용법과 운동요법을 병행함에도 불구하고 적절한 혈당조절이 되지 않는 인슐린 비의존형 당뇨병 환자는 경구용 혈당강하제를 복용하게 하는 것이 일반적이며, 경구용 혈당강하제는 설포닐우레아계 약물과 비구아니드계 약물 등으로 구분될 수 있다.Currently used diabetic drugs are roughly divided into oral hypoglycemic agents and insulin injections. In general, insulin injections for insulin-dependent diabetics without pregnancy in the body, gestational diabetes patients, and insulin-independent diabetes patients whose oral hypoglycemics are poorly controlled are given adequate insulin injections, despite the combination of diet and exercise therapy. Insulin-independent diabetic patients who do not have blood sugar control are generally allowed to take oral hypoglycemic agents, and oral hypoglycemic agents may be classified into sulfonylurea drugs and biguanide drugs.
글리피자이드(glipizide), 글리클라자이드(gliclazide), 글리퀴돈(gliquidone), 글리벤클라마이드(glibenclamide) 및 클로르프로파마이드(chlorpropamide) 등의 설포닐우레아계 약물은 췌장에서 인슐린 분비를 촉진하는 작용을 나타내지만, 췌장에서 인슐린 분비가 전혀 없는 인슐린 의존형 당뇨병 환자에게는 사용할 수 없으며, 췌장에서 인슐린 분비 능력이 상대적으로 감소된 인슐린 비의존형 당뇨병 환자나 기형아 출산, 유산, 사산 등이 우려되므로 가임기 여성에게는 사용할 수 없다는 단점이 있다. 또한, 대부분의 설포닐우레아계 약물은 간에서 대사되어 신장으로 배설되므로 간기능 및 신장기능 장애 환자에게는 주의하여 사용하여야 한다.Sulfonylurea-based drugs such as glipizide, gliclazide, gliquidone, glibenclamide, and chlorpropamide have been shown to promote insulin secretion in the pancreas. However, it cannot be used for insulin-dependent diabetics who have no insulin secretion in the pancreas and cannot be used for women of childbearing age due to concerns about insulin-independent diabetes patients with relatively reduced insulin secretion in the pancreas, birth defects, miscarriage, and stillbirth. There are disadvantages. In addition, since most sulfonylurea-based drugs are metabolized in the liver and excreted into the kidney, they should be used with caution in patients with hepatic and renal dysfunction.
메트포르민(metformin) 등의 비구아니드계 약물은 작용기전이 분명하지 않지만 췌장에서 인슐린 분비를 증가시키는 작용은 없는 것으로 밝혀져 있으며, 설포닐우레아계 약물보다 혈당강하효과가 약한 반면에, 저혈당을 일으킬 가능성도 낮다. 그러나 소화기계 부작용의 발생빈도가 높아 치료초기에 오심, 구토, 설사, 발진 등 이 나타나며, 젖산혈증(lactic acidosis)을 유발하여 생명을 위협하는 치명적인 부작용을 일으키므로, 현재 미국에서는 실험용 약제로만 사용하고 있다.Although biguanide-based drugs such as metformin have no clear mechanism of action, they have not been shown to increase insulin secretion in the pancreas, and have a lower hypoglycemic effect than sulfonylurea-based drugs. low. However, due to the high incidence of side effects of the digestive system, nausea, vomiting, diarrhea and rash appear at the beginning of treatment, and cause lactic acidosis and cause life-threatening side effects. have.
따라서, 현재 사용되고 있는 설포닐우레아계 또는 비구아니드계의 약물은 상기의 단점이나 부작용이 있으므로 국내외적으로 증가 추세에 있는 당뇨성 질환을 더 바람직하게 치료할 수 있는 보다 부작용이 적고 안전한 혈당 강하제를 개발할 필요가 있다. 이와 같이, 현재 화학적으로 합성된 항당뇨제의 여러가지 심각한 부작용의 발생과 함께 약물 내성의 발생으로 인한 약물 효과가 떨어지고 있으므로, 새로운 항당뇨 활성을 갖는 신규 물질을 찾고자 하는 많은 연구가 진행중이다.Therefore, the currently used sulfonylurea-based or biguanide-based drugs have the above disadvantages or side effects, and therefore, there is a need to develop a safer blood glucose lowering agent with less side effects and more desirable to treat the diabetic disease that is increasing at home and abroad. There is. As described above, since the drug effects due to the development of drug resistance have been reduced along with the occurrence of various serious side effects of the chemically synthesized antidiabetic agent, many studies are in progress to find a new substance having new antidiabetic activity.
3-브로모-4,5-디하이드록시벤즈알데하이드(3-Bromo-4,5-dihydroxybenzaldehyde)는 홍조류에서 분리된 천연 브로모페놀(bromphenol) 화합물로서, 브로모페놀은 하나 이상의 벤젠 고리, 브롬 및 하이드록실 치환기를 갖는 구조의 화합물이다. 브로모페놀 화합물은 항균 활성을 비롯해 다양한 생물학적 활성에 대하여 보고되고 있으며, 대한민국 등록특허 제10-1596133호에서는 브로모페놀의 한 종류인 3-브로모-4,5-디하이드록시벤즈알데하이드를 탈모방지 활성을 개시하고 있다. 3-Bromo-4,5-dihydroxybenzaldehyde is a natural bromophenol compound isolated from red algae, and bromophenol is one or more benzene rings, bromine And a compound having a hydroxyl substituent. Bromophenol compounds have been reported for a variety of biological activities, including antimicrobial activity, the Republic of Korea Patent No. 10-1596133 a hair loss of one type of bromophenol 3-bromo-4,5-dihydroxybenzaldehyde. Preventive activity is initiated.
본 발명의 목적은 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드를 유효성분으로 포함하는, 당뇨병 예방 또는 치료용 약학적 조성물 및 당뇨병 예방 또는 개선용 건강기능식품을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for preventing or treating diabetes and a dietary supplement for preventing or improving diabetes, comprising the compound 3-bromo-4,5-dihydroxybenzaldehyde as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물인 3-브로모-4,5-디하이드록시벤즈알데하이드(3-Bromo-4,5-dihydroxybenzaldehyde) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 당뇨병 예방 또는 치료용 약학적 조성물을 제공한다:In order to achieve the above object, the present invention is 3-bromo-4,5-dihydroxybenzaldehyde (3-Bromo-4,5-dihydroxybenzaldehyde) or a pharmaceutically acceptable compound thereof Provided is a pharmaceutical composition for preventing or treating diabetes, comprising a salt as an active ingredient:
[화학식 1][Formula 1]
또한, 본 발명은 상기 화학식 1로 표시되는 화합물인 3-브로모-4,5-디하이드록시벤즈알데하이드(3-Bromo-4,5-dihydroxybenzaldehyde) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 당뇨병 예방 또는 개선용 건강기능식품을 제공한다:In addition, the present invention is a compound represented by the formula (1) 3-bromo-4,5-dihydroxybenzaldehyde (3-Bromo-4,5-dihydroxybenzaldehyde) or a pharmaceutically acceptable salt thereof as an active ingredient It provides a dietary supplement for preventing or improving diabetes, which includes:
본 발명의 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드는 베타세포(β-cell)의 세포사멸이 유도된 조건에서 베타세포의 세포사멸 및 인슐린 분비 저하를 억제하는 효과를 나타내므로, 상기 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드는 베타세포의 세포사멸 및 인슐린 분비 저하로 인해 발생하는 당뇨병의 예방 또는 치료에 유용하게 사용될 수 있다. Compound 3-bromo-4,5-dihydroxybenzaldehyde of the present invention exhibits an effect of inhibiting beta cell death and decreased insulin secretion under conditions in which cell death of beta cells is induced. The compound 3-bromo-4,5-dihydroxybenzaldehyde may be usefully used for the prevention or treatment of diabetes caused by beta cell death and decreased insulin secretion.
도 1은 폴리시포니아 자포니카(Polysiphonia japonica)로부터 분리된 3-브로모-4,5-디하이드록시벤즈알데하이드 (3-Bromo-4,5-dihydroxybenzaldehyde, PS6-1로 표기)의 HPLC 분석 결과이다.
도 2은 3-브로모-4,5-디하이드록시벤즈알데하이드 (3-Bromo-4,5-dihydroxybenzaldehyde, PS6-1로 표기)의 농도별 처리에 따른 베타세포의 세포 생존율을 나타낸 결과이다.
도 3는 베타세포에 대한 3-브로모-4,5-디하이드록시벤즈알데하이드 (3-Bromo-4,5-dihydroxybenzaldehyde, PS6-1로 표기)의 세포 보호 효과를 나타낸 결과이다 (A: 팔미트산(PA) 처리 시 베타세포의 세포 생존률; B: 3-브로모-4,5-디하이드록시벤트알데하이드(PS6-1) 전처리 후 팔미트산 처리 시 베타세포의 세포 생존률).
도 4은 베타세포에 대한 3-브로모-4,5-디하이드록시벤즈알데하이드 (3-Bromo-4,5-dihydroxybenzaldehyde, PS6-1로 표기)의 세포사멸(apoptosis) 억제 효과를 나타낸 결과이다 (A: 베타세포의 형광이미지 분석 결과; B: 베타세포의 비정상적인 핵의 비율(abnormal nucleic contents) 결과; Control: 무처리군; PA: 팔미트산; PS6-1: 3-브로모-4,5-디하이드록시벤즈알데하이드).
도 5는 베타세포에 대한 3-브로모-4,5-디하이드록시벤즈알데하이드 (3-Bromo-4,5-dihydroxybenzaldehyde, PS6-1로 표기)의 세포괴사(necrosis) 억제 효과를 나타낸 결과이다 (A: 베타세포의 형광이미지 분석 결과; B: 죽은 세포의 비율; Control: 무처리군; PA: 팔미트산; PS6-1: 3-브로모-4,5-디하이드록시벤즈알데하이드).
도 6는 3-브로모-4,5-디하이드록시벤즈알데하이드 처리가 베타세포의 세포사멸에 관계되는 단백질(Bcl-2, Bax 및 caspase-3)에 미치는 효과를 나타낸 것이다 (A: 웨스턴 블롯 결과; B: 각 단백질 발현량을 정량화한 결과; PA: 팔미트산; PS6-1: 3-브로모-4,5-디하이드록시벤즈알데하이드).
도 7은 3-브로모-4,5-디하이드록시벤즈알데하이드 처리가 베타세포의 미토콘드리아 사이토크롬 c(cytochrome c)의 발현에 미치는 효과를 나타낸 것이다 (A: 웨스턴 블롯 결과; B: 사이토크롬 c의 발현량을 정량화한 결과; PA: 팔미트산; PS6-1: 3-브로모-4,5-디하이드록시벤즈알데하이드).
도 8은 3-브로모-4,5-디하이드록시벤즈알데하이드 처리가 베타세포의 미토콘드리아 사이토크롬 c(cytochrome c)의 방출에 미치는 효과를 나타낸 것이다 (A: 콘포컬 현미경으로 관찰한 결과; B: 사이토크롬 c의 방출량을 정량화한 결과; PA: 팔미트산; PS6-1: 3-브로모-4,5-디하이드록시벤즈알데하이드).
도 9은 3-브로모-4,5-디하이드록시벤즈알데하이드 처리가 베타세포의 ROS(reactive oxygen species)의 생성에 미치는 효과를 나타낸 것이다 (A: 베타세포의 형광이미지 분석 결과; B: ROS 생성량을 정량화한 결과; PA: 팔미트산; PS6-1: 3-브로모-4,5-디하이드록시벤즈알데하이드).
도 10는 3-브로모-4,5-디하이드록시벤즈알데하이드 처리가 베타세포의 인슐린 분비 기능 유지에 미치는 효과를 나타낸 것이다 (PA: 팔미트산; PS6-1: 3-브로모-4,5-디하이드록시벤즈알데하이드).1 shows the results of HPLC analysis of 3-bromo-4,5-dihydroxybenzaldehyde (denoted as 3-Bromo-4,5-dihydroxybenzaldehyde, PS6-1) isolated from Polysiphonia japonica.
Figure 2 is a result showing the cell viability of beta cells according to the concentration-specific treatment of 3-bromo-4,5-dihydroxybenzaldehyde (3-Bromo-4,5-dihydroxybenzaldehyde, denoted PS6-1).
Figure 3 is a result showing the cell protective effect of 3-bromo-4,5-dihydroxybenzaldehyde (denoted 3-Bromo-4,5-dihydroxybenzaldehyde, PS6-1) on beta cells (A: arm Cell viability of beta cells upon treatment with mytic acid (PA) B: Cell survival of beta cells upon palmitic acid treatment after 3-bromo-4,5-dihydroxybentaldehyde (PS6-1) pretreatment).
4 is a result showing the apoptosis inhibitory effect of 3-bromo-4,5-dihydroxybenzaldehyde (denoted as 3-Bromo-4,5-dihydroxybenzaldehyde, PS6-1) on beta cells. (A: fluorescence image analysis of beta cells; B: abnormal nucleic contents of beta cells; control: untreated group; PA: palmitic acid; PS6-1: 3-bromo-4, 5-dihydroxybenzaldehyde).
5 is a result showing the effect of inhibiting the cell necrosis (necrosis) of 3-bromo-4,5-dihydroxybenzaldehyde (denoted as 3-Bromo-4,5-dihydroxybenzaldehyde, PS6-1) on beta cells (A: fluorescence image analysis of beta cells; B: proportion of dead cells; Control: untreated group; PA: palmitic acid; PS6-1: 3-bromo-4,5-dihydroxybenzaldehyde).
Figure 6 shows the effect of 3-bromo-4,5-dihydroxybenzaldehyde treatment on proteins (Bcl-2, Bax and caspase-3) involved in apoptosis of cells (A: Western blot Results: B: Quantification of each protein expression level; PA: palmitic acid; PS6-1: 3-bromo-4,5-dihydroxybenzaldehyde).
Figure 7 shows the effect of 3-bromo-4,5-dihydroxybenzaldehyde treatment on the expression of mitochondrial cytochrome c in beta cells (A: Western blot results; B: Cytochrome c) Quantification of the expression level of PA: palmitic acid; PS6-1: 3-bromo-4,5-dihydroxybenzaldehyde).
Figure 8 shows the effect of 3-bromo-4,5-dihydroxybenzaldehyde treatment on the release of mitochondrial cytochrome c of beta cells (A: Confocal microscopy; B; : Result of quantification of the amount of cytochrome c released; PA: palmitic acid; PS6-1: 3-bromo-4,5-dihydroxybenzaldehyde).
Figure 9 shows the effect of 3-bromo-4,5-dihydroxybenzaldehyde treatment on the production of reactive oxygen species (ROS) of beta cells (A: fluorescence image analysis of beta cells; B: ROS Quantification of product yield; PA: palmitic acid; PS6-1: 3-bromo-4,5-dihydroxybenzaldehyde).
10 shows the effect of 3-bromo-4,5-dihydroxybenzaldehyde treatment on maintaining insulin secretion function of beta cells (PA: palmitic acid; PS6-1: 3-bromo-4, 5-dihydroxybenzaldehyde).
본 발명에서 사용되는 용어 "예방"은 본 발명의 조성물의 투여로 질환의 증세를 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.As used herein, the term "prevention" refers to any action that inhibits or delays the onset of a disease by administration of a composition of the present invention.
본 발명에서 사용되는 용어 "치료" 및 "개선"은 본 발명의 조성물의 투여로 상기 질환의 증세가 호전 또는 이롭게 변경되는 모든 행위를 의미한다.As used herein, the terms "treatment" and "improvement" refer to any action in which the symptoms of the disease improve or benefit altered by administration of the composition of the present invention.
본 발명에서 사용되는 용어 "투여"는 임의의 적절한 방법으로 환자에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다.As used herein, the term "administration" means providing a patient with a given composition of the present invention in any suitable manner.
본 발명에서 사용되는 용어 "환자"는 본 발명의 조성물을 투여하여 증상이 호전될 수 있는 질환을 가진 인간, 원숭이, 개, 염소, 돼지 또는 쥐 등 모든 동물을 의미한다.As used herein, the term "patient" refers to any animal, such as a human, monkey, dog, goat, pig or rat, having a disease that can improve symptoms by administering the composition of the present invention.
본 발명에서 사용되는 용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜 또는 위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 이는 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시에 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.As used herein, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit or risk ratio applicable to medical treatment, which means the type of disease, the severity, the activity of the drug, the drug Sensitivity to, time of administration, route of administration and rate of administration, duration of treatment, factors including drug used concurrently, and other factors well known in the medical arts.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1로 표시되는 화합물인 3-브로모-4,5-디하이드록시벤즈알데하이드, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 당뇨병 예방 또는 치료용 약학적 조성물을 제공한다:The present invention provides a pharmaceutical composition for preventing or treating diabetes, comprising 3-bromo-4,5-dihydroxybenzaldehyde, or a pharmaceutically acceptable salt thereof, as a compound represented by the following Formula 1 as an active ingredient: to provide:
[화학식 1][Formula 1]
상기 화합물은 폴리시포니아 자포니카(Polysiphonia Japonica)로부터 분리된 화합물일 수 있으나, 이에 한정되지 않는다. The compound may be a compound separated from Polysiphonia Japonica , but is not limited thereto.
상기 화합물은 베타세포의 세포사멸(apoptosis) 또는 괴사(necrosis)를 억제하는 것일 수 있다. 구체적으로, 상기 화합물은 세포사멸을 억제하는 B 세포 림프종 2(B-cell lymphoma 2, Bcl-2) 단백질, 세포사멸 전구단백질(pro-apoptotic protein)인 Bcl-2-연관 X(Bcl-2-associated X, Bax) 단백질 또는 카스파제-3(caspase-3) 단백질의 발현을 조절할 수 있다. The compound may be to inhibit apoptosis or necrosis of beta cells. Specifically, the compound is B-cell lymphoma 2 (Bcl-2) protein that inhibits apoptosis, Bcl-2-associated X (Bcl-2-), which is a pro-apoptotic protein expression of an associated X, Bax) protein or caspase-3 protein.
상기 화합물은 베타세포의 Bcl-2 단백질의 발현 감소를 억제하는 것일 수 있다. 또한, 상기 화합물은 베타세포의 Bax 단백질 또는 caspase-3 단백질의 발현 증가를 억제하는 것일 수 있다. The compound may be to inhibit the decrease in the expression of Bcl-2 protein in beta cells. In addition, the compound may be to inhibit the expression of the beta-cell Bax protein or caspase-3 protein.
상기 화합물은 베타세포의 미토콘드리아의 기능 저하를 억제하는 것일 수 있다. 구체적으로, 상기 화합물은 베타세포 미토콘드리아의 사이토크롬 c(cytochrome c) 방출 또는 활성산소종(ROS, reacitve oxygen species) 생성을 억제하는 것일 수 있다. The compound may be to inhibit the degradation of mitochondria of beta cells. Specifically, the compound may be to inhibit cytochrome c release or reactive oxygen species (ROS) generation of the beta-cell mitochondria.
상기 화합물은 베타세포의 인슐린 분비 저하를 억제하는 것일 수 있다. The compound may be to inhibit the insulin secretion of beta cells.
본 발명의 구체적인 실시예에서, 본 발명자들은 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드(3-Bromo-4,5-dihydroxybenzaldehyde)는 독성물질 팔미트산(PA)으로부터 베타세포를 보호하는 효과를 가짐을 확인하였다 (도 2 및 도 3 참조). In a specific embodiment of the present invention, the inventors of the compound 3-bromo-4,5-dihydroxybenzaldehyde (3-Bromo-4,5-dihydroxybenzaldehyde) is a beta cell from the toxic palmitic acid (PA) It was confirmed to have a protective effect (see FIGS. 2 and 3).
또한 본 발명자들은 팔미트산이 처리된 세포군과 본 발명의 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드를 전처리한 후 팔미트산을 처리한 세포군의 형광이미지를 분석한 결과, 팔미트산을 처리한 세포군에서 세포사멸(apoptosis) 및 괴사(necrosis)가 증가하였으나, 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드를 처리한 세포군에서는 세포사멸 및 괴사가 억제됨을 확인하였다 (도 4 및 도 5 참조). In addition, the present inventors analyzed fluorescence images of palmitic acid-treated cell groups and palmitic acid-treated cell groups after pretreatment of the compound 3-bromo-4,5-dihydroxybenzaldehyde of the present invention. Apoptosis and necrosis were increased in the acid-treated cell group, but apoptosis and necrosis were inhibited in the cell group treated with compound 3-bromo-4,5-dihydroxybenzaldehyde ( 4 and 5).
또한 본 발명자들은 팔미트산이 처리된 세포군과 본 발명의 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드를 전처리한 후 팔미트산을 처리한 세포군의 Bcl-2 단백질, Bax 단백질 및 caspase-3 단백질의 발현량을 측정한 결과, 팔미트산을 처리한 세포군에서 Bcl-2 단백질의 발현량이 감소하고, Bax 단백질 및 caspase-3 단백질의 발현량이 증가하였으나, 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드를 처리한 세포군에서는 Bcl-2 단백질의 발현 감소가 억제되고, Bax 단백질 및 caspase-3 단백질의 발현 증가가 억제됨을 확인하였다 (도 6 참조).In addition, the present inventors pretreated the palmitic acid treated cell group and the compound 3-bromo-4,5-dihydroxybenzaldehyde of the present invention and then treated with palmitic acid Bcl-2 protein, Bax protein and caspase. As a result of measuring the expression level of -3 protein, the expression level of Bcl-2 protein was decreased and the expression levels of Bax protein and caspase-3 protein were increased in the cell group treated with palmitic acid, but the compound 3-bromo-4, In the cell group treated with 5-dihydroxybenzaldehyde, decreased expression of Bcl-2 protein was inhibited and increased expression of Bax protein and caspase-3 protein was inhibited (see FIG. 6).
또한 본 발명자들은 팔미트산이 처리된 세포군과 본 발명의 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드를 전처리한 후 팔미트산을 처리한 세포군의 사이토크롬 c(cytochrome c)의 발현량 및 방출을 측정한 결과, 팔미트산을 처리한 세포군에서 사이토크롬 c의 발현량 및 방출량이 증가하였으나, 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드를 처리한 세포군에서는 사이토크롬 c의 발현량 및 방출량 증가가 억제됨을 확인하였다 (도 7 및 도 8 참조).In addition, the present inventors expressed the cytochrome c of the cell group treated with palmitic acid and the cell group treated with palmitic acid after pretreatment with the compound 3-bromo-4,5-dihydroxybenzaldehyde of the present invention. As a result of measuring the amount and release, the expression and release of cytochrome c were increased in the cell group treated with palmitic acid, but the cytochrome was found in the cell group treated with compound 3-bromo-4,5-dihydroxybenzaldehyde. It was confirmed that an increase in the amount of expression and release of c was suppressed (see FIGS. 7 and 8).
또한 본 발명자들은 팔미트산이 처리된 세포군과 본 발명의 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드를 전처리한 후 팔미트산을 처리한 세포군의 ROS(reactive oxygen species) 생성량을 측정한 결과, 팔미트산을 처리한 세포군에서 ROS 생성량이 증가하였으나, 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드를 처리한 세포군에서는 ROS 생성이 억제됨을 확인하였다 (도 9 참조).In addition, the present inventors measured the amount of ROS (reactive oxygen species) production of palmitic acid-treated cell groups and palmitic acid-treated cell groups after pretreatment with compound 3-bromo-4,5-dihydroxybenzaldehyde. As a result, the amount of ROS produced was increased in the cell group treated with palmitic acid, but it was confirmed that ROS production was inhibited in the cell group treated with compound 3-bromo-4,5-dihydroxybenzaldehyde (see FIG. 9).
또한 본 발명자들은 팔미트산이 처리된 세포군과 본 발명의 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드를 전처리한 후 팔미트산을 처리한 세포군의 인슐린 분비량을 측정한 결과, 팔미트산을 처리한 세포군에서 인슐린 분비가 감소되었으나, 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드를 처리한 세포군에서는 인슐린 분비 저하가 억제됨을 확인하였다 (도 10 참조).In addition, the present inventors measured the insulin secretion of the palmitic acid treated cell group and the palmitic acid treated cell group after pretreatment with the compound 3-bromo-4,5-dihydroxybenzaldehyde of the present invention. Insulin secretion was reduced in the cell group treated with acid, but the decrease in insulin secretion was inhibited in the cell group treated with compound 3-bromo-4,5-dihydroxybenzaldehyde (see FIG. 10).
따라서, 본 발명의 화합물 3-브로모-4,5-디하이드록시벤즈알데하이드는 베타세포의 세포사멸이 유도된 조건에서 베타세포의 세포사멸 및 괴사를 억제하고, 미토콘드리아의 기능 저하를 억제하며, 인슐린 분비 저하를 억제할 수 있음을 확인하였으므로, 3-브로모-4,5-디하이드록시벤즈알데하이드는 베타세포의 세포사멸 및 인슐린 분비 저하로 인해 발생하는 당뇨병의 예방 또는 치료에 유용하게 사용될 수 있다. Therefore, the compound 3-bromo-4,5-dihydroxybenzaldehyde of the present invention inhibits apoptosis and necrosis of beta cells under conditions in which apoptosis of beta cells is induced, and suppresses the degradation of mitochondria, Since it was confirmed that the insulin secretion can be suppressed, 3-bromo-4,5-dihydroxybenzaldehyde can be usefully used for the prevention or treatment of diabetes caused by beta cell death and decreased insulin secretion. have.
본 발명은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용되는 염, 이로부터 제조될 수 있는 가능한 용매화물, 수화물, 라세미체, 또는 입체이성질체를 모두 포함한다.The present invention includes all compounds represented by the formula (1) or pharmaceutically acceptable salts thereof, and possible solvates, hydrates, racemates, or stereoisomers which may be prepared therefrom.
본 발명의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용되는 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, 하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.It can be used in the form of a compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof, acid salts formed by the pharmaceutically acceptable free acid is useful as the salt. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, Xylene Sulfonate, Phenyl Acetate, Phenylpropionate, Phenyl Butyrate, Citrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate , Naphthalene-2-sulfonate or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1로 표시되는 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다.The acid addition salts according to the present invention can be dissolved in conventional methods, for example, by dissolving a compound represented by the formula (1) in an excess of an aqueous solution of an acid, which salt is a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile It can be prepared by precipitation using.
또한, 동량의 화학식 1로 표시되는 화합물, 및 산 수용액 또는 알코올을 가열하고, 이어서 이 혼합물을 증발시켜서 건조하거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.It is also possible to prepare an equivalent amount of the compound represented by the formula (1) and an aqueous acid solution or alcohol, followed by evaporation of the mixture to dryness or precipitation of the precipitated salt by suction filtration.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.Bases can also be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).
상기 조성물을 제제화할 경우, 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다.When formulating the composition, it is prepared using commonly used diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants.
경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 화학식 1로 표시되는 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose) 또는 락토오스(lactose) 또는 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which solid preparations contain at least one excipient such as starch in at least one compound represented by Formula 1 of the present invention. , Calcium carbonate, sucrose or sucrose, lactose or gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
비수성용제, 현탁용제로는 프로필렌글리콜, 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, 글리세롤, 젤라틴 등이 사용될 수 있다.As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
본 발명에 따른 조성물은 약제학적으로 유효한 양으로 투여한다. 본 발명에 있어서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The composition according to the invention is administered in a pharmaceutically effective amount. In the present invention, “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level means the type, severity, and activity of the patient's disease. , Drug sensitivity, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of drugs, and other factors well known in the medical arts. The compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with a minimum amount without side effects, which can be readily determined by one skilled in the art.
구체적으로, 본 발명에 따른 화합물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 1 kg 당 0.1 mg 내지 100 mg, 바람직하게는 0.5 mg 내지 10 mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 질환의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the compound according to the present invention may vary depending on the age, sex, and weight of the patient, and in general, 0.1 mg to 100 mg, preferably 0.5 mg to 10 mg per 1 kg of body weight is administered daily or every other day. Or divided into 1 to 3 times a day. However, the dosage may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
본 발명의 조성물에 추가로 동일 또는 유사한 기능을 나타내는 유효성분을 1종 이상 함유할 수 있다.The composition of the present invention may further contain one or more active ingredients exhibiting the same or similar functions.
또한, 본 발명은 하기 화학식 1로 표시되는 화합물인 3-브로모-4,5-디하이드록시벤즈알데하이드, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 당뇨병 예방 또는 개선용 건강기능식품을 제공한다:In addition, the present invention comprises a 3-bromo-4,5-dihydroxybenzaldehyde, or a pharmaceutically acceptable salt thereof as a compound represented by the following formula (1) as an active ingredient, preventing or improving diabetes health function Provide food:
[화학식 1][Formula 1]
본 발명의 화합물이 첨가되는 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the kind of food to which the compound of the present invention is added. Examples of foods to which the above-mentioned substances may be added include dairy products, various soups, drinks, meat, sausages, breads, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, and the like, and include all health foods in the conventional sense.
본 발명의 화합물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강식품 중의 상기 화합물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The compound of the present invention may be added to a food as it is, or used with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement). Generally, the amount of the compound in the health food can be added at 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for health and hygiene or health control purposes, the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
본 발명에 따른 건강식품 조성물이 음료 조성물인 경우, 지시된 비율로 필수 성분으로서 상기 화합물을 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 등과 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 내지 20 g, 바람직하게는 약 5 내지 10 g이다.When the health food composition according to the present invention is a beverage composition, there is no particular limitation on other ingredients except for containing the compound as essential ingredients in the indicated ratios, and various flavors or natural carbohydrates as additional ingredients are used as in general beverages. It may contain. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of said natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 10 g per 100 compositions of the present invention.
또한, 본 발명에 따른 건강식품 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, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition, the health food composition according to the present invention is a flavor, such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, Alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like. Others may contain pulp for the production of natural fruit juices and fruit juice beverages and vegetable beverages.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 제한되지 않으나, 본 발명의 화합물 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.These components can be used independently or in combination. The proportion of such additives is not limited, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the compound of the present invention.
이하, 본 발명을 실시예 및 실험예에 의해서 상세히 설명한다.Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.
단 하기 실시예 및 실험예는 본 발명을 예시하기 위한 것일 뿐, 본 발명이 하기 실시예 및 실험예에 의해서 한정되는 것은 아니다.However, the following Examples and Experimental Examples are only for illustrating the present invention, the present invention is not limited by the following Examples and Experimental Examples.
<< 실시예Example 1> 3- 1> 3- 브로모Bromo -4,5--4,5- 디하이드록시벤즈알데하이드Dihydroxybenzaldehyde (3- (3- BromoBromo -4,5-dihydroxybenzaldehyde)의 제조-4,5-dihydroxybenzaldehyde)
한국 제주도 해안에서 적색 해조인 폴리시포니아 자포니카(Polysiphonia japonica)를 채취하여 준비하였다. 채취한 시료를 수돗물로 3회 세척하여 표면의 염분, 착생식물 및 모래 등을 제거하고, 신선한 물로 주의 깊게 세척(rinse)하였다. 세척이 완료된 시료를 -70℃의 의료용 냉동고에서 보관하였다. 추출을 수행하기 전에 감압 하에서 냉동된 시료를 동결건조(lyophilize) 및 균질화(homogenize)하였다. 상기 분말화된 폴리시포니아 자포니카(Polysiphonia japonica) (500 g)을 80% 수성에탄올(2L) 용액으로 3회 추출하고 여과하였다. 여과액을 진공 조건에서 증발시켜, 80% 수성에탄올 추출물을 수득하였다. 이를 증류수에 용해하고, 클로로포름으로 분획하였다. 상기 클로로포름 분획물 1.2 g을 클로로포름-수성메탄올 혼합물(30:1 ~ 1:1)을 단계 용리액으로 하여 실리카 칼럼 크로마토그래피를 수행하여, 활성 분획을 분리하였다. 실리카 겔 크로마토그래피로부터 수득한 결합된 활성 분획은 80% 수성메탄올을 이용하여 Sephadex LH-20 칼럼 (Sigma)으로 분별하고, 역상 HPLC로 최종 생성물인 3-브로모-4,5-디하이드록시벤즈알데하이드(3-Bromo-4,5-dihydroxybenzaldehyde)을 수득하였다 (도 1). Polysiphonia japonica , a red seaweed, was prepared from Jeju, South Korea. The collected sample was washed three times with tap water to remove salts, creeping plants and sand from the surface, and carefully rinsed with fresh water. Washed samples were stored in a medical freezer at -70 ° C. Frozen samples were lyophilized and homogenized under reduced pressure prior to performing the extraction. The powdered Polysiphonia japonica (500 g) was extracted three times with 80% aqueous ethanol (2 L) solution and filtered. The filtrate was evaporated in vacuo to give 80% aqueous ethanol extract. It was dissolved in distilled water and fractionated with chloroform. 1.2 g of the chloroform fraction was subjected to silica column chromatography using a chloroform-water methanol mixture (30: 1 to 1: 1) as a step eluent to separate the active fraction. The combined active fractions obtained from silica gel chromatography were fractionated by Sephadex LH-20 column (Sigma) using 80% aqueous methanol, and the final product 3-bromo-4,5-dihydroxybenz by reverse phase HPLC. Aldehyde (3-Bromo-4,5-dihydroxybenzaldehyde) was obtained (FIG. 1).
<< 실험예Experimental Example 1> 팔미트 산(PA) 독성에 대한 3- 1> 3- for Palmitic Acid (PA) Toxicity 브로모Bromo -4,5--4,5- 디하이드록시벤즈알데Dihydroxybenzaldehyde 하이드의 베타세포 보호 효과Hyde Protects Against Beta Cells
<1-1> 3-<1-1> 3- 브로모Bromo -4,5--4,5- 디하이드록시벤즈알데하이드의Dihydroxybenzaldehyde 세포 독성 평가 Cytotoxicity Assessment
3-브로모-4,5-디하이드록시벤즈알데하이드(3-Bromo-4,5-dihydroxybenzaldehyde, 이하 PS6-1)의 독성 여부를 확인하기 위해 베타세포의 세포 생존율을 평가하였다.Cell viability of beta cells was evaluated to determine whether 3-bromo-4,5-dihydroxybenzaldehyde (3-Bromo-4,5-dihydroxybenzaldehyde, hereinafter PS6-1) was toxic.
구체적으로, 베타세포(4x104 cells/well) Asfari et al., 1992, Endocrinology, 130(1), 167-178에 기재된 랫트 인슐린종(Ins-1) 세포를 분양받은 것으로, 96웰 플레이트에 분주하고, 16시간 후에 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1)를 각각 0, 25, 50 및 100 μM 농도로 처리하였다. 24시간 후에 100 ㎕의 새로운 세포 배양액으로 교환하고, Cell Counting Kit-8(CCK-8, Dojindo Molecular Technologies) 용액 10 ㎕를 첨가하여 2시간 동안 반응시킨 후 450 nm에서 흡광도를 측정하였다. 무처리 대조군 세포의 생존율을 100%로 하여, 베타세포의 생존율을 계산하였다. Specifically, beta cells (4x10 4 cells / well) were injected with 96-well plates of rat insulin species (Ins-1) cells described in Asfari et al., 1992, Endocrinology, 130 (1), 167-178. After 16 hours, 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1) was treated at concentrations of 0, 25, 50 and 100 μM, respectively. After 24 hours, 100 µl of fresh cell culture was exchanged, and 10 µl of Cell Counting Kit-8 (CCK-8, Dojindo Molecular Technologies) solution was added thereto, reacted for 2 hours, and the absorbance was measured at 450 nm. The survival rate of the beta cells was calculated by making the survival rate of
그 결과, 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1) 처리시 베타세포 생존율의 감소가 나타나지 않아 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1)은 세포독성을 갖지 않는 것으로 확인되었으며, 오히려 세포 증식을 유도하는 것으로 나타났다(도 2). As a result, there was no decrease in beta cell viability upon treatment with 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1), resulting in 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1). ) Was found not to have cytotoxicity, but rather appeared to induce cell proliferation (FIG. 2).
<1-2> 팔미트 산(PA)의 세포 독성 평가<1-2> Cytotoxicity Evaluation of Palmitic Acid (PA)
3-브로모-4,5-디하이드록시벤트알데하이드(PS6-1) 대신 팔미트 산(palmitic acid; PA, Sigma) 0.1, 0.2, 0.4, 및 0.8 mM를 베타세포에 각각 처리한 것을 제외하고, 실험예 1-1과 동일한 방법으로 베타세포의 세포 생존율을 평가하였다.Except for treating beta cells with 0.1, 0.2, 0.4, and 0.8 mM of palmitic acid (PA, Sigma) instead of 3-bromo-4,5-dihydroxybentaldehyde (PS6-1), respectively. , Cell survival rate of beta cells was evaluated in the same manner as in Experiment 1-1.
<1-3> 팔미트산(PA) 독성에 대한 3-<1-3> 3- Against Palmitic Acid (PA) Toxicity 브로모Bromo -4,5--4,5- 디하이드록시벤즈알데하이드Dihydroxybenzaldehyde 의 베타세포 보호 효과Beta cell protective effect
독성물질로 알려진 팔미트산(palmitic acid; PA)에 대한 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1)의 베타세포 보호효과를 확인하기 위해 세포 생존율을 측정하였다. Cell viability was measured to determine the beta cell protective effect of 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1) on palmitic acid (PA), a known toxic substance.
구체적으로, 베타세포(4x104 cells/well)를 96웰 플레이트에 분주하고, 16시간 후에 50 μM의 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1)를 세포에 전처리하였다. 1시간 후, 0.2 mM의 팔미트 산을 처리하고 24시간 째에, 100 ㎕의 새로운 세포 배양액으로 교환하였다. Cell Counting Kit-8(CCK-8, Dojindo Molecular Technologies) 용액 10 ㎕를 첨가하여 2시간 동안 반응시킨 후 450 nm에서 흡광도를 측정하였다. 무처리 대조군 세포의 생존율을 100%로 하여, 베타세포의 생존율을 계산하였다.Specifically, beta cells ( 4 × 10 4 cells / well) were dispensed into 96-well plates, and 16 hours later, 50 μM of 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1) was pretreated with the cells. . After 1 hour, 0.2 mM palmitic acid was treated and, at 24 hours, exchanged with 100 μl of fresh cell culture. 10 μl of a solution of Cell Counting Kit-8 (CCK-8, Dojindo Molecular Technologies) was added and reacted for 2 hours, and then absorbance was measured at 450 nm. The survival rate of the beta cells was calculated by making the survival rate of
그 결과, 팔미트산(PA)은 농도의존적으로 베타세포의 생존율을 감소시키는 것으로 나타나 세포독성이 있음을 확인하였으나(도 3A), 3-브로모-4,5-디하이드록시벤즈알데하이드로 전처리 된 세포에 팔미트 산을 처리한 경우, 무처리군과 비슷한 생존율을 나타내어 팔미트산 독성에 대해 3-브로모-4,5-디하이드록시벤즈알데하이드가 베타세포 보호 효과를 가짐을 확인하였다(도 3B). As a result, palmitic acid (PA) was found to decrease the survival rate of beta cells in a concentration-dependent manner, confirming that it is cytotoxic (FIG. 3A), but pretreated with 3-bromo-4,5-dihydroxybenzaldehyde. When the treated cells were treated with palmitic acid, the survival rate was similar to that of the untreated group, indicating that 3-bromo-4,5-dihydroxybenzaldehyde had beta-cell protective effect against palmitic toxicity ( 3B).
<< 실험예Experimental Example 2> 3- 2> 3- 브로모Bromo -4,5--4,5- 디하이드록시벤즈알데하이드의Dihydroxybenzaldehyde 세포 사멸(apoptosis) 및 괴사(necrosis) 억제 효과 확인 Confirmation of inhibitory effect on apoptosis and necrosis
팔미트산 처리시 유발되는 베타세포의 세포사멸 및 세포괴사에 대한 3-브로모-4,5-디하이드록시벤즈알데하이드의 효과를 확인하고자 하였다. To determine the effect of 3-bromo-4,5-dihydroxybenzaldehyde on apoptosis and cell necrosis of beta cells induced by palmitic acid treatment.
구체적으로, β-세포(1x105 cells/well)를 24웰 플레이트에 분주하고, 16시간 후에 50 μM의 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1)를 세포에 전처리하였다. 1시간 후 0.2 mM의 팔미트산을 처리하고, 24시간 째에 세포사멸(apoptosis) 관찰 목적의 DAPI(10 ㎍/ml) 및 세포괴사(necrosis) 관찰 목적의 PI(propidium iodide, 50 ㎍/ml, Sigma)로 각각 10분간 염색한 후 형광이미지를 분석하였다 (Axio imagzer Z1, Zeiss).Specifically, β-cells (1 × 10 5 cells / well) were dispensed into 24-well plates, and after 16
형광이미지 분석 결과, 팔미트산을 처리한 세포군에서 세포사멸이 증가하였고, 세포사멸 시 나타나는 비정상적인 핵의 비율이 증가한 것으로 나타났으나, 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1)를 전처리한 세포에서는 팔미트산(PA)에 의한 세포사멸이 유도되지 않는 것으로 나타났다 (도 4).Fluorescence image analysis showed that apoptosis was increased in the cell group treated with palmitic acid, and the percentage of abnormal nuclei during apoptosis was increased, but 3-bromo-4,5-dihydroxybenzaldehyde (PS6) was observed. It was shown that apoptosis by palmitic acid (PA) was not induced in cells pretreated with -1) (FIG. 4).
세포괴사를 확인하기 위한 실험에서도 마찬가지로, 팔미트산을 처리한 세포군에서는 세포괴사가 증가하였으나, 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1)를 전처리한 세포에서는 팔미트산(PA)에 의한 세포괴사가 거의 유도되지 않는 것으로 나타나(도 5), 3-브로모-4,5-디하이드록시벤즈알데하이드는 세포사멸 및 세포괴사 억제 효과가 있는 것으로 확인되었다. Similarly, in the experiment for confirming cell necrosis, cell necrosis increased in the cell group treated with palmitic acid, but palmitic in cells pre-treated with 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1). It was shown that cell necrosis by acid (PA) was hardly induced (FIG. 5), and 3-bromo-4,5-dihydroxybenzaldehyde was found to have an effect of inhibiting cell death and cell necrosis.
<< 실험예Experimental Example 3> 3- 3> 3- 브로모Bromo -4,5--4,5- 디하이드록시벤즈알데하이드의Dihydroxybenzaldehyde 세포사멸 단백질 조절 여부 확인 Determine whether apoptosis protein is regulated
상기 실험예 2-1에서 확인된 세포사멸 억제 효과와 관련하여 세포사멸에 관계된 단백질(Bcl-2, Bax 및 caspase-3))의 발현을 조사하였다. Expression of proteins related to apoptosis (Bcl-2, Bax and caspase-3) was investigated in relation to the apoptosis inhibitory effect confirmed in Experimental Example 2-1.
구체적으로, 베타세포(4x106 cells/well)를 6웰 플레이트에 분주하고, 16시간 후에 50 μM의 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1)를 세포에 전처리하였다. 1시간 후 0.2 mM의 팔미트산을 처리하고, 24시간 째에 용해 완충액(lysis buffer; 50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 0.25% sodium deoxycholate, 1% Triton X-100, 및 protease inhibitor cocktail (GenDEPOT))으로 세포를 얼음에서 20분 동안 파괴하였다. 파괴된 세포를 원심분리(16,000 rpm, 15 min, 4℃)하여 수득한 상층액을 5X 샘플 버퍼(sample buffer)와 혼합하고, SDS-PAGE 젤에서 전기영동하여 PVDF 멤브레인에 전이시켰다. 1차 항체로 Bcl-2 (Cell signaling, Cat. # 2876), Bax (Cell signaling, Cat. # 2772) 및 caspase-3(Cell signaling, Cat. # 9662)에 대한 항체를, 2차 항체로 마우스(Invitrogen, Cat #. G-21040) 및 레빗(Jackson Lab., Cat. #. 111-035-003) 항체를 제조사의 프로토콜에 따라 처리한 후 발색 반응을 통해 단백질 발현을 확인하였다. 단백질 밴드의 정량을 위해 ImageJ(https://imagej.nih.gov/ij/)를 사용하였다. Specifically, beta cells (4 × 10 6 cells / well) were dispensed into 6-well plates, and after 16 hours, 50 μM of 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1) was pretreated with the cells. . After 1 hour, 0.2 mM palmitic acid was treated, and at 24 hours, lysis buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 0.25% sodium deoxycholate, 1% Triton X-100, and protease). Inhibitor cocktail (GenDEPOT)) was used to destroy the cells for 20 minutes on ice. The supernatant obtained by centrifugation (16,000 rpm, 15 min, 4 ° C.) of the broken cells was mixed with 5 × sample buffer and electrophoresed on an SDS-PAGE gel to transfer to the PVDF membrane. As a primary antibody, antibodies against Bcl-2 (Cell signaling, Cat. # 2876), Bax (Cell signaling, Cat. # 2772), and caspase-3 (Cell signaling, Cat. # 9662) were used as secondary antibodies. (Invitrogen, Cat #. G-21040) and Levitt (Jackson Lab., Cat. #. 111-035-003) antibodies were treated according to the manufacturer's protocol, and protein expression was confirmed by color reaction. ImageJ (https://imagej.nih.gov/ij/) was used for quantification of the protein bands.
그 결과, 세포사멸을 억제하는 Bcl-2 단백질은 팔미트산 처리시 크게 감소되었으나, 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1) 처리군에서는 Bcl-2 단백질의 발현량이 회복되었다. 세포사멸 전구단백질(pro-apoptotic protein)인 Bax 및 caspase-3는 팔미트산 처리시 크게 증가되었으나, 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1) 처리군에서는 무처리군보다 낮은 수준의 단백질 발현을 나타내어, 3-브로모-4,5-디하이드록시벤즈알데하이드는 세포사멸 억제효과가 있는 것으로 확인되었다 (도 6).As a result, the Bcl-2 protein that inhibits apoptosis was greatly reduced when palmitic acid treatment, but the expression of Bcl-2 protein in the 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1) treatment group The volume has recovered. Bax and caspase-3, pro-apoptotic proteins, were significantly increased when treated with palmitic acid, but not treated with 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1). By expressing a lower level of protein expression than the group, it was confirmed that 3-bromo-4,5-dihydroxybenzaldehyde has an apoptosis inhibitory effect (FIG. 6).
<< 실험예Experimental Example 4> 3- 4> 3- 브로모Bromo -4,5--4,5- 디하이드록시벤즈알데하이드의Dihydroxybenzaldehyde 미토콘드리아 보호 효과 확인 Confirm mitochondrial protection
<4-1> 3-<4-1> 3- 브로모Bromo -4,5--4,5- 디하이드록시벤즈알데하이드의Dihydroxybenzaldehyde 사이토크롬 c( Cytochrome c ( cytochromecytochrome c) 조절 여부 확인 c) Check for adjustment
팔미트산과 같은 독성물질은 미토콘드리아 기능 저하에 영향을 주는 것으로 알려져있다. 따라서 미토콘드리아의 기능 보호에 미치는 3-브로모-4,5-디하이드록시벤즈알데하이드의 효과를 알아보고자, 사이토크롬 c의 발현 여부를 확인하였다. Toxins such as palmitic acid are known to affect mitochondrial deterioration. Therefore, to determine the effect of 3-bromo-4,5-dihydroxybenzaldehyde on the protection of mitochondria, it was confirmed whether the expression of cytochrome c.
항체로 사이토크롬 c에 대한 항체(Santacruz, Cat. #. SC-13561)를 이용한 것을 제외하고 실험예 3에 기재된 방법에 따라 웨스턴 블롯을 수행하였다. Western blot was performed according to the method described in
그 결과, 팔미트산 처리시 사이토크롬 c의 발현량은 크게 증가하였으나, 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1) 처리군에서는 무처리군과 비슷한 수준으로 발현량이 감소하여, 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1)가 미토콘드리아의 기능 보호 효과가 있는 것으로 나타났다(도 7).As a result, the expression level of cytochrome c was significantly increased when palmitic acid was treated, but the expression level was similar to that of the untreated group in the 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1) group. Decreasing, 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1) appeared to have a mitochondrial functional protective effect (FIG. 7).
<4-2> 3-<4-2> 3- 브로모Bromo -4,5--4,5- 디하이드록시벤즈알데하이드의Dihydroxybenzaldehyde 사이토크롬 c( Cytochrome c ( cytochromecytochrome c) 방출 조절 관찰 c) observing emission control
실험예 4-1에 의해 사이토크롬 c(cytochrome c)의 발현이 조절되는 것을 확인하여, 세포사멸시 사이토크롬 c의 세포질로의 방출 변화를 현미경 상에서 확인하였다.It was confirmed that the expression of cytochrome c is controlled by Experimental Example 4-1, and the change of release of cytochrome c into the cytoplasm at the time of cell death was confirmed on a microscope.
구체적으로, 베타세포(1x105 cell/well)를 커버슬립(coverslip)에 분주하고, 각각 0 및 50 μM의 3-브로모-4,5-디하이드록시벤즈알데하이드를 세포에 전처리하였다. 1시간 후 0.2 mM의 팔미트산을 처리하고, 24시간 째에 커버슬립을 PBS로 2회 세척한 후 4% 파라포름알데하이드로 상온에서 15분 동안 고정시켰다. 고정된 세포는 사이토크롬 c에 대한 1차 항체(Santacruz, Cat. #. SC-13561)와 12시간 동안 4℃에서 반응시킨 후 형광이 태그된 2차 항체Invitrogen, Cat #. G-21040)로 2시간 동안 상온에서 반응시켰다. 슬라이드 글래스에 항체 반응된 세포를 mounting solution(Vector Laboratories)을 이용하여 마운팅 한 후, 콘포컬 현미경(Zeiss, Germany)으로 이미지를 분석하였다. Specifically, beta cells (1 × 10 5 cells / well) were dispensed onto coverslips and the cells were pretreated with 0 and 50 μM of 3-bromo-4,5-dihydroxybenzaldehyde, respectively. After 1 hour, 0.2 mM palmitic acid was treated, and at 24 hours, the coverslip was washed twice with PBS and then fixed at room temperature for 15 minutes with 4% paraformaldehyde. The immobilized cells were reacted with a primary antibody against cytochrome c (Santacruz, Cat. #. SC-13561) at 4 ° C. for 12 hours, followed by fluorescently tagged secondary antibody Invitrogen, Cat #. G-21040) at room temperature for 2 hours. After the antibody-reacted cells on the slide glass was mounted using a mounting solution (Vector Laboratories), the image was analyzed by a confocal microscope (Zeiss, Germany).
그 결과, 팔마트산(PA)을 처리하여 세포사멸이 유도된 군에서는 사이토크롬 c의 세포질로의 방출이 두드러지게 증가하였으나, 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1) 처리군에서는 무처리군과 유사한 수준으로 사이토크롬 c의 방출이 억제되는 것으로 확인되었다(도 8). As a result, the release of cytochrome c into the cytoplasm was significantly increased in the group induced by apoptosis by treatment with palmatic acid (PA), but 3-bromo-4,5-dihydroxybenzaldehyde (PS6- 1) In the treated group, it was confirmed that the release of cytochrome c is suppressed to a similar level as the untreated group (Fig. 8).
<4-3> 3-<4-3> 3- 브로모Bromo -4,5--4,5- 디하이드록시벤즈알데하이드의Dihydroxybenzaldehyde ROSROS (reactive oxygen species) 조절 여부 확인to regulate reactive oxygen species
과도하게 누적된 ROS는 미토콘드리아의 기능을 저하시킨다. 이에 ROS 양의 변화를 현미경 상에서 확인하고자 하였다. Excessive accumulation of ROS reduces the function of mitochondria. Therefore, the change in the amount of ROS was to be confirmed on a microscope.
구체적으로, β-세포(4x104 cells/well)를 96웰 플레이트에 분주하고, 16시간 후에 각각 0 및 50 μM의 3-브로모-4,5-디하이드록시벤즈알데하이드를 세포에 전처리하였다. 1시간 후 0.2 mM의 팔미트 산을 처리하고, 15시간 째에 DCFH-DA(Dichlorofluorescin diacetate, Sigma)로 ROS의 양 및 형광이미지를 측정하였다.Specifically, β-cells ( 4 × 10 4 cells / well) were dispensed into 96-well plates and after 16
그 결과, 팔미트산(PA) 처리로 세포사멸이 유도된 군에서는 ROS 생성 증가가 두드러지게 나타났으나, 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1) 처리군에서는 ROS 생성이 크게 억제되는 것으로 확인되었다(도 9). As a result, in the group induced by apoptosis by palmitic acid (PA) treatment, the increase in ROS production was remarkable, but in the 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1) treatment group It was confirmed that ROS production was greatly suppressed (FIG. 9).
<< 실험예Experimental Example 5> 3- 5> 3- 브로모Bromo -4,5--4,5- 디하이드록시벤즈알데하이드의Dihydroxybenzaldehyde 인슐린 분비 기능 보호 효과 Insulin Secretion Function Protective Effect
앞서 실험예을 통해 3-브로모-4,5-디하이드록시벤즈알데하이드 처리에 의해 베타세포가 세포사멸로부터 보호받는 것을 확인하였다. 이에 3-브로모-4,5-디하이드록시벤즈알데하이드 처리시 세포의 기능도 함께 보존되는지 확인하기 위해 베타세포의 주요한 기능인 인슐린 분비 능력을 검사하였다.It was confirmed through the experimental example that the beta cells are protected from apoptosis by 3-bromo-4,5-dihydroxybenzaldehyde treatment. In order to confirm whether the function of the cell is also preserved during 3-bromo-4,5-dihydroxybenzaldehyde treatment, insulin secretion ability, a major function of beta cells, was examined.
구체적으로, β-세포(1x105 cells/well)를 24웰 플레이트에 분주하고, 16시간 후에 50 μM의 3-브로모-4,5-디하이드록시벤즈알데하이드를 세포에 전처리하였다. 1시간 후 0.2 mM의 팔미트 산을 처리하고 24시간 째에 KRB buffer(Krebs-Ringer Bicarbonate Buffer)를 2시간 동안 처리하여 기아(starvation) 상태를 만들었다. 그 다음 각각 3 mM 및 17 mM 글루코오스를 첨가하였고, 2시간 후에 세포 배양액으로 분비된 인슐린을 ELISA kit(ALPCO)를 이용하여 정량하였다. 인슐린 함량은 세포의 DNA함량에 따른 인슐린 분비량으로 계산하였다. Specifically, β-cells (1 × 10 5 cells / well) were dispensed into 24-well plates and after 16
그 결과, 3mM 글루코오스를 첨가한 경우, 팔미트산(PA) 처리군 및 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1) 처리군 모두 대조군인 무처리군과 비교하여 유의한 차이를 나타내지 않았다. 그러나 인슐린 분비가 유도되는 17mM 글루코오스를 첨가한 경우, 팔미트산(PA) 처리군에서 인슐린 분비가 현저히 저하되었으나, 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1) 처리군에서는 무처리군과 유사한 수준의 인슐린 분비량을 나타내었다. 이는 3-브로모-4,5-디하이드록시벤즈알데하이드(PS6-1)는 베타세포의 사멸뿐 아니라 베타세포의 기능을 보호할 수 있음을 제시한다(도 10). As a result, when 3 mM glucose was added, both the palmitic acid (PA) treatment group and the 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1) treatment group were significantly compared with the control group. There was no difference. However, when 17 mM glucose was induced to induce insulin secretion, insulin secretion was significantly decreased in palmitic acid (PA) treatment group, but 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1) treatment group was added. Showed similar levels of insulin secretion as the untreated group. This suggests that 3-bromo-4,5-dihydroxybenzaldehyde (PS6-1) can protect beta cells as well as killing beta cells (FIG. 10).
Claims (8)
[화학식 1]
A pharmaceutical composition for preventing or treating diabetes, comprising 3-bromo-4,5-dihydroxybenzaldehyde, or a pharmaceutically acceptable salt thereof, as a compound represented by the following Formula 1 as an active ingredient:
[Formula 1]
The pharmaceutical composition for preventing or treating diabetes of claim 1, wherein the compound inhibits apoptosis or necrosis of beta cells.
The method of claim 1, wherein the compound is to inhibit the expression of beta-cell B-cell lymphoma 2 (Bcl-2) protein, pharmaceutical composition for preventing or treating diabetes.
The method of claim 1, wherein the compound inhibits increased expression of Bcl-2-associated X (Bax) protein or caspase-3 protein of beta cells. Prophylactic or therapeutic pharmaceutical compositions.
The pharmaceutical composition of claim 1, wherein the compound inhibits cytochrome c release or reactive oxygen species (ROS) production of beta cell mitochondria.
The pharmaceutical composition for preventing or treating diabetes of claim 1, wherein the compound inhibits beta cell insulin secretion.
The pharmaceutical composition for preventing or treating diabetes of claim 1, wherein the diabetes is type 1 diabetes or type 2 diabetes.
[화학식 1]
A dietary supplement for preventing or improving diabetes, comprising 3-bromo-4,5-dihydroxybenzaldehyde, or a pharmaceutically acceptable salt thereof, as a compound represented by the following Formula 1 as an active ingredient:
[Formula 1]
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