KR20240056426A - A composition for improving, preventing and treating of myocardial damage comprising Cirsium setidens extract - Google Patents
A composition for improving, preventing and treating of myocardial damage comprising Cirsium setidens extract Download PDFInfo
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- KR20240056426A KR20240056426A KR1020230138276A KR20230138276A KR20240056426A KR 20240056426 A KR20240056426 A KR 20240056426A KR 1020230138276 A KR1020230138276 A KR 1020230138276A KR 20230138276 A KR20230138276 A KR 20230138276A KR 20240056426 A KR20240056426 A KR 20240056426A
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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Abstract
본 발명은 심장독성 약물에 의한 심근 손상의 개선, 예방 또는 치료용 조성물에 관한 것으로 고려엉겅퀴(Cirsium setidens) 추출물을 유효성분으로 함유함으로써, 심장독성 약물에 의한 심근 손상을 개선, 예방 또는 치료할 수 있다. 또한, 독성이 없으므로 식품의 형태로 섭취할 수 있다. The present invention relates to a composition for improving, preventing or treating myocardial damage caused by cardiotoxic drugs. By containing an extract of Cirsium setidens as an active ingredient, it is possible to improve, prevent or treat myocardial damage caused by cardiotoxic drugs. . Additionally, since it is non-toxic, it can be consumed in food form.
Description
본 발명은 고려엉겅퀴(Cirsium setidens) 추출물을 유효성분으로 함유하여 심장독성 약물에 의한 심근 손상을 개선, 예방 또는 치료할 수 있는 조성물에 관한 것이다.The present invention relates to a composition that contains an extract of Cirsium setidens as an active ingredient and can improve, prevent, or treat myocardial damage caused by cardiotoxic drugs.
항암제를 이용한 치료는 환자의 생존율을 높이는데 기여하였으나, 부작용으로 기억력 저하, 인지기능 저하 또는 심장독성 등이 나타난다. Treatment with anticancer drugs has contributed to increasing the patient's survival rate, but side effects include memory decline, cognitive decline, and cardiotoxicity.
구체적으로, 항암제는 약 41%의 환자에게서 심장독성을 유발하여 심근세포 사멸을 유도하며, 대표적인 예로 방실이 차단되는 현상이 나타난다.Specifically, anticancer drugs cause cardiotoxicity in approximately 41% of patients, leading to myocardial cell death, and a typical example is atrioventricular blockage.
심근은 심장을 구성하고 심장 수축의 본체가 되는 근육으로서, 대사적으로 극히 활발하다. 이러한 심근은 미토콘드리아가 개별 섬유 부피의 30% 이상 존재하여 고에너지 인산염의 예비가 매우 부족하여 호기성 대사가 필수적이다.Myocardium is the muscle that makes up the heart and is the main body of heart contraction, and is metabolically extremely active. In these myocardium, mitochondria exist in more than 30% of the volume of individual fibers, so reserves of high-energy phosphate are very low, so aerobic metabolism is essential.
심근세포 사멸은 아데노신 삼인산염(ATP) 수준이 매우 낮고 혐기성 해당이 실질적으로 중단됨에 따라 진행된다. 최근 다양한 질환의 치료제 투여로 인한 부작용의 증가가 문제가 되고 있으며, 특히 세포 간 신호전달 억제효과를 나타내는 퀴논계 화합물 항암제인 독소루비신과 혈관확장제인 나트륨 니트로르푸시드(disodiumCardiomyocyte death proceeds as adenosine triphosphate (ATP) levels are very low and anaerobic glycolysis is virtually halted. Recently, the increase in side effects due to the administration of treatments for various diseases has become a problem, especially doxorubicin, a quinone-based anticancer drug that exhibits an inhibitory effect on signaling between cells, and sodium nitrorfuside (disodium), a vasodilator.
nitroferricyanide, SNP)와 같은 약물은 세포 내 활성 산소종 증가 및 미토콘드리아 기능을 저하시켜 심근세포의 사멸을 유도함에 따라, 심장 기능 저하 및 다양한 심장 질환을 유발시킬 수 있다. Drugs such as nitroferricyanide (SNP) increase intracellular reactive oxygen species and decrease mitochondrial function, leading to the death of cardiomyocytes, which can lead to decreased cardiac function and various heart diseases.
그러나 포유동물 심근세포는 잠재적으로 증식이 제한되어 있어 심각한 손상을 당한 경우 충분한 재생이 이뤄지지 않는다.However, mammalian cardiomyocytes have limited proliferation potential and do not regenerate sufficiently when severely damaged.
손상된 심근의 치료방법으로 재관류 손상 후 염증반응을 통하여 비가역적 손상세포 제거를 통한 치료가 있으나, 심근세포의 재생이 어렵기 때문에 근본적으로 완전한 치유가 어렵다. 따라서 손상유발 인자에 대하여 심장세포를 보호하고 이를 통한 심장세포의 손실을 예방하는 것이 가장 좋은 방법이다.Treatment methods for damaged myocardium include removal of irreversibly damaged cells through an inflammatory response after reperfusion injury, but complete healing is fundamentally difficult because regeneration of myocardial cells is difficult. Therefore, the best way is to protect heart cells against damage-causing factors and prevent heart cell loss.
한편, 고려엉겅퀴(Cirsium setidens)는 콜레스테롤의 수치를 낮춰 혈액순환을 돕고 혈관질환을 예방하는 효과를 가지며, 최근에는 곤드레 추출물이 간 독성을 중화시키고 보호하는 데 효과가 있다는 사실이 알려진 바 있지만, 고려엉겅퀴가 항암제를 이용한 치료의 부작용에 미치는 영향에 대해서는 알려진 바 없다.Meanwhile, Korean thistle ( Cirsium setidens ) has the effect of lowering cholesterol levels, helping blood circulation and preventing vascular diseases, and it has recently been known that thistle extract is effective in neutralizing and protecting liver toxicity. There is no known effect of milk thistle on the side effects of treatment with anticancer drugs.
본 발명의 목적은 고려엉겅퀴(Cirsium setidens) 추출물을 유효성분으로 함유하여 심장독성 약물에 의한 심근 손상을 개선 또는 예방할 수 있는 식품 조성물을 제공하는데 있다.The purpose of the present invention is to provide a food composition that can improve or prevent myocardial damage caused by cardiotoxic drugs by containing an extract of Cirsium setidens as an active ingredient.
또한, 본 발명의 다른 목적은 고려엉겅퀴(Cirsium setidens) 추출물을 유효성분으로 함유하여 심장독성 약물에 의한 심근 손상을 예방 또는 치료할 수 있는 약학 조성물을 제공하는데 있다.In addition, another object of the present invention is to provide a pharmaceutical composition that can prevent or treat myocardial damage caused by cardiotoxic drugs by containing an extract of Cirsium setidens as an active ingredient.
또한, 본 발명의 또 다른 목적은 고려엉겅퀴(Cirsium setidens) 추출물을 유효성분으로 함유하여 심장독성 약물에 의한 심근 손상을 심근 손상의 개선 또는 예방용 반려동물을 위한 식품 조성물을 제공하는데 있다.In addition, another object of the present invention is to provide a food composition for companion animals for improving or preventing myocardial damage caused by cardiotoxic drugs, containing an extract of Cirsium setidens as an active ingredient.
또한, 본 발명의 또 다른 목적은 고려엉겅퀴(Cirsium setidens) 추출물 및 항암제를 유효성분으로 함유하는 항암 치료용 병용제제를 제공하는데 있다.In addition, another object of the present invention is to provide a combination preparation for anticancer treatment containing an extract of Cirsium setidens and an anticancer agent as active ingredients.
상기한 목적을 달성하기 위한 본 발명의 심근 손상의 개선 또는 예방을 위한 식품 조성물은 고려엉겅퀴(Cirsium setidens) 추출물을 유효성분으로 함유할 수 있다.The food composition for improving or preventing myocardial damage of the present invention to achieve the above object may contain an extract of Cirsium setidens as an active ingredient.
상기 심근 손상은 심장독성 약물에 의한 심근세포 사멸로 유도될 수 있다.The myocardial damage may be induced by myocardial cell death by cardiotoxic drugs.
상기 심장독성 약물은 암 세포 손상, 암 세포 성장 억제 활성 또는 암 전이 억제 활성을 제공하는 항암제일 수 있다.The cardiotoxic drug may be an anticancer agent that provides cancer cell damage, cancer cell growth inhibitory activity, or cancer metastasis inhibitory activity.
상기 항암제는 화학항암제 및 표적항암제로 이루어진 군에서 선택된 1종 이상일 수 있다.The anticancer agent may be one or more types selected from the group consisting of chemical anticancer agents and targeted anticancer agents.
상기 화학항암제는 독소루비신(doxorubicin), 에피루비신(epirunicin), 미톡산트론(mitoxantrone), 이다루비신(idarubicin), 다우노루비신(daunorubicin) 및 발루비신(valrubicin)으로 이루어진 군에서 선택되며; 상기 표적항암제는 오시머티닙(osmertinib), 엘로티닙(erlotinib), 게피티니브(gefitinib), 크리조티닙(crizotinib), 세리티닙(ceritinib), 알렉티닙(alectinib), 브리가티닙(brigatinib), 보수티닙(bosutinib), 다사티닙(dasatinib), 이마티닙(imatinib), 닐로티닙(nilotinib), 포나티닙(ponatinib), 이브루티닙(ibrutinib), 카보잔티닙(cabozantinib), 라파티닙(lapatinib), 반데타닙(vandetanib), 아파티닙(afatinib), 룩소리티닙(ruxolitiib), 토파시티닙(tofacitinib), 엑시티닙(axitinib), 렌바티닙(lenvatinib), 닌테다닙(nintedanib), 파조파닙(pazopanib), 레고라페닙(regorafenib), 소라페니브(sorafenib), 수니티닙(sunitinib), 다사티닙(dasatinib) 및 엑시티닙(axitinib)으로 이루어진 군에서 선택될 수 있다. The chemical anticancer agent is selected from the group consisting of doxorubicin, epirubicin, mitoxantrone, idarubicin, daunorubicin, and valrubicin; The targeted anticancer agents include osmertinib, erlotinib, gefitinib, crizotinib, ceritinib, alectinib, and brigatinib. , bosutinib, dasatinib, imatinib, nilotinib, ponatinib, ibrutinib, cabozantinib, lapatinib ), vandetanib, afatinib, ruxolitiib, tofacitinib, axitinib, lenvatinib, nintedanib, pa It may be selected from the group consisting of pazopanib, regorafenib, sorafenib, sunitinib, dasatinib, and axitinib.
상기 고려엉겅퀴 추출물은 물, 탄소수 1 내지 4의 저급알코올, 에틸렌글리콜, 에틸에테르 또는 이들의 혼합용매로 추출된 것일 수 있다.The Korean thistle extract may be extracted with water, lower alcohol having 1 to 4 carbon atoms, ethylene glycol, ethyl ether, or a mixed solvent thereof.
상기 탄소수 1 내지 4의 저급알코올은 20 내지 80%의 메탄올, 에탄올, 부탄올 또는 프로판올일 수 있다.The lower alcohol having 1 to 4 carbon atoms may be 20 to 80% methanol, ethanol, butanol, or propanol.
또한, 상기한 다른 목적을 달성하기 위한 본 발명의 심근 손상의 예방 또는 치료를 위한 약학 조성물은 고려엉겅퀴(Cirsium setidens) 추출물을 유효성분으로 함유할 수 있다.In addition, the pharmaceutical composition for preventing or treating myocardial damage of the present invention to achieve the above-described other purposes may contain an extract of Cirsium setidens as an active ingredient.
또한, 상기한 또 다른 목적을 달성하기 위한 본 발명의 심근 손상의 개선 또는 예방용 반려동물을 위한 식품 조성물은 고려엉겅퀴(Cirsium setidens) 추출물을 유효성분으로 함유할 수 있다.In addition, the food composition for companion animals for improving or preventing myocardial damage of the present invention to achieve the above-described other purpose may contain Cirsium setidens extract as an active ingredient.
또한, 상기한 또 다른 목적을 달성하기 위한 본 발명의 항암제에 의해 유발되는 심장 독성의 예방을 위한 항암 치료용 병용제제는 고려엉겅퀴(Cirsium setidens) 추출물 및 항암제를 유효성분으로 함유할 수 있다.In addition, the combination preparation for anticancer treatment to prevent cardiac toxicity caused by the anticancer agent of the present invention to achieve the above-described other purpose may contain Cirsium setidens extract and an anticancer agent as active ingredients.
상기 항암 치료용 병용제제는 고려엉겅퀴(Cirsium setidens) 추출물 및 항암제가 혼합된 형태이거나, 고려엉겅퀴(Cirsium setidens) 추출물 및 항암제가 각각 제제화되어 동시적 또는 순차적으로 투여될 수 있다.The combination preparation for anticancer treatment may be a mixture of Cirsium setidens extract and anticancer agent, or the Cirsium thistle extract and anticancer agent may be formulated separately and administered simultaneously or sequentially.
본 발명의 심장독성 약물에 의한 심근 손상의 개선, 예방 또는 치료용 조성물은 독성이 없으며, 심장독성 약물에 의한 심근 손상에 대한 개선, 예방 또는 치료 효과가 매우 뛰어나 경쟁력 있는 식품 조성물, 나아가 건강기능식품 또는 약학 조성물로 활용될 수 있다.The composition for improving, preventing or treating myocardial damage caused by cardiotoxic drugs of the present invention is non-toxic and has an excellent effect for improving, preventing or treating myocardial damage caused by cardiotoxic drugs, making it a competitive food composition and even a health functional food. Alternatively, it can be used as a pharmaceutical composition.
도 1은 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 독소루비신(doxorubicin)으로 처리 시 H9C2 심근세포의 생존율을 측정한 그래프이다.
도 2는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 독소루비신(doxorubicin)으로 처리 시 MDA-MB-231 유방암 세포의 생존율을 측정한 그래프이다.
도 3a는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 오시머티닙(osmertinib)으로 처리 시 H9C2 심근세포의 생존율을 측정한 그래프이며; 도 3b는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 엘로티닙(erlotinib)으로 처리 시 H9C2 심근세포의 생존율을 측정한 그래프이고; 도 3c는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 게피티니브(gefitinib)로 처리 시 H9C2 심근세포의 생존율을 측정한 그래프이다.
도 4a는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 오시머티닙(osmertinib)으로 처리 시 A549 폐암 세포의 생존율을 측정한 그래프이며; 도 4b는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 엘로티닙(erlotinib)으로 처리 시 A549 폐암 세포의 생존율을 측정한 그래프이고; 도 4c는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 게피티니브(gefitinib)로 처리 시 A549 폐암 세포의 생존율을 측정한 그래프이다.
도 5a는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 시 산소 소비량을 나타낸 그래프이며; 도 5b는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 시 최대 호흡을 나타낸 그래프이고; 도 5c는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 시 아데노신 삼인산(ATP) 생산을 포함한 미토콘드리아 호흡을 나타낸 그래프이다.
도 6a는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 DOX로 처리 시 미토콘드리아의 막 전위를 나타낸 것이며; 도 6b는 상기 도 6a의 TMRM 발현량을 정량화한 그래프이다.
도 7a는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 시 SOD1 및 SOD2의 발현을 나타낸 웨스턴 블롯이며; 도 7b는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 시 총 SOD, SOD1 및 SOD2의 활성을 나타낸 그래프이고; 도 7c는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 DOX로 처리 시 미토콘드리아의 막 전위의 발현을 나타낸 사진이며; 도 7d는 상기 도 7c의 MitoSOXTM 발현량을 정량화한 그래프이다.
도 8a는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물 및 DOX를 처리 후 기록하는 일정을 나타낸 그래프이며; 도 8b는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물 처리 시 총 활성 전극을 나트낸 사진 및 그래프이고; 도 8c는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물 처리 시 비트 주기를 측정한 것이며; 도 8d는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물 처리 시 탈분극 스파이크의 시작부터 재분극 파동의 피크까지의 시간으로 측정된 그래프 및 이를 시간에 따라 정량화한 그래프이고; 도 8e는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물 처리 시 전도 속도를 나타낸 사진 및 이를 시간에 따라 정량화한 그래프이며; 도 8f는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물 처리 시 수축성을 나타낸 그래프이다.
도 9a는 Control군, Dox군, 고려엉겅퀴 추출물군, Berberine 20군 및 Berberine 40군의 분당 심장 박동수를 나타낸 그래프이며; 도 9b는 Control군, Dox군, 고려엉겅퀴 추출물군, Berberine 20군 및 Berberine 40군의 RR interval을 나타낸 그래프이고; 도 9c는 Control군, Dox군, 고려엉겅퀴 추출물군, Berberine 20군 및 Berberine 40군의 QT interval을 나타낸 그래프이며; 도 9d는 Control군, Dox군, 고려엉겅퀴 추출물군, Berberine 20군 및 Berberine 40군의 ST segment를 나타낸 그래프이다.
도 10a는 Control군, Dox군, 고려엉겅퀴 추출물군 및 Berberine 20군의 CK(creatin kinase)를 나타낸 그래프이며; 도 10b는 Control군, Dox군, 고려엉겅퀴 추출물군 및 Berberine 20군의 LHD(lactate dehydrogenase)를 나타낸 그래프이고; 도 10c는 Control군, Dox군, 고려엉겅퀴 추출물군 및 Berberine 20군의 AST(aspartate aminotransferase)를 나타낸 그래프이며; 도 10d는 Control군, Dox군, 고려엉겅퀴 추출물군 및 Berberine 20군의 ALT(alanine aminotransferase)를 나타낸 그래프이다.
도 11은 Control군, Dox군, 고려엉겅퀴 추출물군의 심장조직의 섬유화 정도를 측정한 도면이다.
도 12는 Control군, Dox군, 고려엉겅퀴 추출물군의 심근세포 사멸화 정도를 측정한 도면이다.Figure 1 is a graph measuring the survival rate of H9C2 cardiomyocytes when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with doxorubicin.
Figure 2 is a graph measuring the survival rate of MDA-MB-231 breast cancer cells when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with doxorubicin.
Figure 3a is a graph measuring the survival rate of H9C2 cardiomyocytes when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with osmertinib; Figure 3b is a graph measuring the survival rate of H9C2 cardiomyocytes when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with erlotinib; Figure 3c is a graph measuring the survival rate of H9C2 cardiomyocytes when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with gefitinib.
Figure 4a is a graph measuring the survival rate of A549 lung cancer cells when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with osmertinib; Figure 4b is a graph measuring the survival rate of A549 lung cancer cells when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with erlotinib; Figure 4c is a graph measuring the survival rate of A549 lung cancer cells when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with gefitinib.
Figure 5a is a graph showing oxygen consumption when treated with Korean thistle extract prepared according to Example 1 of the present invention; Figure 5b is a graph showing maximum respiration when treated with Korean thistle extract prepared according to Example 1 of the present invention; Figure 5c is a graph showing mitochondrial respiration, including adenosine triphosphate (ATP) production, when treated with Korean thistle extract prepared according to Example 1 of the present invention.
Figure 6a shows the membrane potential of mitochondria when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with DOX; Figure 6b is a graph quantifying the TMRM expression level of Figure 6a.
Figure 7a is a Western blot showing the expression of SOD1 and SOD2 upon treatment with Korean thistle extract prepared according to Example 1 of the present invention; Figure 7b is a graph showing the activities of total SOD, SOD1, and SOD2 when treated with Korean thistle extract prepared according to Example 1 of the present invention; Figure 7c is a photograph showing the expression of mitochondrial membrane potential when treated with DOX after treatment with Korean thistle extract prepared according to Example 1 of the present invention; Figure 7d is a graph quantifying the expression level of MitoSOXTM of Figure 7c.
Figure 8a is a graph showing the schedule for recording after processing the Korean thistle extract and DOX prepared according to Example 1 of the present invention; Figure 8b is a photograph and graph showing the total active electrode when treated with Korean thistle extract prepared according to Example 1 of the present invention; Figure 8c shows the beat cycle measured when processing the Korean thistle extract prepared according to Example 1 of the present invention; Figure 8d is a graph measured as the time from the start of the depolarization spike to the peak of the repolarization wave when treated with the Korean thistle extract prepared according to Example 1 of the present invention, and a graph quantified over time; Figure 8e is a photograph showing the conduction speed upon treatment with the Korean thistle extract prepared according to Example 1 of the present invention and a graph quantifying this over time; Figure 8f is a graph showing the shrinkage upon treatment of the Korean thistle extract prepared according to Example 1 of the present invention.
Figure 9a is a graph showing the heart rate per minute of the Control group, Dox group, Korean thistle extract group, Berberine 20 group, and Berberine 40 group; Figure 9b is a graph showing the RR interval of the Control group, Dox group, Korean thistle extract group, Berberine 20 group, and Berberine 40 group; Figure 9c is a graph showing the QT interval of the Control group, Dox group, Korean thistle extract group, Berberine 20 group, and Berberine 40 group; Figure 9d is a graph showing the ST segment of the Control group, Dox group, Korean thistle extract group, Berberine 20 group, and Berberine 40 group.
Figure 10a is a graph showing CK (creatin kinase) in the Control group, Dox group, Korean thistle extract group, and Berberine 20 group; Figure 10b is a graph showing LHD (lactate dehydrogenase) of the Control group, Dox group, Korean thistle extract group, and Berberine 20 group; Figure 10c is a graph showing AST (aspartate aminotransferase) in the Control group, Dox group, Korean thistle extract group, and Berberine 20 group; Figure 10d is a graph showing ALT (alanine aminotransferase) in the Control group, Dox group, Korean thistle extract group, and Berberine 20 group.
Figure 11 is a diagram measuring the degree of fibrosis of heart tissue in the Control group, Dox group, and Korean thistle extract group.
Figure 12 is a diagram measuring the degree of cardiomyocyte apoptosis in the Control group, Dox group, and Korean thistle extract group.
본 발명은 고려엉겅퀴(Cirsium setidens) 추출물을 유효성분으로 함유하여 심장독성 약물에 의한 심근 손상을 개선, 예방 또는 치료할 수 있는 조성물에 관한 것이다.The present invention relates to a composition that contains an extract of Cirsium setidens as an active ingredient and can improve, prevent, or treat myocardial damage caused by cardiotoxic drugs.
상기 심근 손상은 심장독성 약물에 의한 심근세포 사멸로 유도되는 것으로서, 상기 심장독성 약물은 암 세포 손상, 암 세포 성장 억제 활성 또는 암 전이 억제 활성을 제공하는 항암제일 수 있다.The myocardial damage is induced by cardiomyocyte cell death by a cardiotoxic drug, and the cardiotoxic drug may be an anticancer agent that provides cancer cell damage, cancer cell growth inhibitory activity, or cancer metastasis inhibitory activity.
상기 항암제는 화학항암제 및 표적항암제로 이루어진 군에서 선택된 1종 이상일 수 있다. 상기 화학항암제는 활성산소(free radical) 생성에 의해 심장독성이 발생하여 심근세포 사멸을 유도하는 것으로서, 구체적으로 독소루비신(doxorubicin), 에피루비신(epirunicin), 미톡산트론(mitoxantrone), 이다루비신(idarubicin), 다우노루비신(daunorubicin) 및 발루비신(valrubicin)으로 이루어진 군에서 선택될 수 있다. 또한, 상기 표적항암제는 종양신생혈관이나 종양세포증식 기전에 관련되는 티로신카나아제(tyrosine kinase)를 억제하는 메카니즘을 통해 항암작용을 수행하는데, 심근세포(cardiomyocytes)의 생존에 관련된 티로신카나아제(tyrosine kinase)가 억제되므로 심근독성 및 심근세포 사멸이 유도되는 것으로서, 구체적으로 오시머티닙(osmertinib), 엘로티닙(erlotinib), 게피티니브(gefitinib), 크리조티닙(crizotinib), 세리티닙(ceritinib), 알렉티닙(alectinib), 브리가티닙(brigatinib), 보수티닙(bosutinib), 다사티닙(dasatinib), 이마티닙(imatinib), 닐로티닙(nilotinib), 포나티닙(ponatinib), 이브루티닙(ibrutinib), 카보잔티닙(cabozantinib), 라파티닙(lapatinib), 반데타닙(vandetanib), 아파티닙(afatinib), 룩소리티닙(ruxolitiib), 토파시티닙(tofacitinib), 엑시티닙(axitinib), 렌바티닙(lenvatinib), 닌테다닙(nintedanib), 파조파닙(pazopanib), 레고라페닙(regorafenib), 소라페니브(sorafenib), 수니티닙(sunitinib), 다사티닙(dasatinib) 및 엑시티닙(axitinib)으로 이루어진 군에서 선택될 수 있다.The anticancer agent may be one or more types selected from the group consisting of chemical anticancer agents and targeted anticancer agents. The chemical anticancer drugs cause cardiotoxicity by producing free radicals and induce cardiomyocyte cell death, specifically doxorubicin, epirubicin, mitoxantrone, and idarubicin. It may be selected from the group consisting of idarubicin, daunorubicin, and valrubicin. In addition, the targeted anticancer agent performs anticancer activity through a mechanism of inhibiting tyrosine kinase, which is involved in tumor neovascularization and tumor cell proliferation mechanisms. Tyrosine kinase, which is involved in the survival of cardiomyocytes, is Since myocardial toxicity and myocardial cell death are induced due to inhibition of kinase, specifically osmertinib, erlotinib, gefitinib, crizotinib, and ceritinib. ), alectinib, brigatinib, bosutinib, dasatinib, imatinib, nilotinib, ponatinib, ibrutinib (ibrutinib), cabozantinib, lapatinib, vandetanib, afatinib, ruxolitiib, tofacitinib, axitinib, lenvatinib, nintedanib, pazopanib, regorafenib, sorafenib, sunitinib, dasatinib, and Exiti It may be selected from the group consisting of axitinib.
이하, 본 발명을 상세하게 설명한다. Hereinafter, the present invention will be described in detail.
본 발명의 심근 손상을 개선, 예방 또는 치료할 수 있는 조성물은 고려엉겅퀴(Cirsium setidens) 추출물을 유효성분으로 함유한다.The composition of the present invention that can improve, prevent, or treat myocardial damage contains Korean thistle ( Cirsium setidens ) extract as an active ingredient.
고려엉겅퀴(곤드레, Cirsium setidens)는 초롱꽃목 국화과의 여러해살이풀로서 줄기의 높이는 1 m이고 뿌리는 곧으며, 줄기는 가지가 많고 잎은 호생, 중앙부의 것은 잎자루가 있고, 나형, 타원상 피침형, 끝이 뾰족하다.Korean thistle ( Cirsium setidens ) is a perennial herb of the Asteraceae family of the order Campanula. It has a stem height of 1 m and straight roots. The stem has many branches and the leaves are alternate, the central ones have petioles, and are spiral-shaped and oval-lanceolate. , the end is sharp.
상기 고려엉겅퀴는 추출용매와 1 : 5 내지 25의 중량비, 바람직하게는 1 : 8 내지 15의 중량비로 혼합하여 80 내지 110 ℃에서 5 내지 15시간, 바람직하게는 7 내지 10시간 동안 추출한 후 50 내지 60 ℃에서 감압농축을 수행하여 추출물을 제조한다. 상기 고려엉겅퀴와 추출용매의 중량비가 상기 범위를 벗어나는 경우에는 추출물에 고려엉겅퀴의 유효성분이 적은 양으로 추출될 수 있다.The Korean thistle is mixed with the extraction solvent at a weight ratio of 1:5 to 25, preferably 1:8 to 15, extracted at 80 to 110 ° C. for 5 to 15 hours, preferably 7 to 10 hours, and then extracted for 50 to 10 hours. The extract is prepared by performing reduced pressure concentration at 60°C. If the weight ratio of the Korean thistle and the extraction solvent is outside the above range, the active ingredient of the Korean thistle may be extracted in a small amount in the extract.
추출온도가 상기 하한치 미만인 경우에는 고려엉겅퀴의 유효성분이 적은 양으로 추출될 수 있으며, 상기 상한치 초과인 경우에는 독성물질이 발생할 수 있다.If the extraction temperature is below the above lower limit, the active ingredients of Korean thistle may be extracted in a small amount, and if the extraction temperature is above the above upper limit, toxic substances may be generated.
상기 각 추출물을 추출하는 추출용매는 물, 탄소수 1 내지 4의 저급알코올, 에틸렌글리콜, 에틸에테르 또는 이들의 혼합용매이다. 상기 저급알코올로는 20 내지 80%의 메탄올, 에탄올, 부탄올 또는 프로판올을 들 수 있다.The extraction solvent for extracting each of the above extracts is water, lower alcohol having 1 to 4 carbon atoms, ethylene glycol, ethyl ether, or a mixed solvent thereof. The lower alcohol may include 20 to 80% methanol, ethanol, butanol, or propanol.
상기 추출용매로는 특별히 한정하는 것은 아니지만 물로 추출된 열수 추출물이 심장독성 약물에 의한 심근 손상의 개선, 예방 또는 치료에 바람직하게 작용한다. The extraction solvent is not particularly limited, but hot water extracts extracted with water are preferred for improving, preventing, or treating myocardial damage caused by cardiotoxic drugs.
본 발명의 고려엉겅퀴 추출물은 심장독성 약물에 의한 심근 손상의 개선, 예방 또는 치료용 조성물로 사용될 뿐만 아니라 병용제제로도 사용될 수 있다.The Korean thistle extract of the present invention can be used not only as a composition for improving, preventing, or treating myocardial damage caused by cardiotoxic drugs, but also as a combination agent.
본 발명의 항암 치료용 병용제제는 항암제에 의해 유발되는 심장 독성의 예방을 위한 것으로서, 고려엉겅퀴(Cirsium setidens) 추출물 및 항암제를 유효성분으로 함유할 수 있다.The combination preparation for anticancer treatment of the present invention is intended to prevent cardiac toxicity caused by anticancer drugs, and may contain Cirsium setidens extract and anticancer drugs as active ingredients.
상기 항암 치료용 병용제제는 고려엉겅퀴(Cirsium setidens) 추출물 및 항암제가 혼합된 형태이거나, 고려엉겅퀴(Cirsium setidens) 추출물 및 항암제가 각각 제제화되어 동시적 또는 순차적으로 투여될 수 있다.The combination preparation for anticancer treatment may be a mixture of Cirsium setidens extract and anticancer agent, or the Cirsium thistle extract and anticancer agent may be formulated separately and administered simultaneously or sequentially.
상기 항암제는 암 세포 이동 억제 또는 암 전이 억제 활성을 제공하는 것이라면 특별히 한정되지 않지만, 바람직하게는 독소루비신(doxorubicin), 오시머티닙(osmertinib), 엘로티닙(erlotinib) 및 게피티니브(gefitinib)로 이루어진 군에서 선택된 1종 이상을 들 수 있다.The anticancer agent is not particularly limited as long as it provides activity to inhibit cancer cell migration or cancer metastasis, but is preferably composed of doxorubicin, osmertinib, erlotinib, and gefitinib. One or more types selected from the group may be mentioned.
본 명세서에서 고려엉겅퀴를 언급하면서 사용되는 용어 '추출물'은 추출용매를 처리하여 얻은 조추출물뿐만 아니라 고려엉겅퀴 추출물의 가공물도 포함한다. 예를 들어, 고려엉겅퀴 추출물은 감압 증류 및 동결 건조 또는 분무 건조 등과 같은 추가적인 과정에 의해 분말 상태로 제조될 수 있다.The term 'extract' used in this specification while referring to Korean thistle includes not only the crude extract obtained by processing with an extraction solvent, but also the processed product of the Korean thistle extract. For example, Korean thistle extract can be prepared in powder form by additional processes such as reduced pressure distillation and freeze-drying or spray drying.
또한, 본 발명의 고려엉겅퀴 추출물은 광의로는 고려엉겅퀴를 동물에게 투여할 수 있도록 제형화된 고려엉겅퀴 가공물, 예컨대, 고려엉겅퀴 분말도 포함하는 의미를 갖는다. 비록 본 발명에서 고려엉겅퀴로 실험을 진행하긴 하였으나, 고려엉겅퀴 가공물과 같은 형태로도 목적하는 효과를 달성할 수 있음은 당업자라면 예상가능할 것이다.In addition, the Korean thistle extract of the present invention, in a broad sense, also includes Korean thistle processed products formulated so that Korean thistle can be administered to animals, such as Korean thistle powder. Although experiments were conducted with Korean thistle in the present invention, those skilled in the art would be able to predict that the desired effect can be achieved even in the form of a processed Korean thistle.
한편, 본 명세서에서 용어 '유효성분으로 함유하는'이란 고려엉겅퀴 추출물의 효능 또는 활성을 달성하는 데 충분한 양을 포함하는 것을 의미한다. 일예로, 상기 고려엉겅퀴 추출물은 10 내지 1500 ㎍/㎖, 바람직하게는 100 내지 1000 ㎍/㎖의 농도로 사용된다. 고려엉겅퀴 추출물은 천연물로서 과량 투여하여도 인체에 부작용이 없으므로 본 발명의 조성물 내에 포함되는 고려엉겅퀴 추출물의 양적 상한은 당업자가 적절한 범위 내에서 선택하여 실시할 수 있다.Meanwhile, in this specification, the term 'containing as an active ingredient' means containing a sufficient amount to achieve the efficacy or activity of the Korean thistle extract. For example, the Korean thistle extract is used at a concentration of 10 to 1500 μg/ml, preferably 100 to 1000 μg/ml. Since the Korean thistle extract is a natural product and has no side effects on the human body even when administered in excessive amounts, the upper quantitative limit of the Korean thistle extract contained in the composition of the present invention can be selected within an appropriate range by a person skilled in the art.
본 발명의 약제학적 조성물은 상기 유효 성분 이외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조될 수 있으며, 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다.The pharmaceutical composition of the present invention can be prepared using pharmaceutically suitable and physiologically acceptable auxiliaries in addition to the active ingredients, and the auxiliaries include excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, Lubricants or flavoring agents can be used.
상기 약제학적 조성물은 투여를 위해서 상기 기재한 유효 성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 약제학적 조성물로 바람직하게 제제화할 수 있다.For administration, the pharmaceutical composition may be preferably formulated as a pharmaceutical composition containing one or more pharmaceutically acceptable carriers in addition to the active ingredients described above.
상기 약제학적 조성물의 제제 형태는 과립제, 산제, 정제, 피복정, 캡슐제, 좌제, 액제, 시럽, 즙, 현탁제, 유제, 점적제 또는 주사 가능한 액제 등이 될 수 있다. 예를 들어, 정제 또는 캡슐제의 형태로의 제제화를 위해, 유효 성분은 에탄올, 글리세롤, 물 등과 같은 경구, 무독성의 약제학적으로 허용 가능한 불활성 담체와 결합될 수 있다. 또한, 원하거나 필요한 경우, 적합한 결합제, 윤활제, 붕해제 및 발색제 또한 혼합물로 포함될 수 있다. 적합한 결합제는 이에 제한되는 것은 아니나, 녹말, 젤라틴, 글루코스 또는 베타-락토오스와 같은 천연 당, 옥수수 감미제, 아카시아, 트래커캔스 또는 소듐올레이트와 같은 천연 및 합성 검, 소듐 스테아레이트, 마그네슘 스테아레이트, 소듐 벤조에이트, 소듐 아세테이트, 소듐 클로라이드 등을 포함한다. 붕해제는 이에 제한되는 것은 아니나, 녹말, 메틸 셀룰로스, 아가, 벤토니트, 잔탄 검 등을 포함한다.The pharmaceutical composition may be in the form of granules, powders, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, drops, or injectable solutions. For example, for formulation in the form of tablets or capsules, the active ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Additionally, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included in the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tracacance or sodium oleate, sodium stearate, magnesium stearate, sodium Includes benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.
액상 용액으로 제제화되는 조성물에 있어서 허용 가능한 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다.Acceptable pharmaceutical carriers for compositions formulated as liquid solutions include those that are sterile and biocompatible, such as saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and One or more of these ingredients can be mixed and used, and other common additives such as antioxidants, buffers, and bacteriostatic agents can be added as needed. In addition, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
더 나아가 해당분야의 적절한 방법으로 Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화할 수 있다.Furthermore, it can be preferably formulated according to each disease or ingredient using a method disclosed by Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA, as an appropriate method in the field.
본 발명의 약제학적 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구 투여인 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있으며, 바람직하게는 경구 투여이다.The pharmaceutical composition of the present invention can be administered orally or parenterally, and in case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc., and is preferably administered orally. .
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사는 소망하는 치료 또는 예방에 효과적인 투여량을 용이하게 결정 및 처방할 수 있다. 본 발명의 바람직한 구현예에 따르면, 본 발명의 약제학적 조성물의 1일 투여량은 0.001-10 g/㎏이다.The appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity. Usually, a skilled physician can easily determine and prescribe an effective dosage for the desired treatment or prevention. According to a preferred embodiment of the present invention, the daily dosage of the pharmaceutical composition of the present invention is 0.001-10 g/kg.
본 발명의 약제학적 조성물은 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention can be prepared in unit dosage form by formulation using a pharmaceutically acceptable carrier and/or excipient, or can be prepared by placing it in a multi-dose container. At this time, the formulation may be in the form of a solution, suspension, or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, granule, tablet, or capsule, and may additionally contain a dispersant or stabilizer.
또한, 본 발명은 고려엉겅퀴 추출물을 유효성분으로 함유하는 심장독성 약물에 의한 심근 손상의 개선, 예방 또는 치료용 식품 조성물을 제공한다.Additionally, the present invention provides a food composition for improving, preventing, or treating myocardial damage caused by cardiotoxic drugs, containing Korean thistle extract as an active ingredient.
본 발명에 따른 식품 조성물은 상기 약제학적 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 음료류, 알코올 음료류, 과자류, 다이어트바, 유제품, 육류, 초코렛, 피자, 라면, 기타 면류, 껌류, 아이스크림류, 비타민 복합제, 건강보조식품류 등이 있다.The food composition according to the present invention can be formulated in the same way as the pharmaceutical composition and used as a functional food or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, alcoholic beverages, confectionery, diet bars, dairy products, meat, chocolate, pizza, ramen, other noodles, gum, ice cream, vitamin complexes, and health supplements. etc.
본 발명의 식품 조성물은 유효성분으로서 고려엉겅퀴 추출물뿐만 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함할 수 있으며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 [타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등]) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다. 예컨대, 본 발명의 식품 조성물이 드링크제와 음료류로 제조되는 경우에는 본 발명의 고려엉겅퀴 추출물 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 및 각종 식물 추출액 등을 추가로 포함시킬 수 있다.The food composition of the present invention may contain not only Korean thistle extract as an active ingredient, but also ingredients commonly added during food production, including, for example, proteins, carbohydrates, fats, nutrients, seasonings, and flavoring agents. . Examples of the above-mentioned carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, oligosaccharides, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents, natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used. For example, when the food composition of the present invention is manufactured as a drink or beverage, in addition to the Korean thistle extract of the present invention, citric acid, high fructose corn syrup, sugar, glucose, acetic acid, malic acid, fruit juice, and various plant extracts may be additionally included. .
본 발명은 상기 고려엉겅퀴 추출물을 유효성분으로 포함하는 심근 손상의 개선, 예방 또는 치료용 식품 조성물을 포함하는 건강기능식품을 제공한다. 건강기능식품이란, 고려엉겅퀴 추출물을 음료, 차류, 향신료, 껌, 과자류 등의 식품소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용시 발생할 수 있는 부작용 등이 없는 장점이 있다. 이와 같이 하여 얻어지는 본 발명의 건강기능식품은, 일상적으로 섭취하는 것이 가능하기 때문에 매우 유용하다. 이와 같은 건강기능식품에 있어서의 고려엉겅퀴 추출물의 첨가량은, 대상인 건강기능식품의 종류에 따라 달라 일률적으로 규정할 수 없지만, 식품 본래의 맛을 손상시키지 않는 범위에서 첨가하면 되며, 대상 식품에 대하여 통상 0.01 내지 50 중량%, 바람직하기로는 0.1 내지 20 중량%의 범위이다. 또한, 환제, 과립제, 정제 또는 캡슐제 형태의 건강기능식품의 경우에는 통상 0.1 내지 100 중량% 바람직하기로는 0.5 내지 80 중량%의 범위에서 첨가하면 된다. 한 구체예에서, 본 발명의 건강기능식품은 환제, 정제, 캡슐제 또는 음료의 형태일 수 있다.The present invention provides a health functional food containing a food composition for improving, preventing or treating myocardial damage containing the Korean thistle extract as an active ingredient. Health functional foods are foods manufactured by adding Korean thistle extract to food ingredients such as beverages, teas, spices, gum, and confectionery, or by encapsulating, powdering, or suspending them, and have specific health effects when consumed. However, unlike regular drugs, it has the advantage of not having any side effects that may occur when taking the drug for a long time since it is made from food. The health functional food of the present invention obtained in this way is very useful because it can be consumed on a daily basis. The amount of Korean thistle extract added in such health functional foods cannot be uniformly specified as it depends on the type of health functional food being targeted. However, it can be added within the range that does not damage the original taste of the food, and is usually the same for the target food. It is in the range of 0.01 to 50% by weight, preferably 0.1 to 20% by weight. In addition, in the case of health functional foods in the form of pills, granules, tablets, or capsules, it is usually added in the range of 0.1 to 100% by weight, preferably 0.5 to 80% by weight. In one embodiment, the health functional food of the present invention may be in the form of a pill, tablet, capsule, or beverage.
또한, 본 발명은 심근 손상의 개선, 예방 또는 치료용 의약 또는 식품의 제조를 위한 고려엉겅퀴 추출물의 용도를 제공한다. 상기한 바와 같이 고려엉겅퀴 추출물은 심근 손상의 개선, 예방 또는 치료를 위한 용도로 이용될 수 있다.In addition, the present invention provides the use of Korean thistle extract for the production of medicine or food for improving, preventing or treating myocardial damage. As mentioned above, Korean thistle extract can be used to improve, prevent, or treat myocardial damage.
또한, 본 발명은 포유동물에게 유효량의 고려엉겅퀴 추출물을 투여하는 것을 포함하는 심근 손상의 개선, 예방 또는 치료 방법을 제공한다.Additionally, the present invention provides a method for improving, preventing, or treating myocardial damage comprising administering an effective amount of Korean thistle extract to a mammal.
여기에서 사용된 용어 "포유동물"은 치료, 관찰 또는 실험의 대상인 포유동물을 말하며, 바람직하게는 인간을 말한다.As used herein, the term “mammal” refers to a mammal, preferably a human, that is the subject of treatment, observation or experiment.
여기에서 사용된 용어 "유효량"은 연구자, 수의사, 의사 또는 기타 임상의에 의해 생각되는 조직계, 동물 또는 인간에서 생물학적 또는 의학적 반응을 유도하는 유효 성분 또는 약학적 조성물의 양을 의미하는 것으로, 이는 해당 질환 또는 장애의 증상의 완화를 유도하는 양을 포함한다. 본 발명의 유효 성분에 대한 유효량 및 투여횟수는 원하는 효과에 따라 변화될 수 있다. 그러므로, 투여될 최적의 투여량은 당업자에 의해 쉽게 결정될 수 있으며, 질환의 종류, 질환의 중증도, 조성물에 함유된 유효성분 및 다른 성분의 함량, 제형의 종류, 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 본 발명의 예방, 치료 또는 개선 방법에 있어서, 본 발명의 치료방법에서 고려엉겅퀴 추출물을 유효 성분으로 포함하는 조성물은 경구, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 경피, 국소, 안구내 또는 피내 경로를 통해 통상적인 방식으로 투여할 수 있다.As used herein, the term “effective amount” means the amount of an active ingredient or pharmaceutical composition that is believed by a researcher, veterinarian, physician, or other clinician to induce a biological or medical response in a tissue system, animal, or human, which means that It includes amounts that induce relief of symptoms of a disease or disorder. The effective amount and frequency of administration of the active ingredient of the present invention may vary depending on the desired effect. Therefore, the optimal dosage to be administered can be easily determined by a person skilled in the art, and can be determined based on the type of disease, the severity of the disease, the content of the active ingredient and other ingredients contained in the composition, the type of dosage form, and the patient's age, weight, and general health. It can be adjusted according to various factors, including condition, gender and diet, administration time, administration route and secretion rate of the composition, treatment period, and concurrently used drugs. In the prevention, treatment or improvement method of the present invention, the composition containing the Korean thistle extract as an active ingredient is administered orally, rectally, intravenously, intraarterially, intraperitoneally, intramuscularly, intrasternally, transdermally, It can be administered in the conventional manner via topical, intraocular or intradermal routes.
본 발명은 고려엉겅퀴 추출물을 유효성분으로 포함하는 심근 손상의 예방 또는 개선용 사료 조성물을 제공할 수 있다.The present invention can provide a feed composition for preventing or improving myocardial damage containing extract of Korean thistle as an active ingredient.
상기 ‘사료 조성물’은 유효성분으로 고려엉겅퀴 추출물 이외에, 식품의 기준 및 규격(‘식품공전’)에 기재된 식품으로 사용가능한 식품 원료, 식품첨가물 공전에 기재된 식품첨가물을 사용할 수 있고, 식품으로 사용가능한 식품 원료 또는 식품첨가물이 아니더라도 ‘사료 등의 기준 및 규격’ 별표 1의 단미사료의 범위에 해당하는 원료, 별표 2의 보조사료의 범위에 해당하는 원료를 사용할 수 있다.In addition to Korean thistle extract as an active ingredient, the 'feed composition' can use food raw materials that can be used as food as described in the Food Standards and Specifications ('Food Code'), and food additives that can be used as food. Even if they are not food raw materials or food additives, raw materials that fall within the scope of single feed in Annex Table 1 of the ‘Standards and Specifications for Feed, etc.’ and raw materials that fall within the scope of supplementary feed in Annex Table 2 can be used.
상기 ‘사료 조성물’은 ‘사료 등의 기준 및 규격’에 따른 보조사료 중 추출제일 수 있고, 상기 보조사료를 포함하는 배합사료일 수 있다.The ‘feed composition’ may be an extractant among supplementary feeds in accordance with ‘Standards and specifications for feed, etc.’, or may be a compound feed containing the above supplementary feed.
상기 고려엉겅퀴 추출물을 유효성분으로 사료 조성물을 제조하는 경우 고려엉겅퀴 추출물은 심근 손상의 예방 또는 개선을 나타내는 함량이면 특별히 한정할 필요는 없으나, 예를 들어 0.1 내지 99 중량%, 0.5 내지 95 중량%, 1 내지 90 중량%, 2 내지 80 중량%, 3 내지 70 중량%, 4 내지 60 중량%, 5 내지 50 중량%로 포함될 수 있다.When preparing a feed composition using the Korean thistle extract as an active ingredient, there is no need to specifically limit the content of the Korean thistle extract as long as it prevents or improves myocardial damage, for example, 0.1 to 99% by weight, 0.5 to 95% by weight, It may be included in 1 to 90% by weight, 2 to 80% by weight, 3 to 70% by weight, 4 to 60% by weight, and 5 to 50% by weight.
상기 사료 조성물에서 유효성분인 고려엉겅퀴 추출물은 섭취 동물의 상태, 체중, 질병의 유무나 정도 및 기간에 따라 다르지만, 통상의 기술자에 의해 적절하게 선택될 수 있다. 예들 들어 1일 투여량을 기준으로 1 내지 5,000 mg, 바람직하게는 5 내지 2,000 mg, 더욱 바람직하게는 10 내지 1,000 mg, 더더욱 바람직하게는 20 내지 800 mg, 가장 바람직하게는 50 내지 500 mg일 수 있고, 투여 횟수는 특별히 한정할 필요는 없으나 1일 3회 내지 1주일에 1회의 범위 내에서 통상의 기술자가 조절할 수 있다. 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있다.The Korean thistle extract, which is an active ingredient in the feed composition, varies depending on the condition, body weight, presence, degree, and period of disease of the ingesting animal, but may be appropriately selected by a person skilled in the art. For example, based on the daily dosage, it may be 1 to 5,000 mg, preferably 5 to 2,000 mg, more preferably 10 to 1,000 mg, even more preferably 20 to 800 mg, and most preferably 50 to 500 mg. There is no need to specifically limit the number of administrations, but a person skilled in the art can adjust it within the range of three times a day to once a week. In the case of long-term intake for health and hygiene purposes or health control, it may be below the above range.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시하나, 하기 실시예는 본 발명을 예시하는 것일 뿐 본 발명의 범주 및 기술사상 범위 내에서 다양한 변경 및 수정이 가능함은 당업자에게 있어서 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속하는 것도 당연한 것이다.Hereinafter, preferred embodiments are presented to aid understanding of the present invention. However, the following examples are merely illustrative of the present invention, and it is clear to those skilled in the art that various changes and modifications are possible within the scope and spirit of the present invention. It is natural that such variations and modifications fall within the scope of the attached patent claims.
실시예 1. Example 1.
고려엉겅퀴 지상부와 80% 에탄올 수용액을 1 : 10의 중량비로 혼합하여 80 ℃에서 8시간 동안 환류추출하여 고려엉겅퀴 추출물을 수득하였다.The aerial parts of Korean thistle and 80% ethanol aqueous solution were mixed at a weight ratio of 1:10 and extracted under reflux at 80°C for 8 hours to obtain a Korean thistle extract.
<시험예 Ⅰ> <Test Example Ⅰ> In vitroIn vitro
실시예에서 제조된 추출액을 여과한 후 여액을 60 ℃ 이하에서 감압농축하여 이용하였다.Prepared in Examples After filtering the extract, the filtrate was concentrated under reduced pressure below 60°C and used.
시험예 1. H9C2 심근세포 생존율 측정_독소루비신(doxorubicin)Test Example 1. Measurement of H9C2 cardiomyocyte survival rate_doxorubicin
H9C2 심근세포 (ATCC, Manassas, VA, USA)의 세포 생존율을 측정하기 위해 96-well plate에 1 X 104 cells/well을 seeding 하였다 (Day 0). 24시간 후 (Day 1), 추출물 샘플을 12.5, 25, 50, 100, 200, 400, 800, 1600 ug/mL의 농도로 배지에 희석한 뒤 100 uL씩 세포에 처리하였다. 24시간 후 (Day 2), 음성 대조군 (Cont.)을 제외하고 Doxorubicin HCl (Apexbio, Houston, TX, USA)을 2 uM의 농도로 100 uL씩 세포에 처리하였다. 48시간 후 (Day 4), 세포 생존율 측정을 위해 WST-1 용액 (Roche, Pleasanton, CA, USA)을 10 uL씩 배지에 처리한 뒤, 2시간 동안 37 ℃에서 incubation 하였다. 그 후, SpectraMax 190 흡광도 Microplate Reader (Molecular Devices, San Jose, CA, USA)를 이용하여 450 nm와 650 nm (Reference)에서 Optical density (OD) 값을 측정하였다. Cell viabilit는 OD450 - OD650로 산출하였으며, 음성 대조군을 100%, 0.1% Triton X-100 처리군을 0%로 Normalization 하였다. 데이터는 3회의 독립실험을 통한 평균 ± 표준편차로 표기되었으며, 그룹간 유의성은 students' t-test (GraphPad)로 계산되었다. ****, p < 0.001 (vs. Dox군) To measure the cell viability of H9C2 cardiomyocytes (ATCC, Manassas, VA, USA), 1 24 hours later (Day 1), the extract samples were diluted in medium to concentrations of 12.5, 25, 50, 100, 200, 400, 800, and 1600 ug/mL, and then treated with 100 uL each of the cells. 24 hours later (Day 2), except for the negative control group (Cont.), cells were treated with 100 uL of Doxorubicin HCl (Apexbio, Houston, TX, USA) at a concentration of 2 uM. 48 hours later (Day 4), to measure cell viability, 10 uL of WST-1 solution (Roche, Pleasanton, CA, USA) was added to the medium and incubated at 37°C for 2 hours. Afterwards, optical density (OD) values were measured at 450 nm and 650 nm (Reference) using a SpectraMax 190 Absorbance Microplate Reader (Molecular Devices, San Jose, CA, USA). Cell viabilit was calculated as OD 450 - OD 650 , and the negative control group was normalized to 100% and the 0.1% Triton X-100 treated group was normalized to 0%. Data were expressed as mean ± standard deviation from three independent experiments, and significance between groups was calculated using students' t-test (GraphPad). ****, p < 0.001 (vs. Dox group)
도 1은 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 독소루비신(doxorubicin)으로 처리 시 H9C2 심근세포의 생존율을 측정한 그래프이다.Figure 1 is a graph measuring the survival rate of H9C2 cardiomyocytes when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with doxorubicin.
도 1에 도시된 바와 같이, Doxorubicin으로 처리하지 않은 음성 대조군에 비하여 Doxorubicin으로 처리된 Dox군(Doxorubicin만 처리한 군)은 약 30%의 세포가 감소한 반면, 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 전처리된 H9c2 세포는 Doxorubicin의 독성으로 부터 보호되어 상대적으로 높은 세포 생존율을 보이는 것을 확인하였다. As shown in Figure 1, compared to the negative control group not treated with Doxorubicin, the Dox group treated with Doxorubicin (group treated only with Doxorubicin) had a decrease in cells of about 30%, while the Korean thistle extract prepared according to Example 1 It was confirmed that H9c2 cells pretreated with were protected from the toxicity of doxorubicin and showed a relatively high cell survival rate.
특히, 400 내지 800 ug/ml 농도의 고려엉겅퀴 추출물이 전처리된 H9c2 세포는 Doxorubicin가 처리 되지 않은 세포(음성 대조군)과 유사한 수준의 세포 생존율을 보이며, 1600 ug/ml 농도의 고려엉겅퀴 추출물이 전처리된 H9c2 세포는 Doxorubicin가 처리 되지 않은 세포(음성 대조군) 보다 더욱 우수한 세포 생존율을 보이는 것을 확인하였다. In particular, H9c2 cells pretreated with Korean thistle extract at a concentration of 400 to 800 ug/ml showed a cell viability similar to that of cells not treated with doxorubicin (negative control), and cells pretreated with Korean thistle extract at a concentration of 1600 ug/ml showed a cell viability similar to that of cells not treated with doxorubicin (negative control). It was confirmed that H9c2 cells showed better cell survival than cells not treated with Doxorubicin (negative control).
이러한 결과는 고려엉겅퀴 추출물의 전처리가 항암제인 독소루비신(doxorubicin)의 독성으로 부터 심근세포 H9c2를 보호한다는 것을 의미한다.These results mean that pretreatment with Korean thistle extract protects cardiomyocyte H9c2 from the toxicity of doxorubicin, an anticancer drug.
시험예 2. MDA-MB-231 유방암 세포 생존율 측정_독소루비신(doxorubicin)Test Example 2. MDA-MB-231 Breast cancer cell survival rate measurement_doxorubicin
H9C2 심근세포 대신 MDA-MB-231 유방암 세포 (ATCC, Manassas, VA, USA)를 사용하여 상기 시험예 1과 동일한 방법으로 세포 생존율을 측정하였다. ###, p < 0.001 (vs. 음성 대조군); ***, p < 0.001 (vs. Dox군) Cell survival rate was measured in the same manner as Test Example 1, using MDA-MB-231 breast cancer cells (ATCC, Manassas, VA, USA) instead of H9C2 cardiomyocytes. ###, p < 0.001 (vs. negative control); ***, p < 0.001 (vs. Dox group)
도 2는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 독소루비신(doxorubicin)으로 처리 시 MDA-MB-231 유방암 세포의 생존율을 측정한 그래프이다.Figure 2 is a graph measuring the survival rate of MDA-MB-231 breast cancer cells when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with doxorubicin.
도 2에 도시된 바와 같이, Doxorubicin으로 처리하지 않은 음성 대조군에 비하여 Doxorubicin을 처리한 Dox군은 삼중음성 유방암 세포인 MDA-MB-231 세포의 생존율이 약 45%로 감소하였으며, 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 전처리된 MDA-MB-231 세포 역시 Dox군과 유사한 세포 생존율을 보이는 것을 확인하였다.As shown in Figure 2, compared to the negative control group not treated with Doxorubicin, the survival rate of MDA-MB-231 cells, which are triple negative breast cancer cells, was reduced to about 45% in the Dox group treated with Doxorubicin, according to Example 1 It was confirmed that MDA-MB-231 cells pretreated with the prepared Korean thistle extract also showed a cell survival rate similar to that of the Dox group.
이러한 결과는 고려엉겅퀴 추출물이 항암제인 독소루비신(doxorubicin)의 암세포 사멸 효과를 저해하지 않음을 의미한다.These results mean that Korean thistle extract does not inhibit the cancer cell killing effect of doxorubicin, an anticancer drug.
시험예 3. H9C2 심근세포 생존율 측정_오시머티닙(osmertinib), 엘로티닙(erlotinib) 및 게피티니브(gefitinib)Test Example 3. Measurement of H9C2 cardiomyocyte survival rate_osmertinib, erlotinib, and gefitinib
Doxorubicin 이외에 다른 항암제들의 독성으로부터 심근세포의 세포 생존율을 확인하기 위하여 심근세포 독성을 유발하는 것으로 잘 알려진 TKI (Tyrosine kinase inhibitor) 계열의 대표적 항암제들에 대한 고려엉겅퀴 추출물의 심근세포 보호 효과를 측정하였다.In order to confirm the cell survival rate of cardiomyocytes from the toxicity of anticancer drugs other than doxorubicin, the protective effect of Korean thistle extract on cardiomyocyte cells was measured against representative anticancer drugs of the TKI (Tyrosine kinase inhibitor) class, which are well known to cause cardiomyocyte toxicity.
H9C2 심근세포 (ATCC, Manassas, VA, USA)의 세포 생존율을 측정하기 위해 96-well plate에 1 X 104 cells/well을 seeding 하였다 (Day 0). 24시간 후 (Day 1), 추출물 샘플을 50, 100, 200 ug/mL의 농도로 배지에 희석한 뒤 100 uL씩 세포에 처리하였다. 24시간 후 (Day 2), 음성 대조군을 제외하고 Osimertinib, Erlotinib, Gefitinib을 각각 10, 40, 30 uM의 농도로 100 uL씩 세포에 처리하였다. 48시간 후 (Day 4), 세포 생존율 측정을 위해 WST-1 용액 (Roche, Pleasanton, CA, USA)을 10 uL씩 배지에 처리한 뒤, 2시간 동안 37 ℃에서 incubation 하였다. 그 후, SpectraMax 190 흡광도 Microplate Reader (Molecular Devices, San Jose, CA, USA)를 이용하여 450 nm와 650 nm (Reference)에서 Optical density (OD) 값을 측정하였다. Cell viability는 OD450 - OD650로 산출하였으며, 음성 대조군을 100%, 0.1% Triton X-100 처리군을 0%로 Normalization 하였다. 데이터는 3회의 독립실험을 통한 평균 ± 표준편차로 표기되었으며, 그룹간 유의성은 students' t-test (GraphPad)로 계산되었다. ###, p < 0.0001 (vs. 음성 대조군); ***, p < 0.001 (vs. Dox군); ****, p < 0.0001 (vs. Dox군) To measure the cell viability of H9C2 cardiomyocytes (ATCC, Manassas, VA, USA), 1 24 hours later (Day 1), the extract sample was diluted in medium at concentrations of 50, 100, and 200 ug/mL and then treated with 100 uL of each cell. 24 hours later (Day 2), except for the negative control group, cells were treated with 100 uL of Osimertinib, Erlotinib, and Gefitinib at concentrations of 10, 40, and 30 uM, respectively. After 48 hours (Day 4), to measure cell viability, 10 uL of WST-1 solution (Roche, Pleasanton, CA, USA) was added to the medium and incubated at 37°C for 2 hours. Afterwards, optical density (OD) values were measured at 450 nm and 650 nm (Reference) using a SpectraMax 190 Absorbance Microplate Reader (Molecular Devices, San Jose, CA, USA). Cell viability was calculated as OD 450 - OD 650 , and the negative control group was normalized to 100% and the 0.1% Triton X-100 treated group was normalized to 0%. Data were expressed as mean ± standard deviation from three independent experiments, and significance between groups was calculated using students' t-test (GraphPad). ###, p < 0.0001 (vs. negative control); ***, p < 0.001 (vs. Dox group); ****, p < 0.0001 (vs. Dox group)
도 3a는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 오시머티닙(osmertinib)으로 처리 시 H9C2 심근세포의 생존율을 측정한 그래프이며; 도 3b는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 엘로티닙(erlotinib)으로 처리 시 H9C2 심근세포의 생존율을 측정한 그래프이고; 도 3c는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 게피티니브(gefitinib)로 처리 시 H9C2 심근세포의 생존율을 측정한 그래프이다.Figure 3a is a graph measuring the survival rate of H9C2 cardiomyocytes when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with osmertinib; Figure 3b is a graph measuring the survival rate of H9C2 cardiomyocytes when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with erlotinib; Figure 3c is a graph measuring the survival rate of H9C2 cardiomyocytes when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with gefitinib.
도 3a 내지 도 3c에 도시된 바와 같이, Osmertinib을 처리 시 세포 생존율은 약 70%이고, Erlotinib을 처리 시 세포 생존율은 약 50%이며, Gefitinib을 처리 시 세포 생존율은 약 65%인 것을 확인하였다. As shown in Figures 3A to 3C, when treated with Osmertinib, the cell survival rate was about 70%, when treated with Erlotinib, the cell survival rate was about 50%, and when treated with Gefitinib, the cell survival rate was about 65%.
반면, 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 전처리된 H9c2 세포는 각 항암제 단독 처리한 군에 비하여 상대적으로 높은 세포 생존율을 보이는 것을 확인하였다.On the other hand, it was confirmed that H9c2 cells pretreated with the Korean thistle extract prepared according to Example 1 showed a relatively high cell survival rate compared to the group treated with each anticancer agent alone.
이러한 결과는 고려엉겅퀴 추출물의 전처리가 독소루비신(doxorubicin) 뿐만 아니라 다른 항암제들로부터 심근세포 H9c2를 보호한다는 것을 의미한다.These results mean that pretreatment with Korean thistle extract protects cardiomyocyte H9c2 not only from doxorubicin but also from other anticancer drugs.
시험예 4. A549 폐암 세포 생존율 측정_오시머티닙(osmertinib), 엘로티닙(erlotinib) 및 게피티니브(gefitinib) Test Example 4. Measurement of A549 lung cancer cell viability_osmertinib, erlotinib, and gefitinib
오시머티닙(osmertinib), 엘로티닙(erlotinib) 및 게피티니브(gefitinib)로 이루어진 3종의 TKIs 계열 항암제는 주로 비소세포성폐암의 치료를 위해 임상적 적용된다. 그러므로 고려엉겅퀴 추출물이 3종의 TKIs 계열 항암제의 비소세포성폐암세포 사멸 효능을 저해하는지 확인하기 위하여 실험을 실시하였다. Three types of TKIs anticancer drugs, consisting of osmertinib, erlotinib, and gefitinib, are mainly applied clinically for the treatment of non-small cell lung cancer. Therefore, an experiment was conducted to determine whether Korean thistle extract inhibits the non-small cell lung cancer cell killing effect of three types of TKIs anticancer drugs.
비소세포성폐암 세포주인 A549 폐암 세포 (ATCC, Manassas, VA, USA, 위 항암제가 주로 적용)의 세포 생존율을 측정하기 위해 96-well plate에 3 X 103 cells/well을 seeding 하였다 (Day 0). 24시간 후 (Day 1), 추출물 샘플을 50, 100, 200 ug/mL의 농도로 배지에 희석한 뒤 100 uL씩 세포에 처리하였다. 24시간 후 (Day 2), 음성 대조군을 제외하고 Osimertinib, Erlotinib, Gefitinib 을 각각 10, 40, 30 uM의 농도로 100 uL씩 세포에 처리하였다. 72시간 후 (Day 5), 세포 생존율 측정을 위해 WST-1 용액 (Roche, Pleasanton, CA, USA)을 10 uL씩 배지에 처리한 뒤, 2시간 동안 37 ℃에서 incubation 하였다. 그 후, SpectraMax 190 흡광도 Microplate Reader (Molecular Devices, San Jose, CA, USA)를 이용하여 450 nm와 650 nm (Reference)에서 Optical density (OD) 값을 측정하였다. Cell viabilit는 OD450 - OD650로 산출하였으며, 음성 대조군을 100%, 0.1% Triton X-100 처리군을 0%로 Normalization 하였다. 데이터는 3회의 독립실험을 통한 평균 ± 표준편차로 표기되었으며, 그룹간 유의성은 students' t-test (GraphPad)로 계산되었다. ####, p < 0.0001 (vs. 음성 대조군)To measure the cell survival rate of A549 lung cancer cells (ATCC, Manassas, VA, USA, mainly applied with the above anticancer drugs), a non-small cell lung cancer cell line, 3 . 24 hours later (Day 1), the extract sample was diluted in medium at concentrations of 50, 100, and 200 ug/mL and then treated with 100 uL of each cell. 24 hours later (Day 2), except for the negative control group, cells were treated with 100 uL of Osimertinib, Erlotinib, and Gefitinib at concentrations of 10, 40, and 30 uM, respectively. 72 hours later (Day 5), to measure cell viability, 10 uL of WST-1 solution (Roche, Pleasanton, CA, USA) was added to the medium and incubated at 37°C for 2 hours. Afterwards, optical density (OD) values were measured at 450 nm and 650 nm (Reference) using a SpectraMax 190 Absorbance Microplate Reader (Molecular Devices, San Jose, CA, USA). Cell viabilit was calculated as OD 450 - OD 650 , and the negative control group was normalized to 100% and the 0.1% Triton X-100 treated group was normalized to 0%. Data were expressed as mean ± standard deviation from three independent experiments, and significance between groups was calculated using students' t-test (GraphPad). ####, p < 0.0001 (vs. negative control)
도 4a는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 오시머티닙(osmertinib)으로 처리 시 A549 폐암 세포의 생존율을 측정한 그래프이며; 도 4b는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 엘로티닙(erlotinib)으로 처리 시 A549 폐암 세포의 생존율을 측정한 그래프이고; 도 4c는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 게피티니브(gefitinib)로 처리 시 A549 폐암 세포의 생존율을 측정한 그래프이다.Figure 4a is a graph measuring the survival rate of A549 lung cancer cells when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with osmertinib; Figure 4b is a graph measuring the survival rate of A549 lung cancer cells when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with erlotinib; Figure 4c is a graph measuring the survival rate of A549 lung cancer cells when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with gefitinib.
도 4a 내지 도 4c에 도시된 바와 같이, 3종의 각 TKIs 계열 항암제로 처리하지 않은 음성 대조군에 비하여 3종의 각 항암제로 처리한 osmertinib군, erlotinib군 및 gefitinib군은 A549 폐암 세포의 생존율이 각각 약 18%, 약 42%, 약 63%로 감소하였으며, 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 전처리된 A549 폐암 세포의 각 생존율은 상기 3종의 항암제로만 처리한 osmertinib군, erlotinib군 및 gefitinib군과 유사한 것을 확인하였다.As shown in Figures 4a to 4c, the survival rate of A549 lung cancer cells in the osmertinib group, erlotinib group, and gefitinib group treated with each of the three types of anticancer drugs compared to the negative control group that was not treated with each of the three types of anticancer drugs. It decreased to about 18%, about 42%, and about 63%, and the survival rates of A549 lung cancer cells pretreated with the Korean thistle extract prepared according to Example 1 were osmertinib group, erlotinib group, and gefitinib treated with only the three anticancer drugs. It was confirmed that it was similar to the group.
이러한 결과는 고려엉겅퀴 추출물이 항암제인 오시머티닙(osmertinib), 엘로티닙(erlotinib) 및 게피티니브(gefitinib)의 비소세포성폐암세포 사멸 효과를 저해하지 않음을 의미한다.These results mean that Korean thistle extract does not inhibit the non-small cell lung cancer cell killing effect of the anticancer drugs osmertinib, erlotinib, and gefitinib.
시험예 5. 산소 소비량Test Example 5. Oxygen consumption
실시간 산소 소비량(OCR)은 세포외 플럭스 분석기(Seahorse XFe96 분석기, Agilent Technologies, Palo Alto, CA, USA)를 사용하여 측정되었다. 측정 전 약 90% 컨플루언스(confluence)에 도달하도록 적절한 농도로 XF 세포 배양 마이크로플레이트에 1X104 세포를 세포에 접종하였다. 플레이트를 CO2가 없는 인큐베이터에서 37 ℃로 1시간 동안 인큐베이션한 후 제조업체의 지침에 따라 완충되지 않은 기본 배지(Agilent Technologies)를 사용하여 세포를 Mito Stress 테스트에 적용하였다. 세포 산소 소비량은 기본 조건(첨가 전)과 올리고마이신(1.5μM), FCCP(1.0μM) 및 안티마이신 A 및 로테논(1.0μM) 첨가 후 측정되었다. OCR은 혼합(150초), 대기(120초), 측정(210초)의 3주기로 세포외 플럭스 분석기를 사용하여 모니터링되었으며, 상기 주기는 각 주사 후에 반복되었다. 최대 호흡 및 아데노신 삼인산(ATP) 생산을 포함한 미토콘드리아 호흡은 다음 수학식으로 계산되었다. Real-time oxygen consumption (OCR) was measured using an extracellular flux analyzer (Seahorse XFe96 analyzer, Agilent Technologies, Palo Alto, CA, USA). Before measurement, 1X10 4 cells were inoculated into an XF cell culture microplate at an appropriate concentration to reach about 90% confluence. Plates were incubated for 1 hour at 37°C in a CO 2 -free incubator, and then cells were subjected to the Mito Stress test using unbuffered basal medium (Agilent Technologies) according to the manufacturer's instructions. Cellular oxygen consumption was measured under basal conditions (before addition) and after addition of oligomycin (1.5 μM), FCCP (1.0 μM), and antimycin A and rotenone (1.0 μM). OCR was monitored using an extracellular flux analyzer with three cycles of mixing (150 s), waiting (120 s), and measurement (210 s), which were repeated after each injection. Mitochondrial respiration, including maximal respiration and adenosine triphosphate (ATP) production, was calculated using the following equation:
[수학식 1][Equation 1]
최대 호흡 = FCCP 치료 후 OCR - 비미토콘드리아 OCRMaximal respiration = OCR after FCCP treatment - non-mitochondrial OCR
[수학식 2][Equation 2]
ATP 생산 = 기본 OCR - 올리고마이신 처리 후 OCRATP production = baseline OCR - OCR after oligomycin treatment
도 5a는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 시 산소 소비량을 나타낸 그래프이며; 도 5b는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 시 최대 호흡을 나타낸 그래프이고; 도 5c는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 시 아데노신 삼인산(ATP) 생산을 포함한 미토콘드리아 호흡을 나타낸 그래프이다.Figure 5a is a graph showing oxygen consumption when treated with Korean thistle extract prepared according to Example 1 of the present invention; Figure 5b is a graph showing maximum respiration when treated with Korean thistle extract prepared according to Example 1 of the present invention; Figure 5c is a graph showing mitochondrial respiration, including adenosine triphosphate (ATP) production, when treated with Korean thistle extract prepared according to Example 1 of the present invention.
도 5a 내지 도 5c에 도시된 바와 같이, 미토콘드리아의 실시간 산소 소비량(OCR)은 고려엉겅퀴 추출물(100 ug/ml)의 전처리 시 DOX로만 처리된 H9c2 세포에 비하여 증가하였으며, 최대 호흡수 및 ATP 생산 역시 고려엉겅퀴 추출물의 전처리 시 DOX로만 처리된 H9c2 세포에 비하여 증가하는 것을 확인하였다. As shown in Figures 5A to 5C, real-time oxygen consumption (OCR) of mitochondria increased compared to H9c2 cells treated only with DOX upon pretreatment with Korean thistle extract (100 ug/ml), and maximum respiratory rate and ATP production also increased. It was confirmed that pretreatment with Korean thistle extract increased compared to H9c2 cells treated only with DOX.
시험예 6. 미토콘드리아 막 전위 측정Test Example 6. Measurement of mitochondrial membrane potential
8웰 플레이트에 씨드된 H9c2 1x104 세포를 24시간 동안 고려엉겅퀴 추출물로 전처리하고 48시간 동안 2 uM DOX를 처리하였다. 72시간 후 세포 성장 배지를 제거하고 미토콘드리아 막 전위를 관찰하기 위해 세포를 100 nM의 테트라메틸로다민, 메틸 에스테르(TMRM)에 30분 동안 노출시켰다. 이는 막 전위가 손상되지 않은 활성 미토콘드리아에 축적되는 세포 투과성 염료이다. Hoechst 33422는 핵 염색(5 ug/mL)에 사용되었으며, 염색 후 미리 예열된 HBSS 완충액으로 세포를 3회 세척하였다. 이미지는 20X 대물렌즈(Nikon ECLIPSE 80i)로 촬영하고 NIS-Elements 버전 5.21(Nikon)을 사용하여 분석되었다. H9c2 1x10 4 cells seeded in an 8-well plate were pretreated with Korean thistle extract for 24 hours and treated with 2 uM DOX for 48 hours. After 72 hours, the cell growth medium was removed and the cells were exposed to 100 nM of tetramethylrhodamine, methyl ester (TMRM) for 30 minutes to observe mitochondrial membrane potential. It is a cell-permeable dye that accumulates in active mitochondria where the membrane potential is intact. Hoechst 33422 was used for nuclear staining (5 ug/mL), and after staining, cells were washed three times with pre-warmed HBSS buffer. Images were taken with a 20X objective (Nikon ECLIPSE 80i) and analyzed using NIS-Elements version 5.21 (Nikon).
도 6a는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 DOX로 처리 시 미토콘드리아의 막 전위를 나타낸 것이며; 도 6b는 상기 도 6a의 TMRM 발현량을 정량화한 그래프이다.Figure 6a shows the membrane potential of mitochondria when treated with Korean thistle extract prepared according to Example 1 of the present invention and then treated with DOX; Figure 6b is a graph quantifying the TMRM expression level of Figure 6a.
도 6a 내지 도 6b에 도시된 바와 같이, 살아있는 세포의 미토콘드리아 막 전위는 고려엉겅퀴 추출물로 처리 시 농도 의존적으로 크게 보호되는 것을 확인하였다.As shown in Figures 6a and 6b, it was confirmed that the mitochondrial membrane potential of living cells was significantly protected in a concentration-dependent manner when treated with Korean thistle extract.
시험예 7. SOD 발현 및 활성 측정 Test Example 7. Measurement of SOD expression and activity
7-1. 웨스턴 블롯 분석을 위해 총 용해물의 단백질을 15 μg으로 조정하고 SDS-PAGE에서 분리한 후 분리된 단백질을 PVDF(폴리비닐리덴 디플루오라이드) 멤브레인으로 옮긴 다음 EveryBlot Blocking Buffer로 차단하였다. TBST로 세척한 후 막을 1차 항체와 함께 4 ℃에서 밤새 인큐베이션하였다. 7-1. For Western blot analysis, the total protein of the lysate was adjusted to 15 μg and separated on SDS-PAGE, and the separated proteins were transferred to a PVDF (polyvinylidene difluoride) membrane and blocked with EveryBlot Blocking Buffer. After washing with TBST, the membrane was incubated with primary antibody overnight at 4°C.
7-2. SOD 활성은 EZ-SOD 분석 키트(Dogenbio Co., Korea)를 사용하여 측정하였으며, 희석된 시료 20 μL를 각 시료 웰과 미처리군 2의 웰에 첨가하고, 미처리군 1 및 미처리군 3의 웰에 각각 20 μL의 ddH2O를 첨가하였다. 각 웰에 200 μL의 WST 작업 용액을 첨가하고, 상기 미처리군 2 및 미처리군 3의 각 웰에 20μL의 희석 완충액을 첨가하였다. 미처리군 1과 시료 웰에 효소 작동 용액을 각각 20 μL 첨가한 후, 플레이트를 37 ℃에서 20분간 반응시켰다. 흡광도는 450 nm에서 측정되었고 결과 값은 동일한 조건에서 3번 반복되었다.7-2. SOD activity was measured using the EZ-SOD assay kit (Dogenbio Co., Korea), and 20 μL of the diluted sample was added to each sample well and the well of untreated group 2, and to the wells of untreated group 1 and untreated group 3. 20 μL of ddH2O was added to each. 200 μL of WST working solution was added to each well, and 20 μL of dilution buffer was added to each well of untreated group 2 and untreated group 3. After adding 20 μL of the enzyme working solution to the untreated group 1 and the sample well, the plate was incubated at 37°C for 20 minutes. Absorbance was measured at 450 nm and the results were repeated three times under the same conditions.
[수학식 3][Equation 3]
SOD 활성(%) = (OD 미처리군 1 - OD 미처리군 3) - (OD 샘플 - OD 미처리군 2) / (OD 미처리군 1 - OD 미처리군 3) X 100SOD activity (%) = (OD untreated group 1 - OD untreated group 3) - (OD sample - OD untreated group 2) / (OD untreated group 1 - OD untreated group 3)
7-3. 8웰 플레이트에 씨드된 H9c2 1x104 세포를 24시간 동안 고려엉겅퀴 추출물로 전처리하고 48시간 동안 2uM DOX로 처리하여 72시간 후 세포 성장 배지를 제거하였다. 미토콘드리아 막전위를 관찰하기 위해 세포를 미토콘드리아 과산화물 지표인 MitoSOXTM(TMRM) 5 uM에 10분간 노출시켰다. 상기 MitoTracker는 미토콘드리아 염색에 사용되었다(100 nM, 45분). 염색 후 미리 예열된 HBSS 완충액으로 세포를 3회 세척하고, 이미지는 20X 대물렌즈(Nikon ECLIPSE 80i)로 촬영되며 NIS-Elements 버전 5.21(Nikon)을 사용하여 분석되었다.7-3. H9c2 1x10 4 cells seeded in an 8-well plate were pretreated with Korean thistle extract for 24 hours and treated with 2uM DOX for 48 hours, and the cell growth medium was removed after 72 hours. To observe mitochondrial membrane potential, cells were exposed to 5 uM of MitoSOXTM (TMRM), a mitochondrial peroxide indicator, for 10 minutes. The MitoTracker was used for mitochondrial staining (100 nM, 45 minutes). After staining, cells were washed three times with pre-warmed HBSS buffer, and images were taken with a 20X objective (Nikon ECLIPSE 80i) and analyzed using NIS-Elements version 5.21 (Nikon).
도 7a는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 시 SOD1 및 SOD2의 발현을 나타낸 웨스턴 블롯이며; 도 7b는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 시 총 SOD, SOD1 및 SOD2의 활성을 나타낸 그래프이고; 도 7c는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물로 처리 후 DOX로 처리 시 미토콘드리아의 막 전위의 발현을 나타낸 사진이며; 도 7d는 상기 도 7c의 MitoSOXTM 발현량을 정량화한 그래프이다.Figure 7a is a Western blot showing the expression of SOD1 and SOD2 upon treatment with Korean thistle extract prepared according to Example 1 of the present invention; Figure 7b is a graph showing the activities of total SOD, SOD1, and SOD2 when treated with Korean thistle extract prepared according to Example 1 of the present invention; Figure 7c is a photograph showing the expression of mitochondrial membrane potential when treated with DOX after treatment with Korean thistle extract prepared according to Example 1 of the present invention; Figure 7d is a graph quantifying the expression level of MitoSOXTM of Figure 7c.
도 7a 내지 도 7b에 도시된 바와 같이, 고려엉겅퀴 추출물로 처리 시 항산화 효소인 슈퍼옥사이드 디스뮤타제 SOD1 및 SOD2의 단백질 발현과; 총 SOD, SOD1 및 SOD2의 효소 활성이 증가하는 것을 확인하였다.As shown in Figures 7a and 7b, when treated with Korean thistle extract, protein expression of superoxide dismutase SOD1 and SOD2, which are antioxidant enzymes; It was confirmed that the enzymatic activities of total SOD, SOD1, and SOD2 increased.
또한 도 7c 내지 도 7d에 도시된 바와 같이, 세포내 및 미토콘드리아 산화 스트레스는 고려엉겅퀴 추출물로 처리된 H9c2 세포에서 유의하게 감소되는 것을 확인하였다.Additionally, as shown in Figures 7c to 7d, intracellular and mitochondrial oxidative stress was confirmed to be significantly reduced in H9c2 cells treated with Korean thistle extract.
시험예 8. 전기생리학적 특징 측정Test Example 8. Measurement of electrophysiological characteristics
인간 유도 만능 줄기 세포 유래 심근세포(hiPSC-CM)를 사용하여 심장 기능을 측정하기 위하여 MEA 데이터 수집 시스템(Maestro Edge, Axion BioSystems, Germany)을 사용하였다. MEA 플레이트에는 전극 간이 있는 질화 티타늄 전극 매트릭스가 포함되며, 상기 MEA 플레이트를 70% 에탄올 용액으로 멸균하고 Matrigel(354277, Corning)로 코팅하였다. 박동 심근세포를 MEA 플레이트 중앙의 CM 배지에 최소 3일 동안 플레이팅하였으며, 실험 당일 녹음은 기준선에서 5분, 독소루비신(DOX) 적용 후 10분 동안 수행되었다. 비트 기간 평균, 비트 불규칙성, FP 지속 시간 및 스파이크 진폭에 대해 필드 전위 신호를 분석하였고, FP 지속 시간은 Fridericia 공식[수정된 FPD(FPDc)]을 사용하여 박동률로 정규화되었다. A MEA data acquisition system (Maestro Edge, Axion BioSystems, Germany) was used to measure cardiac function using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). The MEA plate included a titanium nitride electrode matrix with interelectrode electrodes, and the MEA plate was sterilized with 70% ethanol solution and coated with Matrigel (354277, Corning). Beating cardiomyocytes were plated in CM medium in the center of MEA plates for at least 3 days, and on the day of the experiment, recordings were performed for 5 min at baseline and 10 min after doxorubicin (DOX) application. Field potential signals were analyzed for beat period average, beat irregularity, FP duration, and spike amplitude, with FP duration normalized to beat rate using the Fridericia formula [modified FPD (FPDc)].
데이터는 Cardiac Analysis Tool v.3.2.2(Axion BioSystems)로 분석되었다.Data were analyzed with Cardiac Analysis Tool v.3.2.2 (Axion BioSystems).
도 8a는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물 및 DOX를 처리 후 기록하는 일정을 나타낸 그래프이며; 도 8b는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물 처리 시 총 활성 전극을 나트낸 사진 및 그래프이고; 도 8c는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물 처리 시 비트 주기를 측정한 것이며; 도 8d는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물 처리 시 탈분극 스파이크의 시작부터 재분극 파동의 피크까지의 시간으로 측정된 그래프 및 이를 시간에 따라 정량화한 그래프이고; 도 8e는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물 처리 시 전도 속도를 나타낸 사진 및 이를 시간에 따라 정량화한 그래프이며; 도 8f는 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물 처리 시 수축성을 나타낸 그래프이다.Figure 8a is a graph showing the schedule for recording after processing the Korean thistle extract and DOX prepared according to Example 1 of the present invention; Figure 8b is a photograph and graph showing the total active electrode when treated with Korean thistle extract prepared according to Example 1 of the present invention; Figure 8c shows the beat cycle measured when processing the Korean thistle extract prepared according to Example 1 of the present invention; Figure 8d is a graph measured as the time from the start of the depolarization spike to the peak of the repolarization wave when treated with the Korean thistle extract prepared according to Example 1 of the present invention, and a graph quantified over time; Figure 8e is a photograph showing the conduction speed upon treatment with the Korean thistle extract prepared according to Example 1 of the present invention and a graph quantifying this over time; Figure 8f is a graph showing the shrinkage upon treatment of the Korean thistle extract prepared according to Example 1 of the present invention.
상기 도 8a는 7일의 기준선(BL)과 DOX 치료 후 기간(DOX Tx.)(12시간 및 24시간)의 두 시점에 걸쳐 수행되었으며, 도 8b는 전기적으로 활성인 세포의 외부 장 전위를 반사하여 총 활성 전극을 측정하였고, 도 8c는 비트 주기 및 비트 주기 불규칙성을 측정하였으며, 도 8d는 탈분극 스파이크의 시작부터 재분극 파동의 피크까지의 시간으로 FPD(Field Potential Duration)를 측정하였고 상기 FPD는 Fredericia의 공식(FPDc = FPD/RR1/3, 여기서 RR = 인터스파이크/비트 간 간격)을 사용하여 속도 보정(FPDc)되었다. 상기 FPD는 심전도(ECG)의 QT 간격과 밀접하게 연관되어 있는 심장 활동 전위를 설명한다. 도 8e 및 도 8f는 전도 속도, 심장을 통한 전기 전파의 속도와 방향을 설명하는 전기생리학적 특성인 수축성이다(심장의 생체역학적 특성을 설명하는 주요 매개변수이다).Figure 8a was performed over two time points: a 7-day baseline (BL) and a post-DOX treatment period (DOX Tx.) (12 and 24 hours), and Figure 8b shows reflected external field potentials of electrically active cells. The total active electrodes were measured, Figure 8c measured the beat period and beat period irregularity, Figure 8d measured FPD (Field Potential Duration) as the time from the start of the depolarization spike to the peak of the repolarization wave, and the FPD was measured by Fredericia. Rate correction (FPDc) was performed using the formula: FPDc = FPD/RR1/3, where RR = interspike/inter-bit spacing. The FPD describes the cardiac action potential, which is closely related to the QT interval of the electrocardiogram (ECG). Figures 8e and 8f show conduction velocity, contractility, an electrophysiological property that describes the speed and direction of electrical propagation through the heart (a key parameter that describes the biomechanical properties of the heart).
도 8a 내지 도 8f에 도시된 바와 같이, DOX로 처리 시 세포는 총 활성 전극의 감소를 나타내었으나 고려엉겅퀴 추출물의 처리 시 세포는 DOX만 처리한 세포에 비해 더 높은 수준의 활성 전극을 나타내는 것을 확인하였다(도 8b). 추가적으로, 고려엉겅퀴 추출물 처리된 세포는 빠른 박동 기간과 더 높은 박동 기간 불규칙성 값 모두에서 개선되는 것을 확인하였다(도 8c). As shown in Figures 8a to 8f, when treated with DOX, cells showed a decrease in total active electrodes, but when treated with Korean thistle extract, cells showed a higher level of active electrodes compared to cells treated only with DOX. (Figure 8b). Additionally, cells treated with Korean thistle extract showed improvement in both faster beat duration and higher beat period irregularity values (Figure 8c).
QT 간격은 DOX 유발 심장 독성에 대한 연구에서 임상 보고서, 생체 내 및 시험관 내에서 가장 일반적으로 평가되는 매개변수이다. MEA 분석에서 FPD(Field Potential Duration) 기록 데이터는 높은 신호와 함께 R/G 및 T 피크가 명확하게 표시되는 것을 확인하였다. 구타 클러스터에서 DOX는 hiPSC-CM의 FPDc를 연장시켰으나 200 μg/ml 고려엉겅퀴 추출물로 전처리하면 FPDc가 80% 감소하는 것을 확인하였다(도 8d). 모든 전극으로부터의 전계 전위 신호를 평가함으로써 신호 전파를 평가한 결과 전도 속도는 DOX 치료 중에 느려지고 고려엉겅퀴 추출물로 처리 시 증가하는 것을 확인하였다(도 8e). 추가 MEA 분석을 통해 DOX로 인해 수축성(박동 진폭)이 약 60% 감소한 것으로 관찰되었으나 고려엉겅퀴 추출물로 처리 시 감소율이 20%로 감소하여 독성이 낮음을 확인하였다(도 8f). The QT interval is the most commonly assessed parameter in studies of DOX-induced cardiotoxicity in clinical reports, in vivo and in vitro. In the MEA analysis, Field Potential Duration (FPD) recording data confirmed that R/G and T peaks were clearly displayed along with high signals. In the gutta cluster, DOX extended the FPDc of hiPSC-CM, but pretreatment with 200 μg/ml Korean thistle extract reduced the FPDc by 80% (Figure 8d). Signal propagation was evaluated by evaluating the electric field potential signals from all electrodes, and it was confirmed that the conduction speed slowed down during DOX treatment and increased when treated with Korean thistle extract (Figure 8e). Through additional MEA analysis, it was observed that contractility (pulsation amplitude) was reduced by about 60% due to DOX, but when treated with Korean thistle extract, the reduction rate was reduced to 20%, confirming low toxicity (Figure 8f).
이러한 결과로 고려엉겅퀴 추출물이 독소루비신 유발 심장 독성에서 발생하는 심장 전기생리학의 일부를 완화시킨는 것을 확인하였다.These results confirmed that Korean thistle extract alleviated some of the cardiac electrophysiology occurring in doxorubicin-induced cardiac toxicity.
<시험예 Ⅱ> <Test Example Ⅱ> In vivoIn vivo
동물실험animal testing
18~22 g의 C57BL/6 마우스(6주령, 한국, 숫컷)를 실험에 사용하였다. 아크릴 케이지 (45 X 60 X 25 cm)에서 사육되었으며, 충분한 사료와 물이 공급되며 적절한 인공조도로 12시간의 낮, 밤을 조절하였다(am 8:00부터 낮). 그리고 일정한 온도 (20~24 ℃) 및 습도 (45~65%)를 유지시켜 주었다. 바뀐 환경에 적응하도록 일주일간 살펴보며 수면주기를 유지하고, 이상행동을 확인하였다. C57BL/6 mice (6 weeks old, Korea, male) weighing 18 to 22 g were used in the experiment. They were raised in acrylic cages (45 And constant temperature (20-24 ℃) and humidity (45-65%) were maintained. We monitored them for a week to help them adapt to the changed environment, maintained their sleep cycle, and checked for abnormal behavior.
동물의 프로토콜은 한국식품연구원의 기관 동물 관리 및 사용위원회(IACUC)에 의해 승인되었으며, 실험동물은 체중변화가 일정하고 건강한 동물만을 선별하여 임의 배치법에 의해 구분하였다.The animal protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of the Korea Food Research Institute, and only healthy animals with consistent body weight changes were selected and classified by random placement method.
항암제 (Doxorubicin)에 의한 심근 독성 마우스 모델 제작을 위하여 Doxorubicin을 1주일에 한 번씩 4주에 걸쳐 (총 4회) 총 약물 누적 용량이 20 mg/kg에 도달 할 때 까지 마우스의 복강 (IP; intraperitoneal)에 주사한 후 1주 뒤 (Doxorubicin의 첫 투약일로 5주)에 실험에 이용하였다. 200 uL의 0.9% saline를 투여한 음성 대조군(Control), 200 uL Dox 용액을 5 mg/kg씩 총 4회 투여한 Dox군, Doxorubicin 투여 첫날부터 해부 이틀 전까지 매일 400 mg/kg씩 실시예 1의 추출물을 경구투여한 고려엉겅퀴 추출물군, Doxorubicin 투여 첫날부터 해부 이틀 전까지 매일 20 mg/kg씩 Berberine chloride를 경구 투여한 Berberine 20군 및 매일 40 mg/kg씩 Berberine chloride를 경구투여한 Berberine 40군으로 나누었으며 실험군마다 4마리씩 사용하였다. To create a mouse model of myocardial toxicity caused by an anticancer drug (Doxorubicin), doxorubicin was administered intraperitoneally (IP; intraperitoneal) to mice once a week for 4 weeks (4 times in total) until the total cumulative drug dose reached 20 mg/kg. ) was used in the experiment 1 week after injection (5 weeks from the first dose of Doxorubicin). Negative control group (Control) administered 200 uL of 0.9% saline, Dox group administered 200 uL Dox solution at 5 mg/kg a total of 4 times, and 400 mg/kg daily from the first day of Doxorubicin administration to two days before dissection. Divided into the Korean thistle extract group, which was administered the extract orally, the Berberine 20 group, which was orally administered 20 mg/kg berberine chloride daily from the first day of doxorubicin administration to two days before dissection, and the Berberine 40 group, which was orally administered 40 mg/kg berberine chloride daily. 4 animals were used in each experimental group.
해부 전날 심전도 장비 (Heart Monitoring ECGenie, Mouse Specifics Inc.)를 활용하여 심전도를 측정하였으며, 해부 후 심장조직을 채취하여 4% formaldehyde 용액에 고정 후 조직분석을 수행하였다(n=4). 데이터는 4마리 마우스로 부터 얻은 평균 ± 표준오차로 표기되었으며, 그룹간 유의성은 students' t-test (GraphPad)로 계산되었다. #, p < 0.05 (vs. Cont.군); ###, p < 0.001 (vs. Cont.군); *, p < 0.05 (vs. Dox군); **, p < 0.01 (vs. Dox군); ***, p < 0.001 (vs. Dox군)The day before the dissection, the electrocardiogram was measured using an electrocardiogram device (Heart Monitoring ECGenie, Mouse Specifics Inc.). After the dissection, heart tissue was collected, fixed in 4% formaldehyde solution, and tissue analysis was performed (n=4). Data are expressed as mean ± standard error from four mice, and significance between groups was calculated using students' t-test (GraphPad). #, p < 0.05 (vs. Cont. group); ###, p < 0.001 (vs. Cont. group); *, p < 0.05 (vs. Dox group); **, p < 0.01 (vs. Dox group); ***, p < 0.001 (vs. Dox group)
시험예 9. 항암제로 인한 심근독성 마우스 모델의 분당 심장박동수, 신전도 측정 Test Example 9. Measurement of heart rate per minute and extensibility in mouse model of myocardial toxicity caused by anticancer drugs
도 9a는 Control군, Dox군, 고려엉겅퀴 추출물군, Berberine 20군 및 Berberine 40군의 분당 심장 박동수를 나타낸 그래프이며; 도 9b는 Control군, Dox군, 고려엉겅퀴 추출물군, Berberine 20군 및 Berberine 40군의 RR interval을 나타낸 그래프이고; 도 9c는 Control군, Dox군, 고려엉겅퀴 추출물군, Berberine 20군 및 Berberine 40군의 QT interval을 나타낸 그래프이며; 도 9d는 Control군, Dox군, 고려엉겅퀴 추출물군, Berberine 20군 및 Berberine 40군의 ST segment를 나타낸 그래프이다.Figure 9a is a graph showing the heart rate per minute of the Control group, Dox group, Korean thistle extract group, Berberine 20 group, and Berberine 40 group; Figure 9b is a graph showing the RR interval of the Control group, Dox group, Korean thistle extract group, Berberine 20 group, and Berberine 40 group; Figure 9c is a graph showing the QT interval of the Control group, Dox group, Korean thistle extract group, Berberine 20 group, and Berberine 40 group; Figure 9d is a graph showing the ST segment of the Control group, Dox group, Korean thistle extract group, Berberine 20 group, and Berberine 40 group.
도 9a 내지 도 9d에 도시된 바와 같이, Control군의 분당 심장 박동수는 약 760회 정도인 반면, Dox군의 분당 심장 박동수는 약 670회 정도로 낮아지며, 실시예 1의 고려엉겅퀴 추출물을 투여한 군은 약 760회의 심장박동수를 보여 berberine 40 군과 유사한 것을 확인하였다. As shown in Figures 9a to 9d, the heart rate per minute of the Control group is about 760 beats, while the heart rate per minute of the Dox group is lowered to about 670 beats, and the group administered the Korean thistle extract of Example 1 It was confirmed that the heart rate was about 760 beats, similar to the berberine 40 group.
심장박동의 저하는 심전도상 RR interval, QT interval, ST segment의 지연을 동반한다. 도 9b 내지 도 9d의 결과도 Dox군에서 증가된 3가지 요인들이 고려엉겅퀴 추출물의 투여로 Control 군, Berberine 20 군 및 Berberine 40군과 유사한 수준으로 회복되는 것을 확인하였다.A decrease in heart rate is accompanied by delays in the RR interval, QT interval, and ST segment on the electrocardiogram. The results of Figures 9b to 9d also confirmed that the three factors increased in the Dox group were restored to a similar level as the Control group, Berberine 20 group, and Berberine 40 group by administration of Korean thistle extract.
이러한 결과는 독소루비신(doxorubicin)에 의해 발생한 비정상적인 심장기능이 고려엉겅퀴 추출물의 투여로 완화될 수 있음을 의미한다.These results mean that abnormal cardiac function caused by doxorubicin can be alleviated by administration of Korean thistle extract.
시험예 10. 항암제로 인한 심근독성 마우스 모델의 심근독성 관련 혈액지표 및 간독성 지표 평가Test Example 10. Evaluation of blood indicators and hepatotoxicity indicators related to myocardial toxicity in mouse model of myocardial toxicity caused by anticancer drugs
해부전 안와 채혈을 통하여 혈액을 확보하였으며, serum을 분석에 사용하였다. 심근독성 지표인 CK(creatin kinase), LHD(lactate dehydrogenase) 및 간손상 지표인 AST(aspartate aminotransferase, GOT), ALT(alanine aminotransferase, GPT)를 측정하였다.Blood was obtained through orbital blood collection before dissection, and serum was used for analysis. The myocardial toxicity indicators, such as creatin kinase (CK) and LHD (lactate dehydrogenase), and the liver damage indicators, such as AST (aspartate aminotransferase, GOT) and ALT (alanine aminotransferase, GPT), were measured.
도 10a는 Control군, Dox군, 고려엉겅퀴 추출물군 및 Berberine 20군의 CK(creatin kinase)를 나타낸 그래프이며; 도 10b는 Control군, Dox군, 고려엉겅퀴 추출물군 및 Berberine 20군의 LHD(lactate dehydrogenase)를 나타낸 그래프이고; 도 10c는 Control군, Dox군, 고려엉겅퀴 추출물군 및 Berberine 20군의 AST(aspartate aminotransferase)를 나타낸 그래프이며; 도 10d는 Control군, Dox군, 고려엉겅퀴 추출물군 및 Berberine 20군의 ALT(alanine aminotransferase)를 나타낸 그래프이다. Figure 10a is a graph showing CK (creatin kinase) in the Control group, Dox group, Korean thistle extract group, and Berberine 20 group; Figure 10b is a graph showing LHD (lactate dehydrogenase) of the Control group, Dox group, Korean thistle extract group, and Berberine 20 group; Figure 10c is a graph showing AST (aspartate aminotransferase) in the Control group, Dox group, Korean thistle extract group, and Berberine 20 group; Figure 10d is a graph showing ALT (alanine aminotransferase) in the Control group, Dox group, Korean thistle extract group, and Berberine 20 group.
도 10a 내지 도 10d에 도시된 바와 같이, Doxorubicin의 독성에 의한 심장조직 손상에 따라 증가된 serum CK, LDH은 실시예 1의 고려엉겅퀴 추출물을 투여한 군에서 Control군 및 Berberine 20군 수준으로 감소하는 것을 확인하였다.As shown in Figures 10a to 10d, the increased serum CK and LDH due to cardiac tissue damage caused by the toxicity of doxorubicin decreased to the levels of the Control group and the Berberine 20 group in the group administered the Korean thistle extract of Example 1. confirmed.
시험예 11. 항암제로 인한 심근독성 마우스 모델의 심근조직 섬유화 측정Test Example 11. Measurement of myocardial tissue fibrosis in mouse model of myocardial toxicity caused by anticancer drugs
해부 후 심장조직을 채취하여 4% formaldehyde 용액에 고정 후 Massion's Trichrome staining을 통하여 심장조직의 섬유화 정도를 확인하였다. 섬유화된 심근세포는 파란색으로 염색되며, 항암제인 독소루비신(doxorubicin)의 누적 사용은 심근세포의 사멸과 섬유화를 유발하여 결과적으로 정상적인 심장 기능 수행이 불가능하다는 사실이 알려져 있다.After dissection, heart tissue was collected, fixed in 4% formaldehyde solution, and the degree of fibrosis of the heart tissue was confirmed through Massion's Trichrome staining. Fibrotic myocardial cells are stained blue, and it is known that cumulative use of the anticancer drug doxorubicin causes death and fibrosis of myocardial cells, ultimately making normal cardiac function impossible.
도 11은 Control군, Dox군, 고려엉겅퀴 추출물군의 심장조직의 섬유화 정도를 측정한 도면이다.Figure 11 is a diagram measuring the degree of fibrosis of heart tissue in the Control group, Dox group, and Korean thistle extract group.
도 11에 도시된 바와 같이, Doxorubicin이 투여된 Dox군은 심근세포에서 섬유화가 발생하였으며, Doxorubicin과 실시예 1의 고려엉겅퀴 추출물이 투여된 고려엉겅퀴 추출물 군은 심근세포에서는 섬유화 흔적이 발견되지 않은 것을 확인하였다. As shown in Figure 11, fibrosis occurred in the cardiomyocytes of the Dox group administered with doxorubicin, and no traces of fibrosis were found in the cardiomyocytes of the Korean thistle extract group administered with doxorubicin and the Korean thistle extract of Example 1. Confirmed.
이러한 결과는 고려엉겅퀴 추출물의 투여가 독소루비신(doxorubicin)으로 인해 유발되는 심근세포의 섬유화를 예방, 치료 또는 억제시킬 수 있음을 의미한다.These results mean that administration of Korean thistle extract can prevent, treat, or inhibit fibrosis of cardiomyocytes caused by doxorubicin.
시험예 12. 항암제로 인한 심근독성 마우스 모델의 심근세포 사멸 측정Test Example 12. Measurement of cardiomyocyte cell death in mouse model of myocardial toxicity caused by anticancer drugs
해부 후 심장조직을 채취하여 4% formaldehyde 용액에 고정 후 TUNEL staining을 통하여 심근세포의 사멸 정도를 확인하였다. 항암제인 독소루비신(doxorubicin)에 의하여 사멸한 심근세포의 핵은 갈색으로 염색되고, 정상 심근세포의 핵은 파란색으로 염색된다. 항암제인 독소루비신(doxorubicin)의 누적 사용은 심근세포의 사멸을 유도한다.After dissection, heart tissue was collected, fixed in 4% formaldehyde solution, and the degree of death of myocardial cells was confirmed through TUNEL staining. The nuclei of cardiomyocytes killed by the anticancer drug doxorubicin are stained brown, and the nuclei of normal cardiomyocytes are stained blue. Cumulative use of the anticancer drug doxorubicin induces the death of cardiomyocytes.
도 12는 Control군, Dox군, 고려엉겅퀴 추출물군의 심근세포 사멸화 정도를 측정한 도면이다.Figure 12 is a diagram measuring the degree of cardiomyocyte apoptosis in the Control group, Dox group, and Korean thistle extract group.
도 12에 도시된 바와 같이, Doxorubicin이 투여된 Dox군은 심근세포의 사멸이 발생한 것을 확인하였으며, Doxorubicin과 실시예 1의 고려엉겅퀴 추출물이 투여된 고려엉겅퀴 추출물군은 심근세포의 사멸 흔적이 발견되지 않은 것을 확인하였다.As shown in Figure 12, it was confirmed that death of cardiomyocytes occurred in the Dox group administered with doxorubicin, and in the Korean thistle extract group administered with doxorubicin and the Korean thistle extract of Example 1, no traces of death of cardiomyocytes were found. It was confirmed that it was not.
이러한 결과는 고려엉겅퀴 추출물의 투여가 독소루비신(doxorubicin)으로 인해 유발되는 심근세포의 사멸을 예방, 치료 또는 억제시킬 수 있음을 의미한다.These results mean that administration of Korean thistle extract can prevent, treat, or inhibit the death of cardiomyocytes caused by doxorubicin.
<시험예 Ⅲ><Test Example Ⅲ>
시험예 13. 고려엉겅퀴 추출물의 성분 분석Test Example 13. Component analysis of Korean thistle extract
본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물의 대사산물 프로파일을 조사하기 위해 20마이크로그램의 CBW를 초고성능 지질 크로마토그래피(UPLC) 시스템에 주입한 후 삼중 사중극자 질량 분석법(TQ/MS) 분석을 수행하고 24분에 걸쳐 전체 이온 크로마토그램을 획득하였다. To investigate the metabolite profile of the Korean thistle extract prepared according to Example 1 of the present invention, 20 micrograms of CBW was injected into an ultra-performance lipid chromatography (UPLC) system and then subjected to triple quadrupole mass spectrometry (TQ/MS). Analysis was performed and full ion chromatograms were acquired over 24 minutes.
위 표 1에 나타낸 바와 같이, 본 발명의 실시예 1에 따라 제조된 고려엉겅퀴 추출물은 클로로겐산(Chlorogenic acid)이 3125.46 μg/g으로 가장 높은 함량이 확인되었으며, 캠퍼롤(kaempferol 3-O-beta-rutinoside, Nicotiflorin)은 두 번째로 풍부한 물질인 것을 확인하였다.As shown in Table 1 above, the Korean thistle extract prepared according to Example 1 of the present invention had the highest chlorogenic acid content of 3125.46 μg/g, and kaempferol 3-O-beta- rutinoside, Nicotiflorin) was confirmed to be the second most abundant substance.
하기에 본 발명의 분말을 함유하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Below, a formulation example of a composition containing the powder of the present invention is described, but the present invention is not intended to be limited, but merely explained in detail.
제제예 1. 산제의 제조Formulation Example 1. Preparation of powder
실시예 1에서 얻은 추출물 분말 500 mg500 mg of extract powder obtained in Example 1
유당 100 mg100 mg lactose
탈크 10 mgTalc 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled into an airtight bubble to prepare a powder.
제제예 2. 정제의 제조Formulation Example 2. Preparation of tablets
실시예 1에서 얻은 추출물 분말 300 mg300 mg of extract powder obtained in Example 1
옥수수전분 100 mgCorn starch 100 mg
유당 100 mg100 mg lactose
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 manufactured by compressing them according to a typical tablet manufacturing method.
제제예 3. 캅셀제의 제조Formulation Example 3. Preparation of capsules
실시예 1에서 얻은 추출물 분말 200 mg200 mg of extract powder obtained in Example 1
결정성 셀룰로오스 3 mg3 mg crystalline cellulose
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 충전하여 캡슐제를 제조한다.Capsules are prepared by mixing the above ingredients and filling them into gelatin capsules according to a typical capsule manufacturing method.
제제예 4. 주사제의 제조Formulation Example 4. Preparation of injections
실시예 1에서 얻은 추출물 분말 600 mg600 mg of extract powder obtained in Example 1
만니톨 180 mgMannitol 180 mg
주사용 멸균 증류수 2974 mgSterile distilled water for injection 2974 mg
Na2HPO4,12H2O 26 mgNa 2 HPO 4, 12H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플 당 상기의 성분 함량으로 제조한다.It is prepared with the above ingredients per ampoule according to the usual manufacturing method for injections.
제제예 5. 액제의 제조Formulation Example 5. Preparation of liquid formulation
실시예 1에서 얻은 추출물 분말 4 g4 g of extract powder obtained in Example 1
이성화당 10 g10 g isomerized sugar
만니톨 5 g5 g mannitol
정제수 적량Proper amount of purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100g으로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.According to the usual liquid preparation method, add and dissolve each ingredient in purified water, add an appropriate amount of lemon flavor, mix the above ingredients, add purified water, adjust the total to 100g by adding purified water, and then fill in a brown bottle and sterilize. to produce a liquid.
제제예 6. 과립제의 제조Formulation Example 6. Preparation of granules
실시예 1에서 얻은 추출물 분말 1,000 mg1,000 mg of extract powder obtained in Example 1
비타민 혼합물 적량Vitamin mixture dosage
비타민 A 아세테이트 70 ㎍Vitamin A acetate 70 μg
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 ㎍Vitamin B12 0.2 ㎍
비타민 C 10 mgVitamin C 10 mg
비오틴 10 ㎍Biotin 10 μg
니코틴산아미드 1.7 mgNicotinamide 1.7 mg
엽산 50 ㎍Folic acid 50 μg
판토텐산 칼슘 0.5 mgCalcium pantothenate 0.5 mg
무기질 혼합물 적량Mineral mixture appropriate 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 mgMonobasic Potassium 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 과립제에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 과립제 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강기능식품 조성물 제조에 사용할 수 있다.The composition ratio of the above vitamin and mineral mixture is a mixture of ingredients relatively suitable for granules in a preferred embodiment, but the mixing ratio may be modified arbitrarily. The above ingredients are mixed according to a typical granule manufacturing method, and then the granules are mixed. It can be prepared and used to manufacture a health functional food composition according to a conventional method.
제제예 7. 기능성 음료의 제조Formulation Example 7. Preparation of functional beverage
실시예 1에서 얻은 추출물 분말 1,000 mg 1,000 mg of extract powder obtained in Example 1
구연산 1,000 mg1,000 mg citric acid
올리고당 100 g100 g oligosaccharides
매실농축액 2 g2 g plum concentrate
타우린 1 g1 g taurine
정제수를 가하여 전체 900 mLAdd purified water to make a total of 900 mL.
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1 시간 동안 85 ℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 L 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 기능성 음료 조성물 제조에 사용한다. After mixing the above ingredients according to a typical health drink manufacturing method, stirring and heating at 85°C for about 1 hour, the resulting solution was filtered, placed in a sterilized 2 L container, sealed, sterilized, stored in the refrigerator, and then refrigerated. Used for manufacturing the functional beverage composition of the invention.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 수요계층, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.The composition ratio is a preferred embodiment of mixing ingredients relatively suitable for beverages of preference, but the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as demand class, country of demand, and intended use.
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KR102213913B1 (en) | 2019-11-07 | 2021-02-09 | 인제대학교 산학협력단 | Pharmaceutical composition for preventing or treating myocardial damage comprising Spinochrome D |
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KR102213913B1 (en) | 2019-11-07 | 2021-02-09 | 인제대학교 산학협력단 | Pharmaceutical composition for preventing or treating myocardial damage comprising Spinochrome D |
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