KR20210155781A - A composition for preventing, alleviating or treating a sepsis or septic shock - Google Patents
A composition for preventing, alleviating or treating a sepsis or septic shock Download PDFInfo
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- KR20210155781A KR20210155781A KR1020210078082A KR20210078082A KR20210155781A KR 20210155781 A KR20210155781 A KR 20210155781A KR 1020210078082 A KR1020210078082 A KR 1020210078082A KR 20210078082 A KR20210078082 A KR 20210078082A KR 20210155781 A KR20210155781 A KR 20210155781A
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- sepsis
- interferon beta
- present
- septic shock
- sirt1
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Abstract
Description
본 발명은 패혈증 또는 패혈증성 쇼크의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, improving or treating sepsis or septic shock.
박테리아 감염 및 기타 강력한 자극은 전신적 염증 또는 전신적 염증성 반응 증후군 (Systemic Inflammatory Response Syndrome, SIRS)을 일으킬 수 있는 면역 반응을 개시한다. 심각한 SIRS는 다양한 중증도의 발열, 저독혈증(hypotoxemia), 트라킵니아 (trachypnea), 빈박, 내피 염증, 심근 기능부전, 과유합(過癒合), 정신 상태 이상, 혈관 허탈(虛脫) 및 궁극적으로는 기관 손상, 예컨대 급성 호흡 곤란 증후군, 응고장애, 심부전, 신부전, 쇼크 및/또는 혼수를 수반하는 다기관 기능부전 증후군 (multiple organ failure syndrome, MODS)을 일으킨다.Bacterial infection and other strong stimuli initiate an immune response that can lead to systemic inflammation or Systemic Inflammatory Response Syndrome (SIRS). Severe SIRS includes fever of varying severity, hypotoxemia, trachypnea, tachycardia, endothelial inflammation, myocardial insufficiency, hyperunion, mental status abnormalities, vascular collapse and ultimately It causes multiple organ failure syndrome (MODS) with organ damage such as acute respiratory distress syndrome, coagulopathy, heart failure, renal failure, shock and/or coma.
패혈증은 전신 염증반응과 더불어 감염이 확인되거나 의심되는 상황으로 정의된다. 중증 패혈증(severe sepsis)은 패혈증에서 장기기능부전(organ dysfunction: 저혈압, 저산소증, 핍뇨증, 대사성산증, 혈소판 감소증, 의식장애)이 동반되는 경우로 정의된다. 패혈증성 쇼크(septic shock)는 중증 패혈증에서 수액요법이나 혈압상승제를 투여하여도 혈압이 정상화되지 않는 경우로 정의한다. 패혈증은 중증 패혈증 및 궁극적으로는 패혈증성 쇼크의 임상적 단계로 진행될 수 있다. 임상적 패혈증은 넓은 의미에서 미생물성 작용제에 의한 침윤이 감염의 임상적 증상과 관련이 있는 상태로 정의된다. 패혈증의 임상적 증상으로는 (1) 체온 > 38℃ 또는 < 36℃; (2) 심박수 > 1분 당 90회; (3) 호흡수 > 1분 당 20회 또는 PaC02 < 32 mmHg; (4) 백혈구 수 > 12000/cu mm, < 4,000/cu mm 또는 > 10% 비성숙 (밴드) 형태; (5) 기관기능부전, 과유합, 또는 고혈압 등이 있을 수 있다.Sepsis is defined as a situation in which an infection is confirmed or suspected along with a systemic inflammatory response. Severe sepsis is defined as a case of sepsis accompanied by organ dysfunction (hypotension, hypoxia, oliguria, metabolic acidosis, thrombocytopenia, and impaired consciousness). Septic shock is defined as a case in which blood pressure is not normalized in severe sepsis despite the administration of fluid therapy or antihypertensive agents. Sepsis can progress to the clinical stage of severe sepsis and ultimately septic shock. Clinical sepsis is broadly defined as a condition in which infiltration by microbial agents is associated with clinical symptoms of infection. Clinical symptoms of sepsis include (1) body temperature >38°C or <36°C; (2) heart rate > 90 beats per minute; (3) respiratory rate > 20 breaths per minute or PaC0 2 < 32 mmHg; (4) leukocyte count > 12000/cu mm, < 4,000/cu mm or > 10% immature (band) morphology; (5) There may be organ dysfunction, hyperunion, or hypertension.
감염이 발생하면, 감염 부위의 대식세포가 활성화되어 TNF-α 및 IL6를 분비함으로써, 조직으로의 혈장 단백질 방출량이 증가되고, 조직으로의 식세포와 림프구의 이동 증가 및 혈관벽에 대한 혈소판의 부착 증가를 초래한다. 이러한 방식으로, 국소 혈관이 폐색되고 병원체가 감염 부위에 집중된다. 특히, 패혈증은 전신성 감염이 일어나며 TNF-α에 의해 유도된 심각한 혈관 폐색이 수반된다. 또한 TNF-α의 전신적 방출은 혈관확장 및 혈관의 투과성 증가로 인한 혈장 체적의 손실을 초래하여 쇼크를 야기한다. 패혈증성 쇼크에서, TNF-α는 파종성 혈관 내 응고(혈액 응고)를 더욱 촉발하여 작은 혈관에서의 혈병 생성 및 혈액 응고 단백질들의 대량 소모를 초래한다. 환자의 혈액 응고 능력이 상실되기 때문에, 예컨대 신장, 간, 심장 및 폐 등과 같은 중요한 기관들이 정상적인 관류의 부전으로 인해 손상된다. 중증 패혈증과 패혈증성 쇼크의 사망률은 각각 25~30%, 40~70%에 달하는 것으로 보고되어 있다.When infection occurs, macrophages at the site of infection are activated and secrete TNF-α and IL6 to increase plasma protein release into tissues, increase migration of phagocytes and lymphocytes into tissues, and increase adhesion of platelets to blood vessel walls. cause In this way, local blood vessels are occluded and pathogens are concentrated at the site of infection. In particular, sepsis results in systemic infection and is accompanied by severe vascular occlusion induced by TNF-α. In addition, systemic release of TNF-α results in loss of plasma volume due to vasodilation and increased vascular permeability, resulting in shock. In septic shock, TNF-α further triggers disseminated intravascular coagulation (blood coagulation), resulting in clot formation in small blood vessels and massive depletion of blood clotting proteins. Because the patient's ability to clot is lost, vital organs such as the kidneys, liver, heart and lungs are damaged due to the failure of normal perfusion. The mortality rates of severe sepsis and septic shock have been reported to reach 25-30% and 40-70%, respectively.
여러 경우의 패혈증에서는 대장균(E. coli)이 병원체이지만, 예를 들어 클렙시엘라 (Klebsiella), 엔테로박터(Enterobacter), 세라티아(Serratia) 및 슈도모나스 (Pseudomonas) 와 같은 다른 그람-음성 박테리아도 이러한 상태를 개시할 수 있다. 포도상구균(Staphlococcus) 등의 그람-양성 미생물, 전신적 바이러스 및 진균 감염도 일부 경우에서 패혈증을 개시한다.In many cases of sepsis, but Escherichia coli (E. coli) is a pathogen, for example, when keulrep Ella (Klebsiella), Enterobacter (Enterobacter), Serratia other Gram-like (Serratia) and Pseudomonas (Pseudomonas) - negative bacteria such state can be initiated. Gram-positive microorganisms such as Staphlococcus , systemic viral and fungal infections also initiate sepsis in some cases.
비뇨 생식관, 위장관 및 기도가 패혈증을 초래하는 가장 통상적인 감염 부위이다. 기타의 패혈증-관련 감염 부위로는 창상, 화상 및 골반 감염 부위 및 정맥 내 카테터 감염 부위 등이 있다.The urogenital tract, gastrointestinal tract and airways are the most common sites of infection that result in sepsis. Other sepsis-related sites of infection include wounds, burns, and pelvic infection sites and intravenous catheter infections.
패혈증은 감염 원인균과 숙주의 면역, 염증 그리고 응고계통 사이의 복잡한 상호작용의 결과로 발생하는 것으로 이해되고 있다. 숙주의 반응 정도와 감염 원인균의 특성 모두 패혈증의 예후에 중대한 영향을 미친다. 패혈증에서 관찰되는 장기부전은 숙주의 감염 원인균에 반응이 부적절한 경우에 발생하며, 만일 숙주의 감염 원인균에 대한 반응이 지나치게 증폭된다면 숙주 자체의 장기손상을 유발할 수 있다. 이러한 개념을 바탕으로 숙주의 염증 반응에 주도적인 역할을 수행하는 전 염증성 사이토카인(proinflammatory cytokines)인 TNF-α, IL1β IL6 등에 대한 길항 물질이 패혈증의 치료제로 시도되었으나 대부분 실패하였으며, 기계환기치료, 활성 단백질 C(activated protein C) 투여, 글루코코르티코이드 치료 등이 현재 시도되고 있으나 여러 가지 한계점이 지적되고 있다. 따라서, 높은 사망률을 보임에도 아직까지 뚜렷한 치료제가 개발되지 않은 패혈증 및 패혈증성 쇼크를 예방, 개선 또는 치료하기 위한 새로운 치료제에 대한 필요성이 요구되고 있다.Sepsis is understood to occur as a result of complex interactions between the pathogen and the host's immune, inflammatory, and coagulation systems. Both the degree of host response and the characteristics of the causative organism have a significant influence on the prognosis of sepsis. Organ failure observed in sepsis occurs when the host's response to the causative organism is inadequate, and if the host's response to the causative organism is excessively amplified, it can cause organ damage to the host itself. Based on this concept, antagonists to TNF-α, IL1β and IL6, which are proinflammatory cytokines that play a leading role in the inflammatory response of the host, have been tried as therapeutic agents for sepsis, but most have failed. Although active protein C (activated protein C) administration and glucocorticoid treatment are currently being tried, several limitations have been pointed out. Therefore, there is a need for a new therapeutic agent for preventing, improving, or treating sepsis and septic shock for which a distinct therapeutic agent has not yet been developed despite showing a high mortality rate.
본 발명의 일 목적은 패혈증 또는 패혈증성 쇼크의 예방, 개선 또는 치료용 조성물을 제공하는 것이다.One object of the present invention is to provide a composition for preventing, improving or treating sepsis or septic shock.
그러나, 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당 업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those of ordinary skill in the art from the following description.
본 발명의 일 구현 예에는 인터페론 베타; 및 하기 화학식 1로 표시되는 화합물로 이루어진 군으로부터 선택되는 적어도 하나를 유효성분으로 포함하는 패혈증 또는 패혈증성 쇼크의 예방, 개선, 또는 치료용 조성물에 관한 것이다:In one embodiment of the present invention, interferon beta; And it relates to a composition for preventing, improving, or treating sepsis or septic shock comprising at least one selected from the group consisting of compounds represented by the following formula (1) as an active ingredient:
[화학식 1][Formula 1]
본 발명의 다른 구현 예에는 인터페론 베타; 및 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 패혈증 또는 패혈증성 쇼크의 예방, 개선 또는 치료용 조성물에 관한 것이다.Another embodiment of the present invention includes interferon beta; And it relates to a composition for preventing, improving or treating sepsis or septic shock comprising the compound represented by Formula 1 as an active ingredient.
본 발명의 상기 인터페론 베타는 인터페론의 두 가지 아이소폼인 인터페론 베타 1a(IFN-β1a) 또는 인터페론 베타 1b(IFN-β1b)를 포함하는 것일 수 있다. 인터페론 베타 1a는 인간 인터페론 베타 유전자를 포함하는 중국 햄스터 난소(chinese hamster ovary, CHO)로부터 생산되고, 166개 아미노산 잔기로 구성되어 있으며, 크기가 25 kD인 당화된(glycosylated) 단백질이고, 인터페론 베타 1b는 대장균으로부터 생산되는 165개의 아미노산 잔기로 구성된 단백질로서, 당이 결여되어 있고, 아미노산 1번 메티오닌(methionine) 잔기가 결여되어 있으며, 17번 시스테인(cysteine) 잔기가 세린(serine)으로 치환되어 있다.The interferon beta of the present invention may include two isoforms of interferon, interferon beta 1a (IFN-β1a) or interferon beta 1b (IFN-β1b). Interferon beta 1a is a glycosylated protein produced from Chinese hamster ovary (CHO) containing the human interferon beta gene, consisting of 166 amino acid residues, and having a size of 25 kD, interferon beta 1b is a protein composed of 165 amino acid residues produced from E. coli, which lacks a sugar, lacks an amino acid 1 methionine residue, and has a cysteine residue 17 substituted with serine.
본 발명의 목적상 상기 인터페론 베타는 인터페론 베타 1a 또는 1b일 수 있으나, 이에 제한되는 것은 아니다.For the purposes of the present invention, the interferon beta may be interferon beta 1a or 1b, but is not limited thereto.
본 발명의 상기 화학식 1로 표시되는 화합물은 3-카르바모일-1-[(2R,3R,4S,5R)-3,4-디히드록시-5-(히드록시메틸)옥소란-2-일]피리딘-1-이움(3-Carbamoyl-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyridin-1-ium)이다.The compound represented by Formula 1 of the present invention is 3-carbamoyl-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2- yl]pyridin-1-ium (3-Carbamoyl-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyridin-1-ium).
본 발명의 상기 인터페론 베타; 및 상기 화학식 1로 표시되는 화합물은 SIRT1(silent mating type information regulation 2 homolog; sirtuin 1)의 발현을 유도할 수 있다.The interferon beta of the present invention; And the compound represented by Formula 1 may induce the expression of SIRT1 (silent mating
본 발명의 상기 SIRT1은 NAD+ 의존적 탈아세틸효소로서 여러 단백질의 리신 잔기를 탈아세틸화하여 단백질의 기능을 조절하는 효소로 알려져 있으며(Ageing Res, Vol.1 페이지 313-326, (2002)), NAD+ 의존적 class ² 히스톤 탈아세틸 활성을 가진 효모의 Sir2와 가장 유사하다. 특히, Nuclear factor-kB, p53등의 전사인자에 붙어 있는 아세틸기를 잘라내어 이들의 기능을 조절한다(Cancer Res, Vol.64 페이지 7513-7525, (2004); Cell, Vol.107, 페이지 149-159, (2001); Trends Endocrinol Metab, Vol.17 페이지 186-191, (2006)). 또한, SIRT1은 유전자 발현억제와 관련이 있는 크로마틴 재구성, DNA 손상 반응, 식이 제한에 동반된 수명연장 등에 관여한다(Chen et al., Science 310, 1641, 2005). 즉, SIRT1은 효모의 Sir2처럼 히스톤 탈아세틸화를 통해 크로마틴을 재구성하고 유전자의 발현을 억제하며, 히스톤 단백질 외에도 세포성장, 스트레스 반응, 내분비조절 등에 관련된 다양한 전사인자의 탈아세틸화를 유도한다. 이와 같은 SIRT1의 발현이 증가되는 경우에는 염증성 사이토카인의 발현 수준이 감소되고, 염증을 억제할 수 있는 사이토카인의 발현 수준이 증가되어 패혈증 또는 패혈증성 쇼크를 매우 효과적으로 치료할 수 있다. 본 발명의 목적상, 상기 인터페론 베타 및 상기 화학식 1로 표시되는 화합물은 각각 투여되었을 때 SIRT1의 발현을 증가시키고, 나아가 병용 투여하였을 때에는 SIRT1의 발현을 각각 단독으로 투여한 경우와 비교하여 높이 증가시켜 패혈증 또는 패혈증성 쇼크의 치료에 현저한 시너지 효과가 발휘되도록 수 있다.The SIRT1 of the present invention is a NAD+-dependent deacetylase and is known as an enzyme that deacetylates lysine residues of various proteins to regulate the function of proteins (Ageing Res, Vol.1 pages 313-326, (2002)), NAD+ It is most similar to Sir2 in yeast with
본 발명의 상기 패혈증은 병원성 그람 음성 세균이 생체에 감염된 경우, 세포벽 성분인 리포폴리사카라이드(lipopolysaccharide, LPS)가 독소로 작용하여 생체의 면역체계가 비정상적으로 활성화되어 유발되는 염증반응으로, 전신에 감염증을 일으키거나 증상이 심할 경우 쇼크를 동반하기도 한다.The sepsis of the present invention is an inflammatory reaction caused by abnormal activation of the immune system of the living body by lipopolysaccharide (LPS), a cell wall component, acting as a toxin when pathogenic Gram-negative bacteria are infected in the living body. It may cause an infection or, if the symptoms are severe, may be accompanied by shock.
본 발명의 상기 패혈증성 쇼크는 저혈압과 관류 이상을 수반한 패혈증으로서, 패혈증으로 인한 생명 위협적인 저혈압과 기관 부전이 발생되므로, 그 원인이 되는 패혈증을 치료하는 경우에는 패혈증성 쇼크 역시 예방, 개선 또는 치료할 수 있다.The septic shock of the present invention is sepsis accompanied by hypotension and perfusion abnormality, and since life-threatening hypotension and organ failure due to sepsis occur, septic shock is also prevented, improved, or can be treated
본 발명의 상기 조성물은 약학 조성물 또는 식품 조성물로 사용될 수 있다.The composition of the present invention may be used as a pharmaceutical composition or a food composition.
본 발명의 상기 "예방"은 본 발명의 상기 조성물을 이용하여 패혈증 또는 패혈증성 쇼크에 의해 기인된 증상을 차단하거나, 그 증상을 억제 또는 지연시킬 수 있는 모든 행위라면 제한없이 포함될 수 있다.The "prevention" of the present invention may be included without limitation, as long as it is any action capable of blocking or suppressing or delaying symptoms caused by sepsis or septic shock using the composition of the present invention.
본 발명의 상기 "치료"는 본 발명의 상기 조성물을 이용하여 패혈증 또는 패혈증성 쇼크에 의해 기인된 증상이 호전될 수 있도록 하거나, 이롭게 될 수 있도록 하는 모든 행위라면 제한없이 포함될 수 있다.The "treatment" of the present invention may be included without limitation, as long as it is any action that allows the symptoms caused by sepsis or septic shock to be improved or to be beneficial by using the composition of the present invention.
본 발명의 상기 "개선"은 본 발명의 상기 조성물을 이용하여 패혈증 또는 패혈증성 쇼크에 의해 기인된 증상이 호전 또는 이롭게 변경되는 모든 행위라면 제한없이 포함될 수 있다.The "improvement" of the present invention may be included without limitation as long as the symptoms caused by sepsis or septic shock are improved or beneficially changed using the composition of the present invention.
본 발명의 상기 약학 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사 용액의 형태로 제형화되어 사용될 수 있다. 바람직하게 상기 약학 조성물은 기관 내 투여 또는 흡입 투여용; 또는 주사제로 사용될 수 있도록 제형화될 수 있으나, 이에 제한되는 것은 아니다. 본 발명의 목적상 유효성분이 목적하는 기관에 예방 또는 치료에 적합한 수율로 도달될 수 있도록 흡입 투여용 등으로 제형화될 수 있으나, 이에 제한되는 것은 아니다.The pharmaceutical composition of the present invention is not limited thereto, but each is formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods to be used. can Preferably, the pharmaceutical composition is for intratracheal administration or inhalation administration; Or it may be formulated to be used as an injection, but is not limited thereto. For the purpose of the present invention, the active ingredient may be formulated for inhalation administration, etc. so that it can reach a target organ in a yield suitable for prevention or treatment, but is not limited thereto.
본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 상기 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등이 사용될 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등이 혼합되어 사용될 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등이 사용될 수 있다. 본 발명의 약학 조성물의 제형은 상술한 바와 같은 약학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(Elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화할 수 있다.The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a dye, a flavoring agent, etc., in the case of oral administration, and in the case of an injection, a buffer, a preservative, An analgesic agent, a solubilizer, an isotonic agent, a stabilizer, etc. may be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. may be used. The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, in the case of oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injection, it can be prepared in the form of unit dosage ampoules or multiple dosage forms have. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
본 발명의 상기 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항 응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Examples of carriers, excipients and diluents suitable for the formulation of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate , cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used. In addition, fillers, anti-agglomeration agents, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives and the like may be further included.
본 발명의 상기 약학 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투여될 수 있고, 바람직하게는 경구투여될 수 있으나, 이에 제한되는 것은 아니다.The route of administration of the pharmaceutical composition of the present invention is, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal. It may be administered orally or parenterally, and preferably may be administered orally, but is not limited thereto.
본 발명의 상기 비경구는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.The parenteral of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
본 발명의 상기 약학 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여 시간, 투여 경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약무 형태, 투여 경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50 mg/kg 또는 0.001 내지 50 mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형화될 수 있다.The pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. It can be variously changed, and the dosage of the pharmaceutical composition varies depending on the patient's condition, body weight, degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg/day per day kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
본 발명의 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 포함하는 것 외에 특별한 제한점은 없으며, 통상의 음료와 같이 다양한 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 구체적으로, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어, 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등) 등일 수 있다.When the food composition of the present invention is prepared in the form of a beverage, there is no particular limitation except for including the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients, like a conventional beverage. . Specifically, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, and polysaccharides such as sucrose, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol are used as natural carbohydrates. may include The flavoring agent may be a natural flavoring agent (taumatine, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agent (saccharin, aspartame, etc.).
본 발명의 상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등이 더 포함될 수 있다.The food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, A pH adjuster, a stabilizer, a preservative, glycerin, alcohol, a carbonation agent used in carbonated beverages, and the like may be further included.
본 발명의 상기 식품 조성물에 포함되는 성분들은 독립적으로 또는 조합하여 사용될 수 있다. 상기 첨가제의 비율은 본 발명의 핵심적인 요소에 해당하지 아니하지만, 본 발명의 식품 조성물 100 중량부 당 0.1 내지 약 50 중량부의 범위에서 선택될 수 있으나, 이에 제한되는 것은 아니다.The ingredients included in the food composition of the present invention may be used independently or in combination. The proportion of the additive is not a key element of the present invention, but may be selected from 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.
본 발명의 상기 화장료 조성물은 화장수, 영양로션, 영양에센스, 마사지 크림, 미용목욕물첨가제, 바디로션, 바디밀크, 배스오일, 베이비오일, 베이비파우더, 샤워겔, 샤워크림, 선스크린로션, 선스크린크림, 선탠크림, 스킨로션, 스킨크림, 자외선차단용 화장품, 클렌징밀크, 탈모제화장용, 페이스 및 바디로션, 페이스 및 바디크림, 피부미백크림, 핸드로션, 헤어로션, 화장용 크림, 쟈스민오일, 목욕비누, 물비누, 미용비누, 샴푸, 손세정제(핸드클리너), 약용비누비의료용, 크림비누, 페이셜 워시, 전신 세정제, 두피 세정제, 헤어린스, 화장비누, 치아 미백용 겔, 치약 등의 형태로 제조될 수 있다. 본 발명의 조성물은 화장료 조성물의 제조에 통상적으로 사용하는 용매나, 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다.The cosmetic composition of the present invention is a lotion, nutritional lotion, nutritional essence, massage cream, cosmetic bath water additive, body lotion, body milk, bath oil, baby oil, baby powder, shower gel, shower cream, sunscreen lotion, sunscreen cream , suntan cream, skin lotion, skin cream, sunscreen cosmetics, cleansing milk, depilatory makeup, face and body lotion, face and body cream, skin whitening cream, hand lotion, hair lotion, cosmetic cream, jasmine oil, bath Manufactured in the form of soap, water soap, beauty soap, shampoo, hand sanitizer (hand cleaner), medicated soap, medical, cream soap, facial wash, whole body cleaner, scalp cleaner, hair rinse, cosmetic soap, tooth whitening gel, toothpaste, etc. can be The composition of the present invention may further include a solvent or a suitable carrier, excipient or diluent commonly used in the preparation of cosmetic compositions.
본 발명은 패혈증 또는 패혈증성 쇼크의 예방, 개선 또는 치료용 조성물에 관한 것으로서, 본 발명의 화합물은 인터페론 베타와 병용하여 투여되었을 때, 패혈증 또는 패혈증성 쇼크의 치료에 현저한 시너지 효과를 발휘할 수 있다.The present invention relates to a composition for preventing, ameliorating or treating sepsis or septic shock, and when the compound of the present invention is administered in combination with interferon beta, it can exert a remarkable synergistic effect in the treatment of sepsis or septic shock.
도 1은 본 발명의 일 실시예에 따른 혈관내피세포 특이 SIRT1 결실마우스의 제조과정 및 혈관내피세포에서의 SIRT1 발현억제를 확인한 것을 나타낸 것이다. 구체적으로, PCR을 통한 Floxed SIRT1 유전자와 Tek 프로모터 하위 위치에 Cre 리콤비나제(recombinase) (Tek-Cre)를 지니는 마우스의 탐색(A), Tek-Cre 유전자와 두 allele 모두 Floxed SIRT1 유전자를 지닌 마우스 혈관내피세포에서의 SIRT1발현이 소실되어 있음을 확인(B)한 것이다. 여기서, WT; 정상마우스 (wild type) 및 KO; SIRT1 유전자 결실 마우스 (knockout)를 의미한다.
도 2는 본 발명의 일 실시예에 따른 세포내 NAD 농도를 증가시키는 것으로 알려진 니코틴아미드(nicotinamide), NMN(nicotinamide mononucleotide). NR(nicotinamide riboside)의 구조와 이들을 인터페론 베타와 병용투여 시 패혈증 유발 마우스의 생존율에 미치는 효과를 나타낸 것이다. 구체적으로, 상기 NAD 농도를 증가시키는 화합물의 구조를 나타낸 것이고, 인터페론 베타와 각각의 니코틴아미드(B), NMN(C) 또는 NR(D)를 병용하여 투여한 뒤 패혈증 마우스의 생존율 변화를 나타낸 것이다.
도 3은 본 발명의 일 실시예에 따른 난황낭 내피세포(Mouse Yolk Sac Endothelial Cells, MYSECs)에 인터페론 베타(IFN-β)를 24시간동안 0 내지 1000 U/ml까지 농도별로 처리한 것(A)과 1000 U/ml로 시간별로 처리한 것 (B)를 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른 대식세포 또는 혈관내피세포 특이 SIRT1 유전자 결실 마우스에서 인터페론 베타와 NR의 병용 투여에 따른 패혈증 마우스의 생존율 변화를 측정한 것을 나타낸 것이다.
도 5는 본 발명의 일 실시예에 따른 인터페론 베타 및 NR의 병용 투여에 의한 패혈증 마우스에서의 염증성 사이토카인의 분비량에 미치는 영향을 ELISA 방식을 통해 혈중 내 TNF-α 및 IL6 농도를 측정한 결과를 나타낸 것이다.
도 6는 인터페론 베타 및 NR의 투여에 의한 패혈증 마우스에서의 장기손상에 미치는 영향을 인터페론 베타 또는 NR을 처리한 패혈증 마우스의 적출된 장기의 조직 절편을 헤마톡시린-에오신 염색을 통해 확인한 결과를 나타낸 것이다.1 shows the manufacturing process of a vascular endothelial cell-specific SIRT1 deletion mouse according to an embodiment of the present invention and confirming the inhibition of SIRT1 expression in vascular endothelial cells. Specifically, detection of mice carrying Cre recombinase (Tek-Cre) at the Floxed SIRT1 gene and Tek promoter sub-position by PCR (A), Tek-Cre gene and both alleles. Mice carrying the Floxed SIRT1 gene It was confirmed that SIRT1 expression in vascular endothelial cells was lost (B). where WT; normal mice (wild type) and KO; SIRT1 gene deletion mice (knockout).
Figure 2 is nicotinamide (nicotinamide), NMN (nicotinamide mononucleotide) known to increase the intracellular NAD concentration according to an embodiment of the present invention. This study shows the structure of NR (nicotinamide riboside) and its effect on the survival rate of sepsis-induced mice when co-administered with interferon beta. Specifically, it shows the structure of the compound that increases the NAD concentration, and shows the change in survival rate of sepsis mice after administration of interferon beta and each of nicotinamide (B), NMN (C) or NR (D) in combination. .
3 is a process of interferon beta (IFN-β) to yolk sac endothelial cells (MYSECs) according to an embodiment of the present invention at different concentrations from 0 to 1000 U/ml for 24 hours (A) and 1000 U/ml treated by time (B) are shown.
Figure 4 shows the measurement of the change in the survival rate of sepsis mice according to the co-administration of interferon beta and NR in macrophage or endothelial cell-specific SIRT1 gene deletion mice according to an embodiment of the present invention.
Figure 5 is the effect of the combined administration of interferon beta and NR according to an embodiment of the present invention on the secretion amount of inflammatory cytokines in sepsis mice through the ELISA method the results of measuring the concentration of TNF-α and IL6 in the blood it has been shown
6 shows the effect of the administration of interferon beta and NR on organ damage in sepsis mice through hematoxylin-eosin staining of tissue sections of sepsis mice treated with interferon beta or NR. will be.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example
실험 방법experimental method
[실험 방법 1] [Test Method 1] 실험 동물laboratory animal
몸무게가 20 내지 24 g이고, 7-8 주령인 수컷 C57BL/6 마우스를 나라바이오텍(서울, 한국)에서 구입하였다. SIRT1 loxP/loxP 마우스(B6.129-SirtatmqYgu/J)와 Tek-Cre 마우스(B6.Cg-Tg(Tek-cre)1Ywa/J)는 Jackson Laboratory (미국, Maine주)에서 구입하였다. 20-24 ℃의 항온조건에서 12시간은 조명하고, 12시간은 빛을 차단하였으며, 사료는 일반사료로 자유식이하는 조건에서 마우스를 사육하였다. 본 실험은 전북대학교 동물실험윤리위원회의 준칙에 의거하여 실험하였다.Male C57BL/6 mice weighing 20 to 24 g and aged 7-8 weeks were purchased from Nara Biotech (Seoul, Korea). SIRT1 loxP/loxP mice (B6.129-SirtatmqYgu/J) and Tek-Cre mice (B6.Cg-Tg(Tek-cre)1Ywa/J) were purchased from Jackson Laboratory (Main, USA). In a constant temperature condition of 20-24 ℃, the light was illuminated for 12 hours and the light was blocked for 12 hours. This experiment was conducted in accordance with the rules of the Animal Experimentation Ethics Committee of Chonbuk National University.
[실험 방법 2] [Experimental method 2] 패혈증 동물 모델sepsis animal model
맹장 결찰 및 천공(cecal ligation and puncture, CLP) 방식에 의해 패혈증을 유도하였다. 마우스를 ketamine 500 ㎕, rompun 120 ㎕, 인산 완충 식염수(phosphate buffered saline, PBS) 500 ㎕로 마취시키고 복강 정중부를 절개한 후 맹장을 외부로 노출시켜 회맹장판(ileocecal valve)의 말단을 6.0-실크 봉합선 (silk suture)으로 결찰하고, 18 게이지 니들을 사용하여 1회 천자한 후 1-2 mm의 배설물 방울을 짜내어 복막 강으로 되돌리고, 개복 부위는 4.0-실크로 봉합하였다. 여기서, 맹장은 노출시켰으나 결찰 또는 천자를 행하지 않은 채 복강으로 되돌린 동물군을 sham 대조군 동물 모델로 사용하였다.Sepsis was induced by cecal ligation and puncture (CLP) method. The mouse was anesthetized with 500 μl of ketamine, 120 μl of rompun, and 500 μl of phosphate buffered saline (PBS), and the mid-peritoneal incision was made and the cecum was exposed to the outside, and the end of the ileocecal valve was closed with 6.0-silk suture. It was ligated with a silk suture, punctured once using an 18 gauge needle, and 1-2 mm of fecal droplets were squeezed out and returned to the peritoneal cavity, and the laparotomy was sutured with 4.0-silk. Here, a group of animals in which the cecum was exposed but returned to the abdominal cavity without ligation or puncture was used as a sham control animal model.
[실험 방법 3] [Experimental method 3] 약물 투여drug injection
대조군의 경우, 상기 실험 방법 2에서와 같이 CLP를 실시한 후 6시간 및 18시간에 두 번 마우스 복강 내로 PBS를 주사하였다. 한편, 실험군의 경우, CLP를 실시한 후 6시간 및 18시간에, 0.4 ㎍의 인터페론 베타(IFN-β, 미국 Bio-Techne) 와 9.4 μmole의 니코틴아미드(nicotinamide), NMN(nicotinamide mononucleotide, 미국 SigmaAldrich) 또는 NR(nicotinamide riboside, 미국 SigmaAldrich)를 PBS에 녹여 마우스 복강 내로 주사하였다.For the control group, PBS was injected intraperitoneally twice at 6 hours and 18 hours after CLP as in
[실험 방법 4] [Test Method 4] 대식세포 및 혈관내피세포 특이 SIRT1 유전자 결실 마우스 모델 제조Preparation of macrophage and vascular endothelial cell-specific SIRT1 gene deletion mouse model
Hah등이 보고한 방식 (PLOS one, 9(2), e87733, 2014)에 의해 대식세포 특이 SIRT1 유전자 결실 마우스를 제조하였다. 혈관내피세포 특이 SIRT1 유전자 결실 마우스를 얻기 위하여 SIRT1 loxP/loxP 마우스 (B6.129-SirtatmqYgu/J)와 Tek-Cre 마우스 (B6.Cg-Tg(Tek-cre)1Ywa/J)를 교배하였다. 지노타이핑(Genotyping)에 사용한 프라이머는 하기 표 1과 같다. 여기서, 대조군 마우스는 SIRT1 loxP/loxP 마우스를 사용하였다.Macrophage-specific SIRT1 gene deletion mice were prepared by the method reported by Hah et al. (PLOS one, 9(2), e87733, 2014). To obtain endothelial cell-specific SIRT1 gene deletion mice, SIRT1 loxP/loxP mice (B6.129-SirtatmqYgu/J) and Tek-Cre mice (B6.Cg-Tg(Tek-cre)1Ywa/J) were crossed. Primers used for genotyping are shown in Table 1 below. Here, SIRT1 loxP/loxP mice were used as control mice.
도 1의 (A) 및 (B)에서 보는 바와 같이, 혈관내피세포 특이 SIRT1 결실 마우스 제작 결과, 정상(WT)에서는 SIRT1이 발현되지만 결실시킨 마우스(K/O)에서는 SIRT1이 발현되지 않음을 확인할 수 있었다.As shown in (A) and (B) of Figure 1, as a result of preparing vascular endothelial cell-specific SIRT1-deleted mice, it was confirmed that SIRT1 was expressed in normal (WT) but SIRT1 was not expressed in deleted mice (K/O). could
[실험 방법 5] [Test Method 5] 폐에서 혈관 내피세포의 분리Isolation of vascular endothelial cells from lungs
마우스의 폐를 가위로 잘게 절단한 후 3 mg/ml의 콜라게나제 Ⅱ (미국 Sigma)를 첨가하고, 37℃에서 45분간 반응시키고, 15분마다 반응이 잘 이뤄질 수 있도록 흔들어 주었다. 반응액을 21 게이지에 8회 통과시켜 단일세포 부유액으로 연화시키고, 40 μm의 나일론 메쉬(Nylon mesh)로 걸러 낸 후 혈청을 첨가하여 반응을 정지시켰다. 세포를 300 xg로 10 분간 원심분리시켜 CD31 microbeads (독일 Miltenyi Biotec) 10 ㎕와 0.5% BSA가 첨가된 autoMACS Rinsing Solution (독일 Miltenyi Biotec) 90 ㎕로 재부유시키고 4℃에서 15분간 반응시켰다. 반응액을 4℃에서 300 xg로 10 분간 원심분리시켜 세포를 수집한 후 MACS buffer (독일 Miltenyi Biotec) 3 ml로 부유시키고 LS column (독일 Miltenyi Biotec)을 이용하여 CD31을 발현하는 혈관내피세포를 분리하였다.After the mouse's lungs were chopped with scissors, 3 mg/ml of collagenase II (Sigma, USA) was added, reacted at 37° C. for 45 minutes, and shaken every 15 minutes to ensure that the reaction was well achieved. The reaction solution was passed through a 21 gauge 8 times to soften it into a single cell suspension, filtered through a 40 μm nylon mesh, and added with serum to stop the reaction. The cells were centrifuged at 300 x g for 10 minutes, resuspended in 10 μl of CD31 microbeads (Miltenyi Biotec, Germany) and 90 μl of autoMACS Rinsing Solution (Miltenyi Biotec, Germany) supplemented with 0.5% BSA, and reacted at 4°C for 15 minutes. The reaction solution was centrifuged at 300 x g at 4°C for 10 minutes to collect cells, suspended in 3 ml of MACS buffer (Miltenyi Biotec, Germany), and LS column (Miltenyi Biotec, Germany) to isolate CD31-expressing vascular endothelial cells. did
[실험 방법 6] [Test Method 6] 마우스 난황낭 내피세포(Mouse Yolk Sac Endothelial Cells, MYSECs)의 배양Culture of Mouse Yolk Sac Endothelial Cells (MYSECs)
마우스 난황낭 내피세포를 Cell Biologics, INC (미국 시카고)에서 구입하여 10% FBS(fetal bovine serum), 0.2% 글루타맥스(glutamax), 0.5% 페니실린/스트렙토마이신(penicillin/streptomycin)이 함유된 DMEM 배지에서 5% CO2 상에서 4℃에서 배양하였다. 1 내지 2 계대 배양후에 세포가 배양 접시내에서 80-90% 정도까지 찰 때 6 웰 플레이트에 재접종하였다. 여기서, 인터페론 베타가 미치는 영향을 확인하기 위해, 약물을 처리할 때에는 미리 FBS가 제거된 무혈청 배지에서 24시간 동안 배양한 뒤에 인터페론 베타를 처리하였다.Mouse yolk sac endothelial cells were purchased from Cell Biologics, INC (Chicago, USA) and DMEM medium containing 10% FBS (fetal bovine serum), 0.2% glutamax, 0.5% penicillin/streptomycin Incubated at 4° C. in 5% CO 2 . After 1 or 2 passages, the cells were re-inoculated into a 6-well plate when the cells were filled to about 80-90% in the culture dish. Here, in order to confirm the effect of interferon beta, when the drug was treated, interferon beta was treated after culturing for 24 hours in a serum-free medium from which FBS was previously removed.
[실험 방법 7] [Test Method 7] 면역 블롯immunoblot
4% 프로테아제 억제제 칵테일(protease inhibitor cocktail, 스위스 Roche, cOmplete™)과, 10% 포스파타제 억제제(phosphatase inhibitor, 스위스 Roche, PhosSTOP™)가 첨가된 단백질 추출액(미국 ThermoFisher Scientific, MPER™)을 세포에 넣어 1 시간 동안 세포를 용해시켰다. 이후, 12000 rpm으로 4℃에서 10 분간 원심분리 한 뒤에 상층액을 수득하고 단백질의 양을 측정하였다. 그런 다음, 20 ㎍의 단백질을 7.5% SDS-폴리아크릴아미드(sodium dodecyl sulfate-polyacrylamide) 겔(gel) 전기영동을 실시하였다. 전기영동이 끝난 겔의 단백질을 PVDF(Polyvinylidene fluoride) 막으로 4℃, 80~120V에서 120-150 분 동안 이동시키고 3% 탈지유로 상온에서 1시간 동안 0.1% Tris Buffered Saline-Tween 20 (TBS-Tween 20, pH 7.4)으로 처리하여 비특이적 항체 결합을 예방하였다. 특정한 일차 항체인 항-SIRT1 (미국 millipore sigma) 또는 항-βactin을 12시간 동안 반응시키고 0.1% TBS-Tween 20 용액으로 5분씩 3회 세척하였다. 일차 항원에 특이적인 이차 항체는 anti-Mouse IgG 및 anti-Rabbit IgG가 결합된 홍당무 과산화효소(horseradish peroxidase)를 이용하여 40분 동안 반응하고 TBS-Tween 20 용액으로 5분씩 4회 세척하였다. 최종적으로 ECL kit (Amersham Pharmacia Biotech, Uppsala, Sweden)의 안내서에 기술된 방법에 따라 발색시켜 확인하였다.4% protease inhibitor cocktail (Roche, Switzerland, cOmplete™) and 10% phosphatase inhibitor (Roche, Switzerland, PhosSTOP™) are added to the protein extract (ThermoFisher Scientific, USA, MPER™) into the cells 1 Cells were lysed for an hour. Thereafter, after centrifugation at 12000 rpm at 4° C. for 10 minutes, the supernatant was obtained and the amount of protein was measured. Then, 20 ㎍ of the protein was subjected to 7.5% SDS-polyacrylamide (sodium dodecyl sulfate-polyacrylamide) gel electrophoresis. After electrophoresis, the protein in the gel was transferred to a PVDF (Polyvinylidene fluoride) membrane at 4°C, 80-120V for 120-150 minutes, and 3% skim milk was used for 1 hour at room temperature with 0.1% Tris Buffered Saline-Tween 20 (TBS-Tween). 20, pH 7.4) to prevent non-specific antibody binding. A specific primary antibody, anti-SIRT1 (US millipore sigma) or anti-βactin, was reacted for 12 hours and washed three times for 5 minutes with 0.1% TBS-
[실험 방법 8] [Test Method 8] TNF-α와 IL6의 ELISA 측정ELISA measurement of TNF-α and IL6
실험 방법 2에 기재된 방법과 같이 패혈증을 유도하고 18시간 후에 마우스의 안면 정맥으로부터 채취한 혈액을 원심분리한 후 혈청 TNF-α와 IL6 농도를 TNF-α와 IL6 ELISA 키트 (한국, Koma Biotechnology)를 이용하여 제조사가 제시한 방법을 이용하여 측정하였다.As in the method described in
[실험 방법 9] [Test Method 9] 헤마톡실린 및 에오신(Hematoxylin and Eosin) 염색Hematoxylin and Eosin staining
패혈증 유도 전후 및 약물처리 후 마우스 신장, 폐 및 간 조직의 변화를 관찰하기 위하여, 상기 장기들을 10% paraformaldehyde로 4℃에서 24시간 고정시켰다. 그 고정된 장기의 조직을 파라핀으로 엠베딩(embedding)한 뒤에, 5 μm의 크기로 절편화 하였다. 절편화된 조직을 자일렌으로 탈 파라핀화하고, 에탄올 농도별(100, 90, 80 및 70%)로 각 5분씩 가수한 후, 헤마톡실린 용액(Sigma)에 3분 동안 염색하였다. 염색된 조직은 수세한 뒤 에오신 용액을 이용해 3분 동안 다시 염색시켰다. 염색이 완료된 후 흐르는 물에 잘 씻은 조직은 다시 에탄올을 이용하여 농도별(70, 80, 90 및 100%)로 각각 5분씩 탈수시키고, 자일렌을 이용하여 씻은 후 봉입하였다. 염색된 조직은 광학현미경으로 관찰하였다.To observe changes in mouse kidney, lung and liver tissues before and after sepsis induction and after drug treatment, the organs were fixed with 10% paraformaldehyde at 4° C. for 24 hours. After embedding the fixed organ tissue with paraffin, it was sectioned to a size of 5 μm. The sectioned tissue was deparaffinized with xylene, hydrated for 5 minutes at each ethanol concentration (100, 90, 80, and 70%), and then stained with hematoxylin solution (Sigma) for 3 minutes. The stained tissue was washed with water and re-stained for 3 minutes using an eosin solution. After staining was completed, the tissues washed well in running water were dehydrated for 5 minutes each by concentration (70, 80, 90, and 100%) using ethanol again for 5 minutes, washed with xylene, and then sealed. The stained tissue was observed under an optical microscope.
[실험 방법 10] [Test Method 10] 난황낭 내피세포에서 SIRT1 발현 억제Inhibition of SIRT1 expression in yolk sac endothelial cells
내피세포의 투과성에 대한 SIRT1의 역할을 규명하기 위하여 난황낭 내피세포(MYSECs)에서 SIRT1의 발현을 RNAi를 이용하여 발현을 억제시켰다. SIRT1 siRNA 및 control siRNA인 Stealth siSIRT1 (siRNA ID MSS234959) 및 Stealth siControl (siRNA ID 462001)을 Thermo Fisher Scientific, Inc 으로부터 구입하였다. Stealth siSIRT1 (50 nM) 및 Stealth siControl (50 nM) 은 Lipofectamine® RNAiMAX (미국 Thermo Fisher Scientific, Inc)를 이용하여 난황낭 내피세포(MYSECs)에 제조사의 안내서에 따라 형질전환 시켰다. 형질전환한지 24 시간 후 면역블롯을 실시하여 SIRT1 발현 억제정도를 측정하였다.To investigate the role of SIRT1 on the permeability of endothelial cells, the expression of SIRT1 in yolk sac endothelial cells (MYSECs) was suppressed using RNAi. SIRT1 siRNA and control siRNAs Stealth siSIRT1 (siRNA ID MSS234959) and Stealth siControl (siRNA ID 462001) were purchased from Thermo Fisher Scientific, Inc. Stealth siSIRT1 (50 nM) and Stealth siControl (50 nM) were transformed into yolk sac endothelial cells (MYSECs) using Lipofectamine® RNAiMAX (Thermo Fisher Scientific, Inc, USA) according to the manufacturer's instructions. 24 hours after transformation, immunoblotting was performed to measure the degree of inhibition of SIRT1 expression.
[실험 방법 11] [Test Method 11] 통계처리Statistical processing
데이터는 평균 ± 표준편차로 표시하였으며, Student's t-test에 의해서 P<0.05인 것을 유의한 것으로 간주하였다.Data were expressed as mean ± standard deviation, and P<0.05 was considered significant by Student's t-test.
실험 결과Experiment result
[실험 결과 1] [Experimental Result 1] 마우스 패혈증 모델에서 인터페론 베타와 본원의 화합물의 병용처리에 따른 생존율 분석Analysis of survival rate according to combination treatment of interferon beta and the present compound in a mouse sepsis model
실험 방법 2에 기재된 바와 같이 맹장 결찰 및 천공(cecal ligation and Puncture, 이하 CLP) 수술을 통해 유도된 마우스 패혈증 모델에서 실험 방법 3에 기재된 바와 같이 인터페론 베타 및 니코틴아미드, NMN 또는 NR과의 병용 투여에 따른 생존율 변화를 확인하여 도 2에 나타내었다.As described in
도 2에 나타낸 바와 같이, 패혈증을 유도한 마우스에 인터페론 베타를 투여하고 4 일이 지난 후의 마우스의 생존율이 40%에 해당하였다. 또한, 니코틴아미드 또는 NMN을 병용 투여하는 경우에는 인터페론 베타의 패혈증 치료 효과가 상승되지 않았다. 그러나, NR을 병용 투여하는 경우에는 인터페론 베타에 의한 패혈증 치료 효과가 60%로, 단독 투여와 비교하여 20% 정도 상승되었다. As shown in FIG. 2 , the survival rate of mice 4 days after administration of interferon beta to mice induced to sepsis was 40%. In addition, when nicotinamide or NMN was administered in combination, the sepsis treatment effect of interferon beta was not increased. However, when NR was administered in combination, the sepsis treatment effect by interferon beta was 60%, which was increased by about 20% compared to administration alone.
상기 결과를 통해, 세포 내 NAD양을 높이는 것으로 알려진 니코틴아미드, NMN 및 NR 중에서 특히 NR 만이 인테페론 베타와 병용하여 투여되었을 때, 패혈증을 치료하여 생존율을 상승시킬 수 있음을 알 수 있다. 따라서, 인터페론 베타와 NR의 병용 투여는 패혈증으로 인한 마우스의 사망률을 현저히 낮춰 효과적인 패혈증 또는 패혈증 쇼크의 예방 또는 치료에 유용하게 이용될 수 있다.From the above results, it can be seen that among nicotinamide, NMN, and NR, which are known to increase the amount of intracellular NAD, especially when only NR is administered in combination with interferon beta, sepsis can be treated and survival rate can be increased. Therefore, co-administration of interferon beta and NR can be usefully used for effective prevention or treatment of sepsis or septic shock by significantly lowering the mortality of mice due to sepsis.
[실험 결과 2] [Experimental Result 2] 난황낭 내피세포에서 인터페론 베타 처리 후 SIRT1 발현량 측정Measurement of SIRT1 expression level after interferon beta treatment in yolk sac endothelial cells
난황낭 내피세포(MYSECs)에 인터페론 베타(0, 100, 200,400, 1000 units/ml)를 농도 별로 24시간 처리하고, 면역 블롯을 통해 SIRT1 발현량을 비교 확인하였다. 또한 1000 units/ml의 인터페론 베타를 시간별로 처리하고 SIRT1 발현량을 면역 블롯을 통해 비교하였다. 상기 면역 블롯 결과는 도 3의 (A) 및 (B)에 나타내었다.The yolk sac endothelial cells (MYSECs) were treated with interferon beta (0, 100, 200, 400, and 1000 units/ml) for 24 hours at each concentration, and SIRT1 expression levels were compared and confirmed by immunoblotting. In addition, 1000 units/ml of interferon beta was treated by time, and the expression level of SIRT1 was compared through immunoblot. The immunoblot results are shown in FIGS. 3A and 3B .
도 3의 (A) 및 (B)에 나타낸 바와 같이, 난황낭 내피세포(MYSECs)에 인터페론 베타를 처리하였을 때 SIRT1 단백질 발현 수준이 농도 의존적으로 증가하였고 (A), 1000 units/ml의 인터페론을 처리한지 2시간 후부터 SIRT1 단백질의 발현 수준이 증가되기 시작하였다 (B).As shown in (A) and (B) of Figure 3, when the yolk sac endothelial cells (MYSECs) were treated with interferon beta, the SIRT1 protein expression level was increased in a concentration-dependent manner (A), and interferon of 1000 units/ml was treated After 2 hours, the expression level of SIRT1 protein started to increase (B).
[실험 결과 3] [Experimental Result 3] 대식세포 또는 혈관내피세포 특이 SIRT1 유전자 결실 마우스에서 인터페론 베타와 NR의 병용투여에 따른 패혈증 마우스 생존율 분석Analysis of the survival rate of sepsis mice following co-administration of interferon beta and NR in macrophage or endothelial cell-specific SIRT1 gene deletion mice
실험 방법 2 내지 4에 기재된 대식세포 또는 혈관내피세포 특이 SIRT1 유전자 결실 마우스에서 인터페론 베타와 NR의 병용투여에 따른 패혈증 마우스의 생존율을 측정하여 그 결과를 도 4의 (A) 내지 (C)에 나타내었다.In the macrophage or endothelial cell-specific SIRT1 gene deletion mice described in
도 4의 (A) 내지 (C)에 나타낸 바와 같이, SIRT1이 정상적으로 발현되어 있는 대조군 마우스는 인터페론 베타만 투여했을 때 40%, NR만 투여했을 때 20%, 병용 투여했을 때 60%의 패혈증 마우스 생존율을 보여 인터페론 베타 및 NR 각각이 패혈증 치료효과를 보였을 뿐만 아니라, 병용 투여시 패혈증을 치료하는데 있어 현저한 상승 효과가 있음을 확인하였다 (A). 반면, 대식세포 또는 혈관내피세포 특이 SIRT1 유전자 결실 마우스에서는 인터페론 베타 및 NR 각각이 패혈증 치료효과를 보이지 않았을 뿐만 아니라, 병용 투여시에도 패혈증을 치료하는데 있어 현저한 상승 효과가 확인되지 않았다 (B 및 C). As shown in (A) to (C) of Figure 4, control mice in which SIRT1 was normally expressed were 40% when administered only with interferon beta, 20% when only NR was administered, and 60% of sepsis mice when administered in combination. It was confirmed that interferon beta and NR each showed a sepsis treatment effect as well as a significant synergistic effect in treating sepsis when administered in combination (A). On the other hand, in mice with macrophage or endothelial cell-specific SIRT1 gene deletion, interferon beta and NR each did not show a sepsis therapeutic effect, and no significant synergistic effect was observed in treating sepsis even when administered in combination (B and C) .
상기 결과를 통해, 대식세포 및 혈관내피세포의 SIRT1 발현이 인터페론 베타 및 NR에 의한 패혈증 보호작용에 직접 연관되어 있음을 알 수 있다.From the above results, it can be seen that the expression of SIRT1 in macrophages and endothelial cells is directly related to the sepsis protection by interferon beta and NR.
[실험 결과 4] [Experimental Result 4] 인터페론 베타 및 NR의 투여에 의한 패혈증 마우스에서의 염증성 사이토카인의 분비량에 미치는 영향Effects of interferon beta and NR administration on inflammatory cytokine secretion in sepsis mice
실험 방법 2 및 3에 기재된 바와 같이 맹장 결찰 및 CLP 수술을 통해 유도된 마우스 패혈증 모델에서, 패혈증 유도 18시간 후에 인터페론 베타 및 NR의 병용 투여에 따른 혈청내 염증성 사이토카인의 변화를 ELISA 방식에 따라 측정하여 도 5에 나타내었다. As described in
도 5에 나타낸 바와 같이, 패혈증을 유도한 마우스에 인터페론 베타 또는 NR를 투여하면 패혈증의 인해 증가된 염증성 사이토카인인 TNF-α 및 IL6의 혈중 농도가 감소된 것을 확인하였다. 나아가, 인터페론 베타 및 NR을 병용하여 투여하는 경우, 염증성 사이토카인 모두의 발현 수준을 감소시키는데 시너지 효과가 있음을 확인하였다. As shown in FIG. 5 , it was confirmed that administration of interferon beta or NR to mice induced sepsis reduced the blood levels of inflammatory cytokines TNF-α and IL6 increased due to sepsis. Furthermore, when administered in combination with interferon beta and NR, it was confirmed that there is a synergistic effect in reducing the expression level of both inflammatory cytokines.
상기 결과를 통해, 인터페론 베타와 NR의 병용 투여는 패혈증으로 인한 염증성 사이토카인의 혈중 농도 수준을 감소시키는데 현저한 시너지 효과가 존재하여, 패혈증 또는 패혈증 쇼크를 매우 효과적으로 예방 또는 치료할 수 있음을 알 수 있다.From the above results, the co-administration of interferon beta and NR has a significant synergistic effect in reducing the blood concentration level of inflammatory cytokines due to sepsis, and it can be seen that sepsis or septic shock can be very effectively prevented or treated.
[실험 결과 5] [Experimental Result 5] 인터페론 베타 및 NR의 투여에 의한 패혈증 마우스에서의 장기손상에 미치는 영향Effects of interferon beta and NR administration on organ damage in sepsis mice
실험 방법 2 및 3에 기재된 바와 같이 맹장 결찰 및 CLP 수술을 통해 유도된 마우스 패혈증 모델에서, 패혈증 유도 18시간 후에 인터페론 베타와 NR의 투여에 따른 장기손상의 변화를 측정하여 도 6에 나타내었다.As described in
도 6에 나타낸 바와 같이, 맹장 결찰 및 CLP 수술을 통해 마우스에 패혈증을 유도할 시 신장의 경우에는 신장 피질 및 수질, 그리고 신세뇨관에 염증성 세포의 침입으로 부종이 관찰되었으며, 폐에서는 폐포벽이 두꺼워지는 폐조직 손상과 염증성 세포의 침윤이 관찰되었고, 간세포의 부종 및 염증세포의 침윤이 관찰되었다. As shown in Figure 6, when sepsis is induced in mice through cecal ligation and CLP surgery, edema was observed due to invasion of inflammatory cells into the renal cortex and medulla, and renal tubules in the kidney, and the alveolar wall thickened in the lung. Lung tissue damage and inflammatory cell infiltration were observed, hepatocyte edema and inflammatory cell infiltration were observed.
그러나, 패혈증을 유도한 마우스에 인터페론 베타 및 NR을 병용하여 투여하면 패혈증으로 인하여 발생된 부종, 염증성 세포 침윤 등이 저하되는 것을 확인하였다. 상기 결과를 통해, 인터페론 베타 및 NR의 병용 투여는 패혈증으로 인한 장기손상, 즉 장기 부종 및 염증성 세포 침윤을 억제하여 효과적인 패혈증 또는 패혈증 쇼크를 예방 또는 치료할 수 있음을 알 수 있다.However, it was confirmed that edema and inflammatory cell infiltration caused by sepsis were reduced when interferon beta and NR were co-administered to sepsis-induced mice. From the above results, it can be seen that co-administration of interferon beta and NR can effectively prevent or treat sepsis or septic shock by inhibiting organ damage caused by sepsis, that is, organ edema and inflammatory cell infiltration.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
<110> INDUSTRIAL COOPERATION FOUNDATION JEONBUK NATIONAL UNIVERSITY <120> A composition for preventing, alleviating or treating a sepsis or septic shock <130> PDPB204099k01 <150> KR 1020200073269 <151> 2020-06-16 <160> 6 <170> KoPatentIn 3.0 <210> 1 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Sirt1-loxP sense primer <400> 1 ggttgactta ggtcttgtct g 21 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Sirt1-loxP anti-sense primer <400> 2 cgtcccttgt aatgtttccc 20 <210> 3 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Tek-Cre sense primer <400> 3 gcggtctggc agtaaaaact atc 23 <210> 4 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Tek-Cre anti-sense primer <400> 4 gtgaaacagc attgctgtca ctt 23 <210> 5 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Internal Control sense primer <400> 5 ctaggccaca gaattgaaag atct 24 <210> 6 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Internal Control anti-sense primer <400> 6 gtaggtggaa attctagcat catcc 25 <110> INDUSTRIAL COOPERATION FOUNDATION JEONBUK NATIONAL UNIVERSITY <120> A composition for preventing, alleviating or treating a sepsis or septic shock <130> PDPB204099k01 <150> KR 1020200073269 <151> 2020-06-16 <160> 6 <170> KoPatentIn 3.0 <210> 1 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Sirt1-loxP sense primer <400> 1 ggttgactta ggtcttgtct g 21 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Sirt1-loxP anti-sense primer <400> 2 cgtcccttgt aatgtttccc 20 <210> 3 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Tek-Cre sense primer <400> 3 gcggtctggc agtaaaaact atc 23 <210> 4 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Tek-Cre anti-sense primer <400> 4 gtgaaacagc attgctgtca ctt 23 <210> 5 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Internal Control sense primer <400> 5 ctaggccaca gaattgaaag atct 24 <210> 6 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Internal Control anti-sense primer <400> 6 gtaggtggaa attctagcat catcc 25
Claims (10)
[화학식 1]
interferon beta (IFN-beta); And a pharmaceutical composition for the prevention or treatment of sepsis or septic shock comprising at least one selected from the group consisting of compounds represented by Formula 1 as an active ingredient:
[Formula 1]
상기 약학 조성물은 인터페론 베타; 및 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 것인, 약학 조성물.According to claim 1,
The pharmaceutical composition is interferon beta; And, a pharmaceutical composition comprising the compound represented by Formula 1 as an active ingredient.
상기 인터페론 베타는 인터페론 베타 1a 또는 1b인 것인, 약학 조성물.According to claim 1,
The interferon beta is interferon beta 1a or 1b, the pharmaceutical composition.
상기 인터페론 베타; 및 상기 화학식 1로 표시되는 화합물은 SIRT1(silent mating type information regulation 2 homolog; sirtuin 1)의 발현을 유도하는 것인, 약학 조성물.According to claim 1,
the interferon beta; And the compound represented by Formula 1 is to induce the expression of SIRT1 (silent mating type information regulation 2 homolog; sirtuin 1), a pharmaceutical composition.
상기 약학 조성물은 염증성 사이토카인(cytokine)의 혈중 농도를 감소시키는 것인, 약학 조성물.According to claim 1,
The pharmaceutical composition is to reduce the blood concentration of inflammatory cytokines (cytokine), the pharmaceutical composition.
[화학식 1]
interferon beta (IFN-beta); And a food composition for preventing or improving sepsis or septic shock comprising at least one selected from the group consisting of compounds represented by the following formula (1) as an active ingredient:
[Formula 1]
상기 식품 조성물은 인터페론 베타; 및 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 것인, 식품 조성물.7. The method of claim 6,
The food composition is interferon beta; And, the food composition comprising the compound represented by Formula 1 as an active ingredient.
상기 인터페론 베타는 인터페론 베타 1a 또는 1b인 것인, 식품 조성물.7. The method of claim 6,
The interferon beta is interferon beta 1a or 1b, the food composition.
상기 인터페론 베타; 및 상기 화학식 1로 표시되는 화합물은 SIRT1(silent mating type information regulation 2 homolog; sirtuin 1)의 발현을 유도하는 것인, 식품 조성물.7. The method of claim 6,
the interferon beta; And the compound represented by Formula 1 is to induce the expression of SIRT1 (silent mating type information regulation 2 homolog; sirtuin 1), the food composition.
상기 식품 조성물은 염증성 사이토카인(cytokine)의 혈중 농도를 감소시키는 것인, 식품 조성물.7. The method of claim 6,
The food composition is to reduce the blood concentration of inflammatory cytokines (cytokine), the food composition.
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KR20120095324A (en) * | 2011-02-18 | 2012-08-28 | 주식회사 스템디알 | Composition for preventing or treating sepsis or septic shock comprising sirt1 expression inducer |
KR20150050406A (en) * | 2013-10-29 | 2015-05-08 | 한림대학교 산학협력단 | Pharmaceutical composition comprising nicotinamide riboside as active ingredient for treatment or prevention of sepsis |
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KR102594908B1 (en) | 2023-10-30 |
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