[보고서]천연물유래 autoinflammation 기반 퇴행성뇌질환 억제물질 발굴

김윤철

천연물유래 autoinflammation 기반 퇴행성뇌질환 억제물질 발굴
Discovery of the degenerative brain diseases drug candidates based on auto-inflammation from natural products 원문보기

보고서 정보
주관연구기관	원광대학교 WonKwang University
연구책임자	김윤철
보고서유형	최종보고서
발행국가	대한민국
언어	한국어
발행년월	2020-01
과제시작연도	2016
주관부처	미래창조과학부 Ministry of Science, ICT and Future Planning
등록번호	TRKO202000003626
과제고유번호	1711043184
사업명	개인연구지원
DB 구축일자	2020-07-29
키워드	천연물.오토인플라메이숀.퇴행성뇌질환.간장.꾸지뽕나무.선도물질.Natural products.Autoinflammation.Degenerative brain disease.Soy sauce.Cudrania tricuspidata.Lead compound.

초록 ▼

□ 연구의 목적 및 내용
본 연구에서는 최근 보고된 autoinflammation 개념과 알츠하이머병에서의 IL-1β 역할의 중요성에 착안하여 선행연구로부터 얻어진 결과를 토대로 알츠하이머병을 비롯한 퇴행성뇌질환 치료제 개발을 위한 최적의 천연물 유래 선도물질 3개 이상을 도출하고자 하였음. NMR data-guided isolation system을 활용한 활성물질을 분리 및 MS, NMR 등의 기기 분석을 이용한 활성물질의 구조 규명 및 이들 물질들을 LPS/RAW264.7 cell system에 적용하여 발견된 항염증 효과물질에 대해 LPS/BV2 cell system, glutamate/HT22 cell system에서 항염증효과와 세포보호효과를 검정하였으며, 당초 계획하였던 Aβ를 제반 여건 상 사용하지 못하였으나 LPS를 독성 유발물질로 사용한 rat primary microglial cell system을 통한 항염증 기전연구를 진행하여 당초목표인 천연물유래 퇴행성 뇌질환 치료제 선도물질 3종 이상을 도출하였음

□ 연구결과
꾸지뽕나무(Cudrania tricuspidata) 근피로부터 항염증활성을 지표로 추적분리, 구조규명을 실시하여 1,6,7-trihydroxy-2-(1,1-dimethyl-2-propenyl)-3-methoxy xanthone (1), cudratricusxanthone N (2), macluraxanthone B (3), cudraxanthone D (4), cudraflavone C (5), kuwanon C (6), cudratricusxanthone L (7), cudraflavanone D (8), (+)-dihydrokaempferol (9), steppogenin (10), cudraxanthone M (11), cudracuspixanthone A (12), cudraflavanone A (13), cudraxanthone L (14), cudratricusxanthone A (15) 등 15종의 화합물이 분리되었으며 간장으로 부터 3-phenyllactic acid methyl ester (16), hydroxyphenylacetic acid (17), prolyl-isoleucine (18), prolyl-leucine (19), N-acetyl-isoleucine (20), 3-oxo-3-[(2-phenylethyl) amino]-propanoic acid (21), prolyl-tyrosine (22), uracil (23), 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (24), citroside B (25), 1-methyl-3,4-dihydro-β-carboline (26), 1-methyl-1,2,3,4-tetrahydro-β-carboline-1-carboxylic acid (27) (4-hydroxyphenyl) acetic acid methyl ester (28), 3-indoleacetic acid (29), flazine (30) 등 15종의 화합물을 분리하였음. 분리 동정된 화합물에 대하여 LPS/BV2 cell system, LPS/rat primary microglial cell system을 적용하여 항염증활성을 검증한 결과, 꾸지뽕나무 근피에서 분리된 cudratricusxanthone A, steppogenin, cudratricusxanthone L, cudraflavanone A, cudraflavanone D 등 5개의 화합물과 간장에서 분리된 3-indoleacetic acid, flazine의 2개 화합물에서 우수한 항염증효과 활성을 확인하였음. 추가적으로 BV2 세포와 1차 미세아교세포에서 NF-κB, MAPK에서의 항염증 활성을 진행하였음. 그 결과 우수한 NF-κB, MAPK 억제효과를 확인할수 있었으며 이를 학술지에 게재함

□ 연구결과의 활용계획
■ 꾸지뽕나무 근피와 간장으로부터 얻어진 활성화된 미세아교세포에 대한 항염증 활성물질 7개 화합물에 대하여 알츠하이머병 등 퇴행성뇌질환 동물모델에서의 효능평가기술을 보유한 다른 연구자들과 공동연구를 통하여 이들 질환에 대한 치료활성을 검증함으로써 새로운 만성, 퇴행성 뇌질환 치료제 개발을 위한 심화연구를 수행하고자 함
■ 근래에 들어서 연구 및 건강관련 제품개발의 유망 소재로 이용되고 있는 꾸지뽕나무에 대한 새로운 건강기능성 정보를 제공함으로써 고부가가치를 창출할 수 있도록 지원하고자 함
■ 본 연구에서 발굴한 선도물질을 이용하여 최근 뇌염증과 당뇨병과의 연관성이 제시되고 있는 점에 착안하여 본 연구실에서 보유하고 있는 PTP1B에 관한 연구를 진행함으로써 새로운 당뇨병 조절물질을 발견하고자 함
■ 본 연구를 통해서 얻어진 결과와 산업재산권을 국내 제약회사에게 기술이전 또는 공동연구를 추진하여 산업화 가능성을 타진하고자 함

(출처 : 한글요약문 4p)

Abstract ▼

□ Purpose& contents
Alzheimer's disease is a growing problem, and there is no known cure for this serious disease. Based on the both new notion of autoinflammation and key molecule in Alzheimer's disease, we would like to find three lead compounds which are the most suitable for the development of this neurodegenerative disease. Various anti-neuroinflammatory compounds had been isolated and elucidated their chemical structures through the NMR spectral data-guided fractionation, MS, NMR analyses, and cell-based bioassay screening system. Promising active compounds which derived from LPS/RAW264.7 cell system had been tested using LPS/BV2 cell system and glutamate/HT22 cell system. Futhermore, these active compounds reconfirmed their anti-neuroinflammatory activities by LPS/primary microglial cell system to yield seven lead compounds.

□ Result
Fifteen compounds including 1,6,7-trihydroxy-2-(1,1-dimethyl-2-propenyl)-3-methoxy xanthone (1), cudratricusxanthone N (2), macluraxanthone B (3), cudraxanthone D (4), cudraflavone C (5), kuwanon C (6), cudratricusxanthone L (7), cudraflavanone D (8), ( )-dihydrokaempferol (9), steppogenin (10), cudraxanthone M (11), cudracuspixanthone A (12), cudraflavanone A (13), cudraxanthone L (14), cudratricusxanthone A (15) had been isolated and identified from the root barks of Cudrania tricuspidata. Fifteen compounds such as 3-phenyllactic acid methyl ester (16), hydroxyphenylacetic acid (17), prolyl-isoleucine (18), prolyl-leucine (19), N-acetyl-isoleucine (20), 3-oxo-3-[(2-phenylethyl) amino]-propanoic acid (21), prolyl-tyrosine (22), uracil (23), 1-methyl-1,2,3,4-tetrahydro- β-carboline-3-carboxylic acid (24), citroside B (25), 1-methyl-3,4-dihydro-β-carboline (26), 1-methyl-1,2,3,4-tetrahydro-β-carboline-1-carboxylic acid (27) (4-hydroxyphenyl) acetic acid methyl ester (28), 3-indoleacetic acid (29), flazine (30) had been isolated and identified from soy sauce. From the in vitro anti-neuroinflammatory and neuroprotective assay systems, LPS/BV2 cell and glutamate/HT22 cell systems, seven compounds showed the promising activity. These compounds had been further confirmed their anti-neurodegerative activities using LPS/primary microglial cell system. It had been suggested that their mechanism of action is related with the inhibition of NF-κB and MAPK pathways.

□ Expected Contribution
■ Further collaboration studies with researchers who have the neurodegenerative in vivo models to develop the anti-neurodegenerative agents using the results derived from this work.
■ The results of this work will be provide the useful information on Cudrania tricuspidata which is promising material in health industrial area.
■ The anti-neurodegenerative compounds derived from this research will be afford as the candidates for the anti-diabetes because the relationship neurodegeneration with type 2 diabetes is brought up recently.
■ Further collaboration studies with the pharmaceutical companies to develop the new anti-neurodegenerative diseases.

(출처 : SUMMARY 5p)

목차 Contents

표지 ... 1
목차 ... 2
연구계획 요약문 ... 3
연구결과 요약문 ... 4
한글요약문 ... 4
SUMMARY ... 5
연구내용 및 결과 ... 6
1. 연구개발과제의 개요 ... 6
2. 국내외 기술개발 현황 ... 8
3. 연구수행 내용 및 결과 ... 12
4. 목표달성도 및 관련분야에의 기여도 ... 46
5. 연구결과의 활용계획 ... 53
6. 연구과정에서 수집한 해외 과학기술정보 ... 53
7. 주관연구책임자 대표적 연구실적 ... 54
8. 참고문헌 ... 55
9. 연구성과 ... 56
10. 국가과학기술지식정보서비스에 등록한 연구시설‧장비 현황 ... 62
11. 연구개발과제 수행에 따른 연구실 등의 안전조치 이행실적 ... 62
12. 기타사항 ... 62
[별첨1] 대 표 연 구 실 적 ... 63
[별첨2] 세부 목표 관련 증빙 ... 76
끝페이지 ... 92

표/그림 (31)

표 The effects of compound 8 (CTC4421016; cudraflavanone D) on TNF-α (A), IL-1β (B), IL-12 (C), and IL-6 (D) mRNA expression in the condition of LPS stimulation. Cells were pre-treated for 3 h with the indicated concentrations of compound 8 and then stimulated for 12 h with LPS (1 μg/mL). The data represent the mean values of 3 experiments ± SD. *p < 0.05 compared with the group treated with LPS
표 The effects of compound 8 (CTC4421016; cudraflavanone D) on the protein expression of iNOS and COX-2 (C) in BV2 microglia stimulated with LPS. Cells were pre-treated for 3 h with the indicated concentrations of compound 8 and then stimulated for 24 h with LPS (1 μg/mL). The data represent the mean values of 3 experiments ± SD. *p < 0.05 compared with the group treated with LPS
표 The effects of compound 8 (CTC4421016; cudraflavanone D) on IκB-α phosphorylation and degradation (A), NF-κB activation (B, C), immunofluorescence for NF-κB localization (D) and NF-κB DNA binding activity (E) in BV2 microglia. Cells were pre-treated for 3 h with the indicated concentrations of compound 8, and stimulated for 1 h with LPS (1 μg/mL). The data represent the mean values ± SD of 3 experiments. *p < 0.05 compared with the group treated with LPS
표 Effects of compound 8 (CTC4421016; cudraflavanone D) on ERK, JNK, and p38 MAPK phosphorylation and protein expression. Cells were pre-treated for 3 h with the indicated concentrations of compound 8 and stimulated for 30 min with LPS (1 μg/mL) (A, B, and C). The levels of (A) phosphorylated-ERK (p-ERK), (B) phosphorylated-JNK (p-JNK), and (C) phosphorylated-p38 MAPK (p-p38 MAPK) were determined by western blotting. Representative blots from three independent experiments with similar results and densitometric evaluations are shown. Data shown represent the mean values of three experiments ± S.D. *p < 0.05 compared to the group treated with LPS alone
표 The effects of cudratricusxanthone A (1) on TNF-α (A), IL-1β (B), IL-12 (C), and IL-6 (D) mRNA expression stimulated with LPS. Cells were pre-treated for 3 h with the indicated concentrations of 1 and then stimulated for 12 h with LPS (1 μg/mL). The data represent the mean values of 3 experiments ± SD. *p < 0.05 compared with the group treated with LPS
표 The effects of cudratricusxanthone A (1) on the PGE2 production (A) and protein expression of iNOS and COX-2 (B) in BV2 microglia stimulated with LPS. Cells were pretreated for 3 h with the indicated concentrations of cudratricusxanthone A (1) and then stimulated for 24 h with LPS (1 μg/mL). The LPS treatment was performed in the presence. The data represent the mean values of 3 experiments ± SD. *p < 0.05 compared with the group treated with LPS
표 The effects of cudratricusxanthone A (1) on IκB-α phosphorylation and degradation (A), NF-κ B activation (B, C), immunofluorescence for NF-κB localization (D) and NF-κB DNA binding activity (E) in BV2 microglia. Cells were pre-treated for 3 h with the indicated concentrations of cudratricusxanthone A (1), and stimulated for 1 h with LPS (1 μg/mL). The data represent the mean values ± SD of 3 experiments. *p < 0.05 compared with the group treated with LPS
표 Effects of cudratricusxanthone A (1) on ERK, JNK, and p38 MAPK phosphorylation and protein expression. Cells were pre-treated for 3 h with the indicated concentrations of cudraflavone D and stimulated for 30 min with LPS (1 μg/mL) (A, B, and C). The levels of (A) phosphorylated-ERK (p-ERK), (B) phosphorylated-JNK (p-JNK), and (C) phosphorylated-p38 MAPK (p-p38 MAPK) were determined by Western blotting. Representative blots from three independent experiments with similar results and densitometric evaluations are shown
표 The effects of 3-indoleacetic acid and flazine on the LPS-induced TNF-α (A and E), IL-12 (B and F), IL-1β (C and G), and IL-6 (D and H) mRNA expression in BV2 cells. Cells were pretreated with 3-indoleacetic acid and flazine (10–80 μM) for 3 h and then incubated with 1 μg/ml LPS for 12 h. The data represent the mean values ± SD of 3 experiments. *p < 0.05 compared with the group treated with LPS
표 The effects of 3-indoleacetic acid and flazine on the protein expression of iNOS and COX-2 in LPS-induced BV2 cells. Cells were pretreated with 3-indoleacetic acid and flazine (10–80 μM) for 3 h and then incubated with 1 μg/ml LPS for 24 h. Western blot analyses were performed and representative blots of three independent experiments are shown. Band intensity was quantified by densitometry and normalized to actin, and the values are presented at the bottom of the each band
표 The effects 3-indoleacetic acid and flazine on IκB-a phosphorylation and degradation (A and B), and NF-κB complex protein levels of cytosol (C and D) and nuclear (E and F). Cells were pretreated with 3-indoleacetic acid and flazine (20–80 μM) for 3 h and then incubated with 1 μg/ml LPS for 1 h. Cytosol and nuclear extracts were prepared for a western blot of p65 and p50 of NF-κB, using specific anti-p65 and anti-p50 monoclonal antibodies. Band intensity was quantified by densitometry and normalized to b-actin and PCNA, and the values are presented at the bottom of the each band
표 The effects of steppogenin (1) on TNF-α (A), IL-1β (B), IL-12 (C), and IL-6 (D) mRNA expression stimulated with LPS. Cells were pre-treated for 3 h with the indicated concentrations of 1 and then stimulated for 12 h with LPS (1 μg/mL). The data represent the mean values of 3 experiments ± SD. *p < 0.05 compared with the group treated with LPS
표 The effects of steppogenin (1) on the PGE2 production (A) and protein expression of iNOS and COX-2 (B) in BV2 microglia stimulated with LPS. Cells were pretreated for 3 h with the indicated concentrations of 1 and then stimulated for 24 h with LPS (1 μg/mL). The LPS treatment was performed in the presence. The data represent the mean values of 3 experiments ± SD. *p < 0.05 compared with the group treated with LPS
표 The effects of steppogenin (1) on IκB-α phosphorylation and degradation (A), NF-κB activation (B, C), NF-κB DNA binding activity (E), and immunofluorescence for NF-κB localization (E) in BV2 microglia. Cells were pre-treated for 3 h with the indicated concentrations of steppogenin (1), and stimulated for 1 h with LPS (1 μg/mL). The data represent the mean values ± SD of 3 experiments. *p < 0.05 compared with the group treated with LPS
표 Effects of steppogenin (1) on ERK, JNK, and p38 MAPK phosphorylation and protein expression. Cells were pre-treated for 3 h with the indicated concentrations of cudraflavone D and stimulated for 30 min with LPS (1 μg/mL) (A, B, and C). The levels of (A) phosphorylated-ERK (p-ERK), (B) phosphorylated-JNK (p-JNK), and (C) phosphorylated-p38 MAPK (p-p38 MAPK) were determined by Western blotting. Representative blots from three independent experiments with similar results and densitometric evaluations are shown
표 The effects of steppogenin (1) on TNF-α (A), IL-1β (B), IL-12 (C), and IL-6 (D) mRNA expression stimulated with LPS. Cells were pre-treated for 3 h with the indicated concentrations of 1 and then stimulated for 12 h with LPS (1 μg/mL). The data represent the mean values of 3 experiments ± SD. *p < 0.05 compared with the group treated with LPS
표 The effects of steppogenin (1) on the nitrite production (A) and protein expression of iNOS and COX-2 (B) in primary microglial cells stimulated with LPS. Cells were pretreated for 3 h with the indicated concentrations of 1 and then stimulated for 24 h with LPS (1 μg/mL). The LPS treatment was performed in the presence. The data represent the mean values of 3 experiments ± SD. *p < 0.05 compared with the group treated with LPS
표 The effects of steppogenin (1) on IκB-α phosphorylation and degradation (A), NF-κB activation (B, C), and immunofluorescence for NF-κB localization (D) in primary microglial cells. Cells were pre-treated for 3 h with the indicated concentrations of steppogenin (1), and stimulated for 1 h with LPS (1 μg/mL). The data represent the mean values ± SD of 3 experiments. *p < 0.05 compared with the group treated with LPS
표 The effects of cudratricusxanthone L (1) on TNF-α (A), IL-1β (B), IL-12 (C), and IL-6 (D) mRNA expression stimulated with LPS. Cells were pre-treated for 3 h with the indicated concentrations of 1 and then stimulated for 12 h with LPS (1 μg/mL). The data represent the mean values of 3 experiments ± SD. *p < 0.05 compared with the group treated with LPS
표 The effects of cudratricusxanthone L (1) on the PGE2 production (A) and protein expression of iNOS and COX-2 (B) in BV2 microglia stimulated with LPS. Cells were pretreated for 3 h with the indicated concentrations of 1 and then stimulated for 24 h with LPS (1 μg/mL). The LPS treatment was performed in the presence. The data represent the mean values of 3 experiments ± SD. *p < 0.05 compared with the group treated with LPS
표 The effects of cudratricusxanthone L (1) on IκB-α phosphorylation and degradation (A), NF-κ B activation (B, C), NF-κB DNA binding activity (E), and immunofluorescence for NF-κB localization (E) in BV2 microglia. Cells were pre-treated for 3 h with the indicated concentrations of cudratricusxanthone L (1), and stimulated for 1 h with LPS (1 μg/mL). The data represent the mean values ± SD of 3 experiments. *p < 0.05 compared with the group treated with LPS
표 Effects of cudratricusxanthone L (1) on ERK, JNK, and p38 MAPK phosphorylation and protein expression. Cells were pre-treated for 3 h with the indicated concentrations of cudraflavone D and stimulated for 30 min with LPS (1 μg/mL) (A, B, and C). The levels of (A) phosphorylated-ERK (p-ERK), (B) phosphorylated-JNK (p-JNK), and (C) phosphorylated-p38 MAPK (p-p38 MAPK) were determined by Western blotting. Representative blots from three independent experiments with similar results and densitometric evaluations are shown
표 The effects of cudratricusxanthone L (1) on TNF-α (A), IL-1β (B), IL-12 (C), and IL-6 (D) mRNA expression stimulated with LPS. Cells were pre-treated for 3 h with the indicated concentrations of 1 and then stimulated for 12 h with LPS (1 μg/mL). The data represent the mean values of 3 experiments ± SD. *p < 0.05 compared with the group treated with LPS
표 The effects of cudratricusxanthone L (1) on the nitrite production (A) and protein expression of iNOS and COX-2 (B) in primary microglial cells stimulated with LPS. Cells were pretreated for 3 h with the indicated concentrations of 1 and then stimulated for 24 h with LPS (1 μg/mL). The LPS treatment was performed in the presence. The data represent the mean values of 3 experiments ± SD. *p < 0.05 compared with the group treated with LPS
표 The effects of cudratricusxanthone L (1) on IκB-α phosphorylation and degradation (A), NF-κ B activation (B, C), and immunofluorescence for NF-κB localization (D) in primary microglial cells. Cells were pre-treated for 3 h with the indicated concentrations of cudratricusxanthone L (1), and stimulated for 1 h with LPS (1 μg/mL). The data represent the mean values ± SD of 3 experiments. *p < 0.05 compared with the group treated with LPS
표 Effect of cudraflavanone A on the production of LPS-induced pro-inflammatory cytokines in BV2 cells. Cells were pretreated with/without the indicated concentration of cudraflavanone A for 3 h and then stimulated with LPS (1 μg/mL) for 24 h. The concentration of cytokines was measured by ELISA. *p < 0.005, **p < 0.01, and ***p < 0.001 in comparison with LPS-treated group
표 Effect of cudraflavanone A on LPS-induced nitrite (A) and PGE2 (B) production, iNOS and COX-2 protein expression (C), and COX-2 enzyme activity (D) in BV2 cells. (A, B, and C) Cells were pretreated with/without the indicated concentration of cudraflavanone A for 3 h and then stimulated with LPS (1 μg/mL) for 24 h. ***p < 0.001 in comparison with LPS-treated group. Representative blots from three independent experiments are shown. (D) COX-2 enzyme was treated with the indicated concentrations of cudraflavanone A for 5 min. DuP-697 was used as positive COX-2 inhibitor controls. Values shown are means ± SD of three independent experiments. ***p < 0.001 in comparison with COX-2 enzyme treated group
$Effect of cudraflavanone A on the LPS-induced activation of NF-κB in BV2 cells. Cells were pre-treated with the indicated concentrations of cudraflavanoen A for 3 h and then stimulated with LPS (1 μg/mL) for 1 h. Nuclear and cytosolic extracts were isolated and the levels of p65 and p50 in the nuclear fraction and p-IκB-α and IκB-α in the cytosolic fraction were determined by Western blot analysis. PCNA and actin were used as internal controls. The experiment was repeated three times, and similar results were obtained$ 표 Effect of cudraflavanone A on the LPS-induced activation of NF-κB in BV2 cells. Cells were pre-treated with the indicated concentrations of cudraflavanoen A for 3 h and then stimulated with LPS (1 μg/mL) for 1 h. Nuclear and cytosolic extracts were isolated and the levels of p65 and p50 in the nuclear fraction and p-IκB-α and IκB-α in the cytosolic fraction were determined by Western blot analysis. PCNA and actin were used as internal controls. The experiment was repeated three times, and similar results were obtained
표 Effects of cudraflavanone A on ERK, JNK, and p38 MAPK phosphorylation and protein expression. Cells were pre-treated for 3 h with the indicated concentrations of cudraflavone D and stimulated for 30 min with LPS (1 μg/mL) (A, B, and C). The levels of (A) phosphorylated-ERK (p-ERK), (B) phosphorylated-JNK (p-JNK), and (C) phosphorylated-p38 MAPK (p-p38 MAPK) were determined by Western blotting. Representative blots from three independent experiments with similar results and densitometric evaluations are shown
$Effects of cudraflavanone A on the HO-1 expression (A) and Nrf2 nuclear translocation (B) in BV2 cells. (A) Cells were treated with cudraflavanone A for 12 h at various concentrations and Western blot analysis for HO-1 expression was performed. Representative blots of three independent experiments are shown. (B) Cells were treated with 40 μM of cudraflavanone A for 0.5, 1, and 1.5 h, and the levels of Nrf2 protein in each fraction were determined by Western blot analysis. The experiment was repeated three times and similar results were obtained. **p < 0.01 in comparison with 0 h treated group$ 표 Effects of cudraflavanone A on the HO-1 expression (A) and Nrf2 nuclear translocation (B) in BV2 cells. (A) Cells were treated with cudraflavanone A for 12 h at various concentrations and Western blot analysis for HO-1 expression was performed. Representative blots of three independent experiments are shown. (B) Cells were treated with 40 μM of cudraflavanone A for 0.5, 1, and 1.5 h, and the levels of Nrf2 protein in each fraction were determined by Western blot analysis. The experiment was repeated three times and similar results were obtained. **p < 0.01 in comparison with 0 h treated group
표 Effect of SnPP on the inhibitory actions of cudraflavanone A on the production and expression of nitrite (A), PGE2 (B), and iNOS protein (C). Cells were pre-treated with 50 μM of SnPP and incubated with or without cudraflavanone A (40 μM) for 24 h. (A) Nitrite levels were determined using the Griess reaction. **p < 0.001. (B) PGE2 was quantified by ELISA. **p < 0.01 and ***p < 0.001. (C) Lysates were prepared from cells pre-treated with/without 50 μM SnPP for 1 h, 40 μM of cudraflavanone A for 3 h and then with LPS (1 μg/mL) for 24 h. iNOS protein expression was determined by Western blot analysis and representative blots from three independent experiments are shown

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천연물유래 autoinflammation 기반 퇴행성뇌질환 억제물질 발굴
Discovery of the degenerative brain diseases drug candidates based on auto-inflammation from natural products 원문보기