• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.194-199
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• 2002

Many oxidative metabolites of tetrahydrocannabinols (THCs), active components of marijuana, were pharmacologically active, and 11-hydroxy-THCs, 11-oxo-${\Delta}^8$-THC, 7-oxo-${\Delta}^8$-THC, 8$\beta$, 9$\beta$-epoxyhexahydrocannabinol (EHHC), 9$\alpha$, l0$\alpha$-EHHC and 3'-hydroxy-${\Delta}^9$-THC were more active than THC in pharmacological effects such as catalepsy, hypothermia and barbiturate synergism in mice. Cannabidiol (CBD), another major component, was biotransfomred to two novel metabolites, 6-hydroxymethyl-${\Delta}^9$-THC and 3-pentyl-6, 7, 7a, 8, 9, lla-hexahydro-I, 7-dihydroxy-7, 1O-dimethyldibenzo[b, d]oxepin (PHDO) through 8R, 9-epoxy-CBD and 85, 9-epoxy-CBD, respectively. Both metabolites exhibited some pharmacological effects comparable to d9 - THe. Cannabinol (CBN), the other major component, was mainly metabolized to ll-hydroxy-CBN by hepatic microsomes of animals including humans. The pharmacological effects of the metabolite were higher than those of CBN demonstrating that II-hydroxylation of CBN is metabolic activation pathway of the cannabinoid as is the case in THCs. Tolerance and reciprocal cross-tolerance developed to pharmacological effects d8 - THC and ll-hydroxy-d8-THC , and the magnitude of tolerance development produced by the metabolite was significantly higher than that by d8-THC. The results indicate that ll-hydroxy-d8-THC has an important role not only in the pharmacological effects but also its tolerance development of d8 - THe. THCs and their metabolites competed to the specific binding of CP-55, 940, an agonist of cannabinoid receptor, to synaptic membrane from bovine cerebral cortex. The Ki value of THCs and their metabolites were closely paralleled to their pharmacological effects in mice. A novel cytochrome P450 (cyp2c29) was purified and identified as a major enzyme responsible for the metabolic activation of d8-THC at the II-position in the mouse liver. cDNA of CYP2C29 was cloned from a mouse cDNA library and its sequence was determined. The oxidation mechanism of THC by cyp2c29 was proposed.

• 정보처리학회논문지B
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• 제10B권3호
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• pp.281-286
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• 2003

실생활에서 해결하고자 하는 문제에 대해 수많은 feature들이 수집되어지나 그 feature들을 모두 문제 해결에 활용하는 것은 어렵다. 모든 feature들에 대한 정확한 자료의 수집이 어려우며 관련된 feature들을 모두 학습에 이용할 경우 복잡한 학습 모델이 생성되어지며 좋은 수행 결과도 얻을 수 없다. 또한 수집된 자료들 간에는 상호 관계나 계층적 관계가 존재하는데, 경험적 지식이나 통계적 방법을 이용하여 feature들간의 관계를 분석함으로써 feature의 수를 줄일 수 있다. 휴리스틱 기법은 반복적인 시행 착오와 경험을 통한 학습으로써 미래가 불확실하고 완전한 정보를 갖고 있지 못할 때, 인간의 사고 기능을 통하여 기억이나 경험을 살려, 스스로 해결방안을 모색하면서 점차로 해에 접근해 가는 방법이다. 전문가들은 경험에 의한 의견 수렴 과정을 거쳐 해당 문제 영역에 접근 가능하며, 이러한 특성을 학습에 사용될 feature의 수를 줄이는데 활용할 수 있다. 전문가들은 원시 자료들을 이용하여 새로운 feature들을 생성할 수 있다 새로이 산출된 feature들과 원시 데이터 내의 feature들을 혼합하여 학습 모델 생성에 이용한다. 본 논문에서는 휴리스틱 함수를 이용하여 학습에 사용될 feature의 수를 줄이고, 추출된 feature들을 신경망의 입력값으로 사용하는 기계 학습 모델을 제시한다. 모델의 성능 평가를 위해 프로야구 경기의 승패 예측 문제를 이용하였다. 실험 결과는 신경 회로망과 휴리스틱 모델을 단독으로 사용했을 때 보다 두 기법을 혼합한 모델이 신경 회로망의 복잡성을 감소시킬 뿐 아니라 분류(classification)의 정확성이 향상되었다.아니라 Hep G2 세포에서도 명백히 단백질의 발현을 관찰할 수 있었다. 또한, Hep G2와 COS세포 모두에서 endogenous RXR의 발현이 일어남을 확인하였고 RXR expression plasmid를 transfection시켰을 때 두 세포 모두에서 단백질의 발현이 현저하게 증가되었다. Constitutive Androstane Receptor (CAR)에 의한 CYP2B의 PBRU 활성효과를 다르게 분화된 세포에서 차이가 일어나는지를 비교하기 위하여 CAR에 의해 매개되는 PBRU의 transactivation효과를 Hep G2와 COS세포에서 조사하였다. Hep G2 세포에서는 transfection된 CAR의 발현에 의해 firefly luciferase 보고단백질의 활성이 약 12배 증가하였다. CAR 발현유전자를 15 ng transfection하였을 때 주어진 보고유전자의 양에 대하여 최대반응을 나타내었고 CYP2B1PBRU가 제거된 CYP2C1 promotor/firefly luciferase를 보고유전자로 사용하였을 때는 CAR에 의한 luciferase의 활성이 나타나지 않았다. Hep G2와는 달리, COS세포에서는 transfection된 CAR의 발현이 PBRU에 의한 firefly luciferase보고단백질의 발현에 영향을 주지 못하였다. 이러한 결과들은 분화된 세포의 종류에 따라서 constitutive androstane receptor의 CYP2BPBRU 활성효과가 다르게 나타날 수 있음을 제시할 뿐만 아니라, 간세포에서 Phenobarbital에 의한 PBRU의 활성유도에 영향을 주는 endogenous 매개 인자들 중 CAR와 RXR과는 다

• 약학회지
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• 제53권5호
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• pp.259-264
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• 2009

The present study was to investigate the effect of naringin, a flavonoid, on the pharmacokinetics of losartan in rats. Pharmacokinetic parameters of losartan in rats were determined after an oral administration of losartan (9 mg/kg) in the presence or absence of naringin (0.5, 2.5 and 10 mg/kg). The pharmacokinetic parameters of losartan were significantly altered by the presence of naringin compared with the control group (given losartan alone). Presence of naringin significantly (p<0.05, 2.5 mg/kg; p<0.01, 10 mg/kg) increased the area under the plasma concentration?time curve (AUC) of losartan by 43.7~63.0% and peak plasma concentration ($C_{max}$) of losartan by 31.7~45.5%. Consequently, the absolute bioavailability (AB) of losartan in the presence of naringin was 43.8~62.9%, which was enhanced significantly (p<0.05, p<0.01) compared to that in the oral control group (22.4%). The relative bioavailability (R.B.) of losartan increased by 1.44- to 1.63-fold in the presence of naringin. However, there was no significant change in the peak plasma concentration ($T_{max}$) and terminal half-life ($t_{1/2}$) of losartan in the presence of naringin. In conclusion, the presence of naringin significantly enhanced the oral bioavailability of losartan, implying that presence of naringin might be mainly effective to inhibit the cytochrome P450 (CYP)3A-mediated metabolism, resulting in reducing gastrointestinal and hepatic first-pass metabilism and Pglycoprotein (P-gp)-mediated efflux of losartan in small intestine. Concurrent use of naringin or naringin-containing dietary supplement with losartan should require close monitoring for potential drug interactions.

• 한방안이비인후피부과학회지
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• 제20권1호통권32호
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• pp.130-144
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• 2007

UV-irradiated skin shows acutely erythema, edema, pigmantation (sunbum) and chronically coarse wrinkling, roughness, dryness, laxity (photoaging). Jawoongo(紫雲膏, JW) is clinically useful external application and effective bum, sunburn, wound and symptom of dryness(燥症) in skin disease. In this experiment, we examined if JW could cure the UVB-mediated acute skin damages, inhibit UVB-mediated oxidative stress and inflammation of skin, and block the photoaging. In vivo test, we found that JW could effectively cure the UVB-mediated acute skin damages(erythema, edema, angiogenesis, hyperplasia, infiltration of lymphocytes) and inhibit expression of HSP70, CYP1A1 and p53. We also found that JW could repair destruction of collagen fiber and inhibit activation of MMP-9, and inhibit expression of $NF-{\kappa}B$ p65, iNOS, hyperplasia of keratynocyte. In vitro test, we found that JW could inhibit expression of IKK, iNOS mRNA, and production of NO. These findings shows that JW could cure the UVB-mediated acute skin damages, inhibit UVB-mediated oxidative stress and inflammation of skin, and block photoaging.

• Toxicological Research
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• 제23권3호
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• pp.189-196
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• 2007

Cytochrome P450 (P450) enzymes are the major catalysts involved in the biotransformation of various drugs, pollutants, carcinogens, and many endogenous compounds. Most of chemical carcinogens are not active by themselves but they require metabolic activation. P450 isozymes playa pivotal role in the metabolic activation. The activation of arylamines and heterocyclic arylamines (HAAs) involves critical N-hydroxylation, usually by P450. CYP1A2 plays an important role in these reactions. Broad exposure to many of these compounds might cause carcinogenicity in animals and humans. On the other hand, P450s can be also involved in the bioactivation of other chemicals including alcohols, aflatoxin B1, acetaminophen, and trichloroethylene, both in humans and in experimental animals. Understanding the P450 metabolic activation of many chemicals is necessary to develop rational strategies for prevention of their toxicities in human health. An important part is the issues of extrapolation between species in predicting risks and variation of P450 enzyme activities in humans.

• 한국식품영양과학회지
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• 제45권6호
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• pp.805-811
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• 2016

본 연구는 에탄올로 유도한 알코올성 지방간 동물모델에서 굴 열수 추출물의 알코올성 간 손상 개선 효과를 평가하기 위해 수행되었다. 6주령의 SD rat(male)을 총 6개 군으로 분리하였으며, 양성대조군으로 헛개나무 열매 추출물(500 mg/kg b.w.)을 처리하였다. 6주 동안 하루 간격으로 CGW를 50, 200, 800 mg/kg b.w. 농도로 경구 투여하였으며, control군을 제외한 나머지군은 40% ethanol 5 g/kg b.w.를 6주간 투여하였다. 43일째 실험동물을 희생시켜 혈액 분석 및 간 조직의 항산화 효과 분석을 통해 에탄올로 유도한 동물모델에서 굴 열수 추출물의 알코올성 간 손상 회복 효과를 확인한 결과, 에탄올에 의해 증가한 ALT와 ${\gamma}-GT$의 수준이 CGW를 투여함으로써 유의적으로 감소하였으며, 항산화효소 활성이 증가한 것을 확인할 수 있었다. 에탄올에 의해 손상된 간 조직의 손상 정도를 평가하기 위해 수행한 조직병리학적 검사에서는 에탄올의 투여로 증가한 지방변성 비율 및 간세포 수와 같은 인자들이 굴 열수 추출물의 투여로 유의적으로 회복된 것을 확인하였다. 또한, 에탄올에 의해 증가한 CYP2E1의 발현이 굴 열수 추출물의 투여로 유의적으로 감소하였다. 이러한 연구 결과들로 보았을 때 본 실험에서 굴 추출물의 다당류 및 폴리페놀의 항산화 작용으로 알코올로 유도된 간 손상을 억제할 수 있음을 예상할 수도 있지만, 이후 추가적인 연구로 다른 활성성분의 규명과 관련 활성 기작을 탐구하고자 한다. 본 연구진은 이와 같은 결과를 바탕으로 굴 열수 추출물이 알코올성 지방간 동물모델에서 항산화 방어시스템의 강화를 통해 간 손상을 회복시킴을 확인할 수 있었고, 이러한 연구 성과들로 굴 추출물이 알코올성 간 손상 개선에 있어 효과적인 대안으로서 더욱 더 많은 분야에서 연구되기를 바라는 바이다.

• Asian-Australasian Journal of Animal Sciences
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• 제27권12호
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• pp.1695-1704
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• 2014

Maternal malnutrition during pregnancy may give rise to female offspring with disrupted ovary functions in adult age. Neonatal ovary development predisposes adult ovary function, yet the effect of maternal nutrition on the neonatal ovary has not been described. Therefore, here we show the impact of maternal protein restriction on the expression of folliculogenic and steroidogenic genes, their regulatory microRNAs and promoter DNA methylation in the ovary of neonatal piglets. Sows were fed either standard-protein (SP, 15% crude protein) or low-protein (LP, 7.5% crude protein) diets throughout gestation. Female piglets born to LP sows showed significantly decreased ovary weight relative to body weight (p<0.05) at birth, which was accompanied with an increased serum estradiol level (p<0.05). The LP piglets demonstrated higher ratio of bcl-2 associated X protein/B cell lymphoma/leukemia-2 mRNA (p<0.01), which was associated with up-regulated mRNA expression of bone morphogenic protein 4 (BMP4) (p<0.05) and proliferating cell nuclear antigen (PCNA) (p<0.05). The steroidogenic gene, cytochrome P450 aromatase (CYP19A1) was significantly down-regulated (p<0.05) in LP piglets. The alterations in ovarian gene expression were associated with a significant down-regulation of follicle-stimulating hormone receptor mRNA expression (p<0.05) in LP piglets. Moreover, three microRNAs, including miR-423-5p targeting both CYP19A1 and PCNA, miR-378 targeting CYP19A1 and miR-210 targeting BMP4, were significantly down-regulated (p<0.05) in the ovary of LP piglets. These results suggest that microRNAs are involved in mediating the effect of maternal protein restriction on ovarian function through regulating the expression of folliculogenic and steroidogenic genes in newborn piglets.

• Toxicological Research
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• 제34권2호
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• pp.151-162
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• 2018

Anti-diabetes activity of Catharsius molossus (Ca, a type of dung beetle) glycosaminoglycan (G) was evaluated to reduce glucose, creatinine kinase, triglyceride and free fatty acid levels in db mice. Diabetic mice in six groups were administrated intraperitoneally: Db heterozygous (Normal), Db homozygous (CON), Heuchys sanguinea glycosaminoglycan (HEG, 5 mg/kg), dung beetle glycosaminoglycan (CaG, 5 mg/kg), bumblebee (Bombus ignitus) queen glycosaminoglycan (IQG, 5 mg/kg) and metformin (10 mg/kg), for 1 month. Biochemical analyses in the serum were evaluated to determine their anti-diabetic and anti-inflammatory actions in db mice after 1 month treatment with HEG, CaG or IQG treatments. Blood glucose level was decreased by treatment with CaG. CaG produced significant anti-diabetic actions by inhiting creatinine kinase and alkaline phosphatase levels. As diabetic parameters, serum glucose level, total cholesterol and triglyceride were significantly decreased in CaG5-treated group compared to the controls. Dung beetle glycosaminoglycan, compared to the control, could be a potential therapeutic agent with anti-diabetic activity in diabetic mice. CaG5-treated group, compared to the control, showed the up-regulation of 48 genes including mitochondrial yen coded tRNA lysine (mt-TK), cytochrome P450, family 8/2, subfamily b, polypeptide 1 (Cyp8b1), and down-regulation of 79 genes including S100 calcium binding protein A9 (S100a9) and immunoglobulin kappa chain complex (Igk), and 3-hydroxy-3-methylglutaryl-CoenzymeAsynthase1 (Hmgcs1). Moreover, mitochondrial thymidine kinase (mt-TK), was up-regulated, and calgranulin A (S100a9) were down-regulated by CaG5 treatment, indicating a potential therapeutic use for anti-diabetic agent.

• Journal of Nutrition and Health
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• 제50권3호
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• pp.217-224
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• 2017

Purpose: Although it is well known thatmortality and morbidity due to cardiovascular diseases are higher in salt-sensitive subjects than in salt-resistant subjects, their underlying mechanisms related to obesity remain unclear. Here, we focused on salt-sensitive gene variants unrelated to monogenic obesity that interacted with sodium intake in humans. Methods: This review was written based on the modified $3^rd$ step of Khans' systematic review. Instead of the literature, subject genes were based on candidate genes screened from our preliminary Genome-Wide Association Study (GWAS). Finally, literature related to five genes strongly associated with salt sensitivity were analyzed to elucidate the mechanism of obesity. Results: Salt sensitivity is a measure of how blood pressure responds to salt intake, and people are either salt-sensitive or salt-resistant. Otherwise, dietary sodium restriction may not be beneficial for everyone since salt sensitivity may be associated with inherited susceptibility. According to our previous GWAS studies, 10 candidate genes and 11 single nucleotide polymorphisms (SNPs) associated with salt sensitivity were suggested, including angiotensin converting enzyme (ACE), ${\alpha}$-adducin1 (ADD1), angiotensinogen (AGT), cytochrome P450 family 11-subfamily ${\beta}$-2 ($CYP11{\beta}$-2), epithelial sodium channel (ENaC), G-protein b3 subunit (GNB3), G protein-coupled receptor kinases type 4 (GRK4 A142V, GRK4 A486V), $11{\beta}$-hydroxysteroid dehydrogenase type-2 (HSD $11{\beta}$-2), neural precursor cell-expressed developmentally down regulated 4 like (NEDD4L),and solute carrier family 12(sodium/chloride transporters)-member 3 (SLC 12A3). We found that polymorphisms of salt-sensitive genes such as ACE, $CYP11{\beta}$-2, GRK4, SLC12A3, and GNB3 may be positively associated with human obesity. Conclusion: Despite gender, ethnic, and age differences in genetics studies, hypertensive obese children and adults who are carriers of specific salt-sensitive genes are recommended to reduce their sodium intake. We believe that our findings can contribute to the prevention of early-onset of chronic diseases in obese children by facilitating personalized diet-management of obesity from childhood to adulthood.

• Korean Journal of Acupuncture
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• 제19권1호
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• pp.7-13
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• 2002

1. 천궁약침액은 1${\times}$에서 15.1%의 cytochrome P4501A1 저해효과를 나타냈으며 그 억제효과는 약침액의 농도가 높을수록 증가하였다. 2 천궁약침액은 benzo[a]pyrene과 세포의 DNA 결합을 유의성있게 억제시켰다. 이상의 결과를 종합해 볼때 천궁약침액은 효과적으로 cytochrome P4501A1 효소를 저해했으며, 발암물질과 DNA의 결합을 억제시켜 외부 물질 또는 대사물에 의해 일어날 수 있는 돌연변이와 암 발생을 억제할 것으로 사료된다.