• BMB Reports
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• 제30권5호
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• pp.370-377
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• 1997

A novel assay method is described for rapid quantitation of reaction rate of sterol ${\Delta}^7$-reductase (${\Delta}^7$-SR) which catalyzes reduction of the ${\Delta}^7$-double bond of sterols. Of six different organ tissues-liver, small intestine, brain, lung, kidney, and testis-. ${\Delta}^7$-SR activity was detected only in liver (2.30 nmol/min/mg protein) and testis (0.11 nmol/min/mg protein). Using a newly developed method which employs diet-induced enzyme proteins and ergosterol as substrate, we assessed both kinetics ($K_m=210\;{\mu}M$, $V_{max}=1.93\;nmol/min/mg$) and inhibition of the rat hepatic ${\Delta}^7$-SR against well-studied cholesterol lowering agents such as triparanol ($IC_{50}=16\;{\mu}M$). 3-$\beta$-[2-(diethylamino)ethoxy]androst-5-en-17-one (U18666A) ($IC_{50}=5.2\;{\mu}M$), and trans-1.4-bis(2-chlorobenzylaminomethyl)cyclohexane dihydrochloride (AY-9944) ($IC_{50}=0.25\;{\mu}M$). Of the three well-known AY-9944-sensitive cholesterogenic enzymes (i.e., ${\Delta}^7$-SR, sterol ${\Delta}^8$-isomerase, and sterol ${\Delta}^14$-reductase). ${\Delta}^7$-SR was found to be the most sensitive enzyme with a noncompetitive inhibition of this compound ($K_i=0.109\;{\mu}M$). Substrate specificity studies of the microsomal ${\Delta}^7$-SR indicate that the relative reaction rate for 7-dehydrocholesterol and ergosterol are 5.6-fold and 1.6-fold higher than that for lathosterol. ${\Delta}^7$-SR activity was also modulated by feeding rats a diet supplemented with 0.5% ergosterol (>2.6-fold) in addition to 5.0% cholestyramine plus 0.1% lovastatin ($\simeq$5.0-fold). Finally, microsomal ${\Delta}^7$-SR was solubilized by 1.5% 3-[3-(cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS) and enriched on PEG (0~10%) precipitation, which should be suitable for further purification of the enzyme.

• Journal of Pharmaceutical Investigation
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• 제32권3호
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• pp.191-197
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• 2002

Polymer based physical mixtures or solid dispersions containing solubilizing compositions[OA, tween80 and SLS] were prepared using a spray-dryer. Lovastatin(LOS), simvastatin(SIMS), aceclofenac(AFC) and cisapride(CSP) were selected as poorly water-soluble drugs. Dextrin, poly(vinylalcohol) (PVA), poly(vinylpyrrolidone)(PVP) and polyethylene glycol(PEG) were chosen as solubilizing carriers for solid dispersions. The solid dispersions containing solubilizing compositions without drug were prepared without using organic solvents or tedious changes of formulation compositions. This system could be used to quickly screen the dissolution profiles of poorly water-soluble drugs by simply mixing with drugs thereafter. In case of solid dispersion containing drug, organic solvent systems could be used to solubilize model drugs. The dissolution rates of the drugs were higher when mixed with drug and solid dispersions containing solubilizing compositions. However, solid dispersions of LOS, AFC, and CSP simultaneously containing drug and solubilizing compositions in organic solvent systems were more useful than physical mixtures of drug and solid dispersions without drug except SIMS. Based on solubilizing capability of polymer based physical mixtures in gelatin hard capsules, optimal solid dispersion system of poorly water-soluble drugs could be formulated. However, it should be noted that dissolution rate of poorly water-soluble drugs were highly dependent on drug properties, solubilizing compositions and polymeric carriers.

• 한국임상약학회지
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• 제5권2호
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• pp.61-69
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• 1995

Hyperlipidemia is a major predisposing factor of atherosclerosis and cerebrovascular accidents. In effort to develope a hypolipidemic drug from medicinal herb, We tested three prescriptions of traditional medicine for the lipid lowering effect on diet-induced hyperlipidemic rats. GyejI-Bokryung-Hwan, Ohyak-Sunki-San, and Shihoga-Yongol-Moryu-Tang were selected based on the comnon prescriptions for patients with hyperlipidemia-related diseases. Water extract from each prescriptions was made by the method used in the clinical setting, and administered intragastrically once a day, for 4 weeks. Fenofibrate and lovastatin were given by the same method as the control drugs. Blood levels of total cholesterol(TC), high density lipoprotein(HDL), low density lipoprotein (LDL), and triglyceride(TG) were measured before, 1, 2, 3, and 4 weeks after starting the drug administration. All of the traditional prescriptions did not show lipid lowering effect, while fenofibrate lower the blood cholesterol levels(TC;from 215mg/dl before to 182m41 at 4 weeks-point of drug administration, and LDL ;from 203mg/dl before to aut 161, and 163mg/dl at 3 and 4 week-point respectively). Oyak-Sunki-San increased the level of TC (from 283mg/dl to over 350mg/dl starting from the first week of drug administratin). Effects on TG variable in the cases of traditional medicines and control drug In conclusion, any of the three traditional medical prescriptions did not decrease the level of blood cholesterol.

• Preventive Nutrition and Food Science
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• 제5권4호
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• pp.184-188
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• 2000

HMG-CoA reductase is th rate-limiting enzyme of cholesterol biosynthesis. As intracellular levels of cholesterol should be regulated elaborately in response to external stimuli an internal needs, the expression of the HMG-CoA reductase gene is regulated intricately at several different levels from transcription to post-translational modification. In this study, we investigated the regulatory mechanism of HMG-CoA reductase gene expression at the post-transcriptional/pre-translational levels in a baby hamster kidney cell line, C100. when 25-hydroxycholesterol was added to cells cultured in medium containing 5% delipidized fetal bovine serum and 25$\mu$M lovastatin, the levels of HMG-CoA reductase mRNA decreased rapidly, which seemed to be due to the increased degradation of reductase mRNA. These suppressive effects of 25-hydroxycholesterol on MG-CoA reductase mRNA levels were blocked by a translation inhibitor, cycloheximide. Similarly, actinomycin D and 5,6-dichloro-1-$\beta$-D-ribofuranosylbenzimidazole, transcription inhibitors, blocked the 25-hydroxycholesterol-mediated degradation of HMG-CoA reductase mRNA. These results indicate that new protein/RNA synthesis is required for the degradation of HMG-CoA reductase mRNA. In addition, data from the transfection experiments shows that cis-acting determinants, regulating the stability of reductase mRNA, were scattered in the sequence corresponding to 1766-4313 based on the sequence of Syrian hamster HMG-CoA reductase cDNA. Our data suggests that sterol-mediated destabilization of reductase mRNA might be one of the important regulatory mechanism of HMG-CoA reductase gene expression.

• Journal of Ginseng Research
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• 제29권4호
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• pp.159-166
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• 2005

Ginsenosides, a group of Panax ginseng saponins, exert the lowering effects of plasma cholesterol levels in animals. We had reported earlier that ginsenoside Rb2 upregulate low-density lipoprotein receptor (LDLR) expression via a mechanism that is dependent of the activation of sterol response element binding protein 2 (SREBP-2) expression. This study was conducted to determine the effects of ginsenoside Rb2 on the expression of the hepatic LDLR expression at cellular levels using HepG2 cells, and to evaluate whether the sterol response element binding protein 1 (SREBP-l) was involved in the regulation of LDLR expression. Incubation of HepG2 cells in serum-free medium supplemented with cholesterol $(10{\mu}g/ml)$ for 8 hours decreased the mRNAs of LDLR mRNA by $12\%$ and SREBP-l mRNA by $35\%$. Ginsenoside Rb2 antagonized the repressive effects of cholesterol and increased both LDLR and SREBP-l mRNA expression to 1.5- and 2-fold, respectively. Furthermore, Western blot and confocal microscopic analyses with SREBP-l polyclonal antibody revealed that ginsenoside Rb2 enhanced the maturation of the SREBP-1 from the inactive precursor form in ER membrane to the active transcription factor form in nucleus. These results suggest that ginsenoside Rb2 upregulates LDLR expression via a mechanism that is dependent of the activation of not only SREBP-2 expression, but also SREBP-1 expression and maturation, and also indicate that the pharmacological value of ginsenoside Rb2 may be distinguished from that of lovastatin which is reported that it upregulate LDLR through SREBP-2 only, not through SREBP-1.

• 대한본초학회지
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• 제30권6호
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• pp.83-91
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• 2015

Objectives : The present study was conducted to examine whether Cynanchi wilfordii radix (CWR) with or without fermentation has an ameliorative effect on hyperlipidemia in rats.Methods : We analyzed the contents of Conduritol F on Cynanchi wilfordii radix. The experimental animals were divided into six groups; normal diet fed group (N), high cholesterol fed control group (Con), Lovastatin 20 mg/kg (L), CWR-W 300 mg/kg (CWR-W), and CWR-F 300 mg/kg on hyperlipidemia model induced by feeding 1.25% cholesterol. Rats were administrated orally every day for 8 weeks. And lipid profile of serum and weight change were observed.Results : The vehicle displayed a markedly increased body weight and significantly increased liver and epididymal fat weight, however, the administration of CWR improved the body, liver, and epididymal fat weights. All drug treatment reduced significantly the serum level of total cholesterol and LDL-cholesterol elevated by intake of high cholesterol diet. TG displayed a reducing tendency all drug treatment, however, CWR-W decreased significantly. Atherogenic index and cardiac risk factor increased high cholesterol diet fed control group, while the administration of CWR-W and CWR-F decreased significantly. The major index of liver injury such as AST and ALT improved in all drug treatment.Conclusions : These results suggest that CWR extended the effect of lipid enhanced. Therefore CWR with or without fermentation may be useful for therapeutic treatment of clinical conditions associated with hyperlipidemia. Finally, these require more investigations about the action mechanism of CWR in the future.

• Biomolecules & Therapeutics
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• 제19권4호
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• pp.472-476
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• 2011

Hypercholesterolemia indirectly increases the risk of arterial and venous thrombosis by enhancing the ability of platelets to aggregate. Yacon (Smallanthus sonchifolius) is composed of fructooligosaccharides, proteins, minerals and phenolic compounds, and has potential benefits for the management of diabetes. This study investigated whether the consumption of yacon in the diet inhibits platelet aggregation under hypercholesterolemic conditions. Male New Zealand white rabbits were fed one of five dietary interventions: a normal control diet, 0.5% cholesterol diet, 0.5% cholesterol diet+a low dose of yacon (0.5 g/kg body weight given orally each day), 0.5% cholesterol diet+a high dose of yacon (2.5 g/kg body weight given orally each day), or a 0.5% cholesterol diet+lovastatin (2 mg/kg body weight given orally each day). After 8 weeks, blood was collected to measure the amount of collagen- and thrombin-induced platelets present. Yacon inhibited the platelet aggregation induced by low doses of agonists (0.5 ${\mu}g/mL$ collagen and 0.02 units/ml thrombin) in a concentration-dependent manner. In addition, yacon concentration-dependently inhibited collagen-induced arachidonic acid liberation. Moreover, n-hexane, chloroform and ethyl acetate fractions showed a marked and selective inhibition of the platelet aggregation induced by collagen, again in a dose-dependent manner. These fractions, especially that of chloroform, significantly suppressed platelet aggregation. The results of this study demonstrate that when yacon is added to a cholesterol-enriched diet, cholesterol-induced platelet aggregation returns to control levels. This may also be beneficial in preventing atherosclerosis and reducing risk factors for coronary artery disease and stroke.

• 한국임상약학회지
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• 제31권4호
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• pp.278-284
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• 2021

Background: Osteoporosis is a disease that affects the quality of life and imposes a high socioeconomic burden. Studies have reported that statins, a HMG CoA reductase inhibitor, have a positive or negative effect on osteoporosis. The purpose of this study was to analyze the correlation between statins and osteoporosis risk. Methods: We used the total patient sample data of the Health Insurance Review and Assessment Service (HIRA-NPS-2018). We analyzed the prevalence of osteoporosis in adult patients of Korea who were diagnosed with dyslipidemia and were prescribed statins at the same time. The odds ratio (OR) according to the intensity and type of statin was used to confirming the prevalence. Results: Among the 1,138,899 patients included in the study, 143,895 patients used statins and 27,524 patients (19.13%) were diagnosed with osteoporosis in the statin group. The OR value of statin group was 0.96 (95% CI 0.94-0.98), confirming that the prevalence of osteoporosis decreased, and a significant decrease was seen in all statin intensity. Some of the moderate-intensity statins rather increased the prevalence of osteoporosis, but atorvastatin and rosuvastatin obtained positive results at both medium- and high-intensity doses, and lovastatin, a low-intensity statin, showed the greatest reduction in the prevalence of osteoporosis. Conclusion: We found that the prevalence of osteoporosis was reduced in the statin group, and there was a constant correlation regardless of gender or age. However, a large, prospective, double-blind and randomized study is needed for a long period of time to demonstrate the effectiveness of statins.

• 비만대사연구학술지
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• 제1권1호
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• pp.14-25
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• 2022

In 1971, Dr. Akira Endo succeeded in isolating a cholesterol synthesis inhibitor, compactin. Later, compactin was renamed mevastatin, meaning that it stops the synthesis of mevalonate, which is considered the first statin. However, mevastatin is not commercially released, whereas lovastatin, developed by Alfred Albert of Merk in 1979, was the first commercially developed statin. After the 4S study, the first largescale clinical trial with statins conducted in Scandinavia showed a dramatic secondary preventive effect against cardiovascular disease, and the effectiveness of statins in patients with dyslipidemia was repeatedly demonstrated. Subsequently, many oral drugs that affect blood lipid concentration; statins and ezetimibe aimed at reducing low-density lipoprotein (LDL)) cholesterol; fibrates and omega 3 formulations aimed at reducing triglycerides were widely developed and used in Korea. In this article, we review the results of clinical studies on representative cardiovascular diseases for four types of oral drugs for dyslipidemia, which are currently the most commonly used in Korea.

• 생명과학회지
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• 제24권11호
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• pp.1209-1216
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• 2014

본 연구는 영지버섯 균사체로부터 얻은 수용성 베타글루칸(SBG)이 고지방식이로 유도한 흰쥐의 항고지혈 효과 및 혈중 지질수준에 미치는 영향을 조사하였다. 5주령의 수컷 흰쥐에 고지방식이를 2주간 급여하여 비만을 유도하고, 그 후 2주 동안 다음과 같은 5가지 group의 식이를 급여하였다: 1) 일반사료 식이군(NC), 2) 고지방사료 식이군(HC), 3) 고지방사료 및 고농도(200 mg/kg) SBG 식이군(HC-HSBG) 4) 고지방사료 및 저농도(20 mg/kg) SBG 식이군(HC-LSBG), 5) 고지방사료 및 로바스타틴(lovastatin) 식이군(HC-Lov). 실험 결과, 식이 효율(Food efficiency ratio)은 고지방식이를 급여한 군들에서 일반사료 식이군에 비하여 증가하였으나 통계적 유의성은 없었다. 혈액학적 결과에서 고농도 및 저농도의 SBG와 로바스타틴 투여군은 고지방식이만 급여한 군(HC)보다 호중구와 중성구 수치가 유의성 있게 증가하였다. 또한 혈청 내 총콜레스테롤, 중성지질 및 LDL-C는 고농도 및 저농도 SBG 투여군 모두에서 유의성 있게 감소되었다. 이 같은 결과는 화학적으로 황화된 수용성 베타글루칸(SBG)이 흰쥐에서 혈중 콜레스테롤 수치를 낮추어 항고지혈증 효과를 나타내는 것을 의미한다.