Aspects of Antithrombotic Effect of HMG-CoA Reductase Inhibitors

Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are widely used for the treatment of hypercholesteremia and have showed remarkable activity in preventing cardiovascular morbidity and mortality. Recent studies demonstrated that statins have significant antithrombotic effect in addition to cholesterollowering action. Although the efficacy of statins for reducing cardiovascular events has historically been ascribed to their inhibitory activity on cholesterol synthesis, the degree of low-density lipoprotein cholesterol reduction by statins generally does not correlate with the magnitude of coronary risk reduction.

Nrf2-inducing and HMG-CoA reductase inhibitory activities of a polyphenol-rich fraction of Guazuma ulmifolia leaves

Objective: To fractionate and identify polyphenols from Guazuma ulmifolia Lam. leaves, and to explore their antioxidant, 5-hydroxy-3-methylglutaryl-coenzyme A(HMG-Co A) reductase inhibitory, and Nrf2 modulatory activities.Methods: The 1,1-diphenyl-2-picrylhydrazyl assay was used to evaluate the antioxidant activity of a polyphenolic fraction of the extract of Guazuma ulmifolia Lam. leaves. THP-1 gene reporter cell lines constructed with a transcriptional response element specific for Nrf2 and a minimal promoter for the firefly luciferase–green fluorescent protein transgene were used to determine the effect of the polyphenolic fraction on the Nrf2 signaling pathway. Furthermore, an assay of HMG-Co A reductase inhibitory activity was performed by using a commercial enzyme kit. Polyphenolic compounds were identified by liquid chromatographytandem mass spectrometry.Results: The polyphenolic fraction showed fairly strong antioxidant activity [IC50 =(14.90 ± 4.70) μg/m L] and inhibited HMG-Co A reductase activity by 69.10%, which was slightly lower than that by pravastatin(84.37%) and quercetin(84.25%). Additionally, the polyphenolic fraction activated the Nrf2 antioxidant signaling pathway at 500 μg/m L. Eleven subfractions resulting from the column chromatography separation of the polyphenolic fraction also showed relatively strong antioxidant activities(IC50: 17.46–217.14 μg/m L). The subfraction(F6) stimulated the Nrf2 signaling pathway and had HMG-Co A reductase inhibitory activity(65.43%). Moreover, the subfraction contained two main flavonoids: quercetin and quercimeritrin.Conclusions: The polyphenolic fraction of Guazuma ulmifolia could induce antioxidant genes via the Nrf2/antioxidant regulatory elements pathway, and is a promising candidate for an inhibitor of HMG-Co A reductase.

Relation between Baseline Lipid Levels and Effectiveness of HMG-CoA Reductase Inhibitors in Patients with Hyperlipidemia

Objective To evaluate whether the effects of HMG - CoA reductase inhibitors on patients with hyperlipidemia are closely related to baseline lipid levels. Methods The data analyzed originated from 3 separate multicenter clinical trials with similar designs during 1994 to 1999. 166 patients with mean age 58. 9±9. 2 years were involved in Simvastatin Clinical Trial with simvastatin 10 mg once daily for 8 weeks. 146 patients with mean age 57. 9±8. 7years were involved in Lovastatin Clinical Trial with lovastatin 20 mg once daily for 8 weeks. 105 patients with mean age 57. 8±9. 3 years were involved in Atorvastatin Clinical Trial with atorvastatin 10 mg once daily for 6 weeks. Baseline total cholesterol (TC) was more than 5. 98 mmol. L - 1, and baseline triglyceride (TG) was less than 4. 52 mmo. L - 1. The patients were grouped by baseline lipid levels. Results The higher the baseline TC, low density lipoprotein cholesterol (LDL - C) and TG levels were, the more effective the simvastatin, lovastatin, or atorvastatin was in reducing serum TC, LDL - C, and TG, respectively. A positive linear correlation was found between baseline values and effects of simvastatin, lovastatin, or atorvastatin in reducing serum TC, LDL - C, and TG, respectively. Conclusion The changes of reduction on serum lipid with HMG - CoA reductase inhibitors in patients with hyperlipidemia were influenced by baseline lipid levels.

Inhibitory roles of protein kinase B and peroxisome proliferator-activated receptor gamma coactivator on hepatic HMG-CoA reductase promoter activity

Since we had previously demonstrated that siRNAs to tristetraprolin (TTP) markedly inhibited insulin stimulation of hepatic HMG-CoA reductase (HMGR) transcription, we investigated the effects of transfecting rat liver with TTP constructs. We found that transfecting diabetic rats with TTP did not increase HMGR transcription but rather led to modest inhibition. We then investigated whether co-transfection with protein kinase B, hepatic form (AKT2), might lead to phosphorylation and result in activation of HMGR transcription. We found that this treatment resulted in near complete inhibition of transcription. Transfection with peroxisome proliferator-activated receptor g coactivator (PGC-1a) also inhibited HMGR transcription. These results show that although TTP is needed for activation of HMGR transcription, it cannot by itself activate this process. AKT2 and PGC-1a, which mediate the activation of gluconeogenic genes by insulin, exert the opposite effect on HMGR.

The use of 5-alpha reductase inhibitors in the treatment of benign prostatic hyperplasia

Benign prostatic hyperplasia(BPH)is characterized by an enlarged prostate,lower urinary tract symptoms(LUTS),and a decreased urinary flow rate.Common in older men,BPH is a progressive disease that can eventually lead to complications including acute urinary retention(AUR)and the need for BPH-related surgery.Both normal and abnormal prostate growth is driven by the androgen dihydrotestosterone(DHT),which is formed from testosterone under the influence of 5-alpha reductase.Thus,5-alpha reductase inhibitors(5-ARIs)effectively reduce the serum and intraprostatic concentration of DHT,causing an involution of prostate tissue.Two 5-ARIs are currently available for the treatment of BPHdfinasteride and dutasteride.Both have been demonstrated to decrease prostate volume,improve LUTS and urinary flow rates,which ultimately reduces the risk of AUR and BPH-related surgery.Therefore,either alone or in combination with other BPH medications,5-ARIs are a mainstay of BPH management.

Changes in aortic endothelium ultrastructure in male rats following castration, replacement with testosterone and administration of 50α-reductase inhibitor

Aim： To investigate the relationship between low androgen level and ultrastructure of vascular endothelium. Methods： Forty-eight male Sprague-Dawley rats were randomly divided into four groups： group A, normal rats with sham castration; group B, castrated rats; group C, castrated rats given testosterone （T） undecanoate; and group D, intact rats treated with 5α-reductase inhibitor. After 10 weeks of treatment or castration, rats in different groups were killed and serum T, free T （FT） and dihydrotestosterone （DHT） were measured. The aortic endothelia were scanned under electron microcopy and the Vascular Endothelium Structure Score （VESS） was computed. Results： Serum T and FT concentrations of rats in group B were significantly lower than those of the other three groups （P 〈 0.01）; DHT concentrations of group D rats were significantly decreased （P 〈 0.01 ） when compared with those of groups A and C. Rats in groups B and D rats （with low androgen levels） had obvious damage to their endothelial surfaces, which appeared crimpled, rough, adhesive and ruptured, and had high destruction of VESS. Conclusion： These results suggest that low concentrations of T and DHT are associated with ultrastructural damage of the aortic endothelia in male rats.

Aldo-keto reductases:Role in cancer development and theranostics

Aldo-keto reductases(AKRs)are a superfamily of enzymes that play crucial roles in various cellular processes,including the metabolism of xenobiotics,steroids,and carbohydrates.A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers.AKRs are aberrantly expressed in a wide range of malignant tumors.Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance.AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression.Inhibition of aldose reductase(AR),either alone or in combination with chemotherapeutic drugs,has evolved as a pragmatic therapeutic option for cancer.Several classes of synthetic aldo-keto reductase(AKR)inhibitors have been developed as potential anticancer agents,some of which have shown promise in clinical trials.Many AKR inhibitors from natural sources also exhibit anticancer effects.Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies.These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy.In this review,we discuss the physiological functions of human AKRs,the aberrant expression of AKRs in malignancies,the involvement of AKRs in the acquisition of cancer hallmarks,and the role of AKRs in oncogenic signaling,and drug resistance.Finally,the potential of aldose reductase inhibitors(ARIs)as anticancer drugs is summarized.

Medical therapy for clinical benign prostatic hyperplasia:α1 Antagonists,5α reductase inhibitors and their combination

Medical therapy for clinical benign prostatic hyperplasia(BPH)has advanced significantly in the last 2 decades.Many new a1 antagonists and 5a reductase inhibitors(5ARi)are now commercially available.The practicing urologist must decide on the most appropriate medication for his patients,taking into consideration various factors like efficacy,dosing regime,adverse effects,cost,patient’s socioeconomic background,expectations,drug availability and his own clinical experience.The use of combination therapy added further to the complexity in clinical judgment when prescribing.We highlight some of the key points in prescribing a1 antagonists,5ARi and their combination,based on our viewpoints and experience as urologists in an Asian clinical setting.

A novel thioredoxin reductase inhibitor inhibits cell growth and induces apoptosis in HL-60 and K562 cells

Human thioredoxin reductase (TrxR) system is associated with cancer cell growth and anti-apoptosis process. Effects of 1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone)ethane (BBSKE),a novel TrxR inhibitor,were investigated on human leu-kemia cell lines HL-60 and K562. BBSKE treatment induced cell growth inhibition and apoptosis in both cell lines. Apoptosis induced by BBSKE is through Bcl-2/Bax and caspase-3 pathways. Ehrlich's ascites carcinoma-bearing mice were used to inves-tigate the anti-tumor effect of BBSKE in vivo. Tumor-bearing mice treated with BBSKE showed an increase of life span with a comparable effect to cyclophosphamide (CTX). These results suggest a potential usage of BBSKE as a therapeutic agent against non-solid tumors.

A systematic review of the effects and mechanisms of preoperative 5α-reductase inhibitors on intraoperative haemorrhage during surgery for benign prostatic hyperplasia

5α-reductase inhibitors （5α-RIs）, including finasteride and dutasteride, are commonly used medical therapies for benign prostatic hyperplasia （BPH）. Many studies reported that preoperative 5α-RI had impact on intraoperative haemorrhage during surgery for BPH, but it was still in controversial. So, we conducted a systematic review of the effects and mechanisms of 5α-RIs on intraoperative bleeding for BPH. MEDLINE, EMBASE, the Cochrane Controlled Trail Register of Controlled Trials and the reference lists of retrieved studies were searched in the analysis. Sixteen publications involving 15 different randomized controlled trials （RCTs） and a total of 1156 patients were used in the analysis, including 10 RCTs for finasteride and five RCTs for dutasteride. We found that preoperative finasteride treatment decreases microvessel density （MVD） in resected prostate specimens. Total blood loss, blood loss per gram of resected prostate tissue and decreases in haemoglobin were all greatly reduced in the finasteride group as compared to controls. Dutasteride appeared to have no effect on bleeding. This meta-analysis shows that preoperative finasteride treatment could decrease intraoperative haemorrhage during surgery for BPH. Preoperative dutasteride had no effect on intraoperative haemorrhage, but further high-qualitv prospective studies are still needed to confirm this observation.

Screening of traditional Chinese medicine monomers as ribonucleotide reductase M2 inhibitors for tumor treatment

BACKGROUND Ribonucleotide reductase(RR)is a key enzyme in tumor proliferation,especially its subunit-RRM2.Although there are multiple therapeutics for tumors,they all have certain limitations.Given their advantages,traditional Chinese medicine(TCM)monomers have become an important source of anti-tumor drugs.Therefore,screening and analysis of TCM monomers with RRM2 inhibition can provide a reference for further anti-tumor drug development.AIM To screen and analyze potential anti-tumor TCM monomers with a good binding capacity to RRM2.METHODS The Gene Expression Profiling Interactive Analysis database was used to analyze the level of RRM2 gene expression in normal and tumor tissues as well as RRM2's effect on the overall survival rate of tumor patients.TCM monomers that potentially act on RRM2 were screened via literature mining.Using AutoDock software,the screened monomers were docked with the RRM2 protein.RESULTS The expression of RRM2 mRNA in multiple tumor tissues was significantly higher than that in normal tissues,and it was negatively correlated with the overall survival rate of patients with the majority of tumor types.Through literature mining,we discovered that berberine,ursolic acid,gambogic acid,cinobufagin,quercetin,daphnetin,and osalmide have inhibitory effects on RRM2.The results of molecular docking identified that the above TCM monomers have a strong binding capacity with RRM2 protein,which mainly interacted through hydrogen bonds and hydrophobic force.The main binding sites were Arg330,Tyr323,Ser263,and Met350.CONCLUSION RRM2 is an important tumor therapeutic target.The TCM monomers screened have a good binding capacity with the RRM2 protein.

Pre-Androgen Ablation Prostate Cancer Patients Who Bleed Do Well with 5 Alpha Reductase Inhibitors

Background: Patients with gross haematuria are sometimes found to have prostate cancer after clinical evaluation. The treatment of such haematuria could be very challenging. Use of a 5 alpha reductase inhibitor like dutasteride has been found helpful in bleeding prostate cancer patients if they have not undergone hormonal manipulation before they developed haematuria. Patients and Method: 26 patients with gross haematuria of prostatic origin who had histologic confirmation of adenocarcinoma of the prostate but who have not had chemical or surgical castration were randomized to receive daily dutasteride in addition to vigorous saline irrigation and antibiotics on one arm and vigorous saline irrigation and antibiotics only as control on the other arm. The time taken before haematuria resolved and the amount of irrigation fluid used were noted. Statistical analysis was done using SPSS. Student’s t-test and Kaplan Meier survival analysis were used to test various variables at 0.5 significant levels. Results: Of the 26 patients 12(46.2%) received 0.5 mg oral dutasteride in addition to saline irrigation while 14 (53.8%) received saline irrigation only. Haematuria stopped in all of 12 (100%) patients on dutasteride arm but on 12 (85.7%) of the 14 patients on the control arm. It took significantly shorter time and lesser volume of irrigation fluid before haematuria resolved in those treated with dutasteride than in those on the control arm. Conclusion: Dutasteride is effective in the control of acute haematuria in pre-androgen ablation prostate cancer patients.

Towards Application of Bioactive Natural Products Containing Isoprenoids for the Regulation of HMG-CoA Reductase—A Review

Recognition of the biological properties of numerous “natural products” has fueled the current focus of this field, namely, the search for new drugs, antibiotics, insecticides, and herbicides. Based on their biosynthetic origins, natural products can be divided into three major groups: the isoprenoids, alkaloids, and phenolic compounds. Isoprenoids are structurally the most diverse group of secondary natural metabolites with different roles in the growth, development, and reproduction of a diverse range of prokaryotic and eukaryotes cells. Mevalonate and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways are known to be responsible for biosynthesis of numerous isoprenoids. HMG-CoA reductase is a rate-determining enzyme in mevalonate pathway, producing intermediates such as farnesyl and geranylgeranyl pyrophosphates, which lead to by-products such as cholesterol. Earlier studies have demonstrated that the inhibition of HMG-CoA reductase is one of the most effective approaches for treating hypercholesterolemia and eventually cardiovascular disease (CVD). Statins are HMG-CoA reductase inhibitors and the most prescribed group of drugs worldwide in treating hypercholesterolemia;however the application of this group of drugs may be expensive and has side effects including rashes and gastrointestinal symptoms. For these reasons, there is an important need to examine the viability of natural products as an alternative to statin treatment. This article is a review of different aforementioned areas with a focus on isoprenoids that can be used for the regulation of HMG-CoA reductase.

Differential expression of 5-alpha reductase sozymes in the prostate and its clinical implications

The development of human benign or malignant prostatic diseases is closely associated with androgens, primarily testosterone （T） and dihydrotestosterone （DHT）. T is converted to DHT by 5-alpha reductase （5-AR） isozymes. Differential expression of 5-AR isozymes is observed in both human benign and malignant prostatic tissues. 5-AR inhibitors （5-ARI） are commonly used for the treatment of benign prostatic hyperplasia （BPH） and were once promoted as chemopreventive agents for prostate cancer （PCa）. This review discusses the role of the differential expression of 5-AR in the normal development of the human prostate and in the pathogenesis and progression of BPH and PCa.

HMG-CoA还原酶抑制剂三维药效团的构建

以作用于鼠肝脏细胞的21个3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂(RI)为训练集,训练集化合物具备结构多样性,来源于相同药理模型,活性值IC50范围在0.3-8000nmol·L-1.利用Catalyst计算HMG-CoA还原酶抑制剂最优药效团由一个氢键受体,一个氢键给体,一个疏水基团和一个芳香环特征组成.药效团模型Fixedcost值,Totalcost值和Configurationcost值分别为88.75、111.5和16.98.训练集化合物活性计算值与实测值相关系数为0.8883,偏差值为1.269,交叉验证结果表明,药效团模型具有较高的置信度,对测试集化合物活性值的预测结果显示有较好的预测能力,可用于数据库搜索发现新的具有该活性的化合物,也可用于中药或天然产物药物的研究开发.

血脂调节剂的研究——Ⅰ.HMG-CoA还原酶抑制剂M-8614A及MH-2688B产生菌的筛选

利用酶联免疫吸附测定法,酶标β-羟基β-甲基-戊二酸单酰铺酶A(HMG-CoA)还原酶抑制剂Compactin抗体,定向筛选血脂调节剂。从青霉M-8614菌株发酵液中分离到M-8614A。该物质理化性质及波谱解释表明与Mevastatin为同一物质。 M-8614菌株用亚硝酸盐等诱变剂处理,从诱变株MH-2688发酵液中分离到MH-2688B。该物质理化性质及波谱解释表明与Lovastatin为同一物质。

HMG-CoA还原酶抑制剂的合成(下)

Several synthetic methods for hypolipidemic HMG-CoA reductase inhibitors were reviewed, including thepreparation of the side chains with the suitable groups such as aldehydo, acetylenyl, sulfonyl, phosphono or amino as well as thecondensation of these chains with the heteroaromatic compounds by Wittig-Hornor or Julia-Kocienski Olefination reaction.

Inhibitory effect of fluvastatin on ileal ulcer formation in rats induced by nonsteroidal antiinflammatory drug

AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs)cause gastrointestinal damage as one of their side effects in humans and experimental animals. Lipid peroxidation plays an important role in NSAID-induced ulceration. The aim of this study was to investigate the inhibitory effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitors on the ulceration in small intestines of rats.METHODS: The effects of three HMG-CoA reductase inhibitors, fluvastatin, pravastatin and atorvastatin on ileal ulcer formation in 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) thiophene (BFMeT)-treated rats were examined. Antioxidative activity of the inhibitors was measured by a redox-linked colorimetric method.RESULTS: Fluvastatin, which was reported to have antioxidative activity, repressed the ileal ulcer formation in rats treated with BFMeT an NSAIDs. However, the other HMG-CoA reductase inhibitors (pravastatin and atorvastatin)did not repress the ileal ulcer formation. Among these HMG-CoA reductase inhibitors, fluvastatin showed a significantly stronger reducing power than the others(pravastatin, atorvastatin).CONCLUSION: Fluvastatin having the antioxidaitive activity suppresses ulcer formation in rats induced by NSAIDs.

HMG-CoA还原酶抑制剂对自发性高血压大鼠血管平滑肌细胞增殖的作用

探讨羟甲基戊二酰辅酶A还原酶抑制剂对自发性高血压大鼠血管平滑肌细胞增殖的抑制作用及其机制。培养自发性高血压大鼠主动脉血管平滑肌细胞 ,应用不同浓度HMG CoA还原酶抑制剂洛伐他汀、辛伐他汀和氟伐他汀及血管紧张素Ⅱ、甲羟戊酸等干预后 ,进行细胞计数和 3 H TdR掺入率测定。结果发现 ,洛伐他汀、辛伐他汀和氟伐他汀均呈浓度依赖性抑制小牛血清和血管紧张素Ⅱ诱导的血管平滑肌细胞数和 3 H TdR掺入率增加 ;但以氟伐他汀的抑制作用最大 ,辛伐他汀次之 ,洛伐他汀最小。 10 - 3 mol L甲羟戊酸几乎完全逆转洛伐他汀、辛伐他汀和氟伐他汀对血管平滑肌细胞增殖的抑制作用。提示此 3种HMG CoA还原酶抑制剂均能抑制高血压大鼠血管平滑肌细胞增殖 ,但作用并不完全相同 ;甲羟戊酸代谢途径可能参与血管平滑肌细胞增殖过程。

HMG-CoA还原酶抑制剂的3D-QSAR研究

HMG-CoA reductase converts HMG-CoA to mevalonate,with this catalysis constituting a committed step in the biosynthesis of cholesterol.So,it’s primary drone in treatment coronary artery disease.At present,several statins are available in the drug market,however,up to now the quantitative structure-activity relationship of all of known inhibitors hasn’t been reported.In order to provide a theoretical guide for the synthesis of novel inhibitors,the quantitative structure-activity relationship of the inhibitors of HMG-CoA reductase were performed by using 3D-QSAR approach: comparative molecular field analysis(CoMFA).The computed obtained CoMFA model with(q^2=0.4,) r^2=0.955,SE=0.110,F=85.335.It not only can be used to explain the structure-activity relationship of compound but also has powerful predictive ability.