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.

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.

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 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.

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.

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.

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.

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.

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.

High-throughput fluorescent screening of thioredoxin reductase inhibitors to inhibit Mycobacterium tuberculosis

Tuberculosis(TB)is a chronic infectious disease,which is caused by the pathogen Mycobacterium tuberculosis(Mtb)and reemerged as a global health risk with a significant proportion of multi-drug resistant and extensively drug resistant TB cases.It is very urgent to find some novel high-confidence drug targets in Mtb for discovering the effective anti-TB agents.Thioredoxin reductase(TrxR)has been identified to be a highly viable target for anti-TB drugs for its important role in protecting the pathogen from thiol-specific oxidizing stress,regulating intracellular dithiol/disulfide homeostasis and DNA replication and repair.In the present work,a near-infrared(NIR)fluorescent probe DDAT was developed for the detection of TrxR activity and used to high-throughput screen the TrxR inhibitors from natural products.Two screened TrxR inhibitors from Sappan Lignum and microbial metabolites that were further used to inhibit Mycobacterium tuberculosis.All the results indicate that DDAT is a practical fluorescent molecular tool for the discovery of potential anti-TB drugs.

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.

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.

Search of inhibitors of aldose reductase for treatment of diabetic cataracts using machine learning

Purpose:Patients with diabetes mellitus have an elevated chance of developing cataracts,a degenerative visionimpairing condition often needing surgery.The process of the reduction of glucose to sorbitol in the lens of the human eye that causes cataracts is managed by the Aldose Reductase Enzyme(AR),and it is been found that AR inhibitors may mitigate the onset of diabetic cataracts.There exists a large pool of natural and synthetic AR inhibitors that can prevent diabetic complications,and the development of a machine-learning(ML)prediction model may bring new AR inhibitors with better characteristics into clinical use.Methods:Using known AR inhibitors and their chemical-physical descriptors we created the ML model for prediction of new AR inhibitors.The predicted inhibitors were tested by computational docking to the binding site of AR.Results:Using cross-validation in order to find the most accurate ML model,we ended with final cross-validation accuracy of 90%.Computational docking testing of the predicted inhibitors gave a high level of correlation between the ML prediction score and binding free energy.Conclusions:Currently known AR inhibitors are not used yet for patients for several reasons.We think that new predicted AR inhibitors have the potential to possess more favorable characteristics to be successfully implemented after clinical testing.Exploring new inhibitors can improve patient well-being and lower surgical complications all while decreasing long-term medical expenses.

他汀类药物在慢性肝病中的作用

慢性肝病是肝脏由炎症、纤维化,向肝硬化、肝癌进展的“魔鬼三部曲”,是全球肝病科医生面临的巨大挑战。他汀类药物自问世以来,在心血管疾病和高脂血症治疗中发挥了巨大作用,近年来其同样显示出在慢性肝病中具有改善肝脂肪变性、抗炎、调节肝星状细胞表型、降低门静脉压力、改善肝脏微循环等关键环节的重要潜力。本文综述了他汀类药物在慢性肝病基础和临床研究中的最新进展,为慢性肝病的研究和防治提供新的见解。

安徽省冠心病和缺血性脑卒中二级预防用药的现况调查

目的调查安徽省冠心病和缺血性脑卒中患者二级预防用药情况,及与个体特征的相关关系。方法问卷调查安徽省15个县/区的145543例35~75岁的常住居民,自报冠心病和缺血性脑卒中患病情况和相关药物使用情况,并采用单变量因素和多变量混合效应模型分析其相关关系。结果自报患有冠心病或缺血性脑卒中的有3636例,患病率为2.49%。单因素回归分析显示,服用抗血小板药物或他汀类药物的患者中,男性、城市、非农民和高收入人群的药物使用率高于女性、农村、农民和低收入人群;超重和肥胖增加了服用二级药物风险,差异有统计学意义。多因素回归分析显示,女性(OR=0.69,95%CI:0.56~0.84,P<0.05)、农民(OR=0.39,95%CI:0.32~0.48,P<0.05)抗血小板药或他汀类药物的服用可能性低,而城市(OR=1.50,95%CI:1.24~1.81,P<0.05)、高中以上(OR=1.36,95%CI:1.05~1.77,P=0.021)和高血压患者(OR=1.56,95%CI:1.28~1.91,P<0.05)的药物使用可能性高。结论安徽省冠心病和缺血性脑卒中患者二级预防药物使用率较低,可针对低靶点人群采取干预措施,增强心血管疾病人群二级预防的药物依从性。

预防对比剂相关性急性肾损伤的研究进展

对比剂相关性急性肾损伤(CA-AKI)是在诊断或介入手术中使用对比剂所引起的一种严重并发症,目前已成为住院患者新发急性肾功能不全的主要原因之一。选择相对低毒的对比剂,减少对比剂暴露的时间和剂量对CA-AKI有一定的预防作用,他汀等药物以及术前术后的水化能够降低CA-AKI的风险,目前纳米药物已被证明在动物模型中获益。该文就当前CA-AKI的防治进行综述,为进一步深入研究新的干预措施奠定基础,并为临床治疗提供理论依据。

新型醛糖还原酶抑制1-乙酰基-1H-吲哚-3-乙酸酯的合成及其抑制活性

醛糖还原酶抑制剂(ARIs)抑制多元醇途径的醛糖还原酶是治疗糖尿病并发症的重要策略。以2-氯苯甲酸为起始原料,在碱性条件下经铜催化,与甘氨酸反应生成氯代邻羧基苯基甘氨酸,再与乙酸酐反应,生成N-乙酰基邻羧基苯甲酸。然后在吡啶催化下合环,生成1-乙酰基-^(1)H-吲哚-3-乙酸酯(AIA),总收率为79.0%,纯度为99.0%。通过^(1)H NMR、^(13)C NMR和MS(ESI)对其结构进行表征,并对该化合物的的醛糖还原酶抑制活性进行测定,IC 50=9.4×10^(-2)μM。

硫氧还蛋白还原酶结构与肿瘤治疗的研究进展

硫氧还蛋白还原酶(thioredoxin reductase,TrxR)是硫氧还蛋白(thioredoxin,Trx)系统里主要的功能蛋白,在调节多种细胞氧化还原信号通路中起关键作用。近年来,TrxR/Trx被越来越多地认为是肿瘤发展的重要调节剂,因此靶向TrxR/Trx是一种很有前景的肿瘤治疗策略。该文对TrxR的结构特点、与肿瘤相关的生理功能、TrxR抑制剂进行综述,以对TrxR的研究提供参考。

沙库巴曲缬沙坦联合匹伐他汀治疗冠心病合并心力衰竭的临床疗效

【目的】探讨沙库巴曲缬沙坦联合匹伐他汀治疗冠心病(CHD)合并心力衰竭(HF)的临床疗效。【方法】回顾性分析2020年2月至2022年2月本院收治的82例CHD合并HF患者的临床资料,根据治疗方法不同将其分为对照组(在常规治疗的基础上给予匹伐他汀治疗)和观察组(在对照组的基础上给予沙库巴曲缬沙坦治疗),每组41例。比较两组临床疗效、心功能指标[左心室射血分数(LVEF)、左心室舒张末期内径(LVEDD)、左心室收缩末期内径(LVESD)]、6 min步行实验(6MWT)距离、生活质量[明尼苏达心衰生活质量量表(LHFQ)评分],统计治疗期间不良反应发生情况。【结果】观察组总有效率高于对照组,差异有统计学意义(P<0.05)。治疗后,两组LVEF高于治疗前,LVEDD、LVESD低于治疗前,且观察组与对照组比较,差异均有统计学意义(P<0.05)。治疗后,两组6MWT距离大于治疗前,LHFQ评分低于治疗前,且观察组与对照组比较,差异均有统计学意义(P<0.05)。两组不良反应发生率比较,差异无统计学意义(P>0.05)。【结论】沙库巴曲缬沙坦联合匹伐他汀治疗CHD合并HF疗效较好,可显著改善患者心功能,提高患者生活质量,且安全性高。