Long noncoding RNAs HAND2-AS1 ultrasound microbubbles suppress hepatocellular carcinoma progression by regulating the miR-873-5p/tissue inhibitor of matrix metalloproteinase-2 axis

BACKGROUND Increasing data indicated that long noncoding RNAs(lncRNAs)were directly or indirectly involved in the occurrence and development of tumors,including hepatocellular carcinoma(HCC).Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues,but its role in HCC progression is unclear.Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes.AIM To study the role of ultrasound microbubbles(UTMBs)mediated HAND2-AS1 in the progression of HCC,in order to provide a new reference for the treatment of HCC.METHODS In vitro,we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs,and detected cell proliferation,apoptosis,invasion and epithelial-mesenchymal transition(EMT)by cell counting kit-8 assay,flow cytometry,Transwell invasion assay and Western blotting,respectively.In addition,we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior.Next,the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2(TIMP2)overexpression vector,and we detected cell proliferation,apoptosis,invasion and EMT.In vivo,we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability.RESULTS We found that UTMBs carrying HAND2-AS1 restricted cell proliferation,invasion,and EMT,encouraged apoptosis,and HAND2-AS1 silencing eliminated the effect of UTMBs.Additionally,miR-873-5p targets the gene HAND2-AS1,which also targets the 3’UTR of TIMP2.And miR-873-5p mimic counteracted the impact of HAND2-AS1.Further,miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs.We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase(MMP)2/MMP9.In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice.CONCLUSION LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression.

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.

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.

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.

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.

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.

Primary 4-3-oxosteroid 5β-reductase deficiency:Two cases in China

Aldo-keto reductase 1D1(AKR1D1) deficiency,a rare but life-threatening form of bile acid deficiency,has not been previously described in China.Here,we describe the first two primary 4-3-oxosteroid 5β-reductase deficiency patients in China's Mainland diagnosed by fast atom bombardment-mass spectroscopy of urinary bile acids and confirmed by genetic analysis.A high proportion of atypical 3-oxo-4-bile acids in the urine indicated a deficiency in 4-3-oxosteroid 5β-reductase.All of the coding exons and adjacent intronic sequence of the AKR1D1 gene were sequenced using peripheral lymphocyte genomic DNA of two patients and one of the patient's parents.One patient exhibited compound heterozygous mutations:c.396C>A and c.722A>T,while the other was heterozygous for the mutation c.797G>A.Based on these mutations,a diagnosis of primary 4-3-oxosteroid 5β-reductase deficiency could be confirmed.With ursodeoxycholic acid treatment and fat-soluble vitamin supplements,liver function tests normalized rapidly,and the degree of hepatomegaly was markedly reduced in both 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.

左炔诺孕酮联合miRNA-21-5p抑制剂对子宫内膜癌细胞增殖、转移的作用及机制

目的利用左炔诺孕酮(LNG)和miRNA-21-5p抑制剂(inhibitor)联合靶向多发性肿瘤抑制基因磷酸酶基因(PTEN)评估对子宫内膜癌细胞增殖、转移的作用。方法将实验用人子宫内膜癌细胞分为Control组、LNG处理组、LNG处理+miR-21 NC组和LNG处理+miR-21 inhibitor组;免疫组化检测LNG治疗前后子宫内膜癌患者内膜组织中PTEN表达;CCK8和流式细胞仪筛选LNG最佳作用浓度和时间;实时荧光定量(qRT)-聚合酶链反应(PCR)法检测miR-21-5p inhibitor处理后miR-21-5p mRNA表达水平;LNG联合miR-21-5p inhibitor处理后CCK8检测增殖,流式检测凋亡,Transwell检测侵袭,划线检测迁移,Western印迹检测细胞中PTEN、磷脂酰肌醇3-激酶(PI3K)、p-PI3K、丝氨酸/苏氨酸激酶(AKT)和p-AKT蛋白表达水平。结果与治疗前比,LNG治疗后子宫内膜组织中PTEN表达水平显著升高(P=0.000)。筛选出LNG最佳浓度为100μmol/L,时间为24 h。miR-21-5p inhibitor处理后miR-21-5p表达显著降低(P<0.05)。与Control组相比,LNG组处理后细胞凋亡及PTEN表达显著升高,细胞迁移、侵袭能力及细胞活力显著下降(P<0.05),miR-21-5p、p-AKT/AKT、p-PI3K/PI3K表达也明显下降(P<0.05);与LNG组相比,LNG+miR-21-5p inhibitor组细胞活力、细胞凋亡、迁移、侵袭能力、miR-21-5p表达、p-AKT/AKT、p-PI3K/PI3K明显下降,PTEN表达则明显升高(P<0.05)。结论LNG联合miR-21-5p inhibitor具有协同抑制子宫内膜癌细胞增殖、转移的作用,此过程与靶向上调PTEN并抑制PI3K/AKT通路活化相关。

Synthesis and Crystal Structure of a Novel Ethyl 5-(4-(2-Phenylacetamido)phenyl)-1H-pyrazole-3-carboxylate as an Acrosin Inhibitor

The title compound （ethyl5-（4-（2-phenylacetamido）phenyl）-lH-pyrazole-3-carboxylate, C20H19N3O3） was synthesized by the reaction of Claisen condensation, cyclization, reduction and acylation. The structure was characterized by X-ray diffraction, MS, NMR and IR. It belongs to the monoclinic system, space group C2/c with a = 22.723（9）, b = 9.324（4）, c = 18.890（8） A, β = 114.259（6）°, V = 3649（3） A^3, Dc = 1.272 Mg·m^3, Z = 8, Mr = 349.38, p = 0.087 mm^-1, F（000） = 1472, the final R = 0.0615 and wR = 0.1643. The biological test shows that the title compound has a moderate acrosin inhibition activity.

Synthesis of 1-aryl-3-(3,4-dihydro-2H-chromen-5-yl) ureas as TNF-αinhibitors

A new series of compounds, 1-aryl-3-（3,4-dihydro-2H-chromen-5-yl） ureas, have been synthesized and their structures were confirmed by FAB-MS and IH NMR. The preliminary pharmacological screening showed that these compounds inhibited TNF-α production in lipopolysaccharide （LPS）-stimulated THP-1 cells.

酶标仪法5α-还原酶抑制剂体外筛选模型的建立

目的:建立酶标仪法5α-还原酶抑制剂体外筛选模型。方法:取6只雌性SD大鼠肝脏制备5α-还原酶,检测酶活性后,利用96孔板、酶标仪及酶标仪法分析软件建立5α-还原酶抑制剂体外筛选模型,并通过已知5α-还原酶抑制剂爱普列特及非那甾胺验证模型的可靠性。实验分别设置0、30、60 nmol/L爱普列特组及0、30、60 nmol/L非那甾胺组,96孔板依次加入终浓度0～40μmol/L系列睾酮溶液、22μmol/L的NADPH、终浓度0～60 nmol/L爱普列特或0～60 nmol/L非那甾胺及20μl 5α-还原酶,Tris-HCl缓冲液将每孔溶液体积调至200μl。将96孔板放置于酶标仪中,分别测定0、10 min的A340 nm,并对读取数据进行分析。结果:5α-还原酶的Km值为3.794μmol/L,Vmax为0.271μmol/(L.min);爱普列特的酶抑制常数(Ki)为148.2 nmol/L,半数抑制浓度(IC50)为31.5 nmol/L,曲线图分析为反竞争性抑制剂;非那甾胺的Ki为158.8 nmol/L,IC50为13.6 nmol/L,曲线图分析为竞争性抑制剂;二者结果均同文献报道相同。结论:建立的体外快速筛选模型能够有效地筛选5α-还原酶抑制剂。

Hsa-miR-205-5p对食管鳞癌细胞系耐药的影响

目的研究hsa-miR-205-5p对食管鳞癌铂类化疗耐药的影响。方法首先用RT-PCR法检测hsa-miR-205-5p在食管鳞癌耐药细胞系EcA109和敏感细胞系KYSE150中的表达。然后在EcA109和KYSE150中分别转染hsa-miR-205-5p mimics,mimics NC和hsa-miR-205-5p inhibitor,inhibitor NC,用MTT和CCK8法检测奥沙利铂浓度为60,120,240,480,960μmol/L对细胞增殖的影响。结果 hsa-miR-205-5p在食管癌耐药细胞系EcA109比在敏感细胞系KYSE150中低表达(P<0.05)。MTT和CCK8实验结果表明,与转染NC组相比,随着奥沙利铂浓度的增加,转染hsa-miR-205-5p mimics组的EcA109细胞抑制率上升(P<0.05),转染hsa-miR-205-5p inhibitor组的KYSE150细胞抑制率下降(P<0.05)。结论转染hsa-miR-205-5p mimics后Ec A109细胞对奥沙利铂敏感性提高,转染hsa-miR-205-5p inhibitor后KYSE150细胞对奥沙利铂耐药性增加。说明hsa-miR-205-5p过表达可抑制食管鳞癌细胞产生耐药性。

单用α肾上腺受体阻滞剂与联合5α-还原酶抑制剂治疗良性前列腺增生疗效的Meta分析

目的:比较单用α肾上腺受体阻滞剂与α肾上腺受体阻滞剂联合5α-还原酶抑制剂治疗良性前列腺增生(BPH)的疗效。方法:检索中/英文公开发表的随机对照试验(RCT)。计算机检索Pub Med、EMbase、the Cochrane Central Register of Controlled Trials(CENTRAL)、CNKI、CBM、VIP、万方数据库。检索时间为建库至2015年6月30日。同时,手检纳入文献的参考文献。按纳入排除标准进行RCT的筛选、资料提取和质量评价后,采用Rev Man 5.2软件进行Meta分析。结果:共纳入4个研究,403例患者。Meta分析结果显示:有效性方面,两组在降低IPSS评分[SMD=0.89,95%CI(-0.66,2.45)P=0.26]、提高最大尿流率[SMD=-3.67,95%CI(-8.88,1.54)P=0.17]、减少残余尿量[SMD=0.62,95%CI(-0.97,2.22)P=0.17]上无明显统计学差异;与单用药物相比,联合用药在减少前列腺体积上[SMD=6.94,95%CI(2.06,11.81)P=0.005]效果更好,两组在出现不良反应(头晕[SMD=0.57,95%CI(0.16,1.98)P=0.38]、性功能减退[SMD=0.57,95%CI(0.16,1.98)P=0.38])上无明显统计学差异。结论:单用α肾上腺受体阻滞剂与α肾上腺受体阻滞剂联合5α-还原酶抑制剂相比,两者疗效相似,对于前列腺体积不大的患者,单用α肾上腺受体阻滞剂即可达到很好的疗效,避免了不必要的经济负担;对于前列腺体积较大的患者,则推荐联合用药。对于前列腺具体多大的体积才是单用α肾上腺受体阻滞剂与联合5α-还原酶抑制剂治疗的分界阈值,则需要更多高质量、大样本的RCT进一步论证。

5α-还原酶抑制剂治疗前列腺增生体积≥30 mL患者临床疗效观察

目的研究5α还原酶抑制剂对前列腺体积≥30 mL前列腺增生患者的治疗效果。方法将我院泌尿外科2016年1月—2017年1月住院、门诊200例前列腺体积≥30 mL前列腺增生患者随机分为2组,对照组:盐酸坦洛新缓释胶囊0.2 mg口服,每天1次;治疗组:非那雄胺5 mg口服qd,盐酸坦洛新缓释胶囊0.2 mg口服,每天1次。2组用药6个月后,根据最大尿流率(mL/s)、前列腺体积(mL)、残余尿量(mL)、I-PSS评分评定疗效。结果治疗组和对照组患者最大尿流率均较治疗前提高,前列腺体积、残余尿、I-PSS评分均较治疗前降低,且治疗组的改善幅度优于对照组,差异有统计学意义(P<0.05)。结论 5α还原酶抑制剂对前列腺体积≥30mL前列腺增生患者的治疗有明显效果。

裂木质素类化合物与5α-还原酶的构效关系研究

5-α还原酶(5-αreductase,5-AR)是治疗良性前列腺增生的关键酶。前期研究发现裂木质素类化合物有抑制5-AR的作用,为了深化对荨麻属裂木质素类植物的研究,并探索裂木质素类抑制剂对5-AR的抑制作用及二者构效关系,采用同源模建的方法构建5-AR的三维空间结构模型,并利用Ramachandran plot、verify3D和ERRAT程序对模型进行评价,同时通过分子力学等方法对最优模型进行优化。利用分子对接的方法将5-α还原酶抑制剂(5α-reductase inhibitors,5-ARI)对接到12个活性位点,其中5个位点与配体对接成功,并预测了41种裂木质素化合物的ADMET性质。本文研究结果对裂木质素类化合物的药物设计具有一定的理论指导作用,并且为良性前列腺增生的治疗研究提供新思路。

围手术期应用5α-还原酶抑制剂在经尿道双极等离子电切术治疗较大体积良性前列腺增生中的优势探讨

目的探讨围手术期常规应用5α-还原酶抑制剂(5ARI)在经尿道双极等离子电切术(TUPKP)治疗较大体积良性前列腺增生(BPH)患者的术中术后优势。方法选取2014年10月至2019年8月铜陵市人民医院治疗的192例较大体积BPH患者的临床资料进行回顾性分析。按围手术期是否应用5ARI分为联合用药组(n=107)和单纯电切组(n=85)。比较两组患者术中手术时间、失血量、出血强度、前列腺切除组织量、前列腺腺体与尿道下黏膜微血管密度(MVD)变化,术后尿色转清时间、冲洗液体量、国际前列腺症状评分(IPSS)、生活质量评分(QOL)、最大尿流率(Qmax)变化以及继发性出血并发症发生情况。结果联合用药组患者的手术时间、失血量、出血强度、前列腺腺体、尿道下黏膜MVD均小于单纯电切组患者,差异具有统计学意义(P<0.05);但两组患者前列腺组织切除量、IPSS、QOL、Qmax比较,差异无统计学意义(P>0.05);联合用药组患者术后尿色转清时间、冲洗液体量、继发性出血发生率明显小于单纯电切组患者,差异具有统计学意义(P<0.05)。结论围手术期应用5ARI在TUPKP治疗较大体积BPH中,能明显减少术中术后出血风险,具有安全可靠、效率高、恢复快等优势,适合在广大基层医院应用推广。

5α-还原酶抑制剂非那甾胺的合成

以甾烯酮酸为起始原料 ,经酰胺化、氧化开环、环合、氢化、脱氢合成了非那甾胺 .优化了氢化反应及氢化产物分离条件 ,控制 5 β异构体杂质含量低于 2 % ,经脱氢、纯化 ,得到符合药用要求的非那甾胺 ,适合工业化生产 .

新的前列腺癌治疗剂17-( 5′-异噁唑基 )雄甾-4,16-二烯-3-酮合成方法的改进(英文)

17 (5′ 异唑基 )雄甾 4 ,16 二烯 3 酮 (4,L 39)是最有希望的P4 5 0 17α和 5α 还原酶的双重抑制剂 ,对前列腺癌及前列腺肥大具有潜在的治疗作用。对其合成路线进行改进 ,收率极大提高。首先 ,Claisen缩合物 2用羟胺在乙醇中环和得到纯 5′ 异唑 3a ,用Swern氧化反应直接氧化 3a ,然后在在酸中异构化后得到L 39(4)。或者 ,化合物 2在无水甲酸中与羟胺环和得到 3 甲酯物 (6 ) ,后者以改良奥氏氧化法直接氧化生成 4 烯 3 酮物 (4)。

5α-还原酶抑制剂联合α受体阻滞剂治疗前列腺增生的临床疗效

目的探讨5α-还原酶抑制剂(非那雄胺)联合α受体阻滞剂(特拉唑嗪)治疗前列腺增生(BPH)的临床疗效。方法选取2012年1月—2014年6月达州市达川区南城社区卫生服务中心收治的BPH患者124例,随机分为观察组与对照组,各62例。观察组给予非那雄胺联合特拉唑嗪治疗,对照组给予特拉唑嗪治疗,比较两组的国际前列腺症状评分表(IPSS)评分、最大尿流率(Qmax)、前列腺体积、残余尿量。结果治疗前,两组患者IPSS评分、Qmax、前列腺体积、残余尿量比较,差异无统计学意义(P>0.05);治疗6个月后观察组IPSS评分低于对照组,Qmax高于对照组,前列腺体积小于对照组,残余尿量少于对照组,差异有统计学意义(P<0.05)。结论非那雄胺联合特拉唑嗪治疗BPH的疗效显著,可缩小前列腺体积,减少残余尿量,改善患者的排尿功能及相关临床症状。