Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

Monoamine Oxidase-B Inhibitor Rasagiline Effects on Motor and Non-Motor Symptoms in Individuals with Parkinson’s Disease: A Systematic Review and Meta-Analysis

Objective: In the manuscript titled Monoamine Oxidase-B Inhibitor Rasagiline Effects on Motor and Non-Motor Symptoms in Individuals with Parkinsons Disease: A Systematic Review and Meta-Analysis, the objective was to conduct a systematic review with meta-analysis to investigate the effects that Rasagiline has on motor and non-motor symptoms in individuals with PD. Introduction: Rasagiline is a second-generation monoamine oxidase-B (MAO-B) inhibitor used both as monotherapy and adjunctive therapy for Parkinsons Disease (PD). Methods: A systematic literature search and meta-analysis were performed with randomized control trials that investigated the effects of Rasagiline on motor and non-motor symptoms in individuals with PD. The systematic search was conducted in PubMed, Cochrane, and EBSCO databases. Methodological quality was assessed using the Cochrane Grading Recommendations Assessment, Development and Evaluation approach. Results: Fourteen studies were included in our review. There were trivial to small and statistically significant improvements in motor symptoms for individuals with PD treated with Rasagiline compared to placebo. Non-motor symptoms showed no significant improvement with Rasagiline compared to placebo in five of six meta-analyses. Results were based on very low to moderate certainty of evidence. Conclusion: 1 mg/day Rasagiline significantly improved Parkinsonian motor symptoms in individuals with PD compared with placebo. For all outcomes, the 1 mg/day Rasagiline group was favored over the placebo group.

A novel fluorogenic probe for monoamine oxidase assays

Monoamine oxidase is flavoenzymes, widely distributed in mammals. It is well recognized that MAOs serve an important role in metabolism that they have close relationship with health .Along with the discoveries between MAOs and neurotic disease, more and more studies have been jumped in .In this paper, we design a new probe for assaying the activities of MAOs. The results showed that the probe [7-（3-aminopropoxy）coumarin] is simple, effective and sensitive for MAOB.

Preliminary in vitro evaluation of neuroprotective and monoamine oxidase type B inhibitory effects of newly synthesized 8-aminocaffeines

The expected growth of the elderly population at highest risk for Parkinson’s disease(PD)in the next decades makes the identification of factors that promote or prevent the disease an important goal.In addition,new therapies-aiming to delay the progression of PD are also needed(Prediger,2010).However,there have been few clinical trials designed to investigate neuroprotection.Thus the application of an appropriate in vitro model such as the neuroblastoma SH-SY5Y cell line is extremely helpful.These cells were selected due to its human origin,catecholaminergic neuronal properties,and ease of maintenance(Xicoy et al.,2017).

DNA methylation of the Monoamine Oxidases A and B genes in postmortem brains of subjects with schizophrenia

Aims: We focused on DNA methylation of the promoter regions of the Monoamine Oxidase (MAO) A and B genes from postmortem brains of subjects with schizophrenia. Methods: We determined levels of DNA methylation using genomic DNA samples purified from four brain areas: prefrontal cortex (PFC), hippocampus, occipital cortex and nucleus accumbens (NAc), by a bisulfite sequencing method from seven normal subjects and six subjects with schizophrenia. Results: Although very few methylated CpGs of the MAOA and MAOB genes were detected in male samples, various DNA methylation patterns were present in female samples, and some differences were found in such patterns between normal subjects and subjects with schizophrenia. In the PFC, the average level of methylation of both genes was significantly higher in subjects with schizophrenia than in normal subjects. The content of highly methylated alleles of the MAOA gene in the NAc was significantly associated with schizophrenia, with similar results obtained for the MAOB gene in both the NAc and PFC. Some CpG sites showed higher levels of methylation in schizophrenia than in normal subjects. Conclusions: Levels of methylation were quite high in NAc and PFC in female subjects with schizophrenia compared with those in female normal subjects.

Association of adverse effects with monoamine oxidase type B inhibitor and catechol-o-methyl transferase inhibitor combination therapy in Parkinson’s disease patients

Currently, levodopa is the most effective and commonly used medication to control motor symptoms in Parkinson’s disease (PD). However, its long-term use is associated with adverse effects (AEs). Combination therapy of a monoamine oxidase type B inhibitor (MAOBI) with levodopa or a catechol-O-methyl transferase inhibitor (COMTI) with levodopa provides benefits to PD patients. Direct comparison of efficacy and side effect profiles is complex. The aim of this study is to investigate the different AE profiles of MAOBI and COMTI combination therapies. Data used to analyze the AEs of different PD medications were retrieved from “The Boston University Medical Center’s Parkinson’s Disease and Movement Disorder Database”. Ten categories of AEs were compared between patients receiving MAOBI and COMTI combination treatment. In total, 87 subjects were included in the analysis. Out of ten AEs, the presence of dementia was signifi- cantly different between the MAOBI and COMTI groups with an OR of 6.9 (COMTI vs MAOBI, 95% CI 1.3 - 37.0). Motor fluctuations were also found to be differently distributed in the two medication groups with an OR of 3.1 (COMTI vs MAOBI, 95% CI 1.0 - 9.8). In this retrospective database analysis of patients treated with combination treatment for PD, combination therapy of a COMTI with levodopa was more likely to be associated with dementia and motor fluctuations than a MAOBI with levodopa.

Tyramine in Malt Beverages Interfering with Monoamine Oxidase Inhibitor Drugs

The objective of this review is the determination of tyramine in 13 nonalcoholic beers (Maoshaieer) of Tehran market and survey of it’s probably interaction with monoamine oxidase inhibitor drugs (MAOIs) has been investigated. Tyramine was at the highest levels in Baltika (111.34 ± 8.19 μg/ml) and at the lowest level in Bitmalt (8.01 ± 2.09 μg/ml). Comparing different flavors of malt drinks, the highest tyramine content was shown for classic or normal flavor (average 72.99 ± 30.87 μg/ml), while the lowest value belonged to cantaloupe flavored drinks (average 10.55 ± 1.29 μg/ml). In our study, it is seen that there is a significant difference between import and Iranian non-alcoholic beers, the import ones has more tyramine than Iranians. A number of 10 kinds of 13 samples interact whit MAOIs in one serving (250 ml) usage 18.50 mg. The highest tyramine content of Iranian ones is 17.74 mg/250ml and for import ones is 27.83 mg/250ml.

A Strategy to Employ Clitoria ternatea as a Prospective Brain Drug Confronting Monoamine Oxidase (MAO) Against Neurodegenerative Diseases and Depression

Ayurveda is a renowned traditional medicine practiced in India from ancient times and Clitoria ternatea is one such prospective medicinal herb incorporated as an essential constituent in a brain tonic called as medhya rasayan for treating neurological disorders.This work emphasises the significance of the plant as a brain drug there by upholding Indian medicine.The phytochemicals from the root extract were extricated using gas chromatography–mass spectrometry assay and molecular docking against the protein Monoamine oxidase was performed with four potential compounds along with four reference compounds of the plant.This persuades the prospect of C.ternatea as a remedy for neurodegenerative diseases and depression.The in silico assay enumerates that a major compound(Z)-9,17-octadecadienal obtained from the chromatogram with a elevated retention time of 32.99 furnished a minimum binding affinity energy value of-6.5 kcal/mol against monoamine oxidase(MAO-A).The interactions with the amino acid residues ALA 68,TYR 60 and TYR 69 were analogous to the reference compound kaempferol-3-monoglucoside with a least score of-13.90/-12.95 kcal/mol against the isoforms(MAO)A and B.This study fortifies the phytocompounds of C.ternatea as MAO-inhibitors and to acquire a pharmaceutical approach in rejuvenating Ayurvedic medicine.

A fluorogenic-inhibitor-based probe for profiling and imaging of monoamine oxidase A in live human glioma cells and clinical tissues

Monoamine oxidase A(MAO-A)plays a critical role in the development of glioma and other neurological disorders.Specific analysis of MAO-A activities and its drug interactions in intact tissue is important for biological and pharmacological research,but highly challenging with current chemical tools.Fluorogenic-inhibitor-based probes offer improved selectivity,sensitivity,and effectiveness to image and profile endogenous targets in an activity-based manner from mammalian cells,which are however rare.Herein,we report HD1 as the first fluorogenic-inhibitor-based probe that can selectively label endogenous MAO-A from various mammalian cells and clinical tissues.The probe was delicately designed based on N-propargyl tetrahydropyridine,a small MAO-A-specific fluorogenic and inhibitory war-head,so that the probe becomes fluorescent upon in situ enzymatic oxidation and covalent labeling of MAO-A.With the excellent binding affinity(in vitro K_(i)=285 n M)and fluorogenic properties,HD1 offers a promising approach to simultaneously image endogenous MAO-A activities by super-resolution fluorescence microscopy and study its drug interactions by subsequent activity-based protein profiling,in both live cells and human glioma tissues.

酶抑制剂及其构效优化在阿尔茨海默病中的应用

阿尔茨海默病(Alzheimer’s disease,AD)是一种以进行性认知功能障碍和行为损害为特征的中枢神经系统退行性病变,而临床上缺乏有效治疗AD的药物。近些年来研究发现,多种酶抑制剂如胆碱酯酶抑制剂、单胺氧化酶抑制剂、分泌酶抑制剂等能改善胆碱能系统的障碍、Aβ的产生和沉积、Tau蛋白的过度磷酸化、氧化应激损伤、突触可塑性下降等AD发生发展的不同环节,从而改善AD症状和认知功能。本文综述了近年来酶抑制剂或抑制剂构效优化靶向调节胆碱酯酶、单胺氧化酶、分泌酶等在AD治疗中的研究进展,以期为AD的治疗和药物研发提供新思路。

Determination of dietary copper requirement by the monoamine oxidase activity in kidney of broilers from 1 to 21 days of age

The current dietary copper(Cu)requirement(8 mg/kg)of broilers is mainly based on growth,hemoglobin concentration,or hematocrit,which might not be the most sensitive indices to evaluate dietary Cu requirements of broilers.The present study was carried out to estimate dietary Cu requirements of broilers fed a conventional corn-soybean meal diet from 1 to 21 d of age using biochemical or molecular biomarkers.A total of 3841-d-old Arbor Acres male broilers were randomly allocated to 1 of 6 treatments with 8 replicates and fed a Cu-unsupplemented corn-soybean meal basal diet containing 5.17 mg Cu/kg by analysis and the basal diet supplemented with 3,6,9,12 or 15 mg Cu/kg as CuSO4,5H2O for 21 d.Regression analysis was performed to estimate the optimal dietary Cu level using the broken-line model.Dietary supplemental Cu level affected(P<0.05)Cu contents in serum and liver and kidney monoamine oxidase(MAO)activity,but had no effects(P>0.05)on the growth performance,Cu contents in heart,kidney,pancreas and spleen,Cu-and zinc-containing superoxide dismutase(CuZnSOD)activity and ceruloplasmin content in serum,CuZnSOD and cytochrome c oxidase(COX)activities and ceruloplasmin,CuZnSOD,MAO A,MAO B,COX 4I1 and COX 1 mRNA and protein expressions in the above tissues of broilers.As dietary supplemental Cu levels increased,Cu contents in serum and liver increased linearly(P<0.05),but kidney MAO activity decreased linearly and quadratically(P<0.05).The estimated dietary Cu requirement based on the fitted broken-line model(P=0.035)of kidney MAO activity was 11.30 mg/kg.In conclusion,kidney MAO activity is a new and sensitive criterion to evaluate the dietary Cu requirement of broilers,and the dietary Cu requirement was 11.30 mg/kg for broilers fed the conventional corn-soybean meal diet from 1 to 21 d of age,which is higher than the current National Research Council(NRC)Cu requirement(8 mg/kg)of broilers.

Specific tracking of monoamine oxidase A in heart failure models by a far-red fluorescent probe with an ultra large Stokes shift

Monoamine oxidase A(MAO-A) is a prominent myocardial source of reactive oxygen species(ROS), and its expression and activity are strongly increased in failing hearts. Therefore, accurate evaluation of MAOA activity in cardiomyocytes is of great importance for understanding its biological functions and early diagnosing the progression of heart failure. However, so far, there is no report on the fluorescent diagnosis of heart failure by a specific probe for MAO-A. In this work, two far-red emissive fluorescent turn-on probes(KXS-M1 and KXS-M2) for the highly selective and sensitive detection of MAO-A were fabricated.Both probes exhibit good response to MAO-A, one of which, KXS-M2, performs better than the other one in terms of a fluorescence increment and sensitivity. Using the pioneering probe KXS-M2, specific fluorescence imaging of MAO-A in glucose-deprived H9c2 cardiac cells, zebrafish and isoprenaline-induced failing heart tissues was achieved, proving that KXS-M2 can serve as a powerful tool for the diagnosis and treatment of heart failure.

抗帕金森病药物诱发5⁃羟色胺综合征1例

5⁃羟色胺综合征是一种用药产生的药物不良反应,其主要特征是神经肌肉的过度兴奋,大多数情况下该病症状轻微,但在某些情况下可能会严重危及生命。本文报道1例87岁帕金森病(Parkinson’s disease,PD)患者起初因肺部感染、发热入院,经相应治疗后临床症状改善,但随后病情又波动,出现高热、大汗、意识障碍、肌张力高、肌酸激酶升高。医生结合上述临床表现,逐条分析抗PD药物种类剂量以及合并抗感染用药史后,发现患者超剂量服用司来吉兰,并与加用的抗感染药物利奈唑胺发生药物不良反应,及时诊断5⁃羟色胺综合征,并进行积极妥善处理,停用相关药物,结合物理降温、大量补液等对症支持治疗,使患者病情在24 h内得到有效控制,发病3 d后患者症状基本好转,发病5 d后其症状完全缓解。5⁃羟色胺综合征重在预防,临床医生应加强对此病的认识。

基于多巴胺系统调节的治疗抽动障碍中药作用探讨

近年来,抽动障碍(TD)的患病率逐年增加,虽不危及生命,但已成为危害儿童身心健康的常见严重慢性疾病之一,对家庭和社会也有着不同程度的影响。TD作为一种神经发育障碍性疾病,其发病因素及发病机制尚不清晰,但中医药在治疗TD中的临床疗效确切,而从多巴胺系统对TD作用机制的研究逐渐深入,文章从中药调控多巴胺系统对TD的影响出发进行综述。

基于网络药理学、分子对接及实验验证探讨当归挥发油改善血管性痴呆的作用机制

目的基于网络药理学、分子对接及实验验证探讨当归挥发油(Volatile oil of Angelica Sinensis Radix,VOASR)改善血管性痴呆(Vascular dementia,VaD)的作用机制。方法(1)采用气相色谱-质谱联用(GC-MS)法对VOASR的主要化学成分进行分析鉴定,确定百分含量排前5位的化合物。通过Swiss Target Prediction数据库筛选出VOASR 5个主要化学成分的作用靶点,通过OMIM、GeneCards、Drugbank数据库收集VaD疾病相关靶点。对VOASR主要化学成分的作用靶点与VaD疾病相关靶点取交集,得到二者共同靶点即为VOASR干预VaD的潜在作用靶点。运用STRING数据库对交集靶点构建蛋白相互作用(PPI)网络,并分析判断关键靶点。使用R语言的Bioconductor软件包对共同靶点进行GO功能富集分析及KEGG通路富集分析,并使用Cytoscape 3.7.2软件构建VOASR干预VaD的“药物-成分-疾病-靶点-通路”网络。采用AutoDock Vina软件进行分子对接,分析5个主要化学成分与关键靶点蛋白的结合能力,进一步筛选出VOASR治疗VaD的核心靶点。(2)体内实验:将C57BL/6小鼠随机分为假手术组、模型组、VOASR组(105 mg·kg^(-1)),每组6只。采用单侧颈总动脉结扎术(UCCAO)构建VaD小鼠模型;术后灌胃给药(10 mL·kg^(-1)),每日1次,持续3周。采用Morris水迷宫实验评估VaD小鼠的认知功能;采用免疫组织化学法及Western Blot法检测小鼠海马组织中多巴胺受体D2(DRD2)、单胺氧化酶A(MAOA)蛋白表达情况。结果(1)VOASR中相对百分含量排前5位的核心化学成分分别为(E)-Ligustilide(E-藁本内酯)、Z-Butylidenephthalide(Z-正丁烯基苯酞)、Senkyunolide H(洋川芎内酯H)、Spathulenol(桉油烯醇)、3-Butylphthalide[3-丁基-1(3H)-异苯并呋喃酮],占总含量的97.32%。共筛选得到VOASR中5个主要化学成分的作用靶点92个,VaD疾病相关靶点1181个,得到共同靶点(交集靶点)31个。分析得到VOASR治疗VaD的关键靶点包括VEGFA、PTGS2、ICAM1、VCAM1、F2、FGF2、CCR5、PIK3R1、MAPK14、MPO、SELE、DRD2、MAOA、ADRA1A、ELANE。VOASR治疗VaD的潜在作用靶点与脂多糖的反应、神经递质水平的调节、突触传递、多巴胺能等生物学过程有关,主要涉及多巴胺能突触、钙离子信号通路、神经活性配体-受体相互作用、MAPK信号通路、NF-κB信号通路等。分子对接结果显示,E-藁本内酯-DRD2、洋川芎内酯H-MAOA的结合能力最优。(2)与假手术组比较,模型组小鼠的逃避潜伏期明显延长(P<0.05,P<0.01),穿越平台次数显著减少(P<0.001);小鼠海马区中的MAOA、DRD2阳性表达显著上调(P<0.01,P<0.001),MAOA、DRD2蛋白表达水平明显上升(P<0.05)。与模型组比较,VOASR组小鼠的逃避潜伏期明显缩短(P<0.05,P<0.01),穿越平台次数显著增加(P<0.001);小鼠海马区中的MAOA、DRD2阳性表达明显下调(P<0.05,P<0.01),MAOA、DRD2蛋白表达水平明显下降(P<0.05,P<0.01)。结论VOASR可以有效改善VaD小鼠的认知功能,可能是通过E-藁本内酯、洋川芎内酯H等核心化学成分,作用于DRD2、MAOA等关键靶点,通过多巴胺能突触、钙离子信号通路、MAPK信号通路等多条信号通路来实现的,具有多成分、多靶点、多通路的特点。

单胺氧化酶A基因多态性与急性脑卒中后抑郁及奥氮平疗效的相关性分析

目的探讨单胺氧化酶A(MAOA)基因多态性与急性脑卒中后抑郁及奥氮平疗效的相关性。方法回顾性选取2020年9月至2022年9月南方医科大学珠江医院收治的172例急性脑卒中患者作为研究对象,根据汉密尔顿抑郁量表(HAMD)评分将患者分为抑郁组(HAMD评分≥8分,76例)和非抑郁组(HAMD评分<8分,96例),抑郁组患者均接受奥氮平口服治疗。检测所有患者MAOA串联重复序列(MAOA-uVNTR)基因型及等位基因分布,收集一般资料、治疗前HAMD评分、美国国立卫生研究院卒中量表(NIHSS)评分和日常生活能力量表(ADL)评分以及抑郁组患者治疗后的各项评分。使用多因素Logistic回归模型分析急性脑卒中后抑郁的影响因素、MAOA基因多态性与影响因素的交互作用及不同基因型与奥氮平疗效的相关性。结果2组家庭年收入、家庭关系、卒中次数、病灶数目、NIHSS评分、ADL评分比较差异均有统计学意义(均P<0.05)。基因多态性检测结果显示,抑郁组LL型28例(36.8%)、SL型26例(34.2%)、SS型22例(28.9%),非抑郁组LL型16例(16.7%)、SL型42例(43.8%)、SS型38例(39.6%),2组基因型分布比较差异有统计学意义(P=0.033)。多因素Logistic回归分析结果显示,卒中次数、病灶数目、NIHSS评分、ADL评分是急性脑卒中后抑郁的独立影响因素(均P<0.05);将上述因素与MAOA-uVNTR基因代入Logistic回归模型进行交互作用分析,结果显示NIHSS评分与MAOA-uVNTR基因存在交互作用(P<0.05)。奥氮平治疗后,LL型、SL型、SS型患者HAMD、NIHSS评分均低于治疗前,ADL评分高于治疗前,且SL型和SS型患者HAMD、NIHSS评分均低于LL型患者,ADL评分高于LL型患者(均P<0.05);以LL型为参考,奥氮平对SS型的疗效更优(比值比=2.786,95%置信区间:2.432~3.564,P=0.016)。结论MAOA基因多态性与急性脑卒中后抑郁及奥氮平疗效存在相关性。

单胺氧化酶A(MAOA)在前列腺癌进展中的作用

单胺氧化酶A(monoamine oxidase A,MAOA)是一种催化单胺类神经递质和膳食胺氧化脱氨反应的线粒体酶,在神经精神疾病的发病、进展和治疗中发挥着重要作用。最近有研究发现前列腺癌(prostate cancer,PCa)中的MAOA表达升高与肿瘤的进展密切相关,是驱动PCa异质性转化的重要因素。本文主要综述了MAOA在前列腺癌不同病程发展中的作用,包括前列腺癌的发生、发展、侵袭、转移以及耐药。讨论了MAOA在肿瘤微环境中的作用及其抑制剂的潜在用途,进一步提出了在临床前模型中开展基于靶向MAOA的治疗研究,推动相关临床试验,以期为PCa的治疗提供新的潜在治疗靶点。

血清MAO和IL-6水平诊断慢性肾衰竭并发心力衰竭的价值及与心功能分级的关系

目的研究血清单胺氧化酶(monoamine oxidase,MAO)、白细胞介素(interleukin,IL)-6水平与慢性肾衰竭(chronic renal failure)并发心力衰竭(heart failure)患者心功能分级的相关性。方法选择2021年6月~2022年5月邯郸明仁医院肾病科及透析中心慢性肾衰竭并发心力衰竭患者80例作为试验组,按照美国纽约心脏病学会(New York Heart Association,NYHA)分级将试验组患者分为:心功能Ⅰ级20例,心功能Ⅱ级20例,心功能Ⅲ级20例和心功能Ⅳ级20例,同期选择单纯慢性肾衰竭患者80例作为对照A组,健康体检者80例作为对照B组,分别测定各组的血清MAO,IL-6和N-末端B型钠尿肽前体(N-terminal B-type natriuretic peptide precursor,NTproBNP)水平,分析其与慢性肾衰竭并发心力衰竭患者心功能分级的关系。其中试验组、对照A组符合疾病诊断标准,经各项检查确诊,且病情稳定,实验前均未接受治疗,另外所有观察对象与家属签订知情书。结果试验组MAO(8.56±1.85U/L),IL-6(128.56±17.48ng/L)和NT-proBNP(872.04±11.25pg/ml)水平均高于对照A组(3.14±1.01U/L,97.42±12.36ng/L,195.79±6.87pg/ml)和对照B组(2.87±0.85U/L,77.69±8.15ng/L,66.04±5.48pg/ml),差异均具有统计学意义(F=478.790,300.850,220577.310,均P<0.05)。心功能Ⅰ级MAO,IL-6,NT-proBNP水平分别为3.77±1.05U/L,104.26±15.47ng/L和381.25±8.44pg/ml,心功能Ⅱ级MAO,IL-6,NT-proBNP水平分别为5.26±1.35U/L,113.15±16.89ng/L和579.31±10.10pg/ml,心功能Ⅲ级MAO,IL-6,NT-proBNP水平分别为7.48±2.09U/L,125.73±17.02ng/L和782.08±11.24pg/ml,心功能Ⅳ级MAO,IL-6,NT-proBNP水平分别为8.99±2.67U/L,130.58±17.96ng/L,901.54±12.10pg/ml,试验组中心功能Ⅳ级患者的血清MAO,IL-6,NT-proBNP水平均高出心功能Ⅰ,Ⅱ,Ⅲ级患者,差异具有统计学意义(F=29.750,172.220,9414.430,均P<0.05)。联合诊断的敏感度(97.50%)、特异度(95.00%)、ROC曲线下面积(0.893)高出单一MAO(86.25%,83.75%,0.600)和IL-6(87.50%,83.75%,0.580),差异具有统计学意义(χ^(2)=0.004,7.207,6.664,均P<0.05)。血清MAO,IL-6,NT-proBNP指标均与慢性肾衰竭并发心力衰竭患者心功能分级呈现正相关性(r=0.562~0.781,P<0.05)。结论血清MAO,IL-6与慢性肾衰竭并发心力衰竭患者心功能分级存在密切关联性,不仅能够诊断疾病,同时还可对心功能分级进行评估,另外联合诊断的敏感度以及特异度更高。

抗阿尔兹海默症灯盏乙素苷元衍生物设计、合成及活性研究

基于阿尔兹海默症(AD)发病机制的复杂性,为了开发多功能的抗AD药物,根据多靶点导向配体(Multi-target directed ligands,MTDLs)策略,以灯盏乙素苷元为骨架,通过不同的连接体,连接具有胆碱酯酶抑制作用的N,N-双取代氨基甲酸酯片段和具有单胺氧化酶抑制作用的炔丙胺、N-甲基炔丙胺片段,设计并合成9个双靶点抗AD化合物,结构经过1HNMR、13CNMR和ESI-MS鉴定。对目标化合物进行胆碱酯酶和单胺氧化酶的活性测试,其中2-(4-((二甲基氨基甲酰基)氧基)苯基)-5,6-二羟基-4-氧代-4H-色烯-7-基5-(甲基(丙-2-炔-1-基)氨基)-5-氧代戊酸酯对两种酶具有相对较好的抑制活性。酶动力学结果说明该化合物对乙酰胆碱酯酶是混合型抑制。上述化合物不仅对自身和Cu2+诱导的A_(β1-42)聚集具有良好的抑制作用(87.57%和82.22%),而且还能诱导自身和Cu^(2+)诱导的Aβ_(1-42)原纤维的分解(75.01%和77.40%)。该化合物可以进行进一步结构优化和活性测试,为多靶点抗阿尔兹海默症提供候选化合物。

姜黄素联合单胺氧化酶A抑制剂氯吉灵对肺癌细胞增殖的影响

目的 研究姜黄素(curcumin, Cur)联合单胺氧化酶A(monoamine oxidase A,MAOA)抑制剂氯吉灵(clorgyline, Clo)对肺癌细胞增殖的影响及作用机制。方法 CCK-8法检测不同浓度Cur和Clo对肺癌细胞H460增殖的作用;Western Blot检测Cur、Clo、Cur联合Clo对H460细胞MAOA表达水平的影响;裸鼠移植瘤模型研究Cur、Clo、Cur联合Clo对H460细胞体内增殖的抑制作用;免疫组织化学(immunohistochemistry, IHC)检测裸鼠移植瘤组织中各治疗组的Ki67蛋白表达变化,TUNEL染色检测裸鼠移植瘤组织中各治疗组细胞的凋亡水平。结果 Cur、 Clo、Cur联合Clo对H460细胞增殖均有抑制作用,且呈现剂量依赖性;并且能够抑制H460细胞裸鼠移植瘤的生长(P<0.01),降低Ki67的表达水平,增加细胞凋亡,且联合组呈现更显著的抑制效果(P<0.01)。结论Cur联合Clo抑制H460肺癌细胞的增殖,其机制可能与降低细胞增殖蛋白Ki67的表达、增加细胞凋亡有关。