Harmine

harmine
  • 文章类型: Journal Article
    Harmine(HM),从植物中提取的β-咔啉生物碱,是中药(TCM)的重要组成部分,以其多种药理活性而闻名。血小板减少症,一种常见且具有挑战性的血液病,经常与严重的疾病共存。先前的研究表明,HM和血小板减少症之间存在相关性,但是机制需要进一步阐明。这项研究的目的是阐明HM对血小板减少症影响的潜在机制,并开发新的治疗策略。流式细胞术,Giemsa染色,和Phalloidin染色用于评估HM对Meg-01和HEL细胞分化和成熟的影响。使用辐射诱导的血小板减少小鼠模型来评估HM对体内血小板产生的影响。网络药理学,分子对接,和蛋白质印迹被用来研究HM的靶标和机制。结果表明,HM在体外剂量依赖性地促进Meg-01和HEL细胞的分化和成熟,并在体内恢复受照射小鼠的血小板水平。随后,发现HM通过上调Rac1,Cdc42,JNK的表达参与血小板产生的生物学过程,5-HTR2A此外,还证实了HM对5-HTR2A的靶向性及其与下游Rac1/Cdc42/JNK的相关性。总之,HM通过5-HTR2A和Rac1/Cdc42/JNK途径调节巨核细胞分化和血小板生成,为血小板减少症提供潜在的治疗策略。
    Harmine (HM), a β-carboline alkaloid extracted from plants, is a crucial component of traditional Chinese medicine (TCM) known for its diverse pharmacological activities. Thrombocytopenia, a common and challenging hematological disorder, often coexists with serious illnesses. Previous research has shown a correlation between HM and thrombocytopenia, but the mechanism needs further elucidation. The aim of this study was to clarify the mechanisms underlying the effects of HM on thrombocytopenia and to develop new therapeutic strategies. Flow cytometry, Giemsa staining, and Phalloidin staining were used to assess HM\'s impact on Meg-01 and HEL cell differentiation and maturation in vitro. A radiation-induced thrombocytopenic mouse model was employed to evaluate HM\'s effect on platelet production in vivo. Network pharmacology, molecular docking, and protein blotting were utilized to investigate HM\'s targets and mechanisms. The results demonstrated that HM dose-dependently promoted Meg-01 and HEL cell differentiation and maturation in vitro and restored platelet levels in irradiated mice in vivo. Subsequently, HM was found to be involved in the biological process of platelet production by upregulating the expressions of Rac1, Cdc42, JNK, and 5-HTR2A. Furthermore, the targeting of HM to 5-HTR2A and its correlation with downstream Rac1/Cdc42/JNK were also confirmed. In conclusion, HM regulates megakaryocyte differentiation and thrombopoiesis through the 5-HTR2A and Rac1/Cdc42/JNK pathways, providing a potential treatment strategy for thrombocytopenia.
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  • 文章类型: Journal Article
    作为配体的小分子靶向多功能核糖核酸(RNA)用于治疗接合。这项研究探讨了抗癌DNA嵌入剂harmine如何与RNA的各种基序相互作用,包括单链A型聚(rA),三叶草的叶子tRNAphe,和双链A形式聚(rC)-聚(rG)。Harmine按顺序显示出对多核苷酸的亲和力,聚(rA)>tRNAphe>聚(rC)·聚(rG)。虽然用poly(rC)poly(rG)没有检测到诱导的圆二色性变化,据报道,poly(rA)的结构发生了显着变化,随后是tRNAphe,并且在附着的生物碱非手性分子中同时发生了光学活性的启动。在25°C时,亲和力进一步显示放热和熵驱动的结合。相互作用还突出了与harmine结合的疏水转移(ΔGhyd)的热容(ΔCop)和吉布斯能贡献。分子对接计算表明,与tRNAphe和poly(rC)·poly(rG)相比,harmine对poly(rA)具有更高的亲和力。随后进行了分子动力学模拟,以研究harmine与poly(A)的结合方式和稳定性。tRNAphe,和聚(rC)·聚(rG)。结果表明,harmine采用与poly(rA)和tRNAphe的部分嵌入结合,其特征是用聚(rA)观察到明显的堆垛力和更强的结合自由能,而用tRNAphe观察到相对较弱的结合自由能。相比之下,聚(rC)·聚(rG)的堆叠力相对较不明显,并采用凹槽结合模式。它也得到了亚铁氰化物猝灭分析的支持。所有这些发现都明确地提供了对harmine结合特异性的详细见解,其他RNA基序上的单链聚(rA),可能表明poly(rA)与harmine的自我结构形成及其作为基于RNA的药物靶向的先导化合物的潜力。
    Small molecules as ligands target multifunctional ribonucleic acids (RNA) for therapeutic engagement. This study explores how the anticancer DNA intercalator harmine interacts various motifs of RNAs, including the single-stranded A-form poly (rA), the clover leaf tRNAphe, and the double-stranded A-form poly (rC)-poly (rG). Harmine showed the affinity to the polynucleotides in the order, poly (rA) > tRNAphe > poly (rC)·poly (rG). While no induced circular dichroism change was detected with poly (rC)poly (rG), significant structural alterations of poly (rA) followed by tRNAphe and occurrence of concurrent initiation of optical activity in the attached achiral molecule of alkaloid was reported. At 25 °C, the affinity further showed exothermic and entropy-driven binding. The interaction also highlighted heat capacity (ΔC o p ) and Gibbs energy contribution from the hydrophobic transfer (ΔG hyd) of binding with harmine. Molecular docking calculations indicated that harmine exhibits higher affinity for poly (rA) compared to tRNAphe and poly (rC)·poly (rG). Subsequent molecular dynamics simulations were conducted to investigate the binding mode and stability of harmine with poly(A), tRNAphe, and poly (rC)·poly (rG). The results revealed that harmine adopts a partial intercalative binding with poly (rA) and tRNAphe, characterized by pronounced stacking forces and stronger binding free energy observed with poly (rA), while a comparatively weaker binding free energy was observed with tRNAphe. In contrast, the stacking forces with poly (rC)·poly (rG) were comparatively less pronounced and adopts a groove binding mode. It was also supported by ferrocyanide quenching analysis. All these findings univocally provide detailed insight into the binding specificity of harmine, to single stranded poly (rA) over other RNA motifs, probably suggesting a self-structure formation in poly (rA) with harmine and its potential as a lead compound for RNA based drug targeting.
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  • 文章类型: Journal Article
    背景:由于抗菌素耐药性(AMR)已成为全球健康危机,我们迫切需要针对AMR感染的新策略。Quorumsensing(QS),负责细菌通讯和致病性,是作为抗AMR感染的有希望的治疗方法之一的抗毒力药物的目标之一。
    方法:我们确定了一种天然化合物,Harmine,通过基于铜绿假单胞菌三种QS受体的虚拟筛选(P.铜绿假单胞菌),并探讨了Harmine对QS控制和致病性相关表型的影响,包括绿脓苷的产生,细胞外蛋白酶排泄,生物膜的形成,和抽搐运动的铜绿假单胞菌PA14。Harmine对秀丽隐杆线虫的保护作用(C.确定了线虫)和小鼠感染模型,并探索了Harmine与常用抗生素的协同作用。通过分子对接分析阐明了Harmine的QS抑制作用的机制,转录组学分析,和目标验证分析。
    结果:体外结果表明Harmine对绿脓苷的产生具有QS抑制作用,细胞外蛋白酶排泄,生物膜的形成,以及铜绿假单胞菌PA14的抽搐运动,体内结果显示Harmine对秀丽隐杆线虫和小鼠感染模型的保护作用。有趣的是,当联合使用时,毒理学会增加PA14和铜绿假单胞菌临床分离株对多粘菌素B和卡那霉素的敏感性。此外,组胺下调了一系列与致病性相关的QS控制基因,其潜在机制可能涉及竞争性拮抗自诱导受体LasR,RhlR,和PqsR。
    结论:这项研究揭示了Harmine对QS靶标的潜在抗毒力,建议使用Harmine及其衍生物作为抗毒力化合物。
    BACKGROUND: As antimicrobial resistance (AMR) has become a global health crisis, new strategies against AMR infection are urgently needed. Quorum sensing (QS), responsible for bacterial communication and pathogenicity, is among the targets for anti-virulence drugs that thrive as one of the promising treatments against AMR infection.
    METHODS: We identified a natural compound, Harmine, through virtual screening based on three QS receptors of Pseudomonas aeruginosa (P. aeruginosa) and explored the effect of Harmine on QS-controlled and pathogenicity-related phenotypes including pyocyanin production, exocellular protease excretion, biofilm formation, and twitching motility of P. aeruginosa PA14. The protective effect of Harmine on Caenorhabditis elegans (C. elegans) and mice infection models was determined and the synergistic effect of Harmine combined with common antibiotics was explored. The underlaying mechanism of Harmine\'s QS inhibitory effect was illustrated by molecular docking analysis, transcriptomic analysis, and target verification assay.
    RESULTS: In vitro results suggested that Harmine possessed QS inhibitory effects on pyocyanin production, exocellular protease excretion, biofilm formation, and twitching motility of P. aeruginosa PA14, and in vivo results displayed Harmine\'s protective effect on C. elegans and mice infection models. Intriguingly, Harmine increased susceptibility of both PA14 and clinical isolates of P. aeruginosa to polymyxin B and kanamycin when used in combination. Moreover, Harmine down-regulated a series of QS controlled genes associated with pathogenicity and the underlying mechanism may have involved competitively antagonizing autoinducers\' receptors LasR, RhlR, and PqsR.
    CONCLUSIONS: This study shed light on the anti-virulence potential of Harmine against QS targets, suggesting the possible use of Harmine and its derivates as anti-virulence compounds.
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  • 文章类型: Journal Article
    Harmine存在于各种药用植物中,其对结肠癌细胞的影响尚不清楚。这里,我们发现,harmine通过抑制FAK/AKT和ERK1/2/CREB的磷酸化水平,对结肠癌细胞的增殖具有明显的抑制作用。此外,harmine还抑制结肠癌细胞的迁移,并抑制MMP-2,MMP-9和VEGF的表达水平。此外,harmine通过调节Bcl-2和Bax的表达诱导结肠癌细胞凋亡。总之,我们的发现表明,harmine对结肠癌细胞的发展具有显著的抑制作用。
    Harmine is present in a variety of medicinal plants, and its effects on colon cancer cells remain unclear. Here, we found that harmine exhibited significant inhibitory effects on the proliferation of colon cancer cells by inhibiting the phosphorylation levels of the FAK/AKT and ERK1/2/CREB. Furthermore, harmine also inhibited the migration of colon cancer cells and suppressed the expression levels of MMP-2, MMP-9, and VEGF. Additionally, harmine-induced apoptosis in colon cancer cells by regulating the expression of Bcl-2 and Bax. In conclusion, our findings suggest that harmine exerts a significant inhibitory effect on the development of colon cancer cells.
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  • 文章类型: Journal Article
    全球有五亿三千七百万人患有糖尿病。在大多数糖尿病患者中,产生胰岛素的β细胞数量减少,但大多数个体仍有一些残留的β细胞。然而,许多常用的糖尿病药物都不能增加人的β细胞数量。最近,抑制双重酪氨酸调节激酶1A(DYRK1A)的小分子已被证明可诱导人β细胞复制的免疫组织化学标记,并且这通过刺激β细胞上的胰高血糖素样肽1(GLP1)受体(GLP1R)的药物而增强。然而,这些免疫组织化学结果是否转化为体内人β细胞数量的实际增加还有待证明.DYRK1A抑制剂与GLP1R激动剂(GLP1RAs)是否影响人β细胞存活也是未知的。这里,在携带人胰岛移植物的小鼠肾脏中使用优化的免疫标记启用的溶剂清除器官三维成像(iDISCO+)方案,我们证明了DYRK1A抑制剂与exendin-4的组合在糖尿病和非糖尿病小鼠中在3个月内平均增加体内实际人β细胞质量4至7倍,并逆转糖尿病。人α细胞质量没有改变。人β细胞群的增加是通过包括增强人β细胞增殖的机制发生的。函数,和生存。人β细胞存活率的增加是介导的,在某种程度上,通过胰岛激素原VGF。一起,这些发现证明了DYRK1A抑制剂-GLP1RA联合治疗糖尿病的治疗潜力和良好的临床前安全性.
    Five hundred thirty-seven million people globally suffer from diabetes. Insulin-producing β cells are reduced in number in most people with diabetes, but most individuals still have some residual β cells. However, none of the many diabetes drugs in common use increases human β cell numbers. Recently, small molecules that inhibit dual tyrosine-regulated kinase 1A (DYRK1A) have been shown to induce immunohistochemical markers of human β cell replication, and this is enhanced by drugs that stimulate the glucagon-like peptide 1 (GLP1) receptor (GLP1R) on β cells. However, it remains to be demonstrated whether these immunohistochemical findings translate into an actual increase in human β cell numbers in vivo. It is also unknown whether DYRK1A inhibitors together with GLP1R agonists (GLP1RAs) affect human β cell survival. Here, using an optimized immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO+) protocol in mouse kidneys bearing human islet grafts, we demonstrate that combination of a DYRK1A inhibitor with exendin-4 increases actual human β cell mass in vivo by a mean of four- to sevenfold in diabetic and nondiabetic mice over 3 months and reverses diabetes, without alteration in human α cell mass. The augmentation in human β cell mass occurred through mechanisms that included enhanced human β cell proliferation, function, and survival. The increase in human β cell survival was mediated, in part, by the islet prohormone VGF. Together, these findings demonstrate the therapeutic potential and favorable preclinical safety profile of the DYRK1A inhibitor-GLP1RA combination for diabetes treatment.
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  • 文章类型: Journal Article
    背景:Harmine具有许多药理活性,并且已发现显着抑制瘢痕疙瘩成纤维细胞的纤维化。DNA损伤修复(DDR)对预防纤维化至关重要。本研究旨在探讨harmine对肺纤维化的影响及其机制。
    方法:用博来霉素和TGF-β1构建体内外肺纤维化模型,然后用harmine治疗,探讨harmine治疗实验性肺纤维化的作用及其相关机制。然后,RNA测序用于进一步研究抗肺纤维化的关键DDR相关基因和药物靶标。最后,通过实时定量PCR(RT-qPCR)和Westernblot验证DDR相关基因的表达水平。
    结果:我们的体内实验表明,harmine治疗可以改善患有肺纤维化的小鼠的体重减轻和肺功能,并减少组织纤维化。结果证实,harmine可以抑制TGF-β1诱导的MRC-5细胞的活力和迁移,诱导它们的凋亡,并抑制F-肌动蛋白的表达,表明harmine可以抑制从肺成纤维细胞到肺成肌细胞的表型转变。此外,RNA测序鉴定出1692个差异表达基因(DEGs),筛选出10个DDR相关基因为关键DDR相关基因。RT-qPCR和westernblotting表明,harmine可以下调CHEK1,ERCC1,ERCC4,POLD1,RAD51,RPA1,TOP1和TP53的表达,而上调FEN1,H2AX和GADD45α的表达。
    结论:Harmine可能通过调节DDR相关基因并激活TP53-Gadd45α通路来抑制肺纤维化。
    BACKGROUND: Harmine has many pharmacological activities and has been found to significantly inhibit the fibrosis of keloid fibroblasts. DNA damage repair (DDR) is essential to prevent fibrosis. This study aimed to investigate the effects of harmine on pulmonary fibrosis and its underlying mechanisms.
    METHODS: Bleomycin and TGF-β1 were used to construct pulmonary fibrosis models in vivo and in vitro, then treated with harmine to explore harmine\'s effects in treating experimental pulmonary fibrosis and its related mechanisms. Then, RNA sequencing was applied to investigate further the crucial DDR-related genes and drug targets of harmine against pulmonary fibrosis. Finally, the expression levels of DDR-related genes were verified by real-time quantitative PCR (RT-qPCR) and western blot.
    RESULTS: Our in vivo experiments showed that harmine treatment could improve weight loss and lung function and reduce tissue fibrosis in mice with pulmonary fibrosis. The results confirmed that harmine could inhibit the viability and migration of TGF-β1-induced MRC-5 cells, induce their apoptosis, and suppress the F-actin expression, suggesting that harmine could suppress the phenotypic transition from lung fibroblasts to lung myoblasts. In addition, RNA sequencing identified 1692 differential expressed genes (DEGs), and 10 DDR-related genes were screened as critical DDR-related genes. RT-qPCR and western blotting showed that harmine could down-regulate the expression of CHEK1, ERCC1, ERCC4, POLD1, RAD51, RPA1, TOP1, and TP53, while up-regulate FEN1, H2AX and GADD45α expression.
    CONCLUSIONS: Harmine may inhibit pulmonary fibrosis by regulating DDR-related genes and activating the TP53-Gadd45α pathway.
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  • 文章类型: Journal Article
    背景:本研究旨在阐明P.harmala生物碱提取物的潜在抗癌活性和机制,harmine(HAR),和harmaline(HAL)在HCT-116结直肠癌细胞中的作用。
    结果:P.harmala的生物碱是从harmala种子中提取的。HCT-116细胞用P.harmala生物碱提取物处理,HAR和HAL.通过MTT法测定细胞毒性,通过流式细胞术和吖啶橙(AO)/溴化乙锭(EB)双重染色检测凋亡活性,用流式细胞仪分析细胞周期分布。通过实时PCR检测Bcl-2相关X蛋白(Bax)和糖原合酶激酶3β(GSK3β)的mRNA表达。此外,Bax的表达,Bcl-2、GSK3β和p53蛋白,通过蛋白质印迹确定。调查结果表明,P.harmala生物碱提取物,治疗24和48小时后,HAR和HAL对HCT116细胞具有明显的细胞毒性。我们表明,在HCT116细胞系中,P.harmala的生物碱提取物在G2期诱导细胞凋亡和细胞周期停滞。观察到GSK3β和Bcl-2的下调以及Bax和p53的上调。
    结论:本研究的结果表明,苦参生物碱提取物具有抗癌活性,有可能进一步研究开发未来的抗癌化疗药物。
    BACKGROUND: The present study aimed to elucidate the potential anticancer activity and mechanism of P. harmala\'s alkaloid extract, harmine (HAR), and harmaline (HAL) in HCT-116 colorectal cancer cells.
    RESULTS: P. harmala\'s alkaloid was extracted from harmala seeds. HCT-116 cells were treated with P. harmala\'s alkaloid extract, HAR and HAL. Cytotoxicity was determined by MTT assay, apoptotic activity detected via flow cytometry and acridine orange (AO)/ethidium bromide (EB) dual staining, and cell cycle distribution analyzed with flow cytometry. The mRNA expression of Bcl-2-associated X protein (Bax) and glycogen synthase kinase-3 beta (GSK3β) was measured by real-time PCR. Furthermore, the expression of Bax, Bcl-2, GSK3β and p53 proteins, were determined by western blotting. The findings indicated that, P. harmala\'s alkaloids extract, HAR and HAL were significantly cytotoxic toward HCT116 cells after 24 and 48 h of treatment. We showed that P. harmala\'s alkaloid extract induce apoptosis and cell cycle arrest at G2 phase in the HCT116 cell line. Downregulation of GSK3β and Bcl-2 and upregulation of Bax and p53 were observed.
    CONCLUSIONS: The findings of this study indicate that the P. harmala\'s alkaloid extract has anticancer activity and may be further investigated to develop future anticancer chemotherapeutic agents.
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  • 文章类型: Journal Article
    神经退行性疾病(NDD)包括一系列以神经元的特定功能障碍和持续衰退为特征的疾病,胶质细胞,大脑和脊髓内的神经网络。大多数NDD表现出相似的根本原因,包括氧化应激,神经炎症,线粒体功能失调.乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BChE)水平升高,脑源性神经营养因子(BDNF)和谷氨酸转运体亚型1(GLT-1)的表达降低,是导致NDDs发病的重要因素。此外,双特异性酪氨酸磷酸化调节激酶1A(DYRK1A)基因已成为临床前水平治疗NDD的重要靶点.它显著有助于大脑发育缺陷,早发性神经变性,神经元丢失,和唐氏综合症的痴呆症。此外,受损的泛素-蛋白体系统(UPS)也在NDD中起病理作用。UPS的故障导致异常的蛋白质积聚或α-突触核蛋白的聚集。α-突触核蛋白是一种高度可溶的未折叠蛋白,在帕金森病和其他突触核蛋白病中积聚在路易体和路易神经突。最近的研究强调了天然产物相对于常规疗法在对抗NDD方面的有希望的潜力。生物碱已成为对抗NDD的有希望的候选人。Harmine是三环β-咔啉生物碱(harmala生物碱),具有一个吲哚核和一个六元吡咯环。它是从巴尼斯特草caapi和PeganumharmalaL.中提取的,并具有多种药理特性,包括神经保护,抗氧化剂,抗炎,抗抑郁药,等。据报道,Harmine通过降低炎症介质的水平来介导其神经保护作用,NADPH氧化酶,AChE,BChE和活性氧(ROS)。然而,已经观察到增加BDNF的水平,GLT-1和抗氧化酶,以及蛋白激酶A(PKA)介导的UPS激活。这篇综述旨在讨论参与harmine神经保护作用的各种介质的机制相互作用。
    Neurodegenerative diseases (NDDs) encompass a range of conditions characterized by the specific dysfunction and continual decline of neurons, glial cells, and neural networks within the brain and spinal cord. The majority of NDDs exhibit similar underlying causes, including oxidative stress, neuroinflammation, and malfunctioning of mitochondria. Elevated levels of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), alongside decreased expression of brain-derived neurotrophic factor (BDNF) and glutamate transporter subtype 1 (GLT-1), constitute significant factors contributing to the pathogenesis of NDDs. Additionally, the dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) gene has emerged as a significant target for the treatment of NDDs at the preclinical level. It significantly contributes to developmental brain defects, early onset neurodegeneration, neuronal loss, and dementia in Down syndrome. Moreover, an impaired ubiquitin-proteosome system (UPS) also plays a pathological role in NDDs. Malfunctioning of UPS leads to abnormal protein buildup or aggregation of α-synuclein. α-Synuclein is a highly soluble unfolded protein that accumulates in Lewy bodies and Lewy neurites in Parkinson\'s disease and other synucleinopathies. Recent research highlights the promising potential of natural products in combating NDDs relative to conventional therapies. Alkaloids have emerged as promising candidates in the fight against NDDs. Harmine is a tricyclic β-carboline alkaloid (harmala alkaloid) with one indole nucleus and a six-membered pyrrole ring. It is extracted from Banisteria caapi and Peganum harmala L. and exhibits diverse pharmacological properties, encompassing neuroprotective, antioxidant, anti-inflammatory, antidepressant, etc. Harmine has been reported to mediate its neuroprotective via reducing the level of inflammatory mediators, NADPH oxidase, AChE, BChE and reactive oxygen species (ROS). Whereas, it has been observed to increase the levels of BDNF, GLT-1 and anti-oxidant enzymes, along with protein kinase-A (PKA)-mediated UPS activation. This review aims to discuss the mechanistic interplay of various mediators involved in the neuroprotective effect of harmine.
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  • 文章类型: Journal Article
    单纯疱疹病毒(HSV)感染在人类中非常普遍,产生从溃疡性病变到失明和危及生命的脑炎等严重疾病的症状。目前,没有可用的疫苗,和一些现有的抗病毒治疗可能是无效的或导致不良反应。因此,需要新的抗HSV药物。在这份报告中,9,9'-norharmane二聚体(nHo-二聚体)的体外抗HSV作用,属于β-咔啉(βC)生物碱家族,进行了评估。二聚体没有表现出杀病毒性质,并且不妨碍病毒颗粒的附着或渗透步骤。只有在孵育培养基中二聚体的恒定存在下才能发挥抗病毒作用。并且发现其作用机制涉及后来的病毒感染事件。荧光寿命成像数据的分析表明,当存在于细胞外孵育培养基中时,nHo-二聚体很好地内化到细胞中,优先积累到包括线粒体在内的核周细胞器中。用不含nHo-二聚体的新鲜培养基洗涤宿主细胞后,信号减弱,表明化合物从细胞中部分释放。这与以下观察结果一致:当生物碱始终存在于孵育培养基中时,抗病毒作用仅表现出来。
    Herpes simplex virus (HSV) infections are highly widespread among humans, producing symptoms ranging from ulcerative lesions to severe diseases such as blindness and life-threatening encephalitis. At present, there are no vaccines available, and some existing antiviral treatments can be ineffective or lead to adverse effects. As a result, there is a need for new anti-HSV drugs. In this report, the in vitro anti-HSV effect of 9,9\'-norharmane dimer (nHo-dimer), which belongs to the β-carboline (βC) alkaloid family, was evaluated. The dimer exhibited no virucidal properties and did not impede either the attachment or penetration steps of viral particles. The antiviral effect was only exerted under the constant presence of the dimer in the incubation media, and the mechanism of action was found to involve later events of virus infection. Analysis of fluorescence lifetime imaging data showed that the nHo-dimer internalized well into the cells when present in the extracellular incubation medium, with a preferential accumulation into perinuclear organelles including mitochondria. After washing the host cells with fresh medium free of nHo-dimer, the signal decreased, suggesting the partial release of the compound from the cells. This agrees with the observation that the antiviral effect is solely manifested when the alkaloid is consistently present in the incubation media.
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  • 文章类型: Journal Article
    尽管癌症和疟疾在病因和病理生理上没有联系,由于它们的相似性,成功地将抗疟疾药物重新用于癌症,反之亦然是已知的,并用于临床环境和药物研究和发现。随着癌细胞和疟原虫对已知药物的耐药性不断增强,迫切需要发现新的化学型并丰富抗癌和抗疟疾药物组合。在本文中,我们介绍了harmiprims的设计和合成,由harmine组成的杂种,具有抗癌和抗疟原虫活性的β-咔啉型生物碱,和伯氨喹,8-氨基喹啉抗疟药具有低抗增殖活性,通过三唑或脲共价结合。对其体外抗增殖活性的评估表明,N-9取代的三唑型harmisprime是对MCF-7最具选择性的化合物,而C1取代的脲基型杂合体是对所有测试细胞系最具活性的化合物。另一方面,二聚harmisr是没有毒性的。尽管分光光度研究和热变性实验表明harmibrims与ds-DNA凹槽结合,细胞定位显示harmiprims不进入细胞核或线粒体,因此,预计不会抑制DNA相关过程。细胞周期分析显示,C1取代的脲基型杂种在24小时后诱导G1期停滞并减少S期细胞数量,坚持48小时,尽管G1的增加不太明显,可能是由于适应性细胞反应。相比之下,N-9取代的三唑型哈米普利对细胞周期的影响不明显,特别是在48小时后,这与其对MCF-7细胞系的中等活性一致。另一方面,筛选它们对红细胞的抗疟原虫活性,肝,疟原虫生命周期的配子细胞阶段表明,二聚harmisprime发挥强大的三阶段抗疟原虫活性,而计算分析表明其在PfHsp90的ATP结合位点内的结合。
    Although cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of harmine, an alkaloid of the β-carboline type bearing anticancer and antiplasmodial activities, and primaquine, 8-aminoquinoline antimalarial drug with low antiproliferative activity, covalently bound via triazole or urea. Evaluation of their antiproliferative activities in vitro revealed that N-9 substituted triazole-type harmiprime was the most selective compound against MCF-7, whereas C1-substituted ureido-type hybrid was the most active compound against all cell lines tested. On the other hand, dimeric harmiprime was not toxic at all. Although spectrophotometric studies and thermal denaturation experiments indicated binding of harmiprims to the ds-DNA groove, cell localization showed that harmiprims do not enter cell nucleus nor mitochondria, thus no inhibition of DNA-related processes can be expected. Cell cycle analysis revealed that C1-substituted ureido-type hybrid induced a G1 arrest and reduced the number of cells in the S phase after 24 h, persisting at 48 h, albeit with a less significant increase in G1, possibly due to adaptive cellular responses. In contrast, N-9 substituted triazole-type harmiprime exhibited less pronounced effects on the cell cycle, particularly after 48 h, which is consistent with its moderate activity against the MCF-7 cell line. On the other hand, screening of their antiplasmodial activities against the erythrocytic, hepatic, and gametocytic stages of the Plasmodium life cycle showed that dimeric harmiprime exerts powerful triple-stage antiplasmodial activity, while computational analysis showed its binding within the ATP binding site of PfHsp90.
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