Phellodendrine

黄柏
  • 文章类型: Journal Article
    黄柏(PCC)抗病的药理机制,尤其是膀胱癌(BC),从未系统地报道过。本研究旨在探讨PCC治疗BC的潜在机制。首先,运用网络药理学研究黄柏和黄柏碱抗膀胱癌的潜在作用机制。然后,我们使用生物信息学分析来验证基因表达分析之间的相关性,生存分析和共同目标。最后,分子对接用于计算黄柏碱与常见靶标的结合能。共预测了PCC的264个目标,从4个数据库中获得391个BC相关目标。有54个潜在目标,315个生物过程,和120条信号通路涉及PCC抗BC。CDKN2A表达增加,ESR1,JUN,IL6、AR、根据基因表达谱交互式分析版本2,BC中的PTGS2水平降低。JUN的高表达,MYC,EGFR,EGF和VEGFA和PPARG的低表达与短总生存期(OS)相关。AKT1、EGFR、EGF和IL1β的低表达与低无病生存率(DFS)相关。对黄柏和BC目标交叉点的搜索产生了11个共同目标,50个生物过程,和13个信号通路参与。高AURKA和FASN和低ESR1,JUN,ABCB1和PTGS1在BC中表达。FASN的高表达,ABCC1,PTGS1,JUN,PIK3CA与短操作系统有关,PIK3CA和ABCC1的高表达与不良DFS预后相关.黄柏碱对PTGS2蛋白显示出更好的结合亲和力,对接评分为-7.183,MM-GBSA结果为-46.47kcal/mol。本研究通过网络药理学和生物信息学揭示了PCC和黄柏碱抗BC的潜在机制。
    The pharmacological mechanism of Phellodendri Chinensis cortex (PCC) against diseases, especially bladder cancer (BC), has never been reported systematically. This study was designed to explore potential mechanism of PCC in treatment of BC. First, we used network pharmacology to discover the potential mechanism of Phellodendri Chinensis cortex and phellodendrine against bladder cancer. Then, we used bioinformatics analysis to verify the correlation between gene expression analysis, survival analysis and common targets. Finally, molecular docking was used to calculate the binding energies of phellodendrine and common targets.A total of 264 targets for PCC were predicted, and 391 BC-related targets were obtained from 4 databases. There were 54 potential targets, 315 biological processes, and 120 signaling pathways involved for PCC against BC. The CDKN2A expression increased and the ESR1, JUN, IL6, AR, and PTGS2 levels decreased in BC according to Gene Expression Profiling Interactive Analysis version 2. The high expression of JUN, MYC, EGFR, and EGF and low expression of VEGFA and PPARG were associated with short overall survival (OS). The high expression of AKT1, EGFR, and EGF and low expression of IL1β were associated with poor disease-free survival (DFS). The search of the intersection of phellodendrine and BC targets yielded 11 common targets, 50 biological processes, and 13 signaling pathways involved. High AURKA and FASN and low ESR1, JUN, ABCB1, and PTGS1 were expressed in BC. The high expression of FASN, ABCC1, PTGS1, JUN, and PIK3CA was associated with short OS, the high expression of PIK3CA and ABCC1 was associated with poor DFS prognosis. Phellodendrine showed a better binding affinity for PTGS2 protein with a docking score of -7.183 and a MM-GBSA result of -46.47 kcal/mol. This study revealed potential mechanism of PCC and phellodendrine against BC through network pharmacology and bioinformatics.
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  • 文章类型: Journal Article
    玉米赤霉烯酮(ZEN)是一种常见的真菌毒素,在各种谷物中具有生殖毒性。对绵羊等畜牧业构成严重威胁,以及人类的生殖健康。因此,研究毒性机制和筛选拮抗药物具有重要意义。在这项研究中,基于天然化合物库和以前的Smart-seq2结果,选择抗氧化和抗凋亡药物作为潜在拮抗药物进行筛选。三种天然植物化合物(氧化苦参碱,芦丁,使用定量聚合酶链反应(qPCR)和活性氧检测,筛选了黄柏碱)在体外抵抗ZEN对绵羊卵母细胞的生殖毒性的能力。这些化合物表现出不同的药理作用,特别是影响抗氧化剂的表达(GPX,SOD1和SOD2),自噬(ATG3,ULK2和LC3),和凋亡(CAS3,CAS8和CAS9)基因。OxysophoridinepromotedGPX,SOD1、ULK2和LC3表达,同时抑制CAS3和CAS8的表达。芦丁促进SOD2和ATG3的表达,并抑制CAS3和CAS9的表达。黄柏碱促进SOD2和ATG3的表达,并抑制CAS9表达。然而,所有化合物都促进细胞周期相关基因的表达,主轴检查点,卵母细胞成熟,和积云扩展因子。虽然三种药物在增强抗氧化能力方面有不同的调节机制,增强自噬,抑制细胞凋亡,它们都维持了稳定的细胞内环境和正常的细胞周期,促进卵母细胞成熟和卵丘扩张因子的释放,and,最终,对抗ZEN生殖毒性,促进绵羊卵母细胞体外成熟。这项研究确定了三种拮抗ZEN对绵羊卵母细胞生殖毒性的药物,并比较了它们的作用机制,为其在绵羊养殖业的后续应用提供数据支持和理论依据,减少养殖业的损失,ZEN生殖毒性拮抗剂和各种毒素拮抗剂的筛选,改进ZEN生殖毒性机制的研究,甚至保护人类的生殖健康。
    Zearalenone (ZEN) is a common fungal toxin with reproductive toxicity in various grains. It poses a serious threat to ovine and other animal husbandry industries, as well as human reproductive health. Therefore, investigating the mechanism of toxicity and screening antagonistic drugs are of great importance. In this study, based on the natural compound library and previous Smart-seq2 results, antioxidant and anti-apoptotic drugs were selected for screening as potential antagonistic drugs. Three natural plant compounds (oxysophoridine, rutin, and phellodendrine) were screened for their ability to counteract the reproductive toxicity of ZEN on ovine oocytes in vitro using quantitative polymerase chain reaction (qPCR) and reactive oxygen species detection. The compounds exhibited varying pharmacological effects, notably impacting the expression of antioxidant (GPX, SOD1, and SOD2), autophagic (ATG3, ULK2, and LC3), and apoptotic (CAS3, CAS8, and CAS9) genes. Oxysophoridine promoted GPX, SOD1, ULK2, and LC3 expression, while inhibiting CAS3 and CAS8 expression. Rutin promoted SOD2 and ATG3 expression, and inhibited CAS3 and CAS9 expression. Phellodendrine promoted SOD2 and ATG3 expression, and inhibited CAS9 expression. However, all compounds promoted the expression of genes related to cell cycle, spindle checkpoint, oocyte maturation, and cumulus expansion factors. Although the three drugs had different regulatory mechanisms in enhancing antioxidant capacity, enhancing autophagy, and inhibiting cell apoptosis, they all maintained a stable intracellular environment and a normal cell cycle, promoted oocyte maturation and release of cumulus expansion factors, and, ultimately, counteracted ZEN reproductive toxicity to promote the in vitro maturation of ovine oocytes. This study identified three drugs that antagonize the reproductive toxicity of ZEN on ovine oocytes, and compared their mechanisms of action, providing data support and a theoretical basis for their subsequent application in the ovine breeding industry, reducing losses in the breeding industry, screening of ZEN reproductive toxicity antagonists and various toxin antagonists, improving the study of ZEN reproductive toxicity mechanisms, and even protection of human reproductive health.
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  • 文章类型: Journal Article
    近年来过敏反应的发病率稳步上升,促使人们对鉴定可以预防或治疗过敏性疾病的有效和安全的天然化合物越来越感兴趣。黄柏。长期以来一直被用作过敏性疾病的治疗方法,其主要成分是黄柏碱。然而,黄柏碱治疗过敏性疾病的疗效尚待评估。肥大细胞是过敏反应的主要效应,它们不仅被IgE依赖性途径激活,而且还通过不依赖IgE的途径通过人MRGPRX2,大鼠对应物MRGPRB3。因此,本研究探讨黄柏碱通过该家族受体在体内外治疗过敏性疾病的作用及机制。这些分析表明,黄柏碱的给药足以防止C48/80引起的小鼠足部肿胀和伊文思蓝渗出,并抑制C48/80诱导的RBL-2H3大鼠嗜碱性白血病细胞脱颗粒,和β-HEX,HIS,IL-4和TNF-α释放。此外,黄柏碱可以通过改变其结构来降低MRGPRB3的mRNA表达和MRGPRX2的反应性。它能够降低Ca2+水平,CaMK的磷酸化水平,PLCβ1,PKC,ERK,JNK,p38和p65,并抑制IκB-α的降解。这些分析表明,小檗碱通过改变MRGPRB3/MRGPRX2蛋白的构象,抑制PLC的激活并下调内质网中Ca2的释放。从而抑制PKC的激活,随后抑制下游MAPK和NF-κB信号,最终抑制过敏反应。因此,专注于开发黄柏碱作为新型抗过敏药物的研究可能有进一步的价值。
    The incidence of allergic reactions has risen steadily in recent years, prompting growing interest in the identification of efficacious and safe natural compounds that can prevent or treat allergic diseases. Phellodendron amurense Rupr. has long been applied as a treatment for allergic diseases, whose primary component is phellodendrine. However, the efficacy of phellodendrine as a treatment for allergic diseases remains to be assessed. Mast cells are the primary effectors of allergic reactions, which are not only activated by IgE-dependent pathway, but also by IgE-independent pathways via human MRGPRX2, rat counterpart MRGPRB3. As such, this study explored the effect and mechanism of phellodendrine through this family receptors in treating allergic diseases in vitro and in vivo. These analyses revealed that phellodendrine administration was sufficient to protect against C48/80-induced foot swelling and Evans blue exudation in mice, and suppressed C48/80-induced RBL-2H3 rat basophilic leukemia cells degranulation, and β-HEX, HIS, IL-4, and TNF-α release. Moreover, phellodendrine could reduce the mRNA expression of MRGPRB3 and responsiveness of MRGPRX2 by altering its structure. It was able to decrease Ca2+ levels, phosphorylation levels of CaMK, PLCβ1, PKC, ERK, JNK, p38, and p65, and inhibit the degradation of IκB-α. These analyses indicate that berberine inhibits the activation of PLC and downregulates the release of Ca2+ in the endoplasmic reticulum by altering the conformation of MRGPRB3/MRGPRX2 protein, thereby inhibiting the activation of PKC and subsequently inhibiting downstream MAPK and NF-κB signaling, ultimately suppressing allergic reactions. There may thus be further value in studies focused on developing phellodendrine as a novel anti-allergic drug.
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  • 文章类型: Journal Article
    黄柏,黄柏的特征和重要活性成分之一,已被证明具有抗炎作用。然而,黄柏碱对炎症的潜在机制仍不清楚。
    在这项研究中,通过网络药理学和实验验证,探讨黄柏碱对炎症的作用机制。
    使用PubChem和SwissADME数据库评估黄柏碱的药物相似性和其他特征。用多个数据库分析黄柏碱治疗炎症的靶标。其他广泛的分析,包括蛋白质-蛋白质相互作用,基因本体论,和京都百科全书的基因和基因组途径富集与STRING数据库完成,Cytoscape软件,和DAVID数据库。此外,黄柏碱的抗炎作用在RAW264.7中得到证实。
    网络药理学结果表明黄柏碱具有药物潜力。黄柏直接作用于12个目标,包括PTGS1,PTGS2,HTR1A,和PIK3CA,然后调节cAMP,雌激素,TNF,血清素能突触,等信号通路发挥抗炎作用。实验结果表明,黄柏碱与LPS组相比,在24h内降低IL-6水平,改变PTGS1、PTGS2、HSP90ab1、AKT1、HTR1A、PI3CA,F10
    我们的研究初步揭示了黄柏碱对炎症的治疗机制,具有多个靶点和途径。黄柏碱可能是与cAMP和TNF信号通路相关的炎症相关疾病的潜在治疗方法。
    Phellodendrine, one of the characteristic and important active components of Cortex phellodendri, has been proven to show anti-inflammatory effects. However, the underlying mechanism of phellodendrine on inflammation remains largely unclear.
    In this study, network pharmacology and experimental validation were used to explore the underlying mechanism of phellodendrine on inflammation.
    PubChem and SwissADME database were used to evaluate the drug-likeness and other characteristics of phellodendrine. The targets of phellodendrine for the treatment of inflammation were analyzed with multiple databases. Other extensive analyses including protein-protein interaction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were accomplished with the STRING database, Cytoscape software, and DAVID database. Moreover, the effect of phellodendrine on anti-inflammation was proven in RAW264.7.
    The network pharmacology results indicated that phellodendrine had drug potential. Phellodendrine acted directly on 12 targets, including PTGS1, PTGS2, HTR1A, and PIK3CA, and then regulated cAMP, estrogen, TNF, serotonergic synapse, and other signaling pathways to exert anti-inflammatory effects. The experimental results showed that phellodendrine reduced the levels of IL-6 compared with the LPS group in 24 h and changed the mRNA expression of PTGS1, PTGS2, HSP90ab1, AKT1, HTR1A, PI3CA, and F10.
    Our research preliminarily uncovered the therapeutic mechanisms of phellodendrine on inflammation with multiple targets and pathways. Phellodendrine may be a potential treatment for inflammation-related diseases related to the cAMP and TNF signaling pathways.
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  • 文章类型: Journal Article
    探讨黄柏碱通过AMPK/mTOR通路对溃疡性结肠炎(UC)的治疗作用。招募志愿者观察复方黄柏液(黄柏擦剂)的治疗效果。采用网络药理学方法对复方黄柏液的主要成分进行分析。进一步分析黄柏碱的靶标。培养Caco-2细胞,用H2O2刺激体外细胞模型。LC3、AMPK、p-AMPK,通过蛋白质印迹和免疫荧光实验检测mTOR和p-mTOR。通过表达谱芯片测序分析黄柏碱的治疗效果。肠道菌群的测序进一步阐明了黄柏碱的治疗作用。与对照组相比,复方黄柏液能显著改善肠黏膜愈合。网络药理学分析表明黄柏碱是复方黄柏液的主要成分。此外,这种生物碱靶向AMPK信号通路。动物实验结果表明黄柏碱与模型组比较,可减轻UC的肠道损伤。细胞实验结果表明黄柏碱处理可以激活p-AMPK/mTOR信号通路,以及自噬。表达谱芯片测序显示黄柏碱可促进粘膜愈合,减轻炎症反应。肠道菌群检测结果表明,黄柏碱治疗可增加菌群丰度和有益菌含量。黄柏碱可能通过调节AMPK-mTOR信号通路促进自噬,从而减少由于UC引起的肠损伤。
    To investigate the therapeutic effects of phellodendrine in ulcerative colitis (UC) through the AMPK/mTOR pathway. Volunteers were recruited to observe the therapeutic effects of Compound Cortex Phellodendri Liquid (Huangbai liniment). The main components of Compound Cortex Phellodendri Liquid were analysed via network pharmacology. The target of phellodendrine was further analysed. Caco-2 cells were cultured, and H2 O2 was used to stimulate in vitro cell model. Expression levels of LC3, AMPK, p-AMPK, mTOR and p-mTOR were detected via Western blotting and through immunofluorescence experiments. The therapeutic effects of phellodendrine were analysed via expression spectrum chip sequencing. The sequencing of intestinal flora further elucidated the therapeutic effects of phellodendrine. Compared with the control group, Compound Cortex Phellodendri Liquid could substantially improve the healing of intestinal mucosa. Network pharmacology analysis revealed that phellodendrine is the main component of Compound Cortex Phellodendri Liquid. Moreover, this alkaloid targets the AMPK signalling pathway. Results of animal experiments showed that phellodendrine could reduce the intestinal damage of UC compared with the model group. Findings of cell experiments indicated that phellodendrine treatment could activate the p-AMPK /mTOR signalling pathway, as well as autophagy. Expression spectrum chip sequencing showed that treatment with phellodendrine could promote mucosal healing and reduce inflammatory responses. Results of intestinal flora detection demonstrated that treatment with phellodendrine could increase the abundance of flora and the content of beneficial bacteria. Phellodendrine may promote autophagy by regulating the AMPK-mTOR signalling pathway, thereby reducing intestinal injury due to UC.
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  • 文章类型: Journal Article
    1. Phellodendrine possesses numerous pharmacological activities. However, whether phellodendrine affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear.2. In this study, the inhibitory effects of phellodendrine on eight human liver CYP isoforms (i.e. 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs).3. The results showed that phellodendrine inhibited the activity of CYP1A2, 3A4 and 2C9, with IC50 values of 20.56, 14.98 and 16.30 μM, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that phellodendrine was not only a non-competitive inhibitor of CYP3A4, but also a competitive inhibitor of CYP1A2 and 2C9, with Ki values of 7.15, 10.52 and 7.98 μM, respectively. In addition, phellodendrine is a time-dependent inhibitor for CYP3A4 with Kinact/KI value of 0.046/11.57 μM-1 min-1.4. The in vitro studies of phellodendrine with CYP isoforms indicate that phellodendrine could inhibit the activities of CYP1A2, 3A4 and 2C9. Further clinical studies are needed to evaluate the significance of this interaction.
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  • 文章类型: Journal Article
    Phellodendrine, a quaternary ammonium alkaloid extracted from the dried bark of Phellodendrom chinensis Schneid and Phellodendrom amurense Rupr, has the effect of suppressing cellular immune response, reducing blood pressure and antinephritis. However, few investigations have been conducted for the pharmacokinetic study of phellodendrine. Thus, a rapid, simple and reliable ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry (UHPLC-QQQ MS/MS) method has been established for quantification of phellodendrine in rat plasma and tissues by using magnoflorine as internal standard. The chromatographic separation was achieved on an Agilent ZORBAX SB-C18 column (4.6mm×50mm, 1.8μm) by gradient elution using 0.1% aqueous formic acid (A) and methanol (B). Triple quadrupole mass detection with multiple reaction monitoring mode was used to monitor the ion transitions, at m/z 342.20→192.20 for phellodendrine and m/z 342.20→58.20 for internal standard, respectively. The developed method was fully validated and successfully applied to the pharmacokinetics and tissue distribution study of phellodendrine after intravenous administration. The lower limits of quantification were 0.5ng/mL for plasma samples, 2.5ng/g for brain and 1ng/g for other tested tissues. Precisions and accuracy values were within the Food and Drug Administration acceptance criteria, the recovery and matrix effects were between 87.8-113.5%. The area under the curve (AUC0-t) ranged from 15.58 to 57.41mg/L min and Cmax were between 1.63-4.93mg/L. The results showed that phellodendrine was eliminated in 120min in plasma and most of tissues and the highest concentrations of phellodendrine were found in the kidney. This study may provide a basis for the further study of phellodendrine.
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  • 文章类型: Journal Article
    OBJECTIVE: This study is to investigate the effect of phellodendrine (PHE) against AAPH-induced oxidative stress and find out the biological mechanism of PHE by using the zebrafish embryo model.
    METHODS: After treatments by AAPH or PHE, the mortality and heartbeat of zebrafish embryos were recorded and the production of reactive oxygen species (ROS), lipid-peroxidation and the rate of cell death were detected by fluorescence spectrophotometry respectively. Whereafter, the pathways of PHE against AAPH-induced oxidative stress were screened by inhibitors to explore its biological mechanism. The related genes and proteins expressions were analyzed by real-time quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) and western blotting.
    RESULTS: The PHE obviously improved the decreased survival rate and abnormally elevated heart-beating rate of zebrafish embryos caused by AAPH. Especially 200μg/mL of PHE make the survival rate increased to 90.26±1.40% at 72hfp and the heartbeat back to normal. Besides, AAPH caused a significant increase in the production of reactive oxygen species (ROS), lipid-peroxidation and cell death rate, all of which could be decreased after PHE treatment dose-dependently. And PHE exerted the protective activity against AAPH-induced oxidative stress through down-regulating AKT phosphorylation and NF-kB3 expression, which associate with modulation of IKK phosphorylation in zebrafish embryos.
    CONCLUSIONS: The PHE showed a good antioxidant effect in vivo, and the mechanism has been stated that the PHE can down-regulating AKT, IKK, NF-kB phosphorylation and COX-2 expression induced by AAPH. Moreover, the PHE also ameliorated the ROS-mediated inflammatory response.
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