Evodiamine,rutaecarpine,and dehydroevodiamine have been demonstrated as the major alkaloids in the fruits of Euodia rutaecarpa,a well-known traditional Chinese medicine with central nervous system activities.To study ...Evodiamine,rutaecarpine,and dehydroevodiamine have been demonstrated as the major alkaloids in the fruits of Euodia rutaecarpa,a well-known traditional Chinese medicine with central nervous system activities.To study their cerebrospinal fluid pharmacokinetics and cerebral nuclei distribution,the alkaloids were mixed at the weight ratio of 1:1:1 and orally administered via gavage to the rats at each dose of 15 mg/kg.A quick and reliable ultra-performance liquid chromatographic-tandem mass spectrometry method was developed and applied for the simultaneous analysis of the alkaloids in rat cerebrospinal fluid and cerebral nuclei collected at different time points.Non-compartmental pharmacokinetic profiles were calculated,and the distribution in cerebral nuclei was compared.All the tested compounds were absorbed into rat cerebrospinal fluid and distributed to the brain nuclei quickly.Their distribution in different nuclei varied,as evodiamine mainly in cerebellum and brainstem,rutaecarpine with its maximum in the brainstem,and dehydroevodiamine mostly in the cerebellum and hippocampus.They were eliminated from the brain rapidly without long-time accumulation.In summary,this study revealed the targeting discrepancy of evodiamine,rutaecarpine,and dehydroevodiamine in the brain,and highlighted the possibility for drug candidates in the encephalopathy treatment of the fruits of E.rutaecarpa.展开更多
Objective:High-fat diet is one of the main risk factors that disrupt the balance of gut microbiota,which eventually will induce colorectal cancer(CRC).Evodiamine(EVO)is a wildly used multifunctional traditional Chines...Objective:High-fat diet is one of the main risk factors that disrupt the balance of gut microbiota,which eventually will induce colorectal cancer(CRC).Evodiamine(EVO)is a wildly used multifunctional traditional Chinese medicine extract.In this study,we investigated the role of gut microbiota in high-fat dietpropelled CRC and the potential of EVO for CRC chemoprevention.Methods:Gut microbiota,serum D-lactic acid and endotoxin from 38 patients with colon cancer and 18 healthy subjects were detected by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay(ELISA).In addition,body mass index,phospho-signal transducer and activator of transcription 3(p-STAT3)expression in cancer tissues and paracancerous tissues were detected by immunohistochemistry.A mouse intestinal inflammatory tumor model was established by azomethane/sodium dextran sulfate,followed by treatment with EVO and 5-aminosalicylic acid(ASA).Gut microbiota and inflammatory factors were detected by quantitative polymerase chain reaction,while serum D-lactic acid and endotoxin were detected by ELISA.Furthermore,cell proliferation,cell apoptosis,and interleukin(IL)-6/STAT3/P65 pathway were evaluated by 5-ethynyl-20-deoxyuridine,terminal-deoxynucleotidyl transferase-mediated nick-end labeling,and Western blot assays.Results:In patients with colon cancer,the numbers of Enterococcus faecalis and Escherichia coli were increased,while those of Bifidobacterium,Campylobacter and Lactobacillus were decreased.Serum endotoxin and D-lactic acid levels and p-STAT3 levels were significantly increased.In the mouse model,both EVO and ASA inhibited tumor formation,decreased the proliferation of tumor cells,and induced apoptosis of tumor cells.Compared with the control group,the numbers of E.faecalis and E.coli were decreased,while Bifidobacterium,Campylobacter and Lactobacillus numbers were increased.In the EVO group,serum endotoxin and D-lactic acid levels and inflammatory factors were significantly decreased.Further,the IL6/STAT3/P65 signaling pathway was inhibited in the EVO group.Conclusion:EVO may inhibit the occurrence of colon cancer by regulating gut microbiota and inhibiting intestinal inflammation.The potential mechanism involves inhibition of the IL6/STAT3/P65 signaling pathway,revealing its potential therapeutic significance in clinical applications.展开更多
OBJECTIVE: To explore the effects of evodiamine on ovarian cancer cells and the mechanisms underlying such effects.METHODS: Human ovarian cancer cells HO-8910 PM were treated with evodiamine at 0, 1.25,2.5, and 5 μM ...OBJECTIVE: To explore the effects of evodiamine on ovarian cancer cells and the mechanisms underlying such effects.METHODS: Human ovarian cancer cells HO-8910 PM were treated with evodiamine at 0, 1.25,2.5, and 5 μM for 1-4 d. 3-(4,5-Dimethiylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay was used to detect the growth inhibition rate of evodiamine-treated HO-8910 PM cells. The cell cycle was observed via propidium iodide(PI) staining. Apoptosis induction was assessed via Annexin V-fluorescein isothiocyanate/propidium iodide(Annexin V-FITC/PI) double staining assay. To verify the mechanism of apoptosis, caspase-dependent apoptotic pathway-related protein was detected by Western blot analysis. The expression levels of mitogen-activated protein kinase(MAPK)and/or phosphatidylinositol-3-kinase(PI3K)/pro-tein kinase B(Akt) pathway-related proteins were also investigated.RESULTS: Evodiamine significantly inhibited the proliferation of HO-8910 PM cells in a dose- and time-dependent manner. Evodiamine induced G2/M arrest with an increase of cyclin B1 level, and promoted cell apoptosis with a decrease of B cell lymphoma/lewkmia-2(Bcl-2) and an increase of Bcl-2-associated X protein(Bax) level. In addition,evodiamine treatment led to the activation of caspase-8, caspase-9, and caspase-3 and the cleavage of poly(ADP-ribose)-polymerase(PARP). Evodiamine targeted the MAPK and/or PI3K/Akt pathways by reducing the expression and activity of PI3 K, Akt, and extracellular signal-regulated kinase mitogen-activated protein kinase(ERK1/2 MAPK)and the activity of p38 MAPK.CONCLUSION: Evodiamine can inhibit the growth of ovarian cancer cells by G2/M arrest and intrinsic and extrinsic apoptosis. In addition, evodiamine-induced PI3K/Akt, ERK1/2 MAPK, and p38 MAPK signaling may be involved in cell death.展开更多
A series of novel E-ring modified evodiamine derivatives were designed and synthesized as antitumor agents. Their capacity to interfere with the catalytic activity of topoisomerase Ⅰ and Ⅱ was evaluated by the relax...A series of novel E-ring modified evodiamine derivatives were designed and synthesized as antitumor agents. Their capacity to interfere with the catalytic activity of topoisomerase Ⅰ and Ⅱ was evaluated by the relaxation assay. In vitro antitumor activity results revealed that compound 12 showed good antitumor activity with a broad spectrum. Its binding modes with topoisomerase Ⅰ and Ⅱ were clarified by molecular docking.展开更多
Objective To identify anti-tumor effects of the ethanol extract from radix of Actinidia chinensis(EERAC) and Evodiamine(Evo) on colon carcinoma SW480 cells,and investigate their regulation of CCR7 expression and the u...Objective To identify anti-tumor effects of the ethanol extract from radix of Actinidia chinensis(EERAC) and Evodiamine(Evo) on colon carcinoma SW480 cells,and investigate their regulation of CCR7 expression and the underlying mechanism in colon carcinoma.Methods Radix of Actinidia chinensis was extracted by ethanol.MTT assay and growth curve method were used to detect the inhibition of SW480 cells after being treated with EERAC and Evo.RT-PCT and Western-blot were used to detect the CCR7 expression regulated by EERAC and Evo at the level of protein and mRNA respectively in SW480 cells.Results MTT results showed that EERAC and Evo significantly inhibited the growth of SW480 cells with obvious time-and dose-dependent effect.The 50% inhibitory concentration(IC50) of EERAC was 9.14 mg/mL,while the IC50 of Evo was 2.11 μg/mL.RT-PCR results showed that the expression of CCR7 mRNA in EERAC and Evo group was 29.99% and 18.03% respectively,which was obviously lower than that(56.27%) in control group.Western-blot proved that the expression of CCR7 protein in EERAC and Evo group was 29.03% and 15.28% respectively,which was also significantly reduced when compared to that of 42.48% in control group.Conclusion Ethanol extract from radix of Actinidiae chinensis and Evodiamine could effectively inhibit proliferation and growth of SW480 cells,significantly down-regulate the functional expression of CCR7,and thereby suppress the tumor metastasis.展开更多
Objective Transdifferentiation exists between stromal cells or between stromal cells and cancer cells.Evodiamine and berberine are predominant pharmacological components of Zuojin pill,a prescription of Traditional Ch...Objective Transdifferentiation exists between stromal cells or between stromal cells and cancer cells.Evodiamine and berberine are predominant pharmacological components of Zuojin pill,a prescription of Traditional Chinese Medicine,playing crucial functions in remolding of tumor microenvironment.This study aimed to explore the effect of combination of evodiamine with berberine(cBerEvo)on the phenotypic transition of colon epithelial cells induced by tumor-associated fibroblasts,as well as the involved mechanisms.Methods Human normal colon epithelial cell line HCoEpiC cells were treated with the prepared conditioned medium of CCD-18 Co,a human colon myofibroblast line,to induce epithelial-mesenchymal transition.Phase contrast microscope was used to observe the morphological changes.Epithelial-mesenchymal transition markers including E-cadherin,vimentin and alpha-smooth muscle actin(α-SMA)were observed with immunofluorescence microscopy.Migration was assessed by wound healing assay.Western blotting was used to detect the expressions of E-cadherin,vimentin,α-SMA,Snail,ZEB1 and Smads.Results In contrast to the control,the tumor-associated fibroblasts-like CCD-18 Co cells induced downregulation of E-cadherin and up-regulation of vimentin,α-SMA,Snail and ZEB1(P<0.05),and promoted migration of HCoEpiCs(P<0.05),with over expression of Smads including Smad2,p-Smad2,Smad3,p-Smad3 and Smad4(P<0.05),which were abolished by a transforming growth factor-β(TGF-β)receptor inhibitor LY364947 and by cBerEvo in a concentration dependent manner.In addition,cBerEvo-inhibited ratios of p-Smad2/Smad2 and p-Smad3/Smad3 were also dose dependent.Conclusion The above results suggest that cBerEvo can regulate the differentiation of colon epithelial cells induced by CCD-18 Co through suppressing activity of TGF-β/Smads signaling pathway.展开更多
Background: Alzheimer's disease(AD) is a complex neurodegenerative disease. Due to the complexity of its molecular pathogenesis and the interaction of the numerous factors involved, the etiology and pathogenesis o...Background: Alzheimer's disease(AD) is a complex neurodegenerative disease. Due to the complexity of its molecular pathogenesis and the interaction of the numerous factors involved, the etiology and pathogenesis of AD have not been fully elucidated. Therefore, effective treatment for AD remains to be developed. Evodiamine, a quinolone alkaloid, has been found to improve learning and memory ability to in the APP^(swe)/PS1^(ΔE9) mouse model of dementia. However, the cytotoxicity and physicochemical properties of evodiamine have limited its use in the treatment of AD.Methods: Evodiamine and its derivatives were effectively synthesized by EDCImediated condensation at room temperature. These target compounds contained 1 thio-and 21 oxo-evodiamine derivatives with different substituted groups. The cytotoxicity of evodiamine and its derivatives and the neuroprotective effects of the evodiamine derivatives against H_2O_2-induced cell loss in SH-SY5 Y cells were investigated using the WST-8 assay. The Morris water-maze test was used to detect the effect of evodiamine and its derivatives on improving learning and memory in APP^(swe)/PS1^(ΔE9) mice.Results: In this study, a series of oxo-and thio-evodiamine derivatives was synthesized. Several derivatives showed lower cytotoxicity and stronger neuroprotective effects than evodiamine and elicited enhanced cognitive improvement, especially in the test of spatial memory in APP^(swe)/PS1^(ΔE9) mice.Conclusion: Our study provides insights for developing novel evodiamine derivatives for chemical intervention and treatment of AD.展开更多
Background:Traditional Chinese medicine involves complex ingredients and mixtures of ingredients that often exhibit low bioavailability,and excipients are often lacking to increase the absorption-enhancing effects.Thi...Background:Traditional Chinese medicine involves complex ingredients and mixtures of ingredients that often exhibit low bioavailability,and excipients are often lacking to increase the absorption-enhancing effects.This study modified the generation 4 polyamidoamine dendrimer with polyethylene glycol of different molecular weights(5000,2000,1000)to form a series of polyamidoamine-co-polyethylene glycol(PAMAM-co-PEG)as a novel class of oral absorption enhancers.Evodiamine,the major alkaloid found in the traditional Chinese medicine Wu Zhu Yu(Fructus Evodiae),was used as a model drug to verify the absorption-enhancing effects and the safety of this alkaloid.Methods:This study utilized the solubility determination method documented in the Pharmacopoeia of the People’s Republic of China(2015 edition)and the D0 values recommended in the US FDA guidelines to comprehensively evaluate the solubility of evodiamine.The permeability of evodiamine was assessed using the apparent permeability coefficient in experiments based on in vitro cell models.Multiple aspects of the biological safety of PAMAM-co-PEG were explored using the MTT assay,LDH assay,and total protein release of the rat intestinal tract.Moreover,the absorption-enhancing effects of PAMAM-co-PEG at different molecular weights on evodiamine were verified via the use of in vitro cell models and in vivo intestinal loop circulation experiments with rats.Results:Evodiamine exhibited low solubility and permeability and was classified into class IV compounds using the biopharmaceutical classification system.PAMAM-co-PEG 2000 demonstrated improvement in the biosafety and absorption-enhancement effect of evodiamine at a specific concentration.This study showed that 0.05%(w/v)of PAMAM-co-PEG 2000 increased the cumulative penetration of evodiamine via cell transport by 1.32 times,and 0.10%(w/v)of PAMAM-co-PEG 2000 increased the area under curve value of evodiamine by 1.31 times.Conclusion:Evodiamine possesses low solubility and permeability and leads to poor oral bioavailability and a certain degree of cytotoxicity.PAMAM-co-PEG 2000 was found to be a potentially safe and efficient oral absorption enhancer.The results of this study might create a foundation for the development of novel excipients suitable for the complex active ingredients of traditional Chinese medicine.展开更多
Evodiamine is an indole quinazoline alkaloid with anti-tumor activity,which may be developed into a drug for the treatment of tumor.It was found that evodiamine could inhibit or even block the signal pathways of Wnt/...Evodiamine is an indole quinazoline alkaloid with anti-tumor activity,which may be developed into a drug for the treatment of tumor.It was found that evodiamine could inhibit or even block the signal pathways of Wnt/β-catenin,mTOR,NF--κB,PI3K/AKT,Hippo-YAP and BMP in many kinds of cancer cells,thus interfering with cell division and differentiation,increasing the rate of apoptosis,and down-regulating the expression of various cancer cell markers.Such as B-cell lymphoma 2(Bcl-2),B-cell lymphoma super-large(Bcl-XL),cyclooxygenase 2(COX-2),Survivin,vascular endothelial growth factor(VEGF)and matrix metallopeptidase 9(MMP-9),which have a strong inhibitory effect on asymmetric division,malignant proliferation and angiogenesis of tumor cells.This paper summarizes evodiamine in digestive system tumors by regulating Wnt/β-catenin,mTOR,PI3K/AKT,BMP and other signal pathways,interfering with cell division,differentiation and apoptosis,inhibiting the expression of tumor-related marker genes,and preventing tumor cell migration and invasion,so as to provide a basis for the clinical application and further research of evodiamine in the future.展开更多
The antitumor activities of two alkaloids, evodiamine（EVO） and rutaecarpine（RUT）, against MCF-7, SMMC-7721 and SW-1353 cells growth in vitro were investigated by MTT assay. The results showed that the anti-tumor e...The antitumor activities of two alkaloids, evodiamine（EVO） and rutaecarpine（RUT）, against MCF-7, SMMC-7721 and SW-1353 cells growth in vitro were investigated by MTT assay. The results showed that the anti-tumor effects of two alkaloids were remarkably different. In order to discover the relationship of antitumor activity and structures of the compounds, the dihedral angle, Natural Electron Configuration, frontier molecular orbital profiles（HOMO, LUMO）and bandgaps of these two compounds have been studied based on density functional theory（DFT）by means of DFT-B3LYP/6-31G（d） in Gaussian 03. The calculation results of dihedral angle showed that EVO, due to the existence of methyl group attached to the N（14） atom, have non-planar and twisted structures, which decrease the stability of EVO and increase the activity of EVO. Furthermore, the bandgaps of RUT are lower than that of EVO, indicating RUT has higher stability than EVO, so the activity of EVO is higher than that of RUT. In addition, the negative charge of N14 atom in EVO is lower than that of in RUT, so the positive charge of N（14） atom in EVO is higher than that of in RUT, which suggests that the nucleophile is easier to aggress the N（14） atom in EVO than that in RUT, so the reason of the different antitumor activities of EVO and RUT may be attacked by nucleophile.展开更多
Evodiamine(EVO),one of the bioactive components of traditional Chinese medicine,has been widely concerned for its anti-tumor properties in recent years.In this review,the anti-tumor mechanism of EVO was reviewed from ...Evodiamine(EVO),one of the bioactive components of traditional Chinese medicine,has been widely concerned for its anti-tumor properties in recent years.In this review,the anti-tumor mechanism of EVO was reviewed from the aspects of inducing tumor cell apoptosis(internal pathway,external pathway and other pathways),inducing autophagy,inhibiting tumor stem cells,inhibiting cell proliferation and migration,inhibiting peripheral vascular proliferation,and recent research progress of EVO anti-tumor drugs.展开更多
Objective:To investigate the therapeutic effect of evodiamine(EVO)on the expression of hexokinase(HK),lactate dehydrogenase A(LDHA),and pyruvate kinase M(PKM),key enzymes of glycolysis,in the tumor-bearing mice after ...Objective:To investigate the therapeutic effect of evodiamine(EVO)on the expression of hexokinase(HK),lactate dehydrogenase A(LDHA),and pyruvate kinase M(PKM),key enzymes of glycolysis,in the tumor-bearing mice after modeling mouse colon cancer cells(CT26).Methods:A tumor-bearing mouse model was generated by administering axillary injection of CT26 and intraperitoneally injecting different doses of EVO.The therapeutic effects of EVO on CT26 tumor-bearing mice were evaluated by measuring the thymus and spleen indices,tumor volume,tumor suppression rate,and other related indicators in the tumor tissues of mice in each group after the administration of EVO,in addition,histopathological changes in the tumor tissues of the mice in the groups were studied by hematoxylin and eosin staining.The expression levels of HK,LDHA,and PKM in the tumor tissues of each group of mice were measured by performing Western blot to investigate the mechanism of EVO treatment in CT26 tumor-bearing mice.Results:EVO inhibited the growth of tumors in CT26-bearing mice and enhanced their splenic and thymic indices.Western blot results showed that EVO reduced the expression levels of HK,LDHA,and PKM proteins in the tumor tissues of CT26 tumor-bearing mice.Conclusion:EVO has a therapeutic effect on CT26 tumor-bearing mice,and its mechanism of action may be related to the low expression of key enzymes HK,LDHA and PKM of glycolysis in tumor tissues.展开更多
OBJECTIVE Glioblastoma multiforme(GBM) is the most malignant primary tumor of the central nervous system and is associated with a very poor prognosis.No further improvements in outcomes have been reported since radiot...OBJECTIVE Glioblastoma multiforme(GBM) is the most malignant primary tumor of the central nervous system and is associated with a very poor prognosis.No further improvements in outcomes have been reported since radiotherapy-temozolomide therapy was introduced.Therefore,de.veloping new agents to treat GBM is important.This study aimed to evaluate the anti-tumor effect of evodiamine(Evo) on GBM cells,and to determine the underlying mechanisms involved.METHODS U251,LN229,HEB and PC12 cells were treated with various concentrations of evodiamine for 24 and48 hours,cell viability was measured by MTT assay.The U251 and LN229 cells were treated with evo.diamine(0-10 μmol·L^(-1)) for 24 h,and then stained with Hoechst 33258.An Annexin V-FITC Apoptosis Detection Kit was used to detect apoptosis in the cells.Reactive oxygen species(ROS) production was detected using dichlorofluorescein diacetate(DCFH-DA) staining.The changes in mitochondrial mem.brane potential(MMP) were assessed by JC-1 after cells were treated with evodiamine.The expres.sion levels of p-PI3K,PI3K,p-Akt,Akt,Bax,Bcl-2,p-p38,p38,p-JNK,JNK,p-ERK,ERK,Cytochrome c,Caspase-3,cleaved Caspase-3,PRAP,and cleaved PARP were measured by Western blot analy.ses.RESULTS According to MTT assay results,Evo significantly inhibited the cell proliferation in a time-and dose-dependent manner.Fluorescence microscopy and flow cytometry analyses revealed that Evo induced cell apoptosis in a concentration-dependent manner.Moreover,Evo induced reactive oxygen species(ROS) production and mitochondrial membrane potential(MMP) disruption.Finally,Evo induced apoptosis in cancer cells by suppressing PI3K/AKT signaling and inducing MAPK phos.phorylation(p38 and JNK,but not ERK) to regulate apoptotic proteins(Bax,Bcl-2,Cytochrome c,Cas.pase-3,and PARP).CONCLUSION In summary,Evo inhibits cell proliferation by inducing cellular apoptosis via suppressing PI3K/AKT and activating MAPK in GBM;these results indicate that Evo may be regarded as a new approach for GBM treatment.展开更多
A great challenge in multi-targetingdrug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations.Inspired by our previous efforts in designing ...A great challenge in multi-targetingdrug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations.Inspired by our previous efforts in designing antitumor evodiamine derivatives,herein selective histone deacetylase 1(HDAC1)and topoisomerase 2(TOP2)dual inhibitors were successfully identified,which showed potent in vitro and in vivo antitumor potency.Particularly,compound 30 a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model(TGI=75.2%,150 mg/kg,p.o.)without significant toxicity,which was more potent than HDAC inhibitor vorinostat,TOP inhibitor evodiamine and their combination.Taken together,this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.展开更多
Here,evodiamine(EVO)and the photosensitizer indocyanine green(ICG)were integrated into a liposomal nanoplatform for noninvasive diagnostic imaging and combinatorial therapy against oral squamous cell carcinoma(OSCC).E...Here,evodiamine(EVO)and the photosensitizer indocyanine green(ICG)were integrated into a liposomal nanoplatform for noninvasive diagnostic imaging and combinatorial therapy against oral squamous cell carcinoma(OSCC).EVO,as an active component extracted from traditional Chinese medicine,not only functioned as an antitumor chemotherapeutic agent but was also capable of 68Ga-chelation,thus working as a contrast agent for positron emission tomography/computed tomography(PET/CT)imaging.Moreover,EVO could exhibit peroxidase-like catalytic activity,converting endogenous tumor H2O2 into cytotoxic reactive oxygen species(ROS),enabling Chemo catalytic therapy beyond the well-known chemotherapy effect of EVO.As proven by in vitro and in vivo experiments,guided by optical imaging and PET/CT imaging,we show that the theragnostic liposomes have a significant inhibiting effect on in situ tongue tumor through photodynamic therapy combined with chemodynamic chemotherapy.展开更多
Objective: To investigate the effects of evodiamine(Evo), a component of Evodiaminedia rutaecarpa(Juss.) Benth, on cardiomyocyte hypertrophy induced by angiotensin Ⅱ(Ang Ⅱ) and further explore the potential mechanis...Objective: To investigate the effects of evodiamine(Evo), a component of Evodiaminedia rutaecarpa(Juss.) Benth, on cardiomyocyte hypertrophy induced by angiotensin Ⅱ(Ang Ⅱ) and further explore the potential mechanisms. Methods: Cardiomyocytes from neonatal Sprague Dawley rats were isolated and characterized, and then the cadiomyocyte cultures were randomly divided into control, model(Ang Ⅱ 0.1 μmol/L), and Evo(0.03, 0.3, 3 μmol/L) groups. The cardiomyocyte surface area, protein level, intracellular free calcium([Ca]i) concentration, activity of nitric oxide synthase(NOS) and content of nitric oxide(NO) were measured, respectively. The m RNA expressions of atrial natriuretic factor(ANF), calcineurin(CaN), extracellular signal-regulated kinase-2(ERK-2), and endothelial nitric oxide synthase(e NOS) of cardiomyocytes were analyzed by real-time reverse transcriptionpolymerase chain reaction. The protein expressions of calcineurin catalytic subunit(CnA) and mitogen-activated protein kinase phosphatase-1(MKP-1) were detected by Western blot analysis. Results: Compared with the control group, Ang Ⅱ induced cardiomyocytes hypertrophy, as evidenced by increased cardiomyocyte surface area, protein content, and ANF m RNA expression; increased intracellular free calcium([Ca]i) concentration and expressions of CaN m RNA, CnA protein, and ERK-2 m RNA, but decreased MKP-1 protein expression(P<0.05 or P<0.01). Compared with Ang Ⅱ, Evo(0.3, 3 μmol/L) significantly attenuated Ang Ⅱ-induced cardiomyocyte hypertrophy, decreased the [Ca]i concentration and expressions of CaN m RNA, CnA protein, and ERK-2 m RNA, but increased MKP-1 protein expression(P<0.05 or P<0.01). Most interestingly, Evo increased the NOS activity and NO production, and upregulated the e NOS m RNA expression(P<0.05). Conclusion: Evo significantly attenuated Ang Ⅱ-induced cardiomyocyte hypertrophy, and this effect was partly due to promotion of NO production, reduction of [Ca]i concentration, and inhibition of CaN and ERK-2 signal transduction pathways.展开更多
目的研究吴茱萸碱(evodiamine,EVO)调控叉头盒蛋白M1(fork-head box protein M1,FOXM1)对结直肠癌耐药细胞HCT8/5-FU增殖和凋亡的影响。方法采用CCK-8法与EdU实验技术,评估EVO对细胞增殖活性的作用效果;通过克隆形成实验,探讨EVO对细胞...目的研究吴茱萸碱(evodiamine,EVO)调控叉头盒蛋白M1(fork-head box protein M1,FOXM1)对结直肠癌耐药细胞HCT8/5-FU增殖和凋亡的影响。方法采用CCK-8法与EdU实验技术,评估EVO对细胞增殖活性的作用效果;通过克隆形成实验,探讨EVO对细胞克隆形成能力的影响;采用流式细胞术对凋亡细胞比例进行量化;蛋白质免疫印迹分析技术检测Bcl-2、Bax、FOXM1、β-catenin、c-MYC、CyclinD1蛋白水平的变化;分子对接探究EVO与FOXM1的相互作用关系;裸鼠移植瘤模型验证EVO在体内对HCT8/5-FU细胞的影响。结果CCK-8实验显示EVO抑制HCT8/5-FU细胞增殖且呈时间和浓度依赖性;EdU实验发现EVO处理组新增殖细胞明显减少;克隆形成实验结果显示EVO明显抑制HCT8/5-FU细胞的克隆形成能力;流式细胞计数发现EVO组细胞的凋亡率明显增高;Western blot显示FOXM1、β-catenin在HCT8/5-FU细胞中明显高表达,EVO能下调细胞中FOXM1、β-catenin、c-MYC、CyclinD1、Bcl-2表达,上调Bax表达;分子对接显示EVO与FOXM1之间具有较强的互作能力;体内实验显示EVO能明显抑制HCT8/5-FU皮下移植瘤的生长且能调控相关蛋白的表达;HE染色发现EVO组的瘤体细胞核固缩和碎裂明显。结论EVO可能通过下调FOXM1蛋白表达抑制Wnt通路激活,从而抑制HCT8/5-FU细胞增殖诱导其凋亡。展开更多
基金National Natural Science Foundation of China(Grant No.81773865)the National Key R&D Program of China(Grant No.2018YFC1704500,2018YFC1704506)。
文摘Evodiamine,rutaecarpine,and dehydroevodiamine have been demonstrated as the major alkaloids in the fruits of Euodia rutaecarpa,a well-known traditional Chinese medicine with central nervous system activities.To study their cerebrospinal fluid pharmacokinetics and cerebral nuclei distribution,the alkaloids were mixed at the weight ratio of 1:1:1 and orally administered via gavage to the rats at each dose of 15 mg/kg.A quick and reliable ultra-performance liquid chromatographic-tandem mass spectrometry method was developed and applied for the simultaneous analysis of the alkaloids in rat cerebrospinal fluid and cerebral nuclei collected at different time points.Non-compartmental pharmacokinetic profiles were calculated,and the distribution in cerebral nuclei was compared.All the tested compounds were absorbed into rat cerebrospinal fluid and distributed to the brain nuclei quickly.Their distribution in different nuclei varied,as evodiamine mainly in cerebellum and brainstem,rutaecarpine with its maximum in the brainstem,and dehydroevodiamine mostly in the cerebellum and hippocampus.They were eliminated from the brain rapidly without long-time accumulation.In summary,this study revealed the targeting discrepancy of evodiamine,rutaecarpine,and dehydroevodiamine in the brain,and highlighted the possibility for drug candidates in the encephalopathy treatment of the fruits of E.rutaecarpa.
基金supported by Wenzhou Science and Technology Bureau Project(to Zhu Liqing,No.Y20190088)。
文摘Objective:High-fat diet is one of the main risk factors that disrupt the balance of gut microbiota,which eventually will induce colorectal cancer(CRC).Evodiamine(EVO)is a wildly used multifunctional traditional Chinese medicine extract.In this study,we investigated the role of gut microbiota in high-fat dietpropelled CRC and the potential of EVO for CRC chemoprevention.Methods:Gut microbiota,serum D-lactic acid and endotoxin from 38 patients with colon cancer and 18 healthy subjects were detected by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay(ELISA).In addition,body mass index,phospho-signal transducer and activator of transcription 3(p-STAT3)expression in cancer tissues and paracancerous tissues were detected by immunohistochemistry.A mouse intestinal inflammatory tumor model was established by azomethane/sodium dextran sulfate,followed by treatment with EVO and 5-aminosalicylic acid(ASA).Gut microbiota and inflammatory factors were detected by quantitative polymerase chain reaction,while serum D-lactic acid and endotoxin were detected by ELISA.Furthermore,cell proliferation,cell apoptosis,and interleukin(IL)-6/STAT3/P65 pathway were evaluated by 5-ethynyl-20-deoxyuridine,terminal-deoxynucleotidyl transferase-mediated nick-end labeling,and Western blot assays.Results:In patients with colon cancer,the numbers of Enterococcus faecalis and Escherichia coli were increased,while those of Bifidobacterium,Campylobacter and Lactobacillus were decreased.Serum endotoxin and D-lactic acid levels and p-STAT3 levels were significantly increased.In the mouse model,both EVO and ASA inhibited tumor formation,decreased the proliferation of tumor cells,and induced apoptosis of tumor cells.Compared with the control group,the numbers of E.faecalis and E.coli were decreased,while Bifidobacterium,Campylobacter and Lactobacillus numbers were increased.In the EVO group,serum endotoxin and D-lactic acid levels and inflammatory factors were significantly decreased.Further,the IL6/STAT3/P65 signaling pathway was inhibited in the EVO group.Conclusion:EVO may inhibit the occurrence of colon cancer by regulating gut microbiota and inhibiting intestinal inflammation.The potential mechanism involves inhibition of the IL6/STAT3/P65 signaling pathway,revealing its potential therapeutic significance in clinical applications.
文摘OBJECTIVE: To explore the effects of evodiamine on ovarian cancer cells and the mechanisms underlying such effects.METHODS: Human ovarian cancer cells HO-8910 PM were treated with evodiamine at 0, 1.25,2.5, and 5 μM for 1-4 d. 3-(4,5-Dimethiylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay was used to detect the growth inhibition rate of evodiamine-treated HO-8910 PM cells. The cell cycle was observed via propidium iodide(PI) staining. Apoptosis induction was assessed via Annexin V-fluorescein isothiocyanate/propidium iodide(Annexin V-FITC/PI) double staining assay. To verify the mechanism of apoptosis, caspase-dependent apoptotic pathway-related protein was detected by Western blot analysis. The expression levels of mitogen-activated protein kinase(MAPK)and/or phosphatidylinositol-3-kinase(PI3K)/pro-tein kinase B(Akt) pathway-related proteins were also investigated.RESULTS: Evodiamine significantly inhibited the proliferation of HO-8910 PM cells in a dose- and time-dependent manner. Evodiamine induced G2/M arrest with an increase of cyclin B1 level, and promoted cell apoptosis with a decrease of B cell lymphoma/lewkmia-2(Bcl-2) and an increase of Bcl-2-associated X protein(Bax) level. In addition,evodiamine treatment led to the activation of caspase-8, caspase-9, and caspase-3 and the cleavage of poly(ADP-ribose)-polymerase(PARP). Evodiamine targeted the MAPK and/or PI3K/Akt pathways by reducing the expression and activity of PI3 K, Akt, and extracellular signal-regulated kinase mitogen-activated protein kinase(ERK1/2 MAPK)and the activity of p38 MAPK.CONCLUSION: Evodiamine can inhibit the growth of ovarian cancer cells by G2/M arrest and intrinsic and extrinsic apoptosis. In addition, evodiamine-induced PI3K/Akt, ERK1/2 MAPK, and p38 MAPK signaling may be involved in cell death.
基金supported by National Natural Science Foundation of China(Nos.81222044,81373278)Key Project of Science and Technology of Shanghai(No.11431920402)+2 种基金the National Basic Research Program of China(No.2014CB541800)Shanghai Rising Star Program(No.12QH1402600)Shanghai Municipal Health Bureau(No.XYQ2011038)
文摘A series of novel E-ring modified evodiamine derivatives were designed and synthesized as antitumor agents. Their capacity to interfere with the catalytic activity of topoisomerase Ⅰ and Ⅱ was evaluated by the relaxation assay. In vitro antitumor activity results revealed that compound 12 showed good antitumor activity with a broad spectrum. Its binding modes with topoisomerase Ⅰ and Ⅱ were clarified by molecular docking.
基金supported by Hunan Natural Science Foundation(No:2009FJ3029)Changsha High-tech Project(No:K0902033-31).
文摘Objective To identify anti-tumor effects of the ethanol extract from radix of Actinidia chinensis(EERAC) and Evodiamine(Evo) on colon carcinoma SW480 cells,and investigate their regulation of CCR7 expression and the underlying mechanism in colon carcinoma.Methods Radix of Actinidia chinensis was extracted by ethanol.MTT assay and growth curve method were used to detect the inhibition of SW480 cells after being treated with EERAC and Evo.RT-PCT and Western-blot were used to detect the CCR7 expression regulated by EERAC and Evo at the level of protein and mRNA respectively in SW480 cells.Results MTT results showed that EERAC and Evo significantly inhibited the growth of SW480 cells with obvious time-and dose-dependent effect.The 50% inhibitory concentration(IC50) of EERAC was 9.14 mg/mL,while the IC50 of Evo was 2.11 μg/mL.RT-PCR results showed that the expression of CCR7 mRNA in EERAC and Evo group was 29.99% and 18.03% respectively,which was obviously lower than that(56.27%) in control group.Western-blot proved that the expression of CCR7 protein in EERAC and Evo group was 29.03% and 15.28% respectively,which was also significantly reduced when compared to that of 42.48% in control group.Conclusion Ethanol extract from radix of Actinidiae chinensis and Evodiamine could effectively inhibit proliferation and growth of SW480 cells,significantly down-regulate the functional expression of CCR7,and thereby suppress the tumor metastasis.
基金supported by the National Natural Science Foundation of China(81903985,the running period is 2020.1-2022.12)Natural Science Foundation of Guangdong Province(2018A030310060,the running period is 2018.6-2021.5)Postdoctoral Research Foundation of China(2018M643353,the running period is 2018.9-2019.7)。
文摘Objective Transdifferentiation exists between stromal cells or between stromal cells and cancer cells.Evodiamine and berberine are predominant pharmacological components of Zuojin pill,a prescription of Traditional Chinese Medicine,playing crucial functions in remolding of tumor microenvironment.This study aimed to explore the effect of combination of evodiamine with berberine(cBerEvo)on the phenotypic transition of colon epithelial cells induced by tumor-associated fibroblasts,as well as the involved mechanisms.Methods Human normal colon epithelial cell line HCoEpiC cells were treated with the prepared conditioned medium of CCD-18 Co,a human colon myofibroblast line,to induce epithelial-mesenchymal transition.Phase contrast microscope was used to observe the morphological changes.Epithelial-mesenchymal transition markers including E-cadherin,vimentin and alpha-smooth muscle actin(α-SMA)were observed with immunofluorescence microscopy.Migration was assessed by wound healing assay.Western blotting was used to detect the expressions of E-cadherin,vimentin,α-SMA,Snail,ZEB1 and Smads.Results In contrast to the control,the tumor-associated fibroblasts-like CCD-18 Co cells induced downregulation of E-cadherin and up-regulation of vimentin,α-SMA,Snail and ZEB1(P<0.05),and promoted migration of HCoEpiCs(P<0.05),with over expression of Smads including Smad2,p-Smad2,Smad3,p-Smad3 and Smad4(P<0.05),which were abolished by a transforming growth factor-β(TGF-β)receptor inhibitor LY364947 and by cBerEvo in a concentration dependent manner.In addition,cBerEvo-inhibited ratios of p-Smad2/Smad2 and p-Smad3/Smad3 were also dose dependent.Conclusion The above results suggest that cBerEvo can regulate the differentiation of colon epithelial cells induced by CCD-18 Co through suppressing activity of TGF-β/Smads signaling pathway.
基金National Natural Science Foundation of China,Grant/Award Number 31970508Drug Innovation Major Project,Grant/Award Number 2018ZX09711-001-005Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences,Grant/Award Number CAMS-I2M and 2016-I2M-1-004。
文摘Background: Alzheimer's disease(AD) is a complex neurodegenerative disease. Due to the complexity of its molecular pathogenesis and the interaction of the numerous factors involved, the etiology and pathogenesis of AD have not been fully elucidated. Therefore, effective treatment for AD remains to be developed. Evodiamine, a quinolone alkaloid, has been found to improve learning and memory ability to in the APP^(swe)/PS1^(ΔE9) mouse model of dementia. However, the cytotoxicity and physicochemical properties of evodiamine have limited its use in the treatment of AD.Methods: Evodiamine and its derivatives were effectively synthesized by EDCImediated condensation at room temperature. These target compounds contained 1 thio-and 21 oxo-evodiamine derivatives with different substituted groups. The cytotoxicity of evodiamine and its derivatives and the neuroprotective effects of the evodiamine derivatives against H_2O_2-induced cell loss in SH-SY5 Y cells were investigated using the WST-8 assay. The Morris water-maze test was used to detect the effect of evodiamine and its derivatives on improving learning and memory in APP^(swe)/PS1^(ΔE9) mice.Results: In this study, a series of oxo-and thio-evodiamine derivatives was synthesized. Several derivatives showed lower cytotoxicity and stronger neuroprotective effects than evodiamine and elicited enhanced cognitive improvement, especially in the test of spatial memory in APP^(swe)/PS1^(ΔE9) mice.Conclusion: Our study provides insights for developing novel evodiamine derivatives for chemical intervention and treatment of AD.
基金This research was funded by National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2015ZX09501005)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(No.2016-I2M-1-012).
文摘Background:Traditional Chinese medicine involves complex ingredients and mixtures of ingredients that often exhibit low bioavailability,and excipients are often lacking to increase the absorption-enhancing effects.This study modified the generation 4 polyamidoamine dendrimer with polyethylene glycol of different molecular weights(5000,2000,1000)to form a series of polyamidoamine-co-polyethylene glycol(PAMAM-co-PEG)as a novel class of oral absorption enhancers.Evodiamine,the major alkaloid found in the traditional Chinese medicine Wu Zhu Yu(Fructus Evodiae),was used as a model drug to verify the absorption-enhancing effects and the safety of this alkaloid.Methods:This study utilized the solubility determination method documented in the Pharmacopoeia of the People’s Republic of China(2015 edition)and the D0 values recommended in the US FDA guidelines to comprehensively evaluate the solubility of evodiamine.The permeability of evodiamine was assessed using the apparent permeability coefficient in experiments based on in vitro cell models.Multiple aspects of the biological safety of PAMAM-co-PEG were explored using the MTT assay,LDH assay,and total protein release of the rat intestinal tract.Moreover,the absorption-enhancing effects of PAMAM-co-PEG at different molecular weights on evodiamine were verified via the use of in vitro cell models and in vivo intestinal loop circulation experiments with rats.Results:Evodiamine exhibited low solubility and permeability and was classified into class IV compounds using the biopharmaceutical classification system.PAMAM-co-PEG 2000 demonstrated improvement in the biosafety and absorption-enhancement effect of evodiamine at a specific concentration.This study showed that 0.05%(w/v)of PAMAM-co-PEG 2000 increased the cumulative penetration of evodiamine via cell transport by 1.32 times,and 0.10%(w/v)of PAMAM-co-PEG 2000 increased the area under curve value of evodiamine by 1.31 times.Conclusion:Evodiamine possesses low solubility and permeability and leads to poor oral bioavailability and a certain degree of cytotoxicity.PAMAM-co-PEG 2000 was found to be a potentially safe and efficient oral absorption enhancer.The results of this study might create a foundation for the development of novel excipients suitable for the complex active ingredients of traditional Chinese medicine.
基金National Natural Science Foundation of China(No.81660827)Huang Guihua inheritance Studio Construction Project of famous traditional Chinese Medicine of Guangxi University of traditional Chinese Medicine(No.[2017]2)。
文摘Evodiamine is an indole quinazoline alkaloid with anti-tumor activity,which may be developed into a drug for the treatment of tumor.It was found that evodiamine could inhibit or even block the signal pathways of Wnt/β-catenin,mTOR,NF--κB,PI3K/AKT,Hippo-YAP and BMP in many kinds of cancer cells,thus interfering with cell division and differentiation,increasing the rate of apoptosis,and down-regulating the expression of various cancer cell markers.Such as B-cell lymphoma 2(Bcl-2),B-cell lymphoma super-large(Bcl-XL),cyclooxygenase 2(COX-2),Survivin,vascular endothelial growth factor(VEGF)and matrix metallopeptidase 9(MMP-9),which have a strong inhibitory effect on asymmetric division,malignant proliferation and angiogenesis of tumor cells.This paper summarizes evodiamine in digestive system tumors by regulating Wnt/β-catenin,mTOR,PI3K/AKT,BMP and other signal pathways,interfering with cell division,differentiation and apoptosis,inhibiting the expression of tumor-related marker genes,and preventing tumor cell migration and invasion,so as to provide a basis for the clinical application and further research of evodiamine in the future.
基金Supported by the National Natural Science Foundation of China(81001669,81373944)the Natural Science Basic Research Plan in Shaanxi Province(2016JM8028)
文摘The antitumor activities of two alkaloids, evodiamine（EVO） and rutaecarpine（RUT）, against MCF-7, SMMC-7721 and SW-1353 cells growth in vitro were investigated by MTT assay. The results showed that the anti-tumor effects of two alkaloids were remarkably different. In order to discover the relationship of antitumor activity and structures of the compounds, the dihedral angle, Natural Electron Configuration, frontier molecular orbital profiles（HOMO, LUMO）and bandgaps of these two compounds have been studied based on density functional theory（DFT）by means of DFT-B3LYP/6-31G（d） in Gaussian 03. The calculation results of dihedral angle showed that EVO, due to the existence of methyl group attached to the N（14） atom, have non-planar and twisted structures, which decrease the stability of EVO and increase the activity of EVO. Furthermore, the bandgaps of RUT are lower than that of EVO, indicating RUT has higher stability than EVO, so the activity of EVO is higher than that of RUT. In addition, the negative charge of N14 atom in EVO is lower than that of in RUT, so the positive charge of N（14） atom in EVO is higher than that of in RUT, which suggests that the nucleophile is easier to aggress the N（14） atom in EVO than that in RUT, so the reason of the different antitumor activities of EVO and RUT may be attacked by nucleophile.
基金Shandong Key R&D Program of Shandong Province(No.2017GSF218084)Qingdao Applied Basic Research Program(No.19-6-2-31-cg).
文摘Evodiamine(EVO),one of the bioactive components of traditional Chinese medicine,has been widely concerned for its anti-tumor properties in recent years.In this review,the anti-tumor mechanism of EVO was reviewed from the aspects of inducing tumor cell apoptosis(internal pathway,external pathway and other pathways),inducing autophagy,inhibiting tumor stem cells,inhibiting cell proliferation and migration,inhibiting peripheral vascular proliferation,and recent research progress of EVO anti-tumor drugs.
基金the Affiliated Fuzhou First Hospital of Fujian Medical University,the Fuzhou Science and Technology planning project(2020-WS-123).
文摘Objective:To investigate the therapeutic effect of evodiamine(EVO)on the expression of hexokinase(HK),lactate dehydrogenase A(LDHA),and pyruvate kinase M(PKM),key enzymes of glycolysis,in the tumor-bearing mice after modeling mouse colon cancer cells(CT26).Methods:A tumor-bearing mouse model was generated by administering axillary injection of CT26 and intraperitoneally injecting different doses of EVO.The therapeutic effects of EVO on CT26 tumor-bearing mice were evaluated by measuring the thymus and spleen indices,tumor volume,tumor suppression rate,and other related indicators in the tumor tissues of mice in each group after the administration of EVO,in addition,histopathological changes in the tumor tissues of the mice in the groups were studied by hematoxylin and eosin staining.The expression levels of HK,LDHA,and PKM in the tumor tissues of each group of mice were measured by performing Western blot to investigate the mechanism of EVO treatment in CT26 tumor-bearing mice.Results:EVO inhibited the growth of tumors in CT26-bearing mice and enhanced their splenic and thymic indices.Western blot results showed that EVO reduced the expression levels of HK,LDHA,and PKM proteins in the tumor tissues of CT26 tumor-bearing mice.Conclusion:EVO has a therapeutic effect on CT26 tumor-bearing mice,and its mechanism of action may be related to the low expression of key enzymes HK,LDHA and PKM of glycolysis in tumor tissues.
基金supported by Jiangsu Provincial Special Programme of Medical Science(BL2014035) Changzhou Science and Technology Support Program(CE20155060+2 种基金CE20165048) Changzhou High-Level Medical Talents Training Project(2016CZBJ006) Changzhou Municipal Commissions o
文摘OBJECTIVE Glioblastoma multiforme(GBM) is the most malignant primary tumor of the central nervous system and is associated with a very poor prognosis.No further improvements in outcomes have been reported since radiotherapy-temozolomide therapy was introduced.Therefore,de.veloping new agents to treat GBM is important.This study aimed to evaluate the anti-tumor effect of evodiamine(Evo) on GBM cells,and to determine the underlying mechanisms involved.METHODS U251,LN229,HEB and PC12 cells were treated with various concentrations of evodiamine for 24 and48 hours,cell viability was measured by MTT assay.The U251 and LN229 cells were treated with evo.diamine(0-10 μmol·L^(-1)) for 24 h,and then stained with Hoechst 33258.An Annexin V-FITC Apoptosis Detection Kit was used to detect apoptosis in the cells.Reactive oxygen species(ROS) production was detected using dichlorofluorescein diacetate(DCFH-DA) staining.The changes in mitochondrial mem.brane potential(MMP) were assessed by JC-1 after cells were treated with evodiamine.The expres.sion levels of p-PI3K,PI3K,p-Akt,Akt,Bax,Bcl-2,p-p38,p38,p-JNK,JNK,p-ERK,ERK,Cytochrome c,Caspase-3,cleaved Caspase-3,PRAP,and cleaved PARP were measured by Western blot analy.ses.RESULTS According to MTT assay results,Evo significantly inhibited the cell proliferation in a time-and dose-dependent manner.Fluorescence microscopy and flow cytometry analyses revealed that Evo induced cell apoptosis in a concentration-dependent manner.Moreover,Evo induced reactive oxygen species(ROS) production and mitochondrial membrane potential(MMP) disruption.Finally,Evo induced apoptosis in cancer cells by suppressing PI3K/AKT signaling and inducing MAPK phos.phorylation(p38 and JNK,but not ERK) to regulate apoptotic proteins(Bax,Bcl-2,Cytochrome c,Cas.pase-3,and PARP).CONCLUSION In summary,Evo inhibits cell proliferation by inducing cellular apoptosis via suppressing PI3K/AKT and activating MAPK in GBM;these results indicate that Evo may be regarded as a new approach for GBM treatment.
基金supported by National Natural Science Foundation of China(grants 81872742 to Guoqiang Dong and 81725020 to Chunquan Sheng)the National Key R&D Program of China(grant 2017YFA0506000 to Chunquan Sheng)the Innovation Program of Shanghai Municipal Education Commission(Grant 2019-01-07-00-07-E00073 to Chunquan Sheng,China)
文摘A great challenge in multi-targetingdrug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations.Inspired by our previous efforts in designing antitumor evodiamine derivatives,herein selective histone deacetylase 1(HDAC1)and topoisomerase 2(TOP2)dual inhibitors were successfully identified,which showed potent in vitro and in vivo antitumor potency.Particularly,compound 30 a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model(TGI=75.2%,150 mg/kg,p.o.)without significant toxicity,which was more potent than HDAC inhibitor vorinostat,TOP inhibitor evodiamine and their combination.Taken together,this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.
基金This work was supported by Jiangsu provincial natural science foundation(BK20180136,BK20180138,BK20191121)Project of invigorating health care through science,technology and education Jiangsu provincial medical youth talent(QNRC2016121)Nanjing clinical research center for oral diseases(NO.2019060009).
文摘Here,evodiamine(EVO)and the photosensitizer indocyanine green(ICG)were integrated into a liposomal nanoplatform for noninvasive diagnostic imaging and combinatorial therapy against oral squamous cell carcinoma(OSCC).EVO,as an active component extracted from traditional Chinese medicine,not only functioned as an antitumor chemotherapeutic agent but was also capable of 68Ga-chelation,thus working as a contrast agent for positron emission tomography/computed tomography(PET/CT)imaging.Moreover,EVO could exhibit peroxidase-like catalytic activity,converting endogenous tumor H2O2 into cytotoxic reactive oxygen species(ROS),enabling Chemo catalytic therapy beyond the well-known chemotherapy effect of EVO.As proven by in vitro and in vivo experiments,guided by optical imaging and PET/CT imaging,we show that the theragnostic liposomes have a significant inhibiting effect on in situ tongue tumor through photodynamic therapy combined with chemodynamic chemotherapy.
基金Supported by the National Natural Science Foundation of China(No.81160528)Foundation of Administration of Traditional Chinese Medicine of Guizhou Province(No.2009-79)
文摘Objective: To investigate the effects of evodiamine(Evo), a component of Evodiaminedia rutaecarpa(Juss.) Benth, on cardiomyocyte hypertrophy induced by angiotensin Ⅱ(Ang Ⅱ) and further explore the potential mechanisms. Methods: Cardiomyocytes from neonatal Sprague Dawley rats were isolated and characterized, and then the cadiomyocyte cultures were randomly divided into control, model(Ang Ⅱ 0.1 μmol/L), and Evo(0.03, 0.3, 3 μmol/L) groups. The cardiomyocyte surface area, protein level, intracellular free calcium([Ca]i) concentration, activity of nitric oxide synthase(NOS) and content of nitric oxide(NO) were measured, respectively. The m RNA expressions of atrial natriuretic factor(ANF), calcineurin(CaN), extracellular signal-regulated kinase-2(ERK-2), and endothelial nitric oxide synthase(e NOS) of cardiomyocytes were analyzed by real-time reverse transcriptionpolymerase chain reaction. The protein expressions of calcineurin catalytic subunit(CnA) and mitogen-activated protein kinase phosphatase-1(MKP-1) were detected by Western blot analysis. Results: Compared with the control group, Ang Ⅱ induced cardiomyocytes hypertrophy, as evidenced by increased cardiomyocyte surface area, protein content, and ANF m RNA expression; increased intracellular free calcium([Ca]i) concentration and expressions of CaN m RNA, CnA protein, and ERK-2 m RNA, but decreased MKP-1 protein expression(P<0.05 or P<0.01). Compared with Ang Ⅱ, Evo(0.3, 3 μmol/L) significantly attenuated Ang Ⅱ-induced cardiomyocyte hypertrophy, decreased the [Ca]i concentration and expressions of CaN m RNA, CnA protein, and ERK-2 m RNA, but increased MKP-1 protein expression(P<0.05 or P<0.01). Most interestingly, Evo increased the NOS activity and NO production, and upregulated the e NOS m RNA expression(P<0.05). Conclusion: Evo significantly attenuated Ang Ⅱ-induced cardiomyocyte hypertrophy, and this effect was partly due to promotion of NO production, reduction of [Ca]i concentration, and inhibition of CaN and ERK-2 signal transduction pathways.
文摘目的研究吴茱萸碱(evodiamine,EVO)调控叉头盒蛋白M1(fork-head box protein M1,FOXM1)对结直肠癌耐药细胞HCT8/5-FU增殖和凋亡的影响。方法采用CCK-8法与EdU实验技术,评估EVO对细胞增殖活性的作用效果;通过克隆形成实验,探讨EVO对细胞克隆形成能力的影响;采用流式细胞术对凋亡细胞比例进行量化;蛋白质免疫印迹分析技术检测Bcl-2、Bax、FOXM1、β-catenin、c-MYC、CyclinD1蛋白水平的变化;分子对接探究EVO与FOXM1的相互作用关系;裸鼠移植瘤模型验证EVO在体内对HCT8/5-FU细胞的影响。结果CCK-8实验显示EVO抑制HCT8/5-FU细胞增殖且呈时间和浓度依赖性;EdU实验发现EVO处理组新增殖细胞明显减少;克隆形成实验结果显示EVO明显抑制HCT8/5-FU细胞的克隆形成能力;流式细胞计数发现EVO组细胞的凋亡率明显增高;Western blot显示FOXM1、β-catenin在HCT8/5-FU细胞中明显高表达,EVO能下调细胞中FOXM1、β-catenin、c-MYC、CyclinD1、Bcl-2表达,上调Bax表达;分子对接显示EVO与FOXM1之间具有较强的互作能力;体内实验显示EVO能明显抑制HCT8/5-FU皮下移植瘤的生长且能调控相关蛋白的表达;HE染色发现EVO组的瘤体细胞核固缩和碎裂明显。结论EVO可能通过下调FOXM1蛋白表达抑制Wnt通路激活,从而抑制HCT8/5-FU细胞增殖诱导其凋亡。
