Abstract
Evodiamine (EVO) is a major alkaloid compound extracted from the dry unripened fruit Evodiae fructus (Evodia rutaecarpa Benth., Rutaceae). EVO has a variety of pharmacological activities, such as anti-obesity, anti-allergenic, analgesic, anti-tumor, anti-ulcerogenic, and neuroprotective activities. EVO has varying efficacies in animal models and humans. Here, the physicochemical properties of EVO are presented, and the EVO’s functions and mechanisms of action in various chronic diseases are reviewed. EVO is worth exploring in more depth in the future for its potential use in various chronic diseases.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- Evodiamine
- Physico-chemical properties
- Cell signaling pathways
- Pharmacological activities
- Mechanisms of action
- Chronic diseases
1 Introduction
Evodiamine (EVO) is the main bioactive component extracted from the dry unripened fruit of Evodiae fructus (Chinese name is Wu-Chu-Yu) or other Tetradium genus of plants. EVO has a variety of pharmacological activities, such as anti-obesity, anti-inflammatory, and anti-tumor. The role of EVO in various chronic diseases and its possible mechanisms of action are outlined here.
2 Physicochemical Properties of Evodiamine
EVO (CAS: 518-17-2) is a plant alkaloid and its systematic name is 21-methyl-3,13,21-triazapentacyclo[11.8.0.02,10.04,9.015,20] henicosa-2(10),4,6,8,15,17,19-heptaen-14-one (Fig. 1). EVO is a pale yellow crystal with no perceptible odor or taste. The main physicochemical parameters of EVO are listed in Table 1. EVO can be assayed using an ultraviolet spectrophotometer at 225 nm or by a high-performance liquid chromatography system using an internal standard method [1].
3 Modulation of Cell Signaling Pathways by Evodiamine
3.1 Anti-obese Action
EVO induces the phosphorylation of EGFR, PKCα, and ERK, and it inhibits adipogenesis via the EGFR–PKCα–ERK signaling pathway [2]. EVO inhibits adipocyte differentiation in 3T3-L1 and C3H10T1/2 cells [3]. The anti-obese mechanism of action of EVO is reported to be similar to that of capsaicin [4].
3.2 Anti-inflammatory and Anti-allergenic Action
EVO exerts an anti-inflammation activity on human umbilical vein endothelial cells (HUVEC) with high glucose by suppressing the P2X4 receptor (P2X4R) signaling pathway, accompanied by the downregulation of NF-κB, TNFR-ɑ, P2X4R, and intracellular reactive oxygen species (ROS), and upregulation of the nitric oxide (NO) level [5]. EVO inhibits the secretion of interleukin (IL)-10 and decreases production of IL-2 from the LPS-stimulated endothelial cells [6]. EVO inhibits LIGHT-induced migration via the suppression of ROS production and NADPH oxidase activation in human monocytes [7]. EVO represses hypoxia-induced COX-2 expression by inhibiting hypoxia-inducible factor 1-alpha which is mediated by the dephosphorylation of Akt and p70S6K in RAW264.7 cells [8]. EVO exerts an anti-allergenic effect by inhibiting the protein levels of TNF-α and IL-4 induced by the IgE–antigen complex in RBL-2H3 cells [9].
3.3 Analgesic Effect
EVO induces significant increases in intracellular calcium and inward currents in dorsal root ganglion neurons and the transient receptor potential (TRP) V1-transfected HEK293 cells, which suggests that EVO suppresses thermal hyperalgesia by activating TRPV1 channels [10].
3.4 Mechanistic Aspects of Evodiamine in Cancer Cells
EVO has a high binding affinity and selectivity to potential vanilloid-1 (TRPV1). It may be used for the treatment of cancer cells by acting as a TRPV1 agonist [11] or aryl hydrocarbon receptor (AhR) antagonist [12].
3.4.1 Respiratory System Tumor Cells
3.4.1.1 Lung Cancer Cells
EVO inhibits the A549 cell proliferation via metadherin suppression and apoptosis activation [13]. EVO induces arrest at G2/M phase and apoptosis via the mitochondrial and endoplasmic reticulum pathways in H446 and H1688 cells [14].
3.4.1.2 Nasopharyngeal Carcinoma Cells
EVO inhibits the invasion and metastasis of NPC cells via repressing the expression and activity of MMP2 and attenuating the phosphorylation level of ERK1/2 [15].
3.4.2 Circulating Tumor Cells
3.4.2.1 Leukemia Cells and Resistant Leukemia Cells
EVO inhibits the K562 cell proliferation by regulating the peroxisome proliferator-activated receptor-gamma (PPARγ) pathway via downregulating cell cycle control protein cyclin D1 and upregulating cyclin-dependent kinase inhibitor p21 [16].
3.4.2.2 Resistant Leukemia Cells
EVO exhibits increased inhibition against camptothecin-resistant K562, THP-1, CCRF-CEM, and CCRF-CEM/C1 cells by acting as a dual catalytic inhibitor of topoisomerases I and II [17].
3.4.3 Digestive System Tumor Cells
3.4.3.1 Gastric Cancer Cells and Cancer Stem Cells
EVO inhibited proliferation and induced apoptosis in SGC7901 cells via suppressing survivin and increasing caspase-3 mRNA [18]. EVO inhibits proliferation and sphere formation ability of gastric cancer stem cells (GCSCs) via repressing the Wingless and INT-1 (Wnt)/β-catenin signaling pathway and represses the induced pluripotent stem cell factors and epithelial-to-mesenchymal transition (EMT) factors [19].
3.4.3.2 Oral Cancer Cells
EVO inhibits MC3 and HSC4 cell proliferation and induces apoptosis by reducing phosphorylated AKT expression [20].
3.4.3.3 Colorectal Cancer Cells
EVO exerts anti-proliferative effects by downregulating IGF-1/HIF-1α expression in LoVo cells [21]. In HCT-116 cells, EVO inhibits proliferation, induces S and G2/M arrest, induces apoptosis via the p53 signaling pathway, and inhibits migration by downregulating the expression of matrix metalloproteinase 3 (MMP3) by inactivating the JAK2/STAT3 pathway [22]. In HCT-116/L-OHP cells, EVO inhibited growth and induced apoptosis in a dose- and time-dependent manner, reduced the accumulation of rhodamine 123 and the activity of ATPase, and inhibited phosphorylation of the NF-κB pathway, such as p50/p65. Thus, EVO may suppress ABCG2-mediated drug resistance (MDR) by inhibiting the p50/NF-κB pathway [23].
3.4.3.4 Pancreatic Cancer Cells
EVO increases the anti-pancreatic cancer effect of gemcitabine in SW1990 cells via downregulating PI3K/Akt pathway [24].
3.4.3.5 Hepatocellular Carcinoma Cells
EVO inhibits STAT3 tyrosine 705 signaling by inducing phosphatase shatterproof 1 in HepG2 cells [25].
3.4.4 Urologic Cancer Cells
3.4.4.1 Renal Proximal Tubular Epithelial Cells
EVO inhibited transforming growth factor (TGF)-β1-induced epithelial–mesenchymal transition (EMT) in rat NRK52E cells. Smad-2 and the PPARγ signal pathway participated in promoting the effects of evodiamine [26].
3.4.4.2 Bladder Cancer Cells
EVO enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in 253J and T24 cells through an mTOR/S6K1-mediated reduction of Mcl-1 levels [27].
3.4.5 Genital Carcinoma Cells
3.4.5.1 Breast Cancer Cells and Resistant Breast Cancer Cells
As a topoisomerase-1 inhibitor, EVO facilitates the formation of topoisomerase I-DNA cleavable complex in MCF-7 breast cancer cells [28]. EVO induces apoptosis of doxorubicin (DOX)-sensitive MCF-7 and DOX-resistant MCF-7/ADR cells by increasing cleaved poly(ADP-ribose) polymerase (PARP), caspase-7/9, and caspase activities, as well as inhibiting the Ras/MEK/ERK cascade and inhibitors of apoptosis (IAPs) [29].
3.4.5.2 Ovarian Cancer Cells
EVO has anti-proliferative effects on ovarian epithelial cancer cells, A2780 and A2780/PTX(R), induces G2/M arrest mediated by cyclin B1 and Cdc2, and, via the MAPK signaling pathway, improves chemo-resistance by downregulating MDR-1 expression [30].
3.4.6 Brain Tumor Cells
3.4.6.1 Glioblastoma Cells
EVO stimulates U87 cells to tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) via the death receptor pathway by increasing the death receptor (DR) 4, DR5, caspase-8, and cleaved caspase-3 [31].
3.4.6.2 Neuronal Cells
When tested against the S, XS [11], L(G), L(A), XL [17], and XL [18] alleles, 2 μM EVO increased 5-HTT promoter (the serotonin transporter) activities by 220, 80, 310, 180, 175, and 102 %, respectively. EVO increased promoter activity depending on the genetic variation of the 5-HTTLPR polymorphism [32].
3.4.7 Osteosarcoma Cells
EVO inhibits OS 143B cell proliferation by upregulating phosphatase and tensin homolog (PTEN) levels through blocking PI3K/Akt signaling [33].
3.5 Antibacterial Effect
Through inhibiting topoisomerase I and supercoiled plasmid DNA relaxation, EVO has a significantly lower minimal inhibitory concentration (MIC) compared with five antibiotics including cefotaxime and aztreonam (128 vs. >512 µg/mL) against the clinical isolate of Klebsiella pneumoniae [34].
3.6 Anti-virus Effect
EVO acts against influenza A virus (IAV) by markedly inhibiting IAV replication and IAV-induced autophagy via the AMPK/TSC2/mTOR signal pathway, blocking LC3-II, p62 and EGFP-LC3 aggregation; retarding Atg5–Atg12/Atg16 heterotrimer formation; decreasing Atg5, Atg7, and Atg12 expressions; and blocking TNF-α, IL-1β, IL-6, and IL-8 cytokine release [35].
3.7 Effects on Cerebral or Cardiac Ischemia
EVO induces transient receptor potential vanilloid-1 (TRPV1) and calcium-mediated protective autophagy through a calcium/c-Jun N-terminal kinase (JNK) pathway in U87-MG astrocytes [36]. EVO inhibits β1-AR activity by downregulating cAMP and PKA in Chinese hamster ovary cells with high expression levels of β1-AR (β1-AR/CHO-S cells) [37]. EVO may prevent cardiac ischemia–reperfusion injury via energy modulation [37].
3.8 Insulin-Sensitizing Effect or Insulin Resistance
EVO activates AMP-activated protein kinase (AMPK) via the Ca(2+)-dependent PI3K/Akt/CaMKII signaling pathway and promotes the high molecular weight adiponectin multimerization in 3T3-L1 adipocytes [38].
4 Role of Evodiamine in Chronic Diseases
EVO is an indole alkaloid extracted from the traditional Chinese medicinal herb Evodia rutaecarpa (Rutaceae family). EVO and E. rutaecarpa are currently used for the treatment of headaches, abdominal pain, vomiting, colds, and reduced blood circulation in the clinic practices of doctors of traditional Chinese medicine in some southeast countries such as China, Japan, and Korea.
Chronic disease is defined by the World Health Organization as a generally slow-progressing disease of long duration. EVO plays positive roles in curing some chronic diseases, such as cancer, diabetes, and cardiovascular diseases [39], by intervening on the risk factors and underlying determinants linked with chronic diseases. EVO may be a potential therapeutic drug against other chronic diseases such as renal tubulointerstitial fibrosis [26], atherogenesis [7], hypoxia [8], glioma [31], hypomotility disorders [40], and IgE-induced allergenic diseases, including atopic dermatitis and rhinitis [9]. EVO may prevent cardiac ischemia–reperfusion injury via energy modulation [37].
5 Biological Activities of Evodiamine in Animal Models
EVO possesses a variety of biological activities, such as anti-obesity, anti-inflammatory, anti-nociceptive, anti-cancer, antibacterial, and antidepressant-like effects. The biological effects of EVO are tested in various animal models.
5.1 Anti-obese Effect
EVO suppresses neuropeptide Y (NPY) and agouti gene-related protein (AgRP) mRNA level in the hypothalamus and decreases the food intake in male rats [41]. EVO acts as a nonpungent vanilloid receptor agonist. When the mice were fed evodiamine as 0.03 % of their diet for 12 days or the rats were given with evodiamine-containing ethanol extract of Evodia fruits at 0.02 % for 21 days, the body weights, perirenal and epididymal fat weights, the levels of free fatty acid in sera, and total lipids, triglyceride and cholesterol in the liver decreased markedly compared with the control group [4]. EVO influences lipid metabolism by decreasing the expression of lipogenesis genes, such as the expression of peroxisome proliferator-activated receptor-g (PPARg), sterol-regulatory element binding protein (SREBP-1c), and fatty acid synthase, as well as increasing the expression of lipolysis genes, such as the expression of hormone-sensitive lipase. In addition, EVO reduces body weight and heat [42]. EVO reduces body weight gain and the blood glucose levels in db/db mice [3].
5.2 Anti-allergic Effect
EVO has anti-allergic effects and inhibits passive cutaneous anaphylaxis (PCA) reaction and scratching behaviors in ICR mice [9].
5.3 Analgesic Effect
EVO pretreatment decreased thermal hyperalgesia induced by intraplantar injection of capsaicin in adult rats [10]. The analgesic effect of EVO may be due to the desensitization of TRPV1 in sensory neurons [10].
5.4 Anti-tumor Effects
EVO (20 mg/kg/day) significantly inhibited xenograft HepG2 tumor growth in nude mice by blocking STAT3 signaling after 13 days being orally administered [25].
5.5 Anti-ulcerogenic Activity
Pretreatment of EVO markedly suppressed the Rho, Rho-kinase 1 and 2, and cytosolic and nucleic necrosis factor (NF)-κBp65 expression against ethanol-induced gastric ulcer in mice [43]. Evodiamine pretreatment obviously increased the glutathione, superoxide dismutase, and catalase levels in sera and lowered the malonaldehyde level and myeloperoxidase activity in the stomachs of mice [43].
5.6 Neuroprotective Effect
EVO protects the brain from cerebral ischemic damage in mice through upregulating pAkt, pGSK3β, and claudin-5, downregulating NF-κB expression, and ameliorating blood–brain barrier permeability [44].
5.7 Antidepressant-Like Effect
EVO can reverse the chronic unpredictable mild stress-induced behavioral deficits and biochemical changes in chronic unpredictable mildly stressed rats. The mechanisms are related to the modulation of the monoamine transmitters and brain-derived neurotropic factor tropomyosin-related kinase B [45].
5.8 Alzheimer’s Disease
EVO improves the learning ability and memory in transgenic mice with Alzheimer’s disease by reversing the glucose uptake inhibition and decreasing IL-1β, IL-6, TNF-α, and COX-2 expression [46].
5.9 Prevention of Insulin Resistance
EVO reduces the insulin-stimulated mammalian target of rapamycin and ribosomal S6 protein kinase (mTOR-S6K) signaling and insulin receptor substrate 1 (IRS1) serine phosphorylation in white adipose tissues and improves glucose tolerance in obese/diabetic KK-Ay mice [47].
5.10 Cardiotonic Effect or Remedy for Cardiac Diseases
EVO evokes transient positive inotropic and chronotropic effects on the atria of the guinea pig, which is due to its interaction with the vanilloid receptors and the release of the calcitonin gene-related peptide antagonist (CGRP) [4]. EVO attenuates myocardial infarct size, improves metabolism disorders between fatty acids and glucose, increases ATP and Ca(2+)-ATPase activity, and reduces the peroxisome proliferator-activated receptor-α (PPARα) protein level in the myocardial ischemia–reperfusion (I/R) rats [37].
5.11 Other Effects
EVO exerts stimulatory effects on rat jejunal contractility, exhibiting its potential role in relieving hypomotility disorders [40]. EVO improves the undesirable effects of some drugs while preserving their pharmacological activities. For example, the side effects (adipogenesis, body weight gain, and hepatotoxicity) of rosiglitazone can be attenuated by being co-administered with EVO, but the blood glucose-lowering effect of rosiglitazone is still well preserved [3].
6 Biological Activities of Evodiamine in Humans
There are few reports of the biological activities of EVO in humans. Evodiae fructus is reported to be used as an analgesic in traditional Chinese medicine [10]. The typical commercial preparation of traditional Chinese medicines containing EVO is the Zuojin pill. The Zuojin pill is composed of Evodiae fructus and Rhizoma (the mass ratio is 1:6). The Zuojin pill inhibits gastric emptying and the secretion of gastric acid. The Zuojin pill also has an obvious anti-ulcer effect [48]. The Zuojin pill is officially listed in the Chinese Pharmacopoeia.
7 Conclusions
EVO is a major bioactive alkaloid isolated and purified from the Chinese herbal drug “Wu-Chu-Yu” (Evodiae fructus). It possesses a multitude of positive effects, such as anti-cancer and anti-nociceptive effects on different cells, including stem cells, animals, and humans through modulating diverse targeting regions or through various signaling pathways. Evodiae fructus or the extraction of Evodiae fructus, such as ethanol, methanol, and chloroform extracts, exhibits some effects similar to those of EVO [49]. EVO can be used alone or in combination with other drugs. The combination therapy of EVO with gemcitabine augments its therapeutic effects [24]. Furthermore, EVO shows little toxicity against normal cells [50] in contrast to its positive effects.
In the future, three measures are recommended to be pursued in order to promote the clinical application of EVO in the treatment of chronic diseases: First is to develop a new EVO delivery system, such as a supermolecular nanoemulsion [51] or a phospholipid complex [1], in order to modify the pharmacokinetic behavior and increase the bioavailability of EVO; second is to chirally separate two EVO stereoisomers because sometimes the S-(+) EVO is more effective than the R-(−) evodiamine [52]; third is to synthesize new derivatives with much better potency and less toxicity [53], such as carbamates [54], compared with the parent drug EVO.
References
Tan Q, Liu S, Chen X, Wu M, Wang H, Yin H, He D, Xiong H, Zhang J (2012) Design and evaluation of a novel evodiamine-phospholipid complex for improved oral bioavailability. AAPS Pharm Sci Tech 13(2):534–547
Wang T, Wang Y, Yamashita H (2012) Evodiamine inhibits adipogenesis via the EGFR-PKCalpha-ERK signaling pathway. FEBS Lett 583(22):3655–3659
Bak EJ, Park HG, Kim JM, Kim JM, Yoo YJ, Cha JH (2010) Inhibitory effect of evodiamine alone and in combination with rosiglitazone on in vitro adipocyte differentiation and in vivo obesity related to diabetes. Int J Obes (Lond). 34(2):250–260
Kobayashi Y, Nakano Y, Kizaki M, Hoshikuma K, Yokoo Y, Kamiya T (2001) Capsaicin-like anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist. Planta Med 67(7):628–633
Lv Q, Xue Y, Li G, Zou L, Zhang X, Ying M, Wang S, Guo L, Gao Y, Li G, Xu H, Liu S, Xie J, Liang S (2015) Beneficial effects of evodiamine on P2X4-mediated inflammatory injury of human umbilical vein endothelial cells due to high glucose. Int Immunopharmacol 28(2):1044–1049
Hu Y, He K, Zhu H (2015) Chinese herbal medicinal ingredients affect secretion of NO, IL-10, ICAM-1 and IL-2 by endothelial cells. Immunopharmacol Immunotoxicol 37(3):324–328
Heo SK, Yun HJ, Yi HS, Noh EK, Park SD (2009) Evodiamine and rutaecarpine inhibit migration by LIGHT via suppression of NADPH oxidase activation. J Cell Biochem 107(1):123–133
Liu YN, Pan SL, Liao CH, Huang DY, Guh JH, Peng CY, Chang YL, Teng CM (2009) Evodiamine represses hypoxia-induced inflammatory proteins expression and hypoxia-inducible factor 1alpha accumulation in RAW264.7. Shock. 32(3):263–269
Shin YW, Bae EA, Cai XF, Lee JJ, Kim DH (2007) In vitro and in vivo antiallergic effect of the fructus of Evodia rutaecarpa and its constituents. Biol Pharm Bull 30(1):197–199
Iwaoka E, Wang S, Matsuyoshi N, Kogure Y, Aoki S, Yamamoto S, Noguchi K, Dai Y (2016) Evodiamine suppresses capsaicin-induced thermal hyperalgesia through activation and subsequent desensitization of the transient receptor potential V1 channels. J Nat Med 70(1):1–7
Ivanova B, Spiteller M (2014) Evodiamine and rutaecarpine alkaloids as highly selective transient receptor potential vanilloid 1 agonists. Int J Biol Macromol 65:314–324
Yu H, Tu Y, Zhang C, Fan X, Wang X, Wang Z, Liang H (2010) Evodiamine as a novel antagonist of aryl hydrocarbon receptor. Biochem Biophys Res Commun 402(1):94–98
Zou Y, Qin X, Xiong H, Zhu F, Chen T, Wu H (2015) Apoptosis of human non-small-cell lung cancer A549 cells triggered by evodiamine through MTDH-dependent signaling pathway. Tumour Biol 36(7):5187–5193
Fang C, Zhang J, Qi D, Fan X, Luo J, Liu L, Tan Q (2014) Evodiamine induces G2/M arrest and apoptosis via mitochondrial and endoplasmic reticulum pathways in H446 and H1688 human small-cell lung cancer cells. PLoS ONE 9(12):e115204
Peng X, Zhang Q, Zeng Y, Li J, Wang L, Ai P (2015) Evodiamine inhibits the migration and invasion of nasopharyngeal carcinoma cells in vitro via repressing MMP-2 expression. Cancer Chemother Pharmacol 76(6):1173–1184
Sun C, Zhang G, Luan S, Luan C, Shao H, Dong F, Liu X (2015) Evodiamine inhibits the proliferation of leukemia cell line K562 by regulating peroxisome proliferators-activated receptor gamma (PPARγ) pathway. J Recept Signal Transduct Res. doi:10.3109/10799893.2015.1122040
Pan X, Hartley JM, Hartley JA, White KN, Wang Z, Bligh SW (2012) Evodiamine, a dual catalytic inhibitor of type I and II topoisomerases, exhibits enhanced inhibition against camptothecin resistant cells. Phytomedicine 19(7):618–624
Shen H, Zhao S, Xu Z, Zhu L, Han Y, Ye J (2015) Evodiamine inhibits proliferation and induces apoptosis in gastric cancer cells. Oncol Lett. 10(1):367–371
Wen Z, Feng S, Wei L, Wang Z, Hong D, Wang Q (2015) Evodiamine, a novel inhibitor of the Wnt pathway, inhibits the self-renewal of gastric cancer stem cells. Int J Mol Med 36(6):1657–1663
Sachita K, Kim Y, Yu HJ, Cho SD, Lee JS (2015) In vitro assessment of the anticancer potential of evodiamine in human oral cancer cell lines. Phytother Res 29(8):1145–1151
Huang J, Chen ZH, Ren CM, Wang DX, Yuan SX, Wu QX, Chen QZ, Zeng YH, Shao Y, Li Y, Wu K, Yu Y, Sun WJ, He BC (2015) Antiproliferation effect of evodiamine in human colon cancer cells is associated with IGF-1/HIF-1α downregulation. Oncol Rep. doi:10.3892/or.2015.4309
Zhao LC, Li J, Liao K, Luo N, Shi QQ, Feng ZQ, Chen DL (2015) Evodiamine induces apoptosis and inhibits migration of HCT-116 human colorectal cancer cells. Int J Mol Sci 16(11):27411–27421
Sui H, Zhou LH, Zhang YL, Huang JP, Liu X, Ji Q, Fu XL, Wen HT, Chen ZS, Deng WL, Zhu HR, Li Q (2015) Evodiamine suppresses ABCG2 mediated drug resistance by inhibiting p50/NF-κB pathway in colorectal cancer. J Cell Biochem. doi:10.1002/jcb.25451
Wei WT, Chen H, Wang ZH, Ni ZL, Liu HB, Tong HF, Guo HC, Liu DL, Lin SZ (2012) Enhanced antitumor efficacy of gemcitabine by evodiamine on pancreatic cancer via regulating PI3K/Akt pathway. Int J Biol Sci. 8(1):1–14
Yang J, Cai X, Lu W, Hu C, Xu X, Yu Q, Cao P (2013) Evodiamine inhibits STAT3 signaling by inducing phosphatase shatterproof 1 in hepatocellular carcinoma cells. Cancer Lett 328(2):243–251
Wei J, Li Z, Yuan F (2014) Evodiamine might inhibit TGF-beta1-induced epithelial-mesenchymal transition in NRK52E cells via Smad and PPAR-gamma pathway. Cell Biol Int 38(7):875–880
Zhang T, Qu S, Shi Q, He D, Jin X (2014) Evodiamine induces apoptosis and enhances TRAIL-induced apoptosis in human bladder cancer cells through mTOR/S6K1-mediated downregulation of Mcl-1. Int J Mol Sci 15(2):3154–3171
Chan AL, Chang WS, Chen LM, Lee CM, Chen CE, Lin CM, Hwang JL (2009) Evodiamine stabilizes topoisomerase I-DNA cleavable complex to inhibit Chan topoisomerase I activity. Molecules 14(4):1342–1352
Wang S, Wang L, Shi Z, Zhong Z, Chen M, Wang Y (2014) Evodiamine synergizes with doxorubicin in the treatment of chemoresistant human breast cancer without inhibiting P-glycoprotein. PLoS ONE 9(5):e97512
Zhong ZF, Tan W, Wang SP, Qiang WA, Wang YT (2015) Anti-proliferative activity and cell cycle arrest induced by evodiamine on paclitaxel-sensitive and -resistant human ovarian cancer cells. Sci Rep. 5:16415
Khan M, Bi Y, Qazi JI, Fan L, Gao H (2015) Evodiamine sensitizes U87 glioblastoma cells to TRAIL via the death receptor pathway. Mol Med Rep. 11(1):257–262
Hu Y, Ehli EA, Hudziak JJ, Davies GE (2012) Berberine and evodiamine influence serotonin transporter (5-HTT) expression via the 5-HTT-linked polymorphic region. Pharmacogenomics J. 12(5):372–378
Meng ZJ, Wu N, Liu Y, Shu KJ, Zou X, Zhang RX, Pi CJ, He BC, Ke ZY, Chen L, Deng ZL, Yin LJ (2015) Evodiamine inhibits the proliferation of human osteosarcoma cells by blocking PI3K/Akt signaling. Oncol Rep 34(3):1388–1396
Wu JY, Chang MC, Chen CS, Lin HC, Tsai HP, Yang CC, Yang CH, Lin CM (2013) Topoisomerase I inhibitor evodiamine acts as an antibacterial agent against drug-resistant Klebsiella pneumoniae. Planta Med 79(1):27–29
Dai JP, Li WZ, Zhao XF, Wang GF, Yang JC, Zhang L, Chen XX, Xu YX, Li KS (2012) A drug screening method based on the autophagy pathway and studies of the mechanism of evodiamine against influenza A virus. PLoS ONE 7(8):e42706
Liu AJ, Wang SH, Hou SY, Lin CJ, Chiu WT, Hsiao SH, Chen TH, Shih CM (2013) Evodiamine induces transient receptor potential vanilloid-1-mediated protective autophagy in U87-MG astrocytes. Evid Based Complement Alternat Med 2013:354840
Xue H, Cheng Y, Wang X, Yue Y, Zhang W, Li X (2015) Rutaecarpine and evodiamine selected as β1-AR inhibitor candidates using β1-AR/CMC-offline-UPLC/MS prevent cardiac ischemia-reperfusion injury via energy modulation. J Pharm Biomed Anal 115:307–314
Liu LH, Xie JY, Guo WW, Wu GY, Chen ZF, Yi JY, Zhang L, Zhang ZJ, Li Z (2014) Evodiamine activates AMPK and promotes adiponectin multimerization in 3T3-L1 adipocytes. J Asian Nat Prod Res 16(11):1074–1083
Wei J, Ching LC, Zhao JF, Shyue SK, Lee HF, Kou YR, Lee TS (2013) Essential role of transient receptor potential vanilloid type 1 in evodiamine-mediated protection against atherosclerosis. Acta Physiol (Oxf) 207(2):299–307
Xiong YJ, Chen DP, Peng JY, Wang JY, Lv BC, Liu FF, Lin Y (2015) Characteristics of evodiamine-exerted stimulatory effects on rat jejunal contractility. Nat Prod Res 29(4):388–391
Shi J, Yan J, Lei Q, Zhao J, Chen K, Yang D, Zhao X, Zhang Y (2009) Intragastric administration of evodiamine suppresses NPY and AgRP gene expression in the hypothalamus and decreases food intake in rats. Brain Res 1247:71–78
Jiang DF, Li WT, Yang HL, Zhang ZZ, Chen D, Sun C (2014) Long-term effects of evodiamine on expressions of lipogenesis and lipolysis genes in mouse adipose and liver tissues. Genet Mol Res 13(1):1038–1046
Zhao Z, Gong S, Wang S, Ma C (2015) Effect and mechanism of evodiamine against ethanol-induced gastric ulcer in mice by suppressing Rho/NF-κB pathway. Int Immunopharmacol 28(1):588–595
Zhao T, Zhang X, Zhao Y, Zhang L, Bai X, Zhang J, Zhao X, Chen L, Wang L, Cui L (2014) Pretreatment by evodiamine is neuroprotective in cerebral ischemia: up-regulated pAkt, pGSK3β, down-regulated NFκB expression, and ameliorated BBB permeability. Neurochem Res 39(8):1612–1620
Jiang ML, Zhang ZX, Li YZ, Wang XH, Yan W, Gong GQ (2015) Antidepressant-like effect of evodiamine on chronic unpredictable mild stress rats. Neurosci Lett 588:154–158
Yuan SM, Gao K, Wang DM, Quan XZ, Liu JN, Ma CM, Qin C, Zhang LF (2011) Evodiamine improves congnitive abilities in SAMP8 and APP(swe)/PS1(ΔE9) transgenic mouse models of Alzheimer’s disease. Acta Pharmacol Sin 32(3):295–302
Wang T, Kusudo T, Takeuchi T, Yamashita Y, Kontani Y, Okamatsu Y, Saito M, Mori N, Yamashita H (2013) Evodiamine inhibits insulin-stimulated mTOR-S6K activation and IRS1 serine phosphorylation in adipocytes and improves glucose tolerance in obese/diabetic mice. PLoS ONE 8(12):e83264
Doe J (2015) http://www.wiki8.com/zuojinwan_23586. Accessed 23 Dec 2015
Matsuda H, Wu JX, Tanaka T, Iinuma M, Kubo M (1997) Antinociceptive activities of 70 % methanol extract of evodiae fructus (fruit of Evodia rutaecarpa var. bodinieri) and its alkaloidal components. Biol Pharm Bull 20(3):243–248
Liao CH, Pan SL, Guh JH, Chang YL, Pai HC, Lin CH, Teng CM (2005) Antitumor mechanism of evodiamine, a constituent from Chinese herb Evodiae fructus, in human multiple-drug resistant breast cancer NCI/ADR-RES cells in vitro and in vivo. Carcinogenesis 26(5):968–975
Hu J, Sun L, Zhao D, Zhang L, Ye M, Tan Q, Fang C, Wang H, Zhang J (2014) Supermolecular evodiamine loaded water-in-oil nanoemulsions: enhanced physicochemical and biological characteristics. Eur J Pharm Biopharm 88(2):556–564
De Petrocellis L, Schiano Moriello A, Fontana G, Sacchetti A, Passarella D, Appendino G, Di Marzo V (2014) Effect of chirality and lipophilicity in the functional activity of evodiamine and its analogues at TRPV1 channels. Br J Pharmacol 171(10):2608–2620
Wang S, Fang K, Dong G, Chen S, Liu N, Miao Z, Yao J, Li J, Zhang W, Sheng C (2015) Scaffold diversity inspired by the natural product evodiamine: discovery of highly potent and multitargeting antitumor agents. J Med Chem 58(16):6678–6696
Huang G, Kling B, Darras FH, Heilmann J, Decker M (2014) Identification of a neuroprotective and selective butyrylcholinesterase inhibitor derived from the natural alkaloid evodiamine. Eur J Med Chem 81:15–21
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Tan, Q., Zhang, J. (2016). Evodiamine and Its Role in Chronic Diseases. In: Gupta, S., Prasad, S., Aggarwal, B. (eds) Drug Discovery from Mother Nature. Advances in Experimental Medicine and Biology, vol 929. Springer, Cham. https://doi.org/10.1007/978-3-319-41342-6_14
Download citation
DOI: https://doi.org/10.1007/978-3-319-41342-6_14
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-41341-9
Online ISBN: 978-3-319-41342-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)