| In vitro: |
| Phytother Res. 2015 Apr 22. | | In Vitro Assessment of the Anticancer Potential of Evodiamine in Human Oral Cancer Cell Lines.[Pubmed: 25903972] | Evodiamine, a bioactive alkaloid, has been regarded as having antioxidant, antiinflammatory, and anticancer properties.
METHODS AND RESULTS:
In the present study, we explored the effects of Evodiamine on cell growth and apoptosis in human oral cancer cell lines. Our data revealed that Evodiamine significantly inhibited the proliferation of human oral cancer cells and resulted in the cleavages of PARP (poly (ADP-ribose) polymerase) and caspase-3, in addition to causing the typical characteristics of apoptosis. Evodiamine also increased Bax protein levels and caused translocation of Bax into mitochondria and Bax oligomerization. In addition, Evodiamine decreased expression of myeloid cell leukemia (Mcl-1) at the transcriptional modification, and knockdown of Mcl-1 clearly resulted in an increase in expression of Bax and active Bax, resulting in induction of apoptosis. Evodiamine reduced expression of phosphorylated AKT, and LY294002 potentiated Evodiamine-induced apoptosis by regulating Mcl-1 protein.
CONCLUSIONS:
Our results suggest that Evodiamine induces apoptosis in human oral cancer cells through the AKT pathway. These findings provide a rationale for its clinical application in the treatment of oral cancer. | | Planta Med. 2001 Apr;67(3):244-8. | | The positive inotropic and chronotropic effects of evodiamine and rutaecarpine, indoloquinazoline alkaloids isolated from the fruits of Evodia rutaecarpa, on the guinea-pig isolated right atria: possible involvement of vanilloid receptors.[Pubmed: 11345696] | Cardiotonic effects of Evodiamine and rutaecarpine, constituents of the fruits of Evodia rutaecarpa Bentham Rutaceae, were evaluated on guinea pig isolated atria. Comparison with capsaicin, a vanilloid receptor agonist, revealed similar positive inotropic and chronotropic activity, as judged from antagonistic effects of the competitive vanilloid receptor (capsaicin receptor) antagonist capsazepine, the non-competitive vanilloid receptor antagonist ruthenium red, the calcitonin gene related peptide antagonist CGRP(8-37), the P2X purinoceptor antagonist PPADS, and various desensitization studies.
METHODS AND RESULTS:
Evodiamine and rutaecarpine produced transient positive inotropic and chronotropic effects on the guinea-pig isolated atria, followed by a desensitizing effect to additional administration. Dose-response relationships for Evodiamine, rutaecarpine and capsaicin were obtained. All the compounds evoked positive inotropic and chronotropic effects in a concentration-dependent manner. Maximal contractions for Evodiamine, rutaecarpine and capsaicin were observed at concentrations of 1 microM, 3 microM and 0.3 microM, respectively. The cardiotonic responses evoked by both Evodiamine and rutaecarpine were shifted to the right by capsazepine, an established antagonist of vanilloid receptor (capsaicin-receptor). The effects of both Evodiamine (1 microM) and rutaecarpine (3 microM) were abolished by pretreatment with a desensitizing dosage of capsaicin (1 microM), developing cross-tachyphylaxis between these compounds. The effects of Evodiamine (1 microM), rutaecarpine (3 microM) and capsaicin (0.3 microM) were also significantly reduced by pretreatment with ruthenium red (10 microM) and CGRP (8-37) (10 microM). The effects of Evodiamine, rutaecarpine and capsaicin were not affected by pretreatment with PPADS (100 microM), a highly selective P2X purinoceptor antagonist, and the possibility of the involvement of the P2X purinoceptor was excluded.
CONCLUSIONS:
These results suggest that the positive inotropic and chronotropic effects on the guinea-pig isolated right atria induced by both Evodiamine and rutaecarpine could be attributed to their interaction with vanilloid receptors and the resultant release of CGRP, a cardiotonic neurotransmitter, from capsaicin-sensitive nerves as with capsaicin. | | Planta Med. 2003 May;69(5):425-8. | | The nociceptive and anti-nociceptive effects of evodiamine from fruits of Evodia rutaecarpa in mice.[Pubmed: 12802723 ] | Recently, the authors reported that Evodiamine, a major alkaloidal principle of Evodia fruits (Evodia rutaecarpa, Rutaceae), had vanilloid receptor agonistic activity comparable to capsaicin. In spite of the similarities in the actions of Evodiamine and capsaicin in vitro, the effects of Evodiamine on sensory neurons in vivo had not been investigated.
METHODS AND RESULTS:
We demonstrate here that Evodiamine sensitizes and desensitizes the capsaicin-sensitive sensory afferents in mice, resulting in nociceptive action and antinociceptive actions. The nociceptive action (paw licking behaviour) was dose dependently induced by intradermal injection (i.d.) of Evodiamine to the hind paw and was suppressed by the co-treatment with capsazepine, a vanilloid receptor specific agonist, in a dose-dependent manner. The treatment with higher dosages of Evodiamine showed sustained antinociceptive effects. The acetic acid-induced writhing was significantly suppressed by the intraperitoneal Evodiamine administration 3 days before, without any observable effects on spontaneous motor activity. The response of the isolated ileum from the mice with or without high dosages of Evodiamine administration indicated the sensory neuron specific desensitizing effect of Evodiamine. The isolated ileum from vehicle-treated mice contracted in response to both the sensory nerve stimulation by 10 microM capsaicin and the mimicked vagal stimulation by 2 microM carbachol. However, the isolated ileum from Evodiamine-treated mice lost its response to sensory nerve stimuli but retained its response to vagus nerve stimuli.
The suppression of acetic acid-induced writhing and the desensitization of visceral sensory neurons strongly correlated [regression coefficient (r) = 0.955].
CONCLUSIONS:
Thus, we demonstrate that Evodiamine shows the analgesic action by desensitizing sensory nerves. |
|
| In vivo: |
| Planta Med. 2001 Oct;67(7):628-33. | | Capsaicin-like anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist.[Pubmed: 11582540 ] | Evodiamine, a major alkaloidal principle of Evodia fruits (Evodia rutaecarpa, Rutaceae), showed vanilloid receptor agonistic activities comparable to capsaicin. The Chinese literature refers to Evodia fruits as a "hot nature" herb. In spite of the similarities in the actions of Evodiamine and capsaicin in vitro, Evodiamine has no perceptible taste, including a peppery hot taste. Therefore, the effectiveness of Evodiamine and the extract of Evodia fruits in preventing obesity on male C3H mice, or male SD rats were examined.
METHODS AND RESULTS:
When Evodiamine was supplemented at 0.03% of the diet and fed to mice for 12 days, the perirenal fat weight became significantly lower than in the control group. The epididymal fat mass was also decreased in the Evodiamine diet group. When Evodiamine was supplemented at 0.02% in the form of ethanol extract of Evodia fruits to the high-fat diet and fed to rats for 21 days, the body weight, the perirenal fat weight, epididymal fat weight, the levels of serum free fatty acid, total lipids in the liver, triglyceride in the liver, and cholesterol level in the liver were significantly reduced as compared with the control diet group. Furthermore, both lipolytic activity in the perirenal fat tissue and specific GDP binding in brown adipose tissue mitochondria, as the biological index of enhanced heat production, were significantly increased in the Evodiamine fed rats. Fasting mice subcutaneously administered 1-3 mg/kg Evodiamine showed decreased core body temperature by 1-2 degrees C. This hypothermic effect was prevented by the pretreatment of intraperitoneally administered 10 mg/kg capsazepine, a vanilloid receptor antagonist. On the other hand, food-sated mice subcutaneously administered 1-3 mg/kg Evodiamine showed unchanged core body temperature and increased tail skin temperature by more than 5 degrees C, suggesting the increased energy expenditure by enhanced heat dissipation.
CONCLUSIONS:
In conclusion, we have demonstrated that a novel non-pungent vanilloid receptor agonist, Evodiamine, mimics the characteristic anti-obese effects induced by capsaicin. Evodiamine would induce heat loss and heat production at the same time and dissipate food energy, preventing the accumulation of perivisceral fat and the body weight increase. | | Pharmacology . 2016;97(1-2):43-7. | | Effects of Evodiamine on the Pharmacokinetics of Dapoxetine and Its Metabolite Desmethyl Dapoxetine in Rats[Pubmed: 26588583] | | Abstract
The objective of this work was to investigate the effect of orally administered Evodiamine on the pharmacokinetics of dapoxetine and its active metabolite desmethyl dapoxetine in rats. Twelve healthy male Sprague-Dawley rats were randomly divided into 2 groups: the control group (received oral 10 mg/kg dapoxetine alone) and the combination group (10 mg/kg dapoxetine orally co-administered with 100 mg/kg Evodiamine). The plasma concentration of dapoxetine and desmethyl dapoxetine were estimated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and different pharmacokinetic parameters were calculated using the Drug and Statistics 2.0 software. Compared to the control group, the pharmacokinetic parameter of t1/2, AUC(0-∞) and Tmax of dapoxetine in combination group was significantly increased by 63.3% (p < 0.01), 44.8% (p < 0.01) and 50.4% (p < 0.01), respectively. Moreover, Evodiamine had significantly decreased the pharmacokinetic parameter of t1/2 and AUC(0-∞) of desmethyl dapoxetine. This study demonstrated that Evodiamine inhibits the metabolism of dapoxetine. Henceforth, the pharmacodynamic influence of this interaction should be taken into consideration while prescribing dapoxetine to the patients already taking Evodiamine. | | Tumour Biol . 2016 Sep;37(9):12791-12803. | | Evodiamine exerts anti-tumor effects against hepatocellular carcinoma through inhibiting β-catenin-mediated angiogenesis[Pubmed: 27449032] | | Abstract
Hepatocellular carcinoma (HCC) is a highly vascular tumor with high microvessel density and high levels of circulating vascular endothelial growth factor (VEGF). Thus, the angiogenesis pathway is an attractive therapeutic target for HCC. The anti-tumor effects of Evodiamine, a quinolone alkaloid isolated from Euodia rutaecarpa (Juss.) Benth. (Rutaceae), were investigated in a mouse xenograft model using BALB/c nude mice, various HCC cell lines (HepG2, SMMC-7721, H22), and human umbilical vein endothelial cells (HUVECs). The effects of Evodiamine on tumor volumes and weights, levels of tumor markers, angiogenesis in vivo and in vitro, cell viability, and cell migration and invasion were measured, and the mechanism through which its effects are achieved was investigated. Transcriptional regulation of VEGFa via interaction with β-catenin was established by luciferase activity assays and electrophoretic mobility shift assays. In a subcutaneous H22 xenograft model, Evodiamine inhibited tumor growth and reduced serum tumor markers and the levels of β-catenin and VEGFa. It also blocked VEGF-induced angiogenesis in a Matrigel plug assay. Evodiamine suppressed cellular proliferation, invasion, and migration and inhibited tube formation of HUVECs. Moreover, in a concentration-dependent manner, Evodiamine reduced the number of capillary sprouts from Matrigel-embedded rat thoracic aortic rings. Also, Evodiamine suppressed various biomarkers of angiogenesis and the expression of β-catenin. Evodiamine decreased β-catenin levels activated by LiCl, which led to reduced expression of VEGFa. In addition, β-catenin interacted with VEGFa and transcriptionally regulated VEGFa, an effect inhibited by Evodiamine in HCCs. Moreover, in an SMMC-7721 xenograft model, Evodiamine suppressed tumor growth, various biomarkers of angiogenesis, and the levels of β-catenin and VEGFa. Evodiamine has anti-tumor effects on HCCs through inhibiting β-catenin, which interacts with and reduces VEGFa expression, thus inhibiting angiogenesis. These results indicate that Evodiamine, which inhibits cellular invasion and migration and blocks angiogenesis, is a potential therapeutic agent for HCCs. |
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