Screening of active compounds as neuromedin U2 receptor agonist from natural products

Zheng, Xiangkuo; Hu, Yinghe; Liu, Jianhui; Ouyang, Keqing

doi:10.1016/j.bmcl.2005.07.003

Cited by 20 publications

(11 citation statements)

References 12 publications

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“…Other data have shown that NMU suppresses food intake by acting through the NMUR2 receptor in the brain, as intracerebroventricular administration of NMU markedly suppresses food intake in rats (Howard et al, 2000). Icariin, a flavonol glycoside found in certain herbs, has recently been shown to stimulate NMUR2 (Zheng et al, 2005), but its mechanism of action needs to be further characterized. Recently, Neuromedin S (NMS) has been identified in rat brain and has been shown to be an endogenous ligand for NMUR1 and NMUR2 (Ida et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

McRoberts

Berr

et al. 2006

Oncogene

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Most deaths from urinary bladder cancer are owing to metastatic disease. A reduction in Rho GDP Dissociation Inhibitor 2 (RhoGDI2) protein has been associated with increased risk of metastasis in patients with locally advanced bladder cancer, whereas in animal models, RhoGDI2 reconstitution in cells without expression results in lung metastasis suppression. Recently, we noted an inverse correlation between tumor RhoGDI2 and Neuromedin U (NMU) expression, suggesting that NMU might be a target of the lung metastasis suppressor effect of RhoGDI2. Here we evaluated whether NMU is regulated by RhoGDI2 and is functionally important in tumor progression. We used small interfering RNA knockdown of endogenous RhoGDI2 in poorly tumorigenic and nonmetastatic human bladder cancer T24 cells and observed increased NMU RNA expression. Although NMU overexpression did not increase the monolayer growth of T24 or related T24T poorly metastatic human bladder cancer cells, it did augment anchorage-independent growth for the latter. Overexpression of NMU in T24 and T24T cells significantly promoted tumor formation of both cell lines in nude mice, but did not alter the growth rate of established tumors. Furthermore, NMU-overexpressing xenografts were associated with lower animal body weight than control tumors, indicating a possible role of NMU in cancer cachexia. NMU overexpression in T24T cells significantly enhanced their lung metastatic ability. Bioluminescent in vivo imaging revealed that lung metastases in T24T grew faster than the same tumors in the subcutaneous microenvironment. In conclusion, NMU is a RhoGDI2-regulated gene that appears important for tumorigenicity, lung metastasis and cancer cachexia, and thus a promising therapeutic target in cancer.

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Section: Discussionmentioning

confidence: 99%

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

McRoberts

Berr

et al. 2006

Oncogene

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“…25) We had demonstrated the feasibility of using this assay to perform high-throughput screening of a small molecule library. 21,22) In this paper, we successfully used this screening system to first discover p-synephrine (Fig. 1A), which could strongly activate NMU2R in a dose dependent manner (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Differences were considered statistically significant when p <0.05. previous studies, we developed a stable cell line that could respond to both Gs and Gq-coupled NMU2R. 21,22) Through combining with forskolin, the activating response would be increased. As shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…The microplate assay used luciferase as the reporter that enables simple and rapid screening of natural product library to identify new NMU2R agonists, and we had found flavonoid glycoside (icariin, hesperidin and nobiletin) could activate the reporter gene response evidently. [21][22][23] Further, the false-positive results were ruled out with negative cell line and RNA interfere method.…”

Section: -4)mentioning

confidence: 99%

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<i>p</i>-Synephrine: A Novel Agonist for Neuromedin U2 Receptor

Zheng

Guo

Wang

et al. 2014

Biological & Pharmaceutical Bulletin

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In the brain, Neuromedin U2 receptor (NMU2R) is prominent in the hypothalamic regions and is known to be associated with regulation of several important physiological functions, including food intake, energy balance, stress response, and nociception. In this article, by random screening of compounds using the model of high-throughput screening for NMU2R stable expression, NMU2R negative and NMU2R short hairpin RNA (shRNA) knockdown HEK293 cell lines, for the first time, we discovered that p-synephrine, which is the primary protoalkaloid in Citrus aurantium (bitter orange) and is widely used in weight loss and weight management products, is a highly potent and selective NMU2R agonist. In NMU2R activating ability experiments, p-synephrine was found binding to NMU2R with high efficacy and potency; the efficacy, 50% of the maximum possible effect (EC 50 ) and potency values were determined to be 7.207, 6.604 and 0.227 µmol/L for the NMU2R, respectively. Our researches have important theoretical value for elucidating the mechanisms of p-synephrine in body weight and energy balance regulation. These data provide further evidence for widespread roles for p-synephrine and its receptors in the brain.

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“…12 Especially, icariin, epimedin A, epimedin B, epimedin C and hyperin are known to be the biologically active flavonoid glycosides from this plant and these flavonoid compounds have mainly been considered as marker compounds of Herba Epimedii. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] Analytical tools such as thin-layer chromatography, high performance liquid chromatography, capillary zone electrophoresis, fourier transform infrared spectroscopy, micellar electrokinetic capillary chromatography and mass spectrometry have been developed for the analysis of Herba Epimedii and its related products. [31][32][33][34][35][36][37] However, these studies focused only quantitative analysis of selected marker compounds which are not promising approaches for the quality control of multi-component herbal drugs.…”

Section: Introductionmentioning

confidence: 99%

Quantitative and Pattern Recognition Analyses for the Quality Evaluationof Herba Epimedii by HPLC

2009

Bulletin of the Korean Chemical Society

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In this study, quantitative and pattern recognition analyses for the quality evaluation of Herba Epimedii using HPLC was developed. For quantitative analysis, five major bioactive constituents, hyperin, epimedin A, epimedin B, epimedin C, and icariin were determined. Analysis was carried out on Capcell pak C18 column (250×4.6 mm, 5 µm) with a mobile phase of mixture of acetonitrile and 0.1% formic acid, using UV detection at 270 nm. The linear behavior was observed over the investigated concentration range (2-50 µg/mL; r 2 > 0.99) for all analytes. The intraand inter-day precisions were lower than 4.3% (as a relative standard deviation, RSD) and accuracies between 95.1% and 104.4%. The HPLC analytical method for pattern recognition analysis was validated by repeated analysis of one reference sample. The RSD of intra-and inter-day variation of relative retention time (RRT) and relative peak area (RPA) of the 12 selected common peaks were below 0.8% and 4.7%, respectively. The developed methods were applied to analysis of twenty Herba Epimedii extract samples. Contents of hyperin, epimedin A, epimedin B, epimedin C, and icariin were calculated to be 0~0.79, 0.69~1.91, 0.93~9.58, 0.65~3.05, and 2.43~11.8 mg/g dried plant. Principal component analysis (PCA) showed that most samples were clustered together with the reference samples but several apart from the main cluster in the PC score plot, indicating differences in overall chemical composition between two clusters. The present study suggests that quantitative determination of marker compounds combined with pattern-recognition method can provide a comprehensive approach for the quality assessment of herbal medicines.

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Screening of active compounds as neuromedin U2 receptor agonist from natural products

Cited by 20 publications

References 12 publications

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

<i>p</i>-Synephrine: A Novel Agonist for Neuromedin U2 Receptor

Quantitative and Pattern Recognition Analyses for the Quality Evaluationof Herba Epimedii by HPLC

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