Optimizing Combinations of Flavonoids Deriving from Astragali Radix in Activating the Regulatory Element of Erythropoietin by a Feedback System Control Scheme

Evidence-Based Complementary and Alternative Medicine, Apr 2013

Identifying potent drug combination from a herbal mixture is usually quite challenging, due to a large number of possible trials. Using an engineering approach of the feedback system control (FSC) scheme, we identified the potential best combinations of four flavonoids, including formononetin, ononin, calycosin, and calycosin-7-O-β-D-glucoside deriving from Astragali Radix (AR; Huangqi), which provided the best biological action at minimal doses. Out of more than one thousand possible combinations, only tens of trials were required to optimize the flavonoid combinations that stimulated a maximal transcriptional activity of hypoxia response element (HRE), a critical regulator for erythropoietin (EPO) transcription, in cultured human embryonic kidney fibroblast (HEK293T). By using FSC scheme, 90% of the work and time can be saved, and the optimized flavonoid combinations increased the HRE mediated transcriptional activity by ~3-fold as compared with individual flavonoid, while the amount of flavonoids was reduced by ~10-fold. Our study suggests that the optimized combination of flavonoids may have strong effect in activating the regulatory element of erythropoietin at very low dosage, which may be used as new source of natural hematopoietic agent. The present work also indicates that the FSC scheme is able to serve as an efficient and model-free approach to optimize the drug combination of different ingredients within a herbal decoction.

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Optimizing Combinations of Flavonoids Deriving from Astragali Radix in Activating the Regulatory Element of Erythropoietin by a Feedback System Control Scheme

Optimizing Combinations of Flavonoids Deriving from Astragali Radix in Activating the Regulatory Element of Erythropoietin by a Feedback System Control Scheme Hui Yu,1,2 Wendy L. Zhang,3 Xianting Ding,4 Ken Y. Z. Zheng,3 Chih-Ming Ho,5 Karl W. K. Tsim,3 and Yi-Kuen Lee2 1State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu, China 2Department of Mechanical Engineering, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 3Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong 4School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China 5Center for Cell Control, Mechanical and Aerospace Engineering Department, Biomedical Engineering Department, University of California, Los Angeles, CA 90095-1597, USA Received 4 February 2013; Accepted 22 March 2013 Academic Editor: Shao Li Copyright © 2013 Hui Yu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Identifying potent drug combination from a herbal mixture is usually quite challenging, due to a large number of possible trials. Using an engineering approach of the feedback system control (FSC) scheme, we identified the potential best combinations of four flavonoids, including formononetin, ononin, calycosin, and calycosin-7-O-β-D-glucoside deriving from Astragali Radix (AR; Huangqi), which provided the best biological action at minimal doses. Out of more than one thousand possible combinations, only tens of trials were required to optimize the flavonoid combinations that stimulated a maximal transcriptional activity of hypoxia response element (HRE), a critical regulator for erythropoietin (EPO) transcription, in cultured human embryonic kidney fibroblast (HEK293T). By using FSC scheme, 90% of the work and time can be saved, and the optimized flavonoid combinations increased the HRE mediated transcriptional activity by ~3-fold as compared with individual flavonoid, while the amount of flavonoids was reduced by ~10-fold. Our study suggests that the optimized combination of flavonoids may have strong effect in activating the regulatory element of erythropoietin at very low dosage, which may be used as new source of natural hematopoietic agent. The present work also indicates that the FSC scheme is able to serve as an efficient and model-free approach to optimize the drug combination of different ingredients within a herbal decoction. 1. Introduction Traditional Chinese medicine (TCM) has played an important role in primary health care in China of over thousands of years [1]. In contrast to isolated, bioactive, single natural products in Western medicine, TCM uses a mixture of active ingredients; this represents a holistic approach in disease prevention. TCM has attracted a lot of attention for serving as complementary health food supplements with low toxicity and fewer complications [2, 3]. Astragali Radix (AR; Huangqi), the dried root of Astragalus membranaceus (Fisch.) Bunge or A. membranaceus (Fisch.) Bunge var. mongholicus (Bunge) P. K. Hsiao, is one of the most widely used Chinese herbs as a health food supplement to reinforce “Qi” (vital energy) [4]. Pharmacological study has demonstrated that the water extract of AR possesses many biological functions, including hepatoprotective effects, neuroprotective effects against ischemic brain injury, hematopoietic, antioxidative, antihypertensive, immunological properties, cardiotonic, and antiaging activities [5, 6]. Previous study also showed that the AR extract could improve hematopoietic functions by regulating erythropoietin (EPO) expression. EPO is an erythrocyte-specific hematopoietic growth factor produced by kidney and liver [7]. Failure to increase the amount of circulating EPO under hypoxia stress can lead to anemia [8]. Hypoxia response element (HRE), a critical regulator for EPO transcription, is located on the promoter region of the EPO gene. Under hypoxia condition, the activated hypoxia-induced factor (HIF) binds onto HRE and subsequently initiates EPO gene expression [9]. The AR regulating EPO expression was through an induction of the transcriptional activity of HRE [10]. One of major components in AR was flavonoid, for example, formononetin, ononin, calycosin, and calycosin-7-O-β-D-glucoside. These four flavonoids can induce the expression of EPO [11]; however, the effect of a combination of these flavonoids has not been revealed. Indeed, the combined mixture is mimicking partly the scenario of a herbal mixture. A major problem in combinatorial therapies lies in the number of possible combinations [12, 13], which becomes more challenging in optimizing Chinese herbal mixtures. Besides, the combined effe (...truncated)


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Hui Yu, Wendy L. Zhang, Xianting Ding, Ken Y. Z. Zheng, Chih-Ming Ho, Karl W. K. Tsim, Yi-Kuen Lee. Optimizing Combinations of Flavonoids Deriving from Astragali Radix in Activating the Regulatory Element of Erythropoietin by a Feedback System Control Scheme, Evidence-Based Complementary and Alternative Medicine, 2013, 2013, DOI: 10.1155/2013/541436