Lack of molecular evidence for targets diminishes the scientific validity of the claimed usefulness of TCM, despite the availability of empiric clinical experience. However, while about 100,000 herbal formulae have been recorded and there are many empiric examples of successful clinical use of TCM, relationship of the essential phytochemical components in each of the formulae to molecular targets/pathway has not been identified for most TCM due to lack of suitable methodology to tackle the complex mechanisms. Theoretically, multiple active phytochemical components in the TCM formulae may simultaneously target multiple molecules/pathways and thus potentially achieve superior effect as compared to single compounds alone. Traditional Chinese herbal medicines often consist of a combination of individual herbs to form specific formulae aimed to increase therapeutic efficacy and reduce adverse effects. In contrast to target-oriented Western medicine, TCM uses a holistic and synergistic approach to restore the balance of Yin- Yang of body energy so the body's normal function, or homeostasis, can be restored. Traditional Chinese medicines (TCMs) have been used in China and other Asian countries for over 5,000 years for the prevention and treatment of a variety of diseases. This study identified SWT as an Nrf2 activator and phytoestrogen, suggesting its use as a nontoxic chemopreventive agent, and demonstrated the feasibility of combining microarray gene expression profiling with CMAP mining to discover mechanisms of actions and to identify new health benefits of TCMs. The CMAP profiles of chemopreventive agents withaferin A and resveratrol also showed high similarity to the profiles of SWT. The CMAP profiles of estradiol-treated MCF-7 cells showed an excellent match with SWT treatment, consistent with SWT's widely claimed use for women's diseases and indicating a phytoestrogenic effect. Furthermore, the gene expression profile of differentially expressed genes related to SWT treatment was used to compare with those of 1,309 compounds in the CMAP database. Consistently, treatment with SWT and its four herbal ingredients resulted in an increased antioxidant response element (ARE)-luciferase reporter activity in MCF-7 and HEK293 cells. The Nrf2-regulated genes HMOX1, GCLC, GCLM, SLC7A11 and NQO1 were upreguated by SWT in a dose-dependent manner, which was validated by real-time RT-PCR. Pathway analysis using differentially expressed genes related to the treatment effect identified that expression of genes in the nuclear factor erythroid 2-related factor 2 (Nrf2) cytoprotective pathway was most significantly affected by SWT, but not by estradiol or ferulic acid. The human breast cancer MCF-7 cells treated with 0.1 µM estradiol or 2.56 mg/ml of SWT showed dramatic gene expression changes, while no significant change was detected for ferulic acid, a known bioactive compound of SWT. We demonstrated that this approach can be used to elucidate new molecular targets using a model TCM herbal formula Si-Wu-Tang (SWT) which is widely used for women's health. To pursue a systematic approach to discovery of mechanisms of action of traditional Chinese medicine (TCM), we used microarrays, bioinformatics and the “Connectivity Map” (CMAP) to examine TCM-induced changes in gene expression.
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