| The dietary supplement market and number of supplement consumers has grown significantly since the passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA). Among dietary supplement products, herbals accounted for an estimated total retail value of {dollar}3.24 billion in the U.S. in 1996 (Johnston, 1997), a considerable portion of total supplement sales which were estimated at {dollar}15.7 billion in 2000 (Blendon et al., 2001). Although the industry and number of products has continued to grow, there is still a considerable lack of scientific evidence to clearly support efficacy, and in some cases, safety of these products. Thus, examination of efficacy and safety of specific dietary supplement products is necessary.; The hypothesis of this dissertation is that the anti-inflammatory properties of the herbal constituents apigenin (chamomile), ginsenoside Rb1 (ginseng), and, particularly, parthenolide (feverfew), are mediated in part by inhibition of proinflammatory cytokines.; The specific objectives of these studies were to (1) evaluate the potential anti-inflammatory properties of the three herbal constituents, apigenin, ginsenoside Rb1 and parthenolide on lipopolysaccaharide (LPS)-induced proinflammatory cytokine protein production (interleukin [IL]-6 and tumor necrosis factor [TNF]-α), and relate these effects to the intact animal model; (2) determine the effect of route, dose and dose-timing of parthenolide administration on inhibition of LPS-induced serum IL-6 and TNF-α production in vivo; and (3) assess the relationship between serum cytokine protein production and proinflammatory cytokine gene expression in the spleen and liver of parthenolide co-treated mice.; Apigenin, ginsenoside Rb1 and parthenolide inhibited LPS-induced IL-6 and/or TNF-α production in cell culture. Although cytokine inhibition was observed in mice sera, the pattern of inhibition differed from cell culture data suggesting the cell culture model employed could only be used to approximate potential in vivo effects, and must be confirmed using appropriately designed animal models. Based on evaluation of route, dose and dose-timing of parthenolide administration on inhibition of LPS-induced IL-6 and TNF-α, intraperitoneal injection of 5 mg/kg parthenolide as a co-treatment with LPS was determined. Protein and mRNA comparison studies revealed that changes in serum IL-6 and TNF-α correlated with mRNA expression in spleen, but not liver. mRNA levels of IL-6 were reduced, TNF-α and COX-2 unchanged, and IL-1β mRNA increased in spleen of parthenolide plus LPS co-treated animals compared to LPS-treated only. No significant effects were observed in liver. The overall expression of each gene was significantly higher in spleen when compared to liver.; Taken together, these studies contribute to the understanding of the anti-inflammatory properties, and potential mechanisms of inhibition, of the herbal constituents apigenin, ginsenoside Rb1 and, more specifically, parthenolide on inflammatory mediators. The methods and results of these studies can be used to further elucidate parthenolide's, and other herbal constituents' and extracts', molecular mechanism for inhibitory effects on inflammation, and potential as human therapeutics in the treatment of inflammatory conditions. |
