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Grant Abstract: Artemisinin bioavailablity via an orally consumed dry leaf herbal therapeutic

Grant Number: 3R15AT008277-01S1
PI Name: Weathers
Project Title: Artemisinin bioavailablity via an orally consumed dry leaf herbal therapeutic

Abstract: Artemisia annua L. is a medicinal plant used in Traditional Chinese Medicine for >2000 years to treat a variety of conditions. Its main component, artemisinin (AN), is the foremost drug against malaria and also has antibacterial, anti-inflammatory, anticancer, and anthelminthic properties. AN and dried leaf A. annua (DLA) are currently marketed in the US as dietary supplements by both Swanson and Nutricology. A. annua also produces other phytochemicals including flavonoids, terpenes, and phenolic acids that along with AN have shown antioxidant and anti-inflammatory activity, so the plant has broad potential as a dietary supplement to counteract and protect against acute as well as chronic health conditions. Previously we and others showed that compared to pure AN, AN-delivered DLA orally is >40-fold more bioavailable and its solubility is ~ 7 times higher in intestinal digestates of DLA. AN and A. annua extracts also reduced pro-inflammatory cytokines IL-6 and IL-8 >70-fold compared to pure AN in an in vitro model, indicating the whole plant may prove useful as a dietary supplement inflammation antagonist. AN and phytochemicals in A. annua may protect against conditions occurring in a diversity of organs and tissues, so understanding absorption, distribution, metabolism, and excretion (ADME) of AN delivered orally as DLA vs. pure AN is important. Many conditions also cause inflammation, so the role of DLA in inflammation is of concern for its use as a supplement. We hypothesize that AN from DLA has higher solubility and bioavailability than pure AN, so AN from DLA should better accumulate in organs and tissues, persist longer in the blood and yield better downstream biological responses, i.e. inflammation reduction.
Using our high AN-producing A. annua cultivar (SAM) and artemisinin-null mutant (GLS) we will compare both ADME as well as inflammation reduction in rats, information useful for using A. annua as a dietary supplement. The project will engage both undergraduate and graduate students in the experiments. Aim 1: To compare DLA-delivered AN with pure AN to determine how improved bioavailability alters the ADME of AN. Using rats treated orally with either pure AN or DLA, we will harvest blood, major organs and tissues, and urine over 12 hr and analyze extracts for AN, the AN liver metabolite deoxyartemisinin (dAN), and total flavonoid content.
Aim 2: To compare anti-inflammatory efficacy of DLA-delivered AN vs. pure AN and dried leaves of our ANdeficient mutant, GLS. Rats with LPS-induced inflammation will be treated with pure AN, DLA or GLS and inflammatory cytokine levels measured in the serum over 8 hr. This will help measure a critical downstream biological response of enhanced bioavailable AN when the more complex plant material is present. This IACUC approved project will provide in vivo results to better understand the bioavailability of DLAdelivered AN and its efficacy as a dietary supplement for reducing systemic inflammation.

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