# Impacts of Diverse Natural Products on Honey Bee Viral Loads and Health
## 4 Discussion
Hymenoptera only showed altered expression in treatment with one natural product, hesperidin, with significantly lower levels in treatment vs. the control (\(p=0.0475\)). Cinnamic acid is the first molecule in the phenylpropanol pathway and is the source of most hydroxycinnamic acid derivatives such as coumaric, caffeic, ferulic, and sinapic acids normally present in plant material in either ester or glycosidic forms [61]. Cinnamic acid is well known for its antioxidant, antitumor, antimicrobial, and antimycobacterial properties [62]. Cinnamic acid and hesperidin both also lowered hypenoptera levels (\(p=0.0392\) and \(p=0.0475\), respectively), whereas apidaecin and vitellogenin showed no significant changes with the natural products tested here. Together with the effect on viruses, pathogenic agents, or beneficial microbes, we can see that NPs have a range of effects on honey bee physiology, and further research on the mechanisms behind such effects could be of great value to further understand the many potential uses of these potent compounds. Whereas some extracts show potential promise in their use as prophylaxis or treatment of disease, our success rate in finding compounds with significant impacts was low. It is also important to note that some compounds were eliminated from further study, as initial tests showed toxicity (i.e., decanoic acid and berberine) to honey bees (all life stages must be  
\begin{table}
\begin{tabular}{c c c} \hline \hline  
considered), highlighting the importance of standardized and thorough testing of products. One way to overcome adverse effects is via delivery methods. For example, miticide oxalic acid is vaporized as a means of colony treatment, rather than being introduced via feeding bees. Moreover, chemical modifications of NP structures using computer-based docking simulations may also increase their potency or selectivity [18]. Nevertheless, we feel it is important to first assess the dosing, uptake by bees in sugar water, acute toxicity (or related sublethal effects) and effects on the honey bee gut microbiome, proteomics, and metabolomics. For promising candidates, it will be important to next assess impacts at the colony and apiary levels, measuring both disease loads and, ultimately, colony growth and survival. On the market today are numerous honey bee nutritional supplements for which a natural product is the purported active ingredient. None of these are approved as drugs by the U.S. Food and Drug Administration. To be approved as a drug, the chemical must (1) be safe and (2) effective in honey bees; (3) have an acceptable environmental impact; (4) be manufactured with good practices; and (5) be safe for people to consume a small amount in honey. Few chemicals satisfy all five of these criteria and it can take years and millions of dollars to demonstrate the safety and efficacy of a successful candidate. One promise of natural products, as compared to synthetic chemicals, is a richer, more complex, and more diverse space of structure. Moreover, the acceptable daily intake, toxicity, manufacturability, and environmental impact of many natural products are already known. This prior information may substantially reduce the time and cost of conducting regulatory studies. One source of potential natural product drugs is the U.S. Food and Drug Administration (FDA) catalog of over 450 compounds, plant extracts, and classes of plant-based molecules, which it considers \"generally regarded as safe\" (GRAS) for human consumption [63] when consumed at a reasonable level. A compound derived from this list that is safe and effective in honey bees could be more likely to receive regulatory approval. Low-cost regulatory approval would benefit beekeepers with a product retail price that does not need to subsidize millions of dollars of regulatory studies. This consideration is especially important for honey bees because hive products make their way into the lives of humans as wax and royal jelly in cosmetics, pollen and honey as food, and bee venom in apitherapy.