**3. Conclusions**

Alkaline extract of licorice roots showed greater anti‐HIV activity than the water extract, while the water extract, especially the flavonoid‐rich fraction, showed greater anti‐HSV activ‐ ity than the alkaline extract (**Table 1**), suggesting that water and alkaline extracts might show different site of actions against these two viruses.

It was unexpected that five polymethoxyflavonoids including tricin showed very low level of anti‐HSV activity (**Table 1**), since tricin has been reported to show a broad antiviral spectrum [17–20]. It remains to be investigated whether the combination of these compounds with acy‐ clovir [5] or ganciclovir [21] may increase viability of infected cells.

The present study also demonstrated that neoisoliquiritin apioside showed the highest anti‐ tumor activity. Isoliquiritin has been reported to inhibit granuloma angiogenesis and tube formation in vascular endothelial cells [22]. Further studies are required to elucidate the mechanism by which this compound induces such high tumor specificity.

We have recently reported that titanium dioxide nanoparticles (TiO2 NPs) were incorporated into vacuoles of HGF cells and aggravated the gingival inflammation (characterized by the enhanced prostaglandin E2 production and COX‐1 and COX‐2 protein expression, and the reduction of intracellular concentrations of amino acid, urea cycle, polyamine, *S*‐adenosylmethione and glutathione synthetic pathways) [23]. This finding recommends carful use of dental materials containing TiO2 NPs for patients with gingivitis or periodontitis. It remains to be investigated whether glycyrrhiza extracts or their fractions can neutralize the aggravation effects of TiO<sup>2</sup> NPs.

More than 80 reports have investigated the anti‐inflammatory effect of Kampo medicines (reviewed in Refs. [24] and [25]). However, basic research and clinical studies for the treat‐ ment of oral diseases are much less [26–30], and little is known about the relative potency of Kampo medicines. Potent antiviral, anti‐inflammatory, antitumor, and anti‐UV activities of licorice extracts, demonstrated here, suggest their possible applicability for treating several oral diseases and manufacturing cosmetic products.

QSAR analysis is a useful technique to predict the most active three‐dimensional structure. The next step is to synthesize the compound with predicted structure and then investigate the biological activity. This prediction‐synthesis‐confirmation cycle should be repeated until obtaining the expected biological activity (**Figure 8**). The applicability of such compounds on oral diseases should be tested.

**Figure 8.** Scheme of manufacturing new anti‐HSV agents from licorice extracts.
