## 5 Biological Activities of Zerumbone (ZER)
### Other Pharmacological Activities  
Various other pharmacological activities are also reported for ZER such as immunomodulatory activity, neuroprotective effect, antinociceptive, anti-platelet and anti-melanogenic activities (Table 4). Different studies reported the immunomodulatory properties of ZER. [PERSON] et al. revealed ZER activates mice thymocytes, splenocytes and peripheral blood mononuclear cells (PBMC) at dose dependent pattern [153]. A similar study assessed a commercially obtained ZER on human peripheral blood, where it showed that ZER activates human lymphocytes and upregulates interleukin-12p70 cytokine [154]. For neuroprotective effect of ZER, [PERSON] et al. reported that ZER oxide protects NG108-15 cells from H\({}_{2}\)O\({}_{2}\) induced oxidative stress [155]. Apart from that, ZER has a gastoprotective effect, where ZER reduces submucosal edema and leukocyte infiltration. On the other hand, a recent in vivo study reported the antinociceptive activity of ZER on mouse, where ZER suppresses inflammatory mediators without any signs of sedation [156]. An in vivo assessment reported the anti-platelet action of ZER investigated from human blood [157]. For the anti-melanogenic activity, a recent study reported that ZER attenuates melanin accumulation in \(\alpha\)-melanoma cells [158].  
\begin{table}
\begin{tabular}{p{113.8 pt} p{113.8 pt} p{113.8 pt}} \hline \hline
**In Vitro/In Vivo** & **Model Cells/Animals** & **Activity** & **References** \\ \hline \multicolumn{3}{p{113.8 pt}}{**Hepatoprotective activity**} \\ \hline \hline \multirow{3}{*}{In vitro} & C57 BL/6 mice & In a chronic liver injury model induced by CCl\({}_{4}\), ZER treatment alleviated the hepatocellular toxicity and inhibited activation of primary hepatic stellate cells. & [159] \\  & & ZER restored the activities of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. It also reduces the release of pro-inflammatory cytokines such as IL-6 and TNF-\(\alpha\), and inactivated the TLR4/NF-\(\kappa\)/B/COX-2 pathway in acute liver injury induced by CCl\({}_{4}\) in mice. & [160] \\ \cline{1-1} \cline{3-3}  & Rats & ZER possessed protective activity against paracetamol-induced acute hepatotoxicity. & [161] \\ \hline \hline \multicolumn{3}{p{113.8 pt}}{**Immunosuppressive and Immunomodulatory activities**} \\ \hline \hline \multirow{3}{*}{In vivo} & Male wistar rats & ZER inhibited the migration of neutrophils, expressions of CD11b/CD18 integrin, phagocytic activity, and production of reactive oxygen species & [162] \\ \cline{1-1} \cline{3-3}  & CD18 integrin expression and phagocytic engulfment & ZER showed strong inhibition on the phagocytosis of neutrophils\(\_\)Z & [163] \\ \cline{1-1} \cline{3-3}  & & ZER reduced ovalbumin (OVA)-specific immunoglobulin E (IgGE) and induced IgG2a antibody production. It also reduced the production of eotaxin, keratinocyte-derived chemokine (KC), IL-4, IL-5, IL-10, and IL-13, and promoted Th1 cytokine interferon (IFN)-\(\gamma\) production. & [164] \\ \cline{1-1} \cline{3-3}  & Zymogen and PMA based chemiluminescence assay & ZER significantly inhibited intracellular and extracellular reactive oxygen species (ROS) production. & [165] \\ \hline \hline \end{tabular}
\end{table}
Table 4: Other pharmacological activities of ZER.  
Although zerumbone shows promising biological activities, its low water solubility and poor bioavailability are the limiting factors for wider applications of various formulations containing zerumbone. Few studies have been reported aimed at improving the solubility and bioavailability of zerumbone such as formulation inclusion complexes with cyclodextrin [8; 175], nanostructured lipid careers [9], etc.