# A Review on Bioactive Compounds and Pharmacological Activities of _Citrus unshiu_
## 4 Pharmacological Activities of Satsuma Mandarin
### Skin-Protective Activity  
Bioactives from _C. unshiu_ shown skin-protective activities through a variety of mechanisms. In vitro experiment showed that fermented _C. unshiu_ peel extracts (hesperetin and naringenin) with the Schizophyllum commune QG143 strain significantly increased the biosynthesis of collagen in human dermal fibroblasts exposed to ultraviolet and decreased photoaging skin through a mechanism that involves the reduction of MMP-1 mRNA expression and \(\beta\)-galactosidase (SA-\(\beta\)-gal) levels [91]. Treatment with HMF extracted from _C. unshiu_ peel suppressed collagenase activity and increased type I procollagen synthesis in vitro via upregulation and/or downregulation of protein/gene expression in the ultraviolet-induced human dermal fibroblast neonatal cells [92]. An experiment was performed using human keratinocyte cells and the atopic dermatitis mouse model to investigate the effects of premature _C. unshiu_ ethanolic extracts on atopic dermatitis. _C. unshiu_ treatment led to a significant decrease in the mRNA/protein expression of inflammatory chemokines in TNF-\(\alpha\)- and IFN-\(\gamma\)-induced keratinocyte cells through suppression of signal transducer and activator of transcription 1 (STAT1) phosphorylation. In dinitrochlorobenzene (DNCB)-treated mice, _C. unshiu_ significantly reduced atopic dermatitis symptoms (e.g., redness, wrinkles) in the dorsal skin and the production of T-helper-type (Th1/Th2) cytokines [93]. An experiment on the anti-inflammatory effects of immature _C. unshiu_ ethanolic extracts on atopic dermatitis demonstrated that quercetin caused an inhibitory effect on the protein/mRNA expression of thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) produced in keratinocyte cells through the downregulation of the Janus kinase (JAK)/STAT signaling pathway [50]. Fermentation of _C. unshiu_ byproducts with nuruk (a starter inoculated with airborne microorganisms) for 15 days reduced oxidative stress induced by H2O2 in human keratinocyte cells [94]. The ethanolic extracts of fermented dried _C. unshiu_ using _Bacillus subtilis_ showed skin moisturizing efficacy in keratinocyte cells through stimulating the formation of hyaluronic acid and the expression of serine palmitoyltransferase (SPT) and filaggrin. The extracts also exerted anti-inflammatory activity in murine macrophages by decreasing the release of LPS-stimulated NO, iNOS, COX-2, TNF-\(\alpha\), IL-6, and prostaglandin 2 (PGE2) [95]. In experimental Swiss albino mice, the combination of _C. unshiu_ or hesperidin and prednisolone effectively suppressed ear swelling during the effector/induction phase of contact dermatitis induced by picryl chloride [96]. The ethanolic extracts of _C. unshiu_ showed a reduction in oxidative stress and an inhibition of tyrosinase enzyme responsible for melanin synthesis in melena cells, without inducing any toxic effect. Oral administration of _C. unshiu_ extracts to guinea pigs also demonstrated a reduction of ultraviolet-induced skin pigmentation [97]. Oral administration of _C. unshiu_ powder to ultraviolet B-irradiated hairless mice dorsal skin led to a significant increase in skin moisture content and a decrease in transepidermal water loss, basement membrane degradation, and epidermal hyperplasia [98]. Experimental studies that have evaluated the skin-protective activity of _C. unshiu_ bioactives are summarized in Table 5.  
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Model Type** & ** Bioactive Compounds** & **Extraction Techniques and Application in Treatment** & **Therapeutic** & **Target Genes/Signaling** & **Ref. ** \\ \hline \multirow{6}{*}{Human dermal fibroblasts fibroblasts} & & \multicolumn{3}{c}{Dermal fibroblasts were treated with the aqueous extracts of \(C\). \(\min\) weight at different concentrations} & \multicolumn{1}{c}{} & \\  & & (0.205-0.17\%, w/ \(\
u\)) for 2 th in the submerged culture of \(S\). \(S\). \(S\). \(S\). \(S\). \(S\). \(S\). \(S\). \(S\).