## 5 Discussion
### What Are the Modulatory Targets of Plant Extracts and Phytochemicals?  
As summarized in Figure 2, various plant extracts and phytochemicals activate MITF, alleviate oxidative stress, or block stress hormone-induced response in melanocytes.  
Figure 2: Effects of plant extracts and phytochemicals on the MITF-melanogenic pathways (**A**), ROS-mediated oxidative stress (**B**), and the stress hormone-mediated response (**C**) in melanocytic cells and animal models. Extracts and phytochemicals derived from the same plant are indicated with the same color boxes. The stimulatory and suppressive effects are indicated by blue sharp arrows and red blunt arrows, respectively. Abbreviations; CAT, catalase; CREB, cyclic AMP response element-binding protein; EA, _Eriodictyon angustifolium_; ERK, extracellular signal-regulated kinase; GCLM, glutamate-cysteine ligase’s modifier subunit; GP, _Gynostemma pentaphyllum_; GPX1, glutathione peroxidase 1; HO1, heme oxygenase 1; JNK, c-jun N-terminal kinase; KEAP1, kelch-like ECH-associated protein 1; MAPK, mitogen-activated protein kinase; MITF, microphthalmia-associated transcription factor; NOO1, NAD(P)H quinone oxidoreductase 1; NRF2, nuclear factor erythroid 2-related factor 2; OGG1, 8-oxogenanine DNA glycosylase; PKA, protein kinase A; PM, _Polygonum multiflorum_; PMEL, premelanosome protein; POMC, pro-opiomelanocortin; PUVA, psoralen plus UVA; ROS, reactive oxygen species; SODI, superoxide dismutase 1; TRXR1, thioredoxin reductase 1; TSG, 2,3,5,4\({}^{\prime}\)-tetrahydrooxystilbene-2-O-\(\beta\)-D-glucose; TYR, tyrosinase; TXRP1, tyrosinase-related protein 1; TYRP2, tyrosinase-related protein 1; \(\beta\)2 AR, \(\beta\)2 adrenergic receptor.  
MITF and target genes impacted by H\({}_{2}\)O\({}_{2}\)[143; 144; 145]. EA extract and sterubin activated the \(\beta\)-catenin-dependent WNT signaling pathway and increased the expression of MITF and target genes impacted by X-ray irradiation [151; 152]. Adzuki bean extract activated PKA and increased the expression of MITF and target genes [155]. The extract of Fuzhuan brick tea stimulated the phosphorylation of p38 MAPK, JNK, and ERK, which was associated with an increased expression of MITF and target genes [156].  
The extracts of PM and its component (emodin), the extract of EA and its components (hydroxygenkwaninm, sterubin, and luteolin), the extract of Fuzhuan brick tea, and a carotenoid compound, bixin, all could alleviate oxidative stress in cells. The PM extract and emodin reduced the H\({}_{2}\)O\({}_{2}\)-induced cellular ROS levels [141; 145]. The EA extract and its components, such as hydroxygenkwanin, sterubin, and luteolin, reduced the intracellular ROS level, oxidative DNA damage, and mitochondrial damage induced by X-ray irradiation [150; 151; 153]. The extract of Fuzhuan brick tea and bixin activated NRF2 and alleviated oxidative stress triggered by hydroquinone treatment or PUVA phototherapy [156; 158].  
Moreover, the extract of GP leaves and an alkaloid compound, rhythmophiline, blocked the stress hormone-induced response in cells. They inhibited the action of norepinephrine or resiniferatoxin and restored the melanogenesis pathway [157; 159].