Table 3 Example predicted pathways from source to targets

Predicted pathway

UV- > Singlet_oxygen_kerat- > Ceramide_kerat- > PLA2_kerat- > Arachidonic_Acid_kerat- > PGE2_kerat- > PTGER3_melan- > PLC_melan- > DAG_melan- > PRKCB_melan- > TYR_melan- > Eumelanin_melan/ Pheomelanin_melan

Validation

PGE2 acts as a ligand for PTGER3 receptor. COX2 is the enzyme involved in the conversion of arachidonic acid to PGE2. UV induced COX2 and increased PGE2 production in keratinocytes [42-45].

Predicted pathway

UV- > Singlet_oxygen_kerat- > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > PTGS2_kerat

Validation

Antioxidants like Astaxanthin are shown to inhibit UV induced PGE2 production possibly by down regulating COX2 expression [46].

Biological process

UV mediated melanogenesis [Tyrosinase expression]-paracrine effect

Predicted pathway

UV- > Singlet_oxygen_kerat- > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > KITLG_kerat - > KIT_melan- > PIK3CA_melan- > PDPK1_melan- > AKT1_melan- > CREB1_melan- > MITF_melan- > TYR_melan- > Eumelanin_melan/ Pheomelanin_melan

Validation

KIT mediated regulation of MITF activity is shown to involve PI3K/AKT signaling [47].

Predicted pathway

UVA- > Singlet_oxygen_kerat- > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > NOS2_kerat- > Nitric_oxide_kerat- > GUCY1A2_melan- > cGMP_melan- > PRKG1_melan- > CREB1_melan- > MITF_melan- > TYR_melan- > melanogenesis

Validation

C-phycocyanin, a phycobiliprotein from spirulina that has antioxidant function inhibits melanogenesis by decreasing activity of CREB and suppressing tyrosinase expression [48]. Compound, MHY498 inhibited sodium nitroprusside (SNP, a NO donor)-induced NO generation, and suppressed tyrosinase expression, MITF stimulation and melanin synthesis through cGMP-mediated signaling pathway in B16F10 melanoma cells [49].

Biological process

UV mediated alpha MSH production

Predicted pathway

UVA- > Lipid_Peroxidation_kerat- > 4HNE_kerat- > DNA_Damage_kerat- > TP53_kerat- > alpha_MSH_kerat

Validation

UV releases singlet oxygen upon lipid peroxidation [50]. N-acetylcysteine with antioxidant properties can suppress alphaMSH and ACTH production in response to UV [51]. AlphaMSH is synthesised in keratinocytes in a p53 dependent manner [52].

Biological process

UV mediated melanocyte dendrite formation-paracrine effect

Predicted pathway

UV- > Singlet_oxygen_kerat- > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > KITLG_kerat- > KIT_melan- > PIK3CA_melan- > RAC1_melan- > RAC1:PARD6A:CDC42_melan- > PRKCZ_melan- > Dendrite_formation_melan

Validation

UVB exposure increased tree branch-like dendrites and activated Rac1 in a time-dependent manner in B16 melanoma cells [53]. Transiently expressed Rac1 activated mutants induces the formation of dendrite-like structures in human melanoma cell lines [34].

Biological process

UV mediated NFKB1 activation and secretion of paracrine factors

Predicted pathway

UV- > Singlet_oxygen_kerat- > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > EDN1_kerat

Predicted pathway

UV- > Singlet_oxygen_kerat- > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > CSF2_kerat

Predicted pathway

UV- > Singlet_oxygen_kerat- > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > KITLG_kerat

Validation

UV is known activate NFkappaB in keratinocytes [54,55].

Biological process

UV mediated melanocyte proliferation-paracrine effect

Predicted pathway

UVA- > Singlet_oxygen_kerat- > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > CSF2_kerat- > CSF2RA_melan- > CSF2RA:JAK1_melan- > STAT3_melan- > CCND1_melan- > CDK4:CCND1_melan- > Cell_proliferation_melan

Validation

Korean Red Ginseng extract or its saponin (KRGE or SKRG) decreased the expression of CSF2 in keratinocytes induced by UVB irradiation and also decreased proliferation of melanocytes [56].

Biological process

UV induced melanosome phagocytosis

Predicted pathway

UVA- > Singlet_oxygen_kerat- > Ceramide_kerat- > PRKCZ_kerat- > NFKB1_kerat- > F2RL1_kerat- > RHOA_kerat- > Melanosome_phagocytosis_kerat

Validation

In a co-culture system model constructed using the primary human melanocytes and keratinocytes, increased melanosome transfer and also upregulation of F2RL1 protein in the keratinocytes is observed when treated with low concentrations of H(2)O(2) [57]. Madecassoside (MA), a pentacyclic triterpene significantly inhibited UVR-induced melanin synthesis and melanosome transfer in a co culture system of keratinocytes and melanocytes and also inhibited F2RL1 expression in keratinocytes [58].