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Table 3 Example predicted pathways from source to targets

From: A molecular systems approach to modelling human skin pigmentation: identifying underlying pathways and critical components

Biological process UV mediated melanogenesis [Tyrosinase activation]-paracrine effect
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].
  1. Validation refers to observations from literature that could possibly support the existence of such pathways.