# Soriasis: From Pathogenesis to Pharmacological and Nano-Technological-Based Therapeutics
## 3 Current Marketed Therapies
However, this is still controversial [53; 54]. The mechanism of vitamin D is mediated by the vitamin D receptor (VDR),  
Figure 3: The physiological pathway of vitamin D synthesis and activation. (**A**) Ultraviolet radiation promotes the conversion of 7-dehydrocholesterol to pre–vitamin D\({}_{3}\), which isomerizes to vitamin D\({}_{3}\) (also called chocalciferol) in the skin, due to sun heat. Diet supplements directly provide Vitamin D\({}_{3}\), also called ergocalciferol. In the liver, a 25-hydroxylation by CYP2R1 is carried out, thus leading to the formation of 25-hydroxyvitamin D\({}_{3}\). In the kidney, CYP27B1 further hydroxylates 25-hydroxyvitamin D\({}_{3}\) at the 1-\(\alpha\) position, resulting in the formation of the active hormone 1\(\alpha\),25-dihydroxyvitamin D\({}_{3}\). The active form of vitamin D then enters into the cell via diffusion or endocytic receptor for transcription. Inside the cell, vitamin D binds to both vitamin D receptors at the nucleus and cell membrane. In the nucleus, both active forms of vitamin D and its receptor form a regulatory complex that finally leads to the beginning of the transcription process. In the cell membrane, binding to vitamin D receptors lead to several intracellular signal transductions. (**B**) An alternative pathway has been described. In this case, 25-hydroxyvitamin D\({}_{3}\) and 1\(\alpha\),25-dihydroxyvitamin D\({}_{3}\) metabolites are hydroxylated by other two cytochromes: on the one hand, a dominant gain-of-function mutation in CYP3A4, mainly located in the liver, leads to acceleration in vitamin D inactivation; on the other hand, hydroxylation by CYP24A1, mainly located in the mitochondria, gives rise to the formation of an active metabolite, 24R,25(OH)\({}_{2}\)D\({}_{3}\). This molecule has been described to bind to FAM57B2 in fractured bones. This leads to the production of lactosylceramide (LacCer), which is essential for the callus formation and fracture healing. and after its activation, it interacts with retinoid X receptor (RXR) to form a heterodimeric complex. The VDR-RXR complex is recruited to the vitamin D response elements (VDREs) in the promoter of target genes to regulate their expression. This process is described as the genomic action of vitamin D in contrast to the nongenomic action, which is the direct effect that vitamin D has on the previously mentioned signalling pathways [38]. Allelic variations in individual VDR genes may determine a different response to treatment: the isoform A of VDR is associated with a greater therapeutic response in psoriatic patients [43]. In this sense, VDR ligands inhibit the expression of pro-inflammatory cytokines produced by T lymphocytes, which are responsible for the exacerbation of the skin inflammation. Apart from that, 1\(\alpha\),25(OH)2D3 enhances expression of IL-10 within the psoriatic lesions. Moreover, biological activity of vitamin D3 analogues leads to suppression of the T cell-mediated immune response [41]. In addition, there is evidence that one active form of vitamin D3 synthetized by CYP11A1, 20(OH)D3, has anti-proliferative, pro-differentiation, and anti-inflammatory effects on cultured skin cells, comparable to or better than those of 25 OHD. Thus, it has been proposed as a new candidate for primary or adjuvant therapy of hyperproliferative or inflammatory disorders, such as psoriasis [55]. As it has been mentioned, apart from the classical activation route for vitamin D, alternative routes have been described, such as the CYP11A1 route, which leads to hydroxy metabolites. The traditional role of CYP11A1 was associated to initial steroid synthesis, solely in steroidogenic organs using cholesterol as the substrate [55]. This involved hydroxylations at C22 and C20, followed by oxidative cleavage of the bond between C20 and C22 to produce pregnolone, a precursor to all steroids [55]. However, it has now been documented that alternative substrates from cholesterol have been identified, such as 7 DHC, vitamins D2 and D3, ergosterol, and lumisterol [56].