The presence of functional opioid receptors on epidermal keratinocytes, with attendant regulation of keratinocyte proliferation and differentiation, indicates their novel role in maintaining ...epidermal homeostasis. Expression of proenkephalin precursors and neuropeptide products in the same compartment opens an opportunity for studying the role of this endogenous opioid circuitry, with its regulators, in modulating epidermal barrier function.
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•CYP11A1 can metabolize cholesterol, 7-dehydrocholesterol and vitamin D.•CYP11A1 can metabolize plant sterols, ergosterol and derivatives of cholesterol.•CYP11A1 can metabolize ...hydroxy-derivatives of 7-dehydrocholesterol.•Novel CYP11A1-derived metabolites display biological activity in vitro.•CYP11A1 might metabolize precursors to cholesterol and other secosteroids.
CYP11A1, found only in vertebrates, catalyzes the first step of steroidogenesis where cholesterol is converted to pregnenolone. The purified enzyme, also converts desmosterol and plant sterols including campesterol and β-sitosterol, to pregnenolone. Studies, initially with purified enzyme, reveal that 7-dehydrocholesterol (7DHC), ergosterol, lumisterol 3, and vitamins D3 and D2 also serve as substrates for CYP11A1, with 7DHC being better and vitamins D3 and D2 being poorer substrates than cholesterol. Adrenal glands, placenta, and epidermal keratinocytes can also carry out these conversions and 7-dehydropregnenolone has been detected in the epidermis, adrenal glands, and serum, and 20-hydroxyvitamin D3 was detected in human serum and the epidermis. Thus, this metabolism does appear to occur in vivo, although its quantitative importance and physiological role remain to be established. CYP11A1 action on 7DHC in vivo is further supported by detection of Δ7steroids in Smith-Lemli-Opitz syndrome patients. The activity of CYP11A1 is affected by the structure of the substrate with sterols having steroidal or Δ7-steroidal structures undergoing side chain cleavage following hydroxylations at C22 and C20. In contrast, metabolism of vitamin D involves sequential hydroxylations that start at C20 but do not lead to cleavage. Molecular modeling using the crystal structure of CYP11A1 predicts that other intermediates of cholesterol synthesis could also serve as substrates for CYP11A1. Finally, CYP11A1-derived secosteroidal hydroxy-derivatives and Δ7steroids are biologically active when administered in vitro in a manner dependent on the structure of the compound and the lineage of the target cells, suggesting physiological roles for these metabolites.
This article is part of a special issue entitled ‘SI: Steroid/Sterol signaling’.
Summary Because melanogenesis can affect immune responses to and chemotherapy and radiotherapy for melanoma, we analyzed overall survival and disease-free survival times in melanoma patients in ...relation to the degree of tumor pigmentation. Clinicopathologic data were obtained from the Oncology Centre, Prof Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland. The overall survival and disease-free survival analyses were performed using the log-rank test, whereas differences between mean/median overall survival and disease-free survival (days) were analyzed using the Student t test. In patients with metastatic disease, those with melanotic melanomas exhibited significantly shorter disease-free survival and overall survival than those with amelanotic lesions. Similarly, melanin-producing lymph node metastases were linked to shorter overall survival and disease-free survival, which was confirmed by a significantly longer mean/median disease-free survival for amelanotic versus melanotic metastases. Melanogenesis shortens overall survival and disease-free survival in patients with metastatic melanoma. Inhibition of melanogenesis appears a rational adjuvant approach to the therapy of metastatic melanoma.
We have previously described new pathways of vitamin D3 activation by CYP11A1 to produce a variety of metabolites including 20(OH)D3 and 20,23(OH)
2
D3. These can be further hydroxylated by CYP27B1 ...to produce their C1α-hydroxyderivatives. CYP11A1 similarly initiates the metabolism of lumisterol (L3) through sequential hydroxylation of the side chain to produce 20(OH)L3, 22(OH)L3, 20,22(OH)
2
L3 and 24(OH)L3. CYP11A1 also acts on 7-dehydrocholesterol (7DHC) producing 22(OH)7DHC, 20,22(OH)
2
7DHC and 7-dehydropregnenolone (7DHP) which can be converted to the D3 and L3 configurations following exposure to UVB. These CYP11A1-derived compounds are produced in vivo and are biologically active displaying anti-proliferative, anti-inflammatory, anti-cancer and pro-differentiation properties. Since the protective role of the classical form of vitamin D3 (1,25(OH)
2
D3) against UVB-induced damage is recognized, we recently tested whether novel CYP11A1-derived D3- and L3-hydroxyderivatives protect against UVB-induced damage in epidermal human keratinocytes and melanocytes. We found that along with 1,25(OH)
2
D3, CYP11A1-derived D3-hydroxyderivatives and L3 and its hydroxyderivatives exert photoprotective effects. These included induction of intracellular free radical scavenging and attenuation and repair of DNA damage. The protection of human keratinocytes against DNA damage included the activation of the NRF2-regulated antioxidant response, p53-phosphorylation and its translocation to the nucleus, and DNA repair induction. These data indicate that novel derivatives of vitamin D3 and lumisterol are promising photoprotective agents. However, detailed mechanisms of action, and the involvement of specific nuclear receptors, other vitamin D binding proteins or mitochondria, remain to be established.
Vitamin D3 is the precursor of the steroid hormone calcitriol (1α,25-dihydroxyvitamin D3), a potent agonist of the transcription factor vitamin D receptor (VDR). Calcitriol has received large ...appreciation due to the impact not only on mineral homeostasis, but also on metabolic diseases, immunological disorders, and cancer. A supraphysiological dose of calcitriol is required to reduce the proliferation of cancer cells. However, the dose will lead to calcemic side effects such as hypercalcemia and hypercalciuria. Although several analogs of 1α,25(OH)2D3 have shown potent anticancer or anti-inflammatory activity on cell cultures or in animal models, few vitamin D analogs have been successfully applied in the treatment of cancer or inflammatory diseases. This review will present and discuss vitamin D analogs that have the potential to be used as anticancer or anti-inflammatory agents.
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•Anticancer and anti-inflammatory mechanism of calcitriol through vitamin D receptor.•Vitamin D analogs in clinical trials and preclinical studies.•Crystal structures and binding interactions of VDR with different vitamin D analogs.
The skin, including the hypodermis, is the largest body organ and is in constant contact with the environment. Neurogenic inflammation is the result of the activity of nerve endings and mediators ...(neuropeptides secreted by nerve endings in the development of the inflammatory reaction in the skin), as well as interactions with other cells such as keratinocytes, Langerhans cells, endothelial cells and mast cells. The activation of TRPV-ion channels results in an increase in calcitonin gene-related peptide (CGRP) and substance P, induces the release of other pro-inflammatory mediators and contributes to the maintenance of cutaneous neurogenic inflammation (CNI) in diseases such as psoriasis, atopic dermatitis, prurigo and rosacea. Immune cells present in the skin (mononuclear cells, dendritic cells and mast cells) also express TRPV1, and their activation directly affects their function. The activation of TRPV1 channels mediates communication between sensory nerve endings and skin immune cells, increasing the release of inflammatory mediators (cytokines and neuropeptides). Understanding the molecular mechanisms underlying the generation, activation and modulation of neuropeptide and neurotransmitter receptors in cutaneous cells can aid in the development of effective treatments for inflammatory skin disorders.
Hydroxyderivatives of vitamin D3, including classical 1,25(OH)
D3 and novel CYP11A1‑derived hydroxyderivatives, exert their biological activity by acting as agonists on the vitamin D receptor (VDR) ...and inverse agonists on retinoid‑related orphan receptors (ROR)α and γ. The anticancer activities of CYP11A1‑derived hydroxyderivatives were tested using cell biology, tumor biology and molecular biology methods in human A431 and SCC13 squamous (SCC)‑ and murine ASZ001 basal (BCC)‑cell carcinomas, in comparison with classical 1,25(OH)
D3. Vitamin D3‑hydroxyderivatives with or without a C1α(OH) inhibited cell proliferation in a dose‑dependent manner. While all the compounds tested had similar effects on spheroid formation by A431 and SCC13 cells, those with a C1α(OH) group were more potent in inhibiting colony and spheroid formation in the BCC line. Potent anti‑tumorigenic activity against the BCC line was exerted by 1,25(OH)
D3, 1,20(OH)
D3, 1,20,23(OH)
D3, 1,20,24(OH)
D3, 1,20,25(OH)
D3 and 1,20,26(OH)
D3, with smaller effects seen for 25(OH)D3, 20(OH)D3 and 20,23(OH)
D3. 1,25(OH)
D3, 1,20(OH)
D3 and 20(OH)D3 inhibited the expression of GLI1 and β‑catenin in ASZ001 cells. In A431 cells, these compounds also decreased the expression of GLI1 and stimulated involucrin expression. VDR, RORγ, RORα and CYP27B1 were detected in A431, SCC13 and ASZ001 lines, however, with different expression patterns. Immunohistochemistry performed on human skin with SCC and BCC showed nuclear expression of all three of these receptors, as well as megalin (transmembrane receptor for vitamin D‑binding protein), the level of which was dependent on the type of cancer and antigen tested in comparison with normal epidermis. Classical and CYP11A1‑derived vitamin D3‑derivatives exhibited anticancer‑activities on skin cancer cell lines and inhibited GLI1 and β‑catenin signaling in a manner that was dependent on the position of hydroxyl groups. The observed expression of VDR, RORγ, RORα and megalin in human SCC and BCC suggested that they might provide targets for endogenously produced or exogenously applied vitamin D hydroxyderivatives and provide excellent candidates for anti‑cancer therapy.
Vitamin D is a natural photoproduct that has many beneficial effects on different organs, including skin. Active forms of vitamin D and its derivatives exert biological effects on skin cells, thus ...maintaining skin homeostasis. In keratinocytes, they inhibit proliferation and stimulate differentiation, have anti-inflammatory properties, act as antioxidants, inhibit DNA damage and stimulate DNA repair after ultraviolet (UV) exposure. In melanocytes, they also inhibit cell proliferation, inhibit apoptosis and act as antioxidants. In fibroblasts, they inhibit cell proliferation, affect fibrotic processes and collagen production, and promote wound healing and regeneration. On the other hand, skin cells have the ability to activate vitamin D directly. These activities, along with the projected topical application of vitamin D derivatives, are promising for skin care and photo protection and can be used in the prevention or possible reversal of skin aging.
Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH)(2)D3, as well as 1-hydroxyvitamin D3 to 1alpha,20-dihydroxyvitamin D3 (1,20(OH)(2)D3). It also cleaves the ...side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL).
To define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1alpha,25-dihydroxyvitamin D3 (1,25(OH)(2)D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH)(2)D3 being either equipotent or slightly less potent than 1,25(OH)(2)D3, while 1,20(OH)(2)D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH)(2)D3 was the most potent, 20(OH)D3, 20,23(OH)(2)D3 and 1,20(OH)(2)D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 microg/kg, whereas, 1,20(OH)(2)D3 was slightly to moderately calcemic and 1,25(OH)(2)D3 had strong calcemic activity.
We identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.
UVB radiation mediates inflammatory responses causing skin damage and defects in epidermal differentiation. 1α,25-Dihydroxyvitamin D
(1,25(OH)
D
) interacts with the vitamin D
receptor (VDR) to ...regulate inflammatory responses. Additionally, 1,25(OH)
D
/VDR signaling represents a potential therapeutic target in the treatment of skin disorders associated with inflammation and poor differentiation of keratinocytes. Since the protective effect of 1,25(OH)
D
against UVB-induced skin damage and inflammation is recognized, CYP11A1-derived vitamin D
-hydroxyderivatives including 20(OH)D
, 1,20(OH)
D
, 20,23(OH)
D
and 1,20,23(OH)
D
were tested for their anti-inflammatory and skin protection properties in UVB-irradiated human epidermal keratinocytes (HEKn). HEKn were treated with secosteroids for 24 h pre- and post-UVB (50 mJ/cm
) irradiation. Secosteroids modulated the expression of the inflammatory response genes (IL-17, NF-κB p65, and IκB-α), reducing nuclear-NF-κB-p65 activity and increasing cytosolic-IκB-α expression as well as that of pro-inflammatory mediators, IL-17, TNF-α, and IFN-γ. They stimulated the expression of involucrin (IVL) and cytokeratin 10 (CK10), the major markers of epidermal differentiation, in UVB-irradiated cells. We conclude that CYP11A1-derived hydroxyderivatives inhibit UVB-induced epidermal inflammatory responses through activation of IκB-α expression and suppression of NF-kB-p65 activity and its downstream signaling cytokines, TNF-α, and IFN-γ, as well as by inhibiting IL-17 production and activating epidermal differentiation.
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