Novel approaches for the treatment of psoriasis

DiSepio, Daniel; Chandraratna, Roshantha A.S.; Nagpal, Sunil

doi:10.1016/s1359-6446(99)01335-5

Cited by 18 publications

(14 citation statements)

References 78 publications

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“…Loss-of-function mutations in FLG strongly predispose individuals to atopic dermatitis (40). Similarly, psoriasis exhibits abnormal or psoriatic keratinocyte differentiation, which is characterized by decreased expression of LOR and FLG (41). Activation of LXR stimulates keratinocyte differentiation and lipid synthesis, thus leading to epidermal barrier formation (2)(3)(4)(5).…”

Section: Discussionmentioning

confidence: 99%

Liver X Receptor-Retinoid X Receptor (LXR-RXR) Heterodimer Cistrome Reveals Coordination of LXR and AP1 Signaling in Keratinocytes

Shen¹,

Bai²,

Chang³

et al. 2011

Journal of Biological Chemistry

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Liver X receptors (LXRs) play a critical role in regulating lipid synthesis and transport in numerous tissues. In the skin, activation of LXR induces keratinocyte differentiation and improves epidermal permeability barrier homeostasis. To elucidate the mechanism of LXR action in skin, we mapped its cistrome by identifying LXR␤-RXR␣ binding sites using ChIP-on-chip in normal human epidermal keratinocytes (NHEKs). The cistrome was integrated with transcription data to obtain a global view of LXR action in keratinocyte biology. Here, we identify 2035 LXR␤-RXR␣ binding sites containing 4794 LXR response elements in NHEKs and show the presence of consensus heterodimer active regions in genes involved in keratinocyte lipid transport/synthesis and terminal differentiation. Bioinformatics analysis of the cistrome revealed an enrichment of AP1 cisregulatory motifs in the vicinity of the LXR␤-RXR␣ binding sites. Importantly, we have demonstrated a direct interaction between LXR and Jun/Fos, indicating that the cooperation between LXR and AP1 may orchestrate keratinocyte differentiation. Finally, we corroborated these results by genome-wide mapping of the c-Fos and c-Jun cistromes in NHEKs, demonstrating that 77% of all the LXR␤-RXR␣ binding regions show the presence of AP1 motifs at adjacent locations. Our findings provide new insight into the mechanism of LXR action in keratinocyte differentiation, lipid production and barrier formation, further strengthening the validation of LXR as a potential therapeutic target for skin disorders including skin aging, psoriasis, and atopic dermatitis.Liver X receptors (LXR␣/NR1H3 and LXR␤/NR1H2) 4 are nuclear receptors that play critical roles in lipid metabolism and transport. Both LXR isoforms are also expressed in the skin, including in epidermal keratinocytes and fibroblasts (1-3). An ordered process of keratinocyte differentiation and lipid production in the epidermis results in the formation of a waterimpermeable barrier, which is crucial for all of the physiological functions of the skin. LXRs are important regulators of epidermal biology, because their activation by specific ligands leads to stimulation of keratinocyte differentiation, epidermal lipid synthesis, and anti-inflammatory responses in skin cells (1-3). LXR ligands stimulate keratinocyte differentiation by inducing the expression of genes involved in cornified envelope formation, namely transglutaminase 1 (TGM1), involucrin (IVL), loricrin (LOR), and filaggrin (FLG) (3, 4). Epidermally produced neutral lipids such as cholesterol, ceramides, and fatty acids are essential for skin barrier formation and maintenance. Accordingly, LXR agonists upon topical application augment epidermal lipid synthesis in murine skin (5), presumably by inducing expression of the ABC family of lipid transporters and lipid synthesis genes. LXR ligands induce the expression of lipid transporters (ABCA1, ABCG1, ABCA2, ABCA12, and ABCA13) and lipid synthesis genes (SCD and FASN) in keratinocytes (3, 6). ABCA1 and ABCG1 are known cholesterol tr...

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Section: Discussionmentioning

confidence: 99%

Liver X Receptor-Retinoid X Receptor (LXR-RXR) Heterodimer Cistrome Reveals Coordination of LXR and AP1 Signaling in Keratinocytes

Shen¹,

Bai²,

Chang³

et al. 2011

Journal of Biological Chemistry

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“…An estimated 25% of sufferers have contemplated suicide as a result of having to suffer from the disease itself and also the social stigma of visible and unsightly symptoms 2 . The cause of psoriasis is unknown, although it appears to be an autoimmune disease with the likelihood of genetic predisposition 3 .…”

Section: Introductionmentioning

confidence: 99%

“…New therapies incorporating nanotechnology, and an increased understanding of psoriasis, have brought us closer to the goal of a safe and efficacious treatment of the disease 3 . Novel topical carriers have been evaluated for enhancing skin penetration of MTX exemplified by microemulsion 8,9 , nanogel 10 , niosomes 11 , liposomal hydrogel 12 , deformable liposomes 5,6 and solid lipid nanoparticles (SLNs) 7,13 .…”

Section: Introductionmentioning

confidence: 99%

A novel nanogel formulation of methotrexate for topical treatment of psoriasis: optimization, in vitro and in vivo evaluation

Avasatthi

Pawar

Dora

et al. 2015

Pharmaceutical Development and Technology

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“…Dithranol can be used alone, but is typically prescribed with other drugs, e.g. cyclosporine, coal tar, salicylic acid or ultraviolet irradiation (13,14). However, the undesired effects of dithranol, and its intrinsic instability, remain a concern and lead to compliance issues.…”

Section: Introductionmentioning

confidence: 99%

Topical Delivery of a Naproxen-Dithranol Co-drug: In Vitro Skin Penetration, Permeation, and Staining

2010

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Novel approaches for the treatment of psoriasis

Cited by 18 publications

References 78 publications

Liver X Receptor-Retinoid X Receptor (LXR-RXR) Heterodimer Cistrome Reveals Coordination of LXR and AP1 Signaling in Keratinocytes

Liver X Receptor-Retinoid X Receptor (LXR-RXR) Heterodimer Cistrome Reveals Coordination of LXR and AP1 Signaling in Keratinocytes

A novel nanogel formulation of methotrexate for topical treatment of psoriasis: optimization, in vitro and in vivo evaluation

Topical Delivery of a Naproxen-Dithranol Co-drug: In Vitro Skin Penetration, Permeation, and Staining

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