Acefylline activates filaggrin deimination by peptidylarginine deiminases in the upper epidermis

Autor: Jean-Louis Vidaluc, Hélène Duplan, Sandrine Bessou-Touya, Hidenari Takahara, Guy Serre, Stephane Poigny, Sylvie Daunes-Marion, Marie-Florence Galliano, Marie-Claire Méchin, Michel Simon, Laura Cau
Přispěvatelé: Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Pharmacochimie Pierre Fabre Dermo-Cosmétique, Centre de Recherche Pierre Fabre (Centre de R&D Pierre Fabre), PIERRE FABRE-PIERRE FABRE, Ibaraki University
Rok vydání: 2015
Předmět:
0301 basic medicine
Keratinocytes
Models
Molecular
Hydrolases
Protein Conformation
MESH: Protein-Arginine Deiminases
Epidermal barrier
Filaggrin Proteins
Biochemistry
MESH: Dose-Response Relationship
Drug
MESH: Humans Hydrolases / metabolism
chemistry.chemical_compound
MESH: Structure-Activity Relationship
MESH: Protein Conformation
MESH: Theophylline / chemistry
MESH: Epidermis / enzymology
Intermediate Filament Proteins
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
MESH: Keratinocytes / drug effects
Cells
Cultured
Skin
MESH: Enzyme Activators / administration & dosage
Citrullination
MESH: Administration
Cutaneous
medicine.anatomical_structure
MESH: Keratinocytes / enzymology
Post-translational modification
MESH: Intermediate Filament Proteins / metabolism
Filaggrin
MESH: Models
Molecular
MESH: Cells
Cultured
MESH: Enzyme Activation
MESH: Theophylline / administration & dosage
MESH: Theophylline / analogs & derivatives
MESH: Enzyme Activators / chemistry
Enzyme Activators
Dermatology
MESH: Theophylline / pharmacology
Administration
Cutaneous
Xanthine
Small Molecule Libraries
03 medical and health sciences
Enzyme activator
Structure-Activity Relationship
MESH: Computer Simulation
Theophylline
MESH: Small Molecule Libraries
MESH: Enzyme Activators / pharmacology
Stratum corneum
medicine
Humans
Computer Simulation
Enhancer
Molecular Biology
MESH: Epidermal Cells Epidermis / drug effects
030102 biochemistry & molecular biology
Epidermis (botany)
Dose-Response Relationship
Drug
Activator (genetics)
Enzyme Activation
030104 developmental biology
chemistry
Epidermal Cells
MESH: Protein Processing
Post-Translational
Protein-Arginine Deiminases
Epidermis
MESH: Intermediate Filament Proteins / chemistry
Protein Processing
Post-Translational
Zdroj: Journal of Dermatological Science
Journal of Dermatological Science, Elsevier, 2016, 81 (2), pp.101-106. ⟨10.1016/j.jdermsci.2015.11.006⟩
ISSN: 1873-569X
0923-1811
DOI: 10.1016/j.jdermsci.2015.11.006⟩
Popis: International audience; Background: Peptidylarginine deiminases (PADs) catalyze deimination (or citrullination), a calcium-dependent post-translational modification involved in several physiological processes and human diseases, such as rheumatoid arthritis and cancer. Deimination of filaggrin (FLG) by PAD1 and PAD3 during the last steps of keratinocyte differentiation is a crucial event for the epidermis function and homeostasis. This allows the complete degradation of FLG, leading to the production of free amino acids and their derivatives that are essential for epidermal photoprotection and moisturizing of the stratum corneum. Objective: To increase the flux of this catabolic pathway, we searched for activators of PADs. Methods: A large chemical library was screened first in silico and then by using an automated assay based on an indirect colorimetric measurement of recombinant human PAD activity. Potential activators were then confirmed using a recombinant human FLG as a substrate, and secondly after topical application at the surface of three-dimensional reconstructed human epidermis. Results: The data obtained after the library screening pointed to xanthine derivatives as potential PAD activators. Among seven xanthine derivatives tested at 50-300μM, caffeine, theobromine and acefylline proved to be the most potent enhancers of in vitro deimination of FLG by PAD1 and PAD3. After topical application of a gel formulation containing 3% acefylline at the surface of reconstructed epidermis, immunoblotting analysis showed an increase in the total amount of deiminated proteins, and confocal microscopy showed an enhanced deimination in the stratum corneum. This demonstrated the activation of PADs in living cells. Conclusion: As a PAD activator, acefylline will be useful to study the role of deimination and could be proposed to increase or correct the hydration of the cornified layers of the epidermis.
Databáze: OpenAIRE
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