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2.
J Cosmet Dermatol ; 22(8): 2308-2317, 2023 Aug.
Article in English | MEDLINE | ID: mdl-36891608

ABSTRACT

BACKGROUND: Redness of the facial skin is an important cosmetic concern. Although qualitative and quantitative modifications of sebum on the skin surface are major pathogenic factors of chronic inflammatory skin conditions, the relationship between skin redness, sebum, and mild inflammation on the cheeks of healthy subjects remains elusive. AIMS: We aimed to explore the correlation between cheek redness and sebum and inflammatory cytokines in the stratum corneum (SC) of healthy subjects. We also examined the effects of representative sebum lipids on the gene expression of inflammatory cytokines in cultured keratinocytes. PATIENTS/METHODS: This study included 198 healthy participants. Skin sebum was analyzed using flow injection analysis, and skin redness was assessed using a spectrophotometer. Inflammatory cytokines in tape-stripped SC were measured using enzyme-linked immunosorbent assay. RESULTS: Cheek redness parameters positively correlated with the amount of skin sebum and the proportion of monounsaturated free fatty acids (C16:1 and C18:1) in the sebum. They also positively correlated with the interleukin (IL)-36γ/IL-37 ratio in the SC. Among the representative sebum lipids examined, oleic acid (C18:1, cis-9) dose- and time-dependently regulated the mRNA expression of IL-36γ and IL-37 in cultured keratinocytes, and this effect was attenuated by the N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonist, MK801. CONCLUSIONS: Skin surface sebum may be related to cheek redness in healthy subjects, and oleic acid-induced IL-36γ through NMDA-type glutamate receptors may be a link between them. Our study provides a possible skincare strategy for mitigating unfavorable increase in skin redness by targeting the facial skin sebum, particularly oleic acid.


Subject(s)
Oleic Acid , Sebum , Humans , Cytokines/metabolism , Erythema , Interleukins/metabolism , N-Methylaspartate/metabolism , N-Methylaspartate/pharmacology , Oleic Acid/pharmacology , Sebum/metabolism , Skin
3.
J Dermatol Sci ; 97(1): 50-56, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31836270

ABSTRACT

BACKGROUND: NIPAL4, encoding the NIPA-like domain containing 4 protein (NIPAL4), is one of the causative genes of autosomal recessive congenital ichthyosis (ARCI). The physiological role of NIPAL4 and the pathogenetic mechanisms of ARCI caused by NIPAL4 mutations remain unclear. OBJECTIVE: To clarify the changes of ceramide components in the lesional stratum corneum (SC) and the gene expression profile in the lesional skin of an ARCI patient with a novel frameshift mutation in NIPAL4. METHODS: We performed ultrastructural and immunohistochemical analyses of the skin. We used RNA sequencing to determine the mRNA expression in the skin of the patient and healthy individuals. We investigated ceramide components using tape stripped SC samples from the patient. RESULTS: mRNA expression profiling in the patient's skin showed significant upregulation of IL-17/TNFα-related genes (IL17C, IL36A, IL36G, S100A7A, S100A9) and psoriasis hallmark genes (VNN3, LCE3D, PLA2G4D), and significant downregulation of lipid-associated genes (GAL, HAO2, FABP7). Ceramide analysis in the patient's SC revealed amounts of CER[NS] with carbon chain-length (C) 32-52 were increased, while amounts of most acylceramide with C66:2 - C72:2 were reduced relatively to those in healthy individuals. After the retinoid treatment, CER[NS] with carbon chains C46-54, CER[EOH] and CER[EOP] increased. CONCLUSION: IL-17C and IL-36 family cytokines might be involved in the pathogenetic process of ARCI with NIPAL4 mutations. Reduced amounts of the acylceramides in the SC are associated with the skin phenotype due to NIPAL4 mutations. Efficacy of the oral retinoid treatment might be due to restored amounts of CER[EOH] and CER[EOP] in the SC.


Subject(s)
Ceramides/analysis , Epidermis/chemistry , Etretinate/administration & dosage , Ichthyosis/pathology , Receptors, Cell Surface/genetics , Administration, Oral , DNA Mutational Analysis , Epidermis/drug effects , Epidermis/pathology , Frameshift Mutation , Homozygote , Humans , Ichthyosis/drug therapy , Ichthyosis/genetics , Male , Middle Aged , Treatment Outcome
4.
J Clin Invest ; 130(2): 890-903, 2020 02 03.
Article in English | MEDLINE | ID: mdl-31671075

ABSTRACT

The corneocyte lipid envelope, composed of covalently bound ceramides and fatty acids, is important to the integrity of the permeability barrier in the stratum corneum, and its absence is a prime structural defect in various skin diseases associated with defective skin barrier function. SDR9C7 encodes a short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7) recently found mutated in ichthyosis. In a patient with SDR9C7 mutation and a mouse Sdr9c7-KO model, we show loss of covalent binding of epidermal ceramides to protein, a structural fault in the barrier. For reasons unresolved, protein binding requires lipoxygenase-catalyzed transformations of linoleic acid (18:2) esterified in ω-O-acylceramides. In Sdr9c7-/- epidermis, quantitative liquid chromatography-mass spectometry (LC-MS) assays revealed almost complete loss of a species of ω-O-acylceramide esterified with linoleate-9,10-trans-epoxy-11E-13-ketone; other acylceramides related to the lipoxygenase pathway were in higher abundance. Recombinant SDR9C7 catalyzed NAD+-dependent dehydrogenation of linoleate 9,10-trans-epoxy-11E-13-alcohol to the corresponding 13-ketone, while ichthyosis mutants were inactive. We propose, therefore, that the critical requirement for lipoxygenases and SDR9C7 is in producing acylceramide containing the 9,10-epoxy-11E-13-ketone, a reactive moiety known for its nonenzymatic coupling to protein. This suggests a mechanism for coupling of ceramide to protein and provides important insights into skin barrier formation and pathogenesis.


Subject(s)
Ceramides/metabolism , Epidermis/enzymology , Oxidoreductases/metabolism , Animals , Catalysis , Ceramides/genetics , Disease Models, Animal , Genetic Diseases, Inborn/enzymology , Genetic Diseases, Inborn/genetics , Humans , Ichthyosis/enzymology , Ichthyosis/genetics , Mice , Mice, Knockout , Oxidoreductases/genetics
5.
J Lipid Res ; 59(12): 2413-2420, 2018 12.
Article in English | MEDLINE | ID: mdl-30348640

ABSTRACT

Neu-Laxova syndrome (NLS) is a very rare autosomal recessive congenital disorder characterized by disturbed development of the central nervous system and the skin and caused by mutations in any of the three genes involved in de novo l-serine biosynthesis: PHGDH, PSAT1, and PSPH l-Serine is essential for the biosynthesis of phosphatidylserine and sphingolipids. The extracellular lipid of the stratum corneum, of which sphingolipid constitutes a significant part, plays a primary role in skin barrier function. Here, we describe a Japanese NLS pedigree with a previously unreported nonsense mutation in PHGDH and a unique inversion of chromosome 1. In addition, the levels of 11 major ceramide classes in the tape-stripped stratum corneum of the NLS patient's skin were assessed by LC/MS. Notably, lower amounts of ceramides of all classes were found in the patient's stratum corneum than in those of controls. This is the first report to demonstrate the reduction of ceramides in the stratum corneum of an NLS patient due to PHGDH mutations. The clinical findings and a detailed analysis of ceramides from the stratum corneum in the family extend the spectrum of clinical anomalies and give us a clue to the pathomechanisms of ichthyosis in NLS patients with phosphoglycerate dehydrogenase deficiency.


Subject(s)
Abnormalities, Multiple/metabolism , Brain Diseases/metabolism , Carbohydrate Metabolism, Inborn Errors/metabolism , Ceramides/metabolism , Fetal Growth Retardation/metabolism , Ichthyosis/metabolism , Limb Deformities, Congenital/metabolism , Microcephaly/metabolism , Phosphoglycerate Dehydrogenase/deficiency , Phosphoglycerate Dehydrogenase/metabolism , Psychomotor Disorders/metabolism , Seizures/metabolism , Adult , Amino Acids/metabolism , Female , Gestational Age , Humans , Immunohistochemistry , Infant, Newborn , Male , Pregnancy , Sphingolipids/metabolism , Exome Sequencing , Young Adult
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