New Treatments for Atopic Dermatitis Targeting Skin Barrier Repair via the Regulation of FLG Expression

Dębińska, Anna

doi:10.3390/jcm10112506

Cited by 24 publications

(16 citation statements)

References 207 publications

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“…Thyssen and Kezic [80] provided an excellent overview of the multifactorial environmental and genetic causes of AD. An extensive review by Dębi ńska [81] describes treatments for AD currently approved or in clinical trials, with specific focus on factors that regulate expression of the filaggrin gene.…”

Section: Mutations That Cause Loss Of Filaggrinmentioning

confidence: 99%

The Discovery and Function of Filaggrin

Hoober

Eggink

2022

IJMS

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Keratohyalin granules were discovered in the mid-19th century in cells that terminally differentiate to form the outer, cornified layer of the epidermis. The first indications of the composition of these structures emerged in the 1960s from a histochemical stain for histidine, followed by radioautographic evidence of a high incidence of histidine incorporation into newly synthesized proteins in cells containing the granules. Research during the next three decades revealed the structure and function of a major protein in these granules, which was initially called the ‘histidine-rich protein’. Steinert and Dale named the protein ‘filaggrin’ in 1981 because of its ability to aggregate keratin intermediate filaments. The human gene for the precursor, ‘profilaggrin,’ was reported in 1991 to encode 10, 11 or 12 nearly identical repeats. Remarkably, the mouse and rat genes encode up to 20 repeats. The lifetime of filaggrin is the time required for keratinocytes in the granular layer to move into the inner cornified layer. During this transition, filaggrin facilitates the collapse of corneocytes into ‘building blocks’ that become an impermeable surface barrier. The subsequent degradation of filaggrin is as remarkable as its synthesis, and the end-products aid in maintaining moisture in the cornified layer. It was apparent that ichthyosis vulgaris and atopic dermatitis were associated with the absence of this protein. McLean’s team in 2006 identified the cause of these diseases by discovering loss-of-function mutations in the profilaggrin gene, which led to dysfunction of the surface barrier. This story illustrates the complexity in maintaining a healthy, functional epidermis.

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Section: Mutations That Cause Loss Of Filaggrinmentioning

confidence: 99%

The Discovery and Function of Filaggrin

Hoober

Eggink

2022

IJMS

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“…Skin barrier dysfunction is associated with the reduced production of terminal differentiation-associated molecules, such as FLG and LOR, that are crosslinked by TGM1 to create a stable cornified protein shell known as the CE [ 22 , 23 , 24 ]. Results of a previous study revealed that Lactobacillus rhamnosus fermentation broth, when added to human epidermal skin model cells grown in vitro, improved epidermal barrier function by increasing the expression levels of LOR and FLG mRNAs [ 2 ].…”

Section: Discussionmentioning

confidence: 99%

Screening and Research on Skin Barrier Damage Protective Efficacy of Different Mannosylerythritol Lipids

Jing

Guo

et al. 2022

Molecules

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Mannosylerythritol lipids (MELs) may prevent skin barrier damage, although their protective mechanisms and active monomeric constituents remain unclear. Here, three MELs were extracted from Candida antarctica cultures containing fermented olive oil then purified using silica gel-based column chromatography and semipreparative HPLC. All three compounds (MEL-A, MEL-B, MEL-C) were well separated and stable, and reliable materials were used for NMR and HRESIMS chemical structure determinations and for assessing MELs’ protective effects against skin damage. Notably, MEL-B and MEL-C effectively protected HaCaT cells from UVB-induced damage by upregulating the contents of filaggrin (FLG) and transglutaminase-1 (TGM1), as determined via ELISA. Moreover, MEL-B treatment (20 μg/mL) of UVB-irradiated HaCaT cells led to the upregulation of both the expression of mRNA genes and the key proteins FLG, LOR, and TGM1, which are known to be decreased in damaged skin cells. Additionally, histopathological analysis results revealed a markedly reduced intracellular vacuolation and cell damage, reflecting improved skin function after MEL-B treatment. Furthermore, immunofluorescence results revealed that MEL-B protected EpiKutis® three-dimensional cultured human skin cells from sodium dodecyl sulfate-induced damage by up-regulating FLG, LOR, and TGM1 expression. Accordingly, MELs’ protection against skin barrier damage depended on MEL-B monomeric constituent activities, thus highlighting their promise as beneficial ingredients for use in skin-care products.

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“…Epidermal skin barrier dysfunction and inflammation play key roles in the development of AD [ 49 ], and epidermal structural proteins such as FLG, LOR, and involucrin are key players in epidermal skin barrier formation [ 50 ]. FLG is a major cytoskeleton protein of the cornified envelope, and LOR is a main structural cornified envelope protein that constitutes 70–85% of total protein mass in the cornified layer [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Involucrin is an assembly and scaffold protein of the cornified envelope [ 19 ]. Reduced expressions of these epidermal barrier proteins are major pathological characteristics in the skin of AD patients [ 50 ]. Reduced levels of FLG and LOR expressions are associated with barrier disruption and skin inflammation, weakening of the epidermal barrier function, and are also observed in inflamed skin [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

1-Iodohexadecane Alleviates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis in Mice: Possible Involvements of the Skin Barrier and Mast Cell SNARE Proteins

et al. 2022

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Atopic dermatitis (AD) is a chronic inflammatory dermal disease with symptoms that include inflammation, itching, and dry skin. 1-Iodohexadecane is known as a component of Chrysanthemum boreale essential oil that has an inhibitory effect on AD-like lesions. However, its effects on AD-related pathological events have not been investigated. Here, we explored the effects of 1-iodohexadecane on AD lesion-related in vitro and in vivo responses and the mechanism involved using human keratinocytes (HaCaT cells), mast cells (RBL-2H3 cells), and a 2,4-dinitrochlorobenzene (DNCB)-induced mouse model (male BALB/c) of AD. Protein analyses were performed by immunoblotting or immunohistochemistry. In RBL-2H3 cells, 1-iodohexadecane inhibited immunoglobulin E-induced releases of histamine and β-hexosaminidase and the expression of VAMP8 protein (vesicle-associated membrane proteins 8; a soluble N-ethylmaleimide-sensitive factor attachment protein receptor [SNARE] protein). In HaCaT cells, 1-iodohexadecane enhanced filaggrin and loricrin expressions; in DNCB-treated mice, it improved AD-like skin lesions, reduced epidermal thickness, mast cell infiltration, and increased filaggrin and loricrin expressions (skin barrier proteins). In addition, 1-iodohexadecane reduced the β-hexosaminidase level in the serum of DNCB-applied mice. These results suggest that 1-iodohexadecane may ameliorate AD lesion severity by disrupting SNARE protein-linked degranulation and/or by enhancing the expressions of skin barrier-related proteins, and that 1-iodohexadecane has therapeutic potential for the treatment of AD.

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New Treatments for Atopic Dermatitis Targeting Skin Barrier Repair via the Regulation of FLG Expression

Cited by 24 publications

References 207 publications

The Discovery and Function of Filaggrin

The Discovery and Function of Filaggrin

Screening and Research on Skin Barrier Damage Protective Efficacy of Different Mannosylerythritol Lipids

1-Iodohexadecane Alleviates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis in Mice: Possible Involvements of the Skin Barrier and Mast Cell SNARE Proteins

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