Asunto(s)

Dermatitis Atópica , Exones , Proteínas Filagrina , Proteínas de Filamentos Intermediarios , Humanos , Dermatitis Atópica/genética , Dermatitis Atópica/diagnóstico , Proteínas de Filamentos Intermediarios/genética , Exones/genética , Masculino , Femenino , Mutación con Pérdida de Función , Adulto , Índice de Severidad de la Enfermedad

RESUMEN

Filaggrin (FLG) is an essential structural protein expressed in differentiated keratinocytes. Insufficient FLG expression contributes to the pathogenesis of chronic inflammatory skin diseases. Saikosaponin A (SSA), a bioactive oleanane-type triterpenoid, exerts anti-inflammatory activity. However, the effects of topically applied SSA on FLG expression in inflamed skin remain unclear. This study aimed to evaluate the biological activity of SSA in restoring reduced FLG expression. The effect of SSA on FLG expression in HaCaT cells was assessed through various biological methods, including reverse transcription PCR, quantitative real-time PCR, immunoblotting, and immunofluorescence staining. TNFα and IFNγ decreased FLG mRNA, cytoplasmic FLG protein levels, and FLG gene promoter-reporter activity compared to the control groups. However, the presence of SSA restored these effects. A series of FLG promoter-reporter constructs were generated to investigate the underlying mechanism of the effect of SSA on FLG expression. Mutation of the AP1-binding site (mtAP1) in the -343/+25 FLG promoter-reporter abrogated the decrease in reporter activities caused by TNFα + IFNγ, suggesting the importance of the AP1-binding site in reducing FLG expression. The SSA treatment restored FLG expression by inhibiting the expression and nuclear localization of FRA1 and c-Jun, components of AP1, triggered by TNFα + IFNγ stimulation. The ERK1/2 mitogen-activated protein kinase signaling pathway upregulates FRA1 and c-Jun expression, thereby reducing FLG levels. The SSA treatment inhibited ERK1/2 activation caused by TNFα + IFNγ stimulation and reduced the levels of FRA1 and c-Jun proteins in the nucleus, leading to a decrease in the binding of FRA1, c-Jun, p-STAT1, and HDAC1 to the AP1-binding site in the FLG promoter. The effect of SSA was evaluated in an animal study using a BALB/c mouse model, which induces human atopic-dermatitis-like skin lesions via the topical application of dinitrochlorobenzene. Topically applied SSA significantly reduced skin thickening, immune cell infiltration, and the expression of FRA1, c-Jun, and p-ERK1/2 compared to the vehicle-treated group. These results suggest that SSA can effectively recover impaired FLG levels in inflamed skin by preventing the formation of the repressor complex consisting of FRA1, c-Jun, HDAC1, and STAT1.

Asunto(s)

Proteínas Filagrina , Proteínas de Filamentos Intermediarios , Ácido Oleanólico , Proteínas Proto-Oncogénicas c-fos , Saponinas , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacología , Humanos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Saponinas/farmacología , Ratones , Animales , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas de Filamentos Intermediarios/genética , Piel/metabolismo , Piel/efectos de los fármacos , Regiones Promotoras Genéticas/efectos de los fármacos , Interferón gamma/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas Proto-Oncogénicas c-jun/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Células HaCaT , Regulación hacia Abajo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/efectos de los fármacos , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/genética

RESUMEN

Symmetrical acral keratoderma (SAK) is a rare skin disorder with symmetric hyperkeratotic patches on the acral regions. Variants in the filaggrin gene (FLG) have been associated with SAK since 2020. To explore the clinical and genetic basis in six patients with SAK. Whole-exome sequencing, direct sequencing, and prediction of protein structure and function were performed. In this study, we identified two novel variants, c.3320del and c.4909del, and seven previously reported variants, c.3099C>G, c.4544C>A, c.6950_6957del, c.7264G>T, c.7945del, c.8117C>G, c.12064A>T. The findings of this study bolster the existing evidence implicating FLG variants in SAK, introducing two novel variants to the database of FLG variants associated with the condition.

Asunto(s)

Proteínas Filagrina , Proteínas de Filamentos Intermediarios , Humanos , Proteínas de Filamentos Intermediarios/genética , Femenino , Masculino , Secuenciación del Exoma , Adulto , Queratodermia Palmoplantar/genética , Persona de Mediana Edad

RESUMEN

Intermediate filaments (IFs) comprise a large family of versatile cytoskeletal proteins, divided into six subtypes with tissue-specific expression patterns. IFs have a wide repertoire of cellular functions, including providing structural support to cells, as well as active roles in mechanical support and signaling pathways. Consequently, defects in IFs are associated with more than 100 diseases. In this Cell Science at a Glance article, we discuss the established classes of IFs and their general features, their functions beyond structural support, and recent advances in the field. We also highlight their involvement in disease and potential use as clinical markers of pathological conditions. Finally, we provide our view on current knowledge gaps and the future directions of the IF field.

Asunto(s)

Filamentos Intermedios , Filamentos Intermedios/metabolismo , Humanos , Animales , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas de Filamentos Intermediarios/genética , Transducción de Señal , Citoesqueleto/metabolismo

RESUMEN

Benvitimod has been successfully used in the treatment of psoriasis and atopic dermatitis (AD). However, the mechanism remains to be clarified. We aim to assess the effects of benvitimod on MC903-induced dermatitis in mice and to investigate the effects of benvitimod on filaggrin (FLG), involucrin (IVL), and loricrin (LOR) expressions and possible mechanism. MC903-induced mouse AD model was used to evaluate the effects of benvitimod. Filaggrin, involucrin, and loricrin protein and mRNA expressions in lesions of mice dermatitis were measured by Western blot and quantitative real-time PCR. In vitro, normal human epidermal keratinocytes (NHEKs) were cultured and benvitimod was used to treat NHEKs primed with IL-4 and IL-13. Then AHR and OVOL1 in NHEKs were knocked down to evaluate the role of AHR and OVOL1 in the effects of benvitimod. Topical treatment of benvitimod repaired skin barrier and alleviated skin inflammation in mouse AD model. This effect was inhibited by pretreatment with an AHR antagonist. Benvitimod upregulated the filaggrin, involucrin, and loricrin expressions in lesions of mouse AD model. In addition, benvitimod upregulated the filaggrin, involucrin, and loricrin expressions in NHEKs. Knockdown of AHR or OVO-like (OVOL)1 abrogated the upregulation of filaggrin, involucrin, and loricrin induced by benvitimod. Benvitimod attenuated MC903-induced mouse dermatitis and upregulated filaggrin, involucrin, and loricrin expressions via AHR-OVOL1 axis.

Asunto(s)

Dermatitis Atópica , Modelos Animales de Enfermedad , Proteínas Filagrina , Proteínas de Filamentos Intermediarios , Queratinocitos , Precursores de Proteínas , Receptores de Hidrocarburo de Aril , Regulación hacia Arriba , Proteínas Filagrina/metabolismo , Animales , Precursores de Proteínas/metabolismo , Precursores de Proteínas/genética , Ratones , Humanos , Queratinocitos/metabolismo , Queratinocitos/efectos de los fármacos , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas de Filamentos Intermediarios/genética , Dermatitis Atópica/metabolismo , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Regulación hacia Arriba/efectos de los fármacos , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Células Cultivadas , Piel/patología , Piel/metabolismo , Piel/efectos de los fármacos , Ratones Endogámicos BALB C , Transducción de Señal/efectos de los fármacos , Proteínas de Unión al ADN , Factores de Transcripción

RESUMEN

Loss-of-function (LoF) mutations in the filaggrin gene (FLG) constitute the strongest genetic risk for atopic dermatitis (AD). A latitude-dependent difference in the prevalence of LoF FLG mutations was systematically evaluated. A systematic review and meta-analysis were performed to estimate the prevalence of LoF FLG mutations in AD patients and the general population by geography and ethnicity. Risk of bias was assessed by Newcastle-Ottawa Scale and Jadad score. StatsDirect, version 3 software was used to calculate all outcomes. PubMed and EMBASE were searched until 9th December 2021. Studies were included if they contained data on the prevalence of LoF FLG mutations in AD patients or from the general population or associations between AD and LoF FLG mutations and were authored in English. Overall, 248 studies and 229 310 AD patients and individuals of the general population were included in the quantitative analysis. The prevalence of LoF FLG mutations was 19.1% (95% CI, 17.3-21.0) in AD patients and 5.8% (95% CI, 5.3-6.2) in the general population. There was a significant positive association between AD and LoF FLG mutations in all latitudes in the Northern hemisphere, but not in all ethnicities. The prevalence of LoF FLG mutations became gradually more prevalent in populations residing farther north of the Equator but was negligible in Middle Easterners and absent in most African populations. FLG LoF mutations are common and tend to increase with northern latitude, suggesting potential clinical implications for future AD management. The existence of possible genetic fitness from FLG LoF mutations remains unknown.

Asunto(s)

Dermatitis Atópica , Proteínas Filagrina , Proteínas de Filamentos Intermediarios , Mutación con Pérdida de Función , Dermatitis Atópica/genética , Dermatitis Atópica/epidemiología , Humanos , Proteínas de Filamentos Intermediarios/genética , Aptitud Genética , Prevalencia , Predisposición Genética a la Enfermedad , Mutación

RESUMEN

By analyzing the expression patterns of inner root sheath (IRS) specific genes during different developmental stages of hair follicle (HF) in Tan sheep embryos and at birth, this study aims to reveal the influence of the IRS on crimped wool. Skin tissues from the scapular region of male Tan sheep were collected at 85 days (E85) and 120 days (E120) of fetal development, and at 0 days (D0), 35 days (D35), and 60 days (D60) after birth, with four samples at each stage. Real-time quantitative polymerase chain reaction (RT-qPCR) was employed to determine the relative expression levels of IRS type I keratin genes (KRT25, KRT26, KRT27, KRT28), type II keratin genes (KRT71, KRT72, KRT73, KRT74), and the trichohyalin gene (TCHH) in the skin of Tan sheep at different stages. Results showed that the expression levels of all IRS-specific genes peaked at D0, with the expression of all genes significantly higher than at E85 (P < 0.01), except for KRT73 and TCHH. The expression levels of KRT25, KRT26, and KRT72 were also significantly higher than at E120 (P < 0.01). Furthermore, the expression levels of KRT27, KRT28, KRT71, and KRT74 were significantly higher than both at E120 and D35 (P < 0.01). The expression levels of other genes at different stages showed no significant difference (P > 0.05). Conclusion: The IRS-specific genes exhibit the highest expression levels in Tan sheep at the neonatal stage. The expression levels of KRT71, KRT72, and TCHH, which are consistent with the pattern of wool crimp, may influence the morphology of the IRS and thereby affect the crimp of Tan sheep wool.

Asunto(s)

Regulación del Desarrollo de la Expresión Génica , Folículo Piloso , Animales , Folículo Piloso/metabolismo , Folículo Piloso/crecimiento & desarrollo , Ovinos/genética , Ovinos/crecimiento & desarrollo , Masculino , Lana/metabolismo , Lana/crecimiento & desarrollo , Queratinas Tipo II/genética , Queratinas Tipo II/metabolismo , Queratinas/genética , Queratinas/metabolismo , Queratinas Tipo I/genética , Queratinas Tipo I/metabolismo , Proteínas de Filamentos Intermediarios

RESUMEN

Reactive pustular eruptions (RPEs) can manifest in a variety of conditions, including pustular psoriasis (PP) and adult-onset immunodeficiency syndrome due to anti-interferon-γ autoantibody (AOID). These RPEs can be attributed to different causes, one of which is genetic factors. However, the genetic basis for pustular skin diseases remains poorly understood. In our study, we conducted whole-exome sequencing on a cohort of 17 AOID patients with pustular reactions (AOID-PR) and 24 PP patients. We found that 76% and 58% of the AOID-PR and PP patients, respectively, carried rare genetic variations within the filaggrin (FLG) gene family. A total of 12 out of 21 SNPs on FLG had previously received clinical classifications, with only p.Ser2706Ter classified as pathogenic. In contrast, none of the FLG3 SNPs identified in this study had prior clinical classifications. Overall, these variations had not been previously documented in cases of pustular disorders, and two of them were entirely novel discoveries. Immunohistochemical analysis of skin biopsies revealed that FLG variants like p.Ser860Trp, p.Gly3903Ter, p.Gly2440Glu, and p.Glu2133Asp caused reductions in FLG levels similar to the pathogenic FLG p.Ser2706Ter. These results highlight rare FLG variants as potential novel genetic risk factors contributing to pustule formation in both AOID and PP.

Asunto(s)

Pueblo Asiatico , Proteínas Filagrina , Proteínas de Filamentos Intermediarios , Polimorfismo de Nucleótido Simple , Humanos , Proteínas de Filamentos Intermediarios/genética , Femenino , Masculino , Pueblo Asiatico/genética , Adulto , Persona de Mediana Edad , Secuenciación del Exoma , Predisposición Genética a la Enfermedad , Psoriasis/genética , Psoriasis/patología , Anciano , Interferón gamma/genética , Interferón gamma/metabolismo , Autoanticuerpos/inmunología , Piel/patología , Piel/metabolismo

RESUMEN

BACKGROUND: Psoriasis is a disease of overactive immune system. OVOL1 and Filaggrin have been associated with many inflammatory skin lesions. To the best of our knowledge, the correlation between OVOL1 and Filaggrin in psoriasis was not previously investigated. This work aims to search the immunohistochemical expression and correlation between OVOL1 and Filaggrin in psoriasis. MATERIALS AND METHODS: Slides cut from paraffin blocks of 30 psoriasis cases and 30 control subjects were stained with OVOL1 and Filaggrin. Clinicopathological data were correlated with the results of staining. RESULTS: OVOL1 and Filaggrin expression in epidermis showed a significant gradual reduction from normal skin to peri-lesional and psoriasis biopsies (P < 0.001). In contrast, psoriasis dermis showed a significant overexpression of OVOL1 in inflammatory cells in relation to peri-lesional biopsies (P < 0.002). OVOL1 demonstrated a significant direct correlation with Filaggrin expression in psoriasis (r = 0.568, P < 0.004). OVOL1 and Filaggrin expression in psoriasis skin epidermis demonstrated a statistically significant negative correlation with PASI score. CONCLUSION: OVOL1 and Filaggrin might be involved in psoriasis-associated inflammation and skin hyperproliferation. OVOL1 might have a protective barrier function in the skin and could be used to stratify progressive disease. Filaggrin may play a role in progression of psoriasis. OVOL1 inhibition could be considered in suppression of Filaggrin function. OVOL1 agonists may be beneficial in psoriasis treatment.

Asunto(s)

Proteínas Filagrina , Inmunohistoquímica , Proteínas de Filamentos Intermediarios , Psoriasis , Humanos , Psoriasis/patología , Psoriasis/metabolismo , Femenino , Proteínas de Filamentos Intermediarios/metabolismo , Masculino , Adulto , Persona de Mediana Edad , Piel/patología , Piel/metabolismo , Adulto Joven , Anciano , Biomarcadores/análisis , Biomarcadores/metabolismo , Estudios de Casos y Controles , Biopsia , Relevancia Clínica , Proteínas de Unión al ADN , Factores de Transcripción

RESUMEN

Porcine placental extract (PPE) is commonly used in various health foods and cosmetics. PPE use in cosmetics predominantly consist of the water-soluble fraction derived from the entire placenta. In this report, we examined the effect of the hydrophobic constituents of the PPE, specifically the sphingolipid-enriched fraction designated as the sphingolipid-enriched porcine placental extract (SLPPE), on the expression of genes associated with skin function in cultured normal human epidermal keratinocytes. Using quantitative RT-PCR (qRT-PCR) analysis, we found that SLPPE concentrations ranging from 25 to 100 µg/mL upregulated the gene expression of key components associated with the cornified envelope structure (filaggrin (FLG), involucrin (IVL) and loricrin (LOR)), cornification enzymes (transglutaminase 1 (TGM1) and TGM5) and the desquamation enzymes (kallikrein 5 (KLK5) and KLK7). Additionally, KLK5p and FLG protein (FLGp) were detected in the culture supernatants of keratinocytes treated with SLPPE at these concentrations. These findings suggest that SLPPE is possible to promote the cornification and desquamation in epidermal keratinocytes, and it may offer potential benefits in cosmetics.

Asunto(s)

Proteínas Filagrina , Calicreínas , Queratinocitos , Esfingolípidos , Transglutaminasas , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Humanos , Animales , Transglutaminasas/metabolismo , Transglutaminasas/genética , Porcinos , Esfingolípidos/metabolismo , Calicreínas/metabolismo , Calicreínas/genética , Extractos Placentarios/farmacología , Células Cultivadas , Femenino , Proteínas de Filamentos Intermediarios/genética , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Embarazo

RESUMEN

Intermediate filaments (IFs), being traditionally the least studied component of the cytoskeleton, have begun to receive more attention in recent years. IFs are found in different cell types and are specific to them. Accumulated data have shifted the paradigm about the role of IFs as structures that merely provide mechanical strength to the cell. In addition to this role, IFs have been shown to participate in maintaining cell shape and strengthening cell adhesion. The data have also been obtained that point out to the role of IFs in a number of other biological processes, including organization of microtubules and microfilaments, regulation of nuclear structure and activity, cell cycle control, and regulation of signal transduction pathways. They are also actively involved in the regulation of several aspects of intracellular transport. Among the intermediate filament proteins, vimentin is of particular interest for researchers. Vimentin has been shown to be associated with a range of diseases, including cancer, cataracts, Crohn's disease, rheumatoid arthritis, and HIV. In this review, we focus almost exclusively on vimentin and the currently known functions of vimentin intermediate filaments (VIFs). This is due to the structural features of vimentin, biological functions of its domains, and its involvement in the regulation of a wide range of basic cellular functions, and its role in the development of human diseases. Particular attention in the review will be paid to comparing the role of VIFs with the role of intermediate filaments consisting of other proteins in cell physiology.

Asunto(s)

Filamentos Intermedios , Vimentina , Vimentina/metabolismo , Vimentina/química , Humanos , Filamentos Intermedios/metabolismo , Animales , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas de Filamentos Intermediarios/química

RESUMEN

Multiple risk factors have been associated with the development of atopic dermatitis (AD). Recent advances in understanding the role of genetics in this disease have been made, with discovery of the filaggrin (FLG) gene as the most notable so far. In addition to FLG gene mutations as a risk factor for AD, a positive family history of atopic or allergic disease in either parent has been shown to confer a greater risk of developing AD. Atopic dermatitis usually presents early in life and is thought to represent the initial step in the "atopic march," which is characterized by the development of other atopic diseases later in life such as asthma, allergic rhinitis, and/or rhinoconjunctivitis, food allergies, and hay fever. Other comorbid diseases that have been associated with AD include increase risk of viral and bacterial skin infections, neuropsychiatric diseases such as attention-deficit hyperactivity disorders (ADHD), and autistic spectrum disorder (ASD). Patients with AD have also been found to have worse sleep quality overall compared to patients without AD. In this chapter, we will discuss the risk factors associated with development of atopic dermatitis as well as the most commonly reported comorbidities in patients with this disease.

Asunto(s)

Dermatitis Atópica , Humanos , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/etiología , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/etiología , Comorbilidad , Dermatitis Atópica/genética , Dermatitis Atópica/epidemiología , Proteínas Filagrina , Predisposición Genética a la Enfermedad , Proteínas de Filamentos Intermediarios/genética , Mutación , Factores de Riesgo

RESUMEN

Atopic dermatitis is a multi-pathogenic disease characterized by chronic skin inflammation and barrier dysfunction. Therefore, improving the skin's ability to form an epidermal barrier and suppressing the production of cytokines that induce type 2 inflammatory responses are important for controlling atopic dermatitis symptoms. (-)-Blebbistatin, a non-muscle myosin II inhibitor, has been suggested to improve pulmonary endothelial barrier function and control inflammation by suppressing immune cell migration; however, its efficacy in atopic dermatitis is unknown. In this study, we investigated whether (S)-(-)-blebbistatin O-benzoate, a derivative of (-)-blebbistatin, improves dermatitis symptoms in a mite antigen-induced atopic dermatitis model using NC/Nga mice. The efficacy of the compound was confirmed using dermatitis scores, ear thickness measurements, serum IgE levels, histological analysis of lesions, and filaggrin expression analysis, which is important for barrier function. (S)-(-)-Blebbistatin O-benzoate treatment significantly reduced the dermatitis score and serum IgE levels compared to those in the vehicle group (p < 0.05). Furthermore, the histological analysis revealed enhanced filaggrin production and a decreased number of mast cells (p < 0.05), indicating that (S)-(-)-blebbistatin O-benzoate improved atopic dermatitis symptoms in a pathological model. In vitro analysis using cultured keratinocytes revealed increased expression of filaggrin, loricrin, involucrin, and ceramide production pathway-related genes, suggesting that (S)-(-)-blebbistatin O-benzoate promotes epidermal barrier formation. Furthermore, the effect of (S)-(-)-blebbistatin O-benzoate on type 2 alarmin cytokines, which are secreted from epidermal cells upon scratching or allergen stimulation and are involved in the pathogenesis of atopic dermatitis, was evaluated using antigens derived from mite feces. The results showed that (S)-(-)-blebbistatin O-benzoate inhibited the upregulation of these cytokines. Based on the above, (S)-(-)-blebbistatin O-benzoate has the potential to be developed as an atopic dermatitis treatment option that controls dermatitis symptoms by suppressing inflammation and improving barrier function by acting on multiple aspects of the pathogenesis of atopic dermatitis.

Asunto(s)

Benzoatos , Citocinas , Dermatitis Atópica , Epidermis , Proteínas Filagrina , Compuestos Heterocíclicos de 4 o más Anillos , Animales , Humanos , Masculino , Ratones , Antígenos Dermatofagoides/inmunología , Benzoatos/farmacología , Benzoatos/uso terapéutico , Citocinas/metabolismo , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Dermatitis Atópica/metabolismo , Modelos Animales de Enfermedad , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Epidermis/patología , Proteínas Filagrina/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Inmunoglobulina E/sangre , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas de Filamentos Intermediarios/genética , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Alarminas/efectos de los fármacos

RESUMEN

Intermediate filaments (IFs) are integral components of the cytoskeleton which provide cells with tissue-specific mechanical properties and are involved in a plethora of cellular processes. Unfortunately, due to their intricate architecture, the 3D structure of the complete molecule of IFs has remained unresolved. Even though most of the rod domain structure has been revealed by means of crystallographic analyses, the flanked head and tail domains are still mostly unknown. Only recently have studies shed light on head or tail domains of IFs, revealing certainsecondary structures and conformational changes during IF assembly. Thus, a deeper understanding of their structure could provide insights into their function.

Asunto(s)

Filamentos Intermedios , Dominios Proteicos , Filamentos Intermedios/metabolismo , Filamentos Intermedios/genética , Filamentos Intermedios/química , Humanos , Animales , Proteínas de Filamentos Intermediarios/genética , Proteínas de Filamentos Intermediarios/química , Proteínas de Filamentos Intermediarios/metabolismo , Citoesqueleto , Modelos Moleculares

RESUMEN

OBJECTIVE:   This study aimed to investigate the ultraviolet (UV) protection/repair benefits of a patented Amino Acid Complex (AAComplex). METHODS: I) AAComplex was incubated with dermal fibroblasts, with/without UVA, and collagen I was measured with a GlasBoxPlus device. II) A lotion, with/without AAComplex (1%) was applied topically to skin explants, following UVA irradiation, and quantified for health-related biomarkers (TNFalpha, histamine, and MMP-1). III) A broad spectrum sunscreen with SPF 46 and a skincare serum containing AAComplex (2%) were assessed using epidermal equivalents, in the presence of UV irradiation, for effects on IL-1alpha, thymine dimers, Ki-67, filaggrin and Nrf2. RESULTS: I) Collagen I synthesis in dermal fibroblasts was significantly decreased after UVA compared to without UV. The presence of AAComplex prevented this decrease. II) UVA irradiation of skin explants increased histamine, TNFα, and MMP-1. Hydrocortisone aceponate cream significantly decreases all 3 biomarkers. AAComplex contained lotion also significantly decreased all 3 biomarkers, the no AAComplex control lotion only reduced histamine. III) With the regimen of sunscreen + AAComplex contained skincare serum, the significant reduction in IL-1alpha was observed along with a complete recovery of Ki-67 and stimulation of filaggrin and Nrf2T. No thymine dimer positive cell was observed indicating the most positive skin impact from the regiment.  Conclusion: This research using different human skin models demonstrated that AAComplex can provide protection and damage repair caused by UV, at the ingredient level also when formulated in a serum or lotion formula. Skin may be best protected from UV damage when the regimen is used.   J Drugs Dermatol. 2024;23(5):366-375. doi:10.36849/JDD.7916.

Asunto(s)

Fibroblastos , Proteínas Filagrina , Metaloproteinasa 1 de la Matriz , Factor 2 Relacionado con NF-E2 , Factor de Necrosis Tumoral alfa , Rayos Ultravioleta , Humanos , Rayos Ultravioleta/efectos adversos , Fibroblastos/efectos de los fármacos , Fibroblastos/efectos de la radiación , Fibroblastos/metabolismo , Metaloproteinasa 1 de la Matriz/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Piel/efectos de la radiación , Piel/efectos de los fármacos , Piel/metabolismo , Protectores Solares/administración & dosificación , Protectores Solares/química , Protectores Solares/farmacología , Aminoácidos/administración & dosificación , Aminoácidos/farmacología , Aminoácidos/química , Interleucina-1alfa/metabolismo , Histamina/sangre , Crema para la Piel/administración & dosificación , Biomarcadores/metabolismo , Colágeno Tipo I , Proteínas de Filamentos Intermediarios/metabolismo , Antígeno Ki-67/metabolismo , Dímeros de Pirimidina , Células Cultivadas

RESUMEN

OBJECTIVE: To report variants in 26 candidate genes and describe the clinical features of Italian patients with keratoconus (KC). SUBJECTS/METHODS: Sixty-four patients with a confirmed diagnosis of KC were enrolled in this genetic association study. Patients were classified into two study groups according to whether they had a confirmed diagnosis of progressive or stable KC. A purpose-developed Next Generation Sequencing (NGS) panel was used to identify and analyse the coding exons and flanking exon/intron boundaries of 26 genes known to be associated with KC and corneal dystrophies. Interpretation of the pathogenic significance of variants was performed using in silico predictive algorithms. RESULT: The targeted NGS research identified a total of 167 allelic variants of 22 genes in the study population; twenty-four patients had stable keratoconus (n. 54 variants) and forty patients had progressive disease (n. 113 variants). We identified genetic variants of certain pathogenic significance in five patients with progressive KC; in addition, eight novel genetic variants were found in eight patients with progressive KC. Mutations of FLG, LOXHD1, ZNF469, and DOCK9 genes were twice more frequently identified in patients with progressive than stable disease. Filaggrin gene variants were found in 49 patients (76% of total), of whom 32 patients (80% of progressive KC group) had progressive disease. CONCLUSIONS: Targeted NGS research provided new insights into the causative effect of candidate genes in the clinical phenotype of keratoconus. Filaggrin mutations were found to represent a genetic risk factor for development of progressive disease in Italy.

Asunto(s)

Proteínas Filagrina , Secuenciación de Nucleótidos de Alto Rendimiento , Queratocono , Mutación , Humanos , Queratocono/genética , Queratocono/diagnóstico , Femenino , Masculino , Italia , Adulto , Persona de Mediana Edad , Adulto Joven , Adolescente , Proteínas de Filamentos Intermediarios/genética , Estudios de Asociación Genética , Proteínas Activadoras de GTPasa/genética , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Transcripción

Asunto(s)

Proteínas Filagrina , Humanos , Proteínas de Filamentos Intermediarios/genética , Mutación , Nanoporos , Secuenciación de Nanoporos/métodos

RESUMEN

The World Allergy Organization recommends probiotics in the prevention of atopic dermatitis in high-risk populations. Mutations in the filaggrin gene (FLG) result in an increased risk of atopic dermatitis through disruption of the skin keratin layer. This exploratory study investigated whether the preventive effect of maternal probiotics was evident in children with and without FLG mutations. DNA was collected from children (n = 228) from the Probiotic in the Prevention of Allergy among Children in Trondheim (ProPACT) study. Samples were analysed for 3 common FLG mutations (R501X, R2447X, and 2282del4). Overall, 7% of children had heterozygous FLG mutations; each child had only one of the 3 mutations. Mutation status had no association with atopic dermatitis (RR = 1.1; 95% CI 0.5 to 2.3). The risk ratio (RR) for having atopic dermatitis following maternal probiotics was 0.6 (95% CI 0.4 to 0.9) and RR was similar if the child expressed an FLG mutation (RR = 0.6; 95% CI 0.1 to 4.1) or wildtype FLG (RR = 0.6; 95% CI 0.4 to 0.9). The preventive  effect of probiotics for atopic dermatitis was also evident in children without FLG mutation. Larger confirmatory studies are needed.

Asunto(s)

Dermatitis Atópica , Proteínas Filagrina , Proteínas de Filamentos Intermediarios , Mutación , Probióticos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Dermatitis Atópica/genética , Dermatitis Atópica/prevención & control , Dermatitis Atópica/diagnóstico , Suplementos Dietéticos , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Heterocigoto , Proteínas de Filamentos Intermediarios/genética , Fenómenos Fisiologicos Nutricionales Maternos , Fenotipo , Probióticos/uso terapéutico , Probióticos/administración & dosificación , Factores de Riesgo , Resultado del Tratamiento

RESUMEN

The soft epidermis of mammals derives from the accumulation of keratohyaline granules in the granular layer, before maturing into corneocytes. Main proteins accumulated in the granular layer are pro-filaggrin and filaggrin that determine keratin clumping and later moisturization of the stratum corneum that remains flexible. This soft epidermis allows the high sensitivity of mammalian skin. Presence and thickness of the stratum granulosum varies among different species of mammals and even between different body regions of the same animal, from discontinuous to multilayered. These variations are evident using antibodies for filaggrin, a large protein that share common epitopes among placentals. Here we have utilized filaggrin antibodies (8959 and 466) and an acidic keratin antibody (AK2) for labeling placental, marsupial and monotreme epidermis. AK2 labeling appears mainly to detect K24 keratin, and less likely other acidic keratins. Immunoreactivity for filaggrin is absent in platypus, discontinuous in Echidna and in the tested marsupials. In placentals, it is inconstantly or hardly detected in the thin epidermis of bat, rodents, and lagomorphs with a narrow, mono-stratified and/or discontinuous granular layer. In contrast, where the granular layer is continuous or even stratified, both filaggrin and AK2 antibodies decorate granular cells. The ultrastructural analysis using the AK2 antibody on human epidermis reveals that a weak labeling is associated with keratohyalin granules and filamentous keratins of transitional keratinocytes and corneocytes. This observation suggests that basophilic filaggrin interacts with acidic keratins like K24 and determines keratin condensation into corneocytes of the stratum corneum.

Asunto(s)

Epidermis , Proteínas Filagrina , Proteínas de Filamentos Intermediarios , Queratinas , Proteínas de Filamentos Intermediarios/metabolismo , Animales , Queratinas/metabolismo , Epidermis/metabolismo , Humanos , Mamíferos/metabolismo , Queratinocitos/metabolismo , Inmunohistoquímica

RESUMEN

Loss-of-function (LoF) variants in the filaggrin (FLG) gene are the strongest known genetic risk factor for atopic dermatitis (AD), but the impact of these variants on AD outcomes is poorly understood. We comprehensively identified genetic variants through targeted region sequencing of FLG in children participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort. Twenty FLG LoF variants were identified, including 1 novel variant and 9 variants not previously associated with AD. FLG LoF variants were found in the cohort. Among these children, the presence of 1 or more FLG LoF variants was associated with moderate/severe AD compared with those with mild AD. Children with FLG LoF variants had a higher SCORing for Atopic Dermatitis (SCORAD) and higher likelihood of food allergy within the first 2.5 years of life. LoF variants were associated with higher transepidermal water loss (TEWL) in both lesional and nonlesional skin. Collectively, our study identifies established and potentially novel AD-associated FLG LoF variants and associates FLG LoF variants with higher TEWL in lesional and nonlesional skin.

Asunto(s)

Dermatitis Atópica , Proteínas Filagrina , Proteínas de Filamentos Intermediarios , Mutación con Pérdida de Función , Fenotipo , Dermatitis Atópica/genética , Dermatitis Atópica/patología , Humanos , Masculino , Femenino , Preescolar , Estudios Prospectivos , Lactante , Proteínas de Filamentos Intermediarios/genética , Predisposición Genética a la Enfermedad , Niño , Hipersensibilidad a los Alimentos/genética