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1.
PLoS One ; 19(4): e0300687, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38593151

RESUMO

Fabry disease (FD) is a lysosomal storage disorder of X-linked inheritance. Mutations in the α-galactosidase A gene lead to cellular globotriaosylceramide (Gb3) depositions and triggerable acral burning pain in both sexes as an early FD symptom of unknown pathophysiology. We aimed at elucidating the link between skin cells and nociceptor sensitization contributing to FD pain in a sex-associated manner. We used cultured keratinocytes and fibroblasts of 27 adult FD patients and 20 healthy controls. Epidermal keratinocytes and dermal fibroblasts were cultured and immunoreacted to evaluate Gb3 load. Gene expression analysis of pain-related ion channels and pro-inflammatory cytokines was performed in dermal fibroblasts. We further investigated electrophysiological properties of induced pluripotent stem cell (iPSC) derived sensory-like neurons of a man with FD and a healthy man and incubated the cells with interleukin 8 (IL-8) or fibroblast supernatant as an in vitro model system. Keratinocytes displayed no intracellular, but membrane-bound Gb3 deposits. In contrast, fibroblasts showed intracellular Gb3 and revealed higher gene expression of potassium intermediate/small conductance calcium-activated potassium channel 3.1 (KCa 3.1, KCNN4) in both, men and women with FD compared to controls. Additionally, cytokine expression analysis showed increased IL-8 RNA levels only in female FD fibroblasts. Patch-clamp studies revealed reduced rheobase currents for both iPSC neuron cell lines incubated with IL-8 or fibroblast supernatant of women with FD. We conclude that Gb3 deposition in female FD patient skin fibroblasts may lead to increased KCa3.1 activity and IL-8 secretion. This may result in cutaneous nociceptor sensitization as a potential mechanism contributing to a sex-associated FD pain phenotype.


Assuntos
Doença de Fabry , Adulto , Masculino , Humanos , Feminino , Doença de Fabry/complicações , Doença de Fabry/genética , Doença de Fabry/diagnóstico , Interleucina-8/genética , Pele/metabolismo , alfa-Galactosidase/genética , Citocinas , Fibroblastos/metabolismo , Dor
2.
Sci Rep ; 14(1): 7962, 2024 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-38575628

RESUMO

The underlying study was carried out aiming at transdermal drug delivery (TDD) of Goniothalamus macrophyllus as sono-photo-sensitizer (SPS) using microneedle (MN) arrays with iontophoresis (MN-IP), electroporation (MN-EP) in conjunction with applying photodynamic therapy (PDT), sonodynamic therapy (SDT) and sono-photodynamic therapy (SPDT) as an up-to-date activated cancer treatment modality. Study was conducted on 120 male Swiss Albino mice, inoculated with Ehrlich ascites carcinoma (EAC) divided into 9 groups. We employed three different arrays of MN electrodes were used (parallel, triangular, and circular), EP, IP with different volts (6, 9, 12 V), an infrared laser and an ultrasound (pulsed and continuous wave) as our two energy sources. Results revealed that parallel 6 V TDD@MN@IP@EP can be used as effective delivery system for G. macrophyllus from skin directly to target EAC cells. In addition MN@IP@EP@TDD G. macrophyllus is a potential SPS for SPDT treatment of EAC. With respect to normal control mice and as opposed to the EAC untreated control mice, MN@EP@IP TDD G. macrophyllus in the laser, ultrasound, and combination activated groups showed a significant increase in the antioxidant markers TAC level and the GST, GR, Catalase, and SOD activities, while decrease in lipid peroxidation oxidative stress parameter MDA levels. In addition significantly increased apoptotic genes expressions (p53, caspase (3, 9), Bax, and TNF alpha) and on the other hand decreased anti- apoptotic (Bcl-2) and angiogenic (VEGF) genes expressions. Moreover significantly ameliorate liver and kidney function decreasing ALT, AST, urea and creatinine respectively. Furthermore MN@IP@EP@TDD G. macrophyllus combined with SPDT was very effective at reducing the growth of tumors and even causing cell death according to microscopic H&E stain results. This process may be related to a sono- and/or photochemical activation mechanism. According to the findings, MN@IP@EP@TDD G. macrophyllus has a lot of potential as a novel, efficient delivery method that in combination with infrared laser and ultrasound activation SPDT demonstrated promising anticancer impact for treating cancer.


Assuntos
Carcinoma , Goniothalamus , Masculino , Animais , Camundongos , Iontoforese , Administração Cutânea , Pele/metabolismo , Eletroporação/métodos , Carcinoma/metabolismo
3.
AAPS PharmSciTech ; 25(4): 72, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38575745

RESUMO

Atopic dermatitis is a skin condition characterized by lichenification (thickening and increased skin marking), eczematous lesions, dry skin, itching, and pruritus. Eugenol is an aromatic polyphenolic compound that has attracted the attention of researchers due to its anti-inflammatory, anti-oxidant, and anti-cancer properties. The primary goal of the present study was to develop and evaluate eugenol-loaded transethosomes for the treatment of AD. Eugenol-loaded transethosomes were formulated using the ethanol injection method and subsequently subjected to particle size analysis, zeta potential, entrapment efficiency, deformability index, and HRTEM analysis. Transethosomal gel was prepared by direct-dispersion method by using Carbopol 940®. Results showed transethosomes to be lipid bilayer structures with acceptable size, and high entrapment efficiency. Transethosomal formulation showed shear-thinning behavior. Eugenol-loaded transethosomal gel was significantly able to enhance the retention of the drug in the skin. Transethosomal gel was significantly able to reduce Ear thickness, DLC, TLC, and IL-6 levels in mice model of AD. These results indicate that the eugenol-loaded transethosomal gel could be a promising carrier for the topical administration of eugenol for the treatment of AD.


Assuntos
Dermatite Atópica , Eugenol , Animais , Camundongos , Eugenol/farmacologia , Absorção Cutânea , Administração Cutânea , Dermatite Atópica/tratamento farmacológico , Portadores de Fármacos/química , Pele/metabolismo , Antioxidantes/metabolismo
4.
PLoS One ; 19(4): e0299501, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38603673

RESUMO

Mathematical models of epidermal and dermal transport are essential for optimization and development of products for percutaneous delivery both for local and systemic indication and for evaluation of dermal exposure to chemicals for assessing their toxicity. These models often help directly by providing information on the rate of drug penetration through the skin and thus on the dermal or systemic concentration of drugs which is the base of their pharmacological effect. The simulations are also helpful in analyzing experimental data, reducing the number of experiments and translating the in vitro investigations to an in-vivo setting. In this study skin penetration of topically administered caffeine cream was investigated in a skin-on-a-chip microfluidic diffusion chamber at room temperature and at 32°C. Also the transdermal penetration of caffeine in healthy and diseased conditions was compared in mouse skins from intact, psoriatic and allergic animals. In the last experimental setup dexamethasone, indomethacin, piroxicam and diclofenac were examined as a cream formulation for absorption across the dermal barrier. All the measured data were used for making mathematical simulation in a three-compartmental model. The calculated and measured results showed a good match, which findings indicate that our mathematical model might be applied for prediction of drug delivery through the skin under different circumstances and for various drugs in the novel, miniaturized diffusion chamber.


Assuntos
Cafeína , Absorção Cutânea , Animais , Camundongos , Cafeína/farmacologia , Composição de Medicamentos , Microfluídica , Administração Cutânea , Pele/metabolismo , Modelos Teóricos
5.
Skin Res Technol ; 30(4): e13666, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38606717

RESUMO

BACKGROUND: It is known that heparinoid, a mucopolysaccharide polysulfate, is effective in improving rough skin and promoting blood circulation as medicines for diseased areas. However, heparinoid has a molecular weight of more than 5000 and cannot penetrate healthy stratum corneum. OBJECTIVE: We tested the efficacy of sulfated oligosaccharides with a molecular weight of less than 2000 on the human skin barrier function and moisturizing function. METHODS: We measured the transepidermal water loss (TEWL) of a three-dimensional human epidermis model cultured for 3 days after topical application of sulfated oligosaccharides, then observed the effects on TEWL suppression. The mRNA levels of proteins involved in intercellular lipid transport and storage in the stratum corneum, and moisture retention were measured using RT-qPCR. RESULTS: An increase in the mRNA levels of the ATP-binding cassette subfamily A member 12 (ABCA12), which transports lipids into stratum granulosum, was confirmed. Increases were also observed in the mRNA levels of filaggrin (FLG), which is involved in the generation of natural moisturizing factors, and of caspase-14, calpain-1 and bleomycin hydrolase, which are involved in the degradation of FLG. Antibody staining confirmed that the application of sodium trehalose sulfate to 3D model skin resulted in more ABCA12, ceramide, transglutaminase1, and FLG than those in controls. In a randomized, placebo-controlled, double-blind study, participants with low stratum corneum water content applied a lotion and emulsion containing sodium trehalose sulfate to their faces for 4 weeks. Sodium trehalose sulfate decreased the TEWL and increased the stratum corneum water content. CONCLUSION: These results suggest that cosmetics containing sodium trehalose sulfate act on the epidermis by increasing barrier factors and moisturizing factors, thereby ameliorating dry skin.


Assuntos
Heparinoides , Trealose , Humanos , Trealose/farmacologia , Trealose/metabolismo , Heparinoides/metabolismo , Heparinoides/farmacologia , Pele/metabolismo , Epiderme/metabolismo , Higiene da Pele , Água/metabolismo , RNA Mensageiro/metabolismo , Sódio/metabolismo , Sódio/farmacologia
6.
Biofabrication ; 16(3)2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38569494

RESUMO

The ever-stricter regulations on animal experiments in the field of cosmetic testing have prompted a surge in skin-related research with a special focus on recapitulation of thein vivoskin structurein vitro. In vitrohuman skin models are seen as an important tool for skin research, which in recent years attracted a lot of attention and effort, with researchers moving from the simplest 2-layered models (dermis with epidermis) to models that incorporate other vital skin structures such as hypodermis, vascular structures, and skin appendages. In this study, we designed a microfluidic device with a reverse flange-shaped anchor that allows culturing of anin vitroskin model in a conventional 6-well plate and assessing its barrier function without transferring the skin model to another device or using additional contraptions. Perfusion of the skin model through vascular-like channels improved the morphogenesis of the epidermis compared with skin models cultured under static conditions. This also allowed us to assess the percutaneous penetration of the tested caffeine permeation and vascular absorption, which is one of the key metrics for systemic drug exposure evaluation.


Assuntos
Epiderme , Pele , Animais , Pele/metabolismo , Epiderme/química , Epiderme/metabolismo , Absorção Cutânea , Cafeína/farmacologia , Cafeína/análise , Cafeína/metabolismo , Perfusão
7.
J Drugs Dermatol ; 23(4): SF378083s5-SF378083s10, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38564405

RESUMO

Skin aging is influenced by various exogenous and endogenous factors, ranging from ultraviolet (UV) light exposure and environmental toxins to biological sources, such as those that arise from normal metabolic processes (eg, free radicals). Glycation is the normal process by which glucose and other reducing sugars react with proteins to form an array of heterogeneous biomolecular structures known as advanced glycation end-products (AGEs) over time. However, AGEs are toxic to human cells and are implicated in the acceleration of inflammatory and oxidative processes, with their accumulation in the skin being associated with increased skin dulling and yellowing, fine lines, wrinkles, and skin laxity. Clinicians should become cognizant of how AGEs develop, what their biological consequences are, and familiarize themselves with available strategies to mitigate their formation. J Drugs Dermatol.  2024;23:4(Suppl 1):s5-10.


Assuntos
Produtos Finais de Glicação Avançada , Reação de Maillard , Humanos , Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/toxicidade , Açúcares/efeitos adversos , Açúcares/metabolismo , Pele/metabolismo , Radicais Livres/metabolismo
8.
J Diabetes ; 16(4): e13548, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38599828

RESUMO

OBJECTIVE: Several studies have demonstrated a significant association between the presence of the ear lobe crease (ELC) and cardiovascular disease. Advanced glycation end-products (AGEs) can affect the structures and functions of proteins and contribute to the development of diabetic complications. However, few studies have reported the relationship between AGEs and ELC. The purpose of this study was to investigate the correlation of skin autofluorescence (SAF)-AGEage (SAF-AGEs × age/100) with ELC. METHODS: This cross-sectional study enrolled 6500 eligible participants from two communities in Beijing. Skin autofluorescence (SAF) was used to measure skin AGEs (SAF-AGEs). SAF-AGEage was defined as AGEs × age/100. Binary logistic regression analysis and linear regression analysis nested in logistic models were applied to test outcomes. RESULTS: The overall prevalence of ELC with an average age of 62.7 years participants was 57.1% (n = 3714). Age, fasting blood glucose, systolic blood pressure, and lipoprotein cholesterol were all greater in participants with ELC. ELC-positive participants had higher prevalence of coronary heart disease. Logistic analysis showed a significantly positive relationship between quartiles of SAF-AGEage and ELC (odds ratio [OR] 1.526, 95% CI 1.324-1.759; OR 2.072, CI 1.791-2.396; and OR 2.983, CI 2.551-3.489) for the multivariate-adjusted models, respectively. Stratified research revealed that those with a history of diabetes, hypertension, or coronary heart disease experienced the connection between SAF-AGEage and ELC. CONCLUSION: ELC is associated with coronary heart disease, and the SAF-AGE has a potential role in ELC development in elder people.


Assuntos
Doença das Coronárias , Diabetes Mellitus , Humanos , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Estudos Transversais , Produtos Finais de Glicação Avançada/metabolismo , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Pele/metabolismo
9.
Int Wound J ; 21(4): e14862, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38572823

RESUMO

Oral mucosa is an ideal model for studying scarless wound healing. Researchers have shown that the key factors which promote scarless wound healing already exist in basal state of oral mucosa. Thus, to identify the other potential factors in basal state of oral mucosa will benefit to skin wound healing. In this study, we identified eight gene modules enriched in wound healing stages of human skin and oral mucosa through co-expression analysis, among which the module M8 was only module enriched in basal state of oral mucosa, indicating that the genes in module M8 may have key factors mediating scarless wound healing. Through bioinformatic analysis of genes in module M8, we found IGF2 may be the key factor mediating scarless wound healing of oral mucosa. Then, we purified IGF2 protein by prokaryotic expression, and we found that IGF2 could promote the proliferation and migration of HaCaT cells. Moreover, IGF2 promoted wound re-epithelialization and accelerated wound healing in a full-thickness skin wound model. Our findings identified IGF2 as a factor to promote skin wound healing which provide a potential target for wound healing therapy in clinic.


Assuntos
Pele , Cicatrização , Humanos , Pele/metabolismo , Reepitelização , Mucosa Bucal , Fibroblastos/metabolismo , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo
10.
Int J Biol Macromol ; 265(Pt 1): 130954, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38499125

RESUMO

Designing multifunctional wound dressings is a prerequisite to prevent infection and stimulate healing. In this study, a bilayer scaffold (BS) with a top layer (TL) comprising 3D printed pectin/polyacrylic acid/platelet rich fibrin hydrogel (Pec/PAA/PRF) and a bottom nanofibrous layer (NL) containing Pec/PAA/simvastatin (SIM) was produced. The biodegradable and biocompatible polymers Pec and PAA were cross-linked to form hydrogels via Ca2+ activation through galacturonate linkage and chelation, respectively. PRF as an autologous growth factor (GF) source and SIM together augmented angiogenesis and neovascularization. Because of 3D printing, the BS possessed a uniform distribution of PRF in TL and an average fiber diameter of 96.71 ± 18.14 nm was obtained in NL. The Young's modulus of BS was recorded as 6.02 ± 0.31 MPa and its elongation at break was measured as 30.16 ± 2.70 %. The wound dressing gradually released growth factors over 7 days of investigation. Furthermore, the BS significantly outperformed other groups in increasing cell viability and in vivo wound closure rate (95.80 ± 3.47 % after 14 days). Wounds covered with BS healed faster with more collagen deposition and re-epithelialization. The results demonstrate that the BS can be a potential remedy for skin tissue regeneration.


Assuntos
Fibrina Rica em Plaquetas , Sinvastatina/farmacologia , Sinvastatina/metabolismo , Pectinas/farmacologia , Pectinas/metabolismo , Pele/metabolismo , Impressão Tridimensional
11.
Exp Dermatol ; 33(3): e15052, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38483134

RESUMO

Skin forms the outer barrier of the body. Upon injury, successful wound healing in normal skin restores tissue damage and counteracts the loss of extracellular matrix (ECM) proteins and cells. Collagens and elastin are the most abundant structural proteins of the ECM. In homeostasis, collagen type I is the prevalent form, but it is replaced by type III collagen upon wounding, and only later remodelled. In turn, unsuccessful healing results in scars, which tend to be inflexible and inelastic as compared to normal elastic dermis. Scar inelasticity may be due to the absence of mature elastin fibre formation and cross-linking. In this review, the available information on the process of formation of new collagen and elastic fibres during wound healing is analysed. The distinct roles of elastin and collagen proteins during healing are revisited and future research directions proposed which may help improve clinical management of open wounds and scars.


Assuntos
Cicatriz , Matriz Extracelular , Humanos , Cicatriz/metabolismo , Matriz Extracelular/metabolismo , Colágeno/metabolismo , Pele/metabolismo , Elastina/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Cicatrização
12.
Int J Nanomedicine ; 19: 2733-2754, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38505165

RESUMO

Nanohydrogels (NH) are biodegradable polymers that have been extensively studied and utilized for various biomedical applications. Drugs in a topical medication are absorbed via the skin and carried to the intended location, where they are metabolized and eliminated from the body. With a focus on their pertinent contemporary treatments, this review aims to give a complete overview of recent advances in the creation and application of polymer NH in biomedicine. We will explore the key features that have driven advances in nanotechnology and discuss the significance of nanohydrogel-based formulations as vehicles for delivering therapeutic agents topically. The review will also cover the latest findings and references from the literature to support the advancements in nanotechnological technology related to the preparation and application of NH. In addition, we will also discuss the unique properties and potential applications of NH as drug delivery systems (DDS) for skin applications, underscoring their potential for effective topical therapeutic delivery. The challenge lies in efficiently delivering drugs through the skin's barrier to specific areas with high control. Environmentally sensitive systems, like polymer-based NH, show promise in treating dermatological conditions. Polymers are pivotal in developing these drug delivery systems, with NH offering advantages such as versatile drug loading, controlled release, and enhanced skin penetration.


Assuntos
Sistemas de Liberação de Medicamentos , Pele , Pele/metabolismo , Polímeros/metabolismo , Preparações Farmacêuticas , Nanotecnologia
13.
Nagoya J Med Sci ; 86(1): 1-15, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38505726

RESUMO

Whole-exome and whole-genome sequencing have become widespread in approximately the last 15 years, and the predisposing factors and pathomechanisms of inflammatory keratinization diseases, which have been unknown for a long time, have gradually been revealed. Hence, various inflammatory keratinization diseases are recognized to cause innate immunity hyperactivation. Therefore, we have been advocating for the clinical entity, "autoinflammatory keratinization diseases (AiKDs)" since 2017. AiKDs are inflammatory keratinization diseases caused by autoinflammatory-related pathomechanisms in the skin. The aberrant activation of innate immunity and the resultant autoinflammation in the epidermis and the superficial dermis in AiKDs cause hyperkeratosis in the epidermis. Our initially proposed concept of AiKDs included generalized pustular psoriasis and related conditions, pityriasis rubra pilaris type V, and familial keratosis lichenoides chronica. Since then, the number of diseases known to be AiKDs has increased as previously unknown disease-causing factors and pathogenetic mechanisms of inflammatory keratinization diseases have been clarified one by one. To date, porokeratosis, hidradenitis suppurative, keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome, and AiKDs associated with epidermal growth factor receptor (EGFR) deficiency or with hepatitis and autism have been recognized as AiKDs. The concept of AiKDs is considered extremely useful in our precise understanding of the pathogeneses behind inflammatory keratinization diseases and our appropriate treatment method selection. The number of AiKDs is expected to grow with the clarification of the pathomechanisms of further inflammatory keratinization diseases.


Assuntos
Ceratose , Neoplasias Cutâneas , Humanos , Ceratose/complicações , Ceratose/metabolismo , Ceratose/patologia , Pele/metabolismo , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologia , Síndrome
14.
Sci Rep ; 14(1): 6294, 2024 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-38491063

RESUMO

Real-time quaking-induced conversion assay (RT-QuIC) exploits templating activity of pathogenic prion protein for ultrasensitive detection of prions. We have utilized second generation RT-QuIC assay to analyze matching post-mortem cerebrospinal fluid and skin samples of 38 prion disease patients and of 30 deceased neurological controls. The analysis of cerebrospinal fluid samples led to 100% sensitivity and 100% specificity, but some samples had to be diluted before the analysis to alleviate the effect of present RT-QuIC inhibitors. The analysis of the corresponding skin samples provided 89.5% sensitivity and 100% specificity. The median seeding dose present in the skin was one order of magnitude higher than in the cerebrospinal fluid, despite the overall fluorescent signal of the skin samples was comparatively lower. Our data support the use of post-mortem cerebrospinal fluid for confirmation of prion disease diagnosis and encourage further studies of the potential of skin biopsy samples for intra-vitam prion diseases´ diagnostics.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Humanos , Príons/metabolismo , Doenças Priônicas/diagnóstico , Pele/metabolismo , Proteínas Priônicas , Bioensaio , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano
15.
Biochem Biophys Res Commun ; 705: 149745, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38452514

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease where Th2-type immune responses are dominant. In the lesional skin of AD, keratinocytes show differentiation defects and secrete proinflammatory cytokines and chemokines, amplifying Th2-type responses in AD. We previously reported that inducible loss of B-cell lymphoma 6 (Bcl6), a transcription repressor and a master transcriptional regulator of follicular helper T cells and germinal center B cells, in the whole body results in upregulation of Th2-related cytokines in mouse skin. However, the role of Bcl6 in keratinocytes remains to be clarified. Here, we observed that BCL6 positively regulates the expression of keratinocyte differentiation markers and plasma membrane localization of adherence junctional proteins in keratinocyte cell culture. Although keratinocyte-specific loss of Bcl6 alone did not induce AD-like skin inflammation, it aggravates MC903-induced AD-like skin inflammation in mice. In addition, Bcl6 expression is decreased in the epidermis of lesional skin from MC903-induced AD-like skin inflammation in mice. These results strongly suggest that Bcl6 downregulation in keratinocytes contributes to the development and aggravation of AD-like skin inflammation in mice.


Assuntos
Calcitriol/análogos & derivados , Dermatite Atópica , Camundongos , Animais , Epiderme/metabolismo , Pele/metabolismo , Queratinócitos/metabolismo , Citocinas/metabolismo , Inflamação/patologia , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo
16.
Nat Commun ; 15(1): 2328, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38499530

RESUMO

Cornified skin appendages, such as hair and nails, are major evolutionary innovations of terrestrial vertebrates. Human hair and nails consist largely of special intermediate filament proteins, known as hair keratins, which are expressed under the control of the transcription factor Hoxc13. Here, we show that the cornified claws of Xenopus frogs contain homologs of hair keratins and the genes encoding these keratins are flanked by promoters in which binding sites of Hoxc13 are conserved. Furthermore, these keratins and Hoxc13 are co-expressed in the claw-forming epithelium of frog toe tips. Upon deletion of hoxc13, the expression of hair keratin homologs is abolished and the development of cornified claws is abrogated in X. tropicalis. These results indicate that Hoxc13-dependent expression of hair keratin homologs evolved already in stem tetrapods, presumably as a mechanism for protecting toe tips, and that this ancestral genetic program was coopted to the growth of hair in mammals.


Assuntos
Queratinas Específicas do Cabelo , Fatores de Transcrição , Animais , Humanos , Fatores de Transcrição/metabolismo , Pele/metabolismo , Cabelo/metabolismo , Queratinas/genética , Queratinas/metabolismo , Anfíbios , Mamíferos/metabolismo
17.
Exp Dermatol ; 33(3): e15046, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38509711

RESUMO

Desmoplakin (DSP) is a desmosomal component expressed in skin and heart, essential for desmosome stability and intermediate filament connection. Pathogenic variants in the DSP gene encoding DSP, lead to heterogeneous skin, adnexa and heart-related phenotypes, including skin fragility, woolly hair (WH), palmoplantar keratoderma (PPK) and arrhythmogenic/dilated cardiomyopathy (ACM/DCM). The ambiguity of computer-based prediction analysis of pathogenicity and effect of DSP variants, indicates a necessity for functional analysis. Here, we report a heterozygous DSP variant that was not previously described, NM_004415.4:c.3337C>T (NM_004415.4(NP_004406.2):p.(Arg1113*)) in a patient with PPK, WH and ACM. RNA and protein analysis revealed ~50% reduction of DSP mRNA and protein expression. Patient's keratinocytes showed fragile cell-cell connections and perinuclear retracted intermediate filaments. Epidermal growth factor receptor (EGFR) is a transmembrane protein expressed in the basal epidermal layer involved in proliferation and differentiation, processes that are disrupted in the development of PPK, and in the regulation of the desmosome. In skin of the abovementioned patient, evident EGFR upregulation was observed. EGFR inhibition in patient's keratinocytes strongly increased DSP expression at the plasma membrane, improved intermediate filament connection with the membrane edges and reduced the cell-cell fragility. This cell phenotypic recovery was due to a translocation of DSP to the plasma membrane together with an increased number of desmosomes. These results indicate a therapeutic potential of EGFR inhibitors for disorders caused by DSP haploinsufficiency.


Assuntos
Desmoplaquinas , Receptores ErbB , Doenças do Cabelo , Ceratodermia Palmar e Plantar , Humanos , Desmoplaquinas/genética , Desmoplaquinas/metabolismo , Epiderme/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Doenças do Cabelo/genética , Queratinócitos/metabolismo , Ceratodermia Palmar e Plantar/genética , Fenótipo , Pele/metabolismo
18.
EMBO Mol Med ; 16(4): 870-884, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38462666

RESUMO

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing, and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Preclinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGFß pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support the clinical development of antivirals for the treatment of patients with RDEB and potentially other fibrotic diseases.


Assuntos
Carbamatos , Epidermólise Bolhosa Distrófica , Imidazóis , Pirrolidinas , Valina/análogos & derivados , Humanos , Animais , Camundongos , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Epidermólise Bolhosa Distrófica/patologia , Qualidade de Vida , Colágeno Tipo VII/metabolismo , Colágeno Tipo VII/uso terapêutico , Fibrose , Antivirais/farmacologia , Antivirais/uso terapêutico , Pele/metabolismo , Pele/patologia
19.
Int J Biol Macromol ; 265(Pt 2): 130958, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38503369

RESUMO

In this study, polyethylene glycol was grafted onto pullulan polysaccharides, resulting in the development of a novel adhesive termed PLUPE, offering superior drug loading capacity and rapid release efficiency. The efficacy of PLUPE was rigorously evaluated through various tests, including the tack test, shear strength test, 180° peel strength test, and human skin adhesion test. The results demonstrated that PLUPE exhibited a static shear strength that was 4.6 to 9.3 times higher than conventional PSAs, ensuring secure adhesion for over 3 days on human skin. A comprehensive analysis, encompassing electrical potential evaluation, calculation of interaction parameters, and FT-IR spectra, elucidated why improved the miscibility between the drug and PSAs, that the significant enhancement of intermolecular hydrogen bonding in the PLUPE structure. ATR-FTIR, rheological, and thermodynamic analyses further revealed that the hydrogen bonding network in PLUPE primarily interacted with polar groups in the skin. This interaction augmented the fluidity and free volume of PSA molecules, thereby promoting efficient drug release. The results confirmed the safety profile of PLUPE through skin irritation tests and MTT assays, bolstering its viability for application in TDDS patches. In conclusion, PLUPE represented a groundbreaking adhesive solution for TDDS patches, successfully overcoming longstanding challenges associated with PSAs.


Assuntos
Adesivos , Glucanos , Polietilenoglicóis , Humanos , Adesivos/química , Polietilenoglicóis/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Pele/metabolismo , Liberação Controlada de Fármacos , Polissacarídeos/farmacologia , Polissacarídeos/metabolismo , Administração Cutânea , Adesivo Transdérmico
20.
Int J Pharm ; 654: 123992, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38479485

RESUMO

Linagliptin is a dipeptidyl peptidase-4 inhibitor used for the management of type-2 diabetes. US FDA-approved products are available exclusively as oral tablets. The inherent drawbacks of the oral administration route necessitate exploring delivery strategies via other routes. In this study, we investigated the feasibility of transdermal administration of linagliptin through various approaches. We compared chemical penetration enhancers (oleic acid, oleyl alcohol, and isopropyl myristate) and physical enhancement techniques (iontophoresis, sonophoresis, microneedles, laser, and microdermabrasion) to understand their potential to improve transdermal delivery of linagliptin. To our knowledge, this is the first reported comparison of chemical and physical enhancement techniques for the transdermal delivery of a moderately lipophilic molecule. All physical enhancement techniques caused a significant reduction in the transepithelial electrical resistance of the skin samples. Disruption of the skin's structure post-treatment with physical enhancement techniques was further confirmed using characterization techniques such as dye binding, histology, and confocal microscopy. In vitro permeation testing (IVPT) demonstrated that the passive delivery of linagliptin across the skin was < 5 µg/sq.cm. Two penetration enhancers - oleic acid (93.39 ± 8.34 µg/sq.cm.) and oleyl alcohol (424.73 ± 42.86 µg/sq.cm.), and three physical techniques - iontophoresis (53.05 ± 0.79 µg/sq.cm.), sonophoresis (141.13 ± 34.22 µg/sq.cm.), and laser (555.11 ± 78.97 µg/sq.cm.) exceeded the desired target delivery for therapeutic effect. This study established that linagliptin is an excellent candidate for transdermal delivery and thoroughly compared chemical penetration and physical transdermal delivery strategies.


Assuntos
Álcoois Graxos , Linagliptina , Absorção Cutânea , Administração Cutânea , Linagliptina/metabolismo , Ácido Oleico/metabolismo , Pele/metabolismo , Iontoforese/métodos , Sistemas de Liberação de Medicamentos/métodos
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