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1.
Nat Commun ; 12(1): 5127, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493721

RESUMO

Intricate color patterns are a defining aspect of morphological diversity in the Felidae. We applied morphological and single-cell gene expression analysis to fetal skin of domestic cats to identify when, where, and how, during fetal development, felid color patterns are established. Early in development, we identify stripe-like alterations in epidermal thickness preceded by a gene expression pre-pattern. The secreted Wnt inhibitor encoded by Dickkopf 4 plays a central role in this process, and is mutated in cats with the Ticked pattern type. Our results bring molecular understanding to how the leopard got its spots, suggest that similar mechanisms underlie periodic color pattern and periodic hair follicle spacing, and identify targets for diverse pattern variation in other mammals.


Assuntos
Gatos/genética , Regulação da Expressão Gênica no Desenvolvimento , Pigmentação/genética , Animais , Animais Domésticos , Gatos/crescimento & desenvolvimento , Epiderme/crescimento & desenvolvimento , Epiderme/metabolismo , Genótipo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Queratinócitos/metabolismo , Mutação , Fenótipo , Análise de Célula Única , Pele/anatomia & histologia , Pele/crescimento & desenvolvimento , Pele/metabolismo , Via de Sinalização Wnt
2.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360617

RESUMO

Atopic dermatitis (AD or eczema) is the most common chronic inflammatory skin disorder worldwide. Ceramides (Cer) maintain skin barrier functions, which are disrupted in lesional skin of AD patients. However, Cer status during the pre-lesional phase of AD is not well defined. Using a variation of human AD-like preclinical model consisting of a 7-day topical exposure to ovalbumin (OVA), or control, we observed elevation of Cer C16 and C24. Skin mRNA quantification of enzymes involved in Cer metabolism [Cer synthases (CerS) and ceramidases (Asah1/Asah2)], which revealed augmented CerS 4, 5 and 6 and Asah1. Given the overall pro-apoptotic nature of Cer, local apoptosis was assessed, then quantified using novel morphometric measurements of cleaved caspase (Casp)-3-restricted immunofluorescence signal in skin samples. Apoptosis was induced in response to OVA. Because apoptosis may occur downstream of endoplasmic reticulum (ER) stress, we measured markers of ER stress-induced apoptosis and found elevated skin-associated CHOP protein upon OVA treatment. We previously substantiated the importance of mast cells (MC) in initiating early skin inflammation. OVA-induced Cer increase and local apoptosis were prevented in MC-deficient mice; however, they were restored following MC reconstitution. We propose that the MC/Cer axis is an essential pathogenic feature of pre-lesional AD, whose targeting may prevent disease development.


Assuntos
Apoptose , Ceramidas/metabolismo , Dermatite Atópica/patologia , Eczema/patologia , Mastócitos/patologia , Pele/patologia , Animais , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Eczema/induzido quimicamente , Eczema/tratamento farmacológico , Eczema/metabolismo , Feminino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/toxicidade , Pele/efeitos dos fármacos , Pele/metabolismo
3.
Molecules ; 26(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34443336

RESUMO

We develop a suitable delivery system for niaouli essential oil (NEO) using a nanoemulsification method for acne vulgaris. Prepared nanoemulsions (NEs) were characterized for droplet dimension, rheology, surface charge, and stability. The ability of NEO formulations against Propionibacterium acnes and Staphylococcus epidermidis was investigated and all formulations showed antiacne potential in vitro. Ex vivo permeation studies indicated significant improvement in drug permeations and steady state flux of all NEO-NEs compared to the neat NEO (p < 0.05). On the basis of the studied pharmaceutical parameters, enhanced ex vivo skin permeation, and marked effect on acne pathogens, formulation NEO-NE4 was found to be the best (oil (NEO; 10% v/v); Kolliphor EL (9.25% v/v), Carbitol (27.75% v/v), and water (53% v/v)). Concisely, the in vitro and ex vivo results revealed that nanoemulsification improved the delivery as well as bioactivities of NEO significantly.


Assuntos
Portadores de Fármacos/química , Melaleuca/química , Nanoestruturas/química , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Emulsões , Óleos Voláteis/metabolismo , Permeabilidade , Pele/metabolismo , Staphylococcus epidermidis/efeitos dos fármacos
4.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360634

RESUMO

Autophagy is an attractive process to researchers who are seeking novel potential treatments for various diseases. Autophagy plays a critical role in degrading damaged cellular organelles, supporting normal cell development, and maintaining cellular homeostasis. Because of the various effects of autophagy, recent human genome research has focused on evaluating the relationship between autophagy and a wide variety of diseases, such as autoimmune diseases, cancers, and inflammatory diseases. The skin is the largest organ in the body and provides the first line of defense against environmental hazards, including UV damage, chemical toxins, injuries, oxidative stress, and microorganisms. Autophagy takes part in endogenous defense mechanisms by controlling skin homeostasis. In this manner, regulating autophagy might contribute to the treatment of skin barrier dysfunctions. Various studies are ongoing to elucidate the association between autophagy and skin-related diseases in order to find potential therapeutic approaches. However, little evidence has been gathered about the relationship between autophagy and the skin. In this review, we highlight the previous findings of autophagy and skin barrier disorders and suggest potential therapeutic strategies. The recent research regarding autophagy in acne and skin aging is also discussed.


Assuntos
Autofagia , Dermatopatias/etiologia , Humanos , Terapia de Alvo Molecular , Permeabilidade , Pele/metabolismo , Dermatopatias/metabolismo , Dermatopatias/terapia
5.
Molecules ; 26(15)2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34361642

RESUMO

The skin is the largest multifunctional organ in the human body, serving as an excellent barrier against chemical and biological hazards [...].


Assuntos
Produtos Biológicos/uso terapêutico , Dermatopatias/tratamento farmacológico , Pele/metabolismo , Humanos , Pele/patologia , Dermatopatias/metabolismo , Dermatopatias/patologia
6.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445349

RESUMO

Adrenoleukodystrophy (X-ALD) is an X-linked genetic disorder caused by mutation of the ATP-binding cassette subfamily D member 1 gene, which encodes the peroxisomal membrane protein, adrenoleukodystrophy protein (ALDP). ALDP is associated with the transport of very-long-chain fatty acids (VLCFAs; carbon chain length ≥ 24) into peroxisomes. Defective ALDP leads to the accumulation of saturated VLCFAs in plasma and tissues, which results in damage to myelin and the adrenal glands. Here, we profiled the glycosphingolipid (GSL) species in fibroblasts from X-ALD patients. Quantitative analysis was performed using liquid chromatography-electrospray ionization-tandem mass spectrometry with a chiral column in multiple reaction monitoring (MRM) mode. MRM transitions were designed to scan for precursor ions of long-chain bases to detect GSLs, neutral loss of hexose to detect hexosylceramide (HexCer), and precursor ions of phosphorylcholine to detect sphingomyelin (SM). Our results reveal that levels of C25 and C26-containing HexCer, Hex2Cer, NeuAc-Hex2Cer, NeuAc-HexNAc-Hex2Cer, Hex3Cer, HexNAc-Hex3Cer, and SM were elevated in fibroblasts from X-ALD patients. In conclusion, we precisely quantified SM and various GSLs in fibroblasts from X-ALD patients and determined structural information of the elevated VLCFA-containing GSLs.


Assuntos
Adrenoleucodistrofia/metabolismo , Fibroblastos/metabolismo , Glicoesfingolipídeos/metabolismo , Adrenoleucodistrofia/patologia , Biópsia , Estudos de Casos e Controles , Células Cultivadas , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Feminino , Fibroblastos/patologia , Glicoesfingolipídeos/química , Humanos , Masculino , Pele/metabolismo , Pele/patologia
7.
Eur J Pharm Sci ; 166: 105985, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34455087

RESUMO

Non-ideal behaviour of mixed ions is disclosed in skin absorption experiments of mixed halide anions in excised pig skin. Comparison of skin absorption of pure and mixed ions shows enhanced penetration of chaotropic ions from mixed solutions. An experimental design and statistical analysis using a Scheffé {3,2} simplex-lattice allows investigating the full ternary diagram of anion mixtures of fluoride, bromide and iodide. Synergism in mixed absorption is observed for chaotropic bromide and iodide anions. A refined analysis highlighting specific interactions is made by considering the ratio of the absorbed amount to the ion activity instead of the directly measured absorbed amount. Statistical analysis discards non-significant effects and discloses specific interactions. Such interactions between bromide and iodide cause an absorption enhancement of their partner by a factor of 2-3 with respect to the case of ideal mixing. It is proposed that enhanced absorption from mixed solution involves the formation of neutral complex species of mixed bromide and iodide with endogenous magnesium or calcium inside stratum corneum.


Assuntos
Absorção Cutânea , Água , Animais , Ânions/metabolismo , Fluoretos/metabolismo , Pele/metabolismo , Soluções , Suínos , Água/metabolismo
8.
Biomolecules ; 11(8)2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34439887

RESUMO

The SARS-CoV-2 pandemic has completely disrupted the health systems of the entire planet. From the earliest months, it became increasingly clear that in addition to affecting the upper airways and lungs, there were other organs that could be affected. Among these, the skin became a real "sentinel signal" to be able to even suspect COVID-19. Background: this study deals with a little-explored issue for now: the study of skin immunopathology in SARS-CoV-2 positive subjects ascertained using the most reliable methods available. Methods: we used skin biopsy samples from SARS-CoV-2 positive and negative patients, studying morphology (Hematoxylin-Eosin), T lymphocyte population (CD4 and CD8), three markers such as HMGB-1, TIM-3 and HO-1 by immunohistochemistry. Results: although the presence of the CD4 and CD8 T population did not differ statistically significantly, we found greater activation and release of HMGB-1 in skin samples from SARS-CoV-2 positive patients, greater immunolabeling for TIM-3 at the level of CD4 and CD8 and a reduced expression of Heme oxygenase 1. Conclusions: these results support the possibility that there is immune deregulation in SARS-CoV-2 positive patients who develop skin manifestations of various kinds.


Assuntos
COVID-19/complicações , Proteína HMGB1/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Dermatopatias/metabolismo , Pele/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pele/patologia , Dermatopatias/etiologia , Dermatopatias/patologia , Linfócitos T/metabolismo
9.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361001

RESUMO

Epidermal progenitor cells divide symmetrically and asymmetrically to form stratified epidermis and hair follicles during late embryonic development. Flightless I (Flii), an actin remodelling protein, is implicated in Wnt/ß-cat and integrin signalling pathways that govern cell division. This study investigated the effect of altering Flii on the divisional orientation of epidermal progenitor cells (EpSCs) in the basal layer during late murine embryonic development and early adolescence. The effect of altering Flii expression on asymmetric vs. symmetric division was assessed in vitro in adult human primary keratinocytes and in vivo at late embryonic development stages (E16, E17 and E19) as well as adolescence (P21 day-old) in mice with altered Flii expression (Flii knockdown: Flii+/-, wild type: WT, transgenic Flii overexpressing: FliiTg/Tg) using Western blot and immunohistochemistry. Flii+/- embryonic skin showed increased asymmetrical cell division of EpSCs with an increase in epidermal stratification and elevated talin, activated-Itgb1 and Par3 expression. FliiTg/Tg led to increased symmetrical cell division of EpSCs with increased cell proliferation rate, an elevated epidermal SOX9, Flap1 and ß-cat expression, a thinner epidermis, but increased hair follicle number and depth. Flii promotes symmetric division of epidermal progenitor cells during murine embryonic development.


Assuntos
Divisão Celular , Proteínas dos Microfilamentos/genética , Células-Tronco Embrionárias Murinas/metabolismo , Pele/metabolismo , Transativadores/genética , Animais , Células Cultivadas , Queratinócitos/citologia , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Fatores de Transcrição SOX9/metabolismo , Pele/embriologia , Transativadores/metabolismo , beta Catenina/metabolismo
10.
Int J Mol Sci ; 22(16)2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34445455

RESUMO

Glycerol is used in many skin care products because it improves skin function. Anecdotal reports by patients on the National Psoriasis Foundation website also suggest that glycerol may be helpful for the treatment of psoriasis, although to date no experimental data confirm this idea. Glycerol entry into epidermal keratinocytes is facilitated by aquaglyceroporins like aquaporin-3 (AQP3), and its conversion to phosphatidylglycerol, a lipid messenger that promotes keratinocyte differentiation, requires the lipid-metabolizing enzyme phospholipase-D2 (PLD2). To evaluate whether glycerol inhibits inflammation and psoriasiform lesion development in the imiquimod (IMQ)-induced mouse model of psoriasis, glycerol's effect on psoriasiform skin lesions was determined in IMQ-treated wild-type and PLD2 knockout mice, with glycerol provided either in drinking water or applied topically. Psoriasis area and severity index, ear thickness and ear biopsy weight, epidermal thickness, and inflammatory markers were quantified. Topical and oral glycerol ameliorated psoriasiform lesion development in wild-type mice. Topical glycerol appeared to act as an emollient to induce beneficial effects, since even in PLD2 knockout mice topical glycerol application improved skin lesions. In contrast, the beneficial effects of oral glycerol required PLD2, with no improvement in psoriasiform lesions observed in PLD2 knockout mice. Our findings suggest that the ability of oral glycerol to improve psoriasiform lesions requires its PLD2-mediated conversion to phosphatidylglycerol, consistent with our previous report that phosphatidylglycerol itself improves psoriasiform lesions in this model. Our data also support anecdotal evidence that glycerol can ameliorate psoriasis symptoms and therefore might be a useful therapy alone or in conjunction with other treatments.


Assuntos
Glicerol/farmacologia , Imiquimode/efeitos adversos , Psoríase/tratamento farmacológico , Pele/metabolismo , Animais , Aquaporina 3/genética , Aquaporina 3/metabolismo , Modelos Animais de Doenças , Humanos , Imiquimode/farmacologia , Camundongos , Camundongos Knockout , Fosfolipase D/deficiência , Fosfolipase D/metabolismo , Psoríase/induzido quimicamente , Psoríase/genética , Psoríase/metabolismo
11.
Eur J Pharm Sci ; 166: 105975, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34391880

RESUMO

Anti-cutaneous melanoma activity of the skin-delivered gambogic acid (GA) has been reported in our previous study. However, it is difficult for GA to diffuse passively through intact skin without any enhancement means. In this study, a combination of chemical enhancers (EN: azone and propylene glycol) and physical ultrasound (US) was used to improve the percutaneous permeation of GA and enhance the anti-melanoma activity. The enhancement effect of the combination of EN and US (EN-US) on GA in vitro and in vivo was studied, and the enhancement mechanism and skin irritation were also evaluated. We showed that the parameters of US application at a constant frequency (30 kHz) with a duty cycle of 100% and intensity of 1.75 W/cm2 for 20 min were optimal. In vitro, EN-US showed a considerable enhancement of the permeation of GA, and the enhancement effect was stronger than that with the use of EN or US alone. In vivo antitumor study showed that the tumor growth was significantly inhibited after percutaneous administration of GA by EN-US, more than in the intravenous injection group. The penetration enhancement mechanism revealed that EN-US not only altered the structure of lipid bilayers and keratins to reduce the barrier effect of the stratum corneum but also produced diffusion channels in the skin under the cavitation effect of US, thereby promoting the skin penetration of GA. In addition, there was no observable skin irritation in mice after treatment with EN-US. Our study demonstrated that the combination of EN and US improved the skin permeation and retention of GA to enhance the anti-melanoma activity. This method also provides technical guidance for the future development of topical and transdermal therapeutic system of GA.


Assuntos
Melanoma , Neoplasias Cutâneas , Administração Cutânea , Animais , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Camundongos , Permeabilidade , Pele/metabolismo , Absorção Cutânea , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Xantonas
12.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361066

RESUMO

Ceramides, a class of sphingolipids containing a backbone of sphingoid base, are the most important and effective structural component for the formation of the epidermal permeability barrier. While ceramides comprise approximately 50% of the epidermal lipid content by mass, the content is substantially decreased in certain inflammatory skin diseases, such as atopic dermatitis (AD), causing improper barrier function. It is widely accepted that the endocannabinoid system (ECS) can modulate a number of biological responses in the central nerve system, prior studies revealed that activation of endocannabinoid receptor CB1, a key component of ECS, triggers the generation of ceramides that mediate neuronal cell fate. However, as the impact of ECS on the production of epidermal ceramide has not been studied, we here investigated whether the ECS stimulates the generation of epidermal ceramides in an IL-4-treated in vitro model of skin inflammation using N-palmitoyl serinol (PS), an analog of the endocannabinoid N-palmitoyl ethanolamine. Accordingly, an IL-4-mediated decrease in cellular ceramide levels was significantly stimulated in human epidermal keratinocytes (KC) following PS treatment through both de novo ceramide synthesis- and sphingomyelin hydrolysis-pathways. Importantly, PS selectively increases ceramides with long-chain fatty acids (FAs) (C22-C24), which mainly account for the formation of the epidermal barrier, through activation of ceramide synthase (CerS) 2 and Cer3 in IL-4-mediated inflamed KC. Furthermore, blockade of cannabinoid receptor CB1 activation by AM-251 failed to stimulate the production of total ceramide as well as long-chain ceramides in response to PS. These studies demonstrate that an analog of endocannabinoid, PS, stimulates the generation of specific ceramide species as well as the total amount of ceramides via the endocannabinoid receptor CB1-dependent mechanism, thereby resulting in the enhancement of epidermal permeability barrier function.


Assuntos
Ceramidas/metabolismo , Inflamação/metabolismo , Queratinócitos/metabolismo , Propanolaminas/farmacologia , Propilenoglicóis/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Pele/metabolismo , Células Cultivadas , Humanos , Técnicas In Vitro , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Propanolaminas/química , Propilenoglicóis/química , Pele/citologia , Pele/efeitos dos fármacos
13.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361084

RESUMO

Skin may be affected by many disorders that can be treated by topical applications of drugs on the action site. With the advent of nanotechnologies, new efficient delivery systems have been developed. Particularly, lipid-based nanosystems such as liposomes, ethosomes, transferosomes, solid lipid nanoparticles, nanostructured lipid carriers, cubosomes, and monoolein aqueous dispersions have been proposed for cutaneous application, reaching in some cases the market or clinical trials. This review aims to provide an overview of the different lipid-based nanosystems, focusing on their use for topical application. Particularly, biocompatible nanosystems able to dissolve lipophilic compounds and to control the release of carried drug, possibly reducing side effects, are described. Notably, the rationale to topically administer antioxidant molecules by lipid nanocarriers is described. Indeed, the structural similarity between the nanosystem lipid matrix and the skin lipids allows the achievement of a transdermal effect. Surely, more research is required to better understand the mechanism of interaction between lipid-based nanosystems and skin. However, this attempt to summarize and highlight the possibilities offered by lipid-based nanosystems could help the scientific community to take advantage of the benefits derived from this kind of nanosystem.


Assuntos
Permeabilidade da Membrana Celular , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Lipídeos/química , Nanopartículas/administração & dosagem , Pele/metabolismo , Animais , Humanos , Nanopartículas/química
14.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445132

RESUMO

Saponarin{5-hydroxy-2-(4-hydroxyphenyl)-6-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]-7-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxychromen-4-one}, a flavone found in young green barley leaves, is known to possess antioxidant, antidiabetic, and hepatoprotective effects. In the present study, the anti-inflammatory, anti-allergic, and skin-protective effects of saponarin were investigated to evaluate its usefulness as a functional ingredient in cosmetics. In lipopolysaccharide-induced RAW264.7 (murine macrophage) cells, saponarin (80 µM) significantly inhibited cytokine expression, including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, inducible nitric oxide synthase, and cyclooxygenase (COX)-2. Saponarin (80 µM) also inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 involved in the mitogen-activated protein kinase signaling pathway in RAW264.7 cells. Saponarin (40 µM) significantly inhibited ß-hexosaminidase degranulation as well as the phosphorylation of signaling effectors (Syk, phospholipase Cγ1, ERK, JNK, and p38) and the expression of inflammatory mediators (tumor necrosis factor [TNF]-α, IL-4, IL-5, IL-6, IL-13, COX-2, and FcεRIα/γ) in DNP-IgE- and DNP-BSA-stimulated RBL-2H3 (rat basophilic leukemia) cells. In addition, saponarin (100 µM) significantly inhibited the expression of macrophage-derived chemokine, thymus and activation-regulated chemokine, IL-33, thymic stromal lymphopoietin, and the phosphorylation of signaling molecules (ERK, p38 and signal transducer and activator of transcription 1 [STAT1]) in TNF-α- and interferon (IFN)-γ-stimulated HaCaT (human immortalized keratinocyte) cells. Saponarin (100 µM) also significantly induced the expression of hyaluronan synthase-3, aquaporin 3, and cathelicidin antimicrobial peptide (LL-37) in HaCaT cells, which play an important role as skin barriers. Saponarin remarkably inhibited the essential factors involved in the inflammatory and allergic responses of RAW264.7, RBL-2H3, and HaCaT cells, and induced the expression of factors that function as physical and chemical skin barriers in HaCaT cells. Therefore, saponarin could potentially be used to prevent and relieve immune-related skin diseases, including atopic dermatitis.


Assuntos
Antialérgicos/farmacologia , Anti-Inflamatórios/farmacologia , Apigenina/farmacologia , Glucosídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Citocinas/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Células HaCaT , Humanos , Mediadores da Inflamação/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Células RAW 264.7 , Pele/efeitos dos fármacos , Pele/metabolismo
15.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281245

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in the nuclear lamina. This accumulation elicits several alterations at the nuclear, cellular, and tissue levels that are phenotypically reflected in a systemic disorder with important alterations, mainly in the cardiovascular system, bones, skin, and overall growth, which results in premature death at an average age of 14.5 years. In 2020, lonafarnib became the first (and only) FDA approved drug for treating progeria. In this context, the present review focuses on the different therapeutic strategies currently under development, with special attention to the new small molecules described in recent years, which may represent the upcoming first-in-class drugs with new mechanisms of action endowed with effectiveness not only to treat but also to cure progeria.


Assuntos
Piperidinas/uso terapêutico , Progéria/terapia , Piridinas/uso terapêutico , Envelhecimento/genética , Senilidade Prematura/genética , Núcleo Celular/metabolismo , Senescência Celular/genética , Fibroblastos/metabolismo , Humanos , Lamina Tipo A/genética , Laminopatias/terapia , Mutação , Lâmina Nuclear/genética , Lâmina Nuclear/fisiologia , Fenótipo , Progéria/genética , Progéria/metabolismo , Pele/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia
16.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299063

RESUMO

Regulatory T cells (Tregs) suppress immune responses and maintain immunological self-tolerance and homeostasis. We currently investigated relationships between skin barrier condition and Treg behavior using skin barrier-disrupted mice. Skin barrier disruption was induced by repeated topical application of 4% sodium dodecyl sulfate (SDS) on mice. The number of CD4+ forkhead box protein P3 (Foxp3)+ Tregs was higher in 4% SDS-treated skins than in controls. This increasing was correlated with the degree of acanthosis. The numbers of interleukin (IL)-10+ and transforming growth factor (TGF)-ß+ Tregs also increased in 4% SDS-treated skins. Localization of IL-33 in keratinocytes shifted from nucleus to cytoplasm after skin barrier disruption. Notably, IL-33 promoted the migration of Tregs in chemotaxis assay. The skin infiltration of Tregs was cancelled in IL-33 neutralizing antibody-treated mice and IL-33 knockout mice. Thus, keratinocyte-derived IL-33 may induce Treg migration into barrier-disrupted skin to control the phase transition between healthy and inflammatory conditions.


Assuntos
Movimento Celular , Quimiotaxia , Dermatite/patologia , Interleucina-33/fisiologia , Pele/patologia , Linfócitos T Reguladores/imunologia , Animais , Dermatite/imunologia , Dermatite/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pele/metabolismo
17.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299088

RESUMO

Ceramides (Cers) with α-hydroxylated acyl chains comprise about a third of all extractable skin Cers and are required for permeability barrier homeostasis. We have probed here the effects of Cer hydroxylation on their behavior in lipid models comprising the major SC lipids, Cer/free fatty acids (C 16-C 24)/cholesterol, and a minor component, cholesteryl sulfate. Namely, Cers with (R)-α-hydroxy lignoceroyl chains attached to sphingosine (Cer AS), dihydrosphingosine (Cer AdS), and phytosphingosine (Cer AP) were compared to their unnatural (S)-diastereomers and to Cers with non-hydroxylated lignoceroyl chains attached to sphingosine (Cer NS), dihydrosphingosine (Cer NdS), and phytosphingosine (Cer NP). By comparing several biophysical parameters (lamellar organization by X-ray diffraction, chain order, lateral packing, phase transitions, and lipid mixing by infrared spectroscopy using deuterated lipids) and the permeabilities of these models (water loss and two permeability markers), we conclude that there is no general or common consequence of Cer α-hydroxylation. Instead, we found a rich mix of effects, highly dependent on the sphingoid base chain, configuration at the α-carbon, and permeability marker used. We found that the model membranes with unnatural Cer (S)-AS have fewer orthorhombically packed lipid chains than those based on the (R)-diastereomer. In addition, physiological (R)-configuration decreases the permeability of membranes, with Cer (R)-AdS to theophylline, and increases the lipid chain order in model systems with natural Cer (R)-AP. Thus, each Cer subclass makes a distinct contribution to the structural organization and function of the skin lipid barrier.


Assuntos
Ceramidas/química , Transição de Fase , Pele/química , Pele/metabolismo , Esfingosina/análogos & derivados , Esfingosina/química , Acilação , Humanos , Hidroxilação , Permeabilidade
18.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299118

RESUMO

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor expressed in all skin cell types, plays a key role in physiological and pathological processes. Several studies have shown that this receptor is involved in the prevention of inflammatory skin diseases, e.g., psoriasis, atopic dermatitis, representing a potential therapeutic target. We tested the safety profile and the biological activity of NPD-0614-13 and NPD-0614-24, two new synthetic AhR ligands structurally related to the natural agonist FICZ, known to be effective in psoriasis. NPD-0614-13 and NPD-0614-24 did not alter per se the physiological functions of the different skin cell populations involved in the pathogenesis of inflammatory skin diseases. In human primary keratinocytes stimulated with tumor necrosis factor-α or lipopolysaccharide the compounds were able to counteract the altered proliferation and to dampen inflammatory signaling by reducing the activation of p38MAPK, c-Jun, NF-kBp65, and the release of cytokines. Furthermore, the molecules were tested for their beneficial effects in human epidermal and full-thickness reconstituted skin models of psoriasis. NPD-0614-13 and NPD-0614-24 recovered the psoriasis skin phenotype exerting pro-differentiating activity and reducing the expression of pro-inflammatory cytokines and antimicrobial peptides. These data provide a rationale for considering NPD-0614-13 and NPD-0614-24 in the management of psoriasis.


Assuntos
Anti-Inflamatórios/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Catecóis/farmacologia , Diferenciação Celular , Inflamação/tratamento farmacológico , Compostos Organometálicos/farmacologia , Psoríase/tratamento farmacológico , Receptores de Hidrocarboneto Arílico/metabolismo , Pele/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Ligantes , Psoríase/metabolismo , Psoríase/patologia , Pele/metabolismo , Pele/patologia
19.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299150

RESUMO

Cera Flava (CF), a natural extract obtained from beehives, is widely used in dermatological products owing to its wound healing, wrinkle reduction, UV-protective, and skin cell turnover stimulation effects. However, its effect on AD-like skin lesions is unknown. In this study, we used a mouse model of AD to evaluate the effects of CP at the molecular and phenotypic levels. Topical house dust mite (HDM) sensitization and challenge were performed on the dorsal skin of NC/Nga mice to induce AD-like cutaneous lesions, phenotypes, and immunologic responses. The topical application of CF for 6 weeks relieved HDM-induced AD-like phenotypes, as quantified by the dermatitis severity score, scratching frequency, and skin moisture. CP decreased immunoglobulin E, histamine, and thymic stromal lymphopoietin levels. Histopathological analysis showed that CF decreased epidermal thickening and the number of mast cells. CF attenuated HDM-induced changes in the expression of skin barrier-related proteins. Furthermore, CF decreased the mRNA levels of inflammatory factors, including interleukin (IL)-1ß, IL-4, IL-13, IL-8, TARC, MDC, and RANTES, in dorsal skin tissue via the TLR2/MyD88/TRAF6/ERK pathway. CF influences skin barrier function and immune regulation to alleviate AD symptoms. It may therefore be an effective alternative to topical steroids for the treatment of AD.


Assuntos
Dermatite Atópica/tratamento farmacológico , Inflamação/prevenção & controle , Pele/efeitos dos fármacos , Ceras/farmacologia , Animais , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Histamina/metabolismo , Imunoglobulina E/metabolismo , Fatores Imunológicos/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Pyroglyphidae , Pele/imunologia , Pele/metabolismo , Pele/patologia
20.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298861

RESUMO

The pathogenesis of hidradenitis suppurativa (HS) is yet to be fully understood. However, inflammation is a key element in the development of skin lesions. The aim of this study was to evaluate the expression of monocyte chemotactic protein-1-induced protein-1 (MCPIP1) in the skin of patients suffering from HS. Skin biopsies of 15 patients with HS and 15 healthy controls were obtained and processed for immunohistochemistry, western blot, and real time PCR. The highest mean MCPIP1 mRNA expression was found in the inflammatory lesional skin of HS patients. It was significantly higher than MCPIP1 mRNA expression in the biopsies from both healthy controls and non-lesional skin of HS patients. Western blot analysis indicated that expression of MCPIP1 was elevated within both lesional and non-lesional skin compared to the healthy control. The increased MCPIP1 mRNA and protein expression level in HS lesions may indicate its possible role in the disease pathogenesis.


Assuntos
Hidradenite Supurativa/metabolismo , Queratinócitos/metabolismo , Ribonucleases/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica/métodos , Inflamação/metabolismo , Masculino , RNA Mensageiro/metabolismo , Pele/metabolismo
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