Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 61.956
Filtrar
1.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204077

RESUMO

Skin cancers are growing in incidence worldwide and are primarily caused by exposures to ultraviolet (UV) wavelengths of sunlight. UV radiation induces the formation of photoproducts and other lesions in DNA that if not removed by DNA repair may lead to mutagenesis and carcinogenesis. Though the factors that cause skin carcinogenesis are reasonably well understood, studies over the past 10-15 years have linked the timing of UV exposure to DNA repair and skin carcinogenesis and implicate a role for the body's circadian clock in UV response and disease risk. Here we review what is known about the skin circadian clock, how it affects various aspects of skin physiology, and the factors that affect circadian rhythms in the skin. Furthermore, the molecular understanding of the circadian clock has led to the development of small molecules that target clock proteins; thus, we discuss the potential use of such compounds for manipulating circadian clock-controlled processes in the skin to modulate responses to UV radiation and mitigate cancer risk.


Assuntos
Carcinogênese/patologia , Relógios Circadianos/fisiologia , Neoplasias Cutâneas/fisiopatologia , Fenômenos Fisiológicos da Pele , Pele/patologia , Pele/fisiopatologia , Animais , Carcinogênese/efeitos da radiação , Relógios Circadianos/efeitos da radiação , Humanos , Fatores de Risco , Pele/efeitos da radiação , Fenômenos Fisiológicos da Pele/efeitos da radiação
2.
Biomolecules ; 11(6)2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34200112

RESUMO

The SARS-CoV-2 pandemic has dramatically changed our lives and habits. In just a few months, the most advanced and efficient health systems in the world have been overwhelmed by an infectious disease that has caused 3.26 million deaths and more than 156 million cases worldwide. Although the lung is the most frequently affected organ, the skin has also resulted in being a target body district, so much so as to suggest it may be a real "sentinel" of COVID-19 disease. Here we present 17 cases of skin manifestations studied and analyzed in recent months in our Department; immunohistochemical investigations were carried out on samples for the S1 spike-protein of SARS-CoV-2, as well as electron microscopy investigations showing evidence of virions within the constituent cells of the eccrine sweat glands and the endothelium of small blood vessels. Finally, we conduct a brief review of the COVID-related skin manifestations, confirmed by immunohistochemistry and/or electron microscopy, described in the literature.


Assuntos
COVID-19/patologia , SARS-CoV-2/isolamento & purificação , Dermatopatias/virologia , Pele/patologia , Adolescente , Adulto , COVID-19/diagnóstico , COVID-19/virologia , Criança , Eritema/diagnóstico , Eritema/patologia , Eritema/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/fisiologia , Pele/virologia , Dermatopatias/diagnóstico , Dermatopatias/patologia , Adulto Jovem
3.
Nat Commun ; 12(1): 4105, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215755

RESUMO

CCCH zinc finger proteins resolve immune responses by degrading the mRNAs of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-6. Here we report that one such family member, monocyte chemotactic protein-induced protein 3 (MCPIP3, also named ZC3H12C or Regnase-3), promotes skin inflammation by simultaneously enhancing TNF in macrophages and repressing IL-6 in plasmacytoid dendritic cells (pDCs). MCPIP3 is positively associated with psoriasis pathogenesis, and highly expressed by macrophages and pDCs. MCPIP3-deficient macrophages produce less TNF and IL-12p40. However, MCPIP3-deficient pDCs secrete significantly more IL-6. This enhanced intradermal IL-6 may alleviate imiquimod-induced skin inflammation. As a result, MCPIP3-deficient mice are protected from imiquimod-induced psoriasiform lesions. Furthermore, early exposure to pDC-derived IL-6 suppresses macrophage-derived TNF and IL-12p40. Mechanistically, MCPIP3 could directly degrade mRNAs of IL-6, Regnase-1, and IκBζ. In turn, Regnase-1 could degrade MCPIP3 mRNAs. Our study identifies a critical post-transcriptional mechanism that synchronizes myeloid cytokine secretion to initiate autoimmune skin inflammation.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Citocinas/metabolismo , Dermatite/metabolismo , Endorribonucleases/metabolismo , Inflamação/metabolismo , Células Mieloides/metabolismo , Ribonucleases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Quimiocina CCL2 , Células Dendríticas , Endorribonucleases/deficiência , Endorribonucleases/genética , Epigenômica , Humanos , Imiquimode , Inflamação/patologia , Interleucina-6/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Psoríase , Ribonucleases/deficiência , Ribonucleases/genética , Pele/patologia , Fator de Necrose Tumoral alfa/metabolismo
5.
Nutrients ; 13(6)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34207960

RESUMO

Psoriasis is an immune-mediated systemic disease that may be treated with probiotics. In this study, probiotic strains that could or could not decrease interleukin (IL)-17 levels were applied to imiquimod (IMQ)-induced psoriasis-like mice via oral administration. Bifidobacteriumadolescentis CCFM667, B. breve CCFM1078, Lacticaseibacillusparacasei CCFM1074, and Limosilactobacillus reuteri CCFM1132 ameliorated psoriasis-like pathological characteristics and suppressed the release of IL-23/T helper cell 17 (Th17) axis-related inflammatory cytokines, whereas B. animalis CCFM1148, L. paracasei CCFM1147, and L. reuteri CCFM1040 neither alleviated the pathological characteristics nor reduced the levels of inflammatory cytokines. All effective strains increased the contents of short-chain fatty acids, which were negatively correlated with the levels of inflammatory cytokines. By performing 16S rRNA gene sequencing, the diversity of gut microbiota in psoriasis-like mice was found to decrease, but all effective strains made some specific changes to the composition of gut microbiota compared to the ineffective strains. Furthermore, except for B. breve CCFM1078, all other effective strains decreased the abundance of the family Rikenellaceae, which was positively correlated with psoriasis-like pathological characteristics and was negatively correlated with propionate levels. These findings demonstrated effects of strain-specificity, and how probiotics ameliorated psoriasis and provide new possibilities for the treatment of psoriasis.


Assuntos
Microbioma Gastrointestinal , Probióticos/uso terapêutico , Psoríase/dietoterapia , Psoríase/microbiologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bifidobacterium/fisiologia , Citocinas/imunologia , Citocinas/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Feminino , Imiquimode , Interleucinas/análise , Interleucinas/metabolismo , Lactobacillaceae/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Probióticos/farmacologia , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Células Th17/imunologia
6.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200205

RESUMO

Skin is innervated by a multitude of sensory nerves that are important to the function of this barrier tissue in homeostasis and injury. The role of innervation and neuromediators has been previously reviewed so here we focus on the role of the transient receptor potential cation channel, subfamily V member 1 (TRPV1) in wound healing, with the intent of targeting it in treatment of non-healing wounds. TRPV1 structure and function as well as the outcomes of TRPV1-targeted therapies utilized in several diseases and tissues are summarized. In skin, keratinocytes, sebocytes, nociceptors, and several immune cells express TRPV1, making it an attractive focus area for treating wounds. Many intrinsic and extrinsic factors confound the function and targeting of TRPV1 and may lead to adverse or off-target effects. Therefore, a better understanding of what is known about the role of TRPV1 in skin and wound healing will inform future therapies to treat impaired and chronic wounds to improve healing.


Assuntos
Dermatopatias/patologia , Pele/patologia , Canais de Cátion TRPV/metabolismo , Cicatrização , Animais , Humanos , Pele/efeitos dos fármacos , Pele/metabolismo , Dermatopatias/tratamento farmacológico , Dermatopatias/metabolismo
7.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200222

RESUMO

Collagen hydrolysates have been suggested as a favorable antiaging modality in skin photoaged by persistent exposure to ultraviolet radiation (UV). The current study evaluated the beneficial effect of collagen hydrolysates (fsCH) extracted from Pangasius hypophthalmus fish skin on wrinkle formation and moisture preservation in dorsal skin of hairless mice challenged with UV-B. Inter-comparative experiments were conducted for anti-photoaging among fsCH, retinoic acid (RA), N-acetyl-D-glucosamine (NAG), and glycine-proline-hydroxyproline (GPH). Treating human HaCaT keratinocytes with 100-200 µg/mL fsCH reciprocally ameliorated the expression of aquaporin 3 (AQP3) and CD44 deranged by UV-B. The UV-B-induced deep furrows and skin thickening were improved in parched dorsal skin of mice supplemented with 206-412 mg/kg fsCH as well as RA and GPH. The UV-B irradiation enhanced collagen fiber loss in the dorsal dermis, which was attenuated by fsCH through enhancing procollagen conversion to collagen. The matrix metalloproteinase expression by UV-B in dorsal skin was diminished by fsCH, similar to RA and GPH, via blockade of collagen degradation. Supplementing fsCH to UV-B-irradiated mice decreased transepidermal water loss in dorsal skin with reduced AQP3 level and restored keratinocyte expression of filaggrin. The expression of hyaluronic acid synthase 2 and hyaluronidase 1 by UV-B was remarkably ameliorated with increased production of hyaluronic acid by treating fsCH to photoaged mice. Taken together, fsCH attenuated photoaging typical of deep wrinkles, epidermal thickening, and skin water loss, like NAG, RA, or GPH, through inhibiting collagen destruction and epidermal barrier impairment.


Assuntos
Colágeno/farmacologia , Proteínas na Dieta/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Dermatopatias/tratamento farmacológico , Pele/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Animais , Masculino , Camundongos , Camundongos Pelados , Pele/patologia , Pele/efeitos da radiação , Envelhecimento da Pele/patologia , Envelhecimento da Pele/efeitos da radiação , Dermatopatias/etiologia , Dermatopatias/patologia
8.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199374

RESUMO

BACKGROUND: Skinboosters represent the latest category of hyaluronan (HA) hydrogels released for aesthetic purposes. Different from originally developed gels, they are intended for more superficial injections, claiming a skin rejuvenation effect through hydration and possibly prompting biochemical effects in place of the conventional volumetric action. Here, three commercial skinboosters were characterized to unravel the scientific basis for such indication and to compare their performances. METHODS: Gels were evaluated for water-soluble/insoluble-HA composition, rheology, hydration, cohesivity, stability and effect, in vitro, on human dermal fibroblasts towards the production of extracellular matrix components. RESULTS: Marked differences in the insoluble-hydrogel amount and in the hydrodynamic parameters for water-soluble-HA chains were evidenced among the gels. Hydration, rigidity and cohesivity also varied over a wide range. Sensitivity to hyaluronidases and Reactive Oxygen Species was demonstrated allowing a stability ranking. Slight differences were found in gels' ability to prompt elastin expression and in ColIV/ColI ratio. CONCLUSIONS: A wide panel of biophysical and biochemical parameters for skinboosters was provided, supporting clinicians in the conscious tuning of their use. Data revealed great variability in gels' behavior notwithstanding the same clinical indication and unexpected similarities to the volumetric formulations. Data may be useful to improve customization of gel design toward specific uses.


Assuntos
Ácido Hialurônico/química , Hialuronoglucosaminidase/genética , Hidrogéis/química , Pele/efeitos dos fármacos , Elastina/química , Fibroblastos/efeitos dos fármacos , Humanos , Hialuronoglucosaminidase/química , Injeções , Espécies Reativas de Oxigênio/química , Rejuvenescimento/fisiologia , Reologia , Pele/crescimento & desenvolvimento , Pele/patologia , Envelhecimento da Pele/genética , Viscosidade
9.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206295

RESUMO

The present study investigated the effect of spray-dried algae-rosemary particles against pollution-induced damage using ex-vivo human biopsies exposed to diesel engine exhaust (DEE). For this, the complexation of hydroalcoholic rosemary extract with Chlorella (RCH) and Spirulina (RSP) protein powders was conducted. The process efficiency and concentration of rosmarinic acid (RA), carnosic acid (CA), and carnosol (CR) phenolic compounds of both products were compared. The RSP spray-dried production was more efficient, and RSP particles presented higher CR and CA and similar RA concentrations. Therefore, spray-dried RSP particles were prioritized for the preparation of a gel formulation that was investigated for its ability to mitigate pollution-induced skin oxinflammatory responses. Taken altogether, our ex-vivo data clearly demonstrated the ability of RSP gel to prevent an oxinflammatory phenomenon in cutaneous tissue by decreasing the levels of 4-hydroxynonenal protein adducts (4HNE-PA) and active matrix metalloproteinase-9 (MMP-9) as well as by limiting the loss of filaggrin induced by DEE exposure. Our results suggest that the topical application of spirulina-rosemary gel is a good approach to prevent pollution-induced skin aging/damage.


Assuntos
Antioxidantes , Chlorella/química , Cinamatos/química , Depsídeos/química , Exposição Ambiental/efeitos adversos , Rosmarinus/química , Envelhecimento da Pele/efeitos dos fármacos , Pele , Antioxidantes/química , Antioxidantes/farmacologia , Células Cultivadas , Humanos , Pele/lesões , Pele/metabolismo , Pele/patologia
10.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202733

RESUMO

Thymoquinone is a natural bioactive with significant therapeutic activity against multiple ailments including wound healing. The poor aqueous solubility and low skin permeability limit its therapeutic efficacy. The present investigation aimed to improve the biopharmaceutical attributes of thymoquinone to enhance its topical efficacy in wound healing. A nanoemulsion-based hydrogel system was designed and characterized as a nanotechnology-mediated drug delivery approach to improve the therapeutic efficacy of thymoquinone, utilizing a high-energy emulsification technique. The black seed oil, as a natural home of thymoquinone, was utilized to improve the drug loading capacity of the developed nanoemulsion system and reduced the oil droplet size to <100 nm through ultrasonication. The influence of formulation composition, and the ultrasonication process conditions, were investigated on the mean globule size and polydispersity index of the generated nanoemulsion. Irrespective of surfactant/co-surfactant ratio and % concentration of surfactant/co-surfactant mixture, the ultrasonication time had a significant (p < 0.05) influence on the mean droplet size and polydispersity index of the generated nanoemulsion. The developed nanoemulgel system of thymoquinone demonstrated the pseudoplastic behavior with thixotropic properties, and this behavior is desirable for topical application. The nanoemulgel system of thymoquinone exhibited significant enhancement (p < 0.05) in skin penetrability and deposition characteristics after topical administration compared to the conventional hydrogel system. The developed nanoemulgel system of thymoquinone exhibited quicker and early healing in wounded Wistar rats compared to the conventional hydrogel of thymoquinone, while showing comparable healing efficacy with respect to marketed silver sulfadiazine (1%) cream. Furthermore, histopathology analysis of animals treated with a developed formulation system demonstrated the formation of the thick epidermal layer, papillary dermis along with the presence of extensive and organized collagen fibers in newly healed tissues. The outcome of this investigation signifies that topical delivery of thymoquinone through nanoemulgel system is a promising candidate which accelerates the process of wound healing in preclinical study.


Assuntos
Benzoquinonas , Sistemas de Liberação de Medicamentos , Nanopartículas , Absorção Cutânea/efeitos dos fármacos , Pele/metabolismo , Cicatrização/efeitos dos fármacos , Administração Tópica , Animais , Benzoquinonas/química , Benzoquinonas/farmacocinética , Benzoquinonas/farmacologia , Emulsões , Nanopartículas/química , Nanopartículas/uso terapêutico , Ratos , Ratos Wistar , Pele/patologia
11.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203694

RESUMO

Proper functioning of cells-their ability to divide, differentiate, and regenerate-is dictated by genomic stability. The main factors contributing to this stability are the telomeric ends that cap chromosomes. Telomere biology and telomerase activity have been of interest to scientists in various medical science fields for years, including the study of both cancer and of senescence and aging. All these processes are accompanied by telomere-length modulation. Maintaining the key levels of telomerase component (hTERT) expression and telomerase activity that provide optimal telomere length as well as some nontelomeric functions represents a promising step in advanced anti-aging strategies, especially in dermocosmetics. Some known naturally derived compounds contribute significantly to telomere and telomerase metabolism. However, before they can be safely used, it is necessary to assess their mechanisms of action and potential side effects. This paper focuses on the metabolic potential of natural compounds to modulate telomerase and telomere biology and thus prevent senescence and skin aging.


Assuntos
Envelhecimento/metabolismo , Produtos Biológicos/farmacologia , Pele/patologia , Telomerase/metabolismo , Telômero/metabolismo , Animais , Humanos , Pele/efeitos dos fármacos
12.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203771

RESUMO

Melanoma develops from malignant transformations of the pigment-producing melanocytes. If located in the basal layer of the skin epidermis, melanoma is referred to as cutaneous, which is more frequent. However, as melanocytes are be found in the eyes, ears, gastrointestinal tract, genitalia, urinary system, and meninges, cases of mucosal melanoma or other types (e.g., ocular) may occur. The incidence and morbidity of cutaneous melanoma (cM) are constantly increasing worldwide. Australia and New Zealand are world leaders in this regard with a morbidity rate of 54/100,000 and a mortality rate of 5.6/100,000 for 2015. The aim of this review is to consolidate and present the data related to the aetiology and pathogenesis of cutaneous melanoma, thus rendering them easier to understand. In this article we will discuss these problems and the possible impacts on treatment for this disease.


Assuntos
Melanoma/etiologia , Neoplasias Cutâneas/etiologia , Animais , Predisposição Genética para Doença , Humanos , Melanoma/genética , Melanoma/patologia , Fatores de Risco , Transdução de Sinais/efeitos da radiação , Pele/patologia , Pele/efeitos da radiação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
13.
Molecules ; 26(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203841

RESUMO

Screening for systemic amyloidosis is typically carried out with abdominal fat aspirates with varying reported sensitivities. Fat aspirates are preferred for use in primary screening instead of organ biopsies as they are less invasive and thereby minimize the potential risk of complications. At Odense Amyloidosis Center, we performed a prospective study on whether the combined use of fat aspirate and tru-cut skin biopsy could increase the diagnostic sensitivity. Both fat aspirates and skin biopsies were screened with Congo Red staining, and positive biopsies were subsequently subtyped using immunoelectron microscopy and mass spectrometry. Seventy-six patients were included. In total, 24 patients had systemic amyloidosis (11 AL, 12 wtATTR, 1 AA), and 6 patients had localized amyloidosis. Combined fat aspirate and skin biopsy were Congo Red-positive in 15 patients (overall sensitivity (OS) 62.5%). Fat aspirates were positive in 14 patients (OS 58.3%), and the skin biopsy was positive in 5 patients (OS 20.8%). In only one patient did the skin biopsy add extra diagnostic information. The sensitivity differed between AL and ATTR amyloidosis-81.8% and 41.7%, respectively. Using skin biopsy as the only screening method is not recommended.


Assuntos
Proteínas Amiloidogênicas/análise , Amiloidose/diagnóstico , Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Tecido Adiposo/patologia , Adulto , Idoso , Amiloide/análise , Amiloidose/metabolismo , Biópsia/efeitos adversos , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/metabolismo , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Pele/patologia , Coloração e Rotulagem/métodos , Gordura Subcutânea/patologia
14.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205035

RESUMO

Hyperpigmentation is a dermatological condition characterized by the overaccumulation and/or oversecretion of melanin pigment. The efficacy of curcumin as an anti-melanogenic therapeutic has been recognized, but the poor stability and solubility that have limited its use have inspired the synthesis of novel curcumin analogs. We have previously reported on comparisons of the anti-melanogenic activity of four novel chemically modified curcumin (CMC) analogs, CMC2.14, CMC2.5, CMC2.23 and CMC2.24, with that of parent curcumin (PC), using a B16F10 mouse melanoma cell model, and we have investigated mechanisms of inhibition. In the current study, we have extended our findings using normal human melanocytes from a darkly pigmented donor (HEMn-DP) and we have begun to study aspects of melanosome export to human keratinocytes. Our results showed that all the CMCs downregulated the protein levels of melanogenic paracrine mediators, endothelin-1 (ET-1) and adrenomedullin (ADM) in HaCaT cells and suppressed the phagocytosis of FluoSphere beads that are considered to be melanosome mimics. All the three CMCs were similarly potent (except CMC2.14, which was highly cytotoxic) in inhibiting melanin production; furthermore, they suppressed dendricity in HEMn-DP cells. CMC2.24 and CMC2.23 robustly suppressed cellular tyrosinase activity but did not alter tyrosinase protein levels, while CMC2.5 did not suppress tyrosinase activity but significantly downregulated tyrosinase protein levels, indicative of a distinctive mode of action for the two structurally related CMCs. Moreover, HEMn-DP cells treated with CMC2.24 or CMC2.23 partially recovered their suppressed tyrosinase activity after cessation of the treatment. All the three CMCs were nontoxic to human dermal fibroblasts while PC was highly cytotoxic. Our results provide a proof-of-principle for the novel use of the CMCs for skin depigmentation, since at low concentrations, ranging from 5 to 25 µM, the CMCs (CMC2.24, CMC2.23 and CMC2.5) were more potent anti-melanogenic agents than PC and tetrahydrocurcumin (THC), both of which were ineffective at melanogenesis at similar doses, as tested in HEMn-DP cells (with PC being highly toxic in dermal fibroblasts and keratinocytes). Further studies to evaluate the efficacy of CMCs in human skin tissue and in vivo studies are warranted.


Assuntos
Curcumina/farmacologia , Hiperpigmentação/tratamento farmacológico , Melaninas/biossíntese , Melanoma Experimental/tratamento farmacológico , Adrenomedulina/genética , Animais , Curcumina/análogos & derivados , Curcumina/química , Endotelina-1/genética , Humanos , Hiperpigmentação/metabolismo , Hiperpigmentação/patologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Melaninas/antagonistas & inibidores , Melanócitos/efeitos dos fármacos , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Melanossomas/efeitos dos fármacos , Melanossomas/genética , Camundongos , Fagocitose/genética , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia
15.
Nat Commun ; 12(1): 4404, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285225

RESUMO

Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-ß (TGFß) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFß induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFß on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFß-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFß signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.


Assuntos
Autofagia/genética , Epigênese Genética , Histona Acetiltransferases/metabolismo , Escleroderma Sistêmico/patologia , Fator de Crescimento Transformador beta/metabolismo , Adulto , Idoso , Animais , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Biópsia , Estudos de Casos e Controles , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Fibroblastos , Fibrose , Técnicas de Inativação de Genes , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Células NIH 3T3 , Cultura Primária de Células , Receptores de Fatores de Crescimento Transformadores beta , Transdução de Sinais/genética , Pele/citologia , Pele/patologia , Proteína Smad3/metabolismo , Adulto Jovem
16.
BMC Infect Dis ; 21(1): 652, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34229603

RESUMO

BACKGROUND: Palmoplantar hyperkeratosis is a cutaneous manifestation that had not been clearly associated with infection by the human T-cell lymphotropic virus, which is a retrovirus that in most cases does not develop clinical pathologies and its symptoms may be undetected. The skin is one of the most affected organs, however until now only seborrheic dermatitis, xerosis/ichthyosis and infective dermatitis associated with HTLV-1 have been described as cutaneous clinical manifestations of this disease. CASE PRESENTATION: We present the case of a 36-year-old male patient with serologically documented HTLV-1 infection, who presented symptoms of diarrhea, malabsorption due to Strongyloides stercoralis, and in whom a physical examination revealed an association with generalized xerosis and palmoplantar keratoderma confirmed by skin biopsy. Other infectious etiologies and malignancy were ruled out. This clinical manifestation was managed with dermal hydration, and skin care which improved the thickened skin and make it less noticeable. CONCLUSIONS: According to our experience, this is the first reported case of palmoplantar keratoderma associated with a human lymphotropic virus infection. This is a skin manifestation that has not been confirmed in conjunction with HTLV-I before. This implies that palmoplantar keratoderma is a new clinical manifestation of this infection, that should be considered in the initial approach of patients in endemic areas with these dermatological characteristics.


Assuntos
Infecções por HTLV-I/complicações , Ceratodermia Palmar e Plantar/etiologia , Adulto , Biópsia , Humanos , Ceratodermia Palmar e Plantar/terapia , Masculino , Pele/patologia
19.
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
20.
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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...