RESUMO
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, structured knowledge to mitigate a patient's specific risk of developing adverse events are limited. Nevertheless, there is an exponential growth of clinical studies combining conventional therapies such as radiation therapy (RT) with ICIs. Cutaneous reactions are among the most common adverse events after monotherapy with either ICIs or RT. So far, little is known about interindividual differences for the risk of developing severe tissue toxicity after the combination of RT with ICIs, and the underlying biological mechanisms are ill defined. We used experimental models of RT-induced skin injury to analyze skin toxicity after simultaneous application of ICIs. We compared different RT regimens such as fractionated or stereotactic RT with varying dose intensity. Strikingly, we found that simultaneous application of RT and ICIs did not significantly aggravate acute skin injury in two different mouse strains. Detailed examination of long-term tissue damage of the skin revealed similar signs of epidermal hyperplasia, dermal fibrosis, and adnexal atrophy. In summary, we here present the first experimental study demonstrating the excellent safety profiles of concurrent treatment with RT and ICIs. These findings will help to interpret the development of adverse events of the skin after radioimmunotherapy and guide the design of new clinical trials and clinical decision-making in individual cases. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Inibidores de Checkpoint Imunológico , Dermatopatias , Animais , Camundongos , Pele , Reino UnidoRESUMO
BACKGROUND AND OBJECTIVE: Atopic dermatitis (AD) is a chronic inflammatory itchy skin condition. Genomic- and epigenetic wide association studies provide insights into the genetic susceptibility and potential underlying disease pathogenesis. This study sought to functionally characterise an AD-associated single nucleotide polymorphism (SNP) located deep intronic of the tight junction protein 2 (TJP2) gene (9q21.11 locus), identified through a genome-wide association study (GWAS). METHODS: The association between the 9q21.11 locus (rs7872806) and AD was identified through a GWAS of 956 cases and 723 controls. TJP2 expression in peripheral blood mononuclear cells (PBMCs) was assessed against the rs7872806 genotypes. Allele-specific methylation was evaluated at CpG sites 10kb up- and down-stream of the 9q21.11 locus. Effects of DNA methylation on TJP2 expression was validated via in vitro methylation and 5-aza-2'-deoxycytidine-induced transcriptional activation studies. Trans-epidermal water loss measurements were used to determine skin barrier function. RESULTS: The major allele of rs7872806 was determined to increase AD risk by 2.64-fold (adjusted p-value=2.40 x 10-18, OR=0.38), associated with increased methylation levels at cg13920460 site (p<0.001) and lower TJP2 expression in PBMCs (Pearson's p=1.09 x 10-6, Pearson's R=-0.313, p<0.001). Methylation inhibition by 5-aza-2'-deoxycytidine increased TJP2 promoter activity by up to 85%. Elimination of the cg13920460 methylation site increased expression by approximately 25%. The rs7872806 major allele was also found to be associated with increased trans-epidermal water loss (p<0.001). CONCLUSION: Epigenetic influence at CpG site cg13920460 is associated with rs7872806 located deep intronic at 9q21.11. The SNP confers susceptibility to AD through altering TJP2 expression and promoting trans-epidermal water loss.
RESUMO
BACKGROUND: Ultraviolet (UV) irradiation to skin induces biological responses to protect and heal the wounded tissue. Cutaneous blood vessels play an important role in maintaining skin homeostasis, by inducing angiogenesis and vasodilation. However, the vascular dynamics in vivo, such as morphological changes over time and their depth dependency, are not fully understood. METHODS: Ten Asian males were enrolled in this study and received UV (UVA + UVB) irradiation at two minimal erythema dose (MED) to the inner upper arm. Changes in epidermal thickness and vascular structures associated with UV irradiation were evaluated over time for 28 days by optical coherence tomography angiography (OCTA). This technique enables non-invasive visualization of three-dimensional vascular networks in human skin based on OCT assessment of skin structures with near-infrared light. RESULTS: Notable dilation of vascular structures and increases in epidermal thickness were observed after UV irradiation. Vessel density was markedly increased from the papillary dermis to the upper reticular dermis at a depth of 200 µm. These increases in vascular density showed significant persistence even at 28 days after UV irradiation. CONCLUSION: We visualized the vascular structural changes caused by UV irradiation and revealed that the effects of a single UV irradiation at 2 MED persisted for up to 28 days after exposure. The OCTA technique allows not only the in situ assessment of micro-vasculature in human skin but also its monitoring of vascular dynamics over time.
Assuntos
Angiografia/métodos , Vasos Sanguíneos/diagnóstico por imagem , Eritema/diagnóstico por imagem , Pele/diagnóstico por imagem , Raios Ultravioleta/efeitos adversos , Adulto , Vasos Sanguíneos/patologia , Dilatação Patológica/diagnóstico por imagem , Epiderme/metabolismo , Epiderme/patologia , Eritema/etiologia , Eritema/patologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/metabolismo , Masculino , Pele/patologia , Pigmentação da Pele/efeitos da radiação , Fatores de Tempo , Tomografia de Coerência ÓpticaRESUMO
Given the increasing levels of air pollution, understanding the direct shielding response of the skin to air pollutants as a whole under exclusion of the influence from the inside of body is important. We applied topically the water soluble ambient air pollutants to the mouse skin and observed the histological response using 0.3 mM of H2SO3 as a positive control. Water soluble air pollutants samples, WSAP24h and WSA72h, were collected by pumping the outdoor air into ddH2O for 24 and 72 h respectively during two periods with different air quality index (AQI). Morphological examination showed apparent thickening of the epidermal layer in the H2SO3 skin section and in the sections applied with WSAP24h and WSAP72h without significant difference in the extent of epidermal hyperplasia among three groups. The cell viability assay showed no cytotoxic effect by the treatment of H2SO3 and WSAP24h in human skin fibroblast WS-1 cells. WSAP72h sample revealed a dose-dependent cytotoxicity to skin fibroblasts at 48 hr. The evidences indicated that the barrier function of the skin by epidermis hyperplasia could be activated by the insult of a component of air pollution, and the protection could be hold against a more complex and concentrated ambient air pollutants.
Assuntos
Poluentes Atmosféricos/toxicidade , Monitoramento Ambiental/métodos , Pele/efeitos dos fármacos , Água/química , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Humanos , Camundongos , SolubilidadeRESUMO
Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. However, the pathogenesis of psoriasis is multifactorial and is not fully understood. MicroRNAs (miRNAs) represent a promising class of small, noncoding RNA molecules that have a large impact on cellular functions by regulating gene expression. Here we reported that microRNA-187 (miR-187), which is one of the most dynamic microRNAs identified in the deep screening miRNAs profile, is downregulated in inflammatory cytokines-stimulated keratinocytes and psoriatic skins. By luciferase activity assay and gain-of-function studies, we showed that miR-187 inhibits keratinocytes hyperproliferation by targeting CD276. Moreover, overexpression of miR-187 decreases acanthosis and reduces the disease severity in psoriasis mouse models. Taken together, the results of our study implies miR-187 as a critical factor in psoriasis pathogenesis, which could be a potent target for psoriasis treatment.
Assuntos
Proliferação de Células , Queratinócitos/metabolismo , MicroRNAs/metabolismo , Psoríase/metabolismo , Pele/metabolismo , Animais , Antígenos B7/genética , Antígenos B7/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocinas/farmacologia , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Psoríase/genética , Psoríase/patologia , Psoríase/prevenção & controle , Pele/efeitos dos fármacos , Pele/patologiaRESUMO
Psoriasis (PS) is a common inflammatory and incurable skin disease affecting 2-3% of the human population. Although genome-wide association studies implicate more than 60 loci, the full complement of genetic factors leading to disease is not known. Rare, highly penetrant, gain-of-function, dominantly acting mutations within the human caspase recruitment domain family, member 14 (CARD14) gene lead to the development of PS and psoriatic arthritis (PSA) (a familial p.G117S and de-novo p.E138A alteration). These residues are conserved in mouse and orthologous Knock-In (KI) mutations within Card14 were created. The Card14tm.1.1Sun allele (G117S) resulted in no clinically or histologically evident phenotype of the skin or joints in young adult or old mice. However, mice carrying the Card14tm2.1Sun mutant allele (E138A) were runted and developed thick, white, scaly skin soon after birth, dying within two weeks or less. The skin hyperplasia and inflammation was remarkable similarity to human PS at the clinical, histological, and transcriptomic levels. For example, the skin was markedly acanthotic and exhibited orthokeratotic hyperkeratosis with minimal inflammation and no pustules and transcripts affecting critical pathways of epidermal differentiation and components of the IL17 axis (IL23, IL17A, IL17C, TNF and IL22) were altered. Similar changes were seen in a set of orthologous microRNAs previously associated with PS suggesting conservation across species. Crossing the Card14tm2.1Sun/WT mice to C57BL/6NJ, FVB/NJ, CBA/J, C3H/HeJ, and 129S1/SvImJ generated progeny with epidermal acanthosis and marked orthokeratotic hyperkeratosis regardless of the hybrid strain. Of these hybrid lines, only the FVB;B6N(129S4) mice survived to 250â¯days of age or older and has led to recombinant inbred lines homozygous for Card14E138A that are fecund and have scaly skin disease. This implicates that modifiers of PS severity exist in mice, as in the familial forms of the disease in humans.
Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/fisiologia , Mutação com Ganho de Função , Genes Modificadores , Guanilato Ciclase/genética , Guanilato Quinases/fisiologia , Inflamação/genética , Proteínas de Membrana/genética , Psoríase/genética , Dermatopatias/genética , Animais , Feminino , Técnicas de Introdução de Genes , Humanos , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Psoríase/patologia , Índice de Gravidade de Doença , Dermatopatias/patologia , TranscriptomaRESUMO
The discovery of new therapeutic drugs with the efficacious and safe ability to prevent epidermal hyperplasia is extremely urgent for psoriasis. Cryptotanshinone (CTS), an active component isolated from the root of Salvia miltiorrhiza Bunge, has been reported to have antibacterial and antitumor effects. However, its effects on psoriasis have not been reported. Here, we investigated the therapeutic effects of CTS on imiquimod (IMQ)-induced psoriatic-like skin model and explored the underlying mechanisms. Our results revealed that CTS effectively alleviates IMQ-induced epidermal hyperplasia. In vitro studies also indicated that CTS potently inhibits the growth of keratinocytes. We further found that STAT3, a transcription factor for the cell growth, is the key mediator of CTS on the proliferation of keratinocytes. Taken together, our findings indicated that the curative effects of CTS on psoriasis are accomplished mainly through modulating STAT3, which providing evidences to develop CTS as a potential therapeutic agent for patients with psoriasis.
Assuntos
Proliferação de Células/efeitos dos fármacos , Epiderme/patologia , Fenantrenos/uso terapêutico , Psoríase/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Linhagem Celular , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/tratamento farmacológico , Hiperplasia/patologia , Imiquimode , Queratinócitos , Masculino , Camundongos Endogâmicos C57BL , Fenantrenos/farmacologia , Psoríase/induzido quimicamente , Psoríase/patologiaRESUMO
Microalgae represent a source of bio-active compounds such as carotenoids with potent anti-inflammatory and antioxidant properties. We aimed to investigate the effects of fucoxanthin (FX) in both in vitro and in vivo skin models. Firstly, its anti-inflammatory activity was evaluated in LPS-stimulated THP-1 macrophages and TNF-α-stimulated HaCaT keratinocytes, and its antioxidant activity in UVB-irradiated HaCaT cells. Next, in vitro and ex vivo permeation studies were developed to determine the most suitable formulation for in vivo FX topical application. Then, we evaluated the effects of a FX-containing cream on TPA-induced epidermal hyperplasia in mice, as well as on UVB-induced acute erythema in hairless mice. Our results confirmed the in vitro reduction of TNF-α, IL-6, ROS and LDH production. Since the permeation results showed that cream was the most favourable vehicle, FX-cream was elaborated. This formulation effectively ameliorated TPA-induced hyperplasia, by reducing skin edema, epidermal thickness, MPO activity and COX-2 expression. Moreover, FX-cream reduced UVB-induced erythema through down-regulation of COX-2 and iNOS as well as up-regulation of HO-1 protein via Nrf-2 pathway. In conclusion, FX, administered in a topical formulation, could be a novel natural adjuvant for preventing exacerbations associated with skin inflammatory pathologies as well as protecting skin against UV radiation.
Assuntos
Eritema/tratamento farmacológico , Hiperplasia/tratamento farmacológico , Pomadas/farmacologia , Pele/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Xantofilas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo/efeitos dos fármacos , Eritema/metabolismo , Feminino , Humanos , Hiperplasia/metabolismo , Interleucina-6/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , L-Lactato Desidrogenase/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Pelados , Óxido Nítrico Sintase Tipo II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Pele/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Follicular hyperkeratosis along with hyperplasia of the follicular and interfollicular epithelia are major histopathological characteristics of hidradenitis suppurativa (HS). The presence of an occasional thickening of lesional skin in some folliculitis decalvans (FD) patients and histological similarities between FD and HS led us to look for epidermal hyperplasia and follicular hyperkeratosis in FD patients. PATIENTS AND METHOD: We performed a retrospective histological analysis of 26 patients with FD. OBJECTIVE: We sought to find out whether the presence of hyperplasia of the interfollicular epidermis and of the follicular epithelia could be verified in FD, with reference to the work of von Laffert et al. concerning HS. RESULTS: The main quantitative and qualitative data were: follicular hyperkeratosis (77%), hyperplasia of the interfollicular epidermis (92%) with a psoriasiform aspect (88%), atrophy of the follicular epithelia (85%), plasma cells in infiltrate (92%) in large quantities (42%), follicular microcysts (60%), atrophy of the sebaceous glands (85%) and polytrichia (54%). CONCLUSION: Epidermal hyperplasia, sometimes psoriasiform and follicular microcysts, are significant histological signs of FD, which have been ignored until now although they seem very common.
Assuntos
Epiderme , Foliculite , Plasmócitos , Glândulas Sebáceas , Epiderme/metabolismo , Epiderme/patologia , Feminino , Foliculite/metabolismo , Foliculite/patologia , Humanos , Hiperplasia , Masculino , Plasmócitos/metabolismo , Plasmócitos/patologia , Glândulas Sebáceas/metabolismo , Glândulas Sebáceas/patologiaRESUMO
Chronic inflammatory skin diseases such as psoriasis have a significant impact on society. Currently, the major topical treatments have many side effects, making their continued use in patients difficult. Microalgae have emerged as a source of bio-active molecules such as glycolipids with potent anti-inflammatory properties. We aimed to investigate the effects of a glycolipid (MGMG-A) and a glycolipid fraction (MGDG) obtained from the microalga Isochrysis galbana on a TPA-induced epidermal hyperplasia murine model. In a first set of experiments, we examined the preventive effects of MGMG-A and MGDG dissolved in acetone on TPA-induced hyperplasia model in mice. In a second step, we performed an in vivo permeability study by using rhodamine-containing cream, ointment, or gel to determinate the formulation that preserves the skin architecture and reaches deeper. The selected formulation was assayed to ensure the stability and enhanced permeation properties of the samples in an ex vivo experiment. Finally, MGDG-containing cream was assessed in the hyperplasia murine model. The results showed that pre-treatment with acetone-dissolved glycolipids reduced skin edema, epidermal thickness, and pro-inflammatory cytokine production (TNF-α, IL-1ß, IL-6, IL-17) in epidermal tissue. The in vivo and ex vivo permeation studies showed that the cream formulation had the best permeability profile. In the same way, MGDG-cream formulation showed better permeation than acetone-dissolved preparation. MGDG-cream application attenuated TPA-induced skin edema, improved histopathological features, and showed a reduction of the inflammatory cell infiltrate. In addition, this formulation inhibited epidermal expression of COX-2 in a similar way to dexamethasone. Our results suggest that an MGDG-containing cream could be an emerging therapeutic strategy for the treatment of inflammatory skin pathologies such as psoriasis.
Assuntos
Glicolipídeos/administração & dosagem , Glicolipídeos/uso terapêutico , Haptófitas/química , Hiperplasia/prevenção & controle , Dermatopatias/prevenção & controle , Administração Tópica , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/análise , Citocinas/biossíntese , Composição de Medicamentos , Feminino , Glicolipídeos/farmacocinética , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Queratinócitos/efeitos dos fármacos , Camundongos , Pomadas , Pele/patologia , Absorção Cutânea , Dermatopatias/induzido quimicamente , Dermatopatias/patologia , Acetato de TetradecanoilforbolRESUMO
Psoriasis is a chronic inflammatory skin disorder that is accompanied by an imbalance between the proliferation and differentiation of keratinocytes. A number of studies have suggested an association between obesity and severe psoriasis; however, it remains to be clarified whether obesity exacerbates psoriasis. To address this unsolved question, we induced psoriasiform dermatitis in mouse models for obesity. We found that obesity exaggerated the severity of psoriasiform dermatitis induced by topical application of the Toll-like receptor (TLR) 7 agonist, imiquimod. Ear swelling and epidermal hyperplasia were more prominent in the obese mice than in the control mice. When compared to imiquimod-treated control mice, imiquimod-treated obese mice expressed higher levels of psoriasis mediators, interleukin-17A (IL-17A) and IL-22 in the skin. Food intake restriction partially abrogated enhanced ear swelling and cytokine overproduction in obese mice. Furthermore, the obesity environment and imiquimod treatment synergistically induced an IL-17A downstream molecule, regenerating islet-derived 3γ (Reg3γ), which is a critical molecule for psoriatic epidermal hyperplasia. Palmitic acid, one of the fatty acids released by subcutaneous adipocytes, increased the expression of REG3A (a human homologue of mouse Reg3γ) in both the HaCaT keratinocyte cell line and normal human keratinocytes. Taken together, these results strongly suggest that obesity exacerbates psoriasiform dermatitis in mice by upregulating IL-17A, IL-22 and Reg3γ.
Assuntos
Aminoquinolinas/efeitos adversos , Epiderme/patologia , Interleucina-17/metabolismo , Interleucinas/metabolismo , Obesidade/complicações , Psoríase/induzido quimicamente , Psoríase/metabolismo , Aminoquinolinas/farmacologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Feminino , Humanos , Hiperplasia , Imiquimode , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Glicoproteínas de Membrana/agonistas , Camundongos , Camundongos Mutantes , Proteínas Associadas a Pancreatite , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas/metabolismo , Psoríase/patologia , Receptor 7 Toll-Like/agonistas , Interleucina 22RESUMO
Pseudocarcinomatous hyperplasia can occasionally be observed in biopsies of CD30-positive lymphoproliferative disorders. It is important to be cognizant of this association, because epithelial hyperproliferation can overshadow large atypical lymphoid cells, leading to an erroneous diagnosis of squamous cell carcinoma (SCC) or keratoacanthoma. Herein, we present a case of anaplastic large cell lymphoma (ALCL) with pseudocarcinomatous hyperplasia simulating a poorly differentiated carcinoma and review the literature on this subject. Immunohistochemical staining with p63 helped delineate the infiltrating tongues of pseudocarcinomatous hyperplasia from the malignant infiltrate. We present this case to raise awareness of the potential for pseudocarcinomatous hyperplasia to occur in the setting of CD30+ lymphoproliferative disorders. Clinicians and dermatopathologists should consider the possibility of ALCL or lymphomatoid papulosis when examining lesions with features of inflamed SCC, especially if the tumor presents on a site or in a patient that is not typical of SCC.
Assuntos
Carcinoma de Células Escamosas/patologia , Linfoma Anaplásico de Células Grandes/patologia , Neoplasias Cutâneas/patologia , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Diagnóstico Diferencial , Humanos , Hiperplasia , Ceratoacantoma/metabolismo , Ceratoacantoma/patologia , Antígeno Ki-1/metabolismo , Linfoma Anaplásico de Células Grandes/metabolismo , Papulose Linfomatoide/metabolismo , Papulose Linfomatoide/patologia , Masculino , Proteínas de Membrana/metabolismo , Neoplasias Cutâneas/metabolismoRESUMO
The nucleoside adenosine is a known regulator of immunity and inflammation that mediates, at least in part, the anti-inflammatory effect of methotrexate, an immunosuppressive agent widely used to treat autoimmune inflammatory diseases. Adenosine A2A receptors play a key role in the inhibition of the inflammatory process besides promoting wound healing. Therefore, we aimed to determine the topical effect of a selective agonist, CGS-21680, on a murine model of skin hyperplasia with a marked inflammatory component. Pretreatment with either CGS-21680 (5 µg per site) or the reference agent dexamethasone (200 µg/site) prevented the epidermal hyperplasia and inflammatory response induced by topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA, 2 nmol/site) for three consecutive days. The histological analysis showed that both CGS-21680 and dexamethasone produced a marked reduction of inflammatory cell infiltrate, which correlated with diminished myeloperoxidase (MPO) activity in skin homogenates. Both treatments reduced the levels of the chemotactic mediators LTB4 and CXCL-1, and the inflammatory cytokine TNF-α, through the suppression of NFκB phosphorylation. The immunohistochemical analysis of the hyperproliferative markers cytokeratin 6 (CK6) and Ki67 revealed that while both agents inhibit the number of proliferating cells in the epidermis, CGS-21680 treatment promoted dermal fibroblasts proliferation. Consistently, increased collagen deposition in dermis was observed in tissue sections from agonist-treated mice. Our results showed that CGS 21680 efficiently prevents phorbol-induced epidermal hyperplasia and inflammation in mice without the deleterious atrophic effect of topical corticosteroids.
Assuntos
Agonistas do Receptor A2 de Adenosina/administração & dosagem , Agonistas do Receptor A2 de Adenosina/uso terapêutico , Adenosina/análogos & derivados , Epiderme/patologia , Inflamação/prevenção & controle , Fenetilaminas/administração & dosagem , Fenetilaminas/uso terapêutico , Dermatopatias/prevenção & controle , Adenosina/administração & dosagem , Adenosina/farmacologia , Adenosina/uso terapêutico , Agonistas do Receptor A2 de Adenosina/farmacologia , Administração Tópica , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Proliferação de Células , Colágeno/metabolismo , Citocinas/metabolismo , Dexametasona/administração & dosagem , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Feminino , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Hiperplasia/prevenção & controle , Inflamação/induzido quimicamente , Inflamação/patologia , Camundongos , Peroxidase/metabolismo , Fenetilaminas/farmacologia , Dermatopatias/induzido quimicamente , Dermatopatias/patologia , Acetato de Tetradecanoilforbol/efeitos adversosRESUMO
Homeostasis of the skin barrier is essential for maintaining normal skin function. Gasdermin A (GSDMA) is highly expressed in the skin and associated with many skin diseases, such as melanoma and psoriasis. In mice, GSDMA is encoded by three gene homologues, namely Gsdma1, Gsdma2, and Gsdma3. Although Gsdma3 gain-of-function mutations cause hair loss and skin inflammation, Gsdma3-deficient mice do not show any visible phenotypes in skin and hair structures. To explore the physiological function of GSDMA, we generated conventional Gsdma1/2/3 knockout (KO) mice. These mice showed significantly alleviated epidermal hyperplasia and inflammation induced by phorbol 12-myristate 13-acetate (PMA). Furthermore, the alleviation of epidermal hyperplasia depended on the expression of Gsdma1/2/3 specifically in keratinocytes. Mechanistically, Gsdma1/2/3 depletion downregulated epidermal growth factor receptor (EGFR) ligands, leading to the decreased EGFR-Stat3/Akt signalling. These results demonstrate that depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia partially by inhibiting the EGFR-Stat3/Akt pathway.
Assuntos
Epiderme , Receptores ErbB , Hiperplasia , Queratinócitos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt , Fator de Transcrição STAT3 , Transdução de Sinais , Acetato de Tetradecanoilforbol , Animais , Fator de Transcrição STAT3/metabolismo , Receptores ErbB/metabolismo , Receptores ErbB/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Acetato de Tetradecanoilforbol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Epiderme/patologia , Epiderme/metabolismo , Epiderme/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , GasderminasRESUMO
Photosensitivity disorder caused by sunlight, including ultraviolet (UV) rays, often occurs in connective tissue diseases such as lupus erythematosus. In addition, UVA (320-400 nM) and UVB (280-320 nM) trigger the progression of skin inflammation in the patients. Therefore, it is crucial to evaluate skin damage under UV exposure using experimental animals to clarify the relationship between connective tissue disease and photosensitivity disorder. In this chapter, our original protocol for evaluating UVA-dependent skin damage, which is known as photoaging via oxidative stress, is described.
Assuntos
Dermatite , Lúpus Eritematoso Sistêmico , Transtornos de Fotossensibilidade , Animais , Humanos , Estresse Oxidativo , Raios Ultravioleta/efeitos adversosRESUMO
Psoriasis is a common chronic disease, and existing treatment regimens often exhibit certain toxicities and side effects. Zerumbone (Zer) may possess therapeutic effect, and the objective of this study is to investigate the effect of Zer on psoriasis. A mouse model of psoriasis was established using imiquimod cream, and the role of Zer on the pathological alterations in psoriatic mouse skin was evaluated by psoriasis area and severity index (PASI) score; the effect of Zer on keratinocyte proliferation was evaluated via hematoxylin and eosin staining, Zen image analysis, and immunofluorescence; Immunohistochemistry and enzyme-linked immunoassay were used to evaluate the effect of Zer on tissue inflammatory responses, while malondialdehyde (MDA) and glutathione (GSH) levels were measured to elucidate the role of Zer in modulating oxidative stress; the signaling pathway regulated by Zer was evaluated by western blotting. The results demonstrated that Zer could alleviate the pathological manifestations of psoriasis, reduce PASI score, reduce skin pathological damage and epidermal hyperplasia, diminish the number of CD8+ T cells and cytokine expression levels, decrease the level of MDA and GSH and increase the expression of Nrf and HO-1. Zer was found to regulate the NLRP3/nuclear factor-kappa B (NF-κB) signaling pathway. In conclusion, Zer ameliorated the symptoms of psoriasis in mice, suppressed the keratinocyte hyperproliferation, and mitigates inflammation and oxidative stress in psoriatic skin tissue by regulating the NLRP3/NF-κB pathway.
RESUMO
Herpesvirus infections of sturgeon pose a potential threat to sturgeon culture efforts worldwide. A new epitheliotropic herpesvirus named Acipenser herpesvirus 3 (AciHV-3) was detected in hatchery-reared Lake Sturgeon Acipenser fulvescens displaying skin lesions in central Canada. The growths were discovered in the fall, reached average prevalence levels of 0.2-40% and eventually regressed. No unusual mortality was observed. The cellular changes within the lesions included epithelial hyperplasia and were reminiscent of other herpesvirus infections. The virus was not evident in lesions examined by electron microscopy. Skin tissue homogenates from symptomatic sturgeon produced atypical cytopathic effects on a primary Lake Sturgeon cell line, and next-generation sequence analysis of the DNA samples revealed the presence of an alloherpesvirus. A new genotyping PCR assay targeting the major capsid protein sequence detected AciHV-3 in symptomatic Lake Sturgeon as well as other apparently healthy sturgeon species. Bayesian inference of phylogeny reconstructed with a concatenation of five alloherpesvirus core proteins revealed a new Alloherpesviridae lineage isomorphic with a new genus. The presence of AciHV-3 homologs in cell lines and sturgeon sequence datasets, low sequence divergence among these homologs and branching patterns within the genotyping phylogeny provide preliminary evidence of an endogenous virus lifestyle established in an ancestral sturgeon.
Assuntos
Candidíase/microbiologia , Carcinoma Verrucoso/patologia , Neoplasias Bucais/patologia , Mucosa/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/uso terapêutico , Candida albicans/isolamento & purificação , Candidíase/tratamento farmacológico , Candidíase/patologia , Carcinogênese/patologia , Criança , Feminino , Humanos , Hiperplasia/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/microbiologia , Neoplasias Bucais/ultraestrutura , Mucosa/microbiologia , Mucosa/ultraestrutura , Estudos RetrospectivosRESUMO
Psoriasis is a highly inflammatory autoimmune-mediated skin disease. The strongest evidence has pointed to the influential role of interleukin (IL) -17A in the aberrant pathology of psoriasis. Henceforth, targeting the IL-17A cytokine is of prime importance in controlling the disease severity of psoriasis. Reportedly, 3, 3'- diindolylmethane (DIM) is a phytochemical that alleviated acute atopic dermatitis. Howbeit, the therapeutic intervention of DIM against IL-17A/IL-17RA interaction and its signaling mediated pathogenesis in psoriasis remains unexplored. In the current report, we decoded the molecular basis of DIM in psoriasis. Docking analysis has reported that DIM identified an IL-17A binding region in the functional fibronectin-III-like domain of IL-17RA and abrogated IL-17A/IL-17RA interaction. In-vitro experiments demonstrated that DIM impeded IL-17A mediated hyper-proliferative phenotype of psoriatic-like keratinocytes. Furthermore, DIM abated the catabolic effects of IL-17A stimulated expression of pathogenic mediators like HMGB-1, Cyr-61, CCL-20, and VEGF via blunted activation of JAK/STAT pathway in psoriatic like keratinocytes. Profoundly, DIM restricted the reprogramming of psoriatic-like keratinocytes to overexpress IL-17RA in concert with IL-17A stimulation. In line with in-vitro studies, DIM also ameliorated skin lesions and epidermal hyperplasia in an imiquimod-induced mice model of psoriasis. Additionally, DIM also reduced STAT-3 phosphorylation and associated expression of Cyr-61, CCL-20, and VEGF in psoriatic mice. However, if DIM has a direct effect on STAT-3 inhibition or it negatively regulates STAT-3 function via blockade of IL-17A/IL-17RA interaction needs to be investigated in the future. Conclusively, our studies demonstrated that the blockade of IL-17A/IL-17RA interaction is a novel therapeutic perspective of DIM against the progression of psoriasis disease.
Assuntos
Dermatite , Psoríase , Animais , Dermatite/patologia , Modelos Animais de Doenças , Imiquimode/farmacologia , Indóis , Interleucina-17/metabolismo , Janus Quinases/metabolismo , Queratinócitos , Camundongos , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Psoríase/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Pele/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Background: Ultraviolet B (UVB) exposure leads to formation of photoproducts leading to cellular damage. Prevention using sunscreen can sometimes be inadequate and can be an economic burden. Recent studies have suggested the photoprotective effect of curcumin. Objective: To examine the acute and chronic photoprotective effect of topical curcumin, using cyclobutyl pyrimidine dimers (CPD) and 8-hydroxy2'deoxyguanosine (8-OHdG) expression as markers of DNA-induced damage, and epidermal hyperplasia on UVB-induced mice. Methods: Three treatment groups were established. Group A (negative control) consisted of 5 mice, Group B and C were further divided into two categories to assess acute and chronic effects of topical curcumin and UVB radiation. Each consisted of six subgroups of five mice. Subgroup 1; UVB exposure only (positive control) subgroup 2; acetone and UVB exposure, subgroup 3-6; topical curcumin application of 100nM, 1µM, 10µM, and 100µM concentrations, respectively. In Group C, there were two categories that received 3x/week UVB exposure for three weeks which effects were being observed at 24 hours and 10 days after the last exposure. The topical curcumin dose was 2mg/mL/cm2 applied 30 minutes prior to 343mJ/cm2/day UVB irradiation. Skin biopsy was done one hour after the last UVB exposure for immunohistochemical and histopathology examinations. Results: Topical curcumin showed a limited yet robust protective effect against CPD and 8-OHdG expression in Group B, while in Group C all concentrations showed significant CPD and 8-OHdG inhibition after 10 days of UVB exposure. The 10µM and 100µM concentrations showed the best epidermal hyperplasia inhibition effect (p<0.05). No significant differences were found in terms in efficacy either in single nor daily application. Conclusion: Topical curcumin can prevent the formation of the photoproducts CPD and 8-OHdG and epidermal hyperplasia in both acute and chronic exposure in UVB-induced mice.