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1.
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
2.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281197

RESUMO

Psoriasis, a long-lasting and multifactorial skin disease, is related to comorbidities such as metabolic disease, depression, and psoriatic arthritis. Psoriasis occurs due to a variety of factors including keratinocyte hyperproliferation, inflammation, and abnormal differentiation. Proinflammatory cytokines upregulated by increased activation of keratinocytes and immune cells in the skin trigger progression of psoriasis. This study aimed to investigate the effects of anoctamin1 (ANO1) on psoriasis development in vitro and in vivo. We analyzed the proliferation of HaCaT keratinocytes and ANO1-related ERK and AKT signaling pathways after ANO1 inhibitor (T16Ainh-A01 and Ani9) treatment and knock-down of ANO1. Furthermore, after applying imiquimod (IMQ) cream or coapplying IMQ cream and T16Ainh-A01 on mouse ears, we not only observed psoriatic symptoms, including ear thickening, but also quantified the effects of treatment on ERK and AKT signaling-involved proteins and proinflammatory cytokines. Inhibition of ANO1 attenuated the proliferation of HaCaT cells and induced reduction of pERK1/2. Coapplication of IMQ and T16Ainh-A01 on ears of mice reduced not only symptoms of IMQ-induced psoriasis such as thickening and erythema, but also expression of ANO1 and pERK1/2 compared to that of application of IMQ alone. In addition, the expression levels of IL-17A, IL-17F, IL-22, IL-23, IL-6, IL-1ß, and TNF-α increased after applying IMQ and were significantly reduced by coapplying IMQ and T16Ainh-A01. These results aid in understanding the underlying mechanisms of ANO1 in epidermal layer keratinocyte hyperproliferation and suggest the potential of ANO1 as a target to treat psoriasis.


Assuntos
Anoctamina-1/farmacologia , Queratinócitos/efeitos dos fármacos , Psoríase/induzido quimicamente , Acetamidas/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HaCaT , Humanos , Hidrazonas/farmacologia , Imiquimode/efeitos adversos , Imiquimode/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Interleucinas/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Psoríase/metabolismo , Psoríase/patologia , Pirimidinas/farmacologia , Tiazóis/farmacologia
3.
Obstet Gynecol ; 137(6): 1043-1053, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33957649

RESUMO

OBJECTIVE: To evaluate the histologic response rate of high-grade squamous intraepithelial lesions (HSIL) of the cervix after topical application of 5% imiquimod cream. METHODS: In this phase II trial, women with cervical HSIL (cervical intraepithelial neoplasia [CIN] 2-3) were randomly assigned to 250 mg of 5% imiquimod cream applied to the cervix weekly for 12 weeks, followed by loop electrosurgical excision procedure (LEEP) without preceding treatment. The sample size was calculated based on the HSIL regression rates previously reported by Grimm et al. The primary outcome was rate of histologic regression (to CIN 1 or less) in LEEP specimens. Prespecified secondary endpoints included surgical margin status and adverse events. Outcomes were stratified by human papillomavirus type and lesion grade (CIN 2 or CIN 3). Results were reported according to per protocol (PP) and intention-to-treat (ITT) analyses. RESULTS: Ninety women were enrolled: 49 in the experimental group and 41 in the control group. In the PP population, histologic regression was observed in 23 of 38 participants (61%) in the experimental group compared with 9 of 40 (23%) in the control group (P=.001). Surgical margins were negative for HSIL in 36 of 38 participants (95%) in the experimental group and 28 of 40 (70%) in the control group (P=.004). In the ITT population, rates of histologic regression also were significantly higher in the experimental group. Rates of adverse events in the experimental group were 74% (28/38) in the PP population and 78% (35/45) in the ITT population. Adverse events were mild, with abdominal pain being the most common. Three patients in the experimental group had grade 2 adverse events, including vaginal ulcer, vaginal pruritus with local edema, and moderate pelvic pain. CONCLUSION: Weekly topical treatment with imiquimod is effective in promoting regression of cervical HSIL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03233412.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasia Intraepitelial Cervical/tratamento farmacológico , Imiquimode/uso terapêutico , Lesões Intraepiteliais Escamosas Cervicais/tratamento farmacológico , Lesões Intraepiteliais Escamosas Cervicais/patologia , Neoplasias do Colo do Útero/tratamento farmacológico , Administração Tópica , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasia Intraepitelial Cervical/patologia , Neoplasia Intraepitelial Cervical/cirurgia , Terapia Combinada , Eletrocirurgia , Feminino , Humanos , Imiquimode/administração & dosagem , Imiquimode/efeitos adversos , Análise de Intenção de Tratamento , Margens de Excisão , Pessoa de Meia-Idade , Gradação de Tumores , Infecções por Papillomavirus/virologia , Lesões Intraepiteliais Escamosas Cervicais/cirurgia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia , Adulto Jovem
4.
J Nanobiotechnology ; 19(1): 105, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858431

RESUMO

BACKGROUND: Carbon dots (CDs) with multifaceted advantages have provided hope for development brand-new nanodrug for treating thorny diseases. This study developed a green and simple calcination method to prepare novel CDs as promising drug for psoriasis treatment. The as-prepared CDs using Phellodendri Chinensis Cortex (PCC) as sole precursor were characterized by a series of methods, mainly including electron microscopy, optical technology and X-ray photoelectron spectroscopy (XPS). RESULTS: Results displayed that fluorescence (Quantum yield = 5.63%) and nontoxic PCC-based CDs (PCC-CDs) with abundant chemical groups exhibited solubility and tiny sizes at average of (1.93 ± 0.53) nm, which may be beneficial for its inherent biological activity. Moreover, by using the typical imiquimod (IMQ)-induced psoriasis-like skin mouse model, we firstly demonstrated the pronounced anti-psoriasis activity of as-prepared PCC-CDs on ameliorating the appearance, psoriasis area and severity index (PASI) scores as well as histopathological morphology of both back skin tissues and right ears in IMQ-induced mouse. Further potential mechanisms behind the anti-psoriasis activities may be related to suppress M1 polarization and relatively promote M2 polarization of macrophage both in vitro and in vivo. CONCLUSION: These results suggested that PCC-CDs have potential to be an anti-psoriasis candidate for clinical applications to treat psoriasis, which not only provided an evidence for further broadening the biological application of CDs, but also provided a potential hope for application nanodrugs to treat thorny diseases.


Assuntos
Carbono/uso terapêutico , Imiquimode/efeitos adversos , Inflamação/tratamento farmacológico , Psoríase/tratamento farmacológico , Animais , Carbono/química , Citocinas/metabolismo , Modelos Animais de Doenças , Imiquimode/química , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Psoríase/induzido quimicamente , Psoríase/patologia , Células RAW 264.7 , Pele/patologia
7.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33450859

RESUMO

Severe psoriasis, a chronic inflammatory skin disease is increasingly being effectively managed by targeted immunotherapy but long-term immunotherapy poses health risk and loss of response. Therefore, there is a need for alternative therapy strategies. Mesenchymal stem/stromal cell (MSC) exosomes are widely known for their potent immunomodulatory properties. Here we investigated if topically applied MSC exosomes could alleviate psoriasis-associated inflammation. Topically applied fluorescent exosomes on human skin explants were confined primarily to the stratum corneum with <1% input fluorescence exiting the explant over a 24-h period. Nevertheless, topically applied MSC exosomes in a mouse model of imiquimod (IMQ) psoriasis significantly reduced IL-17 and terminal complement activation complex C5b-9 in the mouse skin. MSC exosomes were previously shown to inhibit complement activation, specifically C5b-9 complex formation through CD59. Infiltration of neutrophils into the stratum corneum is characteristic of psoriasis and neutrophils are a major cellular source of IL-17 in psoriasis through the release of neutrophil extracellular traps (NETs). We propose that topically applied MSC exosomes inhibit complement activation in the stratum corneum and this alleviates IL-17 release by NETS from neutrophils that accumulate in and beneath the stratum corneum.


Assuntos
Exossomos/metabolismo , Imiquimode/efeitos adversos , Células-Tronco Mesenquimais/metabolismo , Psoríase/etiologia , Psoríase/patologia , Administração Tópica , Animais , Biomarcadores , Biópsia , Modelos Animais de Doenças , Camundongos , Permeabilidade , Fenótipo , Psoríase/terapia , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Absorção Cutânea
8.
Dermatol Ther ; 34(1): e14355, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32990395

RESUMO

Imiquimod 5% is approved for topical treatment of actinic keratosis (AKs), superficial basal cell carcinoma and condylomata acuminata, the 3.75% formulation for the treatment of AKs and genital warts. Imiquimod has also been used off-label in various other skin conditions (eg, Bowen's disease, lentigo maligna, vulvar intraepithelial neoplasia). As a toll-like receptor 7/8 (TLR7/8) agonist imiquimod induces a local inflammatory response by increased production of cytokines, co-stimulatory molecules, activation of Nk-cells and antigen-specific T-cells. In addition to imiquimod-associated adverse effects at non-application sites such as fever, vertigo or myalgia there have been anecdotal reports of distant inflammatory mucosal reactions-a side effect not declared in the medicinal product information. In this scoping review we collected a total of seven cases of patients with lesions of the oral mucosa and lips and summarized pathophysiological hypotheses to explain this type of side effect. The review is complemented with an illustrated report of a 87-year-old female patient of ours suffering from chronic lymphocytic leukemia (CLL) who developed severe oral mucosal and labial reactions following application of imiquimod 3.75% for treatment of AKs. She denied accidental transfer of imiquimod and was tested negative for herpes simplex virus (PCR) and bacteria (culture) from lesional swabs.


Assuntos
Carcinoma Basocelular , Neoplasias Cutâneas , Adjuvantes Imunológicos/efeitos adversos , Administração Tópica , Idoso de 80 Anos ou mais , Aminoquinolinas/efeitos adversos , Carcinoma Basocelular/tratamento farmacológico , Feminino , Humanos , Imiquimode/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico
9.
Acta Derm Venereol ; 101(1): adv00358, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33170301

RESUMO

A systematic literature review was conducted to identify and qualitatively assess randomized controlled trials in immunocompetent patients ≥ 18 years with head- region lesions of actinic keratoses who were treated with field-directed, lesion-directed and other therapies. Network meta-analysis was used to quantitatively evaluate field-directed therapies (5-fluorouracil formulations, diclofenac sodium, imiquimod, ingenol mebutate, 5-aminolevulinic acid or methyl aminolevulinate plus photodynamic therapy) using complete clearance or partial clearance of actinic keratoses lesions, and adverse event-related withdrawals as a proxy of acceptability. Of 2,863 references identified, 75 trials reported in 151 publications were included. In summary, comparative network meta-analysis evaluation showed that 5-fluorouracil formulations were the most efficacious interventions examined. 5-fluorouracil 4%, which was recently approved, showed a comparable efficacy profile to 5-fluorouracil 5%, and had satisfactory acceptability outcomes.


Assuntos
Diterpenos , Ceratose Actínica , Fotoquimioterapia , Diterpenos/uso terapêutico , Humanos , Imiquimode/efeitos adversos , Ceratose Actínica/diagnóstico , Ceratose Actínica/tratamento farmacológico , Metanálise em Rede , Resultado do Tratamento
10.
Int J Mol Sci ; 21(22)2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33202847

RESUMO

Emerging evidence has demonstrated that Toll-like receptors (TLRs) are associated with autoimmune diseases. In this study, we investigated the role of TLR2 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although TLR2 signaling is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, TLR2 deficiency unexpectedly exacerbated psoriasiform skin inflammation. Importantly, messenger RNA (mRNA) levels of Foxp-3 and IL-10 in the lesional skin were significantly decreased in TLR2 KO mice compared with wild-type mice. Furthermore, flow cytometric analysis of the lymph nodes revealed that the frequency of regulatory T cells (Tregs) among CD4-positive cells was decreased. Notably, stimulation with Pam3CSK4 (TLR2/1 ligand) or Pam2CSK4 (TLR2/6 ligand) increased IL-10 production from Tregs and DCs and the proliferation of Tregs. Finally, adoptive transfer of Tregs from wild-type mice reduced imiquimod-induced skin inflammation in TLR2 KO mice. Taken together, our results suggest that TLR2 signaling directly enhances Treg proliferation and IL-10 production by Tregs and DCs, suppressing imiquimod-induced psoriasis-like skin inflammation. Enhancement of TLR2 signaling may be a new therapeutic strategy for psoriasis.


Assuntos
Imiquimode/efeitos adversos , Interleucina-10 , Psoríase , Pele , Linfócitos T Reguladores , Receptor 2 Toll-Like/deficiência , Animais , Imiquimode/farmacologia , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-10/genética , Interleucina-10/imunologia , Camundongos , Camundongos Knockout , Psoríase/induzido quimicamente , Psoríase/genética , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Receptor 2 Toll-Like/imunologia
13.
Biol Res ; 53(1): 48, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33081840

RESUMO

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease. Keratinocytes hyperproliferation and excessive inflammatory response contribute to psoriasis pathogenesis. The agents able to attenuate keratinocytes hyperproliferation and excessive inflammatory response are considered to be potentially useful for psoriasis treatment. Daphnetin exhibits broad bioactivities including anti-proliferation and anti-inflammatory. This study aims to evaluate the anti-psoriatic potential of daphnetin in vitro and in vivo, and explore underlying mechanisms. METHODS: HaCaT keratinocytes was stimulated with the mixture of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α (M5) to establish psoriatic keratinocyte model in vitro. Cell viability was measured using Cell Counting Kit-8 (CCK-8). Quantitative Real-Time PCR (qRT-PCR) was performed to measure the mRNA levels of hyperproliferative marker gene keratin 6 (KRT6), differentiation marker gene keratin 1 (KRT1) and inflammatory factors IL-1ß, IL-6, IL-8, TNF-α, IL-23A and MCP-1. Western blotting was used to detect the protein levels of p65 and p-p65. Indirect immunofluorescence assay (IFA) was carried out to detect p65 nuclear translocation. Imiquimod (IMQ) was used to construct psoriasis-like mouse model. Psoriasis severity (erythema, scaling) was scored based on Psoriasis Area Severity Index (PASI). Hematoxylin and eosin (H&E) staining was performed to examine histological change in skin lesion. The expression of inflammatory factors including IL-6, TNF-α, IL-23A and IL-17A in skin lesion was measured by qRT-PCR. RESULTS: Daphnetin attenuated M5-induced hyperproliferation in HaCaT keratinocytes. M5 stimulation significantly upregulated mRNA levels of IL-1ß, IL-6, IL-8, TNF-α, IL-23A and MCP-1. However, daphnetin treatment partially attenuated the upregulation of those inflammatory cytokines. Daphnetin was found to be able to inhibit p65 phosphorylation and nuclear translocation in HaCaT keratinocytes. In addition, daphnetin significantly ameliorate the severity of skin lesion (erythema, scaling and epidermal thickness, inflammatory cell infiltration) in IMQ-induced psoriasis-like mouse model. Daphnetin treatment attenuated IMQ-induced upregulation of inflammatory cytokines including IL-6, IL-23A and IL-17A in skin lesion of mice. CONCLUSIONS: Daphnetin was able to attenuate proliferation and inflammatory response induced by M5 in HaCaT keratinocytes through suppression of NF-κB signaling pathway. Daphnetin could ameliorate the severity of skin lesion and improve inflammation status in IMQ-induced psoriasis-like mouse model. Daphnetin could be an attractive candidate for future development as an anti-psoriatic agent.


Assuntos
Adjuvantes Imunológicos , Anti-Inflamatórios , Imiquimode , Inflamação , Psoríase , Umbeliferonas , Adjuvantes Imunológicos/efeitos adversos , Animais , Anti-Inflamatórios/farmacologia , Proliferação de Células , Humanos , Imiquimode/efeitos adversos , Inflamação/tratamento farmacológico , Queratinócitos , Camundongos , Camundongos Endogâmicos BALB C , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Coelhos , Umbeliferonas/farmacologia
14.
Dermatol Online J ; 26(7)2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32898412

RESUMO

The use of imiquimod 5% cream, a topical immunomodulator for the treatment of lentigo maligna (LM) was first described in 2000. Subsequent studies have indicated that imiquimod might be an effective nonsurgical treatment in patients who refuse to have, or are ineligible for surgery because of comorbidities, tumor size, or risk of cosmetic disfigurement. Herein, we outline our experience with treating LM on the nose in an 88-year-old skin cancer patient with significant comorbidities. Given our patient's strong preference against surgical intervention, he was treated with topical imiquimod cream applied once daily for a total of 12 weeks. A two-week treatment holiday was required for severe nausea and vomiting, treated effectively with ondansetron wafers. There were no clinical or dermoscopic signs of LM recurrence 12 months posttreatment. Topical imiquimod is an effective alternative to excision in nonsurgical candidates.


Assuntos
Antineoplásicos/administração & dosagem , Tratamento Conservador , Sarda Melanótica de Hutchinson/tratamento farmacológico , Imiquimode/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Vômito/induzido quimicamente , Administração Tópica , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Esquema de Medicação , Humanos , Imiquimode/efeitos adversos , Masculino , Náusea/induzido quimicamente
15.
Dermatol Ther ; 33(6): e14165, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32772481

RESUMO

Despite of the emerging new systemic and local oncologic treatments (immunotherapy and checkpoint inhibitors, oncolytic viral treatments and injected immunostimulants) the management of skin melanoma metastasis can be still challenging. The main aim of this review was to assess the efficacy and the role of imiquimod in local metastatic melanoma disease. An extensive literature review was performed from September 2000 to March 2020 using PubMed, MEDLINE, Embase, and Cochrane Library databases. Selected articles regarded topical imiquimod, its mode of action as an antitumoral agent and its applications in melanoma metastases treatment. We analyzed a total of 18 published article of clinical cases and small case series and five studies: two retrospective large case series, two Phase I and II clinical trials and one cohort non randomized study. Generally, the treatment is safe and well tolerated. Imiquimod lead to an unstable locoregional control. The use of topical imiquimod for the treatment of MM cutaneous metastases should be considered in selected cases and in palliative settings.


Assuntos
Antineoplásicos , Melanoma , Neoplasias Cutâneas , Administração Tópica , Aminoquinolinas/efeitos adversos , Antineoplásicos/efeitos adversos , Humanos , Imiquimode/efeitos adversos , Melanoma/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Cutâneas/tratamento farmacológico
16.
J Drugs Dermatol ; 19(8): 756-762, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32804451

RESUMO

Background: Real-world data for actinic keratosis treatment in the United States is lacking. Objectives: To understand real-world treatment patterns for actinic keratosis by type and modality, and compare effectiveness and safety of therapies, either alone or in combination. Methods: Medical charts of 429 patients were identified; clinical and outcome data were analyzed. Results: The first treatment after the index diagnosis was most frequently a procedure, followed by a topical agent. Treatment with 5-fluorouracil, ingenol mebutate, imiquimod, cryotherapy, or cryotherapy plus one topical (CRYO+One Topical) reduced actinic keratoses by 66.0%, 69.3%, 72.5%, 72.9%, and 73.0%, respectively; ≥75% clearance (AKCLEAR 75) was achieved in 57.1%, 72.7%, 57.1%, 62.4%, and 62.0% of those patients. Treatment effectiveness was positively correlated with the number of baseline actinic keratoses for topical and for procedural plus topical combination treatments, but not for procedural treatments alone. Adverse reactions (ARs) were more common with cryotherapy (9.7%); local skin responses (LSRs) were more common with field-directed (18.5%-43.1%) and CRYO+One Topical therapy (21.3%). Limitations: This was a retrospective study of limited duration and population size. Conclusions: The most commonly used treatments for patients with 6 or more actinic keratoses were topicals and a procedure plus topical combination, which also achieved higher rates of complete clearance than a procedure alone. ARs and LSRs were few in frequency and type.


Assuntos
Antineoplásicos/administração & dosagem , Crioterapia/métodos , Ceratose Actínica/terapia , Administração Cutânea , Idoso , Antineoplásicos/efeitos adversos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Crioterapia/efeitos adversos , Diterpenos/administração & dosagem , Diterpenos/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Imiquimode/administração & dosagem , Imiquimode/efeitos adversos , Ceratose Actínica/diagnóstico , Ceratose Actínica/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Pele/patologia , Resultado do Tratamento , Estados Unidos
17.
Cells ; 9(8)2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32707926

RESUMO

The pathogenesis of psoriasis, an immune-mediated chronic skin barrier disease, is not fully understood yet. Here, we identified lysophosphatidic acid (LPA) receptor 5 (LPA5)-mediated signaling as a novel pathogenic factor in psoriasis using an imiquimod-induced psoriasis mouse model. Amounts of most LPA species were markedly elevated in injured skin of psoriasis mice, along with LPA5 upregulation in injured skin. Suppressing the activity of LPA5 with TCLPA5, a selective LPA5 antagonist, improved psoriasis symptoms, including ear thickening, skin erythema, and skin scaling in imiquimod-challenged mice. TCLPA5 administration attenuated dermal infiltration of macrophages that were found as the major cell type for LPA5 upregulation in psoriasis lesions. Notably, TCLPA5 administration attenuated the upregulation of macrophage NLRP3 in injured skin of mice with imiquimod-induced psoriasis. This critical role of LPA5 in macrophage NLRP3 was further addressed using lipopolysaccharide-primed bone marrow-derived macrophages. LPA exposure activated NLRP3 inflammasome in lipopolysaccharide-primed cells, which was evidenced by NLRP3 upregulation, caspase-1 activation, and IL-1ß maturation/secretion. This LPA-driven NLRP3 inflammasome activation in lipopolysaccharide-primed cells was significantly attenuated upon LPA5 knockdown. Overall, our findings establish a pathogenic role of LPA5 in psoriasis along with an underlying mechanism, further suggesting LPA5 antagonism as a potential strategy to treat psoriasis.


Assuntos
Imiquimode/efeitos adversos , Inflamassomos/metabolismo , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Psoríase/sangue , Psoríase/induzido quimicamente , Receptores de Ácidos Lisofosfatídicos/sangue , Animais , Células da Medula Óssea/citologia , Células Cultivadas , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/genética , Transdução de Sinais/genética , Pele/lesões , Pele/metabolismo , Transfecção , Regulação para Cima/genética
18.
Mol Med Rep ; 22(3): 2263-2272, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32705251

RESUMO

Psoriasis is a chronic inflammatory skin disease characterized by well­defined scaly papules and plaques. Interleukin (IL)­17 is involved in its pathogenesis and promotes the proliferation of epidermal keratinocytes through signal transducer and activator of transcription 3 (STAT3) activation. Shikonin, a natural naphthoquinone isolated from Lithospermum erythrorhizon, possesses anti­inflammatory and immunosuppressive properties and can suppress IL­17­induced vascular endothelial growth factor expression by inhibiting the JAK/STAT3 pathway. In the present study, MTS, iCELLigence and RT­qPCR were used to determine the optimal concentration and duration of IL­17 or shikonin acting on HaCaT cells. The changes in the expression levels of genes associated with the IL­6/STAT3 pathway in differentially treated cells were analyzed via RT2Profiler™ PCR Array. Small interfering RNA was used to silence the expression levels of the target gene CCAAT/enhancer­binding protein δ (CEBPD). Western blotting and immunohistochemistry were used to evaluate the effect of shikonin on imiquimod­induced psoriasis in mice and the expression levels of CEBPD. Shikonin reversed IL­17­mediated downregulation of the tumor suppressor CEBPD in HaCaT cells. Moreover, low levels of CEBPD in the imiquimod­induced mouse model of psoriasis were restored by shikonin treatment, which ameliorated excessive keratinocyte proliferation. Taken together, these findings suggest that CEBPD plays a key role in the pathogenesis of psoriasis and can be targeted by shikonin as a potential therapeutic strategy.


Assuntos
Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Imiquimode/efeitos adversos , Interleucina-17/efeitos adversos , Naftoquinonas/administração & dosagem , Psoríase/tratamento farmacológico , Animais , Proteína delta de Ligação ao Facilitador CCAAT/genética , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Células HaCaT , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Naftoquinonas/farmacologia , Psoríase/induzido quimicamente , Psoríase/genética , Psoríase/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Mol Pain ; 16: 1744806920934998, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32580615

RESUMO

Activation of glial cells has been shown to play an important role in chronic itch. However, whether glial cells play an important role in the development of psoriasis-induced chronic itch has not been fully elucidated. This study investigated the role of spinal glial cells in psoriasis-induced chronic itch. To develop a mouse model of psoriasis-induce chronic itch, we used 5% imiquimod cream to receive a daily topical application on the shaved back skin for seven consecutive days. The results showed that the expression of microglial marker ionized calcium binding adaptor molecule-1 was significantly increased after 5% imiquimod treatment in cervical spinal cord dorsal horn (C3-C4), and the intrathecal microglial inhibitor minocycline or PLX5622 diet suppressed both spontaneous itch and microglial activation. Furthermore, we found that the number of scratches and alloknesis score in female mice was significantly greater than in male mice after 5% imiquimod treatment. Our results indicate that microglia mediate chronic psoriatic itch induced by imiquimod.


Assuntos
Imiquimode/efeitos adversos , Microglia/patologia , Prurido/induzido quimicamente , Prurido/patologia , Psoríase/induzido quimicamente , Psoríase/patologia , Animais , Doença Crônica , Feminino , Masculino , Camundongos Endogâmicos C57BL
20.
Sci Rep ; 10(1): 9510, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528072

RESUMO

Endothelin-1 (ET-1) is well known as the most potent vasoconstrictor, and can evoke histamine-independent pruritus. Recently, its involvement in cutaneous inflammation has begun to draw attention. The upregulation of ET-1 expression in the epidermis of human psoriasis patients has been reported. It was also demonstrated that ET-1 can stimulate dendritic cells to induce Th17/1 immune responses. However, the role of the interaction between ET-1 and ET-1 receptors in the pathogenesis of psoriasis remains elusive. Here, we investigated the effects of ET-1 receptor antagonist on imiquimod (IMQ) -induced psoriasiform dermatitis in mouse. Psoriasis-related cytokines such as IL-17A and TNF-α induced ET-1 expression in human keratinocytes. Topical application of selective endothelin A receptor (ETAR) antagonist ambrisentan significantly attenuated the development of IMQ-induced psoriasiform dermatitis and also significantly inhibited the histological inflammation and cytokine expression (TNF-α, IL-12p40, IL-12 p19, and IL-17) in the lesional skin of the mouse model. Furthermore, topical application of ambrisentan suppressed phenotypic and functional activation of dendritic cells in lymph nodes. Our findings indicate that the ET-1 and ETAR axis plays an important role in the pathogenesis of psoriasis and is a potential therapeutic target for treating psoriasis.


Assuntos
Antagonistas dos Receptores de Endotelina/administração & dosagem , Antagonistas dos Receptores de Endotelina/farmacologia , Imiquimode/efeitos adversos , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Receptores de Endotelina/metabolismo , Pele/efeitos dos fármacos , Administração Tópica , Animais , Citocinas/metabolismo , Antagonistas dos Receptores de Endotelina/uso terapêutico , Endotelina-1/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Fenilpropionatos/administração & dosagem , Fenilpropionatos/farmacologia , Fenilpropionatos/uso terapêutico , Psoríase/metabolismo , Psoríase/prevenção & controle , Piridazinas/administração & dosagem , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Pele/patologia
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