Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 385
Filtrar
1.
Arterioscler Thromb Vasc Biol ; 38(11): 2576-2589, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354239

RESUMO

Objective- ACAT1 (Acyl-CoA cholesterol acyltransferase 1) esterifies cellular free cholesterol, thereby converting macrophages to cholesteryl ester-laden foam cells in atherosclerotic lesions and cutaneous xanthoma. Paradoxically, however, loss of ACAT1 in bone marrow causes the aggravation of atherosclerosis and the development of severe cutaneous xanthoma in hyperlipidemic mice. Recently, it has been reported that cholesterol crystals activate NLRP3 (NACHT, LRR [leucine-rich repeats], and PYD [pyrin domain] domain-containing protein 3) inflammasomes, thereby contributing to the development of atherosclerosis. The present study aimed to clarify the role of NLRP3 inflammasomes in the worsening of atherosclerosis and cutaneous xanthoma induced by ACAT1 deficiency. Approach and Results- Ldlr-null mice were transplanted with bone marrow from WT (wild type) mice and mice lacking ACAT1, NLRP3, or both. After the 4 types of mice were fed high-cholesterol diets, we compared their atherosclerosis and skin lesions. The mice transplanted with Acat1-null bone marrow developed severe cutaneous xanthoma, which was filled with numerous macrophages and cholesterol clefts and had markedly increased expression of inflammatory cytokines, and increased atherosclerosis. Loss of NLRP3 completely reversed the cutaneous xanthoma, whereas it improved the atherosclerosis only partially. Acat1-null peritoneal macrophages showed enhanced expression of CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein) and TNF-α (tumor necrosis factor-α) but no evidence of inflammasome activation, after treatment with acetylated LDL (low-density lipoprotein). Conclusions- Elimination of ACAT1 in bone marrow-derived cells aggravates cutaneous xanthoma and atherosclerosis. The development of cutaneous xanthoma is induced mainly via the NLRP3 inflammasome activation.


Assuntos
Acetil-CoA C-Acetiltransferase/metabolismo , Doenças da Aorta/enzimologia , Aterosclerose/enzimologia , Medula Óssea/enzimologia , Inflamassomos/metabolismo , Macrófagos Peritoneais/enzimologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Placa Aterosclerótica , Dermatopatias/enzimologia , Xantomatose/enzimologia , Acetil-CoA C-Acetiltransferase/deficiência , Acetil-CoA C-Acetiltransferase/genética , Animais , Doenças da Aorta/genética , Doenças da Aorta/patologia , Doenças da Aorta/prevenção & controle , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Medula Óssea/patologia , Transplante de Medula Óssea , Células Cultivadas , Colesterol na Dieta , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Macrófagos Peritoneais/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fenótipo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transdução de Sinais , Dermatopatias/genética , Dermatopatias/patologia , Dermatopatias/prevenção & controle , Xantomatose/genética , Xantomatose/patologia , Xantomatose/prevenção & controle
2.
Curr Pharm Des ; 24(20): 2303-2310, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30019640

RESUMO

The skin is often introduced as the largest organ of the human body which - being uniquely exposed to external stress - faces several types of challenges, from physical, chemical, biological, and immunological origin. Therefore, the skin is also a site where inflammation, oxidative stress and cellular damage occurs regularly. Heme oxygenase (HO), primarily functioning in the catabolism of heme, is a very important cytoprotective enzyme that has antioxidant, anti-inflammatory and anti-apoptotic properties. Given the need for an enzyme with such a combination of attributes in the skin, it is not surprising that HO is involved in physiological processes as well as pathological conditions of the skin. In the recent decade, a huge effort was undertaken to identify treatments that modify HO-activity for the treatment of inflammatory or malignant skin diseases. In this review, we highlight the role of HO in the skin in physiological conditions as well as in relevant dermatological diseases such as atopic dermatitis, psoriasis and melanoma.


Assuntos
Heme Oxigenase (Desciclizante)/metabolismo , Dermatopatias/tratamento farmacológico , Dermatopatias/enzimologia , Fenômenos Fisiológicos da Pele , Pele/enzimologia , Animais , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos
3.
Skin Therapy Lett ; 23(3): 5-9, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29772037

RESUMO

The class of medications known as Janus kinase inhibitors block cytokine-mediated signaling via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which plays an important role in immunoregulation and normal cell growth. This class includes the drugs tofacitinib, approved for the treatment of rheumatoid arthritis, and ruxolitinib, approved for the treatment of myelofibrosis and polycythemia rubra vera. The most common adverse events (AEs) reported in patients taking tofacitinib are infections, whereas the most common AEs in patients taking ruxolitinib are anemia and thrombocytopenia. Both first and second generation Janus kinase inhibitors have become promising treatment modalities for dermatologic conditions such as psoriasis, atopic dermatitis, alopecia areata, vilitigo, dermatomyositis, and graft-versus-host disease. Future promising areas of investigation include treatment of cutaneous lupus, cutaneous T-cell lymphoma, melanoma, allergic contact dermatitis, and lichen planus.


Assuntos
Anti-Inflamatórios/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Dermatopatias/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Dermatologia , Humanos , Inibidores de Janus Quinases/efeitos adversos , Dermatopatias/enzimologia
5.
Front Immunol ; 9: 569, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29619028

RESUMO

Persistent activation of mitogen-activated protein kinase (MAPK) is believed to be involved in psoriasis pathogenesis. MAPK phosphatase-1 (MKP-1) is an important negative regulator of MAPK activity, but the cellular and molecular mechanisms of MKP-1 in psoriasis development are largely unknown. In this study, we found that the expression of MKP-1 was decreased in the imiquimod (IMQ)-induced psoriasiform mouse skin. MKP-1-deficient (MKP-1-/-) mice were highly susceptible to IMQ-induced skin inflammation, which was associated with increased production of inflammatory cytokines and chemokines. MKP-1 acted on both hematopoietic and non-hematopoietic cells to regulate psoriasis pathogenesis. MKP-1 deficiency in macrophages led to enhanced p38 activation and higher expression of interleukin (IL)-1ß, CXCL2, and S100a8 upon R848 stimulation. Moreover, MKP-1 deficiency in the non-hematopoietic compartments led to an enhanced IL-22 receptor signaling and higher expression of CXCL1 and CXCL2 upon IMQ treatment. Collectively, our data suggest a critical role for MKP-1 in the regulation of skin inflammation.


Assuntos
Fosfatase 1 de Especificidade Dupla/deficiência , Psoríase/enzimologia , Dermatopatias/enzimologia , Pele/enzimologia , Animais , Citocinas/genética , Citocinas/metabolismo , Fosfatase 1 de Especificidade Dupla/genética , Imiquimode , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Psoríase/induzido quimicamente , Psoríase/genética , Índice de Gravidade de Doença , Pele/metabolismo , Pele/patologia , Dermatopatias/induzido quimicamente , Dermatopatias/genética
6.
Ann Rheum Dis ; 77(5): 744-751, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29431122

RESUMO

OBJECTIVES: The enzyme poly(ADP-ribose) polymerase-1 (PARP-1) transfers negatively charged ADP-ribose units to target proteins. This modification can have pronounced regulatory effects on target proteins. Recent studies showed that PARP-1 can poly(ADP-ribosyl)ate (PARylate) Smad proteins. However, the role of PARP-1 in the pathogenesis of systemic sclerosis (SSc) has not been investigated. METHODS: The expression of PARP-1 was determined by quantitative PCR and immunohistochemistry. DNA methylation was analysed by methylated DNA immunoprecipitation assays. Transforming growth factor-ß (TGFß) signalling was assessed using reporter assays, chromatin immunoprecipitation assays and target gene analysis. The effect of PARP-1 inactivation was investigated in bleomycin-induced and topoisomerase-induced fibrosis as well as in tight-skin-1 (Tsk-1) mice. RESULTS: The expression of PARP-1 was decreased in patients with SSc, particularly in fibroblasts. The promoter of PARP-1 was hypermethylated in SSc fibroblasts and in TGFß-stimulated normal fibroblasts. Inhibition of DNA methyltransferases (DNMTs) reduced the promoter methylation and reactivated the expression of PARP-1. Inactivation of PARP-1 promoted accumulation of phosphorylated Smad3, enhanced Smad-dependent transcription and upregulated the expression of TGFß/Smad target genes. Inhibition of PARP-1 enhanced the effect of TGFß on collagen release and myofibroblast differentiation in vitro and exacerbated experimental fibrosis in vivo. PARP-1 deficiency induced a more severe fibrotic response to bleomycin with increased dermal thickening, hydroxyproline content and myofibroblast counts. Inhibition of PARylation also exacerbated fibrosis in Tsk-1 mice and in mice with topoisomerase-induced fibrosis. CONCLUSION: PARP-1 negatively regulates canonical TGFß signalling in experimental skin fibrosis. The downregulation of PARP-1 in SSc fibroblasts may thus directly contribute to hyperactive TGFß signalling and to persistent fibroblast activation in SSc.


Assuntos
Fibroblastos/fisiologia , Fibrose/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Escleroderma Sistêmico/genética , Dermatopatias/genética , Adulto , Idoso , Animais , Metilação de DNA/genética , Modelos Animais de Doenças , Regulação para Baixo/genética , Feminino , Fibrose/induzido quimicamente , Fibrose/enzimologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases , Escleroderma Sistêmico/enzimologia , Transdução de Sinais , Pele/metabolismo , Pele/patologia , Dermatopatias/enzimologia , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem
7.
Cell Death Dis ; 8(10): e3148, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-29072680

RESUMO

UV irradiation elicits acute inflammation in the skin by increasing proinflammatory cytokine production in keratinocytes. However, the downstream protein target(s) that link UV radiation to the activation of signaling pathways responsible for cytokine expression have not been fully elucidated. In this study, we report a novel role of transglutaminase 2 (TG2), a member of the TG enzyme family whose activities are critical for cornified envelope formation, in mediating UV-induced inflammation. Our results showed that TG2-deficient mice exhibited reduced inflammatory responses to UV irradiation, including reduced erythema, edema, dilation of blood vessels, inflammatory cell infiltration, and levels of inflammatory cytokines. Using primary mouse keratinocytes and HaCaT cells, we found that UV irradiation-induced cytokine production by activating TG2, but not by upregulating TG2 expression, and that ER calcium release triggered by the UV-induced activation of phospholipase C was required for TG2 activation. Moreover, TG2 activity enhanced p65 phosphorylation, leading to an increase in NF-κB transcriptional activity. These results indicate that TG2 is a critical mediator of cytokine expression in the UV-induced inflammatory response of keratinocytes, and suggest that TG2 inhibition might be useful for preventing UV-related skin disorders, such as photoaging and skin cancer caused by chronic UV exposure.


Assuntos
Citocinas/biossíntese , Proteínas de Ligação ao GTP/metabolismo , Dermatopatias/enzimologia , Pele/enzimologia , Pele/efeitos da radiação , Transglutaminases/metabolismo , Animais , Apoptose/fisiologia , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Knockout , Transdução de Sinais , Pele/metabolismo , Dermatopatias/etiologia , Dermatopatias/metabolismo , Raios Ultravioleta
8.
J Am Acad Dermatol ; 76(4): 736-744, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28139263

RESUMO

New molecularly targeted therapeutics are changing dermatologic therapy. Janus kinase-signal transducer and activator of transcription (JAK-STAT) is an intracellular signaling pathway upon which many different proinflammatory signaling pathways converge. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on JAK-STAT signaling, and inhibition of this pathway using JAK inhibitors might be a useful therapeutic strategy for these diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo. Additional evidence suggests that JAK inhibition might be broadly useful in dermatology, with early reports of efficacy in several other conditions. JAK inhibitors can be administered orally or used topically and represent a promising new class of medications. The use of JAK inhibitors in dermatology is reviewed here.


Assuntos
Anti-Inflamatórios/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Janus Quinases/antagonistas & inibidores , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Dermatopatias/tratamento farmacológico , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/enzimologia , Anti-Inflamatórios/efeitos adversos , Azetidinas/efeitos adversos , Azetidinas/uso terapêutico , Ensaios Clínicos como Assunto , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/enzimologia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/classificação , Humanos , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Psoríase/tratamento farmacológico , Psoríase/enzimologia , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Dermatopatias/enzimologia , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Vitiligo/tratamento farmacológico , Vitiligo/enzimologia
9.
J Am Acad Dermatol ; 76(4): 745-753.e19, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28169015

RESUMO

BACKGROUND: Janus kinase (JAK) inhibitors are emerging as a promising new treatment modality for many inflammatory conditions. OBJECTIVE: Our aim was to systematically review the available data on the use of JAK inhibitors in cutaneous diseases. METHODS: This is a systematic review of PubMed and ClinicalTrials.gov. RESULTS: One hundred thirty-four articles matched our search terms, of which 78 were original articles and 12 reports on adverse events. Eighteen clinical trials were found. JAK inhibitors have been extensively studied for psoriasis, showing beneficial results that were comparable to the effects achieved by etanercept. Favorable results were also observed for alopecia areata. Promising preliminary results were reported for vitiligo, dermatitis, graft versus host disease, cutaneous T cell lymphoma, and lupus erythematosus. The most common adverse events reported were infections, mostly nasopharyngitis and upper respiratory tract infections. LIMITATIONS: It was not possible to perform a meta-analysis of the results. CONCLUSIONS: This systematic review shows that while JAK inhibitors hold promise for many skin disorders, there are still gaps regarding the correct dosing and safety profile of these medications for dermatologic indications. Additional trials are necessary to address these gaps.


Assuntos
Anti-Inflamatórios/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Janus Quinases/antagonistas & inibidores , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Dermatopatias/tratamento farmacológico , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/enzimologia , Anti-Inflamatórios/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Azetidinas/efeitos adversos , Azetidinas/uso terapêutico , Fármacos Dermatológicos/efeitos adversos , Erupção por Droga/etiologia , Humanos , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Psoríase/tratamento farmacológico , Psoríase/enzimologia , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais/efeitos dos fármacos , Dermatopatias/enzimologia , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico
10.
Nat Genet ; 48(12): 1564-1569, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27749843

RESUMO

Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.


Assuntos
Dor Crônica/genética , Doenças do Tecido Conjuntivo/genética , Variações do Número de Cópias de DNA/genética , Disautonomia Familiar/genética , Gastroenteropatias/genética , Prurido/genética , Dermatopatias/genética , Triptases/sangue , Triptases/genética , Adolescente , Adulto , Idoso , Criança , Dor Crônica/sangue , Dor Crônica/enzimologia , Doenças do Tecido Conjuntivo/sangue , Doenças do Tecido Conjuntivo/enzimologia , Disautonomia Familiar/sangue , Disautonomia Familiar/enzimologia , Feminino , Gastroenteropatias/sangue , Gastroenteropatias/enzimologia , Humanos , Masculino , Pessoa de Meia-Idade , Prurido/sangue , Prurido/enzimologia , Dermatopatias/sangue , Dermatopatias/enzimologia , Adulto Jovem
11.
PLoS One ; 11(10): e0164080, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27711196

RESUMO

The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p)JAK1, (p)JAK2, (p)JAK3, (p)TYK2, pSTAT1, pSTAT2 and pSTAT3. The epidermis carried in all ISDs, except for CLE, a strong JAK3 signature. The dermal infiltrate showed a more diverse expression pattern. JAK1, JAK2 and JAK3 were significantly overexpressed in PG and AD suggesting the need for pan-JAK inhibitors. In contrast, psoriasis and LP showed only JAK1 and JAK3 upregulation, while AA and CLE were characterized by a single dermal JAK signal (pJAK3 and pJAK1, respectively). This indicates that the latter diseases may benefit from more targeted JAK inhibitors. Our in vitro keratinocyte psoriasis model displayed reversal of the psoriatic JAK profile following tofacitinib treatment. This direct interaction with keratinocytes may decrease the need for deep skin penetration of topical JAK inhibitors in order to exert its effects on dermal immune cells. In conclusion, these results point to the important contribution of the JAK/STAT pathway in several ISDs. Considering the epidermal JAK3 expression levels, great interest should go to the investigation of topical JAK3 inhibitors as therapeutic option of ISDs.


Assuntos
Janus Quinase 3/metabolismo , Terapia de Alvo Molecular , Dermatopatias/tratamento farmacológico , Administração Tópica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Lactente , Inflamação/complicações , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/genética , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Dermatopatias/complicações , Dermatopatias/enzimologia , Adulto Jovem
13.
Life Sci ; 145: 274-83, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26475762

RESUMO

AIMS: Although epidemiological studies have investigated associations between occupational pesticide exposures and different adverse health outcomes, they have rarely assessed individuals at two time-points of a same crop season with different pesticide use. MATERIAL AND METHODS: Clinical symptoms, physical examination signs, hematological and clinical chemistry parameters were measured in 189 intensive agriculture workers and 91 healthy control subjects from Almeria coastline (Southeastern Spain) to evaluate potential effects of pesticide exposure. KEY FINDINGS: Greenhouse workers showed an increased risk of ocular and skin signs relative to controls at the period of high pesticide exposure (OR: 4.80 and 2.87, respectively); however, no differences were observed for clinical symptoms. A greater risk for ECG changes (OR: 3.35) and altered spirometry (OR: 5.02) was found at the period of low exposure. Erythrocyte acetylcholinesterase was significantly decreased in greenhouse workers relative to controls in both periods. Assessment of hematological parameters revealed increased counts of erythrocytes, leukocytes, platelets and hemoglobin in greenhouse workers relative to controls, and also in the period of high versus low pesticide exposure. Changes in clinical chemistry parameters included decreased levels of glucose, creatinine, total cholesterol, triglyceride and alkaline phosphatase in greenhouse workers relative to controls; however, these parameters were raised in the period of high versus low pesticide exposure. SIGNIFICANCE: These findings suggest that chronic occupational exposure to pesticides of lower toxicity than former compounds under integrated production systems elicit mild toxic effects, particularly targeting the skin and eyes, as well as subtle subclinical (biochemical) changes of unknown long-term consequences.


Assuntos
Doenças dos Trabalhadores Agrícolas/induzido quimicamente , Oftalmopatias/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Praguicidas/efeitos adversos , Dermatopatias/induzido quimicamente , Acetilcolinesterase/metabolismo , Adulto , Doenças dos Trabalhadores Agrícolas/sangue , Doenças dos Trabalhadores Agrícolas/enzimologia , Agricultura/métodos , Contagem de Células Sanguíneas , Oftalmopatias/sangue , Oftalmopatias/enzimologia , Fazendeiros , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dermatopatias/sangue , Dermatopatias/enzimologia , Espanha/epidemiologia
15.
Food Funct ; 6(8): 2794-802, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26165701

RESUMO

This work reports the antioxidant, antimicrobial, and inhibitory effects of methanol and water extracts from Ganoderma applanatum (GAM: methanol extract and GAW: water extract) and G. resinaceum (GRM: methanol extract and GRW: water extract) against cholinesterase, tyrosinase, α-amylase and α-glucosidase. The total phenolics, flavonoids contents, and HPLC profile of phenolic components present in the extracts, were also determined. Antioxidant activities were investigated by using different assays, including DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum and metal chelating assays. Antimicrobial activity of the tested Ganoderma extracts was also studied by the broth microdilution method. Generally, the highest antioxidant (59.24 mg TEs per g extract for DPPH, 41.32 mg TEs per g extract for ABTS, 41.35 mg TEs per g extract for CUPRAC, 49.68 mg TEs per g extract for FRAP, 130.57 mg AAEs per g extract for phosphomolybdenum and 26.92 mg EDTAEs per g extract) and enzyme inhibitory effects (1.47 mg GALAEs per g extract for AChE, 1.51 mg GALAEs per g extract for BChE, 13.40 mg KAEs per g extract for tyrosinase, 1.13 mmol ACEs per g extract for α-amylase and 2.20 mmol ACEs per g extract for α-glucosidase) were observed in GRM, which had the highest concentrations of phenolics (37.32 mg GAEs g(-1) extract). Again, Ganoderma extracts possess weak antibacterial and antifungal activities. Apigenin and protocatechuic acid were determined as the main components in GRM (1761 µg per g extract) and GAM (165 µg per g extract), respectively. The results suggest that the Ganoderma species may be considered as a candidate for preparing new food supplements and can represent a good model for the development of new drug formulations.


Assuntos
Anti-Infecciosos/química , Antioxidantes/química , Inibidores Enzimáticos/química , Ganoderma/química , Fenóis/química , Extratos Vegetais/química , Doença de Alzheimer/enzimologia , Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Bactérias/efeitos dos fármacos , Colinesterases/metabolismo , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus/enzimologia , Inibidores Enzimáticos/farmacologia , Fungos/efeitos dos fármacos , Humanos , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Dermatopatias/enzimologia , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo
16.
Cancer Biol Ther ; 16(9): 1281-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26061397

RESUMO

Radiation therapy (RT) the front-line treatment after surgery for early breast cancer patients is associated with acute skin toxicities in at least 40% of treated patients. Monocyte-derived macrophages are polarized into functionally distinct (M1 or M2) activated phenotypes at injury sites by specific systemic cytokines known to play a key role in the transition between damage and repair in irradiated tissues. The role of M1 and M2 macrophages in RT-induced acute skin toxicities remains to be defined. We investigated the potential value of M1 and M2 macrophages as predictive factors of RT-induced skin toxicities in early breast cancer patients treated with adjuvant RT after lumpectomy. Blood samples collected from patients enrolled in a prospective clinical study (n = 49) were analyzed at baseline and after the first delivered 2Gy RT dose. We designed an ex vivo culture system to differentiate patient blood monocytes into macrophages and treated them with M1 or M2-inducing cytokines before quantitative analysis of their "M1/M2" activation markers, iNOS, Arg1, and TGFß1. Statistical analysis was performed to correlate experimental data to clinical assessment of acute skin toxicity using Common Toxicity Criteria (CTC) grade for objective evaluation of skin reactions. Increased ARG1 mRNA significantly correlated with higher grades of erythema, moist desquamation, and CTC grade. Multivariate analysis revealed that increased ARG1 expression in macrophages after a single RT dose was an independent prognostic factor of erythema (p = 0 .032), moist desquamation (p = 0 .027), and CTC grade (p = 0 .056). Interestingly, multivariate analysis of ARG1 mRNA expression in macrophages stimulated with IL-4 also revealed independent prognostic value for predicting acute RT-induced toxicity factors, erythema (p = 0 .069), moist desquamation (p = 0 .037), and CTC grade (p = 0 .046). To conclude, our findings underline for the first time the biological significance of increased ARG1 mRNA levels as an early independent predictive biomarker of RT-induced acute skin toxicities.


Assuntos
Arginase/metabolismo , Neoplasias da Mama/radioterapia , Carcinoma Ductal de Mama/enzimologia , Macrófagos/enzimologia , Lesões por Radiação/enzimologia , Dermatopatias/enzimologia , Arginase/genética , Neoplasias da Mama/enzimologia , Carcinoma Ductal de Mama/radioterapia , Células Cultivadas , Feminino , Humanos , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/metabolismo , Prognóstico , Fator de Crescimento Transformador beta/metabolismo
19.
Exp Dermatol ; 24(4): 285-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25644735

RESUMO

Acral peeling skin syndrome (APSS, MIM #609796) is a rare autosomal recessive disorder characterized by superficial exfoliation and blistering of the volar and dorsal aspects of hands and feet. The level of separation is at the junction of the stratum granulosum and stratum corneum. APSS is caused by mutations in the TGM5 gene encoding transglutaminase-5, which is important for structural integrity of the outermost epidermal layers. The majority of patients originate from Europe and carry a p.(Gly113Cys) mutation in TGM5. In this study, we report both European and non-European families carrying other mutations in the TGM5 gene. In 5 patients, we found 3 novel mutations: c.1001+2_1001+3del, c.1171G>A and c.1498C>T. To confirm their pathogenicity, we performed functional analyses with a transglutaminase activity assay, determined alternative splicing by reverse-transcribed PCR analysis and used databases and in silico prediction tools.


Assuntos
Mutação , Dermatopatias/congênito , Transglutaminases/genética , Processamento Alternativo , Sequência de Aminoácidos , Substituição de Aminoácidos , Células Cultivadas , Criança , Pré-Escolar , Análise Mutacional de DNA , Europa (Continente) , Feminino , Células HEK293 , Humanos , Mutação INDEL , Lactente , Kuweit , Masculino , Dados de Sequência Molecular , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Países Baixos/etnologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Dermatopatias/enzimologia , Dermatopatias/genética , Transfecção , Transglutaminases/metabolismo
20.
J Med Chem ; 58(2): 598-612, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25489658

RESUMO

The inhibition of kallikreins 5 and 7, and possibly kallikrein 14 and matriptase, (that initiates the kallikrein proteolytic cascade) constitutes an innovative way to treat some skin diseases such as Netherton syndrome. We present here the inhibitory properties of coumarin-3-carboxylate derivatives against these enzymes. Our small collection of these versatile organic compounds was enriched by newly synthesized derivatives in order to obtain molecules selective against one, two, three enzymes or acting on the four ones. We evidenced a series of compounds with IC50 values in the nanomolar range. A suicide mechanism was observed against kallikrein 7 whereas the inactivation was either definitive (suicide type) or transient for kallikreins 5 and 14, and matriptase. Most of these potent inhibitors were devoid of cytotoxicity toward healthy human keratinocytes. In situ zymography investigations on skin sections from human kallikrein 5 transgenic mouse revealed significant reduction of the global proteolytic activity by several compounds.


Assuntos
Cumarínicos/farmacologia , Calicreínas/antagonistas & inibidores , Inibidores de Serino Proteinase/farmacologia , Dermatopatias/tratamento farmacológico , Humanos , Serina Endopeptidases/fisiologia , Dermatopatias/enzimologia , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA