Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
Lakartidningen ; 1212024 Aug 06.
Artigo em Sueco | MEDLINE | ID: mdl-39105358

RESUMO

One of the primary indicators of this condition is a painful and migratory dermatitis. Additionally, early signs often include weight loss and diabetes. Patients with glucagonoma commonly first encounter general practitioners or dermatologists. Unfortunately, due to the nonspecific nature of symptoms such as eczema-like dermatitis, weight loss and diabetes, diagnosis is frequently delayed, often by 2-3 years. Consequently, by the time patients are diagnosed, the tumor has usually grown and metastasized, often spreading to the liver. As a result, surgical intervention is often not possible, and treatment options are usually limited to palliative care. However, with early diagnosis of glucagonoma, treatment can be curative. Therefore, it is crucial for medical professionals who initially meet these patients, including dermatologists, general practitioners, endocrinologists, and others, to be aware of this condition to ensure an early diagnosis. By recognizing the signs and symptoms early, doctors can potentially improve patient outcomes and save lives.


Assuntos
Glucagonoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Glucagonoma/diagnóstico , Glucagonoma/terapia
3.
Sci Rep ; 9(1): 3596, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837648

RESUMO

Cutibacterium acnes is an abundant skin commensal with several proposed mutualistic functions. A protein with strong antioxidant activity was recently identified from the C. acnes secretome. This protein, termed RoxP, facilitated aerobic bacterial growth in vitro and ex vivo. As reducing events naturally occurred outside of the bacterial cell, it was further hypothesized that RoxP could also serve to modulate redox status of human skin. The biological function of RoxP was here assessed in vitro and in vivo, through oxidatively stressed cell cultures and through protein quantification from skin affected by oxidative disease (actinic keratosis and basal cell carcinoma), respectively. 16S rDNA amplicon deep sequencing and single locus sequence typing was used to correlate bacterial prevalence to cutaneous RoxP abundances. We show that RoxP positively influence the viability of monocytes and keratinocytes exposed to oxidative stress, and that a congruent concentration decline of RoxP can be observed in skin affected by oxidative disease. Basal cell carcinoma was moreover associated with microbial dysbiosis, characterized by reduced C. acnes prevalence. C. acnes's secretion of RoxP, an exogenous but naturally occurring antioxidant on human skin, is likely to positively influence the human host. Results furthermore attest to its prospective usability as a biopharmaceutical.


Assuntos
Antioxidantes/farmacologia , Proteínas de Bactérias/farmacologia , Infecções por Bactérias Gram-Positivas/metabolismo , Queratinócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Acne Vulgar/tratamento farmacológico , Acne Vulgar/metabolismo , Acne Vulgar/microbiologia , Acne Vulgar/patologia , Idoso , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/microbiologia , Carcinoma Basocelular/patologia , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Queratinócitos/metabolismo , Queratinócitos/microbiologia , Pessoa de Meia-Idade , Propionibacterium acnes/isolamento & purificação , Propionibacterium acnes/metabolismo , Pele/efeitos dos fármacos , Pele/microbiologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/microbiologia , Neoplasias Cutâneas/patologia
4.
Proc Natl Acad Sci U S A ; 111(35): E3669-78, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25136095

RESUMO

Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by γδ T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fcγ receptor III, mast cells, and histamine) and adaptive immune players (αß T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-α secretion and stimulation of local γδ T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA.


Assuntos
Artrite Psoriásica/induzido quimicamente , Artrite Psoriásica/imunologia , Interleucina-17/imunologia , Mananas/farmacologia , Animais , Artrite Psoriásica/metabolismo , Dermatite/imunologia , Dermatite/patologia , Modelos Animais de Doenças , Humanos , Interleucina-17/metabolismo , Articulações/imunologia , Articulações/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/imunologia , NADPH Oxidases/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
5.
PLoS One ; 7(12): e52772, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23300768

RESUMO

BACKGROUND: Tissue factor pathway inhibitor 2 (TFPI-2) is a matrix-associated serine protease inhibitor with an enigmatic function in vivo. Here, we describe that TFPI-2 is present in fibrin of wounds and also expressed in skin, where it is up-regulated upon wounding. METHODOLOGY AND PRINCIPAL FINDINGS: Neutrophil elastase cleaved TFPI-2, and a C-terminal fragment was found to bind to bacteria. Similarly, a prototypic peptide representing this C-terminal part, EDC34, bound to bacteria and bacterial lipopolysaccharide, and induced bacterial permeabilization. The peptide also induced leakage in artificial liposomes, and displayed a random coil conformation upon interactions with liposomes as well as lipopolysaccharide. EDC34 was antibacterial against both Gram-negative and Gram-positive bacteria in physiological buffer conditions. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that the C-terminus of TFPI-2 encodes for antimicrobial activity, and may be released during wounding.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Glicoproteínas/farmacologia , Fragmentos de Peptídeos/farmacologia , Pele/metabolismo , Sequência de Aminoácidos , Antibacterianos , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/metabolismo , Bacillus subtilis/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Expressão Gênica , Glicoproteínas/química , Glicoproteínas/metabolismo , Humanos , Elastase de Leucócito/química , Lipopolissacarídeos/química , Viabilidade Microbiana/efeitos dos fármacos , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Proteólise , Pseudomonas aeruginosa/efeitos dos fármacos , Pele/patologia , Staphylococcus aureus/efeitos dos fármacos , Técnicas de Cultura de Tecidos
6.
PLoS One ; 6(11): e27505, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22096585

RESUMO

During bleeding the skin is subjected to oxidative insults from free heme and radicals, generated from extracellular hemoglobin. The lipocalin α(1)-microglobulin (A1M) was recently shown to have reductase properties, reducing heme-proteins and other substrates, and to scavenge heme and radicals. We investigated the expression and localization of A1M in skin and the possible role of A1M in the protection of skin tissue from damage induced by heme and reactive oxygen species. Skin explants, keratinocyte cultures and purified collagen I were exposed to heme, reactive oxygen species, and/or A1M and investigated by biochemical methods and electron microscopy. The results demonstrate that A1M is localized ubiquitously in the dermal and epidermal layers, and that the A1M-gene is expressed in keratinocytes and up-regulated after exposure to heme and reactive oxygen species. A1M inhibited the heme- and reactive oxygen species-induced ultrastructural damage, up-regulation of antioxidation and cell cycle regulatory genes, and protein carbonyl formation in skin and keratinocytes. Finally, A1M bound to purified collagen I (K(d) = 0.96×10(-6) M) and could inhibit and repair the destruction of collagen fibrils by heme and reactive oxygen species. The results suggest that A1M may have a physiological role in protection of skin cells and matrix against oxidative damage following bleeding.


Assuntos
alfa-Globulinas/metabolismo , Heme/farmacologia , Espécies Reativas de Oxigênio/farmacologia , Pele/metabolismo , alfa-Globulinas/genética , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Colágeno Tipo I/metabolismo , Humanos , Imuno-Histoquímica , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/ultraestrutura , Microscopia Eletrônica de Transmissão , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Radioimunoensaio , Reação em Cadeia da Polimerase em Tempo Real , Pele/ultraestrutura
7.
J Biol Chem ; 285(36): 28387-98, 2010 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-20592020

RESUMO

Tissue factor pathway inhibitor (TFPI) inhibits tissue factor-induced coagulation, but may, via its C terminus, also modulate cell surface, heparin, and lipopolysaccharide interactions as well as participate in growth inhibition. Here we show that C-terminal TFPI peptide sequences are antimicrobial against the gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungi Candida albicans and Candida parapsilosis. Fluorescence studies of peptide-treated bacteria, paired with analysis of peptide effects on liposomes, showed that the peptides exerted membrane-breaking effects similar to those seen for the "classic" human antimicrobial peptide LL-37. The killing of E. coli, but not P. aeruginosa, by the C-terminal peptide GGLIKTKRKRKKQRVKIAYEEIFVKNM (GGL27), was enhanced in human plasma and largely abolished in heat-inactivated plasma, a phenomenon linked to generation of antimicrobial C3a and activation of the classic pathway of complement activation. Furthermore, GGL27 displayed anti-endotoxic effects in vitro and in vivo in a mouse model of LPS shock. Importantly, TFPI was found to be expressed in the basal layers of normal epidermis, and was markedly up-regulated in acute skin wounds as well as wound edges of chronic leg ulcers. Furthermore, C-terminal fragments of TFPI were associated with bacteria present in human chronic leg ulcers. These findings suggest a new role for TFPI in cutaneous defense against infections.


Assuntos
Anti-Infecciosos/imunologia , Lipoproteínas/química , Fragmentos de Peptídeos/imunologia , Sequência de Aminoácidos , Animais , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Bovinos , Ativação do Complemento , Complemento C3a/biossíntese , Complexo de Ataque à Membrana do Sistema Complemento/biossíntese , Feminino , Fungos/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Úlcera da Perna/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Ratos , Pele/lesões , Pele/metabolismo
8.
PLoS Pathog ; 4(8): e1000116, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18797515

RESUMO

Fungi, such as Candida spp., are commonly found on the skin and at mucosal surfaces. Yet, they rarely cause invasive infections in immunocompetent individuals, an observation reflecting the ability of our innate immune system to control potentially invasive microbes found at biological boundaries. Antimicrobial proteins and peptides are becoming increasingly recognized as important effectors of innate immunity. This is illustrated further by the present investigation, demonstrating a novel antifungal role of histidine-rich glycoprotein (HRG), an abundant and multimodular plasma protein. HRG bound to Candida cells, and induced breaks in the cell walls of the organisms. Correspondingly, HRG preferentially lysed ergosterol-containing liposomes but not cholesterol-containing ones, indicating a specificity for fungal versus other types of eukaryotic membranes. Both antifungal and membrane-rupturing activities of HRG were enhanced at low pH, and mapped to the histidine-rich region of the protein. Ex vivo, HRG-containing plasma as well as fibrin clots exerted antifungal effects. In vivo, Hrg(-/-) mice were susceptible to infection by C. albicans, in contrast to wild-type mice, which were highly resistant to infection. The results demonstrate a key and previously unknown antifungal role of HRG in innate immunity.


Assuntos
Candidíase/imunologia , Imunidade Inata , Proteínas/imunologia , Animais , Sítios de Ligação , Candida/imunologia , Parede Celular , Ergosterol/metabolismo , Camundongos , Ligação Proteica , Proteínas/metabolismo , Especificidade por Substrato
11.
Thromb Haemost ; 92(2): 281-7, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15269823

RESUMO

Recently it was demonstrated by Gautam, et al. that release of neutrophil-borne heparin-binding protein (HBP), also known as CAP37/azurocidin, induced endothelial hyperpermeability and neutrophil efflux. Here, we show that chronic leg ulcer fluid, in contrast to wound fluid from acute wounds, contains highly increased levels of HBP. Immunohistochemistry demonstrated the presence of HBP in chronic ulcer tissues. Furthermore, secreted products of Pseudomonas aeruginosa were found to induce release of HBP from human neutrophils. Our data suggest a possible link between bacterial presence and HBP-release in chronic ulcers. Thus, targeting HBP offers an interesting option for reduction of endothelial barrier dysfunction in chronic ulcers.


Assuntos
Proteínas Sanguíneas/fisiologia , Proteínas de Transporte/fisiologia , Granulócitos/metabolismo , Úlcera da Perna/patologia , Pseudomonas aeruginosa/metabolismo , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Peptídeos Catiônicos Antimicrobianos , Aprotinina/metabolismo , Biópsia , Proteínas Sanguíneas/biossíntese , Western Blotting , Proteínas de Transporte/biossíntese , Estudos de Coortes , Meios de Cultivo Condicionados/farmacologia , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Endotélio Vascular/metabolismo , Granulócitos/microbiologia , Humanos , Imuno-Histoquímica , Inflamação , Úlcera da Perna/microbiologia , Dados de Sequência Molecular , Neutrófilos/metabolismo , Cicatrização
12.
J Invest Dermatol ; 121(3): 640-6, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12925227

RESUMO

Chronic venous ulcers are characterized by chronic inflammation. Heme and iron, originating from blood cell hemolysis as well as extravascular necrosis, have been implicated as important pathogenic factors due to their promotion of oxidative stress. It was recently reported that the plasma and tissue protein alpha1-microglobulin is involved in heme metabolism. The protein binds heme, and a carboxy-terminally processed form, truncated alpha1-microglobulin, also degrades heme. Here, we show the presence of micromolar levels of heme and free iron in chronic leg ulcer fluids. Micromolar amounts of alpha1-microglobulin was also present in the ulcer fluids and bound to added radiolabeled heme. Truncated alpha1-microglobulin was found in the ulcer fluids and exogenously added alpha1-microglobulin was processed into the truncated alpha1-microglobulin form. Histochemical analysis of chronic wound tissue showed the presence of iron deposits, heme/porphyrins in infiltrating cells basement membranes and fibrin cuffs around vessels, and alpha1-microglobulin ubiquitously distributed but especially abundant in basement membranes around vessels and at fibrin cuffs. Our results suggest that alpha1-microglobulin constitutes a previously unknown defense mechanism against high heme and iron levels during skin wound healing. Excessive heme and iron, which are not buffered by alpha1-microglobulin, may underlie the chronic inflammation in chronic ulcers.


Assuntos
alfa-Globulinas/metabolismo , Heme/metabolismo , Úlcera Varicosa/metabolismo , Líquidos Corporais/imunologia , Líquidos Corporais/metabolismo , Radioisótopos de Carbono , Carcinoma Hepatocelular , Doença Crônica , Dermatite/imunologia , Dermatite/metabolismo , Humanos , Ferro/metabolismo , Neoplasias Hepáticas , Estresse Oxidativo/imunologia , Ligação Proteica/imunologia , Protoporfirinas/metabolismo , Células Tumorais Cultivadas , Úlcera Varicosa/imunologia , Cicatrização/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA