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1.
Microbiol Spectr ; 9(1): e0055021, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34406812

RESUMO

Bacterial bloodstream infection (BSI) represents a significant complication in hematologic patients. However, factors leading to BSI and progression to end-organ disease and death are understood only partially. The study analyzes host and microbial risk factors and assesses their impact on BSI development and mortality. A total of 96 patients with hematological malignancies and BSI were included in the study. Host-associated risk factors and all causes of mortality were analyzed by multivariable logistic regression at 30 days after BSI onset of the first neutropenic episode. The multidrug-resistant profile and biofilm production of bacterial isolates from primary BSI were included in the analysis. Median age was 60 years. The underlying diagnoses were acute leukemia (55%), lymphoma (31%), and myeloma (14%). A total of 96 bacterial isolates were isolated from BSIs. Escherichia coli was the most common isolate (29.2%). Multidrug-resistant bacteria caused 10.4% of bacteremia episodes. Weak biofilm producers (WBPs) were significantly (P < 0.0001) more abundant (72.2%) than strong biofilm producers (SBPs) (27.8%). Specifically, SBPs were 7.1% for E. coli, 93.7% for P. aeruginosa, 50% for K. pneumoniae, and 3.8% for coagulase-negative staphylococci. Mortality at day 30 was 8.3%, and all deaths were attributable to Gram-negative bacteria. About 22% of all BSIs were catheter-related BSIs (CRBSIs) and mostly caused by Gram-positive bacteria (79.0%). However, CRBSIs were not correlated with biofilm production levels (P = 0.75) and did not significantly impact the mortality rate (P = 0.62). Conversely, SBP bacteria were an independent risk factor (P = 0.018) for developing an end-organ disease. In addition, multivariate analysis indicated that SBPs (P = 0.013) and multidrug-resistant bacteria (P = 0.006) were independent risk factors associated with 30-day mortality. SBP and multidrug-resistant (MDR) bacteria caused a limited fraction of BSI in these patients. However, when present, SBPs raise the risk of end-organ disease and, together with an MDR phenotype, can independently and significantly concur at increasing the risk of death. IMPORTANCE Bacterial bloodstream infection (BSI) is a significant complication in hematologic patients and is associated with high mortality rates. Despite improvements in BSI management, factors leading to sepsis are understood only partially. This study analyzes the contribution of bacterial biofilm on BSI development and mortality in patients with hematological malignancies (HMs). In this work, weak biofilm producers (WBPs) were significantly more abundant than strong biofilm producers (SBPs). However, when present, SBP bacteria raised the risk of end-organ disease in HM patients developing a BSI. Besides, SBPs, together with a multidrug-resistant (MDR) phenotype, independently and significantly concur at increasing the risk of death in HM patients. The characterization of microbial biofilms may provide key information for the diagnosis and therapeutic management of BSI and may help develop novel strategies to either eradicate or control harmful microbial biofilms.

2.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299118

RESUMO

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor expressed in all skin cell types, plays a key role in physiological and pathological processes. Several studies have shown that this receptor is involved in the prevention of inflammatory skin diseases, e.g., psoriasis, atopic dermatitis, representing a potential therapeutic target. We tested the safety profile and the biological activity of NPD-0614-13 and NPD-0614-24, two new synthetic AhR ligands structurally related to the natural agonist FICZ, known to be effective in psoriasis. NPD-0614-13 and NPD-0614-24 did not alter per se the physiological functions of the different skin cell populations involved in the pathogenesis of inflammatory skin diseases. In human primary keratinocytes stimulated with tumor necrosis factor-α or lipopolysaccharide the compounds were able to counteract the altered proliferation and to dampen inflammatory signaling by reducing the activation of p38MAPK, c-Jun, NF-kBp65, and the release of cytokines. Furthermore, the molecules were tested for their beneficial effects in human epidermal and full-thickness reconstituted skin models of psoriasis. NPD-0614-13 and NPD-0614-24 recovered the psoriasis skin phenotype exerting pro-differentiating activity and reducing the expression of pro-inflammatory cytokines and antimicrobial peptides. These data provide a rationale for considering NPD-0614-13 and NPD-0614-24 in the management of psoriasis.


Assuntos
Anti-Inflamatórios/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Catecóis/farmacologia , Diferenciação Celular , Inflamação/tratamento farmacológico , Compostos Organometálicos/farmacologia , Psoríase/tratamento farmacológico , Receptores de Hidrocarboneto Arílico/metabolismo , Pele/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Ligantes , Psoríase/metabolismo , Psoríase/patologia , Pele/metabolismo , Pele/patologia
3.
Exp Dermatol ; 29(9): 833-839, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32779245

RESUMO

Acne is the most common skin disease in adolescent Westernized populations. Several data support the involvement of the mammalian target of rapamycin complex 1 (mTORC1) signalling in the interplay between androgens, insulin, insulin-like growth factor (IGF1) and high-glycaemic index diet in acne. The peroxisome proliferator-activated receptor γ (PPARγ) is involved in both differentiation and anti-inflammatory response. Low differentiated sebocytes showed decreased expression of PPARγ and increased level of insulin and IGF-1 receptors, resulting in the production of acne-like sebum and inflammatory mediators. In this viewpoint, we discuss how in acne the dysregulation of proliferation and differentiation processes in sebocytes and keratinocytes may be associated with altered response to androgens and other hormones, such as insulin or IGF-1. Moreover, we propose PPARγ modulation as an innovative therapeutic approach to normalize sebocyte differentiation process, interfering with the different mechanisms involved in altered pilosebaceous unit.

4.
Acta Derm Venereol ; 100(10): adv00157, 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32449780

RESUMO

Although recent therapeutic developments raise hope, melanoma remains a devastating disease with a need for new treatment targets. In other tumours prohormone convertases have been shown to be pro-tumourigenic as they are involved in processing preforms of matrix-metalloproteinases, growth factors and adhesion molecules. The aim of this study was to look for new treatment options for melanoma, by investigating the role of the prohormone convertase Paired basic Amino acid-Cleaving Enzyme 4 (PACE4/PCSK6) in melanoma cell lines and human melanoma tissue. PACE4-transfected A375 melanoma cells displayed significantly increased proliferation, MMP-2 production, gelatinase activity and migratory capacity in vitro compared with sham-transfected cells. In vivo, elevated PACE4 expression resulted in significantly increased tumour growth on immunodeficient mice. In the majority of 45 human primary melanomas and melanoma metastases ex vivo PACE4 immunoreactivity was detectable, while it was absent in in situ melanomas. These results indicate PACE4 as a regulator of melanoma cell aggressiveness.


Assuntos
Melanoma/enzimologia , Pró-Proteína Convertases/metabolismo , Serina Endopeptidases/metabolismo , Neoplasias Cutâneas/enzimologia , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Camundongos Pelados , Camundongos SCID , Terapia de Alvo Molecular , Invasividade Neoplásica , Pró-Proteína Convertases/antagonistas & inibidores , Pró-Proteína Convertases/genética , Serina Endopeptidases/genética , Inibidores de Serino Proteinase/uso terapêutico , Transdução de Sinais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Carga Tumoral
5.
FASEB J ; 34(5): 6302-6321, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32157742

RESUMO

Bovine colostrum, the first milk secreted by the mammary glands of cows shortly after they have given birth, provides a natural source of bioactive substances helpful to promote tissue development and repair, and to maintain a healthy immune system. Owing to its properties, the use of colostrum in the treatment of human diseases is under investigation. We evaluated the biological activity of colostrum on human primary keratinocytes, focusing on its effects with regard to a proliferation/differentiation balance. Using cellular and molecular approaches, we showed that colostrum favors a cell cycle withdrawal by increasing the expression of p21/WAF1 and p27/KIP1. It also promotes the transition of keratinocytes from a proliferating to a differentiating state, as assessed by a decrease in keratin 5 and an increase in keratin 16. We demonstrated the ability of colostrum to induce the expression of early and late differentiation markers (keratin 1, involucrin, and filaggrin) and the synthesis of caspase 14 and bleomycin hydrolase, the two main enzymes involved in filaggrin maturation. Moreover, we showed that bovine colostrum is able to promote keratinocyte stratification and terminal differentiation not only in two-dimensional (2D), but also in a more physiological system of three-dimensional (3D) skin equivalents. Finally, we demonstrated that colostrum stimulates cell differentiation through the PI3K/PLC-γ1/PKCα pathways mainly associated to tyrosine kinase receptors. These results suggest the possibility to benefit from colostrum properties for the treatment of skin diseases characterized by altered differentiation and perturbed barrier function.


Assuntos
Diferenciação Celular , Colostro/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Queratinócitos/citologia , Pele/citologia , Animais , Bovinos , Células Cultivadas , Feminino , Humanos , Queratinócitos/metabolismo , Gravidez , Pele/metabolismo
6.
Free Radic Biol Med ; 115: 266-277, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29229551

RESUMO

Pleural mesothelioma is a deadly form of cancer. The prognosis is extremely poor due to the limited treatment modalities. Uptake of asbestos fibres, the leading cause of mesothelioma, lead to the accumulation of reactive-oxygen-species (ROS). Interestingly, increasing ROS production by using ROS-generating drugs may offer a strategy to selectively trigger cell death. Exemestane, an aromatase inhibitor, has previously shown anti-tumor properties in mesothelioma preclinical models suggesting a role of G protein-coupled receptor 30 (GPR30) in the drug response. As exemestane, in addition to blocking estrogen biosynthesis, generates ROS that are able to arrest the growth of breast cancer, we explored the role of ROS, antioxidant defense system, and ROS-induced signalling pathways in mesothelioma cells during exemestane response. Here we report that exemestane treatment reduced cell proliferation with an increase in ROS production and reduction of cyclic adenosine monophosphate (cAMP) levels in MSTO-H211, Ist-Mes1, Ist-Mes2 and MPP89 exemestane-sensitive mesothelioma cell lines, but not in NCI-H2452 exemestane-insensitive mesothelioma cells. Exemestane induced a significant antioxidant response in NCI-H2452 cells, as highlighted by an increase in γ-glutamylcysteine levels, catalase (Cat), superoxide-dismutase and (SOD) and glutathione-peroxidase (GSH-Px) activity and nuclear factor E2-related factor 2 (Nrf2) activation, responsible for drug insensitivity. Conversely, exemestane elevated ROS levels along with increased ERK phosphorylation and a reduction of p-STA3 in exemestane-sensitive mesothelioma cells. ROS generation was the crucial event of exemestane action because ROS inhibitor N-acetyl-L-cysteine (NAC) abrogated p-ERK and p-STAT3 modulation and cellular death. Exemestane also modulates ERK and STAT3 signalling via GPR30. Results indicate an essential role of ROS in the antiproliferative action of exemestane in mesothelioma cells. It is likely that the additional oxidative insults induced by exemestane results in the lethal effects of mesothelioma cells by increasing ROS production. As such, manipulating ROS levels with exemestane seems to be a feasible strategy to selectively kill mesothelioma cells with less toxicity to normal cells by regulating ERK and STAT3 activity.


Assuntos
Androstadienos/farmacologia , Antineoplásicos/farmacologia , Inibidores da Aromatase/farmacologia , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Acetilcisteína/farmacologia , Asbestos/efeitos adversos , Morte Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , AMP Cíclico/metabolismo , Exposição Ambiental/efeitos adversos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio , Receptores Acoplados a Proteínas G , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Resultado do Tratamento
7.
Sci Rep ; 7(1): 9241, 2017 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-28835664

RESUMO

Increasing attention is addressed to identify products able to enhance skin photoprotection and to prevent skin carcinogenesis. Several studies have demonstrated that the α-melanocyte stimulating hormone (αMSH), acting on a functional MC1R, provides a photoprotective effect by inducing pigmentation, antioxidants and DNA repair. We discovered a link between αMSH and the nuclear receptor Peroxisome Proliferator-Activated Receptor-γ (PPARγ), suggesting that some of the αMSH protective effects may be dependent on PPARγ transcriptional activity. Moreover, we demonstrated that the activation of PPARγ by the parrodiene 2,4,6-octatrienoic acid (Octa) induces melanogenesis and antioxidant defence in human melanocytes and counteracts senescence-like phenotype in human fibroblasts. In this study, we demonstrate that the activation of PPARγ by Octa exerts a protective effect against UVA- and UVB-induced damage on normal human keratinocytes (NHKs), the major target cells of UV radiation. Octa promotes the antioxidant defence, augments DNA repair and reduces the induction of proteins involved in UV-induced DNA damage response. Our results contribute to deepen the analysis of the αMSH/PPARγ connection and suggest perspectives for the development of new molecules and formulations able to prevent cutaneous UV damage by acting on the different skin cell populations through PPARγ activation.


Assuntos
Ácidos Graxos Insaturados/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/enzimologia , Queratinócitos/efeitos da radiação , PPAR gama/agonistas , Protetores contra Radiação/farmacologia , Raios Ultravioleta/efeitos adversos , Antioxidantes/metabolismo , Células Cultivadas , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Queratinócitos/patologia , PPAR gama/genética , PPAR gama/metabolismo , Receptor Tipo 1 de Melanocortina/genética , Receptor Tipo 1 de Melanocortina/metabolismo , alfa-MSH/metabolismo
8.
Oncotarget ; 8(65): 108463-108479, 2017 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-29312543

RESUMO

Although the medical treatment of colorectal cancer has evolved greatly in the last years, a significant portion of early-stage patients develops recurrence after therapies. The current clinical trials are directed to evaluate new drug combinations and treatment schedules. By the use of patient-derived or established colon cancer cell lines, we found that the tyrosine kinase receptor HER3 is involved in the mechanisms of resistance to therapies. In agreement, the immunohistochemical analysis of total and phospho-HER3 expression in 185 colorectal cancer specimens revealed a significant correlation with lower disease-free survival. Targeting HER3 by the use of the monoclonal antibody patritumab we found induction of growth arrest in all cell lines. Despite the high efficiency of patritumab in abrogating the HER3-dependent activation of PI3K pathway, the HER2 and EGFR-dependent MAPK pathway is activated as a compensatory mechanism. Interestingly, we found that the MEK-inhibitor trametinib inhibits, as expected, the MAPK pathway but induces the HER3-dependent activation of PI3K pathway. The combined treatment results in the abrogation of both PI3K and MAPK pathways and in a significant reduction of cell proliferation and survival. These data suggest a new strategy of therapy for HER3-overexpressing colon cancers.

9.
Brain Res Bull ; 120: 151-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26592472

RESUMO

The activation of microglia and subsequent release of toxic pro-inflammatory factors are crucially associated with neurodegenerative disease, characterized by increased oxidative stress and neuroinflammation, including Alzheimer and Parkinson diseases and multiple sclerosis. Dihydroasparagusic acid is the reduced form of asparagusic acid, a sulfur-containing flavor component produced by Asparagus plants. It has two thiolic functions able to coordinate the metal ions, and a carboxylic moiety, a polar function, which may enhance excretion of the complexes. Thiol functions are also present in several biomolecules with important physiological antioxidant role as glutathione. The aim of this study is to evaluate the anti-inflammatory and antioxidant potential effect of dihydroasparagusic acid on microglial activation in an in vitro model of neuroinflammation. We have used lipopolysaccharide to induce an inflammatory response in primary rat microglial cultures. Our results suggest that dihydroasparagusic acid significantly prevented lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators such as nitric oxide, tumor necrosis factor-α, prostaglandin E2, as well as inducible nitric oxide synthase and cyclooxygenase-2 protein expression and lipoxygenase activity in microglia cells. Moreover it effectively suppressed the level of reactive oxygen species and affected lipopolysaccharide-stimulated activation of mitogen activated protein kinase, including p38, and nuclear factor-kB pathway. These results suggest that dihydroasparagusic acid's neuroprotective properties may be due to its ability to dampen induction of microglial activation. It is a compound that can effectively inhibit inflammatory and oxidative processes that are important factors of the etiopathogenesis of neurodegenerative diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Inflamação/tratamento farmacológico , Microglia/efeitos dos fármacos , Tiofenos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/imunologia , Avaliação Pré-Clínica de Medicamentos , Inflamação/metabolismo , Lipopolissacarídeos , Microglia/metabolismo , NF-kappa B/metabolismo , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Óxido Nítrico/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
PLoS One ; 10(6): e0128663, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26068861

RESUMO

One of the many functions of skin is to protect the organism against a wide range of pathogens. Antimicrobial peptides (AMPs) produced by the skin epithelium provide an effective chemical shield against microbial pathogens. However, whereas antibacterial/antifungal activities of AMPs have been extensively characterized, much less is known regarding their wound healing-modulatory properties. By using an in vitro re-epithelialisation assay employing special cell-culture inserts, we detected that a derivative of the frog-skin AMP esculentin-1a, named esculentin-1a(1-21)NH2, significantly stimulates migration of immortalized human keratinocytes (HaCaT cells) over a wide range of peptide concentrations (0.025-4 µM), and this notably more efficiently than human cathelicidin (LL-37). This activity is preserved in primary human epidermal keratinocytes. By using appropriate inhibitors and an enzyme-linked immunosorbent assay we found that the peptide-induced cell migration involves activation of the epidermal growth factor receptor and STAT3 protein. These results suggest that esculentin-1a(1-21)NH2 now deserves to be tested in standard wound healing assays as a novel candidate promoter of skin re-epithelialisation. The established ability of esculentin-1a(1-21)NH2 to kill microbes without harming mammalian cells, namely its high anti-Pseudomonal activity, makes this AMP a particularly attractive candidate wound healing promoter, especially in the management of chronic, often Pseudomonas-infected, skin ulcers.


Assuntos
Proteínas de Anfíbios/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Receptores ErbB/metabolismo , Queratinócitos/metabolismo , Pele/metabolismo , Cicatrização/efeitos dos fármacos , Animais , Anuros , Linhagem Celular , Humanos , Queratinócitos/patologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/patologia , Fator de Transcrição STAT3/metabolismo , Pele/patologia , Dermatopatias Bacterianas/tratamento farmacológico , Dermatopatias Bacterianas/metabolismo , Dermatopatias Bacterianas/patologia , Úlcera Cutânea/tratamento farmacológico , Úlcera Cutânea/metabolismo , Úlcera Cutânea/patologia
12.
Exp Dermatol ; 24(4): 245-51, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25644500

RESUMO

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that modulate the expression of multiple different genes involved in the regulation of lipid, glucose and amino acid metabolism. PPARs and cognate ligands also regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses. This includes a role in mediating skin and pilosebaceous unit homoeostasis: PPARs appear to be essential for maintaining skin barrier permeability, inhibit keratinocyte cell growth, promote keratinocyte terminal differentiation and regulate skin inflammation. They also may have protective effects on human hair follicle (HFs) epithelial stem cells, while defects in PPARγ-mediated signalling may promote the death of these stem cells and thus facilitate the development of cicatricial alopecia (lichen planopilaris). Overall, however, selected PPARγ modulators appear to act as hair growth inhibitors that reduce the proliferation and promote apoptosis of hair matrix keratinocytes. The fact that commonly prescribed PPARγ-modulatory drugs of the thiazolidine-2,4-dione class can exhibit a battery of adverse cutaneous effects underscores the importance of distinguishing beneficial from clinically undesired cutaneous activities of PPARγ ligands and to better understand on the molecular level how PPARγ-regulated cutaneous lipid metabolism and PPARγ-mediated signalling impact on human skin physiology and pathology. Surely, the therapeutic potential that endogenous and exogenous PPARγ modulators may possess in selected skin diseases, ranging from chronic inflammatory hyperproliferative dermatoses like psoriasis and atopic dermatitis, via scarring alopecia and acne can only be harnessed if the complexities of PPARγ signalling in human skin and its appendages are systematically dissected.


Assuntos
PPAR gama/fisiologia , Fenômenos Fisiológicos da Pele , Animais , Cabelo/fisiologia , Doenças do Cabelo/etiologia , Doenças do Cabelo/fisiopatologia , Humanos , Mediadores da Inflamação/fisiologia , Ligantes , PPAR gama/agonistas , Transdução de Sinais , Pele/efeitos dos fármacos , Pele/patologia , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/fisiologia , Dermatopatias/tratamento farmacológico , Dermatopatias/fisiopatologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/prevenção & controle , Tiazolidinedionas/farmacologia
13.
Part Fibre Toxicol ; 11: 74, 2014 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-25498254

RESUMO

BACKGROUND: Diesel exhaust particles (DEP) are major constituents of ambient air pollution and their adverse health effect is an area of intensive investigations. With respect to the immune system, DEP have attracted significant research attention as a factor that could influence allergic diseases interfering with cytokine production and chemokine expression. With this exception, scant data are available on the impact of DEP on lymphocyte homeostasis. Here, the effects of nanoparticles from Euro 4 (E4) and Euro 5 (E5) light duty diesel engines on the phenotype and function of T lymphocytes from healthy donors were evaluated. METHODS: T lymphocytes were isolated from peripheral blood obtained from healthy volunteers and subsequently stimulated with different concentration (from 0.15 to 60 µg/ml) and at different time points (from 24 h to 9 days) of either E4 or E5 particles. Immunological parameters, including apoptosis, autophagy, proliferation levels, mitochondrial function, expression of activation markers and cytokine production were evaluated by cellular and molecular analyses. RESULTS: DEP exposure caused a pronounced autophagic-lysosomal blockade, thus interfering with a key mechanism involved in the maintaining of T cell homeostasis. Moreover, DEP decreased mitochondrial membrane potential but, unexpectedly, this effect did not result in changes of the apoptosis and/or necrosis levels, as well as of intracellular content of adenosine triphosphate (ATP). Finally, a down-regulation of the expression of the alpha chain of the interleukin (IL)-2 receptor (i.e., the CD25 molecule) as well as an abnormal Th1 cytokine expression profile (i.e., a decrease of IL-2 and interferon (IFN)-γ production) were observed after DEP exposure. No differences between the two compounds were detected in all studied parameters. CONCLUSIONS: Overall, our data identify functional and phenotypic T lymphocyte parameters as relevant targets for DEP cytotoxicity, whose impairment could be detrimental, at least in the long run, for human health, favouring the development or the progression of diseases such as autoimmunity and cancer.


Assuntos
Poluentes Atmosféricos/toxicidade , Regulação para Baixo/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Ativação Linfocitária/efeitos dos fármacos , Fuligem/toxicidade , Linfócitos T/efeitos dos fármacos , Emissões de Veículos/toxicidade , Adulto , Poluentes Atmosféricos/química , Poluentes Atmosféricos/metabolismo , Autofagia/efeitos dos fármacos , Transporte Biológico , Biomarcadores/metabolismo , Células Cultivadas , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Cinética , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pessoa de Meia-Idade , Tamanho da Partícula , Fuligem/química , Fuligem/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/ultraestrutura , Emissões de Veículos/análise , Adulto Jovem
15.
J Invest Dermatol ; 134(4): 1001-1011, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24166135

RESUMO

Peroxisome proliferator-activated receptor γ (PPARγ) antagonizes inflammatory signals by interfering with NF-κB nuclear translocation. Consistently, PPARγ agonists have been proposed in various inflammatory skin disorders, but their wide use has been limited by severe side effects. Classes of compounds with specific PPARγ agonism have been designed to selectively target inflammatory pathways. Among these compounds, GED-0507-34L has been developed and recently used in phase II clinical trials for inflammatory bowel diseases. This study was aimed at assessing the role of GED-0507-34L in preclinical models of inflammatory skin diseases. The compound modulated PPARγ function and suppressed the inflammatory process inhibiting NF-κB nuclear translocation with the consequent reduction of inflammatory cytokines expression, such as IL-6, IL-8, IL-12, IL-21, IL-23, tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) in normal human keratinocytes and lymphocytes treated with lipopolysaccharide (LPS) or TNF-α. Moreover, an altered proliferation and expression of differentiation markers induced by TNF-α were also counteracted. In psoriasis-like skin lesions elicited in mice by IL-21, topical application of GED-0507-34L reduced cellular infiltrate and epidermal hyperplasia, normalizing the differentiation process. The results indicate that GED-0507-34L possesses anti-inflammatory properties useful for the management of patients with inflammatory skin diseases including psoriasis. Phase I trial on patients is ongoing.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Compostos de Anilina/uso terapêutico , Inflamação/tratamento farmacológico , PPAR gama/metabolismo , Fenilpropionatos/uso terapêutico , Propionatos/uso terapêutico , Pele/patologia , Compostos de Anilina/química , Animais , Biópsia , Adesão Celular , Proliferação de Células , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Epiderme/metabolismo , Humanos , Queratinócitos/citologia , Lipopolissacarídeos/química , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fenilpropionatos/química , Propionatos/química , Ligação Proteica , Psoríase/metabolismo , Interferência de RNA , Pele/efeitos dos fármacos
16.
Exp Dermatol ; 22(1): 41-7, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23278893

RESUMO

Azelaic acid (AzA) has been used for the treatment for inflammatory skin diseases, such as acne and rosacea. Interestingly, an improvement in skin texture has been observed after long-time treatment with AzA. We previously unrevealed that anti-inflammatory activity of AzA involves a specific activation of PPARγ, a nuclear receptor that plays a relevant role in inflammation and even in ageing processes. As rosacea has been considered as a photo-aggravated disease, we investigated the ability of AzA to counteract stress-induced premature cell senescence (SIPS). We employed a SIPS model based on single exposure of human dermal fibroblasts (HDFs) to UVA and 8-methoxypsoralen (PUVA), previously reported to activate a senescence-like phenotype, including long-term growth arrest, flattened morphology and increased synthesis of matrix metalloproteinases (MMPs) and senescence-associated ß-galactosidase (SA-ß-gal). We found that PUVA-treated HDFs grown in the presence of AzA maintained their morphology and reduced MMP-1 release and SA-ß-galactosidase-positive cells. Moreover, AzA induced a reduction in ROS generation, an up-modulation of antioxidant enzymes and a decrease in cell membrane lipid damages in PUVA-treated HDFs. Further evidences of AzA anti-senescence effect were repression of p53 and p21, increase in type I pro-collagen and abrogation of the enhanced expression of growth factors, such as HGF and SCF. Interestingly, PUVA-SIPS showed a decreased activation of PPARγ and AzA counteracted this effect, suggesting that AzA effect involves PPARγ modulation. All together these data showed that AzA interferes with PUVA-induced senescence-like phenotype and its ability to activate PPAR-γ provides relevant insights into the anti-senescence mechanism.


Assuntos
Senescência Celular/efeitos dos fármacos , Fármacos Dermatológicos/farmacologia , Ácidos Dicarboxílicos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , PPAR gama/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , Senescência Celular/efeitos da radiação , Colágeno Tipo I/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fibroblastos/citologia , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Metoxaleno/farmacologia , Terapia PUVA , Fenótipo , Fosfolipídeos/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Pró-Colágeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Células-Tronco/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta , beta-Galactosidase/metabolismo
17.
Pigment Cell Melanoma Res ; 24(4): 618-30, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21762468

RESUMO

Given the importance of the tanning response in protecting human skin from the harmful effects of UV radiation, one important research priority is to identify novel molecules that are capable of promoting pigmentation and/or antioxidant defence. Parrodienes share some structural features with carotenoids and retinoids, stimulate cell antioxidant defence and counteract senescence-like phenotype in fibroblasts. We selected the parrodiene-derivative 2,4,6-octatrienoic acid (Octa) to study its impact on key parameters of melanogenesis and antioxidant defence in organ-cultured human skin and in normal human melanocytes. Octa promoted melanogenesis by up-regulating tyrosinase and microphthalmia-associated transcription factor expression. This correlated with an increase of melanin content in both human epidermis in situ and cultured human epidermal melanocytes. Moreover, Octa increased the biological antioxidant potential content and the expression and activity of catalase. Activation of peroxisome proliferator-activated receptor (PPAR)-γ was necessary to evoke these effects. These data strongly encourage the systematic study of Octa as a novel candidate promoter of human skin photoprotection.


Assuntos
Antioxidantes/metabolismo , Ácidos Graxos Insaturados/farmacologia , Melaninas/biossíntese , Melanócitos/efeitos dos fármacos , Melanócitos/imunologia , PPAR gama/metabolismo , Catalase/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Epiderme/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Masculino , Melanócitos/citologia , Melanócitos/enzimologia , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Monofenol Mono-Oxigenase/biossíntese , Monofenol Mono-Oxigenase/genética , Técnicas de Cultura de Órgãos , PPAR gama/antagonistas & inibidores , PPAR gama/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Couro Cabeludo/efeitos dos fármacos , Couro Cabeludo/fisiologia , Pigmentação da Pele/efeitos dos fármacos
18.
J Immunol ; 185(3): 1903-11, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20610647

RESUMO

Acne is the most common inflammatory skin disease in which IL-1 plays a central role. Although alpha-melanocyte-stimulating hormone has immunomodulatory effects, its usefulness as an anti-inflammatory agent in acne is hampered owing to its lipid- and pigment-inducing effects via activation of melanocortin receptors (MC-Rs). We used the immortalized human sebocyte line SZ95 as an in vitro model to investigate the anti-inflammatory potential of KdPT, a tripeptide derivative of the C-terminal end of alpha-melanocyte-stimulating hormone. KdPT potently suppressed IL-1beta-induced IL-6 and IL-8 expression. Mechanistically, KdPT decreased IL-1beta-mediated IkappaBalpha degradation, reduced nuclear accumulation of p65, and attenuated DNA binding of NF-kappaB. Moreover, KdPT reduced IL-1beta-mediated generation of intracellular reactive oxygen species, which contributed to IL-1beta-mediated cytokine induction. KdPT also reduced cell surface binding of fluorochrome-labeled IL-1beta in SZ95 sebocytes. Analysis of the crystal structure of the complex between IL-1beta/IL-1R type I (IL-1RI), followed by computer modeling of KdPT and subsequent modeling of the peptide receptor complex with the crystal structure of IL-1RI via manual docking, further predicted that the tripeptide, through several H-bonds and one hydrophobic bond, interacts with the IL-1RI. Importantly, KdPT did not bind to MC-1Rs, as demonstrated by blocking experiments with a peptide analog of Agouti signaling protein and by binding assays using MC-1R-expressing B16 melanoma cells. Accordingly, KdPT failed to induce melanogenesis. Our data demonstrate a promising anti-inflammatory potential of KdPT and point toward novel future directions in the treatment of acne-as well as of various other IL-1-mediated inflammatory diseases-with this small molecule.


Assuntos
Citocinas/antagonistas & inibidores , Imunossupressores/farmacologia , Interleucina-1beta/antagonistas & inibidores , Fragmentos de Peptídeos/fisiologia , Glândulas Sebáceas/citologia , Glândulas Sebáceas/imunologia , Transdução de Sinais/imunologia , alfa-MSH/fisiologia , Animais , Linhagem Celular , Linhagem Celular Transformada , Citocinas/biossíntese , Proteínas de Ligação a DNA/fisiologia , Humanos , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/metabolismo , Proteínas I-kappa B/antagonistas & inibidores , Proteínas I-kappa B/metabolismo , Interleucina-1beta/fisiologia , Interleucina-6/antagonistas & inibidores , Interleucina-8/antagonistas & inibidores , Melanoma Experimental , Camundongos , Inibidor de NF-kappaB alfa , Glândulas Sebáceas/metabolismo
19.
Exp Dermatol ; 19(9): 813-20, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20545756

RESUMO

Azelaic acid (AzA), a nine-carbon dicarboxylic acid, is an agent for the topical treatment of acne. It has also been shown to be effective in rosacea; however, the mechanism of action has not been clarified. Because inflammation is a common feature of both conditions, we investigated the effects of azelaic acid on the inflammatory response of normal human keratinocytes to ultraviolet B light, which is a photosensitizer agent in rosacea. AzA, at 20 mM, a concentration achievable following topical application of a 15% gel, suppresses ultraviolet B light-induced interleukins-1beta, -6 and tumor necrosis factor-alpha mRNA expression and protein secretion. Mechanistically, azelaic acid significantly reduced the ultraviolet B light-induced nuclear translocation of nuclear factor kB p65 subunit and the phosphorylation of the p38 mitogen and stress-activated protein kinase. Moreover, as peroxisome proliferators-activated receptor gamma, (PPARgamma) which has a crucial role in the control of inflammation, is activated by fatty acids and products of lipid peroxidation, we further investigated the effect of azelaic acid on the expression of this nuclear receptor. AzA induced peroxisome proliferators-activated receptor-gamma mRNA and its transcriptional activity. The PPARgamma antagonist GW9662 abrogated the inhibitory effects of AzA on the UVB-induced pro-inflammatory cytokines release and on the cell proliferation. Our study provides new insights into the molecular mechanisms of the activity of azelaic acid and lands additional evidences for its therapeutic effects on inflammatory skin diseases, such as rosacea.


Assuntos
Acne Vulgar/tratamento farmacológico , Fármacos Dermatológicos/farmacologia , Ácidos Dicarboxílicos/farmacologia , Queratinócitos/efeitos dos fármacos , NF-kappa B/metabolismo , Células Cultivadas , Citocinas/metabolismo , Fármacos Dermatológicos/uso terapêutico , Ácidos Dicarboxílicos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Genes Reporter , Humanos , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , PPAR gama/agonistas , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rosácea/tratamento farmacológico , Transcrição Genética/efeitos dos fármacos , Raios Ultravioleta , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Dermatoendocrinol ; 1(2): 68-71, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20224686

RESUMO

The principal activity of mature sebaceous glands is producing and secreting sebum, which is a complex mixture of lipids. Sebum composition is different among species and this difference is probably due to the function that sebum has to absolve. In human sebum there are unique lipids, such as squalene and wax esters not found anywhere else in the body nor among the epidermal surface lipids. Moreover, they correspond to major components supplying the skin with protection. However, the ultimate role of human sebum, as well the metabolic pathways regulating its composition and secretion rate, are far from a complete understanding. Increased sebum secretion is considered, among all features, the major one involved in the pathophysiology of acne. Along with increased sebum secretion rate, quali- and quantitative modifications of sebum are likely to occur in this pathology. Understanding the factors and mechanisms that regulate sebum production is needed in order to identify new targets that can be addressed to achieve a selective modulation of lipid biosynthesis as a novel therapeutic strategy to correct lipid disregulations in acne and other disorders of the pilosebaceous unit.

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