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1.
Bioanalysis ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38629337

RESUMO

Ligand-binding assays (LBAs) rely on the reversible, noncovalent binding between the analyte of interest and the assay reagents, and understanding their dynamic equilibrium is key to building robust LBA methods. Although the dynamic interplay of free and bound fractions can be calculated using mathematical models, these are not routinely applied. This approach is costly in terms of both assay development time and reagents, and can result in an under-exploration of the possible parameter combinations. Therefore, we have created a user-friendly simulation tool to facilitate LBA development (the BiSim Tool). We describe the models driving the mathematical simulations and the main features of our software solution by means of case studies, illustrating the tool's value in drug development. To support drug development for all patients worldwide, the BiSim Tool is now available as an open-source code project and as a free web-based tool at https://proteinbindingsimulation.shinyapps.io/BiSim-ProteinBindingSimulation [1].

2.
Bioanalysis ; 15(13): 757-771, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37526064

RESUMO

It is widely acknowledged by the bioanalytical and biomarker community that biomarker assay validations should be fit-for-purpose depending on the context of use. The challenge is how to consistently apply these principles in teams responsible for measuring a disparate array of biomarkers, often on multiple analytical platforms, at various stages of the drug discovery and development pipeline and across diverse biology focus areas. To drive consistency, while maintaining the necessary flexibility to allow validations to be driven by scientific rationale and taking into consideration the context of use and associated biological and (pre)analytical factors, a framework applicable across biomarker assays was developed. Herein the authors share their perspective to engage in the ongoing conversation around fit-for-purpose biomarker assay validation.


Assuntos
Descoberta de Drogas , Biomarcadores
3.
J Chromatogr A ; 1699: 464002, 2023 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-37126878

RESUMO

Determination of the levels of protein cross-linking catalysed by the activity of transglutaminase 2 in various disease states has remained a significant challenge. The ability to quantify the isopeptide ε-(γ-glutamyl) lysine, which can form as a heterogeneous bond within or between proteins has significant analytical and clinical potential as a biomarker in biofluids such as human urine. Increased transglutaminase 2 activity is associated with a number of diseases, such as fibrosis. Previously published methods have been based on classical amino acid analysis, however they require a complex multi-enzyme digestion in order to achieve complete protein digestion, whilst leaving the isopeptide cross link intact. These methods require high levels of enzymes, which contaminate the analysis and alter the dynamics of digestion. The amino acid analysis detection also lacked selectivity, especially where the levels of crosslink are expected to be low relative to the background protein levels. We have systematically addressed these challenges, by optimising the precipitation of the protein in urine, the use of innovative immobilised enzyme technology, which allows for efficient digestion without enzyme contamination and LC-MS/MS detection based on multiple reaction monitoring. This method was validated for its analytical performance characteristics, showing the method has a sensitivity of 0.1 ng/mL of ε-(γ-glutamyl) lysine in human urine with precision of less than 20% CV, and is selective as no interferences were observed that may adversely affect the analysis. As such this approach represents a significant advance in the ability to detect and quantify ε-(γ-glutamyl) lysine.


Assuntos
Lisina , Proteína 2 Glutamina gama-Glutamiltransferase , Humanos , Cromatografia Líquida , Transglutaminases , Espectrometria de Massas em Tandem , Biomarcadores , Dipeptídeos/análise
4.
Bioanalysis ; 14(13): 911-917, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35904153

RESUMO

Since 2011, the European Bioanalysis Forum has been discussing the topic of context-of-use for biomarker assays, in support of a cross-industry implementation of its principles. The discussions have led to the acknowledgement of the challenges that we face as an industry in implementing these principles. In addition to scientific recommendations, the European Bioanalysis Forum has addressed these challenges by providing recommendations on organizational design, and what works in both sponsor and contract research organizations, to support and enable context-of-use across biomarker strategies. Here, we highlight the key considerations for organizational design to help ensure that biomarker assays are characterized and validated according to the right context-of-use, to ensure that the right decisions based on the biomarker data can be made during drug development.


Assuntos
Bioensaio , Biomarcadores/análise
5.
Shock ; 52(2): 208-214, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30124596

RESUMO

Sepsis in humans and experimental animals is characterized by an acute inflammatory response. glucocorticoids (GCs) are widely used for the treatment of many inflammatory disorders, yet their effectiveness in sepsis is debatable. One of the major anti-inflammatory proteins induced by GCs is glucocorticoid-induced leucine zipper (GILZ, coded by the TSC22D3 gene). We found that TSC22D3 mRNA expression is downregulated in white blood cells of human sepsis patients. Interestingly, transgenic GILZ-overexpressing mice (GILZ-tg) showed better survival rates in the cecal ligation and puncture (CLP) model of mouse sepsis. To our surprise, GILZ had only mild anti-inflammatory effects in this model, as the systemic proinflammatory response was not significantly reduced in GILZ-tg mice compared with control mice. During CLP, we observed reduced bacterial counts in blood of GILZ-tg mice compared with control mice. We found increased expression of Tsc22d3 mRNA specifically in peritoneal exudate cells in the CLP model, as well as increased capacity for bacterial phagocytosis of CD45 GILZ-tg cells compared with CD45 GILZ-wt cells. Hence, we believe that the protective effects of GILZ in the CLP model can be linked to a more efficient phagocytosis.


Assuntos
Peritonite/metabolismo , Peritonite/prevenção & controle , Sepse/metabolismo , Sepse/prevenção & controle , Fatores de Transcrição/metabolismo , Animais , Ceco/lesões , Humanos , Interleucina-6/sangue , Antígenos Comuns de Leucócito/metabolismo , Ligadura/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peritonite/sangue , Peritonite/etiologia , Fagocitose/genética , Fagocitose/fisiologia , Punções/efeitos adversos , Sepse/etiologia , Fatores de Transcrição/genética
6.
Sci Rep ; 7(1): 8941, 2017 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-28827617

RESUMO

The transcriptional activity of the glucocorticoid receptor (GR) is co-determined by its ability to recruit a vast and varying number of cofactors. We here identify Striatin-3 (STRN3) as a novel interaction partner of GR that interferes with GR's ligand-dependent transactivation capacity. Remarkably, STRN3 selectively affects only GR-dependent transactivation and leaves GR-dependent transrepression mechanisms unhampered. We found that STRN3 down-regulates GR transactivation by an additional recruitment of the catalytic subunit of protein phosphatase 2A (PPP2CA) to GR. We hypothesize the existence of a functional trimeric complex in the nucleus, able to dephosphorylate GR at serine 211, a known marker for GR transactivation in a target gene-dependent manner. The presence of STRN3 appears an absolute prerequisite for PPP2CA to engage in a complex with GR. Herein, the C-terminal domain of GR is essential, reflecting ligand-dependency, yet other receptor parts are also needed to create additional contacts with STRN3.


Assuntos
Autoantígenos/metabolismo , Proteínas de Ligação a Calmodulina/metabolismo , Regulação para Baixo , Proteína Fosfatase 2/metabolismo , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/genética , Células A549 , Sítios de Ligação , Núcleo Celular/metabolismo , Células HEK293 , Células HeLa , Humanos , Fosforilação , Mapas de Interação de Proteínas , Multimerização Proteica , Receptores de Glucocorticoides/metabolismo , Ativação Transcricional
7.
J Immunol ; 199(7): 2515-2527, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28848068

RESUMO

Dual-specificity phosphatase 3 (DUSP3) is a small phosphatase with poorly known physiological functions and for which only a few substrates are known. Using knockout mice, we recently reported that DUSP3 deficiency confers resistance to endotoxin- and polymicrobial-induced septic shock. We showed that this protection was macrophage dependent. In this study, we further investigated the role of DUSP3 in sepsis tolerance and showed that the resistance is sex dependent. Using adoptive-transfer experiments and ovariectomized mice, we highlighted the role of female sex hormones in the phenotype. Indeed, in ovariectomized females and in male mice, the dominance of M2-like macrophages observed in DUSP3-/- female mice was reduced, suggesting a role for this cell subset in sepsis tolerance. At the molecular level, DUSP3 deletion was associated with estrogen-dependent decreased phosphorylation of ERK1/2 and Akt in peritoneal macrophages stimulated ex vivo by LPS. Our results demonstrate that estrogens may modulate M2-like responses during endotoxemia in a DUSP3-dependent manner.


Assuntos
Fosfatases de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/metabolismo , Endotoxemia/enzimologia , Endotoxemia/prevenção & controle , Estrogênios/metabolismo , Macrófagos/fisiologia , Choque Séptico/prevenção & controle , Animais , Coinfecção/complicações , Fosfatases de Especificidade Dupla/deficiência , Endotoxemia/genética , Endotoxemia/microbiologia , Feminino , Tolerância Imunológica , Lipopolissacarídeos/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Knockout , Ovariectomia , Fosforilação , Caracteres Sexuais , Transdução de Sinais
8.
J Immunol ; 199(1): 48-61, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28515280

RESUMO

Although glucocorticoids (GCs) are a mainstay in the clinical management of asthma, the target cells that mediate their therapeutic effects are unknown. Contrary to our expectation, we found that GC receptor (GR) expression in immune cells was dispensable for successful therapy of allergic airway inflammation (AAI) with dexamethasone. Instead, GC treatment was compromised in mice expressing a defective GR in the nonhematopoietic compartment or selectively lacking the GR in airway epithelial cells. Further, we found that an intact GR dimerization interface was a prerequisite for the suppression of AAI and airway hyperresponsiveness by GCs. Our observation that the ability of dexamethasone to modulate gene expression in airway epithelial cells coincided with its potency to resolve AAI supports a crucial role for transcriptional regulation by the GR in this cell type. Taken together, we identified an unknown mode of GC action in the treatment of allergic asthma that might help to develop more specific therapies in the future.


Assuntos
Asma/tratamento farmacológico , Dexametasona/farmacologia , Células Epiteliais/efeitos dos fármacos , Glucocorticoides/farmacologia , Receptores de Glucocorticoides/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Animais , Asma/imunologia , Asma/fisiopatologia , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Glucocorticoides/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/imunologia , Camundongos , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/genética , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Transdução de Sinais
9.
Microbiol Mol Biol Rev ; 80(2): 495-522, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27169854

RESUMO

Glucocorticoids (GCs) have been widely used for decades as a first-line treatment for inflammatory and autoimmune diseases. However, their use is often hampered by the onset of adverse effects or resistance. GCs mediate their effects via binding to glucocorticoid receptor (GR), a transcription factor belonging to the family of nuclear receptors. An important aspect of GR's actions, including its anti-inflammatory capacity, involves its interactions with various proteins, such as transcription factors, cofactors, and modifying enzymes, which codetermine receptor functionality. In this review, we provide a state-of-the-art overview of the protein-protein interactions (PPIs) of GR that positively or negatively affect its anti-inflammatory properties, along with mechanistic insights, if known. Emphasis is placed on the interactions that affect its anti-inflammatory effects in the presence of inflammatory and microbial diseases.


Assuntos
Glucocorticoides/fisiologia , Receptores de Glucocorticoides/fisiologia , Animais , Anti-Inflamatórios/farmacologia , Núcleo Celular/metabolismo , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/imunologia , Glucocorticoides/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Mapas de Interação de Proteínas , Processamento de Proteína Pós-Traducional , Fatores de Transcrição STAT/fisiologia , Transdução de Sinais , Fator de Crescimento Transformador beta/fisiologia
10.
Nat Commun ; 6: 7796, 2015 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-26183376

RESUMO

Acute lung injury (ALI) is a severe inflammatory disease for which no specific treatment exists. As glucocorticoids have potent immunosuppressive effects, their application in ALI is currently being tested in clinical trials. However, the benefits of this type of regimen remain unclear. Here we identify a mechanism of glucocorticoid action that challenges the long-standing dogma of cytokine repression by the glucocorticoid receptor. Contrarily, synergistic gene induction of sphingosine kinase 1 (SphK1) by glucocorticoids and pro-inflammatory stimuli via the glucocorticoid receptor in macrophages increases circulating sphingosine 1-phosphate levels, which proves essential for the inhibition of inflammation. Chemical or genetic inhibition of SphK1 abrogates the therapeutic effects of glucocorticoids. Inflammatory p38 MAPK- and mitogen- and stress-activated protein kinase 1 (MSK1)-dependent pathways cooperate with glucocorticoids to upregulate SphK1 expression. Our findings support a critical role for SphK1 induction in the suppression of lung inflammation by glucocorticoids, and therefore provide rationales for effective anti-inflammatory therapies.


Assuntos
Lesão Pulmonar Aguda/imunologia , Glucocorticoides/farmacologia , Macrófagos/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/efeitos dos fármacos , Receptores de Glucocorticoides/agonistas , Animais , Imunoprecipitação da Cromatina , Citocinas/efeitos dos fármacos , Citocinas/imunologia , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação , Lisofosfolipídeos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Quinases S6 Ribossômicas 90-kDa/imunologia , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Ativação Transcricional/efeitos dos fármacos , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
11.
EMBO Mol Med ; 7(8): 1004-17, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25995337

RESUMO

TNF is a central actor during inflammation and a well-recognized drug target for inflammatory diseases. We found that the mouse strain SPRET/Ei, known for extreme and dominant resistance against TNF-induced shock, displays weak expression of TNF receptor 1 protein (TNFR1) but normal mRNA expression, a trait genetically linked to the major TNFR1 coding gene Tnfrsf1a and to a locus harbouring the predicted TNFR1-regulating miR-511. This miRNA is a genuine TNFR1 regulator in cells. In mice, overexpression of miR-511 down-regulates TNFR1 and protects against TNF, while anti-miR-511 up-regulates TNFR1 and sensitizes for TNF, breaking the resistance of SPRET/Ei. We found that miR-511 inhibits endotoxemia and experimental hepatitis and that this miR is strongly induced by glucocorticoids and is a true TNFR1 modulator and thus an anti-inflammatory miR. Since minimal reductions of TNFR1 have considerable effects on TNF sensitivity, we believe that at least part of the anti-inflammatory effects of glucocorti-coids are mediated by induction of this miR, resulting in reduced TNFR1 expression.


Assuntos
Glucocorticoides/metabolismo , MicroRNAs/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/biossíntese , Fator de Necrose Tumoral alfa/metabolismo , Animais , Regulação para Baixo , Camundongos
12.
J Immunol ; 194(11): 5094-102, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25911755

RESUMO

Psoriasis is a chronic inflammatory skin disease affecting 2-3% of the world population and is mainly characterized by epidermal hyperplasia, scaling, and erythema. A prominent role for TNF in the pathogenesis of psoriasis has been shown, and consequently various types of TNF antagonists such as etanercept and infliximab have been used successfully. Recently, increasing amounts of data suggest that type I IFNs are also crucial mediators of psoriasis. To investigate whether blocking their respective receptors would be useful, TNFR1- and IFNAR1-deficient mice were challenged with Aldara, which contains imiquimod, and is used as an experimental model to induce psoriasis-like skin lesions in mice. Both transgenic mice showed partial protection toward Aldara-induced inflammation compared with control groups. Additionally, TNFR1 knockout mice showed sustained type I IFN production in response to Aldara. Double knockout mice lacking both receptors showed superior protection to Aldara in comparison with the single knockout mice and displayed reduced levels of IL-12p40, IL-17F, and S100A8, indicating that the TNF and type I IFN pathways contribute significantly to inflammation upon treatment with Aldara. Our findings reveal that dual inhibition of TNFR1 and IFNAR1 may represent a potential novel strategic treatment of psoriasis.


Assuntos
Interferon Tipo I/metabolismo , Psoríase/imunologia , Receptor de Interferon alfa e beta/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/metabolismo , Aminoquinolinas/farmacologia , Animais , Anticorpos Monoclonais/uso terapêutico , Calgranulina A/metabolismo , Etanercepte , Imiquimode , Imunoglobulina G/uso terapêutico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/imunologia , Infliximab , Interferon Tipo I/biossíntese , Subunidade p40 da Interleucina-12/metabolismo , Interleucina-17/metabolismo , Subunidade p19 da Interleucina-23/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Psoríase/induzido quimicamente , Receptor de Interferon alfa e beta/metabolismo , Receptores do Fator de Necrose Tumoral/uso terapêutico , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Pele/imunologia , Pele/patologia
13.
J Immunol ; 194(10): 4951-62, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25876765

RESUMO

DUSP3 is a small dual-specificity protein phosphatase with an unknown physiological function. We report that DUSP3 is strongly expressed in human and mouse monocytes and macrophages, and that its deficiency in mice promotes tolerance to LPS-induced endotoxin shock and to polymicrobial septic shock after cecal ligation and puncture. By using adoptive transfer experiments, we demonstrate that resistance to endotoxin is macrophage dependent and transferable, and that this protection is associated with a striking increase of M2-like macrophages in DUSP3(-/-) mice in both the LPS and cecal ligation and puncture models. We show that the altered response of DUSP3(-/-) mice to sepsis is reflected in decreased TNF production and impaired ERK1/2 activation. Our results demonstrate that DUSP3 plays a key and nonredundant role as a regulator of innate immune responses by mechanisms involving the control of ERK1/2 activation, TNF secretion, and macrophage polarization.


Assuntos
Fosfatase 3 de Especificidade Dupla/imunologia , Imunidade Inata/imunologia , Macrófagos/imunologia , Choque Séptico/imunologia , Transdução de Sinais/imunologia , Transferência Adotiva , Animais , Western Blotting , Fosfatase 3 de Especificidade Dupla/deficiência , Citometria de Fluxo , Deleção de Genes , Humanos , Tolerância Imunológica , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
Biol Chem ; 396(11): 1223-31, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25910399

RESUMO

Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases. However, steroid therapies are accompanied by severe side-effects during long-term treatment. The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. Recent discoveries using conditional GR mutant mice and genomic approaches reveal that transactivation of anti-inflammatory acting genes is essential to suppress many inflammatory disease models. This novel view radically changes the concept to design selective acting GR ligands with a reduced side-effect profile.


Assuntos
Regulação para Baixo/genética , Inflamação/genética , Receptores de Glucocorticoides/genética , Animais , Humanos , Inflamação/imunologia , Ligantes , Receptores de Glucocorticoides/metabolismo , Ativação Transcricional/genética
15.
Cytokine Growth Factor Rev ; 26(1): 25-33, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25434285

RESUMO

Psoriasis is a skin disease where various cytokines play a detrimental role, yet our understanding of the disease is still limited. TNF is a validated drug target in psoriasis and other autoimmune diseases, but its use is associated with side effects. Some paradoxical side effects of anti-TNF treatment are supposedly associated with type I IFNs, which are also implicated in the pathogenesis of psoriasis. Recently, the IL-23/IL-17 axis has been associated with psoriasis as well, and new drugs targeting this axis have already been developed. Findings suggest that these cytokines are interwoven. We discuss recent findings reinforcing the role of TNF, Type I IFNs and IL-17 in the pathogenesis of psoriasis and the apparent inflammatory interplay between these three cytokines.


Assuntos
Interferon Tipo I/fisiologia , Interleucina-17/fisiologia , Psoríase/imunologia , Psoríase/fisiopatologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Humanos , Mediadores da Inflamação , Interleucina-23/fisiologia
16.
Methods Mol Biol ; 1204: 83-94, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25182763

RESUMO

The Microarray Assay for Realtime Coregulator-Nuclear receptor Interaction (MARCoNI) technology allows the identification of nuclear receptor-coregulator interactions via flow-through microarrays. As such, differences in the coregulator profile between distinct nuclear receptors or of a single receptor in agonist or antagonist mode can be investigated, even in a single run. In this chapter, the method how to perform these peptide microarrays with cell lysates containing the overexpressed glucocorticoid receptor is described, as well as the influence of assay parameters, variations to the protocol, and data analysis.


Assuntos
Análise Serial de Proteínas/métodos , Receptores de Glucocorticoides/metabolismo , Animais , Células HEK293 , Humanos , Software
17.
Endocr Rev ; 35(4): 671-93, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24937701

RESUMO

Glucocorticoids are among the most prescribed drugs worldwide for the treatment of numerous immune and inflammatory disorders. They exert their actions by binding to the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily. There are several GR isoforms resulting from alternative RNA splicing and translation initiation of the GR transcript. Additionally, these isoforms are all subject to several transcriptional, post-transcriptional, and post-translational modifications, all of which affect the protein's stability and/or function. In this review, we summarize recent knowledge on the distinct GR isoforms and the processes that generate them. We also review the importance of all known transcriptional, post-transcriptional, and post-translational modifications, including the regulation of GR by microRNAs. Moreover, we discuss the crucial role of the putative GR-bound DNA sequence as an allosteric ligand influencing GR structure and activity. Finally, we describe how the differential composition and distinct regulation at multiple levels of different GR species could account for the wide and diverse effects of glucocorticoids.


Assuntos
Regulação da Expressão Gênica/fisiologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/fisiologia , Animais , Humanos , MicroRNAs/fisiologia , Mutação/genética , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Processamento de Proteína Pós-Traducional/fisiologia , Receptores de Glucocorticoides/química , Transcrição Gênica/fisiologia
18.
Cell Rep ; 7(4): 938-9, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24856295

RESUMO

Recent papers from Mahata et al. and Bereshchenko et al. reveal how steroids steer immune responses by tipping T helper (Th) subset balances and activities. Pregnenolone produced by Th2 cells mediates immunosuppressive responses, and glucocorticoids stimulate regulatory T cell development via the induction of GILZ expression.


Assuntos
Glucocorticoides/metabolismo , Pregnenolona/biossíntese , RNA/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Células Th2/imunologia , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Humanos
19.
Cytokine Growth Factor Rev ; 25(1): 21-33, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24412262

RESUMO

Pro-inflammatory cytokines are involved in the pathogenesis of many inflammatory diseases, and the excessive expression of many of them is normally counteracted by glucocorticoids (GCs), which are steroids that bind to the glucocorticoid receptor (GR). Hence, GCs are potent inhibitors of inflammation, and they are widely used to treat inflammatory diseases, such as asthma, rheumatoid arthritis and inflammatory bowel disease. However, despite the success of GC therapy, many patients show some degree of GC unresponsiveness, called GC resistance (GCR). This is a serious problem because it limits the full therapeutic exploitation of the anti-inflammatory power of GCs. Patients with reduced GC responses often have higher cytokine levels, and there is a complex interplay between GCs and cytokines: GCs downregulate pro-inflammatory cytokines while cytokines limit GC action. Treatment of inflammatory diseases with GCs is successful when GCs dominate. But when cytokines overrule the anti-inflammatory actions of GCs, patients become GC insensitive. New insights into the molecular mechanisms of GR-mediated actions and GCR are needed for the design of more effective GC-based therapies.


Assuntos
Resistência a Medicamentos/fisiologia , Glucocorticoides/metabolismo , Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Cromatina/metabolismo , Citocinas/uso terapêutico , Glucocorticoides/biossíntese , Humanos , Inflamação/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Processamento de Proteína Pós-Traducional , Receptores de Glucocorticoides/metabolismo
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