Corticoterapia / Corticotherapy

Glicocorticosteroides são fármacos efetivos no tratamento de doenças inflamatórias e imunes. Agem em praticamente todas as células do corpo, antagonizando os efeitos patogênicos de inúmeras doenças. A maior parte de seus efeitos parece ser produto de sua ligação a receptores específicos armazenados no interior das células. Suas ações moduladoras da transcrição genética iniciam-se com a ligação ao seu receptor e posterior conexão aos genes alvo, num processo que conta com a participação de outros fatores e envolve múltiplos mecanismos (ação genômica). Os genes alvo incluem aqueles responsáveis por mediadores inflamatórios, como quimiocinas, citocinas, fatores de crescimento e seus receptores. Além de seus efeitos sobre o DNA, estimulando a produção de produtos anti-inflamatórios ou inibindo a transcrição de genes pró-inflamatórios, via acetilação ou deacetilação das histonas, respectivamente, os glicocorticosteroides possuem outros mecanismos de ação que não envolvem regulação genética (ação não genômica). Aparentemente, por mecanismos ainda não esclarecidos, os efeitos da corticoterapia são produto da associação das ações genômicas com as não genômicas. Os glicocorticosteroides representam o grande pilar terapêutico da asma, com efeitos sobre as células estruturais e funcionais do trato respiratório. Nessa situação particular, na qual costumam ser empregados continuadamente por períodos prolongados, com risco potencial de efeitos indesejáveis relevantes, é fundamental desvendar os processos envolvidos em seus mecanismos de ação para tentar desenvolver meios de reduzir os riscos associados e potencializar os efeitos desejados.

Glucocorticosteroids are effective drugs in the treatment of inflammatory and immune diseases. They act on virtually every cell in the body by antagonizing the pathogenic effects of numerous diseases. Most of its effects appear to be the product of its binding to specific receptors stored within cells. Its modulatory actions on genetic transcription begin with a linkage to its receptor and later connection to target genes, in a process that counts on the participation of other factors and involves multiple mechanisms (genomic action). Target genes include those responsible for inflammatory mediators, such as chemokines, cytokines, growth factors, and their receptors. In addition to its effects on DNA, stimulating the production of anti-inflammatory products or inhibiting the transcription of pro-inflammatory genes, via acetylation or deacetylation of histones, respectively, glucocorticosteroids have other mechanisms of action that do not involve genetic regulation (non-genomic effect). Apparently, by mechanisms not yet clarified, the effects of corticotherapy are the product of the association of genomic and non-genomic actions. Glucocorticosteroids represent the great therapeutic pillar of asthma, with effects on structural and functional cells of the respiratory tract. In this particular situation, where they are often used for prolonged periods, with a potential risk of relevant undesirable effects, it is essential to uncover the processes involved in their mechanisms of action in order to develop ways to reduce the associated risks and potentiate the desired effects.

Mechanism of dexamethasone inhibiting U937 cell adhesion and phagocytose function / 中华创伤杂志

ObjectiveTo investigate the mechanism of dexamethasone (Dex) in inhibiting monocyte adhesion and phagocytose function.Methods Under the stimulation of phorbo1-12-myristate-13-acetate (PMA),U937 monocytes cultured in vitro were treated with Dex and Fasudil respectively.The adhesion rate of U937 monocles to human umbilical vein endothelial cells (HUVECs) and their phagocytic ability of India ink were studied.The protein content and activity of rho-associated coiled-coil protein kinase 1 ( ROCK1 ) as well as the effects of mifepristone and cycloheximide on Dex were determined.ResultsBoth DEX and Fasudil could significantly inhibit the adhesion tate and phagocytosis of U937 cells stimulated by PMA and suppressed the activity of ROCK1.While mifepristone and cycloheximide could not alter these effects of DEX.ConclusionDEX interferes with the adhesion and phagocytosis function of U937 cells by inhibiting ROCKI activity.

Localización extra nuclear de receptores esteroides y activación de mecanismos no genómicos / Extra nuclear localization of steroid receptors and non genomic activation mechanisms

Los receptores de hormonas esteroides han sido considerados históricamente como factores de transcripción nucleares. Sin embargo, en los últimos años surgieron evidencias que indican que su activación desencadena eventos rápidos, independientes de la transcripción y que involucran a diferentes segundos mensajeros; muchos de estos receptores han sido localizados en la membrana celular. Por otra parte, se han caracterizado varios receptores de hormonas esteroides noveles, de estructura molecular diferente al receptor clásico, localizados principalmente en la membrana celular. Esta revisión enfoca los diferentes efectos iniciados por los glucocorticoides, mineralocorticoides, andrógenos, estrógenos y progesterona, y los posibles receptores involucrados en los mismos.

Steroid hormone receptors have been historically considered as nuclear transcription factors. Nevertheless, in the last years, many of them have been detected in the cellular membrane. It has been postulated that their activation can induce transcription independent rapid events involving different second messengers. In addition, several novel steroid hormone receptors, showing a different molecular structure than the classical ones, have also been characterized and most of them are also located in the plasmatic membrane. This review focuses on the variety of effects initiated by glucocorticoids, mineralocorticoids, androgens, estrogens and progesterone, and the possible receptors involved mediating these effects.

Effects of Progesterone on the Growth Regulation in Classical Progesterone Receptor-negative Malignant Melanoma Cells / 华中科技大学学报（医学）（英德文版）

This study investigated the growth-regulating effects of progesterone(Prog)on nPR-negative malignant melanoma cells and the possible mechanisms.A375 and A875 cells were cultured and treated with Prog of different concentrations.For signal transduction pathway studies,the cells were pretreated with Prog receptor antagonist(RU486,1×10 7 mol/L)or MAPK inhibitor (U0126,5×10-6 mol/L)for 1 h and then co-incubated with prog(10-9 mol/L)for another 24 h.Indirect immunofluorescence assay,MTT,flow cytornetry and Western blotting were used for assessing the nPR expression,cell growth,cell apoptosis and ERK1/2 Phosphorylation,respectively.Our results showed that lower progesterone concentration promoted the proliferation of both A375 and A875 cells,but this growth-stimulatory effect decreased at progesterone concentration of 1 × 10-7mol/L or higher.The response could be abolished by MAPK inhibitor U0126,but could not be blocked by progesterone antagonist RU486.Flow cytometry exhibited that high concentration(≥1×10-7 mol/L)progesterone increased the apoptosis of the two cells in a dose-dependent manner.The level of ERK 1/2 phosphorylation was increased by a lower progesterone concentration,but reduced by a higber concentration(1×10-6 mol/L).These results suggest progesterone exerts growth-regulating effects on nPR-negative tumor cells through a non-genomic mechanism.

The physiological meaning of rapid responses to steroid hormones in epithelia

No abstract available.