RESUMEN
Greater understanding of molecular pathophysiology has led to the recognition that an excessive type 2 inflammatory response is at the basis of the pathophysiology of several inflammatory diseases including atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP). Given the availability of biological agents that can permit management of specific disease endotypes, this reinforces the need for detailed characterization of these diseases through a multidisciplinary approach. Herein, these three conditions are briefly overviewed and practical guidance for a multidisciplinary approach to management is presented. Since type 2 inflammation is suppressed by steroids, drugs such as glucocorticoids have long been the workhorse of medical therapy. However, steroids have well-known local and systemic adverse effects, especially when used at high doses over prolonged periods of time, which is problematic when treating chronic diseases such as AD, asthma, and CRSwNP. Moreover, a substantial proportion of patients remain refractive to therapy. In the attempt to overcome these limitations, greater understanding of the molecular mechanisms of type 2 inflammation have led to the development of targeted biological drugs such as dupilumab, a fully human monoclonal antibody that targets the α chain of the IL-4 receptor. Dupilumab represents a unique therapy for type 2 inflammatory diseases and to date is the only therapy approved for AD, asthma, and CRSwNP. In terms of multidisciplinary management of type 2 inflammatory conditions, the main healthcare professionals involved include a dermatologist, pneumologist or allergologist, and ENT specialist. The model proposed herein takes into account the complex management of patients with type 2 inflammatory conditions and the new biological agents available. A multidisciplinary team can provide a central point for patient management, improve outcomes and specialist referrals, reduce costs, and guarantee that the most appropriate therapeutic decisions are made, as well as aid in management of adverse events. The multidisciplinary model should be structured and dedicated, but at the same time simple and flexible in order to not risk slowing down the patient's care. At present, it is believed that a structured multidisciplinary approach is currently the best means to optimize care of patients with type 2 inflammatory conditions.
RESUMEN
Unrepaired DNA damage during embryonic development can be potentially inherited by a large population of cells. However, the quality control mechanisms that minimize the contribution of damaged cells to developing embryos remain poorly understood. Here, we uncovered an ATR- and CHK1-mediated transcriptional response to replication stress (RS) in mouse embryonic stem cells (ESCs) that induces genes expressed in totipotent two-cell (2C) stage embryos and 2C-like cells. This response is mediated by Dux, a multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals. In response to RS, DUX triggers the transcription of 2C-like markers such as murine endogenous retrovirus-like elements (MERVL) and Zscan4. This response can also be elicited by ETAA1-mediated ATR activation in the absence of RS. ATR-mediated activation of DUX requires GRSF1-dependent post-transcriptional regulation of Dux mRNA. Strikingly, activation of ATR expands ESCs fate potential by extending their contribution to both embryonic and extra-embryonic tissues. These findings define a novel ATR dependent pathway involved in maintaining genome stability in developing embryos by controlling ESCs fate in response to RS.
Asunto(s)
Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Diferenciación Celular , Proliferación Celular/fisiología , Células Cultivadas , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Quimera , Cromatografía Liquida , Clonación Molecular , Daño del ADN , Células Madre Embrionarias , Regulación de la Expresión Génica , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Secuencia de ARN , Espectrometría de Masas en TándemRESUMEN
Although the aetiology of amyotrophic lateral sclerosis (ALS) is still elusive, increased attention has been put forward on events related to neuroinflammation and an active participation of glial cells in the ALS pathogenesis has been suggested. However, the specific role of many proinflammatory mediators that usually accompany the inflammatory changes is still largely unknown. High mobility group box protein 1 (HMGB1) is an ubiquitous nuclear protein that exerts numerous extranuclear and extracellular functions, including a proinflammatory activity, able to induce cytokines expression and activate inflammatory cells. To investigate whether this protein may play a role in the inflammatory events in ALS, we examined both expression and localization of HMGB1 in the lumbar spinal cord of SOD1G93A transgenic mice, a well established mouse model of familial ALS, at different stages of the disease. Intense HMGB1 reactivity was detected in ventral horn motor neurons of both non-transgenic and SOD1G93A mice and there was no difference in its expression between presymptomatic SOD1G93A mice and controls. With the progression of the disease, degenerating neurons showed a reduction of HMGB1 immunoreactivity which could reflect an extracellular release of this protein. By contrast, in the reactive glial cells HMGB1 was remarkably expressed in the nucleus, but not in the cytosol, likely contributing to the proliferation and/or hypertrophy of these cells. These results suggest that HMGB1 may have a different involvement in the motor neurons and glial cells in response to the neurotoxic environment in the spinal cord of SOD1G93A mice, and it may contribute to the progression of inflammatory and neurodegenerative processes.
Asunto(s)
Esclerosis Amiotrófica Lateral/patología , Proteína HMGB1/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patología , Esclerosis Amiotrófica Lateral/genética , Animales , Modelos Animales de Enfermedad , Inmunohistoquímica/métodos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Superóxido Dismutasa/genética , Factores de TiempoRESUMEN
The domestic dog could be a valuable model for studying and developing assisted reproduction in taxonomically related endangered Canids. However, the efficiency of in vitro oocyte maturation is very low in this species compared to that of other mammalian species and this limits the development of reproductive biotechnologies, such as in vitro embryo production, cryopreservation, or nucleus transfer. In canine species the female gamete has unique characteristics: the oocyte is exposed to high concentration of progesterone in the follicular environment, it is ovulated in the dictyate state, and resumes and completes meiosis in the oviduct. Therefore, optimum conditions for in vitro maturation of dog oocytes may differ from other mammalian models in which follicles, where estrogens are the dominant hormones, ovulate oocytes at the Metaphase II stage of the first meiotic division. An in vitro culture system needs to be based on in vivo conditions in order to create a microenvironment similar to that in which oocyte development occurs physiologically, but little is known on mechanisms regulating oocyte maturation in the dog. This review analyzes the known factors involved in canine oocyte maturation in vivo and in vitro in order to suggest on which aspects future investigations may be focused.