Proinsulin attenuates the loss of vision and delays apoptosis of photoreceptors in a mouse model of retinitis pigmentosa.

34 p. 8 fig. 2 supl. fig.purpose. Retinitis pigmentosa (RP) is a heterogeneous group of inherited conditions that lead to blindness and for which there is no effective therapy. Apoptosis of photoreceptors is a common feature in animal models of the disease. Thus, the authors studied the therapeutic potential of proinsulin, an antiapoptotic molecule active during retinal development. methods. Transgenic mice expressing human proinsulin (hPi) in the skeletal muscle were generated in a mixed C57BL/6:SJL background and were back-crossed to a C57BL/6 background. Two independent lineages of transgenic mice were established in which hPi production in muscle was constitutive and not regulated by glucose levels. hPi levels in serum, muscle, and retina were determined with a commercial ELISA kit, visual function was evaluated by electroretinographic (ERG) recording, and programmed cell death was assessed by TUNEL. Immunohistochemistry was used to evaluate retinal structure preservation and oxidative damage. results. Transgenic expression of hPi in the rd10 retinal degeneration mouse model led to prolonged vision, as determined by ERG recording, in a manner that was related to the level of transgene expression. This attenuation of visual deterioration was correlated with a delay in photoreceptor apoptosis and with the preservation of retinal cytoarchitecture, particularly that of the cones. conclusions. These results provide a new basis for possible therapies to counteract retinitis pigmentosa and a new tool to characterize the mechanisms involved in the progress of retinal neurodegenerationSupported by Spanish Ministerio de Educación y Ciencia Grants SAF2001-1038, SAF2004-05870, and SAF2007-66175 (EJdlR, PdlV); BFU2004-02352 (FdP); SAF2005-01262 (FB); Spanish Ministerio de Sanidad y Consumo Grant RETIC RD-06 (FdP, FB); Comunidad de Madrid Grants 8.5-0019.1/2001 (EJdlR) and 08.5-0049/2003 and CCG06-UAH/BIO-0711 (PdlV); Fundación Médica Mutua Madrileña (EJdlR); and Fundaluce (PdlV). SC and NR-M were supported by postgraduate fellowships from the Ministerio de Educación y Ciencia, PB by a Ramón y Cajal contract from the Ministerio de Educación y Ciencia, AIA by a postdoctoral contract from the Fondo de Investigaciones Sanitarias, and VG-V by an I3P postdoctoral contract from the European Social FundPeer reviewe

Effectiveness of telephone monitoring in primary care to detect pneumonia and associated risk factors in patients with SARS-CoV-2

Improved technology facilitates the acceptance of telemedicine. The aim was to analyze the effectiveness of telephone follow-up to detect severe SARS-CoV-2 cases that progressed to pneumonia. A prospective cohort study with 2-week telephone follow-up was carried out March 1 to May 4, 2020, in a primary healthcare center in Barcelona. Individuals aged =15 years with symptoms of SARS-CoV-2 were included. Outpatients with non-severe disease were called on days 2, 4, 7, 10 and 14 after diagnosis; patients with risk factors for pneumonia received daily calls through day 5 and then the regularly scheduled calls. Patients hospitalized due to pneumonia received calls on days 1, 3, 7 and 14 post-discharge. Of the 453 included patients, 435 (96%) were first attended to at a primary healthcare center. The 14-day follow-up was completed in 430 patients (99%), with 1798 calls performed. Of the 99 cases of pneumonia detected (incidence rate 20.8%), one-third appeared 7 to 10 days after onset of SARS-CoV-2 symptoms. Ten deaths due to pneumonia were recorded. Telephone follow-up by a primary healthcare center was effective to detect SARS-CoV-2 pneumonias and to monitor related complications. Thus, telephone appointments between a patient and their health care practitioner benefit both health outcomes and convenience. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Autophagy in motor neuron diseases.

Motor neuron diseases (MNDs) are a wide group of neurodegenerative disorders characterized by the degeneration of a specific neuronal type located in the central nervous system, the motor neuron (MN). There are two main types of MNs, spinal and cortical MNs and depending on the type of MND, one or both types are affected. Cortical MNs innervate spinal MNs and these control a variety of cellular targets, being skeletal muscle their main one which is also affected in MNDs. A correct functionality of autophagy is necessary for the survival of all cellular types and it is particularly crucial for neurons, given their postmitotic and highly specialized nature. Numerous studies have identified alterations of autophagy activity in multiple MNDs. The scientific community has been particularly prolific in reporting the role that autophagy plays in the most common adult MND, amyotrophic lateral sclerosis, although many studies have started to identify physiological and pathological functions of this catabolic system in other MNDs, such as spinal muscular atrophy and spinal and bulbar muscular atrophy. The degradation of selective cargo by autophagy and how this process is altered upon the presence of MND-causing mutations is currently also a matter of intense investigation, particularly regarding the selective autophagic clearance of mitochondria. Thorough reviews on this field have been recently published. This chapter will cover the current knowledge on the functionality of autophagy and lysosomal homeostasis in the main MNDs and other autophagy-related topics in the MND field that have risen special interest in the research community

Axonal damage, autophagy and neuronal survival

2 páginas -- PAGS nros. 286-288In recent years autophagy modulation has been shown to reduce or increase neuronal cell death in several models of neurodegeneration. How autophagy exerts these dual effects is currently unknown. Here we review recent evidence from our laboratory demonstrating that autophagy can protect the cell soma after axonal traumatic injury. Damage in the optic nerve induces retinal ganglion cell (RGC) death in glaucoma and other retinal diseases and is often modeled by axotomy of the optic nerve in laboratory animals. Using this well-known model of RGC degeneration we show that autophagy is strongly upregulated following the insult and before cell death. Enhancement of autophagy by pharmacological treatment with rapamycin decreases the number of degenerating neurons. Conversely, axotomy in Atg4B (-/-) mice increases the number of dying cells in the retinal ganglion cell layer. Similar findings were observed in Atg5 (flox/flox) mice following specific downregulation of the autophagy regulator ATG5 in RGCs, by intravitreal injection of a cre-expressing vector. Taken together, these findings point to a cytoprotective role of autophagy following axonal damage in vivoPeer reviewe

Autophagy in stem cells: repair, remodelling and metabolic reprogramming

14 p.-6 fig.Autophagy is a catabolic pathway by which cellular components are delivered to the lysosome for degradation and recycling. Autophagy serves as a crucial intracellular quality control and repair mechanism but is also involved in cell remodelling during development and cell differentiation. In addition, mitophagy, the process by which damaged mitochondria undergo autophagy, has emerged as key regulator of cell metabolism. In recent years, a number of studies have revealed roles for autophagy and mitophagy in the regulation of stem cells, which represent the origin for all tissues during embryonic and postnatal development, and contribute to tissue homeostasis and repair throughout adult life. Here, we review these studies, focussing on the latest evidence that supports the quality control, remodelling and metabolic functions of autophagy during the activation, self-renewal and differentiation of embryonic, adult and cancer stem cells.P.B. is supported by Spain's Ministerio de Economía y Competitividad [BFU2015-65623 (FEDER funding) and BFU2015-71869-REDT], European Cooperation in Science and Technology (COST) Action Transautophagy (CA15138) and the European Union Horizon 2020 Marie Skłodowska-Curie Innovative Training Networks (ITN-ETN) under grant agreement 765912. N.R.-M. is supported by a grant from the Muscular Dystrophy Association (MDA376743) and a Juan de la Cierva Incorporación fellowship from Spain's Ministerio de Economía y Competitividad. P.C. is supported by funding from the Institut National de la Santé et de la Recherche Médicale (INSERM), the Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes-Sorbonne Paris Cité and grants from the Institut National Du Cancer (INCa) and the Agence Nationale de la Recherche (ANR).Peer reviewe

Neuroplasticity changes in Alzheimer's and Creutztfeldt-Jakob's diseases. Relationships to involutive phenomena | Alteraciones de los fenómenos de neuroplasticidad en las enfermedades de Alzheimer y Creutzfeldt-Jakob. Interrelaciones con fenómenos involutivos

Changes in neuroplasticity and neuronal adaptative mechanisms have been postulated as origin and/or main pathophysiological factor in neurodegenerative diseases. To analyze these theories, a comparative morphohistochemical study on the cerebral (prefrontal) and cerebellar (neocerebellar) cortex from Alzheimer's (AD) and Creutzfeldt-Jakob (CJD) post-mortem brains has been carried out. Variations in putative markers of neuroplasticity and neuronal adaptation (synaptic proteins such as drebrin and SNAP-25; nuclear factor NF kappa Beta -NFkB-; neuronal isoform of oxide nitric synthase -nNOS) have been studied in close association with neuropathological markers (beta-protein deposition - amyloid in AD and PrPsc in CJD-; microglial activation, induction of iNOS and cyclooxygenase 2 -COX-2). Results have shown sharp variations in these markers when compared AD and CJD; cerebral and cerebellar cortex; different areas of these anatomical regions; and different sets of neurons and glial cells. The meaining of somme of these markers (NFkB; nNOS; synaptic proteins) could be variable (plastic/adaptative or involutive), depending on different factors (disease, anatomical region, general or local factors, etc.). Neuroplasticity is evident in several brain regions or neurons, but this neuronal feature decreases in different form depending also on the disease and the anatomical region. Their relationships to the neuropathological findings were also variable. In conclusion, the activation of these putative markers of neuroplasticity, considering as therapeutical targets, in advanced steps of the diseases, could activate neuronal involutive phenomena in several regions or neurons.Peer Reviewe

Lysosomal membrane permeabilization in Parkinson disease

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Balance between autophagic pathways preserves retinal homeostasis

48 p.-4 fig.-4 fig S.Aging contributes to the appearance of several retinopathies and is the largest risk factor for aged-related macular degeneration, major cause of blindness in the elderly population. Accumulation of undegraded material as lipofuscin represents a hallmark in many pathologies of the aged eye. Autophagy is a highly conserved intracellular degradative pathway that plays a critical role in the removal of damaged cell components to maintain the cellular homeostasis. A decrease in autophagic activity with age observed in many tissues has been proposed to contribute to the aggravation of age-related diseases. However, the participation of different autophagic pathways to the retina physiopathology remains unknown. Here, we describe a marked reduction in macroautophagic activity in the retina with age, which coincides with an increase in chaperone-mediated autophagy (CMA). This increase in CMA is also observed during retinal neurodegeneration in the Atg5flox/flox; nestin-Cre mice, a mouse model with downregulation of macroautophagy in neuronal precursors. In contrast to other cell types, this autophagic cross talk in retinal cells is not bi-directional and CMA inhibition renders cone photoreceptor very sensitive to stress. Temporal and cell-type-specific differences in the balance between autophagic pathways may be responsible for the specific pattern of visual loss that occurs with aging. Our results show for the first time a cross talk of different lysosomal proteolytic systems in the retina during normal aging and may help the development of new therapeutic intervention for age-dependent retinal diseases.This work was supported by grants from MINECO (Spain), SAF-2009-08086 to PB, and CONSOLIDER CSD2010-000454 to PB and EJdR, and from NIH (AG031782 and AG038072) to AMC. NRM was a recipient of a FPU fellowship from MICINNPeer reviewe