Ayuno intermitente y restricción calórica como tratamiento coadyuvante en enfermedad de Alzheimer y esclerosis múltiple / Intermittent Fasting and Caloric Restriction as an Adjunctive Treatment in Alzheimer's Disease and Multiple Sclerosis

Las enfermedades de Alzheimer y esclerosis múltiple son neurodegenerativas, con tratamientos complejos y de costos elevados, orientados a disminuir la progresión de la sintomatología. Sin embargo, a causa de la falta de terapias adecuadas y de los posibles efectos adversos ocasionados por tratamientos de primera línea, es necesario implementar mejores abordajes terapéuticos complementarios que no produzcan mayores efectos secundarios y mejoren la sintomatología de dichas patologías. La restricción calórica y el ayuno intermitente han demostrado ser estrategias novedosas y beneficiosas en enfermedades neurodegenerativas, a través de mecanismos inmunitarios, metabólicos y fisiológicos. Con el objetivo de determinar el uso del ayuno intermitente y la restricción calórica como tratamiento coadyuvante en esclerosis múltiple y enfermedad de Alzheimer, se realizó una revisión narrativa de artículos originales en revistas científicas, en idiomas inglés y español, de 2018 a 2022. El uso de la restricción calórica y ayuno intermitente han generado cambios positivos produciendo disminución de estados proinflamatorios, estrés oxidativo y envejecimiento. Se consideran abordajes que modulan la progresión de la enfermedad y mejoran la función cognitiva por vías de señalización de monofosfato de adenosina cinasa, factor de crecimiento similar a la insulina y la enzima sirtuina, generando un efecto neuroprotector.

Alzheimer's disease and multiple sclerosis are neurodegenerative disorders with expensive and complex treatments aimed at reducing the progression of symptoms. However, due to the lack of adequate therapies and the possible adverse effects caused by first-line treatments, it's necessary to implement better complementary therapeutic approaches that do not produce major side effects and improve symptoms. Caloric restriction and intermittent fasting have been shown to be novel and beneficial strategies in neurodegenerative diseases, through immune, metabolic, and physiological mechanisms. To determine the use of intermittent fasting and caloric restriction as a new treatment in multiple sclerosis and Alzheimer's disease, a narrative review of original articles in both national and international scientific journals, in English and Spanish languages with no greater obsolescence than five years. The use of caloric restriction and intermittent fasting have generated positive changes, producing a decrease in pro-inflammatory states, oxidative stress, and aging. Approaches that modulate disease progression and improve cognitive function of adenosine monophosphate kinase, insulin-like growth factor, and sirtuin enzyme pathways are considered, generating a neuroprotective effect.

Probióticos y prebióticos en pacientes con enfermedad celíaca y sensibilidad al gluten no celíaca / Probiotics and prebiotics for patients with celiac disease and non-celiac gluten sensitivity

La enfermedad celíaca y la sensibilidad al gluten no celíaca han tenido un aumento en su incidencia, esto las ha convertido en tema de interés en la búsqueda de enfoques terapéuticos innovadores que ayuden a mejorar los síntomas intestinales y extraintestinales. Esta revisión pretende determinar los efectos del uso de probióticos y prebióticos en la enfermedad celíaca y sensibilidad al gluten no celíaca. Se realizó una búsqueda en bases de datos HINARI, PubMed y Scopus en idioma español e inglés, se incluyeron artículos originales y de revisión con un máximo de cinco años desde su publicación. El uso de probióticos y prebióticos para la enfermedad celíaca ha mostrado beneficios restaurando la composición del microbiota intestinal, en especial con el uso de Lactobacilli y Bifidobacterium spp.; en la sensibilidad al gluten no celíaca, el uso se ve limitado al no conocer con exactitud su fisiopatología; no obstante, se propone como mejor pauta terapéutica una dieta libre de gluten. El uso de probióticos y prebióticos podría aliviar los síntomas gastrointestinales y mejorar la disbiosis en pacientes con enfermedad celíaca y sensibilidad al gluten no celíaca. Sin embargo, se necesitan más estudios que evidencien los beneficios de su uso como alternativa terapéutica

Celiac disease and non-celiac gluten sensitivity are entities that have shown an increase in incidence, making them a topic of interest to provide innovative therapeutic approaches and improve intestinal and extraintestinal symptoms. This review intends to determine the effects of the use of probiotics and prebiotics in celiac disease and non-celiac gluten sensitivity. A narrative review was undertaken by searching for original and review articles no older than five years since publication through data bases consulted: HINARI, PubMed and Scopus in Spanish and English. The use of probiotics and prebiotics in celiac disease has shown benefits by restoring the composition of the intestinal microbiota, especially with the use of Lactobacilli and Bifidobacterium spp.; in non-celiac gluten sensitivity, its use is limited as its pathophysiology is not exactly known, therefore, a gluten-free diet is currently considered to be the best therapeutic guideline. The use of probiotics and prebiotics could alleviate gastrointestinal symptoms and improve dysbiosis in patients with celiac disease and non-celiac gluten sensitivity. However, more studies are needed to demonstrate the benefits of its use as a therapeutic alternative

Long-term effects of an undergraduate palliative care course: a prospective cohort study in El Salvador.

BACKGROUND: International organisations recommend the inclusion of palliative care undergraduate education as a way to meet increasing demand; the long-term effects, however, are unknown. Since 2013 the Dr José Matías Delgado University has offered an undergraduate course for palliative care. AIMS: To assess whether a palliative care course results in improvement in self-perceived comfort among students and if it lasts up to 4 years later; and to examine students' knowledge of palliative care and assess the relationship between comfort and knowledge. DESIGN: This is a prospective cohort study where students attending the course were requested to complete the Scale of Self-Perceived Comfort in palliative care pre and post course. Participants were contacted in 2018 and a group without palliative care education was established as a control group, matched one-to-one according to current academic level. They were asked to complete the Scale of Self-Perceived Comfort questionnaire together with the Palliative Care Knowledge Test. SETTINGS/PARTICIPANTS: 83 students who attended the course between the years 2014 and 2017 and 101 controls. RESULTS: In the postcourse test, participants had a 1.13-point increase (p≤0.001) in comfort, which persisted 4 years later and was superior to the control group by 0.6 points (p≤0.001). The control group showed no difference in the precourse test despite having more clinical experience (p=0.68). The students outscored the control group in the knowledge test by 4.2 points (p≤0.001). There appears to be no correlation between comfort and knowledge. CONCLUSION: A palliative care undergraduate course results in improvement in student comfort and knowledge which persists up to 4 years later.

PDGFR signaling blockade in marrow stroma impairs lung cancer bone metastasis.

Bone microenvironment and cell-cell interactions are crucial for the initiation and development of metastasis. By means of a pharmacologic approach, using the multitargeted tyrosine kinase inhibitor sunitinib, we tested the relevance of the platelet-derived growth factor receptor (PDGFR) axis in the bone marrow (BM) stromal compartment for the initiation and development of lung cancer metastasis to bone. PDGFRß was found to be the main tyrosine kinase target of sunitinib expressed in BM stromal ST-2 and MC3T3-E1 preosteoblastic cells. In contrast, no expression of sunitinib-targeted receptors was found in A549M1 and low levels in H460M5 lung cancer metastatic cells. Incubation of ST-2 and human BM endothelial cells with sunitinib led to potent cell growth inhibition and induction of apoptosis in a dose-dependent manner. Similarly, sunitinib induced a robust proapoptotic effect in vivo on BM stromal PDGFRß(+) cells and produced extensive disruption of tissue architecture and vessel leakage in the BM cavity. Pretreatment of ST-2 cells with sunitinib also hindered heterotypic adhesion to lung cancer cell lines. These effects were correlated with changes in cell-cell and cell-matrix molecules in both stromal and tumor cells. Pretreatment of mice with sunitinib before intracardiac inoculation of A549M1 or H460M5 cells caused marked inhibition of tumor cells homing to bone, whereas no effect was found when tumor cells were pretreated before inoculation. Treatment with sunitinib dramatically increased overall survival and prevented tumor colonization but not bone lesions, whereas combination with zoledronic acid resulted in marked reduction of osteolytic lesions and osseous tumor burden. Thus, disruption of the PDGFR axis in the BM stroma alters heterotypic tumor-stromal and tumor-matrix interactions, thereby preventing efficient engagement required for bone homing and osseous colonization. These results support the notion that concomitant targeting of the tumor and stromal compartment is a more effective approach for blocking bone metastasis.

Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Abeta levels.

Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPP(wt)) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but beta-amyloid peptide (Abeta(42)) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Abeta(42) were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Abeta-independent pathogenic pathways in Alzheimer's disease.

Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer's disease mouse model.

Clinical trials with rosiglitazone, a potent agonist at peroxisome proliferator-activated receptor gamma (PPARgamma) suggest an improvement of cognitive function in Alzheimer's disease (AD) patients. The mechanisms mediating this potential beneficial effect remain to be fully elucidated. In mice overexpressing mutant human amyloid precursor protein (hAPP), a model of AD, we found that memory impairment in the object recognition test was prevented and also reversed by chronic rosiglitazone treatment. Given the possible involvement of glucocorticoid receptors (GR) in the actions of PPARgamma-ligands, we studied the effect of chronic rosiglitazone treatment on GR levels in the hippocampus of hAPP mice. An early down-regulation of GR, not related to elevated plasma corticosterone levels, was found in different hippocampal subfields of the transgenic mice and this decrease was prevented by rosiglitazone. In parallel with behavioural studies, rosiglitazone also normalized GR levels in older animals. This effect may contribute to explain the attenuation of memory decline by PPARgamma activation in an AD mouse model.

Involvement of the vascular wall in regenerative processes after CA1 ischemic neuronal death.

The involvement of vascular wall in response to neuronal death was challenged here using a transient forebrain ischemia model in gerbil, which causes CA1 neuronal death and trigger neurogenesis in hippocampus. We found an important vascular reaction in CA1 5 days after ischemia evaluated by Von Willebrand factor and Vimentin immunoreactivity, as well as increased expression of angiogenic and neurogenic regulators: Vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2). Analysing the morphology and cell phenotype by confocal microscopy, we confirmed the colocalization of the neurogenic markers (bromodeoxyuridine-neuronal nuclei-TOPRO-3) in newborn cells associated to vascular walls in CA1 and dentate gyrus of hippocampus 32 days after ischemia. The results indicate that vascular tissues may participate in neurogenesis after brain ischemia, reinforce the notion that blood vessels represent a source of neuronal progenitor cells in damaged brain areas and suggest that molecular and cellular manipulation of the vascular wall may expand the possibilities of novel regenerative therapies.

Ischemia induces cell proliferation and neurogenesis in the gerbil hippocampus in response to neuronal death.

We studied hippocampal cellular proliferation and neurogenesis processes in a model of transient global cerebral ischemia in gerbils by labelling dividing cells with 5'-Bromo-2'-deoxyuridine (BrdU). Surrounding the region of selective neuronal death (CA1 pyramidal layer of the hippocampus), an important increase in reactive astrocytes and BrdU-labelled cells was detected 5 days after ischemia. A similar result was found in the dentate gyrus (DG) 12 days after ischemia. The differentiation of the BrdU+ cells was investigated 28 days after BrdU administration by analyzing the morphology, anatomic localization and cell phenotype by triple fluorescent labelling (BrdU, adult neural marker NeuN and DNA marker TOPRO-3) using confocal laser-scanning microscopy. This analysis showed increased neurogenesis in the DG in case of ischemia and triple positive labelling in some newborn cells in CA1. Seven brain hemispheres from gerbils subjected to ischemia did not develop CA1 neuronal death; hippocampus from these hemispheres did not show any of the above mentioned findings. Our results indicate that ischemia triggers proliferation in CA1 and neurogenesis in the DG in response to CA1 pyramidal neuronal death, independently of the reduced cerebral blood flow or the cell migration from subventricular zone (SVZ).

Neuroprotective effects of serotonin 5-HT 1A receptor activation against ischemic cell damage in gerbil hippocampus: Involvement of NMDA receptor NR1 subunit and BDNF.

It is known that the activation of 5-hydroxytryptamine receptor type 1A (5HT(1A) receptor) may protect against brain damage induced by transient global ischemia. The biochemical mechanisms that underlie this neuroprotective effect remain however to be fully elucidated. Given that serotonergic drugs may regulate N-methyl-d-aspartate (NMDA) receptor function, which is implicated in events leading to ischemia-induced neuronal cell death, and also stimulate the expression of brain-derived neurotrophic factor (BDNF), which is down-regulated in cerebral ischemia, we sought to determine the effects of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on the levels of NMDA receptor NR1 subunit and BDNF in gerbil hippocampus after transient global cerebral ischemia. Pretreatment with 8-OH-DPAT (1 mg/kg) prevented the neuronal loss in CA1 subfield 72 h after ischemia and also the dramatic decrease in BDNF immunoreactivity observed in this area at an earlier time. NMDA receptor NR1 levels in whole hippocampus were not affected 24 h after ischemia, but the levels of the subunit phosphorylated at the protein kinase A (PKA) site, pNR1(Ser897), were significantly increased, and this increase was prevented by the same 8-OH-DPAT dose, a probable consequence of the increased phosphatase 1 (PP1) enzyme activity found in ischemic gerbils pretreated with the 5-HT(1A) receptor agonist. The results indicate that both NR1 subunit phosphorylation and the neurotrophin BDNF account, at least in part, for the neuroprotective effect of 8-OH-DPAT on cell damage induced by global ischemia in the gerbil hippocampus and support the potential interest of 5-HT1A receptor activation in the search for neuroprotective strategies.