Efecte de la suplementació dietètica amb proteïnes plasmàtiques en la progressió de la malaltia de l'Alzheimer. Paper de la microbiota i l'eix intestí-cervell en aquest efecte

[cat] La malaltia d’Alzheimer (AD) és el tipus de demència més comú durant l’envelliment i una de les malalties neurodegeneratives més severes. L’AD es caracteritza per una pèrdua de memòria, la deposició de pèptids beta- amiloides (Aβ) i l’agregació de la proteïna Tau hiperfosforilada (p-tau), que promouen la formació de les plaques amiloides i els cabdells neurofibrilars, respectivament; així com la neuroinflamació i l’activació de la micròglia. D’altra banda, durant l’envelliment, hi ha disbacterosi, i s’indueix un increment dels bacteris patogènics, la permeabilitat intestinal i l’estat pro-inflamatori. Conseqüentment, la disbacteriosi pot contribuir al desenvolupament de l’AD a través de diferents elements de l’eix intestí-cervell. La suplementació dietètica amb plasma porcí assecat per atomització (SDP) redueix el deteriorament cognitiu dels ratolins SAMP8 envellits, té efectes anti-inflamatoris a la mucosa intestinal en diferents models murins; i efectes prebiòtics en animals joves. Atesos aquests antecedents, la hipòtesi que es planteja en aquesta tesi és que els efectes prebiòtics del plasma assecat poden estar implicats en els seus efectes neuroprotectors. Es van utilitzar ratolins SAMP8 de 2 mesos d’edat (grup de referència) i de 6 mesos d’edat, que es van dividir en dos grups segons el pinso experimental que van rebre durant 4 mesos, pinso control o pinso suplementat amb l’SDP al 8%. Els ratolins envellits presentaven un empitjorament de la funció cognitiva amb una reducció de la memòria a curt i llarg termini, a més d’una menor abundància cortical d’una neurotrofina relacionada amb la plasticitat sinàptica, com és el BDNF. La suplementació amb l’SDP va prevenir aquests efectes. La senescència va promoure l’augment del fragment beta soluble de la proteïna precursora amiloide (sAPP-β) i la generació de pèptids neurotòxics Aβ. La suplementació amb l’SDP va disminuir l’abundància d’aquests marcadors, així com també va reduir l’expressió de la β-secretasa 1 (Bace1), essencial en aquesta via amiloidogènica. L’envelliment va incrementar l’abundància de la proteïna p-tau i de les proteïnes quinases encarregades de la seva hiperfosforilació, la qual cosa es va prevenir amb la suplementació amb l’SDP. La micròglia, les cèl·lules immunitàries específiques del sistema nerviós central, estava més activada al còrtex dels ratolins senescents, i aquest procés va anar acompanyat d’una major neuroinflamació. La suplementació amb l’SDP va atenuar la neuroinflamació i l’activació de la micròglia posant de manifest els seus efectes anti-inflamatoris. Així doncs, la suplementació amb l’SDP redueix els marcadors neuropatològics de l’AD. Paral·lelament, es va demostrar que els ratolins SAMP8 envellits mostraven un major grau d’inflamació sistèmica i a la mucosa de còlon. Aquest procés inflamatori anava acompanyat d’una disminució de l’expressió de les proteïnes relacionades amb la producció de moc (Muc2, Tff3) i del complex d’unió (Ocludina). La suplementació amb l’SDP va atenuar la inflamació sistèmica i del còlon, i va millorar l’estructura de la barrera. Aquests efectes de l’envelliment es van relacionar amb la reducció de l’abundància de bacteris promotors de la salut, com per exemple, els gèneres Lactobacillus i Pediococcus, i en va incrementar d’altres associats amb la inflamació, com els gèneres Johnsonella i Erysipelothrix. En canvi, la suplementació amb l’SDP va exercir efectes prebiòtics, i va induir el creixement dels bacteris probiòtics i en va disminuir els patogènics. En conclusió, els efectes anti-inflamatoris de la suplementació amb l’SDP redueixen la inflamació sistèmica, a la mucosa de còlon, a més presenta propietats neuroprotectores en els ratolins envellits; aquests efectes es correlacionen amb la promoció d’espècies probiòtiques, la qual cosa suggereixen que l’eix intestí cervell pot estar involucrat en la prevenció de l’AD.[eng] Alzheimer's disease (AD) is the most common type of dementia during aging and one of the most severe neurodegenerative diseases. AD is characterized by memory loss, amyloid-beta (Aβ) deposition, aggregation of hyperphosphorylated Tau protein (p-tau), leading to neuroinflammation and activation of microglia. Aging is also accompanied by dysbiosis, which is an alteration of the microbiota, where increases pathogenic bacteria; as well as increased intestinal permeability and inflammation. Consequently, dysbiosis may contribute to the development of AD via the gut-brain axis. Supplementation with spray-dried porcine plasma (SDP) attenuates cognitive decline in aged SAMP8 mice, reduces inflammatory response of the intestinal mucosa in different murine models and shows prebiotic effects in weaned animals. Therefore, the hypothesis proposed is that the prebiotic effects of SDP may be involved in its neuroprotective effects. Experiments were performed in 2-month-old SAMP8 mice fed a standard diet and in 6-month-old SAMP8 mice fed a control or an 8% SDP supplemented diet for 4 months. Aging impaired short- and long-term memory, reduced cortical BDNF abundance, and increased soluble beta amyloid precursor protein (sAPP-β) and Aβ peptides. SDP supplementation prevented all these aging effects, and reduced the expression of β-secretase1 (Bace1), which is essential in the amyloidogenic pathway. Aging increased the abundance of p-tau and the kinases responsible for its hyperphosphorylation, which was also prevented by SDP supplementation. Senescence activated microglia, the immune cells specific to the central nervous system, increasing neuroinflammation. These effects were attenuated by SDP supplementation. Thus, SDP supplementation reduces neuropathological markers of AD. In parallel, aged SAMP8 mice showed increased systemic and colonic inflammation, as well as, reduced Muc2, Tff3 and Occludin expression. SDP supplementation attenuated systemic and colonic inflammation, and improved barrier structure. Aging reduced the abundance of health-promoting bacteria, such as Lactobacillus and Pediococcus, and increased inflammation-associated bacteria, such as Johnsonella and Erysipelothrix. In contrast, SDP supplementation induced the growth of probiotic bacteria and decreased the pathogenic ones. In conclusion, SDP supplementation has anti-inflammatory and neuroprotective effects, as well as prebiotic properties in aged mice, suggesting that the gut-brain axis may be involved in the effect of SDP on AD progression

Dietary Supplementation with Spray-Dried Porcine Plasma Attenuates Colon Inflammation in a Genetic Mouse Model of Inflammatory Bowel Disease

Dietary supplementation with spray-dried porcine plasma (SDP) can modulate the immune response of gut-associated lymphoid tissue. SDP supplementation reduces acute mucosal inflammation, as well as chronic inflammation associated with aging. The aim of this study was to analyze if SDP supplementation could ameliorate colitis in a genetic mouse model of inflammatory bowel disease (IBD). Wild-type mice and Mdr1a knockout (KO) mice were administered a control diet or an SDP-supplemented diet from day 21 (weaning) until day 56. The histopathological index, epithelial barrier, and intestinal immune system were analyzed in the colonic mucosa. KO mice had higher epithelial permeability, increased Muc1 and Muc4 expression, and lower abundance of E-cadherin and Muc2 (all p < 0.001). SDP prevented these effects (all p < 0.05) and decreased the colonic inflammation observed in KO mice, reducing neutrophil and monocyte infiltration and activation and the percentage of activated T helper lymphocytes in the colonic mucosa (all p < 0.05). SDP also diminished proinflammatory cytokine expression and increased the anti-inflammatory IL-10 concentration in the colonic mucosa (all p < 0.05). In conclusion, dietary supplementation with SDP enhances colon barrier function and reduces mucosal inflammation in a mouse model of IBD

Reply to Nifli, A.-P. Comment on 'Rosell-Cardona et al. Dietary Spray-Dried Porcine Plasma Reduces Neuropathological Alzheimer's Disease Hallmarks in SAMP8 Mice. Nutrients 2021, 13, 2369'

Thank you for your comments on our recent work of the effects of supplementation with spray-dried porcine plasma (SDP) on neuropathological markers of Alzheimer's disease (AD) [1]. The author widely describes the use of blood and blood containing food in different countries and its use in different periods of age, but we would like to point out that SDP is a plasma product, so it does not content the blood cells fraction. Therefore, despite the fact that, as the author indicates, the consumption of raw blood and the SDP supplement improve the barrier function in the intestine [2,3] as well as food digestibility and growth [4], it should be noted that there are large differences between the two products, both in terms of the com

Multiplex RNA-based detection of clinically relevant MET alterations in advanced non-small cell lung cancer

We studied MET alterations in 474 advanced non-small-cell lung cancer (NSCLC) patients by nCounter, an RNA-based technique. We identified 3% with MET Δex14 mRNA and 3.5% with very-high MET mRNA expression, a surrogate of MET amplification. MET alterations identified by nCounter correlated with clinical benefit from MET inhibitors. Quantitative mRNA-based techniques can improve the selection of patients for MET-targeted therapies. MET inhibitors have shown activity in non-small-cell lung cancer patients (NSCLC) with MET amplification and exon 14 skipping (METΔex14). However, patient stratification is imperfect, and thus, response rates have varied widely. Here, we studied MET alterations in 474 advanced NSCLC patients by nCounter, an RNA-based technique, together with next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and reverse transcriptase polymerase chain reaction (RT-PCR), exploring correlation with clinical benefit. Of the 474 samples analyzed, 422 (89%) yielded valid results by nCounter, which identified 13 patients (3%) with MET Δex14 and 15 patients (3.5%) with very-high MET mRNA expression. These two subgroups were mutually exclusive, displayed distinct phenotypes and did not generally coexist with other drivers. For MET Δex14, 3/8 (37.5%) samples positive by nCounter tested negative by NGS. Regarding patients with very-high MET mRNA, 92% had MET amplification by FISH and/or NGS. However, FISH failed to identify three patients (30%) with very-high MET RNA expression, among which one received MET tyrosine kinase inhibitor treatment deriving clinical benefit. Our results indicate that quantitative mRNA-based techniques can improve the selection of patients for MET-targeted therapies

BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer

Altres ajuts: Fellowship Award of the International Association for the Study of Lung Cancer i grant of the Italian Association for Cancer Research (AIRC My First AIRC Grant n° 14282).Abstract.BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR

Dietary Spray-Dried Porcine Plasma Reduces Neuropathological Alzheimer’s Disease Hallmarks in SAMP8 Mice

Alzheimer’s disease (AD) is characterized by the aberrant processing of amyloid precursor protein (APP) and the accumulation of hyperphosphorylated tau, both of which are accompanied by neuroinflammation. Dietary supplementation with spray-dried porcine plasma (SDP) has anti-inflammatory effects in inflammation models. We investigated whether dietary supplementation with SDP prevents the neuropathological features of AD. The experiments were performed in 2- and 6-month-old SAMP8 mice fed a control diet, or a diet supplemented with 8% SDP, for 4 months. AD brain molecular markers were determined by Western blot and real-time PCR. Senescent mice showed reduced levels of p-GSK3β (Ser9) and an increase in p-CDK5, p-tau (Ser396), sAPPβ, and the concentration of Aβ40, (all p &lt; 0.05). SDP prevented these effects of aging and reduced Bace1 levels (all p &lt; 0.05). Senescence increased the expression of Mme1 and Ide1 and pro-inflammatory cytokines (Il-17 and Il-18; all p &lt; 0.05); these changes were prevented by SDP supplementation. Moreover, SDP increased Tgf-β expression (p &lt; 0.05). Furthermore, in aged mice, the gene expression levels of the microglial activation markers Trem2, Ym1, and Arg1 were increased, and SDP prevented these increases (all p &lt; 0.05). Thus, dietary SDP might delay AD onset by reducing its hallmarks in senescent mice

Reply to Nifli, A.-P. Comment on “Rosell-Cardona et al. Dietary Spray-Dried Porcine Plasma Reduces Neuropathological Alzheimer’s Disease Hallmarks in SAMP8 Mice. Nutrients 2021, 13, 2369”

Thank you for your comments on our recent work of the effects of supplementation with spray-dried porcine plasma (SDP) on neuropathological markers of Alzheimer’s disease (AD) [...

Dietary Spray-Dried Porcine Plasma Reduces Neuropathological Alzheimer's Disease Hallmarks in SAMP8 Mice

Alzheimer's disease (AD) is characterized by the aberrant processing of amyloid precursor protein (APP) and the accumulation of hyperphosphorylated tau, both of which are accompanied by neuroinflammation. Dietary supplementation with spray-dried porcine plasma (SDP) has anti-inflammatory effects in inflammation models. We investigated whether dietary supplementation with SDP prevents the neuropathological features of AD. The experiments were performed in 2- and 6-month-old SAMP8 mice fed a control diet, or a diet supplemented with 8% SDP, for 4 months. AD brain molecular markers were determined by Western blot and real-time PCR. Senescent mice showed reduced levels of p-GSK3β (Ser9) and an increase in p-CDK5, p-tau (Ser396), sAPPβ, and the concentration of Aβ40, (all p < 0.05). SDP prevented these effects of aging and reduced Bace1 levels (all p < 0.05). Senescence increased the expression of Mme1 and Ide1 and pro-inflammatory cytokines (Il-17 and Il-18; all p < 0.05); these changes were prevented by SDP supplementation. Moreover, SDP increased Tgf-β expression (p < 0.05). Furthermore, in aged mice, the gene expression levels of the microglial activation markers Trem2, Ym1, and Arg1 were increased, and SDP prevented these increases (all p < 0.05). Thus, dietary SDP might delay AD onset by reducing its hallmarks in senescent mice. View Full-Text Keywords: neuroinflammation; dietary supplementation; aging; plasma proteins; Alzheimer's disease; SAMP

Reply to Nifli, A.-P. Comment on “Rosell-Cardona et al. Dietary Spray-Dried Porcine Plasma Reduces Neuropathological Alzheimer’s Disease Hallmarks in SAMP8 Mice. <i>Nutrients</i> 2021, <i>13</i>, 2369”

Thank you for your comments on our recent work of the effects of supplementation with spray-dried porcine plasma (SDP) on neuropathological markers of Alzheimer’s disease (AD) [...

The Neuroprotective Effects of Spray-Dried Porcine Plasma Supplementation Involve the Microbiota&minus;Gut&minus;Brain Axis

Dietary supplementation with spray-dried porcine plasma (SDP) reduces the Alzheimer&rsquo;s disease (AD) hallmarks in SAMP8 mice. Since gut microbiota can play a critical role in the AD progression, we have studied if the neuroprotective effects of SDP involve the microbiota&minus;gut&minus;brain axis. Experiments were performed on two-month-old SAMP8 mice fed a standard diet and on six-month-old SAMP8 mice fed a control diet or an 8% SDP supplemented diet for four months. Senescence impaired short- and long-term memory, reduced cortical brain-derived neurotrophic factor (BDNF) abundance, increased interleukin (Il)-1&beta;, Il-6, and Toll-like receptor 2 (Tlr2) expression, and reduced transforming growth factor &beta; (Tgf-&beta;) expression and IL-10 concentration (all p &lt; 0.05) and these effects were mitigated by SDP (all p &lt; 0.05). Aging also increased pro-inflammatory cytokines in serum and colon (all p &lt; 0.05). SDP attenuated both colonic and systemic inflammation in aged mice (all p &lt; 0.05). SDP induced the proliferation of health-promoting bacteria, such as Lactobacillus and Pediococcus, while reducing the abundance of inflammation-associated bacteria, such as Johnsonella and Erysipelothrix (both q &lt; 0.1). In conclusion, SDP has mucosal and systemic anti-inflammatory effects as well as neuroprotective properties in senescent mice; these effects are well correlated with SDP promotion of the abundance of probiotic species, which indicates that the gut&ndash;brain axis could be involved in the peripheral effects of SDP supplementation