Implication of salivary lactoferrin and periodontal-mediated infections in Alzheimer's disease

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Aquaporin 5 in Alzheimer's disease: a link between oral and brain pathology?

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Regulación de la producción de citoquinas por patrones moleculares de la pared de hongos

Las células dendríticas son presentadores de antígenos que reconocen los patrones moleculares asociados a los hongos y desencadenan señales que modulan la respuesta inflamatoria e inician la inmunidad adaptativa. La regulación del balance de la producción de las citoquinas IL-10, IL-23 e IL-12 p70 es crucial para modular de forma precisa la respuesta al patógeno. En presencia de zymosan, las células dendríticas liberan preferentemente IL-10 e IL-23 y escasa cantidad de IL-12 p70. La producción de IL-10 se explica por la formación de un complejo supramolecular en el sito CRE del promotor de il10 formado por P-CREB y sus co-activadores CBP y TORC2. La regulación negativa de IL-12 p70 es debida a la presencia en el promotor de il12p35 de las moléculas represoras de la familia NOTCH, de histonas deacetilasas y de TLE.Departamento de Bioquímica y Biología Molecular y Fisiologí

Análisis del comportamiento de las presas de escollera ante un vertido por coronación.

El objetivo del estudio es caracterizar el inicio y proceso de rotura de las presas de escollera debido a un sobrevertido y desarrollar un sistema informático para su análisis y seguimiento. El inicio y proceso de rotura se está caracterizando mediante la realización de ensayos en modelo físico a diversas escalas. El método de cálculo se basa en la combinación de métodos avanzados de elementos finitos y de partículas utilizando una formulación lagrangiana para modelar tanto la cinemática de las partículas del fluido como la deformación de la estructura. La validación del método se hará comparando sus resultados con los del análisis experimental de modelos de presas a escala de distinto tamaño. El nuevo método de cálculo permitirá analizar con detalle el estado tensodeformacional de la presa y su posible rotura bajo la acción del flujo de agua durante un sobrevertido teniendo en cuenta la no linealidad geométrica y mecánica de la estructura, así como efectos acoplados de interacción fluido-estructura. El método de cálculo propuesto será una herramienta de gran utilidad para evaluar con precisión la estabilidad y, por tanto, la seguridad de una presa de escollera en situación de avenida extraordinaria que origine un sobrevertido

Reduced Salivary Lactoferrin Levels in Early-Onset Alzheimer's Disease

Grants from Instituto de Salud Carlos III (PI22CIII/00042), CIBERNED (CB07/502, CB06/05/1111, PI2021/03), the Spanish Ministry of Economy and Competitiveness (PID2020-119978RB-I00) and the Andalucía-FEDER Program (UPO-1380913).S

Prebiotic properties of non-fructosylated α-galactooligosaccharides from PEA (Pisum sativum L.) using infant fecal slurries

The interest for naturally-occurring oligosaccharides from plant origin having prebiotic properties is growing, with special focus being paid to supplemented products for infants. Currently, non-fructosylated α-galactooligosaccharides (α-GOS) from peas have peaked interest as a result of their prebiotic activity in adults and their mitigated side-effects on gas production from colonic bacterial fermentation. In this study, commercially available non-fructosylated α-GOS from peas and β-galactooligosaccharides (β-GOS) derived from lactose were fermented using fecal slurries from children aged 11 to 24 months old during 6 and 24 h. The modulatory effect of both GOS on different bacterial groups and bifidobacteria species was assessed; non-fructosylated α-GOS consumption was monitored throughout the fermentation process and the amounts of lactic acid and short-chain fatty acids (SCFA) generated were analyzed. Non-fructosylated α-GOS, composed mainly of manninotriose and verbascotetraose and small amounts of melibiose, were fully metabolized and presented remarkable bifidogenic activity, similar to that obtained with β-GOS. Furthermore, non-fructosylated α-GOS selectively caused an increase on the population of Bifidobacterium longum subsp. longum and Bifidobacterium catenulatum/pseudo-catenulatum. In conclusion, non-fructosylated α-GOS could be used as potential ingredient in infant formula supplemented with prebiotic oligosaccharides.This research was funded by the Spanish Ministry of Economy, Industry and Competitiveness, grant numbers AGL2017-83772-R and AGL2017-84614-C2-1-R (AEI/FEDER,UE); the Spanish Ministry of Science, Innovation and Universities grant number RTI2018-101273-J-I00 (JIN Program) and AGR2011-7626 from Junta de Andalucía

Disturbed circadian rhythm and retinal degeneration in a mouse model of Alzheimer's disease

The circadian clock is synchronized to the 24 h day by environmental light which is transmitted from the retina to the suprachiasmatic nucleus (SCN) primarily via the retinohypothalamic tract (RHT). Circadian rhythm abnormalities have been reported in neurodegenerative disorders such as Alzheimer's disease (AD). Whether these AD-related changes are a result of the altered clock gene expression, retina degeneration, including the dysfunction in RHT transmission, loss of retinal ganglion cells and its electrophysiological capabilities, or a combination of all of these pathological mechanisms, is not known. Here, we evaluated transgenic APP/PS1 mouse model of AD and wild-type mice at 6- and 12-month-old, as early and late pathological stage, respectively. We noticed the alteration of circadian clock gene expression not only in the hypothalamus but also in two extra-hypothalamic brain regions, cerebral cortex and hippocampus, in APP/PS1 mice. These alterations were observed in 6-month-old transgenic mice and were exacerbated at 12 months of age. This could be explained by the reduced RHT projections in the SCN of APP/PS1 mice, correlating with downregulation of hypothalamic GABAergic response in APP/PS1 mice in advanced stage of pathology. Importantly, we also report retinal degeneration in APP/PS1 mice, including Aβ deposits and reduced choline acetyltransferase levels, loss of melanopsin retinal ganglion cells and functional integrity mainly of inner retina layers. Our findings support the theory that retinal degeneration constitutes an early pathological event that directly affects the control of circadian rhythm in AD.This study was supported by grants from Instituto de Salud Carlos III (PI2021/00679; PI22CIII/00042), Hospital Universitario 12 de Octubre Research Institute (2022/0068), FEDER, and CIBERNED (CB07/502, PI2021/03).S

Differentially Aquaporin 5 Expression in Submandibular Glands and Cerebral Cortex in Alzheimer’s Disease

Impaired brain clearance mechanisms may result in the accumulation of aberrant proteins that define Alzheimer's disease (AD). The water channel protein astrocytic aquaporin 4 (AQP4) is essential for brain amyloid-beta clearance, but it is known to be abnormally expressed in AD brains. The expression of AQPs is differentially regulated during diverse brain injuries, but, whereas AQP4 expression and function have been studied in AD, less is known about AQP5. AQP5 functions include not only water transport but also cell migration mediated by cytoskeleton regulation. Moreover, AQP5 has been reported to be expressed in astrocytes, which are regulated after ischemic and traumatic injury. Additionally, AQP5 is particularly abundant in the salivary glands suggesting that it may be a crucial factor in gland dysfunction associated with AD. Herein, we aim to determine whether AQP5 expression in submandibular glands and the brain was altered in AD. First, we demonstrated impaired AQP5 expression in submandibular glands in APP/PS1 mice and AD patients. Subsequently, we observed that AQP5 expression was upregulated in APP/PS1 cerebral cortex and confirmed its expression both in astrocytes and neurons. Our findings propose AQP5 as a significant role player in AD pathology, in addition to AQP4, representing a potential target for the treatment of AD

Eicosanoids in the Innate Immune Response: TLR and Non-TLR Routes

The variable array of pattern receptor expression in different cells of the innate immune system explains the induction of distinct patterns of arachidonic acid (AA) metabolism. Peptidoglycan and mannan were strong stimuli in neutrophils, whereas the fungal extract zymosan was the most potent stimulus in monocyte-derived dendritic cells since it induced the production of PGE2, PGD2, and several cytokines including a robust IL-10 response. Zymosan activated κB-binding activity, but inhibition of NF-κB was associated with enhanced IL-10 production. In contrast, treatments acting on CREB (CRE binding protein), including PGE2, showed a direct correlation between CREB activation and IL-10 production. Therefore, in dendritic cells zymosan induces il10 transcription by a CRE-dependent mechanism that involves autocrine secretion of PGE2, thus unraveling a functional cooperation between eicosanoid production and cytokine production

Senescent synovial fibroblasts accumulate prematurely in rheumatoid arthritis tissues and display an enhanced inflammatory phenotype

[Abstract] Background Accumulation of senescent cells has been associated with pro-inflammatory effects with deleterious consequences in different human diseases. The purpose of this study was to analyze cell senescence in human synovial tissues (ST), and its impact on the pro-inflammatory function of synovial fibroblasts (SF). Results The expression of the senescence marker p16INK4a (p16) was analyzed by immunohistochemistry in rheumatoid arthritis (RA), osteoarthritis (OA), and normal ST from variably aged donors. The proportion of p16(+) senescent cells in normal ST from older donors was higher than from younger ones. Although older RA and OA ST showed proportions of senescent cells similar to older normal ST, senescence was increased in younger RA ST compared to age-matched normal ST. The percentage of senescent SA-β-gal(+) SF after 14 days in culture positively correlated with donor’s age. Initial exposure to H2O2 or TNFα enhanced SF senescence and increased mRNA expression of IL6, CXCL8, CCL2 and MMP3 and proteins secretion. Senescent SF show a heightened IL6, CXCL8 and MMP3 mRNA and IL-6 and IL-8 protein expression response upon further challenge with TNFα. Treatment of senescent SF with the senolytic drug fenofibrate normalized IL6, CXCL8 and CCL2 mRNA expression. Conclusions Accumulation of senescent cells in ST increases in normal aging and prematurely in RA patients. Senescence of cultured SF is accelerated upon exposure to TNFα or oxidative stress and may contribute to the pathogenesis of synovitis by increasing the production of pro-inflammatory mediators.Instituto de Salud Carlos III; FIS 16/00032Insituto de Salud Carlos III; RETICS RD16/0012 RIE