RESUMEN
Early pathological upregulation of adenosine A2A receptors (A2ARs), one of the caffeine targets, by neurons is thought to be involved in the development of synaptic and memory deficits in Alzheimer's disease (AD) but mechanisms remain ill-defined. To tackle this question, we promoted a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice developing AD-like amyloidogenesis. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioural changes were not linked to major change in the development of amyloid pathology but rather associated with increased phosphorylated tau at neuritic plaques. Moreover, proteomic and transcriptomic analyses coupled with quantitative immunofluorescence studies indicated that neuronal upregulation of the receptor promoted both neuronal and non-neuronal autonomous alterations, i.e. enhanced neuroinflammatory response but also loss of excitatory synapses and impaired neuronal mitochondrial function, presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction, as seen in the brain of patients, contributes to amyloid-related pathogenesis and underscores the potential of A2AR as a relevant therapeutic target for mitigating cognitive impairments in this neurodegenerative disorder.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Trastornos de la Memoria , Ratones Transgénicos , Neuronas , Receptor de Adenosina A2A , Sinapsis , Animales , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/genética , Trastornos de la Memoria/patología , Ratones , Receptor de Adenosina A2A/metabolismo , Receptor de Adenosina A2A/genética , Sinapsis/metabolismo , Sinapsis/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Hipocampo/metabolismo , Hipocampo/patología , Presenilina-1/genética , Modelos Animales de Enfermedad , Placa Amiloide/patología , Placa Amiloide/metabolismo , Masculino , Ratones Endogámicos C57BLRESUMEN
PURPOSE: Hydrocephalus is a brain disease prevalent in the pediatric population that presents complex pathophysiology and multiple etiologies. The best treatment is still ventricular shunting. Mechanical obstruction is the most frequent complication, but the resulting pathological effects are still unknown. OBJECTIVE: Evaluation and comparison of clinical, histopathological, and immunohistochemical aspects in the acute phase of experimental hydrocephalus induced by kaolin, after treatment with adapted shunt, and after shunt obstruction and posterior disobstruction. METHODS: Wistar rats aged 7 days were used and divided into 4 groups: control group without kaolin injection (n = 6), untreated hydrocephalic group (n = 5), hydrocephalic group treated with ventriculosubcutaneous shunt (DVSC) (n = 7), and hydrocephalic group treated with shunt, posteriorly obstructed and disobstructed (n = 5). The animals were submitted to memory and spatial learning evaluation through the Morris water maze test. The rats were sacrificed at 28 days of age and histological analysis of the brains was performed with luxol fast blue, in addition to immunohistochemical analysis in order to evaluate reactive astrocytosis, inflammation, neuronal labeling, and apoptotic activity. RESULTS: The group with shunt obstruction had worse performance in memory tests. Reactive astrocytosis was more evident in this group, as was the inflammatory response. CONCLUSIONS: Obstruction of the shunt results in impaired performance of behavioral tests and causes irreversible histopathological changes when compared to findings in the group with treated hydrocephalus, even after unblocking the system. The developed model is feasible and efficient in simulating the clinical context of shunt dysfunction.
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Hidrocefalia , Caolín , Niño , Humanos , Ratas , Animales , Ratas Wistar , Gliosis/patología , Hidrocefalia/cirugía , Encéfalo/patologíaRESUMEN
Due to time zones, sun time and local time rarely match. The difference between local and sun time, which we designate by Solar Jet Lag (SoJL), depends on location within a time zone and can range from zero to several hours. Daylight saving time (DST) simply adds 1 h to SoJL, independently of the location. We hypothesised that the impact of DST is particularly problematic in patients with delayed sleep-wake phase disorder (DSWPD), worsening their sleep debt. DSWPD is characterised by a chronic misalignment between the internal and social timing, reflected by an inability to fall asleep and wake-up at conventional or socially acceptable times. We analysed the clinical records of 162 DSWPD patients from a sleep medicine centre in Lisbon, Portugal (GMTzone), and separated them into two groups: the ones diagnosed across DST or across Standard Time (ST). We included 82 patients (54.9% male; age: median [Q1 , Q3 ] 34.5 [25.0, 45.3]; range 16-92; 54 in DST and 28 in ST) who had Dim Light Melatonin Onset (DLMO) measured as a marker for the circadian phase and sleep timing (onset, SO, mid-point, MS and end, SE) self-reported separately for work- and work-free days. Differences between ST and DST were compared using Mann-Whitney or Student's t-tests. On a weekly average, patients in DST slept less (difference between medians of 37 min. p < .01), mainly due to sleep on workdays (SDw, p < .01), which also correlated with SoJL (rsp = .38, p < .01). While the time from DLMO to SO was similar in those in ST or those in DST, the time from DLMO to SE was significantly shorter for those in DST. The average duration between DLMO and sleep end was close to 10.5 h in ST, the biological night length described in the literature. Our results favour perennial ST and suggest assigning time-zones close to sun time to prevent social jetlag and sleep deprivation.
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Ritmo Circadiano , Melatonina , Humanos , Masculino , Femenino , Sueño , Privación de Sueño , TiempoRESUMEN
In this study, a combination of coagulation/flocculation and Fenton processes was studied as tertiary treatment in order to generate treated water susceptible to reuse. The combination of both processes has never been applied in disinfection of real urban wastewater. The best removals of turbidity and enterobacteria were achieved when applying a coagulant (FeCl3) dosage of 120 mg/L and the natural pH of the effluent (7.14). The following Fenton reaction presented the maximal enterobacteria inactivation after 120 min at 25 °C, when using hydrogen peroxide and added iron concentrations of 100 mg/L and 7 mg/L, respectively. The abundance of antibiotic resistant (amoxicillin and sulfamethoxazole) enterobacteria and total enterobacteria, enterococci, and heterotrophs, and antibiotic resistance genes - ARG - (sul1, blaTEM and qnrS) was evaluated before and after each step of the treatment. Values below 10 CFU/100 mL were achieved for total and resistant cultivable enterobacteria immediately after treatment and after storage for 72 h, therefore meeting the strictest limit imposed for E. coli. Physico-chemical parameters also met the established limits for water reuse. Despite harbouring a rich and diverse bacterial community, the final stored disinfected wastewater contained high relative abundance of potentially hazardous bacteria. Such results point out the need of a deep microbiological characterization of treated wastewater to evaluate the risk of its reuse in irrigation.
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Aguas Residuales , Purificación del Agua , Desinfección/métodos , Escherichia coli , Floculación , Oxidación-Reducción , Bacterias , Enterobacteriaceae , Peróxido de Hidrógeno/química , Agua , Purificación del Agua/métodos , Eliminación de Residuos Líquidos/métodosRESUMEN
Background and objective: Age estimation is an important tool when dealing with human remains or undocumented minors. Although the skull, the skeleton or the hand-wrist are used in age estimation as maturity indicators, they often present a lack of good conditions for a correct identification or estimation. Few systematic reviews (SRs) have been recently published; therefore, this umbrella review critically assesses their level of evidence and provides a general, comprehensive view. Materials and methods: Considering the review question "What is the current evidence on age determination approaches in Forensic Dentistry?" an electronic database search was conducted in four databases (PubMed, Cochrane, WoS, LILACS) up to December 2022, focusing on SRs of age estimation through forensic dentistry procedures. The methodological quality was analyzed using the measurement tool to assess SRs criteria (AMSTAR2). Results: Eighteen SRs were included: five of critically low quality, six of low quality, three of moderate quality and four of high quality. The SRs posited that Willems' method is more accurate and less prone to overestimation; most methods seem to be geographically sensitive; and 3D-imaging and artificial intelligence tools demonstrate high potential. Conclusions: The quality of evidence on age estimation using dental approaches was rated as low to moderate. Well-designed clinical trials and high-standard systematic reviews are essential to corroborate the accuracy of the different procedures for age estimation in forensic dentistry.
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Inteligencia Artificial , Odontología Forense , Humanos , Bases de Datos Factuales , PubMed , RadiofármacosRESUMEN
Alzheimer's disease (AD) is the most common form of dementia, which is neuropathologically characterized by extracellular senile plaques containing amyloid-ß and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Previous studies have suggested a role for septin (SEPTIN) protein family members in AD-associated cellular processes. Here, we elucidated the potential role of presynaptic SEPTIN5 protein and its post-translational modifications in the molecular pathogenesis of AD. RNA and protein levels of SEPTIN5 showed a significant decrease in human temporal cortex in relation to the increasing degree of AD-related neurofibrillary pathology. Conversely, an increase in the phosphorylation of the functionally relevant SEPTIN5 phosphorylation site S327 was observed already in the early phases of AD-related neurofibrillary pathology, but not in the cerebrospinal fluid of individuals fulfilling the criteria for mild cognitive impairment due to AD. According to the mechanistic assessments, a link between SEPTIN5 S327 phosphorylation status and the effects of SEPTIN5 on amyloid precursor protein processing and markers of autophagy was discovered in mouse primary cortical neurons transduced with lentiviral constructs encoding wild type SEPTIN5 or SEPTIN5 phosphomutants (S327A and S327D). C57BL/6 J mice intrahippocampally injected with lentiviral wild type SEPTIN5 or phosphomutant constructs did not show changes in cognitive performance after five to six weeks from the start of injections. However, SEPTIN5 S327 phosphorylation status was linked to changes in short-term synaptic plasticity ex vivo at the CA3-CA1 synapse. Collectively, these data suggest that SEPTIN5 and its S327 phosphorylation status play a pivotal role in several cellular processes relevant for AD.
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Hipocampo/metabolismo , Ovillos Neurofibrilares/metabolismo , Septinas/metabolismo , Sinapsis/metabolismo , Animales , Autofagia/fisiología , Modelos Animales de Enfermedad , Hipocampo/patología , Humanos , Ratones , Ovillos Neurofibrilares/patología , Neuronas/metabolismo , Neuronas/patología , Fosforilación , Sinapsis/patologíaRESUMEN
AIM: Molar incisor hypomineralization (MIH) is a prevalent oral health condition whose knowledge by dentists is key to the best clinical outcome. This study aimed to evaluate the knowledge, perceptions and clinical experiences of MIH among Portuguese dentists. METHODS: A cross-sectional structured questionnaire was distributed nationally through a web-based survey platform. Data concerning demographic variables, years of experience, dental specialty, MIH prevalence, diagnosis, severity, training demands and clinical management of MIH were collected. We calculated a knowledge score (KS), and compared data between Pediatric Dentists (PDs), General Dental Practitioners (GDPs) and other dental specialties (ODS). RESULTS: Overall, 2.2% of Portuguese dentists (n = 257) answered the questionnaire. Most participants reported having identified MIH in their practice (82.5%), with PD reporting the prevalence appeared to have increased, and practically all (91.7%) considered it a public health problem. Resin composite was often the used material to restore MIH teeth (56.0%), however PDs indicated glass ionomer cements as the preferred and preformed crowns a better option. The average KS on MIH was 41.3 (± 5.7), with GDPs having a similar score than PDs. Most respondents (94.9%) reported a lack of information about MIH and were willing to receive appropriate clinical training. CONCLUSIONS: The average knowledge on MIH was considered low among Portuguese dentists. Respondents perceived an increased incidence of MIH, despite the lack of prevalence data in Portugal. The material of choice was Glass Ionomer and performed crowns, by PDs, while GDPs and ODS reported poor confidence to manage MIH. These results may serve future programs to increase knowledge, perceptions and clinical experiences towards MIH.
Asunto(s)
Hipoplasia del Esmalte Dental , Odontólogos , Niño , Estudios Transversales , Hipoplasia del Esmalte Dental/diagnóstico , Hipoplasia del Esmalte Dental/epidemiología , Hipoplasia del Esmalte Dental/terapia , Humanos , Diente Molar , Percepción , Portugal/epidemiología , Prevalencia , Rol ProfesionalRESUMEN
Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca2+ influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.
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Envejecimiento/metabolismo , Depresión Sináptica a Largo Plazo , Neuronas/metabolismo , Receptor de Adenosina A2A/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Adenosina/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Células Cultivadas , Hipocampo/metabolismo , Humanos , Ratones , Ratas , Ratas Sprague-Dawley , Memoria EspacialRESUMEN
OBJECTIVE: In recent years, Molar Incisor Hypomineralization (MIH) has become a subject that concerns the Paediatric Dentistry Community. The aim of the present umbrella review was to analyse previously published systematic reviews (SRs) on MIH in children and adolescents. METHODS: Electronic database search was conducted (including PubMed, Embase, Scopus, Cochrane, Web of Science, and LILACS) until July 2020. Studies were included, if they were SR on MIH in children and adolescents. The methodological quality of SRs was judged by use of the MeaSurement Tool to Assess systematic Reviews 2. The primary outcomes included prevalence, aetiology, and clinical management of MIH. Data extraction and methodological quality assessment were performed. RESULTS: Eighteen systematic reviews were included for data extraction. Among these, two were focussing on prevalence, five addressed aetiology, one highlighted the mechanical and chemical characteristics of enamel in MIH, one underlined the association between MIH and dental caries, six addressed the treatment, and one focussed on hypomineralization of primary teeth as a predictor of MIH. The results showed a high worldwide prevalence of MIH and an unknown aetiology of MIH, but reporting that the aetiology is most likely multifactorial. Different treatment approaches used were desensitizing and remineralizing products, resin infiltration, fissure sealant, atraumatic restorative treatment, resin composite restoration, and stainless steel crown (SSC), but also extraction associated with orthodontic treatment of the permanent first molars (PFMs) was reported on. The AMSTAR criteria 2 was applied, where six studies were assessed as having critically low quality, two studies as having low quality, and nine studies as having moderate quality. CONCLUSIONS: MIH is highly prevalent worldwide and has most likely a multifactorial aetiology. Different treatment approaches according to the degree of severity of lesion(s) are reported on. The quality of evidence produced by the available SRs was not favourable. More well-designed clinical trials and high standard systematic reviews are necessary to elucidate better MIH characteristics and treatment outcomes.
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Tratamiento Restaurativo Atraumático Dental , Caries Dental , Hipoplasia del Esmalte Dental , Adolescente , Niño , Hipoplasia del Esmalte Dental/diagnóstico , Hipoplasia del Esmalte Dental/epidemiología , Hipoplasia del Esmalte Dental/terapia , Humanos , Incisivo , Diente Molar , PrevalenciaRESUMEN
Accumulating data support the role of tau pathology in cognitive decline in ageing and Alzheimer's disease, but underlying mechanisms remain ill-defined. Interestingly, ageing and Alzheimer's disease have been associated with an abnormal upregulation of adenosine A2A receptor (A2AR), a fine tuner of synaptic plasticity. However, the link between A2AR signalling and tau pathology has remained largely unexplored. In the present study, we report for the first time a significant upregulation of A2AR in patients suffering from frontotemporal lobar degeneration with the MAPT P301L mutation. To model these alterations, we induced neuronal A2AR upregulation in a tauopathy mouse model (THY-Tau22) using a new conditional strain allowing forebrain overexpression of the receptor. We found that neuronal A2AR upregulation increases tau hyperphosphorylation, potentiating the onset of tau-induced memory deficits. This detrimental effect was linked to a singular microglial signature as revealed by RNA sequencing analysis. In particular, we found that A2AR overexpression in THY-Tau22 mice led to the hippocampal upregulation of C1q complement protein-also observed in patients with frontotemporal lobar degeneration-and correlated with the loss of glutamatergic synapses, likely underlying the observed memory deficits. These data reveal a key impact of overactive neuronal A2AR in the onset of synaptic loss in tauopathies, paving the way for new therapeutic approaches.
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Complemento C1q/metabolismo , Neuronas/metabolismo , Receptor de Adenosina A2A/genética , Receptor de Adenosina A2A/metabolismo , Sinapsis/patología , Tauopatías/genética , Tauopatías/patología , Animales , Autopsia , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Trastornos de la Memoria/etiología , Trastornos de la Memoria/psicología , Ratones , Ratones Transgénicos , Mutación , Aprendizaje Espacial , Tauopatías/psicología , Proteínas tau/genéticaRESUMEN
Avulsion is one of the most serious dental traumatic injuries with a reserved prognosis. This case report describes multiple trauma lesions in permanent central incisors of an eight-year-old girl and a four-year follow-up. The right upper incisor suffered avulsion, remained 16 h extraorally, and was replanted after extraoral endodontic therapy. The left maxillary central incisor suffered a noncomplicated crown fracture with concomitant subluxation. The present case adds to the literature a rare occurrence of success in a severe case with poor prognosis. For this reason, the International Association for Dental Traumatology (IADT) guidelines should be followed and, even in extreme situations, replantation should always be considered.
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Avulsión de Diente , Fracturas de los Dientes , Niño , Femenino , Estudios de Seguimiento , Humanos , Incisivo/cirugía , Avulsión de Diente/complicaciones , Avulsión de Diente/cirugía , Fracturas de los Dientes/cirugía , Reimplante DentalRESUMEN
Parkinson's disease and other synucleinopathies are characterized by the accumulation of aggregated α-synuclein in intracellular proteinaceous inclusions. The progressive nature of synucleinopathies seems to be related to the cell-to-cell spreading of α-synuclein pathology, and several possible mechanisms have been put forward to explain this phenomenon. In our recent study, we found that α-synuclein oligomers interact with cellular prion protein in glutamatergic synapses. This interaction triggered a signaling cascade involving phosphorylation of Fyn kinase and activation of the N-methyl-d-aspartate receptor, thereby leading to synaptic dysfunction. Here, we present relevant plasma membrane proteins that have been described to interact with α-synuclein and discuss the possible pathological implications. We focus primarily on the prion protein and propose a pathological mechanism in which the interaction between α-synuclein and prion protein leads to the formation of cofilin/actin rods, culminating in long-term potentiation impairment and cognitive dysfunction. We posit that deciphering the mechanisms involved in sensing specific forms of extracellular α-synuclein and transducing this information may prove invaluable in our quest to devise novel diagnostic and therapeutic approaches in PD and other synucleinopathies. © 2018 International Parkinson and Movement Disorder Society.
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Encéfalo/patología , Enfermedades Neurodegenerativas/patología , Proteínas Priónicas/metabolismo , Sinapsis/metabolismo , alfa-Sinucleína/metabolismo , Animales , Encéfalo/metabolismo , Trastornos del Conocimiento/etiología , Humanos , Modelos Biológicos , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/metabolismo , Transducción de Señal , Sinapsis/patologíaRESUMEN
α-Synuclein misfolding and aggregation is a hallmark in Parkinson's disease and in several other neurodegenerative diseases known as synucleinopathies. The toxic properties of α-synuclein are conserved from yeast to man, but the precise underpinnings of the cellular pathologies associated are still elusive, complicating the development of effective therapeutic strategies. Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced α-synuclein toxicity in vitro and in vivo, in Drosophila and in mice. Glycation affected primarily the N-terminal region of α-synuclein, reducing membrane binding, impaired the clearance of α-synuclein, and promoted the accumulation of toxic oligomers that impaired neuronal synaptic transmission. Strikingly, using glycation inhibitors, we demonstrated that normal clearance of α-synuclein was re-established, aggregation was reduced, and motor phenotypes in Drosophila were alleviated. Altogether, our study demonstrates glycation constitutes a novel drug target that can be explored in synucleinopathies as well as in other neurodegenerative conditions.
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Enfermedades Neurodegenerativas/metabolismo , Agregación Patológica de Proteínas/metabolismo , alfa-Sinucleína/metabolismo , alfa-Sinucleína/toxicidad , Envejecimiento/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Modelos Animales de Enfermedad , Drosophila , Inhibidores Enzimáticos/farmacología , Femenino , Glicosilación/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/fisiología , Masculino , Ratones , Ratones Transgénicos , Procesamiento Proteico-Postraduccional , Piruvaldehído/farmacología , Ratas , Levaduras/efectos de los fármacos , Levaduras/fisiología , alfa-Sinucleína/efectos de los fármacos , alfa-Sinucleína/fisiologíaRESUMEN
Abnormal accumulation of aggregated α-synuclein (aSyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and related synucleinopathies. Recent studies suggest a neuroprotective role of adenosine A2A receptor (A2AR) antagonists in PD. Nevertheless, the precise molecular mechanisms underlying this neuroprotection remain unclear. We assessed the impact of A2AR blockade or genetic deletion (A2AR KO) on synaptic plasticity and neuronal cell death induced by aSyn oligomers. We found that impairment of LTP associated with aSyn exposure was rescued in A2AR KO mice or upon A2AR blockade, through an NMDA receptor-dependent mechanism. The mechanisms underlying these effects were evaluated in SH-SY5Y cells overexpressing aSyn and rat primary neuronal cultures exposed to aSyn. Cell death in both conditions was prevented by selective A2AR antagonists. Interestingly, blockade of these receptors did not interfere with aSyn oligomerization but, instead, reduced the percentage of cells displaying aSyn inclusions. Altogether, our data raise the possibility that the well-documented effects of A2AR antagonists involve the control of the latter stages of aSyn aggregation, thereby preventing the associated neurotoxicity. These findings suggest that A2AR represent an important target for the development of effective drugs for the treatment of PD and related synucleinopathies.
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Neuronas/metabolismo , Receptor de Adenosina A2A/metabolismo , alfa-Sinucleína/metabolismo , Antagonistas del Receptor de Adenosina A2/toxicidad , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Línea Celular Tumoral , Potenciales Postsinápticos Excitadores , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/patología , Ratas Wistar , Receptor de Adenosina A2A/genética , Proteínas Recombinantes/metabolismo , Técnicas de Cultivo de Tejidos , alfa-Sinucleína/genéticaRESUMEN
The development of adenosine A2A receptor antagonists has received much interest in recent years for the treatment of neurodegenerative diseases. Based on docking studies, a new series of 2-arylbenzoxazoles has been identified as potential A2AR antagonists. Structure-affinity relationship was investigated in position 2, 5 and 6 of the benzoxazole heterocycle leading to compounds with a micromolar affinity towards the A2A receptor. Compound F1, with an affinity of 1 µm, presented good absorption, distribution, metabolism and excretion properties with an excellent aqueous solubility (184 µm) without being cytotoxic at 100 µm. This compound, along with low-molecular weight compound D1 (Ki = 10 µm), can be easily modulated and thus considered as relevant starting points for further hit-to-lead optimisation.
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Antagonistas del Receptor de Adenosina A2/farmacología , Benzoxazoles/farmacología , Diseño de Fármacos , Receptor de Adenosina A2A/metabolismo , Antagonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A2/química , Benzoxazoles/síntesis química , Benzoxazoles/química , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Modelos Moleculares , Estructura Molecular , Solubilidad , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
AD (Alzheimer's disease) is the most prevalent form of dementia in the aged population. Definitive diagnosis of AD is based on the presence of senile plaques and neurofibrillary tangles that are identified in post-mortem brain specimens. A third pathological component is inflammation. AD results from multiple genetic and environmental risk factors. Among other factors, epidemiological studies report beneficial effects of caffeine, a non-selective antagonist of adenosine receptors. In the present review, we discuss the impact of caffeine and the adenosinergic system in AD pathology as well as consequences in terms of pathology and therapeutics.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Cafeína/uso terapéutico , Antagonistas de Receptores Purinérgicos P1/uso terapéutico , Animales , Humanos , Receptores Purinérgicos P1/metabolismoRESUMEN
Sedation is a depression of a patient's state of consciousness, induced by medications, that can reach different levels of intensity during a medical procedure. Conscious sedation produces a minimally depressed level of consciousness without impairment of the ability to maintain an open airway, of protective reflexes or of responses to verbal and physical stimulation. This umbrella review is aimed at critically assessing the available systematic reviews (SRs) and meta-analyses (MA) on sedation in children/adolescents. An electronic database search was conducted that included Pubmed-Medline, Web of Science, Cochrane, Scopus, Scielo, Embase, LILACS and TRIP and the scope of which extended until January 2023. The risk of bias (RoB) of SRs was analyzed using the Measurement Tool to Assess SRs criteria 2 (AMSTAR2). Of 998 entries, 37 SRs were included. In terms of methodological quality, eight studies were assessed as having critically low quality, four studies had low quality, nine studies had moderate quality, and sixteen were considered to be of high quality. Based on the current guidelines, the most employed drugs in pediatric dentistry for sedation are nitrous oxide and midazolam; however, the available evidence supporting their use is insufficient and of low/critically low quality. The combined technique is recommended (nitrous oxide (30-50%) + midazolam). The optimal dose of oral midazolam is 0.75 mg/kg. The level of methodological quality of SRs is expected to increase according to the results and future directions of this umbrella review.
RESUMEN
Polyalcohol liquefaction can be performed by acid or base catalysis, producing polyols with different properties. This study compared the mechanical properties of foams produced using polyols from liquefied Cytisus scoparius obtained by acid and base catalysis and using two different foam catalysts. The differences were monitored using FTIR analysis. Acid-catalyzed liquefaction yielded 95.1%, with the resultant polyol having an OH index of 1081 mg KOH/g, while base catalysis yielded 82.5%, with a similar OH index of 1070 mg KOH/g. Generally, compressive strength with dibutyltin dilaurate (DBTDL) ranged from 16 to 31 kPa (acid-liquefied polyol) and 12 to 21 kPa (base-liquefied polyol), while with stannous octoate (TIN), it ranged from 17 to 42 kPa (acid) and 29 to 68 kPa (base). Increasing water content generally decreased the compressive modulus and strength of the foams. Higher water content led to a higher absorption at 1670 cm-1 in the FTIR spectrum due to the formation of urea. Higher isocyanate indices generally improved compressive strength, but high amounts led to unreacted isocyanate that could be seen by a higher absorption at 2265 cm-1 and 3290 cm-1. DBTL was shown to be the best foam catalyst due to higher trimer conversion seen in the spectra by a higher absorption at 1410 cm-1. Acid- and base-derived polyols lead to different polyurethane foams with different FTIR spectra, particularly with a higher absorption at 1670 cm-1 for foams from acid-derived liquefaction.
RESUMEN
Hazelnut shells (HS), scientifically known as Corylus avellana L. shells, are waste produced by companies that process nuts. The main objective of this study was to find an efficient way to maximize the chemical potential of HS by solubilizing the hemicelluloses, which could then be used to recover sugars and, at the same time, increase the lignin content of this material to produce adhesives or high-strength foams. In order to optimize the pre-hydrolysis process, two different temperatures (160 and 170 °C) and times varying from 15 to 180 min were tested. All the remaining solid materials were then liquefied using polyalcohols with acid catalysis. The chemical composition of hazelnut shells was determined before and after the pre-hydrolysis. All of the process was monitored using Fourier Transform Infrared Spectroscopy with Attenuated Total Reflectance (FTIR-ATR) by determining the spectra of solids and liquids after the pre-hydrolysis and liquefaction steps. The highest solubilization of hazelnut shells was found for 170 °C and 180 min, resulting in a 25.8% solubilization. Chemical analysis after the hydrolysis process showed a gradual increase in the solubilization of hemicelluloses as both the temperature and time of the reactor were increased. Simultaneously, the percentages of α-cellulose and lignin in the material also increased with rises in temperature and duration. FTIR-ATR allowed for the detection of significant spectral changes in the hazelnut shells from their initial state to the solid residue and further into the liquefied phase. This confirmed that pre-hydrolysis was effective in enhancing the chemical composition of the material, making it more suitable for the production of adhesives, polyurethane foams, or in the production of bioplastics and composite materials, combined with other biopolymers or synthetic polymers to enhance the mechanical properties and biodegradability of the resulting materials.