Investigação dos efeitos de oligômeros β-amiloide no metabolismo energético cerebral e potencial efeito neuroprotetor da guanosina em camundongos

A Doença de Alzheimer (DA) tem grande impacto na qualidade de vida das pessoas com a doença e na vida dos familiares por ser uma das doenças neurodegenerativas mais prevalentes, de curso crônico e com prejuízo cognitivo progressivo. Ainda não há tratamento capaz de impedir ou reverter a progressão da DA e a severidade dos sintomas vai aumentando com o tempo, causando importante perda cognitiva, funcional e comportamental nas fases mais avançadas. Nesses estágios mais críticos da doença, há grande necessidade de auxílio de outras pessoas para as atividades da vida diária, maior risco de acidentes e maior frequência de internações hospitalares. Os oligômeros β-amiloide (AβOs) têm grande potencial tóxico e estão envolvidos no dano e morte neuronal em fase que precede a formação das placas amiloide, uma vez que os oligômeros se difundem facilmente pelo cérebro e são capazes de se ligar a receptores e a membranas lipídicas alterando suas funções. Além disso, estudos vem indicando que ocorre falha energética no cérebro de pessoas com DA e essa também pode ser uma das vias pelas quais a doença se inicia e progride. Nesse contexto, ocorre produção ineficiente de ATP e alterações mitocondriais que culminam em um ciclo de deterioração celular: aumento da fosforilação oxidativa para suprir a necessidade energética, com consequente formação de mais espécies reativas, e dano a moléculas e estruturas celulares que agravam intensamente a capacidade de produzir ATP. Por esse ciclo, ocorre disfunção sináptica, redução das espinhas dendríticas e morte neuronal. Neste trabalho, utilizamos um modelo de DA, induzido com AβOs, e avaliamos a memória de curto prazo. Como estratégia terapêutica, utilizamos a Guanosina, um nucleosídeo purinérgico que interage com o sistema glutamatérgico, evitando a excitotoxicidade presente em situações patológicas. A hipótese deste estudo é verificar: i) a contribuição da administração in vivo (via injeção ICV) de oligômeros beta-amiloide nas alterações energéticas, por meio de avaliação mitocondrial e ii) se a administração in vivo (via gavagem) da Guanosina tem efeito neuroprotetor nesse contexto. Os resultados mostram que os AβOs causam déficit de memória de curto prazo na tarefa de reconhecimento de objetos após 24 horas da administração e a GUO recupera o déficit causado pelos AβOs. Em 48h, os AβOs reduziram a captação e oxidação de glutamato em fatias de hipocampo, e reduziram as defesas antioxidantes, sem aumentar o dano oxidativo. Não houve alterações significativas de expressão de genes e de conteúdo de proteínas relacionadas a metabolismo bioenergético cerebral, dinâmica mitocondrial, e membrana sináptica. A GUO recuperou a captação de glutamato, sem alterar a oxidação e apresentou proteção antioxidante. Na avaliação das funções mitocondriais na pré-sinapse (utilizando sinaptossoma e/ou mitocôndria sinaptossomal isolada), os AβOs reduziram a capacidade respiratória reserva e os níveis de ATP, aumentaram a produção de peróxido de hidrogênio, desregularam o tamponamento de Ca2+ e modificaram a morfologia mitocondrial. Enquanto isso, a GUO recuperou a homeostase do Ca2+ e reduziu a proporção de mitocôndrias danificadas. Assim, compreendemos que a GUO apresenta efeito protetor no metabolismo do hipocampo e na atividade mitocondrial, impedindo a deterioração induzida pelos AβOs em funções essenciais para o funcionamento da pré-sinapse hipocampal, incluindo processos de aprendizado e memória.Alzheimer's disease (AD) has a significant impact on people’s quality of life of with the disease and on the lives of family members as it is one of the most prevalent neurodegenerative diseases, with a chronic course and with progressive cognitive impairment. There is still no treatment able to prevent or reverse the AD’s progression, and the severity of symptoms increases over time, causing a critical cognitive, functional, and behavioral loss in the most advanced stages. In these more critical phases of the disease, there is an increased demand for help from others for the daily living activities, increased risk of accidents, and higher frequency of hospital admissions. Amyloid-β oligomers (AβOs) have high toxic potential and are involved in neuronal damage and death in the phase that precedes the formation of amyloid plaques since oligomers easily diffuse through the brain and can bind to receptors and lipid membranes, changing their functions. Also, studies have indicated that energy failure occurs in the brain of people with AD and this can also be one of the mechanisms through which the disease starts and progresses. In this context, there is inefficient production of ATP and mitochondrial changes that culminate in a cycle of cellular deterioration: increased phosphorylative activity to supply the energy need, with the consequent formation of more reactive species, and damage to molecules and cellular structures that aggravate more intensely the ability to produce ATP. Through this cycle, synaptic dysfunction, reduction of dendritic spines and neuronal death occur. In this work, we used an AD model, induced with AβOs, and evaluated short-term memory. As a therapeutic strategy, we used Guanosine, a purinergic nucleoside that interacts with the glutamatergic system, avoiding the excitotoxicity present in pathological situations. The hypothesis in this study is to verify: i) the contribution of in vivo administration of β-amyloid oligomers (via ICV injection) in energy changes, through mitochondrial evaluation and ii) if the in vivo administration of Guanosine (via gavage) has a neuroprotective effect in this context. The results show that AβOs cause short-term memory deficits in the object recognition task in 24 h, and GUO recovers the deficit caused by AβOs. After 48 h AβOs reduced glutamate uptake and oxidation in hippocampus slices, and reduced antioxidant defenses, without increasing oxidative damage. There were no significant changes in gene expression, protein content to brain bioenergetic metabolism, mitochondrial dynamics, and synaptic membrane. GUO recovered glutamate uptake without changing oxidation and provided antioxidant protection. In the assessment of mitochondrial functions in the pre-synapse (using synaptosome preparation or isolated mitochondria from synaptosome), AβOs reduced the spare respiratory capacity and ATP levels, increased hydrogen peroxide production, deregulated Ca2+ buffering, and led to changes in mitochondrial morphology. Meanwhile, GUO recovered Ca2+ homeostasis and reduced the ratio of damaged mitochondria. Thus, we understand that GUO has a protective effect on the hippocampus metabolism and mitochondrial activity, preventing the deterioration of essential functions for the functioning of the hippocampal pre-synapse, including learning and memory processes

Multidrug-resistant tuberculous orchiepididymitis: a brief case report

Tuberculosis (TB) is one of the leading causes of death by infectious diseases worldwide. Multidrug-resistant tuberculosis is a growing problem, especially in countries with high TB prevalence. Although the lungs are the organs most frequently affected by this disease, Mycobacterium tuberculosis can harm any organ, including the urogenital tract, causing extrapulmonary tuberculosis, which leads to a challenging diagnosis and consequent treatment delays. In this article, we present a case of orchiepididymitis caused by multidrug-resistant TB (MDR-TB) with a significantly delayed diagnosis, the proposed treatment according to the resistance profile, and the clinical outcomes

Septic shock, hyperferritinemic syndrome, and multiple organ dysfunction without respiratory failure in a patient with disseminated histoplasmosis and advanced HIV disease

AIDS-related disseminated histoplasmosis (DH) can cause septic shock and multiorgan dysfunction with mortality rates of up to 80%. A 41-year-old male presented with fever, fatigue, weight loss, disseminated skin lesions, low urine output, and mental confusion. Three weeks before admission, the patient was diagnosed with HIV infection, but antiretroviral therapy (ART) was not initiated. On day 1 of admission, sepsis with multiorgan dysfunction (acute renal failure, metabolic acidosis, hepatic failure, and coagulopathy) was identified. A chest computed tomography showed unspecific findings. Yeasts suggestive of Histoplasma spp. were observed in a routine peripheral blood smear. On day 2, the patient was transferred to the ICU, where his clinical condition progressed with reduced level of consciousness, hyperferritinemia, and refractory septic shock, requiring high doses of vasopressors, corticosteroids, mechanical ventilation, and hemodialysis. Amphotericin B deoxycholate was initiated. On day 3, yeasts suggestive of Histoplasma spp. were observed in the bone marrow. On day 10, ART was initiated. On day 28, samples of peripheral blood and bone marrow cultures revealed Histoplasma spp. The patient stayed in the ICU for 32 days, completing three weeks of intravenous antifungal therapy. After progressive clinical and laboratory improvement, the patient was discharged from the hospital on oral itraconazole, trimethoprim-sulfamethoxazole, and ART. This case highlights the inclusion of DH in the differential diagnosis of patients with advanced HIV disease, septic shock and multiorgan dysfunction but without respiratory failure. In addition, it provides early in-hospital diagnosis and treatment and comprehensive management in the ICU as determining factors for a good outcome

Septic shock, hyperferritinemic syndrome, and multiple organ dysfunction without respiratory failure in a patient with disseminated histoplasmosis and advanced HIV disease

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Cerebral ketone body oxidation is facilitated by a high fat diet enriched with advanced glycation end products in normal and diabetic rats

Diabetesmellitus(DM)causesimportantmodificationsintheavailabilityanduseofdifferentenergysubstratesinvariousorgansandtissues.Similarly,dietarymanipulationssuchashighfatdietsalsoaffectsystemicenergymetabolism.However,howthebrainadaptstothesesituationsremainsunclear.Toinvestigatetheseissues,controlandalloxan-inducedtypeIdiabeticratswerefedeitherastandardorahighfatdietenrichedwithadvancedglycationendproducts(AGEs)(HAGEdiet).TheHAGEdietincreasedtheirlevelsofbloodketonebodies,andthiseffectwasexacerbatedbyDMinduction.Todeterminetheeffectsofdietand/orDMinductiononkeycerebralbioenergeticparameters,bothketonebodies(b-hydroxybutyricacid)andlactateoxidationweremeasured.Inparallel,theexpressionofMonocarboxylateTransporter1(MCT1)and2(MCT2)isoformsinhippocampalandcorticalslicesfromratssubmittedtothesedietswasassessed.KetonebodyoxidationincreasedwhilelactateoxidationdecreasedinhippocampalandcorticalslicesinbothcontrolanddiabeticratsfedaHAGEdiet.Inparallel,theexpressionofbothMCT1andMCT2increasedonlyinthecerebralcortexindiabeticratsfedaHAGEdiet.TheseresultssuggestashiftinthepreferentialcerebralenergysubstrateutilizationinfavorofketonebodiesinanimalsfedaHAGEdiet,aneffectthat,inDManimals,isaccompaniedbytheenhancedexpressionoftherelatedtransporters

Cerebral Ketone Body Oxidation Is Facilitated by a High Fat Diet Enriched with Advanced Glycation End Products in Normal and Diabetic Rats.

Diabetes mellitus (DM) causes important modifications in the availability and use of different energy substrates in various organs and tissues. Similarly, dietary manipulations such as high fat diets also affect systemic energy metabolism. However, how the brain adapts to these situations remains unclear. To investigate these issues, control and alloxan-induced type I diabetic rats were fed either a standard or a high fat diet enriched with advanced glycation end products (AGEs) (HAGE diet). The HAGE diet increased their levels of blood ketone bodies, and this effect was exacerbated by DM induction. To determine the effects of diet and/or DM induction on key cerebral bioenergetic parameters, both ketone bodies (β-hydroxybutyric acid) and lactate oxidation were measured. In parallel, the expression of Monocarboxylate Transporter 1 (MCT1) and 2 (MCT2) isoforms in hippocampal and cortical slices from rats submitted to these diets was assessed. Ketone body oxidation increased while lactate oxidation decreased in hippocampal and cortical slices in both control and diabetic rats fed a HAGE diet. In parallel, the expression of both MCT1 and MCT2 increased only in the cerebral cortex in diabetic rats fed a HAGE diet. These results suggest a shift in the preferential cerebral energy substrate utilization in favor of ketone bodies in animals fed a HAGE diet, an effect that, in DM animals, is accompanied by the enhanced expression of the related transporters