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Abstract Background It is well established that vaccination of humans and transgenic animals against fibrillar Aβ prevents amyloid accumulation in plaques and preserves cognitive function in transgenic mouse models. However, autoimmune side effects have halted the development of vaccines based on full length human Aβ. Further development of an effective vaccine depends on overcoming these side effects while maintaining an effective immune response. Results We have previously reported that the immune response to amyloid oligomers is largely directed against generic epitopes that are common to amyloid oligomers of many different proteins and independent of a specific amino acid sequence. Here we have examined whether we can exploit this generic immune response to develop a vaccine that targets amyloid oligomers using a non-human random sequence amyloid oligomer. In order to study the effect of vaccination against generic oligomer epitopes, a random sequence oligomer (3A) was selected as it forms oligomers that react with the oligomer specific A11 antibody. Oligomer mimics from 3A peptide, Aβ, islet amyloid polypeptide (IAPP), and Aβ fibrils were used to vaccinate Tg2576 mice, which develop a progressive accumulation of plaques and cognitive impairment. Vaccination with the 3A random sequence antigen was just as effective as vaccination with the other antigens in improving cognitive function and reducing total plaque load (Aβ burden) in the Tg2576 mouse brains, but was associated with a much lower incidence of micro hemorrhage than Aβ antigens. Conclusion These results shows that the amyloid Aβ sequence is not necessary to produce a protective immune response that specifically targets generic amyloid oligomers. Using a non-human, random sequence antigen may facilitate the development of a vaccine that avoids autoimmune side effects.

Diabetes is a metabolic disease with a high worldwide prevalence and an important factor in mortality and disability in the population. Complications can be reduced or prevented with lifestyle changes in physical activity, dietary habits, and smoking cessation. High-protein diets (HPDs, >30% or >1.0 g/Kg/day) decrease hyperglycemia in part due to their content of branched-chain amino acids (BCAAs), mainly leucine. Leucine (and other BCAAs) improve glucose metabolism by directly signaling in the medio-basal hypothalamus (MBH), increasing liver insulin sensitivity. To determine the effectiveness of an HPD to lower hyperglycemia, we analyzed the results of published clinical studies focusing on the levels of fasting plasma glucose and/or glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM). We carried out a systematic search for clinical studies using HPDs. We searched five databases (Scopus, Web of Science, PubMed, Epistemonikos, and Cochrane), collecting 179 articles and finally selecting 8 articles to analyze their results. In conclusion, HPDs are an effective alternative to reduce hyperglycemia in patients with T2DM, especially so-called Paleolithic diets, due to their higher-quality protein from animal and vegetal sources and their exclusion of grains, dairy products, salt, refined fats, and added sugars.

Background: Morin is a flavonoid found in many edible fruits. The hippocampus and entorhinal cortex play crucial roles in memory formation and consolidation. This study aimed to characterize the effect of morin on recognition and space memory in healthy C57BL/6 adult mice and explore the underlying molecular mechanism., Methods: Morin was administered i.p. at 1, 2.5, and 5 mg/kg/24 h for 10 days. The Morris water maze (MWM), novel object recognition, novel context recognition, and tasks were conducted 1 day after the last administration. The mice's brains underwent histological characterization, and their protein expression was examined using immunohistochemistry and Western blot techniques., Results: In the MWM and novel object recognition tests, mice treated with 1 mg/kg of morin exhibited a significant recognition index increase compared to the control group. Besides, they demonstrated faster memory acquisition during MWM training. Additionally, the expression of pro-brain-derived neurotrophic factor (BDNF), BDNF, and postsynaptic density protein 95 proteins in the hippocampus of treated mice showed a significant increase. In the entorhinal cortex, only the pro-BDNF increased. Morin-treated mice exhibited a significant increase in the hippocampus's number and length of dendrites., Conclusion: This study shows that morin improves recognition memory and spatial memory in healthy adult mice., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Aging reduces homeostasis and contributes to increasing the risk of brain diseases and death. Some of the principal characteristics are chronic and low-grade inflammation, a general increase in the secretion of proinflammatory cytokines, and inflammatory markers. Aging-related diseases include focal ischemic stroke and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Flavonoids are the most common class of polyphenols and are abundantly found in plant-based foods and beverages. A small group of individual flavonoid molecules (e.g., quercetin, epigallocatechin-3-gallate, and myricetin) has been used to explore the anti-inflammatory effect in vitro studies and in animal models of focal ischemic stroke and AD and PD, and the results show that these molecules reduce the activated neuroglia and several proinflammatory cytokines, and also, inactivate inflammation and inflammasome-related transcription factors. However, the evidence from human studies has been limited. In this review article, we highlight the evidence that individual natural molecules can modulate neuroinflammation in diverse studies from in vitro to animal models to clinical studies of focal ischemic stroke and AD and PD, and we discuss future areas of research that can help researchers to develop new therapeutic agents.

A sedentary lifestyle and excessive nutrient intake resulting from the consumption of high-fat and calorie-rich diets are environmental factors contributing to the rapid growth of the current pandemic of type 2 diabetes mellitus (DM2). Fasting hyperglycemia, an established hallmark of DM2, is caused by excessive production of glucose by the liver, resulting in the inability of insulin to suppress endogenous glucose production. To prevent inappropriate elevations of circulating glucose resulting from changes in nutrient availability, mammals rely on complex mechanisms for continuously detecting these changes and to respond to them with metabolic adaptations designed to modulate glucose output. The mediobasal hypothalamus (MBH) is the key center where nutritional cues are detected and appropriate modulatory responses are integrated. However, certain environmental factors may have a negative impact on these adaptive responses. For example, consumption of a diet enriched in saturated fat in rodents resulted in the development of a metabolic defect that attenuated these nutrient sensing mechanisms, rendering the animals prone to developing hyperglycemia. Thus, high-fat feeding leads to a state of "metabolic disability" in which animals' glucoregulatory responses fail. We postulate that the chronic faltering of the hypothalamic glucoregulatory mechanisms contributes to the development of metabolic disease.

Brain aging and neurodegenerative diseases share the hallmarks of slow and progressive loss of neuronal cells. Flavonoids, a subgroup of polyphenols, are broadly present in food and beverage and numerous studies have suggested that it could be useful for preventing or treating neurodegenerative diseases in humans. Dihydromyricetin (DHM) is one of the main flavonoids of some Asian medicinal plants that are used to treat diverse illness. The effects of DHM have been studied in different in vitro systems of oxidative damage and neuroinflammation, as well as in animal models of several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Here we analyzed the most important effects of DHM, including its antioxidant, anti-inflammatory, and neuroprotective effects, as well as its ability to restore GABA neurotransmission and improve motor and cognitive behavior. We propose new areas of research that might contribute to a better understanding of the mechanism of action of this flavonoid, which could help develop a new therapy for aging and age-related brain diseases., (Copyright © 2019 Martínez-Coria, Mendoza-Rojas, Arrieta-Cruz and López-Valdés.)

Cacalolides are a kind of sesquiterpenoids natural compounds synthesized by Psacalium decompositum (A. Gray) H. Rob. & Brettell or Psacalium peltatum (Kunth) Cass. Antioxidant and hypoglycemic effects have been found for cacalolides such as cacalol, cacalone or maturine, however, their effects on inflammatory processes are still largely unclear. The main aim of this study was to investigate the biological activities of secondary metabolites from P. decompositum and P. peltatum through two approaches: (1) chemoinformatic and toxicoinformatic analysis based on ethnopharmacologic background; and (2) the evaluation of their potential anti-inflammatory/anti-allergic effects in bone marrow-derived mast cells by IgE/antigen complexes. The bioinformatics properties of the compounds: cacalol; cacalone; cacalol acetate and maturin acetate were evaluated through Osiris DataWarrior software and Molinspiration and PROTOX server. In vitro studies were performed to test the ability of these four compounds to inhibit antigen-dependent degranulation and intracellular calcium mobilization, as well as the production of reactive oxygen species in bone marrow-derived mast cells. Our findings showed that cacalol displayed better bioinformatics properties, also exhibited a potent inhibitory activity on IgE/antigen-dependent degranulation and significantly reduced the intracellular calcium mobilization on mast cells. These data suggested that cacalol could reduce the negative effects of the mast cell-dependent inflammatory process.

The most common dementias such as Alzheimer's disease, vascular dementia, Lewy body dementia, and frontotemporal dementia are associated with a decline in cognitive and social abilities. Although the molecular mechanisms of tissue damage in these dementias are not completely understood, these neurodegenerative illnesses share certain alterations such as neuroinflammation and gliosis. Increasing evidence suggests that microgliosis and astrogliosis play a key role in neuroinflammation observed in these dementias. Here we provide an overview of the participation of microglia and astrocytes in the neuroinflammatory response in common dementias.

Previous findings indicate that the acquisition and consolidation of recognition memory involves dopaminergic activity. Although dopamine deregulation has been observed in Alzheimer's disease (AD) patients, the dysfunction of this neurotransmitter has not been investigated in animal models of AD. The aim of this study was to assess, by in vivo microdialysis, cortical and hippocampal dopamine, norepinephrine, and glutamate release during the acquisition of object recognition memory (ORM) in 5- and 10-mo-old triple-transgenic Alzheimer's disease mice (3xTg-AD) and to relate the extracellular changes to 24-h memory performance. Five- and 10-mo-old wild-type mice and 5-mo-old 3xTg-AD showed significant cortical but not hippocampal dopamine increase during object exploration. On a 24-h ORM test, these three groups displayed significant ORM. In contrast, 10-mo-old 3xTg-AD mice showed impaired dopamine release in the insular cortex during ORM acquisition, as well as significant impairment in ORM. In addition, cortical administration of a dopamine reuptake blocker produced an increase of dopamine levels in the 10-mo-old 3xTg-AD mice and attenuated the memory impairment. These data suggest that activation of the dopaminergic system in the insular cortex is involved in object recognition memory, and that dysfunction of this system contributes to the age-related decline in cognitive functioning of the 3xTg-AD mice.

Chicken embryonic adipofibroblasts (CEA) accumulate intracytoplasmic lipids when cultured in medium containing chicken serum (CS), but not in medium with fetal bovine serum (FBS). To characterize this process of lipid accumulation, we evaluated the expression of the enzyme glycerol-3-phosphate dehydrogenase (E.C.1.1.1.8) (GPDH), first in chicken tissues and then in CEA cultured under diverse conditions. GPDH activity in adipose depots from 4-wk-old broiler chickens was similar or higher than that shown by liver, the main organ for fatty acid synthesis in chickens, while skeletal muscle had the lowest levels of GPDH. In vitro, GPDH activity increased in CEA cultured in the presence of CS but not in medium with FBS, paralleling the lipid accumulation by these cells. Both lipid accumulation and GPDH activity were further increased in CEA cultured in the presence of embryonic CS. Our results show that GPDH is highly expressed in avian tissues related to lipid metabolism and therefore can be a reliable marker for avian adipogenesis, and suggest that ECS is an optimum source for the purification of avian adipogenic factors.