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Physical activity has been demonstrated to improve cognitive function, thereby preventing/slowing neurodegenerative diseases (NDs). Biological responses to physical activity and vulnerabilities to NDs are emerging to be gender-related. Herein, known ND-associated markers (β-amyloid, tau, α-synuclein), main sex steroid hormones, antioxidant responses, and key gene transcription modulators were evaluated in the blood of physically active and sedentary women and men. In our hands, females presented higher basal erythrocytes β-amyloid and α-synuclein amounts than males. Regular physical activity was able to significantly reduce the erythrocyte content of β-amyloid in females and the tau levels in males, suggesting that these differences may be mediated by organizational actions of sex steroid hormones during development. Furthermore, despite a comparable plasma antioxidant capability (AOC) between males and females, in the latter group, physical activity significantly enhances AOC versus peroxynitrite radicals only. Finally, regular physical activity modulated the levels of transcription factor Nrf2 in erythrocytes, as well as the plasma concentration of the microRNA miR-195 and miR-153, suggesting the promotion of antioxidant/autophagic processes associated with ND-related proteins. Overall, these results could shed light on how cerebral adaptations to physical activity differ between males and females, especially with regard to blood accumulation of ND proteins and mechanisms of antioxidant responses to regular exercise., (© 2024. The Author(s).)

Despite recent FDA approvals, Alzheimer's disease (AD) still represents an unmet medical need. Among the different available therapeutic approaches, the development of multitarget molecules represents one of the most widely pursued. In this work, we present a second generation of dual ligands directed toward highly networked targets that are deeply involved in the development of the disease, namely, Histone Deacetylases (HDACs) and Glycogen Synthase Kinase 3β (GSK-3β). The synthesized compounds are highly potent GSK-3β, HDAC2, and HDAC6 inhibitors with IC 50 values in the nanomolar range of concentrations. Among them, compound 4 inhibits histone H3 and tubulin acetylation at 0.1 μM concentration, blocks hyperphosphorylation of tau protein, and shows interesting immunomodulatory and neuroprotective properties. These features, together with its ability to cross the blood-brain barrier and its favorable physical-chemical properties, make compound 4 a promising hit for the development of innovative disease-modifying agents.

Background: COVID-19 reduces lung functionality causing a decrease of blood oxygen levels (hypoxemia) often related to a decreased cellular oxygenation (hypoxia). Besides lung injury, other factors are implicated in the regulation of oxygen availability such as pH, partial arterial carbon dioxide tension (PaCO 2 ), temperature, and erythrocytic 2,3-bisphosphoglycerate (2,3-BPG) levels, all factors affecting hemoglobin saturation curve. However, few data are currently available regarding the 2,3-BPG modulation in SARS-CoV-2 affected patients at the hospital admission., Material and Methods: Sixty-eight COVID-19 patients were enrolled at hospital admission. The lung involvement was quantified using chest-Computer Tomography (CT) analysed with automatic software (CALIPER). Haemoglobin concentrations, glycemia, and routine analysis were evaluated in the whole blood, while partial arterial oxygen tension (PaO 2 ), PaCO 2 , pH, and HCO 3 - were assessed by arterial blood gas analysis. 2,3-BPG levels were assessed by specific immunoenzymatic assays in RBCs., Results: A higher percentage of interstitial lung disease (ILD) and vascular pulmonary-related structure (VRS) volume on chest-CT quantified with CALIPER had been found in COVID-19 patients with a worse disease outcome (R = 0.4342; and R = 0.3641, respectively). Furthermore, patients with lower PaO 2 showed an imbalanced acid-base equilibrium (pH, p = 0.0208; PaCO 2 , p = 0.0496) and a higher 2,3-BPG levels (p = 0.0221). The 2,3-BPG levels were also lower in patients with metabolic alkalosis (p = 0.0012 vs. no alkalosis; and p = 0.0383 vs. respiratory alkalosis)., Conclusions: Overall, the data reveal a different pattern of activation of blood oxygenation compensatory mechanisms reflecting a different course of the COVID-19 disease specifically focusing on 2,3-BPG modulation., Competing Interests: Declaration of competing interest The authors declared no potential conflict of interests., (© 2024 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Colorectal cancer (CRC) often involves wild-type p53 inactivation by MDM2 and MDM4 overexpression, promoting tumor progression and resistance to 5-fluoruracil (5-FU). Disrupting the MDM2/4 heterodimer can proficiently reactivate p53, sensitizing cancer cells to 5-FU. Herein, we developed 16 peptides based on Pep3 ( 1 ), the only known peptide acting through this mechanism. The new peptides, notably 3 and 9 , showed lower IC 50 values than 1 . When incorporated into tumor-targeted biodegradable nanoparticles, these exhibited cytotoxicity against three different CRC cell lines. Notably, NPs/ 9 caused a significant increase in p53 levels associated with a strong increment of its main downstream target p21 inducing apoptosis. Also, the combined treatment of 9 with 5-FU caused the activation of nucleolar stress and a synergic apoptotic effect. Hence, the co-delivery of MDM2/4 heterodimer disruptors with 5-FU through nanoparticles might be a promising strategy to overcome drug resistance in CRC.

The Apolipoprotein E (ApoE) has been known to regulate cholesterol and β-amyloid (Aβ) production, redistribution, and elimination, in the central nervous system (CNS). The ApoE ε4 polymorphic variant leads to impaired brain cholesterol homeostasis and amyloidogenic pathway, thus representing the major risk factor for Alzheimer's Disease (AD). Currently, less is known about the molecular mechanisms connecting ApoE ε4-related cholesterol metabolism and cholinergic system degeneration, one of the main AD pathological features. Herein, in vitro cholinergic neuron models were developed in order to study ApoE neuronal expression and investigate the possible interplay between cholesterol metabolism and cholinergic pathway impairment prompted by ε4 isoform. Particularly, alterations specifically occurring in ApoE ε4-carrying neurons (i.e. increased intracellular ApoE, amyloid precursor protein (APP) and Aβ levels, elevated apoptosis, and reduced cell survival) were recapitulated. ApoE ε4 expression was found to increase intracellular cholesterol accumulation, by regulating the related gene expression, while reducing cholesterol precursor acetyl-CoA, which in turn fuels the acetylcholine (ACh) synthesis route. In parallel, although the ACh intracellular signalling was activated, as demonstrated by the boosted extracellular ACh as well as increased IP 3 and Ca 2+ , the PKCε activation via membrane translocation was surprisingly suppressed, probably explained by the cholesterol overload in ApoE ε4 neuron-like cells. Consequently, the PKC-dependent anti-apoptotic and neuroprotective roles results impaired, reliably adding to other causes of cell death prompted by ApoE ε4. Overall, the obtained data open the way to further critical considerations of ApoE ε4-dependent cholesterol metabolism dysregulation in the alteration of cholinergic pathway, neurotoxicity, and neuronal death., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Obstructive sleep apnoea syndrome (OSAS) is a sleep-disordered breathing characterized by nocturnal collapses of the upper airway resulting in cycles of blood oxygen partial pressure oscillations, which lead to tissue and cell damage due to intermittent hypoxia (IH) episodes. Since OSAS-derived IH may lead to cognitive impairment through not fully cleared mechanisms, herein we developed a new in vitro model mimicking IH conditions to shed light on its molecular effects on microglial cells, with particular attention to the inflammatory response. The in vitro model was set-up and validated by measuring the hypoxic state, HIF-1α levels, oxidative stress by ROS production and mitochondrial activity by MTS assay. Then, the mRNA and protein levels of certain inflammatory markers (NF-κB and interleukin 6 (IL-6)) after different IH treatment protocols were investigated. The IH treatments followed by a normoxic period were not able to produce a high inflammatory state in human microglial cells. Nevertheless, microglia appeared to be in a state characterized by increased expression of NF-κB and markers related to a primed phenotype. The microglia exposed to IH cycles and stimulated with exogenous IL-1β resulted in an exaggerated inflammatory response with increased NF-κB and IL-6 expression, suggesting a role for primed microglia in OSAS-driven neuroinflammation., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

MDM2 and MDM4 are key negative regulators of p53, an important protein involved in several cell processes (e.g. cell cycle and apoptosis). Not surprisingly, the p53 tumor suppressor function is inactivated in tumors overexpressing these two proteins. Therefore, both MDM2 and MDM4 are considered important therapeutic targets for an effective reactivation of the p53 function. Herein, we present our studies on the development of spiropyrazoline oxindole small molecules able to inhibit MDM2/4-p53 protein-protein interactions (PPIs). Twenty-seven potential spiropyrazoline oxindole dual inhibitors were prepared based on in silico structural optimization studies of a hit compound with MDM2 and MDM4 proteins. The antiproliferative activity of the target compounds was evaluated in cancer cell lines harboring wild-type p53 and overexpressing MDM2 and/or MDM4. The most active compounds in SJSA-1 cells, 2q and 3b, induce cell death via apoptosis and control cell growth by targeting the G0/G1 cell cycle checkpoint in a concentration-dependent manner. The ability of the five most active spiropyrazoline oxindoles in dissociating p53 from MDM2 and MDM4 was analyzed by an immunoenzymatic assay. Three compounds inhibited MDM2/4-p53 PPIs with IC 50 values in the nM range, while one compound inhibited more selectively the MDM2-p53 PPI over the MDM4-p53 PPI. Collectively, these results show: i) 3b may serve as a valuable lead for obtaining selective MDM2-p53 PPI inhibitors and more efficient anti-osteosarcoma agents; ii) 2a, 2q and 3f may serve as valuable leads for obtaining dual MDM2/4 inhibitors and more effective p53 activators., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The human brain is primarily composed of lipids, and their homeostasis is crucial to carry on normal neuronal functions. In order to provide an adequate amount of lipid transport in and out of the central nervous system, organisms need a set of proteins able to bind them. Therefore, alterations in the structure or function of lipid-binding proteins negatively affect brain homeostasis, as well as increase inflammation and oxidative stress with the consequent risk of neurodegeneration. In this regard, lifestyle changes seem to be protective against neurodegenerative processes. Nutraceutical supplementation with antioxidant molecules has proven to be useful in proving cognitive functions. Additionally, regular physical activity seems to protect neuronal vitality and increases antioxidant defenses. The aim of the present review was to investigate mechanisms that link lipid-binding protein dysfunction and oxidative stress to cognitive decline, also underlining the neuroprotective effects of diet and exercise.

Introduction: α-syn aggregates represent the pathological hallmark of synucleinopathies as well as a frequent copathology (almost 1/3 of cases) in AD. Recent research indicates a potential role of α-syn species, measured in CSF with conventional analytical techniques, in the differential diagnosis between AD and synucleinopathies (such as DLB). Pioneering studies report the detection of α-syn in blood, however, conclusive investigations are controversial. Ultrasensitive seed amplification techniques, enabling the selective quantification of α-syn seeds, may represent an effective solution to identify the α-syn component in AD and facilitate a biomarker-guided stratification., Areas Covered: We performed a PubMed-based review of the latest findings on α-syn-related biomarkers for AD, focusing on bodily fluids. A dissertation on the role of ultrasensitive seed amplification assays, detecting α-syn seeds from different biological samples, was conducted., Expert Opinion: α-syn may contribute to progressive AD neurodegeneration through cross-seeding especially with tau protein. Ultrasensitive seed amplification techniques may support a biomarker-drug co-development pathway and may be a pathophysiological candidate biomarker for the evolving ATX(N) system to classify AD and the spectrum of primary NDDs. This would contribute to a precise approach to AD, aimed at implementing disease-modifying treatments.

Background: Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β protein (Aβ) within brain blood vessels that develops in elderly people and Alzheimer's disease (AD) patients. Therefore, the investigation of biomarkers able to differentiate CAA patients from AD patients and healthy controls (HC) is of great interest, in particular in peripheral fluids., Objective: The current study aimed to detect the neurodegenerative disease (ND)-related protein (i.e., Aβ1-40, Aβ1-42, tau, and α-synuclein) levels in both red blood cells (RBCs) and plasma of CAA patients and HC, evaluating their role as putative peripheral biomarkers for CAA., Methods: For this purpose, the proteins' concentration was quantified in RBCs and plasma by homemade immunoenzymatic assays in an exploratory cohort of 20 CAA patients and 20 HC., Results: The results highlighted a significant increase of Aβ1-40 and α-synuclein concentrations in both RBCs and plasma of CAA patients, while higher Aβ1-42 and t-tau levels were detected only in RBCs of CAA individuals compared to HC. Moreover, Aβ1-42/Aβ1-40 ratio increased in RBCs and decreased in plasma of CAA patients. The role of these proteins as candidate peripheral biomarkers easily measurable with a blood sample in CAA needs to be confirmed in larger studies., Conclusion: In conclusion, we provide evidence concerning the possible use of blood biomarkers for contributing to CAA diagnosis and differentiation from other NDs.