18 kDa TSPO targeting drives polarized human microglia towards a protective and restorative neurosteroidome profile.

An aberrant pro-inflammatory microglia response has been associated with most neurodegenerative disorders. Identifying microglia druggable checkpoints to restore their physiological functions is an emerging challenge. Recent data have shown that microglia produce de novo neurosteroids, endogenous molecules exerting potent anti-inflammatory activity.

Design, synthesis and biological evaluation of new H2S-releasing rivastigmine derivatives as neuroprotective molecules.

Alzheimer's disease (AD) represents one of the main challenges for the 21st century medical research as no disease-modifying agent has been successfully progressed to the market, while the number of people affected by AD is estimated to grow exponentially over the next years. The complex network of triggering factors involved in the insurgence and progression of AD can be rightly addressed as one of the main reasons behind the difficulty in identifying new pharmacological approaches. For this reason, the discovery and development of drugs endowed with pleiotropic activity remain the most valuable, but at the same time challenging, approaches to tackle down AD.

Neurosteroids and Translocator Protein (TSPO) in neuroinflammation.

Neurosteroids have a crucial role in physiological intrinsic regulations of the Central Nervous System functions. They are derived from peripheral steroidogenic sources and from the de novo neurosteroidogenic capacity of brain cells. Significant alterations of neurosteroid levels have been frequently observed in neuroinflammation and neurodegenerative diseases.

GFP Farnesylation as a Suitable Strategy for Selectively Tagging Exosomes.

Exosomes are small extracellular vesicles (EVs) constituting fully biological, cell-derived nanovesicles with great potential in cell-to-cell communication and drug delivery applications. The current gold standard for EV labeling and tracking is represented by fluorescent lipophilic dyes which, however, importantly lack selectivity, due to their unconditional affinity for lipids. Herein, an alternative EV fluorescent labeling approach is in-depth evaluated, by taking advantage of green fluorescent protein (GFP) farnesylation (GFP-f), a post-translational modification to directly anchor GFP to the EV membrane.

Sex Differences in Blood Accumulation of Neurodegenerative-Related Proteins and Antioxidant Responses to Regular Physical Exercise.

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.

Trazodone counteracts the response of microglial cells to inflammatory stimuli.

Microglia are resident brain cells that regulate neuronal development and innate immunity. Microglia activation participates in the cellular response to neuroinflammation, thus representing a possible target for pharmacological strategies aimed to counteract the onset and progression of brain disorders, including depression. Antidepressant drugs have been reported to reduce neuroinflammation by acting also on glial cells.

Extracellular adenosine oppositely regulates the purinome machinery in glioblastoma and mesenchymal stem cells.

Glioblastoma (GB) is a lethal brain tumor that rapidly adapts to the dynamic changes of the tumor microenvironment (TME). Mesenchymal stem/stromal cells (MSCs) are one of the stromal components of the TME playing multiple roles in tumor progression. GB progression is prompted by the immunosuppressive microenvironment characterized by high concentrations of the nucleoside adenosine (ADO).

The Citrus flavanone naringenin prolongs the lifespan in C. elegans and slows signs of brain aging in mice.

Aging is one of the main risk factors for neurodegenerative disorders, which represent a global burden on healthcare systems. Therefore, identifying new strategies to slow the progression of brain aging is a compelling challenge. In this article, we first assessed the potential anti-aging effects of the Citrus flavanone naringenin (NAR), an activator of the enzyme sirtuin-1 (SIRT1), in a 3R-compliant and short-lived aging model (i.

First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer's Disease.

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).

Human oligodendrocyte-like cell differentiation is promoted by TSPO-mediated endogenous steroidogenesis.

Mature oligodendrocytes (OLs) arise from oligodendrocyte precursor cells that, in case of demyelination, are recruited at the lesion site to remyelinate the axons and therefore restore the transmission of nerve impulses. It has been widely documented that exogenously administered steroid molecules are potent inducers of myelination. However, little is known about how neurosteroids produced de novo by OLs can impact this process.

Multi-biomarker approach to evaluate the toxicity of chlorpyrifos (active ingredient and a commercial formulation) on different stages of Biomphalaria straminea.

Biomphalaria straminea is a freshwater gastropod native to South America and used in toxicological assessments. Our aim was to estimate 48 h-LC and sub-chronic effects after the exposure to low concentrations of chlorpyrifos as commercial formulation (CF) and active ingredient (AI) on B. straminea adult, embryos and juveniles.

Drug Mechanism: A bioinformatic update.

A drug Mechanism of Action (MoA) is a complex biological phenomenon that describes how a bioactive compound produces a pharmacological effect. The complete knowledge of MoA is fundamental to fully understanding the drug activity. Over the years, many experimental methods have been developed and a huge quantity of data has been produced.

Development and Nanoparticle-Mediated Delivery of Novel MDM2/MDM4 Heterodimer Peptide Inhibitors to Enhance 5-Fluorouracil Nucleolar Stress in Colorectal Cancer Cells.

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 (), the only known peptide acting through this mechanism.

Regular exercise delays microvascular endothelial dysfunction by regulating antioxidant capacity and cellular metabolism.

Aging is the basis for several unfavorable conditions, including cardiovascular diseases (CVDs). In this sense, regular physical activity (regular PA) has been proven to delay cellular aging and prevent endothelial dysfunction related to CVDs. Despite numerous studies involving athletes, little is known about cellular and molecular mechanisms of regular PA among master athletes.

Apolipoprotein E ε4 triggers neurotoxicity via cholesterol accumulation, acetylcholine dyshomeostasis, and PKCε mislocalization in cholinergic neuronal cells.

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.

The human microglial surveillant phenotype is preserved by de novo neurosteroidogenesis through the control of cholesterol homeostasis: Crucial role of 18 kDa Translocator Protein.

Neurodegenerative disease-associated microglia commonly exhibit harmful cholesterol accumulation that impairs their ability to resolve the neuroinflammatory response, contributing to disease onset and progression. Neurosteroids, whose levels have been often found significantly altered in brain diseases, are the most potent endogenous anti-inflammatory molecules exerting beneficial effects on activities of brain cells, including microglia. For the first time, the impact of neurosteroidogenesis on cholesterol homeostasis for the immune surveillance phenotype maintenance was investigated in a human microglia in vitro model.

The relationship of separation anxiety with the age of onset of panic disorder.

Aim: This study aimed to investigate whether separation anxiety (SA) constitutes a dimension related to age at onset of panic disorder (PD), in homogeneous subgroups of outpatients with PD, based on their age of onset and symptom severity.

Methods: A sample of 232 outpatients with PD was assessed with the Panic Disorder Severity Scale (PDSS) and the Sheehan Disability Scale (SDS) for functional impairments. Separation anxiety was evaluated using structured interviews and questionnaires.

Intermittent hypoxia treatments cause cellular priming in human microglia.

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.

Oxidative Stress-Related Signaling Pathways Predict Oocytes' Fertilization In Vitro and Embryo Quality.

Oocyte development and fertilization are largely influenced by the microenvironment of the follicular fluid (FF), and the exploration of its molecular/metabolic composition may help in improving in vitro fertilization (IVF) outcomes. Here, the concentrations of molecules related to oxidative stress/inflammation were measured in FF from follicles at oocyte retrieval during IVF. Here, the FF antioxidant potential was correlated with the number of retrieved/mature oocytes and the number of fertilized ones.

Exploring the Role of Lipid-Binding Proteins and Oxidative Stress in Neurodegenerative Disorders: A Focus on the Neuroprotective Effects of Nutraceutical Supplementation and Physical Exercise.

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.

Identification of a Novel p53 Modulator Endowed with Antitumoural and Antibacterial Activity through a Scaffold Repurposing Approach.

Intracellular pathogens, such as , have been recently shown to induce degradation of p53 during infection, thus impairing the protective response of the host cells. Therefore, p53 reactivation by disruption of the p53-MDM2 complex could reduce infection and restore pro-apoptotic effect of p53. Here, we report the identification of a novel MDM2 inhibitor with potential antitumoural and antibacterial activity able to reactivate p53.

Targeting TSPO Reduces Inflammation and Apoptosis in an In Vitro Photoreceptor-Like Model of Retinal Degeneration.

The 18 kDa translocator protein (TSPO) is predominantly located in the mitochondrial outer membrane, playing an important role in steroidogenesis, inflammation, survival, and cell proliferation. Its expression in the CNS, and mainly in glial cells, is upregulated in neuropathologies and brain injury. In this study, the potential of targeting TSPO for the therapeutic treatment of inflammatory-based retinal neurodegeneration was evaluated by means of an in vitro model of lipopolysaccharide (LPS)-induced degeneration in 661 W cells, a photoreceptor-like cell line.

Quantum computing algorithms: getting closer to critical problems in computational biology.

The recent biotechnological progress has allowed life scientists and physicians to access an unprecedented, massive amount of data at all levels (molecular, supramolecular, cellular and so on) of biological complexity. So far, mostly classical computational efforts have been dedicated to the simulation, prediction or de novo design of biomolecules, in order to improve the understanding of their function or to develop novel therapeutics. At a higher level of complexity, the progress of omics disciplines (genomics, transcriptomics, proteomics and metabolomics) has prompted researchers to develop informatics means to describe and annotate new biomolecules identified with a resolution down to the single cell, but also with a high-throughput speed.