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).

Functional Heterodimerization between the G Protein-Coupled Receptor GPR17 and the Chemokine Receptors 2 and 4: New Evidence.

GPR17, a G protein-coupled receptor, is a pivotal regulator of myelination. Its endogenous ligands trigger receptor desensitization and downregulation allowing oligodendrocyte terminal maturation. In addition to its endogenous agonists, GPR17 could be promiscuously activated by pro-inflammatory oxysterols and chemokines released at demyelinating lesions.

Exploring Epithelial-Mesenchymal Transition Signals in Endometriosis Diagnosis and In Vitro Fertilization Outcomes.

Endometriosis (EMS) pathogenesis has been related to the release of inflammatory mediators in peritoneal fluid, creating an altered microenvironment that leads to low-grade oocyte/embryos and to the reduction of implantation rates. The Epithelial-Mesenchymal Transition (EMT), an inflammation-related process, can be a further contributing factor to EMS. This study aimed to investigate, among various cytokines and EMT markers (Cadherins, TGF-β, HIF-1α), diagnostic markers of EMS and prognostic factors of in vitro fertilization (IVF) outcomes.

CXCR4 antagonism sensitizes cancer cells to novel indole-based MDM2/4 inhibitors in glioblastoma multiforme.

Glioblastoma Multiforme (GBM) is a highly invasive primary brain tumour characterized by chemo- and radio-resistance and poor overall survival. GBM can present an aberrant functionality of p53, caused by the overexpression of the murine double minute 2 protein (MDM2) and its analogue MDM4, which may influence the response to conventional therapies. Moreover, tumour resistance/invasiveness has been recently attributed to an overexpression of the chemokine receptor CXCR4, identified as a pivotal mediator of glioma neovascularization.

α-Synuclein Heteromers in Red Blood Cells of Alzheimer's Disease and Lewy Body Dementia Patients.

Background: Red blood cells (RBCs) contain the majority of α-synuclein (α-syn) in blood, representing an interesting model for studying the peripheral pathological alterations proved in neurodegeneration.

Objective: The current study aimed to investigate the diagnostic value of total α-syn, amyloid-β (Aβ1-42), tau, and their heteroaggregates in RBCs of Lewy body dementia (LBD) and Alzheimer's disease (AD) patients compared to healthy controls (HC).

Methods: By the use of enzyme-linked immunosorbent assays, RBCs concentrations of total α-syn, Aβ1-42, tau, and their heteroaggregates (α-syn/Aβ1-42 and α-syn/tau) were measured in 27 individuals with LBD (Parkinson's disease dementia, n = 17; dementia with Lewy bodies, n = 10), 51 individuals with AD (AD dementia, n = 37; prodromal AD, n = 14), and HC (n = 60).

High Adenosine Extracellular Levels Induce Glioblastoma Aggressive Traits Modulating the Mesenchymal Stromal Cell Secretome.

Glioblastoma is an aggressive, fast-growing brain tumor influenced by the composition of the tumor microenvironment (TME) in which mesenchymal stromal cell (MSCs) play a pivotal role. Adenosine (ADO), a purinergic signal molecule, can reach up to high micromolar concentrations in TME. The activity of specific adenosine receptor subtypes on glioma cells has been widely explored, as have the effects of MSCs on tumor progression.

Prodromal Intestinal Events in Alzheimer's Disease (AD): Colonic Dysmotility and Inflammation Are Associated with Enteric AD-Related Protein Deposition.

Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer's disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age.

Antioxidant Activity of Compounds Isolated from Promotes Human Gingival Fibroblast Well-Being.

Four new triterpenoid bidesmosidic saponins (-) and a sesquiterpenoid glucoside (), together with nine known phenolic compounds (-), were isolated from the fruits of . Their structures were elucidated using 1D and 2D NMR spectroscopy and mass spectrometry data. The antioxidant capability of the isolated compounds was evaluated in human gingival fibroblasts.

Correction to "Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer's Disease".

[This corrects the article DOI: 10.1021/acsmedchemlett.8b00507.

High Levels of -Amyloid, Tau, and Phospho-Tau in Red Blood Cells as Biomarkers of Neuropathology in Senescence-Accelerated Mouse.

Alzheimer's Disease (AD) is the most common Neurodegenerative Disease (ND), primarily characterised by neuroinflammation, neuronal plaques of -amyloid (A), and neurofibrillary tangles of hyperphosphorylated tau. -Synuclein (-syn) and its heteroaggregates with A and tau have been recently included among the neuropathological elements of NDs. These pathological traits are not restricted to the brain, but they reach peripheral fluids as well.

Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer's Disease.

Several evidence pointed out the role of epigenetics in Alzheimer's disease (AD) revealing strictly relationships between epigenetic and "classical" AD targets. Based on the reported connection among histone deacetylases (HDACs) and glycogen synthase kinase 3β (GSK-3β), herein we present the discovery and the biochemical characterization of the first-in-class hit compound able to exert promising anti-AD effects by modulating the targeted proteins in the low micromolar range of concentration. Compound induces an increase in histone acetylation and a reduction of tau phosphorylation.

Memantine prodrug as a new agent for Alzheimer's Disease.

Hydrogen sulphide has recently drawn much attention due to its potent anti-inflammatory and neuroprotective roles in brain functions. The purpose of the current study was to exploit these beneficial properties of HS to design a new agent for the treatment of Alzheimer's disease (AD). To pursue our aims, we replaced the free amine group of memantine with an isothiocyanate functionality as a putative HS-donor moiety.

Potential Diagnostic Value of Red Blood Cells α-Synuclein Heteroaggregates in Alzheimer's Disease.

A plethora of complex misfolded protein combinations have been found in Alzheimer disease (AD) brains besides the classical pathological hallmarks. Recently, α-synuclein (α-syn) and its heterocomplexes with amyloid-β (Aβ) and tau have been suggested to be involved in the pathophysiological processes of neurodegenerative diseases. These pathological features are not limited to the brain, but can be also found in peripheral fluids.

Long lasting inhibition of Mdm2-p53 interaction potentiates mesenchymal stem cell differentiation into osteoblasts.

The osteoblast generation from Mesenchymal stem cells (MSCs) is tightly coordinated by transcriptional networks and signalling pathways that control gene expression and protein stability of osteogenic "master transcription factors". Among these pathways, a great attention has been focused on p53 and its physiological negative regulator, the E3 ligase Murine double minute 2 (Mdm2). Nevertheless, the signalling that regulates Mdm2-p53 axis in osteoblasts remain to be elucidated, also considering that Mdm2 possesses numerous p53-independent activities and interacts with additional proteins.

Epigenetic Modifications of the -Synuclein Gene and Relative Protein Content Are Affected by Ageing and Physical Exercise in Blood from Healthy Subjects.

Epigenetic regulation may contribute to the beneficial effects of physical activity against age-related neurodegeneration. For example, epigenetic alterations of the gene encoding for -synuclein () have been widely explored in both brain and peripheral tissues of Parkinson's disease samples. However, no data are currently available about the effects of physical exercise on epigenetic regulation in ageing healthy subjects.

α-Synuclein Heterocomplexes with β-Amyloid Are Increased in Red Blood Cells of Parkinson's Disease Patients and Correlate with Disease Severity.

Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid (Aβ) and tau, in both brain and peripheral tissues. In addition to oligomers, the role of the interactions of α-syn with Aβ or tau has gradually emerged. Nevertheless, despite intensive research, NDs have no accepted peripheral markers for biochemical diagnosis.

α-Synuclein Aggregated with Tau and β-Amyloid in Human Platelets from Healthy Subjects: Correlation with Physical Exercise.

The loss of protein homeostasis that has been associated with aging leads to altered levels and conformational instability of proteins, which tend to form toxic aggregates. In particular, brain aging presents characteristic patterns of misfolded oligomers, primarily constituted of β-amyloid (Aβ), tau, and α-synuclein (α-syn), which can accumulate in neuronal membranes or extracellular compartments. Such aging-related proteins can also reach peripheral compartments, thus suggesting the possibility to monitor their accumulation in more accessible fluids.

Computer-Aided Identification and Lead Optimization of Dual Murine Double Minute 2 and 4 Binders: Structure-Activity Relationship Studies and Pharmacological Activity.

The function of p53 protein, also known as "genome guardian", might be impaired by the overexpression of its primary cellular inhibitor, the murine double minute 2 protein (MDM2). However, the recent finding that MDM2-selective inhibitors induce high levels of its homologue MDM4, prompt us to identify, through a receptor-based virtual screening on an in house database, dual MDM2/MDM4 binders. Compound 1 turned out to possess an IC of 93.

α-Synuclein Aggregates with β-Amyloid or Tau in Human Red Blood Cells: Correlation with Antioxidant Capability and Physical Exercise in Human Healthy Subjects.

Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid (Aβ), and tau, in both brain and peripheral tissue. In addition to homo-oligomers, the role of α-syn interactions with Aβ or tau has gradually emerged. The altered protein accumulation has been related to both oxidative stress and physical activity; nevertheless, no correlation among the presence of peripheral α-syn hetero-aggregates, antioxidant capacity, and physical exercise has been discovered as of yet.

Bax Activation Blocks Self-Renewal and Induces Apoptosis of Human Glioblastoma Stem Cells.

Glioblastoma (GBM) is characterized by a poor response to conventional chemotherapeutic agents, attributed to the insurgence of drug resistance mechanisms and to the presence of a subpopulation of glioma stem cells (GSCs). GBM cells and GSCs present, among others, an overexpression of antiapoptotic proteins and an inhibition of pro-apoptotic ones, which help to escape apoptosis. Among pro-apoptotic inducers, the Bcl-2 family protein Bax has recently emerged as a promising new target in cancer therapy along with first BAX activators (BAM7, Compound 106, and SMBA1).

Dual Inhibition of PDK1 and Aurora Kinase A: An Effective Strategy to Induce Differentiation and Apoptosis of Human Glioblastoma Multiforme Stem Cells.

The poor prognosis of glioblastoma multiforme (GBM) is mainly attributed to drug resistance mechanisms and to the existence of a subpopulation of glioma stem cells (GSCs). Multitarget compounds able to both affect different deregulated pathways and the GSC subpopulation could escape tumor resistance and, most importantly, eradicate the stem cell reservoir. In this respect, the simultaneous inhibition of phosphoinositide-dependent kinase-1 (PDK1) and aurora kinase A (AurA), each one playing a pivotal role in cellular survival/migration/differentiation, could represent an innovative strategy to overcome GBM resistance and recurrence.