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.

Discovery of -substituted-2-oxoindolin benzoylhydrazines as c-MET/SMO modulators in EGFRi-resistant non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), the leading cause of cancer-related mortality worldwide, poses a formidable challenge due to its heterogeneity and the emergence of resistance to targeted therapies. While initially effective, first- and third-generation EGFR-tyrosine kinase inhibitors (TKIs) often fail to control disease progression, leaving patients with limited treatment options. To address this unmet medical need, we explored the therapeutic potential of multitargeting agents that simultaneously inhibit two key signalling pathways, the mesenchymal-epithelial transition factor (c-MET) and the G protein-coupled receptor Smoothened (SMO), frequently dysregulated in NSCLC.

Evaluation of orphan maintained biological medicinal products in the European Union between 2018 to 2023: a regulatory perspective.

Objectives: Orphan medicinal products (OMPs) authorized by the European Union (EU) benefit from market exclusivity, fee waivers, and national incentives. Maintaining orphan status during a marketing authorization application requires meeting eligibility criteria, especially demonstrating significant benefit (SB), which is challenging. This study identifies key features linked to successful orphan status maintenance for biological OMPs approved in the EU between 2018 and 2023.

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).

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.

Oxaliplatin(IV) Prodrugs Functionalized with Gemcitabine and Capecitabine Induce Blockage of Colorectal Cancer Cell Growth-An Investigation of the Activation Mechanism and Their Nanoformulation.

The use of platinum-based anticancer drugs, such as cisplatin, oxaliplatin, and carboplatin, is a common frontline option in cancer management, but they have debilitating side effects and can lead to drug resistance. Combination therapy with other chemotherapeutic agents, such as capecitabine and gemcitabine, has been explored. One approach to overcome these limitations is the modification of traditional Pt(II) drugs to obtain new molecules with an improved pharmacological profile, such as Pt(IV) prodrugs.

Interaction of graphene and WS with neutrophils and mesenchymal stem cells: implications for peripheral nerve regeneration.

Graphene and bidimensional (2D) materials have been widely used in nerve conduits to boost peripheral nerve regeneration. Nevertheless, the experimental and commercial variability in graphene-based materials generates graphene forms with different structures and properties that can trigger entirely diverse biological responses from all the players involved in nerve repair. Herein, we focus on the graphene and tungsten disulfide (WS) interaction with non-neuronal cell types involved in nerve tissue regeneration.

Graphene-based nanomaterials for peripheral nerve regeneration.

Emerging nanotechnologies offer numerous opportunities in the field of regenerative medicine and have been widely explored to design novel scaffolds for the regeneration and stimulation of nerve tissue. In this review, we focus on peripheral nerve regeneration. First, we introduce the biomedical problem and the present status of nerve conduits that can be used to guide, fasten and enhance regeneration.

Multimaterial and multiscale scaffold for engineering enthesis organ.

Tendon and ligament injuries are relevant clinical problems in modern society, and the current medical approaches do not guarantee complete recovery of the physiological functionalities. Moreover, they present a non-negligible failure rate after surgery. Failures often occur at the enthesis, which is the area of tendons and ligaments insertion to bones.

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.

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.

Angiogenesis in Disease.

Angiogenesis is a multi-step process by which new blood capillaries are formed starting from preexisting functional vessels [...

Synthesis, chemical characterization, and biological evaluation of a novel auranofin derivative as an anticancer agent.

A novel gold(I) complex inspired by the known medicinal inorganic compounds auranofin and thimerosal, namely ethylthiosalicylate(triethylphosphine)gold(I) (AFETT hereafter), was synthesized and characterised and its structure was resolved through X-ray diffraction. The solution behavior of AFETT and its interactions with two biologically relevant proteins ( human serum albumin and haemoglobin) and with a synthetic dodecapeptide reproducing the C-terminal portion of thioredoxin reductase were comparatively analyzed through P NMR and ESI-MS. Remarkable binding properties toward these biomolecules were disclosed.

Cornus sanguinea Fruits: a Source of Antioxidant and Antisenescence Compounds Acting on Aged Human Dermal and Gingival Fibroblasts.

Five new compounds, a flavonol glycoside ( 1: ), a megastigmane ( 2: ), 2 cyclohexylethanoids ( 3, 4: ), and a phenylethanoid derivative ( 5: ), together with 15 known compounds ( 6: - 20: ) including flavonoid glycosides, cyclohexylethanoids, and phenolic compounds, have been isolated from drupes. All the structures have been determined by 1D and 2D NMR spectroscopic analysis and mass spectrometry data. The antioxidant capability of the most representative isolated compounds was evaluated in the hydrogen peroxide (HO)-induced premature cellular senescence model of human dermal and gingival fibroblasts.

Allosterism vs. Orthosterism: Recent Findings and Future Perspectives on A AR Physio-Pathological Implications.

The development of GPCR (G-coupled protein receptor) allosteric modulators has attracted increasing interest in the last decades. The use of allosteric modulators in therapy offers several advantages with respect to orthosteric ones, as they can fine-tune the tissue responses to the endogenous agonist. Since the discovery of the first A adenosine receptor (AR) allosteric modulator in 1990, several efforts have been made to develop more potent molecules as well as allosteric modulators for all adenosine receptor subtypes.

Ruthenium(II) 1,4,7-trithiacyclononane complexes of curcumin and bisdemethoxycurcumin: Synthesis, characterization, and biological activity.

Two cationic ruthenium(II) 1,4,7-trithiacyclononane ([9]aneS) complexes of curcumin (curcH) and bisdemethoxycurcumin (bdcurcH), namely [Ru(curc)(dmso-S)([9]aneS)]Cl (1) and [Ru(bdcurc)(dmso-S)([9]aneS)]Cl (2) were prepared from the [RuCl(dmso-S)([9]-aneS)] precursor and structurally characterized, both in solution and in the solid state by X-ray crystallography. The corresponding PTA complexes [Ru(curc)(PTA)([9]aneS)]Cl (3) and [Ru(bdcurc)(PTA)([9]aneS)]Cl (4) have been also synthesized and characterized (PTA = 1,3,5-triaza-7-phosphaadamantane). Bioinorganic studies relying on mass spectrometry were performed on complexes 1-4 to assess their interactions with the model protein lysozyme.

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).

Novel positive allosteric modulators of A adenosine receptor acting as bone mineralisation promoters.

Small-molecules acting as positive allosteric modulators (PAMs) of the A adenosine receptor (A AR) could potentially represent a novel therapeutic strategy for pathological conditions characterised by altered bone homeostasis, including osteoporosis. We investigated a library of compounds (-) exhibiting different degrees of chemical similarity with three indole derivatives (-), which have been recently identified by us as PAMs of the A AR able to promote mesenchymal stem cell differentiation and bone formation. Evaluation of mineralisation activity of - in the presence and in the absence of the agonist BAY60-6583 allowed the identification of lead compounds with therapeutic potential as anti-osteoporosis agents.

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.

The Ionophoric Activity of a Pro-Apoptotic VEGF165 Fragment on HUVEC Cells.

Copper plays an important role as a regulator in many pathologies involving the angiogenesis process. In cancerogenesis, tumor progression, and angiogenic diseases, copper homeostasis is altered. Although many details in the pathways involved are still unknown, some copper-specific ligands have been successfully used as therapeutic agents.

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.