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Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a neurodegenerative pathology caused by accumulation of mutant neuroserpin (NS) polymers inside the endoplasmic reticulum (ER) of neurons, leading to cellular toxicity and neuronal death. To date, there is no cure for FENIB, and only palliative care is available for FENIB patients, underlining the urgency to develop therapeutic strategies. The purpose of this work was to create a cellular system designed for testing small molecules able to reduce the formation of NS polymers. Our results show the generation and characterisation of a novel cell culture model for FENIB based on neural stem progenitor cells (NPCs) with inducible expression of either wild type (WT) or G392E NS, a variant that causes severe FENIB. We also report the use of these novel cell lines to explore the effects of four different proteolysis targeting chimaera (PROTAC) compounds, small bivalent molecules engineered to bind to the E3 ubiquitin ligase cereblon, and to NS through a recruiting motif based on the small molecule embelin. This approach aims to enhance the degradation of mutant NS after retro-translocation to the cytosol by facilitating its targeting to the proteasome. Our results show little toxicity and no variation in NS levels with any of the compounds tested. In conclusion, this work sets the basis for future attempts to identify molecules able to prevent NS accumulation inside the ER of cultured cells., (© 2024 The Author(s). Drug Development Research published by Wiley Periodicals LLC.)

Mitochondria-endoplasmic reticulum contacts (MERCs) mediate a close and continuous communication between both organelles that is essential for the transfer of calcium and lipids to mitochondria, necessary for cellular signalling and metabolic pathways. Their structural and molecular characterisation has shown the involvement of many proteins that bridge the membranes of the two organelles and maintain the structural stability and function of these contacts. The crosstalk between the two organelles is fundamental for proper neuronal function and is now recognised as a component of many neurological disorders. In fact, an increasing proportion of MERC proteins take part in the molecular and cellular basis of pathologies affecting the nervous system. Here we review the alterations in MERCs that have been reported for these pathologies, from neurodevelopmental and neuropsychiatric disorders to neurodegenerative diseases. Although mitochondrial abnormalities in these debilitating conditions have been extensively attributed to the high energy demand of neurons, a distinct role for MERCs is emerging as a new field of research. Understanding the molecular details of such alterations may open the way to new paths of therapeutic intervention., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Carbon dots (CDs) are an emerging class of carbon nanoparticles, which for their characteristics have found applications in many fields such as catalysis, materials and biomedicine. Within this context, the application of CDs as antibacterial agents has received much attention in very recent years, while their use as antifungal nanoparticles has been scarcely investigated. Here we report a systematic investigation of the surface functional groups of CDs to study their influence on these nanoparticles' against Candida albicans. Three classes of CDs have been synthesised and fully characterized. A thorough in vitro and in vivo biological screening against C. albicans was performed to test their antifungal, antiadhesion and antibiofilm formation activities. Moreover, the interaction with C. albicans cells was investigated by microscopic analysis. Our results evidence how the presence of a positively polarised surface results crucial for the internalization into COS-7 cells. Positively charged nanoparticles were also able to inhibit adhesion and biofilm formation, to interact with the cellular membrane of C. albicans, and to increase the survival of G. mellonella infected larvae after the injection with positive nanoparticles. The antifungal activity of CDs and their extremely low toxicity may represent a new strategy to combat infections sustained by C.albicans., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Hyaluronic acid (HA) is a naturally occurring biopolymer that has been employed for a plethora of medicinal applications. Nevertheless, as HA is a natural polysaccharide, it can be a substrate able to promote microbial growth and proliferation. Biopolymer-drug conjugates have gained attention over the years to overcome drawbacks of each single component. Within this context, thymol (Thy), a phenolic compound occurring in essential oils (EOs) extracted from Thymus and Origanum , has been largely studied for its antimycotic applications. However, it is characterized by a low water solubility and moderate cytotoxicity. Herein, we report an innovative HA-thymol conjugate (HA-Thy) biomaterial to circumvent the drawbacks of free thymol use by providing the polymer conjugate with the beneficial properties of both components. Preliminary biological tests evidenced the decrease of thymol cytotoxicity for the HA-Thy conjugate, paired with a promising antibiofilm formation activity against Candida albicans , similar to pure thymol, highlighting its potential application as a preservative biomaterial in formulations.

Older people have reduced immune responses to infection and vaccination. B cell activation is key for the efficacy of the vaccine response, but there are several age-related changes in B cells which may contribute to the loss of vaccine efficacy. Different subpopulations of B cells have different functions and phenotypes. These populations can change as we age; older people have been shown to have fewer "IgM memory" cells, regulatory B cells and plasma cells and more IgD-CD27- "double-negative" and "age-related B cells." While the overall quantity of antibody in the blood does not change, the quality of the B cell response changes; producing less specific antibodies upon challenge and more autoreactive antibodies. This could be due to changes in selection pressures, as has been demonstrated by repertoire sequencing of different subsets of B cells at different ages. Other changes in antibody repertoire are seen, including greater levels of IgG2 in older people and altered IgG1 IGHV gene usage. Since B cells rely on their environment for efficient responses, some of these changes may be due to age-related changes in accessory cells/signals. Other changes appear to be intrinsic to older/aged B cells themselves, such as their tendency to produce greater levels of inflammatory cytokines., (© 2020 S. Karger AG, Basel.)