Oxidative Stress in Alzheimer’s Disease: In Vitro Therapeutic Effect of Amniotic Fluid Stem Cells Extracellular Vesicles: Alzheimers disease (AD) is characterized by abnormal protein aggregation, deposition of extracellular β-amyloid proteins (Aβ), besides an increase of oxidative stress. Amniotic fluid stem cells (AFSCs) should have a therapeutic potential for neurodegenerative disorders, mainly through a paracrine effect mediated by extracellular vesicles (EV). Here, we examined the effect of EV derived from human AFSCs (AFSC-EV) on the disease phenotypes in an AD neuron primary culture. We observed a positive effect of AFSC-EV on neuron morphology, viability, and Aβ and phospho-Tau levels. This could be due to the apoptotic and autophagic pathway modulation derived from the decrease in oxidative stress. Indeed, reactive oxygen species (ROS) were reduced, while GSH levels were enhanced. This modulation could be ascribed to the presence of ROS regulating enzymes, such as SOD1 present into the AFSC-EV themselves. This study describes the ROS-modulating effects of extracellular vesicles alone, apart from their deriving stem cell, in an AD in vitro model, proposing AFSC-EV as a therapeutic tool to stop the progression of AD.

The identification of effective pharmacological tools for Alzheimer’s disease (AD) represents one of the main challenges for therapeutic discovery. Due to the variety of pathological processes associated with AD, a promising route for pharmacological intervention involves the development of new chemical entities that can restore cellular homeostasis. To investigate this strategy, we designed and synthetized SG2, a compound related to the thyroid hormone thyroxine, that shares a pleiotropic activity with its endogenous parent compound, including autophagic flux promotion, neuroprotection, and metabolic reprogramming. We demonstrate herein that SG2 acts in a pleiotropic manner to induce recovery in a C. elegans model of AD based on the overexpression of Aβ42 and improves learning abilities in the 5XFAD mouse model of AD. Further, in vitro ADME-Tox profiling and toxicological studies in zebrafish confirmed the low toxicity of this compound, which represents a chemical starting point for AD drug development.

Background/Objectives MC4R expression and its role in colorectal and anaplastic thyroid cancers, where resistance to therapy and lack of standard treatments remain significant challenges, are poorly understood. This study aimed to investigate MC4R as a potential therapeutic target in these cancers using the selective antagonist ML00253764 (ML), alone and in combination with vinorelbine (VNR) and irinotecan (or its active metabolite SN-38). Methods: Human colorectal adenocarcinoma HT-29, Caco-2, and anaplastic thyroid carcinoma 8305C cell lines were used. MC4R expression was assessed by Real-Time PCR with validated primers (Assay ID Hs00271877_s1), immunofluorescence, and Western blotting. Proliferation and apoptosis assays were conducted with ML, and synergy with VNR and SN-38 was evaluated by Combination Index and Loewe methods. ERK1/2 phosphorylation was measured using an ELISA assay. In vivo studies were conducted by injecting tumor cells into Athymic Nude-Foxn1nu mice, treated with ML, VNR, irinotecan, or their combinations. Results: MC4R expression was confirmed in all cell lines. ML treatment inhibited MC4R, producing antiproliferative and pro-apoptotic effects, with IC₅₀ values of 7667 ± 2144.6 nM (8305C), 806.4 ± 321.8 nM (HT-29), and 2993 ± 1135.2 nM (Caco-2). In combination with VNR and SN-38, ML exhibited significant synergy in vitro and reduced tumor volume in vivo without causing weight loss or adverse effects in mice. Conclusions This study identifies ML as a promising therapeutic agent that, when combined with chemotherapy, may offer a novel strategy for treating colorectal and anaplastic thyroid cancers.

Implantable sensors are redefining real‐time, continuous physiological monitoring and hold great promise for personalized medicine. Yet, their clinical application is often hindered by the lack of effective encapsulation materials that simultaneously ensure environmental exposure and protect sensor components, thereby preserving signal fidelity. Although hydrogel‐based systems offer promising features such as biological tissue‐like mechanics and biocompatibility, their use as sensor coatings remains limited. Notably, despite growing interest in bioresorbable implant technologies, few coating systems offer controlled, on‐demand degradability, which represents a key requirement to avoid possible misalignment between coating dissolution rate and sensor lifetime. Here, we present a thermoresponsive hydrogel, consisting of methylcellulose, polyethylene glycol and polyacrylic acid (MC/PEG/PAA), demonstrating its high suitability as a transient encapsulating coating. The system, assembled by physical cross‐linking without using toxic reagents, and extensively characterized in terms of thermal responsiveness, swelling behavior, stability, and mechanical performance, exhibited reversible dissolution upon a mild temperature drop (from ≈37°C to ≈25°C), which was conveniently used to easily enable its degradation under physiological conditions. The hydrogel ability to act as a coating was demonstrated via the encapsulation of a fluorescent model device, confirming its optical transparency and signal‐transmission capability. In vitro studies indicated the hydrogel potential to mitigate inflammatory response, while in vivo biocompatibility, assessed in mice, revealed no signs of systemic toxicity or behavioral changes post‐implantation. Additionally, the hydrogel exhibited safe in vivo biodegradation upon a slight local temperature decrease, completely dissolving within few minutes. The developed coating, integrating good optical transparency, ease of fabrication, and in vivo safety with on‐demand, controllable degradation upon an external low‐temperature stimulus, represents a substantial advancement toward next‐generation bioresorbable implantable devices and paves the way for driving successful transformation in the field.

Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments. Hydrogen sulfide (H₂S) is an endogenous gasotransmitter that exerts pleiotropic neuromodulatory, anti-inflammatory, cytoprotective, and trophic effects within the central nervous system. Objectuves: This study investigated whether chronic inhalation of naturally H₂S-rich sulphureous water, a non-invasive and clinically applicable intervention, exerts neuroprotective effects in 5XFAD mice, a transgenic model of severe AD pathology. Methods: Two-month-old male and female wild-type and 5XFAD mice underwent daily inhalation of saline or sulphureous water for eight weeks. Sulphureous water exposure was well tolerated and did not impair baseline learning or memory in either genotype. A detailed analysis of swim trajectories revealed selective enhancement of spatially accurate navigation strategies in sulphureous water-exposed 5XFAD female mice, with nearly a threefold increase in effective search behaviors, whereas male mice showed no treatment-specific effects. In addition, sulphureous water inhalation significantly reduced the number and area of 6E10⁺ and 11A1⁺ amyloid-β plaques in corticohippocampal regions and decreased cortical microglia number. Transcriptional profiling of cortical tissue revealed strong genotype-dependent upregulation of microglial, inflammatory, and stress-response genes. Sulphureous water exposure selectively modulated inflammatory and stress-response genes, including Cd11b, Cst, Sod1, Tgfb1, and Hsp90a, with distinct genotype-dependent interactions. Results: Overall, chronic inhalation of naturally H₂S-rich sulphureous water during the prodromal phase of AD-like pathology mitigated early amyloid burden, reduced cortical microgliosis, and improved qualitative aspects of spatial navigation, particularly in female mice. Conclusions: These findings warrant further translational investigation of sulphureous water inhalation as a potential preventive or disease-modifying strategy for AD in humans.