Despite decades of research, no therapies are available to halt or slow down the course of neuro-degenerative disorders. Most of the drugs developed to fight neurodegeneration are aimed to alleviate symptoms, but none has proven adequate in altering the course of the pathologies. Cell therapy has emerged as an intriguing alternative to the classical pharmacological approach. Cell therapy consists of the transplantation of stem cells that can be obtained from various embryonal and adult tissues. Whereas the former holds notable ethical issue, adult somatic stem cells can be obtained without major concerns. However, most adult stem cells, such as those derived from the bone marrow, are committed toward the mesodermal lineage, and hence need to be reprogrammed to induce the differentiation into the neurons. The discovery of neural crest stem cells in the dental pulp, both in adults’ molar and in baby teeth (dental pulp stem cells and stem cells from human exfoliated deciduous teeth, respectively) prompted researchers to investigate their utility as therapy in nervous system disorders. In this review, we recapitulate the advancements on the application of these stem cells in preclinical models of neurodegenerative diseases, highlighting differences and analogies in their maintenance, differentiation, and potential clinical application.

Thyroid cancer (TC) incidence is rising, necessitating a refined understanding of its complex biology, particularly for advanced forms. This review synthesizes the state-of-the-art knowledge, guided by the WHO 5th Classification (2022), which incorporates molecular findings and introduces categories like Differentiated High-Grade Thyroid Carcinoma (DHGTC) to better stratify prognosis. The review summarizes the molecular changes in thyroid cancer (TC) by establishing a clear link between specific oncogenic alterations and the resulting tumor phenotype, prognosis, risk stratification and therapeutic vulnerabilities. The central importance of the review lies in its comprehensive integration of these molecular changes with the resulting immunological microenvironment and the rationale for novel, personalized therapies. Moreover, high-level genomic instability within aggressive thyroid malignancies promotes an immunosuppressive tumor microenvironment via the selection and recruitment of suppressive immune components, contributing to immune evasion and poor prognosis. This characteristic immunosuppression identifies the aggressive tumors as prime candidates for targeted immunotherapies. The review implicitly argues that understanding the molecular drivers of this immunosuppression is essential for designing effective clinical trials using these novel agents. Diagnostic advancements, including molecular testing for high-risk mutations (BRAF, TERT) and the integration of Artificial Intelligence (AI) for refined risk stratification, are enabling personalized treatment. The evolving molecular and clinical understanding allows for a paradigm shift toward individualized therapies that balance optimal disease control with minimizing morbidity, especially in the context of high-risk disease.

Proteins tend to misfold upon stressful events that alter their homeostasis, potentially leading to protein aggregation. A tight regulation of synthesis, folding and degradation, defined as proteostasis network (PN), is required to ensure the functionality of the cell. PN is of utmost importance in post-mitotic cells such as neurons, where protein quality must be preserved for their entire lifetime. Most neurodegenerative disorders are associated with dysregulation of this network. Here, we describe the alteration in key components of the PN during chronic stress and link them with the increase in the amyloid burden and with the aggregation of the protein TDP-43, a major player in Amyotrophic Lateral Sclerosis and other neurodegenerative diseases. Neuroblastoma SH-SY5Y cells were treated with a panel of environmental stressors and analyzed after 24 h and 72 h. Treatments resulted in altered PN functionality, including proteasome impairment, halted protein synthesis, engulfed bulk and selective autophagy, in the absence of overt cell death. Thioflavin staining showed increased amyloid burden throughout treatments, associated with phosphorylated TDP-43 (pTDP-43). Biochemical analyses further revealed the cleavage and increased insolubility of pTDP-43. Our results suggest that TDP-43 is a central player during the integrated stress response to chr onic insults and that increased amyloid burden may reflect the global wellfare of a cellular system, pointing toward the alteration of the PN as the main drive for the onset of sporadic neurodegenerative disorders.

Background/Objectives: In this study, we investigated the effect on antioxidant defenses of a tomato extract obtained by supercritical CO₂ extraction (sCO₂TE), evaluating whether this green extraction method preserves biological activity compared to a conventional tomato extract (CTE) and focusing on superoxide dismutase (SOD) and glutathione peroxidase (GPx) regulation, Nuclear factor erythroid 2-related factor 2 (NRF2) activation, reactive oxygen species (ROS) and lipid peroxidation modulation. Methods: Human glioblastoma astrocytoma U-373 cells were pre-treated with sCO₂TE or conventional tomato extract (CTE) and subsequently exposed to sodium arsenite (AsNaO₂) to induce oxidative stress, or lipopolysaccharide (LPS) to trigger inflammatory signaling. Cell viability was assessed by Trypan Blue and MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide]; cell toxicity by propidium iodide staining. Intracellular ROS and lipid peroxidation were measured by flow cytometry. Gene expression of NRF2, SOD1 and GPX1 was analyzed by qRT-PCR, NRF2 activation and modulation of ERK1/2 (Extracellular Signal-Regulated Kinase 1/2) and NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) were evaluated by Western blot. Results: Pre-treatment with sCO₂TE significantly reduced AsNaO₂-induced ROS production and lipid peroxidation, showing a stronger effect compared to CTE. sCO₂TE enhanced the expression of NRF2 phosphorylation and its downstream targets SOD1 and GPX1, particularly under oxidative stress conditions. In addition, sCO₂TE attenuated LPS-induced phosphorylation of ERK1/2 and NF-κB p65, suggesting anti-inflammatory activity. Conclusions: These findings demonstrate that sCO₂TE preserves the antioxidant and anti-inflammatory properties of tomato-derived bioactives. The comparable efficacy of sCO₂TE and CTE supports the use of sCO₂ as a sustainable and solvent-free extraction method for the development of nutraceutical formulations targeting oxidative stress and neuroinflammation.

Neuroglobin (Ngb) is a nerve hemeprotein that acts as a neuroprotectant against multiple brain injuries, including oxidative stress and β-amyloid toxicity. Besides inhibiting apoptosis and scavenging ROS/RNS, Ngb overexpression promotes autophagy, a highly conserved catabolic process essential for maintaining cellular homeostasis under both basal and stress conditions. Although Ngb upregulation has proven effective in animal models of neurological diseases, its effects have not yet been studied in three-dimensional (3D) cell cultures, which better mimic in vivo tissue architecture than monolayers. Therefore, in the present work we developed a simple yet reliable 3D model of Ngb overexpression using human SH-SY5Y neuroblastoma cells and examined its response to 1-methyl-4-phenylpyridinium (MPP+), a well-established in vitro model of Parkinson's disease (PD)-related neurodegeneration. Control and Ngb-overexpressing spheroids were generated using the hanging drop method. Ngb overexpression decreased MPP+ -induced ROS production and cell death, thus validating our 3D model. Additionally, biochemical fractionation and Thioflavin-S staining showed that Ngb upregulation reduces MPP+ -induced impairment of autophagy and amyloid accumulation, key pathological features of neurodegeneration. Overall, our findings emphasize the importance of 3D cultures for studying Ngb-mediated neuroprotection and suggest that Ngb upregulation may prevent the disruption of neuronal proteostasis under neurotoxic stress.