Search Results (6,028)

Aging is often a choice between developing cancer or autoimmune disorders, often due in part to loss of self-tolerance or loss of immunological recognition of rogue-acting tumor cells. Self-tolerance and cell recognition by the immune system are processes very much dependent on the specific signatures of glycans and glycosylated factors present on the cell plasma membrane or in the stromal components of tissue. Glycosylated factors are generated in nearly innumerable variations in nature, allowing for the immensely diverse role of these factors in aging and flexibility necessary for cellular interactions in tissue functionality. In previous studies, we showed that differential expression of TMEM230, an endoplasmic reticulum (ER) protein was associated with specific signatures of enzymes regulating glycan synthesis and processing and glycosylation in rheumatoid arthritis synovial tissue using single-cell transcript sequencing. In this current study, we characterize the genes and pathways co-modulated in all cell types of the synovial tissue with the enzymes regulating glycan synthesis and processing, as well as glycosylation. Genes and biological and molecular pathways associated with hallmarks of aging were in mitochondria-dependent oxidative phosphorylation and reactive oxygen species synthesis, ER-dependent stress and unfolded protein response, DNA repair (UV response and P53 signaling pathways), and senescence, glycolysis and apoptosis regulation through PI3K-AKT-mTOR signaling have been shown to play important roles in aging or neurodegeneration (such as Parkinson’s and Alzheimer’s disease). We propose that the downregulation of TMEM230 and RNASET2 may represent a paradigm for the study of age-dependent autoimmune disorders due to their role in regulating glycosylation, unfolded protein response, and PI3K-AKT-mTOR signaling. Full article

This study investigated the neuroprotective activity of oligomeric stilbenes (OSs) derived from Alpha grape stems in various in vitro models of Parkinson’s disease (PD). Using neurotoxin-induced cellular models, including 1-methyl-4-phenylpyridine (MPP+), paraquat (PQ), 6-hydroxydopamine (6-OHDA), and rotenone, we screened the cytoprotective effects of ampelopsin A (1), ε-viniferin (2), vitisin D (3), vitisin A (4), α-viniferin (5), trans-vitisin B (6), cis-vitisin B (7), and melanoxylin A (8). The results demonstrate that certain stilbenes significantly enhanced cell viability and reduced reactive oxygen species (ROS) levels in neurotoxin-treated Neuro-2a cells. Notably, vitisin A and trans-vitisin B exhibited promising neuroprotective properties by decreasing mitochondrial ROS and cardiolipin peroxidation. This study highlights the potential of these compounds in mitigating oxidative stress and inflammation associated with PD. Additionally, we provided new insights into the antioxidant mechanisms of these stilbenes, including their direct ROS-scavenging abilities. Our findings contribute to the understanding of oligomeric stilbenes as potential therapeutic agents for the prevention and treatment of neurodegenerative diseases, particularly those associated with oxidative damage. Further research is warranted to explore its clinical applications and underlying mechanisms of action. Full article

Parkinson’s Disease (PD) is the most frequent movement disorder and is second only to Alzheimer’s Disease as the most frequent neurodegenerative pathology. Early onset Parkinson’s disease (EOPD) is less common and may be characterized by genetic predisposition. NGS testing might be useful in the diagnostic assessment of these patients. A panel of eight genes (SNCA, PRKN, PINK1, DJ1, LRRK2, FBXO7, GBA1 and HFE) was validated and used as a diagnostic tool. A total of 38 in sequence EOPD patients of the Parkinson’s Disease Unit of our Hospital Institution were tested. In addition, the number of the hexanucleotide repeats of the C9ORF72 gene and the frequency of main HFE mutations were evaluated. Six patients were carriers of likely pathogenic mutations in heterozygosity in the analyzed genes, one of them presented mutations in association and another had a complex genetic background. Their clinical symptoms were correlated with their genotypes. In the cohort of patients, only the p.Cys282Tyr of HFE was significantly decreased in the dominant model and allele contrast comparison. Only one patient with one allele of C9ORF72 containing 10 repeats was identified and clinically described. The clinical signs of sporadic and monogenic PD are often very similar; for this reason, it is fundamental to correlate genotypes and phenotypes, as we tried to describe here, to better classify PD patients with the aim to deepen our knowledge in the molecular mechanisms involved and collaborate in reaching a personalized management and treatment. Full article

Background/Objectives: This paper is significant in highlighting the importance of early and precise diagnosis of Parkinson’s Disease (PD) that affects both motor and non-motor functions to achieve better disease control and patient outcomes. This study seeks to assess the effectiveness of machine learning algorithms optimized to classify PD based on vocal characteristics to serve as a non-invasive and easily accessible diagnostic tool. Methods: This study used a publicly available dataset of vocal samples from 188 people with PD and 64 controls. Acoustic features like baseline characteristics, time-frequency components, Mel Frequency Cepstral Coefficients (MFCCs), and wavelet transform-based metrics were extracted and analyzed. The Chi-Square test was used for feature selection to determine the most important attributes that enhanced the accuracy of the classification. Six different machine learning classifiers, namely SVM, k-NN, DT, NN, Ensemble and Stacking models, were developed and optimized via Bayesian Optimization (BO), Grid Search (GS) and Random Search (RS). Accuracy, precision, recall, F1-score and AUC-ROC were used for evaluation. Results: It has been found that Stacking models, especially those fine-tuned via Grid Search, yielded the best performance with 92.07% accuracy and an F1-score of 0.95. In addition to that, the choice of relevant vocal features, in conjunction with the Chi-Square feature selection method, greatly enhanced the computational efficiency and classification performance. Conclusions: This study highlights the potential of combining advanced feature selection techniques with hyperparameter optimization strategies to enhance machine learning-based PD diagnosis using vocal characteristics. Ensemble models proved particularly effective in handling complex datasets, demonstrating robust diagnostic performance. Future research may focus on deep learning approaches and temporal feature integration to further improve diagnostic accuracy and scalability for clinical applications. Full article

Parkinson’s disease (PD) is the second most common neurodegenerative disease, and its prevalence is expected to double in the next 30 years. Currently, no effective treatment exists for Parkinson’s disease. Thus, the research has focused on discovering new natural compounds with strong neuroprotective potential. This study aimed to investigate the effects of the methanol extract of Desmodesmus arthrodesmiformis EM13 (DaMe) on the mitochondrial damage pathway in an in vitro model of PD. The isolate of Desmodesmus arthrodesmiformis EM13 was first grown under appropriate culture conditions, and then the extract (DaMe) was prepared for use in the experiments. The total lipid and protein contents, fatty acid composition, and elemental content of DaMe were subsequently determined. Human SH-SY5Y neuroblastoma cells were pretreated with nontoxic concentrations of DaMe before 6-hydroxydopamine (6-OHDA) toxicity. Pretreatment with DaMe at concentrations of 100, 250, and 500 µg/mL showed a neuroprotective effect on 6-OHDA-induced SH-SY5Y neuroblastoma cells by decreasing the reactive oxygen species (ROS) production, decreasing the total oxidant status (TOS), increasing the total antioxidant capacity (TAC), increasing the mitochondrial membrane potential (ΔΨm), decreasing the oxidative DNA damage, and regulating gene expressions related to PD and apoptosis. Given the results of our study, we suggest that DaMe can be used as a natural source for producing drugs and dietary supplements intended to treat PD. Full article

Microplastics (MPs), defined as plastic particles smaller than 5 mm, have emerged as a global environmental and public health crisis, infiltrating air, water, soil, and food systems worldwide. MPs originate from the breakdown of larger plastic debris, single-use plastics, and industrial processes, entering food. Emerging evidence underscores the ability of MPs to cross biological barriers, including the blood–brain barrier, triggering neuroinflammatory responses and contributing to neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Polystyrene (PS), a common type of MP, activates microglial cells, releasing pro-inflammatory cytokines like tumor necrosis factor (TNF-α) and interleukins, which increase neuronal damage. MPs have also been linked to cardiovascular diseases, with studies detecting polyethylene (PE) and polyvinyl chloride (PVC) in carotid artery plaques, increasing the risk of myocardial infarction and stroke. Furthermore, MPs disrupt endocrine function, alter lipid metabolism, and induce gut microbiome imbalances, posing multifaceted health risks. In the MENA region, MP pollution is particularly severe, with the Mediterranean Sea receiving an estimated 570,000 tons of plastic annually, equivalent to 33,800 plastic bottles per minute. Studies in Egypt, Lebanon, and Tunisia document high MP concentrations in marine ecosystems, with herbivorous fish like Siganus rivulatus containing over 1000 MPs per individual due to the ingestion of contaminated seaweed. Despite these findings, public awareness and regulatory frameworks remain inadequate, with only 24% of Egyptians demonstrating sufficient knowledge of safe plastic use. This review emphasizes the urgent need for region-specific research, policy interventions, and public awareness campaigns to address MP pollution. Recommendations include sustainable waste management practices, the promotion of biodegradable alternatives, and enhanced monitoring systems to mitigate the health and environmental impacts of MPs in the MENA region. Full article

Peak1-related, kinase-activating pseudokinase 1 (PRAG1), a member of the pseudopodium-enriched atypical kinase (PEAK) family of pseudokinases, has been reported to play a role in regulating cell morphology. However, the molecular mechanism for this function remains elusive. In this study, we demonstrate that PRAG1 forms dynamic condensates in cells mediated by its αN and αJ helices. Importantly, we found that PRAG1 condensates functioned in mediating cell contraction, while condensate-formation-deficient PRAG1 mutants lost this function. Remarkably, the formation of spherical PRAG1 condensates appears to be a common phenomenon in diverse stress models, as well as in dopaminergic (DA) neurons derived from a Parkinson’s disease patient. Our findings reveal a novel mechanism through which PRAG1 drives cell contraction and suggest a potential link between aberrant PRAG1 phase separation and stress-induced cell contraction. PRAG1 condensation drives cell contraction under stress. Full article

The cholinergic pathways in the central nervous system (CNS) play a pivotal role in different cognitive functions of the brain, such as memory and learning. This review takes a dive into the pharmacological side of this important part of CNS function, taking into consideration muscarinic receptors and cholinesterase enzymes. Targeting a specific subtype of five primary muscarinic receptor subtypes (M1-M5) through agonism or antagonism may benefit patients; thus, there is a great pharmaceutical research interest. Inhibition of AChE and BChE, orthosteric or allosteric, or partial agonism of M1 mAChR are correlated with Alzheimer’s disease (AD) symptoms improvement. Agonism or antagonism on different muscarinic receptor subunits may lessen schizophrenia symptoms (especially positive allosteric modulation of M4 mAChR). Selective antagonism of M4 mAChR is a promising treatment for Parkinson’s disease and dystonia, and the adverse effects are limited compared to inhibition of all five mAChR. Additionally, selective M5 antagonism plays a role in drug independence behavior. M3 mAChR overexpression is associated with malignancies, and M3R antagonists seem to have a therapeutic potential in cancer, while M1R and M2R inhibition leads to reduction of neoangiogenesis. Depending on the type of cancer, agonism of mAChR may promote cancer cell proliferation (as M3R agonism does) or protection against further tumor development (M1R agonism). Thus, there is an intense need to discover new potent compounds with specific action on muscarinic receptor subtypes. Chemical structures, chemical modification of function groups aiming at action enhancement, reduction of adverse effects, and optimization of Drug Metabolism and Pharmacokinetics (DMPK) will be further discussed, as well as protein–ligand docking. Full article

The ubiquitin-protein ligase E3A (UBE3A, aka E6-AP), an E3 ligase belonging to the HECT family, plays crucial roles in the stability of various proteins through the proteasomal degradation system. Abnormal UBE3A activity is essential for the initiation and progression of several cancers. A gain of function and an overdosage of maternal UBE3A is associated with an increased risk of autism spectrum disorders. Conversely, a loss of function due to mutations, deletions, paternal duplications, or imprinting defects in neurons leads to Angelman syndrome. Emerging evidence suggests that abnormal UBE3A activity may also contribute to the development of various brain disorders, including schizophrenia, Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease, making UBE3A a protein of significant interest. However, research on UBE3A’s functions in the brain has primarily focused on neurons due to the imprinting of UBE3A in mature neuronal cells, while being obscured in glia. This review outlines the expression of UBE3A in neurons and glial cells based on published studies, highlights newly identified patterns of UBE3A, such as its secretion, and emphasizes the involvement of UBE3A in neurodegenerative diseases. Furthermore, we summarize glial UBE3A and propose a model of bi-directional interactions between the neurons and glia mediated by UBE3A that underlies brain functions. Insights gained from this research could provide new avenues for therapeutic interventions targeting various brain disorders. Full article

Seaweed plays an essential role in the survival of marine life, provides habitats and helps in nutrient recycling. It is rich in valuable nutritious compounds such as pigments, proteins, polysaccharides, minerals, vitamins, omega-rich oils, secondary metabolites, fibers and sterols. Pigments like fucoxanthin and astaxanthin and polysaccharides like laminarin, fucoidan, galactan and ulvan possess immune-modulatory and immune-enhancing properties. Moreover, they show antioxidative, antidiabetic, anticancer, anti-inflammatory, antiproliferative, anti-obesity, antimicrobial, anticoagulation and anti-aging properties and can prevent diseases such as Alzheimer’s and Parkinson’s and cardiovascular diseases. Though seaweed is frequently consumed by Eastern Asian countries like China, Japan, and Korea and has gained the attention of Western countries in recent years due to its nutritional properties, its consumption on a global scale is very limited because of a lack of awareness. Thus, to incorporate seaweed into the global diet and to make it familiar as a functional food, issues such as large-scale cultivation, processing, consumer acceptance and the development of seaweed-based food products need to be addressed. This review is intended to give a brief overview of the present status of seaweed, its nutritional value and its bioactive metabolites as functional foods for human health and diseases owing to its immunity-boosting potential. Further, seaweed as a source of sustainable food and its prospects along with its issues are discussed in this review. Full article

ANXA2 is a multifunctional member of the annexin protein family, implicated in vesicular transport, antioxidant defense, and actin remodeling. Its role in oncogenesis is actively investigated, notably in glioblastoma, astrocytoma, and breast cancer. However, a growing body of literature explores ANXA2’s involvement in neurodegenerative processes. The evidence suggests a potential contribution of ANXA2 to the pathogenesis of primary and secondary tauopathies, as well as Parkinson’s disease. It is crucial to note that the majority of these findings are correlative and necessitate further experimental validation. This review therefore presents a comprehensive analysis of data pertaining to ANXA2’s involvement in various cellular processes, the disruption of which contributes to neurological pathologies. Full article

Supported lipid bilayers (SLBs) that model neuronal membranes are needed to explore the role of membrane lipids in the misfolding and aggregation of amyloid proteins associated with neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease. The neuronal membranes include not only phospholipids, but also significant amounts of cholesterol, sphingomyelin, and gangliosides, which are critical to its biological function. In this study, we explored the conditions for the formation of an SLB, for the five-component lipid mixture composed of zwitterionic 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), anionic 1,2-dioleoyl- sn-glycero-3-phospho-L-serine (DOPS), nonionic cholesterol (Chol), zwitterionic sphingomyelin (SM), and anionic ganglioside (GM), using the quartz crystal microbalance with dissipation monitoring (QCM-D) technique, by varying experimental parameters such as pH, buffer type, temperature, vesicle size, and osmotic stress. SLB formation from this multicomponent lipid system was found challenging because the vesicles adsorbed intact on the quartz crystal and failed to rupture. For most of the variables tested, other than osmotic stress, we found no or only partial vesicle rupture leading to either a supported layer of vesicles or a partial SLB that included unruptured vesicles. When osmotic stress was applied to the vesicles already adsorbed on the surface, by having a different salt concentration in the rinse buffer that follows vesicle flow compared to that of the dilution buffer during vesicle flow and adsorption, vesicle rupture increased, but it remained incomplete. In contrast, when osmotic stress was applied during vesicle flow and adsorption on the surface, by having different salt concentrations in the dilution buffer in which vesicles flowed compared to the hydration buffer in which vesicles were prepared, complete vesicle rupture and successful formation of a rigid SLB was demonstrated. The robustness of this approach to form SLBs by applying osmotic stress during vesicle adsorption was found to be independent of the number of lipid components, as shown by SLB formation from the 1-, 2-, 3-, 4-, and 5-component lipid systems. Full article

Background/Objectives: Parkinson’s disease (PD) is a neuro-degenerative disease for which a radical cure is not available, only symptomatic control. Studies have shown that hypoxia may have disease-modifying effects on PD. Methods: Herein, we investigated whether short-term hypoxia activates astrocytes and whether it has a protective effect on pre-formed fibril (PFF)-treated primary cortical neurons. Results: Long-term hypoxia suppresses astrocyte activation and induces cell death, whereas short-term hypoxia activates astrocytes without affecting cellular apoptosis or viability. Short-term hypoxia restored the cellular apoptosis and viability of PFF-treated neurons and reduced toxic phospho-α-synuclein (p-α-syn) aggregation. Similarly, the short-term hypoxia-exposed astrocyte-conditioned medium rescued cellular apoptosis and the viability of PFF-treated neurons and p-α-syn expression. Quantitative polymerase chain reaction revealed that short-term hypoxia promotes protective A2 astrocytes and suppresses toxic A1 astrocytes. Conclusions: Our findings suggest that short-term hypoxia has a neuro-protective effect against PD by activating protective A2 astrocytes, which rescue PFF-induced neuronal cell death. This provides insights into the clinical implications of short-term hypoxia as a disease-modifying PD strategy. Full article

Neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), represent a growing global health challenge with overlapping biomarkers. Key biomarkers, including α-synucleins, amyloid-β, and Tau proteins, are critical for accurate detection but are often assessed using conventional methods like enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR), which are invasive, costly, and time-intensive. Electrochemical biosensors have emerged as promising tools for biomarker detection due to their high sensitivity, rapid response, and potential for miniaturization. The integration of nanomaterials has further enhanced their performance, improving sensitivity, specificity, and practical application. To this end, this review provides a comprehensive overview of recent advances in electrochemical biosensors for detecting neurodegenerative disease biomarkers, highlighting their strengths, limitations, and future opportunities. By addressing the challenges of early diagnosis, this work aims to stimulate interdisciplinary innovation and improve clinical outcomes for neurodegenerative disease patients. Full article

As the blood–brain barrier (BBB) prevents molecules from accessing the central nervous system (CNS), the traditional systemic delivery of chemical drugs limits the development of neurological drugs. However, in recent years, innovative therapeutic strategies have tried to bypass the restriction of traditional drug delivery methods. In vivo gene therapy refers to emerging biopharma vectors that carry the specific genes and target and infect specific tissues; these infected cells and tissues then undergo fundamental changes at the genetic level and produce therapeutic proteins or substances, thus providing therapeutic benefits. Clinical and preclinical trials mainly utilize adeno-associated viruses (AAVs), lentiviruses (LVs), and other viruses as gene vectors for disease investigation. Although LVs have a higher gene-carrying capacity, the vector of choice for many neurological diseases is the AAV vector due to its safety and long-term transgene expression in neurons. Here, we review the basic biology of AAVs and summarize some key issues in recombinant AAV (rAAV) engineering in gene therapy research; then, we summarize recent clinical trials using rAAV treatment for neurological diseases and provide translational perspectives and future challenges on target selection. Full article