Search Results (1,231)

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the presence of intracellular α-synuclein (αSyn) aggregates known as Lewy bodies (LB). αSyn, a presynaptic protein, is believed to play a crucial role in synaptic function, neurotransmitter release, and neuronal plasticity. However, its misfolding and aggregation are thought to be central to PD pathogenesis. This review provides a comprehensive analysis of αSyn’s role in PD, exploring its normal physiological functions, pathological mechanisms, and therapeutic potential. The pathological transformation of αSyn involves structural alterations that promote oligomerization and fibrillization, leading to toxic gain-of-function effects. These aggregates disrupt cellular homeostasis through mechanisms including mitochondrial dysfunction, oxidative stress, lysosomal impairment, and endoplasmic reticulum stress. Furthermore, pathogenic αSyn is thought to exacerbate neurodegeneration via prion-like spread along interconnected neuronal circuits. Emerging evidence highlights the frequent co-occurrence of other proteinopathies, such as tau and amyloid-β, which may synergistically accelerate disease progression. Targeting αSyn has emerged as a potential therapeutic strategy. Approaches such as immunotherapy, small-molecule inhibitors, gene silencing, and modulation of protein degradation pathways (e.g., autophagy and proteasomal systems) are actively being explored. Additionally, lifestyle-based interventions, particularly exercise, have shown neuroprotective effects, potentially mediated by irisin—a myokine implicated in protein clearance and synaptic resilience—underscoring the importance of multimodal strategies in PD management. Full article

Parkinson’s disease (PD), the second most common neurodegenerative disease, is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta along with the aggregation of α-synuclein in Lewy bodies. Among the pathological mechanisms involved is the alteration of iron homeostasis, which promotes oxidative stress and neuronal damage. Despite therapeutic advances, today, no treatment is available to modify the course of the disease. In this study, we investigated for the first time the neuroprotective potential of bovine lactoferrin (bLf) in both its Native (Nat-) and Holo forms, using rotenone-treated N1E-115 cells to mimic PD phenotype. The results showed that the Nat-bLf was more effective than Holo-bLf in counteracting rotenone-induced cytotoxicity and neurite retraction, preserving neuronal morphology and promoting neuritogenesis, as evidenced by increased β3-Tubulin and Growth-Associated Protein-43 markers (GAP-43). Both forms of bLf preserved Tyrosine Hydroxylase (TH) levels, crucial for dopamine synthesis, reduced the DNA damage marker γ-H2Ax and prevented rotenone-induced downregulation of Divalent Metal Transporter-1 (DMT-1) and Ferroportin (Fpn), key proteins involved in iron uptake and release, thereby limiting intracellular iron accumulation. Notably, only Nat-bLf reduced the levels of α-synuclein and markers of oxidative damage. Conversely, Holo-bLf exhibited pro-oxidant effects and increased α-synuclein accumulation even in absence of rotenone. Overall, these results highlight the differential neuroprotective effects of both Nat- and Holo-form, resulting from their distinct iron saturation level and their ability to modulate protein expression, with the native form emerging as a promising candidate for therapeutic strategies to counteract PD-associated neurodegeneration. Full article

Blocking the protein–protein interaction (PPI) between programmed cell death protein 1 (PD-1) and its ligand PD-L1 is a crucial strategy in cancer immunotherapy. However, existing monoclonal antibody-based therapies have limitations such as high production costs and poor tumor penetration. In this study, we developed a novel cyclic peptide inhibitor, PD-1-0520, through structure-based design. Starting from key fragments of PD-L1 that interact with PD-1, we designed 5 mimetic peptides and further optimized them into 22 cyclic peptide candidates. Through molecular dynamics screening and in vitro and in vivo experimental validation, PD-1-0520 was proven to have potent antitumor activities. Results showed that PD-1-0520 effectively inhibited the PD-1/PD-L1 interaction, restored the immune activity of tumor-infiltrating T cells, and achieved a 68% tumor inhibition rate in B16-F10 tumor-bearing mice without systemic toxicity. It promoted CD8⁺ T cell infiltration into tumors and upregulated activation markers, remodeling the tumor immune microenvironment. These findings demonstrate that PD-1-0520 is a promising immune checkpoint inhibitor, and our design strategy provides a new approach for developing PPI-targeting bioactive inhibitors. Full article

Src homology 2-domain containing protein tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene (Tyrosine-protein phosphatase non-receptor type 11), is a key downstream effector of PD-1/PD-L1 signaling and is likely important, in addition to immune modulation, in tumor development and vascular homeostasis. SHP2 conveys PD-1 mediated inhibitory signaling in T cells, and is emerging as a therapeutic target. Importantly, there is an association between immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs), and cardiovascular complications, underscoring the need to understand SHP2’s role in these processes. This review aims to summarize current knowledge on SHP2/PTPN11 biology, its role in immune regulation, cancer progression, and vascular homeostasis, and to discuss emerging therapeutic strategies targeting this pathway. The concept of using SHP2 inhibitors with immune checkpoint inhibitors (ICIs) is being investigated to address ICI resistance and to improve anti-tumor efficacy substantially. SHP2 is also being studied in non-cancer cell contexts, and signaling responses can differ by large magnitudes depending on the biological context and stimuli. Under normal circumstances, SHP2 promotes vascular homeostasis in endothelial cells (ECs) and myeloid cells and inhibits inflammation, and the reduction in SHP2 activity by oxidative stress, such as in atherosclerosis or diabetes, upregulates inflammation. In contrast, in response to radiation, the fibrotic response and subsequent lung injury were increased by endothelial SHP2 induction via Notch-Jag1 signaling. Vascular smooth muscle cells SHP2 act as a pro-atherogenic effector by enhancing ERK/MAPK signaling, and the upregulation of mitochondria localized SHP2 can also induce cellular senescence-associated inflammation by upregulating mitochondrial reactive oxygen species. Taken together, the two opposite signaling effects of SHP2 suggest that both the immune and vascular system responses appear to be more modulated by the redox, cell, and compartment-specific signaling of SHP2. More studies are needed for mitigating cardiovascular toxicity to patients, particularly with ICI-based treatment regimens. Full article

A carbon-supported palladium-containing polysiloxane macrocatalyst (Pd-PDMS) was developed for pharmaceutical-grade cross-coupling reactions. The catalyst demonstrates exceptional year-long stability at room temperature while maintaining full catalytic activity. Pd-PDMS efficiently promotes three pharmaceutically relevant reactions: Suzuki coupling (80% yield), copper-free Sonogashira coupling (90% yield at 55 °C), and Heck coupling (80% yield at 90 °C). The copper-free Sonogashira protocol eliminates toxic copper cocatalysts, phosphine ligands, and organic bases while operating under mild conditions. Most significantly, palladium contamination in products reaches ultra-low levels of 22 ppb (Sonogashira, Suzuki) and 167 ppb (Heck), representing a 60–450-fold improvement over European Medicines Agency requirements (10 ppm). The catalyst exhibits excellent recyclability without activity loss over multiple cycles, with simple washing protocols between uses. Scanning electron microscopy and X-ray photoelectron spectroscopy confirmed uniform Pd-PDMS coating on carbon fibers, while density functional theory calculations revealed specific coordination interactions between the palladium complex and carbon support at 3.26 Å distance. This convergence of pharmaceutical-grade metal contamination control, exceptional stability, and multi-reaction versatility establishes a significant advancement for sustainable cross-coupling catalysis in pharmaceutical applications. Full article

Catalytic upgrading of bioethanol via a C–C coupling reaction is a sustainable method of producing 1-butanol, a high-performance biofuel. This reaction was studied using a flow-through microreactor system with Pd/MgO-Al₂O₃ and bimetallic Pd-Cu/MgO-Al₂O₃ mixed oxide-based catalysts in a H₂ carrier gas at a pressure of 21 bar and temperatures ranging from 200 to 350 °C. The effect of the metal promoter(s) on the hydrogen transfer reaction steps in the overall reaction was investigated. The palladium promoter significantly improved the activity and butanol selectivity across the entire temperature range. However, the yield of liquid products decreased significantly at temperatures higher than 250 °C, primarily because the decarbonylation side reaction of the acetaldehyde intermediate accelerated. The promoting effect of Pd was most beneficial below 250 °C because the decarbonylation reaction was inhibited by the reversible poisoning effect of CO on multiple Pd sites responsible for decarbonylation. Diluting the Pd phase with Cu increased liquid yields due to gradually decreasing decarbonylation activity. However, the dehydrogenation–hydrogenation activity decreased as well, as did the promoting effect on the corresponding reaction steps in the coupling reaction. Additionally, the product distribution changed dramatically, decreasing 1-butanol selectivity, because metallic Cu can catalyze the formation of ethyl acetate and ketone products. Full article

This study presents a professional development (PD) program designed within the “SciArt—Promoting 21st-century skills through an inclusive STEAM approach to Cultural Heritage” project, which aims to prepare teachers to implement an inclusive, inquiry-based STEAM approach in their classrooms. The approach, developed collaboratively by academics from the arts, sciences, and cultural sectors across Cyprus, Greece, and Portugal, integrates archaeometric methods with cultural heritage to support identity exploration and inclusive pedagogy. The study explores how participating teachers evaluated the PD program, how it influenced their self-efficacy in applying inclusive, inquiry-based STEAM approaches, and how teacher trainers experienced its implementation across different national contexts. The study utilizes both qualitative and quantitative methods of data collection, comprising questionnaires and a focus group. Results show high teacher satisfaction and increased self-efficacy across four thematic areas: inquiry-based learning, science-heritage integration, cultural identity exploration, and use of multimodality for inclusion. Teacher trainers described the process as demanding but professionally enriching, emphasizing the role of interdisciplinary collaboration. These findings highlight the potential of well-supported, theoretically grounded PD programs to build capacity for inclusive STEAM education, while also revealing structural barriers that must be addressed for wider implementation. Full article

Reactive oxygen species (ROS) are highly reactive molecules that, when produced in excess, contribute to oxidative stress, promoting cellular damage and the progression of various diseases, including cancer. Polydatin (PD) is known for its antioxidant, anti-inflammatory, and pro-apoptotic properties, proving effective in several in vitro studies as an antitumor agent. However, its clinical application is limited by low bioavailability, poor water solubility, and chemical instability. To overcome these limitations, nanocarrier systems based on biopolymers, such as chitosan (CS), represent promising strategies for drug delivery. In this study, we developed and optimized CS nanocapsules loaded with Polydatin using the ionotropic gelation method. The final formulation was characterized by UV-Vis spectrophotometry, scanning electron microscopy (SEM), and dynamic and dielectrophoretic light scattering (DLS, DELS). Encapsulation efficiency (EE) and the biological effects of the nanocapsules on cancer cells were also evaluated. To assess their antitumor potential, PD-CS nanoparticles were tested on the human breast cancer SKBR3 cells, analyzing their effects on cell viability. The results demonstrate that CS nanocapsules loaded with PD are able to reduce SKBR3 cell proliferation, highlighting their potential for developing new therapeutic tools for cancer treatment. Full article

Background: Clear cell renal cell carcinoma (ccRCC) is a prevalent urological malignancy, accounting for approximately 1.6% of all cancer-related deaths in 2022. While endocrine-disrupting chemicals (EDCs) have been implicated as risk factors for ccRCC, the toxicological profiles and immune mechanisms underlying Bisphenol A (BPA) exposure in ccRCC progression remain inadequately understood. Materials and Methods: Protein–protein interaction (PPI) analysis and visualization were performed on overlapping genes between ccRCC and BPA exposure. This was followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to elucidate potential underlying mechanisms. Subsequently, 108 distinct machine learning algorithm combinations were evaluated to identify the optimal predictive model. An integrated CoxBoost and Ridge regression model was constructed to develop a prognostic signature, the performance of which was rigorously validated across two independent external datasets. Finally, molecular docking analyses were employed to investigate interactions between key genes and BPA. Results: A total of 114 overlapping targets associated with both ccRCC and BPA were identified. GO and KEGG analyses revealed enrichment in cancer-related pathways, including pathways in cancer, endocrine resistance, PD-L1 expression and PD-1 checkpoint signaling, T-cell receptor signaling, endocrine function, and immune responses. Machine learning algorithm selection identified the combined CoxBoost-Ridge approach as the optimal predictive model (achieving a training set concordance index (C-index) of 0.77). This model identified eight key genes (CHRM3, GABBR1, CCR4, KCNN4, PRKCE, CYP2C9, HPGD, FASN), which were the top-ranked by coefficient magnitude in the prognostic model. The prognostic signature demonstrated robust predictive performance in two independent external validation cohorts (C-index = 0.74 in cBioPortal; C-index = 0.81 in E-MTAB-1980). Furthermore, molecular docking analyses predicted strong binding affinities between BPA and these key targets (Vina scores all <−6.5 kcal/mol), suggesting a potential mechanism through which BPA may modulate their activity to promote renal carcinogenesis. Collectively, These findings suggested potential molecular mechanisms that may underpin BPA-induced ccRCC progression, generating hypotheses for future experimental validation. Conclusions: These findings enhance our understanding of the molecular mechanisms by which BPA induces ccRCC and highlight potential targets for therapeutic intervention, particularly in endocrine and immune-related pathways. This underscores the need for collaborative efforts to mitigate the impact of environmental toxins like BPA on public health. Full article

Background/Objectives: In children developing B-cell acute lymphoblastic leukemia (B-ALL), an immune evasion event takes place where otherwise “silent” preleukemic cells undergo a malignant transformation while escaping immune control, often through unknown mechanisms. Methods and Results: Here, we identify the upregulation of PD-1 expression in preleukemic cells, triggered by Pax5 inactivation in mice and correlating with the time of conversion to leukemia, as a novel marker that favors leukemia evasion. This increase in PD-1 expression is apparent across diverse molecular B-ALL subtypes, both in mice and humans. PD-1 is not required for B-cell leukemogenesis, but, in the absence of PD-1, tumor cells express NK cell inhibitory receptors, highlighting the necessity for leukemic cells to evade the host’s NK immune response in order to exit the bone marrow. PD-1 expression reduces natural antitumor immune responses, but it sensitizes leukemic cells to immune checkpoint blockade strategies in mice and humans. PD-1 targeting confers clinical benefits by restoring NK-mediated tumor cell killing in vitro and eliminating tumor cells in vivo in mice engrafted with B-ALL. Conclusions: These results identify PD-1 as a new therapeutic target against leukemic progression, providing new opportunities for the treatment and possibly also the prevention of childhood B-ALL. Full article

Chlorobenzoic acids (CBAs) are a group of chlorinated persistent environmental pollutants with hard biodegradability, high water solubility, and well-documented carcinogenic and endocrine-disrupting properties. Electrocatalytic hydrodechlorination (ECH) is a highly efficient method under mild conditions without harmful by-products, but the ECH process commonly requires adding precious metal catalysts such as palladium (Pd). To address the economic constraints and more effective utilization of Pd, a palladium/manganese dioxide (Pd/MnO₂) composite catalyst was developed in this study by chemical deposition. This method utilized the excellent electrochemical activity of MnO₂ as a carrier as well as the hydrogen storage and activation capacity of Pd. The test showed the optimal Pd loading was 7.5%, and the removal percent of 2,4-dichlorobenzoic acid (2,4-DCBA), a typical CBA, reached 97.3% using 0.5 g/L of Pd/MnO₂ after 120 min of electrochemical reaction. Under these conditions, the dechlorination percent can also be as high as 89.6%. A higher current density enhanced the dechlorination efficiency but showed the lower current utilization efficiency. In practical applications, current density should be minimized on the premise of compliance with the water treatment requirement. Mechanistic studies showed that MnO₂ synergistically promoted hydrolysis dissociation and hydrogen spillover and facilitated Pd-mediated adsorption of atomic hydrogen (H*) for dehydrogenation of 2,4-DCBA. The presence of MnO₂ can effectively disperse the loaded Pd and reduce the amount of Pd via the above process. The catalyst exhibited excellent stability over multiple cycles, and the 2,4-DCBA removal could still reach more than 80% after the five cycles. This work establishes electrocatalytic strategies for effectively reducing Pd usage and maintaining high removal of typical CBAs to support CBA-related water treatment. Full article

Metabolic immune evasion is a major factor limiting the long-term efficacy of intravesical Bacillus Calmette–Guérin (BCG) therapy in non-muscle-invasive bladder cancer (NMIBC). TIA1 is a stress granule RNA-binding protein with liquid–liquid phase separation (LLPS) capacity. Its role in tumor metabolism and immunotherapy response has been unclear. Here, we demonstrated that high TIA1 expression was independently associated with favorable survival across multiple cohorts. Full-length TIA1 formed cytoplasmic condensates, repressed LDHA/PKM2/HK2, reduced lactate, and lowered extracellular acidification. A condensate-defective ΔLCD (deletion of the low-complexity domain) mutant was inactive. TIA1 showed physical association with these glycolytic mRNAs in human cells, consistent with mRNA-linked control. Condensate-competent TIA1 promoted CD8⁺ T-cell proliferation, increased CD69 and Granzyme-B, and reduced PD-1 in co-culture. TIMER (Tumor Immune Estimation Resource) and spatial-omics supported co-localization with tumoral CD8A. BCG induced this metabolic–immune signature in cell lines, murine models, and patient explants, but the effects were abolished by TIA1 knock-down. Conversely, TIA1 over-expression alone limited tumor growth and recapitulated BCG-mediated glycolytic restraint and T-cell activation. Together, these results support an LLPS-linked, mRNA-associated regulation of tumor glycolysis. BCG-driven glycolytic suppression and CD8⁺ T cell activation track with the condensate-forming capacity of TIA1. TIA1 emerges as a prognostic biomarker and a potential therapeutic axis to improve intravesical immunotherapy in NMIBC. Full article

Interleukin 17 (IL-17) is a crucial mediator at the interface of periodontal dysbiosis and host immunity. This review synthesizes current evidence on IL-17 in periodontitis (PD), its systemic connections, and the role of IL-17 gene variants. Clinical and experimental studies show that IL-17 rises in periodontal disease and is associated with the severity of PD via action on epithelial, stromal and osteoblastic cells to promote chemokine release, neutrophil recruitment, cyclooxygenase 2 and prostaglandin E2 synthesis, RANKL expression, osteoclastogenesis, and matrix metalloproteinase activity. Periodontopathogens Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans pre-activate the local inflammation-maintaining Th17 response. There is converging evidence linking IL-17-centered signaling with rheumatoid arthritis, diabetes mellitus, and psoriasis in favor of a shared inflammatory network in barrier tissues and synovium. Despite these associations, IL-17 biology is contextually determined with mucosal defense and bone homeostatic roles that caution against unidimensional explanations. Evidence on IL-17A and IL-17F polymorphisms is still heterogeneous across populations with modest and variable risk associations with PD. Clinically, IL-17 in gingival crevicular fluid, saliva, or serum is a potential monitoring biomarker when utilized along with conventional indices. Therapeutically, periodontal therapy that reduces microbial burden may inhibit IL-17 function, and IL-17-targeted therapy has to balance potential benefit to inflammation and bone resorption against safety in oral tissues. The following research must utilize harmonized case definitions, standardized sampling, and multiethnic cohorts, and it must include multiomics to be able to differentiate between causal and compensatory IL-17 signals. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and depression, are marked by progressive neuronal dysfunction and loss, yet current treatments remain largely symptomatic with limited disease-modifying efficacy. Glucagon-like peptide-1 (GLP-1), an incretin hormone traditionally associated with metabolic regulation, has emerged as a promising neuroprotective agent. Its receptor, GLP-1R, is expressed in key brain regions implicated in cognition, emotion, and motor control, including the hippocampus, frontal cortex, and substantia nigra. GLP-1R agonists (GLP-1RAs) activate multiple intracellular signaling cascades—cAMP/PKA, PI3K/Akt, and MAPK pathways—that collectively promote neuronal survival, enhance synaptic plasticity, reduce oxidative stress, inhibit apoptosis, and modulate neuroinflammation. These agents also regulate autophagy, promote remyelination, and reprogram microglial phenotypes toward anti-inflammatory states. Preclinical models have shown that GLP-1RAs reduce amyloid-β and tau pathology in AD, preserve dopaminergic neurons in PD, protect astrocytes and neural progenitors after ischemic stroke, and alleviate depressive behaviors. Notably, GLP-1RAs such as liraglutide, exenatide, and dulaglutide can cross the blood–brain barrier and have demonstrated safety and potential efficacy in early-phase clinical trials. These studies report attenuation of cortical atrophy, preservation of cerebral glucose metabolism, and improvements in quality of life, though changes in core AD biomarkers remain inconclusive. Ongoing large-scale trials (e.g., EVOKE, ELAD) are further exploring their therapeutic impact. This review consolidates the mechanistic basis and translational potential of GLP-1RAs in age-related neurodegenerative diseases, highlighting both their promise and the challenges that must be addressed in future clinical applications. Full article

This study aimed to develop seed-based mass propagation techniques for the conservation and horticultural and medicinal uses of Scrophularia koraiensis Nakai, an endemic plant in the Korean Peninsula. Seeds were collected from four different locations (accessions) and subjected to untreated (control), gibberellic acid (GA)-only treatment, cold stratification-only treatment, or a cold stratification + GA treatment. Except for seeds collected from one location, the control group exhibited low germination of below 20% in all other locations. However, the GA-only and cold stratification-only treatments released seed dormancy and promoted germination compared with the control. In particular, the cold stratification-only treatment at 5 °C for 4 weeks resulted in about 80% germination in all accessions and demonstrated positive effects on germination speed and uniformity. These findings indicated that S. koraiensis seeds exhibit non-deep physiological dormancy (PD). Upon comparing the seed dormancy classes across various species of Scrophularia, native to different continents and countries, we confirmed that PD is very well conserved in the genus Scrophularia. Therefore, the study outcomes will provide fundamental and practical insights into the seed dormancy and germination characteristics of various Scrophularia species for future studies. Full article