Search Results (114)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and oxidative stress-driven neuronal damage. Catalase, a key antioxidant enzyme, plays a vital role in decomposing hydrogen peroxide (H₂O₂) into water and oxygen, thereby protecting neurons from reactive oxygen species (ROS)-mediated toxicity. In AD, the catalase function is compromised due to reduced enzymatic activity and aggregation, which not only diminishes its protective role but also contributes to amyloid plaque formation through catalase-Aβ co-oligomers. Hence, therapeutic strategies aimed at simultaneously preventing catalase aggregation and enhancing its enzymatic function are of great interest. In this study, we screened twelve naturally occurring metabolites for their ability to modulate catalase aggregation and activity. Among these, dimethylglycine (DMG) emerged as the most potent candidate. DMG significantly inhibited thermally induced aggregation of catalase and markedly enhanced its enzymatic activity in a concentration-dependent manner. Biophysical analyses revealed that DMG stabilizes catalase by promoting its native folded conformation, as evidenced by increased melting temperature (T_m), higher Gibbs free energy of unfolding (ΔG°), and reduced exposure of hydrophobic residues. TEM imaging and Thioflavin T assays further confirmed that DMG prevented amyloid-like fibril formation. Molecular docking and dynamics simulations indicated that DMG binds to an allosteric site on catalase, providing a structural basis for its dual role in stabilization and activation. These findings highlight DMG as a promising therapeutic molecule for restoring catalase function and mitigating oxidative stress in AD. By maintaining catalase stability and activity, DMG offers potential for slowing AD progression. Full article

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a central therapeutic target in Alzheimer’s disease, as it catalyzes the rate-limiting step in amyloid-β production. Verubecestat (VER), a clinical BACE1 inhibitor, failed in late-stage trials due to limited efficacy and safety concerns. This study employed an integrative computational approach to design VER derivatives with improved binding affinity, stability, and pharmacokinetic profiles. Structural similarity analysis, Molecular docking, frontier molecular orbital (FMO) analysis, pharmacophore modeling, 200 ns molecular dynamics (MD) simulations, MM/PBSA free energy calculations, and per-residue decomposition were performed. In silico ADMET profiling assessed drug-likeness, absorption, and safety parameters. Docking and pharmacophore analyses identified derivatives with stronger complementarity in the BACE1 catalytic pocket. MD simulations revealed that VERMOD-33 and VERMOD-57 maintained low root mean square deviations (RMSDs) and stable binding orientations and induced characteristic flexibility in the flap and catalytic loops surrounding the catalytic dyad (Asp93 and Asp289), consistent with inhibitory activity. MM/PBSA confirmed the superior binding free energies of VERMOD-33 (−51.12 kcal/mol) and VERMOD-57 (−43.85 kcal/mol), both outperforming native VER (−35.33 kcal/mol). Per-residue decomposition highlighted Asp93, Asp289, and adjacent flap residues as major energetic contributors. ADMET predictions indicated improved oral absorption, BBB penetration, and no mutagenicity or toxicity alerts. Rationally designed VER derivatives, particularly VERMOD-33 and VERMOD-57, displayed enhanced binding energetics, stable inhibitory dynamics, and favorable pharmacokinetic properties compared with native VER. These findings provide a computational framework for rescuing VER and support further synthesis and experimental validation of next-generation BACE1 inhibitors for Alzheimer’s disease. Full article

The formation of hemoglobin (Hb) and myoglobin (Mb) supramolecular complexes is examined. These key proteins for oxygen transport and storage undergo conformational transitions, some of which are induced by stress factors, particularly redox-active and toxic substances, e.g., reactive oxygen species (ROS) and reactive carbonyl compounds (RCC). These modifications can lead to partial denaturation, exposure of hydrophobic regions, and loss of stability, promoting self-assembly into high-molecular structures. Reversible associations serve regulatory roles: protein stabilization, transient functional inactivation, and generation of biological signals. Irreversible associations result in the formation of stable aggregates constituting pathological hallmarks of amyloidosis and other proteopathies. Although Hb and Mb fibrillization is not part of their physiological function, under oxidative stress, altered pH, high temperatures, or the presence of post-translational modifications, they can adopt amyloid-like structures characterized by cross-β conformation. Such aggregates exhibit high resistance to proteolysis and accumulate in tissues. Understanding molecular mechanisms behind Hb and Mb aggregation is critical for the diagnosis and timely therapy of amyloid-related diseases. The stability, regular structure, and biocompatibility of Hb and Mb fibrils make them promising for biomedical applications. Functional nanomaterials based on these fibrils are being developed for high-sensitivity biosensors, bioelectronic devices, and nanocarriers for targeted drug delivery. Full article

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

Background: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of relapsed/refractory large B-cell lymphoma (LBCL), but its administration is often complicated by cytokine release syndrome (CRS). Interleukin-6 (IL-6) is widely used to monitor CRS, though its clinical value diminishes after tocilizumab administration. We aimed to evaluate serum amyloid A (SAA), a dynamic acute-phase reactant, as a treatment-independent biomarker of inflammation and toxicity in CAR-T recipients. Methods: This retrospective study included 43 adults with LBCL treated with axicabtagene ciloleucel. SAA and other inflammatory markers were assessed from lymphodepletion through day +11 post-infusion. CRS and ICANS were graded per ASTCT criteria. Statistical analyses included Mann–Whitney U tests, Spearman’s correlation, and ROC curve analysis to evaluate predictive performance. Results: SAA levels peaked at day +4 and normalized by day +11, displaying wave-like kinetics. Levels were significantly higher in patients with any-grade CRS at early timepoints but showed no association with ICANS. SAA correlated strongly with CRP, suPAR, sST2, fibrinogen, ferritin, procalcitonin, and IL-6. Compared to IL-6, SAA was more predictive of CRS at day +2 and +4, and unaffected by tocilizumab. Baseline SAA also correlated with the mEASIX score, suggesting linkage to endothelial stress. Non-responders at 3-month PET had higher baseline SAA than responders (196.0 vs. 17.7 mg/L, p = 0.036), with ROC analysis yielding an AUC of 0.74 and an optimal threshold of 79.8 mg/L. Conclusions: SAA is a robust and dynamic marker of systemic inflammation, with potential utility in both toxicity monitoring and response prediction in the CAR-T setting. Its independence from IL-6 modulation positions it as a promising biomarker for future integration into clinical algorithms. Full article

Inhalation of multi-walled carbon nanotubes (MWCNTs) poses potential health risks due to their structural similarity to asbestos and their ability to induce chronic lung inflammation, fibrosis, and lung cancer in animal models. This study investigated the pulmonary inflammatory and transcriptomic responses of two distinct MWCNTs—NM-401 (long, rigid) and NM-403 (short, thin)—in rats and mice using intratracheal instillation at matched dose levels at two post-exposure time points. Both MWCNTs induced acute neutrophilic inflammation and dose-dependent transcriptomic alterations in both species, with NM-403 eliciting a stronger response. Transcriptomic profiling revealed a substantial overlap in differentially expressed genes across materials and species, particularly at the early time point. Fibrosis-associated genes were upregulated in both species, with more persistent expression observed in rats. Acute phase response genes, including Orosomucoid 1 and Lipocalin 2 were commonly induced, while Serum Amyloid A3 and Orosomucoid 2 were selectively upregulated in mice. Functional enrichment analyses showed conserved activation of immune and inflammatory pathways. Our findings show that even short, non-fiber-like MWCNTs can provoke potent and persistent pulmonary effects, challenging assumptions based solely on MWCNT properties. Despite differences in long-term responses, the overall inflammatory and transcriptional profiles showed strong interspecies concordance, suggesting that both rats and mice are relevant models for assessing MWCNT-induced pulmonary toxicity. Full article

Alzheimer’s disease (AD) is a significant global health challenge, further exacerbated by the anticipated increase in prevalence in the coming years. The accumulation of β-amyloid peptide plays a critical role in the onset of AD; however, emerging evidence suggests that soluble oligomers of β-amyloid may primarily drive the neuronal impairments associated with this condition. Additionally, neurodegenerative diseases like AD are linked to oxidative stress and reduced antioxidant capacity in the brain. Natural products, particularly polysaccharides extracted from mushrooms, have garnered interest due to their neuroprotective properties and the potential to enhance the value of natural sources in addressing human diseases. This study examines the antioxidant and neuroprotective properties of polysaccharides derived from Cyttaria espinosae Lloyd (CePs), a relatively underexplored fungus native to Chile. Using Fourier Transform Infrared Spectroscopy (FT-IR) and Gas Chromatography-Mass Spectrometry (GC-MS), we characterized CePs. We assessed their antioxidant capacity using DPPH and ABTS assays, yielding maximum inhibition rates of 32.14% and 19.10%, respectively, at a concentration of 10 mg mL⁻¹. CePs showed no toxicity in zebrafish embryos and maintained high cell viability in PC-12 cells exposed to amyloid β peptide (Aβ). Our findings suggest that CePs exhibit significant antioxidant and neuroprotective properties against Aβ peptide toxicity while remaining non-toxic to zebrafish embryos. This underscores the potential of the polysaccharides from this mushroom to serve as functional foods that mitigate oxidative stress and warrant further investigation into their mechanisms in the context of the physiopathology of Alzheimer’s disease. Full article

Catalase, a pivotal antioxidant enzyme, plays a central role in converting hydrogen peroxide (H₂O₂) into oxygen and water, thereby safeguarding cells from oxidative damage. In patients with diabetes, obesity, Alzheimer’s disease (AD), and Parkinson’s disease (PD), catalase becomes increasingly susceptible to non-enzymatic glycation, resulting in enzyme inactivation, oxidative stress, and defective mitochondrial function. This review uniquely emphasizes catalase glycation as a converging pathological mechanism that bridges metabolic and neurodegenerative disorders, underscoring its translational significance beyond prior general reviews on catalase function. In patients with metabolic diseases, glycation impairs β-cell function and insulin signaling, while in patients with neurodegeneration, it accelerates protein aggregation, mitochondrial dysfunction, and neuroinflammation. Notably, the colocalization of glycated catalase with amyloid-β and α-synuclein highlights its potential role in protein aggregation and neuronal toxicity, a mechanism not previously addressed. Therapeutically, targeting catalase glycation opens up new avenues for intervention. Natural and synthetic agents can be used to protect catalase activity by modulating glyoxalase activity, heme integrity, or carbonyl stress. Vitamins C and E, along with agents like sulforaphane and resveratrol, exert protection through complementary mechanisms, beyond ROS scavenging. Moreover, novel strategies, including Nrf2 activation and receptor for advanced glycation end products (RAGE) inhibition, are showing promise in restoring catalase activity and halting disease progression. By focusing on glycation-specific mechanisms and proposing targeted therapeutic approaches, this review positions catalase glycation as a novel and clinically relevant molecular target in patients with chronic diseases and a viable candidate for translational research aimed at improving clinical outcomes. Full article

Background/Objectives: Lysozyme-based amyloid aggregates offer a promising platform for RNA delivery due to their stability, cationic nature, biocompatibility, and ability to form well-defined structures. In this study, we evaluated their potential as drug carriers, focusing on the delivery of polyinosinic–polycytidylic acid (Poly(I:C)), an immunostimulatory synthetic RNA. To validate RNA delivery capability and rule out the possibility that observed effects arose from the lysozyme–Poly(I:C) complex itself, small interfering RNA (siRNA) was also used to verify that the successful delivery of intact and functional RNA was the cause of the observed effects. Methods: The aggregates were characterized by particle size, zeta potential, morphology, and RNA encapsulation efficiency. Results: In vitro studies using RAW 264.7 macrophage-like cells demonstrated that Poly(I:C)-loaded aggregates improved RNA uptake and triggered significant immune activation without inducing toxicity. To further confirm the potential of lysozyme amyloids in RNA delivery, GFP siRNA-loaded aggregates were evaluated in A549-GFP cells. A notable decrease in GFP expression, confirmed through confocal microscopy and flow cytometry, confirmed successful intracellular delivery. Conclusions: These results highlight the potential of lysozyme amyloids as non-viral vectors for RNA delivery, with promising applications in immunotherapy. Full article

Background: The biological mediators for the epidemiologic overlap between osteoporosis and dementia are unclear. We undertook a scoping review of clinical studies to identify genetic and biological factors linked with these degenerative conditions, exploring the mechanisms and pathways connecting both conditions. Methods: Studies selected (1) involved clinical research investigating genetic factors or biomarkers associated with dementia or osteoporosis, and (2) were published in English in a peer-reviewed journal between July 1993 and March 2025. We searched Medline Ovid, Embase, PsycINFO, the Cochrane Library, the Web of Science databases, Google Scholar, and the reference lists of studies following the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR). Results: Twenty-three studies were included in this review. These explored the role of the APOE polymorphism (n = 2) and the APOE4 allele (n = 13), associations between TREM2 mutation and late onset AD (n = 1), and associations between amyloid beta and bone remodeling (n = 1); bone-related biomarkers like DKK1, OPG, and TRAIL as predictors of cognitive change (n = 2); extracellular vesicles as bone–brain communication pathways (1); and the role of dementia-related genes (n = 1), AD-related CSF biomarkers (n = 1), and parathyroid hormone (PTH) (n = 1) in osteoporosis–dementia pathophysiology. Conclusions: Bone-related biomarkers active in the Wnt/β-Catenin pathway (Dkk1 and sclerostin) and the RANKL/RANK/OPG pathway (OPG/TRAIL ratio) present consistent evidence of involvement in AD and osteoporosis development. Reports proposing APOE4 as a causal genetic link for both osteoporosis and AD in women are not corroborated by newer observational studies. The role of Aβ toxicity in osteoporosis development is unverified in a large clinical study. Full article

Prion diseases are classically attributed to the accumulation of protease-resistant prion protein (PrP^Sc); however, recent evidence suggests that alternative misfolded prion conformers and systemic inflammatory factors may also contribute to neurodegeneration. This study investigated whether recombinant moPrP^Res, generated by incubating wild-type mouse PrP^C with bacterial lipopolysaccharide (LPS), can induce prion-like disease in FVB/N female mice, whether LPS alone causes neurodegeneration, and how LPS modulates disease progression in mice inoculated with the Rocky Mountain Laboratory (RML) strain of prions. Wild-type female FVB/N mice were randomized into six subcutaneous treatment groups: saline, LPS, moPrP^Res, moPrP^Res + LPS, RML, and RML + LPS. Animals were monitored longitudinally for survival, body weight, and clinical signs. Brain tissues were analyzed histologically and immunohistochemically for vacuolar degeneration, PrP^Sc accumulation, reactive astrogliosis, and amyloid-β plaque deposition. Recombinant moPrP^Res induced a progressive spongiform encephalopathy characterized by widespread vacuolation and astrogliosis, yet with no detectable PrP^Sc by Western blot or immunohistochemistry. LPS alone triggered a distinct neurodegenerative phenotype, including cerebellar amyloid-β plaque accumulation and terminal-stage spongiosis, with approximately 40% mortality by the end of the study. Co-administration of moPrP^Res and LPS resulted in variable regional pathology and intermediate survival (50% at 750 days post-inoculation). Interestingly, RML + LPS co-treatment led to earlier clinical onset and mortality compared to RML alone; however, vacuolation levels were not significantly elevated and, in some brain regions, were reduced. These results demonstrate that chronic endotoxemia and non-infectious misfolded PrP conformers can independently or synergistically induce key neuropathological hallmarks of prion disease, even in the absence of classical PrP^Sc. Targeting inflammatory signaling and toxic prion intermediates may offer novel therapeutic strategies for prion and prion-like disorders. Full article

Background/Objectives: Glycogen synthase kinase-3 beta (GSK3β) is a key enzyme involved in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, contributing to tau hyperphosphorylation, amyloid-beta (Aβ) aggregation, and neuronal dysfunction. Methods: This study applied a machine learning-driven virtual screening approach to identify potent natural inhibitors of GSK3β. A dataset of 3092 natural compounds was analyzed using Support Vector Machine (SVM), Random Forest (RF), and K-Nearest Neighbors (KNN), with feature selection focusing on key molecular descriptors, including lipophilicity (ALogP: −0.5 to 5.0), hydrogen bond acceptors (0–10), and McGowan volume (0.5–2.5). RF outperformed SVM and KNN, achieving the highest test accuracy (83.6%), specificity (87%), and lowest RMSE (0.3214). Results: Virtual screening using AutoDock Vina and molecular dynamics simulations (100 ns, GROMACS 2022) identified artemisinin as the top GSK3β inhibitor, with a binding affinity of −8.6 kcal/mol, interacting with key residues ASP200, CYS199, and LEU188. Dihydroartemisinin exhibited a binding affinity of −8.3 kcal/mol, reinforcing its neuroprotective potential. Pharmacokinetic predictions confirmed favorable drug-likeness (TPSA: 26.3–70.67 Ų) and non-toxicity. Conclusions: While these findings highlight artemisinin-based inhibitors as promising candidates, experimental validation and structural optimization are needed for clinical application. This study demonstrates the effectiveness of machine learning and computational screening in accelerating neurodegenerative drug discovery. Full article

The Rotimer (rotifer-specific biopolymer) like SCO-spondin (R-SSPO/1), predicted as the main component of this biopolymer, is an adequate base for the design of functional small peptides. This macromolecule is interactive and protective against neurotoxic human-type beta-amyloid 1-42 aggregates (agg-Aβ). The current work presents biological investigations and predictable molecular interaction analysis of DSSNDL and PNCRDGSDE peptides that were synthesized based on the sequences of R-SSPO/1. Viability assays (NADH-dependent cellular reduction capacity, intracellular esterase activity, and motility) were performed on differentiated neuro-type cell cultures (SH-SY5Y and PC12) and on Rotimer-depleted rotifers (Euchlanis dilatata and Lecane bulla). A control peptide (STTRPTGTT), not found in Rotimer, was also included in the study. All three peptides are present in both rotifer and human proteomes. Among these small molecules, DSSNDL showed a significant protective effect against the toxicity of agg-Aβ both in vitro and in vivo and presumably interacted with its aggregates. The stagogram analysis of amyloid–peptide complexes and the possible bonding competition of these small molecules against aggregation-specific dyes on agg-Aβ surface suggest that DSSNDL affects the properties of these neurotoxic macromolecules. This effective hexapeptide can serve as a promising candidate for further investigations into the inactivation of beta-amyloid toxicity. Full article

Postoperative peritoneal adhesion and high recurrence rates are critical challenges in the clinical treatment of colorectal cancer. In this study, based on amyloid-like protein self-assembly technology, a novel Janus protein film was developed. The protein film encapsulates glucose oxidase (GOx) and catalase (CAT), which is named PTL@GC. Through a one-step method involving cysteine-reduced lysozyme-induced amyloid-like self-assembly, the film was co-loaded with GOx and CAT to achieve synergistic anti-adhesion and anti-tumor recurrence effects. The Janus film features a hydrophobic side that stably adheres to the intestinal surface without exogenous chemical modification and a hydrophilic side that prevents adhesion. The loaded GOx selectively induces disulfidptosis in SLC7A11-overexpressing tumor cells, while CAT degrades H₂O₂ to alleviate hypoxia and inhibit oxidative stress, significantly reducing adhesion-related fibrosis. The experimental results demonstrate that PTL@GC exhibited excellent mechanical properties, high enzyme activity retention (>90%), and controllable degradability (complete metabolism within 50 days). In animal models, PTL@GC reduced postoperative adhesion area by 22.77%, decreased local tumor burden to 28.42% of the control group, and achieved an inhibition rate of 58.49%, without inducing systemic toxicity. This study presents a biologically safe and functionally synergistic approach to addressing dual complications following colorectal cancer surgery, offering potential insights for future research on multifunctional Janus materials. Full article

Soluble oligomeric forms of Amyloid-β (Aβ) are considered the major toxic species leading to the neurodegeneration underlying Alzheimer’s disease (AD). Therefore, drugs that prevent oligomer formation might be promising. The atypical dipeptide GAL-201 is orally bioavailable and interferes as a modulator of Aβ aggregation. It binds to aggregation-prone, misfolded Aβ monomers with high selectivity and affinity, thereby preventing the formation of toxic oligomers. Here, we demonstrate that the previously observed protective effect of GAL-201 on synaptic plasticity occurs irrespective of shortages and post-translational modifications (tested isoforms: Aβ_1–42, Aβ(p3-42), Aβ_1–40 and 3NTyr(10)-Aβ). Interestingly, the neuroprotective activity of a single dose of GAL-201 was still present after one week and correlated with a prevention of Aβ-induced spine loss. Furthermore, we could observe beneficial effects on spine morphology as well as the significantly reduced activation of proinflammatory microglia and astrocytes in the presence of an Aβ_1–42-derived toxicity. In line with these in vitro data, GAL-201 additionally improved hippocampus-dependent spatial learning in the “tgArcSwe” AD mouse model after a single subcutaneous administration. By this means, we observed changes in the deposition pattern: through the clustering of misfolded monomers as off-pathway non-toxic Aβ agglomerates, toxic oligomers are removed. Our results are in line with previously collected preclinical data and warrant the initiation of Investigational New Drug (IND)-enabling studies for GAL-201. By demonstrating the highly efficient detoxification of β-sheet monomers, leading to the neutralization of Aβ oligomer toxicity, GAL-201 represents a promising drug candidate against Aβ-derived pathophysiology present in AD. Full article