Search Results (32,548)

Background: Immune checkpoint inhibitors (ICIs), such as anti-programmed death (PD)-1 and anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 agents, have revolutionized oncology but are associated with immune-related adverse events (irAEs). Among these, ICI-associated myocarditis (ICI-M) is a rare but life-threatening complication, with mortality rates ranging from 27% to 50%. Objective: This narrative review summarizes the pathogenesis, epidemiology, clinical presentation, diagnostic methods, and management strategies for ICI-induced myocarditis, specifically highlighting emerging biomarkers and immunosuppressive therapeutic approaches. Results and Discussion: ICI-M typically presents within the first 65 days of treatment and is significantly more frequent with combination therapies. Pathologically, it is characterized by myocyte necrosis and massive infiltration of cluster of differentiation (CD)4+ and CD8+ T-cells, often overlapping with myositis (irM/M). Diagnosis relies on a multimodal approach. Management requires immediate ICI cessation and initiation of high-dose corticosteroids as first-line therapy. For steroid-refractory cases, second-line options include mycophenolate mofetil (MMF), intravenous immunoglobulin (IVIG), and emerging therapies like abatacept and ruxolitinib. Rechallenge with ICIs after high-grade ICI-M must be approached with extreme caution by the multidisciplinary team (MDT). Emerging biomarkers and omics techniques hold promise for earlier diagnosis and risk stratification. Conclusions: ICI-M is a rare yet highly lethal cardiac complication demanding high clinical vigilance and timely diagnosis. Management hinges on an aggressive multidisciplinary approach, aiming to minimize toxicity while balancing oncological efficacy. Full article

The detection of chiral properties is crucial for pharmacology and biochemistry, yet standard circular dichroism spectroscopy suffers from low sensitivity when probing minute sample volumes. While complex asymmetric chiral nanostructures can enhance these Circular Dichroic (CD) signals, their fabrication is intricate and costly. In this work, we analyzed an alternative based on extrinsic chirality in achiral square arrays of plasmonic circular NHAs realized via Displacement Talbot Lithography (DTL), thus exploring the chiroptical response arising from symmetry breaking induced by oblique illumination. Unlike isolated nanoparticles, nanohole arrays (NHAs) support propagating Surface Plasmon Polaritons (SPPs), allowing for unique light confinement capabilities essential for high-throughput sensing. A careful characterization in terms of Stokes parameters has been performed over a selected range of different optical angles of incidence and sample orientation to disentangle extrinsic chiral contribution from spurious effects related to sample imperfections. By optimizing such extrinsic chiral contributions, enhanced chiroptical response could be engineered by significantly amplifying the interaction between light and chiral biomolecules trapped within the holes. This methodology establishes DTL-fabricated achiral NHAs as an ultrasensitive, cost-effective platform for the detection and discrimination of enantiomers in biosensing applications. Full article

Orthodontic force magnitude influences angiogenesis during orthodontic tooth movement (OTM); however, the role of senescent cells remains largely unclear. This study investigated the localization of senescent cells and their expression of vascular endothelial growth factor (VEGF) during angiogenesis using a rat horizontal OTM model with different force magnitudes. Nickel–titanium coil springs exerting 60 g or 180 g of orthodontic force were applied to the maxillary first molar of 15-week-old male Sprague–Dawley rats; untreated rats served as controls. Tooth movement was evaluated by stereomicroscopy and micro-computed tomography. Senescent cells (p21, p16) and angiogenesis (CD31 and VEGF) were evaluated by multiplex immunofluorescence. Tooth movement was observed under both the 60 g and 180 g conditions. The 60 g group showed increased cellularity, vascular density, and VEGF expression, suggesting an optimal mechanical force. In contrast, the 180 g group reduced cellularity and angiogenesis, consistent with excessive force. Senescent cells were more abundant in the 60 g group, with over 40% expressing VEGF. These findings suggest that force magnitude influences the presence of VEGF⁺ senescent cells, which may be associated with the angiogenic process in OTM. This work provides insights into the mechanisms underlying optimal force in orthodontic treatment. Full article

Cancer stem cells (CSCs) represent a small but highly resilient tumor subpopulation responsible for sustained growth, metastasis, therapeutic resistance, and recurrence. Their survival is supported by aberrant activation of developmental and inflammatory pathways, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt/mTOR, STAT3, and NF-κB, as well as epithelial–mesenchymal transition (EMT) programs and niche-driven cues. Increasing evidence shows that phytochemicals, naturally occurring bioactive compounds from medicinal plants, can disrupt these networks through multi-targeted mechanisms. This review synthesizes current findings on prominent phytochemicals such as curcumin, sulforaphane, resveratrol, EGCG, genistein, quercetin, parthenolide, berberine, and withaferin A. Collectively, these compounds suppress CSC self-renewal, reduce sphere-forming capacity, diminish ALDH⁺ and CD44⁺/CD24⁻ fractions, reverse EMT features, and interfere with key transcriptional regulators that maintain stemness. Many phytochemicals also sensitize CSCs to chemotherapeutic agents by downregulating drug-efflux transporters (e.g., ABCB1, ABCG2) and lowering survival thresholds, resulting in enhanced apoptosis and reduced tumor-initiating potential. This review further highlights the translational challenges associated with poor solubility, rapid metabolism, and limited bioavailability of free phytochemicals. Emerging nanotechnology-based delivery systems, including polymeric nanoparticles, lipid carriers, hybrid nanocapsules, and ligand-targeted formulations, show promise in improving stability, tumor accumulation, and CSC-specific targeting. These nanoformulations consistently enhance intracellular uptake and amplify anti-CSC effects in preclinical models. Overall, the consolidated evidence supports phytochemicals as potent modulators of CSC biology and underscores the need for optimized delivery strategies and evidence-based combination regimens to achieve meaningful clinical benefit. Full article

Dextrin-based nanosponges (D-NS) are promising candidates for oral drug delivery due to their biocompatibility, mucoadhesive properties, and tunable swelling behavior. In this study, pH-sensitive nanosponges were synthesized using β-cyclodextrin (β-CD), GluciDex^®2 (GLU2), and KLEPTOSE^® Linecaps (LC) as building blocks, crosslinked with pyromellitic dianhydride (PMDA) and citric acid (CA). The nanosponges were mechanically size-reduced via homogenization and ball milling, and characterized by FTIR, TGA, dynamic light scattering (DLS), and zeta potential measurements. Swelling kinetics, cross-linking density (determined using Flory–Rehner theory), rheological behavior, and mucoadhesion were evaluated under simulated gastric and intestinal conditions. The β-CD:PMDA 1:4 NS was selected for drug studies due to its optimal balance of structural stability, swelling capacity (~863% at pH 6.8), and highest apomorphine (APO) loading (8.23%) with 90.58% encapsulation efficiency. All nanosuspensions showed favorable polydispersity index values (0.11–0.30), homogeneous size distribution, and stable zeta potentials, confirming suspension stability. Storage at 4 °C for six months revealed no changes in physicochemical properties or apomorphine (APO) degradation, indicating protection by the nanosponge matrix. D-NS exhibited tunable swelling, pH-responsive behavior, and mucoadhesive properties, with nanoparticle–mucin interactions quantified by the rheological synergism parameter (∆G′ = 53.45, ∆G″ = −36.26 at pH 6.8). In vitro release studies demonstrated slow, sustained release of APO from D-NS in simulated intestinal fluid compared to free drug diffusion, highlighting the potential of D-NS as pH-responsive, mucoadhesive carriers with controlled drug release and defined nanoparticle–mucin interactions. Full article

Microglia-derived small extracellular vesicles (MGEVs) are key mediators of neuroimmune communication, yet their cross-species comparability and translational relevance remain poorly defined. Here, we establish a harmonized framework to compare the molecular and biochemical signatures of sEVs derived from immortalized mouse (BV2) and human (HMC3) microglial cells as well as assess their bioactivity on a human Schwann cell (HuSC) line. MGEVs were isolated via MISEV-aligned size-exclusion chromatography (SEC) and characterized by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and immunoblotting for canonical EV markers CD9, CD63, CD81, TSG101. Human and mouse MGEVs exhibited similar morphology but displayed distinct membrane tetraspanin protein enrichment patterns. Functionally, mouse and human MGEVs attenuated HuSC migration while enhancing HuSC proliferation and their resistance to H₂O₂-induced oxidative stress, with human MGEVs providing stronger protective effects, suggesting they retain similar core functional properties. Short, non-coding-miRNA sequencing analysis identified 196 shared miRNAs (Spearman ρ = 0.72) with species-specific enrichment: human MGEVs-derived miRNAs favored regenerative and metabolic pathways, whereas mouse MGEVs-derived miRNAs aligned more so with inflammatory signaling. This study delivers the first integrated cross-species blueprint of MGEVs, revealing conserved neuroprotective actions alongside species-biased miRNA cargo that define translational boundaries and highlight human-relevant MGEV signatures for therapeutic innovation, therefore contributing to the importance of considering these differences in translational research. Full article

In both Alzheimer’s disease (AD) patients and animal models, senile plaques are generally observed in the cerebral cortex rather than the cerebellum. The mechanisms underlying the regional resistance of the cerebellum to amyloid plaque deposition remain poorly understood. We investigated this cerebellar resistance using 5xFAD mice, an amyloidosis model with high expression of mutant human APP and PSEN1 in the cortex and cerebellum. In aged 5xFAD mice, the cerebellum had minimal amyloid-β (Aβ) deposition despite robust transgene expression, correlating with lower expression levels of IBA1, CD68, TREM2, and CD36 (although elevated expression of CD45 and MHC I) compared to the cortex. Consistent with the absence of plaques, cerebellar tissue lacked the dystrophic VGLUT1-positive synaptic accumulations prominent in the cortex. Cerebellar microglia maintained a distinct, less inflammatory phenotype yet displayed efficient clearance activity. Notably, ASC inflammasome specks—capable of seeding Aβ aggregation—were paradoxically more abundant in the cerebellum, implying that rapid Aβ clearance prevents these seeds from driving plaque formation. Furthermore, key extracellular matrix (ECM) proteoglycans brevican and aggrecan were elevated in the 5xFAD cerebellum. Cerebellar microglia showed enhanced internalization of brevican alongside small Aβ aggregates, exceeding that in cortical microglia. These findings indicate that region-specific microglial and ECM interactions—particularly efficient uptake and degradation of ECM–Aβ co-aggregates—may underlie the cerebellum’s resilience to amyloid plaque pathology. Full article

Glioblastoma multiforme (GBM) is the most aggressive primary brain cancer (with a median survival time of 14.5 months), characterized by heterogeneity. Identifying prognostic molecular subtypes could provide a deeper exposition of GBM biology with potential therapeutic implications. In this study, we classified GBM into two prognostic subtypes, C1-GBM (n = 57; OS: 313 days) and C2-GBM (n = 109; OS: 452 days), using pathway-based signatures derived from RNA-seq data. Unsupervised consensus clustering revealed that only binary classification (cluster number, CN = 2; mean cluster consensus score = 0.84) demonstrated statistically prognostic differences. We characterized C1 and C2 based on oncogenic pathway and immune signatures. Specifically, C1-GBM was categorized as an immune-infiltrated “hot” tumor, with high infiltration of immune cells, particularly macrophages and CD4⁺ T cells, while C2-GBM as an “inherent driving” subtype, showing elevated activity in G2/M checkpoint genes. To predict the C1 or C2 classification and explore therapeutic interventions, we developed a neural network model. By using Weighted Correlation Network Analysis (WGCNA), we obtained the gene co-expression module based on both gene expression pattern and distribution among patients in TCGA dataset (n = 166) and identified nine hub genes as potentially prognostic biomarkers for the neural network. The model showed strong accuracy in predicting C1/C2 classification and prognosis, validated by the external CGGA-GBM dataset (n = 85). Based on the classification of the BP neural network model, we constructed a Cox nomogram prognostic prediction model for the TCGA-GBM dataset. We predicted potential therapeutic small molecular drugs by targeting subtype-specific oncogenic pathways and validated drug sensitivity (C1-GBM: Methotrexate and Cisplatin; C2-GBM: Cytarabine) by assessing IC₅₀ values against GBM cell lines (divided into C1/C2 subtypes based on the nine hub genes) from the Genomics of Drug Sensitivity in Cancer database. This study introduces a pathway-based prognostic molecular classification of GBM with “hot” (C1-GBM) and “inherent driving” (C2-GBM) tumor subtypes, providing a prediction model based on hub biomarkers and potential therapeutic targets for treatments. Full article

Background: Three-dimensional (3D) facial scanning is an objective, non-invasive method for quantifying facial soft-tissue changes following complete denture (CD) rehabilitation. Reliable quantification of these changes in completely edentulous patients can support more predictable aesthetic and functional outcomes. Methods: This prospective before–after observational study included 30 completely edentulous patients (12 men, 18 women; age 48–87 years; mean ± SD: 67.8 ± 9.2 years) who received new maxillary and mandibular CDs. Structured-light 3D facial scans were obtained at baseline (edentulous, without dentures) and post-rehabilitation with dentures in place, in relaxed posture (RP) and maximal intercuspation (MI). Sixty-five validated anthropometric landmarks were analyzed. Primary outcomes were lower facial height (Sn-Gn), nasolabial angle (Cm-Sn-Ls), lower facial convexity (Ls-Li-Pg), mouth width (Ch-Ch), and upper vermilion height (Ls-Sto). Pre–post changes were assessed using paired-sample tests (p < 0.05). Results: Thirty-four of 65 parameters (52.3%) demonstrated significant post-treatment changes (p < 0.05), mainly in the perioral and lower facial regions. The reported parameters were selected due to their clinical relevance in evaluating perioral support and facial profile changes after complete denture treatment. In RP, upper lip thickness increased from 3.69 ± 0.97 mm to 4.96 ± 1.11 mm (Δ = +1.27 mm; p < 0.0001) and lower lip thickness from 6.18 ± 2.69 mm to 7.36 ± 1.52 mm (Δ = +1.18 mm; p = 0.0408). The nasolabial angle decreased from 116.08 ± 9.17° to 108.06 ± 9.56° (Δ = −8.02°; p = 0.0016). In MI, mouth width increased from 55.72 ± 3.43 mm to 57.97 ± 3.13 mm (Δ = +2.25 mm; p = 0.0102). Conclusions: Complete denture rehabilitation produces measurable, clinically relevant improvements in facial soft-tissue morphology in completely edentulous patients, particularly affecting lip support, mouth width, and the nasolabial profile. Structured-light 3D facial scanning provides a reproducible approach to objective outcome assessment and may support individualized denture design. Full article

Dilovasi district of Kocaeli is one of the largest industrial regions, and due to its high production capacity and industrial waste, the soil heavy metal levels in this region are exceptionally high. Consequently, this study focuses on essential elements (B, Ca, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Zn) and non-essential elements that are considered toxic to humans (Al, Cd, Pb), covering a total of thirteen elements. Accordingly, this study aims to highlight the degree of pollution in a Turkish Organized Industrial Zone located in the Dilovasi district of Kocaeli by quantifying the concentrations of the aforementioned elements in Calamintha nepeta subsp. glandulosa plants and soil samples, and by assessing their potential implications for human health. Significant accumulation of heavy metals in both soils and plant parts suggests that metal contamination, especially that of Fe (up to 1009.2 mg kg⁻¹), is a matter of great concern in the Dilovasi district. The results revealed that the concentrations (mg kg⁻¹) of Cr (23.0 ± 0.1), Fe (1292.5 ± 5.6), Pb (36.9 ± 0.1), Zn (151.2 ± 0.8), and Cd (3.6 ± 0.1) were considerably higher. However, the concentrations of Cu, Mn, and Ni were found to be within the permissible limits in accordance with the American Herbal Products Association and the World Health Organization referenced guideline values. Furthermore, heavy metal concentrations in C. nepeta subsp. glandulosa were generally higher in areas characterized by elevated soil metal levels, indicating a clear correspondence between soil contamination and plant metal content. Based on these findings, C. nepeta subsp. glandulosa, a plant with culinary and medicinal value, can be considered a useful bioindicator for assessing local heavy metal contamination. Full article

Chagas disease (CD), caused by Trypanosoma cruzi, is a neglected tropical illness affecting 6–8 million people in Latin America. Reaching scholarly consensus on the host response to T. cruzi infection remains a significant challenge, primarily due to substantial heterogeneity in outcomes driven by both the choice of animal model and the infecting parasite’s discrete typing unit (DTU). This variability complicates the evaluation and comparison of new therapeutic compounds against existing drugs, namely benznidazole and nifurtimox. This study provides a comprehensive, kinetic, multifaceted characterization of the acute infection using the highly virulent T. cruzi Y strain (TcII) in outbred Swiss mice. Here, crucial infection parameters are presented, including the optimal infective dose, the parasitemia dynamics, tissue damage markers, hematological profiles, cytokine production (Th1/Th2/Th17/Th22), and molecular parasite identification in target organs (heart, colon, esophagus, spleen, and liver) across the span of the infection. The novelty of this study lies in the kinetic integration of these parameters within a defined model; rather than presenting isolated data points, we demonstrate how the biochemical, physiological, and clinical signs and immunological responses, with the resulting organ involvement, evolve and interact over time. To complete the report, a necropsy evaluation was performed at the end of the acute, fatal infection, and it is presented here. This study fulfills a long-standing recommendation from diverse drug discovery groups for the creation of a definitive reference model to standardize preclinical testing for anti-Chagasic agents. Full article

Extracellular vesicles (EVs) are emerging as key factors in maintaining cellular homeostasis, critical mediators of intercellular communication, potential biomarkers, and therapeutic tools. While small EVs have been extensively characterized, the molecular signatures of large EVs (including those generated during regulated cell death pathways) remain poorly defined. Here, we investigated the characteristics of large EVs released during apoptosis and pyroptosis by human monocytic cell lines (THP-1 and U937). Apoptosis was induced by staurosporine and blocked using the pan-caspase inhibitor Q-VD-OPh, whereas pyroptosis was triggered by LPS/nigericin and inhibited with a selective NLRP3 inhibitor. We found that both forms of regulated cell death markedly enhanced the release of large EVs. Both apoptotic and pyroptotic large EVs showed increased Annexin V binding and decreased CD9 expression compared with those released by healthy cells. Large EVs derived from apoptotic and pyroptotic cells exhibited distinct proteomic profiles. Pyroptotic large EVs carried interacting protein networks of RNA-binding proteins and chromatin-associated proteins many of which are known damage-associated molecular patterns or alarmins. In contrast, we found that a subpopulation of apoptotic large EVs was characterized by the presence of dsDNA, and active caspase-3/7. Together, our data shed light on the specific protein cargo of large EVs released by cells during apoptosis and pyroptosis. This study identifies candidate markers of large EVs released by dying cells and may enhance our understanding of the role of EVs in regulated cell death. Full article

Autoimmune type 1 diabetes (T1D) results from the failure of the physiologic regulatory mechanisms that are designed to maintain immune tolerance to pancreatic beta cells. Consequently, the design of strategies to restore tolerance to beta cell antigens is an attractive objective of translational research. We have designed ultrasmall nanoparticles (NPs) loaded with a proinsulin (PI) fusion protein and an agonist for the aryl hydrocarbon receptor (AhR), a transcription factor promoting tolerance induction by different immune cells. We report that a 4 week-treatment with these NPs in non-obese diabetic (NOD) mice starting at disease onset induces temporary and sometimes durable disease remission. Mechanistically, short-term NP treatment induces a rapid depletion of islet infiltrates with a dramatic reduction in the number of CD8⁺ T cells and dendritic cells. This is accompanied by the emergence of B lymphocytes producing IL-10. In the rare mice that undergo durable disease remission, the disappearance of islet infiltrates is associated with the emergence of Foxp3⁺ CD4⁺ regulatory T cells, IFN-γ-producing memory T cells in the spleen, and draining lymph nodes (LNs). We conclude that treatment with these NPs could be of interest in the treatment of recent-onset autoimmune diabetes, but is unlikely to be sufficient for the induction of long-term remission as a stand-alone therapy. Full article

Cadmium (Cd) drastically inhibits plant growth and metabolism, whereas arbuscular mycorrhizal (AM) fungi can enhance plant Cd tolerance through metabolic regulation. To clarify tissue-specific responses, we conducted a pot experiment combined with GC-MS to examine how AM fungi influence root and leaf metabolism of ryegrass (Lolium perenne L.) under different Cd levels. Root and leaf metabolomes diverged substantially in composition and function. In total, 83 metabolites were identified in roots, mainly phenolics, amines, and sugars associated with carbon–nitrogen metabolism and stress-defense pathways, whereas 75 metabolites were identified in leaves, largely related to photosynthetic metabolism. Roots were more sensitive to Cd, showing significant metabolic alterations at Cd ≥ 5 mg·kg⁻¹, including disruption of galactose metabolism, while leaves exhibited notable changes only at Cd ≥ 100 mg·kg⁻¹, with suppression of citrate, L-aspartate, and starch and sucrose metabolism. AM fungi modulated plant metabolism more strongly under Cd stress. Specifically, AM fungi restored Cd-suppressed galactose and glyoxylate/dicarboxylate metabolism in roots, enhanced starch and sucrose metabolism and amino acid pathways in leaves, and increased stress-related amino acids and organic acids in both tissues. Overall, AM fungi substantially alleviated Cd-induced metabolic inhibition, particularly at Cd ≥ 50 mg·kg⁻¹, providing mechanistic insight into AM-enhanced Cd tolerance and supporting the application of AM symbiosis in remediation of Cd-contaminated soils. Full article

Background/Objectives: Inadequate characterization of protective antigens poses a significant challenge to the development of vaccines for African swine fever (ASF), particularly for antigen-dependent formulations such as subunit, mRNA, and recombinant viral vector vaccines. To address this, we aimed to screen African swine fever virus (ASFV) antigens and enhance their immunogenicity using a nanoparticle delivery platform. Methods: Here, six ASFV antigens (p30, p54, pE120R, pH124R, pE184L, and CD2v) were purified and used to immunize pigs individually. The effects of antibodies induced by these six antigens on ASFV replication or hemadsorption was evaluated in primary porcine alveolar macrophages (PAMs). These six antigens were, respectively, conjugated to ferritin via SpyTag/SpyCatcher to prepare six ferritin nanoparticles. A cocktail of the six mixed antigens or a cocktail of the six mixed nanoparticles was used to immunize pigs separately, and the differences in induced humoral and cellular immune responses were compared. Results: Antibodies generated against p30, p54, pE120R, pH124R, and pE184L in immunized pigs significantly inhibited ASFV replication in PAMs, while anti-CD2v antibodies specifically obstructed the hemadsorption of ASFV. Notably, immunization with a cocktail of these antigen-conjugated nanoparticles elicited a stronger virus-inhibitory antibody response compared to immunization with a cocktail of antigen monomers. Furthermore, nanoparticle immunization induced robust cellular immunity, evidenced by elevated serum IFN-γ, increased numbers of ASFV-specific IFN-γ-secreting cells, and an expanded CD8⁺ T cell population. Conclusions: Our study identifies a set of promising ASFV antigen candidates and demonstrates that ferritin nanoparticle delivery synergistically enhances both humoral and cellular immune responses against ASFV, providing a rational strategy for multi-antigen ASF vaccine design. Full article