Search Results (29,034)

CAR-T cell therapy remains ineffective in most solid tumours because effector cells infiltrate poorly, undergo exhaustion, and face antigen escape within an immunosuppressive microenvironment. To address this, we developed a hybrid framework that combines a mechanistic spatiotemporal model with machine learning for limited individual-level mechanistic personalisation under data constraints. At its core, we employed a reaction–diffusion–chemotaxis model describing functional and exhausted CAR-T cells, antigen-positive and antigen-negative tumour subpopulations, a chemoattractant, an immunosuppressive factor, and hypoxia. Gradient boosting combined with nested cross-validation was used to recover model-consistent latent-parameter pseudo-labels generated by a limited inverse problem. Within this surrogate-target setting, parameters characterising the tumour microenvironment and CAR-T cell exhaustion were reproduced most robustly, whereas antigen escape and individualised initial conditions were substantially less well constrained. As an auxiliary reference point, we also considered a direct empirical baseline for binary clinical outcomes. This baseline indicated that the observed clinical features contained a more stable signal for disease control than for objective response. A favourable response was associated with high CAR-T cell infiltration and cytotoxic potency, whereas resistance was linked to exhaustion, antigen escape, and a suppressive microenvironment. Overall, the proposed approach should be interpreted as an internally validated, hypothesis-generating proof-of-concept platform for mapping clinical features to mechanistically interpretable surrogate latent targets, rather than as evidence for validated recovery of true patient-specific biological parameters. Full article

Polybrominated diphenyl ethers (PBDEs), widely used as brominated flame retardants, are known to exert persistent adverse effects on the immune systems of humans and other organisms. Previous studies have demonstrated that 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), a prevalent congener, induces apoptosis, impairs phagocytic function, and triggers aberrant immune-inflammatory reactions in RAW264.7 macrophages via the induction of elevated intracellular reactive oxygen species (ROS). However, the underlying regulatory mechanism remains unclear. The nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway is a key cellular defense system against oxidative stress. In this study, we investigated the role of the Nrf2/ARE pathway in BDE-47-induced macrophage immunotoxicity. Network toxicology analysis identified Nrf2 as a hub gene within the BDE-47-associated immunotoxicity network. Molecular docking and molecular dynamics simulations suggested a potential interaction between BDE-47 and the Keap1-Nrf2 complex, with moderate binding affinity. Experimental studies in RAW264.7 cells showed that BDE-47 exposure activated the Nrf2/ARE pathway, as evidenced by Nrf2 nuclear translocation and the differential upregulation of downstream genes (GCLC, GCLM, HO-1, NQO1, SOD1, and CAT). Importantly, Nrf2 knockdown via lentiviral shRNA or pharmacological inhibition with brusatol significantly exacerbated BDE-47-induced apoptosis and immune dysfunction, including enhanced pro-inflammatory cytokine production and impaired phagocytosis. These results demonstrate that Nrf2/ARE pathway activation represents an adaptive antioxidant response and contributes to limiting BDE-47-induced cytotoxicity and immune impairment in macrophages. Full article

Microplastics (MPs), i.e., plastic particles <5 mm, and nanoplastics (NPs), i.e., plastic particles <1 µm, are widespread in the environment. MPs and NPs (MNPs) have also been detected in human tissues. Environmental MNPs exhibit diverse physicochemical properties such as size, shape, and surface degradation. However, most experimental studies have used pristine MNPs, which poorly represent real-world conditions, and only a limited number of studies have focused on preparing environmentally relevant MNPs. Therefore, we focused on the key physicochemical properties of MNPs, particularly their shape, size, and surface degradation, using polyvinyl chloride (PVC) as the model polymer. In this study, fragment and spherical PVC-MNPs were utilized, and surface degradation was introduced through exposure to vacuum ultraviolet (VUV) radiation at a wavelength of 172 nm. Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) analysis revealed the formation of additional carbonyl groups after VUV exposure. We investigated the cytotoxic effects of the degraded and non-degraded PVC-MNPs on A549, Caco-2, and THP-1 cells. The results indicated that the degraded PVC-MNP-treated groups induced higher cytotoxic effects than those in the non-degraded groups. Notably, the degraded PVC-NPs induced stronger cytotoxicity than the degraded PVC-MPs. These findings highlight the potential health risks associated with environmental MNPs. Full article

Colorectal cancer (CRC) is the third most prevalent cancer globally. TASK-1, encoded by the KCNK3 gene, is emerging as a putative target in cancer; it regulates resting membrane potential, cell proliferation, and apoptosis. A series of 27 novel xanthene derivatives, modified at position 9, were synthesized via azide coupling of 2-(9H-xanthen-9-yl)acetohydrazide with selected amines and amino acids, followed by hydrazine-mediated conversion to the corresponding hydrazides. The cytotoxic activity of selected compounds (5a–5g, 6a–6h, 7b, 7f–7h) was evaluated against the HCT-116 cell line in vitro. In addition, molecular docking and molecular dynamics simulations were performed to investigate binding interactions and assess the stability of the protein–ligand complexes. Several compounds (5f, 5g, 6c, 6d, 6f, 6g, 7b, 7f, and 7h) exhibited moderate cytotoxic activity against HCT-116 cells (IC₅₀: 66.97–99.62 µM), compared to cisplatin (IC₅₀: 18.25 µM). Compound 7h demonstrated pronounced antiproliferative effects, evidenced by DAPI staining showing chromatin condensation and apoptotic body formation, along with a marked reduction in cell count and coverage. Molecular docking indicated favorable binding within the TASK-1 potassium channel, and molecular dynamics simulations confirmed the stability of the protein–ligand complex, with consistent interactions, including a key hydrogen bond with Asn240. These findings support 7h as a promising lead candidate. These findings identify xanthene-based derivatives as promising lead compounds for further optimization as TASK-1-targeted therapeutic candidates in colorectal cancer Full article

RNA viruses exhibit high mutation rates, necessitating antivirals targeting conserved infection mechanisms. In this study, viral hemorrhagic septicemia virus (VHSV), a non-human pathogenic negative-sense RNA virus, was used as a surrogate model to enable high-throughput antiviral screening under reduced biosafety conditions. A recombinant VHSV expressing enhanced green fluorescent protein was used to screen 17,265 compounds, 2000 plant extracts, and 100 marine extracts. Among the candidates, the leaf extract of Phellodendron amurense Rupr. (PL extract) exhibited antiviral activity with low cytotoxicity (selectivity index ≈ 10). The extract reduced viral infectivity in a dose-dependent manner and showed cross-activity against snakehead rhabdovirus. Mechanistic analyses indicated that the PL extract acts primarily at early stages of infection. Virucidal assays demonstrated direct, time-dependent inactivation of viral particles, while pre-treatment reduced host cell susceptibility. Time-of-addition experiments confirmed that antiviral activity was restricted to early infection, suggesting interference with viral attachment or entry rather than intracellular replication. Fractionation revealed that activity was associated with the non-polar n-hexane fraction, implicating lipophilic compounds that may disrupt viral envelope integrity or membrane interactions. These findings suggest that P. amurense leaf extract is a promising candidate for broad-spectrum antivirals targeting conserved entry processes in enveloped RNA viruses. Full article

Oxicam derivatives, a class of nonsteroidal anti-inflammatory drugs (NSAIDs), are important scaffolds for developing biologically active compounds. In this study, arylpiperazine oxicam derivatives (PR24–PR50) were examined for membrane interactions, cytotoxic activity, cyclooxygenase inhibition, and potential binding to COX-2 protein. Membrane interactions were examined using differential scanning calorimetry (DSC) in phospholipid bilayers formed from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). All compounds altered the thermotropic properties of the lipid bilayer, showing concentration-dependent decreases in phase transition temperature, indicating incorporation to bilayer and partial disruption of lipid organization. Cytotoxicity, assessed using the MTT assay in breast cancer (MCF-7, MCF-7/DX), colorectal cancer (LOVO, LOVO/DX), and normal V79 cell lines, showed moderate effects, particularly against colorectal cancer cells. Cyclooxygenase inhibition was rather weak, with IC₅₀ values in the high micromolar range, indicating limited anti-inflammatory potential compared with reference COX inhibitors, although docking studies suggested possible interactions with the COX-2 active site. The obtained results indicate that the biological activity of the arylpiperazine oxicam derivatives is primarily associated with cytotoxicity and membrane effects rather than COX inhibition. These limitations should be considered in the design of future membrane-targeted bioactive compounds. Full article

Electrospun poly(ε-caprolactone) (PCL) membranes incorporating Triticum vulgare extract (TVE) were developed as biomimetic scaffolds for periodontal regeneration. Using a ternary solvent system, two experimental formulations (µF-P10 and µF-P10T1) were fabricated and compared against a commercial dermal matrix. SEM analysis revealed bimodal fiber distributions (0.77–1.74 µm) and a surface porosity of 29.86% for TVE-loaded membranes, significantly higher than that of the commercial control (25.26%). FT-IR confirmed that the PCL chemical integrity was preserved, while mechanical testing showed that extract incorporation reinforced the matrix, increasing the Young’s modulus from 2.90 × 10³ Pa to 3.54 × 10³ Pa. UHPLC–MS identified ferulic acid as the primary bioactive component (90%), with release kinetics following a first-order model (R² = 0.998) over 48 h. Biological assays with human gingival fibroblasts (HGF) confirmed non-cytotoxicity (>70% viability). While both membranes supported healing, the µF-P10 formulation showed superior performance, with 80.2% proliferation and 60.6% wound closure, approaching control levels. These findings demonstrate that PCL-TVE electrospun scaffolds effectively combine favorable morphology and controlled release, offering a promising alternative for subepithelial connective tissue regeneration. Full article

The design of multitargeted drug candidates has recently emerged as a highly attractive area of research. Numerous heterometallic compounds have been developed to enhance both the biological efficacy and physicochemical properties of monometallic metallodrugs. Combining classical transition metals with established antitumor activity, such as Pt, Ru, and Au, with other metal-based fragments offers the potential to generate complex compounds with improved pharmacokinetic and pharmacodynamic profiles. Incorporating different bioactive metal cations within a single molecular framework may enhance anticancer activity through metal-specific interactions with distinct biological targets or through improved physicochemical characteristics of the resulting heteronuclear complexes. Recent studies have underscored the significant progress and promising impact of this multitargeted strategy, particularly in systems that combine ruthenium with other biologically active metal centers. This approach may enable selective biological targeting and help overcome drug resistance. This review compiles and analyzes reported ruthenium-based heteronuclear complexes, offering a comprehensive and critical assessment of recent advances in the rational design and synthesis of novel multinuclear compounds as potential chemotherapeutic agents. Particular emphasis is placed on understanding structure–activity relationships, mechanistic pathways, and the role of metal–metal and metal–ligand interactions in modulating biological responses. The findings summarized herein highlight the remarkable efficacy of a wide range of multinuclear ruthenium anticancer complexes and support the hypothesis that synergistic and/or cooperative interactions between distinct metal-based fragments can significantly enhance pharmacological performance, including improved selectivity, stability, and cellular uptake. Furthermore, emerging insights into their modes of action, resistance profiles, and potential for targeted delivery underscore their promise as viable alternatives to conventional therapies. Overall, this dynamic and rapidly evolving field is poised to inspire continued interdisciplinary research and drive the development of next-generation metallodrugs with improved therapeutic indices and clinical potential. Full article

Advanced gastric (GAC) or gastroesophageal junction (GEJAC) adenocarcinoma continues to carry a poor prognosis. Understanding GAC/GEJAC at the molecular level has provided a new understanding and the basis for individualized approaches to treatment. The current biomarker-driven therapy focuses on four areas: microsatellite instability (MSI), human epidermal growth factor receptor-2 (HER2), programmed death ligand-1 (PD-L1) combined positive score, and claudin 18.2 (CLDN18.2). However, because of improving technology, the focus has shifted to cancer cell-surface proteins and peptides. Each of these GAC/GEJAC subgroups provides a different treatment pathway. The agents utilized to treat advanced GAC/GEJAC include immune checkpoint inhibitors (ICIs), chemotherapy, monoclonal antibodies (mAbs), and antibody–drug conjugate (ADC) therapy, as well as bispecific antibodies (BsAbs), but they are certainly not limited to the above. Drug development has shifted in recent years to establish different mechanisms that are attempting more sophisticated and targeted approaches, such as BsAbs and ADCs. Meanwhile, the development of cytotoxics has tapered off. Along with these developments in drug therapy, more therapies directed at CLDN18.2, HER2, MSI, EGFR, HER3 and trophoblast cell-surface antigen 2 (TROP2) are underway. Here we review future areas in advanced GAC, including zanidatamab’s potential role in HER2-positive advanced GAC and deciphering the abundance of anti-CLDN18.2, extending beyond investigative therapies. Full article

The CD33 rs12459419 (C>T; Ala14Val) single-nucleotide polymorphism (SNP) has been reported to modulate treatment response and survival in pediatric patients with acute myeloid leukemia (AML) receiving gemtuzumab ozogamicin (GO), an anti-CD33 antibody linked to the cytotoxic compound calicheamicin. However, it remains unclear whether this SNP also affects CD33 expression on leukemic blasts. Moreover, its prognostic significance in adult AML patients treated with standard chemotherapy without GO has not been investigated. In this study, we retrospectively genotyped 184 adult AML patients who received standard induction chemotherapy for the CD33 rs12459419 SNP genotype and collected CD33 expression data. The observed genotype distribution was 46% (n = 85) CC, 43% (n = 79) CT, and 11% (n = 20) TT. CD33 expression was detected in significantly higher proportions of leukemic blasts in patients with the CC genotype than those with the TT genotype (p = 0.0009). A similar trend was observed between the CT and TT genotypes (p = 0.06). No significant differences in clinical outcome were detected among the three genotype cohorts. Grouping CC and CT genotypes together based on their similar CD33 expression and comparing them to patients with the TT genotype also revealed no differences in overall survival (OS), event-free survival (EFS), or relapse-free survival (RFS). Using a proportion of 90% CD33-positive blasts to define high versus low expression groups also failed to identify a meaningful impact on OS, EFS, or RFS, either across genotypes or independent of genotype. In conclusion, our findings indicate that the CD33 rs12459419 SNP does not affect outcomes or survival in adult AML patients receiving standard chemotherapy in the absence of GO. Furthermore, no association was seen between CD33 expression and clinical outcomes between the three genotypes. To our knowledge, this is the first study to investigate the prognostic impact of the CD33 rs12459419 SNP per se on outcome and survival in adult AML patients treated with chemotherapy without GO. Validation in larger patient cohorts is required to conclusively rule out a prognostic role of the CD33 rs12459419 SNP in AML. Full article

Concurrent alcohol and cannabis use (“crossfading”) is increasingly prevalent, especially among adolescents, yet its toxicological impact on pulmonary innate immunity remains largely unexplored. Alveolar macrophages (AMs) orchestrate inflammatory responses in the lung, and dysregulated macrophage polarization is a hallmark of alcohol-associated lung disease. Although alcohol and cannabinoids individually modulate immune function, the mechanisms by which their co-exposure alters macrophage activation and inflammatory signaling in the lung are largely unknown. AMs are highly sensitive to xenobiotic exposure and play a central role in regulating inflammatory and cytotoxic responses. In this study, we investigated how acute ethanol exposure, synthetic cannabinoid exposure, and their combined exposure affect macrophage viability, polarization, and the release of inflammatory mediators via cannabinoid receptor (CB1R/CB2R)-dependent pathways. Human THP-1-derived macrophages and KG-1 macrophage-like cells were exposed to ethanol, the CB1/CB2 agonist WIN 55,212-2, or both, with selective pharmacological antagonism of CB1R and CB2R. Ethanol exposure activated and polarized macrophages toward a pro-inflammatory M1 phenotype, accompanied by increased secretion of pro-inflammatory cytokines MCP-1, TGF-α, IFN-β, IL-6, and TNF-α. In contrast, WIN 55,212-2 promoted anti-inflammatory M2 polarization and increased IL-10 and IL-4 production. Notably, co-exposure to ethanol and WIN produced an antagonistic immunomodulatory response, characterized by the suppression of ethanol-induced M1 polarization and attenuation of pro-inflammatory cytokine release. Mechanistically, pharmacological CB1R blockade reduced ethanol-induced M1 polarization and cytokine secretion, whereas CB2R blockade exacerbated these effects, underscoring divergent roles for cannabinoid receptors in regulating pulmonary macrophage responses. This study provides novel findings demonstrating the mechanism by which alcohol–cannabinoid co-use reshapes macrophage immune phenotypes and identifies the endocannabinoid system as a potential therapeutic target for alcohol-related inflammatory lung disease. Full article

Background: Modern oncology views immune system dysfunction as a key factor in carcinogenesis. The induction of immunogenic cell death (ICD), a form of regulated cell death capable of activating adaptive immunity, represents a promising therapeutic strategy. Damage-associated molecular patterns (DAMPs) play a central role in this process. This review aims to summarize current knowledge of DAMPs, their release mechanisms during ICD, their classification, and their prognostic and therapeutic significance in antitumor immunity. Methods: We systematically reviewed and synthesized literature published in Pubmed and Google Scholar on ICD and DAMPs, focusing on distinct forms of DAMPs which were categorized based on recognition mechanisms (five classes) and cellular origin (extracellular, mitochondrial, nuclear, and cytosolic). Key molecules, their receptors, downstream signaling pathways, and clinical associations were analyzed. Results: The spatiotemporally coordinated release of the pattern of DAMPs promotes dendritic cell maturation, antigen presentation, activation of cytotoxic T lymphocytes, and elimination of tumor cells. DAMPs can exhibit a dual role: they are able to induce sterile inflammation essential for antitumor immunity, but may also contribute to metastasis and chronic inflammation. Among all DAMPs, high-mobility group box 1 (HMGB1, a nuclear DAMP) and calreticulin (CRT, a cytosolic protein) demonstrate the greatest prognostic value. Other DAMPs (e.g., extracellular matrix components, uric acid) act as signal amplifiers during various forms of cell death. Conclusions: Understanding the spatiotemporal dynamics of DAMP release is critical for activating immune responses against malignant cells. Monitoring DAMPs may improve patient stratification, predict therapeutic responses, and enable personalized immunotherapeutic strategies. Further investigation of ICD mechanisms and DAMP release represents a fundamental basis for developing novel anticancer therapies. Full article

Reactive oxygen species (ROS) are integral components of plant signaling networks that mediate interactions between plants and their environment, thereby regulating diverse physiological and biochemical processes. While controlled ROS production is essential for stress perception and signal transduction, excessive ROS accumulation induces oxidative damage. ROS-mediated lipid peroxidation of polyunsaturated fatty acids leads to the formation of highly electrophilic α,β-unsaturated carbonyl compounds collectively referred to as reactive carbonyl species (RCS). Under severe abiotic stress conditions, excessive RCS accumulation exerts cytotoxic effects and causes widespread cellular dysfunction. In contrast, at subtoxic levels, RCS function as important secondary messengers that modulate stress-responsive signaling pathways, including programmed cell death, stomatal regulation, and adaptive responses to abiotic stresses. This review critically synthesizes current advances in understanding the dual roles of ROS and RCS as both damaging agents and signaling molecules in plants. Particular emphasis is placed on the mechanistic basis of ROS-RCS crosstalk and their interactions in abiotic stress tolerance. Furthermore, this review highlights emerging research gaps and outlines future perspectives aimed at translating redox signaling insights into strategies for improving plant stress resilience under changing environmental conditions. Full article

The present study examined the effect of Enterococcus durans cell-free supernatant (CFS) on interleukin (IL) 8, 10 and 1β gene expressions in the intestinal cell line HT-29 treated with Staphylococcus aureus CFS. HT-29 cells were incubated with E. durans CFS or S. aureus CFS, or S. aureus CFS plus E. durans CFS. All concentrations of E. durans CFS did not show cytotoxicity, while the highest treatment (44.9 μg/mL) with S. aureus CFS induced significant cell death. S. aureus CFS did not modify IL-1β gene expression, while E. durans CFS alone or in combination with S. aureus CFS reduced it. Treatment with S. aureus CFS induced greater expression of the IL-8 gene compared to S. aureus CFS plus E. durans CFS. S. aureus CFS alone or in combination with E. durans CFS increased the expression of the IL-10 gene, while E. durans CFS alone did not modify it. These results suggest a potential protective role of the E. durans secretome in mitigating the inflammatory environment in intestinal cells. This treatment could be useful to protect against possible contact with dangerous soluble microbial products present in food. Full article

Cadmium (Cd) is a pervasive environmental contaminant with potent cytotoxic effects in a wide range of organisms. Although autophagy and apoptosis are recognized as major cellular responses to heavy metal stress, the molecular basis of Cd-induced cell death in insects remains insufficiently understood. In this study, we used fifth-instar day-4 (5L4D) larvae of Bombyx mori and the silkworm-derived Bm-12 cell line to investigate the involvement of three core autophagy-related proteins, Bombyx mori Autophagy-related protein 5(BmATG5), Bombyx mori Autophagy-related protein 6(BmATG6), and Autophagy-related protein 8(BmATG8), in Cd-induced autophagy and apoptosis. Exposure to CdCl₂ markedly induced autophagic and apoptotic responses in both larval midgut tissue and Bm-12 cells, as demonstrated by monodansylcadaverine(MDC) staining, Lyso-Tracker Red staining, DAPI and Hoechst 33258 staining, and DNA fragmentation assays. qPCR and Western blot analyses showed significant upregulation of BmATG5, BmATG6, and BmATG8 following Cd exposure. Notably, the cleaved forms tBmATG5-N (24 kDa) and tBmATG6-C (35 and 37 kDa), as well as the lipidated form BmATG8-PE (12 kDa), accumulated substantially under Cd stress. In parallel, intracellular Ca²⁺ levels and calpain activity were significantly increased, suggesting activation of a calcium-dependent regulatory pathway. Pharmacological inhibition experiments further indicated that autophagy and apoptosis are functionally interconnected during the Cd response. Collectively, these findings demonstrate that BmATG5, BmATG6, and BmATG8, together with their processed forms, play central roles in coordinating autophagy–apoptosis crosstalk during Cd-induced cytotoxicity in Bombyx mori. This study provides new mechanistic insight into heavy metal toxicity in insects and expands our understanding of stress-induced programmed cell death during silkworm metamorphosis. Full article