Search Results (466)

The alveolar epithelium plays a critical role in respiratory function, facilitating air exchange and serving as a barrier against inhaled pathogens. Its unique three-dimensional architecture, in which epithelial cells grow on spherical alveolar structures, significantly increases the surface area-to-volume ratio for efficient gas exchange but poses challenges for in vitro reconstruction. Here, we present a biomimetic alveolar model based on gelatin methacryloyl (GelMA) hydrogel microspheres with precisely controlled sizes and composition fabricated via microfluidic technology. These microspheres function as micro-scaffolds for cell adhesion and growth, and an oxygen-permeable honeycomb microwell array facilitates the rapid assembly of cell-laden microspheres into physiologically relevant alveolar-like structures. Using this model, the effects of toxic gas exposure and pathogen infection, and demonstrated its potential use for both basic physiological studies and pathological applications, was investigated. This system recapitulates key features of the alveolar microenvironment and offers a versatile platform for respiratory research and drug screening. Full article

The acute gouty arthritis (AGA) to chronic gouty arthritis (CGA) transition is a critical phase leading to irreversible joint damage and systemic complications. However, current molecular mechanism investigations have remained limited to single-omics approaches that lack comprehensive multi-omics explorations. We integrate high-depth data-independent acquisition (DIA) proteomics and untargeted metabolomics to analyze serum samples from healthy controls (n =28), AGA (n = 31), and CGA (n = 14) patients to address this gap. Through differential expression analysis, we identified nine persistently dysregulated pivotal proteins with robust discriminative capacity, including the urate excretion regulator ZBTB20 and inflammation/immune-related proteins (GUCY1A2, CNDP1, LYZ, SERPINA5, GSN). Additionally, 11 consistently altered core metabolites with diagnostic potential were detected, indicating perturbations in sex hormones, thyroid hormones, gut microbiota-derived metabolites, environmental exposures, and nutritional factors. Multi-omics KEGG enrichment analysis highlighted thyroid hormone synthesis, AMPK signaling pathway, and taurine and hypotaurine metabolism as central pathways. Correlation network analysis further revealed significant immune dysregulation, illustrating an evolution from acute immune activation to chronic inflammation during AGA-to-CGA progression. Our study establishes that a coordinated disruption of the thyroid hormone–AMPK–taurine metabolic axis and concomitant immune microenvironment remodeling is associated with chronic gout development. These findings provide critical targets for developing early diagnostic indicators and targeted interventions for CGA. Full article

Although cancer biology has advanced considerably, the impact of environmental toxins on carcinogenesis remains underrecognized and scattered across disciplines. Evidence increasingly shows that chronic exposure to a broad range of toxins—including persistent organic pollutants, heavy metals, pesticides, phthalates, microplastics, and fine particulate matter (PM2.5), which significantly contributes to cancer initiation, progression, and treatment resistance. This review synthesizes mechanistic, molecular, and epidemiological findings from 2015 to 2025, identified through systematic searches of PubMed, Scopus, Web of Science, and MeSH. Key pathways include oxidative stress-mediated DNA damage, epigenetic reprogramming (DNA methylation, histone modifications, miRNA dysregulation), hormone receptor modulation, chronic inflammation, immune evasion, and tumor microenvironment remodeling. Case studies of benzene, arsenic, aflatoxins, pesticides, and microplastics detail exposure routes, molecular targets, and associated cancers, highlighting significant public health risks. Ongoing debates persist regarding safe exposure thresholds, latency periods, and the effects of mixed toxin exposures. The review also highlights recent innovations in environmental oncology, including AI-based predictive models, CRISPR screens for susceptibility genes, organoid/3D models, green chemistry interventions, and real-time exposure monitoring, which provide mechanistic insight and inform early detection and personalized prevention strategies. Additionally, regional data gaps, particularly in low- and middle-income countries, indicate the need for stronger interdisciplinary collaboration. By integrating molecular mechanisms, epidemiology, and technological advances, this review offers a comprehensive framework for understanding toxin-induced carcinogenesis and guiding future research, public health policy, and preventive strategies. Full article

Talaporfin sodium (mono-L-aspartyl chlorin e6; NPe6), a second-generation photosensitizer, is clinically used in photodynamic therapy (PDT). It accumulates preferentially in tumors and exhibits deep tissue penetration, rapid systemic clearance, and minimal photosensitivity. However, treatment of deep-seated malignancies remains challenging. Here, we demonstrate that talaporfin sodium undergoes physicochemical reactions with X-rays to generate reactive oxygen species, a mechanism analogous to that of 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX in radiodynamic therapy (RDT). To evaluate its therapeutic efficacy, we employed a pancreatic cancer xenograft model using MIA PaCa-2 cells in mice. Talaporfin sodium was administered intravenously 2 h before X-ray exposure, followed by fractionated X-ray irradiation (3 Gy daily for 3 consecutive days). Talaporfin-mediated RDT significantly inhibited tumor growth compared with radiation therapy alone. Furthermore, an exploratory RNA-seq analysis of xenografts revealed transcriptional signatures of stress and immune activation, suggesting that talaporfin-mediated RDT enhances oxidative and immunogenic responses within the tumor microenvironment. These findings highlight the potential of talaporfin sodium as a clinically translatable radiosensitizer for RDT, offering a promising strategy for the treatment of deep-seated cancers such as pancreatic carcinoma. Full article

Background: Fluid shear stress (FSS) is a biomechanical force that can produce phenotypic changes in the cells that are directly in contact with the flow of fluid. Accumulating evidence indicates high FSS to possess the potential ability to prevent tumor development and suppress cancer growth. However, the exact mechanism of its antitumorigenic effects is still not clear. Objective: In this study, we aimed to investigate the effect of FSS on breast cancer microenvironment via macrophage modulation. Methods: We exposed THP-1 like-macrophages to different levels of FSS. The supernatant from THP1-like-macrophages after exposure to FSS was used as conditioned medium (FSS-CM). Subsequently, we analyzed human breast cancer cells, MCF-7, and endothelial cells, as well as HUVECs cultured with FSS-CM. Results: Study outcomes have demonstrated that low FSS-CM inhibited apoptosis as well as induced tumor migration in MCF-7 cells. Conversely, high FSS-CM promoted apoptosis, inhibited tumor migration, and induced G1-phase arrest in MCF-7 cells. Furthermore, low FSS-CM was found to promote proliferation of HUVECs. Conclusions: In conclusion, this study highlights the complex interplay between FSS and cancer cell behavior. Our findings provide in vitro evidence that high FSS exerts an anti-cancer effect by promoting THP-1-like macrophage polarization toward an anti-tumor phenotype, leading to increased apoptosis and reduced migration in MCF-7 cells. These results suggest that the modulation of macrophage polarization may underlie the therapeutic potential of high FSS in suppressing breast cancer progression. Full article

Spectroscopic techniques offer significant potential for investigating ligand–protein interactions, particularly for assessing conformational modifications and binding affinity. In the present study, a complementary approach combining near-UV circular dichroism (CD) and second-derivative fluorescence spectroscopy was applied to evaluate how two representative nonsteroidal anti-inflammatory drugs—phenylbutazone (PHB, a marker of Sudlow’s site I) and ketoprofen (KP, a marker of Sudlow’s site II)—influence the tertiary structure of human serum albumin in its native form (HSA) and after glycation by glucose (gHSA_GLC), fructose (gHSA_FRC), and glucose–fructose syrup (gHSA_syrup). The results demonstrate that glycation substantially modifies the tertiary structure of HSA and decreases its drug-binding capacity at Sudlow’s sites I and II, with the most pronounced conformational changes observed for gHSA_FRC, confirming fructose as the most reactive glycation agent. PHB induced distinct conformational rearrangements, including a characteristic increase in ellipticity near ~290 nm, indicating perturbations in the chiral microenvironment surrounding Trp214 within Sudlow’s site I. By contrast, KP induced weaker, site-specific structural changes, primarily within Phe-rich hydrophobic domains of site II. Glycation consistently increased the polarity and solvent exposure of aromatic residue microenvironments—particularly within Tyr-rich regions—while the local environment of Trp214 remained comparatively stable. These findings suggest that PHB and KP modulate the conformational flexibility of glycated HSA predominantly by reorganizing Tyr-rich regions rather than directly perturbing Trp214. Overall, the study shows that glycation heterogeneity significantly influences protein–drug interactions, with important implications for altered pharmacokinetics in diabetes and metabolic disorders. The combined application of near-UV CD and second-derivative fluorescence spectroscopy offers a sensitive and complementary strategy for distinguishing structural differences between non-glycated and glycated HSA and for characterizing drug–albumin interactions at the tertiary structural level of the macromolecule. Full article

Background: This study explores the therapeutic potential of radiodynamic therapy (RDT), a combination of the photosensitizer 5-aminolevulinic acid (5-ALA) administration and X-ray irradiation, for high-grade glioma (HGG). The research aims to verify the RDT efficacy in both normoxic and hypoxic environments, examine its mechanisms, and assess its impact on the tumor micro-immune environment to address resistance to RDT. Methods: Glioma cell lines U87MG and U251MG were used in experiments in vitro. The cells were divided into four groups with or without 5-ALA and X-ray exposure. Results: Results demonstrated that RDT was effective under normoxia (20% O₂), increasing reactive oxygen species (ROS) production and significantly decreasing U87MG cell viability in a 5-ALA concentration-dependent manner at 2 Gy and 6 Gy. However, under hypoxic conditions (3% O₂) or long-term 3% O₂ exposure, the RDT effect was not significant compared to controls. The study also found that RDT under normoxia influenced immune reaction-related gene expression, while under hypoxia, it primarily affects genes related to epithelial–mesenchymal transition (EMT). Further analysis revealed that RDT reduces the secretion of soluble PD-L1, a marker of immune checkpoint inhibition, in a 20% O₂ environment. Additionally, RDT suppressed the vascular endothelial growth factor (VEGF), an angiogenesis marker, under 3% O₂ conditions. RDT also reduced the secretion of colony-stimulating factor -1 (CSF-1), a differentiation inhibitory marker for macrophages, in a 20% O₂ environment. Conclusion: In conclusion, this study provides evidence that RDT, combining 5-ALA and X-ray irradiation, has potential as a therapeutic strategy for HGG, especially under normoxic conditions. It may also offer benefits under hypoxia, particularly in inhibiting angiogenesis. The study also highlights the importance of understanding the role of oxygen levels in the efficacy of RDT and its potential impact on immune responses, angiogenesis, and macrophage differentiation in the tumor microenvironment. Further research is needed to fully elucidate the underlying mechanisms and optimize RDT for clinical application. Full article

Micro- and nanoplastics (MNPs) are increasingly recognized as emerging intestinal toxicants. This scoping review maps and integrates evidence from 56 studies (47 primary and 11 review articles, 2000–mid-2025) on how nanoplastics, particularly ≤100 nm polystyrene, disrupt gut homeostasis. The evidence consistently supports a three-stage mechanistic cascade: 1. Oxidative-stress initiation—Nanoplastics generate reactive oxygen species (ROS) and suppress antioxidant defenses, producing redox imbalance in intestinal tissue and commensal bacteria. 2. Barrier dysfunction—Resulting oxidative injury reduces tight-junction proteins, depletes mucus-secreting goblet cells, and activates inflammatory signaling (NF-κB, TLR4). 3. Microbiome reconfiguration—The altered intestinal microenvironment favors Gram-negative expansion and depletion of Gram-positive commensals, observed as decreases in the Firmicutes/Bacteroidetes (F/B) and Gram+/Gram− ratios. High-dose nanoplastic exposures reproducibly induced these effects in mice and zebrafish, whereas environmentally realistic, low-dose PET fragments produced minimal dysbiosis. Functionally important taxa—short-chain-fatty-acid producers (Faecalibacterium, Roseburia) and mucin degraders (Akkermansia muciniphila)—were consistently reduced, linking microbial shifts to epithelial injury and inflammatory tone. Together, these findings define an oxidative–barrier–microbiome axis as the dominant pathway of nanoplastic-induced intestinal disruption. Future work should emphasize environmentally relevant exposures, multi-omics functional endpoints, and mechanistic models that integrate oxidative stress, epithelial pathology, and microbiome ecology to guide realistic human-health risk assessment. Full article

Heat shock proteins (HSPs) are produced in response to stressful conditions, such as temperature, inflammation, infection, or exposure to environmental factors. HSPs are overexpressed in some malignancies, where they modulate the tumor microenvironment and influence cancer cell behavior and survival. Clinical trials for breast, prostate, colon, and lung cancers exist, but not for head and neck squamous cell carcinomas (HNSCCs). Nonetheless, clinical studies on HSPs in HNSCC are still lacking. We review the role of HSPs with regard to physiology and as potential targets for molecular therapy in HNSCC. Full article

Background/Objectives: Colorectal cancer (CRC) exhibits significant molecular heterogeneity, as reflected in Consensus Molecular Subtype (CMS) classification, and demonstrates extensive crosstalk with the microbiome. However, the role of the microbiome in determining subtypes of CRC, and CMS4 in particular, which represents an aggressive, stromal-rich variant associated with poor prognosis, remains poorly understood. Here, we reveal the role of the tumor microbiome in shaping the tumor microenvironment (TME) and its impact on CMS4 determination. Methods: A total of 25 CRC tissues were analyzed using RNA sequencing and classified with CMScaller to identify significantly enriched microbial species. Functional studies were performed using these CMS-specific microbial species and CMS2 organoids co-cultured with stromal (18Co) and immune (THP-1) cells. Results: 16S rRNA profiling of matched CRC tissues showed that Bacteroides fragilis was significantly enriched in CMS4 tumors (linear discriminant analysis score = 4.7). Functional studies revealed that exposure to enterotoxigenic Bacteroides fragilis (ETBF) induced CMS4-like features, including enhanced growth and gene expression patterns resembling those of primary CMS4 tumors. Conclusions: These findings suggest that ETBF contributes to the development of CMS4 and may facilitate the acquisition of aggressive phenotype associated with this CRC subtype. Full article

Background/Objectives: The milieu of inflammatory cytokines present in the prostate cancer (PCa) tumor microenvironment exerts various effects on cancer progression. Chronic exposure to the inflammatory cytokine interleukin-1 (IL-1) has been shown to impact signaling via the RELA/NF-kB pathway; however, the effects of chronic inflammation on the integration of different inflammatory signaling pathways, such as the interleukin-6 (IL-6)/STAT3 axis, requires further exploration. Methods: We generated in vitro subline models by exposing the C4-2 and LNCaP PCa cell lines to either IL-1α or IL-1β for several months. We then treated the resulting sublines with acute IL-1 alone, IL-6 alone, or IL-1/IL-6 in combination and assessed for sensitivity to cytokine signaling. We observed changes in proliferation and quantified using Ki-67 immunostaining. Cell proliferation was assessed after siRNA silencing RELA or STAT3. Results: IL-1/IL-6 signaling in combination enhanced the signaling effects of either cytokine alone, particularly cytostasis. While the chronic IL-1 sublines maintained sensitivity to acute IL-6 signaling, they lost sensitivity to acute IL-1 signaling and did not show the enhanced IL-1/IL-6 cytostatic response. Inhibition of RELA and STAT3 rescued cytostasis after IL-1/IL-6 treatment in parental PCa cell lines, but only STAT3 inhibition rescued proliferation in the chronic IL-1 sublines. Conclusions: Our work shows that IL-1/RELA and IL-6/STAT3 work in parallel to synergistically induce cytostasis. However, chronic IL-1 exposure selects for cells that attenuate IL-1/RELA signaling, subsequently attenuating IL-1/IL-6 synergy. Full article

The long-term conservation of Prunus persica (peach), a crop of significant agronomic and genetic value, remains challenging due to its recalcitrance to conventional cryopreservation methods. Low tolerance to dehydration and cryoprotectant toxicity often results in poor survival and regrowth, thereby limiting the reliability of germplasm storage. This study evaluated whether combining an alginate hydrogel matrix with Pluronic F-68 improves vitrification efficiency and post-thaw regeneration of peach shoot tips by enhancing dehydration dynamics and reducing cryo-injury. Shoot tips were immobilized in thin sodium alginate layers on aluminum foil strips, with the hydrogel providing mechanical stabilization and moderating water loss during exposure to PVS3 and subsequent liquid nitrogen immersion. To further mitigate cryoinjury, Pluronic F-68, a non-ionic surfactant with membrane-stabilizing properties, was incorporated into the system. Differential scanning calorimetry revealed that the hydrogel reached complete vitrification after 120 min in PVS3, whereas encapsulated shoot tips required 150 min for full suppression of crystallization. The optimized system achieved 71% post-cryopreservation survival and 40% regrowth, compared with 25% and 9% in non-encapsulated controls. PF-68 accelerated vitrification kinetics, lowered crystallization enthalpies, and improved post-thaw viability. These findings demonstrate that engineered hydrogel–surfactant matrices can stabilize the microenvironment during vitrification and offer a promising approach for the long-term cryopreservation of peach germplasm. Full article

The field of experimental radiooncology and the quality assessment (QA) aimed at patient safety both profit from the utilisation of biomimetic principles. The work with phantoms based on biological structures of animals or humans, utilising the principles of anatomic mimicry, has a long tradition in radiotherapy research. When phantoms are produced from tissue-equivalent materials, they mimic the radiological properties of tissues and organs, allowing researchers and clinicians to study dose distribution and optimise treatment plans without exposing real patients to radiation. Biomechanical mimicry would take this a step further by creating phantoms that replicate the movement and deformation of organs during physiological movement, such as heartbeat or breathing, enabling a more accurate simulation of dynamic treatment scenarios. Bioinspired sensor technologies, such as artificial skin or integrated detectors, can be used to monitor radiation exposure, organ motion or temperature changes during therapy with high precision. The utility of such a phantom could be further enhanced by creating a realistic tumour microenvironment as an irradiation target, following the principles of microenvironmental biomimicry. Thus, biomimetic strategies can be exploited in the validation of radiotherapy technologies and open new perspectives for adaptive radiotherapy and real-time monitoring. Full article

Background: Colorectal cancer (CRC), particularly the microsatellite-stable (MSS) subtype, remains largely unresponsive to immune checkpoint inhibitors (ICIs) due to immune escape, tumor-associated macrophage (TAM) enrichment, and cytokine-driven suppression that sustain a TAM-dominant tumor microenvironment (TME). To overcome these barriers, a pH-responsive solid lipid nanoparticle (SLN) system was engineered to co-deliver CB-5083 (a VCP/p97 inhibitor), miR-142 (a PD-L1-targeting microRNA), and imiquimod (R, a TLR7 agonist) for spatially confined induction of endoplasmic reticulum stress (ERS) and immune reprogramming in MSS CRC. Methods: The SLNs were coated with PEG–PGA for pH-triggered de-shielding and functionalized with PD-L1- and EGFR-binding peptides plus an ER-homing peptide, enabling tumor-selective and subcellular targeting. Results: The nanoplatform displayed acid-triggered PEG–PGA detachment, selective CRC/TAM uptake, and ER localization. CB-mediated VCP inhibition activated IRE1α/XBP1s/LC3II, PERK/eIF2α/ATF4/CHOP, and JNK/Beclin signaling, driving apoptosis and autophagy, while miR-142 suppressed PD-L1 expression and epithelial–mesenchymal transition markers. R facilitated dendritic cell maturation and M1 polarization. Combined CB + miR + R/SLN-CSW suppressed IL-17, G-CSF, and CXCL1, increased infiltration of CD4⁺ and CD8⁺ T cells, reduced Tregs and M2-TAMs, and inhibited tumor growth in CT-26 bearing mice. The treatment induced immunogenic cell death, reprogramming the TME into a T cell-permissive state and conferring resistance to tumor rechallenge. Biodistribution analysis confirmed tumor-preferential accumulation with minimal off-target exposure, and biosafety profiling demonstrated low systemic toxicity. Conclusions: This TME-responsive nanoplatform therefore integrates ERS induction, checkpoint modulation, and cytokine suppression to overcome immune exclusion in MSS CRC, representing a clinically translatable strategy for chemo-immunotherapy in immune-refractory tumors. Full article

Background: Glucose, a central carbohydrate in higher organisms’ metabolism, can undergo extensive oxidative modification under conditions of excessive inflammation or elevated reactive oxygen and nitrogen species (RONS). Such modifications yield glucose oxidation products (GOPs) with potential biological relevance and toxicity. This study aimed to systematically characterize GOP formation under defined oxidative conditions generated by gas plasma treatment. Methods: D-glucose solutions were prepared at 0.25 mM (hypoglycemic/diabetic range), 2.5 mM (sub-physiological), and 25 mM (peritoneal dialysis fluid). Samples were exposed for up to 20 min to the atmospheric-pressure argon plasma jet kINPen, which produces a wide spectrum of RONS. Treatment time-dependent glucose oxidation was assessed by high-resolution mass spectrometry (HRMS) and tandem mass spectrometry (MS/MS) to identify the oxidation products. Results: Gas plasma exposure generated various oxidation products and their abundance profiles depended on initial glucose concentration and treatment duration. Identified products included 2-keto-D-glucose, 3-deoxyglucosone (3DG), 3,4-dideoxyglucosone-3-ene (3,4DGE), furaldehyde, methylglyoxal, and acetaldehyde. HRMS/MS analysis confirmed diagnostic fragment ions for each GOP and revealed distinct formation across the model scenarios. Conclusions: Cold gas plasma induces a spectrum of glucose oxidation products under biomedically relevant glucose levels. The identified GOPs, many of which have known cytotoxic or signaling properties, provide mechanistic insight into glucose oxidation in inflamed or oxidative microenvironments. These findings support the utility of plasma-based oxidative models for studying GOP-associated biological effects and potential pathophysiological consequences. Full article