Search Results (33,170)

Data suggest that both pancreatic and intestinally produced glucagon-like peptide-1 (GLP-1) increases in response to inflammation. Here, we set out to determine the tissue-specific function of increased GLP-1 during inflammatory stimuli. Using our innovative mouse model of tissue-specific Gcg (the gene that encodes GLP-1) expression, we explored the function of GLP-1 under severe inflammatory conditions induced by lipopolysaccharide (LPS) administration in lean and obese mice. High-fat diet (HFD) increased the LPS-induced suppression of feeding and increased the plasma levels of pro-inflammatory cytokines and GLP-1. Both pancreatic and intestinal Gcg expression contribute to LPS-induced increases in GLP-1, but Gcg was not necessary for the glucoregulatory or suppressed feeding responses to LPS. While Gcg was not necessary for systemic cytokine increases with LPS in either chow- or HFD-fed mice, whole-body Gcg-null animals had increased macrophage accumulation and an increased expression of genes reflecting pro-inflammatory signaling in the pancreas. We then performed flow cytometry on the pancreas from mice expressing a fluorescent marker on the GLP-1 receptor (GLP-1R). In response to LPS, we found that pancreatic CD64+/CD11b+ macrophages expressed the GLP-1R. We conclude that under severe inflammatory conditions, pancreatic production of GLP-1 functions in an immunological rather than a metabolic role to directly regulate local macrophage accumulation. Full article

The effects of cooking duration and the combined effects of cooking fuel, cooking duration, and ventilation remain unclear, particularly in relation to evidence from measured kitchen particulate matter (PM) exposure. Data were sourced from the Henan Rural Cohort Study and Panel study. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Cooking fuel, cooking duration, and kitchen ventilation were obtained, and kitchen PM was monitored using U-MINI208. In qualitative analysis, 9403 participants were enrolled. Individuals with long cooking durations scored 0.36 points lower than those with short ones. Those using solid fuels, particularly with long cooking durations and poor ventilation, had the lowest cognitive scores (β = −2.12) and the highest cognitive dysfunction (CD) risk (OR = 1.88). In quantitative analysis, 135 households and 52 individuals were enrolled. Households utilizing solid fuels, longer cooking durations, or natural ventilation showed significantly increased PM concentrations, and elevated kitchen particulate levels are associated with a decline in MMSE scores. Solid fuel, long cooking duration, and poor ventilation are associated with lower cognitive function, highlighting the importance of transitioning to cleaner energy sources, reducing cooking duration, and improving kitchen environments to protect cognition. Full article

Etrasimod is an oral selective sphingosine-1 phosphate receptor modulator, and its anti-inflammatory mechanism of action in inflammatory bowel diseases is not completely understood. It targets pro-inflammatory immune cells expressing sphingosine-1-phosphate receptors during their migration from the lymphatic system to the circulation and intestinal mucosa. Reductions in certain lymphocyte subsets in the peripheral blood have been reported, but its effects in lymph nodes remain unknown. This study investigated changes in leukocyte subpopulations in peripheral lymph nodes and blood in Crohn’s disease patients treated with etrasimod. Moderate-to-severe Crohn’s disease patients participated in this randomized, double-blind study, within the phase 2 CULTIVATE clinical trial. At baseline and after 14 weeks of etrasimod treatment, peripheral blood and inguinal lymph node biopsies were obtained. Isolated peripheral blood mononuclear cells and lymph node leukocyte populations were analyzed at single cell level using mass cytometry at both timepoints. The immunophenotyping revealed 15 innate and adaptive major immune cell populations, as well as 14 subpopulations of CD4+ and CD8+ T-cells. In peripheral lymph nodes, etrasimod resulted in significant accumulation of naïve, central memory, and effector memory CD4+ T-cells (+10.7%, +4.2%, and +2.3%, respectively; all p = 0.03), as well as naïve CD8+ T-cells (+4.2%; p = 0.03). Conversely, these subsets were reduced in peripheral blood (−6.2%, −6.0%, −2.0%, and −2.2%, respectively; all p = 0.03). Naïve and memory B-cells decreased in the circulation (−1.7%, p = 0.057; −0.6%, p = 0.03, respectively) but were unchanged in the lymph nodes. Innate immune cell populations remained mostly unaffected in both compartments. Our data indicate that etrasimod’s pharmacodynamic effect is related primarily with the attenuation of the T-cell mediated inflammation with minor changes in B-cells. However, additional follow-up studies are needed for the validation of these observations in the context of Crohn’s disease. Full article

Background/Objectives: Oncolytic viruses are an immunotherapeutic approach that can modulate the tumor microenvironment (TME), transforming immunologically ‘cold’ tumors into ‘hot’ ones. Insertion of genes encoding immunomodulatory proteins can further enhance antitumor immune responses. In this study, we compared the antitumor and immunomodulatory effects of the double recombinant vaccinia virus VV-GMCSF-Lact, which carries the human GM-CSF gene, with those of recombinant human GM-CSF (rhGM-CSF) in an immunocompetent murine GL261 glioma model. Methods: The study was conducted using a subcutaneous GL261 glioma model in immunocompetent C57BL/6 mice, comparing intratumoral VV-GMCSF-Lact and rhGM-CSF treatments with evaluation of immune cell populations by flow cytometry, tumor morphology by H&E staining, and tumor transcriptome profiles by RNA sequencing. Results: Flow cytometry showed that VV-GMCSF-Lact reduced the number of immunosuppressive cells in the TME of subcutaneously transplanted gliomas, targeting different components of the TME depending on animal sex. The immunotherapeutic effects of rhGM-CSF were less pronounced and primarily affected peripheral immune cells. Histological analysis revealed a decrease in mitotic figures in tumors from female mice after viral therapy. Transcriptome profiling of GL261 tumors demonstrated divergent gene expression patterns and cellular compositions between treatment groups. VV-GMCSF-Lact treatment was associated with a decreased proportion of malignant GL261 cells and CD8⁺ T lymphocytes, while rhGM-CSF treatment increased proportions of MDSCs, macrophages, NK cells, and tumor-associated neutrophils. Conclusions: Taken together, our data demonstrate that VV-GMCSF-Lact induces antitumor immune responses in murine GL261 glioma in vivo and modulates the tumor microenvironment more effectively than rhGM-CSF alone, supporting its potential for developing new strategies for glioma treatment. Full article

Cardiovascular diseases (CVDs) remain the leading cause of global mortality, with aortic pathologies such as atherosclerosis and thoracic aortic aneurysm posing significant risks due to their asymptomatic nature and potential fatal complications. This study investigates molecular mechanisms underlying CVDs by examining key cellular components of the aortic wall—vascular smooth muscle cells (VSMCs), fibroblasts, and macrophages—and their responses to low-density lipoproteins (LDLs). Using in vitro models, we analyzed phenotypic characteristics, LDL internalization capacity, and secretion/expression of pro-inflammatory mediators (IL-6, IL-8, IL-1β, CCL2) in primary VSMCs (from tunica intima and media), fibroblasts (977hTERT), and THP-1 macrophages. Fluorescence staining with BDP 630/650 revealed that all cell types internalize LDLs, with macrophages showing the highest lipid accumulation. ELISA and RT-qPCR demonstrated cell-specific patterns of cytokine secretion and gene expression, both in control conditions and after LDL exposure. The results indicate that VSMCs and fibroblasts, normally involved in vascular tone maintenance and extracellular matrix (ECM) synthesis, acquire pro-inflammatory features under pathological conditions, including increased secretion of IL-6, IL-8, and CCL2. Macrophages exhibited enhanced expression of the scavenger receptor CD36 and pro-inflammatory cytokines (especially IL-1β) after LDL treatment. Full article

Economic shocks in international systems propagate not only through financial channels but also through real-sector interactions, creating feedback effects that can amplify systemic risk across countries. However, country-level systemic risk assessments often rely on single-layer analyses, potentially overlooking such cross-channel dynamics. To investigate how country-level systemic risk interpretations differ across propagation layers, we constructed a multilayer network that integrates cross-border financial exposures and real-sector trade linkages. Using BIS Locational Banking Statistics and UN Comtrade data for 20 countries from 2000 to 2023, we developed a multilayer contagion framework that combines continuous within-layer propagation based on DebtRank with a threshold-based mechanism that activates cross-layer contagion when critical loss levels are exceeded. Initial shocks were calibrated using sovereign credit default swap (CDS), which implies default probabilities, to reflect market-based credit risk conditions. The results show that countries’ systemic roles and risk transmission patterns vary across layers and over time, and that incorporating cross-layer amplification reveals vulnerabilities not captured by single-layer models. Full article

Cold exposure may influence reproductive health through vascular changes, yet its mechanisms remain underexplored. This study aimed to investigate the impact of cold exposure on uterine blood vessels and the expression of the AMPK/PGC-1α gene and protein in adult female SD rats. A primary dysmenorrhea model was established in female Sprague Dawley rats and subjected to continuous cold exposure. Changes in body weight, ear temperature, and estrous cycle were observed. Superoxide dismutase (SOD) activity and adenosine triphosphate (ATP) levels were measured to assess oxidative stress. Uterine tissue morphology was assessed via small animal ultrasound, microcirculation observed using RFLSI imaging, and vascular morphology along with caspase-3 and AMPK expression evaluated histologically and immunohistochemically. CD31 and TUNEL double immunofluorescence were used to assess vascular endothelial apoptosis levels. Western blot was used to analyze Bax, BCL-2, and pAMPK/AMPK expression levels. In vitro injury models were used to treat human umbilical vein endothelial cells (HUVECs) with cold stimulus using the AMPK inhibitor Compound C. RT-PCR quantified Bax, AMPK, p53, and PGC-1α expression. Hypothermia-exposed rats exhibited significantly reduced body weight and ear temperature (p < 0.05), prolonged estrous cycle (p < 0.01), and decreased uterine index (p < 0.01), accompanied by reduced SOD and ATP levels (p < 0.01, p < 0.05). Ultrasound and flow imaging revealed decreased uterine blood flow velocity in the hypothermia group (p < 0.01). Histomorphology revealed disorganized uterine cell arrangement, reduced uterine vessel count (p < 0.01), and increased mean vessel area (p < 0.01) in cold-exposed uteri. Immunofluorescence detection revealed increased vascular endothelial cell apoptosis (p < 0.05). Western blot results showed that proapoptotic protein Bax was upregulated (p < 0.01), Bcl-2 was downregulated (p < 0.05), p-AMPK and p-AMPK/AMPK ratio were elevated (p < 0.01) after cold exposure; Rt-qPCR results indicated that Bax and P53 mRNA were increased (p < 0.01), while PGC-1α expression was elevated (p < 0.01). Rt-qPCR results showed elevated Bax and p53 mRNA (p < 0.01), along with increased AMPK and PGC-1α expression (p < 0.01) in the cold-exposed group. In human umbilical vein endothelial cells (HUVECs), compound C attenuated cold-induced effects (p < 0.01) and downregulated Bax and AMPK expression (p < 0.01). Cold exposure exacerbates uterine oxidative stress and energy imbalance, disrupts microcirculatory homeostasis, and induces endothelial cell apoptosis. Excessive phosphorylation of AMPK may co-activate PGC-1α, jointly contributing to cold-induced uterine dysfunction and exacerbated dysmenorrhea. This study reveals potential signaling pathways underlying cold-induced uterine vascular abnormalities, providing novel theoretical foundations and targeted intervention strategies for the prevention and treatment of primary dysmenorrhea. Full article

Background/Objectives: Poor aqueous solubility and limited nasal permeability remain key challenges in the intranasal delivery of carbamazepine. In this study, biocompatible bovine serum albumin nanoparticles functionalized with sulfobutyl-β-cyclodextrin (SβCD-BSA NPs), comprising individually cytocompatible components with confirmed physical interactions), were formulated for intranasal delivery of carbamazepine (CBZ). Methods: The ethanolic desolvation method was utilised for the preparation of the nanoparticles, with the functional moiety incorporated during nanoparticle preparation. The effects of different molar ratios of SβCD-BSA and different ethanol volume ratios were studied. For crosslinking, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), a non-toxic crosslinker, was utilised. To determine the role of the SβCD, two preparation samples were formulated, with and without SβCD. Results: The formulation without SβCD incorporation had a mean particle size of 125 ± 0.64 nm, polydispersity index (PDI) of 0.34, encapsulation efficiency (EE%) of 61.5 ± 1.40%, and drug-loading ratio (DL%) of 31.9 ± 1.50%. Conversely, the SβCD-functionalized formulation showed a mean particle size of 128 ± 2.12 nm, PDI of 0.21 ± 0.03, EE of 64.6 ± 0.35%, and DL of 34.28 ± 1.60%. Statistical analysis revealed that the incorporation of SβCD resulted in a statistically significant increase in both DL% and EE% (p < 0.05). Conversely, the observed differences in particle size and PDI were not statistically significant (p > 0.05). This addition provides precise context regarding the comparability of the formulations while highlighting SβCD’s functional benefits in solubility and permeation. The interaction between CBZ and SβCD-BSA was confirmed using Fourier-transform infrared spectroscopy. Lastly, the prepared formulations were characterised by their physicochemical attributes and in vitro biopharmaceutical studies. It was discovered that SβCD plays a dual role, enhancing the solubility of CBZ in one scenario while promoting its nasal permeation, suggesting its potential use in epilepsy treatment. Conclusions: These findings highlight the potential of SβCD-BSA NPs as a versatile pharmaceutics platform for the intranasal delivery of poorly soluble CNS drugs. Full article

Soil provides essential ecosystem services and is pivotal for achieving multiple United Nations (UN) Sustainable Development Goals amid growing population pressures and resource demands. In arid to semi-arid regions such as Maio Island (Cape Verde), nutrient-poor soils and unsustainable land-use practices increase agricultural vulnerability, while volcanic geochemistry introduces elements that are not human friendly, further challenging environmental quality and long-term sustainability. Assessing soil (physical–chemical–biological) condition is therefore crucial for informed environmental and land-use planning. Here, Maio’s topsoil was evaluated using protocols adapted from Santiago, the largest Cape Verdean island. Estimated Background Values (EBVs) indicated naturally elevated V, Cr, Ni, Co, and Cu concentrations, consistent with mafic volcanic terrains. Robust Principal Component Analysis (rPCA) revealed geochemical groupings linked to volcanic–sedimentary units, with the dominant component (PC1) defined by Co–V–Cu–Mn–Ni versus As–Cd. Environmental Risk Indices (ERIs) and Multi-Element ERIs (ME–ERIs) quantified elemental enrichment relative to international land-use standards (residential and agricultural) and subsequently to Maio’s EBVs. The highest exceedances were observed for Cr, Co, Ni, V, and Cu, whereas As, Cd, Hg, Pb, and Zn fell within thresholds. The EBV-based assessment identified fewer exceedances than stricter international guidelines, though a few multi-element “hotspots” persist, highlighting potential land-use constraints and the need for preventive management. Overall, the integrated EBV/ERI/ME–ERI framework establishes an environmental geochemical baseline for Maio and offers a screening tool applicable across the entire archipelago. Full article

Tumor-infiltrating lymphocytes (TILs) are an established predictor of pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) in breast cancer. However, TILs primarily reflect the extent of immune infiltration and provide limited insight into immune functional state. We investigated whether integrating measures of immune infiltration (TILs), effector T-cell presence (CD8), and functional context (immune checkpoint components) may improve prediction of pCR beyond TILs alone. Pretreatment tumor biopsies from 166 patients with early breast cancer treated with standard NACT were assessed for stromal TILs and mRNA expression of CD8, PD-1, LAG-3, and TIM-3. Associations with pCR were evaluated using univariate and multivariable logistic regression, and composite immune phenotypes were constructed to capture functional immune states. In univariate analyses, higher TILs, CD8, PD-1, and LAG-3 were associated with pCR (all p < 0.05), whereas TIM-3 was not (p = 0.801). In multivariable models, TILs remained independently associated with pCR when adjusted for checkpoint markers, but this association was attenuated when CD8 was included, consistent with the strong biological correlation between TILs and CD8, and neither CD8 nor checkpoint markers retained independent significance. PD-1 and LAG-3 expression strongly correlated with CD8 and moderately correlated with TILs, indicating that checkpoint expression predominantly reflects an immune effector–engaged tumor microenvironment. Composite immune phenotypes based on CD8/PD-1 co-expression identified distinct immune functional states, with CD8-high/PD-1-high tumors demonstrating the highest pCR rates. Hierarchical modeling showed modest improvements in discrimination with sequential addition of immune variables to clinical predictors, with the integrative CD8/PD-1 model achieving the highest discrimination within the cohort (AUC = 0.849), although the magnitude of improvement beyond TIL assessment alone was limited. In conclusion, immune infiltration, effector T-cell presence, and functional immune context represent complementary dimensions for pCR prediction following NACT in breast cancer. However, TILs remain the most robust and clinically feasible immune biomarker. Full article

This study investigates the effects of roasting pre-treatment on Lupinus angustifolius protein isolate (LPI) and the resulting structure–function relationships relevant to food applications. Lupin seeds were roasted for 0, 10, 20, and 30 min prior to protein extraction, and the resulting LPI was characterized using circular dichroism (CD), Fourier-transform infrared (FT-IR) spectroscopy, intrinsic fluorescence spectroscopy, and SDS-PAGE. Unroasted LPI exhibited compact native conglutin structures with low solubility (58.64%), surface hydrophobicity (43.34 μg BPB), emulsifying activity (30.71 m²/g), and in vitro protein digestibility (IVPD, 82.84%). Roasting pre-treatment induced a biphasic structural response. Partial conformational changes increased solubility (up to 97.84%), exposed hydrophobic sites (peak 55.79 μg BPB), enhanced emulsifying activity (45.37 m²/g), doubled foaming capacity (210%), and improved IVPD (90.85%), likely due to structural changes that facilitated digestion. CD analysis showed a modest increase in α-helical content (3.43 → 6.74%) with minor fluctuations in β-sheet content, while fluorescence quenching indicated conformational loosening and partial reorganization. SDS-PAGE revealed the formation of soluble oligomers and high-molecular-weight aggregates, consistent with heat-induced association. Prolonged roasting reduced emulsion and foam stability because of aggregation, but maximized antioxidant capacity, likely associated with Maillard reaction products despite the observed depletion of amino acids. Overall, controlled roasting pre-treatment systematically modulates lupin protein structure and functionality, highlighting LPI as a competitive high-performance plant protein ingredient for food applications. Full article

Remote sensing image change detection serves as a core technology in environmental monitoring. While the widespread availability of high-resolution remote sensing data provides essential support for detailed detection, it also presents technical challenges such as complex terrain interference, subtle change recognition, and large-scale scene processing. Current mainstream deep learning methods, despite their global modeling advantages, demonstrate limitations in cross-temporal fine-grained correlation mining and are prone to ambiguous edge localization in changing areas due to spatial detail loss. This paper proposes a high-resolution change detection network (TiBT-Net) that integrates bi-temporal space enhancement with token interaction. The model achieves precise change detection through dynamic token interaction and adaptive enhancement (TDIAE), utilizing deformable attention to capture semantic correlations. It constructs a Bi-Temporal Information Interaction Module (BTII) that enhances spatial details via multi-scale convolutions and channel attention, while introducing a delayed fusion mechanism (DLF) to dynamically balance dual-branch feature contributions. Experimental validations on LEVIR-CD, WHU-CD, and DSIFN-CD datasets achieved F1 scores of 90.38%, 86.74% and 96.28%, respectively, with Intersection-Union Ratios (IoU) of 82.46%, 76.59% and 92.82%. The overall accuracy (OA) reached up to 99.04%. This model effectively resolves the integration conflict between semantic information and spatial details, providing a reliable technical solution for high-precision change detection in complex scenarios. Full article

Food safety, quality, and traceability have become increasingly important in the agrifood industry in recent years, necessitating the use of reliable and rigorous analytical tools to ensure agrifood surveillance. This work focuses on the development and application of a new molecular approach to verify the authenticity of a specific variety of Triticum turgidum ssp. turanicum, commonly known as Khorasan wheat, which is commercially sold under the KAMUT^® trademark. A method based on duplex digital PCR was developed to identify and quantify T. turanicum variety QK-77 used in KAMUT^® brand products. The assay was validated on pure QK-77 variety alone and mixed with other varieties and on other cereal species. The developed PCR-based assay, tested using two digital PCR platforms (cdPCR and pdPCR), has high sensitivity and accuracy and can be applied to quantify the QK-77 variety in commercial grain lots and processed foods. Full article

Sildenafil, a selective phosphodiesterase-5 (PDE5) inhibitor, supports vascular remodeling, but its effects on angiogenesis and regeneration of ischemic muscle tissue are not fully understood. We investigated the function of sildenafil by employing a murine hindlimb model of ischemia, in which ischemia and angiogenesis is induced by femoral artery ligation (FAL) in the lower leg of mice. Then, 7 days after FAL or sham operation, gastrocnemius muscles of sildenafil-treated and control mice were isolated and processed for histological and immunofluorescence analyses. Sildenafil treatment led to reduced apoptotic areas within the ischemic tissue (ascertained via TUNEL assay) and increased angiogenesis, evidenced by a higher capillary-to-muscle fiber ratio and an augmented number of proliferating capillary cells (CD31⁺/CD45⁻/BrdU⁺), compared to controls. We observed a decrease in the total count of leukocytes (CD45⁺) in sildenafil-treated mice. Regarding macrophage infiltration, we found a reduced total number of macrophages (CD68⁺), along with a shift in macrophage polarization toward the pro-angiogenic and anti-inflammatory M2-like phenotype (CD68⁺/MRC1⁺). In summary, we show that sildenafil treatment contributes to angiogenesis and the regeneration of ischemic muscle tissue, most likely by attenuating inflammatory responses and influencing macrophage polarization in direction to regenerative M2-like polarized macrophages. Full article

Articular cartilage, a highly specialised and avascular tissue, exhibits limited regenerative potential following trauma or degenerative conditions such as osteoarthritis (OA). Conventional surgical interventions, including microfracture and autologous chondrocyte implantation (ACI), have shown limited long-term efficacy due to donor site morbidity and restricted cell proliferation. In this context, mesenchymal stromal cells (MSCs) have emerged as a promising alternative owing to their multipotency, self-renewal capacity, and low immunogenicity. While bone marrow (BM) remains the traditional source of MSCs, recent studies have reported that peripheral blood-derived mesenchymal stromal cells (PB-MSCs) may possess chondrogenic, osteogenic, and adipogenic potential comparable to that of BM-derived MSCs. PB-MSCs can be harvested through minimally invasive methods, thereby avoiding the complications associated with BM aspiration. Experimental evidence indicates that PB-MSCs exhibit strong cell viability, proliferative potential, and the ability to synthesise cartilage-specific extracellular matrix proteins, such as type II collagen and sulphated glycosaminoglycans, within three-dimensional scaffolds. Immunophenotypically, PB-MSCs express mesenchymal markers including CD29, CD44, CD90, and CD105 while lacking hematopoietic markers CD34 and CD45. Flow cytometry analyses reveal that CD105⁺ populations increase following cryopreservation, highlighting their clinical utility. In contrast to these experimentally defined PB-MSCs, the term peripheral blood stem cells (PBSCs) is used in clinical studies to describe heterogeneous, non-cultured peripheral blood-derived cell preparations, typically enriched in hematopoietic stem and progenitor cells following granulocyte colony-stimulating factor (G-CSF) mobilisation, without full mesenchymal characterisation. In vitro studies confirm successful tri-lineage differentiation, whereas in vivo investigations have demonstrated effective cartilage regeneration using PB-based clinical approaches, including postoperative intra-articular administration of hyaluronic acid (HA) combined with PBSCs, as well as implantation of PBSCs covered with a collagen membrane. Furthermore, advancements in biomaterial engineering, such as poly(ethylene glycol)–cysteine–arginine–glycine–aspartic acid (PEG-CRGD) hydrogels, have enhanced PB-MSC adhesion, proliferation, and chondrogenic differentiation while promoting immunomodulation through M2 macrophage polarisation. Despite these promising outcomes, the available evidence remains limited and heterogeneous, with substantial variability in cell definitions, experimental models, and clinical study designs, which currently constrains definitive conclusions regarding clinical efficacy. Future research should focus on optimising isolation protocols, understanding molecular pathways governing PB-MSC chondrogenesis, and standardising clinical applications. Overall, PB-MSCs represent a viable, less invasive, and translationally relevant cell source for cartilage regeneration and regenerative orthopaedic therapies Full article