Search Results (42,147)

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease lacking therapies that target underlying cell death pathways. Ferroptosis, an iron-dependent form of lipid peroxidation-driven cell death, has emerged as a key mechanism in vascular remodeling. We investigated whether exogenous ketosis induced by ketone ester (KE) supplementation can suppress ferroptosis and prevent TAAD. TAAD was induced in C57BL/6 mice using β-aminopropionitrile (BAPN). A subset of these mice received KE [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate, 20 g/L] in their drinking water starting on day 15 of the BAPN treatment. Human aortic smooth muscle cells (HASMCs) were treated with the GPX4 inhibitor Ras-Selective Lethal 3 (RSL3) and β-hydroxybutyrate (β-OHB) to investigate ferroptotic markers, lipid peroxidation, and labile iron levels. KE supplementation significantly reduced TAAD incidence (69% → 43%) and improved survival rate (52% → 73%), while preserving aortic structure and reducing elastic fiber fragmentation. Transcriptomic analyses of human TAAD datasets (GSE153434 and GSE52093) and single-cell RNA sequencing data (GSE155468) revealed ferroptosis signatures characterized by decreased GPX4 and increased expression of iron metabolism genes. Mechanistically, KE suppressed BAPN-induced iron accumulation and lipid peroxidation in vivo. In HASMCs, β-OHB inhibited ferroptosis induced by GPX4 inhibition, decreasing lipid peroxidation and labile iron levels. KE restored GPX4 and SLC7A11 expression while suppressing HO-1 in vivo, with effects dependent on Nrf2 signaling in vitro. In summary, ketone ester supplementation protects against TAAD by inhibiting VSMC ferroptosis via GPX4 induction and HO-1 suppression, highlighting a potential therapeutic strategy for aortic disease. Full article

The overexpression of hypoxia-inducible factor-1α (HIF-1α) suppresses STING signaling and modulates lipid metabolism in tumor cells, leading to abnormal lipid droplet (LD) accumulation. Herein, we constructed a manganese dioxide (MnO₂)-based nanomotor (HMIP@A). HMIP@A depletes intracellular hydrogen peroxide (H₂O₂) and glutathione (GSH) to generate oxygen (O₂), reactive oxygen species (ROS), and manganese (Mn²⁺). A dual strategy of “oxygen supplementation” and “small-molecule inhibition” synergistically downregulates HIF-1α, thereby suppressing LD biogenesis. This process sensitizes tumor cells to ROS, leading to severe DNA damage. Released Mn²⁺ and damaged DNA synergistically activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In vitro, HMIP@A markedly increases ROS production, lipid peroxidation (LPO), and DNA damage, thereby inducing tumor cell death, immunogenic cell death (ICD), and dendritic cell (DC) maturation. Furthermore, HMIP@A exhibits excellent penetration in tumor spheroids. Overall, this study provides a theoretical basis for the design of nanomedicines through a strategy integrating metabolic intervention, oxidative damage sensitization, and immune activation. Full article

Brucellosis, acting as a typical chronic zoonotic disease, is caused by the invasion of Brucella into the human body. Outer membrane protein 25 (Omp25), specifically localized on the Brucella membrane, is the main virulence factor of Brucella and participates in multiple links of the damage process. Omp25c, a porin protein of Brucella, is a paralog of Omp25 with high sequence identity. NADH dehydrogenase [ubiquinone] complex I assembly factor 2 (Ndufaf2) has a key function in cell energy metabolism, particularly in the formation and activity of the mitochondrial respiratory chain. Loss of Ndufaf2 results in oxidative stress and mitochondrial DNA (mtDNA) deletion. However, the functional relationship between Omp25c and Ndufaf2, the underlying mechanism of the proteins, remains unclear. In this work, we purified the Omp25c and Ndufaf2proteins. Our data revealed that Omp25c directly interacts with Ndufaf2, as determined using Biacore analysis. In addition, assays revealed that Ompa2c reshapes the host cell’s redox environment by decreasing the oxidized nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide (NAD⁺/NADH) ratioand adenosine triphosphate (ATP) production, whereas Ndufaf2 exerts an opposing regulatory effect; Co-expression results further revealed an antagonistic relationship between the two during metabolic processes. These findings provide a new perspective for elucidating the mechanisms of mitochondrial functional regulation in Brucella–host interactions and lay the theoretical and experimental foundation for drug development targeting metabolic interventions to eliminate intracellular pathogens. Full article

Dietary antioxidants and phytochemicals are believed to support cognitive health, but evidence on composite dietary indices remains limited. This cross-sectional study of 1845 community-dwelling older adults in China investigated the associations of the composite dietary antioxidant index (CDAI) and dietary phytochemical index (DPI) with cognitive function and mild cognitive impairment (MCI). Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA; Beijing version). MCI was diagnosed through a two-stage procedure: MoCA-based preliminary screening (with education-stratified cutoffs: 13/14 for illiterate, 19/20 for 1–6 years, 24/25 for ≥7 years) followed by neurologist confirmation. CDAI was calculated as the sum of the standardized intakes of six antioxidants (selenium, zinc, carotenoids, vitamin A, vitamin C, vitamin E); DPI was defined as the percentage of the total energy intake from phytochemical-rich foods (fruits, vegetables excluding potatoes, legumes including soy products, nuts, seeds, and whole grains). Multivariable linear regression, logistic regression, and receiver operating characteristic (ROC) curve analyses were performed. The basal metabolic rate (BMR) and systemic immune-inflammation index (SII; platelets × neutrophils/lymphocytes) were tested as potential statistical mediators. Each one-unit increase in CDAI was associated with a 0.068-point higher MoCA score (95% CI: 0.012–0.123), and each one-unit increase in DPI was associated with a 0.029-point higher MoCA score (95% CI: 0.008–0.050). BMR and SII partially mediated the association between CDAI and MoCA score, but temporal ordering remains unclear due to the cross-sectional design. When both CDAI and DPI were in the highest quartile, participants had a 46.3% lower risk of MCI compared with those with both indices in the lowest quartile (OR = 0.537, 95% CI: 0.308–0.935). A predictive model incorporating CDAI, inflammatory markers, and red blood cell parameters showed moderate discriminatory ability in this study sample (apparent AUC = 0.731, bootstrap-corrected AUC = 0.728). These findings suggest that a higher combined dietary antioxidant and phytochemical intake may be jointly associated with better cognitive function, although the cross-sectional design precludes causal inference. Full article

Repeat breeder (RB) cows fail to conceive after three or more breeding attempts, yet the uterine factors contributing to this condition remain unclear. Here, we compared uterine fluid composition, endometrial cell responses to uterine fluid, and uterine microbiota between normal pregnant (Normal) and RB cows. Uterine fluid was collected from multiparous Holstein cows classified as Normal (n = 5; conception within three breeding attempts) or RB (no conception after four attempts); RB cows were classified as RB-Rec (n = 4; conceived after uterine lavage) or RB-NoRec (n = 3; did not conceive after uterine lavage). Uterine fluids were applied to bovine endometrial cells, and microbiota composition was analyzed. Concentrations of lipopolysaccharide in the uterine fluid did not differ between the three groups, and uterine fluid from both RB groups significantly increased C-X-C motif chemokine ligand 8 secretion relative to the Normal group. RNA-seq revealed distinct endometrial cell responses to RB-NoRec uterine fluid, with enrichment of immune-related pathways including phagosome, ferroptosis, and cellular senescence. Uterine microbiota profiles differed among groups, with short-chain fatty acid-producing genera (e.g., Fusicatenibacter and Dorea) predominant in Normal cows and inflammation-associated genera (e.g., Trueperella and Helicobacter) predominant in RB-NoRec cows. These data indicate that uterine fluid properties and microbiota composition vary with reproductive status and may modulate endometrial immune activation associated with fertility outcomes. Full article

Type II toxin–antitoxin (TA) systems are significantly expanded in the Mycobacterium tuberculosis complex; however, the functional role of the VapBC40 system in Mycobacterium bovis(M. bovis) pathogenesis remains poorly characterized. This study aimed to investigate the role of VapBC40 in mycobacterial virulence and evaluate its potential as a target for rational vaccine attenuation. We performed evolutionary analysis and yeast two-hybrid assays to characterize VapBC40 system specificity, conducted in vitro macrophage infection models and in vivo murine studies to assess virulence contribution, and evaluated the immunoprotective efficacy of a VapC40 knockout strain. Evolutionary analysis revealed progressive sequence conservation and stringent homologous pairing specificity within the VapBC40 system. The VapC40 toxin correlates with enhanced intracellular bacterial survival, increased host cell death, and more severe pulmonary pathology with systemic dissemination. Based on these findings, we evaluated the vaccine potential of a vapC40 knockout strain. Immunization with this attenuated strain elicited a Th1 cellular immune response, characterized by enhanced IFN-γ production and increased frequency of CD4⁺IFN-γ⁺ T cells. Upon challenge with virulent M. bovis, the knockout strain conferred superior protection compared to the conventional BCG vaccine, significantly reducing lung pathology and restricting extrapulmonary bacterial dissemination. Although the molecular mechanisms underlying VapC40-mediated effects remain to be fully elucidated, our findings suggest an important role of the VapBC40 system in mycobacterial-host interactions and support its potential as a target for next-generation tuberculosis vaccine development. Full article

Background/Objectives: We aim to identify the postoperative acute kidney injury (AKI) risk factors and the predictors of severe AKI derived from routine perioperative elements in patients with aortoiliac occlusive disease who underwent aorto-bifemoral bypass as arterial revascularization. This involves a dynamic assessment throughout the perioperative period. Methods: Preoperative, intraoperative, early postoperative and day-one-after-surgery data were retrospectively reviewed in consecutive patients who underwent elective aorto-bifemoral bypass for aortoiliac occlusive disease classified as TASC II D at the “Prof. C.C. Iliescu” Emergency Institute for Cardiovascular Diseases in Bucharest, Romania, between 2017 and 2023. Results: Preoperative clearance of creatinine (OR 1.037, CI95%: 1.009–1.066), the duration of the surgery (OR 1.435, CI 95%: 1.100–1.873), and the change between the day-one-after-surgery and preoperative systemic inflammatory response index (DeltaSIRI_1_preop) (OR 1.080, CI 95%: 1.012–1.152) were identified as independent risk factors for postoperative AKI in patients undergoing aorto-bifemoral revascularization for aortoiliac occlusive disease. The most severe form of AKI was strongly predicted by the number of packed red blood cells transfused (AUC 0.924, p = 0.001), the patient’s age (AUC 0.895, p = 0.001), and the duration of the surgery (AUC 0.895, p = 0.001). Furthermore, various routine and cost-effective variables related to the preoperative period, the early postoperative period, and the first day after surgery also demonstrated significant predictive value. Conclusions: We conducted a dynamic perioperative assessment of AKI associated with major vascular surgery. This aims to equip clinicians with a practical and cost-effective tool for evaluating AKI, thereby facilitating a more individualized approach to the diagnosis of this complication. 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

Background and Objectives: Invasive cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (AK) are growing burdens on ageing societies and mainly arise from chronic sun exposure. Distinguishing between carcinoma and carcinoma in situ is often clinically challenging but essential for decision-making with respect to targeted therapy. Ex vivo confocal laser scanning microscopy (CLSM) allows histologic examination of native tissue using tissue reflection and nuclear fluorescence staining. The digital staining process almost perfectly mimics conventional haematoxylin and eosin (HE) staining. While the use of CLSM for basal cell carcinoma (BCC) diagnosis is well described, data on cSCC remain scarce. The aim of this study was to compare CLSM with conventional histology in diagnosing and distinguishing cSCC and AK in routine clinical practice. Materials and Methods: Between August 2022 and March 2024, 63 patients with clinically suspected invasive cSCC or AK were enrolled. Biopsy or excision specimens were examined by ex vivo confocal laser scanning microscopy (VivaScope^® 2500 M-G4) followed by acridine orange staining. All samples underwent subsequent routine histopathology, which served as the reference. Two dermatologists independently compared the CLSM findings with the histopathological diagnoses. Results: Eighty-one lesions suspected to be cSCC were assessed using CLSM. The diagnostic accuracy was high across specimen types: cSCC was correctly identified in 24/26 cases (92.3%), AK/Morbus Bowen in 16/17 cases (94.1%), cSCC filia (cutaneous squamous cell carcinoma metastases) in 3/3 cases (100%), and basal cell carcinoma in 9/9 cases (100%). The absence of a tumour was correctly recognized in 19/21 cases (90.5%). In five cases (6.2%), AK and early invasive cSCC could not be differentiated, reflecting the histopathological results. Conclusions: CLSM with digital HE staining is well suited for rapid cSCC and AK diagnosis and differentiation in clinical practice. Full article

The ambient stability of ambient-processed lead-free perovskite absorbers remains a critical challenge toward scalable, eco-friendly photovoltaics. Herein, we systematically investigate the time-dependent structural and morphological evolution of drop-cast ambient-processed Cs₃Sb₂I₉ thin films, being a potential non-toxic and stable solar absorber candidate (energy bandgap ~2 eV) for solar cells, stored under uncontrolled ambient condition (~60% Relative humidity) for 28 days. Sequential X-ray diffraction (XRD) and surface morphology analyses using scanning electron microscope (SEM) reveal that the films preserve their trigonal P3̅m1 phase throughout aging, confirming phase stability. Moderate moisture exposure may induce partial recrystallization and subtle structural reorganization, possibly including minor c-axis realignment, leading to reduced lattice strain and improved crystallite coherence. Even after prolonged aging, no secondary phases or micro-cracks are detected, underscoring the slow degradation kinetics and robust Sb–I bonding that stabilize the layered [Sb₂I₉]³⁻ dimers. The late-stage increase in diffraction intensity and partial recovery of crystallographic parameters could indicate transient structural reorganization, potentially associated with moisture-mediated reordering within an overall degradation pathway. These observations suggest some degree of morphological persistence and structural tolerance of Cs₃Sb₂I₉ under ambient conditions, rather than complete stability. This behavior offers useful insights into ambient processing and the long-term reliability of lead-free perovskite photovoltaics. Full article

Background/Objectives: Denture stomatitis is closely associated with Candida albicans colonization of denture-base surfaces. This in vitro study compared early adhesion (1 h) and initial biofilm formation (24 h) of C. albicans across five denture-base-related material groups using adhered cell counts and adhered/inoculum proportions. Methods: A 5 × 2 factorial design (five material groups; 1 and 24 h) evaluated a comparator pattern resin, heat-polymerized acrylic resin, autopolymerizing acrylic resin, milled CAD/CAM PMMA, and microwave-polymerized acrylic resin. All specimens underwent standardized finishing and mechanical polishing before microbiological testing. Data were log10-transformed and analyzed by two-way ANOVA (material group, time) with Tukey’s post hoc test. An external SEM-based qualitative laboratory report was used as complementary documentation of C. albicans presence after 1 h and 24 h; representative micrographs and quantitative SEM image outputs were unavailable. Results: Material group, time, and their interaction significantly affected adhered C. albicans counts (p < 0.05). At 1 h, the comparator pattern resin showed the highest adhesion, whereas at 24 h, milled CAD/CAM PMMA showed the highest adhered load. For the adhered/inoculum fraction, both material group and time were significant; at 24 h, the heat-polymerized acrylic resin showed the lowest adhered fraction. Conclusions: Under the standardized finishing and mechanical polishing conditions of this in vitro model, the tested material groups showed different C. albicans adhesion/biofilm patterns over time; clinical extrapolation should be made with caution. Full article

Miang, a traditional fermented tea produced from Camellia sinensis var. assamica, is of notable cultural and socio-economic relevance in Northern Thailand. Traditionally, the non-filamentous fungi-based process (NFP) in western Lanna uses only young tea leaves, resulting in substantial amounts of mature leaves being discarded as agricultural waste. This study aimed to utilize the mature tea leaves by adapting the filamentous fungi growth-based process (FFP) of eastern Lanna using selected tannin-tolerant microorganisms, including Aspergillus niger MLF3, Cyberlindera rhodanensis P3, and Lactiplantibacillus pentosus A14-6. Study on fermentation dynamics and bioactive compound formation based on a 2-step fermentation process: 3-day solid-state fermentation with A. niger MLF3, followed by 7-day submerged fermentation by co-culture of C. rhodaninsis P3, and L. pentosus A14-6 in 500 mL sterile distilled water at 30 °C. Increased activities of polysaccharide-degrading enzymes and organic acids were clearly observed during solid-state fermentation, while the significant changes in polyphenol, antioxidant, and reducing sugar content in cell-free supernatant (CFS) were found after submerged fermentation. The obtained CFS shows inhibitory effects of 90 ± 2.5% and 95 ± 1.8% on α-glucosidase and α-amylase, respectively. Analysis of CFS by E-tongue and E-nose clearly indicated the influence of microbial mixture on the taste and aroma of the fermented products. These results demonstrate not only a high-yielding strategy for the effective biotransformation of mature tea leaves into functional drink products but also significant implications for reducing agricultural waste. Full article

Exposure to high-altitude hypoxia leads to complex physiological and molecular adaptations, particularly in skeletal muscle. MicroRNAs (miRNAs), including muscle-enriched (myomiRNAs) and hypoxia-responsive (hypoxamiRNAs), play critical roles in regulating these responses. We investigated miRNA expression changes in the skeletal muscle of healthy, non-smoking Italian adults (mean age 36.7 ± 12.4 years) participating in the Himalayan expedition “Lobuche Peak—Pyramid Exploration & Physiology” conducted in the Sagaramāthā (Mount Everest) National Park, Nepal. The peak overnight stay altitude was ≈5000 m at the Pyramid International Laboratory—Observatory. Muscle biopsies were taken before and after the expedition from Vastus lateralis, at one-third of the distance from the upper margin of the rotula to the anterior superior iliac spine. Small RNA sequencing was used to profile differentially expressed miRNAs. Several miRNAs were differentially expressed (exploratory analysis), suggesting potential involvement in hypoxia-related adaptation. These encompass both canonical myomiRNAs (e.g., miR-206, miR-486-5p) and hypoxamiRNAs (e.g., miR-378a-5p, miR-199a-3p, let-7b-5p). In enrichment analysis, we found several connections between miRNAs and pathways that may play a role in physiological regeneration or differentiation in muscle cells. Among functions, focal adhesion (p-value = 0.001), regulation of actin cytoskeleton (p-value = 0.026), Rap-1 (p-value = 0.007), cAMP (p-value = 0.017), MAPK (p-value = 0.019), and Hippo (p-value = <0.001) signaling pathways were predicted to be the most targeted. These findings provide preliminary insights into physiological adaptation, requiring confirmation in larger and controlled cohorts. Full article

Organic-type solar cells containing an active layer of block copolymer donor PTB7-Fx (x = 0, 20, and 100), based on benzo [1,2-b:4,5-b’]dithiophene and variably fluorinated thieno [3,4-b]thiophene units, and fullerene acceptor [6,6]phenyl-C₇₁-methylbutyrate, were constructed. The active layer thin film of the solar cells was obtained from a dichlorobenzene solution at an established concentration via spin-coating of the donor–acceptor mixture in the presence of solvent additives such as 3% diiodooctane and 1% triethyl phosphate. Organic photovoltaic elements with normal device architecture were prepared on glass substrates using an indium tin oxide anode, a spin-coated hole transporting layer of poly(ethylene dioxythiophene):polystyrenesulfonate, the aforementioned active layer, followed by an electron transporting layer of zinc oxide nanoparticles, and finally a magnetron sputtered silver (Ag) top-electrode. The optical properties, thin film morphology, and the thickness of the active layers were investigated. Additionally, current density–voltage characteristics and impedance spectra of photovoltaic devices were measured. It was found that PTB7-Fx:PC₇₁BM-based solar cells processed in the presence of two types of solvent additives, diiodooctane and triethyl phosphate, with a sputtered Ag top-electrode display similar absorption and quantum efficiency spectra, as well as comparable current density–voltage characteristics and efficiencies to the same devices fabricated without additives. The diiodooctane solvent additive preferably dissolves the fullerene component and has a positive effect on fill factor enhancement, impedance spectra improvement, and amelioration in charge carrier transport and collection, whereas the triethyl phosphate solvent additive preferentially dissolves the copolymer donor and has a more pronounced impact on the refined morphology of the thin film active layers. Full article

Excessive dietary sodium intake has been associated with immune dysregulation, yet its impact on bone health and immune cell dynamics within the bone–immune axis remains poorly understood. We developed a longitudinal murine model to investigate the effects of a high-salt diet (HSD) on bone properties and immunity. Male and female C57BL/6J and Foxp3-GFP mice underwent unilateral nephrectomy and were fed either a normal salt diet (0.2% NaCl) or HSD (4% NaCl) for 20, 60, or 150 days. HSD mice exhibited a transient increase in systolic blood pressure and sustained calciuria without changes in serum calcium or PTH. Progressive impairment of femoral strength and tibial trabecular microarchitecture were observed, along with reduced cortical calcium and phosphorus content. Immune analysis revealed early splenic and bone marrow activation of effector T cells, with increased Th17 and Tc17 populations and a disrupted Th17/Treg balance at 20 days. These changes normalized by 60 days and shifted to suppressed T cell activation at 150 days, suggesting a biphasic immune response. Th17/Treg ratio was associated with bone deterioration. Notably, both sexes showed comparable physiological and immune trends. This integrative model provides a platform to dissect mechanisms linking chronic salt overload, immune dysregulation, and bone fragility. Full article