Search Results (27,635)

Background: Hepatic ischemia–reperfusion (I/R) injury induces systemic oxidative stress and inflammatory responses that may lead to remote lung injury. This study investigated whether taxifolin attenuates hepatic I/R-induced lung damage and examined the involvement of the nuclear factor-κB (NF-κB) and high-mobility group box-1 (HMGB1) signaling axis. Methods: Twenty-eight male Wistar rats were divided into four groups (n = 7): control, taxifolin, hepatic I/R, and taxifolin+I/R. Serum oxidative stress markers (malondialdehyde [MDA], interleukin [IL]-6, total antioxidant/oxidant status [TAS/TOS]) and wet-to-dry lung weight ratio were measured. Lung tissues were evaluated histopathologically and immunohistochemically for NF-κB and HMGB1 expression. Bioinformatics pathway enrichment and molecular docking analyses were also performed. Results: Hepatic I/R significantly increased serum MDA, IL-6, and TOS levels and decreased TAS (p < 0.05). Severe lung injury was observed in the hepatic I/R group (median score: 11), whereas taxifolin pretreatment significantly reduced the injury score (median score: 5, p < 0.001). NF-κB and HMGB1 expression were markedly elevated following hepatic I/R and significantly decreased with taxifolin treatment (p < 0.05). A strong positive correlation was found between NF-κB and HMGB1 expression (r = 0.82, p < 0.001). Pathway enrichment analysis indicated involvement of Toll-like receptor (TLR)-related inflammatory signaling, and docking analysis demonstrated favorable binding of taxifolin to TLR4 and NF-κB p65. Conclusion: Taxifolin attenuated hepatic I/R-induced lung injury by reducing oxidative stress and suppressing HMGB1–TLR4–NF-κB-mediated inflammatory signaling. Full article

Tumor metastasis is closely associated with coagulation and inflammation, particularly via thrombin–PAR1 signaling. However, the potential of natural polysaccharides such as rhamnan sulfate (RS) to modulate these pathways and suppress metastasis remains unclear. We aimed to investigate the effects of orally administered RS derived from Monostroma nitidum on melanoma metastasis and its underlying mechanisms. Male C57BL/6J mice were orally administered water or RS daily. On day 8, saline or B16 melanoma cells were injected intravenously. Mice were treated for 21 days and divided into four groups (control, RS-only, M + W, and M + RS; n = 5/group). Metastasis and related molecular factors were analyzed in plasma, lung, and aortic tissues. Significant lung and aortic metastases were observed in the M + W group but were markedly suppressed in the M + RS group. RS reduced the expression of inflammatory factors (e.g., IL-6, PAR1), proteases, leukocyte activation markers, complement factors, angiogenic factors, and EMT-related factors. Conversely, thrombin, thrombomodulin, plasmin, TAFIa, and tight junction proteins were increased in RS-treated mice. RS suppresses melanoma metastasis by modulating thrombin–PAR1-mediated inflammation and associated pathways. These findings suggest RS as a potential therapeutic agent, although further mechanistic and clinical studies are required. Full article

Objectives: Doxorubicin, a widely used chemotherapeutic agent, is known to induce hepatotoxicity through oxidative stress and inflammatory pathways. Vitamin D has been reported to exert antioxidant and immunomodulatory effects; however, its potential protective role in doxorubicin-induced liver injury remains insufficiently characterized. Materials and Methods: Adult male Wistar albino rats were randomly assigned to six groups (n = 7): Control, Vitamin D (5000 IU/kg), Vitamin D (60,000 IU/kg), Doxorubicin, DOX + Vitamin D (5000 IU/kg), and DOX + Vitamin D (60,000 IU/kg). Vitamin D₃ (cholecalciferol) was administered orally either as a daily dose (5000 IU/kg for 12 days) or as a single bolus dose (60,000 IU/kg). Doxorubicin (6 mg/kg/day, cumulative dose 18 mg/kg) was administered intraperitoneally on days 10–12. Hepatic injury was evaluated using ⁹⁹mTc-pyrophosphate (⁹⁹mTc-PYP) scintigraphy, serum liver enzymes (AST, ALT, LDH, total bilirubin), renal markers (BUN, creatinine), calcium and 25-hydroxyvitamin D [25(OH)D], oxidative stress parameters (MDA, TOS, TAS, GSH, SOD, Nrf2), and inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-10). Results: Doxorubicin markedly increased hepatic ⁹⁹mTc-PYP uptake and significantly elevated AST, ALT, LDH, bilirubin, MDA, TOS, TNF-α, IL-6, and IL-1β levels while reducing Nrf2, GSH, SOD, TAS, and IL-10 (all p < 0.001). Vitamin D supplementation significantly increased serum 25-hydroxyvitamin D [25(OH)D] levels compared with controls (32.3 ± 2.7 vs. 74.1 ± 3.8 and 69.3 ± 3.2 ng/mL for the 5000 and 60,000 IU/kg groups, respectively; p < 0.001) and attenuated DOX-induced hepatic injury, as indicated by reduced radiotracer uptake and improved oxidative and inflammatory markers. Vitamin D also mitigated DOX-associated increases in renal injury markers (BUN and creatinine) without inducing hypercalcemia. No significant differences were observed between the two vitamin D dosing regimens in most outcome measures. Conclusion: Vitamin D supplementation exerted protective effects against doxorubicin-induced liver injury, likely through modulation of oxidative stress and inflammatory pathways. Additionally, ⁹⁹mTc-PYP scintigraphy may serve as a useful imaging tool for detecting acute hepatocellular injury and evaluating therapeutic responses. Full article

Background: Genetic diversity and genetic differentiation between Gossypium hirsutum-Gossypium barbadense introgression lines (ILs) and early-maturing upland cotton lines are critical for resolving the core breeding contradiction in Xinjiang cotton region: narrow genetic basis of early-maturing cultivars and late maturity of ILs with superior fiber quality. Xinjiang is one of the major cotton-producing regions in China, and breeding high-quality early-maturing upland cotton adapted to local ecological conditions is essential for improving cotton yield and quality. However, the genetic relationship and differentiation between the two types of cotton germplasm remain unclear, which hinders the efficient utilization of germplasm resources in breeding. Therefore, this study aimed to clarify the genetic diversity and differentiation between the two germplasm types and identify key candidate loci related to early maturity and fiber quality, providing support for cotton breeding. Results: Here, we used a 40K Single Nucleotide Polymorphism chip to genotype core cotton germplasm in northern Xinjiang, and analyzed their population structure, genetic diversity and functional SNP loci associated with early maturity and fiber quality. The tested materials were clearly divided into two subgroups (ILs and early-maturing lines). Genetic diversity analysis revealed a significantly narrow genetic basis in the early-maturing subgroup, while the IL subgroup had higher genetic diversity. Specifically, the early-maturing subgroup showed lower nucleotide diversity and polymorphism information content compared with the IL subgroup, indicating that the genetic variation of early-maturing cotton germplasm in northern Xinjiang is relatively limited. A total of 25 non-synonymous SNPs were identified, among which the c.A613G:p.T205A mutation in GH_D09G1484 (mRNA-decapping enzyme 1, DCP1) was a characteristic variation of early-maturing cotton, and a possible non-synonymous mutation in GH_A09G2400 (Heat shock transcription factor A6b, HSFA6B) was associated with fiber development. These two candidate genes were annotated to be involved in plant growth and development, further supporting their potential roles in regulating cotton early maturity and fiber quality. Conclusions: This study clarified the genetic differentiation between the two types of germplasms and identified key candidate loci for early maturity and fiber quality, providing precise molecular markers and theoretical support for breeding high-quality early-maturing upland cotton adapted to Xinjiang’s ecological conditions. The results also highlight the value of Gossypium hirsutum–Gossypium barbadense introgression lines in enriching the genetic basis of early-maturing cotton, which can be further utilized to solve the core breeding contradiction in the Xinjiang cotton region. Full article

Background/Objectives: The effects of silver-coated dressing on wound healing, including cytotoxicity, are controversial due to the limited and incongruous results of in vitro versus in vivo research. Multiple factors intervene in wound healing processes and scarring, including pro/anti-inflammatory and pro/anti-fibrosis markers. Herein, to elucidate reported differences between in vitro and in vivo results, the effects of silver-coated dressing on 2D and 3D mono- and cocultures of fibroblasts and adipose-derived stem cells (ADSC) were investigated. Methods: Migration profiles in 2D and 3D assays, α-smooth muscle actin and proliferation marker Ki-67 expression, TGF-β1, TGF-β3, IL-6 and IL-10 levels and/or gene expression were assessed on four culture constructs. Results: In 2D systems at 24 h, silver-treated ADSC monocultures displayed better migration abilities compared to cocultures with high fibroblast ratio. In contrast, changes in the sprouting pattern between treated and untreated samples were non-significant in 3D constructs. TGFβ-1 levels decreased post-treatment, while TGFβ-3 increased, especially in 3D models. IL-6 gene expression was up-regulated following silver exposure in 3D models, mainly for stem cells in mono- and cocultures. Conclusions: Experiment data on 3D constructs suggest that silver-coated dressings do not significant impede wound healing, whereas cytotoxic effects were more pronounced in the 2D cultures. These inconsistencies, also noted in the literature, invite a methodological discussion of the 2D setup implications, recommending 3D constructs as a more appropriate evaluation standard where observable effects are closer to in vivo conditions and more relevant for transfer to clinical applications. Full article

Background and Objectives: Severe COVID-19 frequently fulfills Sepsis-3 criteria and is characterized by thrombo-inflammation and endothelial injury. We evaluated whether a bedside endothelial activation index (EAI = D-dimer/fibrinogen) identifies biologically distinct phenotypes and relates to interleukin-6 (IL-6) response after therapeutic plasma exchange (TPE), and whether baseline IL-6 predicts a ≥50% IL-6 reduction. Methods: Retrospective single-center ICU cohort of adults with SARS-CoV-2 infection, sepsis-related organ dysfunction, and ≥1 TPE session (n = 51). Patients were stratified by median EAI (low vs. high). Outcomes included peri-procedural biomarker/physiology changes (post–baseline), IL-6 responder status (≥50% reduction), correlations with IL-6 reduction (%), and multivariable predictors of response. Results: Compared with low EAI (n = 25), high EAI (n = 26) had higher baseline D-dimer (6.2 vs. 2.2 µg/mL) and lower fibrinogen (2.9 vs. 7.1 g/L) (both p < 0.001). Low EAI showed larger CRP decreases (ΔCRP −84.0 vs. −2.3 mg/L; p = 0.001) and larger fibrinogen falls (Δ −3.1 vs. −0.4 g/L; p < 0.001), while high EAI had larger D-dimer decreases (Δ −2.5 vs. −0.6 µg/mL; p = 0.004) and a modest SOFA improvement (Δ −0.3 vs. +0.1; p = 0.026). IL-6 responders (n = 20) had higher baseline IL-6 than non-responders (365.2 vs. 47.1 pg/mL; p < 0.001). Baseline IL-6 independently predicted response (per doubling: OR 1.94, 95% CI 1.27–2.95; p = 0.002), while age reduced odds (OR 0.91/year, 95% CI 0.84–0.99; p = 0.032). IL-6 reduction correlated with ΔCRP (ρ = −0.41; p = 0.003) and ΔPaO₂/FiO₂ (ρ = 0.37; p = 0.01). Conclusions: EAI stratifies distinct thrombo-inflammatory patterns around TPE, while baseline IL-6 is the dominant predictor of achieving large IL-6 reductions. To emphasize the novelty and clarify the study objective, this exploratory analysis used a phenotype-stratified framework to test whether a simple bedside endothelial activation index could enrich biological response assessment to adjunctive TPE. The prespecified primary outcome was achievement of a ≥50% IL-6 reduction after completion of the TPE course; secondary outcomes included peri-procedural biomarker, oxygenation, SOFA, and ICU endpoints. Full article

Background/Objectives: Retinoblastoma represents the most common intraocular malignancy in childhood; however, the clinical applicability of mitomycin C (MMC) is restricted by dose-dependent ocular toxicity. Consequently, the development of pharmacological strategies that sensitize tumor cells to MMC while allowing dose reduction remains an unmet therapeutic objective. In this context, quercetin, a bioactive flavonoid with pleiotropic anticancer properties, has emerged as a potential chemosensitizing agent. Methods: Human retinoblastoma cell lines Y79 and WERI-Rb1 were exposed to MMC and quercetin, administered either individually or in fixed-ratio combinations. Cytotoxic responses were quantified through dose–response modeling and IC₅₀ determination following 24 and 48 h of treatment. Drug–drug interactions were quantitatively characterized using the Chou–Talalay combination index (CI) approach and isobologram analysis. Cell cycle distribution was assessed by propidium iodide (PI)-based flow cytometric analysis to evaluate treatment-associated alterations in cell cycle progression. Apoptotic cell death was assessed by Annexin V-FITC/PI flow cytometry, while transcriptional modulation of genes associated with apoptosis, cell cycle regulation, and oxidative stress (BAX, BCL-2, TP53, CASP3, CDKN1A, and HMOX1) was evaluated by qRT-PCR. Modulation of tumor-supportive signaling was examined by measuring VEGF and IL-6 secretion. Translational relevance was further investigated using a three-dimensional (3D) tumor spheroid model, and the functional contribution of reactive oxygen species (ROS) was interrogated through N-acetyl-L-cysteine (NAC) rescue experiments. Results: Quercetin significantly enhanced the cytotoxic activity of MMC in both retinoblastoma cell lines, with CI values below 1 across IC₅₀–IC₉₀ effect levels, indicating a synergistic pharmacological interaction. PI–FACS analysis revealed that combined MMC and quercetin treatment induced a pronounced accumulation of cells in the G2/M phase, consistent with cell cycle arrest, with a more marked effect observed in Y79 cells compared with WERI-Rb1 cells. Combination treatment resulted in a pronounced increase in apoptotic cell populations compared with single-agent exposure and triggered a coordinated pro-apoptotic transcriptional response, characterized by increased expression of BAX, TP53, CASP3, CDKN1A, and HMOX1, alongside suppression of BCL-2 and a marked shift in the BAX/BCL-2 ratio. Concurrently, VEGF and IL-6 secretion were significantly reduced, reflecting attenuation of pro-angiogenic and pro-inflammatory signaling. Notably, synergistic cytotoxicity was maintained in 3D tumor spheroids, where combined treatment induced spheroid shrinkage, architectural disruption, and reduced viability. NAC pretreatment diminished ROS accumulation and partially restored cell viability, indicating that oxidative stress contributes to, but does not solely account for, the observed synergistic cytotoxic effect. Conclusions: Collectively, these findings indicate that quercetin appears to function as an effective chemosensitizing adjuvant to MMC in retinoblastoma models, through transcriptional changes consistent with p53-associated apoptotic signaling at the transcriptional level, G2/M cell cycle arrest, and partial involvement of ROS-related cellular stress responses, along with suppression of tumor-supportive signaling pathways. The preservation of synergistic activity in 3D tumor spheroids supports the potential preclinical relevance of this combination. However, these findings are based on transcriptional and phenotypic analyses and should be interpreted as hypothesis-generating, requiring further validation through protein-level and in vivo studies before translational application. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health burden, yet effective therapeutic options remain limited. This study investigated the protective mechanisms of Astragalus membranous extract (AM) against high-fat diet (HFD)-induced MAFLD in mice using an integrated strategy combining network pharmacology, hepatic metabolomics, and 16S rRNA sequencing. UPLC–Q-Orbitrap–MS/MS identified 37 major constituents in AM, mainly phenolic acids and flavonoids. Iristectorin A, isorhamnetin, ononin, and rhamnocitrin were identified as key candidate compounds due to their relatively high abundance and confirmation as absorbed constituents in vivo. Network pharmacology and molecular docking indicated favorable interactions with hub targets (TNF, EGFR, and AKT1; binding energies < −5.0 kcal/mol) and highlighted the involvement of the AGE–RAGE signaling pathway and inflammation- and lipid metabolism-related processes. In vivo, AM significantly attenuated HFD-induced weight gain, decreased serum ALT and AST levels, and reduced hepatic lipid deposition. AM also alleviated oxidative stress by lowering malondialdehyde (MDA) and increasing superoxide dismutase (SOD) activity, while suppressing hepatic IL-1β and IL-6. Moreover, AM improved gut microbial homeostasis by restoring α-diversity and enriching beneficial genera, including Akkermansia and Bacteroides. Hepatic metabolomics further showed that AM partially normalized lipid metabolic disturbances, particularly glycerophospholipid and sphingolipid metabolism. Collectively, these results suggest that AM mitigates MASLD via a multi-component, multi-target mechanism, potentially through modulation of AGE–RAGE-associated inflammatory signaling and the gut–liver axis, supporting its development as a functional food-derived candidate for metabolic liver disorders. Full article

Background: Adjuvant RT remains a standard therapy for breast cancer, reducing recurrence risk and improving survival; however, it can also induce side effects, including pain. Inflammasome-related biomarkers, such as interleukin-18 (IL-18), play a role in inflammation-mediated pain, and we hypothesize that IL-18 may serve as a potential biomarker for breast cancer RT-induced pain. Methods: The association between IL-18 and pain was assessed among breast cancer patients receiving adjuvant RT. Plasma IL-18 protein concentration was quantified before and after RT using Ella SimplePlex technology (Biotechne). Clinically relevant pain outcomes included pre-RT pain (pain score ≥ 4), post-RT pain (pain score ≥ 4), and RT-related pain (increase in pain from <4 pre-RT to ≥4 post-RT). Multivariable logistic regression assessed the association between IL-18 and pain outcomes, adjusting for demographic and treatment-related factors. The joint effect of IL-18 and obesity on pain were also explored. Results: Patients in the highest pre-RT IL-18 quartile experienced higher odds of both post-RT pain (OR = 2.36, 95% CI: 1.15–4.87) and RT-related pain (OR = 2.73, 95% CI: 1.20–6.26). IL-18 levels increased from pre-RT to post-RT with a mean change of 0.07 (SD = 0.35). In addition, patients with elevated pre-RT IL-18 levels and obesity experienced the highest odds of post-RT pain (OR = 3.97, 95% CI: 1.98–7.98) and RT-related pain (OR = 2.84, 95% CI: 1.32–6.09), suggesting a potential combined effect. Conclusions: Elevated pre-RT IL-18 levels were associated with an increased risk of pain following adjuvant RT, particularly in breast cancer patients with obesity. Thus, IL-18 may serve as a potential biomarker for identifying patients at increased risk for RT-related pain and informing treatment decision. Full article

Background/Objectives: Natural killer (NK) cells are key innate lymphoid cells that restrict tumour progression by secreting proinflammatory cytokines and directly lysing malignant cells, with their activity tightly regulated by a balance of activating and inhibitory surface receptors. The natural cytotoxicity receptor NKp44 is induced on NK cells following stimulation with IL-2 or IL-15 and recognizes platelet-derived growth factor D (PDGF-DD) as a ligand. Mechanistic interpretation of NKp44 signalling upon PDGF-DD engagement is confounded by the existence of three distinct NKp44 isoforms (NKp44-1, -2, and -3), each capable of initiating divergent intracellular signalling cascades. Unlike NKp44-2 and -3, NKp44-1 encodes a cytoplasmic tyrosine residue (Y238) that conforms to a putative immunoreceptor tyrosine-based inhibition motif (ITIM) and has been reported to suppress NK cell effector functions in some contexts. However, it remains unclear whether the NKp44 isoforms are translated and expressed in NK cells, and formal evidence defining NKp44-1 signalling in response to engagement by PDGF-DD is lacking. Methods: In this study, we used C-terminal targeting monoclonal antibodies (mAbs) and a NFAT-GFP reporter system to define the expression and signalling properties of NKp44 isoforms in response to PDGF-DD. Results: We demonstrate protein expression of NKp44-1 and NKp44-2-/3 receptors in IL-2 expanded NK cells. We further show that NKp44-1 transduces activating rather than inhibitory signals when engaged by PDGF-DD ligand, albeit weaker than NKp44-3. Intriguingly, we find that Y238 is dispensable for NKp44-1 activating signalling and instead functions as a YXXΦ internalisation motif. Conclusions: Collectively, these findings provide the first evidence that the NKp44-1 and NKp44-2/3 isoforms are expressed in NK cells and establish that PDGF-DD activates signalling through NKp44-1 independently of Y238. This work lays the foundations for future studies investigating how PDGF-DD sensing by the different NKp44 isoforms shapes immune functions in different physiological and pathological contexts. Full article

Background/Objectives: Psoriatic disease is a systemic inflammatory condition associated with increased cardiometabolic risk, but the impact of contemporary systemic therapies and narrowband ultraviolet B (NB-UVB) phototherapy on vascular and systemic inflammatory markers remains incompletely characterized. We aimed to systematically synthesize prospective evidence on treatment-associated changes in vascular inflammation and systemic inflammatory biomarkers in adults with moderate-to-severe psoriatic disease. Specifically, we evaluated changes assessed by 18F-FDG PET/CT imaging and circulating biomarkers following biologic therapies or NB-UVB phototherapy. Methods: We systematically searched MEDLINE, Embase, Web of Science, Scopus, and CENTRAL from inception to 31 January 2026 for prospective interventional and observational studies in adults with psoriasis or psoriatic arthritis treated with biologic agents targeting TNF-α, IL-12/23, IL-17, or IL-23, or with NB-UVB phototherapy. Eligible studies were required to report serial assessments of vascular inflammation by 18F-FDG PET/CT (typically aortic target-to-background ratio) and/or systemic inflammatory markers (high-sensitivity C-reactive protein, interleukin-6, TNF-α, GlycA, or hematologic indices such as the neutrophil-to-lymphocyte ratio) over at least 8 weeks of follow-up. We imposed no language restrictions and included only full-text, peer-reviewed prospective studies. Risk of bias was evaluated using RoB 2 for randomized trials and ROBINS-I for nonrandomized studies. Random-effects meta-analyses were prespecified for outcomes reported by at least two clinically comparable studies; however, because of substantial heterogeneity in reporting and methodology, effect estimates were summarized using a structured narrative synthesis. Results: Thirteen prospective studies (n ≈ 900 adults, published 2015–2025) met inclusion criteria, including four studies with serial 18F-FDG PET/CT imaging and one additional PET/CT study providing baseline observational data on vascular inflammation, as well as eight biomarker-focused prospective cohorts. Across randomized mechanistic trials and observational studies, biologic therapies reduced aortic target-to-background ratio by approximately 6–12% over 12–24 weeks (e.g., mean change from 2.42 to 2.18 with TNF-α inhibition and from 2.51 to 2.20 with IL-17 blockade), and no study reported worsening of PET-derived vascular indices under effective systemic treatment. Biologic and other systemic therapies produced concordant reductions in hs-CRP (typically by 30–50%), IL-6, TNF-α, GlycA, and blood-count-derived indices including neutrophil-to-lymphocyte ratio, with biomarker improvements frequently paralleling reductions in cutaneous disease activity and cardiometabolic risk markers. Two NB-UVB cohorts demonstrated significant hs-CRP reductions of roughly 20–30% and modulation of vitamin D-related inflammatory proteins, suggesting systemic anti-inflammatory effects, although these changes appeared less pronounced than with biologic therapy and were not accompanied by vascular imaging. Conclusions: Contemporary systemic psoriasis therapies, particularly biologic agents targeting the IL-23/Th17 axis and TNF-α, are associated with consistent reductions in aortic vascular inflammation and broad improvements in systemic inflammatory biomarkers, whereas NB-UVB phototherapy confers more modest but measurable systemic anti-inflammatory effects, although the current evidence does not allow differentiation between individual biologic classes in terms of magnitude of effect. Although reductions in vascular and systemic inflammatory markers were observed across therapies targeting TNF-α, IL-12/23, IL-17, and IL-23, the small number of mechanistic imaging studies and absence of head-to-head comparisons do not allow robust differentiation between biologic classes or support a uniform class effect. The convergence of imaging and biomarker data reinforces psoriasis as a clinically relevant model of inflammation-driven atherosclerosis and supports the concept that effective control of psoriatic inflammation may contribute to cardiovascular risk modification, highlighting the need for integrated cardiovascular risk assessment in routine care. However, the imaging evidence base remains limited to four small mechanistic PET/CT studies with relatively short follow-up, which constrains the strength and generalizability of conclusions regarding vascular inflammation. Larger, adequately powered, event-driven prospective trials with standardized imaging and biomarker endpoints are needed to determine whether these vascular and systemic anti-inflammatory effects translate into reduced cardiovascular events in psoriatic disease; because of methodological and reporting heterogeneity across the 13 included studies, these conclusions are based on a structured narrative synthesis rather than a formal quantitative meta-analysis. PROSPERO registration number: CRD420261296646. Full article

Background/Objectives: Epigenetic modifications, particularly DNA methylation, contribute to tumor progression and therapy resistance. Guadecitabine, a hypomethylating agent (HMA), has shown promising clinical activity when combined with carboplatin in preclinical models. We evaluated the combination of guadecitabine with carboplatin as a second-line treatment for extensive-stage small-cell lung cancer (SCLC; NCT03913455), one of the deadliest malignancies. Here, we report methylome changes in peripheral blood mononuclear cells (PBMCs) collected at baseline and during treatment from patients on the trial. Methods: PMBC DNA was analyzed using Infinium HumanMethylationEPIC v1.0 bead chips. Data were processed, and differentially methylated positions (DMPs) were identified and analyzed for pathway enrichment using bioinformatic approaches, and immune deconvolution analyses were conducted to investigate the impact on immune cell composition. Results: Direct comparison of PBMCs between cycle 2 day 5 (C2D5; post-treatment) vs. cycle 1 day 1 (C1D1; pre-treatment) revealed a greater number of hypomethylated DMPs (380 DMPs in C2D5 vs. C1D1 PBMCs; p < 0.05, |β| > 20%). Moreover, when first compared with normal PBMCs from cancer-free controls, the number of hypomethylated DMPs was even greater in C2D5 than in C1D1 (1771 vs. 237 DMPs, respectively; p < 0.05, |β| > 20%). Long interspersed nucleotide elements-1 (LINE-1) were significantly hypomethylated in PBMCs after HMA treatment (C2D5 vs. C1D1). Pathway analysis of hypomethylated DMPs revealed significant alterations in key signaling pathways, including NF-κB, Rho GTPase, and pulmonary fibrosis in C1D1 vs. C2D5. Normal PBMCs to C1D1 PBMCs revealed changes in IL-3 signaling, Fcγ receptor-mediated phagocytosis, and molecular mechanisms of cancer. Deconvolution analysis revealed a greater percentage of monocytes in C1D1 vs. normal PBMCs; after HMA treatment, percentages of monocytes and B cells decreased, while the eosinophil percentage increased in C1D1 vs. C2D5. Conclusions: HMA treatment has a global impact on PBMC methylomes in cancer patients. DNA methylation changes were associated with biological pathways related to PBMC function, and shifts in distinct immune cell populations were observed. Full article

Background: The gut microbiota and plasma metabolites have been shown to contribute to the etiology of post-traumatic stress disorder (PTSD). The relationship between the gut microbiome and plasma metabolome in PTSD is poorly understood. This study aims to integrate the gut microbiome data and plasma metabolome data to elucidate microbial–metabolite associations specific for PTSD in a mouse model. Methods: A PTSD mouse model was induced by single prolonged stress and electric foot shock (SPS&S). We sequenced the gut microbiota composition by 16S rRNA gene sequencing and used ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) for the plasma metabolomic profiling to explore the association between the gut microbiota and the plasma metabolites in mice with PTSD. Results: The PTSD mice exhibited robust anxiety-like behaviors, significantly elevated plasma IL-1β and TNF-α, and profound gut dysbiosis characterized by a marked depletion of Muribaculaceae and Akkermansia and expansion of the Lachnospiraceae_NK4A136_group. The plasma metabolomics identified 24 significantly dysregulated metabolites, including upregulated L-arginine, palmitic acid, and oleic acid, and downregulated uridine. The pathway enrichment analysis revealed coordinated perturbations in arginine biosynthesis, pyrimidine metabolism, unsaturated fatty acid biosynthesis, and glycerophospholipid metabolism. Critically, genus-level correlation analysis uncovered biologically coherent associations. The Muribaculaceae abundance showed strong negative correlations with L-arginine and palmitic acid and positive correlations with L-glutamine and thymidine. Conclusions: This study provides an exploratory investigation into the association network between the gut microbiota and the plasma metabolites in a PTSD mouse model, offering preliminary insights into potential microbe–metabolite interactions in PTSD. Full article

Atherosclerosis, the leading global cause of death, is a chronic inflammatory vascular disease with higher prevalence and earlier onset in men than in women. This study aims to investigate sex differences in the atherogenic endothelial phenotype during early atherosclerosis processes by providing the first comprehensive analysis of hormone-independent responses in human umbilical vein endothelial cells (HUVECs) from opposite-sex twins. HUVECs underwent pro-inflammatory stimulation with TNF-α and supernatant from activated pro-inflammatory THP-1 cells, revealing distinct sex-specific patterns: mRNA expression of focal adhesion proteins talin-I, vinculin, FAK, and α1-actinin increased significantly only in male cells, while paxillin showed elevated mRNA and protein levels in both sexes. Male HUVECs exhibited stronger induction of cell adhesion molecule VCAM-1, pro-inflammatory cytokine IL-1β, and proangiogenic factors Flt-3L, G-CSF, and PDGF-AA, whereas IL-22 secretion was exclusively upregulated in female cells. These sex differences in levels of focal adhesion, adhesion molecules, and cytokine profiles uncover the mechanistic backgrounds of the atherogenic endothelial phenotype, independent of systemic hormones. The findings emphasize cellular sex as a critical biological variable in early atherosclerosis and vascular inflammation. Full article

Bacillus subtilis is aerobic or facultatively anaerobic. After entering the gastrointestinal tract, its spores germinate and colonize the gut, inhibiting the growth of harmful aerobic bacteria (Escherichia coli, Streptococcus, Staphylococcus aureus). However, it remains unclear whether B. subtilis can inhibit Clostridium perfringens type A infection. In this study, B. subtilis PB6 was added to the diets of pregnant sows infected with Clostridium perfringens type A, which significantly improved the reproductive performance and reduced the incidence of bloat in sows and diarrhea in neonatal piglets. The treatment significantly increased the abundance of intestinal probiotics (B. subtilis, Lactobacillus, Limosilactobacillus reuteri, Lactobacillus johnsonii, Muribaculaceae, Lactobacillus amylovorus, and Lactobacillus reuteri) in sows and decreased the relative abundance of Clostridium perfringens type A after feeding B. subtilis administration. These probiotics can repair the intestinal tissue and improve intestinal histomorphology, and enhance the expression of MUC2 and sIgA in sows, thereby further strengthening the mucosal immune function. B. subtilis can also reduce the levels of inflammatory factors (CRP, IL-1β, and IFN-γ) and attenuate the inflammatory response in sows and neonatal piglets. Taken together, our results suggest that dietary supplementation with B. subtilis PB6 could reduce bloat in sows and diarrhea in piglets while improving intestinal barrier function and microbial balance in sows. Full article