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Inflammatory low back pain (IBP) is a key clinical feature of axial spondyloarthritis (axSpA) and an important diagnostic clue in patients presenting with chronic back pain. However, IBP is neither disease-specific nor uniformly expressed across inflammatory joint diseases, and its recognition in routine clinical practice remains challenging. Significant symptom overlap with mechanical low back pain, heterogeneity of clinical presentation, limited specificity of imaging findings, and frequent misuse of classification criteria as diagnostic tools contribute to persistent diagnostic uncertainty and delay. Despite advances in imaging and therapeutics, several critical challenges remain unresolved, including the limited specificity of IBP constructs, the risk of MRI overinterpretation, and the unclear nosological status of axial psoriatic arthritis (axial PsA). Moreover, variability in treatment response across disease phenotypes highlights the need for more precise diagnostic and therapeutic frameworks. This narrative review provides a structured and critical synthesis of current evidence on IBP across inflammatory joint diseases. It emphasizes key diagnostic pitfalls, including imaging-related challenges and misapplication of classification criteria, and highlights disease-specific differences between axSpA, axial PsA, and rheumatoid arthritis. In addition, it outlines clinically relevant considerations for diagnostic evaluation and therapeutic decision-making. Future research should focus on the development of integrated diagnostic models, improved imaging interpretation strategies, and disease-specific therapeutic approaches to optimize patient outcomes.
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Chronic rhinosinusitis (CRS) and asthma represent interrelated inflammatory disorders within the unified airway continuum, sharing overlapping molecular and immunologic mechanisms, clinical features, and therapeutic responses. Epidemiological studies indicate a high prevalence of CRS-asthma comorbidity, which is associated with increased disease severity, healthcare utilization, and impaired quality of life compared with either condition alone. Advances in airway immunology have established type 2 (T2) inflammation, characterized by epithelial barrier dysfunction, eosinophilic infiltration, and cytokine signaling via interleukin (IL)-4, IL-5, IL-13, thymic stromal lymphopoietin (TSLP), and IL-33, as a central pathogenic axis across both upper and lower airways. Non-type 2 (non-T2) endotypes contribute to disease heterogeneity and treatment resistance. This review synthesizes current evidence on shared molecular endotypes, emerging biomarkers, and clinical consequences of CRS-asthma comorbidity, with particular emphasis on biologic therapies targeting immunoglobulin E (IgE), IL-5, and multi-omics profiling and artificial intelligence-assisted analytics, in refining disease stratification, predicting therapeutic response, and guiding integrated treatment strategies. Finally, we highlight key research gaps and propose future directions toward endotype-driven, unified airway care aimed at improved long-term outcomes for patients with CRS-asthma comorbidity.
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Since 1950, approximately 8.3 billion metric tons of virgin plastics have been produced, with 79% accumulating in the natural environment because of low recycling rates. These non-biodegradable materials fragment into micro- and nanoplastics (MNPs) that have become ubiquitous contaminants. Humans are continuously exposed, especially through the inhalation of urban dust and fibres and the ingestion of contaminated food and water. This scoping review aimed to summarise the current evidence regarding the deposition of MNPs in human tissues and their subsequent pathophysiological impacts, with a focus on pathological manifestations across organ systems. Following PRISMA-ScR guidelines for scoping reviews, a comprehensive search was conducted across the PubMed, Scopus, and Cochrane Library databases. Studies investigating human microplastic exposure, tissue deposition, and physiological/pathological consequences were included. Data extraction focused on exposure routes, deposition patterns, and associated tissue alterations or disease processes. Our analysis revealed that MNPs primarily enter the human body through respiratory and digestive pathways. Subsequent deposition was documented across multiple organ systems, with significant accumulation in respiratory tissues, neurological structures, and throughout the gastrointestinal tract. The evidence suggests that these deposited particles can disrupt normal tissue physiology through multiple mechanisms, notably an exacerbation of inflammatory conditions and potentially increasing the risk of malignancy in affected tissues. Dose-dependent relationships between microplastic burden and pathological severity were observed in several studies. This review highlights that microplastics not only penetrate and persist within human tissues but may significantly contribute to inflammatory disease processes and carcinogenesis. These findings underscore the urgent need for enhanced exposure monitoring and further research into the prevention and evaluation of long-term health implications.
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Rheumatoid arthritis (RA) is a chronic autoimmune disorder that significantly impairs mobility and is one of the most prevalent autoimmune diseases worldwide. Extensive research has been conducted to elucidate its pathogenesis, genetic susceptibility, and neurological implications. This review provides a concise overview of RA, with particular emphasis on the gut-brain axis, dietary patterns, and interactions with brain-associated biomolecules, including neurotransmitters, sphingolipids, and glycerophospholipids. A deeper understanding of dynamic host-microbiome interactions may enable the development of personalized therapeutic strategies for RA and facilitate the identification of novel drug targets. In addition, metabolomics approaches are increasingly employed to uncover disease-specific biomarkers and metabolic alterations, contributing to a more precise understanding of RA pathogenesis and improving diagnostic accuracy. Collectively, these insights offer promising directions for future immunological research, with the potential to clarify underlying mechanisms of RA and enhance the quality of life for individuals affected by the disease.
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Background: Bladder cancer (BCa) is characterized by a high recurrence rate, and BCa stem cells (BCSCs) are widely considered the principal driver of drug resistance and metastasis. Although the transcription factor paired-related homeobox 1 (PRRX1) has been reported to regulate stemness in various solid tumors, its role and underlying mechanisms in BCa remain unclear. This study aims to investigate the function of PRRX1 in BCSCs and the potential mechanisms involved.
Methods: BCSCs were isolated from BCa cells, after which the proliferation, migration, invasion, gemcitabine resistance, and PRRX1 expression levels were detected in both BCa cells and BCSCs. Subsequently, BCSCs were transfected with si-PRRX1, and the effects of si-PRRX1 on BCSC proliferation, migration, invasion, stemness, and gemcitabine resistance were further assessed. Lastly, the impact of si-PRRX1 on the transforming growth factor-β (TGF-β)1/Smad axis in BCSCs was assessed to explore a potential mechanistic basis.
Results: Compared with BCa cells, BCSCs exhibited stronger proliferation, migration, invasion, stemness, and gemcitabine resistance, and PRRX1 expression in BCSCs was significantly higher than that in BCa cells (p < 0.05). After PRRX1 was knocked down, the proliferative, migratory, invasive, and stemness-related abilities of BCSCs were weakened, while sensitivity to gemcitabine was enhanced (p < 0.05). In addition, PRRX1 knockdown in BCSCs led to decreased protein expression of TGF-β1 and reduced phosphorylation levels of Smad2 and Smad3, as reflected by lower p-Smad2/Smad2 and p-Smad3/Smad3 ratios (p < 0.05).
Conclusion: PRRX1 knockdown suppresses BCSC proliferation, migration, invasion, stemness, and gemcitabine resistance, an effect that may be related to inhibition of the TGF-β1/Smad axis.
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Background: Colorectal cancer (CRC) remains one of the most prevalent malignancies worldwide. Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has emerged as a critical determinant of tumor progression, particularly through its interplay with dysregulated cholesterol metabolism. However, the role of the immune checkpoint molecule B7-H3 (CD276) in regulating ferroptosis in CRC remains poorly defined. This study aimed to characterize the expression profile of B7-H3 in CRC and elucidate its role and underlying mechanisms in ferroptosis regulation, with a focus on cholesterol metabolic signaling.
Methods: B7-H3 expression was assessed in normal colonic epithelial cells and CRC cell lines by Western blotting. Stable CD276 knockdown and overexpression models were established using lentiviral transduction. Ferroptosis sensitivity was evaluated using Cell Counting Kit-8 (CCK-8) assays following RSL3 treatment, along with measurements of malondialdehyde (MDA), intracellular Fe2+ levels, and ferroptosis-related gene expression. Cholesterol metabolism was assessed by quantifying total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels. Activation of the AKT–SREBP2 signaling axis was examined using Western blotting. Mechanistic validation was performed using the SREBP2 inhibitor betulin and the AKT inhibitor perifosine. An in vivo xenograft model under a high-cholesterol diet was further employed to evaluate the role of B7-H3 in tumor growth and regulation of ferroptosis.
Results: B7-H3 expression was significantly elevated in CRC cell lines (RKO, HCT116, SW480) compared with normal NCM460 cells (p < 0.001), with the highest expression observed in HCT116 cells. Stable CD276 knockdown and overexpression models were successfully established (p < 0.001). CD276 silencing markedly reduced cell viability, enhanced ferroptosis sensitivity, and increased levels of MDA, Fe2+, TC, and LDL-C (p < 0.05), accompanied by upregulation of PTGS2, FTL, and FTH mRNA (p < 0.001) and downregulation of glutathione peroxidase 4 (GPX4) (p < 0.05). In contrast, CD276 overexpression produced the opposite phenotype and significantly protected cells from RSL3-induced viability loss (p < 0.001). Mechanistically, CD276 knockdown increased nuclear SREBP2 (n-SREBP2) levels while reducing the p-AKT/AKT ratio (p < 0.001), whereas CD276 overexpression showed the opposite effect (p < 0.01). Betulin significantly reversed the elevation in TC, LDL-C, MDA, and Fe2+ induced by CD276 knockdown (p < 0.001), while perifosine restored n-SREBP2 expression that had been suppressed by CD276 overexpression (p < 0.01). In vivo, under a high-cholesterol diet, CD276 knockdown significantly reduced tumor volume and weight (p < 0.01), while increasing SREBP2 and COX-2 staining intensity, as well as MDA and Fe2+ levels in tumor tissues (p < 0.001).
Conclusions: B7-H3 is upregulated in CRC and promotes tumor progression by suppressing ferroptosis through modulation of the AKT–SREBP2 axis and cholesterol metabolism. Targeting B7-H3 may represent a promising therapeutic strategy to induce SREBP2-dependent ferroptosis in colorectal cancer.
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Background: Preeclampsia (PE) is a serious pregnancy-related disorder with incompletely understood etiology. The occurrence and development of preeclampsia are closely related to multiple biological regulatory mechanisms, among which circadian rhythm disorders are believed to possibly play an important role in abnormal placental function and immune imbalance. However, systematic research on the expression characteristics of circadian rhythm-related genes in preeclampsia and their potential diagnostic value remains scarce. This study aims to systematically identify the circadian rhythm genes associated with preeclampsia using placental RNA sequencing data, and to evaluate their biological functions and clinical diagnostic potential through comprehensive bioinformatics analysis.
Methods: Placental tissues from 5 PE patients and 6 matched controls were subjected to RNA sequencing. Bioinformatics processing included normalization and differential expression analysis using the limma package, batch-effect correction assessed via principal component analysis (PCA), and identification of circadian rhythm-related differentially expressed genes (CRRDEGs) through Venn analysis. Their expression patterns were displayed with heatmaps. Diagnostic performance was evaluated by generating receiver operating characteristic (ROC) curves and calculating area under the curve (AUC) values using the pROC package. Further functional characterization was conducted via Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) enrichment, supported by protein–protein interaction (PPI), mRNA–miRNA, mRNA–transcription factor (TF), and mRNA–drug network analyses. Immune infiltration was examined with ssGSEA and CIBERSORT algorithms.
Results: We identified 373 differentially expressed genes (DEGs), including five CRRDEGs (MTTP, PROK1, UTS2, NKX2-1, and PRKAA2). Among them, PROK1 and NKX2-1 demonstrated high diagnostic accuracy (AUC ≥0.9). GSEA indicated significant enrichment in autophagy, autoimmune thyroid disease, transcriptional activity, and ribosomal pathways. GO analysis highlighted involvement in circadian regulation, calcium response, and lipid homeostasis. Integrated network analysis suggested relevant miRNAs, TFs, and drugs as potential therapeutic targets. Immune infiltration assessment revealed four immune cell subsets with significantly altered abundance in PE.
Conclusions: This study elucidates the role of circadian rhythm-related genes in the pathogenesis of PE and identifies candidate biomarkers and therapeutic targets. Further validation in expanded cohorts and clinical studies is necessary to translate these findings into early diagnostic and interventional strategies.
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Background: Spinal cord injury (SCI) represents a severe neurological condition with limited effective treatments. Hyperbaric oxygen (HBO) therapy has demonstrated efficacy in alleviating SCI, yet its precise molecular mechanisms remain poorly elucidated. Previous genome-wide transcriptome analysis indicated that HBO downregulates mRNA expression of Heme oxygenase 1 (HMOX1) and Ferritin light chain 1 (FTL1), suggesting a potential link to ferroptosis, a novel form of iron-dependent regulated cell death. Notably, hypoxia-inducible factor-1alpha (HIF-1alpha), a key regulator of cellular response to hypoxia, is upregulated following SCI, and this upregulation is attenuated by HBO intervention. Given the involvement of the HIF-1alpha/HMOX1 axis in regulating ferroptosis, we hypothesized that the therapeutic effect of HBO in SCI may be mediated through modulation of this pathway.
Methods: An SCI-induced mouse model was established and treated with HBO for 7 days. Nissl staining and hematoxylin-eosin staining were performed for histopathological assessment. Real-time quantitative polymerase chain reaction and Western blotting were used to quantify HIF-1alpha/HMOX1 expression and ferroptosis-related proteins (Glutathione Peroxidase 4 (GPX4), Solute Carrier Family 7 Member 11 (SLC7A11)) in spinal cord tissues. Primary rat spinal neurons were treated with Erastin (ferroptosis inducer), HBO, or HIF-1alpha overexpression plasmid. Malondialdehyde (MDA) and Fe2+ levels were measured in vitro employing thiobarbituric acid reactive substances (TBARS) kit and colorimetric assay.
Results: HBO therapy increased Nissl bodies and reduced spinal cord edema and cavitation in SCI mice. It diminished HIF-1alpha/HMOX1 expression and elevated GPX4/SLC7A11 levels in the mouse model and in Erastin-induced neurons. HBO therapy also abrogated Erastin-induced upregulation of MDA and Fe2+. Notably, HIF-1alpha overexpression reversed the protective effects of HBO on ferroptosis.
Conclusion: HBO therapy shows ameliorative effects against SCI, which are associated with the downregulation of the HIF-1alpha/HMOX1 signaling axis and the consequent suppression of ferroptosis. These findings elucidate a novel and promising molecular mechanism underlying HBO's therapeutic effect, providing a potential target for future SCI treatment strategies.
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Background: Cardiovascular-Kidney-Metabolic (CKM) diseases, including coronary heart disease, atherosclerosis, and chronic kidney disease, are significant causes of mortality among diabetic patients. Although diabetes is known to influence these diseases, the underlying biological pathways remain unclear.
Methods: We performed a two-sample Mendelian randomization (MR) analysis to investigate the relationships between type 1 diabetes (T1D), type 2 diabetes (T2D) and CKM traits. Two-step MR analyses were conducted to explore potential pathways involving circulating inflammatory proteins and metabolites. Cross-trait linkage disequilibrium score regression (LDSC) was employed to investigate the genetic association and colocalization analyses were used to assess shared genetic architecture. Additional sensitivity analyses were performed, including exclusion of variants within the major histocompatibility complex/human leukocyte antigen (MHC/HLA) region for T1D.
Results: MR analyses suggested that genetically predicted T2D was associated with increased risks of multiple CKM traits, including coronary heart disease (OR = 1.16, p = 2.01 × 10-5) and myocardial infarction (OR = 1.17, p = 1.46 × 10-4), with consistent results across sensitivity analyses. In contrast, initial associations between T1D and CKM diseases were attenuated and no longer statistically significant after excluding variants within the MHC/HLA region, indicating that these associations were largely driven by this immune-related locus. Two-step MR analyses identified several circulating metabolites associated with both T2D and CKM diseases, suggesting that metabolic factors (e.g., 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC) may partially explain the association between T2D and CKM risk (mediation proportions ranging from 4.56% to 29.31%). For T1D, circulating inflammatory proteins and metabolites were also associated with CKM traits; however, these findings are better interpreted as reflecting shared immune and metabolic pathways rather than causal mediation.
Conclusion: Our findings support a potential causal role of T2D in the development of CKM diseases, partly through circulating metabolites. In contrast, the associations observed for T1D appear to be largely driven by the HLA/MHC region and likely reflect shared immune-mediated genetic architectures rather than a direct causal effect. These results provide insight into distinct biological pathways linking different forms of diabetes with CKM diseases.
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Background: Fracture healing is strongly influenced by mechanical loading conditions, whereas hindlimb unloading induces bone loss and may further compromise skeletal repair. However, the metabolic remodeling of bone tissue under fracture, unloading, and their combination remains insufficiently characterized. This study aimed to investigate metabolic alterations in mouse bone tissue under fracture (Fx), tail-suspension hindlimb unloading group (HU), and fracture combined with tail-suspension hindlimb unloading group (Fx + HU) using untargeted metabolomics.
Methods: Male mice were randomly assigned to four groups: sham control (Sham), Fx, HU, and Fx + HU. Mechanical unloading was induced using a tail-suspension hindlimb unloading model, and fracture was established using a standardized murine fracture procedure. After 3 weeks of intervention, proximal tibial bone tissues were collected for micro-computed tomography (micro-CT) and untargeted metabolomics analysis. Multivariate statistical analyses, including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal PLS-DA (OPLS-DA), were performed to identify metabolic differences among groups. Differential metabolites and enriched pathways were further analyzed.
Results: Micro-CT analysis showed significant deterioration of trabecular bone mass and microarchitecture in the Fx, HU, and Fx + HU groups compared with the Sham group (all p < 0.001), with the Fx + HU group showing the most pronounced impairment. Untargeted metabolomics demonstrated robust analytical reproducibility in both positive and negative ion modes. PCA and supervised multivariate analyses showed clear separation among the four groups, and the Fx + HU group exhibited the greatest metabolic divergence from the others. Differential metabolite screening and pathway enrichment analysis revealed marked alterations in metabolic pathways associated with amino acid metabolism, lipid metabolism, energy metabolism, and oxidative stress-related processes.
Conclusions: Fracture and hindlimb unloading each induced substantial metabolic remodeling in mouse bone tissue, while their combination produced more profound and distinct metabolic perturbations. These findings suggest that mechanical unloading may aggravate bone metabolic dysregulation after fracture and provide exploratory metabolomic evidence for understanding skeletal deterioration under combined injury and unloading conditions.
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Background: Casein kinase I isoform epsilon (CSNK1E), a gene intricately linked to the circadian clock, has been found to be highly expressed in colorectal cancer (CRC). Elevated expression of CSNK1E correlates with shorter disease-free survival in patients, suggesting a significant, albeit not yet fully understood, role in CRC pathogenesis. The specific molecular mechanisms by which CSNK1E contributes to tumor development and progression remain largely unclear. Given its involvement in key signaling pathways, this study aims to elucidate the functional role of CSNK1E and its underlying mechanisms in CRC, with particular emphasis on its relationship with the Wnt/β-catenin pathway, a cornerstone of CRC oncogenesis.
Methods: CRC cells underwent the intervention on the expression of CSNK1E and dishevelled segment polarity protein 1 (DVL1), a protein interacting with CSNK1E in Wnt/β-catenin signaling. The efficiency of gene modulation was evaluated by qRT-PCR. The interaction between these two genes was validated using Co-immunoprecipitation assays. Phenotypic experiments were subsequently conducted in CRC cells, and Western blot analysis was conducted to assess the status of Wnt/DVL1/β-catenin signaling.
Results: Knockdown of CSNK1E inhibited proliferation (p < 0.01), hindered cell cycle transition from the G1 phase to the S phase (p < 0.05), while inducing apoptosis of CRC cells (p < 0.001). Moreover, CSNK1E was found to bind to DVL1; CSNK1E knockdown significantly decreased the expression of DVL1 and β-catenin in CRC cells (p < 0.05), whereas CSNK1E overexpression exerted an opposite effect (p < 0.05). DVL1 upregulation counteracted the inhibitory effects of CSNK1E knockdown, while DVL1 downregulation offset the promotive effects of CSNK1E overexpression on CRC (p < 0.05).
Conclusion: This study unveils that CSNK1E is a pivotal oncoprotein in CRC. It promotes tumor progression by interacting with and stabilizing DVL1, thereby facilitating the activation of the canonical Wnt/β-catenin signaling pathway. These results highlight the CSNK1E/DVL1 axis as a potential novel therapeutic target for CRC treatment.
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Background: Neonatal hyperbilirubinemia (HB) is common in the first postnatal week, and early gut ecological and metabolic features may influence bilirubin homeostasis via the gut–liver axis. We sought birth meconium microbiome–metabolome features linked to HB and evaluated a candidate metabolite in vivo.
Methods: First-pass meconium was collected within 24 h from 219 neonates. A nested case–control subset was analyzed (HB, n = 21; Healthy Controls (HC), n = 39). Microbiota were profiled by 16S rRNA gene sequencing (V3–V4), and metabolites were quantified using a targeted absolute-quantification LC–MS panel (Q300). Community structure was assessed using weighted and unweighted UniFrac distances and tested by analysis of similarities (ANOSIM), with PERMDISP used to evaluate dispersion. Genus-level differences were explored by LEfSe and interpreted cautiously given the low-biomass nature of meconium. Metabolites were compared by univariate testing, visualized by volcano plots, and adjusted using false discovery rate (FDR). Azelaic acid (AzA) was tested in an acetylphenylhydrazine-induced rat model with serum total bilirubin, colonic occludin, colonic β-glucuronidase activity, and fecal 16S profiling.
Results: HB and HC showed modest but statistically significant differences in weighted and unweighted UniFrac distances (weighted R = 0.1965, p = 0.0030; unweighted R = 0.1225, p = 0.0100). Metabolomics showed limited global separation; AzA was lower in HB on nominal testing, but no metabolite remained significant after FDR correction. In rats, AzA was associated with lower serum total bilirubin, directionally higher colonic occludin, decreased colonic β-glucuronidase activity, and suggested a partial shift in fecal community structure toward controls.
Conclusions: Birth meconium profiling nominated lower AzA as a hypothesis-generating signal; the rat experiment provides complementary, biologically plausible evidence. Replication in independent neonatal datasets is warranted.
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Background: Prognostic heterogeneity is significant in patients with heart failure (HF), and traditional risk assessment remains limited. Chronic inflammation activation and metabolic homeostasis imbalance are considered core pathophysiological processes driving HF progression, but evidence for predicting HF prognosis based on the combined use of conventional inflammatory and metabolic markers is still insufficient. This study aimed to evaluate the association of combined inflammatory and metabolic markers with short-term adverse cardiovascular events in HF patients.
Methods: This was a single-center retrospective cohort study that consecutively enrolled 350 patients with heart failure hospitalized between July 2021 and July 2024. Baseline demographic, clinical history, and laboratory parameters were collected. Neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), systemic immune inflammation index (SII), and triglyceride-glucose index (TyG) were calculated. All patients were followed up for 12 months. The primary endpoint was cardiac death or serious events related to the progression of heart failure. Univariate and multivariate logistic regression analyses were used to screen for independent risk factors, and a combined risk model was constructed. The discriminative ability was evaluated using Receiver Operating Characteristic (ROC) curves.
Results: Multivariate logistic regression analysis showed that smoking history (odds ratio (OR) = 2.96, 95% confidence intervals (95% CI): 1.51–5.79), diabetes history (OR = 4.56, 95% CI: 2.35–8.84), elevated NLR (OR = 1.23, 95% CI: 1.08–1.41), elevated C-reactive protein (CRP) (OR = 1.12, 95% CI: 1.04–1.19), and elevated TyG index (OR = 2.57, 95% CI: 1.43–4.61) were independent risk factors for endpoint events in HF patients. The combined risk model constructed from these five factors showed good discriminative ability, with an area under the ROC curve (AUC) of 0.79 (95% CI: 0.72–0.85).
Conclusions: In patients with heart failure, NLR and CRP, reflecting systemic inflammatory burden, and the TyG index, a marker of insulin resistance/metabolic imbalance, are important independent prognostic factors in addition to traditional risk factors such as smoking and diabetes. An assessment strategy integrating inflammatory and metabolic markers holds promise as a simple and practical clinical tool for risk stratification and individualized management of HF patients.
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Background: This study integrated 16S ribosomal ribonucleic acid sequencing and untargeted metabolomics to investigate the mechanisms by which oral microorganisms and Lacticaseibacillus rhamnosus (LGG) influence dental caries development in rats.
Methods: A rat caries model was established to examine the effects of different interventions, including healthy dental plaque suspension (NC_R), caries-associated plaque suspension (M_R), and the probiotic LGG, on oral microbial composition, metabolic profiles, and caries severity.
Results: The caries model group exhibited ecological dysbiosis, characterized by a significant increase in the abundance of cariogenic bacteria such as Streptococcus mutans and a decrease in health-associated genera like Veillonella. Metabolomic analysis identified 105 significantly differential metabolites between the Model and Normal Control (NC) groups. Kyoto Encyclopedia of Genes and Genomes pathway enrichment classification revealed that carbohydrate metabolism pathways were significantly enriched in the Model group, whereas lipid metabolism and cofactor metabolism pathways exhibited higher activity in the NC group. Notably, the sphingolipid metabolism pathway showed the highest significance in differential metabolite enrichment. Probiotic intervention, particularly the combined application of LGG and NC_R, substantially reversed the levels of abnormal metabolites, improved enamel surface area, volume, and mineral density (p < 0.05), and reduced caries scores (p < 0.05).
Conclusion: By integrating microbiome and metabolomics analyses, this study elucidates the interplay between microbial dysbiosis and metabolic dysregulation in the pathogenesis of dental caries. It further reveals a novel anti-caries mechanism of probiotics through their modulation of oral microecological balance and host metabolic networks, particularly via key pathways such as sphingolipid metabolism. This provides experimental evidence for the development of precise caries prevention and control strategies based on microecological regulation.
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Background: Observational and mechanistic studies have linked glycated hemoglobin (HbA1c) and cardiac troponin I (cTnI) to chronic inflammation and thrombosis. We explored how these two routinely available biomarkers relate to arteriovenous fistula (AVF) thrombosis in maintenance hemodialysis (MHD), and quantified their predictive value singly and in combination.
Methods: We reviewed 236 patients with consecutive end-stage renal disease (ESRD) who underwent autogenous AVF creation between January 2021 and June 2023. Baseline demographic, clinical and biochemical variables were recorded. Logistic regression (univariate then multivariate) identified independent correlates of thrombosis. Using the final model, we built a nomogram and evaluated its performance using receiver operating characteristic (ROC) analysis, calibration behavior and decision curve analysis (DCA).
Results: Within 12 months, 25 patients (10.6%) met criteria for AVF thrombosis. Four variables remained independently associated with events: C-reactive protein (CRP) ≥10 mg/L, intradialytic hypotension, HbA1c ≥6.5%, and cTnI ≥0.2 μg/L (all p < 0.05). A nomogram combining these factors demonstrated good discriminative ability (area under the curve [AUC] 0.850; 95% CI 0.741–0.960) and showed acceptable calibration (Hosmer–Lemeshow p = 0.244).
Conclusion: HbA1c and cTnI may serve as sensitive markers for postoperative AVF thrombosis in hemodialysis patients, facilitating earlier risk identification, preventive measures, and timely intervention. Their predictive performance is further enhanced when combined with CRP and intradialytic hypotension.
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Background: The incidence of severe Mycoplasma pneumoniae pneumonia (SMPP) in children has markedly increased in the post-COVID-19 era. Current diagnosis approaches often rely on persistent fever, which may delay early identification. This study aims to evaluate the synergistic value of Lactate Dehydrogenase (LDH) and Interleukin-6 (IL-6) for early stratification.
Methods: We retrospectively analyzed clinical data from 210 hospitalized children with Mycoplasma pneumoniae pneumonia (MPP; 120 severe and 90 non-severe). Independent risk factors were identified using multivariate logistic regression to build a dynamic nomogram. To validate the model's early warning capability and exclude circularity, a specific subgroup analysis was performed on patients admitted in the early phase of illness (fever duration <7 days).
Results: LDH, IL-6, and pre-admission fever duration were independent predictors. The combined nomogram outperformed single biomarkers with an Area Under the Curve (AUC) of 0.827. Crucially, in the early-phase subgroup, both IL-6 and LDH remained significantly elevated in SMPP cases (p < 0.05), proving that pathological signals precede the clinical threshold for severity. The study revealed a “two-axis” mechanism whereby IL-6 quantified systemic inflammation, while LDH reflected local tissue hypoxia (e.g., atelectasis), distinct from the systemic response. Decision Curve Analysis further confirmed the model's clinical utility.
Conclusion: This study proposes a dual-pathology stratification model where IL-6 reflects cytokine storm and LDH indicates tissue injury. The nomogram reliably identifies high-risk children in the early illness phase, facilitating intervention before persistent fever develops.
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Background: Significant brain damage and loss of function are frequent outcomes of ischemic stroke. After ischemic damage, neural stem cells (NSCs) exhibit considerable potential to promote neuroprotection and facilitate neural repair. N-butylphthalide (NBP) efficiently increases the viability of NSCs under hypoxic conditions. Given that the underlying mechanisms remain unknown, this study aims to investigate the protective effects of NBP on NSCs both in vitro and in vivo.
Methods: This study assessed the neuroprotective effects of NBP using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in mice. Neurobehavioral performance of MCAO/R mice was evaluated using neurobehavioral tests, and brain infarct volumes were analyzed. Western blot analysis was used to measure the expression of Nestin, Ki-67, glycogen synthase kinase-3β (GSK-3β), phosphorylation-GSK-3β (p-GSK-3β), and nuclear factor erythroid 2-related factor 2 (NRF2) in brain tissues. In vitro experiments were conducted using NSCs under Oxygen-Glucose Deprivation/Reoxygenation (OGD/R) conditions, followed by treatment with NBP and GSK-3β inhibitors to assess cell viability and the levels of the GSK-3β/NRF2 signaling pathway.
Results: NBP significantly improved the neurobehavioral scores and reduced infarct volumes in MCAO/R mice (p < 0.05). It also increased the expression levels of Nestin and Ki-67, indicating enhanced proliferation of NSCs (p < 0.05). Additionally, NBP upregulated the expression levels of GSK-3β and NRF2 in brain tissues (p < 0.05). In vitro, NBP promoted the viability of NSCs and proliferation under OGD/R conditions, with increased expression levels of Nestin and Ki-67 (p < 0.05). The effect of NBP was partially reversed by GSK-3β inhibitors, indicating that NBP's effects are partially mediated by the GSK-3β/NRF2 signaling pathway (p < 0.05).
Conclusion: By regulating the GSK-3β/NRF2 signaling pathway, this study shows that NBP stimulates proliferation of NSCs and enhances neurofunctional recovery after ischemic stroke. These findings indicate that NBP not only promotes cellular survival and repair but also has the potential to improve overall neurological outcomes.
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Background: Although critically ill pregnant women received specialized management in the Obstetric Critical Care Unit (OCCU), the disease spectrum and prognostic determinants still need to be further explored to optimize the early warning system. This study aims to systematically analyze the disease spectrum and identify risk factors for unfavorable prognosis in critically ill obstetric patients transferred to the OCCU.
Methods: A retrospective cohort study was conducted on 313 obstetric patients admitted to OCCU from 2015 to 2025. According to the prognosis (favorable, n = 222; unfavorable, n = 91), the patients were divided into two groups. The variables were screened using Least Absolute Shrinkage and Selection Operator (LASSO) regression and the independent risk factors were analyzed using multivariate logistic regression.
Results: Main transfer causes were postpartum hemorrhage (34.82%) and preeclampsia/eclampsia (21.73%). Independent risk factors for unfavorable prognosis included older age, lower gestational age, pre-existing heart disease, diabetes, hypertension, placental abruption, higher Acute Physiology and Chronic Health Evaluation II (APACHE II)/Sequential Organ Failure Assessment (SOFA) scores, and elevated D-dimer, Scr, and C-reactive Protein (CRP) levels (all p < 0.05). The integrated prediction model achieved an area under the curve (AUC) of 0.866 (95% CI: 0.819–0.913).
Conclusion: Specific comorbidities, disease severity scores and biomarkers are key prognostic factors. The model shows strong early warning and predictive capabilities.
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Background: Sterol regulatory element-binding protein 1 (SREBP1) is a key regulator of lipid metabolism. However, its role in osteoclast differentiation and bone resorption remains unclear. This study investigated the function of SREBP1-mediated lipid metabolic remodeling in osteoporosis.
Methods: An ovariectomized (OVX) mouse model and SREBP1 conditional knockout mice were used to evaluate bone metabolism in vivo. RAW264.7 cells were stimulated with Receptor Activator of Nuclear Factor κB Ligand (RANKL) to induce osteoclast differentiation in vitro. Fatostatin and oleic acid were used to modulate SREBP1 activity and lipid metabolism.
Results: OVX mice showed significantly increased SREBP1 expression compared with the Control group (p < 0.05). Lipid synthesis enzymes Fatty Acid Synthase (FASN), Acetyl-CoA Carboxylase (ACC), and Stearoyl-CoA Desaturase 1 (SCD1) were also elevated (p < 0.05). Serum bone resorption markers C-terminal Telopeptide of Type I Collagen (CTX-I) and Tartrate-Resistant Acid Phosphatase (TRACP) were increased (p < 0.05), whereas bone formation markers Procollagen Type I N-terminal Propeptide (PINP) and Bone-specific Alkaline Phosphatase (B-ALP) were reduced (p < 0.05). These alterations were partially reversed in OVX+SREBP1 knockout mice (p < 0.05). In vitro, SREBP1 expression progressively increased during RANKL-induced osteoclast differentiation (p < 0.05). This increase correlated with elevated Nuclear Factor of Activated T Cells 1 (NFATC1), Tartrate-Resistant Acid Phosphatase (TRAP), and Cathepsin K (CTSK) expression (p < 0.05). Fatostatin significantly reduced osteoclast formation and bone resorption activity (p < 0.05), and suppressed lipid metabolism enzyme expression (p < 0.05). Oleic acid supplementation partially restored osteoclast differentiation and function (p < 0.05).
Conclusion: SREBP1 promotes osteoclast maturation and bone resorption by regulating lipid metabolism. Targeting SREBP1 or modulating fatty acid metabolism may provide a potential therapeutic strategy for osteoporosis.
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Background: Limb ischemia-reperfusion-induced acute lung injury (LIR-ALI) remains without effective therapies, with macrophage polarization playing a pivotal role in its pathology. This study explored the protective effects of esketamine in LIR-ALI, focusing on its modulation of macrophage polarization through the TLR4/NF-κB/NLRP3 pathway.
Methods: Sprague-Dawley rats subjected to LIR (bilateral femoral artery clamping for 2 hours followed by reperfusion) under mechanical ventilation were treated with esketamine (5 mg/kg) or saline. Lung injury, inflammatory cytokines (Enzyme-linked immunosorbent assay, ELISA), and macrophage polarization markers (iNOS, Arg-1) were evaluated. In vitro, THP-1 macrophages were pretreated with esketamine (50 μM), stimulated with LIR-ALI rat serum, and co-cultured with BEAS-2B epithelial cells. Macrophage polarization (NOS2, Arg-1, CD86, CD206), epithelial cell viability (CCK-8), inflammatory cytokines, oxidative stress markers (superoxide dismutase (SOD), malondialdehyde (MDA)), and TLR4/NF-κB/NLRP3 pathway proteins were assessed. LPS was used to assess pathway dependency.
Results: Esketamine significantly reduced LIR-induced lung pathological damage and inflammatory cell infiltration in rats. It lowered pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and elevated IL-10 in bronchoalveolar lavage fluid (BALF) (p < 0.01), while promoting M2 macrophage polarization (decreased iNOS, increased Arg-1) in lung tissue (p < 0.05). In vitro, esketamine redirected LIR-ALI serum-stimulated macrophages toward the M2 phenotype (decreased NOS2/CD86, increased Arg-1/CD206) (p < 0.001), enhanced BEAS-2B cell viability, and mitigated inflammation and oxidative stress (p < 0.01). These effects were linked to esketamine's inhibition of the TLR4/NF-κB/NLRP3 pathway in macrophages (p < 0.01). LPS reversed esketamine's protective effects, including its modulation of macrophage polarization and the signaling pathway (p < 0.05).
Conclusion: Esketamine mitigates LIR-ALI by promoting M2 macrophage polarization through the suppression of the TLR4/NF-κB/NLRP3 axis, suggesting its potential as a therapeutic strategy for LIR-ALI.
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Background: Polycystic ovarian syndrome (PCOS) is an endocrine disorder characterized by abnormal proliferation and apoptosis of ovarian granulosa cells (GCs), which contribute to follicular dysfunction and impaired ovulation. Although astragaloside IV (AS-IV) has shown anti-proliferative effects, its underlying mechanism remains unclear. This study aims to explore how AS-IV regulates the growth and apoptosis of human ovarian granulosa cell tumor (KGN) cells via glycolysis.
Methods: In this study, the human ovarian granulosa cell tumor line KGN was used as an in vitro model. AS-IV treatment was combined with genetic manipulations, including short hairpin RNA (shRNA)-mediated knockdown of G protein subunit beta 2 (GNB2) and overexpression of peroxisome proliferator-activated receptor gamma (PPARγ) and GNB2, to dissect their roles in AS-IV-mediated effects. The effects of AS-IV on KGN cell proliferation, apoptosis, lactate, pyruvate, and pyruvate kinase m2 (PKM2) levels via the PPARγ/GNB2 were evaluated. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to study PPARγ's transcriptional regulation of GNB2. Ubiquitination and degradation of PKM2 by GNB2 were examined using immunoprecipitation.
Results: AS-IV induced apoptosis and lowered KGN cell growth (p < 0.01). Knockdown of GNB2 expression partially reversed the anti-proliferative and pro-apoptotic effects of AS-IV, indicating that GNB2 mediates AS-IV activity (p < 0.05). PPARγ transcriptionally regulated GNB2 expression, thereby enhancing the effect of AS-IV (p < 0.05). AS-IV upregulated the PPARγ/GNB2, inhibited PKM2 expression, and promoted PKM2 ubiquitination and degradation, further modulating glycolysis (p < 0.05).
Conclusion: This study reveals that AS-IV regulates KGN cell proliferation and apoptosis via the PPARγ/GNB2/PKM2 axis by inhibiting glycolysis. This study provides novel mechanistic insights into the therapeutic potential of AS-IV for PCOS by targeting granulosa cell metabolism and survival.
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Background: N6-methyladenosine (m6A), a type of RNA modification, influences the stability and translation of oncogene transcripts and plays a crucial role in glioblastoma (GBM) stemness and drug resistance. However, its role in epidermal growth factor receptor type III mutation (EGFRvIII) and temozolomide (TMZ)-resistant GBM remains unclear. This study explores the regulatory impact of m6A modification in TMZ-resistant GBM with EGFRvIII, with a focus on resistance genes and tumor stemness.
Methods: Stable EGFRvIII-expressing glioma cell lines were established and treated with TMZ for varying durations. Transcriptome sequencing was then performed to identify resistance-associated genes. The findings were further validated using publicly available transcriptomic datasets from TMZ-resistant GBM. Key genes related to prognosis were identified using Cox regression. The m6A modification patterns and mRNA expression-based stemness index (mRNAsi) were evaluated based on 27 m6A regulators and a one-class logistic regression model. Spearman correlation analysis assessed relationships between candidate genes, m6A scores, and mRNAsi. Cox regression analyzed prognostic differences in GBM patients with varying m6A and mRNAsi levels. U251 and A172 cells stably expressing EGFRvIII (U251OE, A172OE) were cultured, and the expression levels of GARNL3 and RBM15 were examined by fluorescent polymerase chain reaction and Western blotting. Furthermore, the cell proliferative capacity, viability, and apoptosis in A172OE and U251OE cells were assessed following modulation of RBM15 expression in conjunction with TMZ treatment.
Results: GARNL3 was identified as a drug-resistant gene in EGFRvIII-positive GBM, with high expression correlating with better overall survival (p < 0.05). GARNL3 correlated with m6A scores (p < 0.01, r = 0.38) and RBM15 (p < 0.001, r = 0.992). RBM15 promoted GARNL3 protein expression in A172OE and U251OE cells. Concurrently, knockdown of RBM15 not only reduced GARNL3 expression but also enhanced the proliferation and viability of A172OE and U251OE cells under TMZ treatment, while suppressing apoptosis. Conversely, overexpression of RBM15 promoted apoptosis in these cells and enhanced the tumor-inhibitory effects of TMZ. Additionally, in TMZ-resistant EGFRvIII GBM, m6A scores were significantly decreased (p < 0.01), while mRNAsi scores were increased (p < 0.001). Low m6A and high mRNAsi levels correlated with poorer prognosis (p < 0.05).
Conclusion: GARNL3 may contribute to TMZ resistance through RBM15-mediated m6A modification, thereby enhancing tumor cell stemness. However, this mechanism requires further validation.
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Background: Elderly patients with chronic kidney disease (CKD) are at high risk for osteoporosis. Inflammation and abnormal bone metabolism are key underlying mechanisms, yet the diagnostic utility of combining their respective biomarkers remains unclear. This study aimed to evaluate the diagnostic efficacy of inflammatory and bone turnover markers for osteoporosis in elderly CKD patients.
Methods: This single-center retrospective cohort study included 194 elderly (≥60 years) patients with chronic kidney disease who underwent bone mineral density testing between March 2021 and March 2024. Patients were divided into osteoporosis and non-osteoporosis groups based on dual-energy X-ray absorptiometry (DXA) T-score. Inflammatory markers were collected within 24 hours of admission, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophil count, lymphocyte count, monocyte count, platelet count, platelet distribution width, erythrocyte distribution width, mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII) were calculated. Bone turnover markers included serum type I procollagen N-terminal propeptide (P1NP), osteocalcin (OC), and type I collagen crosslinked C-terminal peptide (CTX). Univariate and multivariate logistic regression analyses were performed to identify independent factors influencing osteoporosis, and receiver operating characteristic (ROC) curves were used to evaluate the diagnostic efficacy of individual markers and combined models.
Results: Multivariate logistic regression showed that elevated ESR and SII levels among inflammation-related markers were independently associated with osteoporosis in elderly CKD patients; among bone turnover markers, P1NP, OC, and CTX levels were all independent predictors of osteoporosis (all p < 0.05). The comprehensive model combining ESR, SII, P1NP, OC, and CTX showed excellent discriminative performance, with an area under the ROC curve (AUC) of 0.86 (95% confidence interval (CI): 0.80–0.91), suggesting that the combined assessment of inflammatory and bone metabolism markers can significantly improve the accuracy of osteoporosis identification in elderly CKD patients.
Conclusion: In elderly CKD patients, both inflammatory status and abnormal bone turnover are closely associated with osteoporosis risk. Combining inflammatory markers such as ESR and SII with bone turnover markers such as P1NP, OC, and CTX can improve the screening efficacy for osteoporosis. Combined assessment of inflammatory and bone remodeling markers holds promise as an important supplementary tool for bone health management in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD), providing a more reliable foundation for early intervention.
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Background: Bone marrow mesenchymal stem cell-derived exosomes (BMSC-exo) can promote the metastasis of lung cancer (LC) under hypoxic conditions, but the mechanism needs to be explored. This study aims to investigate the role of adenosylhomocysteinase (AHCY) derived from hypoxia BMSC-exo in the development of LC.
Methods: BMSC-exo under normoxic or hypoxic conditions were identified by transmission electron microscope. The relationship between AHCY and methylcrotonyl-CoA carboxylase subunit 2 (MCCC2) was analyzed by bioinformatics analysis. The expression levels of AHCY in hypoxia BMSC-exo or LC cells treated with hypoxia BMSC-exo were determined by quantitative real-time polymerase chain reaction (qRT-PCR). The viability, migration, invasion, and the expression levels of N-cadherin, E-cadherin and extracellular regulated protein kinases (ERK) pathway-related proteins in LC cells transfected with MCCC2 overexpression plasmid and AHCY specific small interfering RNA (siAHCY) as well as treated with normal/hypoxia BMSC-exo were determined using cell counting kit-8 (CCK-8), transwell assay and Western blotting.
Results: AHCY was highly expressed in hypoxia BMSC-exo (p < 0.001). With the increase in the exosome release inhibitor GW4869 concentration, the total amount of AHCY protein detected in exosomes isolated from equal volumes of conditioned medium derived from hypoxic BMSCs gradually decreased (p < 0.001). Hypoxia BMSC-exo facilitated cell viability, migration, invasion and the expressions of N-cadherin and MCCC2, yet inhibited E-cadherin expression, while these effects were reversed by siAHCY (p < 0.05). AHCY and MCCC2 are positively correlated in LC. SiAHCY downregulated the ratio of p-ERK1/2/ERK1/2, whereas this effect was reversed by MCCC2 overexpression (p < 0.05).
Conclusions: Hypoxia BMSC-exo carries AHCY to up-regulate MCCC2 expression in LC cells, thereby activating the ERK pathway to facilitate the development of LC. This study identifies a novel exosome-mediated mechanism in the tumor microenvironment and highlights potential therapeutic targets for intervention.
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Background: Patients with high-risk acute cholecystitis are challenging to manage because many cannot tolerate early surgery. Percutaneous transhepatic gallbladder drainage (PTGBD) is therefore commonly used; however, the clinical response after drainage is not always satisfactory. Reliable indicators for early identification of patients at risk of poor treatment response remain limited. Although inflammatory and nutritional biomarkers have shown potential value in risk stratification, their role in predicting response to PTGBD has not been fully clarified. Accordingly, this study aims to evaluate the predictive value of the preoperative C-reactive protein/albumin ratio (CAR) for poor treatment response in high-risk patients with acute cholecystitis undergoing PTGBD.
Methods: Clinical data from 309 patients with high-risk acute cholecystitis who underwent PTGBD at our institution between January 2023 and January 2025 were retrospectively reviewed. Based on post-procedural treatment response, patients were categorized into a good response group (n = 231) and a poor response group (n = 78). Receiver operating characteristic (ROC) curve analysis was applied to assess the predictive performance of CAR. Multivariable logistic regression analysis was used to determine independent predictors of poor treatment response, and a predictive model was subsequently developed.
Results: Seventy-eight patients (25.2%) developed poor treatment response. Preoperative CAR was higher in the poor response group than in the good response group [5.82 (3.65–8.96) vs 2.68 (1.35–4.52), p < 0.001]. ROC curve analysis showed that the area under the curve (AUC) of CAR for predicting poor treatment response was 0.812 (95% confidence interval (CI): 0.758–0.866), which was higher than that of C-reactive protein (CRP) (AUC = 0.756) and albumin (AUC = 0.718) (p < 0.05); the optimal cutoff value was 3.85, with a sensitivity of 74.4% and specificity of 76.2%. Multivariable logistic regression analysis showed that CAR ≥3.85 (odds ratio (OR) = 3.42, 95% CI: 1.89–6.18), TG18 Grade III (OR = 2.28, 95% CI: 1.26–4.12), time from onset to PTGBD ≥72 h (OR = 2.15, 95% CI: 1.18–3.92), diabetes mellitus (OR = 1.86, 95% CI: 1.04–3.33), and CCI ≥4 (OR = 1.92, 95% CI: 1.08–3.41) were independent risk factors for poor treatment response (all p < 0.05). The high CAR group (CAR ≥3.85) had longer time to temperature normalization, abdominal pain relief, and WBC normalization compared to the low CAR group (all p < 0.001).
Conclusion: Preoperative CAR shows good performance in identifying high-risk acute cholecystitis patients who are more likely to experience an unfavorable response to PTGBD. A CAR value ≥3.85 is associated with an increased likelihood of poor treatment response and may assist clinicians in early risk stratification and treatment planning.
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Background: Sepsis-induced intestinal injury plays a pivotal role in the progression of sepsis and multiple organ dysfunction syndrome (MODS). This study aimed to investigate the protective effects of Esketamine (ESK) on sepsis-induced intestinal injury, focusing on the modulation of inflammation, oxidative stress, and macrophage polarization via the Toll-like receptor (TLR)4/NF-κB signaling pathway. Additionally, in vitro studies were conducted to further elucidate the molecular mechanisms underlying ESK's effects on macrophage polarization.
Methods: A rat model of sepsis was established using the cecal ligation and puncture (CLP) method. ESK was administered at doses of 30 mg/kg and 60 mg/kg. Serum levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) were measured using ELISA, and histopathological analyses were performed on intestinal tissues to evaluate injury. TLR4/NF-κB pathway markers were assessed using Western blotting and qPCR analyses. In vitro, RAW 264.7 macrophages were treated with lipopolysaccharide (LPS) to induce sepsis-like conditions, followed by ESK treatment. Immunofluorescence staining and flow cytometry were used to evaluate macrophage polarization, focusing on M1 markers (CD86, iNOS) and M2 markers (Arg1, CD206).
Results: ESK treatment significantly ameliorated sepsis-induced intestinal injury in vivo. It reduced serum levels of pro-inflammatory cytokines while increasing the anti-inflammatory cytokine IL-10 compared to the CLP rats (p < 0.05). ESK also promoted M2 macrophage polarization (increased Arg1 and CD206 expression) and inhibited M1 macrophage polarization (decreased CD86 and iNOS expression) compared to the CLP rats (p < 0.05). In vitro, ESK demonstrated similar effects in LPS-stimulated RAW 264.7 cells, modulating macrophage polarization by inhibiting the TLR4/NF-κB signaling pathway compared to the LPS-stimulated cells (p < 0.05). Co-treatment with a TLR4 agonist abrogated these effects, confirming the involvement of TLR4 in the mechanism of action of ESK.
Conclusion: ESK protects against sepsis-induced intestinal injury by modulating macrophage polarization and suppressing inflammation through the TLR4/NF-κB signaling pathway. Both in vivo and in vitro studies demonstrated ESK's ability to shift macrophages towards an anti-inflammatory M2 phenotype, highlighting its potential as a therapeutic agent for sepsis management. This study first investigated the effects of ESK on sepsis-induced intestinal damage and the potential molecular mechanisms involved.
