Inflammatory activation is a major cause to nasal diseases, such as chronic rhinosinusitis and allergic rhinitis. However, in vitro research model to mimic the process of olfactory inflammation and to screen new therapeutic target is still lacking. We established three inflammatory models based on olfactory epithelium (OE) organoids, using lipopolysaccharide (LPS), TNFα treatment and doxycycline induction. The efficacy of these models was evaluated by immunostaining, RNA sequencing, qPCR, and functional assays. These inflammatory organoid models mimicked impairment in cell proliferation and neuronal genesis, and showed upregulation of inflammation-related signaling pathway and downregulation of cell cycle-related pathway. We identified that DNA damage inducible transcript 3 (Ddit3) was upregulated in all inflammatory organoid models. Ddit3 downregulation counteracted apoptosis, alleviated cell proliferation and neuronal differentiation, and recovered the functional response to odor stimulation in all three inflammatory organoid models. Ddit3 deficiency counteracted effect of LPS instillation by promoting cell proliferation, recovering neurogenesis, attenuating inflammation, and improving electrophysiological response to odor mixes in the OE. Single-cell RNA sequencing analysis showed that Ddit3 upregulation in mature olfactory sensory neurons of inducible inflammation model and patients with aging-related olfactory dysfunction correlated with endoplasmic reticulum stress and neuron apoptotic process. We established olfactory inflammation organoid models, and made use of these models to identify Ddit3 as a potential therapeutic target against inflammation-related olfactory neuronal loss and functional deficit.
The aim of this study was to assess the inflammatory status of patients with pancreatic cancer (PC) prior to the initiation of the first course of chemotherapy and to ascertain the most precise systemic inflammation index for predicting overall survival (OS). A single-centre retrospective analysis involving 310 pa- tients with PC was conducted. Blood samples were collected from patients during chemotherapy qualification, either on the first day of chemotherapy or the day before the first chemotherapy dose. The following inflammatory indices were calculated: systemic immune-inflammation index, systemic inflammation response index, and inflammatory benchmark index (IBI). Statistical analyses were performed utilizing appropriate tests (e.g., the log-rank test). All parameters were significant predictors of mortality; however, their area under the curve indicated only a moderate ability to differentiate mortality risk. Among the indices analysed, IBI was the sole metric that predicted OS in adjuvant (p < 0.05) and palliative (p < 0.001) cohorts, alongside disease-free survival (p < 0.04) and progression-free survival (p < 0.009). In the multivariate analysis, only IBI was proven to be statistically associated with OS (p < 0.043). Furthermore, IBI well stratified the tumour stage. All analysed indices related to inflammation and immune response may function as prognostic markers; however, additional studies are required to determine their precise cut-off value. In our investigation, IBI exhibited a distinctive protective effect, culminating in a 65% reduction in mortality, thereby underscoring the importance of C-reactive protein in patient stratification.
Traumatic brain injury (TBI) triggers profound neuroinflammatory responses; however, the regulatory role of small nucleolar RNAs (snoRNAs) in TBI-associated neuroinflammation remains poorly understood. This study evaluated its prognostic value in TBI. A controlled cortical impact (CCI) model was established in male C57BL/6 mice and validated through modified neurological severity scoring (mNSS), hematoxylin-eosin (H&E) staining, and immunostaining for IgG leakage and Nissl substance. Cortical snoRNA expression profiles were assessed using microarray analysis, with differentially expressed candidates confirmed by quantitative real-time PCR (qRT-PCR). The spatial distribution of snoRNAs was determined via fluorescence in situ hybridization (FISH), while the anti-inflammatory effects of snoRNA Gm24418 were evaluated in vivo and vitro. Downstream molecular pathways were identified through transcriptomic sequencing combined with bioinformatics analysis. Mice subjected to CCI exhibited significant motor and cognitive impairments (elevated mNSS), neuronal loss (as indicated by H&E and Nissl staining), and blood-brain barrier disruption (evidenced by IgG extravasation). Microarray analysis identified 47 dysregulated small nucleolar RNAs (snoRNAs), comprising 43 that were downregulated and 4 that were upregulated, with Gm24418 exhibiting the most significant downregulation. FISH confirmed the localization of Gm24418 predominantly in cortical neurons. Overexpression of Gm24418 in N2A cells and mice significantly reduced the levels of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6, and suppressed the activation of Ccl2 and TNF signaling pathways. Mechanistic analyses indicated that Gm24418 overexpression is associated with downregulation of the TNF signaling pathway, thereby attenuating neuroinflammation and promoting the restoration of blood-brain barrier integrity following TBI. Gm24418 is identified as a neuron-specific snoRNA that ameliorates TBI-induced neuropathology through influencing the expression of key inflammatory mediators, including CCL2 and TNF-α, representing a promising novel therapeutic target for post-traumatic neuroinflammation.
Vitamin D and iron metabolism are increasingly recognized as potential modulators of airway inflammation, yet their interrelationship in pediatric asthma remains unclear. This study investigated the associations of serum vitamin D, ferritin, and eosinophilic inflammation with acute asthma exacerbations in children and explored their potential interaction. This single-center retrospective study included 120 children with asthma, comprising 60 with acute exacerbation and 60 in clinical remission. Serum 25-hydroxyvitamin D [25(OH)D], ferritin, interleukin-6 (IL-6), and eosinophil-related indices were measured. Group comparisons, Spearman correlation analysis, univariate and multivariable logistic regression, restricted cubic spline analysis, and decision curve analysis were performed. Compared with the remission group, children with acute exacerbation had significantly higher ferritin levels (median 145 vs. 82 ng/mL, P < 0.001) and eosinophil percentage (6.0% vs. 4.7%, P < 0.001), but lower vitamin D levels (18.6 ± 7.2 vs. 24.3 ± 8.7 ng/mL, P = 0.021). In multivariable logistic regression, ferritin (OR = 1.13, 95% CI 1.07-1.18) and eosinophil percentage (OR = 2.01, 95% CI 1.34-2.70) remained independently associated with acute exacerbation, whereas vitamin D was not statistically significant after adjustment, although the association remained directionally inverse (OR = 0.92, 95% CI 0.84-1.02). No significant interaction between ferritin and vitamin D was observed, but interaction testing was limited by sample size. Restricted cubic spline analysis suggested an inverse linear association between vitamin D level and exacerbation risk. The combined model including ferritin, eosinophil percentage, and vitamin D showed high apparent discrimination (AUC = 0.973, 95% CI 0.952-0.994), although this finding should be interpreted cautiously because of overfitting risk. Ferritin and eosinophil percentage were independent risk factors for acute asthma exacerbation in children. Vitamin D showed an inverse association in unadjusted and dose-response analyses but was not an independent predictor after multivariable adjustment. These findings support a possible link between metabolic and inflammatory pathways in childhood asthma, but larger studies are needed for validation.
Vaccinia virus (VACV) and monkeypox virus (MPXV) are closely related members of the family Poxviridae, genus Orthopoxvirus, both capable of causing systemic infections with potential neurological complications. Although live, replication-competent VACV strains were historically used in smallpox vaccination, their clinical use was associated with rare but severe central nervous system (CNS)-related adverse events. Despite this, the mechanisms underlying VACV-induced CNS pathology, particularly olfactory dysfunction, remain poorly characterized. In this study, we found VACV-VR1354, a tissue culture-adapted derivative of the neurovirulent Western Reserve strain, can invade the CNS via the olfactory route and induce olfactory impairment. By using an intranasal infection model in two inbred mouse strains-C57BL/6N and BALB/c, we demonstrate that VACV-VR1354 efficiently disseminates from the nasal mucosa to the brain, as evidenced by a spatiotemporal gradient of viral DNA load (nasal mucosa > olfactory bulb > cerebrum > cerebellum). Evans blue extravasation assays indicated a transient increase in blood-brain barrier (BBB) permeability in the olfactory bulb, peaking at 7 days post-infection (dpi) and resolving by 14 dpi, with more pronounced effects in C57BL/6N mice. Neuroinvasion was accompanied by robust microglial and astrocytic activation, as well as injury to mature olfactory sensory neurons, particularly at 7 dpi. Transcriptomic profiling of the olfactory bulb revealed significant downregulation of olfactory receptor (OR) genes, with the downregulated genes significantly enriched in olfactory transduction pathways. Concurrently, strong upregulation of proinflammatory cytokines, chemokines, and interferon-stimulated genes (ISGs) was detected in the olfactory bulb tissue, indicative of intense neuroinflammation. Behaviorally, infected C57BL/6N mice exhibited impaired aversion to camphor odor between 14 and 49 dpi, with full functional recovery observed by 56 dpi. Collectively, our findings showed that intranasal infection of mice with VACV-VR1354 leads to a transient increase BBB permeability, neuroinflammation, and reversible olfactory/chemosensory impairment. This murine model recapitulates key features of post-viral olfactory loss and establishes a valuable platform for mechanistic studies of orthopoxvirus neuropathogenesis and therapeutic evaluation of interventions targeting viral neuroinvasion and sensory recovery.
Diabetic nephropathy (DN) involves mitochondrial dysfunction, but the role of complex I subunit NDUFA5 is unclear. This study investigated its protective mechanisms. Using tubule-specific Ndufa5 knockout mice, streptozotocin-induced diabetic mice, and high glucose-treated human kidney-2 (HK-2) cells, we assessed the effects of NDUFA5 manipulation. Renal NDUFA5 expression was reduced in diabetes. Its knockout exacerbated mitochondrial damage, ROS overproduction, and renal injury, while AAV9-mediated overexpression ameliorated these defects. NDUFA5 overexpression also suppressed pro-inflammatory cytokines (interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1)) and nuclear factor-κB (NF-κB) signaling in vivo and in vitro. Mechanistically, NDUFA5 attenuated inflammation by inhibiting mitochondrial reactive oxygen species (mtROS) generation. Thus, NDUFA5 protects against DN, at least in part, by preserving mitochondrial integrity and reducing oxidative stress and inflammation, highlighting its potential as a therapeutic target.
Multiple sclerosis (MS) is a complex multifactorial disease of the central nervous system (CNS) whose pathogenesis has not yet been fully elucidated. Current MS treatments primarily consist of disease-modifying therapies with anti-inflammatory and immunomodulatory properties, which effectively reduce relapse rates and disease activity. However, these therapies often exhibit limited long-term efficacy, may cause severe adverse effects, and remain largely insufficient in preventing the progressive accumulation of irreversible disability driven by axonal and neuronal damage. Although oxidative stress (OS) is not the sole pathologic factor in MS, substantial evidence supports its critical contribution to disease development and progression. In particular, OS is closely associated with key pathological processes such as demyelination and axonal degeneration. OS can act as a signaling mediator that promotes inflammatory responses, while inflammatory processes further amplify OS, forming a self-perpetuating cycle that exacerbates CNS tissue injury. Consequently, increasing attention has been directed toward the development of antioxidant-based therapeutic strategies for MS. Nevertheless, a comprehensive synthesis of MS drug development from the perspective of antioxidant capacity remains lacking, limiting rational therapeutic. This review examines the interplay between inflammation and OS in MS pathology, and summarizes current advances in antioxidant-based therapeutic approaches. By integrating existing evidence, this work aims to clarify the role of OS in MS pathogenesis and to inform the development of effective antioxidant-oriented treatments.
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. Intestinal homeostasis relies on the intricate balance of cell fate decisions within the intestinal epithelium and immune compartments. Ubiquitin-modifying enzymes (UMEs), including E2 conjugating enzymes, E3 ubiquitin ligases, and deubiquitinating enzymes (DUBs), have emerged as pivotal molecular regulators of these processes by orchestrating post-translational modifications that dictate protein stability, activity, and localization. In this review, we systematically summarize the essential roles of UMEs in modulating diverse cell-fate outcomes and their subsequent effects on intestinal barrier integrity and immune responses. Furthermore, we discuss the pathogenic dysregulation of specific UMEs in IBD and highlight their potential as diagnostic biomarkers and therapeutic targets. Finally, we explore emerging strategies, including small-molecule inhibitors and PROTAC technology, for targeting UMEs in clinical applications. By integrating current advances, this review provides novel insights into the ubiquitin-mediated regulation of intestinal cell fate and offers new perspectives for the management of IBD and the prevention of colitis-associated cancer (CAC).
To identify risk factors associated with liver disease severity in patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and develop a risk prediction model. Clinical data were collected from MAFLD patients diagnosed via liver biopsy at the Second Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, from January 2018 to December 2022. Patients were initially grouped by ALT levels to analyze its limitations in MAFLD diagnosis. Pathological reports were used to classify patients into non-significant (S/F/G < 2) and significant (S/F/G ≥ 2) groups based on fibrosis (S), inflammation (G), and steatosis (F) severity. Logistic regression identified independent risk factors for liver disease severity, and a predictive model was established. Model performance was validated using the area under the curve (AUC). Significant differences were observed between ALT-normal and ALT-abnormal groups in AST, GGT, ALP, BMI, hyperlipidemia prevalence, age, and diabetes prevalence (p < 0.05). Univariate analysis revealed age, BMI, AST, ALB, ALP, TG, and high-calorie diet as significant variables (p < 0.05) across inflammation, steatosis, and fibrosis subgroups. When stratified by inflammation severity, multivariate analysis identified sex, age, BMI, ALB, and PcIII as independent predictors of significant inflammation in MAFLD. High BMI and hyperlipidemia were risk factors for MAFLD steatosis. When grouped by fibrosis severity, age, height, BMI, ALB, and PcIII emerged as independent predictors of pathologically significant fibrosis in MAFLD. Patients with G ≥ 2 and/or S ≥ 2 were classified as the significant pathology group, while others formed the non-significant group. A logistic regression model was constructed using regression coefficients and constants, p = 1/(1 + e-Y), Y = -12.486 + 0.913 × Sex +0.442 × BMI + 0.04 × PcIII-0.085 × ALB. The area under the ROC curve was 0.833 (95% CI: 0.797-0.869), with a maximum Youden index of 0.456, corresponding to sensitivity and specificity of 67.3 and 83.3%, respectively. Sex, BMI, PcIII, and ALB are closely associated with MAFLD severity. The logistic regression model demonstrates potential clinical utility for predicting significant liver pathology.
Osteoarthritis (OA) is now increasingly recognized as a disease that affects the entire joint, where synovial inflammation plays a key role in pain, cartilage degeneration, and structural progression. Synovial macrophages (SMs) are key regulators in this process due to their phenotypic plasticity and central roles in amplifying inflammation, disrupting immunometabolism, and interacting with other joint-resident cells. These characteristics make SMs attractive targets for disease-modifying interventions. However, conventional therapies are limited by poor intra-articular retention, low cellular selectivity, and inadequate control over complex pathogenic networks. This review summarizes the biological functions of SMs in OA and explains why they are a mechanistically important and therapeutically accessible target. Next, we provide a structured overview of nanomaterial-based strategies for SM-targeted OA therapy, covering major material platforms, receptor-guided delivery approaches, subset- and state-selective targeting, intracellular functional intervention, and multi-target combination designs. We highlight representative studies that show how nanomedicines can improve local retention, enhance macrophage-specific uptake, and modulate inflammation, metabolism, oxidative stress, and cell fate. Finally, we discuss the major barriers to clinical translation, such as macrophage heterogeneity, safety, pharmacokinetics, and chemistry, manufacturing, and controls (CMC), and outline future directions for biomarker-guided and precision nanotherapy in OA.
Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra resulting in impaired movement coordination. There is no cure, and current therapies only provide symptomatic relief and have adverse side effects over long-term use. There are several biochemical mechanisms implicated in PD, which include oxidative stress, inflammation, and impaired autophagy. Previous studies have shown that a combination of two nutraceuticals, Ubisol-Q10 and ethanolic Ashwagandha root extract was more effective than each used alone at reducing neurodegeneration in a paraquat-induced rat model of PD by targeting the biochemical mechanisms all at once. In previous research, the oral doses of Ubisol-Q10 were low; however, the doses of ethanolic Ashwagandha used were unrealistically high because the extract's hydrophobicity causes poor bioavailability. The current study aims to determine the neuroprotective effects of Ubisol-Q10 and a novel water-soluble formulation of Ashwagandha extract (WS-ASH) on a Paraquat-injected rat model of PD. WS-ASH was prepared using a methodology analogous to that used for creating Ubisol-Q10. To test the efficacy of Ubisol-Q10, WS-ASH, and a combination Tonic solution, premortem gross- and fine-motor tests were conducted on a PD rat model, followed by immunofluorescent staining of biomarkers for inflammation, neurotrophic factors, oxidative stress, senescence, autophagy, and synaptic health. This WS-ASH had significant neuroprotective effects at lower doses. The combination of WS-ASH and Ubisol-Q10 (Tonic) provided a better neuroprotective effect. Importantly, Tonic treatment improved gross- and fine-motor skills of a paraquat-injected rat model of PD compared to the untreated group. Furthermore, the combined treatment led to decreased oxidative stress, decreased inflammation, resumption of autophagy, induced the production of pro-survival neurotrophic factors, and increased synapse-specific protein. The results indicate that this combined formulation has potential for an effective therapy for PD patients.
Phyllodes tumors are uncommon fibroepithelial breast neoplasms with variable biologic behavior. Synchronous bilateral phyllodes tumors are exceptionally rare, and the interpretation of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET-CT) may be confounded by tumor necrosis and inflammation, leading to false-positive nodal staging. A 44-year-old Korean woman presented with a rapidly enlarging, painful, ulcerated left breast mass for 3 months. She had no nipple discharge, fever, or weight loss. A right breast lesion was clinically occult. Ultrasound showed a right breast hypoechoic nodule (BI-RADS 4A) with scant vascularity and an elastography score of 2, and a giant heterogeneous hypervascular left breast mass with enlarged axillary lymph nodes and an elastography score of 4. 18F-FDG PET-CT revealed intense uptake in the left breast mass (SUVmax 11.5) and markedly FDG-avid ipsilateral axillary nodes (SUVmax 9.0), suspicious for metastasis; mild uptake was seen in the right breast nodule (SUVmax 1.7) without definite distant metastasis. Core needle biopsy supported a fibroepithelial neoplasm favoring phyllodes tumor. Final pathology confirmed a left borderline phyllodes tumor and a right benign phyllodes tumor; all 21 axillary lymph nodes showed reactive hyperplasia with sinus histiocytosis and no metastasis. After multidisciplinary review, the patient underwent excision of the right breast mass with frozen-section margin assessment, left total mastectomy including the nipple-areola complex and ulcerated skin to achieve negative margins, and level I-II axillary lymph node dissection because sentinel lymph node biopsy was considered unreliable in the setting of massive ulceration and severe axillary edema. Recovery was uneventful. Ceftriaxone sodium 2.0 g was given intravenously once daily from 1 day before surgery through postoperative day 5. No wound infection, seroma, fever, or unexpected adverse events occurred. At 1 month, CA125, CA15-3, and CA19-9 had normalized. In phyllodes tumors, marked axillary FDG avidity may reflect reactive inflammation rather than true nodal metastasis, particularly in giant ulcerated tumors with necrosis. Management should emphasize complete excision with negative margins and cautious axillary surgery guided by clinicopathologic correlation.
Approximately 2% of the human genome encodes proteins, while the remaining non-coding regions 19 may play critical roles in human diseases. Among these, long non-coding RNAs (lncRNAs) are 20 emerging as key regulators of gene expression through epigenetic, transcriptional, and post-21 transcriptional mechanisms, and may serve as potential biomarkers. In this pilot study, we investigated 22 lncRNAs in Parkinson's disease (PD) patients undergoing a six-week intensive multidisciplinary 23 rehabilitation program. Plasma samples from 26 PD patients were collected before (T0) and after (T1) 24 the intervention. Array profiling of 84 inflammation- and immunity-related lncRNAs revealed that 25 86% were differentially expressed post-intervention, with 55 upregulated (fold change >2) and 17 26 downregulated. Quantitative PCR confirmed significant upregulation of MALAT1, TUG1, and XIST 27 at T1 (p < 0.05). Plasma IL-1β levels were also significantly reduced after rehabilitation (p = 0.01). A 28 2 significant reduction in UPDRS-III scores was observed at T1 (p = 0.031), reflecting improved motor 29 function; however, no significant correlation was found between clinical changes and molecular 30 findings. These preliminary, hypothesis-generating results suggest that rehabilitation may modulate 31 immune-related lncRNAs and inflammatory markers in PD, providing insights into their regulatory 32 roles in neuroinflammation and potential as biomarkers of response to rehabilitative interventions.
The TIME therapeutic model is used for the management of chronic wounds: Tissue (non-viable); Infection/Inflammation; Moisture (imbalance); Edges (non-advancing). These four components will determine the persistence or the healing of any chronic ulcer on the skin's surface and, by analogy, also those of the ulcerated epithelium at the subgingival level. We aimed to evaluate the clinical and microbiological changes recorded after implementation of this personalized subgingival model. Twelve patients with active periodontal or peri-implant pockets were recruited for a feasibility study. Patients were instructed to deeply clean these lesions subgingivally using an angulated interdental brush in a vertical position, twice per day for 15 days. On the first and last days, Löe & Silness gingival index and bleeding on probing (BoP) were recorded and samples were collected using the brush head for the quantitative PCR analysis of 8 bacterial species (commensal and pathogenic). Severe gingival inflammation with profuse bleeding was present at baseline in ten patients. Eight of them complied and adhered with 100% of the treatment. Following self-treatment at home, ten patients exhibited normal or mildly inflamed gums. Seven patients no longer had bleeding, four had slight bleeding and only one moderate bleeding. Microbiologically, the total bacterial load significantly decreased from 7E07 to 9.39E06 cfu/head. This proposed conservative cost-effective subgingival model could significantly improve the inflammatory activity of certain recurrent periodontal or peri-implant pockets, stabilize them and thus minimize their progression. The preliminary findings reflected a reduction or absence of bleeding, a relative decrease in pathogenic species, and the restoration of a microbial community in symbiosis with the host.
Metabolic syndrome (MetS) is characterized by chronic low-grade inflammation and immune dysregulation, which may increase susceptibility to sepsis. However, epidemiologic evidence remains limited. This study aimed to evaluate the association of MetS with the risk of sepsis and sepsis-related mortality. This study included 359,633 participants from the UK Biobank and 152,317 participants from the Kailuan Study. MetS was defined as the presence of ≥3 metabolic abnormalities. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of MetS with risk of sepsis and 28-day mortality following sepsis. Stratified analyses were conducted to assess potential effect modification. In the UK Biobank, we further evaluated the dose-response relationship between the number of MetS components and sepsis outcomes, explored potential mediation by inflammatory and immune biomarkers, and investigated the joint effect of MetS and lifestyle; in the Kailuan Study, we further investigated the impact of MetS evolution on sepsis risk. Sensitivity analyses were performed to evaluate the robustness of the results. During a median follow-up of 13.7 years, 11,040 sepsis cases were identified in the UK Biobank, whereas 5672 cases were documented in the Kailuan Study during a median follow-up of 16.4 years. After multivariable adjustment, MetS was associated with higher risks of sepsis (HR=1.55, 95% CI 1.49-1.61) and 28-day mortality following sepsis (HR=1.51, 95% CI 1.37-1.65) in the UK Biobank; corresponding HRs were 1.32 (95% CI 1.25-1.40) and 1.49 (95% CI 1.32-1.69) in the Kailuan Study, respectively (all P<0.001). These associations were generally consistent across stratified analyses. Moreover, the risk of sepsis outcomes increased with the number of MetS components and was partly mediated by inflammation. Compared with individuals free of MetS, individuals with MetS and an unfavorable lifestyle had substantially higher risks of sepsis (HR=1.91, 95% CI 1.81-2.00) and 28-day mortality following sepsis (HR=1.84, 95% CI 1.64-2.07), whereas those with MetS but a favorable lifestyle showed only a modestly increased risk of sepsis and no excess risk of 28-day mortality (HR=1.18, 95% CI 1.09-1.28 and HR=1.05, 95% CI 0.88-1.27, respectively). In analyses of MetS evolution, using individuals with persistently normal metabolic status as the reference, those with a persistent MetS demonstrated the highest risks of sepsis (HR=1.46, 95% CI 1.32-1.61) and 28-day mortality following sepsis (HR=1.88, 95% CI 1.50-2.35), followed by individuals with progressive MetS (HR=1.17, 95% CI 1.05-1.31 and HR=1.36, 95% CI 1.04-1.77, respectively), whereas those who recovered from MetS did not show a significantly increased risk (HR=1.09, 95% CI 0.96-1.25 and HR=1.19, 95% CI 0.87-1.61, respectively). Sensitivity analyses confirmed the robustness of the findings. This study demonstrated that MetS was associated with an increased risk of sepsis and sepsis-related mortality. These associations were partially mediated through inflammatory responses. The findings highlight the importance of maintaining metabolic health as well as promoting healthy lifestyles as strategies to reduce its burden.
Ovarian cancer is characterized by high mortality, extensive genomic instability driven by copy number alterations, and a highly immunosuppressive tumor microenvironment. Increasing evidence suggests that chronic inflammation and stromal-immune interactions contribute to tumor progression and therapeutic resistance. Bradykinin receptor B1 (BDKRB1), an inflammation-inducible G protein-coupled receptor, has been implicated in tumor-associated inflammatory signaling; however, its genomic determinants and immunological relevance in ovarian cancer remain poorly defined. We performed an integrative multiomics analysis of BDKRB1 using TCGA-OV and multiple independent GEO cohorts. The analytical framework incorporated bulk transcriptomics, copy number variation profiling, single-cell RNA sequencing, immune cell deconvolution, pathway enrichment analysis (GSEA, GSVA, and PROGENy), and pharmacogenomic modeling. Patients were dichotomized into BDKRB1-high and BDKRB1-low groups using cohort-specific median expression to ensure cross-dataset consistency. Associations with genomic instability, TME features, and drug response patterns were systematically evaluated. Quantitative real-time polymerase chain reaction (qRT-PCR) was further performed to validate BDKRB1 expression in ovarian cancer cell lines. BDKRB1 was consistently overexpressed in ovarian cancer and associated with unfavorable clinical outcomes across multiple cohorts. Elevated BDKRB1 expression correlated with increased genomic instability, reflected by higher fractions of the genome altered, gained, and lost. Although copy number variation partially explained BDKRB1 upregulation, the modest correlation suggested additional regulatory mechanisms. Tumors with high BDKRB1 expression exhibited immunosuppressive microenvironmental features, including enrichment of cancer-associated fibroblasts and reduced estimated CD8+ T-cell infiltration, despite concurrent activation of inflammatory signaling pathways. Single-cell transcriptomic analysis further identified fibroblasts as a major cellular source of BDKRB1 expression. Functional analyses indicated associations between BDKRB1 and inflammatory signaling, metabolic pathways, and oncogenic programs. Pharmacogenomic analyses suggested distinct drug sensitivity patterns in BDKRB1-high tumors and identified fasudil as a potential candidate compound for reversing BDKRB1-associated transcriptional signatures. This integrative analysis identifies BDKRB1 as a microenvironment-associated marker linking genomic instability with inflammatory and immunosuppressive tumor ecosystems in ovarian cancer. Although the findings are primarily associative, they provide a systems-level perspective on immune evasion mechanisms and highlight BDKRB1 as a potential biomarker for TME characterization and therapeutic hypothesis generation.
This study aims to systematically assess the effectiveness of Danshen (Salvia miltiorrhiza) extract in animal models of spinal cord injury (SCI) and provide high-quality evidence to support the translation from preclinical research to clinical practice. A systematic review and meta-analysis of 35 randomized controlled trials involving animal models of SCI were conducted. Data were extracted regarding the effects of Danshen extract on motor function (measured by the BBB score), inflammation, oxidative stress, apoptosis, and edema. Subgroup analyses based on model type, drug dosage, and compound type were also performed. Danshen extract significantly improved motor function at multiple time points (3, 7, 14, and 21 days post-injury). The BBB scores were higher in the treatment group across all time points (SMD = 4.53 at 3 days, p < 0.001). Additionally, Danshen reduced inflammatory markers (TNF-α, IL-1β), oxidative stress (MDA), and apoptotic markers (Caspase-3), while increasing antioxidant activity (SOD). It also significantly reduced spinal cord edema, as indicated by decreased water content in the injury areas (SMD = -3.88, p < 0.00001). Subgroup analysis showed the most significant improvements in contusion and ischemic models, with higher doses (>20 mg/kg) and water-soluble phenolic acids providing the best outcomes. Danshen extract exhibits significant potential in treating SCI through its diverse mechanisms, such as reducing inflammation, combating oxidative stress, preventing cell death, and alleviating edema. However, further research is needed to refine treatment protocols and establish its clinical relevance. https://www.crd.york.ac.uk/PROSPERO/recorddashboard.
Epididymitis is a common urogenital infection in adult men caused by sexually transmitted pathogens, urinary tract infections, trauma, or autoimmune mechanisms, with etiologies varying by age. In addition to severe pain and reduced quality of life, it may result in complications such as abscess formation, testicular atrophy, and infertility. Despite its clinical significance, comprehensive analyses of research trends remain limited. Bibliometric and knowledge-mapping approaches can provide quantitative insights into the field's development and hotspots. Using the Web of Science Core Collection and the PubMed Database, we retrieved literature related to epididymitis published from January 1, 2014, to September 10, 2025. Bibliometric analyses of publication volume, journals, authors, institutions, countries, and keywords were conducted using the Bibliometrix R package (v5.1.1), VOSviewer (v1.6.20), and CiteSpace (v6.4. R2). Scientific knowledge maps were generated to identify research hotspots and developmental trends in epididymitis. A total of 497 publications from 2,887 authors across 955 institutions in 67 countries were analyzed. Annual output remained stable at 30-50 articles since 2014. Andrologia was the most influential journal, and Pilatz Adrian was the leading author. China produced the most publications, the United States had the highest total citations, and Germany showed the highest average citation impact and strongest international collaboration. Justus Liebig University Giessen ranked first among institutions. Research trends have shifted from clinical diagnosis toward pathogenic and immunological mechanisms. Human studies focus on clinical features and treatment outcomes, whereas animal studies emphasize immunoinflammatory mechanisms and reproductive impacts. Research on epididymitis is advancing from clinical observation toward molecular immunology and precision therapy. Future studies should further focus on sexually transmitted pathogens, the immunopathological mechanisms of epididymitis, and the relationship between chronic inflammation and male infertility.
Helicobacter pylori is known to be a major pathogen causing gastric diseases via its direct colonization of the gastric mucosa. H. pylori releases Outer Membrane Vesicles (OMVs) throughout the growth process both in planktonic and biofilm phenotypes. The number, size and content of H. pylori OMVs over time, especially in H. pylori biofilm, remain unclear. In this study, we analyzed H. pylori biofilm at 2, 6, and 10 days as well as we extracted and characterized H. pylori pOMVs and bOMVs over time by transmission electron microscopy, nanoparticle tracking analysis, dynamic light scattering, electrophoretic light scattering and proteomic technology. Helicobacter pylori ATCC 43629 formed a multi-structured biofilm with large clusters characterized by mostly live cells and some fractures corresponding to water channels. Analysis of H. pylori OMVs reveals that the bacterial growth time and phenotype affect their number, size, and composition. Proteomic analysis revealed that in the early growth phase pOMVs are enriched with multiple virulence factors associated with host cell destruction whereas during later growth phases vesicles contain factors involved in the metabolic processing. The proteome of bOMVs was much more homogeneous and stable over time: in late growth stages, bOMVs proteomic analysis identified proteins involved in iron accumulation, protection against oxidative stress, immunosuppression in the gastric environment, and virulence promoting inflammation and tumorigenesis. This study suggests that H. pylori induces pathogenicity at least partially by secreting bOMVs that could promote tissue destruction related to tumorigenesis; therefore, the development of gastric cancer could be associated not only with the microorganism itself, but also with OMVs that it produces.
Silver or metallic-appearing urinary tract mucosa is exceedingly rare and typically attributed to exogenous metal exposure. We report a case of a diffusely silver-appearing ureter in a 65-year-old man with a history of squamous cell carcinoma of the bladder and chronic intermittent self-catheterization. Imaging revealed no metallic or calcified material, and histopathology demonstrated extensive squamous metaplasia with marked hyperkeratosis. We hypothesize that dense keratin accumulation produced a pseudo-metallic appearance without true metal deposition. This case highlights a novel gross ureteral appearance likely related to chronic inflammation-induced keratinizing changes, expanding the differential for "silver" urothelial mucosa.