OBJECTIVE:To determine whether urinary or plasma cytokines more effectively differentiate Hunner-type interstitial cystitis (HIC) from non-Hunner-type interstitial cystitis (NHIC), and to develop an interpretable discriminative formula based on the most informative features. METHODS:Paired urine and plasma samples were collected from 47 patients with IC/BPS (15 HIC, 32 NHIC), and urine samples from 84 healthy controls were analyzed for baseline comparison. Twelve cytokines were quantified in each sample. Classification performance was evaluated using AutoGluon automated machine learning with stratified five-fold cross-validation across three feature sets: urine cytokines, plasma cytokines, and their combination. Symbolic regression with the QLattice algorithm, implemented within a nested cross-validation framework with seed averaging and a complexity constraint to reduce overfitting, was employed to generate a simplified discriminative formula. RESULTS:The urine-based model outperformed both plasma-based and combined models (AUC 0.979 ± 0.028 vs. 0.741 ± 0.271 vs. 0.921 ± 0.087). A clear pathophysiological gradient was observed among healthy controls, NHIC, and HIC, with urinary IL-8 elevated 72-fold in HIC and 5-fold in NHIC compared to healthy controls. The QLattice-derived formula, incorporating uIL-17 and uIL-8, achieved a nested cross-validation accuracy of 90.5% (95% CI: 88.5%-92.4%) and an AUC of 0.948 (95% CI: 0.927-0.966). CONCLUSION:Urinary cytokines, specifically IL-8 and IL-17, offer a more effective non-invasive approach for IC/BPS subtyping compared to plasma markers. The two-cytokine formula shows promise as an exploratory discriminative tool. However, external validation in larger, independent cohorts is necessary prior to clinical implementation.
Background Treatment with the synthetic prostacyclin analog iloprost has been shown to attenuate endothelial glycocalyx shedding and organ failure in patients with critical Covid-19. The treatment is currently being investigated in a broader setting of patients with acute respiratory failure. We here investigated the effect on inflammatory and T-cell-derived cytokine and growth-factor responses in patients with critical Covid-19. Methods Post-hoc analysis of a randomized controlled trial (n = 80) in mechanically ventilated patients with SARS-CoV-2 infection and concomitant endotheliopathy, defined as soluble thrombomodulin plasma-levels ≥4 ng/mL. Patients received 72 h iloprost infusion (1 ng/kg/min) or placebo. Blood samples were collected at baseline and 24 h after inclusion. Fifty-four cytokines and growth factors, distributed into six biomarker classes, were measured using the Meso Scale Discovery V-PLEX platform. Results Iloprost treatment, compared with placebo, did not result in statistically significant changes of any of the fifty-four measured biomarkers at 24 h, when adjusting for multiple testing. Likewise, linear mixed-effects models did not identify significant effects of iloprost on any of the six predefined biomarker classes at 24 h. Conclusions In mechanically ventilated patients with SARS-CoV-2 infection and endotheliopathy, iloprost treatment had no detectable effect on inflammatory and T-cell-derived cytokine and growth-factor responses. The findings corroborate that the clinical benefit of iloprost is not attributed to anti-inflammatory effects. We suggest that future studies focus on patient selection for targeted treatment, and on combined treatment with anti-inflammatory and endothelium-stabilizing interventions, in patients with respiratory failure, hyperinflammation, and endotheliopathy.
Coronavirus diseases, particularly COVID-19, been associated with cardiac injury. Given that obesity is a well-known risk factor for severe cases with poorer outcomes, we hypothesized that cardiac involvement in a murine betacoronavirus infection would be exacerbated in pre-obese mice. To test this hypothesis, we fed mice a short-term (4-week) cafeteria diet (Caf), which resulted in increased body fat and mild cardiac histological damage, myocyte hypertrophy and fibrosis. Following the diet, we performed intranasal infection with MHV-A59 and evaluated the lungs and hearts eight days post-infection. In the lungs, infection was acute, caused moderate lung injury and was self-limited in both Chow-fed and Caf-fed mice with similar low viral loads recovered from this tissue. Meanwhile, cardiac fibrosis was significantly exacerbated in the Caf diet mice infected with MHV-A59. We also observed elevated levels of circulating cytokines, TNF and IL-10, as well as increased cardiac oxidative stress, solely in the obese infected mice. In contrast, isolated hearts from lean infected mice showed an increased response to β-adrenergic stimulation, which was damped in the Caf diet infected group. These findings indicate that obesity is a significant risk factor for cardiac issues caused by coronavirus infection by modulating local oxidative stress and systemic inflammation.
Diabetic wounds pose a significant therapeutic challenge. While the antimicrobial peptide LL-37 and adipose-derived stem cells (ADSCs) individually show potential for wound repair, the efficacy and mechanism of their combined treatment remain unclear. This study aimed to investigate the therapeutic effect of LL-37 combined with ADSCs on diabetic wound healing. Clinical samples from diabetic and non-diabetic patients were analyzed, combined with bioinformatics analysis of public datasets (GSE144441 and GSE182906) to identify key genes. A diabetic mouse wound model was established to validate the healing effects of individual and combined LL-37 and ADSCs treatments. In vitro assays, co-culture models were employed to explore the mechanisms involving ADSCs and fibroblasts. Analysis of human diabetic wounds revealed impaired healing associated with deficiency in cathelicidin antimicrobial peptide (CAMP), the precursor of LL-37. In diabetic mice, the combination of LL-37 and ADSCs promoted wound healing more effectively than either treatment alone. LL-37 enhanced ADSC viability in a dose-dependent manner. Mechanistically, LL-37 treatment significantly upregulated the expression of negative regulator of reactive oxygen species (NRROS) in ADSCs. Exosomes derived from these LL-37-primed ADSCs were taken up by fibroblasts, leading to increased NRROS expression in the recipient fibroblasts. Upregulated NRROS subsequently activated both the TGF-β/SMAD and Hippo/TEAD1 signaling pathways. Further experiments confirmed crosstalk between these two pathways, which collectively enhanced fibroblast proliferation and migration. In conclusion, the combination of LL-37 and ADSCs promotes diabetic wound healing by enhancing fibroblast activity. This effect is mediated through exosomal transfer of NRROS from ADSCs to fibroblasts, leading to the activation of the interconnected TGF-β/SMAD and Hippo/TEAD1 signaling pathways.
Visceral leishmaniasis (VL) is associated with impaired Th1 responses, yet the intracellular signalling events linking immunosuppressive pathways to effector dysfunction remain poorly defined. We studied 150 adults in endemic northern Nigeria (50 active VL, 50 healed VL, 50 endemic controls) using flow cytometry, cytokine profiling, targeted RT-qPCR of 13 JAK-STAT pathway genes with dual reference gene normalisation, ex vivo checkpoint blockade, and phospho-flow cytometry for STAT1/STAT3 in both CD4+ T cells and CD14+ macrophages. Active VL was associated with reduced antigen-specific IFN-γ (220 versus 940 pg/mL in healed VL; P < 0.001), elevated IL-10, expanded regulatory T cells, transcriptional upregulation of STAT3 (2.66-fold, adjusted P < 0.001), and downregulation of its negative regulator SOCS3 (0.56-fold, adjusted P = 0.001). A STAT3-dominant phosphorylation profile was present in both CD4+ T cells (pSTAT1/pSTAT3 ratio 1.33) and, more prominently, CD14+ macrophages (ratio 0.51; Kruskal-Wallis P < 0.001 across disease groups). CD14+ pSTAT3 correlated with macrophage infection index (Spearman ρ = 0.52, P < 0.001), linking signalling state to effector function. Combined IL-10 and PD-1 blockade reversed the signalling imbalance in both compartments, restored IFN-γ production up to 4.8-fold, and reduced macrophage infection index by 42%. Pharmacological STAT3 inhibition with Stattic confirmed pSTAT3 reduction by phospho-flow cytometry (-33%, P < 0.001), reproduced transcriptional reprogramming comparable to checkpoint blockade for 9 of 13 genes, and enhanced macrophage parasite clearance (infection index -36%, P < 0.001). These findings across phosphoprotein, transcript, and functional levels identify a STAT3-dominant signalling signature spanning T-cell and macrophage compartments as a consistent feature of immune suppression in human VL and a candidate therapeutic target warranting investigation.
Background B-cell non-Hodgkin lymphoma (B-NHL) and B-cell acute lymphoblastic leukemia (B-ALL) are highly heterogeneous malignancies. While immunochemotherapy and CD19 chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of newly diagnosed (ND) and relapsed or refractory (R/R) disease, clinical outcomes remain inconsistent. This study aims to evaluate a baseline levels of 12-cytokine panel across the ND, R/R, and CAR-T cohorts to identify robust biomarkers predictive of treatment response and long-term prognosis. Methods We enrolled 120 patients (ND B-NHL: n = 42; R/R B-NHL: n = 52; ND B-ALL: n = 10; R/R B-ALL: n = 21) and a separate cohort of 23 patients receiving CD19 CAR-T therapy. Plasma levels of 12 cytokines were quantified and analyzed using ROC curves, Kaplan-Meier survival analysis, and regression analyses to determine independent prognostic factors. Results Baseline cytokine profiling revealed that IL-17 was one of the four markers exhibiting significant inter-group differences (P = 0.034). In the R/R B-NHL cohort, high baseline IL-17 was significantly associated with inferior OS (log-rank P < 0.0001) and shorter progression-free survival (PFS) (P = 0.003). Univariate and multivariate Cox regression confirmed IL-17 as a significant risk factor for poor OS (HR = 1.802, P < 0.001) and PFS (HR = 1.279, P = 0.048) in R/R B-NHL. In CAR-T cohort, IL-17 levels also provided substantial discrimination for PFS (AUC 0.725). Conclusion Our findings indicate that IL-17 may be a potential biomarker with stage-specific clinical associations in B-NHL. Its relevance may vary across disease stages, but overall, it warrants further investigation for risk stratification and individualized treatment monitoring.
Interleukin-6 (IL-6) has an important modulator effect on inflammation and immunity and is involved in the progression of nephrolithiasis (kidney stone). However, whether IL-6 genetic variants affect the pathogenesis of kidney stones remains unclear. The present study conducted a combined investigation of candidate gene-driven screening and systematic screening on whole exome sequencing data from 28 patients of calcium oxalate stones, identifying a non-synonymous single nucleotide polymorphism (SNP) rs13306435 in IL-6 as a candidate research locus, which was further validated using HRM genotyping in an expanded cohort comprising 241 cases and 229 healthy subjects. Western blotting and qRT-PCR were used to assess the effects of this variant on crystal-induced inflammation, while molecular dynamics simulation was employed to analyze structural alterations in the receptor binding complex. In individuals aged ≤40 years, the A allele of rs13306435 was nominally associated with a reduced risk of stone formation, but no association was observed for the whole population. This missense variant causes an aspartate-to-glutamate substitution (D/E), inhibiting calcium oxalate monohydrate (COM)-triggered JAK2/STAT3 activation and inflammatory responses. However, it decreased the binding energy of IL-6/IL-6R/gp130 complex by increasing hydrogen bonds and salt brigdge at remote interfaces, suggesting that enhanced receptor binding does not necessarily translate to increased downstream signaling. Although this variant is not associated with general stone susceptibility, it exhibits notable anti-inflammatory activity by attenuating COM-induced JAK2/STAT3 activation and may influence the progression of stones through this pathway. These findings provide new insights into the role of anti-inflammatory mechanisms in nephrolithiasis.
A single nucleotide polymorphism (SNP) within the human interferon lambda 1 (IFN-L1, IFN-λ1) gene promoter, rs7247086 (C/T) has been reported to be associated with severe dengue and possibly with psoriasis and COVID-19. However, its functional nature is unknown. The present study was undertaken to examine the effect of rs7247086 on transcription, by utilizing promoter and enhancer-reporter assays. We see that the T allele completes a consensus signal transducer and activator of transcription (STAT)-binding site. While we did not find strong evidence to show that the STAT-binding site drove transcription from the IFNL1 gene promoter, we saw that it acts like an enhancer in reporter assays. The T allele of rs7247086 within the STAT-binding site significantly increased transcription of the reporter gene compared to the C allele when incorporated into enhancer-reporter constructs in both HEK293 and A549 cell lines. Mechanistically, we obtained evidence from electrophoretic mobility shift assays to show that the T allele binds to STAT proteins more strongly than the C allele. In a cohort of healthy individuals, we saw that the T allele carriers, specifically males but not females, had significantly increased secretion of IFN-λ1 from their peripheral blood mononuclear cells after stimulation. Lastly, rs7247086 significantly associated with psoriasis, only in males but not in females.
The literature on the Interleukin 17F (IL-17F) rs763780 polymorphism and its association with immune thrombocytopenia (ITP) risk remains inconsistent and controversial. These uncertainties underscore the urgent need for a meta-analysis to objectively synthesize the heterogeneous findings, mitigate bias, and improve statistical power. This study strictly adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and guidelines. A systematic literature search for original studies was conducted across the CNKI, Wanfang Data, Cochrane Library, Web of Science, and PubMed databases, covering publications up to April 5, 2026. Odds ratios and corresponding 95% confidence intervals were calculated to assess the association. STATA 14.2 software was used to synthesize the pooled estimates. A total of eight case-control studies consisting of 805 ITP cases and 841 controls were included. The summarized statistics suggested the detrimental effect of the A allele in the homozygote and recessive models. In the sensitivity analysis, the results that were initially non-significant in the allele, heterozygote, and dominant models became significant after excluding a single dataset, which was also identified as the source of heterogeneity. Region-stratified analyses revealed statistical significance in the Chinese/Japanese and Egyptian subgroups under specific analytic contrasts. When stratified according to age, the children subgroup showed significant associations in a subset of genetic models, while the adult counterpart demonstrated significance across all models. In conclusion, the pooled estimates of the homozygote and recessive models suggested that the rs763780 polymorphism is associated with ITP risk, but this finding requires further validation through large-scale studies.
BACKGROUND:Interleukin-33 (IL-33) and soluble ST2 (sST2) are critical regulators of tissue-derived inflammation, and their dysregulation is usually implicated in various inflammatory disorders. Despite this, how these circulating proteins behave over time in healthy individuals remains poorly defined. Therefore, defining reference concentrations in healthy cohorts is important for interpreting disease-associated changes attributed to these proteins. METHODS:A healthy Finnish cohort (N = 124), consisting of children (7-10y, n = 36), adolescents (11-15y, n = 37), young adults (20-34y, n = 25), and older adults (60-70y, n = 23), received a Tdap3-IPV (aP) booster at day 0. Serum IL-33 and sST2 were measured at baseline (before vaccination) and at days 28 and 365 post-vaccination. For the same time points, serum antibodies specific to aP booster were measured. Baseline serum concentrations of IFN-γ, IL-2, IL-5, IL-10, IL-13, IL-17A and IL-17F were evaluated as predictors of sST2 dynamics. RESULTS:IL-33 was undetectable at a population level (10-30% detectability). In contrast, sST2 was consistently detectable across all time points (median baseline 18.49 ng/mL) but exhibited a significant longitudinal decline over one year (p < 0.001). This longitudinal decline varied by age: older adults showed lower baseline sST2 and minimal change over time, whereas younger age groups showed a more pronounced decline. No associations were observed between IL-33 or sST2 and vaccine responses or baseline cytokines. CONCLUSION:Serum IL-33 was mostly undetectable in healthy individuals. Although serum sST2 concentrations declined over time, these changes were independent of vaccine-induced antibody responses. These results provide reference serum concentrations for the two important proteins.
Musculoskeletal disorders (MSDs) are a leading cause of chronic pain and disability worldwide, yet available pharmacological treatments remain largely ineffective or palliative. Increasing evidence indicates that chronic inflammation in MSDs reflects not only excessive pro-inflammatory signaling but also impaired endogenous anti-inflammatory and pro-resolving mechanisms. In this context, cytokines IL-34 through IL-41 have recently emerged as important regulators of immune activation, tissue remodeling, and tissue regeneration. This review provides a mechanistically informed analysis of the roles of IL-34-IL-41 in the pathogenesis of major MSDs, including inflammatory arthritis, osteoarthritis, osteoporosis, intervertebral disc degeneration, and sarcopenia. A functional dichotomy within this cytokine spectrum is highlighted: IL-34, IL-36, IL-39, and IL-40 act as pro-inflammatory or inflammation-amplifying mediators that promote macrophage activation, osteoclastogenesis, and autoimmune responses, whereas IL-35, IL-37, IL-38, and IL-41 exert anti-inflammatory and pro-resolving effects by suppressing Th1/Th17-driven immunity and fostering regulatory immune phenotypes. Notably, IL-41 also integrates immune modulation with metabolic regulation and muscle repair. We discuss emerging translational strategies targeting this cytokine group and address key unresolved questions related to cytokine redundancy, disease heterogeneity, patient stratification, and safety. Collectively, the available evidence highlights the growing mechanistic and translational relevance of cytokines IL-34 through IL-41 in MSDs.
Background and objective Salivary cytokines can provide information about oral health and systemic diseases. We aimed to assess the salivary concentration of inflammatory cytokines in outpatients with Crohn's disease (CD) and whether the levels are modified by the presence of periodontal diseases. Material and methods This cross-sectional study selected 72 individuals, 35 CD patients and 37 controls. Comprehensive medical and periodontal examinations were performed. Unstimulated saliva was collected and concentrations of interleukin (IL)-1β, IL-4, IL-6, IL-10, IL-12p70, IL-17A, IL-17F, IL-22, IL-23, IL-27, interferon (IFN)-y, and tumoral necrosis factor (TNF)-α were analyzed by a bead-based multiplex assay. Results Salivary concentrations of TNF-α, IL-10 and IL-12p70 were significantly higher in CD patients compared to controls (p < 0.05). Patients taking anti-TNF agents (n = 16) and those taking conventional medication for IBD (n = 14) had significantly higher levels of IL-12p70 and IL-23 than patients taking no medications (p < 0.05). Linear regression analysis showed that CD was positively associated with the salivary concentrations of TNF-α and IL-10, while the percentage of pathological periodontal pockets associated positively with IL-1β and IL-10. Conclusion CD patients showed higher salivary concentrations of TNF-α and IL-10, regardless of the periodontal condition.
A systematic review and a study level meta-analysis was conducted to assess the association between the T-786C polymorphism of the nitric oxide synthase 3 (NOS3) gene with acute coronary syndrome (ACS) or premature coronary artery disease (PCAD). Online databases of PubMed, EMBASE, MEDLINE, Scopus, Cochrane library and Web of Science were systematically searched, yielding 23 different studies (from 22 articles, involving 17,324 subjects), which were included for quantitative synthesis. Study level odds ratios (ORs) and their 95% confidence intervals (CI) were pooled using random effects, employing a Z test. Pooled results suggested a significant association between T-786C polymorphism and ACS or PCAD through dominant and allelic genetic model comparisons (OR, 1.26, 95% CI, 1.09-1.45, p = 0.001 and OR, 1.26, 95% CI, 1.11-1.43, p = 0.0002 respectively). Leave-one-out sensitivity analysis, in addition to the results for the myocardial infarction endpoint, attested to the robustness of the obtained results. Large, prospective investigations are, however, warranted to confirm the presented findings.
BACKGROUND:Cutaneous verrucae (warts) are benign epidermal proliferations caused by human papillomavirus (HPV) infection. The host immune response particularly T helper 17 (Th17) related cytokines such as interleukin-17A (IL-17A) and interleukin-23 (IL-23) plays a critical role in the regulation of viral control and inflammatory responses. However, the systemic levels of these cytokines in patients with verrucae have not been sufficiently characterized. OBJECTIVE:To investigate serum IL-17A and IL-23 levels in patients with cutaneous verrucae, to compare them with those of healthy controls, and to evaluate their associations with age, sex, number of lesions, disease duration, and lesion localization. METHODS:In this case-control study, 49 patients with palmoplantar or anogenital verrucae and 41 age- and sex-matched healthy controls were included. Serum IL-17A and IL-23 levels were measured using enzyme-linked immunosorbent assay (ELISA). Continuous variables were analyzed using the Mann-Whitney U test, and categorical variables using the chi-square test. Correlations between variables were assessed using Spearman correlation analysis. RESULTS:The median serum IL-23 level was 11.8 pg/mL (interquartile range, IQR: 7.8-21.3) in patients with cutaneous verrucae and 8.8 pg/mL (IQR: 7.2-12.0) in controls, with a statistically significant difference (p = 0.018). The median serum IL-17A level was 16.6 pg/mL (IQR: 8.7-37.9) in patients and 16.4 pg/mL (IQR: 10.9-24.5) in controls, with no significant difference between the groups (p = 0.755). A strong positive correlation was observed between IL-17A and IL-23 levels in patients (rs = 0.880, p < 0.001). No significant associations were found between cytokine levels and age, sex, number of lesions, disease duration, or localization. CONCLUSION:Elevated IL-23 levels and its strong positive correlation with IL-17A suggest that the IL-23/IL-17 Axis may play a role in immune activation associated with HPV-related cutaneous verrucae. IL-23 may represent a potential indicator of immune activation associated with cutaneous verrucae; however, its standalone diagnostic utility appears limited. Future studies with larger cohorts and tissue-level analyses are needed to further elucidate the role of Th17-related cytokines in the pathogenesis of verrucae.
This study used epitope screening technology to identify dominant T/B cell epitopes from the Helicobacter pylori virulence factors UreB, CagA, VacA and HpaA, (UCVH) and develop an effective vaccine. These epitopes were fused in series with the cholera toxin B subunit to develop a multivalent fusion vaccine. The immunogenicity of the recombinant vaccine was systematically evaluated after it was administered to C57BL/6 mice. The serum titers of UCVH-specific IgG, IgG1, and IgG2a antibodies and the mucosal sIgA concentration increased significantly. The splenic lymphocytes also increased their secretion of key cytokines, including IFN-γ, IL-4, and IL-17 A. These findings demonstrate the excellent immunogenicity of the cholera toxin B subunit-adjuvanted UCVH multi-epitope vaccine and its ability to induce potent humoral immunity and comprehensive cellular immune responses. They provide a crucial experimental foundation for further optimization of Helicobacter pylori vaccines and subsequent studies on anti-infective protection.
Adipose tissue macrophages (ATMs) have emerged as central regulators at the interface of immunity and metabolism. Accumulating evidence indicates that ATMs play multifaceted roles in the initiation and progression of obesity-associated metabolic disorders, including type 2 diabetes and non-alcoholic fatty liver disease. This review synthesizes current knowledge on ATM functional diversity, with a particular focus on microenvironment-driven polarization, metabolic reprogramming, intercellular communication, and cross-organ immune regulation. We highlight how lipid overload, inflammatory mediators, and oxidative stress cooperatively shape ATM fate and function, endowing these cells with dual capacities to preserve tissue homeostasis or to propagate chronic metabolic inflammation. From a translational perspective, ATMs represent attractive biomarkers and therapeutic targets. Emerging strategies-including small-molecule modulators, natural compounds, and macrophage-targeted delivery systems such as miRNA-loaded nanoparticles-have demonstrated promise in reprogramming ATM phenotypes and alleviating metabolic dysfunction. Moreover, recent advances in single-cell omics, spatial transcriptomics, and fate-mapping technologies are redefining our understanding of ATM heterogeneity and temporal dynamics in human adipose tissue, thereby enabling precision immunometabolic interventions. A deeper elucidation of the immunometabolic mechanisms governing ATMs will provide both a conceptual framework and therapeutic foundation for the precision treatment of metabolic diseases.
BACKGROUND:Beta-thalassemia (β-Thal) is an inherited hemoglobin disorder caused by defective β-globin synthesis, resulting in ineffective erythropoiesis, chronic hemolytic anemia, and altered iron metabolism; it is highly prevalent in Iraq, a country with a complex and not fully characterized immunological profile. Inflammatory cytokine dysregulation in transfusion-dependent patients further compromises hematopoiesis, drives progressive iron overload, and perpetuates immune activation. This study aims to compare the gene expression and protein levels of seven cytokines - IL-1β, IL-4, IL-5, IL-12, IL-13, IL-17F, and TNF-α - between patients with beta-thalassemia and healthy controls. METHODS:This case study included 344 patients with beta-thalassemia and 440 healthy patients of the same age and gender that were collected from Maysan (Al-Amarah) and Najaf, Iraq. The mRNA expression levels were assessed using quantitative real time polymerase chain reaction (qPCR) and included GAPDH as the internal reference gene for all assessments done. The levels of cytokines present in the serum were determined using ELISA method. The statistical tests that were included are: independent samples t-test, Pearson correlation, receiver operating characteristic (ROC) curve, and binary logistic regression. RESULTS:For all of the patients that showed the presence of IL-1β, there was a significant elevation in the mRNA and serum protein levels of IL-12, IL-17F, and TNF-α. The results showed a decrease in the presence of IL-4, IL-5, and IL-13. For all patients, TNF- α showed the greatest ability to diagnose a case of beta-thalassemia (AUC = 0.961). There was a significant positive correlation with serum ferritin, the number of blood transfusions, and splenomegaly. CONCLUSIONS:Pro-inflammatory cytokines TNF-α and IL-1β demonstrated the strongest positive correlations with serum ferritin (r = 0.798 and r = 0.714, respectively), transfusion frequency, and splenomegaly. Conversely, Th2 cytokines IL-4 and IL-13 showed significant inverse correlations with ferritin and positive correlations with hemoglobin, reflecting progressive Th2 suppression with increasing disease burden.
Bladder cancer (BCa) is the most frequently diagnosed malignancy of the urinary system and is characterized by a multifactorial etiology. Multiple growth factors have been implicated in BCa progression. This cross-sectional study investigated whether the pro-angiogenic factors angiopoietin-like 4 (ANGPTL4), insulin-like growth factor 1 (IGF-1), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) could differentiate BCa patients according to the degree of systemic inflammation. Based on histopathological examination, 101 participants were enrolled and divided into a cancer group (CG; n = 69), and a non-cancer group (NCG; n = 32), comprising patients who were not diagnosed with BCa following histopathological evaluation. Healthy control was also recruited from Blood Donor Repository (n = 34). The control group was younger (median min-max years old; CG: 71 (48-92); NCG: 70 (26-86); control: 43 (28-61); p < 0.0001) and had a lower body mass index (BMI) compared to the CG and NCG groups (median min-max kg/m2; CG: 27 (21-43); NCG: 27 (19-37); control: 21 (20-31); p < 0.0001). The CG was stratified by median C-reactive protein (CRP) level (4.53 μg/mL) and further analyzed. Regardless of CRP level, patients in both the CG and NCG groups had higher concentrations of all assessed proangiogenic and proinflammatory markers than healthy controls. Individuals with BCa, regardless of CRP level, were more likely to be smokers compared with NCG (p < 0.001), which was confirmed in a multivariate analysis pointing to smoking as the only variable that significantly differentiated the CG from the NCG (OR = 3.78, 95% CI: 1.36-10.54, p = 0.0109). No significant differences in tumor grade or TNM classification were observed between the low-CRP and high-CRP subgroups. Analysis of inflammatory parameters revealed significant differences in CRP concentrations alone. The high-CRP CG subgroup exhibited significantly higher CRP levels compared with both the low-CRP CG subgroup and the NCG (p < 0.0001). Analysis of proangiogenic markers revealed differences only in VEGF. No significant differences were observed for ANGPTL4, IGF-1, and FGF21, as well as in the counts of leucocytes and platelets.VEGF concentrations differed significantly between subgroups and were highest in the high-CRP CG subgroup compared with the low-CRP CG subgroup and the NCG (median pg/mL: 186.7 vs. 120.5 vs. 120.6, respectively; p = 0.0330). Receiver operating characteristic (ROC) curve analysis of VEGF concentrations showed modest discriminative ability between CG and NCG, with an area under the curve (AUC) of 0.624 (95% CI: 0.529-0.719; p = 0.013). In the CG, multivariable linear regression showed that CRP was independently associated with higher VEGF levels after adjustment for smoking, tumor stage, age, sex, and BMI (β coefficient [95% CI) 0.302 [0.078;0.526]; p = 0.009), corresponding to an approximately 23.3% increase in VEGF for each twofold increase in CRP. Conclusion: These findings indicate that systemic inflammation, reflected by CRP levels, is independently associated with higher VEGF concentrations in BCa patients, supporting a potential link between inflammation and tumor-related angiogenesis.
Chronic stress promotes colonic inflammation by sustaining activation of the hypothalamic-pituitary-adrenal (HPA) axis, inducing oxidative stress, and disrupting barrier integrity, thereby exacerbating inflammatory bowel disease and irritable bowel syndrome. Therefore, there is a need for therapeutic compounds that can ameliorate stress-induced colonic inflammation. Caffeic acid (CA), a naturally occurring polyphenol found in coffee and tea, has shown potential anti-inflammatory and antioxidant properties. This study evaluated the effect of CA in a chronic unpredictable stress (CUS)-induced colon inflammation in rats. Animals were exposed to CUS for 14 weeks, with CA (50 mg/kg, p.o.) administered during the final 4 weeks as an intervention. CUS exposure induced depression-like behaviors, elevated stress hormone levels, and redox imbalance, as evidenced by increased malondialdehyde (MDA), nitrite, and reactive oxygen species (ROS), along with decreased reduced glutathione (GSH) and superoxide dismutase (SOD). Histological analysis revealed significant colonic damage, including crypt shortening, mucosal thickening, goblet cell loss, and mast cell infiltration. These changes were accompanied by reduced expression of tight junction proteins (ZO-1, claudin-1, and occludin) and increased expression of inflammatory mediators (PAR-2, IL-6, IL-1β, and NF-κB). CA treatment ameliorated behavioural alterations, restored redox balance and antioxidant defenses, and preserved mucosal architecture and goblet cell integrity. Mechanistically, CA suppressed PAR-2-mediated NF-κB signalling, thereby restoring intestinal barrier integrity. Collectively, these findings indicate that CA has therapeutic potential to attenuate stress-induced colonic inflammation by modulating stress-associated gastrointestinal disorders.
