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Intestinal permeabilization is central to the pathophysiology of chronic gut inflammation. This study investigated the efficacy of glucoraphanin (GR), prevalent in cruciferous vegetables, particularly broccoli, and its derivative sulforaphane (SF), in inhibiting tumor necrosis factor alpha (TNFα)-induced Caco-2 cell monolayers inflammation and permeabilization through the regulation of redox-sensitive events. TNFα binding to its receptor led to a rapid increase in oxidant production and subsequent elevation in the mRNA levels of NOX1, NOX4, and Duox2. GR and SF dose-dependently mitigated both these short- and long-term alterations in redox homeostasis. Downstream, GR and SF inhibited the activation of the redox-sensitive signaling cascades NF-κB (p65 and IKK) and MAPK ERK1/2, which contribute to inflammation and barrier permeabilization. GR (1 μM) and SF (0.5-1 μM) prevented TNFα-induced monolayer permeabilization and the associated reduction in the levels of the tight junction (TJ) proteins occludin and ZO-1. Both GR and SF also mitigated TNFα-induced increased mRNA levels of the myosin light chain kinase, which promotes TJ opening. Molecular docking suggests that although GR is mostly not absorbed, it could interact with extracellular and membrane sites in NOX1. Inhibition of NOX1 activity by GR would mitigate TNFα receptor downstream signaling and associated events. These findings support the concept that not only SF, but also GR, could exert systemic health benefits by protecting the intestinal barrier against inflammation-induced permeabilization, in part by regulating redox-sensitive pathways. GR has heretofore not been viewed as a biologically active molecule, but rather, the benign precursor of highly active SF. The consumption of GR and/or SF-rich vegetables or supplements in the diet may offer a means to mitigate the detrimental consequences of intestinal permeabilization, not only in disease states but also in conditions characterized by chronic inflammation of dietary and lifestyle origin.

Macrophages sense pathogens and orchestrate specific immune responses. Stimulus specificity is thought to be achieved through combinatorial and dynamical coding by signaling pathways. While NFκB dynamics are known to encode stimulus information, dynamical coding in other signaling pathways and their combinatorial coordination remain unclear. Here, we established live-cell microscopy to investigate how NFκB and p38 dynamics interface in stimulated macrophages. Information theory and machine learning revealed that p38 dynamics distinguish cytokine TNF from pathogen-associated molecular patterns and high doses from low, but contributed little to information-rich NFκB dynamics when both pathways are considered. This suggests that immune response genes benefit from decoding immune signaling dynamics or combinatorics, but not both. We found that the heterogeneity of the two pathways is surprisingly uncorrelated. Mathematical modeling revealed potential sources of uncorrelated heterogeneity in the branched pathway network topology and predicted it to drive gene expression variability. Indeed, genes dependent on both p38 and NFκB showed high scRNAseq variability and bimodality. These results identify combinatorial signaling as a mechanism to restrict NFκB-AND-p38-responsive inflammatory cytokine expression to few cells.

Sleep disruption is a frequent problem of advancing age, often accompanied by low-grade chronic central and peripheral inflammation. We examined whether chronic neuroinflammation in the preoptic and basal forebrain area (POA-BF), a critical sleep-wake regulatory structure, contributes to this disruption. We developed a targeted viral vector designed to overexpress tumor necrosis factor-alpha (TNFα), specifically in astrocytes (AAV5-GFAP-TNFα-mCherry), and injected it into the POA of young mice to induce heightened neuroinflammation within the POA-BF. Compared to the control (treated with AAV5-GFAP-mCherry), mice with astrocytic TNFα overproduction within the POA-BF exhibited signs of increased microglia activation, indicating a heightened local inflammatory milieu. These mice also exhibited aging-like changes in sleep-wake organization and physical performance, including (a) impaired sleep-wake functions characterized by disruptions in sleep and waking during light and dark phases, respectively, and a reduced ability to compensate for sleep loss; (b) dysfunctional VLPO sleep-active neurons, indicated by fewer neurons expressing c-fos after suvorexant-induced sleep; and (c) compromised physical performance as demonstrated by a decline in grip strength. These findings suggest that inflammation-induced dysfunction of sleep- and wake-regulatory mechanisms within the POA-BF may be a critical component of sleep-wake disturbances in aging.

ObjectivesVedolizumab (VDZ) and ustekinumab (UST) are second-line treatments in pediatric patients with ulcerative colitis (UC) refractory to antitumor necrosis factor (anti-TNF) therapy. Pediatric studies comparing the effectiveness of these medications are lacking. Using a registry from ImproveCareNow (ICN), a global research network in pediatric inflammatory bowel disease, we compared the effectiveness of UST and VDZ in anti-TNF refractory UC.MethodsWe performed a propensity-score weighted regression analysis to compare corticosteroid-free clinical remission (CFCR) at 6 months from starting second-line therapy. Sensitivity analyses tested the robustness of our findings to different ways of handling missing outcome data. Secondary analyses evaluated alternative proxies of response and infection risk.ResultsOur cohort included 262 patients on VDZ and 74 patients on UST. At baseline, the two groups differed on their mean pediatric UC activity index (PUCAI) (p = 0.03) but were otherwise similar. At Month 6, 28.3% of patients on VDZ and 25.8% of those on UST achieved CFCR (p = 0.76). Our primary model showed no difference in CFCR (odds ratio: 0.81; 95% confidence interval [CI]: 0.41-1.59) (p = 0.54). The time to biologic discontinuation was similar in both groups (hazard ratio: 1.26; 95% CI: 0.76-2.08) (p = 0.36), with the reference group being VDZ, and we found no differences in clinical response, growth parameters, hospitalizations, surgeries, infections, or malignancy risk. Sensitivity analyses supported these findings of similar effectiveness.ConclusionsUST and VDZ are similarly effective for inducing clinical remission in anti-TNF refractory UC in pediatric patients. Providers should consider safety, tolerability, cost, and comorbidities when deciding between these therapies.

INTRODUCTION: IL6 signaling plays an important role in triggering labor and IL6 is an established biomarker of intrauterine infection/inflammation (IUI) driven preterm labor (PTL). The biology of IL6 during IUI at the maternal-fetal interface was investigated in samples from human subjects and non-human primates (NHP). METHODS: Pregnant women with histologic chorioamnionitis diagnosed by placenta histology were recruited (n=28 term, n=43 for preterm pregnancies from 26-36 completed weeks of gestation). IUI was induced in Rhesus macaque by intraamniotic injection of lipopolysachharide (LPS, n=23). IL1 signaling was blocked using Anakinra (human IL-1 receptor antagonist, n=13), and Tumor necrosis factor (TNF) signaling was blocked by anti TNF-antibody (Adalimumab n=14). The blockers were given before LPS. All animals including controls (intraamniotic injection of saline n=27), were delivered 16h after LPS/saline exposure at about 80% gestation. RESULTS: IUI induced a robust expression of IL6 mRNAs in the fetal membranes (chorion-amnion-decidua tissue) both in humans (term and preterm) and NHP. The major sources of IL6 mRNA expression were the amnion mesenchymal cells (AMC) and decidua stroma cells. Additionally, during IUI in the NHP, ADAM17 (a protease that cleaves membrane bound IL6 receptor (IL6R) to release a soluble form) and IL6R mRNA increased in the fetal membranes, and the ratio of IL6 and soluble forms of IL6R, gp130 increased in the amniotic fluid signifying upregulation of IL6 trans-signaling. Both IL1 and TNF blockade suppressed LPS-induced IL6 mRNAs in the AMC and variably decreased elements of IL6 trans-signaling. DISCUSSION: These data suggest that IL1 and TNF blockers may be useful anti-inflammatory agents via suppression of IL6 signaling at the maternal-fetal interface.

BACKGROUND: The comparative safety and effectiveness of available biologics for post-operative prophylaxis in Crohns disease (CD) is uncertain. Drug persistence may serve as a real-world proxy for tolerability and effectiveness. We evaluated the comparative persistence of non-TNF and TNF antagonists for post-operative prophylaxis and their comparative effectiveness for preventing early endoscopic post-operative recurrence (POR). METHODS: We conducted a single-center, retrospective study of surgically naïve CD subjects undergoing ileocecal or small bowel resection between 1/1/2000 and 12/31/2021 and prescribed a biologic for post-operative prophylaxis. We compared the risk of prophylaxis failure (requiring recurrent surgery or discontinuation of therapy due to persistent POR despite optimized drug level or dose escalation, immunogenicity, and/or adverse event) and early endoscopic POR (Rutgeerts score ≥ i2 within 15 months postoperatively) between non-TNF and TNF antagonist prophylaxis using Cox proportional hazard and logistic regression, respectively, adjusting for demographic and disease characteristics. RESULTS: The study included 291 subjects (81% TNF antagonists). After multivariable adjustment, non-TNF antagonist prophylaxis was associated with a significantly lower risk of prophylaxis failure than TNF antagonists (hazard ratio 0.26; 95% confidence interval (CI) [0.13-0.53]). Prophylaxis with non-TNF and TNF antagonists had similar risk of early endoscopic POR (odds ratio 0.66; 95% CI [0.32-1.36]). Stratifying the non-TNF antagonists by anti-integrin and anti-IL12/23 yielded similar results. CONCLUSION: In a cohort of surgically naïve CD subjects prescribed a biologic for post-operative prophylaxis, non-TNF antagonists had greater persistence than TNF antagonists with similar risk for early endoscopic POR. If confirmed by large, prospective studies, these findings can inform post-operative management strategies in CD.

Objectives:Methods:Results:Conclusion:Resveratrol, a polyphenol found in grapes, has been studied extensively for its potential benefits on metabolic markers and inflammation. While promising results have been observed in animal studies and some human trials, the overall evidence is mixed. Moreover, elevated inflammatory markers have been closely linked to more severe symptoms of Multiple Sclerosis (MS). Therefore, strategies to reduce systemic inflammation could potentially improve outcomes for MS patients. So we aimed to examine the effectiveness of resveratrol supplementation on inflammatory markers in patients with Multiple sclerosis (MS), in a randomized placebo-controlled double-blinded parallel clinical trial.A total of 55 subjects with MS were enrolled in this study and randomly assigned to the two groups who were supplemented with resveratrol at a dose of 500 mg/day or received placebo capsules for 8 weeks. Tumor necrosis factor-alpha (TNF-α), Malondialdehyde (MDA), fasting blood sugar (FBS), triglycerides, total cholesterol, low-density lipoprotein – cholesterol (LDL-C), high-density lipoprotein – cholesterol (HDL-C), and the degree of fatigue were measured at baseline and after the intervention.Resveratrol treatment significantly decreased TNF-α (P < 0.001), and MDA (P < 0.001) compared to the placebo. The respective increase and decrease in FBS and HDL levels were seen in both groups, while the change in participants receiving resveratrol was significantly less pronounced. Changes in the levels of TG and fatigue scale remained unchanged.This study showed that resveratrol supplementation exerted anti-inflammatory and anti-oxidant effects in patients with MS.Trial registration: Iranian Registry of Clinical Trials identifier: IRCT20230315057731N1. [ABSTRACT FROM AUTHOR]

Background: Photobiomodulation (PBM), using red- or near-infrared light, has been used to treat tendinopathies, nerve injuries, osteoarthritis and wounds and evaluated in experimental allergic encephalomyelitis (EAE). To date, only a few studies have been performed in EAE but surprisingly, a few clinical studies in humans have already been performed, despite the paucity of preclinical evidence. Objective: Therefore, this study systematically reviewed the usefulness of PBM in ameliorating the clinical signs of EAE, a commonly used animal model of multiple sclerosis, and determine if there is enough evidence to warrant human studies. Methods: PubMed, EMBASE and Web of Science were searched in July 2024 for studies relating to PBM and EAE without any language restrictions. Since only three studies have been published, all studies were included in the systematic review and data related to clinical signs of EAE was pooled together to conduct a meta-analysis. Non-homogenous data was also reported and thematically synthesized. Results: A meta-analysis of the pooled data from the three included studies demonstrated a significant reduction of the clinical severity of EAE, with a mean reduction of 1.44, 95% CI (−2.45, −0.42), p = 0.006. PBM also significantly reduced other parameters such as infiltration of mononuclear cells, CNS demyelination, apoptosis markers and pro-inflammatory cytokines. However, there was an overall high risk of bias in all of the studies. Conclusion: The meta-analysis supports the use of PBM to ameliorate the symptoms of EAE, but the paucity of studies and the high risk of bias in the included studies warrants further preclinical investigation before conducting human studies. [ABSTRACT FROM AUTHOR]

Objective: This study aims to evaluate the active and chronic lesions in sacroiliac joints and lumbar spine over a decade of TNFi therapy in patients with AS. Methods: The study enrolled patients with AS under treatment with a TNFi for over a decade. The patients underwent a new MRI scan of their lumbar spine and sacroiliac joint (SIJ). Two readers evaluated all images. Inflammation of SIJ (SIS), SIJ structural damage (SSS) including Fat Metaplasia, Erosions, Backfill and Ankylosis, and Spondyloarthritis Research Consortium of Canada Bone marrow edema (SPARCC) spine score were recorded. Results: In the study, 15 patients were included, with 80% being male. The mean age during their first MRI was 38.1 (± 11.9) years old, and the majority (86.7%) tested positive for HLA-B27. While TNFi improved both BASDAI and BASFI scores, there was a noticeable increase in MRI acute lesions in the SIJ over time, where the median score increased from 0 (0–4) to 3 (0–10) after ten years (p = 0.028). After a decade of treatment, the median SPARCC spine score also increased from 0 (0–9) to 5 (0–16), p = 0.093. Finally, it was observed that there was a significant positive correlation between ESR and SIS erosions in cases of chronic lesions (r = 0.819, p < 0.001). Conclusions: While TNFi have significantly improved the treatment of AS, this study shows that acute lesions can still develop despite treatment. A personalized approach that adapts MRI assessment to each patient's specific requirements may help detect changes early and enable doctors to intervene promptly to prevent further damage. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a complex neuropsychiatric disorder. Growing evidence indicates that the activation of the inflammatory response system with interleukin (IL)-2, IL-4, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α) plays an important role in the pathogenesis of schizophrenia,. However, clinical data on cytokine levels in patients with schizophrenia treated with antipsychotics are inconsistent or inconclusive. In this study, we have examined inflammatory factors' alterations and their relationship to changes in clinical symptoms before and after olanzapine treatment of drug-naive patients with first-episode schizophrenia. Methods: We recruited 142 hospitalized patients with first-episode schizophrenia as a study group; blood samples were collected, and the patients were assessed for clinical symptoms at baseline and after 6 weeks of olanzapine treatment. One hundred individuals with no history of mental illness were also recruited as healthy controls. Blood samples were collected, and the serum levels of IL-2, IL-4, IL-8, IL-10, and TNF-α were determined using an enzyme cycling assay. The severity of clinical symptoms was assessed according to the Positive and Negative Syndrome Scale (PANSS). Results: Individuals with schizophrenia had lower IL-8 levels and higher IL-10 levels than healthy controls (P < 0.001). Positive correlations were detected between serum IL-2 and IL-10 concentrations and each subscale of the PANSS (all P < 0.05). Moreover, a negative correlation existed between the serum IL-8 concentration and the PANSS negative score (r = − 0.172, P = 0.040). After 6 weeks of treatment, serum IL-8 levels in the patient group were lower than at baseline (P < 0.001), whereas serum IL-10 and TNF-α levels were higher than at baseline (all P < 0.05). Therefore, serum IL-10 can be determined as an independent risk factor for outcome in patients with first-episode schizophrenia (P = 0.02, OR = 2.327). Furthermore, serum IL-2, IL-10, and TNF-α levels were significantly lower, whereas the serum IL-8 level was significantly higher (P < 0.001) in the healthy control group than in the "response" and "no-response" treatment groups respectively. Conclusions: Our results indicate that serum IL-2, IL-8, IL-10, and TNF-α levels may be involved in the pathophysiological mechanisms of schizophrenia and correlate with the effects of olanzapine. [ABSTRACT FROM AUTHOR]

Introduction: Retinoblastoma (RB) is the most common paediatric intraocular malignancy. The Spleen Tyrosine Kinase (SYK) acts as a proto-oncogene crucial for RB cell survival and is absent in the normal retina, making it a valuable therapeutic target. Aim: Entospletinib, a selective oral SYK inhibitor currently in phase 2 trials for chronic lymphocytic leukaemia, was evaluated for its activity on the RB cell line Y-79. Materials and Methods: The effects of Entospletinib on cell proliferation and death of the human RB Y79 cells were assessed by MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, phase contrast microscopy and AO/EtBr dual labeling. The Annexin-V kit was used to quantify the cell mortality following treatment using flow cytometry. The mRNA levels of caspase-3, BAX, BCL-2, SYK, p53, TNF-and NF-κB were measured using RT-PCR to better understand the mechanism of action of this drug. Western blot was used to further validate the data. Results: Entospletinib treatment led to a time- and dosedependent reduction in cell viability, with significant cytotoxicity observed at an IC50 of 61.3 μM/ml. Annexin V/Propidium Iodide (PI) staining demonstrated a dose-dependent increase in apoptosis. The treatment upregulated mRNA levels of Caspase-3, Bax, and p53 while downregulating SYK, TNF-α, and Bcl-2. RT-PCR and Western blot analyses confirmed a dose-dependent decrease in NF-κB/p65 expression. Conclusion: The study findings suggest that Entospletinib inhibits cell proliferation and induces apoptosis in RB cells by downregulating SYK/TNF-α/NF-κB/p65, highlighting its potential as a promising therapeutic candidate for RB. [ABSTRACT FROM AUTHOR]

Background/Aims: Robust management algorithms are required to reduce the residual risk of colectomy in acute severe ulcerative colitis (ASUC) refractory to standard infliximab salvage therapy. The aim of this study was to evaluate the performance and benefits of alternative ASUC management strategies using simulated prediction models of varying accuracy. Methods: This was a simulation-based modeling study using a hypothetical cohort of 5,000 steroid-refractory ASUC patients receiving standard infliximab induction. Simulated predictive models were used to risk-stratify patients and escalate treatment in patients at high risk of failing standard infliximab induction. The main outcome of interest was colectomy by 3 months. Results: The 3-month colectomy rate in the base scenario where all 5,000 patients received standard infliximab induction was 23%. The best-performing management strategy assigned high-risk patients to sequential Janus kinase inhibitor inhibition and mediumrisk patients to accelerated infliximab induction. Using a 90% area under the curve (AUC) prediction model and optimistic treatment efficacy assumptions, this strategy reduced the 3-month colectomy rate to 8% (65% residual risk reduction). Using an 80% AUC prediction model with only modest treatment efficacy assumptions, the 3-month colectomy rate was reduced to 15% (35% residual risk reduction). Overall management strategy efficacy was highly dependent on predictive model accuracy and underlying treatment efficacy assumptions. Conclusions: This is the first study to simulate predictive model-based management strategies in steroid-refractory ASUC and evaluate their effect on short-term colectomy rates. Future studies on predictive model development should incorporate simulation studies to better understand their expected benefit. [ABSTRACT FROM AUTHOR]

Introduction: Atezolizumab plus bevacizumab (AteBev) combination treatment is widely used as first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC). We aimed to clarify therapeutic issues regarding serum cytokines and the immune reaction in patients with uHCC treated with AteBev. Methods: We analyzed preserved serum from a previous prospective study on adult Japanese patients with chronic liver disease and uHCC who received AteBev treatment at our hospital. In that study, AteBev was administered intravenously every 3 weeks, and blood samples were collected before and after 3 weeks' treatment. Dynamic computed tomography was performed after 6 weeks of treatment to assess response. Results: In the prospective study, 21 of the 59 patients showed partial response (PR) and 19 patients showed stable disease, but 19 patients showed progressive disease (PD). We found that serum levels of tumor necrosis factor-alpha, interleukin (IL)-6, and soluble IL-2 receptor (IL-2R) increased significantly in the PR group, but only soluble IL-2R increased significantly in the PD group. Regulatory T cells decreased significantly in the PD group, but there was no significant change in Th1 or Th2 cells from before to after treatment in any group. As regards soluble MHC-class I, pre-treatment levels were significantly lower in the PD group than in the PR group, and serum levels increased significantly with treatment in the PD group. Conclusion: These findings reveal a need to further improve T-cell priming and to further make T cells recognize tumor antigens in uHCC. [ABSTRACT FROM AUTHOR]

Idiopathic nephrotic syndrome (NS) is a common glomerular disease in children throughout the world; however, the exact pathogenesis of the disease remains unknown. Several studies have shown that tumour necrosis factor-alpha (TNF-α), a proinflammatory cytokine, plays a significant role in the pathogenesis of NS. The literature lacks sufficient data to establish the relationship between TNF-α and NS. This prospective study was conducted on children aged 1–14 years diagnosed with idiopathic NS. All enrolled individuals were followed up from disease onset or relapse of NS until remission or at least 42 days with steroid therapy if remission was not achieved. Serum TNF-α levels were measured at presentation and remission or after 42 days of steroid therapy if remission was not achieved. The role of TNF-α levels in response to steroid therapy in NS was also assessed. One hundred and twelve children (68% boys) with idiopathic NS were enrolled. The median age (interquartile range) at enrolment was 58.5 (37–84.7) months, while the median age at symptom onset was 47.5 (24–60.7) months. The median TNF-α level at presentation was 7.5 (3.5–12.1) pg/ml, and that at remission was 5.25 (1.62–8.8) pg/ml. The median TNF-α levels among first-episode NS at presentation were 3.98 pg/ml and 1.88 pg/ml (P  = .04) at remission, whereas in steroid-resistant NS, it was 6.59 pg/ml at presentation and 9.02 pg/ml at 42 days (P  = .45). There was a significant negative correlation between the duration of steroid therapy and TNF-α levels, with a correlation factor of −0.021 and R 2 of 0.154 (P ≤.001). Serum TNF-α levels decrease with steroid therapy in children with steroid-sensitive NS, which correlates clinically with the achievement of remission. [ABSTRACT FROM AUTHOR]

Objectives: Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) is an adhesion molecule that acts as a coinhibitory receptor in the immune system. We previously demonstrated that CEACAM1 is predominantly expressed on peripheral blood neutrophils in patients with RA. The aim of the present study was to investigate the effects of Janus kinase inhibitors (JAKi) on cytokine-activated human neutrophils and CEACAM1 expression. Methods: Peripheral blood neutrophils were obtained from healthy subjects. Isolated neutrophils were stimulated with tumor necrosis factor-alpha (TNF-α) or granulocyte–macrophage colony-stimulating factor (GM-CSF) in the presence or absence of JAKi. The expression of CEACAM1 in peripheral blood neutrophils was analyzed by flow cytometry. Protein phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 was assessed by western blot using phospho-specific antibodies. Results: We found that TNF-α-induced CEACAM1 expression was marginally suppressed after pretreatment with pan-JAK inhibitor, tofacitinib. Moreover, TNF-α induced STAT1 and STAT3 phosphorylation at the late stimulation phase (4 to 16 h). The expressions of CEACAM1 on neutrophils were markedly up-regulated by GM-CSF not by interleukin (IL)-6 stimulation. All JAKi inhibited GM-CSF-induced CEACAM1 expressions on neutrophils, however, the inhibitory effects of baricitinib were larger compared to those of tofacitinib or filgotinib. Moreover, CEACAM1 was marginally upregulated in interferon (IFN)-γ stimulated neutrophils. Similarly, JAKi inhibited IFN-γ-induced CEACAM1 expressions on neutrophils. Conclusions: We demonstrated that JAKi prevent GM-CSF-induced CEACAM1 expression in neutrophils, and JAKi-induced inhibition depends on their selectivity against JAK isoforms. These findings suggest that JAKi can modulate the expression of CEACAM1 in cytokine-activated neutrophils, thereby limiting their activation. [ABSTRACT FROM AUTHOR]

Purpose: The most harmful atmospheric pollutant for human health is particulate matter (PM). We analyzed the correlation between short-term lag exposure to PM10 and PM2.5, salivary cortisol and TNF-α level, and methylation levels of the TNF-α promoter. Methods: A pilot study including 20 subjects. Eight salivary samples for each subject at various times of the day were collected for comparing cortisol levels and TNFα detection. TNFα promoter methylation levels on salivary DNA were analyzed. Regression analyses were performed using generalized linear mixed models between the different outcomes and 4, 3, 2 and 1 day's lag values of PM10/PM2.5.Generalized additive mixed model (GAMM) was used to evaluate any potential deviation from linearity. Results: Area under the curve with respect to the ground (AUCg) showed a statistically positive association with 4-, 3-, 2-, and 1-day lag of exposure to PM10. Area under the curve with respect to the increase (AUCi) showed a statistically negative association with 4-, 3- and 1-day lag of exposure to PM10. TNFα showed statistically significant association with both exposures, PM10 and PM2.5, at 4-, 3-, 2-, and 1-day lag. Conclusions: Regarding cortisol levels there is an increase of overall hormone levels but a less dynamism of the system to answer to external stressors. Increase of TNF-α may reflect increased levels of oxidative stress and inflammation due to pollution exposure. [ABSTRACT FROM AUTHOR]

Introduction: Cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL6), interferon-gamma (IFN-γ), interleukin 17-alpha (IL17-α), and interleukin 33 (IL33) play critical roles in immune responses and may impact cancer prognosis in future. However, few studies have simultaneously explored the prognostic impact of these cytokines for cancer. In this study, we aim to apply the unsupervised clustering analysis to approach the correlation between the expression of these cytokines and the subsequent prognosis of patients with esophageal squamous cell carcinoma (ESCC). Methods: A robust clustering algorithm was used, the Gaussian mixture method (GMM), through the mclust R package to group patients based on the expression of their cytokines in plasma or tumors. The 324 NTU patients were grouped into 4 clusters, and the 179 GSE53625 patients were grouped into 3 clusters based on expression in plasma and tumors, respectively. Five- and 3-year overall survival (OS) and progression-free survival (PFS) curves of each cluster were compared. Univariate and multivariate Cox regression analyses were also performed. Results: We successfully distinguished the multimodal distribution of cytokines through GMM clustering and discovered the relationship between cytokines and clinical outcomes. We observed that NTU-G3 and NTU-G4 subgroups showed most variation in 5-, 3-year OS and 5-, 3-year PFS with NTU-G3 being associated with poorer prognosis compared to NTU-G4 (p = 0.016, 0.0052, 0.0575, and 0.0168, respectively). NTU-G3 was characterized with higher TNF-α (median = 3.855, N = 78) and lower IL33 (median = 0.000, N = 78), while NTU-G4 showed lower TNF-α (median = 1.76, N = 51) and higher IL33 (median = 1.070, N = 51). The difference was statistically significant for TNF-α and IL33, with p = 0.0002 and p < 0.0001, respectively. A multivariate Cox-regression analysis revealed that GMM clustering and T/N stage were independent factors for prognosis, suggesting that the prognosis might be dependent on these cytokines. Conclusions: Our data suggest that expression patterns of IL33 and TNF-α in plasma might serve as a convenient marker to predict the prognosis of ESCC in the future. [ABSTRACT FROM AUTHOR]

Summary Introduction Methods Results Conclusion Obesity is characterized by chronic low‐grade inflammation. This study presents an updated systematic review and meta‐analysis on the effect of caloric restriction (CR) and intermittent fasting (IF) on plasma inflammatory biomarkers (C‐reactive protein [CRP], tumor necrosis factor [TNF]‐alpha, and interleukin [IL]‐6) in individuals with obesity/overweight compared with unrestricted or ad libitum feeding.PubMed, Web of Science, and SCOPUS databases were searched for randomized controlled trials (RCTs) reporting inflammatory biomarkers after at least 8 weeks of intervention. Standardized mean differences (SMDs) were calculated using a fixed effect model. Heterogeneity was determined using I2 statistics. Sensitivity analysis was conducted using the “leave‐one‐out” approach.Relatively few RCTs have investigated the effect of IF on inflammatory biomarkers than with CR (6 vs. 15). Analysis of pooled data showed that CR was associated with a significant reduction in CRP with low heterogeneity (SMD −0.15 mg/L [95% CI −0.30 to −0.00], p = 0.04; I2 = 0%, p = 0.69) and IL‐6 with high heterogeneity (SMD −0.31 pg/mL [95% CI −0.51 to −0.10], p = 0.004; I2 = 73%, p = 0.001). IF was associated with a significant decrease in TNF‐alpha with moderate heterogeneity (SMD −0.32 pg/mL [95% CI −0.63 to −0.02], p = 0.04; I2 = 44%, p = 0.13). No associations were detected between IF and CRP or IL‐6 and CR and TNF‐alpha.CR may be more effective in reducing chronic low‐grade inflammation than IF. However, there were some concerns regarding the included studies' randomization and allocation sequence concealment process. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus is a significant global health issue with increasing prevalence worldwide. Aim: This study aims to investigate the potential of Tithonia diversifolia extract (TE) in lowering interleukin-35 (IL-35), tumor necrosis factor-alpha (TNF-α), and hematological profile in streptozotocin (STZ)-induced rats. Methods: A total of 24 rats were divided into four treatment groups: control (P0), diabetic induction (P1), diabetic induction + TE (P2), and diabetic induction + quercetin (P3). Diabetes mellitus was induced by a single-dose injection of stz (60 mg/kg). TE treatment was administered orally for 7 days. On the 8th day post-treatment, all animals were euthanized, and blood samples were collected to assess inflammatory parameters, including IL-35, TNF-α, GPx, and hematological profiles. Kidney organs were fixed in 10% buffered neutral formalin for histopathological analysis. Data were analyzed using ANOVA followed by Duncan's test (p < 0.05). Results: Evaluation of the hematological profile revealed significant improvements in the P2 and P3 groups, with decreased leukocytes, hemoglobin, lymphocytes, and neutrophils, as well as significantly lower IL-35 and TNF-α levels observed in diabetic rats following TE treatment. Conclusion: TE treatment exhibited promising effects in reducing inflammatory markers and restoring hematological parameters in diabetic rats, indicating its potential as a therapeutic agent in diabetic rats. [ABSTRACT FROM AUTHOR]

Objective: To assess the associations between phthalates (PAEs) exposure and the levels of inflammatory cytokines in the ovarian microenvironment. Methods: 64 females who were undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) from April to December in 2020 were included in this cross-sectional study. The levels of 10 kinds of phthalate metabolites (mPAEs) and 2 kinds factors in follicular fluid were measured. Multivariable linear regression model and further stratified analysis by age were conducted to analyze the associations between mPAEs and inflammatory factors. Results: There were significant positive associations between mono-butyl phthalate (MBP) and tumor necrosis factor-α (β=0.446, P=0.003) and interleukin-6 (β=0.425, P=0.003) in the follicular fluid. Similarly, there was a significant positive relationship between mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) and tumor necrosis factor-α（β=0.411, P=0.019). In the stratified analysis, MBP still showed significantly the positive association with tumor necrosis factor-α (β=0.667, P= 0.000) and interleukin-6 (β=0.407, P=0.028) in the group aged≥30 years. In contrast, there were no correlations between mPAEs and inflammatory factors within the group aged ＜30 years. Conclusions: Our results suggest that there is strongly association between PAEs exposure and the altered levels of inflammatory factor, and that PAEs exposure may bring changes of inflammatory burden in the ovarian microenvironment. [ABSTRACT FROM AUTHOR]

Airborne particulate matter (PM) contains polycyclic aromatic hydrocarbons (PAHs) as primary toxic components, causing oxidative damage and being associated with various inflammatory skin pathologies such as premature aging, atopic dermatitis, and psoriasis. Coffee cherry pulp (CCS) extract, rich in chlorogenic acid, caffeine, and theophylline, has demonstrated strong antioxidant properties. However, its specific anti-inflammatory effects and ability to protect macrophages against PAH-induced inflammation remain unexplored. Thus, this study aimed to evaluate the anti-inflammatory properties of CCS extract on RAW 264.7 macrophage cells exposed to atmospheric PAHs, compared to chlorogenic acid (CGA), caffeine (CAF), and theophylline (THP) standards. The CCS extract was assessed for its impact on the production of nitric oxide (NO) and expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Results showed that CCS extract exhibited significant antioxidant activities and effectively inhibited protease and lipoxygenase (LOX) activities. The PAH induced the increase in intracellular reactive oxygen species, NO, TNF-α, IL-6, iNOS, and COX-2, which were markedly suppressed by CCS extract in a dose-dependent manner, comparable to the effects of chlorogenic acid, caffeine, and theophylline. In conclusion, CCS extract inhibits PAH-induced inflammation by reducing pro-inflammatory cytokines and reactive oxygen species (ROS) production in RAW 264.7 cells. This effect is likely due to the synergistic effects of its bioactive compounds. Chlorogenic acid showed strong antioxidant and anti-inflammatory activities, while caffeine and theophylline enhanced anti-inflammatory activity. CCS extract did not irritate the hen's egg chorioallantoic membrane. Therefore, CCS extract shows its potential as a promising cosmeceutical ingredient for safely alleviating inflammatory skin diseases caused by air pollution. [ABSTRACT FROM AUTHOR]

Transgenic T-cell receptor (TCR) T cell-based adoptive cell therapies for solid tumors are associated with dramatic initial response rates, but there remain many instances of treatment failure and disease relapse. The association of infusion product cytokine profiles with clinical response has not been explored in the context of TCR T-cell therapy products. Single-cell antigen-dependent secretomic and proteomic analysis of preinfusion clinical TCR T-cell therapy products revealed that TNFα cytokine functionality of CD8+ T cells and phospho-STAT3 signaling in these cells were both associated with superior clinical responsiveness to therapy. By contrast, CD4+ T-helper 2 cell cytokine profiles were associated with inferior clinical responses. In parallel, preinfusion levels of IL15, Flt3-L, and CX3CL1 were all found to be associated with clinical response to therapy. These results have implications for the development of therapeutic biomarkers and identify potential targets for enrichment in the design of transgenic TCR T-cell therapies for solid tumors.

The contribution of immunoregulatory cytokines to the formation of cold airway hyperresponsiveness in asthma patients is important for understanding approaches to therapy. Aim of the study was to investigate the interaction of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) with bronchial phagocytes in non-allergic asthma patients depending on the airway response to cold air. Material and methods. In 41 patients with asthma, standard monitoring of clinical symptoms of the disease was performed with assessment of the level of asthma control using the Asthma Control Test (ACT) questionnaire, basic spirometry, collection of induced and spontaneously produced sputum, as well as exhaled breath condensate (EBC), and a bronchoprovocation test of isocapnic hyperventilation with cold (–20 ºС) air (IHCA), the content of TNF-α, IFN-γ in EBC and cellular composition of sputum. Results. Cold airway hyperresponsiveness was revealed in 15 patients (group 1), and in 26 patients (group 2) bronchial reaction to IHCA was absent. There were no intergroup differences in the level of asthma control (17.1 ± 0.89 and 18.7 ± 0.63 ACT points, respectively; p > 0.05) and indices of lung function (FEV1 91.2 ± 4.07 and 98.8 ± 2.61 %, respectively; p > 0.05). In response to IHCA in sputum of group 1 patients, the number of neutrophils significantly increased, the number of macrophages, structurally integral epithelial cells decreased, proportionally to this, the level of IFN-γ increased significantly in EBC, TNF-α content did not change. Conclusions. The response to isocapnic hyperventilation with cold air in non-allergic asthma patients with cold airway hyperresponsiveness is characterized by an increase in the level of IFN-γ in the exhaled breath condensate with no significant changes in the content of TNF-α. The increase in the proportion of neutrophils in sputum under the influence of cold stimulus is accompanied by a decrease in the number of macrophages and structurally integral epithelial cells because of inflammatory damage, destruction and cytolysis.

Background/Aims Robust management algorithms are required to reduce the residual risk of colectomy in acute severe ulcerative colitis (ASUC) refractory to standard infliximab salvage therapy. The aim of this study was to evaluate the performance and benefits of alternative ASUC management strategies using simulated prediction models of varying accuracy. Methods This was a simulation-based modeling study using a hypothetical cohort of 5,000 steroid-refractory ASUC patients receiving standard infliximab induction. Simulated predictive models were used to risk-stratify patients and escalate treatment in patients at high risk of failing standard infliximab induction. The main outcome of interest was colectomy by 3 months. Results The 3-month colectomy rate in the base scenario where all 5,000 patients received standard infliximab induction was 23%. The best-performing management strategy assigned high-risk patients to sequential Janus kinase inhibitor inhibition and medium-risk patients to accelerated infliximab induction. Using a 90% area under the curve (AUC) prediction model and optimistic treatment efficacy assumptions, this strategy reduced the 3-month colectomy rate to 8% (65% residual risk reduction). Using an 80% AUC prediction model with only modest treatment efficacy assumptions, the 3-month colectomy rate was reduced to 15% (35% residual risk reduction). Overall management strategy efficacy was highly dependent on predictive model accuracy and underlying treatment efficacy assumptions. Conclusions This is the first study to simulate predictive model-based management strategies in steroid-refractory ASUC and evaluate their effect on short-term colectomy rates. Future studies on predictive model development should incorporate simulation studies to better understand their expected benefit.

Background: L-carnitine (LC), an amino acid-like molecule, has been shown to reduce tumor necrosis factor-alpha (TNF-α), although some research has not confirmed its impact. This study aimed to identify the effects of LC supplementation on TNF-α levels through a systematic review and meta-analysis of randomized controlled trials (RCTs). Methods: This study followed the PRISMA 2020 statement and searched the Web of Science, PubMed, Embase, and Scopus for related papers on LC supplementation’s effects on TNF-α in adults. The meta-analysis was performed using the 17th version of the Stata Statistical Software, and the I2 statistic was used to assess the impact of heterogeneity. The Cochrane risk of bias tool was used to evaluate the risk of bias in the included studies. Results: Seventeen RCTs were included based on the full-text review, and the data from 14 studies were included in the meta-analysis. Based on the results, oral LC did not have a significant impact on TNF-α levels (Cohen’s d: -0.19 [95% CI: -0.71 to 0.33]; I2 : 97.39%). However, parenteral LC had significantly reduced TNF-α levels (Cohen’s d: -1.60 [95% CI: -3.06 to -0.15]; I2 : 88.92%). Oral LC doses of 0.75 and 6 g/day were effective, while duration of LC administration was associated with significant findings in 2, 36, and 48 weeks. The dose and duration of LC administration ineffective independently of TNF-α levels (P = 0.35 and P = 0.70 for dose and duration of administration, respectively). Conclusion: In this meta-analysis, oral LC supplementation failed to be superior to TNF-α blockers.

Abstract Background Schizophrenia is a complex neuropsychiatric disorder. Growing evidence indicates that the activation of the inflammatory response system with interleukin (IL)-2, IL-4, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α) plays an important role in the pathogenesis of schizophrenia,. However, clinical data on cytokine levels in patients with schizophrenia treated with antipsychotics are inconsistent or inconclusive. In this study, we have examined inflammatory factors’ alterations and their relationship to changes in clinical symptoms before and after olanzapine treatment of drug-naive patients with first-episode schizophrenia. Methods We recruited 142 hospitalized patients with first-episode schizophrenia as a study group; blood samples were collected, and the patients were assessed for clinical symptoms at baseline and after 6 weeks of olanzapine treatment. One hundred individuals with no history of mental illness were also recruited as healthy controls. Blood samples were collected, and the serum levels of IL-2, IL-4, IL-8, IL-10, and TNF-α were determined using an enzyme cycling assay. The severity of clinical symptoms was assessed according to the Positive and Negative Syndrome Scale (PANSS). Results Individuals with schizophrenia had lower IL-8 levels and higher IL-10 levels than healthy controls (P

Abstract Objectives Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) is an adhesion molecule that acts as a coinhibitory receptor in the immune system. We previously demonstrated that CEACAM1 is predominantly expressed on peripheral blood neutrophils in patients with RA. The aim of the present study was to investigate the effects of Janus kinase inhibitors (JAKi) on cytokine-activated human neutrophils and CEACAM1 expression. Methods Peripheral blood neutrophils were obtained from healthy subjects. Isolated neutrophils were stimulated with tumor necrosis factor-alpha (TNF-α) or granulocyte–macrophage colony-stimulating factor (GM-CSF) in the presence or absence of JAKi. The expression of CEACAM1 in peripheral blood neutrophils was analyzed by flow cytometry. Protein phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 was assessed by western blot using phospho-specific antibodies. Results We found that TNF-α-induced CEACAM1 expression was marginally suppressed after pretreatment with pan-JAK inhibitor, tofacitinib. Moreover, TNF-α induced STAT1 and STAT3 phosphorylation at the late stimulation phase (4 to 16 h). The expressions of CEACAM1 on neutrophils were markedly up-regulated by GM-CSF not by interleukin (IL)-6 stimulation. All JAKi inhibited GM-CSF-induced CEACAM1 expressions on neutrophils, however, the inhibitory effects of baricitinib were larger compared to those of tofacitinib or filgotinib. Moreover, CEACAM1 was marginally upregulated in interferon (IFN)-γ stimulated neutrophils. Similarly, JAKi inhibited IFN-γ-induced CEACAM1 expressions on neutrophils. Conclusions We demonstrated that JAKi prevent GM-CSF-induced CEACAM1 expression in neutrophils, and JAKi-induced inhibition depends on their selectivity against JAK isoforms. These findings suggest that JAKi can modulate the expression of CEACAM1 in cytokine-activated neutrophils, thereby limiting their activation.

Introduction: Retinoblastoma (RB) is the most common paediatric intraocular malignancy. The Spleen Tyrosine Kinase (SYK) acts as a proto-oncogene crucial for RB cell survival and is absent in the normal retina, making it a valuable therapeutic target. Aim: Entospletinib, a selective oral SYK inhibitor currently in phase 2 trials for chronic lymphocytic leukaemia, was evaluated for its activity on the RB cell line Y-79. Materials and Methods: The effects of Entospletinib on cell proliferation and death of the human RB Y79 cells were assessed by MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, phase contrast microscopy and AO/EtBr dual labeling. The Annexin-V kit was used to quantify the cell mortality following treatment using flow cytometry. The mRNA levels of caspase-3, BAX, BCL-2, SYK, p53, TNF-and NF-κB were measured using RT-PCR to better understand the mechanism of action of this drug. Western blot was used to further validate the data. Results: Entospletinib treatment led to a time- and dose-dependent reduction in cell viability, with significant cytotoxicity observed at an IC50 of 61.3 μM/ml. Annexin V/Propidium Iodide (PI) staining demonstrated a dose-dependent increase in apoptosis. The treatment upregulated mRNA levels of Caspase-3, Bax, and p53 while downregulating SYK, TNF-α, and Bcl-2. RT-PCR and Western blot analyses confirmed a dose-dependent decrease in NF-κB/p65 expression. Conclusion: The study findings suggest that Entospletinib inhibits cell proliferation and induces apoptosis in RB cells by downregulating SYK/TNF-α/NF-κB/p65, highlighting its potential as a promising therapeutic candidate for RB.

OBJECTIVE: To investigate the hepatoprotective effects of Unacylated Ghrelin (UAG) at varying doses in the management of acute liver injury in Wistar albino rats. METHODS: This quasi-experimental study was conducted at Department of Physiology, Isra University, Hyderabad, Pakistan from March to August 2023. Thirty Wistar albino rats (200-250 grams) were randomly divided into five groups (n=6). Group A served as the control, while liver injury was induced in Groups B, C, D, and E via intraperitoneal injection of 0.1% CCl₄. Groups C, D, and E were subsequently treated with low, medium, and high doses of UAG, respectively. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and superoxide dismutase (SOD) levels were assessed, along with liver histopathology. RESULTS: Pre-experimental body weights (Mean±SD) for groups A, B, C, D, and E were 227.33±7.75 g, 229.80±2.08 g, 228.70±5.34 g, 231.33±8.69 g, and 236.38±10.63 g, respectively. The liver index was 4.36±0.28, 6.65±0.37, 5.80±0.17, 5.70±0.08, and 5.06±0.23, respectively, across the groups. A statistically significant (p

Background: Diabetes mellitus is a significant global health issue with increasing prevalence worldwide. Aim: This study aims to investigate the potential of Tithonia diversifolia extract (TE) in lowering interleukin-35 (IL-35), tumour necrosis factor-alpha (TNF-α), and haematological profile in streptozotocin-induced rats. Methods: A total of 24 rats were divided into four treatment groups: control (P0), diabetic induction (P1), diabetic induction + TE (P2), and diabetic induction + quercetin (P3). Diabetes mellitus was induced by a single-dose injection of streptozotocin (60 mg/kg). TE treatment was administered orally for 7 days. On the 8th day post-treatment, all animals were euthanized, and blood samples were collected to assess inflammatory parameters, including IL-35, TNF-α, GPx, and hematological profiles. Kidney organs were fixed in 10% buffered neutral formalin for histopathological analysis. Data were analyzed using ANOVA followed by Duncan's test (p < 0.05). Results: Evaluation of the hematological profile revealed significant improvements in the P2 and P3 groups, with decreased leukocytes, hemoglobin, lymphocytes, and neutrophils, as well as significantly lower IL-35 and TNF-α levels observed in diabetic rats following TE treatment. Conclusion: TE treatment exhibited promising effects in reducing inflammatory markers and restoring hematological parameters in diabetic rats, indicating its potential as a therapeutic agent in diabetic rats. [Open Vet J 2024; 14(9.000): 2250-2255]

Objective: In this systematic review, we determined the association of selected inflammatory cytokines in blood and urine with diabetic nephropathy (DN). Methods: A literature search using the key terms "tumor necrosis factor-alpha," "interferon-gamma," and "diabetic nephropathy" was conducted in PubMed from December 2020 to January 2021. Relevant findings from these studies were collated for qualitative synthesis. Results: Based on the synthesis of results, TNF-α and IFN-γ levels were consistently higher among DN patients than T2DM patients with no renal complications and healthy individuals. A negative correlation with the estimated glomerular filtration rate (eGFR) and a positive correlation with the albumin-to-creatinine ratio (ACR) were also noted by most studies which assessed their relationship with renal markers. Conclusion: The findings of this systematic review suggest the association of serum and urinary TNF-α and IFN-γ levels with diabetic nephropathy. However, further studies must be conducted to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: ACOVID-19, caused by the novel coronavirus SARS-CoV-2, presents with varying severity, from mild symptoms to severe disease, including ARDS and multi-organ failure. Identifying early biochemical markers to predict the severity of COVID-19 is crucial for improving patient outcomes. Aims and Objectives: The study aimed to identify distinct patient groups with COVID-19 and healthy controls using cluster analysis of multiple biomarkers. Specifically, it sought to determine if early detected levels of ferritin, D-dimer, and C-reactive protein (CRP) are associated with the severity of COVID-19. Materials and Methods: Biochemical profiles of sixty patients with SARS-CoV-2 RNA-positive testing and thirty healthy controls were collected and analyzed. Two-dimensional automated hierarchy clustering was performed on all biomarkers. The study focused on alterations in the biochemistry markers ferritin, D-dimer, and CRP. Additionally, levels of inflammatory cytokines, particularly interleukin-6 and tumor necrosis factor-alpha, were measured. Results: Ferritin, D-dimer, and CRP levels were significantly higher in COVID-19 patients compared to the control group. Early detected levels of these biomarkers were associated with a higher incidence of severe COVID-19. Elevated levels of inflammatory cytokines, especially interleukin-6 and tumor necrosis factor-alpha, were also observed in COVID-19 patients, indicating the presence of a cytokine storm, which is a major cause of organ dysfunction and mortality in severe cases. Conclusion: Our findings suggest that elevated levels of ferritin, D-dimer, and CRP are indicative of severe COVID-19. Early detection of these biomarkers can help predict the severity of the infection and guide clinical management. The study also underscores the significant role of inflammatory cytokines in the pathogenesis of COVID-19, contributing to the understanding of the cytokine storm that leads to severe disease outcomes.

Abstract Purpose The most harmful atmospheric pollutant for human health is particulate matter (PM). We analyzed the correlation between short-term lag exposure to PM10 and PM2.5, salivary cortisol and TNF-α level, and methylation levels of the TNF-α promoter. Methods A pilot study including 20 subjects. Eight salivary samples for each subject at various times of the day were collected for comparing cortisol levels and TNFα detection. TNFα promoter methylation levels on salivary DNA were analyzed. Regression analyses were performed using generalized linear mixed models between the different outcomes and 4, 3, 2 and 1 day’s lag values of PM10/PM2.5.Generalized additive mixed model (GAMM) was used to evaluate any potential deviation from linearity. Results Area under the curve with respect to the ground (AUCg) showed a statistically positive association with 4-, 3-, 2-, and 1-day lag of exposure to PM10. Area under the curve with respect to the increase (AUCi) showed a statistically negative association with 4-, 3- and 1-day lag of exposure to PM10. TNFα showed statistically significant association with both exposures, PM10 and PM2.5, at 4-, 3-, 2-, and 1-day lag. Conclusions Regarding cortisol levels there is an increase of overall hormone levels but a less dynamism of the system to answer to external stressors. Increase of TNF-α may reflect increased levels of oxidative stress and inflammation due to pollution exposure.

Abstract Background New evidence suggested that propolis might reduce serum levels of inflammatory mediators; therefore, in this study we aimed to prove the potential effect of propolis on serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) through conducting a systematic review and meta-analysis. Methods Databases including PubMed, ClinicalTrials.gov, Scopus, Cochrane Library, and ISI Web of Science were searched until October 2023. In the present meta-analysis, we detected the overall effect sizes using extracted standard mean differences (SMD) and the standard deviations (SDs) from both study groups through DerSimonian and Laird method. Exploring the statistical heterogeneity was done through Cochran’s Q test and I-squared statistic. Results In total, seventeen and sixteen studies were included in the systematic review and meta-analysis, respectively. The overall estimate indicated that the propolis significantly reduced serum levels of IL-6 (SMD = -3.47, 95% confidence interval (95%CI): -5.1, -1.84; p

Introduction: Chronic obstructive pulmonary disease (COPD) is one of the respiratory diseases in which inflammation plays a key role in its development. Exercise training has acritical role in improving chronic inflammation. Nonetheless, the effects of various exercise training on inflammatory markers in these patients are not clear. Therefore, the present study aimed to assess the impact of exercise on the inflammatory markers, including IL-6, TNF-α, and c-reactive protein in patients with COPD. Material & Methods: A systematic search was conducted on PubMed, Web of Science, SID, Magiran, and Google scholar databases for articles published until July 2023. A meta-analysis was performed for the impact of exercise on inflammatory markers in COPD patients. Effect size (SMD) and 95% confidence interval were calculated using random effect model. Moreover, I2 test was employed to determine heterogeneity, while Funnel plot test and Egger test were used to check publication bias. Results: The results of the data analysis of 11 studies on 578 patients with COPD demonstrated that exercise led to a non-significant decrease in circulating CRP values [SMD=-0.413 (-0.100 to 0.175), P=0.16], IL-6 [SMD=-0.164 (-0.69 to 0.36], P=0.54], TNF-α [SMD=-0.358 (-1.44 to 0.72), P=0.51) in COPD patients. Furthermore, the results of the subgroup analysis pointed out that aerobic training [SMD=-0.55, P=0.1] compared to resistance training [SMD=-0.09, P=0.7] led to a decrease in CRP in patients with COPD. Nonetheless, this difference was not significant. Discussion & Conclusion: The findings of the present meta-analysis illustrated that aerobic exercise is probably an effective exercise intervention to reduce CRP in patients with COPD.

Abstract Background Acute liver failure (ALF) is a life-threatening disorder that progresses from self-limiting acute liver injury (ALI). Microcirculatory disturbance characterized by sinusoidal hypercoagulation and subsequent massive hypoxic hepatocyte damage have been proposed to be the mechanism by which ALI deteriorates to ALF; however, the precise molecular pathway of the sinusoidal hypercoagulation remains unknown. Here, we analyzed ALI patients and mice models to uncover the pathogenesis of ALI with microcirculatory disturbance. Methods We conducted a single-center retrospective study for ALI and blood samples and liver tissues were analyzed to evaluate the microcirculatory disturbance in ALI patients (n = 120). Single-cell RNA sequencing analysis (scRNA-seq) was applied to the liver from the concanavalin A (Con A)‑induced mouse model of ALI. Interferon-gamma (IFNγ) and tumor necrosis factor-alpha knockout mice, and primary human liver sinusoidal endothelial cells (LSECs) were used to assess the mechanism of microcirculatory disturbance. Results The serum IFNγ concentrations were significantly higher in ALI patients with microcirculatory disturbance than in patients without microcirculatory disturbance, and the IFNγ was upregulated in the Con A mouse model which presented microcirculatory disturbance. Hepatic IFNγ expression was increased as early as 1 hour after Con A treatment prior to sinusoidal hypercoagulation and hypoxic liver damage. scRNA-seq revealed that IFNγ was upregulated in innate lymphoid cells and stimulated hepatic vascular endothelial cells at the early stage of liver injury. In IFNγ knockout mice treated with Con A, the sinusoidal hypercoagulation and liver damage were remarkably attenuated, concomitant with the complete inhibition of CD40 and tissue factor (TF) upregulation in vascular endothelial cells. By ligand-receptor analysis, CD40-CD40 ligand interaction was identified in vascular endothelial cells. In human LSECs, IFNγ upregulated CD40 expression and TF was further induced by increased CD40-CD40 ligand interaction. Consistent with these findings, hepatic CD40 expression was significantly elevated in human ALI patients with microcirculatory disturbance. Conclusion We identified the critical role of the IFNγ-CD40 axis as the molecular mechanism of microcirculatory disturbance in ALI. This finding may provide novel insights into the pathogenesis of ALI and potentially contribute to the emergence of new therapeutic strategies for ALI patients.

Objective: Neutrophil extracellular traps (NETs) are important factors in initiating and perpetuating inflammation. However, the role of NETs in different subtypes of juvenile idiopathic arthritis (JIA) has been rarely studied. Therefore, we aimed to explore the ability of JIA-derived neutrophils to release NETs and the effect of TNF-α (tumor necrosis factor-alpha) inhibitors on NET formation both in vitro and in vivo, and evaluate the associations of NET-derived products with clinical and immune-related parameters. Methods: The ability of neutrophils to release NETs and the effect of adalimumab on NET formation was assessed via in vitro stimulation and inhibition studies. Plasma NET-derived products were detected to assess the incidence of NET formation in vivo. Furthermore, flow cytometry and western blotting were used to detect NET-associated signaling components in neutrophils. Results: Compared to those derived from HCs, neutrophils derived from patients with oligoarticular-JIA, polyarticular-JIA and enthesitis-related arthritis were more prone to generate NETs spontaneously and in response to TNF-α or PMA in vitro. Excessive NET formation existed in peripheral circulation of JIA patients, and elevated plasma levels of NET-derived products (cell-free DNA and MPO-DNA complexes) could accurately distinguish JIA patients from HCs and were positively correlated with disease activity. Multiple linear regression analysis showed that erythrocyte sedimentation rate and TNF-a levels were independent variables and were positively correlated with cell-free DNA concentration. Notably, TNF-a inhibitors could effectively prevent NET formation both in vitro and in vivo. Moreover, the phosphorylation levels of NET-associated kinases in JIA-derived neutrophils were markedly increased. Conclusion: Our data suggest that NETs might play pathogenic roles and may be involved in TNF-α-mediated inflammation in JIA. Circulating NET-derived products possess potential diagnostic and disease monitoring value. Furthermore, the preliminary results related to the molecular mechanisms of NET formation in JIA patients provide a theoretical basis for NETtargeted therapy. [ABSTRACT FROM AUTHOR]

Background: New evidence suggested that propolis might reduce serum levels of inflammatory mediators; therefore, in this study we aimed to prove the potential effect of propolis on serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) through conducting a systematic review and meta-analysis. Methods: Databases including PubMed, ClinicalTrials.gov, Scopus, Cochrane Library, and ISI Web of Science were searched until October 2023. In the present meta-analysis, we detected the overall effect sizes using extracted standard mean differences (SMD) and the standard deviations (SDs) from both study groups through DerSimonian and Laird method. Exploring the statistical heterogeneity was done through Cochran's Q test and I-squared statistic. Results: In total, seventeen and sixteen studies were included in the systematic review and meta-analysis, respectively. The overall estimate indicated that the propolis significantly reduced serum levels of IL-6 (SMD = -3.47, 95% confidence interval (95%CI): -5.1, -1.84; p < 0.001), CRP (SMD= -1.73, 95%CI: -2.82, -0.65; p = 0.002), and TNF-α (SMD= -1.42, 95%CI= -2.15, -0.68; p < 0.001). These results also revealed geographical region and propolis dose were the critical points to get the beneficial effects. Conclusion: According to our result, propolis supplementation can decrease serum levels of IL-6, CRP, and TNF-α; therefore, it might be considered as complementary therapy for the treatment of certain chronic diseases. [ABSTRACT FROM AUTHOR]

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Skin is the forestage for a series of many-sided functions of tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine with staggering versatility and sizable implications for tissue homeostasis, immune responses, angiogenesis, apoptosis, local and systemic inflammation. An aberrant TNF-α-mediated crosstalk has been linked to the pathogenesis of acute and chronic skin inflammatory diseases, and indeed, TNF-α dysregulation can contribute to the development and progression of psoriasis, vitiligo, local damage following exposition to ultraviolet light radiations, cutaneous lupus erythematosus, and acne vulgaris. Therapies that target TNF-α are conspicuously used in the treatment of different skin disorders, aiming to modulate the in vivo immune functions triggered by many cutaneous cells, including keratinocytes, mast cells, or Langerhans cells, and reduce inflammation taking place within the skin. Herein, we focus on the key relationships between TNF-α and distinct skin non-neoplastic inflammatory or physiologic conditions, showing that a natural induction of TNF-α may have a protective significance but that TNF-α overproduction may be harmful or even lethal. Many questions remain unraveled in the therapeutic practice, and caution should be exercised due to eventual backlashes exerted by TNF-α in maintaining skin health or in provoking skin disease. [ABSTRACT FROM AUTHOR]

Background: Osteoarticular tuberculosis represents 9-20% of extrapulmonary forms and spinal tuberculosis is its most common form. Clinical cases: We present three cases of tuberculous spondylitis in patients aged 22, 36 and 68 years, with 8, 6 and 6 months of evolution and with involvement of L5-S1, T7-T8 and T5-T6, respectively. The two younger patients had disc involvement, and in the first case a pyogenic abscess was initially suspected. Local pain was the initial symptom and the 2 older patients developed inability to walk and urinary and fecal incontinence. The patients received a complete anti-tuberculosis regimen and the postoperative evolution was satisfactory. All showed expression of tumor necrosis factor in the epithelioid and giant cells of the granulomas and activation of nuclear factor ß in the accompanying lymphocytes. Conclusions: The persistence of localized spinal pain, with or without local volume increase, should alert the physician to the possibility of a spinal infectious process, including tuberculosis. [ABSTRACT FROM AUTHOR]

Hemorrhoids are the most common anorectal disorder associated with the abnormal swelling and dilatation of the venous canal, leading to rectal bleeding and the prevalent figure of hemorrhoids is around 37 % worldwide. The major symptoms include prolapsing of mass, constipation, bleeding, and swelling in the anorectal region. A sedentary lifestyle, obesity, reduced fiber diets and low physical activity are some of the major causes of hemorrhoids. However, the rising demand for synthetic chemicals has several unintended consequences that have a substantial impact on the emergence of various illnesses. The current study investigated the antihemorrhoidal ability of the ethanolic extract of Laurus nobilis in high and low doses against the croton oil caused hemorrhoids model. Himalayan pilex pills (an ayurvedic treatment) were utilized as the benchmark drug for comparing all of the results and findings. The phytochemical screening revealed the presence of alkaloids, glycosides, flavonoids, tannins, saponins, phenols, volatile oils and steroids. The anti-hemorrhoidal potential was measured by evaluating blood parameters, inflammatory parameters, recto-anal coefficient and histological parameters was assessed. It was found that the hydroalcoholic leaf extract of Laurus nobilis demonstrated potential anti-hemorrhoidal activity with recto-anal coefficient 1.86±0.04 at the dose of 300 mg/kg and 1.94±0.05 at the dose of 150 mg/kg. The extract also demonstrated an increase in the mean hemoglobin level in the low-dose extract (150 mg/kg) group and the high-dose extract (300 mg/kg) group with values of 7.61±0.81 and 8.99±0.65 (g/dl), respectively. The extract also decreased the levels of tumor necrosis factor-a and interleukin-6. Tumor necrosis factor-alpha decreased to 442.47±71.22 at a low dose (150 mg/kg), whereas for a high dose (300 mg/kg) the tumor necrosis factor-a value was found to be 335.85±82.43. The groups treated with the low dose extract showed the interleukin-6 value of 84.72±3.02 and the group treated with high dose extract depicted the mean value of interleukin-6 at 67.85±1.38. It was also found that a high dose (300 mg/kg) of Laurus nobilis extract exhibited a better therapeutic effect than a low dose (150 mg/kg) of Laurus nobilis extract. Pilex, the standard drug, demonstrated better results than the leaf extract. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's disease (PD) is characterized by dopamine deficiency in the corpus striatum due to the degeneration of dopaminergic neurons in the substantia nigra. Symptoms include bradykinesia, resting tremors, unstable posture, muscular rigidity, and a shuffled gait. Thalictrum foetidum is traditionally used for neurodegenerative disorders. Objectives: This study aimed to explore the therapeutic potential of aqueous ethanolic extract of Thalictrum foetidum (AETF) against Parkinson-like symptoms and to investigate its underlying mechanism. Methodology: Thirty-six albino mice were randomly divided into 6 groups (n = 6): normal control, disease control, standard treatment (levodopa/carbidopa, 100/25 mg/kg), and 3 treatment groups (AETF at 200, 400, and 600 mg/kg). One hour before treatment, haloperidol (1 mg/kg, i. p.) was administered to induce Parkinson's disease in all groups except the normal control group. Results: Behavioral analysis showed significant improvement (P <.001) in motor function, muscular coordination, and reduced muscular rigidity and tremors. AETF also reduced oxidative stress. Histological examination of the brain showed reduced Lewy bodies, neurofibrillary tangles, and plaque formation. Conclusion: AETF alleviated PD symptoms by reducing neurodegeneration, modulating oxidative stress, and inhibiting the expression of nuclear factor-κB (NF-κB) and associated inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). [ABSTRACT FROM AUTHOR]

Background/Aim. Chronic pulpitis (CP) is an inflammatory dental pulp disorder associated with various pathophysiological mechanisms in its origin. The aim of the study was to evaluate the changes in the pulp tissue of osteoprotegerin (OPG) and tumor necrosis factor (TNF)-α and establish their relationship with the histological changes of pulp tissue, as well as with the micromorphological changes, occurring in the mineralized tissue. Methods. The study examined the dental pulp of 41 patients with CP and 12 healthy individuals. The group of the diseased subjects was subdivided based on the presence of communication of the pulp with the oral cavity, i.e., open (n = 22) or closed (clausa) (n = 19) CP. Results. The levels of TNF-α were statistically significantly increased, while OPG levels were decreased in the pulp of patients with CP, compared to the control group. TNF-α levels were almost the same in the pulp of patients with closed CP and the control group, while values were significantly increased in those with open CP compared to control. Histopathological analysis showed a significant increase in the number of mononuclear inflammatory cells in the diseased pulp. Scanning electron microscopy showed distinct changes, which correlate with internal resorption. Conclusion. The results indicate a much greater and intensified process of root resorption in patients with closed CP, which is unassociated with dental pulp OPG and TNF-α level changes. [ABSTRACT FROM AUTHOR]

Endometrial hyperplasia (EH), an abnormal proliferation of the endometrial cells, is considered as one of the most common causes of abnormal uterine bleeding. Previous studies have reported that melatonin plays a fundamental role in disease treatment. This study aimed the comparison of the effects of progesterone, as the most common therapeutic approach, and melatonin with progesterone alone in improvement of non-atypical endometrial hyperplasia (NEH) and changes in pro-inflammatory cytokine levels. Study population consisted of 40 patients with NEH. Patients were divided into two groups, including 20 subjects treated with melatonin and progesterone and 20 individuals treated with progesterone alone. The blood and endometrial sampling was performed from participants before and after a three-month treatment. The histological examination was microscopically done. The serum levels of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) were measured using ELISA. There was no significant difference in the diabetes status and mean age between patients treated with progesterone and melatonin and those treated with progesterone alone. The improvement rate in the EH was significantly higher in individuals treated with progesterone and melatonin than those treated with progesterone alone (p < 0.05). Additionally, the patients treated with progesterone and melatonin showed significant increases inIFN-γ and TNF-αlevels compared to the control group (p < 0.001-P < 0.05). Melatonin supplementation has a beneficial effect in the treatment of EH due perhaps to enhance the level of IFN-γ and TNF-α. [ABSTRACT FROM AUTHOR]

Background: Implant dentistry has become increasingly prevalent, with complications such as peri-implantitis posing challenges. Tumor necrosis factor-alpha (TNF-α) has been implicated in the inflammatory response around dental implants, akin to its role in periodontal diseases. Evaluating TNF-α levels in peri-implant tissues compared to healthy tooth tissues could provide insights into the inflammatory environment and aid in clinical management. Materials and Methods: A cross-sectional study was conducted involving 50 participants with dental implants and healthy adjacent teeth. Peri-implant mucosal samples and gingival tissue around healthy teeth were collected. TNF-α levels were quantified using enzyme-linked immunosorbent assay (ELISA) kits. Statistical analysis was performed to compare TNF-α concentrations between peri-implant tissues and healthy tooth tissues. Results: The mean TNF-α level in peri-implant tissues was found to be 120 pg/mL (standard deviation ± 25 pg/mL), whereas in healthy tooth tissues, it was 60 pg/mL (standard deviation ± 15 pg/mL). Statistical analysis revealed a significant difference (p < 0.05) in TNF-α levels between peri-implant tissues and healthy tooth tissues. Conclusion: Elevated levels of TNF-α in peri-implant tissues suggest a heightened inflammatory response compared to healthy tooth tissues. This underscores the potential role of TNF-α in peri-implantitis pathogenesis and emphasizes the importance of monitoring inflammatory biomarkers for early detection and targeted intervention in implant dentistry. [ABSTRACT FROM AUTHOR]

Muscle fatigue represents the most prevalent symptom of long-term COVID, with elusive pathogenic mechanisms. We performed a longitudinal study to characterize histopathological and transcriptional changes in skeletal muscle in a hamster model of respiratory SARS-CoV-2 infection and compared them with influenza A virus (IAV) and mock infections. Histopathological and bulk RNA sequencing analyses of leg muscles derived from infected animals at days 3, 30, and 60 post-infection showed no direct viral invasion but myofiber atrophy in the SARS-CoV-2 group, which was accompanied by persistent downregulation of the genes related to myofibers, ribosomal proteins, fatty acid β-oxidation, tricarboxylic acid cycle, and mitochondrial oxidative phosphorylation complexes. While both SARS-CoV-2 and IAV infections induced acute and transient type I and II interferon responses in muscle, only the SARS-CoV-2 infection upregulated TNF-α/NF-κB but not IL-6 signaling in muscle. Treatment of C2C12 myotubes, a skeletal muscle cell line, with combined IFN-γ and TNF-α but not with IFN-γ or TNF-α alone markedly impaired mitochondrial function. We conclude that a respiratory SARS-CoV-2 infection can cause myofiber atrophy and persistent energy metabolism suppression without direct viral invasion. The effects may be induced by the combined systemic interferon and TNF-α responses at the acute phase and may contribute to post-COVID-19 persistent muscle fatigue. [ABSTRACT FROM AUTHOR]

Background: Acute liver failure (ALF) is a life-threatening disorder that progresses from self-limiting acute liver injury (ALI). Microcirculatory disturbance characterized by sinusoidal hypercoagulation and subsequent massive hypoxic hepatocyte damage have been proposed to be the mechanism by which ALI deteriorates to ALF; however, the precise molecular pathway of the sinusoidal hypercoagulation remains unknown. Here, we analyzed ALI patients and mice models to uncover the pathogenesis of ALI with microcirculatory disturbance. Methods: We conducted a single-center retrospective study for ALI and blood samples and liver tissues were analyzed to evaluate the microcirculatory disturbance in ALI patients (n = 120). Single-cell RNA sequencing analysis (scRNA-seq) was applied to the liver from the concanavalin A (Con A)‑induced mouse model of ALI. Interferon-gamma (IFNγ) and tumor necrosis factor-alpha knockout mice, and primary human liver sinusoidal endothelial cells (LSECs) were used to assess the mechanism of microcirculatory disturbance. Results: The serum IFNγ concentrations were significantly higher in ALI patients with microcirculatory disturbance than in patients without microcirculatory disturbance, and the IFNγ was upregulated in the Con A mouse model which presented microcirculatory disturbance. Hepatic IFNγ expression was increased as early as 1 hour after Con A treatment prior to sinusoidal hypercoagulation and hypoxic liver damage. scRNA-seq revealed that IFNγ was upregulated in innate lymphoid cells and stimulated hepatic vascular endothelial cells at the early stage of liver injury. In IFNγ knockout mice treated with Con A, the sinusoidal hypercoagulation and liver damage were remarkably attenuated, concomitant with the complete inhibition of CD40 and tissue factor (TF) upregulation in vascular endothelial cells. By ligand-receptor analysis, CD40-CD40 ligand interaction was identified in vascular endothelial cells. In human LSECs, IFNγ upregulated CD40 expression and TF was further induced by increased CD40-CD40 ligand interaction. Consistent with these findings, hepatic CD40 expression was significantly elevated in human ALI patients with microcirculatory disturbance. Conclusion: We identified the critical role of the IFNγ-CD40 axis as the molecular mechanism of microcirculatory disturbance in ALI. This finding may provide novel insights into the pathogenesis of ALI and potentially contribute to the emergence of new therapeutic strategies for ALI patients. [ABSTRACT FROM AUTHOR]

Objective To explore the pathological features of lung tissue in mild chronic obstructive pulmonary disease (COPD) and their association with inflammatory factors. Methods A total of 70 patients who underwent surgery for small lung nodule were prospectively included, and were divided into the normal group (n=10), the mild COPD group (n=50) and the moderate and severe COPD group (n=10). The pathological changes of lung tissue were evaluated after HE, Masson and EVG staining. The expression levels of SMA, Actin and CD31 proteins were detected by immunohistochemistry staining. Tumor necrosis factor α (TNF-α), interleukin-10 (IL-10) protein and mRNA levels were detected by immunohistochemistry and qPCR. Results Pulmonary tissue in mild COPD showed widening of alveolar septum, dilation of small airways, mild thickening of blood vessel wall and inflammatory reaction dominated by lymphocyte infiltration. Immunohistochemistry staining showed that contents of SMA and Actin proteins in mild COPD lung tissue were higher than those in the normal group (P＜0.05). In addition, the TNF- α mRNA and the positive rate of TNF- α in lung tissue of mild COPD were significantly higher than those in the normal group, while the IL-10 mRNA was significantly lower than that of the normal group (all P＜0.05). SMA and Actin were positively correlated with the positive expression of inflammatory cytokine TNF-α, but negatively correlated with the positive expression of IL-10 (all P＜0.05). Conclusion The main pathological changes of lung tissue in mild COPD include small lung blood vessel remodeling ocharacterized by thickening of small blood vessel smooth muscle layer and lymphocyte-dominated inflammatory response, while the increase of pro-inflammatory factor TNF-α and decrease of anti-inflammatory factor IL-10 are associated with pathological changes of COPD. [ABSTRACT FROM AUTHOR]

Introduction: Chronic obstructive pulmonary disease (COPD) is one of the respiratory diseases in which inflammation plays a key role in its development. Exercise training has acritical role in improving chronic inflammation. Nonetheless, the effects of various exercise training on inflammatory markers in these patients are not clear. Therefore, the present study aimed to assess the impact of exercise on the inflammatory markers, including IL-6, TNF-α, and c-reactive protein in patients with COPD. Material & Methods: A systematic search was conducted on PubMed, Web of Science, SID, Magiran, and Google scholar databases for articles published until July 2023. A meta-analysis was performed for the impact of exercise on inflammatory markers in COPD patients. Effect size (SMD) and 95% confidence interval were calculated using random effect model. Moreover, I2 test was employed to determine heterogeneity, while Funnel plot test and Egger test were used to check publication bias. Results: The results of the data analysis of 11 studies on 578 patients with COPD demonstrated that exercise led to a non-significant decrease in circulating CRP values [SMD=-0.413 (-0.100 to 0.175), P=0.16], IL-6 [SMD=-0.164 (-0.69 to 0.36], P=0.54], TNF-α [SMD=-0.358 (-1.44 to 0.72), P=0.51) in COPD patients. Furthermore, the results of the subgroup analysis pointed out that aerobic training [SMD=-0.55, P=0.1] compared to resistance training [SMD=-0.09, P=0.7] led to a decrease in CRP in patients with COPD. Nonetheless, this difference was not significant. Discussion & Conclusion: The findings of the present meta-analysis illustrated that aerobic exercise is probably an effective exercise intervention to reduce CRP in patients with COPD. [ABSTRACT FROM AUTHOR]