Related Inflammatory Response Research Articles

Single-Cell Transcriptomics Reveals the Ameliorative Effect of Oridonin on Septic Liver Injury.

Sepsis is a life-threatening syndrome leading to hemodynamic instability and potential organ dysfunction. Oridonin, commonly used in Traditional Chinese Medicine (TCM), exhibits significant anti-inflammation activity. To explore the protective mechanisms of oridonin against the pathophysiological changes, the authors conducted single-cell transcriptome (scRNA-seq) analysis on septic liver models induced by cecal ligation and puncture (CLP). They obtained a total of 63,486 cells, distributed across 11 major cell clusters, and concentrated their analysis on four specific clusters (hepatocytes/Heps, macrophages, endothelial/Endos and T/NK) based on their changes in proportion during sepsis and under oridonin treatment. Firstly, biological changes in Hep, which are related to metabolic dysregulation and pro-inflammatory signaling, are observed during sepsis. Secondly, they uncovered the dynamic profiles of macrophage's phenotype, indicating that a substantial number of macrophages exhibited a M1-skewed phenotype associated with pro-inflammatory characteristics in septic model. Thirdly, they detected an upregulation of both inflammatory cytokines and transcriptomic factor Nfkb1 expression within Endo, along with slight capillarization during sepsis. Moreover, excessive accumulation of cytotoxic NK led to an immune imbalance. Though, oridonin ameliorated inflammatory-related responses and improved the liver dysfunction in septic mice. This study provides fundamental evidence of the protective effects of oridonin against sepsis-induced cytokine storm.

Bioinformatics Analysis of the Molecular Networks Associated with the Amelioration of Aberrant Gene Expression by a Tyr-Trp Dipeptide in Brains Treated with the Amyloid-β Peptide.

Short-chain peptides derived from various protein sources have been shown to exhibit diverse bio-modulatory and health-promoting effects in animal experiments and human trials. We recently reported that the oral administration of the Tyr-Trp (YW) dipeptide to mice markedly enhances noradrenaline metabolism in the brain and ameliorates the working-memory deficits induced by the β-amyloid 25-35 peptide (Aβ25-35). In the current study, we performed multiple bioinformatics analyses of microarray data from Aβ25-35/YW-treated brains to determine the mechanism underlying the action of YW in the brain and to infer the molecular mechanisms and networks involved in the protective effect of YW in the brain. We found that YW not only reversed inflammation-related responses but also activated various molecular networks involving a transcriptional regulatory system, which is mediated by the CREB binding protein (CBP), EGR-family proteins, ELK1, and PPAR, and the calcium-signaling pathway, oxidative stress tolerance, and an enzyme involved in de novo l-serine synthesis in brains treated with Aβ25-35. This study revealed that YW has a neuroprotective effect against Aβ25-35 neuropathy, suggesting that YW is a new functional-food-material peptide.

Morphofunctional Changes in the Thymus in Prepubertal Male Wistar Rats in LPS-Induced Systemic Inflammatory Response in Relation to Hypoxia Tolerance.

The dynamics of morphofunctional changes in the thymus during the LPS-induced systemic inflammatory response was assessed in prepubertal male Wistar rats in relationship with the resistance to hypoxia. The systemic inflammatory response was modeled by intraperitoneal administration of E. coli O26:B6 LPS. In histological sections of the thymus, the relative number of thymic bodies and proliferative activity of cells were evaluated. The relative number of CD3+CD4+, CD3+CD8+, and CD4+CD8+ cells in the thymus was determined by flow cytometry. The content of HIF-1α and endotoxin was determined in the blood serum. The expression level of Nfkb mRNA was assessed in the liver. The most pronounced changes in the indicators of the functional state of the thymus were detected 3 and 6 h after LPS administration following the increase in the content of HIF-1α and endotoxin in blood serum and Nfkb mRNA expression in the liver. In the thymus, a decrease in the number of thymic bodies consisting of 3-5 epithelial cells and an increase in the number of bodies consisting of 5 or more cells was observed. In 24 h after LPS administration, the relative number of CD3+CD4+ and CD3+CD8+ cells in the thymus decreased. At the same time, the number of Ki-67+ cells in the subcapsular zone of the thymus increased 6 and 24 h after LPS administration. These data should be taken into account in the development of approaches to the treatment of infectious and inflammatory diseases in prepubertal children.

Insights gained from single-cell analysis of immune cells in tofacitinib treatment of Vogt-Koyanagi-Harada disease.

Vogt-Koyanagi-Harada disease (VKH) is an important refractory uveitis mediated by pathological T cells (TCs). Tofacitinib (TOFA) is a JAK- targeted therapy for several autoimmune diseases. However, the specific pathogenesis and targeted therapeutics for VKH remain largely unknown. Based on single-cell RNA sequencing and mass cytometry, we present what we believe is the first multimodal, high-dimensional analysis to generate a comprehensive human immune atlas regarding subset composition, gene signatures, enriched pathways, and intercellular interactions of VKH patients undergoing TOFA therapy. Patients with VKH are characterized by TCs' polarization from naive to effector and memory subsets, together with accrued monocytes and upregulated cytokines and JAK/STAT signaling pathways. In vitro, TOFA reversed Th17/Treg imbalance and inhibited IL-2-induced STAT1/3 phosphorylation. TOFA alleviated VKH symptoms by restoring pathological TCs' polarization and functional marker expression and downregulating cytokine signaling and lymphocyte function. Remarkably, inflammation-related responses and intercellular interactions decreased after TOFA treatment, particularly in monocytes. Notably, we identified 2 inflammation- and JAK-associated monocyte subpopulations that were strongly implicated in VKH pathogenesis and mechanisms involved in TOFA treatment. Here, we provide a potentially novel JAK-targeted therapy for VKH and elaborate on the possible therapeutic mechanisms of TOFA, expanding our knowledge of VKH pathological patterns.

September 2022 Stroke Highlights

September 2022 <i>Stroke</i> Highlights

The SIRT1-HMGB1 axis: Therapeutic potential to ameliorate inflammatory responses and tumor occurrence

Inflammation is a common complication of many chronic diseases. It includes inflammation of the parenchyma and vascular systems. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, which can directly participate in the suppression of inflammation. It can also regulate the activity of other proteins. Among them, high mobility group box 1 (HMGB1) signaling can be inhibited by deacetylating four lysine residues (55, 88, 90, and 177) in quiescent endothelial cells. HMGB1 is a ubiquitous nuclear protein, once translocated outside the cell, which can interact with various target cell receptors including the receptor for advanced glycation end-products (RAGE), toll-like receptor (TLR) 2, and TLR4 and stimulates the release of pro-inflammatory cyto-/chemokines. And SIRT1 has been reported to inhibit the activity of HMGB1. Both are related to the occurrence and development of inflammation and associated diseases but show an antagonistic relationship in controlling inflammation. Therefore, in this review, we introduce how this signaling axis regulates the emergence of inflammation-related responses and tumor occurrence, providing a new experimental perspective for future inflammation research. In addition, it explores diverse upstream regulators and some natural/synthetic activators of SIRT1 as a possible treatment for inflammatory responses and tumor occurrence which may encourage the development of new anti-inflammatory drugs. Meanwhile, this review also introduces the potential molecular mechanism of the SIRT1-HMGB1 pathway to improve inflammation, suggesting that SIRT1 and HMGB1 proteins may be potential targets for treating inflammation.

Celecoxib alleviates denervation-induced muscle atrophy by suppressing inflammation and oxidative stress and improving microcirculation

The molecular mechanism underlying denervation-induced muscle atrophy is complex and incompletely understood. Our previous results suggested that inflammation may play an important role in the early stages of muscle atrophy. Celecoxib is reported to exert anti-inflammatory effects. Here, we explored the effect of celecoxib on denervation-induced muscle atrophy and sought to identify the mechanism involved. We found that celecoxib treatment significantly increased the wet weight ratio and CSA of the tibialisanteriormuscle. Additionally, celecoxib downregulated the levels of COX-2, inflammatory factors and reduced inflammatory cell infiltration. GO and KEGG pathway enrichment analysis indicated that after 3 days of celecoxib treatment in vivo, the differentially expressed genes (DEGs) were mainly associated with the regulation of immune responses related to complement activation; after 14 days, the DEGs were mainly involved in the regulation of oxidative stress and inflammation-related responses. Celecoxib administration reduced the levels of ROS and oxidative stress-related proteins. Furthermore, we found that celecoxib treatment inhibited the denervation-induced up-regulation of the ubiquitin–proteasome and autophagy–lysosomal systems related proteins; decreased mitophagy in target muscles; and increased levels of MHC. Finally, celecoxib also attenuated microvascular damage in denervated skeletal muscle. Combined, our findings demonstrated that celecoxib inhibits inflammation and oxidative stress in denervated skeletal muscle, thereby suppressing mitophagy and proteolysis, improving blood flow in target muscles, and, ultimately, alleviating denervation-induced muscle atrophy. Our results confirmed that inflammatory responses play a key role in denervation-induced muscle atrophy and highlight a novel strategy for the prevention and treatment of this condition.

Body weight index indicates the responses of the fecal microbiota, metabolome and proteome to beef/chicken-based diet alterations in Chinese volunteers

Relationships between meat consumption and gut diseases have been debated for decades, and the gut microbiota plays an important role in this interplay. It was speculated that the gut microbiota and relevant indicators of hosts with different body weight indexes (BMIs) might respond differentially to meat-based diet alterations, since lean and obese hosts have different gut microbiota composition. Forty-five young Chinese volunteers were recruited and assigned to high-, middle- and low-BMI groups. All of the volunteers were given a beef-based diet for 2 weeks and subsequently with a chicken-based diet for another 2 weeks. Body weight and blood indexes were measured, and fecal samples were obtained for 16S rRNA sequencing, metabolome and proteome analyses. The fecal metabolites of the low-BMI volunteers showed greater sensitivity to meat-based diet alterations. In contrast, the fecal proteome profiles and blood indexes of the high- and middle-BMI volunteers indicated greater sensitivity to meat-based diet alterations. Replacing the beef-based diet with the chicken-based diet largely changed operational taxonomic units of Bacteroides genus, and thus probably induced downregulation of immunoglobulins in feces. Compared with the beef-based diet, the chicken-based diet decreased inflammation-related blood indexes, especially in high- and middle-BMI volunteers. This work highlighted the role of BMI as an important factor predicting changes in gut homeostasis in response to meat consumption. Compared with the chicken-based diet, the beef-based diet may induce more allergic and inflammation-related responses in high- and middle- BMI Chinese at the current level.

Cannabidiol and periodontal inflammatory disease: A critical assessment.

Cannabidiol (CBD), a non-psychotropic cannabinoid produced by the genus Cannabis, is a phytoceutical that activates the endocannabinoid system (ECS) through binding to CB1 and CB2 receptors. The ECS is involved in cellular homeostasis and regulates metabolic processes in virtually all mammalian tissues. Published studies on CBD focus, inter alia, on its use in prophylaxis and as an anti-inflammatory agent. Here the authors present a critical assessment of the effects of CBD on inflammatory periodontal diseases caused by bacterial virulence factors, and evaluate critically the possible benefits and drawbacks of CBD use in dentistry. Particular attention is paid to the interaction of CBD with microbially colonized oral tissues, the inflammatory response in relation to the immune response, and the destruction/regeneration of hard and soft tissues of the periodontium.

Integration of segmented regression analysis with weighted gene correlation network analysis identifies genes whose expression is remodeled throughout physiological aging in mouse tissues.

Gene expression alterations occurring with aging have been described for a multitude of species, organs, and cell types. However, most of the underlying studies rely on static comparisons of mean gene expression levels between age groups and do not account for the dynamics of gene expression throughout the lifespan. These studies also tend to disregard the pairwise relationships between gene expression profiles, which may underlie commonly altered pathways and regulatory mechanisms with age. To overcome these limitations, we have combined segmented regression analysis with weighted gene correlation network analysis (WGCNA) to identify high-confidence signatures of aging in the brain, heart, liver, skeletal muscle, and pancreas of C57BL/6 mice in a publicly available RNA-Seq dataset (GSE132040). Functional enrichment analysis of the overlap of genes identified in both approaches showed that immune- and inflammation-related responses are prominently altered in the brain and the liver, while in the heart and the muscle, aging affects amino and fatty acid metabolism, and tissue regeneration, respectively, which reflects an age-related global loss of tissue function. We also explored sexual dimorphism in the aging mouse transcriptome and found the liver and the muscle to have the most pronounced gender differences in gene expression throughout the lifespan, particularly in proteostasis-related pathways. While the data showed little overlap among the age-dysregulated genes between tissues, aging triggered common biological processes in distinct tissues, which we highlight as important features of murine tissue physiological aging.

GABAergic signaling in human and murine NK cells upon challenge with Toxoplasma gondii.

Protective cytotoxic and proinflammatory cytokine responses by NK cells impact the outcome of infections by Toxoplasma gondii, a common parasite in humans and other vertebrates. However, T. gondii can also sequester within NK cells and downmodulate their effector functions. Recently, the implication of GABA signaling in infection and inflammation-related responses of mononuclear phagocytes and T cells has become evident. Yet, the role of GABAergic signaling in NK cells has remained unknown. Here, we report that human and murine NK cells synthesize and secrete GABA in response to infection challenge. Parasitized NK cells secreted GABA, whereas activation stimuli, such as IL-12/IL-18 or parasite lysates, failed to induce GABA secretion. GABA secretion by NK cells was associated to a transcriptional up-regulation of GABA synthesis enzymes (glutamate decarboxylases [GAD65/67]) and was abrogated by GAD inhibition. Further, NK cells expressed GABA-A receptor subunits and GABA signaling regulators, with transcriptional modulations taking place upon challenge with T. gondii. Exogenous GABA and GABA-containing supernatants from parasitized dendritic cells (DCs) impacted NK cell function by reducing the degranulation and cytotoxicity of NK cells. Conversely, GABA-containing supernatants from NK cells enhanced the migratory responses of parasitized DCs. This enhanced DC migration was abolished by GABA-A receptor antagonism or GAD inhibition and was reconstituted by exogenous GABA. Jointly, the data show that NK cells are GABAergic cells and that GABA hampers NK cell cytotoxicity in vitro. We hypothesize that GABA secreted by parasitized immune cells modulates the immune responses to T. gondii infection.

Immunological Aspects Related to the Pathophysiology of Multiple Sclerosis and the Possible Checkpoints for Target Therapy: An Integrative Literature Review

Multiple sclerosis (MS) is the most common chronic demyelinating disease of the central nervous system (CNS), with an autoimmune inflammatory mechanism, but the immunological analysis, described in the pathogenesis of the disease, is not attributed or significantly placed in the universally used criteria. In this regard, this literature review aims to highlight immunological aspects that can be attributed both to the diagnosis and treatment of MS. In this sense, this review compiled and interpreted 41 articles found published between 2010 and 2020, indexed on the platforms: PubMed, Scielo and LILACS. Of these only 6 articles contained the proposed inclusion criteria. It was possible to show that CD4 T lymphocytes are activated by antigen presenting cells (microglia and B lymphocytes), adopting Th1 profiles (producing IFN-γ and TNF-α) and Th17 (producing IL-17 and IL-22); from the activation of B lymphocytes, they are differentiated into plasmocytes that will produce IgG4; due to the action of autoreactive lymphocytes, there is an inflammation at the neuronal level that triggers demyelination. In this sense, it is concluded that there is a need to encourage more research regarding the reduction of the inflammatory response in relation to MS and also the encouragement of clinical studies that are already being followed up, given the positive results presented by them and an improvement in the quality of life of their patients.

Sex dimorphism in inflammatory response to obesity in childhood

BackgroundChildhood overweight and obesity are a global concern, with prevalence rising dramatically over the last decades. The condition is caused by an increase in energy intake and reduction of physical activity, leading to excessive fat accumulation, followed by systemic chronic inflammation and altered function of immune cell responses. This study aimed at providing new insights regarding sex-specificity on the inflammatory response to obesity in the young patient.DesignForty-three Brazilian obese adolescents (Female = 22 and Male=21, BMI (body mass index) Z-score average = 2.78 ± 0.51) and forty-nine eutrophic adolescents (Female = 24 and Male = 25, BMI Z-score average = −0.35 ± 0.88) were enrolled in the study. Anthropometrical analyses and blood cell counts were carried out. Using Luminex®xMAP™ technology, circulating serum cytokines, chemokines, and inflammatory biomarkers were analyzed. Two-way ANOVA test, Tukey’s test, and Spearman’s correlation coefficient were employed, with a significance threshold set at p < 0.05.ResultsWe identified increased levels of serum amyloid A (SAA), platelets, and leukocytes solely in male obese patients. We found a noteworthy sex-dependent pattern in regard to inflammatory response: obese boys showed higher TNFβ, IL15, and IL2 and lower IL10 and IL13, while obese girls showed increased TNFα, CCL3, CCL4, and IP10 content in the circulation. BMI Z-score was significantly linearly correlated with neutrophils, leukocytes, platelets, SAA, TNFα, CCL3, CCL4, IP10, and IL13 levels within the entire cohort (non-sex-dependent).ConclusionsOur data support a complex relationship between adiposity, blood cell count, and circulating inflammatory cytokine content. High SAA levels suggest that this factor may play a critical role in local and systemic inflammation. In the eutrophic group, females presented a lower status of inflammation, as compared to males. Both obese boys and girls showed an increased inflammatory response in relation to eutrophic counterparts. Taken together, results point out to clear sex dimorphism in the inflammatory profile of obese adolescents.

Inflammatory response in relation to COVID-19 and other prothrombotic phenotypes

The haemostatic system acts in concert with inflammation, so that after inflammatory response various mediators activate the haemostatic system through endothelial dysfunction, platelet activation and coagulation promoting thrombosis, which is termed thromboinflammation. In this process, the inflammasome acquires special relevance; its stimulation promotes innate and adaptive immune responses. Inflammasome activation plays an important physiopathological role in several disorders with inflammatory and thrombotic phenomena. The role of thromboinflammation has become relevant in the COVID-19 pandemic, in which a cytokine storm has been described as one of the mechanisms responsible.

Gut Hormone GIP Induces Inflammation and Insulin Resistance in the Hypothalamus

The hypothalamus plays a critical role in controlling energy balance. High-fat diet (HFD) feeding increases the gene expression of proinflammatory mediators and decreases insulin actions in the hypothalamus. Here, we show that a gut-derived hormone, glucose-dependent insulinotropic polypeptide (GIP), whose levels are elevated during diet-induced obesity, promotes and mediates hypothalamic inflammation and insulin resistance during HFD-induced obesity. Unbiased ribonucleic acid sequencing of GIP-stimulated hypothalami revealed that hypothalamic pathways most affected by intracerebroventricular (ICV) GIP stimulation were related to inflammatory-related responses. Subsequent analysis demonstrated that GIP administered either peripherally or centrally, increased proinflammatory-related factors such as Il-6 and Socs3 in the hypothalamus, but not in the cortex of C57BL/6J male mice. Consistently, hypothalamic activation of IκB kinase-β inflammatory signaling was induced by ICV GIP. Further, hypothalamic levels of proinflammatory cytokines and Socs3 were significantly reduced by an antagonistic GIP receptor (GIPR) antibody and by GIPR deficiency. Additionally, centrally administered GIP reduced anorectic actions of insulin in the brain and diminished insulin-induced phosphorylation of Protein kinase B and Glycogen synthase kinase 3β in the hypothalamus. Collectively, these findings reveal a previously unrecognized role for brain GIP signaling in diet-induced inflammation and insulin resistance in the hypothalamus.

Inflammatory Response in Relation to COVID-19 and Other Prothrombotic Phenotypes.

El sistema hemostático actúa en concierto con la inflamación, de forma que tras la respuesta inflamatoria diversos mediadores activan el sistema hemostático a través de disfunción endotelial, activación plaquetar y de coagulación, promoviendo la trombosis, lo que se ha denominado tromboinflamación. En este proceso adquiere especial relevancia el inflamasoma, cuya estimulación promueve respuestas inmunes innata y adaptativa. La activación del inflamasoma juega un papel fisiopatológico importante en diversas patologías que cursan con fenómenos inflamatorios y trombóticos. El papel de la tromboinflamación se ha puesto de relevancia en la pandemia por COVID-19, en la que se ha descrito una tormenta de citocinas como uno de los mecanismos responsables.

Pro-inflammatory effects of crystalline- and nano-sized non-crystalline silica particles in a 3D alveolar model

BackgroundSilica nanoparticles (SiNPs) are among the most widely manufactured and used nanoparticles. Concerns about potential health effects of SiNPs have therefore risen. Using a 3D tri-culture model of the alveolar lung barrier we examined effects of exposure to SiNPs (Si10) and crystalline silica (quartz; Min-U-Sil) in the apical compartment consisting of human alveolar epithelial A549 cells and THP-1-derived macrophages, as well as in the basolateral compartment with Ea.hy926 endothelial cells. Inflammation-related responses were measured by ELISA and gene expression.ResultsExposure to both Si10 and Min-U-Sil induced gene expression and release of CXCL8, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α) and interleukin-1β (IL-1β) in a concentration-dependent manner. Cytokine/chemokine expression and protein levels were highest in the apical compartment. Si10 and Min-U-Sil also induced expression of adhesion molecules ICAM-1 and E-selectin in the apical compartment. In the basolateral endothelial compartment we observed marked, but postponed effects on expression of all these genes, but only at the highest particle concentrations. Geneexpressions of heme oxygenase-1 (HO-1) and the metalloproteases (MMP-1 and MMP-9) were less affected. The IL-1 receptor antagonist (IL-1RA), markedly reduced effects of Si10 and Min-U-Sil exposures on gene expression of cytokines and adhesion molecules, as well as cytokine-release in both compartments.ConclusionsSi10 and Min-U-Sil induced gene expression and release of pro-inflammatory cytokines/adhesion molecules at both the epithelial/macrophage and endothelial side of a 3D tri-culture. Responses in the basolateral endothelial cells were only induced at high concentrations, and seemed to be mediated by IL-1α/β released from the apical epithelial cells and macrophages.

Anti-inflammatory catecholic chitosan hydrogel for rapid surgical trauma healing and subsequent prevention of tumor recurrence

Although occupying pillar position in clinical cancer treatments, surgery itself and surgical trauma would elicit series of local/systemic inflammation-related responses that resulted in high rate of tumor recurrence. Herein, chitosan with conjugated gallic acid (CSG) molecules were coordinated with Fe3+ to form CSG/Fe3+ hydrogel for filling the tumor-resected cavity with considerable wet-adhesion ability and anti-inflammatory performance. With the assistance of doxorubicin hydrochloride (DOX∙HCl), CSG/Fe3+/DOX hydrogel exhibited synergistic photothermal-chemo tumor-inhibited performance under near-infrared (NIR) light irradiation for eradicating residual and/or surgical trauma-recruited cancer cells. Thus, our study attempts to show a paradigm that realizes quick surgical trauma healing, inflammation inhibition and prevention of postsurgical tumor recurrence.

Inflammation in Post-Traumatic Stress Disorder (PTSD): A Review of Potential Correlates of PTSD with a Neurological Perspective.

Post-traumatic stress disorder (PTSD) is a chronic condition characterized by symptoms of physiological and psychosocial burden. While growing research demonstrated signs of inflammation in PTSD, specific biomarkers that may be representative of PTSD such as the detailed neural correlates underlying the inflammatory responses in relation to trauma exposure are seldom discussed. Here, we review recent studies that explored alterations in key inflammatory markers in PTSD, as well as neuroimaging-based studies that further investigated signs of inflammation within the brain in PTSD, as to provide a comprehensive summary of recent literature with a neurological perspective. A search was conducted on studies published from 2009 through 2019 in PubMed and Web of Science. Fifty original articles were selected. Major findings included elevated levels of serum proinflammatory cytokines in individuals with PTSD across various trauma types, as compared with those without PTSD. Furthermore, neuroimaging-based studies demonstrated that altered inflammatory markers are associated with structural and functional alterations in brain regions that are responsible for the regulation of stress and emotion, including the amygdala, hippocampus, and frontal cortex. Future studies that utilize both central and peripheral inflammatory markers are warranted to elucidate the underlying neurological pathway of the pathophysiology of PTSD.

Perioperative Use of Nonsteroidal Anti-inflammatory Drugs Decreases the Risk of Recurrence of Cancer After Colorectal Resection: A Cohort Study Based on Prospective Data.

Perioperative use of nonsteroidal anti-inflammatory drugs (NSAIDs) is known to reduce inflammatory response in relation to surgery. Inflammation may promote recurrence of cancer, thus inhibition by use of NSAIDs could reduce recurrence after surgery. The aim of this study was to examine the association between perioperative use of NSAIDs and cancer recurrence, as well as disease-free survival (DFS) and mortality after colorectal cancer surgery. This was a cohort study based on data from a prospective clinical database, electronic medical records, and nationwide registers, and included patients from six major colorectal centers in Denmark. The primary outcome was cancer recurrence, while secondary outcomes included 5-year mortality and DFS. Overall, 2308 patients undergoing colorectal cancer surgery between 1 January 2006 and 31 December 2009 were included. A total of 909 patients received at least 2days of treatment with NSAIDs, of whom 702 (77.2%) received ibuprofen and 204 (22.4%) received diclofenac. Cox regression analysis adjusting for NSAIDs resulted in decreased recurrence risk (adjusted hazard ratio [HRadjusted] 0.84, 95% confidence interval [CI] 0.72-0.99; p = 0.042). Competing risk analysis confirmed the finding, with an HRadjusted of 0.76 (95% CI 0.60-0.97; p = 0.026). There was no significant effect on mortality or DFS. Sensitivity analysis of the effect of ibuprofen reported an HRadjusted of 0.83 (95% CI 0.70-1.00; p = 0.047). In restricted analyses of localized disease only (Union for International Cancer Control [UICC] I-II) and elective surgery only, no effect was found (localized: HRadjusted 0.81, 95% CI 0.62-1.06, p = 0.12; elective: HRadjusted 0.85, 95% CI 0.72-1.01, p = 0.063). Perioperative use of NSAIDs was associated with a reduced risk of cancer recurrence after resection for colorectal cancer. No effect on 5-year mortality or DFS was found.