NADPH oxidases and cancer

2015 ◽  
Vol 128 (12) ◽  
pp. 863-875 ◽  
Author(s):  
Krishnendu Roy ◽  
Yongzhong Wu ◽  
Jennifer L. Meitzler ◽  
Agnes Juhasz ◽  
Han Liu ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Interferon Γ ◽  
Nadph Oxidases ◽  
Inflammatory Stress ◽  
Over Expression ◽  
Wide Range ◽  
Membrane Bound ◽  
Inflammatory Bowel ◽  
Factor Α ◽  
Respiratory Burst Oxidase

The mechanism by which reactive oxygen species (ROS) are produced by tumour cells remained incompletely understood until the discovery over the last 15 years of the family of NADPH oxidases (NOXs 1–5 and dual oxidases DUOX1/2) which are structural homologues of gp91phox, the major membrane-bound component of the respiratory burst oxidase of leucocytes. Knowledge of the roles of the NOX isoforms in cancer is rapidly expanding. Recent evidence suggests that both NOX1 and DUOX2 species produce ROS in the gastrointestinal tract as a result of chronic inflammatory stress; cytokine induction (by interferon-γ, tumour necrosis factor α, and interleukins IL-4 and IL-13) of NOX1 and DUOX2 may contribute to the development of colorectal and pancreatic carcinomas in patients with inflammatory bowel disease and chronic pancreatitis, respectively. NOX4 expression is increased in pre-malignant fibrotic states which may lead to carcinomas of the lung and liver. NOX5 is highly expressed in malignant melanomas, prostate cancer and Barrett's oesophagus-associated adenocarcinomas, and in the last it is related to chronic gastro-oesophageal reflux and inflammation. Over-expression of functional NOX proteins in many tissues helps to explain tissue injury and DNA damage from ROS that accompany pre-malignant conditions, as well as elucidating the potential mechanisms of NOX-related damage that contribute to both the initiation and the progression of a wide range of solid and haematopoietic malignancies.

scholarly journals Cannabidiol and palmitoylethanolamide are anti-inflammatory in the acutely inflamed human colon

2017 ◽  
Vol 131 (21) ◽  
pp. 2611-2626 ◽  
Author(s):  
Daniel G. Couch ◽  
Chris Tasker ◽  
Elena Theophilidou ◽  
Jonathan N. Lund ◽  
Saoirse E. O’Sullivan
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Human Colon ◽  
Interferon Γ ◽  
Cytokine Levels ◽  
Drug Treatments ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
Trpv1 Antagonist ◽  
Factor Α

Objective: We sought to quantify the anti-inflammatory effects of two cannabinoid drugs, cannabidiol (CBD) and palmitoylethanolamide (PEA), in cultured cell lines and compared this effect with experimentally inflamed explant human colonic tissue. These effects were explored in acutely and chronically inflamed colon, using inflammatory bowel disease and appendicitis explants. Design: Caco-2 cells and human colonic explants collected from elective bowel cancer, inflammatory bowel disease (IBD) or acute appendicitis resections, and were treated with the following drug treatments: vehicle, an inflammatory protocol of interferon γ (IFNγ) and tumour necrosis factor α (TNFα; 10 ng/ml), inflammation and PEA (10 µM), inflammation and CBD (10 µM), and PEA or CBD alone, CBD or vehicle were added simultaneously with IFNγ. Nine intracellular signalling phosphoproteins were determined by multiplex. Inflammatory cytokine secretion was determined using ELISA. Receptor mechanisms were investigated using antagonists for CB1, CB2, PPARα, PPARγ, TRPV1 and GPR55. Results: IFNγ and TNFα treatment increased phosphoprotein and cytokine levels in Caco-2 cultures and colonic explants. Phosphoprotein levels were significantly reduced by PEA or CBD in Caco-2 cultures and colonic explants. CBD and PEA prevented increases in cytokine production in explant colon, but not in Caco-2 cells. CBD effects were blocked by the CB2 antagonist AM630 and TRPV1 antagonist SB366791. PEA effects were blocked by the PPARα antagonist GW6471. PEA and CBD were anti-inflammatory in IBD and appendicitis explants. Conclusion: PEA and CBD are anti-inflammatory in the human colon. This effect is not seen in cultured epithelial cells. Appropriately sized clinical trials should assess their efficacy.

scholarly journals Monocyte Chemotactic Protein 1-Induced Protein 1 Is Highly Expressed in Inflammatory Bowel Disease and Negatively Regulates Neutrophil Activities

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Jian Lin ◽  
Gengfeng Li ◽  
Chunjin Xu ◽  
Huiying Lu ◽  
Cui Zhang ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Proinflammatory Cytokines ◽  
Bowel Disease ◽  
Interferon Γ ◽  
Functional Changes ◽  
Monocyte Chemotactic Protein ◽  
Chemotactic Protein ◽  
Inflammatory Bowel ◽  
Factor Α

Monocyte chemotactic protein 1-induced protein 1 (MCPIP-1) is highly expressed in activated immune cells and plays an important role in negatively regulating immune responses. However, its role in regulating neutrophil functions in the pathogenesis of inflammatory bowel disease (IBD) is still unclear. Here, we found that MCPIP-1 was markedly increased at both the transcriptional and translational levels in inflamed mucosa of IBD patients compared with healthy controls, which was mainly expressed in neutrophils. Interestingly, MG-132, a proteasome inhibitor reducing the degradation of MCPIP-1, further facilitated neutrophils to express MCPIP-1 in vitro. Importantly, MCPIP-1 markedly downregulated the production of ROS, MPO, and proinflammatory cytokines (e.g., interleukin-1β, interleukin-6, tumor necrosis factor-α, interleukin-8, and interferon-γ) and suppressed the migration of IBD neutrophils. Consistently, the same functional changes were observed in neutrophils from mice with myeloid-targeted overexpression of MCPIP-1 as MG-132 did. Altogether, these findings suggest that MCPIP-1 plays a negative role in regulating neutrophil activities through suppressing the production of ROS, MPO, and proinflammatory cytokines and inhibiting the migration. MG-132 may partially modulate the function of neutrophils via the induction of MCPIP-1. Therefore, targeting MCPIP-1 or exogenous supplementation of MG-132 may provide a therapeutic approach in the treatment of IBD.

scholarly journals Role of ICAM-1 in the aggregation and adhesion of human alveolar macrophages in response to TNF-α and INF-γ

2001 ◽  
Vol 10 (6) ◽  
pp. 309-313 ◽  
Author(s):  
Masahiro Sasaki ◽  
Yuriko Namioka ◽  
Takefumi Ito ◽  
Noriko Izumiyama ◽  
Shin Fukui ◽  
...  
Keyword(s):  
Alveolar Macrophages ◽  
Biological Activities ◽  
Surface Expression ◽  
Interferon Γ ◽  
Pulmonary Sarcoidosis ◽  
Tnf Α ◽  
Wide Range ◽  
Inflammatory Granuloma ◽  
Fibrotic Lung Disease ◽  
Factor Α

Intracellular adhesion molecule-1 (ICAM-1)-mediated cell-cell adhesion is thought to play an important role at sites of inflammation. Recent evidence suggests that ICAM-1 surface expression on alveolar macrophages is increased in pulmonary sarcoidosis and that inflammatory granuloma formation is characterized by the aggregation of macrophages. The present study shows that ICAM-1 expression is significantly elevated on alveolar macrophages from patients with sarcoidosis in response to tumor necrosis factor-α (TNF-α) and interferon- γ (INF-γ) compared with healthy controls. Aggregation and adhesion were significantly increased in alveolar macrophages treated with TNF-α and INF-γ, and significantly inhibited in those pretreated with a monoclonal antibody to ICAM-1. Similarly, aggregation and adhesion were inhibited in macrophages treated with heparin, which then exhibited a wide range of biological activities relevant to inflammation. These results suggested that the surface expression of ICAM-1 on alveolar macrophages in response to TNF-α and INF-γ is important in mediating aggregation and adhesion. Additionally, heparin may be useful for developing novel therapeutic agents for fibrotic lung disease.

Immunological mechanisms involved in probiotic-mediated protection against Citrobacter rodentium-induced colitis

2016 ◽  
Vol 7 (3) ◽  
pp. 397-407 ◽  
Author(s):  
Y. Jiang ◽  
G. Yang ◽  
F. Meng ◽  
W. Yang ◽  
J. Hu ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Lactobacillus Rhamnosus ◽  
Interferon Γ ◽  
Interleukin 17 ◽  
Protective Effects ◽  
Citrobacter Rodentium ◽  
Mesenteric Lymph Nodes ◽  
Immunological Mechanisms ◽  
Inflammatory Bowel ◽  
Factor Α

Inflammatory bowel disease is a group of chronic, incurable inflammatory disorders of the gastrointestinal tract that cause severe diarrhoea, intestinal inflammation, pain, fatigue and weight loss. In this study, we first developed a model of Citrobacter rodentium-induced colitis and then evaluated the protective effects of selected probiotics on inflammation. The results showed that administration of a combination of probiotics including Lactobacillus rhamnosus ATCC 53103, Lactobacillus acidophilus ATCC 4356 and Lactobacillus plantarum A significantly increased the production of CD11c+ dendritic cells in the spleen (3.62% vs phosphate buffered saline (PBS)-treated control, P<0.01) and mesenteric lymph nodes (MLNs). In addition, the presence of probiotics significantly up-regulated the development of CD4+/CD25+/Foxp3+ regulatory T cells in MLNs by approximately 2.07% compared to the effect observed in the PBS-treated control (P<0.01) and down-regulated the expression of inflammatory cytokines, including interleukin-17, tumour necrosis factor-α and interferon-γ, by 0.11, 0.11 and 0.15%, respectively, compared to the effect observed in the PBS-treated control (P<0.01).These effects conferred protection against colitis, as shown by histopathological analyses.

scholarly journals Plasma Osteopontin Predicts Inflammatory Bowel Disease Activities

2015 ◽  
Vol 100 (1) ◽  
pp. 38-43 ◽  
Author(s):  
Shihoko Komine-Aizawa ◽  
Hideki Masuda ◽  
Takerou Mazaki ◽  
Motomi Shiono ◽  
Satoshi Hayakawa ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Inflammatory Diseases ◽  
Interferon Γ ◽  
Clinical Activity ◽  
Colon And Rectum ◽  
Inflammatory Bowel ◽  
Macrophage Colony ◽  
Factor Α ◽  
Normal Controls

Abstract A glycoprotein osteopontin (OPN) is involved in inflammatory diseases, but its roles in inflammatory bowel disease (IBD) are controversial. To analyze the involvement of the systemic immune response, we simultaneously examined plasma OPN levels and 17 cytokines. This study included 24 ulcerative colitis (UC) patients, 17 Crohn's disease (CD) patients, and 23 normal controls. Clinical parameters were also examined. The plasma OPN levels of the UC and CD patients were significantly higher than those of the normal controls and correlated significantly with their clinical activity indices. In the UC patients, significant relationships were observed between the levels of plasma OPN and multiple cytokines, including interleukin (IL) −1β, IL-4, IL-5, IL-6, IL-7, IL-13, interferon-γ, tumor necrosis factor-α, and granulocyte-macrophage colony-stimulating factor. In the CD patients, the correlation was not significant except for IL-8. Our findings reflect different inflammatory states of the colon and rectum in both diseases.

scholarly journals A156 SERUM TUMOUR NECROSIS FACTOR-α ANTAGONIST DRUG CONCENTRATIONS IN PATIENTS WITH PYODERMA GANGRENOSUM ASSOSCIATED WITH INFLAMMATORY BOWEL DISEASE

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 162-163
Author(s):  
M Mikail ◽  
A Wilson
Keyword(s):  
Inflammatory Bowel Disease ◽  
Pyoderma Gangrenosum ◽  
Bowel Disease ◽  
Complete Resolution ◽  
Therapeutic Drug ◽  
Drug Concentrations ◽  
Median Serum ◽  
Inflammatory Bowel ◽  
Factor Α ◽  
Necrosis Factor

Abstract Background The utility of therapeutic drug monitoring for guiding the dosing of tumor necrosis factor-α antagonists (TNFAs) in luminal inflammatory bowel disease (IBD) is well-established and well-accepted. TNFAs, specifically infliximab and adalimumab, have become integral to the management of the rare, neutrophilic dermatosis, pyoderma gangrenosum (PG) in IBD. Little is known regarding the target serum TNFA concentrations to guide dosing to achieve resolution of PG in IBD. Aims To describe the serum TNFA concentrations (infliximab or adalimumab) associated with the resolution of PG lesions in patients with IBD. Methods Patients with IBD and associated PG treated with one of infliximab or adalimumab (collectively known as TNFAs) seen at two academic hospitals affiliated with Western University were identified. Serum TNFA concentrations were assessed at the time of PG treatment. Results Nine patients were identified. All patients had IBD-associated PG. Seven patients were treated with infliximab and 2 patients were treated with adalimumab. All patients received standard dosing. Eight patients had complete resolution of their PG, while one had near complete resolution at the time of last follow-up. A median serum infliximab concentration of 3.00 (IQR, 3.52) µg/ml at week 14 and a median serum adalimumab concentration of 2.02 (IQR, 0.98) µg/ml at week 12 were seen at the time of PG treatment. Conclusions Herein, we report low serum TNFA concentrations despite PG healing in a cohort of IBD patients. This is lower than what is in patients for successful TNFA treatment in luminal and fistulising IBD. Funding Agencies NoneNone.

Anti-TNF-α Treatment Reduces the Baseline Procoagulant Imbalance of Patients With Inflammatory Bowel Diseases

2021 ◽  
Author(s):  
Armando Tripodi ◽  
Luisa Spina ◽  
Laura Francesca Pisani ◽  
Lidia Padovan ◽  
Flaminia Cavallaro ◽  
...  
Keyword(s):  
Inflammatory Bowel Diseases ◽  
Coagulation Factors ◽  
Infliximab Treatment ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Thrombosis Risk ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Factor Α

Abstract Background Inflammatory bowel diseases (IBD) are characterized by an increased thrombosis risk of uncertain etiology. Coagulation derangement arising from inflammation may be a triggering factor. We hypothesized that strong inflammation inhibitors (eg, anti-tumor necrosis factor-α drugs) may affect coagulation. Methods Forty patients with IBD were compared with 57 control patients for coagulation factors and endogenous thrombin potential (ETP), the latter being the most sensitive marker of in vivo pro- and anticoagulation balance. We measured ETP in the presence and absence of thrombomodulin (the physiologic protein C [PC] activator). Coagulation at different timepoints was also assessed for 28 of these patients during infliximab treatment. Results The median ETP (nM thrombin × minutes) and range (minimum-maximum) were each higher in patients at baseline than in control patients in both the absence (2120 [1611-3041] vs 1865 [1270-2337]) and the presence (1453 [464-2522] vs 831 [104-1741]) of thrombomodulin. The ETP ratio (with/without thrombomodulin) was high at baseline (0.73 [0.21-0.90] vs 0.45 [0.07-0.85]). The ETP and ETP ratio declined during treatment and were significantly lower at the end than at baseline. Factor (F) VIII and fibrinogen, which were high at baseline, decreased during treatment and at the end were significantly lower than at baseline. The FVIII/PC ratio, which was high in patients at baseline, declined during treatment and at the end was lower than at baseline. C-reactive protein recorded at the end of treatment was lower than at baseline. Conclusions Patients with IBD have a procoagulant imbalance as shown by increased ETP at baseline. The ETP decreases during treatment with infliximab, which is related to decreased FVIII and FVIII/PC ratio. This effect is also related to the improvement of inflammation as shown by decreased fibrinogen and C-reactive protein.

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