Potential role of the NADPH oxidase NOX1 in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice

2012 ◽  
Vol 302 (10) ◽  
pp. G1133-G1142 ◽  
Author(s):  
Masashi Yasuda ◽  
Shinichi Kato ◽  
Naoki Yamanaka ◽  
Maho Iimori ◽  
Daichi Utsumi ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Caspase 3 ◽  
Potential Role ◽  
Chemotherapeutic Agent ◽  
Wild Type ◽  
Villus Height ◽  
Tnf Α ◽  
Nadph Oxidase 1 ◽  
Intestinal Mucositis

Although NADPH oxidase 1 (NOX1) has been shown to be highly expressed in the gastrointestinal tract, the physiological and pathophysiological roles of this enzyme are not yet fully understood. In the present study, we investigated the role of NOX1 in the pathogenesis of intestinal mucositis induced by the cancer chemotherapeutic agent 5-fluorouracil (5-FU) in mice. Intestinal mucositis was induced in Nox1 knockout (Nox1KO) and littermate wild-type (WT) mice via single, daily administration of 5-FU for 5 days. In WT mice, 5-FU caused severe intestinal mucositis characterized by a shortening of villus height, a disruption of crypts, a loss of body weight, and diarrhea. In Nox1KO mice, however, the severity of mucositis was significantly reduced, particularly with respect to crypt disruption. The numbers of apoptotic caspase-3- and caspase-8-activated cells in the intestinal crypt increased 24 h after the first 5-FU administration but were overall significantly lower in Nox1KO than in WT mice. Furthermore, the 5-FU-mediated upregulation of TNF-α, IL-1β, and NOX1 and the production of reactive oxygen species were significantly attenuated in Nox1KO mice compared with that in WT mice. These findings suggest that NOX1 plays an important role in the pathogenesis of 5-FU-induced intestinal mucositis. NOX1-derived ROS production following administration of 5-FU may promote the apoptotic response through upregulation of inflammatory cytokines.

Mo2060 Pathogenic Role of NADPH Oxidase 1 (NOX1)-Derived Reactive Oxygen Species in 5-Fluorouracil-Induced Intestinal Mucositis in Mice

2012 ◽  
Vol 142 (5) ◽  
pp. S-731
Author(s):  
Masashi Yasuda ◽  
Shinichi Kato ◽  
Naoki Yamanaka ◽  
Maho Iimori ◽  
Kazumi Iwata ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Pathogenic Role ◽  
Nadph Oxidase 1 ◽  
Intestinal Mucositis

scholarly journals A Functional NADPH Oxidase Prevents Caspase Involvement in the Clearance of Phagocytic Neutrophils

2007 ◽  
Vol 75 (7) ◽  
pp. 3256-3263 ◽  
Author(s):  
Rachel P. Wilkie ◽  
Margret C. M. Vissers ◽  
Mike Dragunow ◽  
Mark B. Hampton
Keyword(s):  
Nadph Oxidase ◽  
Caspase 3 ◽  
Caspase Activity ◽  
Wild Type ◽  
Caspase Activation ◽  
Effector Caspases ◽  
Nadph Oxidase Complex ◽  
Normal Human ◽  
Active Caspase

ABSTRACT Neutrophils play a prominent role in host defense. Phagocytosis of bacteria leads to the formation of an active NADPH oxidase complex that generates reactive oxygen species for bactericidal purposes. A critical step in the resolution of inflammation is the uptake of neutrophils by macrophages; however, there are conflicting reports on the mechanisms leading to the apoptosis of phagocytic neutrophils. The aim of this study was to clarify the role of effector caspases in these processes. Caspase activity was measured by DEVDase activity assays or immunofluorescence detection of active caspase-3. With normal human and wild-type murine neutrophils there was no caspase activation following phagocytosis of Staphylococcus aureus. However, caspase activity was observed in phagocytic neutrophils with a defective NADPH oxidase, including neutrophils isolated from X-linked gp91phox knockout chronic granulomatous disease mice. These results indicate that a functional NADPH oxidase and the generation of oxidants in the neutrophil phagosome prevent the activation of the cytoplasmic caspase cascade.

Potential Role of NADPH Oxidase 1 Derived ROS in Vascular Remodeling in Monocrotaline-induced Pulmonary Arterial Hypertension of Rats

2010 ◽  
Vol 49 ◽  
pp. S31
Author(s):  
Florian Veit ◽  
Bakytbek Egemnazarov ◽  
Hossein Ardeschir Ghofrani ◽  
Ralph Theo Schermuly ◽  
Werner Seeger ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Nadph Oxidase ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Potential Role ◽  
Nadph Oxidase 1 ◽  
Pulmonary Arterial

scholarly journals Glucagon-like peptide-2 and mouse intestinal adaptation to a high-fat diet

2013 ◽  
Vol 217 (1) ◽  
pp. 11-20 ◽  
Author(s):  
Sara Baldassano ◽  
Antonella Amato ◽  
Francesco Cappello ◽  
Francesca Rappa ◽  
Flavia Mulè
Keyword(s):  
High Fat Diet ◽  
Caspase 3 ◽  
Potential Role ◽  
Intestinal Adaptation ◽  
Cell Number ◽  
Standard Diet ◽  
High Fat ◽  
Villus Height ◽  
Glucagon Like Peptide

Endogenous glucagon-like peptide-2 (GLP2) is a key mediator of refeeding-induced and resection-induced intestinal adaptive growth. This study investigated the potential role of GLP2 in mediating the mucosal responses to a chronic high-fat diet (HFD). In this view, the murine small intestine adaptive response to a HFD was analyzed and a possible involvement of endogenous GLP2 was verified using GLP2 (3–33) as GLP2 receptor (GLP2R) antagonist. In comparison with animals fed a standard diet, mice fed a HFD for 14 weeks exhibited an increase in crypt–villus mean height (duodenum, 27.5±3.0%; jejunum, 36.5±2.9%;P<0.01), in the cell number per villus (duodenum, 28.4±2.2%; jejunum, 32.0±2.9%;P<0.01), and in Ki67-positive cell number per crypt. No change in the percent of caspase-3-positive cell in the villus–crypt was observed. The chronic exposure to a HFD also caused a significant increase in GLP2 plasma levels and in GLP2R intestinal expression. Daily administration of GLP2 (3–33) (30–60 ng) for 4 weeks did not modify the crypt–villus height in control mice. In HFD-fed mice, chronic treatment with GLP2 (3–33) reduced the increase in crypt–villus height and in the cell number per villus through reduction of cell proliferation and increase in apoptosis. This study provides the first experimental evidence for a role of endogenous GLP2 in the intestinal adaptation to HFD in obese mice and for a dysregulation of the GLP2/GLP2R system after a prolonged HFD.

Design and synthesis of novel quinic acid derivatives: in vitro cytotoxicity and anticancer effect on glioblastoma

2020 ◽  
Vol 12 (21) ◽  
pp. 1891-1910
Author(s):  
Akshaya Murugesan ◽  
Suvi Holmstedt ◽  
Kenna C Brown ◽  
Alisa Koivuporras ◽  
Ana S Macedo ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Potential Role ◽  
Chemotherapeutic Agent ◽  
Quinic Acid ◽  
In Vitro Cytotoxicity ◽  
Anticancer Effect ◽  
Design And Synthesis ◽  
Anticancer Properties

Aim: Quinic acid (QA) is a cyclic polyol exhibiting anticancer properties on several cancers. However, potential role of QA derivatives against glioblastoma is not well established. Methodology & results: Sixteen novel QA derivatives and QA-16 encapsulated poly (lactic-co-glycolic acid) nanoparticles (QA-16-NPs) were screened for their anti-glioblastoma effect using standard cell and molecular biology methods. Presence of a tertiary hydroxy and silylether groups in the lead compound were identified for the antitumor activity. QA-16 have 90% inhibition with the IC50 of 10.66 μM and 28.22 μM for LN229 and SNB19, respectively. The induction of apoptosis is faster with the increased fold change of caspase 3/7 and reactive oxygen species. Conclusion: QA-16 and QA-16-NPs shows similar cytotoxicity effect, providing the opportunity to use QA-16 as a potential chemotherapeutic agent.

scholarly journals Troxerutin Prevents 5-Fluorouracil Induced Morphological Changes in the Intestinal Mucosa: Role of Cyclooxygenase-2 Pathway

2020 ◽  
Vol 13 (1) ◽  
pp. 10 ◽  
Author(s):  
João Antônio Leal de Miranda ◽  
Conceição da Silva Martins ◽  
Lázaro de Sousa Fideles ◽  
Maria Lucianny Lima Barbosa ◽  
João Erivan Façanha Barreto ◽  
...  
Keyword(s):  
Chemotherapeutic Agent ◽  
Morphological Changes ◽  
Immunohistochemical Analysis ◽  
Cyclooxygenase 2 ◽  
Villus Height ◽  
Inflammatory Agent ◽  
Cell Counts ◽  
Intestinal Mucositis ◽  
Cox 2

Intestinal mucositis is a common complication associated with 5-fluorouracil (5-FU), a chemotherapeutic agent used for cancer treatment. Troxerutin (TRX), a semi-synthetic flavonoid extracted from Dimorphandra gardneriana, has been reported as a potent antioxidant and anti-inflammatory agent. In the present study, we aimed to evaluate the effect of TRX on 5-FU-induced intestinal mucositis. Swiss mice were randomly divided into seven groups: Saline, 5-FU, TRX-50, TRX-100, TRX-150, Celecoxib (CLX), and CLX + TRX-100. The weight of mice was measured daily. After treatment, the animals were euthanized and segments of the small intestine were collected to evaluate histopathological alterations (morphometric analysis), levels of malondialdehyde (MDA), myeloperoxidase (MPO), glutathione (GSH), mast and goblet cell counts, immunohistochemical analysis, and cyclooxygenase-2 (COX-2) activity. Compared to the saline treatment, the 5-FU treatment induced intense weight loss and reduction in villus height. TRX treatment (100 mg/kg) prevented the 5-FU-induced histopathological changes and decreased oxidative stress by decreasing the MDA levels and increasing GSH concentration. TRX attenuated inflammatory process by decreasing MPO activity, intestinal mastocytosis, and COX-2 expression. TRX also reversed the depletion of goblet cells. Our findings suggest that TRX at a concentration of 100 mg/kg had chemopreventive effects on 5-FU-induced intestinal mucositis via COX-2 pathway.

Role of IL-1β and IL-4 in 5-fluorouracil- induced intestinal mucositis in mice

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 19551-19551
Author(s):  
J. S. Mota ◽  
P. M. Soares ◽  
G. A. Brito ◽  
F. Q. Cunha ◽  
M. L. Souza ◽  
...  
Keyword(s):  
Intestinal Damage ◽  
Clinical Use ◽  
Soluble Receptor ◽  
Wild Type ◽  
Villus Height ◽  
Damage Reduction ◽  
Intestinal Mucositis ◽  
Bonferroni Test ◽  
Deficient Mice

19551 Background: Intestinal mucositis is a frequent side-effect associated to 5-fluorouracil (5-FU) clinical use. The participation of cytokines in the 5-FU- induced intestinal mucositis was not completely elucidated. We evaluated the role of IL-4 and IL-1β in 5- FU induced- intestinal mucositis in mice. Methods: Wild-type C57BL/6 mice or IL-4 deficient mice (-/-) were treated with 5-FU (450 mg/Kg, i.p.). Other group were treated with the soluble receptor IL-1Ra (100 mg/Kg, i.p., per day) or saline. Then, received the 5-FU (450 mg/Kg, ip). After three days, animals were sacrificed and pieces of duodenum (D), jejunum (J) and ileum (I) were harvested for assessment of epithelial damage by morphometry, myeloperoxidase (MPO) activity and cytokines (both in duodenum) quantification by ELISA. Statistical analysis was performed with ANOVA and Bonferroni test. Significance was set at p<0.05. Results: 5-FU induced a significant (p<0.05) epithelial intestinal damage (reduction of villus height/crypts depht reason) in all segments (duodenum-C= 3.3±0.2, 5- FU= 1.0±0.1; jejunum-C= 2.3±0.2, 5-FU= 1.0±0.1; ileum-C= 2.1±0.1, 5-FU= 0.7±0.1), increased MPO activity (n° neutrophil/mg of tissue) (C= 663.5±76.6, 5- FU= 3579±492) and cytokines concentration (pg/ml) (IL-1β: C= 134.8±31.9, 5-FU= 280.3±41.5; KC: C= 123.9±27.3, 5-FU= 177.2±28.2; TNF-a: C= 9.9±0.4, 5-FU= 12.1±1.8). IL-1Ra protected all segments from 5-FU- induced intestinal injury (D= 1.7±0.1, J= 2.0±0.1, I= 1.1±0.1), reduced MPO activity (2061±308) and cytokines concentration (IL-1β= 8.6±41.7; KC= 100±17.1; TNF-a= 7±.1.1). IL4 -/- presented with less epithelial intestinal damage (D= 2.9±0.2, J= 2.0±0.2, I= 1.4±0.1), less MPO activity (1702±315) and cytokines concentration (IL-1β:=86.5± 29.6; KC=105.6± 21.6, TNF-a:=7.4±0.5) . Conclusions: Our data suggest that IL-4 and IL-1β participates in the 5-FU induced- intestinal mucositis in mice. No significant financial relationships to disclose.

Ursodeoxycholic acid abrogates gentamicin-induced hepatotoxicity in rats: Role of NF-κB-p65/TNF-α, Bax/Bcl-xl/Caspase-3, and eNOS/iNOS pathways

Life Sciences ◽  
2020 ◽  
Vol 254 ◽  
pp. 117760 ◽  
Author(s):  
Fares E.M. Ali ◽  
Emad H.M. Hassanein ◽  
Adel G. Bakr ◽  
Ehab A.M. El-Shoura ◽  
Dalia A. El-Gamal ◽  
...  
Keyword(s):  
Ursodeoxycholic Acid ◽  
Caspase 3 ◽  
Tnf Α

scholarly journals NMR and LC-MS-Based Metabolomics to Study Osmotic Stress in Lignan-Deficient Flax

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 767
Author(s):  
Kamar Hamade ◽  
Ophélie Fliniaux ◽  
Jean-Xavier Fontaine ◽  
Roland Molinié ◽  
Elvis Otogo Nnang ◽  
...  
Keyword(s):  
Stress Response ◽  
Osmotic Stress ◽  
Biosynthetic Pathway ◽  
Potential Role ◽  
Plant Secondary Metabolites ◽  
Wild Type ◽  
Osmotic Stress Response ◽  
Transgenic Flax ◽  
Insight Into

Lignans, phenolic plant secondary metabolites, are derived from the phenylpropanoid biosynthetic pathway. Although, being investigated for their health benefits in terms of antioxidant, antitumor, anti-inflammatory and antiviral properties, the role of these molecules in plants remains incompletely elucidated; a potential role in stress response mechanisms has been, however, proposed. In this study, a non-targeted metabolomic analysis of the roots, stems, and leaves of wild-type and PLR1-RNAi transgenic flax, devoid of (+) secoisolariciresinol diglucoside ((+) SDG)—the main flaxseed lignan, was performed using 1H-NMR and LC-MS, in order to obtain further insight into the involvement of lignan in the response of plant to osmotic stress. Results showed that wild-type and lignan-deficient flax plants have different metabolic responses after being exposed to osmotic stress conditions, but they both showed the capacity to induce an adaptive response to osmotic stress. These findings suggest the indirect involvement of lignans in osmotic stress response.

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