scholarly journals Large induction of the chemotactic cytokine RANTES during cutaneous wound repair: a regulatory role for nitric oxide in keratinocyte-derived RANTES expression

2000 ◽  
Vol 347 (1) ◽  
pp. 265-273 ◽  
Author(s):  
Stefan FRANK ◽  
Heiko KÄMPFER ◽  
Christian WETZLER ◽  
Birgit STALLMEYER ◽  
Josef PFEILSCHIFTER
Keyword(s):  
Nitric Oxide ◽  
Wound Repair ◽  
Immunohistochemical Analysis ◽  
Human Keratinocytes ◽  
Negative Regulator ◽  
Chemotactic Cytokine ◽  
Factor Α ◽  
Oxide Synthase

We investigated the role of NO on expressional regulation of the chemotactic cytokine RANTES (regulated upon activation, normal T-cell expressed and secreted) during tissue regeneration using an excisional wound-healing model in mice. Wound repair was characterized by a large and sustained induction of RANTES expression, and inhibition of inducible nitric oxide synthase (iNOS) during repair only slightly decreased RANTES expression levels. Immunohistochemical analysis revealed keratinocytes of the wound margins and the hyperproliferative epithelium to be the main RANTES-expressing cell type within the wound. Therefore we analysed the regulation of RANTES expression in vitro in cultured human keratinocytes of the cell line HaCaT. Here we demonstrate that NO very efficiently suppressed interleukin-1β- and tumour-necrosis-factor-α-induced RANTES expression in keratinocytes. Furthermore, down-regulation of cytokine-induced RANTES mRNA in keratinocytes was dependent on endogenously produced NO, as inhibition of the co-induced iNOS by L-NG-monomethyl-L-arginine increased cytokine-triggered RANTES expression in the cells. Moreover, we observed strongest RANTES-immunopositive labelling in epithelial areas which were characterized by a NO-mediated low cellularity. Thus our data implicate NO as a negative regulator of RANTES expression during wound repair in vivo, as decreased numbers of keratinocytes observed in the absence of wound-derived NO might compensate for the high levels of RANTES expression which are associated with normal repair.

scholarly journals Anti-Inflammatory Effect of 4,5-Dicaffeoylquinic Acid on RAW264.7 Cells and a Rat Model of Inflammation

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3537
Author(s):  
Goeun Jang ◽  
Seulah Lee ◽  
Joonho Hong ◽  
Boram Park ◽  
Dokyung Kim ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nuclear Factor Κb ◽  
Raw264.7 Cells ◽  
Dicaffeoylquinic Acid ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Oxide Synthase

Anti-inflammatory agents that are safer and more effective than the currently used non-steroidal anti-inflammatory drugs are urgently needed. The dicaffeoylquinic acid (diCQA) isomer 4,5-diCQA exhibits antioxidant activity and various other health-promoting benefits; however, its anti-inflammatory properties require further investigation. This study was conducted to evaluate the anti-inflammatory properties of 4,5-diCQA in vitro and in vivo using RAW264.7 cells and a carrageenan-induced inflammation model, respectively. In RAW264.7 cells, 4,5-diCQA pretreatment significantly inhibited lipopolysaccharide-induced expression of nitric oxide, prostaglandin E2, nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, interleukin-1β, and interleukin-6, without inducing cytotoxicity. The inhibitory effects of 4,5-diCQA were mediated by the suppression of nuclear factor-κB nuclear translocation and mitogen-activated protein kinase (MAPK) phosphorylation. Oral administration of 4,5-diCQA at doses of 5, 10, and 20 mg/kg of the body weight suppressed carrageenan-induced edema and the expression of nitric oxide synthase, cyclooxygenase-2, and tumor necrosis factor-α in a dose-dependent manner. Collectively, our results suggest that 4,5-diCQA exerts anti-inflammatory effects by suppressing activation of the nuclear factor-κB and MAPK pathways in vitro and reducing carrageenan-induced edema in vivo. Therefore, 4,5-diCQA shows potential as a natural alternative to non-steroidal anti-inflammatory drugs.

scholarly journals Effects of chitosan on nitric oxide production and inducible nitric oxide synthase activity and mRNA expression in weaned piglets

2018 ◽  
Vol 60 (No. 8) ◽  
pp. 359-366
Author(s):  
J. Li ◽  
B. Shi ◽  
S. Yan ◽  
L. Jin ◽  
Y. Guo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mrna Expression ◽  
Inducible Nitric Oxide Synthase ◽  
No Production ◽  
Weaned Piglets ◽  
Inos Activity ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

The effects of chitosan on nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) activity and gene expression in vivo or vitro were investigated in weaned piglets. In vivo, 180 weaned piglets were assigned to five dietary treatments with six replicates. The piglets were fed on a basal diet supplemented with 0 (control), 100, 500, 1000, and 2000 mg chitosan/kg feed, respectively. In vitro, the peripheral blood mononuclear cells (PBMCs) from a weaned piglet were cultured respectively with 0 (control), 40, 80, 160, and 320 µg chitosan/ml medium. Results showed that serum NO concentrations on days 14 and 28 and iNOS activity on day 28 were quadratically improved with increasing chitosan dose (P < 0.05). The iNOS mRNA expressions were linearly or quadratically enhanced in the duodenum on day 28, and were improved quadratically in the jejunum on days 14 and 28 and in the ileum on day 28 (P < 0.01). In vitro, the NO concentrations, iNOS activity, and mRNA expression in unstimulated PBMCs were quadratically enhanced by chitosan, but the improvement of NO concentrations and iNOS activity by chitosan were markedly inhibited by N-(3-[aminomethyl] benzyl) acetamidine (1400w) (P < 0.05). Moreover, the increase of NO concentrations, iNOS activity, and mRNA expression in PBMCs induced by lipopolysaccharide (LPS) were suppressed significantly by chitosan (P < 0.05). The results indicated that the NO concentrations, iNOS activity, and mRNA expression in piglets were increased by feeding chitosan in a dose-dependent manner. In addition, chitosan improved the NO production in unstimulated PBMCs but inhibited its production in LPS-induced cells, which exerted bidirectional regulatory effects on the NO production via modulated iNOS activity and mRNA expression.

Abstract 18060: TRAIL Promotes Angiogenesis and Ischemia-Induced Neovascularisation via NOX4, H2O2 and Nitric Oxide-Dependent Mechanisms

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Belinda A Di Bartolo ◽  
Sian P Cartland ◽  
Leonel Prado-Lourenco ◽  
Nor Saadah M Azahri ◽  
Thuan Thai ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiogenic Factor ◽  
Tubule Formation ◽  
Nitric Oxide Synthase Inhibitor ◽  
Therapeutic Implications ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
First Time

Background: Angiogenesis and neovascularization are essential processes that follow ischemia insults. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) not only induces endothelial cell (EC) death and inhibits angiogenesis, but also promotes EC migration, invasion and proliferation in vitro . These seemingly opposite effects make its role in angiogenesis in vivo unclear. Using TRAIL -/- and wild-type mice, we sought to determine the role of TRAIL in angiogenesis and neovascularisation. We also sought mechanisms in vitro . Methods and Results: Reduced vascularisation assessed by real-time in vivo 3D Vevo ultrasound imaging and CD31 staining was observed in TRAIL -/- mice 28 d after hindlimb ischemia. Moreover, reduced capillary formation and increased apoptosis was evident in TRAIL -/- muscles even at 3 d after ischemic surgery. We have previously shown that fibroblast growth factor-2 (FGF-2), a potent angiogenic factor, regulates TRAIL gene expression in vascular smooth muscle cells. Indeed, FGF-2 also regulates TRAIL expression in ECs, and FGF-2-inducible proliferation, migration and tubule formation was inhibited with siRNA targeting TRAIL. Notably, both FGF-2 and TRAIL significantly increased NOX4 expression. TRAIL-inducible angiogenic activity in ECs was inhibited with siRNAs targeting NOX4, and consistent with these, NOX4 mRNA was reduced in 3 d ischemic hindlimbs of TRAIL -/- mice. TRAIL stimulated intracellular H 2 O 2 levels in ECs, and TRAIL-inducible proliferation, migration and tubule formation was inhibited with not only PEG-catalase, a H 2 O 2 scavenger, but also blocked with L-NAME, a nitric oxide synthase inhibitor. Conclusions: This is the first demonstration showing that TRAIL promotes angiogenesis in vivo . We show for the first time that the TRAIL stimulates NOX4 expression to mediate nitric oxide-dependent angiogenic effects. This has significant therapeutic implications such that TRAIL may improve the angiogenic response to ischemia and increase perfusion recovery in patients with CVD and diabetes.

scholarly journals Water-Pipe Smoke Exposure-Induced Circulatory Disturbances in Mice, and the Influence of Betaine Supplementation Thereon

2017 ◽  
Vol 41 (3) ◽  
pp. 1098-1112 ◽  
Author(s):  
Abderrahim Nemmar ◽  
Suhail Al-Salam ◽  
Sumaya Beegam ◽  
Priya Yuvaraju ◽  
Abderrahim Oulhaj ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Plasma Concentrations ◽  
Immunohistochemical Analysis ◽  
Plasminogen Activator Inhibitor ◽  
Water Pipe ◽  
Plasminogen Activator Inhibitor 1 ◽  
Factor Α ◽  
Air Control

Background/Aims: It has been shown, both experimentally and clinically, that water-pipe smoke (WPS) exposure adversely affects the cardiovascular system (CVS) through the generation of oxidative stress and inflammation. Betaine, a naturally occurring compound in common foods, has antioxidant and anti-inflammatory actions. However, its potential to mitigate the adverse effect of WPS on the CVS has never been reported before. This is the subject of this study in mice. Methods: Mice were exposed daily for 30 min to either normal air (control), or to WPS for two consecutive weeks. Betaine was administered daily by gavage at a dose of 10mg/kg, 1h before either air or WPS exposure. Results: Betaine mitigated the in vivo prothrombotic effect of WPS in pial arterioles and venules. Moreover, it reversed the WPS-induced decrease in circulating platelets. Likewise, betaine alleviated platelet aggregation in vitro, and the shortening of activated partial thromboplastin time and prothrombin time induced by WPS. Betaine reduced the increase of plasminogen activator inhibitor-1 and fibrinogen concentrations in plasma induced by WPS. Betaine also diminished the WPS-induced increase of plasma concentrations of interleukin 6 and tumor necrosis factor α, and attenuated the increase of lipid peroxidation and superoxide dismutase. Immunohistochemical analysis of the heart revealed an increase in the expression of inducible nitric oxide synthase and cytochrome C by cardiomyocytes of the WPS-exposed mice. These effects were averted by betaine. Conclusion: Our findings suggest that betaine treatment significantly mitigated WPS-induced hypercoagulability, and inflammation, as well as systemic and cardiac oxidative stress.

Coordinate expression of secretory phospholipase A2 and cyclooxygenase-2 in activated human keratinocytes

2000 ◽  
Vol 278 (4) ◽  
pp. C822-C833 ◽  
Author(s):  
Krystyna E. Rys-Sikora ◽  
Raymond L. Konger ◽  
John W. Schoggins ◽  
Rama Malaviya ◽  
Alice P. Pentland
Keyword(s):  
Wound Repair ◽  
Human Keratinocytes ◽  
Plating Density ◽  
Coordinate Expression ◽  
Cox 2 ◽  
Type V ◽  
In Vitro Wounding

PGE2 levels are altered in human epidermis after in vivo wounding; however, mechanisms modulating PGE2 production in activated keratinocytes are unclear. In previous studies, we showed that PGE2 is a growth-promoting autacoid in human primary keratinocyte cultures, and its production is modulated by plating density, suggesting that regulated PGE2 synthesis is an important component of wound healing. Here, we examine the role of phospholipase A2(PLA2) and cyclooxygenase (COX) enzymes in modulation of PGE2 production. We report that the increased PGE2 production that occurs in keratinocytes grown in nonconfluent conditions is also observed after in vitro wounding, indicating that similar mechanisms are involved. This increase was associated with coordinate upregulation of both COX-2 and secretory PLA2 (sPLA2) proteins. Increased sPLA2 activity was also observed. By RT-PCR, we identified the presence of type IIA and type V sPLA2, along with the M-type sPLA2 receptor. Thus the coordinate expression of sPLA2 and COX-2 may be responsible for the increased prostaglandin synthesis in activated keratinocytes during wound repair.

Ethanol suppresses LPS-induced mRNA for nitric oxide synthase II in alveolar macrophages in vivo and in vitro

Alcohol ◽  
1994 ◽  
Vol 11 (6) ◽  
pp. 539-547 ◽  
Author(s):  
Stanley S. Greenberg ◽  
Jianming Xie ◽  
Ye Wang ◽  
Jay Kolls ◽  
Tadeus Malinski ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Alveolar Macrophages ◽  
Oxide Synthase

scholarly journals A Dual Role for Nitric Oxide in NMDA-Mediated Toxicity in vivo

1995 ◽  
Vol 15 (6) ◽  
pp. 904-913 ◽  
Author(s):  
Mordecai Y.-T. Globus ◽  
Ricardo Prado ◽  
J. Sanchez-Ramos ◽  
Weizhao Zhao ◽  
W. Dalton Dietrich ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Injection Site ◽  
Treated Group ◽  
Lesion Size ◽  
Lesion Volume ◽  
Excitotoxic Damage ◽  
Peripheral Areas ◽  
Oxide Synthase

Nitric oxide has been implicated in N-methyl-d-aspartate (NMDA)-mediated damage in vitro; however, its role in excitotoxic damage in vivo is not clear. In the present study we evaluated the histopathological and hemodynamic consequences of intrastriatal injections of various doses of NMDA and determined the effects of nitric oxide synthase inhibition on these changes. NMDA was injected into the striatum at doses of 50, 150, and 300 nmol with or without Nω-nitro-l-arginine methyl ester (L-NAME; 100 μg, locally). Three days following injections histopathological assessment was performed by morphometric analysis of the lesion area in multiple sections taken from the anterior to the posterior borders of the lesion. In animals injected with 150 and 300 nmol of NMDA (±L-NAME), local CBF (lCBF) was determined 30 min following injections using 14C-iodoantipyrine autoradiography. All NMDA-treated animals showed a well-demarcated lesion extending beyond the injection site. The volume of the lesion correlated significantly with the NMDA dose injected. The effects of L-NAME on lesion size were dependent on the dose of the NMDA. The lesion induced by 50 nmol of NMDA was not affected by L-NAME. With a dose of 150 nmol of NMDA, L-NAME induced a 43% increase in lesion volume. In contrast, a 38% decrease in lesion size was observed in animals treated with 300 nmol of NMDA combined with L-NAME. At a dose of 150 nmol, NMDA induced a significant elevation in lCBF, which was restricted to regions close to the injection site including the center areas of the anterior and middle striatum. The increase in lCBF observed with 150 nmol of NMDA was significantly attenuated in the NMDA + L-NAME-treated group. The lCBF changes induced by 300 nmol of NMDA were not significantly different from those in the 150-nmol group; however, the extent of the regions involved was larger. The increases in lCBF were observed in all striatal regions including the central and peripheral areas. L-NAME did not have a significant effect on the lCBF changes induced by NMDA at a dose of 300 nmol. These data suggest that in vivo the involvement of nitric oxide in NMDA toxicity depends on the NMDA dose and on the participation of hemodynamic mechanisms secondary to NMDA exposure.

Molecular targets of nitric-oxide-donating aspirin in cancer

2005 ◽  
Vol 33 (4) ◽  
pp. 701-704 ◽  
Author(s):  
K. Kashfi ◽  
B. Rigas
Keyword(s):  
Nitric Oxide ◽  
Cell Signalling ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Inhibition Of Proliferation ◽  
Mitogen Activated Protein ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

Nitric-oxide-donating aspirin (NO-ASA), consisting of ASA (aspirin) plus an -ONO2 moiety linked to it via a molecular spacer, is a new drug for cancer prevention. NO-ASA seems to overcome the low potency and toxicity of traditional ASA. The -ONO2 moiety is responsible for releasing NO, and it appears to be required for biological activity. In studies in vitro, NO-ASA inhibits the growth of colon, pancreatic, prostate, lung, skin, leukaemia and breast cancer cells, and is up to 6000-fold more potent than traditional ASA. This effect is owing to cell kinetics [inhibition of proliferation, induction of apoptosis (multiple criteria) and blocking the G1 to S cell-cycle transition] and cell signalling [inhibition of Wnt signalling (IC50=0.2 μM), inhibition of NF-κB (nuclear factor κB) activation (IC50=7.5 μM), inhibition of nitric oxide synthase-2 expression (IC50=48 μM), inhibition of MAPK (mitogen-activated protein kinase) signalling (IC50=10 μM) and induction of cyclo-oxygenase-2 at approx. 10 μM]. In studies in vivo, NO-ASA inhibits intestinal carcinogenesis in Min mice (tumour multiplicity was reduced by 59% after 3 weeks, with no effect in control animals and no side effects) and in the N-nitrosobis(2-oxopropyl)amine model of pancreatic cancer, where there was an 89% reduction in NO-ASA (3000 p.p.m. in the diet)-treated animals (P<0.001). There was no statistically significant effect by traditional ASA at equimolar doses. Our data indicate that NO-ASA is a highly promising agent for the prevention and/or treatment of cancer.

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