scholarly journals Spilanthol Inhibits Inflammatory Transcription Factors and iNOS Expression in Macrophages and Exerts Anti-inflammatory Effects in Dermatitis and Pancreatitis

2019 ◽  
Vol 20 (17) ◽  
pp. 4308 ◽  
Author(s):  
Edina Bakondi ◽  
Salam Bhopen Singh ◽  
Zoltán Hajnády ◽  
Máté Nagy-Pénzes ◽  
Zsolt Regdon ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Transcription Factors ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Interferon Γ ◽  
Inos Expression ◽  
Bioactive Molecules ◽  
Inos Mrna ◽  
No Production ◽  
Anti Inflammatory

Activated macrophages upregulate inducible nitric oxide synthase (iNOS) leading to the profuse production of nitric oxide (NO) and, eventually, tissue damage. Using macrophage NO production as a biochemical marker of inflammation, we tested different parts (flower, leaf, and stem) of the medicinal plant, Spilanthes acmella. We found that extracts prepared from all three parts, especially the flowers, suppressed NO production in RAW macrophages in response to interferon-γ and lipopolysaccharide. Follow up experiments with selected bioactive molecules from the plant (α-amyrin, β-caryophylline, scopoletin, vanillic acid, trans-ferulic acid, and spilanthol) indicated that the N-alkamide, spilanthol, is responsible for the NO-suppressive effects and provides protection from NO-dependent cell death. Spilanthol reduced the expression of iNOS mRNA and protein and, as a possible underlying mechanism, inhibited the activation of several transcription factors (NFκB, ATF4, FOXO1, IRF1, ETS, and AP1) and sensitized cells to downregulation of Smad (TF array experiments). The iNOS inhibitory effect translated into an anti-inflammatory effect, as demonstrated in a phorbol 12-myristate 13-acetate-induced dermatitis and, to a smaller extent, in cerulein-induced pancreatitis. In summary, we demonstrate that spilanthol inhibits iNOS expression, NO production and suppresses inflammatory TFs. These events likely contribute to the observed anti-inflammatory actions of spilanthol in dermatitis and pancreatitis.

scholarly journals Anti-Inflammatory Effects of Flavonoids: Genistein, Kaempferol, Quercetin, and Daidzein Inhibit STAT-1 and NF-κB Activations, Whereas Flavone, Isorhamnetin, Naringenin, and Pelargonidin Inhibit only NF-κB Activation along with Their Inhibitory Effect on iNOS Expression and NO Production in Activated Macrophages

2007 ◽  
Vol 2007 ◽  
pp. 1-10 ◽  
Author(s):  
Mari Hämäläinen ◽  
Riina Nieminen ◽  
Pia Vuorela ◽  
Marina Heinonen ◽  
Eeva Moilanen
Keyword(s):  
Nitric Oxide ◽  
Transcription Factor ◽  
Inhibitory Effect ◽  
Inos Expression ◽  
No Production ◽  
Dependent Manner ◽  
Activated Macrophages ◽  
Naturally Occurring ◽  
Anti Inflammatory ◽  
Oxide Synthase

In inflammation, bacterial products and proinflammatory cytokines induce the formation of large amounts of nitric oxide (NO) by inducible nitric oxide synthase (iNOS), and compounds that inhibit NO production have anti-inflammatory effects. In the present study, we systematically investigated the effects of 36 naturally occurring flavonoids and related compounds on NO production in macrophages exposed to an inflammatory stimulus (lipopolysaccharide, LPS), and evaluated the mechanisms of action of the effective compounds. Flavone, the isoflavones daidzein and genistein, the flavonols isorhamnetin, kaempferol and quercetin, the flavanone naringenin, and the anthocyanin pelargonidin inhibited iNOS protein and mRNA expression and also NO production in a dose-dependent manner. All eight active compounds inhibited the activation of nuclear factor-κB (NF-κB), which is a significant transcription factor for iNOS. Genistein, kaempferol, quercetin, and daidzein also inhibited the activation of the signal transducer and activator of transcription 1 (STAT-1), another important transcription factor for iNOS. The present study characterises the effects and mechanisms of naturally occurring phenolic compounds on iNOS expression and NO production in activated macrophages. The results partially explain the pharmacological efficacy of flavonoids as anti-inflammatory compounds.

scholarly journals Acquired interferon γ responsiveness during Caco-2 cell differentiation: effects on iNOS gene expression

Gut ◽  
1999 ◽  
Vol 44 (5) ◽  
pp. 659-665 ◽  
Author(s):  
A M Chavez ◽  
M J Morin ◽  
N Unno ◽  
M P Fink ◽  
R A Hodin
Keyword(s):  
Nitric Oxide ◽  
Cell Differentiation ◽  
Interferon Γ ◽  
Intestinal Barrier Function ◽  
Inos Mrna ◽  
Pyrrolidine Dithiocarbamate ◽  
No Production ◽  
Mrna Induction ◽  
Ifn Γ ◽  
Inos Induction

BACKGROUNDImpairment of intestinal barrier function occurs under a variety of inflammatory conditions and is mediated at least in part by interferon γ (IFN-γ) induced nitric oxide (NO) production. Previous in vivo studies have shown that systemic lipopolysaccharide treatment caused an induction of the rat inducible nitric oxide synthase (iNOS) mRNA primarily in villus cells, rather than in undifferentiated crypt cells.AIMSTo examine iNOS induction by IFN-γ in vitro as a function of enterocyte differentiation.METHODSPreconfluent and postconfluent Caco-2 cells were treated with IFN-γ in the presence or absence of various inhibitors. Northern analyses were performed to assess the magnitude of iNOS mRNA induction. IFN-γ receptor mRNA and protein levels were determined.RESULTSiNOS mRNA induction by IFN-γ occurred at two hours and was not blocked by cycloheximide, indicating that it is an immediate early response. iNOS induction and nitrite/nitrate increases were inhibited by dexamethasone and pyrrolidine dithiocarbamate, supporting an important role for the NF-κB transcription factor in this process. The stimulated iNOS induction was seen almost exclusively under conditions of cellular differentiation—that is, in postconfluent Caco-2 cells. This increased IFN-γ responsiveness seen in postconfluent Caco-2 cells correlated with an increased expression of IFN-γ receptor, whereas T84 and HT-29 cells did not show any significant alterations in either iNOS induction or IFN-γ receptor levels as a function of postconfluent growth.CONCLUSIONSWith regard to iNOS mRNA induction, IFN-γ responsiveness is acquired during Caco-2 cell differentiation, perhaps related to an increase in the numbers of IFN-γ receptors.

scholarly journals Role of Mitogen-Activated Protein Kinases in Peptidoglycan-Induced Expression of Inducible Nitric Oxide Synthase and Nitric Oxide in Mouse Peritoneal Macrophages: Extracellular Signal-Related Kinase, a Negative Regulator

2011 ◽  
Vol 18 (6) ◽  
pp. 994-1001 ◽  
Author(s):  
Kunal H. Bhatt ◽  
Ajit Sodhi ◽  
Rituparna Chakraborty
Keyword(s):  
Nitric Oxide ◽  
Transcription Factors ◽  
Inos Expression ◽  
No Production ◽  
Erk Pathway ◽  
Mitogen Activated Protein Kinases ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

ABSTRACTThe expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) are important host defense mechanisms against pathogens in mononuclear phagocytes. The objectives of this study were to examine the roles of mitogen-activated protein kinases (MAPKs) and transcription factors (nuclear factor-κB [NF-κB] and activating protein 1 [AP-1]) in peptidoglycan (PGN)-induced iNOS expression and NO production in macrophages. PGN is a cell wall component of Gram-positive bacteria that stimulates inflammatory responses bothex vivoandin vivo. PGN stimulates the activation of all three classes of MAPKs, extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38mapkin macrophages, albeit with differential activation kinetics. Using a selective inhibitor of JNK (SP600125) and JNK1/2 small interfering RNA (siRNA) knocked-down macrophages, it was observed that PGN-induced iNOS and NO expression is significantly inhibited. This suggested that JNK MAPK plays an essential role in PGN-induced iNOS expression and NO production. In contrast, inhibition of the ERK pathway using PD98059 dose dependently enhanced PGN-induced iNOS expression and NO production. PGN-induced ERK activation was attenuated in ERK1/2 siRNA knocked-down macrophages; however, NO and iNOS expression were significantly enhanced. An electrophoretic mobility shift assay showed that SP600125 inhibited PGN-induced NF-κB and AP-1 activation, whereas inhibition of the ERK pathway enhanced NF-κB activation, but with no effect on AP-1. These results indicate that the JNK MAPK positively regulate PGN-induced iNOS and NO expression by activating NF-κB and AP-1 transcription factors, whereas the ERK pathway plays a negative regulatory role via affecting NF-κB activity.

scholarly journals Benzophenone and Benzoylphloroglucinol Derivatives from Hypericum sampsonii with Anti-Inflammatory Mechanism of Otogirinin A

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4463 ◽  
Author(s):  
Chun-Yi Huang ◽  
Tzu-Cheng Chang ◽  
Yu-Jing Wu ◽  
Yun Chen ◽  
Jih-Jung Chen
Keyword(s):  
Nitric Oxide ◽  
Inhibitory Effect ◽  
No Production ◽  
Necrosis Factor Alpha ◽  
Aerial Parts ◽  
Arginase 1 ◽  
Potent Inhibition ◽  
Ic50 Values ◽  
Cytokine Tumor Necrosis Factor ◽  
Anti Inflammatory

Three new compounds, 4-geranyloxy-2-hydroxy-6-isoprenyloxybenzophenone (1), hypericumone A (2) and hypericumone B (3), were obtained from the aerial parts of Hypericum sampsonii, along with six known compounds (4–9). The structures of these compounds were determined through spectroscopic and MS analyses. Hypericumone A (2), sampsonione J (8) and otogirinin A (9) exhibited potent inhibition (IC50 values ≤ 40.32 μM) against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation. Otogirinin A (9) possessed the highest inhibitory effect on NO production with IC50 value of 32.87 ± 1.60 μM. The well-known proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α) was also inhibited by otogirinin A (9). Western blot results demonstrated that otogirinin A (9) downregulated the high expression of inducible nitric oxide synthase (iNOS). Further investigations on the mechanism showed that otogirinin A (9) blocked the phosphorylation of MAPK/JNK and IκBα, whereas it showed no effect on the phosphorylation of MAPKs/ERK and p38. In addition, otogirinin A (9) stimulated anti-inflammatory M2 phenotype by elevating the expression of arginase 1 and Krüppel-like factor 4 (KLF4). The above results suggested that otogirinin A (9) could be considered as potential compound for further development of NO production-targeted anti-inflammatory agent.

Hydrogen peroxide downregulates IL-1-driven mesangial iNOS activity: implications for glomerulonephritis

1997 ◽  
Vol 272 (6) ◽  
pp. F721-F728 ◽  
Author(s):  
E. A. Jaimes ◽  
K. A. Nath ◽  
L. Raij
Keyword(s):  
Nitric Oxide ◽  
Hydrogen Peroxide ◽  
Mesangial Cells ◽  
Interleukin 1 ◽  
Inhibitory Effect ◽  
Inos Mrna ◽  
No Production ◽  
Glomerular Injury ◽  
Inos Activity ◽  
Oxide Synthase

In glomerulonephritides, autacoids such as nitric oxide (NO), reactive oxygen species, and prostanoids are produced in increased amounts in response to cytokines such as interleukin-1 (IL-1). These autacoids influence the expression of glomerular injury by their direct as well as interactive actions. We studied the effect of hydrogen peroxide (H2O2) on NO production in rat mesangial cells. We demonstrate that transient exposure of mesangial cells to H2O2 prior to sustained exposure to IL-1 decreased extracellular accumulation of NO2/NO3 and cellular guanosine 3,'5'-cyclic monophosphate (cGMP) content. H2O2 markedly impaired inducible nitric oxide synthase (iNOS) activity induced by IL-1 directly measured by the conversion of L-[14C]arginine to L-[14C]citrulline. Such impairment in iNOS activity was accompanied by a parallel reduction in iNOS protein abundance but not by a reduced expression of iNOS mRNA. The inhibitory effect of H2O2 on NOS activity was further supported by peroxide-induced impairment in IL-1-driven, NO-dependent synthesis of prostaglandin E2. Our studies thus provide the first direct evidence of a posttranscriptional inhibitory effect of H2O2 on iNOS activity. Additionally, our studies uncover the existence of a previously unrecognized effect of H2O2 on the production of NO that may exert influence on the severity of glomerular injury during glomerular inflammation.

scholarly journals Metabolomic Screening of Anti-Inflammatory Compounds from the Leaves of Actinidia arguta (Hardy Kiwi)

Foods ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 47 ◽  
Author(s):  
Gyoung-Deuck Kim ◽  
Jin Lee ◽  
Joong-Hyuck Auh
Keyword(s):  
Nitric Oxide ◽  
Ethanol Extract ◽  
Inhibitory Effect ◽  
Reversed Phase ◽  
No Production ◽  
Actinidia Arguta ◽  
Bioassay Guided Fractionation ◽  
Anti Inflammatory ◽  
Ethanol Extracts

The metabolomic screening of potential anti-inflammatory compounds in the leaves of Actinidia arguta was performed by using LC-MS/MS. Ethanol extracts were prepared, and the anti-inflammatory effects were investigated based on nitric oxide (NO) synthesis and inducible nitric oxide synthase expression in lipopolysaccharide-induced RAW 264.7 macrophages. The 75% ethanol extract showed the highest inhibitory effect on nitric oxide (NO) production, and it was further separated by in vitro bioassay-guided fractionation using preparative LC with reversed-phase column separation. Through multiple steps of fractionation, sub-fraction 1-3 was finally purified, and caffeic acid derivatives, such as caffeoylthreonic acid and danshensu (salvianic acid A), were successfully identified as key anti-inflammatory compounds by LC-MS/MS and metabolomics analyses. This is the first study identifying anti-inflammatory compounds in A. arguta (Actinidia arguta) leaves through bioassay-guided fractionation and metabolomics screening. Results of this study would be useful for the application of A. arguta leaves as a nutraceutical.

scholarly journals Comparison of Inhibitory Effects of Safflower Decoction and Safflower Injection on Protein and mRNA Expressions of iNOS and IL-1β in LPS-Activated RAW264.7 Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Hui Liao ◽  
Yuanping Li ◽  
Xiaoru Zhai ◽  
Bin Zheng ◽  
Linda Banbury ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
National Standard ◽  
Raw264.7 Cells ◽  
Inos Mrna ◽  
No Production ◽  
Mrna Levels ◽  
Real Time Quantitative Pcr ◽  
Dpph Method ◽  
Anti Inflammatory

Objective. Safflower has antioxidant and anti-inflammatory activities. The two forms of preparations for safflower which are widely used in China are injection and decoction. The first step of the process for preparing an injection involves extracting safflower with water, which actually yields a decoction. This study is intended to investigate how the preparation process influences the anti-inflammatory activity of safflower in vitro. Methods. Five samples, including a decoction (sample 1) and an injection (sample 5) of safflower, were prepared according to the national standard WS3-B-3825-98-2012 and were analyzed by the oxygen radical absorbance capacity (ORAC) method and the 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH) method for comparison. Sample 1 and sample 5 were further tested by the Griess assay and ELISA for their effects on nitric oxide (NO) production and interleukin- (IL-) 1β content in lipopolysaccharide- (LPS-) activated RAW264.7 cells. The protein and mRNA levels of inducible nitric oxide synthase (iNOS) and IL-1β were measured by Western blotting and real-time quantitative PCR. Results. Sample 5 showed a significantly higher ORAC value and a lower half inhibitory concentration (IC50) for DPPH scavenging activity as compared to the other four samples (p<0.05). LPS significantly upregulated the mRNA and protein expressions of iNOS and IL-1β as compared to the solvent control (p<0.01). As compared to sample 1, sample 5 significantly decreased NO production, iNOS protein expression, and the contents of IL-1β mRNA and IL-1β protein at both 100 μg/ml and 200 μg/ml (all: p<0.05) and significantly downregulated iNOS mRNA expression at 100 μg/ml (p<0.05). Conclusions. Results of this study demonstrate that the safflower injection prepared according to the national standard has a significant effect of suppressing protein and mRNA expressions of iNOS and IL-1β as compared to its traditional decoction.

scholarly journals Subtilase Cytotoxin Enhances Escherichia coli Survival in Macrophages by Suppression of Nitric Oxide Production through the Inhibition of NF-κB Activation

2012 ◽  
Vol 80 (11) ◽  
pp. 3939-3951 ◽  
Author(s):  
Hiroyasu Tsutsuki ◽  
Kinnosuke Yahiro ◽  
Kotaro Suzuki ◽  
Akira Suto ◽  
Kohei Ogura ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Escherichia Coli ◽  
Inos Expression ◽  
Inos Mrna ◽  
No Production ◽  
Content Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
E Coli ◽  
Inos Promoter ◽  
Subtilase Cytotoxin

ABSTRACTSubtilase cytotoxin (SubAB), which is produced by certain strains of Shiga-toxigenicEscherichia coli(STEC), cleaves an endoplasmic reticulum (ER) chaperone, BiP/Grp78, leading to induction of ER stress and caspase-dependent apoptosis. SubAB alters the innate immune response. SubAB pretreatment of macrophages inhibited lipopolysaccharide (LPS)-induced production of both monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor α (TNF-α). We investigated here the mechanism by which SubAB inhibits nitric oxide (NO) production by mouse macrophages. SubAB suppressed LPS-induced NO production through inhibition of inducible NO synthase (iNOS) mRNA and protein expression. Further, SubAB inhibited LPS-induced IκB-α phosphorylation and nuclear localization of the nuclear factor-κB (NF-κB) p65/p50 heterodimer. Reporter gene and chromatin immunoprecipitation (ChIP) assays revealed that SubAB reduced LPS-induced NF-κB p65/p50 heterodimer binding to an NF-κB binding site on the iNOS promoter. In contrast to the native toxin, a catalytically inactivated SubAB mutant slightly enhanced LPS-induced iNOS expression and binding of NF-κB subunits to the iNOS promoter. The SubAB effect on LPS-induced iNOS expression was significantly reduced in macrophages from NF-κB1 (p50)-deficient mice, which lacked a DNA-binding subunit of the p65/p50 heterodimer, suggesting that p50 was involved in SubAB-mediated inhibition of iNOS expression. Treatment of macrophages with an NOS inhibitor or expression of SubAB byE. coliincreasedE. colisurvival in macrophages, suggesting that NO generated by macrophages resulted in efficient killing of the bacteria and SubAB contributed toE. colisurvival in macrophages. Thus, we hypothesize that SubAB might represent a novel bacterial strategy to circumvent host defense during STEC infection.

scholarly journals Inhibition of CDKS by roscovitine suppressed LPS-induced ·NO production through inhibiting NFκB activation and BH4 biosynthesis in macrophages

2009 ◽  
Vol 297 (3) ◽  
pp. C742-C749 ◽  
Author(s):  
Jianhai Du ◽  
Na Wei ◽  
Tongju Guan ◽  
Hao Xu ◽  
Jianzhong An ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Diseases ◽  
Nuclear Factor Κb ◽  
Inhibitory Effect ◽  
Peritoneal Macrophages ◽  
Inos Mrna ◽  
No Production ◽  
Iκb Kinase ◽  
Cox 2 ◽  
Oxide Synthase

In inflammatory diseases, tissue damage is critically associated with nitric oxide (·NO) and cytokines, which are overproduced in response to cellular release of endotoxins. Here we investigated the inhibitory effect of roscovitine, a selective inhibitor of cyclin-dependent kinases (CDKs) on ·NO production in mouse macrophages. In RAW264.7 cells, we found that roscovitine abolished the production of ·NO induced by lipopolysaccharide (LPS). Moreover, roscovitine significantly inhibited LPS-induced inducible nitric oxide synthase (iNOS) mRNA and protein expression. Our data also showed that roscovitine attenuated LPS-induced phosphorylation of IκB kinase β (IKKβ), IκB, and p65 but enhanced the phosphorylation of ERK, p38, and c-Jun NH2-terminal kinase (JNK). In addition, roscovitine dose dependently inhibited LPS-induced expression of cyclooxygenase-2 (COX)-2, IL-1β, and IL-6 but not tumor necrosis factor (TNF)-α. Tetrahydrobiopterin (BH4), an essential cofactor for iNOS, is easily oxidized to 7,8-dihydrobiopterin (BH2). Roscovitine significantly inhibited LPS-induced BH4 biosynthesis and decreased BH4-to-BH2 ratio. Furthermore, roscovitine greatly reduced the upregulation of GTP cyclohydrolase-1 (GCH-1), the rate-limiting enzyme for BH4 biosynthesis. Using other CDK inhibitors, we found that CDK1, CDK5, and CDK7, but not CDK2, significantly inhibited LPS-induced ·NO production in macrophages. Similarly, in isolated peritoneal macrophages, roscovitine strongly inhibited ·NO production, iNOS, and COX-2 upregulation, activation of NFκB, and induction of GCH-1 by LPS. Together, our data indicate that roscovitine abolishes LPS-induced ·NO production in macrophages by suppressing nuclear factor-κB activation and BH4 biosynthesis, which might be mediated by CDK1, CDK5, and CDK7. Our results also suggest that roscovitine may inhibit inflammation and that CDKs may play important roles in the mechanisms by which roscovitine attenuates inflammation.

scholarly journals Anti-inflammatory potential of Portuguese thermal waters

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
A. Silva ◽  
A. S. Oliveira ◽  
C. V. Vaz ◽  
S. Correia ◽  
R. Ferreira ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Inos Expression ◽  
Mineral Waters ◽  
Thermal Waters ◽  
No Production ◽  
Inflammatory Parameters ◽  
Anti Inflammatory ◽  
Almost All ◽  
Oxide Synthase

AbstractIn light of Medical Hydrology, thermal waters (TW) are all-natural mineral waters that emerge inside a thermal resort and have therapeutic applications. Their beneficial effect has been empirically recognized for centuries, being indicated for symptom alleviation and/or treatment of several diseases, almost all associated with inflammation. Indeed, an anti-inflammatory effect has been attributed to many different Portuguese TW but there is no scientific validation supporting this empiric knowledge. In the present study, we aimed to investigate the anti-inflammatory properties of 14 TW pertaining to thermal centers located in the Central Region of Portugal, and grouped according to their ionic profile. Mouse macrophage cells stimulated with lipopolysaccharide (LPS), a Toll-like receptor 4 agonist, were exposed to culture medium prepared in TW. Metabolism, nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) expression levels and the scavenging capacity of TW, were investigated in vitro. 11 out of 14 TW reduced NO production and/or iNOS expression, and/or scavenging activity, in macrophages exposed to LPS. The sulphated/calcic TW did not show any effect on at least one of the inflammatory parameters evaluated. Two sulphurous/bicarbonate/sodic TW and the sulphurous/chlorinated/sodic TW promoted an increase in NO production and/or iNOS expression. Our results validate, for the first time, the anti-inflammatory properties of Portuguese TW, supporting their therapeutic use in the treatment of inflammation-related diseases and promoting their putative application in cosmetic products and medical devices.

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