scholarly journals Bioactive α-Pyrone Derivatives from the Endophytic Fungus Diaporthe sp. CB10100 as Inducible Nitric Oxide Synthase Inhibitors

2021 ◽  
Vol 9 ◽  
Author(s):  
Hong Pu ◽  
Jianxin Liu ◽  
Yeji Wang ◽  
Yuhui Peng ◽  
Wanying Zheng ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Ellagic Acid ◽  
Endophytic Fungus ◽  
Dependent Manner ◽  
Protein Levels ◽  
Inos Inhibitors ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Inducible nitric oxide synthase (iNOS) produces NO from l-arginine and plays critical roles in inflammation and immune activation. Selective and potent iNOS inhibitors may be potentially used in many indications, such as rheumatoid arthritis, pain, and neurodegeration. In the current study, five new compounds, including a dibenzo-α- pyrone derivative ellagic acid B (5) and four α-pyrones diaporpyrone A–D (9–12), together with three known compounds (6–8), were isolated from the endophytic fungus Diaporthe sp. CB10100. The structures of these new natural products were unambiguously elucidated using NMR, HRESIMS or electronic circular dichroism calculations. Ellagic acid B (5) features a tetracyclic 6/6/6/6 ring system with a fused 2H-chromene, which is different from ellagic acid (4) with a fused 2H-chromen-2-one. Both 2-hydroxy-alternariol (6) and alternariol (7) reduced the expression of iNOS at protein levels in a dose-dependent manner, using a lipopolysaccharide (LPS)-induced RAW264.7 cell models. Also, they decreased the protein expression levels of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6 and monocyte chemotactic protein 1. Importantly, 6 and 7 significantly reduced the production of NO as low as 10 μM in LPS-induced RAW264.7 cells. Molecular docking of 6 and 7 to iNOS further suggests that both of them may interact with iNOS. Our study suggests that 6 and 7, as well as the alternariol scaffold may be further developed as potential iNOS inhibitors.

scholarly journals Activation of Nuclear Factor κB and Induction of Inducible Nitric Oxide Synthase by Ureaplasma urealyticumin Macrophages

2000 ◽  
Vol 68 (12) ◽  
pp. 7087-7093 ◽  
Author(s):  
Y.-H. Li ◽  
Z.-Q. Yan ◽  
J. Skov Jensen ◽  
K. Tullus ◽  
A. Brauner
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Alveolar Macrophages ◽  
Nuclear Factor Κb ◽  
Inos Expression ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

ABSTRACT Chronic lung disease (CLD) of prematurity is an inflammatory disease with a multifactorial etiology. The importance ofUreaplasma urealyticum in the development of CLD is debated, and steroids produce some improvement in neonates with this disease. In the present study, the capability of U. urealyticum to stimulate rat alveolar macrophages to produce nitric oxide (NO), express inducible nitric oxide synthase (iNOS), and activate nuclear factor κB (NF-κB) in vitro was characterized. The effect of NO on the growth of U. urealyticum was also investigated. In addition, the impact of dexamethasone and budesonide on these processes was examined. We found that U. urealyticum antigen (≥4 × 107 color-changing units/ml) stimulated alveolar macrophages to produce NO in a dose- and time-dependent manner (P < 0.05). This effect was further enhanced by gamma interferon (100 IU/ml; P < 0.05) but was attenuated by budesonide and dexamethasone (10−4 to 10−6 M) (P < 0.05). The mRNA and protein levels of iNOS were also induced in response to U. urealyticum and inhibited by steroids.U. urealyticum antigen triggered NF-κB activation, a possible mechanism for the induced iNOS expression, which also was inhibited by steroids. NO induced by U. urealyticum caused a sixfold reduction of its own growth after infection for 10 h. Our findings imply that U. urealyticum may be an important factor in the development of CLD. The host defense response againstU. urealyticum infection may also be influenced by NO. The down-regulatory effect of steroids on NF-κB activation, iNOS expression, and NO production might partly explain the beneficial effect of steroids in neonates with CLD.

Withapubesides A–D: natural inducible nitric oxide synthase (iNOS) inhibitors from Physalis pubescens

2017 ◽  
Vol 15 (47) ◽  
pp. 10016-10023 ◽  
Author(s):  
Gui-Yang Xia ◽  
Tie Yao ◽  
Bing-Yang Zhang ◽  
Yang Li ◽  
Ning Kang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Inos Inhibitors ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Withapubesides A–D (1–4), candidates for the development of iNOS inhibitors, were isolated from Physalis pubescens.

scholarly journals Heme Oxygenase-1 Induction Attenuates Inducible Nitric Oxide Synthase Expression and Proteinuria in Glomerulonephritis

1999 ◽  
Vol 10 (12) ◽  
pp. 2540-2550
Author(s):  
PRASUN K. DATTA ◽  
SEVASTI B. KOUKOURITAKI ◽  
KATHLEEN A. HOPP ◽  
ELIAS A. LIANOS
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Heme Oxygenase ◽  
Inducible Nitric Oxide Synthase ◽  
Inos Expression ◽  
Heme Oxygenase 1 ◽  
Inos Activity ◽  
Protein Levels ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Abstract. In glomerulonephritis, there is intraglomerular activation of inducible nitric oxide synthase (iNOS) leading to high output production of nitric oxide (NO). This can result in supraphysiologic amounts of NO and cause oxidative injury. It is unknown whether mechanisms of cellular defense against NO-mediated injury exist. Induction of the heme catabolizing enzyme heme oxygenase-1 (HO-1), which generates biliverdin, carbon monoxide (CO), and iron (Fe), may provide such a mechanism, as CO and Fe are two negative modulators of iNOS activity and expression. This study assessed whether upregulation of HO-1 by a specific inducer, hemin, negatively modulates iNOS expression and activity in anti-glomerular basement membrane antibody-mediated glomerulonephritis. Glomerular HO-1 expression in nephritic animals was upregulated by treatment with hemin (30 μmol/kg body wt). iNOS and HO-1 mRNA expression were assessed by reverse transcription-PCR of glomerular total RNA from nephritic animals or nephritic animals pretreated with hemin. iNOS activity in glomeruli was measured by assessing conversion of [14C] L-arginine to [14C] L-citrulline. HO-1 protein levels in glomeruli were assessed by Western blot analysis. The effect of hemin treatment on monocyte/macrophage infiltration was assessed by enumeration of ED-1-positive cells in nephritic glomeruli. iNOS and HO-1 were coinduced in nephritic glomeruli. Hemin treatment of nephritic animals resulted in upregulation of glomerular HO-1 levels and a two- to threefold reduction in glomerular iNOS mRNA levels. iNOS activity in glomeruli was significantly reduced in hemin-treated nephritic animals in which proteinuria was also attenuated without a change in monocyte/macrophage infiltration. Hemin (100 to 200 μM) also reduced iNOS protein levels and enzyme activity in cultured mesangial cells stimulated with cytokines. These studies demonstrate that in glomerular immune injury, hemin treatment upregulates glomerular HO-1 with an attendant downregulation of iNOS expression, and thus points to regulatory interaction between the two systems. The beneficial effect of hemin treatment on proteinuria could be linked to downregulation of iNOS.

scholarly journals Molecular cloning and characterization of Ca2+-dependent inducible nitric oxide synthase from guinea-pig lung

1998 ◽  
Vol 333 (3) ◽  
pp. 795-799 ◽  
Author(s):  
Manabu SHIRATO ◽  
Tohru SAKAMOTO ◽  
Yoshiyuki UCHIDA ◽  
Akihiro NOMURA ◽  
Yukio ISHII ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Amino Acid ◽  
Nitric Oxide Synthase ◽  
Guinea Pig ◽  
Inducible Nitric Oxide Synthase ◽  
Inos Mrna ◽  
Dependent Manner ◽  
Calmodulin Antagonist ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

We have isolated a full-length cDNA for an inducible nitric oxide synthase (iNOS) from guinea-pig lung. The cDNA has a 3447 bp open reading frame encoding 1149 amino acid residues. The deduced amino acid sequence is approx. 80% identical with iNOS of human epithelial cells and murine macrophages. Consensus recognition sites for cofactors are highly conserved. COS cell lysate transfected with the guinea-pig iNOS shows significant levels of nitric oxide synthase (NOS) activity, and this is inhibited by 79% by chelation of Ca2+ ions. The NOS activity is restored in a concentration-dependent manner by increasing the free Ca2+ level. The NOS activity is also inhibited by trifluoperazine, a calmodulin antagonist, which suggests that the Ca2+ dependence is due to Ca2+-dependent calmodulin binding to the enzyme. Northern blot analysis reveals that the cloned iNOS mRNA is expressed in the lung and the colon in normal guinea pigs. Stimulation in vivo by lipopolysaccharide induces the expression of iNOS in the kidney, the spleen and the colon, but in the lung the same stimulation decreases its expression. These results suggest that the cloned guinea-pig iNOS is distinct in characteristics and expression from previously described iNOS forms.

scholarly journals Selective Inhibitors of the Inducible Nitric Oxide Synthase as Modulators of Cell Responses in LPS-Stimulated Human Monocytes

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4419
Author(s):  
Marialucia Gallorini ◽  
Monica Rapino ◽  
Helmut Schweikl ◽  
Amelia Cataldi ◽  
Rosa Amoroso ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Human Monocytes ◽  
Monocyte Migration ◽  
Therapeutic Value ◽  
Monocyte Cell ◽  
Inos Inhibitors ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Inducible nitric oxide synthase (iNOS) is a crucial enzyme involved in monocyte cell response towards inflammation, and it is responsible for the production of sustained amounts of nitric oxide. This free radical molecule is involved in the defense against pathogens; nevertheless, its continuous and dysregulated production contributes to the development of several pathological conditions, including inflammatory and autoimmune diseases. In the present study, we investigated the effects of two new iNOS inhibitors, i.e., 4-(ethanimidoylamino)-N-(4-fluorophenyl)benzamide hydrobromide (FAB1020) and N-{3-[(ethanimidoylamino)methyl]benzyl}-l-prolinamidedihydrochloride (CM554), on human LPS-stimulated monocytes, using the 1400 W compound as a comparison. Our results show that CM544 and FAB1020 are selective and decrease cytotoxicity, IL-6 secretion and LPS-stimulated monocyte migration. Furthermore, the modulation of iNOS, nitrotyrosine and Nrf2 were analyzed at the protein level. Based on the collected preliminary results, the promising therapeutic value of the investigated compounds emerges, as they appear able to modulate the pro-inflammatory LPS-stimulated response in the low micromolar range in human monocytes.

Phenylpyrrole derivatives as neural and inducible nitric oxide synthase (nNOS and iNOS) inhibitors

2009 ◽  
Vol 44 (6) ◽  
pp. 2655-2666 ◽  
Author(s):  
Luisa C. López Cara ◽  
M. Encarnación Camacho ◽  
M. Dora Carrión ◽  
Víctor Tapias ◽  
Miguel A. Gallo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Inos Inhibitors ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Abstract 148: Superoxide Promotes Reversible Uncoupling Of Inducible Nitric Oxide Synthase, While Peroxynitrite Induces Irreversible And Complete Enzyme Inactivation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jian Sun ◽  
Lawrence J Druhan ◽  
Jay L Zweier
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Enzyme Inactivation ◽  
No Production ◽  
Dependent Manner ◽  
Inos Activity ◽  
Activity Loss ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Inducible nitric oxide synthase (iNOS) is present in the post-ischemic heart, and plays an important role in the pathogenesis of injury and remodeling. Oxidants formed during reperfusion injury are known to alter NOS function. In this study we compare and contrast how two biologically relevant oxidants, peroxynitrite (ONOO − ) and superoxide (O 2 − ), alter iNOS function and define the mechanisms involved for each. Nitric oxide (NO) generation rate of purified iNOS was quantified by the methemoglobin formation, O 2 −. generation was measured using EPR spin-trapping, and the quaternary structure of iNOS by size-exclusion FPLC. Tetrahydrobiopterin (BH 4 )-replete iNOS (1 μM) was exposed to O 2 −. , and ONOO − in concentrations from 0.01 μM to 500μM and NO production was measured with and without addition of excess BH 4 . ONOO − (50μM) decreased NO production to 19% ± 0.17 and excess BH 4 only partially restored activity to 48% ± 3.4. O 2 −. (50 μM) reduced NO production to 42% ± 1.2 and the excess BH 4 completely restored activity to 100% ± 3.1. ONOO − exerted the highest decrease in NO production rate (96% ± 1.3 activity loss at 500 μM ONOO − ) and no activity was restored by excess BH 4 . In contrast, O 2 −. induced a significant decrease (90% ± 1.2 activity loss at 500 μM O 2 −. ), however excess BH 4 restored the iNOS activity back to 69% ± 5.6.O 2 −. exposure enhanced O 2 −. production from iNOS (up to 155% ± 0.72 at 50 μM O 2 −. ), while ONOO − at higher concentrations (>20μM) reduced O 2 −. production (10% ± 3.2 decrease at 50 μM ONOO − ). We also found that incubation with ONOO − and O 2 −. induced iNOS monomerization. In conclusion, both ONOO − and O 2 −. decrease iNOS NO production in a dose dependent manner. Adding excess BH 4 only partially restore the loss of NO production induced by ONOO − , but almost completely restore the loss of NO production induced by O 2 −.. Therefore, O 2 −. promotes the uncoupling of iNOS and elevates O 2 −. production by oxidizing the protein bound BH 4 with subsequent formation of NOS monomer in a reversible fashion. Conversely, ONOO − induces irreversible enzyme inactivation and decreases both NO and O 2 −. production. Although oxidation of BH 4 is involved in the observed ONOO − induced loss of iNOS activity, there are other causes, including oxidation of critical amino acid residues.

scholarly journals Inducible Nitric Oxide Synthase Does Not Affect Resolution of Murine Chlamydial Genital Tract Infections or Eradication of Chlamydiae in Primary Murine Cell Culture

1998 ◽  
Vol 66 (2) ◽  
pp. 835-838 ◽  
Author(s):  
Kyle H. Ramsey ◽  
Gurwattan S. Miranpuri ◽  
Christoffer E. Poulsen ◽  
Nancy B. Marthakis ◽  
Laima M. Braune ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Genital Tract ◽  
Murine Cell ◽  
Genital Tract Infections ◽  
Inos Inhibitors ◽  
Tract Infections ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

ABSTRACT Mice lacking inducible nitric oxide synthase (iNOS) or treated with iNOS inhibitors resolved chlamydial genital tract infections. Additionally, treatment of primary murine cell cultures with gamma interferon restricted chlamydial growth in the absence of nitric oxide. From these results, iNOS activity is unnecessary for the resolution of chlamydial genital tract infections in mice and inhibition of chlamydial growth in culture.

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