• Journal of Korean Society for Atmospheric Environment
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• v.18 no.E2
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• pp.121-128
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• 2002

This study was carried out to investigate if nitric oxide synthase (NOS) inhibitors modulate airway inflammation induced by diesel exhaust particles (DEP). N$\^$G/-nitro-L-arginine methyl ester (L-NAME), a potent constitutive NOS (cNOS) inhibitor, and aminoguanidine (AG), a selective inducible NOS (iNOS) inhibitor, were administered to mice in their drinking water for 7 weeks. Airway inflammation was elicited by the repeated intratracheal administration of DEP. The results showed that macrophages, inflammatory eosinophils and neutrophils in bronchoalveolar lavage (BAL) fluids by intratracheal DEP instillation were significantly suppressed in the mice treated with two NOS inhibitors toghther with DEP. The suppression of these cells was more effective in AG treated groups than in L -NAME treated groups. NOS inhibitor treatment also reduced interleukin -5 (IL-5 in the BAL fluids and lung homogenates. Additionally, it was found that eosinophil peroxidase (EPO) activity in the BAL fluids was also decreased by NOS inhibitor treatment. These results suggest that nitric oxide (NO) is produced in airway inflammation by repeated DEP instillation, and that iNOS inhibition as well as cNOS inhibition can play a modulating role in this airway inflammation by DEP.

• The Korean Journal of Pharmacology
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• v.31 no.2
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• pp.233-239
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• 1995

To verify the effect of immunosuppressants on the endotoxin-induced increase in iNOS activity, the action of immunosuppressants, dexamethasone (1.5 mg/kg), azathioprine (5 mg/kg/day) and cyclosporine (10 mg/kg), were evaluated in mice pretreated with LPS. The intraperitoneal injection of lipopolysaccharide (10 mg/kg) increased the nitric oxide synthase (NOS) activity in the brain and liver to maximum at 1 and 3 hours, respectively. The increase in NOS activity was blocked by the treatment with NOS inhibitor, LNAME(300 mg/kg) and aminoguanidine(100 mg/kg); a protein inhibitor, cycloheximide (10 mg/kg); and a transcription inhibitor of inducible NOS(iNOS), dexamethasone(1.5 mg/kg). Immunosuppressants, azathioprine (5 mg/kg) and cyclosporine (10 mg/kg), effectively blocked the increase in NOS activity. These results suggest that iNOS expression plays an important role in LPS-induced the increase in NOS activity and that immunosuppressants can be used as candidate for therapeutic agents in endotoxemia.

• Biomolecules & Therapeutics
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• v.14 no.3
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• pp.143-147
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• 2006

In the mouse leukemic monocyte cell line RAW 264.7, the vacuolar-type $(H^+)$-ATPase (V-ATPase) inhibitor bafilomycin $A_1$ at 10 and 100 nM decreased cell growth and survival as determined by 3-(4,5-dimethyl(thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in a concentration-dependent manner. At such concentrations, bafilomycin $A_1$ induced nitric oxide (NO) production through the expression of inducible nitric oxide synthase (iNOS). The bafilomycin $A_1$-induced NO production was inhibited by the NOS inhibitor $N^G$-monomethyl-L-arginine acetate (L-NMMA). Our findings suggest that the V-ATPase inhibitor bafilomycin $A_1$ induces NO production through the expression of iNOS protein.

• The Korean Journal of Physiology and Pharmacology
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• v.7 no.5
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• pp.283-287
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• 2003

While nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) is beneficial for host survival, it is also detrimental to the host. Thus, regulation of iNOS gene expression may be an effective therapeutic strategy for the prevention of unwanted reactions at various pathologic conditions. During the screening process for the possible iNOS regulators, we observed that esculetin is a potent inhibitor of cytokine-induced iNOS expression. The treatment of 3T3-L1 adipocytes with the tumor necrosis factor-${\alpha}$ (TNF) induced iNOS expression, leading to enhanced NO production. TNF-induced NO production was inhibited by esculetin in a dose-dependent manner. Esculetin inhibited the TNF-induced NO production at the transcriptional level through suppression of iNOS mRNA and subsequent iNOS protein expression. These results suggest esculetin, a component of natural products, as a naturally occurring, nontoxic means to attenuate iNOS expression and NO-mediated cytotoxicity.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.4
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• pp.265-271
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• 2009

Nitric oxide (NO) has both neuroprotective and neurotoxic effects depending on its concentration and the experimental model. We tested the effects of NG-nitro-L-arginine methyl ester (L-NAME), a nonselective nitric oxide synthase (NOS) inhibitor, and aminoguanidine, a selective inducible NOS (iNOS) inhibitor, on kainic acid (KA)-induced seizures and hippocampal CA3 neuronal death. L-NAME (50 mg/kg, i.p.) and/or aminoguanidine (200 mg/kg, i.p.) were administered 1 h prior to the intracerebroventricular (i.c.v.) injection of KA. Pretreatment with L-NAME significantly increased KA-induced CA3 neuronal death, iNOS expression, and activation of microglia. However, pretreatment with aminoguanidine significantly suppressed both the KA-induced and L-NAME-aggravated hippocampal CA3 neuronal death with concomitant decreases in iNOS expression and microglial activation. The protective effect of aminoguanidine was maintained for up to 2 weeks. Furthermore, iNOS knockout mice ($iNOS^{-1-}$) were resistant to KA-induced neuronal death. The present study demonstrates that aminoguanidine attenuates KA-induced neuronal death, whereas L-NAME aggravates neuronal death, in the CA3 region of the hippocampus, suggesting that NOS isoforms play different roles in KA-induced excitotoxicity.

• Journal of dental hygiene science
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• v.15 no.6
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• pp.753-760
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• 2015

Although nuclear factor of activated T cell (NFAT) plays a key role in inflammation, its anti-inflammatory effects and mechanism of action in periodontitis are still unknown. This study aimed to identify the effects of NFAT on the proinflammatory mediators activated by lipopolysaccharide (LPS) plus nicotine stimulation in human periodontal ligament cells (hPDLCs). The production of nitric oxide (NO) and prostaglandin $E_2(PGE_2)$ was evaluated using Griess reagent and an enzyme immunoassay, respectively. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and NFAT proteins was evaluated by Western blot analysis. LPS plus nicotine synergistically induced the production of NO and $PGE_2$ and increased the protein expression of iNOS, COX-2 and NFAT. Treatment with an NFAT inhibitor blocked the LPS plus nicotine-stimulated NO and $PGE_2$ release as well as the expression of iNOS and COX-2. Our data suggest that the LPS plus nicotine-induced inflammatory effects on hPDLCs may act through a novel mechanism involving the action of NFAT. Thus, NFAT may provide a potential therapeutic target for the treatment of periodontal disease associated with smoking and dental plaque.

• Archives of Pharmacal Research
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• v.25 no.2
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• pp.151-153
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• 2002

Three pseudoguaianolide type sesquiterpenes, bigelovin(1), 2,3-dihydroaromaticin (2), and ergolide (3) were isolated as inhibitory constituents against inducible nitric oxide synthase (iNOS) from the flowers of Inula britannica var. chinensis. Bigelovin (1) exhibited a highly potent inhibitory activity on lipopolysaccharide (LPS)-induced iNOS in murine macrophage RAW 264.7 cells with an $IC_{50}$ value of 0.46 mM, which is about 8 times more potent than the known selective inhibitor of iNOS, $L-N^6-(1-iminoethyl)Iysine{\;}(IC_{50}{\;}3.49{\;}{\mu}M)$. 2,3-Dihydroaromaticin (2) and ergolide (3) also exhibited potent inhibitory activities on LPS-induced iNOS with $IC_{50}$ values of 1.05 and $0.69{\;}{\mu}M$, respectively.

• Biomedical Science Letters
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• v.29 no.2
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• pp.66-74
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• 2023

Triglyceride (TG) accumulation can cause monocytic death and suppress innate immunity. However, the signaling pathways involved in this phenomenon are not fully understood. This study aimed to examine whether inducible nitric oxide synthase (iNOS) is involved in the TG-induced death of THP-1 monocytes. Results showed that iNOS was upregulated in TG-treated THP-1 monocytes, and iNOS inhibition blocked TG-induced monocytic death. In addition, TG-induced poly (ADP-ribose) polymerase (PARP) cleavage and caspase-3 and -7 activation were suppressed by iNOS inhibition. Furthermore, the expression of X-linked inhibitor of apoptosis protein (XIAP) and survivin, which inhibit caspase-3 and -7, was reduced in TG-treated THP-1 monocytes, but iNOS inhibition recovered the TG-induced downregulation of XIAP and survivin expression. Considering that TG-induced monocytic death is triggered by caspase2 and -8, we investigated whether caspase-2 and -8 are linked to the TG-induced expression of iNOS in THP-1 monocytes. When the activities of caspase-2 and -8 were inhibited by specific inhibitors, the TG-induced upregulation of iNOS and downregulation of XIAP and survivin were restored in THP-1 monocytes. These results suggest that TG-induced monocytic death is mediated by the caspase-2/caspase-8/iNOS/XIAP and survivin/executioner caspase/PARP pathways.

• Archives of Reconstructive Microsurgery
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• v.15 no.1
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• pp.1-9
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• 2006

The purpose of this study is to determine the effects of selective inducible nitric oxide synthase (iNOS) inhibitor N-[3-aminomethyl]benzyl]acetamidine (l400W) on the reperfused cremaster muscle. The extracellular superoxide dismutase knockout ($EC-SOD^{-/-}$) mice was used to make the experimental window for ischemia-reperfusion injury. The muscle was exposed to 4.5 h of ischemia followed by 90 min of reperfusion and the mice received either 3 mg/kg of 1400W or the same amount of phosphate buffered saline (PBS) subcutaneously at 10 min before the start of reperfusion. The results showed that 1400W treatment markedly improved the recovery of the vessel diameter and blood flow in the reperfused cremaster muscle compared to that of PBS group. Histological examination showed reduced edema in the interstitium and muscle fiber, and reduced nitrotyrosine formation (a marker of total peroxinitrite ($ONOO^-$) in 1400W-treated muscle compared to PBS. Our results suggest that iNOS and $ONOO^-$ products are involved in skeletal muscle I/R injury. Reduced I/R injury by using selective inhibition of iNOS is perhaps via limiting cytotoxic $ONOO^-$ generation, a reaction product of nitric oxide (NO) and superoxide anion ($O_2^-$). Thus, inhibition of iNOS appears to be a good treatment strategy in reducing clinical I/R injury.

• Toxicological Research
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• v.21 no.4
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• pp.285-290
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• 2005

We demonstrate that radicicol, a macrocyclic antifungal antibiotic originally isolated from Monosporium bonorden, inhibits LPS-induced expression of iNOS gene in RAW 264.7 cells. Treatment of peritoneal macrophages and RAW 264.7 cells with radicicol inhibited LPS-stimulated nitric oxide production in a dose-related manner. Immunohistochemical staining of iNOS and RTPCR analysis showed that the decrease of NO was due to the inhibition of iNOS gene expression in RAW 264.7 cells. Immunostaining of p65, EMSA, and reporter gene assay showed that radicicol inhibited $NF-\kappa/Rel$ nuclear translocation. DNA binding, and transcriptional activation, respectively. Collectively, these series of experiments indicate that radicicol inhibits iNOS gene expression by blocking $NF-\kappa/Rel$ nuclear translocation. Due to the critical role that NO release plays in mediating inflammatory responses, the inhibitory effects of radicicol on iNOS suggest that radicicol may represent a useful anti-inflammatory agent.