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Antioxidant Down-Regulates Interleukin-18 Expression in Asthma
Lee, Kyung Sun,Kim, So Ri,Park, Seoung Ju,Min, Kyung Hoon,Lee, Ka Young,Jin, Sun Mi,Yoo, Wan Hee,Lee, Yong Chul American Society for PharmacologyExperimental Ther 2006 Molecular pharmacology Vol.70 No.4
<P>An alteration in the balance between a T-helper type 2 cell (Th2) response and a Th1 response may predispose to the development of bronchial asthma. Interleukin-18 (IL-18) has an ability to promote both Th1 and Th2 responses, depending on the surrounding cytokine environment. Reactive oxygen species (ROS) play a crucial role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of asthma. In this study, we used a C57BL/6 mouse model of allergic asthma to examine the effects of antioxidants on the regulation of IL-18 expression. Our present study with ovalbumin-induced murine model of asthma revealed that ROS production in cells from bronchoalveolar lavage fluids was increased and that administration of L-2-oxothiazolidine-4-carboxylic acid or alpha-lipoic acid reduced the increased levels of ROS, the increased expression of IL-18 protein and mRNA, airway inflammation, and bronchial hyperresponsiveness. Our results also showed that antioxidants down-regulated a transcription factor, nuclear factor-kappaB (NF-kappaB), activity. These results indicate that antioxidants may reduce IL-18 expression in asthma by inhibiting the activity of NF-kappaB and suggest that ROS regulate the IL-18 expression.</P>
Park, Young-Kwon,Ahn, Dae-Ro,Oh, Myoungsuk,Lee, Taekyoung,Yang, Eun Gyeong,Son, Miwon,Park, Hyunsung American Society for PharmacologyExperimental Ther 2008 Molecular pharmacology Vol.74 No.1
<P>We have confirmed that the NO donor (+/-)-S-nitroso-N-acetylpenicillamine (SNAP) stabilizes the transactive form of hypoxia-inducible factor-1alpha (HIF-1alpha), leading to the induction of HIF-1alpha target genes such as vascular endothelial growth factor and carbonic anhydrase 9. Activation of HIF-1alpha should require inhibition of the dual system that keeps it inactive. One is ubiquitination, which is triggered by hydroxylation of HIF-1alpha-proline and the subsequent binding of E3 ubiquitin ligase, the von Hippel Lindau (VHL) protein. The other is hydroxylation of HIF-1alpha-asparagine, which reduces the affinity of HIF-1alpha for its coactivator, cAMP responsive element binding protein/p300. We examined the effects of the NO donor SNAP on proline and asparagine hydroxylation of HIF-1alpha peptides by measuring the activities of the corresponding enzymes, HIF-1alpha-specific proline hydroxylase 2 (PHD2) and the HIF-1alpha-specific asparagine hydroxylase, designated factor inhibiting HIF-1alpha (FIH-1), respectively. We found that the SNAP did not prevent PHD2 from hydroxylating the proline of HIF-1alpha. Instead, it blocked the interaction between VHL and the proline-hydroxylated HIF-1alpha, but only when the reducing agents Fe(II) and vitamin C were limiting. The fact that the absence of cysteine 520 of HIF-1alpha abolishes its responsiveness to SNAP suggests that this residue mediates the inhibition by SNAP of the interaction between VHL and HIF-1alpha, presumably by S-nitrosylation of HIF-1alpha. Un-like PHD2, asparagine hydroxylation by FIH-1 was directly inhibited by SNAP, but again only when reducing agents were limiting. Substitution of cysteine 800 of HIF-1alpha with alanine failed to reverse the inhibitory effects of SNAP on asparagine hydroxylation, implying that FIH-1, not its substrate HIF-1alpha, is inhibited by SNAP.</P>
Lee, Kyung Sun,Kim, So Ri,Park, Seoung Ju,Lee, Ho Kyung,Park, Hee Sun,Min, Kyung Hoon,Jin, Sun Mi,Lee, Yong Chul American Society for PharmacologyExperimental Ther 2006 Molecular pharmacology Vol.69 No.6
<P>Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of bronchial asthma. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has been implicated in regulating cell survival signaling through the phosphoinositide 3-kinase (PI3K)/Akt pathway. The key role of PI3K in VEGF-mediated signal transduction is established. However, the effects of PTEN on VEGF-mediated signaling in asthma are unknown. This study aimed to determine the effect of PI3K inhibitors and PTEN on VEGF expression in allergen-induced airway inflammation. We have used a female C57BL/6 mouse model for asthma to determine the role of PTEN in allergen-induced airway inflammation, specifically in the expression of VEGF. Allergen-induced airway inflammation leads to increased activity of PI3K in lung tissue. These mice develop the following typical pathophysiological features of asthma in the lungs: increased numbers of inflammatory cells of the airways; airway hyper-responsiveness; increased expression of interleukin (IL)-4, IL-5, IL-13, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, regulated on activation normal T cell expressed and secreted (RANTES), and eotaxin; increased vascular permeability; and increased levels of VEGF. Administration of PI3K inhibitors or adenoviruses carrying PTEN cDNA reduced the symptoms of asthma and decreased the increased levels of plasma extravasation and VEGF in allergen-induced asthmatic lungs. These results indicate that PTEN reduces VEGF expression in allergen-induced airway inflammation.</P>
Choi, Hyunsung,Chun, Yang-Sook,Kim, Seung-Won,Kim, Myung-Suk,Park, Jong-Wan American Society for PharmacologyExperimental Ther 2006 Molecular pharmacology Vol.70 No.5
<P>Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1alpha and aryl hydrocarbon receptor nuclear translocator (ARNT), plays a key role in cell survival and angiogenesis in hypoxic tumors, and many efforts have been made to develop anticancer agents that target HIF-1alpha. However, although ARNT is also required for HIF-1 activity, ARNT has been disregarded as a therapeutic target. Curcumin is a commonly used spice and coloring agent with a variety of beneficial biological effects, which include tumor inhibition. In the present study, we tested the possibility that curcumin inhibits tumor growth by targeting HIF-1. The effects of curcumin on HIF-1 activity and expression were examined in cancer cell lines and in xenografted tumors. We found that curcumin inhibits HIF-1 activity and that this in turn down-regulates genes targeted by HIF-1. Moreover, of the two HIF-1 subunits, only ARNT was found to be destabilized by curcumin in several cancer cell types, and furthermore, ARNT expression rescued HIF-1 repression by curcumin. We also found that curcumin stimulated the proteasomal degradation of ARNT via oxidation and ubiquitination processes. In mice bearing Hep3B hepatoma, curcumin retarded tumor growth and suppressed ARNT, erythropoietin, and vascular endothelial growth factor in tumors. These results suggest that the anticancer activity of curcumin is attributable to HIF-1 inactivation by ARNT degradation.</P>
Lee, Su-Jun,Lee, Sang Seop,Jung, Hyun-Ju,Kim, Ho-Sook,Park, Soo-Jin,Yeo, Chang-Woo,Shin, Jae-Gook American Society for PharmacologyExperimental Ther 2009 Drug metabolism and disposition: the biological fa Vol.37 No.7
<P>Our objectives were to identify CYP2D6 genetic polymorphisms in a Korean population, to compare the allele frequencies with those of other ethnic groups, and to evaluate variant-induced functional variations in dextromethorphan (DM) metabolism in vitro and in vivo. Thirty-eight single nucleotide polymorphisms of CYP2D6 were identified by direct DNA sequencing in 51 Koreans. An extended set of 707 subjects were screened for the identified variants. A group of 202 healthy subjects was subjected to phenotypic analysis on DM metabolism. CYP2D6*10 was found to be the most frequent allele (45.6%), followed by CYP2D6*1 (32.3%), *2 (9.9%), *5 (5.6%), *41 (2.2%), *49 (1.4%), and some other rare alleles (<1%). The newly identified E418K and S183Stop were assigned as CYP2D6*52 and CYP2D6*60, respectively, by the Human P450 (CYP) Allele Nomenclature Committee. Individuals having the CYP2D6*10/*49 genotype (n = 5) exhibited a significant decrease in CYP2D6 metabolic activity compared with those with the CYP2D6*1/*1 genotype (n = 31) (P < 0.019). Variations in CYP2D6 protein levels in liver tissues (n = 49) were observed with CYP2D6 genotypes, and correlation between the CYP2D6 protein content and the activity was significant (r(2) = 0.7). Given the importance of CYP2D6 in drug metabolism, subjects with the CYP2D6*10/*49 genotype may benefit from genotype analysis to achieve optimal drug therapy.</P>
Kim, Su N.,Seo, Ji Y.,Jung, Da W.,Lee, Min Y.,Jung, Young S.,Kim, Young C. American Society for PharmacologyExperimental Ther 2007 Drug metabolism and disposition: the biological fa Vol.35 No.10
<P>Dichloromethane (DCM) is metabolically converted to carbon monoxide mostly by CYP2E1 in liver, resulting in elevation of blood carboxyhemoglobin (COHb) levels. We investigated the effects of a subtoxic dose of acetaminophen (APAP) on the metabolic elimination of DCM and COHb elevation in adult female rats. APAP, at 500 mg/kg i.p., was not hepatotoxic as measured by a lack of change in serum aspartate aminotransferase, alanine aminotransferase, and sorbitol dehydrogenase activities. In rats pretreated with APAP at this dose, the COHb elevation resulting from administration of DCM (3 mmol/kg i.p.) was enhanced significantly. Also blood DCM levels were reduced, and its disappearance from blood appeared to be increased. Hepatic CYP2E1-mediated activities measured with chlorzoxazone, p-nitrophenol, and p-nitroanisole as substrates were all induced markedly in microsomes of rats treated with APAP. Aminopyrine N-demethylase activity was also increased slightly, but significantly. Western blot analysis showed that APAP treatment induced the expression of CYP2E1 and CYP3A proteins. Neither hepatic glutathione contents nor glutathione S-transferase activity was changed by the dose of APAP used. The results indicate that, contrary to the well known hepatotoxic effects of this drug at large doses, a subtoxic dose of APAP may induce CYP2E1, and to a lesser degree, CYP3A expression. This is the first report that APAP can increase cytochrome P450 (P450)-mediated hepatic metabolism and the resulting toxicity of a xenobiotic in the whole animal. The pharmacological/toxicological significance of induction of P450s by a subtoxic dose of APAP is discussed.</P>
Lee, Kyung Sun,Park, Hee Sun,Park, Seoung Ju,Kim, So Ri,Min, Kyung Hoon,Jin, Sun Mi,Park, Kwang-Hyun,Kim, Uh-Hyun,Kim, Chan Young,Lee, Yong Chul American Society for PharmacologyExperimental Ther 2005 Molecular pharmacology Vol.68 No.5
<P>Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Oxidative stress plays critical roles in airway inflammation. Although reactive oxygen species (ROS) are shown to cause vascular leakage, the mechanisms by which ROS induce increased vascular permeability are not clearly understood. We have used a murine model of asthma to evaluate the effect of l-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine that acts as an antioxidant, more specifically in the increase of vascular permeability. These mice develop the following typical pathophysiological features of asthma in the lungs: increased numbers of inflammatory cells of the airways, airway hyper-responsiveness, increased vascular permeability, and increased levels of vascular endothelial growth factor (VEGF). Administration of OTC markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs. We also showed that at 72 h after ovalbumin inhalation, increased levels of hypoxia-inducible factor-1alpha (a transcriptional activator of VEGF) in nuclear protein extracts of lung tissues were decreased by the administration of OTC. These results indicate that OTC modulates vascular permeability by lowering VEGF expression.</P>