Suppression of tumor necrosis factor-α and inducible nitric oxide synthase gene expression by THI 52, a new synthetic naphthyl-benzylisoquinoline alkaloid

Kang, Young Jin; Lee, Bog K; Lee, Young S.; Seo, Han Geuk; Park, Min K; Kim, Hyo J.; Pyo, Hyang S; Chong, Won Seog; Jung, Hye Jin; Yun‐Choi, Hye Sook; Lee, Duck H; Chang, Ki Churl

doi:10.1016/s0006-2952(02)01549-6

Cited by 16 publications

(8 citation statements)

References 25 publications

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“…The cytokine TNF-α has been shown to play a major role in driving the expression of iNOS in inflammatory states [38,39]. In our experiments, there was increased systemic production of TNF-α, which is consistent with a possible role of this cytokine.…”

Section: Discussionsupporting

confidence: 89%

Paraquat Poisoning Induces TNF-α-Dependent iNOS/NO Mediated Hyporesponsiveness of the Aorta to Vasoconstrictors in Rats

et al. 2013

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Paraquat is a toxic herbicide that may induce acute lung injury, circulatory failure and death. The present work aimed at investigating whether there is systemic inflammation and vascular dysfunction after paraquat exposure and whether these parameters were related. There was neutrophilia and accumulation of neutrophils in lung and bronchoalveolar lavage of animals given paraquat. This was associated with an increase in serum levels of TNF-α. In rats given paraquat, the relaxant response of aortic rings to acetylcholine was not modified but the contractile response to phenylephrine was greatly reduced. Endothelium removal or treatment with non-selective (L-NAME) or selective (L-NIL) inhibitors of inducible nitric oxide synthase (iNOS) restored contraction of aortas. There was greater production of nitric oxide (NO), which was restored to basal level by L-NIL, and greater expression of iNOS in endothelial cells, as seen by Western blot analyses and confocal microscopy. Blockade of TNF-α reduced pulmonary and systemic inflammation and vascular dysfunction. Together, our results clearly show that paraquat causes pulmonary and systemic inflammation, and vascular dysfunction in rats. Vascular dysfunction is TNF-α dependent, associated with enhanced expression of iNOS in aortic endothelial cells and greater NO production, which accounts for the decreased responsiveness of aortas to vasoconstrictors. Blockers of TNF-α may be useful in patients with paraquat poisoning.

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Section: Discussionsupporting

confidence: 89%

Paraquat Poisoning Induces TNF-α-Dependent iNOS/NO Mediated Hyporesponsiveness of the Aorta to Vasoconstrictors in Rats

et al. 2013

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“…Some isoquinoline alkaloids inhibit NO production and iNOS induction in vascular smooth muscle cells and RAW 264.7 cells activated with LPS and/or IFN-␥ (Kang et al, 1999a,b). We have confirmed that THI 52 inhibits both tumor necrosis factor-␣ and iNOS mRNA expression in RAW 264.7 cells activated with LPS via regulation of NF-B activation (Kang et al, 2003). In the present study, we showed that THI 53, a newly synthesized isoquinoline alkaloid and a structural analog of THI 52, blocked NO production and iNOS protein induction in RAW264.7 macrophage cells and in lung tissues from mice after LPS stimulation.…”

Section: Discussionsupporting

confidence: 79%

“…Because higenamine (Kang et al, 1999a) and related isoquinolines (Kang et al, 1999b) effectively reduce iNOS gene expression in RAW 264.7 cells and smooth muscle cells by inhibition of NF-B, we speculate that the isoquinoline molecular backbone may be important for the inhibition of NF-B. In this process, phosphorylation of IB␣ is vulnerable, hindering translocation of p65 from the cytosol to the nucleus (Kang et al, 2003). Indeed, it is possible to affect the LPS-activated protein tyrosine kinase pathway and its signaling cascade including MAPK or JAK/STATs by isoquinolines.…”

mentioning

confidence: 83%

Regulation of Lipopolysaccharide-Induced Inducible Nitric-Oxide Synthase Expression through the Nuclear Factor-κB Pathway and Interferon-β/Tyrosine Kinase 2/Janus Tyrosine Kinase 2-Signal Transducer and Activator of Transcription-1 Signaling Cascades by 2-Naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (THI 53), a New Synthetic Isoquinoline Alkaloid

Kim

Tsoyi²,

Heo³

et al. 2006

J Pharmacol Exp Ther

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The effects of 2-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (THI 53), on nitric oxide (NO) production and inducible nitric-oxide synthase (iNOS) protein induction by lipopolysaccharide (LPS) were investigated in RAW 264.7 cells and mice. In cells, THI 53 concentration dependently reduced NO production and iNOS protein induction by LPS. In addition, THI 53 inhibited NO production and iNOS protein induction in LPS-treated mice. LPS-mediated iNOS protein induction was inhibited significantly by the specific tyrosine kinase inhibitor ␣-cyano-(3-hydroxy-4-nitro)cinnamonitrile (AG126) as well as by THI 53. In addition, a c-Jun NH 2 -terminal kinase (JNK) inhibitor anthra[1,9-cd]pyrazole-6 (2H)-one) (SP600125) but not an extracellular regulated kinase inhibitor [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98029)] or a p38 inhibitor [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB230580)] reduced the iNOS protein level induced by LPS. Moreover, a Janus kinase 2 (JAK2) inhibitor ␣-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG490) dose-dependently prevented LPS-mediated iNOS protein induction. LPS activated phosphorylations of tyrosine kinases, especially tyrosine kinase 2 (Tyk2) and signal transducer and activator of transcription-1 (STAT-1); these were reduced by THI 53. LPS also phosphorylated the JNK pathway; however, this phosphorylation was unaffected by THI 53. Interestingly, a JNK inhibitor (SP600125) and another tyrosine kinase inhibitor (genistein) significantly inhibited STAT-1 phosphorylation, suggesting that the LPS-activated JNK pathway and a tyrosine kinase pathway (especially Tyk2) may link to the STAT-1 pathway, which is involved in iNOS induction. However, THI 53 regulates LPS-mediated iNOS protein induction by affecting the Tyk2/JAK2-STAT-1 pathway, not the JNK pathway. The inhibition by THI 53 of LPS-induced NO production was recovered by a tyrosine phosphatase inhibitor (Na 3 VO 4 ), which supports the possibility that THI 53 inhibits the LPS-induced inflammatory response through regulation of tyrosine kinase pathways. THI 53 also inhibited LPS-mediated interferon (IFN)-␤ production and nuclear factor-B (NF-B) activation. Thus, THI 53 may regulate LPS-mediated inflammatory response through both the NF-B and IFN-␤/Tyk2/JAK2-STAT-1 pathways.The expression of inducible nitric-oxide synthase (iNOS) and the production of large quantities of nitric oxide (NO) may contribute to the pathophysiology of endotoxemia or sepsis (Thiemermann and Vane, 1990). Moreover, mice carrying the null mutant gene for iNOS are resistant to the hypotension and death caused by lipopolysaccharide (LPS) This study was supported by the Korea Science and Engineering Foundation (R13-2005-005-01003-0).H.J.K. and K.T. contributed equally to this work.

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“…NF-nB is an ubiquitous transcription factor that governs the expression of genes encoding chemokines and cytokines in health and in various disease states and plays a central role in a number of signaling pathways in immune cells including many cell types (Zhao et al, 2003). NF-nB response elements have been demonstrated to be essential for the expression of iNOS, COX-2 as well as chemokine mRNA which are involved in inflammatory process by providing NO, prostaglandin, and chemokines such as IL-8 and MCP-1 (Kang et al, 2003;Anto et al, 2002;Mukhopadhyay et al, 2002;Xie et al, 1994). In the present study, treatment with PMA alone increased the NF-nB -DNA complex and the NF-nB activity in U937 cells stimulated with PMA, but scoparone inhibited the NF-nB -DNA complex and NF-nB activity in a concentrationdependent manner.…”

Section: Discussionmentioning

confidence: 99%

Scoparone inhibits PMA-induced IL-8 and MCP-1 production through suppression of NF-κB activation in U937 cells

Jang

Kim

et al. 2006

Life Sciences

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Suppression of tumor necrosis factor-α and inducible nitric oxide synthase gene expression by THI 52, a new synthetic naphthyl-benzylisoquinoline alkaloid

Cited by 16 publications

References 25 publications

Paraquat Poisoning Induces TNF-α-Dependent iNOS/NO Mediated Hyporesponsiveness of the Aorta to Vasoconstrictors in Rats

Paraquat Poisoning Induces TNF-α-Dependent iNOS/NO Mediated Hyporesponsiveness of the Aorta to Vasoconstrictors in Rats

Scoparone inhibits PMA-induced IL-8 and MCP-1 production through suppression of NF-κB activation in U937 cells

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