SIH—a novel lipophilic iron chelator—protects H9c2 cardiomyoblasts from oxidative stress-induced mitochondrial injury and cell death

Šimůnek, Tomáš; Boer, Christa; Bouwman, R. Arthur; Vlasblom, Ronald; Versteilen, Amanda; Štěrba, Martin; Geršl, Vladimír; Hrdina, Radomír; Ponka, P; DELANGE, J

doi:10.1016/j.yjmcc.2005.05.008

Cited by 84 publications

(77 citation statements)

References 46 publications

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“…Thus, the compounds described here are unique in their ability to activate this response via a GPCR. On the other hand, compounds with this scaffold have been reported among agents with antitumor (Boykin and Varma, 1970), proapoptotic (Zhang et al, 2004), antiprion (Bertsch et al, 2005), analgesic (Almasirad et al, 2006), and antioxidant (Simunek et al, 2005) properties. Hence, our findings suggest the possibility that the antitumor and proapoptotic effects reported for arylcarboxylic acid hydrazides could be due, in part, to activation of TNF-␣ production.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Formyl Peptide Receptor-Like 1 Agonists That Induce Macrophage Tumor Necrosis Factor α Production

et al. 2008

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Development of immunomodulatory agents that enhance innate immune responses represents a promising strategy for combating infectious diseases. In the present studies, we screened a series of 71 arylcarboxylic acid hydrazide derivatives for their ability to induce macrophage tumor necrosis factor ␣ (TNF-␣) production and identified six such compounds, including one compound previously shown to be a formyl peptide receptor (FPR/FPRL1) agonist. The two most potent compounds [compound 1, nicotinic acid [5-(3-bromophenyl)-2-furyl]methylene-hydrazide; compound 2, 4-fluoro-benzoic acid [5-(3-trifluoromethyl-phenyl)-2-furyl]-methylene-hydrazide] were selected for further analysis. These compounds induced de novo production of TNF-␣ in a doseand time-dependent manner in human and murine monocyte/ macrophage cell lines and in primary macrophages. These compounds also induced mobilization of intracellular Ca 2ϩ , production of reactive oxygen species, and chemotaxis in human and murine phagocytes. Induction of macrophage TNF-␣ production was pertussis toxin-sensitive, and analysis of the cellular target of these compounds showed that they were FPRL1-specific agonists and that this response was blocked by FPR/FPRL1 and FPRL1-specific antagonists. In addition, pharmacophore modeling showed a high degree of similarity for low-energy conformations of these two compounds to the current pharmacophore model for FPR ligands (Mol Pharmacol 68:1301-1310, 2005). Overall, these compounds represent novel FPRL1 agonists that induce TNF-␣, a response distinct from those induced by other known FPR and FPRL1 agonists.

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Section: Discussionmentioning

confidence: 99%

Identification of Novel Formyl Peptide Receptor-Like 1 Agonists That Induce Macrophage Tumor Necrosis Factor α Production

et al. 2008

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“…THP-1 cells were pretreated with FeS and then loaded with calcein-AM. After washing off the excess calcein-AM, the cells were treated with the nonchelating PPY compound, the iron chelators (PPYeT and PPYaT), and, as a positive control, salicylaldehyde isonicotinyl hydrazone (SIH) (32). As shown in Fig.…”

Section: Chemical Structures Of Ppy-based Iron Chelatorsmentioning

confidence: 99%

Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

Kumari

Iordanskiy

Kovalskyy

et al. 2014

Antimicrob Agents Chemother

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dHIV-1 transcription is activated by the Tat protein, which recruits CDK9/cyclin T1 to the HIV-1 promoter. CDK9 is phosphorylated by CDK2, which facilitates formation of the high-molecular-weight positive transcription elongation factor b (P-TEFb) complex. We previously showed that chelation of intracellular iron inhibits CDK2 and CDK9 activities and suppresses HIV-1 transcription, but the mechanism of the inhibition was not understood. In the present study, we tested a set of novel iron chelators for the ability to inhibit HIV-1 transcription and elucidated their mechanism of action. Novel phenyl-1-pyridin-2yl-ethanone (

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“…To determine whether the abnormality of LPS-induced TRAM/ TRIF-dependent responses in the Hfe KO macrophages is related to the low levels of iron in these cells, we treated WT macrophages with the membrane-permeable iron chelator salicaldehyde isonicotinoyl hydrazone (SIH) in order to reduce the intracellular pool of free iron (25,30). SIH treatment had a clear inhibitory effect on LPS-induced IFN-β expression, but did not affect IFN-β induction in response to poly(I:C) (Figure 4).…”

Section: Figurementioning

confidence: 99%

Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice

Wang¹,

Harrington²,

Trebicka³

et al. 2009

J. Clin. Invest.

116

159

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Mice deficient in the hemochromatosis gene, Hfe, have attenuated inflammatory responses to Salmonella infection associated with decreased macrophage TNF-α and IL-6 biosynthesis after exposure to LPS. In this study, we show that the abnormal cytokine production is related to impaired TLR4 signaling. Despite their abnormal response to LPS, Hfe KO macrophages produced amounts of TNF-α similar to those in WT cells after TLR2 stimulation. Consistent with this finding, LPS-induced activation of Mal/MyD88-dependent events was normal in the mutant macrophages. However, LPS-induced IFN-β expression, a TRAM/TRIF-dependent response activated by TLR4, was reduced by Hfe deficiency. This reduction could be replicated in WT macrophages with the use of iron chelators. In contrast, TLR3-activated expression of IFN-β, a TRIF-dependent response, was normal in Hfe KO macrophages and was unaffected by iron chelation. Our data suggest that low intracellular iron selectively impairs signaling via the TLR4/TRAM/TRIF pathway proximal to TRIF and results in reduced LPS-induced cytokine expression. Furthermore, by mimicking the altered iron metabolism associated with Hfe deficiency, we found that 3 different inhibitors of hepcidin attenuated Salmonella-induced and noninfectious enterocolitis. Thus, manipulation of iron homeostasis could represent a new therapeutic approach to controlling inflammation.

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SIH—a novel lipophilic iron chelator—protects H9c2 cardiomyoblasts from oxidative stress-induced mitochondrial injury and cell death

Cited by 84 publications

References 46 publications

Identification of Novel Formyl Peptide Receptor-Like 1 Agonists That Induce Macrophage Tumor Necrosis Factor α Production

Identification of Novel Formyl Peptide Receptor-Like 1 Agonists That Induce Macrophage Tumor Necrosis Factor α Production

Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice

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