Superoxide scavenging activity of pirfenidone–iron complex
Section snippets
Materials and methods
Chemicals. PFD was purchased from Tocris Bioscience (Bristol, UK); 5,5-dimethyl-1-pyrroline N-oxide (DMPO; purity, 99%), diethylene-triamine-pentaacetic acid (DTPA) and 1,10-phenanthroline from Dojindo Laboratories (Kumamoto, Japan); Cu, Zn-superoxide dismutase (SOD), hypoxanthine cytochrome c, and phorbol myristate acetate (PMA) from Sigma Chemical Co. (St. Louis, MO, USA); dimethyl sulfoxide, iron chloride hexahydrate (FeCl3), and ethanol from Nakalai Tesque Inc., (Kyoto, Japan); Ascorbic
Formation of PFD–iron complex
The spectra of PFD, the PFD–iron complex, and iron chloride at pH 6.8 are shown in Fig. 1. The UV/vis spectrum of the PFD–iron complex was distinct from that of PFD or iron chloride. To elucidate the binding abilities of PFD and iron, we used the competitive 1,10-phenanthroline method. As for the results, we confirmed that the chelating constant of the PFD–iron complex was 5.95. As this value was about half that of EDTA, this suggests that the PFD–iron complex might be formed in a biological
Discussion
In this study, we found the superoxide scavenging activity of the PFD–iron complex in enzymatic and cellular systems. These results suggest that the scavenging effect of the PFD–iron complex contributes to the anti-fibrotic action of PFD used for treating IPF.
The present study demonstrated that a stable PFD–iron complex was produced by the 3:1 reaction between PFD and iron chloride in ethanol and water, and its chelating constant enabled easy formation of the complex in a biological system (
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Pulmonary Fibrosis
2022, Comprehensive PharmacologyPhenylpyrrolidine structural mimics of pirfenidone lacking antifibrotic activity: A new tool for mechanism of action studies
2017, European Journal of PharmacologyCitation Excerpt :In order to produce antifibrotic activity in vitro, concentrations between 1 and 5 mM are required (Conte et al., 2014; Lehtonen et al., 2016b; Nakayama et al., 2008). Pirfenidone's lack of potency, lipophilic nature, and minimal number of heteroatoms (Fig. 1) has led to debate about the potential for pirfenidone to bind to a selective target or pocket, and has stimulated an alternative hypothesis that pirfenidone simply works as a free radical scavenging antioxidant (Mitani et al., 2008; Salazar-Montes et al., 2008). Some very recent work has suggested pirfenidone is an inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK) pathway (Li et al., 2016; Ma et al., 2014; Neri et al., 2016; Yin et al., 2016).
Functional and structural impact of pirfenidone on the alterations of cardiac disease and diabetes mellitus
2014, Cell CalciumCitation Excerpt :As a matter of fact, in these cells a chronic PFD-treatment up-regulates LTCCs independently of the TGF-β1 signaling (depicted in Fig. 2A) [86]. As illustrated in Fig. 2B, this effect does not depend either on Ca2+ as a second messenger, TNF-α signaling or levels of ROS (which represent the known molecular targets of PFD) [77–79]. Thus, it is possible that the stimulation of LTCCs by PFD depends on other, currently unidentified, molecular target.
Effects of pirfenidone on increased cough reflex sensitivity in guinea pigs
2013, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :A phase III trial in Japan showed that pirfenidone caused a significant reduction in the decline of vital capacity and improved progression-free survival [10]. Pirfenidone has been reported to have anti-inflammatory [11,12] and antioxidant [13,14] effects, in addition to antifibrotic effects [15,16], in experimental models. Furthermore, the effects of pirfenidone on bronchial asthma have been investigated recently [17,18], and although the effects of pirfenidone on airway hyper-responsiveness remain controversial, these data suggest the possibility that pirfenidone may be used for the treatment of acute allergic airway diseases and may reduce or prevent airway remodeling.
- 1
Mitani Yoshihiro and Keizo Sato contributed equally to this work.