Protective effects of a superoxide dismutase/catalase mimetic compound against paraquat pneumotoxicity in rat lung

Shopova, Veneta; Dancheva, Violeta; Salovsky, Pencho; Stoyanova, A.

doi:10.1111/j.1440-1843.2009.01531.x

Cited by 8 publications

(2 citation statements)

References 37 publications

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“…Preclinical studies have shown that intraperitoneal (i.p.) administration of EUK-134 prevented HSOS, attenuated kainate-induced neuropathology and protected against paraquat pneumotoxicity in rat models at a dose of 10 mg/kg body weight (Rong et al, 1999; Shopova et al, 2009). EUK-134 at a dose of 12.5 mg/kg body weight every other day seems to be most effective in our wound healing studies.…”

Section: Methodsmentioning

confidence: 99%

ROS constitute a convergence nexus in the development of IGF1 resistance and impaired wound healing in a rat model of type 2 diabetes

Bitar

Al-Mulla

2012

Disease Models &Amp; Mechanisms

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SUMMARYAn indolent non-healing wound and insulin and/or insulin-like growth factor (IGF1) resistance are cardinal features of diabetes, inflammation and hypercortisolemia. Little is known about why these phenomena occur in so many contexts. Do the various triggers that induce insulin and/or IGF1 resistance and retard wound healing act through a common mechanism? Cultured dermal fibroblasts from rats and full-thickness excisional wounds were used as models to test the premise that reactive oxygen species (ROS) play a causal role in the development of IGF1 resistance and impaired wound healing under different but pathophysiologically relevant clinical settings, including diabetes, dexamethasone-induced hypercortisolemia and TNFα-induced inflammation. In normal fibroblasts, IGF1 initiated a strong degree of phosphorylation of insulin receptor substrate 1 (IRS1) (Tyr612) and Akt (Ser473), concomitantly with increased PI3K activity. This phenomenon seemed to be attenuated in fibroblasts that had phenotypic features of diabetes, inflammation or hypercortisolemia. Notably, these cells also exhibited an increase in the activity of the ROS–phospho-JNK (p-JNK)–p-IRS1 (Ser307) axis. The above-mentioned defects were reflected functionally by attenuation in IGF1-dependent stimulation of key fibroblast functions, including collagen synthesis and cell proliferation, migration and contraction. The effects of IGF1 on glucose disposal and cutaneous wound healing were also impaired in diabetic or hypercortisolemic rats. The ROS suppressors EUK-134 and α-lipoic acid, or small interfering RNA (siRNA)-mediated silencing of JNK expression, restored IGF1 sensitivity both in vitro and in vivo, and also ameliorated the impairment in IGF1-mediated wound responses during diabetes, inflammation and hypercortisolemia. Our data advance the notion that ROS constitute a convergence nexus for the development of IGF1 resistance and impaired wound healing under different but pathophysiologically relevant clinical settings, with a proof of concept for the beneficial effect of ROS suppressors.

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Section: Methodsmentioning

confidence: 99%

ROS constitute a convergence nexus in the development of IGF1 resistance and impaired wound healing in a rat model of type 2 diabetes

Bitar

Al-Mulla

2012

Disease Models &Amp; Mechanisms

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“…It may be argued that a subset of these symptoms (e.g. impaired gait, reduced locomotion, and poor posture) stem from a systemic toxicity following paraquat, given that paraquat does affect peripheral organ functioning, most notable the lungs (Shopova et al, 2009;Suntres, 2002). However, if the current paraquat paradigm induced such systemic toxicity, it would be expected that mice would display signs of general illness and respiratory dysfunction.…”

Section: Vehiclementioning

confidence: 99%

Neuroinflammatory mechanisms of Parkinson's Disease

Mangano¹

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The structural biochemistry of the superoxide dismutases

Perry

Shin

Getzoff

et al. 2010

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

454

332

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The discovery of superoxide dismutases (SODs), which convert superoxide radicals to molecular oxygen and hydrogen peroxide, has been termed the most important discovery of modern biology never to win a Nobel Prize. Here, we review the reasons this discovery has been underappreciated, as well as discuss the robust results supporting its premier biological importance and utility for current research. We highlight our understanding of SOD function gained through structural biology analyses, which reveal important hydrogen-bonding schemes and metal-binding motifs. These structural features create remarkable enzymes that promote catalysis at faster than diffusion-limited rates by using electrostatic guidance. These architectures additionally alter the redox potential of the active site metal center to a range suitable for the superoxide disproportionation reaction and protect against inhibition of catalysis by molecules such as phosphate. SOD structures may also control their enzymatic activity through product inhibition; manipulation of these product inhibition levels has the potential to generate therapeutic forms of SOD. Markedly, structural destabilization of the SOD architecture can lead to disease, as mutations in Cu,ZnSOD may result in familial amyotrophic lateral sclerosis, a relatively common, rapidly progressing and fatal neurodegenerative disorder. We describe our current understanding of how these Cu,ZnSOD mutations may lead to aggregation/fibril formation, as a detailed understanding of these mechanisms provides new avenues for the development of therapeutics against this so far untreatable neurodegenerative pathology.

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Protective effects of a superoxide dismutase/catalase mimetic compound against paraquat pneumotoxicity in rat lung

Abstract: EUK-134, a superoxide dismutase/catalase mimetic compound decreased the pneumotoxic effect of paraquat in rats.

Cited by 8 publications

References 37 publications

ROS constitute a convergence nexus in the development of IGF1 resistance and impaired wound healing in a rat model of type 2 diabetes

ROS constitute a convergence nexus in the development of IGF1 resistance and impaired wound healing in a rat model of type 2 diabetes

Neuroinflammatory mechanisms of Parkinson's Disease

The structural biochemistry of the superoxide dismutases

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