The effects of the inhibition of nitrosative stress by aminoguanidine in an experimental model of diabetes mellitus (DM) were investigated.
Twenty-one male Wistar rats were divided into three groups: control (CO), diabetic (DM), and diabetic treated with aminoguanidine (DM+AG). Aminoguanidine (aminoguanidine hemisulfate salt, Sigma Chemical Co., St. Louis, MO, USA) was used at a dose of 50mg/kg (i.p.) during the last 30days of the experiment. The expression levels of liver lipoperoxidation (TBARS - nmol/mg protein), inducible oxide nitric synthase (iNOS), nitrotyrosine and the NFκB nuclear transcription factor p65 were examined using western blot analysis.
The DM group demonstrated an increase in lipoperoxidation and in the expression of iNOS, nitrotyrosine and p65. Aminoguanidine reduced hepatic lipid peroxidation and protein expression levels of iNOS, nitrotyrosine and p65.
Aminoguanidine treatment reduces liver oxidative and nitrosative stress in diabetic animals. In addition, aminoguanidine reduced the expression of p65 in the liver.
"Another interesting result of the present study is the self protection of liver in case of aging and diabetes against an increase in the levels of 3-NT, however 3-NT was significantly propagated by aging and diabetes in other studied tissues. This finding is supported by our previous study demonstrating that liver 3-NT levels were unaffected by diabetes or stobadine treatment in comparison with normal control rats (Cumaoglu et al., 2007), while others demonstrated an increase in the expression of hepatic iNOS and nitrotyrosine in animal model of diabetes (Di Naso et al., 2012). Superoxide anion reacts with NO to form highly toxic peroxynitrite and this could also account for the inactivation of NO in diabetic rats. "
[Show abstract][Hide abstract] ABSTRACT: The increased glyco- and lipo-oxidation events is considered one of the major factors in the accumulation of non-functional damaged proteins, and the antioxidants may inhibit extensive protein modification and nitrosylated protein levels, enhancing the oxidative damage at the cellular levels in aging and diabetes. Because of its central role in the pathogenesis of age-dependent and diabetes-mediated functional decline, we compared the levels of oxidatively modified protein markers, namely AGEs (Advanced Glycation End-protein adducts), 4-HNE (4-hydroxy-nonenal-histidine) and 3-NT (3-nitrotyrosine), in different tissues of young and old rats. Separately, these three oxidative stress parameters were explored in old rats subjected to experimentally induced diabetes and following a long-term treatment with a novel synthetic pyridoindole antioxidant derived from stobadine-SMe1EC2 (2-ethoxycarbonyl-8-methoxy-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indolinium dichloride). Diabetes induced by streptozotocin injection in rats aged 13-15months, and SMe1EC2 treatment was applied during 4months to aged diabetic rats. AGEs and 4-HNE levels were significantly elevated in brain, ventricle and kidney, but not in lens and liver of aged rats when compared with young rats. Diabetes propagated ageing-induced increase in AGEs and 4-HNE in brain, ventricle and kidney, and raised significantly lens and liver AGEs and 4-HNE levels in aged rats. In aged diabetic rats, SMe1EC2 protected only kidney against increase in AGEs, and inhibited significantly 4-HNE levels in brain, kidney, liver and lens that was observed more pronounced in lens. 3-NT was significantly increased in brain of aged rats and in kidney, lens and ventricle of aged diabetic rats, while SMe1EC2 has no protective effect on 3-NT increase. Results demonstrate that (1) the responsiveness of different tissue proteins to glyco-lipo-oxidative and nitrosative stress in course of normal aging was miscellaneous (2) diabetes is major factor contributing to accelerated aging (3) SMe1EC2 selectively inhibited the generation of oxidatively modified proteins, only in a limited number of tissues.
[Show abstract][Hide abstract] ABSTRACT: Clinical evidence indicates diabetes as a majorrisk factor for titaniumimplant treatment with high failure rates and poor osteointegration, but the underlying mechanism involved remains elusive.We hypothesize that reactive oxygen species (ROS) overproduction may contribute to the impaired osteogenesis of porous titanium implants (pTi) under diabetic conditions. To test this hypothesis, we culturedprimary rabbit osteoblasts onto pTi and studied the cellular performance when subjected to normal serum (NS), diabetic serum (DS), DS + NAC (a potent ROS inhibitor) and NS + H(2)O(2)(an oxidant).In-vivo performance of pTi was investigated by transplanting them intofemoral condyledefects of diabetic rabbits, which received vehicle or NAC treatment respectively.Results showed that diabetic conditions induced significant cellular apoptosis, depressedosteoblast function evidenced by impairedcell attachment and morphology, decreased cell proliferation anddifferentiation, andcompromised in-vivo osteogenesis ofpTi, while cellular ROSgeneration was increased derived from mitochondrial dysfunction. Scavenging ROS with NAC markedly attenuated cell apoptosis and osteoblast dysfunction, and improved bone ingrowth within pTi. Furthermore, treatment withH(2)O(2) exerted similar adverse effect on cellular behavior as diabetes. This study furthers our knowledge on the potential role of ROS overproduction in the diabetes-induced impaired osteogenesis of titanium implants, and indicates anti-oxidative treatment as a promising strategy to promote the treatment efficacy of pTi in diabetic patients.
[Show abstract][Hide abstract] ABSTRACT: Objectives
To evaluate whether reduced activity of the anti-inflammatory HSP70 pathway correlates with nonalcoholic fatty liver disease (NAFLD) progression and with markers of oxidative stress because obesity activates inflammatory JNKs, whereas HSP70 exerts the opposite effect.Methods
Adult obese patients (N = 95) undergoing bariatric surgery were divided into steatosis (ST), steatohepatitis (SH), and fibrosis (SH+F) groups. The levels of HSP70, its major transcription factor, HSF1, and JNKs were assessed by immunoblotting hepatic and visceral adipose tissue; data were confirmed by immunohistochemistry. Plasma biochemistry (lipids, HbA1c, HOMA, hepatic enzymes, and redox markers) was also evaluated.ResultsIn both liver and adipose tissue, decreased HSP70 levels, paralleled by similar reductions in HSF1 and reduced plasma antioxidant enzyme activities, correlated with insulin resistance and with NAFLD progression (expression levels were as follows: ST > SH > SH + F). The immunohistochemistry results suggested Kupffer cells as a site of HSP70 inhibition. Conversely, JNK1 content and phosphorylation increased.Conclusions
Decreased HSF1 levels in the liver and fat of obese patients correlated with impairment of HSP70 in an NAFLD stage-dependent manner. This impairment may affect HSP70-dependent anti-inflammation, with consequent oxidative stress and insulin resistance in advanced stages of NAFLD. Possible causal effects of fat cell senescence are discussed.
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