Therapeutic Potential of Cerium Oxide Nanoparticles for the Treatment of Peritonitis Induced by Polymicrobial Insult in Sprague-Dawley Rats.

OBJECTIVES: Peritonitis is a life-threatening disease that is associated with high mortality. The purpose of this study was to determine if cerium oxide nanoparticles can be used to diminish intra-abdominal infection-induced mortality and systemic inflammatory response syndrome in the laboratory rat. DESIGN: Randomized, controlled animal study and cell culture study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats aged 12 weeks, RAW 246.7 macrophage cell line. INTERVENTIONS: Intra-abdominal infection or peritonitis was induced by intraperitoneal injection of cecal material (600 mg/kg in 5% sterile dextrose water at a dosage of 5 mL/kg) obtained from healthy donors. Rats in control and peritonitis groups received 200 µL of sterile deionized water IV via the tail vein, whereas rats in cerium oxide-only group and peritonitis+cerium oxide group received cerium oxide nanoparticles (0.5 mg/kg) IV at the time of polymicrobial injection. Survival rate was monitored for 14 days, while in other experiments, animals were killed at 3 and 18 hours after induction of peritonitis for biochemical analysis. MEASUREMENTS AND MAIN RESULTS: Administration of a single dose (0.5 mg/kg) of cerium oxide nanoparticles IV to rats in the peritonitis group significantly improved survival rates and functioned to restore core body temperature toward baseline. Treatment-induced increases in animal survivability were associated with reduced systemic and hepatic oxidative stress, diminished serum cytokines, and chemokine levels. Changes in serum inflammatory markers with treatment were accompanied by decreased monocyte and lymphocyte extravasation into the peritoneal cavity along with decreased infiltration of macrophages into liver. In the heart, treatment diminished extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase-Stat-3 signaling and attenuated endothelial expression of P-selectin and vascular cell adhesion molecule-1. CONCLUSIONS: Cerium oxide nanoparticles attenuate the systemic inflammatory response associated with peritonitis, suggesting potential use as a novel therapeutic agent for the treatment of severe intra-abdominal infection.

Overload induced heat shock proteins (HSPs), MAPK and miRNA (miR-1 and miR133a) response in insulin-resistant skeletal muscle.

BACKGROUND: Insulin resistance (IR) may decrease muscle adaptability. Heat shock proteins (HSPs), mitogen-activated protein kinases (MAPKs), and miRNA are thought to play a role in muscle hypertrophy but it is unclear if IR may affect their regulation. METHODS: Soleus muscles of lean Zucker (LZ) and insulin resistant obese Zucker (OZ) rats were overloaded for 7 or 21 days and subjected to immunoblotting and RT-PCR. RESULTS: IR was associated with decreased muscle hypertrophy. Overload increased HSP27 phosphorylation in both the LZ and OZ rats at day 7 but only in the LZ at day 21. IR was associated with diminished overload induced MAPK phosphorylation and decreased expression of miR-1 and miR133. Overload decreased mir-1 levels in both the LZ and OZ but to a greater extent in the LZ animals. CONCLUSION: These results suggest that alterations in the regulation of HSPs, MAPKs and miRNA may be associated with the diminished hypertrophy of IR muscle.

Regulation of iron-related molecules in the rat hippocampus: sex- and age-associated differences.

Iron accumulation, especially that of free oxidized ferrous iron, has been shown to induce tissue oxidative damage and contribute to brain aging and the development of neurodegenerative disease. Here we examine whether sex and advanced age affect the expression of iron-related molecules that participate in regulating free iron levels (heme oxygenase 1 (HO1), iron-regulatory protein 1 (IRP1), and ferritin heavy chain (FTH)) and whether changes in the expression of these molecules are associated with differences in the expression of alpha-synuclein (ASN) which is thought to be a critical regulator in the pathogenesis of neurodegeneration. Using a well-established aging animal model, we demonstrate that the expression of HO1, FTH, and IRP1 mRNAs is higher in the female hippocampus than that observed in male Fischer 344/NNiaHSD x Brown Norway/BiNia (F344BN) rats, regardless of age group. Consistent with these sex-associated alterations in iron-related regulators, the expression of ASN mRNA and protein in the female hippocampus was lower than that found in male rats. These results suggest a sex-dependent difference in regulating the expression of molecules involved in iron metabolism and neurodegeneration. A similar finding in humans, if present, may help to shed light on why sex may affect the incidence of neurodegenerative disorders.