Age- and Sex-Associated Changes in mRNA Expression of Neurodegenerative Disorder-Related Molecules in the Hippocampus and Cerebellum of Rat Brain

Age-associated oxidative stress is involved in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, and sex-associated differences may also affect the risk for these neurodegenerative diseases. We compared the effects of aging and sex on the mRNA expression of five molecules that are closely related to oxidative stress, along with Alzheimer’s and Parkinson’s diseases in the hippocampus of both male and female Fischer 344xBrown Norway (F344BN) rats. The reverse transcription polymerase chain reaction was used to determine the mRNA expression level of superoxide dismutase 2 (SOD2), heme oxygenase 1 (HO1), amyloid precursor protein (APP), -site APP-cleaving enzyme 1 (BACE1), and -synuclein (ASN) in the hippocampus of 3 groups of male and female (young rats, aged rats, and very aged F344BN rats). No significant age- or sex-related changes were observed in the expression levels of SOD2, APP, or BACE1 mRNAs. The expression of HO1 mRNA in the very aged female rat hippocampus was significantly higher than that observed in the young female control and the aged females, when compared to male counterparts. No significant age-associated changes were observed in the expression of ASN mRNA; however, the expression of ASN was significantly higher in the hippocampus of male compared to female rats. Because the accumulation of iron in the brain plays a key role in Alzheimer’s and Parkinson’s diseases, we also investigated age- and sex-related expression of five mRNAs that are closely related to iron storage, transportation, and metabolism: ferritin heavy chain (FTH), ferritin light chain (FTL), transferrin receptor (TfR), divalent metal transporter 1 (DMT1), and iron-regulatory protein 1 (IRP1). No significant age-related changes were observed in the expression levels of any of these five molecules. The overall expression of FTH and IRP1 mRNAs was significantly lower in the hippocampus of male rats when compared to females. This study paves the way for the further investigation of age- and sex-related changes in the protein expression and activities of these molecules, and will help clarify the mechanisms by which oxidative damage may affect neurodegenerative diseases

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 I (HOI), iron-regulatory protein I (IRPI), 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 HOI, FTH, and IRPI 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 sexassociated 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

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

Therapeutic potential of cerium oxide nanoparticles for the treatment of peritonitis induced by polymicrobial insult in sprague-dawley rats

© 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. 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