Long-Term Effects of Very Low Dose Particle Radiation on Gene Expression in the Heart: Degenerative Disease Risks

Compared to low doses of gamma irradiation (γ-IR), high-charge-and-energy (HZE) particle IR may have different biological response thresholds in cardiac tissue at lower doses, and these effects may be IR type and dose dependent. Three- to four-month-old female CB6F1/Hsd mice were exposed once to one of four different doses of the following types of radiation: γ-IR 137Cs (40-160 cGy, 0.662 MeV), 14Si-IR (4-32 cGy, 260 MeV/n), or 22Ti-IR (3-26 cGy, 1 GeV/n). At 16 months post-exposure, animals were sacrificed and hearts were harvested and archived as part of the NASA Space Radiation Tissue Sharing Forum. These heart tissue samples were used in our study for RNA isolation and microarray hybridization. Functional annotation of twofold up/down differentially expressed genes (DEGs) and bioinformatics analyses revealed the following: (i) there were no clear lower IR thresholds for HZE- or γ-IR; (ii) there were 12 common DEGs across all 3 IR types; (iii) these 12 overlapping genes predicted various degrees of cardiovascular, pulmonary, and metabolic diseases, cancer, and aging; and (iv) these 12 genes revealed an exclusive non-linear DEG pattern in 14Si- and 22Ti-IR-exposed hearts, whereas two-thirds of γ-IR-exposed hearts revealed a linear pattern of DEGs. Thus, our study may provide experimental evidence of excess relative risk (ERR) quantification of low/very low doses of full-body space-type IR-associated degenerative disease development

Development of calcium alginate –gelatin based microspheres for controlled release of endosulfan as a model pesticide

388-395In the present study controlled release formulations have been developed by encapsulating endosulfan for reducing environmental impact of pesticides within the macromolecular network of calcium alginate and gelatin based microspheres. Various alginate and gelatin based compositions were prepared by crosslinking sodium alginate with calcium ions in the presence of gelatin. The effects of preparation conditions of beads such as varying concentrations of crosslinker, endosulfan, alginate to gelatin ratio and temperature were investigated on the release profiles of endosulfan. The obtained release data were analyzed in accordance with Ficks power law and kinetic parameters of the release process were calculated. The results obtained demonstrate that one can significantly and desirably control the rate of pesticide release by suitably modifying and adjusting the experimental protocol. The soil- pot experiments were also performed to predict the kind of mechanisms the endosulfan may follow while being released in the agricultural fields

The Role of Leukocytes in Diabetic Cardiomyopathy

Diabetes is predominant risk factor for cardiovascular diseases such as myocardial infarction and heart failure. Recently, leukocytes, particularly neutrophils, macrophages, and lymphocytes, have become targets of investigation for their potential role in a number of chronic inflammatory diseases such as diabetes and heart failure. While leukocytes contribute significantly to the progression of diabetes and heart failure individually, understanding their participation in the pathogenesis of diabetic heart failure is much less understood. The present review summarizes the role of leukocytes in the complex interplay between diabetes and heart failure, which is critical to the discovery of new targeted therapies for diabetic cardiomyopathy

Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats

The purpose of this study was to determine whether blocking of G protein βγ (Gβγ) signaling halts heart failure (HF) progression by macrophage phenotype manipulation. Cardiac Gβγ signaling plays a crucial role in HF pathogenesis. Previous data suggested that inhibiting Gβγ signaling reprograms T helper cell 1 (Th1) and Th2 cytokines, suggesting that Gβγ might be a useful drug target for treating HF. We investigated the efficacy of a small molecule Gβγ inhibitor, gallein, in a clinically relevant, experimental autoimmune myocarditis (EAM) model of HF as well as in human macrophage phenotypes in vitro. In the myocardium of HF patients, we observed that G protein coupled receptor kinase (GRK)2 levels were down-regulated compared with healthy controls. In rat EAM, treatment with gallein effectively improved survival and cardiac function, suppressed cardiac remodeling, and further attenuated myocardial protein expression of GRK2 as well as high mobility group box (HMGB)1 and its cascade signaling proteins. Furthermore, gallein effectively inhibited M1 polarization and promoted M2 polarization in vivo in the EAM heart and in vitro in human monocyte-derived macrophages. Taken together, these data suggest that the small molecule Gβγ inhibitor, gallein, could be an important pharmacologic therapy for HF as it can switch the phenotypic reprogramming from M1 to M2 phenotype in a rat model of EAM heart and in human macrophages

Effect of gallein on myocardial histological changes.

<p>(A) H&E staining of left ventricular sections depicting infiltration of inflammatory cells, interstitial edema, vacuolization, and degeneration of cardiac fibers. (B) Masson’s trichrome (MT) staining for fibrosis (blue area) in the cross sectional tissue sections of left ventricle. (C-C1) Toluidine blue (TB) staining for mast cells of the cross sectional slices of heart and their quantification. Scale bar = 20 μm. Each bar represents mean ± SEM, n = 4–5. Normal, age matched normal rats; EAM, rats with experimental autoimmune myocarditis treated with vehicle; EAM+G10, rats with EAM treated with gallein (10 mg/kg/day). ***p<0.001 and *p<0.05 vs Normal; ^###p<0.001 vs EAM.</p

Effect of gallein on M2-like macrophage phenotype in the heart of EAM rats.

<p>IHC staining for (A-A1) CD163, (B-B1) CD36, (C-C1) IL-10 and their quantification data. Scale bar = 20 μm. Each bar represents mean ± SEM, n = 4–5. Normal, age matched normal rats; EAM, rats with experimental autoimmune myocarditis treated with vehicle; EAM+G10, rats with EAM treated with gallein. ***p<0.001 vs Normal; ^###p<0.001 and ^##p<0.01 vs EAM.</p