Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction.

Myocardial apoptosis is a significant problem underlying ischemic heart disease. We previously reported significantly elevated expression of cytoplasmic Omi/HtrA2, triggers cardiomyocytes apoptosis. However, whether increased Omi/HtrA2 within mitochondria itself influences myocardial survival in vivo is unknown. We aim to observe the effects of mitochondria-specific, not cytoplasmic, Omi/HtrA2 on myocardial apoptosis and cardiac function. Transgenic mice overexpressing cardiac-specific mitochondrial Omi/HtrA2 were generated and they had increased myocardial apoptosis, decreased systolic and diastolic function, and decreased left ventricular remodeling. Transiently or stably overexpression of mitochondria Omi/HtrA2 in H9C2 cells enhance apoptosis as evidenced by elevated caspase-3, -9 activity and TUNEL staining, which was completely blocked by Ucf-101, a specific Omi/HtrA2 inhibitor. Mechanistic studies revealed mitochondrial Omi/HtrA2 overexpression degraded the mitochondrial anti-apoptotic protein HAX-1, an effect attenuated by Ucf-101. Additionally, transfected cells overexpressing mitochondrial Omi/HtrA2 were more sensitive to hypoxia and reoxygenation (H/R) induced apoptosis. Cyclosporine A (CsA), a mitochondrial permeability transition inhibitor, blocked translocation of Omi/HtrA2 from mitochondrial to cytoplasm, and protected transfected cells incompletely against H/R-induced caspase-3 activation. We report in vitro and in vivo overexpression of mitochondrial Omi/HtrA2 induces cardiac apoptosis and dysfunction. Thus, strategies to directly inhibit Omi/HtrA2 or its cytosolic translocation from mitochondria may protect against heart injury

Alterations in cell growth and signaling in ErbB3 binding protein-1 (Ebp1) deficient mice

<p>Abstract</p> <p>Background</p> <p>The ErbB3 binding protein-1 (Ebp1) belongs to a family of DNA/RNA binding proteins implicated in cell growth, apoptosis and differentiation. However, the physiological role of Ebp1 in the whole organism is not known. Therefore, we generated <it>Ebp1</it>-deficient mice carrying a gene trap insertion in intron 2 of the <it>Ebp1 (pa2g4) </it>gene.</p> <p>Results</p> <p>Ebp1^-/-mice were on average 30% smaller than wild type and heterozygous sex matched littermates. Growth retardation was apparent from Day 10 until Day 30. IGF-1 production and IGBP-3 and 4 protein levels were reduced in both embryo fibroblasts and adult knock-out mice. The proliferation of fibroblasts derived from Day 12.5 knock out embryos was also decreased as compared to that of wild type cells. Microarray expression analysis revealed changes in genes important in cell growth including members of the MAPK signal transduction pathway. In addition, the expression or activation of proliferation related genes such as AKT and the androgen receptor, previously demonstrated to be affected by Ebp1 expression <it>in vitro</it>, was altered in adult tissues.</p> <p>Conclusion</p> <p>These results indicate that Ebp1 can affect growth in an animal model, but that the expression of proliferation related genes is cell and context specific. The Ebp1^-/-mouse line represents a new <it>in vivo </it>model to investigate Ebp1 function in the whole organism.</p

The ratio between digestible protein and digestible energy affects accumulation and depuration of geosmin and 2-methylisoborneol (2-MIB) in Japanese seabass (Lateolabrax japonicus) raised in a recirculated aquaculture system

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Lithosphere thinning beneath west North China Craton: Evidence from geochemical and Sr-Nd-Hf isotope compositions of Jining basalts

This study shows lithosphere evolution history in the west North China Craton (NCC) from the early Cretaceous to Quaternary by studying the major element, trace element and Sr-Nd-Hf isotope compositions in Jining basalts of 119.6-108.6. Ma, 23.5-21.9. Ma and 1.3-0.11. Ma.The early Cretaceous basalts (119.6-108.6Ma) display enriched characteristics with high contents of incompatible elements, high 87Sr/86Sri, low εNd(t) and low εHf(t). These basalts resulted from partial melting of ancient metasomatized lithospheric mantle, and we consider the 119.6-108.6Ma magmatism as indicating lithosphere thinning in the west NCC. Although the Pacific slab seen seismically in the mantle transition zone beneath eastern China is no older than 60Ma, there exists convincing evidence for the presence of the Paleo-Pacific slab in the transition-zone in the Mesozoic. Thus we propose that the water released from the transition-zone slab hydrated the overlying lithosphere and further converted the base of the lithosphere into asthenosphere. This is the most likely mechanism responsible for the lithosphere thinning in the west NCC and the petrogenesis of the Jining 119.6-108.6Ma basalts.The Jining 23.5-21.9Ma basalts also have high contents of incompatible elements, but they display high εNd(t), high εHf(t) and variably low 87Sr/86Sri. We propose that these Miocene basalts were derived from the asthenosphere with contributions from ancient metasomatized lithospheric mantle during melt ascent. The Jining Quaternary basalts (1.3-0.11Ma) represent the melt of upwelling asthenosphere with low 87Sr/86Sri, high εNd(t) and high εHf(t). Upwelling and decompression melting of the eastward flowing asthenosphere from beneath western plateaus to beneath eastern hilly plains in the Cenozoic is the most plausible mechanism for the petrogenesis of Jining Cenozoic basalts (both of 23.5-21.9Ma and 1.3-0.11Ma), but the Jining 1.3-0.11Ma basalts must have been produced beneath even thinner lithosphere.Taken together geophysical studies and our petrological and geochemical studies of all these three episodes of the Jining basalts, we propose that the lithosphere in the west NCC has been thinning since the early Cretaceous and the thinning continues to the present

Geochemical differences between subduction- and collision-related copper-bearing porphyries and implications for metallogenesis

Porphyry Cu (-Mo-Au) deposits occur not only in continental margin-arc settings (subduction-related porphyry Cu deposits, such as those along the eastern Pacific Rim (EPRIM)), but also in continent-continent collisional orogenic belts (collision-related porphyry Cu deposits, such as those in southern Tibet). These Cu-mineralized porphyries, which develop in contrasting tectonic settings, are characterized by some different trace element (e.g., Th, and Y) concentrations and their ratios (e.g., Sr/Y, and La/Yb), suggesting that their source magmas probably developed by different processes. Subduction-related porphyry Cu mineralization on the EPRIM is associated with intermediate to felsic calc-alkaline magmas derived from primitive basaltic magmas that pooled beneath the lower crust and underwent melting, assimilation, storage, and homogenization (MASH), whereas K-enriched collision-related porphyry Cu mineralization was associated with underplating of subduction-modified basaltic materials beneath the lower crust (with subsequent transformation into amphibolites and eclogite amphibolites), and resulted from partial melting of the newly formed thickened lower crust. These different processes led to the collision-related porphyry Cu deposits associated with adakitic magmas enriched by the addition of melts, and the subduction-related porphyry Cu deposits associated with magmas comprising all compositions between normal arc rocks and adakitic rocks, all of which were associated with fluid-dominated enrichment process. In subduction-related Cu porphyry magmas, the oxidation state (fO2), the concentrations of chalcophile metals, and other volatiles (e.g., S and Cl), and the abundance of water were directly controlled by the composition of the primary arc basaltic magma. In contrast, the high Cu concentrations and fO2 values of collision-related Cu porphyry magmas were indirectly derived from subduction modified magmas, and the large amount of water and other volatiles in these magmas were controlled in part by partial melting of amphibolite derived from arc basalts that were underplated beneath the lower crust, and in part by the contribution from the rising potassic and ultrapotassic magmas. Both subduction- and collision-related porphyries are enriched in potassium, and were associated with crustal thickening. Their high K2O contents were primarily as a result of the inheritance of enriched mantle components and/or mixing with contemporaneous ultrapotassic magmas

New insights into β-glucan-enhanced immunity in largemouth bass Micropterus salmoides by transcriptome and intestinal microbial composition

β-glucan is widely used in aquaculture due to its immunostimulatory effects, but the specific effect and potential regulatory mechanism on largemouth bass (Micropterus salmoides) are still unclear. Here, we evaluated the effects of β-glucan on growth, resistance to Aeromonas schubertii, intestinal health, and transcriptome of largemouth bass to reveal the potential regulators, metabolic pathways, and altered differential microbiota. Four experimental diets were designed with β-glucan supplementation levels of 0 (control), 100 (LA-100), 200 (MA-200), and 300 (HA-300) mg kg-1, and each diet was fed to largemouth bass (79.30 ± 0.50 g) in triplicate for 70 days, followed by a 3-day challenge experiment. Results showed that different β-glucan supplementations had no significant effects on growth performance and whole-body composition. Fish fed a diet with 300 mg kg-1 β-glucan significantly increased the activity of lysozyme than those fed diets with 0 and 100 mg kg-1 β-glucan. In addition, the survival rate of largemouth bass in β-glucan supplementation groups was significantly higher than the control group at 12- and 24-h challenge by Aeromonas schubertii. Transcriptome analysis showed that a total of 1,245 genes were differentially expressed [|log2(fold change)| ≥1, q-value ≤0.05], including 109 immune-related differentially expressed genes (DEGs). Further analysis revealed that significantly upregulated and downregulated DEGs associated with immunity were mapped into 12 and 24 pathways, respectively. Results of intestinal microflora indicated that fish fed a diet with 300 mg kg-1 β-glucan had higher bacterial richness and diversity as evaluated by Sobs, Chao, Ace, and Simpson indices, but no significant differences were found in the comparison groups. Furthermore, 300 mg kg-1 β-glucan significantly increased the relative abundance of Mycoplasma and decreased Proteobacteria (mainly Escherichia-Shigella and Escherichia coli) and Bacillus anthracis in largemouth bass intestinal microflora. The findings of this study provided new insights that will be valuable in future studies to elucidate the mechanism of immunity enhancement by β-glucan

Post-transcriptional regulation of androgen receptor mRNA by an ErbB3 binding protein 1 in prostate cancer

Androgen receptor (AR)-mediated pathways play a critical role in the development and progression of prostate cancer. However, little is known about the regulation of AR mRNA stability and translation, two central processes that control AR expression. The ErbB3 binding protein 1 (EBP1), an AR corepressor, negatively regulates crosstalk between ErbB3 ligand heregulin (HRG)-triggered signaling and the AR axis, affecting biological properties of prostate cancer cells. EBP1 protein expression is also decreased in clinical prostate cancer. We previously demonstrated that EBP1 overexpression results in decreased AR protein levels by affecting AR promoter activity. However, EBP1 has recently been demonstrated to be an RNA binding protein. We therefore examined the ability of EBP1 to regulate AR post-transcriptionally. Here we show that EBP1 promoted AR mRNA decay through physical interaction with a conserved UC-rich motif within the 3′-UTR of AR. The ability of EBP1 to accelerate AR mRNA decay was further enhanced by HRG treatment. EBP1 also bound to a CAG-formed stem-loop in the 5′ coding region of AR mRNA and was able to inhibit AR translation. Thus, decreases of EBP1 in prostate cancer could be important for the post-transcriptional up-regulation of AR contributing to aberrant AR expression and disease progression