Iodine Excess Induces Hepatic Steatosis Through Disturbance of Thyroid Hormone Metabolism Involving Oxidative Stress in BaLB/c Mice

Iodine excess is emerging as a new focus. A better understanding of its hazardous effects on the liver will be of great benefit to health. The aim of this study is to illustrate the effects of iodine excess on hepatic lipid homeostasis and explore its possible mechanisms. One hundred twenty BaLB/c mice were given iodine at different levels (0, 0.3, 0.6, 1.2, 2.4, and 4.8 mg I/L) in drinking water for 1 or 3 months. Lipid parameters and serum thyroid hormones were measured. Hepatic type 1 deiodinase activity and oxidative stress parameters were evaluated. The mRNA expression of sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) was detected by real-time polymerase chain reaction. Dose-dependent increase of hepatic triglyceride content was detected (r?=?0.680, P?<?0.01) in iodine-loaded groups. Evident hepatic steatosis was observed in 2.4 and 4.8 mg I/L iodine-loaded groups. The activities of antioxidant enzymes (glutathione peroxidase and superoxide dismutase) were decreased, and the malondialdehyde level was increased by excessive iodine in both serum and liver in a dose-dependent manner, accompanying the decrease of hepatic D1 activity. That resulted in the increase of serum total thyroxine and the decrease of serum total triiodothyronine in iodine-loaded groups. The mRNA expression of SREBP-1c and FAS was increased in iodine-loaded groups in response to the change of serum triiodothyronine. Present findings demonstrated that iodine excess could dose dependently induce hepatic steatosis. Furthermore, our data suggested that the disturbance of thyroid hormone metabolism involving oxidative stress may play a critical role in iodine excess-induced hepatic steatosis.     

The Alteration of Copper Homeostasis in Inflammation Induced by Lipopolysaccharides

Significant changes of copper homeostasis were triggered by lipopolysaccharides, which result in systemic inflammatory response and contribute to hepatic injury. Administration of lipopolysaccharides resulted in the increase of plasma “free” copper and total copper concentrations, whereas, the decrease of “free” copper and total copper contents in liver tissue. Copper-associated proteins were detected and showed a down-regulation of X-linked inhibitor of apoptosis protein, and up-regulation of copper metabolism domain containing 1 and copper transporter 1. The alteration of these proteins would lower the apoptotic threshold. Meanwhile, the increasing of circulation copper might cause oxidative injury through Fenton reaction and contribute to tissue injury. Our findings underscored the possibility that these changes in systemic copper homeostasis might provide a novel insight of the characteristic of the acute phase of inflammatory response and the underlying influence on tissue injury.     

Manganese-Induced Effects on Cerebral Trace Element and Nitric Oxide of Hyline Cocks

Exposure to Manganese (Mn) is a common phenomenon due to its environmental pervasiveness. To investigate the Mn-induced toxicity on cerebral trace element levels and crucial nitric oxide parameters on brain of birds, 50-day-old male Hyline cocks were fed either a commercial diet or a Mn-supplemented diet containing 600, 900, 1,800 mg kg^?1. After being treated with Mn for 30, 60, and 90 days, the following were determined: the changes in contents of copper (Cu), iron (Fe), zinc (Zn), calcium (Ca), selenium (Se) in brain; inducible nitric oxide synthase-nitric oxide (iNOS-NO) system activity in brain; and histopathology and ultrastructure changes of cerebral cortex. The results showed that Mn was accumulated in brain and the content of Cu and Fe increased. However, the levels of Zn and Se decreased and the Ca content presented no obvious regularity. Exposure to Mn significantly elevated the content of NO and the expression of iNOS mRNA. Activity of total NO synthase (T NOS) and iNOS appeared with an increased tendency. These findings suggested that Mn exposure resulted in the imbalance of cerebral trace elements and influenced iNOS in the molecular level, which are possible underlying nervous system injury mechanisms induced by Mn exposure.     

Effects of small interfering RNA-mediated hepatic glucagon receptor inhibition on lipid metabolism in db/db mice

Hepatic glucose overproduction is a major characteristic of type 2 diabetes. Because glucagon is a key regulator for glucose homeostasis, antagonizing the glucagon receptor (GCGR) is a possible therapeutic strategy for the treatment of diabetes mellitus. To study the effect of hepatic GCGR inhibition on the regulation of lipid metabolism, we generated siRNA-mediated GCGR knockdown (si-GCGR) in the db/db mouse. The hepatic knockdown of GCGR markedly reduced plasma glucose levels; however, total plasma cholesterol was increased. The detailed lipid analysis showed an increase in the LDL fraction, and no change in VLDL HDL fractions. Further studies showed that the increase in LDL was the result of over-expression of hepatic lipogenic genes and elevated de novo lipid synthesis. Inhibition of hepatic glucagon signaling via siRNA-mediated GCGR knockdown had an effect on both glucose and lipid metabolism in db/db mice.     

Characterization in biological traits of entomopathogenic nematodes isolated from North China

In a series of bioassays, thirty-one isolates that were collected from diverse locations in northern China and the laboratory kept isolate Steinernema carpocapsae All, were compared in order to select superior isolates for biological control of Bradysia odoriphaga. Virulence of the isolates against B. odoriphaga was significantly different among nematode isolates. Tolerance of infective juveniles (IJs) to heat, cold, and desiccation differed significantly among and within species. Strains from S. carpocapsae, S. ceratophorum, S. longicaudum, Heterorhabditis indica, and H. bacteriophora were more heat tolerant than strains from S. feltiae, S. hebeiense, S. monticolum, and H. megidis. Heterorhabditis megidis, H. bacteriophora, and S. carpocapsae showed better cold tolerance than the other species. High desiccation tolerance was recorded for S. carpocapsae, S. hebeiense, and S. ceratophorum. The infectivity of IJ of these species against Galleria mellonella larvae was not significantly different between the treated and non-treated IJ after the nematodes had been exposed to 40 °C for 2 h, −5 °C for 8 h or 25% glycerin for 72 h. Nematode survival was significantly affected by exposure time and IJ concentration when exposed to 40 °C or −5 °C. All nematode isolates lost their infectivity against G. mellonella after exposure to −5 °C for 16 h, except for H. megidis LFS10, which had a low infectivity of 3.3%. A hierarchical classification analysis classified the isolates in four main clusters. The fourth cluster, composed of 13 isolates, grouped the isolates that scored well for most traits.     

C-Terminal Membrane Association of Bestrophin 3 and Its Activation as a Chloride Channel

Bestrophin 3 (Best3), a member of the bestrophin Cl^? channel family, is a candidate of cGMP-sensitive, Ca²⁺-activated Cl^? channel in vascular smooth muscle cells. The Best3 channel was recently found to play an important role in vasomotion. However, the mechanism for its activation has not been clarified. In previous studies, we found that a Best3 C-terminal sequence (amino acids 353–404) was associated with the cellular membrane. The sequence includes an autoinhibitory domain (³⁵⁶IPSFLGS³⁶²) and a downstream basic residue domain (amino acids 384–397). In this study, we found that the sequence (368–383) between the two domains is actually a determinant for Best3 C-terminal membrane associability. Deletion of the sequence almost abolished the membrane association but did not activate the Best3 channel. Treatment of Best3-expressing HEK293 cells with the PI3Kα inhibitor IV (a Best3 activator) could not abolish but weakened the Best3 membrane association. The result supports the assumption that the positively charged basic residues in the Best3 C terminus are likely associated with the membranous negatively charged phospholipids, which plays a role in the regulation of Best3 activation. But the relationship between membrane associability and Best3 activation seems more complicated than expected.     

Binding and Movement of Individual Cel7A Cellobiohydrolases on Crystalline Cellulose Surfaces Revealed by Single-molecule Fluorescence Imaging

The efficient catalytic conversion of biomass to bioenergy would meet a large portion of energy requirements in the near future. A crucial step in this process is the enzyme-catalyzed hydrolysis of cellulose to glucose that is then converted into fuel such as ethanol by fermentation. Here we use single-molecule fluorescence imaging to directly monitor the movement of individual Cel7A cellobiohydrolases from Trichoderma reesei (TrCel7A) on the surface of insoluble cellulose fibrils to elucidate molecular level details of cellulase activity. The motion of multiple, individual TrCel7A cellobiohydrolases was simultaneously recorded with ∼15-nm spatial resolution. Time-resolved localization microscopy provides insights on the activity of TrCel7A on cellulose and informs on nonproductive binding and diffusion. We measured single-molecule residency time distributions of TrCel7A bound to cellulose both in the presence of and absence of cellobiose the major product and a potent inhibitor of Cel7A activity. Combining these results with a kinetic model of TrCel7A binding provides microscopic insight into interactions between TrCel7A and the cellulose substrate.     

Negative Regulation of Interferon-induced Transmembrane Protein 3 by SET7-mediated Lysine Monomethylation

Although lysine methylation is classically known to regulate histone function, its role in modulating antiviral restriction factor activity remains uncharacterized. Interferon-induced transmembrane protein 3 (IFITM3) was found monomethylated on its lysine 88 residue (IFITM3-K88me1) to reduce its antiviral activity, mediated by the lysine methyltransferase SET7. Vesicular stomatitis virus and influenza A virus infection increased IFITM3-K88me1 levels by promoting the interaction between IFITM3 and SET7, suggesting that this pathway could be hijacked to support infection; conversely, IFN-α reduced IFITM3-K88me1 levels. These findings may have important implications in the design of therapeutics targeting protein methylation against infectious diseases.     

Inactivation of Max-interacting Protein 1 Induces Renal Cilia Disassembly through Reduction in Levels of Intraflagellar Transport 20 in Polycystic Kidney

Cilia in ciliated cells consist of protruding structures that sense mechanical and chemical signals from the extracellular environment. Cilia are assembled with variety molecules via a process known as intraflagellar transport (IFT). What controls the length of cilia in ciliated cells is critical to understand ciliary disease such as autosomal dominant polycystic kidney disease, which involves abnormally short cilia. But this control mechanism is not well understood. Previously, multiple tubular cysts have been observed in the kidneys of max-interacting protein 1 (Mxi1)-deficient mice aged 6 months or more. Here, we clarified the relationship between Mxi1 inactivation and cilia disassembly. Cilia phenotypes were observed in kidneys of Mxi1-deficient mice using scanning electron microscopy to elucidate the effect of Mxi1 on renal cilia phenotype, and cilia disassembly was observed in Mxi1-deficient kidney. In addition, genes related to cilia were validated in vitro and in vivo using quantitative PCR, and Ift20 was selected as a candidate gene in this study. The length of cilium decreased, and p-ERK level induced by a cilia defect increased in kidneys of Mxi1-deficient mice. Ciliogenesis of Mxi1-deficient mouse embryonic fibroblasts (MEFs) decreased, and this abnormality was restored by Mxi1 transfection in Mxi1-deficient MEFs. We confirmed that ciliogenesis and Ift20 expression were regulated by Mxi1 in vitro. We also determined that Mxi1 regulates Ift20 promoter activity via Ets-1 binding to the Ift20 promoter. These results indicate that inactivating Mxi1 induces ciliary defects in polycystic kidney.