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Anesthetics could induce cognitive dysfunctions, such as Alzheimer's disease in humans or mice. However, the precise molecular mechanism is unclear. Sevoflurane is a common anesthetic widely used in clinical practice. Here, we demonstrated the induction of cognitive dysfunction induced by Sev in mice to corroborate the signaling pathway and the differentially expressed genes (DEGs) followed by analyzing their functions. The cognitive function of mice was measured by the Morris water maze test. Transcriptomic data were annotated with Illumina HiSeq. 2000. Further, the changes in related proteins or genes were analyzed by western blotting and real-time quantitative polymerase chain reaction. Our results showed that Sev could cause a decline in cognitive competence in mice. The transcriptomic data indicated that adding up to 566 genes were upregulated and 1073 genes were downregulated. The genes of Plin4, Lcn2, Lrg1, Foxf1, and Ctla2a were significantly upregulated, while the genes of Arc, Npas4, Egr2, Hes5, and Cdh9 were downregulated dramatically. The Gene Ontology term with the highest enrichment of DEGs are involved in the regulation of cellular and macromolecule metabolism and cation and nucleic acid binding, respectively. The Kyoto encyclopedia of genes and genomes analysis indicated that the mitogen-activated protein kinases (MAPK) pathway was one of the most important metabolic pathways. In addition, the metabolic pathways related to cognitive function, such as the nervous system and neurodegenerative disease showed significant changes. Furthermore, we found that p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase of the MAPK signaling pathway played important roles in this process. In conclusion, these results provide the first important clues for identifying the DEGs and signaling pathways in the hippocampus due to a Sev-induced cognitive deficiency in mice.

Intermittent hypobaric hypoxia can produce a protective effect on both the nervous system and non-nervous system tissues. Intermittent hypobaric hypoxia preconditioning has been shown to protect rats from cardiac ischemia-reperfusion injury by decreasing cardiac iron levels and reactive oxygen species (ROS) production, thereby decreasing oxidative stress to achieve protection. However, the specific mechanism underlying the protective effect of hypobaric hypoxia is unclear. To shed light on this phenomenon, we subjected Sprague-Dawley rats to hypobaric hypoxic preconditioning (8 hours/day). The treatment was continued for 4 weeks. We then measured the iron content in the heart, liver, spleen, and kidney. The iron levels in all of the assessed tissues decreased significantly after hypobaric hypoxia treatment, corroborating previous results that hypobaric hypoxia may produce its protective effect by decreasing ROS production by limiting the levels of catalytic iron in the tissue. We next assessed the expression levels of several proteins involved in iron metabolism (transferrin receptor, L-ferritin, and ferroportin1 [FPN1]). The increased transferrin receptor and decreased L-ferritin levels after hypobaric hypoxia were indicative of a low-iron phenotype, while FPN1 levels remained unchanged. We also examined hepcidin, transmembrane serine proteases 6 (TMPRSS6), erythroferrone (ERFE), and erythropoietin (EPO) levels, all of which play a role in the regulation of systemic iron metabolism. The expression of hepcidin decreased significantly after hypobaric hypoxia treatment, whereas the expression of TMPRSS6 and ERFE and EPO increased sharply. Finally, we measured serum iron and total iron binding capacity in the serum, as well as red blood cell count, mean corpuscular volume, hematocrit, red blood cell distribution width SD, and red blood cell distribution width CV. As expected, all of these values increased after the hypobaric hypoxia treatment. Taken together, our results show that hypobaric hypoxia can stimulate erythropoiesis, which systemically draws iron away from nonhematopoietic tissue through decreased hepcidin levels.

Disruption of iron homeostasis in brain has been found to be closely involved in several neurodegenerative diseases. Recent studies have reported that appropriate intermittent hypobaric hypoxia played a protective role in brain injury caused by acute hypoxia. However, the mechanisms of this protective effect have not been fully understood. In this study, Sprague-Dawley (SD) rat models were developed by hypobaric hypoxia treatment in an altitude chamber, and the iron level and iron related protein levels were determined in rat brain after 4 weeks of treatment. We found that the iron levels significantly decreased in the cortex and hippocampus of rat brain as compared to that of the control rats without hypobaric hypoxia treatment. The expression levels of iron storage protein L-ferritin and iron transport proteins, including transferrin receptor-1 (TfR1), divalent metal transporter 1 (DMT1), and ferroportin1 (FPN1), were also altered. Further studies found that the iron regulatory protein 2 (IRP2) played a dominant regulatory role in the changes of iron hemostasis, whereas iron regulatory protein 1 (IRP1) mainly acted as cis-aconitase. These results, for the first time, showed the alteration of iron metabolism during hypobaric hypoxia in rat models, which link the potential neuroprotective role of hypobaric hypoxia treatment to the decreased iron level in brain. This may provide insight into the treatment of iron-overloaded neurodegenerative diseases. J. Cell. Biochem. 118: 1596-1605, 2017. © 2016 Wiley Periodicals, Inc.

The Rho-kinase (ROCK) plays an important role in the pathogenesis of heart injury. Recent cellular and molecular biology studies indicated a pivotal role of the RhoA/ROCK cascade in many aspects of cardiovascular function such as heart failure, cardiac hypertrophy, and ventricular remodeling following myocardial infarction. However, the signal transduction of RhoA/ROCK and its down-stream signaling pathways remains elusive, and the mechanism of ROCK-mediated isoproterenol (ISO)-induced heart failure is still not thoroughly understood. In the present study, we investigated the effect of the ROCK inhibitor, fasudil hydrochloride hydrate, on ISO-induced heart failure and the potential relationship of RhoA/ROCK to the extracellular signal-regulated kinases (ERK) and the c-jun NH 2-terminal kinase (JNK) pathways. Male Sprague-Dawley (SD) rats, maintained on a normal diet, were randomly divided into four groups given control, ISO alone, ISO with low-dose fasudil, or ISO with high-dose fasudil treatments. Fasudil effectively inhibited ISO-induced heart failure, as evaluated by biometric, hemodynamic, and histological examinations. Consistently, ISO-induced ROCK-1 mRNA expression and myosin phosphatase target subunit-1 (MYPT-1) phosphorylation were markedly suppressed by fasudil. In addition, fasudil significantly decreased ISO-induced JNK activation, ERK translocation to the nucleus and subsequent c-fos, c-jun expression and upregulated c-FLIP(L) expression. Taken together, these results indicate that the RhoA/ROCK pathway is essential for ISO induced heart failure, which can be effectively suppressed by fasudil.

Recycled iron from reticuloendothelial macrophages to erythroid precursors is important to maintain the iron homeostasis. However, the molecular mechanisms underlying iron homeostasis in macrophages are poorly understood. In this study, male Sprague–Dawley rats were treated with recombinant human erythropoietin (rHuEpo, 500 IU/day, s.c.) for 3 days. At the fifth day, peritoneal exudate macrophages were harvested, and then 55Fe uptake and release were measured by liquid scintillation counting method. The expression of divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1) in peritoneal exudate macrophages was detected by RT-PCR and Western blot. In order to exclude the direct effect of rHuEpo on macrophages, the parallel experiments were performed with incubation normal peritoneal exudate macrophages with rHuEpo (2 IU/ml). Our results showed rHuEpo injection reduced the peritoneal exudate macrophages iron retention. The uptake of Fe(II) was decreased via the suppression of DMT1 (+IRE) expression and the release of Fe(II) was increased with increasing the expression of FPN1 in macrophages. Moreover, the expression of HAMP mRNA was four times lower in rHuEpo-treated liver of rats than control group (CG). HAMP mRNA expression was increased; the synthesis of DMT1 had no significant change, whereas the FPN1 was decreased in normal peritoneal exudate macrophages after treatment with rHuEpo in vitro. We conclude that hepcidin may play a major, causative role in the change of FPN1 synthesis and that decreased the iron retention in macrophages of rHuEpo-treated rats. J. Cell. Biochem. 104: 629–641, 2008. © 2008 Wiley-Liss, Inc.

It has been suggested that Hephaestin (Heph), a newly discovered ceruloplasmin homologue, is necessary for iron egress from the enterocytes into circulation via interacting with ferroportin1 (FP1). Based on the putative function of Heph, and the similarity between the process of iron transport in the enterocytes and that in the blood-brain barrier (BBB) cells, it has also been proposed that Heph plays a similar role in exporting iron from the BBB cells and other brain cells as it works in the enterocytes via interacting with FP1. The existence of FP1 in the brain has been demonstrated. In this study, we investigated Heph expression and effects of development and iron in the cortex, hippocampus, striatum, and substantia nigra. The data demonstrated that all the four regions we examined have the ability to express Heph mRNA and protein. The findings also showed that both the development and iron status have a significant effect on Heph expression and the effects of iron status are regionally specific. It was also suggested that Heph expression is probably regulated at the transcriptional level by the development and iron in these brain regions. These findings, together with other published data, support a putative role of Heph in the iron metabolism in the brain.