International journal of molecular medicine
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Rats exposed to single-prolonged stress (SPS) showed enhanced inhibition of the hypothalamic-pituitary-adrenal (HPA) system and alteration in the glucocorticoid/mineralocorticoid receptor. Dysfunction of the HPA axis is one of the core neuroendocrine abnormalities of post-traumatic stress disorder (PTSD). Serotonergic receptor, glucocorticoid receptor (GR) and corticotropin-releasing factor (CRF) have been proposed to play major roles in dysfunction of the HPA axis. ⋯ In this study, we investigated the relationships between the changes of GR in hippocampus as well as CRF in hypothalamus and the activity of 5-HT1A receptor in SPS rats. We exposed rats to SPS with or without prior treatment with WAY100635 (the 5-HT1A receptor antagonist), and observed behavioral changes, GR levels in the hippocampus and CRF levels in the hypothalamus by immunohistochemistry, Western blotting and RT-PCR seven days after SPS. Our results demonstrate that SPS increases expression of GR and CRF, which were partially inhibited by WAY-100635.
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Angiotensin II is well implicated in neointimal proliferation and the resulting restenosis, however, the mechanisms involved remain unclear. The type 2 angiotensin II (AT2) receptor, largely unexpressed in the adult vasculature, however, appears at significant levels after vascular injury. To investigate the specific contribution of AT2 receptor and the interplay of the angiotensin system to neointima, we engineered rat vascular smooth muscle cells (VSMCs) to express the AT2 receptor in a tetracycline-regulated system. ⋯ We conclude that Ang II enhances the MMP-2 expression via AT1R, and that enforces AT2R inhibited the same. These data confirm that AT2R functions to downregulate the effects elicited by Ang II + AT1R signaling and point to the role of MMP and extracellular matrix in vascular injury. The findings provide fresh experimental approaches to prevent or control restenosis through transduction of VSMCs expressing optimal levels of AT2R.
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The nuclear factor (NF)-kappaB/inhibitory (I)kappaBalpha pathway is one of the most important intracellular signal transduction pathways during inflammation which is induced by a variety of major early response cytokines. Recent studies suggest that volatile anesthetics interfere with inflammatory cytokine production through inhibition of intracellular signal transduction pathways. We, therefore, aimed to investigate the effects of the volatile anesthetics sevoflurane and isoflurane on NF-kappaB/IkappaBalpha-dependent intracellular signal transduction in human monocytic THP-1 cells induced by tumor necrosis factor-alpha (TNF-alpha) and production of interleukin-8 (IL-8) and downstream heme oxygenase-1 (HO-1). ⋯ We demonstrated inhibition of TNF-alpha-induced gene expression and release of IL-8 and HO-1 in human monocytic THP-1 cells exposed to both volatile anesthetics. This was associated with an upregulated intracellular IkappaBalpha content followed by decreased NF-kappaB translocation. This was more sustained during exposure to sevoflurane and may provide an additional intracellular mechanism for the anti-inflammatory effects associated with sevoflurane administration.
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Orexin-A (OXA) and orexin-B (OXB) are polypeptides derived from the same 130 amino acid long precursor (prepro-orexin) that bind and activate two closely related orphan G protein-coupled receptors OX1-R and OX2-R. These hypothalamic neuropeptides stimulate food intake and energy expenditure and play a significant role in sleep-wakefulness regulation. Present studies aimed to investigate the effects of orexins on proliferative activity and osteocalcin secretion by cultured rat calvarial osteoblast-like (ROB) cells. ⋯ In contrast, OXA exerted a notable inhibitory effect on the proliferative activity of ROB cells at day 7 of culture, while OXB exerted a similar effect at day 14. Thus, the obtained results suggest that: (i)(ROB) cells are provided with functional OX1-R gene; (ii) in ROB cells expression of this gene seems to be up-regulated by low concentrations of both OXA and OXB; (iii) OXB exerts inhibitory effects on proliferative activity and stimulating effects on osteocalcin secretion by cultured ROB cells; (iv) rat calvarial osteoblasts provided with OX receptor may be a target for circulating orexins. Thus, orexins may be included in the expanding group of neuropeptides involved in the physiological regulation of the major bone cell types.
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Metabolic syndrome is a risk factor for cardiovascular disease. The aim of the present study was to identify genetic variants that confer susceptibility to atherothrombotic cerebral infarction among individuals with metabolic syndrome in order to allow prediction of genetic risk for this condition. The study population comprised 1284 unrelated Japanese individuals with metabolic syndrome, including 313 subjects with atherothrombotic cerebral infarction and 971 controls. ⋯ Among these polymorphisms, the 2445G-->A (Ala54Thr) polymorphism of FABP2 was most significantly associated with this condition. Our results suggest that FABP2, IPF1, FABP1, ROS1, ADIPOQ, ALOX5AP, NOS3, and LGALS2 are susceptibility loci for atherothrombotic cerebral infarction among Japanese individuals with metabolic syndrome. Genotypes for these polymorphisms, especially for the 2445G-->A (Ala54Thr) polymorphism of FABP2, may prove informative for the prediction of genetic risk for atherothrombotic cerebral infarction among such individuals.