Experimental biology and medicine
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Exp. Biol. Med. (Maywood) · Nov 2010
Identification of fetal hemoglobin-inducing agents using the human leukemia KU812 cell line.
Fetal hemoglobin (HbF) ameliorates the clinical severity of sickle cell disease; therefore continued research to identify efficacious HbF-inducing agents is desirable. In this study, we investigated KU812 leukemia cells that express the fetal γ-globin and adult β-globin genes, as a system for screening and discovery of novel HbF inducers. KU812 cells were analyzed in the presence or absence of fetal bovine serum and then expression levels of the globin genes, cell surface markers and transcription factors were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). ⋯ Additional studies showed comparable globin gene response patterns in KU812 and primary erythroid cells after treatments with the various drug inducers. Mechanisms of drug-mediated γ-globin induction in KU812 cells require signaling through the p38 mitogen-activated protein kinase pathway similar to that previously demonstrated in primary erythroid cells. These data suggest that KU812 cells serve as a good screening system to identify potential HbF inducers for the treatment of β-hemoglobinopathies.
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Exp. Biol. Med. (Maywood) · Oct 2010
ReviewCorticotropin-releasing factor signaling and visceral response to stress.
Stress may cause behavioral and/or psychiatric manifestations such as anxiety and depression and also impact on the function of different visceral organs, namely the gastrointestinal and cardiovascular systems. During the past years substantial progress has been made in the understanding of the underlying mechanisms recruited by stressors. Activation of the corticotropin-releasing factor (CRF) signaling system is recognized to be involved in a large number of stress-related behavioral and somatic disorders. This review will outline the present knowledge on the distribution of the CRF system (ligands and receptors) expressed in the brain and peripheral viscera and its relevance in stress-induced alterations of gastrointestinal and cardiovascular functions and the therapeutic potential of CRF(1) receptor antagonists.
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Exp. Biol. Med. (Maywood) · Jul 2010
Effect of noble gases on oxygen and glucose deprived injury in human tubular kidney cells.
The noble gas xenon has been shown to be protective in preconditioning settings against renal ischemic injury. The aims of this study were to determine the protective effects of the other noble gases, helium, neon, argon, krypton and xenon, on human tubular kidney HK2 cells in vitro. Cultured human renal tubular cells (HK2) were exposed to noble gas preconditioning (75% noble gas; 20% O(2); 5% CO(2)) for three hours or mock preconditioning. ⋯ In the absence of OGD, helium was also detrimental (0.909 +/- 0.07; P < 0.01). Xenon caused an increased expression of p-Akt, HIF-1alpha and Bcl-2, while the other noble gases did not modify protein expression. These results suggest that unlike other noble gases, preconditioning with the anesthetic noble gas xenon may have a role in protection against renal ischemic injury.
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Exp. Biol. Med. (Maywood) · Jun 2010
Signaling pathways involved in postconditioning-induced cardioprotection of human myocardium, in vitro.
We examined the respective role and relationship between protein kinase C (PKC), mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) channel and p38 mitogen-activated protein kinase (MAPK) in postconditioning of human myocardium, in vitro. Isometrically contracting, isolated human right atrial trabeculae were exposed to 30 min hypoxia and 60 min reoxygenation. Phorbol 12-myristate 13-acetate (a PKC activator), diazoxide (a mitoK(ATP) opener) and anisomycin (a p38 MAPK activator) were superfused in early reoxygenation alone and with calphostin C (a PKC inhibitor), 5-hydroxy-decanoate (5-HD, a mitoK(ATP) channel inhibitor) and SB 202190 (a p38 MAPK inhibitor). ⋯ In conclusion, PKC activation, opening of mitoK(ATP) channels and p38 MAPK activation in early reoxygenation induced the postconditioning of human myocardium, in vitro. Furthermore, PKC activation was upstream of the opening of mitoK(ATP) channels; p38 MAPK acted on PKC. Therefore, mitoK(ATP) and p38 MAPK seemed to be involved in two independent pathways.
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Exp. Biol. Med. (Maywood) · May 2010
Effects of electro-acupuncture on endothelium-derived endothelin-1 and endothelial nitric oxide synthase of rats with hypoxia-induced pulmonary hypertension.
Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure (PAP), pulmonary vascular remodeling and right ventricular hypertrophy, which are mainly due to endothelial dysfunction. Electro-acupuncture has shown beneficial effects on cardiovascular homeostasis, but little evidence has been obtained on pulmonary effects. The goal of the present study was to investigate whether electro-acupuncture on bladder-13 and -15 points can protect against chronic hypoxia-induced PH by regulating endothelium-derived endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS). ⋯ In lung homogenate, levels of eNOS under hypoxia increased from 684.96 +/- 117.90 to 869.86 +/- 197.61 pg/mg by electro-acupuncture treatment. Levels of ET-1 changed oppositely to eNOS in response to electro-acupuncture (ET-1 in plasma, 29.44 +/- 2.09 versus 20.70 +/- 2.37 pg/mL; ET-1 in lung homogenate, 120.51 +/- 3.03 versus 110.60 +/- 4.04 pg/mg). In conclusion, these results indicated that treatment with electro-acupuncture can protect against hypoxia-induced PH, possibly by regulating the balance of endothelium-derived vasoconstrictors and vasodilators.