Experimental biology and medicine
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Exp. Biol. Med. (Maywood) · Oct 2016
Original Research: Different imiquimod creams resulting in differential effects for imiquimod-induced psoriatic mouse models.
Imiquimod (IMQ)-induced mouse psoriatic model is one of the useful models displaying most of psoriatic features. To compare the modeling efficacy of different IMQ creams, we induced the psoriatic models by topically applying two different brands of IMQ 5% creams to the shaved Balb/c mice skin and assessed the results. Balb/c female mice (n = 24) 8-12 weeks of age were randomly divided into experimental groups A (Likejie), B (Aldara), and control group C (Vaseline); Likejie, Aldara, or Vaseline was topically applied to the back skin for mice in groups A, B, and C, respectively, for six consecutive days. ⋯ The differences between the three groups in dual were statistically significant (P < 0.005 for the groups in dual). Aldara group showed more characteristic alterations of psoriasiform lesions than that of Likejie both macroscopically and histopathologically. The results suggested that different brands of IMQ creams may result in differential efficacy when performing the IMQ-induced psoriasis mouse models.
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Exp. Biol. Med. (Maywood) · Apr 2016
Original Research: A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease.
Sickle cell disease (SCD) is a group of inherited blood disorders that have in common a mutation in the sixth codon of the β-globin (HBB) gene on chromosome 11. However, people with the same genetic mutation display a wide range of clinical phenotypes. Fetal hemoglobin (HbF) expression is an important genetic modifier of SCD complications leading to milder symptoms and improved long-term survival. ⋯ Another HbF-associated SNP, rs2855122 in the cAMP response element upstream of Gγ-globin, was analyzed for functional relevance. Studies performed with siRNA-mediated CREB binding protein (CBP) knockdown in primary erythroid cells demonstrated γ-globin activation and HbF induction, supporting a repressor role for CBP. This study identifies possible molecular determinants of HbF production.
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Exp. Biol. Med. (Maywood) · Mar 2016
Featured Article: Differential regulation of endothelial nitric oxide synthase phosphorylation by protease-activated receptors in adult human endothelial cells.
Protease-activated receptors have been shown to regulate endothelial nitric oxide synthase through the phosphorylation of specific sites on the enzyme. It has been established that PAR-2 activation phosphorylates eNOS-Ser-1177 and leads to the production of the potent vasodilator nitric oxide, while PAR-1 activation phosphorylates eNOS-Thr-495 and decreases nitric oxide production in human umbilical vein endothelial cells. In this study, we hypothesize a differential coupling of protease-activated receptors to the signaling pathways that regulates endothelial nitric oxide synthase and nitric oxide production in primary adult human coronary artery endothelial cells. ⋯ PAR-3, known as the non-signaling receptor, was activated by TFRGAP, a PAR-3 mimicking peptide, and significantly induced the phosphorylation of eNOS-Thr-495 with minimal phosphorylation of eNOS-Ser-1177 with no change in nitric oxide production. In addition, we confirmed that PAR-mediated eNOS-Ser-1177 phosphorylation was Ca(2+)-dependent using the Ca(2+) chelator, BAPTA, while eNOS-Thr-495 phosphorylation was mediated via Rho kinase using the ROCK inhibitor, Y-27632, suggesting protease-activated receptor coupling to Gq and G12/13, respectively. These data suggest a vascular bed specific differential coupling of protease-activated receptors to the signaling pathways that regulate endothelial nitric oxide synthase and nitric oxide production that may be responsible for endothelial dysfunction associated with cardiovascular disease.
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Exp. Biol. Med. (Maywood) · Feb 2016
Transforming growth factor-β-sphingosine kinase 1/S1P signaling upregulates microRNA-21 to promote fibrosis in renal tubular epithelial cells.
Renal fibrosis is a progressive pathological change characterized by tubular cell apoptosis, tubulointerstitial fibroblast proliferation, and excessive deposition of extracellular matrix (ECM). miR-21 has been implicated in transforming growth factor-β (TGF-β)-stimulated tissue fibrosis. Recent studies showed that sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) are also critical for TGF-β-stimulated tissue fibrosis; however, it is not clear whether SphK/S1P interacts with miR-21 or not. In this study, we hypothesized that SphK/S1P signaling is linked to upregulation of miR-21 by TGF-β. ⋯ Blocking S1PR2 also inhibited upregulation of miR-21. Additionally, miR-21 overexpression attenuated the repression of TGF-β-stimulated ECM deposition and epithelial-mesenchymal transition by SphK1 and S1PR2 siRNA. In summary, our study demonstrates a link between SphK1/S1P and TGF-β-induced miR-21 in renal TECs and may represent a novel therapeutic target in renal fibrosis.
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Exp. Biol. Med. (Maywood) · Dec 2015
Pyruvate stabilizes electrocardiographic and hemodynamic function in pigs recovering from cardiac arrest.
Cardiac electromechanical dysfunction may compromise recovery of patients who are initially resuscitated from cardiac arrest, and effective treatments remain elusive. Pyruvate, a natural intermediary metabolite, energy substrate, and antioxidant, has been found to protect the heart from ischemia-reperfusion injury. This study tested the hypothesis that pyruvate-enriched resuscitation restores hemodynamic, metabolic, and electrolyte homeostasis following cardiac arrest. ⋯ Pyruvate treatment also lowered the dosage of vasoconstrictor phenylephrine required to maintain systemic arterial pressure at 15-60 min recovery, hastened clearance of excess glucose, elevated arterial bicarbonate, and raised arterial pH; these statistically significant effects persisted up to 3 h after sodium pyruvate infusion, while infusion-induced hypernatremia subsided. These results demonstrate that pyruvate-enriched resuscitation achieves electrocardiographic and hemodynamic stability in swine during the initial recovery from cardiac arrest. Such metabolically based treatment may offer an effective strategy to support cardiac electromechanical recovery immediately after cardiac arrest.