Activation peptide of coagulation factor IX improves the prognosis after traumatic brain injury.

Recently, coagulation factor IX and its activation peptide have been reported to suppress the permeability of vascular endothelial cells. In this study, the therapeutic effects of a synthesized activation peptide is investigated in traumatic brain injury model rats. In cerebral contusion, dysfunction of the blood brain barrier with increasing vascular permeability promotes the progression of neuropathy after injury.

EGF domain of coagulation factor IX is conducive to exposure of phosphatidylserine.

Lipid rafts are an initiation site for many different signals. Recently, we reported that an EGF domain in activated coagulation factor IX (EGF-F9) increases lipid raft formation and accelerates cell migration. However, the detailed mechanism is not well understood.

Activation peptide of coagulation factor IX regulates endothelial permeability.

Endothelial hyperpermeability is involved in several critical illnesses, and its regulatory mechanisms have been intensively investigated. It was recently reported that the activation peptide of coagulation factor IX enhances cell matrix and intercellular adhesion. The aim of this study was to investigate the role of activation peptide of coagulation factor IX in intercellular adhesion of endothelial cells and evaluate its effects on endothelial permeability.

The first EGF domain of coagulation factor IX attenuates cell adhesion and induces apoptosis.

Coagulation factor IX (FIX) is an essential plasma protein for blood coagulation. The first epidermal growth factor (EGF) motif of FIX (EGF-F9) has been reported to attenuate cell adhesion to the extracellular matrix (ECM). The purpose of the present study was to determine the effects of this motif on cell adhesion and apoptosis.

Long-term gene therapy with Del1 fragment using nonviral vectors in mice with explanted tumors.

Cancer gene therapy using nonviral vectors is useful for long periods of treatment because such vectors are both safe and inexpensive, and thus can be used repeatedly. It has been reported that gene therapy with an E3C1 fragment of Del1 in a mouse explanted tumor model improved prognosis. The present study aimed to analyze the long-term effects of repeated non-viral gene transfer of E3C1.

Coagulation factor IX regulates cell migration and adhesion in vitro.

Coagulation factor IX is thought to circulate in the blood as an inactive zymogen before being activated in the coagulation process. The effect of coagulation factor IX on cells is poorly understood. This study aimed to evaluate the effects of intact coagulation factor IX and its cleavage fragments on cell behavior.

Efficient nonviral gene therapy with FasL and Del1 fragments in mice.

Background: The expression of FasL in cancer cells is currently being explored as a potential cancer therapy. Because high levels of FasL are necessary for effective treatment, current methods typically rely on the use of highly efficient viral vectors. However, because viral vector-based gene therapy is associated with certain risks, the development of effective nonviral routes for gene delivery would be useful.

Effects of zinc deficiency and supplementation on gene expression of bitter taste receptors (TAS2Rs) on the tongue in rats.

Objectives/hypothesis: We examined the effect of zinc deficiency and supplementation on the expression of bitter taste receptor (TAS2R) and epithelial sodium ion channel (ENaC) genes on the tongue in rats.

Study Design: Prospective animal study.

Methods: A total of 36 male Sprague-Dawley rats (3 weeks old) were used.

An epidermal growth factor motif from Del1 protein increases the efficiency of in vivo gene transfer with a non-viral vector.

Increasing the efficiency of gene transfer using non-viral vectors, which have the potential to be safe and economical, would improve upon available options for gene therapy. We previously reported that the third EGF motif of the extracellular matrix protein Del1 (E3) increases the transfection efficiency of non-viral vector methods. Here, we asked if E3 could increase the in vivo transfection efficiency of a polyplex-based approach.

Patients with phantogeusia show increased expression of T2R taste receptor genes in their tongues.

Objectives: The taste receptor gene family T2R has been implicated in the sensation of bitter taste. Phantogeusia is a spontaneous abnormal taste with no external stimulus. We analyzed the expression of T2R taste receptor genes in the tongues of patients with phantogeusia to assess their role in the pathogenesis of phantogeusia.

Patients with hypogeusia show changes in expression of T2R taste receptor genes in their tongues.

Objectives/hypothesis: Taste receptor genes associated with bitterness belong to the T2R gene family. In this study, we compared the expression of genes of the T2R family in the tongues of patients with hypogeusia to those in healthy subjects and examined the possibility that T2R genes are involved in the pathogenesis of hypogeusia.

Study Design: Prospective clinical and basic study.

The extracellular matrix protein Del1 induces apoptosis via its epidermal growth factor motif.

Mouse Del1 is an extracellular matrix protein mainly expressed in the developing embryo. Del1 has three EGF motifs and two discoidin domains. The second EGF motif reportedly contains an RGD sequence that binds to integrin receptors.

The Del1 deposition domain can immobilize 3alpha-hydroxysteroid dehydrogenase in the extracellular matrix without interfering with enzymatic activity.

Developing methods that result in targeting of therapeutic molecules in gene therapies to target tissues has importance, as targeting can increase efficacy and decrease off target-side-effects. Work from my laboratory previously showed that the extracellular matrix protein Del1 is organized in the extracellular matrix (ECM) via the Del1 deposition domain (DDD). In this work, a fusion protein with DDD was made to assay the ability to immobilize an enzyme without disrupting enzymatic function.

An epidermal growth factor-like repeat of Del1 protein increases the efficiency of gene transfer in vitro.

In this paper, we found that Del1, an extracellular matrix protein secreted by embryonic endothelial cells, increases the efficiency of transfection in vitro. Conditioned medium containing Del1 increased transfection by the LacZ gene using several non-viral gene transfer systems, including lipoplex and polyplex methods. Experiments using deletion mutants and fragments of Del1 revealed that the third epidermal growth factor-like repeat (E3) of Del1 mediates the enhancement of gene transfer and, furthermore, that the motif CXDXXXFXCXC is essential.

Discoidin domain of Del1 protein contributes to its deposition in the extracellular matrix.

The extracellular matrix (ECM) acts as a critical factor during morphogenesis. Because the organization of the ECM directly influences the structure of tissues and organs, a determination of the way that ECM organization is regulated should help to clarify morphogenesis. We have analyzed the assembly of Del1, an ECM protein produced by endothelial cells in embryos, in the ECM.

Association between prostaglandin E2 receptor gene and essential hypertension.

Background: Essential hypertension (EH) is a complex multifactorial polygenic disorder that is thought to result from an interaction between an individual's genetic makeup and various environmental factors. In the kidney, prostaglandins (PGs) are important mediators of vascular tone and salt and water homeostasis, and are involved in the mediation and/or modulation of hormonal action. In previous studies, mice deficient in the prostaglandin E2 (PGE(2)) EP2 receptor had resting systolic blood pressure (BP) that was significantly lower than that of wild-type controls.

Overexpression of the Del1 gene causes dendritic branching in the mouse mesentery.

In the present study, we established transgenic mice overexpressing Del1, a ligand of integrins, to examine the effect of overexpression of Del1 on vascular morphogenesis. In the wild-type mouse, mesenteric vessels are shaped like rakes consisting of a long stalk and short branches at the periphery. In contrast, those in transgenic mice showed typical dendritic architecture consisting of a few large primary branches with smaller spreading branches.

Haplotype-based case-control study revealing an association between the adrenomedullin gene and proteinuria in subjects with essential hypertension.

Adrenomedullin (AM) has various physiological actions on the cardiovascular system, including vasodilatation, diuresis, natriuresis, inhibition of aldosterone secretion, and increases of the cardiac output, all of which cause hypotension. Since AM plays a role in the pathophysiology of vascular diseases, genes controlling AM might be involved in the development and etiology of essential hypertension (EH). However, there have been few studies examining the relationship between the AM gene and hypertension.

Association study of calcitonin-receptor-like receptor gene in essential hypertension.

Background: Plasma adrenomedullin (ADM) concentrations increase in patients with hypertension, renal failure, heart failure, essential pulmonary hypertension, myocardial infarction, endotoxin shock, and many other conditions. The ADM receptor is a complex molecule that consists of calcitonin-receptor-like receptor (CRLR) and receptor activity-modifying protein 2 (RAMP2). Because CRLR determines the binding specificity of ADM, the CRLR gene is thought to be a susceptibility gene of hypertension.

An association study in essential hypertension using functional polymorphisms in lymphotoxin-alpha gene.

Background: Lymphotoxin-alpha (LTA), a member of the tumor necrosis factor family, is a cytokine produced by lymphocytes. The substance LTA mediates a wide variety of inflammatory, immunostimulatory, and antiviral responses. In 2002, LTA was identified as a major risk factor for myocardial infarction (MI) in Japanese individuals, in a large-scale case-control study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers in the whole human genome.

P2Y-mediated Ca2+ response is spatiotemporally graded and synchronized in sensory neurons: a two-photon photolysis study.

ATP is thought to be an initiator and modulator of noxious pain sensation. We employed two-photon photolysis to apply ATP locally and transiently, thus mimicking ATP release upon cell damage or exocytosis. Using this technique, an increase in intracellular Ca2+ concentration ([Ca2+]i) was induced via P2Y receptors in individual sensory neurons, or in a neurite region.

The prostacyclin analogue beraprost sodium prevents development of arterial stiffness in elderly patients with cerebral infarction.

Prostacyclin (PGI(2)) inhibits platelet aggregation, smooth muscle cell proliferation, and vasoconstriction. Arterial stiffness assessed by pulse wave velocity (PWV) predicts mortality in various cardiovascular diseases. To study the preventive effects of a prostacyclin analogue, beraprost sodium, on arterial PWV values in elderly patients with cerebral infarction.

Missense mutation of exon 3 in the type A human natriuretic peptide receptor gene is associated with myocardial infarction.

Background: Myocardial infarction (MI) is a complex multifactorial and polygenic disorder that is thought to result from interaction between genetic make-up and various environmental factors. We previously identified a missense mutation, methionine (ATG) to isoleucine (ATC) at nucleotide 1023 (M341I), in exon 3 of the human natriuretic peptide receptor A type (hNPRA) gene. This mutation is associated with increased risk for essential hypertension (EH).

Specific regulation of nucleocytoplasmic distribution of poly(C)-binding protein gene mRNA in mouse development.

Post-transcriptional regulation plays a pivotal role in gene expression. In this study, the intracellular distribution of the murine cytoplasmic poly(C)-binding protein (alphaCP2) gene transcript was investigated. The nucleocytoplasmic mRNA distribution of alphaCP2 was shown to change throughout the course of mouse development.

Haplotype analysis of the prostacyclin synthase gene and essential hypertension.

Previously, we discovered 3 polymorphisms in the prostacyclin synthase (PGIS) gene: 1) T-192G, in the 5-flanking region, a novel single-nucleotide polymorphism (SNP) that is not associated with essential hypertension (EH); 2) a variable number of tandem repeat (VNTR) polymorphism, 6 nucleotides upstream from the ATG start codon, that is associated with risk of cerebral infarction; and 3) C1117A, in exon 8, an SNP that does not cause an amino acid change in codon 373, and that is associated with risk of myocardial infarction (MI). The purpose of the present study was to establish haplotypes of the PGIS gene consisting of these 3 polymorphisms, and to assess the association between these haplotypes and EH. We detected 19 haplotypes.