Biomedical subjects

Kazuhiro Abeyama

Publications and source records attributed to Kazuhiro Abeyama.

11 recordsLinked to original sources

PubMed2007

Hydroxyapatite formed on/in agarose gel induces activation of blood coagulation and platelets aggregation.

We reported earlier that hydroxyapatite (HA) formed on/in agarose gels (HA/agarose) produced by alternate soaking process is a bone-filling material possessing osteoconductive and hemostatic effects. This process could allow us to make bone-like apatite that was formed on/in organic polymer hydrogel matrices. Here, we investigated the mechanism of hemostasis induced by HA/agarose and found that HA/agarose, but not agarose or HA powder, significantly shortened activated partial thromboplastin time (APTT). While HA/agarose did not show significant platelet aggregation, it markedly enhanced adenosine diphosphate (ADP)-induced platelet aggregation. Moreover, Western blot analysis revealed selective adsorption of vitronectin onto HA/agarose. We also observed marked differences between HA powder and HA/agarose in their XRD patterns. The crystallinity of HA powder was much higher compared to that of HA/agarose. Furthermore, 50-100 nm of tube-form aggregations was observed in HA powder on the other hand 100-200 nm of particles was observed in HA/agarose by SEM observation. Thus 100-200 nm of low crystallized particles on the surface structure of HA/agarose may play an important role in hemostasis. Our results demonstrated a crucial role of HA/agarose in the mechanism of hemostasis and suggested a potential role for HA/agarose as a bone-grafting material.

Adenosine Diphosphate↗

PubMed2005

The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism.

Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated formation of activated protein C (APC). We have found that the N-terminal lectin-like domain (D1) of TM has unique antiinflammatory properties. TM, via D1, binds high-mobility group-B1 DNA-binding protein (HMGB1), a factor closely associated with necrotic cell damage following its release from the nucleus, thereby preventing in vitro leukocyte activation, in vivo UV irradiation-induced cutaneous inflammation, and in vivo lipopolysaccharide-induced lethality. Our data also demonstrate antiinflammatory properties of a peptide spanning D1 of TM and suggest its therapeutic potential. These findings highlight a novel mechanism, i.e., sequestration of mediators, through which an endothelial cofactor, TM, suppresses inflammation quite distinctly from its anticoagulant cofactor activity, thereby preventing the interaction of these mediators with cell surface receptors on effector cells in the vasculature.

Animals↗

PubMed2005

Activated protein C, a natural anticoagulant protein, has antioxidant properties and inhibits lipid peroxidation and advanced glycation end products formation.

INTRODUCTION: Activated protein C (APC) is an important natural anticoagulant that is proteolytically generated from protein C (PC) by the modulation of thrombin activity in the presence of thrombomodulin on an endothelial surface. Recent studies have demonstrated that, beyond its anticoagulant acitivities, APC had anti-inflammatory and cytoprotective properties. The mechanisms underlying APC's anti-inflammatory effects remain unknown. Our goal was to elucidate and confirm these mechanisms. METHODS: We first examined the effect of APC on reactive oxygen species (ROS) and inflammatory cytokine production in murine macrophage-like RAW264.7 cells. We further examined the effect of APC on chemically induced lipid peroxidation and advanced glycation end-products (AGE) formation. RESULTS AND CONCLUSIONS: APC in the range of 10-50 microg/mL could reduce lipopolysaccharide (LPS)-induced ROS generation, nuclear factor kappaB (NF-kappaB) activation and resultant proinflammatory cytokine production. Additional cell-free experiments revealed that APC (10-50 microg/mL) had inhibitory effects on lipid peroxidation and AGE formation. These findings suggest that APC, via its intrinsic anti-oxidant properties, may, in settings of oxidant stress, exert important cytoprotective and anti-inflammatory effects that are distinct from its anticoagulant activity as an antioxidant protein. If that is true, APC may contribute to ROS-related chronic disorders including atherosclerosis and diabetes as well as acute shock conditions.

Animals↗

PubMed2004

The antimetastatic role of thrombomodulin expression in islet cell-derived tumors and its diagnostic value.

Islet cell tumors, endocrine neoplasm arising from pancreatic islets of Langerhans, are histologically difficult to diagnose as benign or malignant. Molecular markers are associated with the clinical characteristics that most of insulinoma are usually benign tumors, whereas other islet cell tumors are malignant but have not been identified. In this context, we newly found that an endothelial anticoagulant thrombomodulin was expressed in the normal islet beta cells and insulinoma, but not of other islet components or noninsulinoma islet cell tumors. Clinically, all of the subjects (n=15) of the insulinoma group showed no metastasis together with thrombomodulin expression in the lesions, whereas the other islet cell tumor groups showed a high incidence of metastasis (82%) and a low expression rate of thrombomodulin (6%). To examine the functional role of thrombomodulin, especially regarding the clinical characteristics of islet cell tumors, we tested the effect of exogenous thrombomodulin overexpression on cell adhesiveness and proliferation using MIN6 insulinoma cell line. In cell-based experiments, thrombomodulin overexpression reduced cell proliferation and enhanced Ca2+-independent cell aggregation, possibly through direct interaction with neural cell adhesion molecule. Taken together, these results are suggesting that thrombomodulin may act as antimetastatic molecule of insulinomas. In addition, thrombomodulin is a clinically useful molecular marker not only for identifying beta-cell-origin islet cell tumors (i.e., insulinomas) but also for predicting disease prognosis of islet cell tumors.

Adolescent↗

PubMed2004

Anti-atherogenic effects of an egg yolk-enriched garlic supplement.

It has been suggested that oxidation of low-density lipoprotein (LDL) plays an important role in the initiation and progression of atherosclerosis. In the present study, we determined the anti-atherogenic effects of egg yolk-enriched garlic powder (EGP), which has been used as a traditional health-promoting food in southern Japan since ancient times, on LDL oxidation and oxidant stress-induced cell injury models. We confirmed that EGP inhibits copper-induced LDL oxidation in a dose-dependent manner. We also observed that pretreatment of EGP significantly suppressed the production of peroxides in HL60 cells and protected endothelial cells from hydrogen peroxide-induced cell injury. These findings might, in part, be ascribed to the biodistribution of garlic compounds and egg yolk interaction, and suggest that EGP might be useful in the prevention of atherosclerosis.

Arteriosclerosis↗

PubMed2004

[Inflammation and its regulatory system].

Sepsis or its synonymously termed "SIRS (systemic inflammatory response syndrome)" is a common cause of individual morbidity and mortality in various clinical situations. In such conditions, high mobility group box-1 DNA binding protein (HMGB1), widely known as a nuclear structural protein, has been identified to act as a late mediator of delayed endotoxin lethality. Once released from necrotic damaged cells or secreted by activated monocytes/macrophage, it participates in the development of lethality and it activates downstream cytokine release. In this review, we describe herein the general features of sepsis focusing on the role of HMGB1 in the mechanism of development of systemic inflammation, and also introduce newly established therapeutic concept "Functional HMGB1 inhibition with thrombomodulin" against sepsis/SIRS/DIC.

HMGB1 Protein↗

PubMed2003

Antibiotic cyclic AMP signaling by "primed" leukocytes confers anti-inflammatory cytoprotection.

The mechanism underlying anti-inflammatory effects of macrolide antibiotics remains uncertain. In this study, we first show the evidences concerning the possible link between leukocytic cyclic adenosine monophosphate (cAMP) signaling and the mechanism of anti-inflammatory, cytoprotective actions of macrolides. The clinical range of macrolides (i.e., erythromycin, roxithromycin, and clarithromycin) preferentially inhibited nuclear factor-kappaB activation mediated by reactive oxygen intermediates, inducing cAMP-dependent signaling [i.e., cAMP and cAMP-responsive element-binding protein (CREB)] by "primed" but not "resting" leukocytes. In this context, cAMP/CREB inhibition with adenosine 3':5'-cyclic monophosphothioate, rp-isomer (rp-cAMPs) and CREB decoy oligonucleotides reduced the anti-inflammatory actions of macrolides. These results thus indicate that macrolide-induced cAMP/CREB signaling, selectively by primed leukocytes, plays a major role in the mechanism of anti-inflammatory actions of macrolides.

Animals↗

PubMed2003

Membrane cholesterol but not putative receptors mediates anandamide-induced hepatocyte apoptosis.

The endogenous cannabinoid anandamide, a lipid mediator, induces various physiologic events such as vascular relaxation, inhibition of gap-junctions formation, tumor proliferation, neurologic analgesia, and apoptosis. Although increased concentration of anandamide in plasma has been implicated in pathophysiologic states including endotoxin-induced hypotension, the effects of anandamide on hepatocytes still remain unclear. In this study, we present evidence that plasma anandamide concentration is highly increased in severe hepatitis and cirrhosis patients. In addition, concentrations of anandamide within the pathophysiologic range potently induced apoptosis of hepatoma cell line (Hep G2) and primary hepatocytes, suggesting a possible link between increased anandamide level and hepatocyte damage. Anandamide-induced cell death was preceded by G0/G1 cell-cycle arrest, activation of proapoptotic signaling (i.e., p38 MAPK and JNK), and inhibition of antiapoptotic signaling (i.e., PKB/Akt) pathways. Moreover, anandamide increased susceptibility to oxidative stress-induced hepatocyte damage. In this context, methyl-beta-cyclodextrin (MCD), a membrane cholesterol depletor, or mevastatin, an HMG-CoA reductase inhibitor, or N-acetyl cysteine, an antioxidant, potently inhibited the anandamide-induced proapoptotic events and cell death, whereas putative cannabinoid receptor antagonists did not exhibit an inhibitory effect on anandamide-induced cell death. Furthermore, binding assay using polymyxin beads revealed that anandamide could interact with cholesterol. In conclusion, our data suggest that cholesterol present in the cell membrane determines the fate of hepatocytes exposed to anandamide, possibly functioning as an anandamide receptor.

Animals↗

PubMed2003

Anandamide induces apoptosis in human endothelial cells: its regulation system and clinical implications.

Anandamide (AEA), an endogenous cannabinoid, is generated by macrophages during shock conditions, and is thought to be a causative mediator of septic shock. Thus, we hypothesized that AEA plays a crucial role in endothelial cell (EC) injury. Here, we demonstrate that AEA induces apoptosis in a time-and dose-dependent manner in human umbilical vein endothelial cells (HUVECs). AEA triggered phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and p38 mitogen activated protein kinase. AEA also showed a marked increase of interleukin Ibeta- converting enzyme (ICE)CED-3 family protease (caspase-3) activity. AEA-induced EC death was inhibited by a selective vanilloid receptor 1 (VR1) antagonist, capsazepine, and was enhanced by a VR1 agonist, capsaicin, indicating that AEA induces apoptosis in ECs via VR1. In conclusion, we propose that AEA may play a crucial role in EC injury under conditions of shock, and that the use of inhibitors of the AEA regulation system may have a therapeutic effect under these conditions.

Apoptosis↗

PubMed2001

Enhanced production of vascular endothelial growth factor by human monocytic cells stimulated with endotoxin through transcription factor SP-1.

The effect of endotoxin on the regulation of vascular endothelial growth factor (VEGF) mRNA expression in human monocytic (THP-1) cells was examined. Endotoxic lipopolysaccharide (LPS) from Escherichia coli and synthetic E. coli-type lipid A (LA-15-PP) enhanced VEGF mRNA expression. LPS-induced VEGF mRNA accumulation was regulated, at least in part, at the transcriptional level. Enhancement of VEGF gene expression by LPS was shown by gel shift analysis and use of transcription factor inhibitors to be mediated via the activation of SP-1.

Cells, Cultured↗

PubMedDate not supplied

Decreased total nitric oxide production in patients with duchenne muscular dystrophy.

Plasma nitric oxide (NO) levels in Duchenne muscular dystrophy (DMD) patients were significantly lower than those observed in both healthy controls and in patients with other neuromuscular disorders. The correlation between NO level and ejection fraction was significant (r = -0.384, p = 0.0391) in the DMD group. Disruption of NO systems may contribute to the development of muscular dystrophy and have implications for therapeutic strategies.

Adolescent↗