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Biomedical subjects

I Maruyama

Publications and source records attributed to I Maruyama.

At least 91 records · Page 5Linked to original sources
PubMed1998

A subcloned human esophageal squamous cell carcinoma cell line with low thrombomodulin expression showed increased invasiveness compared with a high thrombomodulin-expressing clone--thrombomodulin as a possible candidate for an adhesion molecule of squamous cell carcinoma.

Thrombomodulin (TM) is an endothelial cell surface glycoprotein which converts thrombin from a procoagulant protease to an anticoagulant. We have previously reported that TM is a useful marker for immunohistochemical diagnosis of angiogenic tumors and also have reported that TM is expressed on squamous cell carcinoma (SCC) of the human esophagus. In addition, the expression of TM is significantly decreased in metastatic foci in lymph nodes compared with that in primary lesions. In order to reveal the biological significance of TM in SCC, we subcloned and established two different cell lines, i.e. TM-high-expressing (TE3HTM) cells and TM-low-expressing (TE3LTM) cells, from a human SCC cell line, TE3, using fluorescence-activated cell sorter (FACS) and examined the biological characteristics of these variant cell lines. These tumor cells revealed very similar morphological figures in ordinary cultured conditions and showed almost equal growth rates under various cultured conditions. By the invasion assay of these tumor cells using matrigel, we found that TE3LTM cells showed significantly increased invasive ability compared with that of TE3HTM cells. Characteristic intercellular localization of TM and a different manner of invasiveness between TE3LTM cells and TE3HTM cells suggest that TM may act as a cell-to-cell interaction molecule.

Carcinoma, Squamous Cell↗
PubMed1998

DX9065a, an Xa inhibitor, inhibits prothrombin-induced A549 lung adenocarcinoma cell proliferation.

In this study we demonstrate that prothrombin activates the cell proliferation of the lung adenocarcinoma A549 cells. The A549 cell expresses factor Xa-like prothrombinase activity on its surface and prothrombin was converted to thrombin on the cell surface. Furthermore, thrombin induced the activation of PKC, increased [Ca2+]i and potentiated MAP kinase activity through thrombin receptor. The mitogenic activity of prothrombin and the conversion to thrombin were completely abolished by the synthetic coagulation factor Xa inhibitor, DX9065a. These findings suggest that DX9065a is an effective agent for a therapeutic strategy against cancer itself and prothrombotic complications associated with malignancy.

Adenocarcinoma↗
PubMed1998

Overproduction of vascular endothelial growth factor/vascular permeability factor is causative in Crow-Fukase (POEMS) syndrome.

Crow-Fukase or POEMS syndrome of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes is a rare multisystem disorder of obscure pathogenesis that is associated with microangiopathy, neovascularization, and accelerated vasopermeability. We examined the levels of the vascular endothelial growth factor/vascular permeability factor (VEGF) in the serum and cerebrospinal fluid (CSF) from 10 patients with this syndrome. Serum VEGF levels were about 15-30 times those in control subjects or patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and other neurological disorders. The CSF VEGF levels, however, were similar to those found in GBS and CIDP. Elevated VEGF levels in the serum decreased in 7 patients with Crow-Fukase syndrome after conventional therapy. The principal isoform of VEGF in Crow-Fukase syndrome was VEGF165. Elevated VEGF was independent of M-protein. Our results suggest that the overproduction of VEGF is important in the pathogenesis of this disorder.

Adult↗
PubMed1998

A novel recombinant soluble human thrombomodulin, ART-123, activates the protein C pathway in healthy male volunteers.

The effect of a novel recombinant soluble human thrombomodulin, ART-123, on protein C activation was investigated by measuring plasma prothrombinase activity in four healthy male volunteers. ART-123 at a dose of 0.3 mg was administered as a bolus intravenous injection for 1 minute. Plasma ART-123 concentration and prothrombinase activity were determined before and immediately, 24, and 48 hours after injection, and thromboelastography was recorded before and immediately and 24 hours after injection. The mean elimination half-life was 19.82 +/- 2.10 hours. Compared with pretreatment levels, ART-123 reduced prothrombinase activity by 44.2 +/- 11.7%, 52.1 +/- 10.8%, and 61.0 +/- 14.7%, respectively, immediately, 24, and 48 hours after injection, suggesting that ART-123 activated the protein C pathway. ART-123 did not affect thromboelastography values. There were no abnormal findings for objective signs or laboratory tests, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, coagulation and hemostatic parameters, blood chemistry, and urinalysis. Based on these observations, ART-123 at a dose of 0.3 mg can activate the protein C pathway in healthy volunteers.

Adult↗
PubMed1998

Inflammatory cytokine production and specific antibody responses against possible causative bacteria in patients with multilesional periapical periodontitis.

We examined the induction of inflammatory cytokines (including interleukin-1, interleukin-6, interleukin-8, and tumor necrosis factor-alpha) by several species of possible causative bacteria in periapical periodontitis. Assays were done on human whole blood cultures from patients with differing numbers of periapical lesions; those having radiographically clear periapical lesions in 10 or more teeth (high lesion group), in one or two teeth (low lesion group), and healthy volunteers having no periapical lesions (no lesion group). Prevotella melaninogenica ATCC 25845 induced interleukin-6 more strongly in subjects from the high lesion group than in the other groups. To ascertain the degree of sensitization by test bacteria, we examined the reactivities of antibodies in serum and saliva from the six subjects to different bacterial species. Porphylomonas gingivalis cells reacted strongly with sera from the high lesion group. Thus, Prevotella melaninogenica and Porphylomonas gingivalis may be involved in multilesional periapical periodontitis by inducing specific cytokines and/or humoral immune responses.

Aggregatibacter actinomycetemcomitans↗
PubMed1998

N epsilon-(carboxymethyl)lysine in blood from maintenance hemodialysis patients may contribute to dialysis-related amyloidosis.

BACKGROUND: Recent studies demonstrated not only that advanced glycation end product could be found in amyloid tissue from patient with dialysis related amyloidosis, but also that amyloid beta2-microglobulin was modified with N(epsilon)-(carboxymethyl)lysine (CML). We wanted to determine if CML could be a biomarker in these patients. METHODS: To raise polyclonal anti-carboxymethyllysine antibody, human serum albumin was carboxymethylated by glyoxylic acid and was immunized to rabbits as antigen. Carboxymethyllysine-hemoglobin (CML-Hb) levels were measured by the dot blotting method using this antibody. RESULTS: The levels of CML-Hb were 6.68 +/- 3.10 nmol CML/mg Hb in nondiabetic hemodialysis patients (N = 70), 6.39 +/- 3.43 nmol CML/mg Hb in diabetic hemodialysis patient (N = 21), and 3.13 +/- 0.88 nmol CML/mg Hb in 47 healthy volunteers. For clinical signs of dialysis-related amyloidosis, 70 nondiabetic hemodialysis patients were scored according Gejyo's criteria. The CML-Hb levels in patients with a high amyloid score as well as a low amyloid score were significantly higher than in patients with negative amyloid score (8.89 +/- 3.53 nmol CMLmg Hb, 7.28 +/- 2.32 nmol CML/mg Hb vs. 5.11 +/- 2.09 nmol CML/mg Hb, P < 0.001, P < 0.05). Furthermore, the CML-Hb levels correlated significantly with serum values of the methylguanidine over creatinine ratio and hyaluronate. CONCLUSIONS: We suggest that CML-Hb is increased in blood from patients on maintenance hemodialysis and is thus a potential biomarker of oxidative damage in these patients. Moreover, CML-modification of protein may play a pathogenic role in the development of dialysis related amyloidosis.

Adult↗
PubMed1998

Difference in incidence and transmission mode of methicillin-resistant Staphylococcus aureus among surgery, orthopedics, and pediatrics wards: a prospective study at a university hospital.

The incidence and circumstances of colonization by methicillin-resistant Staphylococcus aureus were prospectively investigated. Among 404 patients, 15 (3.7%) were carriers on admission, and 43 (10.6%) became colonized, mainly after surgical operation. A different mode of transmission was suggested in each ward.

Adult↗
PubMed1998

Biology of endothelium.

Endothelial cells form a multifunctional cell lining that covers all of the inner surface of blood vessels and regulates several important physiological and pathological reactions. These include inflammation/immune reaction, blood vessel tonus, hemostasis/thrombosis, angiogenesis and so on. Thus, abnormalities of endothelial function may play crucial roles in the development of angitis syndrome, thrombosis/embolism, bleeding disseminated intravascular coagulation (DIC), and neovascularization in some pathological states including tumor growth and diabetic retinopathy. Research on endothelial cells now forms a new frontier termed 'Endotheliology'. Recent advances of the functional and structural aspects of endothelial cells are reviewed here mainly from the viewpoint of endothelial regulation of coagulation and the fibrinolytic system. First we show that the natural endothelial membrane protein thrombomodulin is localized not only on apical endothelial surface but also in caveolae. Since it has been reported that such factors involved in coagulation/fibrinolysis as tissue factor, tissue factor pathway inhibitor (TFPI), thrombin receptor and urokinase receptor are also localized in the caveolae, this membrane structure may act as a special component to regulate coagulation/fibrinolysis on the endothelial membrane surface. Next we demonstrate the signaling pathway of the thrombin receptor. Thrombin cleaves the N-terminus of the receptor as a substrate, exposing a new N-terminus. This newly exposed N-terminus acts as a ligand and activates platelets, endothelial cells and vascular smooth-muscle cells. We have identified that the signal from the thrombin receptor activates NF-kappaB through the activation of protein C kinase, tyrosine kinase and MAP kinase, and results in proliferation of the cells. We have also shown that the receptor is over-expressed on platelets from diabetes patients.

Animals↗
PubMed1998

Increased serum levels of vascular endothelial growth factor in Kawasaki disease.

Vascular endothelial growth factor (VEGF) is an angiogenic mitogen that specifically targets vascular endothelial cells. The objective of this study was to evaluate the role of VEGF in Kawasaki disease (KD), the most common cause of systemic vasculitis in childhood. Serum VEGF levels were measured by ELISA in 22 patients with KD, 22 febrile children with infection, and 19 healthy children. Samples from KD patients were divided into three groups: acute stage (n = 20), subacute stage (n = 13), and convalescent stage (n = 15). The results showed that KD patients in the acute and subacute stages had significantly higher levels of VEGF than did patients with infectious diseases and the healthy control subjects. When compared with the VEGF levels of patients with and without coronary artery lesions (CAL), significantly higher levels of VEGF were observed in the subacute stage in patients with CAL and in patients without CAL in the acute stage. Serial examination revealed that the serum VEGF levels in KD patients with CAL increased from a relatively low level in the acute stage to an extremely high level in the subacute stage. In contrast, patients without CAL were found to have extremely high levels of VEGF only in the acute stage of KD. In KD patients, the serum VEGF levels did not correlate with the inflammatory markers and clinical symptoms. Our results raise the possibility that VEGF is involved in the pathogenesis of KD, especially in the development of CAL. Further study is needed to clarify the biologic effect of VEGF on coronary arteries in KD.

Acute Disease↗
PubMed1998

[Coagulation/fibrinolytic system and platelet in acute coronary syndrome].

Coagulation/fibrinolytic system and platelet function play roles not only in the onset of acute coronary syndrome (ACS) but also in the development of atherosclerosis, which is a major underlying condition of ACS. In this paper we reviewed the involvement of coagulation/fibrinolytic system and platelet in coronary atherosclerosis and ACS. It is well known that hyperchoresterolemia and diabetes mellitus (DM) are the important risk factor for coronary atherosclerosis and ACS. Both oxidized LDL and advanced glycation endproduct (AGE) activate endothelial cells with down-regulating thrombomodulin and tissue plasminogen activator(t-PA) expression. Moreover the oxidized LDL and AGE up-regulate the expression of tissue factor, and t-PA inhibitor, PAI-1. Thus Ox-LDL and AGE impair the endothelial antithrombotic function and result ACS. These may explain the pathomechanism of coronary sclerosis and ACS. In the atherosclerotic lesion with narrowing the lumen, high shear stress may be occurred. Recent observations suggested that high shear stress induces platelets aggregation named as shear stress induced platelet aggregation (SIPA), which may also have very important role for the pathogenesis in ACS.

Acute Disease↗
PubMed1998

[Our challenge in Kagoshima University Hospital--development of more useful clinical laboratory].

In 1995, we newly developed a clinical laboratory system equipped with an expert system, which was named HIPOCLATES (Hospital Intelligent POwers of Clinical Laboratory Automation Technology with Expert System). Since this system includes an expert system, we have been able to support diagnostic and therapeutic procedure in clinics and begin developing a "zonal verification method" and "early-stage DIC diagnosis support system". The former is one of the individual quality control methods and we have attempted to develop a test assurance system in HIPOCLATES using this method. The latter system is to diagnosis DIC in the early phase. Here, we introduce the detail of our project using HIPOCLATES. Following the introduction HIPOCLATES, we attempted to develop a highly integrated system in physiological examinations, and succeeded in establishment PLATON (Physiological LAboratory TOtal Network system) in 1997. Thereafter, we planned a graphic reporting system named GALIREO (Graphic Assistant Laboratory Informational REport Operating system). In GALIREO, we attempted to connect the Department of Clinical Laboratory, Ultrasonic waves test room, Fiberscope test room, Department of Pathology and Surgical center by computer network. Developing these computer network system in our clinical laboratory we want to create electronic medical record linking with THINK (HIS in our hospital). We plan to make these expert system and electronic medical record available to clinical staff via a network to realize evidence-based medicine (EBM) and utilize these to support treatment and education.

Clinical Laboratory Information Systems↗
PubMed1998

Effects of recombinant human soluble thrombomodulin (rhs-TM) on clot-induced coagulation in human plasma.

Recent studies have suggested that clot-bound thrombin plays an important role in thrombus growth. In this study, we examined the effects of recombinant human soluble thrombomodulin (rhsTM) on clot-induced coagulation. rhsTM enhanced the activation of protein C by clots, and attenuated clot-induced thrombin generation and fibrinopeptide A (FPA) production in a dose-dependent manner. The inhibitory effect of rhsTM was abolished by anti-protein C antibody. The inhibitory effect of rhsTM on clot-induced thrombin generation continued for over 60 min after the addition of the clot, while an active site-directed thrombin inhibitor, argatroban, produced a more transient inhibition. rhsTM also inhibited the regrowth of the clot in (125)I-fibrinogen-supplemented plasma. We also examined the effect of rhsTM by thromboelastography, rhsTM reduced the growth of the clot but had little effect on the time to begin clotting, while heparin and Fragmin (low molecular weight heparin) had effects opposite to those of rhsTM. These findings suggest that rhs-TM attenuates the growth of the clot by activating protein C and inhibiting further thrombin generation in the clot.

Antithrombins↗
PubMed1998

Dysregulation of trace element composition in ovariectomized cynomolgus monkey bones.

One of the challenging issues in modern biomedical science is the increasing number of osteoporosis patients due to the expansion of elderly populations. Among aging-related pathogenic changes, alterations in bone function and skeletal pathogenesis is a particularly important issue of concern. Osteoporosis is one of the most serious bone-related pathogenic states, as it causes serious loss of quality of life. Alterations in estrogen levels in accordance with aging are one of the key risk factors for osteoporosis. Complexed estrogen actions on bones can be traced by analyzing bone mineral components, as those elements accumulate as mineral complexes, reflecting the context of multiple cellular reactions such as bone resorption/osteogenesis. We have analyzed bone trace element composition in ovariectomized (OVX-treated) Cynomolgus monkey models in this study. In order to gain insights into the effects of such defects on bone trace element composition, inductively coupled plasma atomic emissions spectrometry (ICP-AES) analysis was performed. Marked changes in bone trace element levels were found in vertebral bones of OVX-treated Cynomolgus monkeys. An assessment of these trace element spectra in OVX model animals is discussed. These results could provide useful markers for understanding the physiological states of bones in postmenopausal women.

Animals↗
PubMed1997

New quinolones, ofloxacin and levofloxacin, inhibit telomerase activity in transitional cell carcinoma cell lines.

It has been demonstrated that some quinolone antibiotics inhibit cell proliferation in vitro. This study showed that ofloxacin and levofloxacin, two well-known new quinolones, had an inhibitory effect on the proliferation of transitional cell carcinoma cell lines at high concentrations (>200 microg/ml). At relatively low concentrations (10-100 microg/ml), however, there was no apparent antiproliferative effect. Despite this, decreased absorbance in the MTT assay was observed at low concentrations and telomerase activity was significantly decreased. These results suggest that the antiproliferative effect of both ofloxacin and levofloxacin may be related to impairment of telomerase activity by some unknown mechanism.

Anti-Infective Agents↗
PubMed1997

Efficient transfer of synthetic ribozymes into cells using hemagglutinating virus of Japan (HVJ)-cationic liposomes. Application for ribozymes that target human t-cell leukemia virus type I tax/rex mRNA.

We investigated the usefulness of ribozymes in inhibiting the expression of human T-cell leukemia virus type I (HTLV-I) gene. Two hammerhead ribozymes that were against HTLV-I rex (RR) and tax (TR) mRNA were synthesized. Both ribozymes were sequence-specific in the in vitro cleavage analysis of run-off transcripts from tax/rex cDNA. Intracellular activities of the ribozymes were studied in HTLV-I tax cDNA-transfected rat embryonic fibroblasts (Rat/Tax cells), which expressed the Tax but not Rex. Ribozymes were delivered into cells using anionic or cationic liposomes fused with hemagglutinating virus of Japan (HVJ). Cellular uptake of ribozymes complexed with HVJ-cationic liposomes was 15-20 times higher cellular uptake than naked ribozymes, and 4-5 times higher than that of ribozymes complexed with HVJ-anionic liposomes. HVJ-cationic liposomes promoted accumulation of ribozymes in cytoplasm and accelerated transport to the nucleus. Tax protein levels were decreased about 95% and were five times lower when the same amount of TR was introduced into the cells using HVJ-cationic, rather than HVJ-anionic liposomes. Inactive ribozyme and tax antisense oligodeoxynucleotides reduced Tax expression by about 20%, whereas RR and tax sense oligodeoxynucleotides had no effect. These results suggest that the ribozymes' effect against tax mRNA was sequence-specific, and HVJ-cationic liposomes can be useful for intracellular introduction of ribozymes.

Animals↗
PubMed1997

Citrulline-argininosuccinate-arginine cycle coupled to Ca2+-signaling in rat pancreatic beta-cells.

Pancreatic beta-cells possess nitric oxide (NO) synthases (NOSs) which synthesize NO and L-citrulline from L-arginine. The present study was designed to explore the mechanism of citrulline and arginine metabolism in beta-cells and its possible coupling to beta-cell functions. The enzymes involved in citrulline-arginine metabolism, argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), and NOS were expressed in rat islets and insulinoma HIT T15 cells. In the presence of stimulatory glucose, L-citrulline and L-argininosuccinate at physiological concentrations (0.1-1 mM) increased cytosolic Ca2+ concentration ([Ca2+]i) in rat beta-cells. The citrulline-induced [Ca2+]i increase was inhibited by a NOS inhibitor, N(G)-monomethyl-L-arginine (NMMA). L-citrulline also stimulated NO production in HIT cells, which was inhibited by NMMA. In conclusion, L-citrulline is metabolized by ASS-ASL-NOS cycle to produce NO, which in turn increases [Ca2+]i in beta-cells.

Animals↗
PubMed1997

Thrombin activates NF-kappa B through thrombin receptor and results in proliferation of vascular smooth muscle cells: role of thrombin in atherosclerosis and restenosis.

We investigated the role of thrombin in the pathogenesis in atherosclerosis and restenosis. First we examined the effect of thrombin on cultured human vascular smooth muscle cells (VSMC). We showed that thrombin acts as a mitogen on VSMC through thrombin receptor. The expression of thrombin receptor was increased in the cell lines of VSMC established from directional coronary atherectomy (DCA). This is more pronounced in the cells from patients with restenosis after PTCA. Next we investigated the signaling pathway from thrombin/thrombin receptor. Thrombin activates thrombin receptor resulting in the exposing of the agonist peptide domain (thrombin receptor agonist peptide, TRAP). The signal from thrombin/thrombin receptor activated protein C kinase, tyrosine kinase, and MAP kinase and resulted in NF-kappa B activation. Furthermore, treatment of the cells with antisense p65 oligodeoxynucleotides of NF-kappa B inhibited the thrombin-stimulated growth of VSMC in vitro. These results suggest that thrombin may have a role in the pathogenesis of atherosclerosis and restenosis after PTCA through the thrombin receptor.

Arteriosclerosis↗