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Hiroshi Kusama

Publications and source records attributed to Hiroshi Kusama.

15 recordsLinked to original sources
PubMed2006

Synthesis and c-Src inhibitory activity of imidazo[1,5-a]pyrazine derivatives as an agent for treatment of acute ischemic stroke.

We synthesized and evaluated a series of C-5 substituted imidazo[1,5-a]pyrazine derivatives to identify potent c-Src inhibitors as potential therapeutic agents for acute ischemic stroke. Among these compounds, compound 14c.HCl demonstrated remarkable central nervous system (CNS) penetration and significant neuroprotective efficacy in vivo in rat models.

Acute Disease↗
PubMed2005

36-kDa microfibril-associated glycoprotein (MAGP-36) is an elastin-binding protein increased in chick aortae during development and growth.

MAGP-36 was discovered in porcine aorta in 1989 and is thought to be one of the microfibril-associated proteins. MAGP-36 has been localized on the surface of elastic fibers or laminae in immunohistochemical studies. However, its functional role in the aorta is obscure. Herein, we report on the binding activity of MAGP-36 to components of the aortic wall and its accumulation pattern in the aorta during development and growth. In vitro, MAGP-36 bound to elastin and collagen in a Ca(2+)-dependent manner, and mediated the adhesion of human aortic smooth muscle cells. This cell adhesion mostly depended on the RGD-containing domain of MAGP-36. We examined the accumulation of MAGP-36 with quantitative Western blot analysis and immunoelectron microscopy in chick aortae during development and growth. The amount of MAGP-36 increased on the surface of elastic fibers or laminae between days 14 and 34 after the start of incubation, and reached a plateau at about 53 days. This accumulation of MAGP-36 roughly correlated with an increase in blood pressure for this period. Thus, MAGP-36 might be a bridging protein that connects elastin to other components of the aortic wall and might play a role in maintaining the integrity of the aortic structure under arterial pressure.

Animals↗
PubMed2004

Bezafibrate stimulates canalicular localization of NBD-labeled PC in HepG2 cells by PPARalpha-mediated redistribution of ABCB4.

Fibrates, including bezafibrate (BF), upregulate the expression of ATP binding cassette protein B4 (ABCB4) through gene transcription in mice. To determine the effects of BF on the expression levels of ABCB4 and on the stimulation of biliary phosphatidylcholine (PC) transport in human HepG2 hepatoblastoma cells, mRNA and protein levels as well as subcellular localization were investigated in the cells treated with BF. The canalicular accumulation of a fluorescent PC was assessed by confocal laser scanning microscopy. Treatment with 300 micromol/l BF for 24 h increased levels of ABCB4 mRNA but not protein by up to 151%. BF caused redistribution of ABCB4 into pseudocanaliculi formed between cells. In association with this redistribution, BF accelerated the accumulation of fluorescent PC in bile canaliculi (up to 163% of that in nontreated cells). Suppression of peroxisome proliferator-activated receptor alpha (PPARalpha) expression by either a small interfering RNA duplex or morpholino antisense oligonucleotide attenuated the BF-induced redistribution of ABCB4. These findings suggest that BF may enhance the capacity of human hepatocytes to direct PC into bile canaliculi via PPARalpha-mediated redistribution of ABCB4 to the canalicular membrane. This provides a rationale for the use of BF to improve cholestasis and/or cholangitis that is attributable to hypofunction of ABCB4.

4-Chloro-7-nitrobenzofurazan↗
PubMed2004

Diagnosis of intra-oral MALT lymphoma using seminested polymerase chain reaction.

Diagnosis of mucosa-associated lymphoid tissue (MALT) lymphoma based on histological examination alone is difficult. We report three patients with histologically suspected MALT lymphoma who developed lymphoproliferative lesions of the sublingual gland. Seminested polymerase chain reaction (PCR) analysis applied to formalin-fixed and paraffin-embedded specimens showed clonal rearrangement of immunoglobulin heavy chain genes in two patients and a polyclonal characteristic in one. The clinical findings and Southern blot analysis confirmed the accuracy of the diagnosis. The molecular method described can be applied routinely to processed specimens to obtain helpful information for the diagnosis of low-grade malignancies of lymphoproliferative disorders, such as MALT lymphoma.

Aged↗
PubMed2004

Effects of clodronate and alendronate on local and systemic changes in bone metabolism in rats with adjuvant arthritis.

We compared the effects of nonaminobisphosphonate (nonamino-BP; clodronate) and amino-BP (alendronate) on the changes in local and systemic bone metabolism associated with chronic inflammation in adjuvant-arthritis rats. A given rat received one of the BPs orally each day for 28 days from the day of adjuvant inoculation. Hindpaw swelling was observed from day 10 after adjuvant inoculation up to day 28 (peak, day 21). Clodronate slightly decreased the hindpaw swelling at doses of 12.5 and 25 mg/kg, p.o./day; however, alendronate (0.125-0.5 mg/kg) did not. Radiological examination of the distal limb joints revealed that only clodronate decreased bone deformation. Urinary deoxypyridinoline increased as arthritis developed, and it was decreased by clodronate. On day 29, pQCT analysis of the 5th lumbar vertebra revealed trabecular bone loss and cortical bone thinning in the arthritis control group, leading to compressive strength being reduced. Both BPs prevented this bone loss and strength reduction. These data suggest that only clodronate decreases inflammation and local bone deformation, while both BPs inhibit the arthritis-related decreases in systemic bone mass and bone strength. Clodronate would be useful in the treatment of inflammation-induced bone deformation and osteopenia.

Alendronate↗
PubMed2004

Primary seminoma in the middle mediastinum.

Primary mediastinal seminoma is a relatively rare tumor usually located in the anterior mediastinum. We report here an extremely rare case of a 66-year-old man with primary seminoma in the middle mediastinum. A physical examination showed lymphadenopathy in the right supraclavicular area. A chest CT confirmed the presence of a tumor occupying the retrotracheal space. A histological examination demonstrated metastatic seminoma from the open biopsy of the lymph node. Abdominal, pelvis, and cerebral CT scan and testicular ultrasound were negative. Thus, primary mediastinal seminoma in the middle mediastinum with supraclavicular lymph node metastasis was diagnosed.

Aged↗
PubMed2004

Subacute cor pulmonale due to tumor embolism.

We describe a patient wih subacute cor pulmonale caused by tumor emboli in the lungs. A 64-year-old female suffering from a subacute progressive cough and shortness of breathing died of severe pulmonary hypertension seven days after admission. Neither chest CT scans nor lung perfusion scintigraphy showed any abnormal findings. Microscopic examination after an autopsy revealed diffuse intravascular tumor emboli occluding not only the small pulmonary arteries and arterioles, but also the lymphatic vessels, which were suggested to be metastases of a breast carcinoma resected five years previously. Thus, pulmonary tumor embolism should be considered in the differential diagnosis of primary pulmonary hypertension, particularly in patients with a past history of cancers.

Autopsy↗
PubMed2003

Clodronate stimulates osteoblast differentiation in ST2 and MC3T3-E1 cells and rat organ cultures.

We investigated the direct effects of various bisphosphonates on osteoblasts. At 10(-5) M, clodronate increased alkaline phosphatase activity in cultured MC3T3-E1 (osteoblast-like line) and ST2 (pluripotent mesenchymal line) cells. Etidronate significantly increased alkaline phosphatase activity at 10(-5) M only in MC3T3-E1 cells. These effects were due to an increase in alkaline phosphatase-positive cell numbers, and the differentiation-enhanced cells were capable of mineralization (von Kossa stain). Other bisphosphonates (pamidronate, alendronate, and incadronate) did not increase alkaline phosphatase activity in either cell line. In cultured rat calvariae, clodronate stimulated the expression of genes for alkaline phosphatase and osteocalcin (osteoblast-differentiation markers), but decreased the expression of the gene for tartrate-resistant acid phosphatase (osteoclast marker). Clodronate, etidronate, and incadronate inhibited protein Tyr phosphatase and Ser/Thr phosphatase activities in MC3T3-E1 cells. These data suggest that clodronate acts directly on mesenchymal cells to enhance osteoblast differentiation, and this effect may be partly expressed through inhibition of protein Tyr phosphatase and/or Ser/Thr phosphatase activity.

Alkaline Phosphatase↗
PubMed2003

Effects of pilocarpine hydrochloride and cevimeline on submandibular/sublingual salivation in rat xerostomia model produced by X-ray irradiation.

The present study was performed to assess the effects of pilocarpine hydrochloride ((3S,4R)-3-ethyl-dihydro-4-[(1-methyl-1H-imidazole-5-yl)methyl]-2(3H)-furanone monohydrochloride, CAS 54-71-7) and cevimeline ((+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate, CAS 153504-70-2), muscarinic receptor agonists, on salivary secretion from the submandibular/sublingual (SM/SL) glands in normal rats and in rats with xerostomia induced by X-ray (15 Gy) irradiation. To clarify their pharmacological safety profiles, the two drugs were further compared with regard to subtype selectivity for muscarinic receptors (M1, M2, and M3) and central nervous, respiratory, and cardiovascular effects. Pilocarpine hydrochloride (0.1-0.8 mg/kg i.d.) and cevimeline (3-30 mg/kg i.d.) dose-dependently increased salivary flow rate and total salivary volume in a 120-min period from SM/SL glands in both normal and irradiated rats, the minimum effective doses for their sialagogic effects being 0.2 and 10 mg/kg, respectively. Both drugs also increased protein output from SM/SL glands to a degree that depended on the increase in salivary volume in normal and irradiated rats. In a binding study using radiolabeled antagonists, neither pilocarpine hydrochloride nor cevimeline displayed subtype selectivity for muscarinic receptors, indicating non-selective muscarinic agonism. Effects on the central nervous system (CNS) were assessed by monitoring changes in body temperature in conscious normal rats. Pilocarpine hydrochloride (0.4-4 mg/kg p.o.) had no effect on body temperature, but cevimeline (30 and 100 mg/kg p.o.) caused a significant hypothermia. In terms of respiratory and cardiovascular effects in anesthetized normal rats, there was no clear difference in safety margin between pilocarpine hydrochloride and cevimeline, both drugs inducing significant changes in respiratory rate, heart rate, and blood pressure at doses close to those inducing sialagogic effects. These results suggest that pilocarpine hydrochloride could be used as a sialagogic drug for postirradiation-induced xerostomia with fewer adverse effects on the CNS.

Animals↗
PubMed2002

Magnetic resonance imaging of lymphomatoid granulomatosis: punctate and linear enhancement preceding hemorrhage.

Lymphomatoid granulomatosis (LG) is an angiocentric and angiodestructive lymphoproliferative disease that mainly involves the lung. Thirty percent of patients with LG have neurological symptoms. We report serial changes in MRI of a patient with LG of the brain. Postcontrast MRI demonstrated multiple punctate and linear areas that preceded hemorrhage, as indicated by hypointensity with surrounding hyperintensity on subsequent T2-weighted images. The diagnostic value of these lesions observed with contrast MR images is discussed. We consider that enhancing areas correspond to walls of small vessels affected by LG.

Adult↗
PubMed2002

Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB.

In this study, we used a coactivator-dependent receptor-ligand interaction assay (CARLA), which is a semifunctional in vitro assay, to determine whether hypolipidemic drugs are ligands for the three peroxisome proliferator-activated receptor isotypes (PPARalpha, delta, and gamma). We also evaluated the transcriptional activities of the three PPAR isotypes by transient transfection assays. We found that bezafibrate was a ligand for PPARalpha, delta, and gamma in the CARLA and that bezafibrate induced transcriptional activation of PPARalpha/RXRalpha, PPARdelta/RXRalpha, and PPARgamma/RXRalpha. Although the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors cerivastatin, fluvastatin, and pitavastatin were not ligands for these three nuclear receptors in the CARLA, they induced transcriptional activation of PPARalpha/RXRalpha, PPARdelta/RXRalpha, and PPARgamma2/RXRalpha. Moreover, cerivastatin, fluvastatin, and pitavastatin synergistically and dose-dependently increased the transcriptional activation of PPARalpha/RXRalpha induced by bezafibrate. In addition, the cerivastatin-induced transcriptional activation of PPARalpha/RXRalpha was decreased by addition of mevalonate, farnesol, geranylgeraniol, or cholesterol and by co-transfection with sterol regulatory element-binding protein-1 (SREBP-1). Moreover, concomitant administration of statins and fibrates also decreased the transactivation of nuclear factor kappaB (NFkappaB) and the activation of NFkappaB by mitogen-activated protein kinase kinase kinase (MEKK) also decreased the transactivation of PPARalpha/RXRalpha.

Anticholesteremic Agents↗
PubMed2002

Study of the insulinotropic effect of the novel antihyperglycemic agent KAD-1229 using HIT T15 cells, a hamster's insulinoma cell line.

The insulinotropic effect of (+)-monocalcium bis [(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinyl-carbonyl)propionate] dihydrate (CAS 145375-43-5, KAD-1229) was assessed by comparing it with those of glibenclamide (CAS 10238-21-8), nateglinide (CAS 105816-04-4), and repaglinide (CAS 135062-02-1) using HIT T15 cells, a hamster insulinoma cell line. Although their potencies were different, KAD-1229, glibenclamide, nateglinide, and repaglinide all concentration-dependently and significantly induced insulin release from these cells. Further, each agent displaced the binding of 3H-glibenclamide to the cell membrane and inhibited 86Rb+ efflux from the cells. These results indicate that KAD-1229, glibenclamide, nateglinide, and repaglinide each exert their insulinotropic effect by binding to the glibenclamide binding sites (sulfonylurea receptors) on pancreatic beta-cells and closing K+ channels. Diazoxide, a K+ channel opener, and nitrendipine, a Ca2+ blocker, suppressed the insulin release induced by KAD-1229 or glibenclamide. These results demonstrate that the insulinotropic actions of KAD-1229 and glibenclamide involve similar underlying pathways.

Animals↗
PubMed2002

Reductions in bone mass, structure, and strength in axial and appendicular skeletons associated with increased turnover after ovariectomy in mature cynomolgus monkeys and preventive effects of clodronate.

Over 16 months, we evaluated the effects of ovariectomy (OVX) and bisphosphonate clodronate (CLO) on bone in 48 cynomolgus monkeys (9-15 years old) fed a normal calcium diet. We established three OVX groups (oral CLO at 0 [OVX control], 12, or 60 mg/kg per day) and one sham-operated (SHAM) group. At 16 months, the bone mineral density (BMD) values (percentage of group baseline; OVX control vs. SHAM) for lumbar bone (L3-L5), proximal femur, midfemur, radius, and tibia were -2.6% versus 11.2%, -3.5% versus 8.9%, -3.0% versus 9.0%, -5.5% versus 15.7%, and -6.7% versus 13.9%, respectively. In OVX control (i) tibia showed significant loss of bone mineral content (BMC; vs. baseline), (ii) urinary deoxypyridinoline (DPD) and serum osteocalcin (OC) levels increased (peak = 182% and 168%, respectively, of SHAM), (iii) in lumbar bone and midfemur, ultimate load (UL) was reduced (vs. SHAM), (iv) in lumbar bone, trabecular bone-formation rates (BFRs) were not changed significantly, but tibial endocortical and intracortical bone formation rates were significantly raised (vs. SHAM), (v) the volumetric BMD (vBMD) and geometry of the tibial cortex (measured by peripheral quantitative computed tomography [pQCT]) were significantly reduced (vs. SHAM). CLO, 60 mg/kg per day but not 12 mg/kg per day, significantly inhibited OVX-induced changes, age-dependent increases in bone mass, and ability to maintain structure. Thus, in OVX mature cynomolgus monkeys (possibly, a unique model of the cortical bone loss secondary to estrogen deficiency), the post-OVX increases in systemic bone markers were slight, but stimulation of local turnover in the cortical envelope was enough to cause bone loss (more so in tibia than in lumbar trabecular bone). High-dose CLO prevented these changes.

Amino Acids↗
PubMedDate not supplied

Effect of KAD-1229, a novel hypoglycaemic agent, on plasma glucose levels after meal load in type 2 diabetic rats.

1. The effects of KAD-1229 (a novel non-sulphonylurea agent), voglibose (an alpha-glucosidase inhibitor) and nateglinide (a non-sulphonylurea antihyperglycaemic agent) on hyperglycaemia induced by a meal load were assessed in diabetic rats. 2. KAD-1229 suppressed the increase in plasma glucose levels seen after a meal load and the area under the curve for plasma glucose levels (AUCglucose) up to 5 h after the meal load. 3. Voglibose also suppressed the increase in plasma glucose levels; however, a significant decrease in AUCglucose following voglibose was not observed. 4. Nateglinide suppressed the increase in plasma glucose levels at 30 min and 1 h after the meal load; however, plasma glucose levels was above control thereafter and the AUCglucose was not decreased. 5. The results indicate that KAD-1229 has an antihyperglycaemic effect and KAD-1229 is suggested to be a suitable agent for controlling post-prandial hyperglycaemia.

Animals↗