Search PubMed⌕ Search

Biomedical subjects

S Hirota

Publications and source records attributed to S Hirota.

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

Microsphere embolism-induced changes in noradrenaline uptake of the cerebral cortex in rats.

The present study was undertaken to elucidate pathophysiological changes in noradrenaline (NA) transporter and Na+/K+-ATPase, key regulators of cation gradient across the plasma membrane, in nerve terminals of the cerebral cortex after microsphere-induced cerebral embolism in rats. The Vmax value of NA uptake, when analyzed by the Eadie-Hofstee plot, tended to decrease on the 1st day and decreased on the 3rd and 7th days after the embolism without any change in the Km value. The NA content in cerebrocortical synaptosomes did not alter on the 1st day, but decreased on the 3rd and 7th days after the embolism. Ouabain (1 mM) inhibited NA uptake on the 1st day, but did not alter the uptake on the 3rd and 7th days after the embolism. The activity of Na+/K+-ATPase of cerebrocortical synaptosomes increased on the 1st day and gradually decreased up to the 7th day after the embolim. These results suggest that NA uptake in nerve terminals of the cerebral cortex decreased after microsphere embolism, which may be due to a reduction in function of NA transporters. The changes in Na+/K+-ATPase following microsphere embolism may represent a compensatory action to maintain ion homeostasis in nerve terminals at an early stage of ischemic injury.

Animals↗
PubMed1998

Roles of four iron centers in Paracoccus halodenitrificans nitric oxide reductase.

Reactions of Paracoccus halodenitrificans nitric oxide reductase (NOR) containing four iron centers, a low spin hemec, a low spin heme b, a high spin heme b and a non-heme iron, have been studied to show the roles of each iron center. Soon after reacting the resting (oxidized) NOR with L-ascorbate, the low spin heme c and low spin heme b were reduced to a considerable extent but the high spin heme b was still in the oxidized form and was reduced slowly. When CO acted on the reduced NOR, the high spin heme b center changed to a low spin state. On the other hand, when NO acted on the resting NOR, no apparent spectral change was observed. However, when NO acted on the reduced NOR (a steady state condition, excess dithionite is present), both of the low spin centers changed to be partly in the oxidized form. A small but clear new EPR signal with g = 4.1 appeared together with some new signals at the g = 2 region soon after the action of NO on the reduced NOR. During incubation at room temperature the nitrosyl-heme signal typical of 5-coordination developed. These results suggested that both the high spin-heme b center and the non-heme iron are the reaction centers and their reductions are indispensable for the enzyme process in contrast to the reaction mechanism proposed for the P-450 type NOR(P-450nor).

Ascorbic Acid↗
PubMed1998

Does the amount of an antitumor agent entrapped in liposomes influence its tissue distribution and cell uptake?

The effects of the amount of a drug entrapped in liposomes and polyethyleneglycol (PEG) modification on the tissue distribution in vivo and cell uptake in vitro have been examined. An increase in the amount of doxorubicin (DOX) entrapped in liposomes induced an increase in the DOX level in the plasma and tumor and a decrease in this level in the liver. The high amount of DOX entrapped demonstrated the usefulness of DOX liposomes for tumor cell uptake in vitro. The cell uptake of the liposomes depended on additional amounts of DOX and liposomal lipid. Furthermore, PEG modification of the surface of the liposomes facilitated the initial rate of liposome uptake into the tumor cells. This facilitation was attributed to the lipohydrophilic property of PEG and the fixed aqueous layer around the liposomes. Therefore, a higher amount of DOX entrapped in liposomes and PEG modification have been confirmed to be beneficial.

Animals↗
PubMed1998

The expression of the KAI1 gene, a tumor metastasis suppressor, is directly activated by p53.

KAI1 is a tumor metastasis suppressor gene that is capable of inhibiting the metastatic process in animals. The expression of the KAI1 gene also is found to be down-regulated during the tumor progression of prostate, breast, lung, bladder, and pancreatic cancers in humans, and this down-regulation appears to be at or posttranscription level. We have found that the tumor suppressor gene p53 can directly activate the KAI1 gene by interacting with the 5' upstream region. The p53 responding region is located at approximately 860 bases upstream of the transcriptional initiation site, and it contains a typical tandem repeat of the p53 consensus-binding sequence. A gel-shift mobility analysis showed that this sequence indeed had the ability to bind to the purified p53 protein. Mutations of this sequence abolished the responsiveness to p53 and also the binding ability to the p53 protein. Furthermore, immunohistochemical analysis of 177 samples of human prostate tumors revealed that the expression of the KAI1 gene was correlated strongly to that of the p53 gene and that the loss of these two markers resulted in poor survivals of patients. Our data indicate a direct relationship between p53 and KAI1 genes and suggest that the loss of p53 function, which is commonly observed in many types of cancer, leads to the down-regulation of the KAI1 gene, which may result in the progression of metastasis.

Base Sequence↗
PubMed1998

Primary cardiac lymphoma diagnosed by percutaneous needle biopsy.

We diagnosed a case of primary cardiac lymphoma using transthoracic needle biopsy. A 70-year-old man was admitted because of dyspnea. Magnetic resonance imaging revealed a tumor mass in the right ventricular free wall. We performed ultrasound guided transthoracic needle biopsy using an 18-G needle, and diagnosed as malignant lymphoma by the biopsy specimen. This method may be useful for the diagnosis of cardiac lymphoma.

Aged↗
PubMed1998

The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract.

Vascularization of organs generally occurs by remodelling of the preexisting vascular system during their differentiation and growth to enable them to perform their specific functions during development. The molecules required by early vascular systems, many of which are receptor tyrosine kinases and their ligands, have been defined by analysis of mutant mice. As most of these mice die during early gestation before many of their organs have developed, the molecules responsible for vascularization during organogenesis have not been identified. The cell-surface receptor CXCR4 is a seven-transmembrane-spanning, G-protein-coupled receptor for the CXC chemokine PBSF/SDF-1 (for pre-B-cell growth-stimulating factor/stromal-cell-derived factor), which is responsible for B-cell lymphopoiesis, bone-marrow myelopoiesis and cardiac ventricular septum formation. CXCR4 also functions as a co-receptor for T-cell-line tropic human immunodeficiency virus HIV-1. Here we report that CXCR4 is expressed in developing vascular endothelial cells, and that mice lacking CXCR4 or PBSF/SDF-1 have defective formation of the large vessels supplying the gastrointestinal tract. In addition, mice lacking CXCR4 die in utero and are defective in vascular development, haematopoiesis and cardiogenesis, like mice lacking PBSF/SDF-1, indicating that CXCR4 is a primary physiological receptor for PBSF/SDF-1. We conclude that PBSF/SDF-1 and CXCR4 define a new signalling system for organ vascularization.

Animals↗
PubMed1998

Effect of carotenoids on the respiratory burst of rat peritoneal macrophages.

The effect of four carotenoids (beta-carotene, lutein, bixin and canthaxanthin) on the respiratory burst of rat peritoneal macrophages was investigated. The results obtained showed that carotenoids suppressed the luminol-dependent chemiluminescence generated from PMA-stimulated macrophages at the beginning and after 2 min of the stimulation. Canthaxanthin and bixin had higher suppressive activity than beta-carotene and lutein. The changes in absorption spectra of carotenoids showed that the absorption by carotenoids was diminished during the stimulation of macrophages by PMA and their absorption peaks were either further diminished or blue-shifted after addition of L-arginine to the system, indicating that the carotenoids were consumed and converted to new compounds during the two processes. By using cell-free systems, it was found that carotenoids could scavenge superoxide anion generated by xanthine/xanthine oxidase system. Their ability to scavenge superoxide anion decreased in the order of canthaxanthin > bixin > lutein > beta-carotene. Canthaxanthin also showed the scavenging effect on superoxide anion generated from irradiation of riboflavin. The hydroxyl radical scavenging activity of carotenoids was investigated in the reaction system of Fe2+ and H2O2. There was little difference among their activities. The reaction between carotenoids and nitric oxide led to the decreasing absorption between 400 and 540 nm and the concomitant appearance of the new absorption peaks between 330 and 395 nm. Bleaching of beta-carotene, bixin and canthaxanthin by peroxynitrite resulted in the increasing absorption between 290 and 365 nm and the diminishing absorption between 400 and 500 nm. But the increasing absorption between 280 and 490 nm was observed in bleaching of lutein by peroxynitrite. Carotenoids inhibited thiobarbituric acid-reactive substance (TBARS) formation in AAPH-induced lipid peroxidation of PC liposomes in air. The results suggest that the suppressive effect of carotenoids on the respiratory burst of macrophages may be just a way by which carotenoids in vivo protect host cells and tissues from harmful effects of oxygen metabolites overproduced by macrophages and enhance the generation of specific immune responses.

Animals↗
PubMed1998

Effect of liposomalization on the antitumor activity, side-effects and tissue distribution of CPT-11.

We have examined the efficacy of liposomalization and polyethyleneglycol (PEG) modification of liposomes on the antitumor activity, side-effects and tissue distribution of irinotecan hydrochloride (CPT-11). PEG-liposome was confirmed to elevate the plasma circulation of CPT-11 and SN-38 (active metabolite) concentrations. The tumor accumulation of CPT-11 and SN-38 was increased by the PEG-modified liposomes. The antitumor activity of CPT-11 increased due to the elevated tumor distribution of CPT-11 and SN-38 levels by the PEG-modified liposomes. In the tumor, CPT-11 was converted to SN-38. Thus, it is considered that passive targeting to the tumor by liposomalization elevated the SN-38 level in the tumor especially and increased the antitumor activity of CPT-11. Furthermore, intestinal disorder, a side toxicity of CPT-11, decreased dependent on the CPT-11 and SN-38 concentrations in the bile by liposomalization. Although the liposomes induce improved tissue distribution of the prodrug, the tissue distribution of active metabolites does not always improve. However, CPT-11-entrapped liposome was useful, as CPT-11 is converted to SN-38 in the tumor. These results suggested that the usefulness of CPT-11 could be extended.

Animals↗
PubMed1998

Strand specificity and absence of hot spots for p53 mutations in ultraviolet B-induced skin tumors of XPA-deficient mice.

We examined the spectrum of p53 mutations found in 40 UV-induced skin tumors of xeroderma pigmentosum group A gene (XPA)-deficient mice. p53 mutations were detected in 48% of the tumors. Nearly all of the mutations were induced at dipyrimidine sites. Ninety-three % of the mutations were G.C-->A.T transitions at dipyrimidine sites, including tandem transitions (CC-->TT), which are the hallmark of the UVB-induced mutation. Seventy-two % of the mutations at dipyrimidine sites could be ascribed to damage on the transcribed strand. In addition, no evident mutational hot spots were detected. This is in contrast to the UVB-induced skin tumors of normal mice, in which 92% of p53 mutations occurred as a result of DNA damage on the nontranscribed strand, and clear hot spots were observed. Thus, XPA-deficient mice showed significant mutation features that might be characteristic of the absence of nucleotide excision repair and may provide a good animal model for the analysis of the high incidence of skin cancer in xeroderma pigmentosum group A patients.

Animals↗
PubMed1998

Observation of Cu-N3- stretching and N3- asymmetric stretching bands for mono-azide adduct of Rhus vernicifera laccase.

Mono-azide adduct of Rhus vernicifera laccase, a multicopper oxidase containing one type-1 (blue) copper, one type-2 (non-blue normal) copper, and a pair of type-3 (binuclear and EPR silent) coppers, of which type-2 and type-3 coppers constitute a trinuclear site, was investigated with resonance Raman (RR) and Fourier transform infrared (FT-IR) spectroscopies as a step toward elucidation of the structure and function of the trinuclear site. The Cu-N3- stretching (vCu-N3-) RR band was observed for azide-bound multicopper oxidases for the first time. The vCu-N3- band was located at 400 cm-1 for mono-14N3- laccase, which shifted to 396 cm-1 with the 15N14N14N3- analog. The N3- asymmetric stretching (v(N3-)asym) band was observed by FT-IR spectroscopy at 2035 cm-1 for mono-14N3- laccase and at 2025 cm-1 for the 15N14N14N3- analog. The vCu-N3- and v(N3-)asym frequencies and their 15N14N14N- isotope shifts for azido laccase correspond well with those of metazido hemocyanin, indicating that both derivatives should have a similar binding geometry of azide.

Azides↗
PubMed1998

Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.

Amino Acid Sequence↗
PubMed1998

Alendronate inhibits osteopontin expression enhanced by parathyroid hormone-related peptide (PTHrP) in the rat kidney.

It has been reported that osteopontin (OPN) plays an important role during urolithiasis as well as bone formation. Generation of stones in the urinary tract may be associated with osteoporosis and bisphosphonates are potent inhibitors of bone resorption, being used with effect in the management of bone disease. We therefore investigated the relationship between alendronate, a bisphosphonate derivative, and OPN expression in the kidney. Alendronate was administered to rats made hypercalcemic by treatment with parathyroid hormone-related peptide (PTHrP). The renal expression of OPN was then evaluated at both protein and mRNA levels. OPN expression was enhanced in the distal tubular cells of hypercalcemic rats and was decreased by alendronate. The observed inhibition of OPN expression suggests an ability of alendronate and other bisphosphonates to act as inhibitors of stone formation in the urinary tract.

Alendronate↗
PubMed1998

A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors.

BACKGROUND & AIMS: The c-kit gene encodes a receptor tyrosine kinase (KIT). Recently, we found gain-of-function mutations of the c-kit gene in gastrointestinal stromal tumors (GISTs). All mutations were confined within the 11 amino acids (Lys-550 to Val-560) in the juxtamembrane domain, but one GIST showed a novel deletion-type mutation at codon 579 (Asp) in the juxtamembrane domain. The aim of this study was to clarify whether the mutation is activating. METHODS: Mutant c-kit cDNA was transfected into an interleukin 3 (IL-3)-dependent Ba/F3 murine lymphoid cell line, and the magnitude of autophosphorylation of the mutant KIT was examined with or without stem cell factor (SCF), a ligand of KIT. An in vitro kinase assay was also performed. The biological behavior of the transfectant was estimated by both an in vitro proliferation assay and in vivo transplantation to nude mice. RESULTS: The mutant KIT exhibited constitutive phosphorylation and strong kinase activity without SCF. The transfectant grew autonomously without IL-3 and SCF, and it formed tumors in nude mice. CONCLUSIONS: Deletion at codon 579 (Asp) in the juxtamembrane domain of the c-kit gene is a novel gain-of-function mutation other than the region between Lys-550 and Val-560.

Amino Acid Sequence↗
PubMed1998

Induction of long-term remission in advanced hepatocellular carcinoma with percutaneous isolated liver chemoperfusion.

OBJECTIVE: The aim of this study was to report the long-term results of percutaneous isolated liver chemoperfusion with hepatic venous isolation and charcoal hemoperfusion (HVI-CHP) in patients with multiple advanced hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: The results of conventional chemotherapy including regional and systemic chemotherapy in patients with HCC remain dismal, and long-term survivors after treatment are rare among patients with multiple advanced HCC. In an effort to improve this situation, we previously developed a novel system of percutaneous isolated liver chemoperfusion with HVI-CHP. METHODS: Doxorubicin (60 to 150 mg/m2) was administered via the hepatic artery, under conditions of extracorporeal drug elimination by HVI-CHP in 28 consecutive patients with advanced HCC (39 total treatments). Hepatic venous isolation and charcoal hemoperfusion was accomplished mainly by the single catheter technique using a newly developed 4-lumen-balloon catheter, which was used to isolate and capture total hepatic venous outflow and, at the same time, to direct the filtered blood to the right atrium. RESULTS: Complete remission was achieved in five patients, of which four received repeated treatments (two or three times). Although 1 of 5 patients with complete remission died of pulmonary metastases at 8 months, the other 4 remain healthy and free of disease at 20, 24, 27, and 42 months after the first treatment. Partial responses were observed in 12 patients. Duration of response in responders (complete and partial) with repeated treatments was significantly longer than that with a single treatment (p = 0.01). The overall survival rate by the Kaplan-Meier method was 39.7% at 5 years. The treatments were well-tolerated, and the primary side effects were mild to moderate chemical hepatitis and reversible myelosuppression. CONCLUSIONS: The results suggest that percutaneous isolated liver chemoperfusion with HVI-CHP is an effective palliative treatment in the majority of patients and yields long-term complete remission in some patients with multiple advanced HCC.

Adult↗
PubMed1998

Disturbed pyloric motility in Ws/Ws mutant rats due to deficiency of c-kit-expressing interstitial cells of Cajal.

Interstitial cells of Cajal (ICC) are believed to initiate the basic contractile activity of the gastrointestinal tract. Interstitial cells of Cajal express c-kit receptor tyrosine kinase and are deficient in Ws/Ws mutant rats with a small deletion of the c-kit gene. As Ws/Ws rats show remarkable bile reflux to the stomach, the contraction pressure of the pylorus was compared between Ws/Ws and control +/+ rats. The contraction pressure of the pylorus was measured using a microtransducer, which was inserted through a pin-hole in the anterior wall of the stomach under anesthesia. The magnitude of bile reflux was estimated by measuring the content of bile acids in the stomach. The c-kit messenger RNA-expressing cells were detected by in situ hybridization. Frequency and the maximum pressure of the contraction were comparable between Ws/Ws and +/+ rats, but the duration of the contraction was significantly shorter in Ws/Ws rats than in +/+ rats. The number of c-kit messenger RNA-expressing ICC in the pylorus of Ws/Ws rats was 1.7% that of +/+ rats. The bile reflux observed in Ws/Ws rats was attributed to the decrease in the duration of the pyloric contraction, which appeared to result from the deficiency of c-kit messenger RNA-expressing ICC.

Animal Feed↗
PubMed1998

[Effects of methylxanthine derivatives on antitumor activity and toxic side effect of adriamycin induced by inhibition of DNA biosynthesis].

The antitumor activity of adriamycin (ADR) was enhanced by combination with theobromine or pentoxifylline. Theobromine increased the concentration of ADR in the tumor without any effects on that in the heart and the liver. The influence of the combination of theobromine or pentoxifylline with ADR on the lipid peroxide level (indicating the ADR-induced side effect) and on DNA biosynthesis (indicating the side effect and antitumor activity) were examined. When ADR was administered into mice, the lipid peroxide level in the liver and the heart increased. However, the combination of theobromine or pentoxifylline did not enhance the ADR-induced increment of the lipid peroxide level in the liver, and moreover, it inhibited that in the heart. The decrease of DNA biosynthesis in the liver and the heart, induced by ADR, were not enhanced by combination with theobromine or pentoxifylline. On the other hand, the combination of theobromine with ADR significantly increased the inhibition of DNA biosynthesis in the tumor. These findings indicate that the combination of theobromine or pentoxifylline with ADR have no effect on the side effects of ADR in the liver and the heart, with the increase of antitumor activity of ADR in the tumor, and it is suggested that these drugs will be of value as a biochemical modulator of ADR.

Animals↗