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T Naka

Publications and source records attributed to T Naka.

At least 55 records · Page 3Linked to original sources
PubMed2000

[Candesartan cilexetil: pharmacological properties and protective effects against organ damage of a novel nonpeptide angiotensin II-receptor antagonist].

The nonpeptide angiotensin II (AII) subtype-1 (AT1) receptor antagonist candesartan cilexetil is completely converted to its active form, candesartan, during gastrointestinal absorption. In in vitro studies, candesartan has been found to act as an insurmountable antagonist at the AT1 receptor that dose-dependently reduces the maximal contractions induced by AII and, at high concentrations, virtually eliminates the AT1-receptor-mediated effects of AII. Receptor binding studies suggest that insurmountable antagonism may be due to tight binding to the AT1 receptor and slow dissociation from it. The antihypertensive efficacy of candesartan cilexetil has been demonstrated in different animal models of hypertension. Candesartan cilexetil exerts a long-lasting antihypertensive action in spontaneously hypertensive rats in the low dose range of 0.1-10 mg/kg. The long-lasting antihypertensive effect of candesartan cilexetil is confirmed by the trough/peak ratio in hypertensive patients. It has been demonstrated that administration of AII receptor antagonists is followed by a rise in AII levels, and the increased AII levels result in competition with the antagonist for binding to the receptor. Insurmountable antagonists would seem to be more advantageous since they would block more efficiently in the presence of increasing AII levels than surmountable antagonists. A growing number of studies indicate that candesartan cilexetil provides end-organ protection in addition to lowering blood pressure. The utility of AT1 antagonists may extend beyond treatment of hypertension, chronic heart failure and renal diseases, as suggested by the potential usefulness of ACE inhibitors in the treatment or prevention of many other cardiovascular diseases.

Angiotensin II↗
PubMed1999

Evaluation of characteristic parameters for the neurotransmitter release mechanisms at the neuromuscular junction.

The process of neurotransmitter release at the neuromuscular junction needs to be represented appropriately in modeling of the synaptic chemical transmission as a reaction-diffusion system. The release mechanisms of the expanding pore and the acceleration are analyzed by the computer simulation with respect to the effects of the characteristic parameters in the mechanisms on spontaneous generation of the miniature endplate current (MEPC), leading to the following evaluation. In the expanding pore mechanism the expanding rate of the pore more than 10 nm ms(-1) and the diffusion coefficient of acetylcholine in the synaptic cleft (D(c)) of about 1.0 x 10(-6) cm2 s(-1) yield the maximum amplitude, the rise time and the decay time constant of the MEPC in agreement with the empirical data. In the active release mechanism the 10-fold acceleration of the natural diffusion and a similar value of D(c) are required to suit for the empirical MEPC.

Acetylcholine↗
PubMed1999

Localization effects of acetylcholine release from a synaptic vesicle at the neuromuscular junction.

A two-dimensional compartment model devised for the appropriate representation of the transient process of the spontaneous generation of miniature endplate current (MEPC) at the neuromuscular junction is applied for clarifying the biochemical significance of the quantal release mechanism of acetylcholine (ACh), a typical neurotransmitter, in the synaptic chemical transmission process. The simulation analysis with the model demonstrates that the localization of the ACh release due to the fusion of a synaptic vesicle with the presynaptic membrane has significant effects on the amplitude of MEPC and that the stronger effects are caused with the smaller diffusion coefficients of ACh in the cleft. The sharpest and highest response of MEPC is achieved when the release area is about 4 times to the natural release through the narrow pore. On the other hand, the actual localization corresponding to the natural release of ACh makes the amplitude of MEPC higher by a factor about 2.5 compared with that in the most extended release of ACh examined, implying that the natural release mechanism works as an amplifier of the MEPC with the fixed amount of ACh available.

Acetylcholine↗
PubMed1999

Undetectable dystrophin can still result in a relatively benign phenotype of dystrophinopathy.

We present here a 28-year-old male patient with Becker muscular dystrophy whose skeletal muscle showed an absence of dystrophin. He has had progressive and predominantly proximal muscular wasting since 5 years of age, but was able to walk until 26 years of age. He showed hypertrophic calves, cardiomyopathy, and an elevated serum creatine kinase level (934 U/1). A skeletal muscle biopsy revealed advanced chronic myopathic changes. Immunohistochemical examination using anti-dystrophin antibodies against C-terminus showed deficiency of the protein. Rod domain and N-terminus were also absent in almost all muscle fibers, but only in a small part of the sample, they were faintly stained. beta-Dystroglycan and utrophin were present only in a small number of muscle fibers. DNA and RT-PCR analysis showed a frame-shift deletion of exons 3-7 in the dystrophin gene. In such an exceptional case as this one, it is important to investigate the factors which determine the severity of dystrophinopathy.

Adult↗
PubMed1999

Negative regulation of cytokine signaling: STAT-induced STAT inhibitor.

The growth and differentiation of cells that make up multicellular entities such as the blood and immune systems are under the control of glycoprotein mediators known as cytokines. These cytokines bind to membrane receptors on the cell surface and initiate a signaling cascade that ends with the transcription of specific sets of genes within the cell nucleus. Although knowledge is accumulating concerning the intracellular signal pathways that are activated by cytokines, little is known about inhibition of cytokine signals. This review will focus on the negative regulation of the Janus tyrosine kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway by proteins related to STAT-induced STAT inhibitor-1 (SSI-1).

Animals↗
PubMed1999

Pharmacologic properties of candesartan cilexetil--possible mechanisms of long-acting antihypertensive action.

Candesartan cilexetil has shown potent and long-lasting antihypertensive effects in clinical trials and in several animal models of hypertension. In spontaneously hypertensive rats, the duration of the antihypertensive effect of candesartan cilexetil was compared to those of losartan, valsartan, eprosartan, and irbesartan at the same degree of maximal blood pressure reduction. A single oral dose of candesartan cilexetil at 0.3 mg/kg reduced maximal blood pressure by about 25 mm Hg, and the antihypertensive effect of candesartan cilexetil lasted the longest, continuing for more than 1 week, without an effect on circadian rhythm. In a rabbit aortic preparation, candesartan, active form of candesartan cilexetil, decreased the maximal contractile response of angiotensin II. This inhibitory mode was different from that of other angiotensin II-receptor antagonists, and showed a shift to the right in the angiotensin II-induced contraction curve and/or a small depression of the maximal response. In kinetic studies using bovine adrenal cortical membrane and tritiated candesartan, both receptor association and dissociation were found to be slow. The dissociation rate of tritiated candesartan binding (t1/2 = 66 min) was five times slower than that of radiolabelled angiotensin II binding (t1/2 = 12 min). The insurmountable inhibition of candesartan in vascular contraction is the result of its tight binding and slow dissociation from angiotensin II AT1 receptors. These characteristics are related to the potency and long duration of action in candesartan cilexetil.

Angiotensin II↗
PubMed1999

Effect of candesartan cilexetil (TCV-116) in rats with chronic renal failure.

BACKGROUND: Inhibition of the renin-angiotensin system by both angiotensin II type 1 receptor antagonists (AT1As) and angiotensin I-converting enzyme inhibitors (ACEIs) shows renoprotective effects in rats with chronic renal failure when treatment is started in the early phase of renal injury. In this study, we examined the renal protective effects of candesartan cilexetil (TCV-116), an AT1A, and enalapril, an ACEI, in the progressive phase of renal injury in 5/6 nephrectomized rats. METHODS: Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were orally administered once a day for 4 weeks (the short-term experiment) or 16 weeks (the long-term experiment) to 5/6 nephrectomized rats beginning 15 weeks after the nephrectomy, that is, after they had already showed marked proteinuria. RESULTS: In vehicle-treated rats, proteinuria, glomerulosclerosis, and interstitial fibrosis developed. Moreover, enhanced expression of transforming growth factor-beta1 (TGF-beta1) in the injured glomeruli was observed. These adverse changes progressed with time, and in the short-term experiment, both drugs inhibited them. In the long-term experiment, the progressive proteinuria and the elevation of blood pressure were similarly attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta1, and interstitial fibrosis, whereas enalapril did not. CONCLUSION: These results indicate that candesartan cilexetil shows potent and long-term preventive effects against the progression of previously developed renal injury.

Angiotensin Receptor Antagonists↗
PubMed1999

Proposal of Sphingomonas suberifaciens (van Bruggen, Jochimsen and Brown 1990) comb. nov., sphingomonas natatoria (Sly 1985) comb. nov., Sphingomonas ursincola (Yurkov et al. 1997) comb. nov., and emendation of the genus Sphingomonas.

Based on the results of a phylogenetic analysis of 16S rRNA and the presence of sphingoglycolipid in cellular lipids of the type strains, transfer of "Rhizomonas" suberifaciens, Blastomonas natatoria and Erythromonas ursincola to the genus Sphingomonas as Sphingomonas suberifaciens (van Bruggen et al 1990) comb. nov., Sphingomonas natatoria (Sly 1985) comb. nov., and Sphingomonas ursincola (Yurkov et al 1997) comb. nov. are herein proposed together with the emendation of genus Sphingomonas. The type strain of S. suberifaciens is van Bruggen Cal=ATCC 49382=NCPPB 3629=IFO 15211=JCM 8521, that of S. natatoria is ATCC 35951 =DSM 3183=NCIMB 12085=JCM10396, and that of S. ursincola is DSM 9006= KR-99.

Base Composition↗
PubMed1999

A new class of diacidic nonpeptide angiotensin II receptor antagonists: candesartan cilexetil.

Blockade of the action of angiotensin II (AII) has long been a target for development of novel antihypertensive agents. We recently discovered a novel class of potent nonpeptide AII receptor antagonists, benzimidazole-7-carboxylic acids including candesartan. Candesartan is a highly potent and insurmountable angiotensin II type-1 receptor (AT1)-selective antagonist. Structure-activity relationship (SAR) studies revealed that the adjacent arrangement of a lipophilic substituent, a tetrazolylbiphenylmethyl moiety and a carboxyl group was the important structural requirement for potent AII antagonistic activity. The benzimidazole ring was found to be one of the most suitable templates arranging these three essential components in correct direction. Especially, the presence of a carboxyl group at the 7-position was found to be essential for insurmountable antagonism. Although candesartan is a very potent AII antagonist, it was found to be absorbed rather inefficiently upon oral administration. To improve bioavailability (BA) of candesartan, chemical modification was examined to yield candesartan cilexetil, a prodrug of candesartan. Candesartan cilexetil is a potent and long-acting blocker that provides effective 24 hr blood pressure control. Our alternative research efforts to improve oral BA was performed by replacement of the tetrazole ring in candesartan by other new acidic bioisosteric heterocyclic rings to find the nonprodrug AII antagonist TAK-536, bearing 5-oxo-1,2,4-oxadiazole ring, which was as potent and orally active as candesartan cilexetil.

Angiotensin Receptor Antagonists↗
PubMed1999

A new class of diacidic nonpeptide angiotensin II receptor antagonists: candesartan cilexetil.

Blockade of the action of angiotensin ii (AII) has long been a target for development of novel antihypertensive agents. We recently discovered a novel class of potent non-peptide AII receptor antagonists, benzimidazole-7-carboxylic acids including candesartan. Candesartan is a highly potent and insurmountable antagonist selective in the angiotensin II type-I receptor (AT1). Structure-activity relationship (SAR) studies revealed that the adjacent arrangement of a lipophilic substituent, a tetrazolylbiphenylmethyl moiety and a carboxyl group was the important structural requirement for potent AII antagonistic activity. Especially, the presence of a carboxyl group at the 7-position was found to be essential for insurmountable antagonism. To improve bioavailability of candesartan, chemical modification was examined to yield candesartan cilexetil, a prodrug of candesartan. Candesartan cilexetil is a potent and long-acting blocker that, when given once-daily to patients, provides effective 24 hr blood pressure control.

Angiotensin II↗
PubMed1998

Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice.

Growth, differentiation, and programmed cell death (apoptosis) are mainly controlled by cytokines. The Janus kinase-signal transducers and activators of transcription (JAK-STAT) signal pathway is an important component of cytokine signaling. We have previously shown that STAT3 induces a molecule designated as SSI-1, which inhibits STAT3 functions. To clarify the physiological roles of SSI-1 in vivo, we generated, here, mice lacking SSI-1. These SSI-1-/- mice displayed growth retardation and died within 3 weeks after birth. Lymphocytes in the thymus and spleen of the SSI-1-/- mice exhibited accelerated apoptosis with aging, and their number was 20-25% of that in SSI-1+/+ mice at 10 days of age. However, the differentiation of lymphocytes lacking SSI-1 appeared to be normal. Among various pro- and anti-apoptotic molecules examined, an up-regulation of Bax was found in lymphocytes of the spleen and thymus of SSI-1-/- mice. These findings suggest that SSI-1 prevents apoptosis by inhibiting the expression of Bax.

Animals↗
PubMed1998

Three distinct domains of SSI-1/SOCS-1/JAB protein are required for its suppression of interleukin 6 signaling.

Cytokine-inducible protein SSI-1 [signal transducers and activators of transcription (STAT)-induced STAT inhibitor 1, also referred to as SOCS-1 (suppressor of cytokine signaling 1) or JAB (Janus kinase-binding protein)] negatively regulates cytokine receptor signaling by inhibition of JAK kinases. The SSI family of proteins includes eight members that are structurally characterized by an SH2 domain and a C-terminal conserved region that we have called the SC-motif. In this study, we investigated the roles of these domains in the function of SSI-1. Results of reporter assays demonstrated that the pre-SH2 domain (24 aa in front of the SH2 domain) and the SH2 domain of SSI-1 were required for the suppression by SSI-1 of interleukin 6 signaling. Coexpression studies of COS7 cells revealed that these domains also were required for inhibition of three JAKs (JAK1, JAK2, and TYK2). Furthermore, deletion of the SH2 domain, but not the pre-SH2 domain, resulted in loss of association of SSI-1 with TYK2. Thus, SSI-1 associates with JAK family kinase via its SH2 domain, and the pre-SH2 domain is required for the function of SSI-1. Deletion of the SC-motif markedly reduced expression of SSI-1 protein in M1 cells, and this reduction was reversed by treatment with proteasome inhibitors, suggesting that this motif is required to protect the SSI-1 molecule from proteolytic degradation. Based on these findings, we concluded that three distinct domains of SSI-1 (the pre-SH2 domain, the SH2 domain, and the SC-motif) cooperate in the suppression of interleukin 6 signaling.

Amino Acid Sequence↗
PubMed1998

Effective TAE therapy using Lipiodol with epirubicin for liver metastases of nonfunctioning islet cell carcinoma of the pancreas.

We report the response of two patients with advanced nonfunctioning islet cell carcinoma of the pancreas with liver metastases treated with a combination of surgi-cal resection and transarterial embolization (TAE), using Lipiodol with epirubicin. After pretreatment evaluation, the two patients were diagnosed with nonfunctioning islet cell carcinoma of the pancreas with liver metastases. Preoperatively, in both patients, TAE was performed through the hepatic arteries, using Lipiodol and sponzel plus epirubicin. Surgical resection of the primary tumor (radical distal pancreatectomy and pancreaticoduodenectomy) was performed. After surgical resection and evaluation of the malignant histopathological features of the neoplasms, chemotherapy, which included oral 5-fluorouracil (FU), and transarterial infusion therapy, using Lipiodol with epirubicin, was administered to the patients. Follow-up evaluation of the two patients by computerized tomography (CT) scan showed a reduction in the size of the metastatic hepatic masses after several chemoembolizations through the hepatic arteries. This combined treatment modality may be an effective therapeutic strategy for improved management of patients with advanced nonfunctioning islet cell carcinoma of the pancreas with liver metastases.

Adult↗
PubMed1998

Aberrant p16INK4 expression related to clinical stage and prognosis in patients with pancreatic cancer.

The p16 tumor suppressor gene is thought to play an important role in cell cycle regulation by encoding for protein products that can inhibit the progression from G1 to S phase in the cell cycle. Recently, the p16 gene has been found to be mutated or deleted in a variety of different types of primary human malignant tumors and human-derived malignant tumor cell lines. In this study, primary ductal pancreatic adenocarcinomas from 32 human patients were analyzed immunohistochemically for expression of p16 protein, with emphasis on the role of abberant p16 protein expression as a prognostic indicator. In addition, the same tumors were also assessed for p53 protein expression, AgNOR counts, and DNA ploidy. Nineteen out of the 32 cases (59%) showed positive immunoreactivity for p16 protein in their tumors and a significant association was found between lack of p16 protein expression, and both advancing clinical stage classification of disease, and poorer survival (p<0.05). The rate of positive immunoreactivity for p53 protein expression was 59%, however, no clear association was found between p53 protein expression, and either clinical stage of disease, or survival. These findings suggest that alteration of the p53 gene may be a relatively early event in pancreatic tumorigenesis, whereas alteration of the p16 gene is more likely to be correlated with tumor progression in pancreatic malignancies. Further survival analysis revealed that all five of the 32 cases that survived for three years or longer had positive immunostaining for p16 protein, and a relatively low level of AgNOR counts. In four out of five of these patients, the tumors also exhibited negative immunostaining for p53 protein and DNA diploidy. These findings suggest that molecular analysis of patient tumor sections may yield potentially useful prognostic indicators for patients undergoing surgical resection for pancreatic cancer.

Aged↗
PubMed1997

Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3.

Upon the corresponding ligand's stimulation, the cytokine receptors activate several signal pathways: JAK-STAT pathway, Ras-MAP kinase pathway and so on. Recently, we demonstrated that one of the STAT3 (signal transducer and activator of transcription-3) target genes could suppress the function of STAT3 and designated as SSI-1(STAT induced STAT inhibitor-1). SSI-1 is thought to play a critical role in negative feedback control of JAK-STAT signaling pathway. In the present study, we identified two novel human genes which products have homologous region in their SH2 domain and its COOH-terminal region to mouse SSI-1. Northern blotting analysis and functional studies demonstrated that SSI-2 and SSI-3 mRNA were also induced by cytokine stimulation and their forced expression in mouse myeloid leukemia cell, M1, suppressed the apoptotic effect of LIF, like SSI-1. We also demonstrated the structure of human SSI-1.

Amino Acid Sequence↗
PubMed1997

Structure and function of a new STAT-induced STAT inhibitor.

The signalling pathway that comprises JAK kinases and STAT proteins (for signal transducer and activator of transcription) is important for relaying signals from various cytokines outside the cell to the inside. The feedback mechanism responsible for switching off the cytokine signal has not been elucidated. We now report the cloning and characterization of an inhibitor of STAT activation which we name SSI-1 (for STAT-induced STAT inhibitor-1). We found that SSI-1 messenger RNA was induced by the cytokines interleukins 4 and 6 (IL-4, IL-6), leukaemia-inhibitory factor (LIF), and granulocyte colony-stimulating factor (G-CSF). Stimulation by IL-6 or LIF of murine myeloid leukaemia cells (M1 cells) induced SSI-1 mRNA expression which was blocked by transfection of a dominant-negative mutant of Stat3, indicating that the SSI-1 gene is a target of Stat3. Forced overexpression of SSI-1 complementary DNA interfered with IL-6- and LIF-mediated apoptosis and macrophage differentiation of M1 cells, as well as IL-6 induced tyrosine-phosphorylation of a receptor glycoprotein component, gp130, and of Stat3. When SSI-1 is overexpressed in COS7 cells, it can associate with the kinases Jak2 and Tyk2. These findings indicate that SSI-1 is responsible for negative-feedback regulation of the JAK-STAT pathway induced by cytokine stimulation.

Amino Acid Sequence↗
PubMed1997

Postoperative delirium following gastrointestinal surgery in elderly patients.

Postoperative delirium is a common complication which can interfere with the surgical treatment and recovery of elderly patients, and is likely to prolong their hospitalization. Unfortunately, there is as yet no completely effective pre- and/or post operative technique of patient care to reduce or prevent postoperative delirium. In this study, 36 patients aged over 70 years undergoing gastrointestinal operations were assessed to examine the relationships between the preoperative cognitive state, the postoperative sleep cycle, and the occurrence of postoperative delirium. All patients were evaluated preoperatively using the revised version of Hasegawa's dementia scale (HDS-R). We correlated those test results and assessed the sleep-wakefulness disturbance postoperatively, to obtain a clinical DMS-III diagnosis of postoperative delirium. The incidence of postoperative delirium was 17% (6/36). The patients who developed postoperative delirium demonstrated preoperative cognitive impairment, and had a short sleep period during the night and a long sleep period during the day. Postoperatively, these results suggest that HDS-R is a useful method of evaluating preoperative cognition in elderly patients. Considering that sleep deficiency is likely to predispose elderly patients to postoperative delirium, techniques to prevent sleep deprivation may be of considerable value in minimizing the incidence of postoperative delirium.

Aged↗