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Biomedical subjects

M Kitagawa

Publications and source records attributed to M Kitagawa.

At least 163 records · Page 9Linked to original sources
PubMed1999

AS-924, a novel orally active bifunctional prodrug of ceftizoxime. Synthesis and relationship between physicochemical properties and oral absorption.

Ceftizoxime (CZX), a parenteral cephalosporin, has potent and broad antibacterial activity. To improve its oral absorption, we synthesized a series of monofunctional and bifunctional prodrugs of CZX. In rabbits, urinary recovery after oral administration of CZX was improved by esterification of the carboxyl group at the C-4 position with various lipophilic moieties (monofunctional prodrugs), and was further increased by introduction of a hydrophilic L-alanine to the amino group on the thiazole ring at the C-7 position (bifunctional prodrugs). Least-squares analysis showed good parabolic correlations between log P and urinary recovery for monofunctional and bifunctional prodrugs, respectively. AS-924, a bifunctional prodrug with a pivaloyloxymethyl and L-alanyl moiety had the best balance of lipophilicity and water-solubility for oral absorption among the prodrugs synthesized.

Administration, Oral↗
PubMed1999

Molecular forms of serum pancreatic stone protein in acute pancreatitis.

CONCLUSION: Elevation of serum pancreatic stone protein-(PSP) S1 suggests activation of trypsinogen in the pancreas. This information would prompt the start of intensive treatment and may improve prognosis of acute pancreatitis (AP). BACKGROUND: PSP exists in two molecular forms, PSP-S2-5 and PSP-S1. PSP-S1 is produced by enzyme cleavage of PSP-S2-5 by trypsin. Total serum PSP rose in AP, but little is known about its molecular forms. In this study, we characterized the molecular forms of serum PSP in AP. METHODS: Sera were taken from 8 patients with severe acute pancreatitis (sAP) and from 11 patients with mild acute pancreatitis (mAP). Serum PSP was characterized by high-performance liquid chromatography (HPLC) followed by the specific enzyme immunoassay (EIA). RESULTS: The total serum PSP in sAP was higher than in mAP, but the difference was not significant. The PSP-S1 was detected in serum in all (7/7) patients in sAP and in 72% (8/11) of patients in mAP. Serum level of PSP-S1 was significantly higher in sAP than that in mAP (p < 0.05), and the cutoff value to distinguish the two groups was 30 ng/mL. Serum PSP-S1 did not show significant correlation with total PSP, immunoreactive trypsin, or C-reactive protein.

Acute Disease↗
PubMed1999

A prospective multicenter trial evaluating diagnostic validity of multivariate analysis and individual serum marker in differential diagnosis of pancreatic cancer from benign pancreatic diseases.

CONCLUSION: A multivariate analysis of CAMPAS-PX2 can increase its diagnostic accuracy in differential diagnosis of pancreatic cancer from benign pancreatic or extrapancreatic disease, when compared with CA19-9 alone. However, the improvement in diagnostic accuracy is still not satisfactory in spite of an elaborate combination of serum markers in diagnosis for pancreatic cancer. Optimal combination of a sensitive serum marker and another diagnostic modality, such as ultrasonography, can be a practical way to improve important diagnostic and cost-effectiveness in diagnosis for pancreatic cancer. BACKGROUND: No specific biological test has yet been developed for diagnosis of pancreatic cancer, although increasing numbers of tumor markers become available. For improvement in the diagnostic and cost effectiveness, it is important to select optimal combination of several serum markers relatively independent of each other. METHODS: A new model of discriminant function, computer-aided multivariate and pattern analysis system for pancreatic cancer examination 2 (CAMPAS-PX2), was developed based on the data of the 23 serum tumor markers from the first prospective trial (1) to differentiate between pancreatic cancer and benign pancreatobiliary disease by logistic regression analysis using a stepwise selection method. In 243 patients suspected of having pancreatic pancreatic cancer by a multicenter prospective study, the diagnostic value of the multivariate analysis, CAMPAS-PX2, was compared with the 23 markers. RESULTS: Pancreatic cancer was subsequently identified in 27 patients. Positive in disease, negative in health, and area under receiver operating characteristic curve were significantly higher by CAMPAS-PX2 (89, 87, 91%) than by CA 19-9 (78, 82, 84%), the most sensitive marker among the 23 markers.

Biomarkers, Tumor↗
PubMed1999

Activation of the transcription factor ISGF3 by interferon-gamma.

The interferon-stimulated gene factor 3 (ISGF3) transcription factor has been extensively studied in the context of the type I interferon (IFN-alpha/beta)-mediated antiviral response; it consists of the major DNA-binding component p48, and the signal transducers and activators of transcription (Stat)1 and Stat2. We show here that type II IFN (IFN-gamma) can also invoke the activation of ISGF3 in mouse primary embryonic fibroblasts. In fact, the two Stat proteins were tyrosine phosphorylated in IFN-gamma stimulated cells. Our present findings reveal an additional mechanism by which these two distinct types of cytokines, IFN-alpha/beta and -gamma, can commonly elicit antiviral activities.

Animals↗
PubMed1999

AS-924, a novel bifunctional prodrug of ceftizoxime.

To improve the oral absorption of ceftizoxime (CZX), 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]- 3-cephem-4- carboxylic acid, we synthesized and evaluated a novel series of bifunctional prodrugs, in which L-alanine was introduced into the aminothiazole-oxime moiety at the C-7 position of the various lipophilic esters of CZX. Among these prodrugs, pivaloyloxymethyl 7beta-[(Z)-2-(2-(S)-alanylaminothiazol-4-yl)-2-methoxyiminoa cetamido]-3-cephem-4-carboxylate hydrochloride (ceftizoxime alapivoxil, AS-924) was well absorbed after oral administration in experimental animals and showed potent therapeutic effects in mice infected with gram-positive and gram-negative bacteria.

Animals↗
PubMed1999

Effect of a new inhibitor of type II phospholipase A2 on experimental acute pancreatitis in rats.

The catalytic activity of type II phospholipase A2 (PLA2) in blood has been reported to increase in acute pancreatitis and to reflect the severity of pancreatitis. In this study, we evaluated the effects of a new inhibitor of type II PLA2, S5920/LY315920Na, on trypsin-taurocholate-induced pancreatitis in rats. Hemorrhagic pancreatitis was induced by an infusion of a mixture of trypsin and taurocholate into the pancreatic duct. S5920/LY315920Na was administered subcutaneously at 0 h and 3 h after the induction of pancreatitis. Survival rates for 24 h in rats treated with 0.1 and 1 mg/kg of S5920/LY315920Na were significantly higher than that in untreated rats (71 and 86% vs. 14%). Serum levels of amylase and lipase in rats treated with 1 mg/kg of S5920/LY315920Na were significantly lower than those in untreated rats (amylase, 6,903 vs. 32,516 U/L; and lipase, 514 vs. 6,710 U/L) at the time of death or 24 h after the induction of pancreatitis. Plasma levels of S5920/LY315920Na were enough to inhibit catalytic activity of PLA2 in plasma for 9 h. A new inhibitor of type II PLA2, S5920/LY315920Na, inhibited catalytic activity of PLA2 and improved the survival rate in experimental hemorrhagic pancreatitis in rats.

Acetates↗
PubMed1999

[Macroamylase].

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Amylases↗
PubMed1999

[Serum trypsin].

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Humans↗
PubMed1998

The effect of VIP/PACAP family of peptides on pancreatic blood flow and secretion in conscious dogs.

The effects of PACAP-38, PACAP-27, VIP and secretin on pancreatic blood flow were compared with those of meals in five conscious dogs using an ultrasound transit-time blood flow meter. All peptides (1-100 pmol/kg) induced dose-related increases of pancreatic blood flow, and fluid and bicarbonate secretion. Only PACAPs stimulated protein secretion. Both PACAPs at doses which did not stimulate pancreatic secretion, induced significant pancreatic vasodilatation. VIP was less potent than PACAP-38 and PACAP-27 at lower doses (1-25 pmol/kg), but was similar to PACAPs at higher doses. The maximal effects of PACAPs and VIP were comparable to those observed after meals. Secretin was a significant but weak vasodilator. When pancreatic secretion was maximally stimulated by secretin, a reduction of vascular resistance was 75% of postprandial peak levels. PACAP(6-38), a competitive antagonist of PACAP, inhibited pancreatic vascular responses to PACAPs, but not those to VIP and secretin. Its inhibitory effects on protein response to PACAPs were not significant. Atropine inhibited pancreatic protein but not the vascular effect of PACAP-27. Pancreatic vasodilatation by PACAPs appears to be mediated by both PACAP-specific and VIP/PACAP common receptors in dogs. PACAP, like VIP, is a good candidate for a mediator of atropine-resistant vasodilatation of the pancreas.

Animals↗
PubMed1998

The role of PKN in the regulation of alphaB-crystallin expression via heat shock transcription factor 1.

We previously reported that PKN, a fatty acid-activated serine/threonine protein kinase, translocates from the cytosol to the nucleus by stresses such as heat shock, sodium arsenite, and serum starvation. To clarify the role of PKN under heat stress, we examined whether PKN regulates the expression of heat shock proteins. Co-expression of heat shock transcription factor 1 (HSF1) and the catalytically active fragment of PKN induced the accumulation of alphaB-crystallin but not HSP27 and HSP70 in HeLa S3 cells. The expression of the reporter gene for alphaB-crystallin promoter was activated by co-expression of HSF1 and the catalytically active fragment of PKN, and this activation was dependent on the protein kinase activity of PKN. Deletion analysis of the alphaB-crystallin promoter region revealed that both the proximal and the distal heat shock elements were necessary for the transactivation. These results raise the possibility that there is a signal transduction pathway mediating stress signals for the accumulation of alphaB-crystallin by HSF1 and PKN.

Catalysis↗
PubMed1998

Activation of cyclin-dependent kinase 2 (Cdk2) in growth-stimulated rat astrocytes. Geranylgeranylated Rho small GTPase(s) are essential for the induction of cyclin E gene expression.

The role of the mevalonate cascade in the control of cell cycle progression in astrocytes has been investigated. Serum stimulation of rat astrocytes in primary culture induces the expression of cyclin E followed by the activation of cyclin-dependent kinase 2 (Cdk2) during G1/S transition. The expression of p27, cyclin D1, and the activities of Cdk4 and Cdk-activating kinase (CAK), composed of Cdk7 and cyclin H, were not affected. Serum did, however, stimulate the expression of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase mRNA at mid-G1 phase. Moreover, an inhibitor of HMG-CoA reductase, pravastatin, reduced cyclin E expression and Cdk2 activation and caused G1 arrest in the astrocytes. In contrast, mevalonate and its metabolite, geranylgeranylpyrophosphate (GGPP) but not farnesylpyrophosphate (FPP), reversed the inhibitory effects of pravastatin on cyclin E expression and Cdk2 activation and allowed G1/S transition. Rho small GTPase(s) were geranylgeranylated and translocated to membranes in the presence of GGPP during G1/S transition. The effect of GGPP on cyclin E expression was abolished by botulinum C3 exoenzyme, which specifically inactivates Rho. These data indicate that geranylgeranylated Rho small GTPase(s) are essential for the induction of cyclin E expression, Cdk2 activation, and G1/S transition in rat astrocytes.

ADP Ribose Transferases↗
PubMed1998

A protein kinase, PKN, accumulates in Alzheimer neurofibrillary tangles and associated endoplasmic reticulum-derived vesicles and phosphorylates tau protein.

A possible role for a protein kinase, PKN, a fatty acid-activated serine/threonine kinase with a catalytic domain homologous to the protein kinase C family and a direct target for Rho, was investigated in the pathology of Alzheimer's disease (AD) using a sensitive immunocytochemistry on postmortem human brain tissues and a kinase assay for human tau protein. The present study provides evidences by light, electron, and confocal laser microscopy that in control human brains, PKN is enriched in neurons, where the kinase is concentrated in a subset of endoplasmic reticulum (ER) and ER-derived vesicles localized to the apical compartment of juxtanuclear cytoplasm, as well as late endosomes, multivesicular bodies, Golgi bodies, secretary vesicles, and nuclei. In AD-affected neurons, PKN was redistributed to the cortical cytoplasm and neurites and was closely associated with neurofibrillary tangles (NFTs) and their major constituent, abnormally modified tau. PKN was also found in degenerative neurites within senile plaques. In addition, we report that human tau protein is directly phosphorylated by PKN both in vitro and in vivo. Thus, our results suggest a specific role for PKN in NFT formation and neurodegeneration in AD damaged neurons.

Aged↗
PubMed1998

Fluid secretion in interlobular ducts isolated from guinea-pig pancreas.

1. Pancreatic HCO3- and fluid secretion were studied by monitoring luminal pH (pHL) and luminal volume simultaneously in interlobular duct segments isolated from guinea-pig pancreas. The secretory rate and HCO3- flux were estimated from fluorescence images obtained following microinjection of BCECF-dextran (70 kDa, 20 microM) into the duct lumen. 2. Ducts filled initially with a Cl--rich solution swelled steadily (2.0 nl min-1 mm-2) when HCO3-/CO2 was introduced, and the luminal pH increased to 8.08. When Cl- was replaced by glucuronate, spontaneous fluid secretion was reduced by 75 %, and pHL did not rise above 7.3. 3. Cl--dependent spontaneous secretion was largely blocked by luminal H2DIDS (500 microM). We conclude that, in unstimulated ducts, HCO3- transport across the luminal membrane is probably mediated by Cl--HCO3- exchange. 4. Secretin (10 nM) and forskolin (1 microM) both stimulated HCO3- and fluid secretion. The final value of pHL (8.4) and the increase in secretory rate (1.5 nl min-1 mm-2) after secretin stimulation were unaffected by substitution of Cl-. 5. The Cl--independent component of secretin-evoked secretion was not affected by luminal H2DIDS. This suggests that a Cl--independent mechanism provides the main pathway for luminal HCO3- transport in secretin-stimulated ducts. 6. Ducts filled initially with a HCO3--rich fluid (125 mM HCO3-, 23 mM Cl-) secreted a Cl--rich fluid while unstimulated. This became HCO3--rich when secretin was applied. 7. Addition of H2DIDS and MIA (10 microM) to the bath reduced the secretory rate by 56 and 18 %, respectively. Applied together they completely blocked fluid secretion. We conclude that basolateral HCO3- transport is mediated mainly by Na+-HCO3- cotransport rather than by Na+-H+ exchange.

Adenosine Triphosphate↗
PubMed1998

Newly synthesized Rho A, not Ras, is isoprenylated and translocated to membranes coincident with progression of the G1 to S phase of growth-stimulated rat FRTL-5 cells.

Ras and Rho are involved in the regulation of signal transduction events governing cell growth and cell proliferation. Protein prenylation is essential for the activation and/or the translocation of these small GTPases; however, protein geranylgeranylation rather than farnesylation is required for G1/S transition. We studied prenylation and translocation of Ras and Rho A during G1/S progression in growth-stimulated rat thyroid FRTL-5 cells. Immunoblot analysis revealed that both Ras and Rho A were detected in membrane fractions at G0. Rho A was eliminated from the membrane fraction during G1 and was not detected on the membrane at mid-G1. Translocation of Rho A from the cytoplasm back to the membranes was observed during late G1 phase. In contrast, Ras remains in the membrane fraction through the cell cycle progression from G1 to S phase. The immunoprecipitation of Rho A from the membrane fraction demonstrated that newly synthesized Rho A, labeled by pulsing cells with [35S]methionine and [35S]cysteine, was geranylgeranylated and associated with the membrane in late G1. These results indicate that Rho A, not Ras, was eliminated from membrane fraction during G1 progression and that newly synthesized Rho A is geranylgeranylated and translocated to membranes during G1/S progression in growth-stimulated FRTL-5 cells.

Animals↗
PubMed1998

A Dumon stent inserted for bronchial stenosis causing a left bronchopericardial fistula: report of a case.

We present herein the case of a 59-year-old man in whom a Dumon stent, inserted as treatment for stenosis of the left main bronchus, caused a left bronchopericardial fistula. The patient initially presented with severe dyspnea caused by main bronchial stenosis of unknown origin for which a Dumon stent was inserted at a local hospital. The Dumon stent migrated to the endobronchus through the stenosis of the left main bronchus a few days later, and his dyspnea remained unresolved. He was subsequently referred to our department 6 months later, where a left pneumonectomy under supportive cardiopulmonary bypass through the femoral artery and vein was performed, and a postoperative pathological diagnosis of bronchial leiomyosarcoma was made. For this rare group of malignant tumors, early diagnosis permits complete surgical resection of the mass and offers the best prognosis. Excision of the tumor should be performed under cardiopulmonary bypass through the femoral vessels when a risk of sudden rupture of the pulmonary artery or vein exists for any reason.

Bronchi↗
PubMed1998

Role of p27Kip1 and cyclin-dependent kinase 2 in the proliferation of non-small cell lung cancer.

The cell cycle is governed by a family of cyclin-dependent kinases (Cdks). Cdk2 forms a functional complex with cyclin E and plays a pivotal role in the regulation of G1/S transition. Cdk2 activity is negatively regulated by interactions with inhibitors. p27Kip1, one of the most potent inhibitors of Cdk2, was recently identified as a powerful negative prognostic marker in non-small cell lung cancer as well as in colorectal and breast cancer. In the present study, the expression of p27 and Ki-67 antigen in nonneoplastic and cancerous lung tissues was determined by immunohistochemistry. After establishing that the antibody-measured p27 labeling index was a good reflection of the level of p27 expression measured by Western blotting, we show that p27 labeling index is decreased in cancerous lung tissues, compared with nonneoplastic lung tissues, and exhibits a significant inverse relation to the proliferation marker Ki-67 antigen, detected with monoclonal antibody MIB-1. Consistent with these data, all cancerous lung tissues showed enhanced degradation activity of p27 compared with nonneoplastic lung tissues and, in addition, increased levels of the phosphorylated form of Cdk2, as determined with Western blot analysis. The H1 histone kinase activity associated with Cdk2 was also increased in non-small cell lung cancers. Statistical analysis showed that proliferative activity as measured by MIB-1 labeling index was highly correlated with Cdk2 activity (r = 0.767, P < 0.0015). These results suggest that p27 and Cdk2 may play an important role in the proliferation of non-small cell cancer.

Adult↗