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Biomedical subjects

K Akimaru

Publications and source records attributed to K Akimaru.

At least 37 records · Page 2Linked to original sources
PubMed1998

Anti-cancer-prostaglandin-induced cell-cycle arrest and its modulation by an inhibitor of the ATP-dependent glutathione S-conjugate export pump (GS-X pump).

The A and J series of prostaglandins (PGs) accumulate in the nuclei to suppress the proliferation of cancer cells. Here we report that Delta7-PGA1 methyl ester, a synthetic anti-cancer PG, increased the level of mRNA for the cyclin-dependent kinase inhibitor p21 in human leukaemia HL-60 cells. The induction of p21 was associated with the accumulation of hypophosphorylated retinoblastoma protein (pRB) and the suppression of c-myc gene expression. Since the p53 gene is deleted in HL-60 cells, the anti-cancer PG is suggested to inhibit cancer cell growth by inducing p21 via a p53-independent pathway. Unlike HL-60 cells, cisplatin-resistant HL-60/R-CP cells were insensitive to Delta7-PGA1 methyl ester. While c-myc expression was transiently suppressed, neither G1 arrest nor hypophosphorylation of pRB was observed with the anti-cancer PG. Plasma membrane vesicles from HL-60/R-CP cells showed an enhanced level of GS-X pump (ATP-dependent glutathione S-conjugate export pump) activity towards the glutathione S-conjugate of Delta7-PGA1 methyl ester (Km 110 nM). GIF-0019 ¿N-carbomethoxy-S-[5-(4-benzoylphenyl)pentyl]glutathione dimethyl ester¿, a specific inhibitor of the GS-X pump, dose-dependently enhanced the cellular sensitivity of HL-60/R-CP cells to Delta7-PGA1 methyl ester and induced G1 arrest. The GS-X pump is suggested to play a pivotal role in modulating the biological action of the anti-cancer PG.

Adenosine Triphosphate↗
PubMed1998

Cholinesterase activity in quails of neuropathy caused by organophosphates.

It is known that some organophosphates produce not only well-known acute toxicity but also characteristic delayed neurotoxicity. Tri-ortho-tolyl phophate (TOTP), which was formerly named Tri-ortho-cresyl phosphaete (TOCP), was first noticed in an incident of poisoning as the compound which produced organophosphate induced delayed neurotoxicity (OPIDN). It is said that triphenyl phosphite (TPP) is also one of the organophosphates which possesses OPIDN. However, it is thought that TPP-induced delayed neurotoxicity (TPP-DN) is not identical with classical OPIDN. An intermediate syndrome was later proposed as the third neurotoxicity caused by organophosphates. We think that TPP is a model chemical of the third neurotoxicity. We compared TOTP with TPP using Japanese quails. We measured cholinesterase (ChE) activity and clearly demonstrated the difference between the two chemicals, that is to say, the activity recovered after 72 hrs from the administration of TPP, whereas the inhibition continued for more than 11 days after the administration of TOTP.

Animals↗
PubMed1996

Coordinated induction of MRP/GS-X pump and gamma-glutamylcysteine synthetase by heavy metals in human leukemia cells.

We recently reported that GS-X pump activity, as assessed by ATP-dependent transport of the glutathione-platinum complex and leukotriene C4, and intracellular glutathione (GSH) levels were remarkably enhanced in cis-diamminedichloroplatinum(II) (cisplatin)-resistant human leukemia HL-60 cells (Ishikawa, T., Wright, C. D., and Ishizuka, H. (1994) J. Biol. Chem. 269, 29085-29093). Now, using Northern hybridization and RNase protection assay, we provide evidence that the multidrug resistance-associated protein (MRP) gene, which encodes a human GS-X pump, is expressed at higher levels in cisplatin-resistant (HL-60/R-CP) cells than in sensitive cells, whereas amplification of the MRP gene is not detected by Southern hybridization. Culturing HL-60/R-CP cells in cisplatin-free medium resulted in reduced MRP mRNA levels, but these levels could be induced to rise within 30 h by cisplatin and heavy metals such as arsenite, cadmium, and zinc. The increased levels of MRP mRNA were closely related with enhanced activities of ATP-dependent transport of leukotriene C4 (LTC4) in plasma membrane vesicles. The glutathione-platinum (GS-Pt) complex, but not cisplatin, inhibited ATP-dependent LTC4 transport, suggesting that the MRP/GS-X pump transports both LTC4 and the GS-Pt complex. Expression of gamma-glutamylcysteine synthetase in the cisplatin-resistant cells was also co-induced within 24 h in response to cisplatin exposure, resulting in a significant increase in cellular GSH level. The resistant cells exposed to cisplatin were cross-resistant to melphalan, chlorambucil, arsenite, and cadmium. These observations suggest that elevated expression of the MRP/GS-X pump and increased GSH biosynthesis together may be important factors in the cellular metabolism and disposition of cisplatin, alkylating agents, and heavy metals.

ATP-Binding Cassette Transporters↗
PubMed1996

In vitro synthesis of an N-myristoylated fusion protein that binds to the liposomal surface.

To increase the efficiency of association of tumor necrosis factor (TNF), a hydrophilic model protein, with liposomes, an N-myristoylation signal sequence was linked to the N-terminus of TNF by gene fusion. A DNA sequence coding for the N-myristoylation signal of Rasheed leukemia virus-gag protein was fused to be 5'-end of the cDNA coding for the mature domain of TNF to give N-myristoylated fusion TNF cDNA. In vitro translation of the mRNA coding for this fusion cDNA using rabbit reticulocyte lysate gave rise to an N-myristoylated fusion TNF with a molecular mass of 18 kDa as determined by the incorporation of [3H]myristic acid and by immunoprecipitation with anti-TNF antibody. Replacement of Gly2 in the myristoylation signal with Ala entirely inhibited the incorporation of [3H]-myristic acid into the fusion protein. A liposome binding assay using Ficoll density gradient centrifugation revealed that incubating the N-myristoylated fusion TNF with dipalmitoyl phosphatidylcholine-liposomes caused the complete binding of the protein to the liposomes, whereas much less of the nonmyristoylated counterpart bound. Thus, N-myristoylated fusion TNF, with high affinity for liposomes, was synthesized by the in vitro translation/transcription system.

Amino Acid Sequence↗
PubMed1996

Induction of MRP/GS-X pump and cellular resistance to anticancer prostaglandins.

We provide evidence that the expression of the human MRP/GS-X pump encoded by the MRP (multidrug resistance associated protein) gene is induced by cisplatin in human leukemia HL-60/R-CP (cisplatin-resistant) cells and modulates cell growth inhibition by delta(7)-prostaglandin A1 (PGA1) methyl ester. The MRP mRNA level in HL-60/R-CP cells increased remarkably after a 24-h incubation with 20 microM cisplatin; interestingly, however, no amplification of the MRP gene was detected. In cisplatin-sensitive HL-60 cells, which express the MRP/GS-X pump at low levels, c-myc expression was substantially suppressed by delta(7)-PGA1 methyl ester and the cell cycle was arrested in G1 phase. By contrast, in HL-60/R-CP cells overexpressing the MRP/GS-X pump, c-myc expression and cell proliferation were much less affected by delta(7)-PGA1 methyl ester. This suggests that induction of the MRP/GS-X pump may confer on cancer cells resistance to anticancer prostaglandins and that the resistance mechanism may involve the increased efflux of PG-glutathione conjugates, as active intermediates, from the cells via the MRP/GS-X pump.

ATP-Binding Cassette Transporters↗
PubMed1995

Adenomyoma of the common hepatic duct.

A very rare case of adenomyoma of the common hepatic duct is described. A 54-year-old woman was admitted with impending obstructive jaundice secondary to adenomyoma of the common hepatic duct. Our impression, formulated from her clinical presentation, endoscopic investigations, and biochemical and radiological findings, was a cancer of the proximal common hepatic duct. The patient was treated successfully by combination surgical resection and hepaticojejunostomy. Despite our obtaining an intraoperative frozen section, final histological examination was required to confirm the diagnosis. The patient remains well 16 months postoperatively. A survey of the world literature revealed that this is the second report of adenomyoma occurring in the common hepatic duct.

Adenomyoma↗
PubMed1995

Hemodynamic evaluation of recombinant human tumor necrosis factor (TNF)-alpha, TNF-SAM2 and liposomal TNF-SAM2 in an anesthetized dog model.

We have evaluated the hemodynamic effects of systemically administered recombinant human tumor necrosis factor (TNF)-alpha, TNF-SAM2 and liposome-bound TNF-SAM2 in an anesthetized mongrel dog model. A dose of 10 micrograms TNF protein/kg of each formulation was injected in a peripheral vein and mean systemic arterial pressure (SAP), heart rate (HR) and cardiac output (CO) were measured. TNF-alpha induced a marked drop in SAP in all three dogs (mean decrease = 59.3 +/- 5.2 mm Hg; to 61.5% of baseline; p = 0.008); whereas TNF-SAM2 caused a smaller and transient drop in SAP in four dogs (mean decrease = 25.5 +/- 10.1 mm Hg; to 81.2% of baseline; p = 0.086). In three dogs administered liposome-bound TNF-SAM2, which retains antitumor activity in vivo, a net slight hypertensive phase and sustained elevated CO occurred, followed by a return to an essentially normotensive state (101.0% of baseline SAP). This model demonstrates that the principal acute systemic toxicity of TNF, i.e., hypotension, can be markedly attenuated by liposomal formulation of a second-generation TNF.

Animals↗
PubMed1995

Human pro-tumor necrosis factor: molecular determinants of membrane translocation, sorting, and maturation.

Human pro-tumor necrosis factor (pro-TNF) is a type II transmembrane protein with a highly conserved 76-residue leader sequence. We have analyzed the behavior, both in a microsomal translocational system and by transfection, of a series of mutants with deletions from the cytoplasmic, transmembrane, and linking domains. Cytoplasmic deletions included the Arg doublet at -49 and -48 and/or the Lys doublet at -58 and -57; additional mutants included deletion of residues -73 to -55 and -73 to -55, -49, and -48. The transmembrane and linking domain mutants included deletions in the -42 to -35 region, combined with the deletion of residues -32 to -1. Two hybrid mutants combined the cytoplasmic deletions with the deletion of residues -32 to -1. All of the cytoplasmic deletion mutants were properly translocated, as were the transmembrane deletion mutants with deletions up to residues -36, -35, -32 to -1, although the last one exhibited reduced efficiency; further incremental deletions, including deletions of residues -38 to -35 and -32 to -1, completely blocked translocation. Both hybrid mutants were effectively translocated; furthermore, transfection analysis revealed competent expression and maturation of both the cytoplasmic and hybrid mutants. Thus, proper expression and maturation of human pro-TNF can be accomplished with as few as approximately 12 of the 26 residues of the native transmembrane domain and with a net negative charge in the cytoplasmic domain flanking the transmembrane region.

Amino Acid Sequence↗
PubMed1995

Formulation and antitumor efficacy of liposomal-caprylated-TNF-SAM2.

The tumor necrosis factor (TNF) mutant TNF-SAM2 has previously been shown to have a therapeutic profile superior to parental TNF. To initially evaluate the characteristics of liposomal formulations of TNF-SAM2, it was modified with the N-hydroxysuccinimide ester of caprylic acid to increase its hydrophobic binding to multilamellar and small unilamellar vesicles (MLVs and SUVs). Native PAGE and fluorescamine analysis of acetylated parental TNF and TNF-SAM2 indicated that these proteins both displayed trimeric structures based on crosslinking/SDS-PAGE analysis and behaved similarly with respect to reactivity of their amino functions. Limited N-terminal sequencing analysis of partially acetylated (approx 3 acetyl groups per trimer) TNF-SAM2 indicated that the N-terminal Val was not modified; this was also concluded based on HPLC/mass spectrometric (LC-MS) analysis of Glu C digests. LC-MS analysis of tryptic digests of the acetylated TNF-SAM2 indicated that Lys-98 was unreactive. Molecular ions corresponding to acetylated Lys-containing peptides for all five other Lys residues could be detected; none appeared hyperreactive, but Lys-11 appeared hyporeactive. MLVs composed of DMPC/DMPG (7:3) and SUVs composed of DPPC/DSPC (1:1) displayed high capacity for binding to caprylated TNF-SAM2. These formulations of caprylated TNF-SAM2 displayed tumor necrotizing and growth-inhibitory activity in a syngeneic tumor model, and may be candidates for clinical development.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Amplification of N-myc gene and increase of urinary VMA and HVA in patients with neuroblastic tumors.

Neuroblastic tumor cases in our departments were evaluated in terms of the stage of the tumor, N-myc amplification, urinary vanillylamndelic acid (VMA)/homovanillic acid (HVA) and survival rate. Two asymptomatic cases, diagnosed when under a year old by mass screening, had no amplifications of N-myc but showed more than one value of urinary VMA/HVA ratio. The patients are now doing well eight years after complete excision of the neuroblastoma which had originated in the sympathetic ganglion. On the other hand, two other symptomatic cases, operated on at the ages of 3 and 5 years, showed remarkable amplifications with less than one value of urinary VMA/HVA, and died from the tumor soon after partial resection of the neuroblastoma and ganglioneuroblastoma which had originated in the adrenal gland and the sympathetic ganglion, respectively. The present monograph reports our cases and discusses prognostic factors.

Child, Preschool↗
PubMed1994

A new technique for performing total thymectomy on rabbits.

Sixty-one Japanese white rabbits underwent total thymectomies. Eight of the animals died of intraoperative hemorrhage or respiratory failure, and twelve died of postoperative hypovolemia, dehydration, malnutrition or wound infections. Forty-one rabbits survived and were used as a total thymectomy model. The whole procedure of our technique is described in detail so that even those with no experience of performing thymectomies can follow it. Some tactics especially how to deal with the thymic vessels and the pleurae, are key points. Our technique permits safe and perfect total thymectomies to be carried out on rabbits.

Animals↗
PubMed1993

Esophago-jejuno-duodenal anastomoses with an ultra-short duodenum.

Reconstruction following total gastrectomy usually requires one of the various methods of esophagojejunal anastomosis. We present herein the case of a 78-year-old woman with gastric carcinoma involving the adjacent organs for which resection of the whole stomach, distal pancreas, transverse colon, and distal duodenum was performed. Reconstruction was carried out with an esophagojejunostomy, followed by a side-to-side anastomosis between the raised jejunal limb and the residual short duodenum. Her postoperative course was uneventful and she was able to lead a relatively comfortable life at home until she died after tumor recurrence caused GI bleeding 1 year postoperatively. This new modified Roux-en-Y with an ultra-short duodenum can be applied for such contiguously invasive gastric carcinoma to achieve a better quality of life, when conventional reconstruction techniques after total gastrectomy are not indicated.

Adenocarcinoma↗
PubMed1993

Subcutaneous wire traction technique without CO2 insufflation for laparoscopic cholecystectomy.

One hundred laparoscopic cholecystectomies were performed since April 1991. Eleven patients were treated with a new technique without CO2 insufflation, using a traction device to elevate the right upper quadrant wall. Two Kirschner wires were introduced subcutaneously to permit the abdominal wall to be lifted for satisfactory laparoscopic view, as the gas insufflation technique yields. Preoperative evacuation of the intestines and intraoperative muscle relaxation are necessary for easy and successful cholecystectomy. Three cases were converted to laparotomy because of remarkably distended intestine due to incorrect endotracheal intubations. No complications related to subcutaneous wire traction technique were noted in this series. Subcutaneous wire traction technique provides a simpler, and possibly safer alternative to the gas insufflation technique.

Cholecystectomy, Laparoscopic↗