Comparison of recombinant types IIA, V and IIC phospholipase A2S, the three related mammalian secretory phospholipase A2 isozymes.
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Amino Acid Sequence↗
Biomedical subjects
M Murakami
Publications and source records attributed to M Murakami.
Diverse functional coupling of prostanoid biosynthetic enzymes in various cell types.
As also detailed in our accompanying papers in this issue, recent studies have revealed functional crosstalk and segregation between PLA2s, COXs, and terminal PG synthases in various cells (Table I). Among the PLA2s, cPLA2 is required for all three responses, and sPLA2-IIA augments the delayed response in preference to the immediate response. sPLA2-IIA associates with proteoglycans on the surface of stimulus-primed cells to exert its functions. COX-1 is utilized only in the immediate response and COX-2 is a prerequisite for the delayed response. The induced immediate response is often mediated by COX-2 rather than by COX-1, especially when the end product is PGE2. In addition to segregated utilization of these enzymes, significant crosstalk and/or synergism between them, which is often cell type specific, is also obvious. For instance, sPLA2 acts as an enhancer of COX-2 expression in rat mast cells, functional cPLA2 is required for sPLA2 induction in rat fibroblasts, and sPLA2 augments cPLA2 and COX-2 expression in mouse osteoblasts via endogenous PGE1. Moreover, differential coupling between COXs and downstream terminal PG synthases is also evident in macrophages, in which COX-1 and COX-2 are preferentially coupled with TXS and PGES, respectively. Thus, different PG-biosynthetic enzymes, acting on different cellular AA pools at different locations and being regulated by separate but interacting mechanisms, confer on the system great versatility in ensuring that both immediate and delayed AA-derived mediators are efficiently generated during cellular responses.
Animals↗
Regulation of prostaglandin, leukotriene, and platelet-activating factor metabolism in mast cells.
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Animals↗
Use of the Harmonic Scalpel in open abdominoperineal surgery for rectal carcinoma.
We describe a technique of open abdominoperineal resection with the use of the Harmonic Scalpel in seven patients. Using this instrument we dissected all pelvic vessels, including the middle hemorrhoidal artery, with no subsequent bleeding. In addition, we divided the levator ani muscles completely in the abdominal procedure alone.
Abdomen↗
Tumor scintigraphy by the method for subtracting the initial image with technetium-99m labeled antibody.
The method for subtracting the initial image from the localization image was evaluated for radioimmunoscintigraphy of tumors with technetium-99m (Tc-99m) labeled antibodies. Monoclonal antibodies were parental mouse and mouse-human chimeric antibodies to carcinoembryonic antigen (CEA), designated F11-39 and ChF11-39, respectively, both of which have been found to discriminate CEA in tumor tissues from the CEA-related antigens. After reduction of the intrinsic disulfide bonds, these antibodies were labeled with Tc-99m. In vivo studies were performed on athymic nude mice bearing the human CEA-producing gastric carcinoma xenografts. Though biodistribution results showed selective and progressive accumulation of Tc-99m labeled antibodies at the tumor site, high radioactivity in blood was inappropriate for scintigraphic visualization of the tumors within a few hours. We examined the subtraction of the initial Tc-99m image from the Tc-99m localization image after a few hours. Subtracted images of the same count reflected the in vivo behavior of the Tc-99m radioactivity. The subtracted scintigrams revealed excellent tumor images with no significant extrarenal background. Visualization of the tumor site was dependent on antigen-specific binding and nonspecific exudation. These results demonstrate that a method of subtraction of the initial image may serve as a potentially useful diagnostic method for an abnormal site for agents with a low pharmacokinetic value.
Animals↗
A new class of COX-2 inhibitor, rutaecarpine from Evodia rutaecarpa.
OBJECTIVE AND DESIGN: We investigated the effect of a new class of COX-2 inhibitor, rutaecarpine, on the production of PGD2 in bone marrow derived mast cells (BMMC) and PGE2 in COX-2 transfected HEK293 cells. Inflammation was induced by lambda-carrageenan in male Splague-Dawley (SD) rats. MATERIAL: Rutaecarpine (8,13-Dihydroindolo[2',3':3,4]pyridol[2,1-b]quinazolin -5(7H)-one) was isolated from the fruits of Evodia rutaecarpa. BMMC were cultured with WEHI-3 conditioned medium. c-Kit ligand and IL-10 were obtained by their expression in baculovirus. METHODS: The generation of PGD2 and PGE2 were determined by their assay kit. COX-1 and COX-2 protein and mRNA expression was determined by BMMC in the presence of KL, LPS and IL-10. TREATMENT: Rutaecarpine and indomethacin dissolved in 0.1% carboxymethyl cellulose was administered intraperitoneally and, 1 h later, lambda-carrageenan solution was injected to right hind paw of rats. Paw volumes were measured using plethysmometer 5 h after lambda-carrageenan injection. RESULTS: Rutaecarpine inhibited COX-2 and COX-1 dependent phases of PGD2 generation in BMMC in a concentration-dependent manner with an IC50 of 0.28 microM and 8.7 microM, respectively. It inhibited COX-2-dependent conversion of exogenous arachidonic acid to PGE2 in a dose-dependent manner by the COX-2-transfected HEK293 cells. However, rutaecarpine inhibited neither PLA2 and COX-1 activity nor COX-2 protein and mRNA expression up to the concentration of 30 microM in BMMC, indicating that rutaecarpine directly inhibited COX-2 activity. Furthermore, rutaecarpine showed in vivo anti-inflammatory activity on rat lambda-carrageenan induced paw edema by intraperitoneal administration. CONCLUSION: Anti-inflammatory activity of Evodia rutaecarpa could be attributed at least in part by inhibition of COS-2.
Alkaloids↗
A case of recurrent hepatocellular carcinoma treated with laparoscopic microwave coagulation therapy after minimally invasive hepatic surgery.
A case of hepatocellular carcinoma (HCC) in which the patient repeatedly underwent minimally invasive hepatic procedures is reported. The patient was a 71-year-old man who underwent transthoracic microwave coagulation therapy (MCT) for initial HCC nodules in segment VIII and subsequent laparoscopic MCT for small intrahepatic recurrent nodules in the left hepatic lobe. At this writing, the patient was alive and well without tumor recurrence 29 months after the initial surgery. Minimally invasive hepatic surgery alleviates perihepatic adhesion and allows subsequent laparoscopic surgery in the case of intrahepatic HCC recurrence.
Aged↗
Immediate increase of portal pressure, reflecting sinusoidal shear stress, induced liver regeneration after partial hepatectomy.
The mechanisms whereby hepatocytes in the normal liver can be primed for replication following partial hepatectomy (PHx) are poorly understood. To determine whether "shear stress," which is induced by acute portal hypertension after PHx, is involved in liver regeneration, we studied liver regeneration in rats with splenic transposition (SPT) in which we can minimize the postoperative elevation of portal pressure. Rats underwent 70% PHx following splenic transposition or sham surgery and were killed at various time points to measure portal pressure and other factors. In the control groups, the portal pressure was significantly increased immediately after surgery, peaking at 48 h, and returning to near the preoperative levels by 168 h after PHx. In the SPT group, although portal pressure increased immediately, it decreased to the control levels 6 h after PHx and thereafter repeatedly increased. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels peaked at 24 and 6 h after PHx, respectively. Proliferative cell analysis was done using MIB-5 antibody, and there were no significant differences between the two groups. Furthermore, liver weight was restored in the same way in both groups. Taken together, the results suggest that an immediate increase in portal pressure is necessary for the initiation of liver regeneration.
Animals↗
Additional microvascular anastomosis in reconstruction after total esophagectomy for cervical esophageal carcinoma.
BACKGROUND: Maintaining sufficient blood flow to the substitute organ after total esophagectomy is essential for decreasing the risk of anastomotic leakage. Additional venous, or arterial and venous, anastomoses between the vessels of the gastric tube and the vessels in the neck after total esophagectomy are described for 11 patients with cervical esophageal carcinoma. METHODS: The tissue blood flow was measured by laser Doppler flowmetry before and after anastomosis. Venous anastomosis was performed for all 11 patients, and arterial anastomosis was added for 7 patients. RESULTS: A significant increase in tissue blood flow was observed after venous anastomosis alone (mean, 19%; P < 0.05) and after arterial and venous anastomoses (mean 43%; P < 0.01). There was no anastomotic leakage or hospital death. CONCLUSIONS: This procedure may reduce the risk of anastomotic leakage especially in the case of pharyngogastrostomy following total esophagectomy.
Anastomosis, Surgical↗
Smoking accelerates absorption of inhaled neutrophil elastase inhibitor FK706.
PURPOSE: We compared the pharmacokinetics of the inhaled novel neutrophil elastase inhibitor FK706 between healthy nonsmokers and smokers. METHODS: Six healthy nonsmokers and six smokers inhaled 50 to 400 mg FK706 in two different doses. Series of plasma concentrations of the SSS form of FK706 (pharmacologically active epimer) were analyzed model dependently and independently. Pharmacokinetic parameters obtained from each group were compared after standardization by doses. RESULTS: The plasma concentration-time curve of inhaled FK706 was apparently different between smokers and nonsmokers. The maximum plasma concentrations (Cmax) were significantly higher in the smokers than in the nonsmokers (smokers, 1.47 +/- 0.62 ng/mL/mg; nonsmokers, 0.49 +/- 0.14 ng/mL/mg [mean +/- SD; P < .01]). The time to reach Cmax (tmax) and elimination half-life (t1/2) were statistically smaller in the smokers compared with the tmax and elimination t1/2 in the nonsmokers (tmax in smokers, 0.44 +/- 0.27 hours; tmax in nonsmokers, 1.17 +/- 0.39 hours [P < .01]; t1/2 in smokers, 1.23 +/- 0.40 hours; t1/2 in nonsmokers, 2.73 +/- 0.57 hours [P < .01]). The area under the plasma concentration-time curve and plasma clearance were not significantly different between the two groups. Model-dependent pharmacokinetic analysis, assuming a flip-flop model, revealed that the absorption rate constant (ka) was about 10 times greater in smokers than the ka in nonsmokers. CONCLUSION: Significant increases of Cmax and ka and reductions of tmax and elimination t1/2 of the inhaled FK706 were observed in the healthy smokers, suggesting that the smoking habit accelerates the drug absorption after inhalation. These results suggest that we should pay attention to the drug-related adverse events caused by smoking, especially when the drug has a narrow therapeutic range.
Adult↗
Suppressive effects of CTLA4-Ig on nasal allergic reactions in presensitized murine model.
Ag-specific T cell activation requires the engagement of T cell receptor (TCR) with antigen in the context of MHC, and the engagement of appropriate costimulatory molecules. It is well established that B7/CD28-CTLA4 costimulatory pathway plays an important role in the induction of T helper (Th) cells in T-cell dependent immune reactions. In this study, we evaluated the effects of blocking the costimulatory pathway by systemic administration of CTLA4-Ig during repeated nasal antigen challenges in systemically presensitized mouse. The antigen-induced early phase nasal symptoms, nasal hyperresponsiveness to histamine and nasal eosinophilia were significantly suppressed by CTLA4-Ig treatment. Elevation of serum level of antigen-specific IgE, but not IgG1 or IgG2a was inhibited by the treatment. In relation to cytokine levels in the tissue extracts of the nasal mucosa, an up-regulation of IL-4 was significantly inhibited, however, the levels of IL-5 and IFN-gamma were not affected by the treatment. These results suggest that B7/CD28-CTLA4 costimulatory pathway plays an important role in on-going Th2-related allergic reactions in the nose.
Abatacept↗
HLA antigens in patients with interferon-alpha-induced autoimmune thyroid disorders in chronic hepatitis C.
BACKGROUND/AIMS: To determine the immunological predisposition to autoimmune thyroid disorders induced by interferon-alpha therapy, human leukocyte antigen (HLA) was analyzed in patients with chronic hepatitis C who developed autoimmune thyroid disorders during or after treatment with interferon-alpha. METHODS: Four hundred and thirty-nine patients with chronic hepatitis C (278 males and 161 females, aged 20-73 years) were treated with interferon-alpha (natural-alpha, 169; alpha-2a, 82; alpha-2b, 188) for 24 weeks. RESULTS: Seventeen of 439 (3.9%) patients developed symptomatic autoimmune thyroid disorders; these included nine cases of hyperthyroidism and eight cases of hypothyroidism. The incidence of HLA-A2, B46 and Cw7 increased in patients with interferon-alpha-induced autoimmune thyroid disorders. Especially, the incidence of HLA-A2 (15/17; 88.2%) was significantly higher than that observed in the general population in Japan (corrected p-value (p(c)): p(c)<0.003). The odds ratios for the relative risk of the autoimmune thyroid disorders were A2, 10.6 [95% confidence interval, 2.4-46.5]; B46, 4.8 [1.6-14.0]; and Cw7, 3.0 [1.1-7.9]. CONCLUSIONS: Our study revealed that HLA-A2 is highly linked to the autoimmune thyroid disorders induced by interferon-alpha-therapy in patients with chronic hepatitis C.
Adult↗
Diffuse central nervous system lupus involving white matter, basal ganglia, thalami and brainstem.
We described an 11-year-old girl with acute central nervous system lupus showing diffuse lesions. She developed generalized convulsions followed by prolonged coma, and her psychomotor ability recovered fully after 3 months of steroid therapy. Cranial magnetic resonance imaging (MRI) showed high signal intensity in the cerebral deep white matter, bilateral basal ganglia, thalami, and brainstem on T2-weighted image. These lesions resolved over 1 month with residual atrophic change in the heads of the caudate nucleus on MRI. Acute SLE leukoencephalopathy may be recognized as a subtype of CNS lupus.
Basal Ganglia↗
Effect of aging on nitric oxide production by rat alveolar macrophages.
Nitric oxide (NO) plays an important role in alveolar macrophages (AM)-mediated defense against infection. The elderly become highly susceptible to respiratory tract infection. Inhibition of NO production significantly suppresses defense against infections. Therefore, it is necessary to elucidate the effect of senescence on NO production of AM. The alveolar microenvironment and lymphocytes affect NO production by AM. We examined whether changes in the alveolar microenvironment, lymphocytes, or AM brought about by aging affect NO production by AM. Bronchoalveolar lavage fluid was used as a substitute for the alveolar microenvironment. The results showed that NO production by AM activated by lymph node cells in bronchoalveolar lavage fluid from old rats in response to concanavalin A decreased compared with that of young rats. AM from aged rats produced less NO than AM from young rats. Bronchoalveolar lavage fluid and lymph node cells from aged rats had no effect on the amount of NO produced by AM. Therefore, age-associated decrease in the functional capacity of AM plays a central role in the decrease of NO production.
Aging↗
Synthesis and autoradiographic localization of muscarinic cholinergic antagonist (+)N-[11C]methyl-3-piperidyl benzilate as a potent radioligand for positron emission tomography.
(+)N-[11C]methyl-3-piperidyl benzilate, a relatively low affinity muscarinic cholinergic receptor antagonist was synthesized by N-[11C]methylation of (+)3-piperidyl benzilate using [11C]methyl iodide. The product was isolated by HPLC, and obtained with radiochemical yield of 60-70% from [11C]methyl iodide, and a specific activity of 500-1000 Ci mmol-1 (18.5-37 GBq mumol-1) at EOS and radiochemical purity of > 98%. In vitro autoradiographic studies showed selective binding for this radiotracer in the different regions of the rat brain: high in corpus striatum, hippocampus and cerebral cortex, and low in cerebellum, consistent with muscarinic cholinergic receptor distributions. This radiotracer thus had potential as radioligand for positron emission tomography.
Animals↗
Prenylagaramides A and B, new cyclic peptides from two strains of oscillatoria agardhii
Prenylagaramides A (1) and B (2), two new cyclic peptides, were isolated from the cultured cyanobacteria Oscillatoria agardhii (NIES-205) and O. agardhii (NIES-596), respectively. The structures of 1 and 2, which both contain a rare O-prenyltyrosine (Ptyr) unit, were established as cyclo(-Ptyr1-Gly2-Thr3-Gly4-Glu5-Phe6-Phe7-Asn8-Pro9-) and cyclo(-Ptyr1-Leu2-Tyr3-Pro4-Ile5-Asn6-Pro7-), respectively, by spectroscopic analysis and chemical degradation.
Journal Article↗
Bovine milk inhibits both adhesion of Helicobacter pylori to sulfatide and Helicobacter pylori-induced vacuolation of vero cells.
Adhesion of Helicobacter pylori to gastric mucosal cells is an initial important step in colonization and infection. To study adhesion, we investigated whether milk inhibits the adhesion of Helicobacter pylori to sulfatide, an acidic glycosphingolipid that exists in human gastric mucosa and to which Helicobacter pylori adheres. As a measure of functional significance, we also studied whether milk inhibits Helicobacter pylori-induced vacuolation of Vero cells. We used sulfatide-coated polystyrene plates and studied the effect of bovine milk on the adhesion of Helicobacter pylori to sulfatide. We used Vero cells for Helicobacter pylori-induced vacuolation. Bovine milk 100- to 200-fold diluted significantly inhibited both adhesion of Helicobacter pylori to sulfatide and Helicobacter pylori-induced vacuolation in Vero cells. Bovine milk significantly inhibited adhesion of Helicobacter pylori to MKN-45 cells and Lewis b antigen-coated polystyrene plates. In addition, these results suggest that bovine milk contains active substances that inhibit both adhesion of Helicobacter pylori to mucosa and vacuole formation. Bovine milk may have a protective effect on the gastric mucosa in Helicobacter pylori-associated gastritis.
Animals↗
Regulation of type V phospholipase A2 expression and function by proinflammatory stimuli.
Types IIA and V secretory phospholipase A2 (sPLA2) are structurally related to each other and their genes are tightly linked to the same chromosome locus. An emerging body of evidence suggests that sPLA2-IIA plays an augmentative role in long-term prostaglandin (PG) generation in cells activated by proinflammatory stimuli; however, the mechanism underlying the functional regulation of sPLA2-V remains largely unknown. Here we show that sPLA2-V is more widely expressed than sPLA2-IIA in the mouse, in which its expression is elevated by proinflammatory stimuli such as lipopolysaccharide. In contrast, proinflammatory stimuli induced sPLA2-IIA in marked preference to sPLA2-V in the rat. Cotransfection of sPLA2-V with cyclooxygenase (COX)-2, but not with COX-1, into human embryonic kidney 293 cells dramatically increased the interleukin-1-dependent PGE2 generation occurring over a 24 h of culture period. Rat mastocytoma RBL-2H3 cells overexpressing sPLA2-V exhibited increased IgE-dependent PGD2 generation and accelerated beta-hexosaminidase exocytosis. These results suggest that sPLA2-V acts as a regulator of inflammation-associated cellular responses. This possible compensation of sPLA2-V for sPLA2-IIA in many, if not all, tissues may also explain why some mouse strains with natural disruption of the sPLA2-IIA gene exhibit few abnormalities during their life-spans.
Animals↗