Lipids and serotonin: a possible link?
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Humans↗
Biomedical subjects
Y Takada
Publications and source records attributed to Y Takada.
Pravastatin-induced changes in receptor-mediated metabolism of low density lipoprotein in guinea pigs.
The effect of pravastatin, an inhibitor of HMG-CoA reductase, on the metabolism of human low density lipoprotein (LDL) was examined in guinea pigs. Pravastatin treatment significantly reduced plasma levels of total cholesterol and LDL-cholesterol by 15.6 mg/dl (38.8%) and 12.7 mg/dl (42.9%), respectively. We investigated the metabolism of LDL in pravastatin-treated and untreated guinea pigs using the simultaneous intravenous injection of 131I-labeled LDL and 125I-labeled, galactose-treated LDL to quantify the LDL receptor pathway. Pravastatin increased the fractional catabolic rate (FCR) of the LDL receptor-dependent pathway. The treatment with pravastatin did not alter the FCR of the LDL receptor-independent pathway. The FCR of the LDL receptor-dependent pathway was higher for LDL isolated from pravastatin-treated subjects than for LDL isolated from control subjects. These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the LDL receptor-mediated pathway.
Animals↗
[Molecular and clinical abnormalities of apolipoprotein A-I].
Several epidemiological and clinical studies have shown an inverse correlation between low plasma concentration of high density lipoprotein (HDL) cholesterol as well as its major protein component, apolipoprotein A-I (apo A-I), and the risk of coronary artery disease. Apo A-I plays an important role in a reverse cholesterol transport. In this model, HDL mediates the cholesterol flux from peripheral cells to the liver. The structure and function of HDL-deficiency syndromes and apo A-I variants provides genetic markers of whether the presence of these molecular defects accounts for low HDL cholesterol levels and the coronary risk.
Apolipoprotein A-I↗
The significant enhancement of fibrinolysis by calcium ion in a cell free system: the shortening of euglobulin clot lysis time by calcium ion.
We investigated the roles of calcium ion (Ca2+) on euglobulin clot lysis time (ECLT) and found that the physiological concentration of Ca2+ significantly (4-5 times) shortened ECLT. The shortening was observed at the concentration of Ca2+ higher than 1.5-2.0 mM. Other divalent cations such as Mg2+, Zn2+ or Mn2+ didn't change ECLT. Anti-tPA antibody or plasminogen activator inhibitor-1 prolonged ECLT in the absence of Ca2+, whereas they had no effect on ECLT shortened by Ca2+. C1 inactivator also had no effect. When barium absorbed plasma was employed, the shortening of ECLT by Ca2+ wasn't observed, whereas it was recovered by the readdition of barium absorbed fraction. When factor X deficient plasma was employed, the shortening of ECLT by Ca2+ was also not observed. Thus, Ca2+ enhances fibrinolysis in a cell free system by a novel pathway in which the presence of factor X is prerequisite.
Absorption↗
[Immunohistological study in Bruch's membrane of senescence accelerated mouse].
Age-related macular degeneration is one of the major causes of severe visual loss is elderly individuals. However, relatively little is known about its etiology. The disease may be associated with senescence. Ultrastructural and immunohistochemical studies on SAM (senescence accelerated mouse) eyes were carried out to learn details of aging changes in the retinal pigment epithelium (RPE) and Bruch's membrane. SAM P 1 mice aged 2, 10, 14 months were examined in this study. The eyes were analysed for type IV collagen and heparan sulfate proteoglycan (HSPG) by the avidin-biotin-peroxidase complexes (ABC) method and post-embeddig immunolocalization with colloidal gold. With the ABC method, the basement membranes of both the RPE and the choriocapillaris showed markedly positive staining when treated with anti-type IV collagen antibody and moderately positive staining when treated with anti-HSPG antibody. In ultrastructural immunolocalization, both basement membranes showed fairly heavy labeling in response to the antibodies to type IV collagen, and moderate labeling in response to the antibodies to HSPG. With aging, the thickness of the basement membrane of the choriocapillaris and gold particle labeling by the antibodies to type IV collagen increased. The gold particle labeling by the antibodies to HSPG increased slightly, but was distributed sparsely. These results showed the advancing process of senescence changes in Bruch's membrane.
Aging↗
[A case report of rectal cancer with lymph node metastasis effectively treated by neoadjuvant chemotherapy of 5-FU oral and low-dose CDDP transarterial administration].
A 52-year-old man was diagnosed as having rectal cancer. Miles' operation with regional lymph node dissection was performed in April 1989. CT scanning and MRI examination performed in May 1992 showed local recurrence in a lymph node of the pelvic cavity (282). We implanted a catheter in the left internal iliac artery and connected it to an implanted injection port through a subcutaneous tunnel. 5-FU was administered orally at 300 mg daily. CDDP was injected through an injection port at a dose of 20 mg/body/day twelve times and 10 mg/body/day six times. CT scanning showed a change in the size of the tumor, with a reduction rate of 75%. Thereafter, we performed a radical operation in September 1992. The histopathological effect was Grade 2.
Administration, Oral↗
[A case of UIP with autoimmune hemolytic anemia].
A 70-year-old male was admitted because of cough and sputum. Chest X-ray showed bilateral interstitial shadows, and usual interstitial pneumonitis was diagnosed by TBLB and BAL. He was followed without medication. The dyspnea increased and the abnormal shadow spread on chest X-ray. Autoimmune hemolytic anemia was newly diagnosed because the RBC count was 195 x 10(4)/mm3, Hb was 8.6 g/dl, and direct Coombs test and warm antibody were positive. In this case, there appears to be a relationship between deterioration of interstitial pneumonia and the on-set of autoimmune hemolytic anemia.
Aged↗
[Proteoglycan in Bruch's membrane of senescence accelerated mouse: localization and age-related changes].
We demonstrated the distribution of sulfated proteoglycans in Bruch's membrane of Senescence Accelerated Mouse histochemically and ultrastructurally using cuprolinic blue in conjunction with specific enzyme treatments and nitrous acid digestion. Two kinds of proteoglycan filaments were observed in the inner and outer collagenous layers, i.e., small collagen fibril-associated filaments (11 nm in average length), and large filaments (32 nm in average length). Intermediate size filaments (25 nm in average length) were seen in the basement membranes of the retinal pigment epithelium and choriocapillaris. Chondroitinase AC treatment eliminated the staining of filaments in the collagenous layers (chondroitin sulfate). Chondroitinase ABC treatment also eliminated the staining of filaments in the collagenous layers (chondroitin sulfate and dermatan sulfate). Nitrous acid eliminated the staining of filaments in both basement membranes (heparan sulfate). Proteoglycans containing chondroitin sulfate and dermatan sulfate were associated uniquely with collagen fibrils. Heparan sulfate proteoglycans were associated with the basement membranes of the pigment epithelium and choriocapillaris. With aging, the thickness of the basement membrane of the choriocapillaris and the staining of the filaments in the basement membranes of the pigment epithelium and choriocapillaris (heparan sulfate proteoglycans) increased. Collagen fibers became disarranged and the staining of both filaments in the collagenous layers decreased. The results of the staining characteristics probably reflect the aging of Bruch's membrane.
Aging↗
Changes in fibrinolytic parameters in male patients with type 2 (non-insulin-dependent) diabetes mellitus.
We examined changes in fibrinolytic parameters in male patients with diabetes mellitus (DM) and controls. DM patients were divided into three groups: patients without retinopathy, patients with simple retinopathy, and patients with proliferative retinopathy. Plasma levels of t-PA (tissue plasminogen activator) and t-PA-PAI-1 (plasminogen activator inhibitor-1) complex increased with increase in age, but those of PAI-1 (total and free) did not change in controls. On the other hand plasma levels of PAI-1 decreased with increase in age in DM patients. Plasma levels of t-PA, t-PA-PAI-1 complex, free and total PAI-1 increased with increase in body mass index in controls, but no significant changes were shown in these parameters in DM patients. When compared with controls, plasma levels of t-PA, t-PA-PAI-1 complex and PAI-1 were lower in DM patients. Plasma levels of UK (urokinase) and Lp(a) were higher in DM patients. ELT (euglobulin clot lysis time) was significantly shorter in DM patients than in controls. Patients without retinopathy showed increased fibrinolytic activities compared with those with retinopathy due to the increased levels of t-PA in plasma. These results seem to indicate that blood vessels release larger amounts of t-PA at the early stage of DM, then release being impaired at its advance stage. It is also suggested that the regulatory control mechanisms of fibrinolytic activity associated with mechanisms of fibrinolytic activity associated with change in age and body mass index are different between patients with DM and normal people.
Adult↗
The potential role of platelet PAl-1 in t-PA mediated clot lysis of platelet rich plasma.
The potential role of platelets in platelet rich plasma clot lysis induced by tissue plasminogen activator (t-PA) was investigated. At the various concentrations of both single chain t-PA (sct-PA) and two chain t-PA (tct-PA) (1.5nM, 3nM, and 6nM), we compared the t-PA mediated lysis time of platelet rich plasma clot (PRP-clot) with that of platelet poor plasma clot (PPP-clot). At the concentrations ranged from 1.5 to 6 nM of both types of t-PA, the clot lysis time of PRP-clot was longer than that of PPP-clot. This elongation was more significant in the tct-PA induced clot lysis than that in the sct-PA induced clot lysis. At the concentration of 3nM of tct-PA, the lysis time of PRP-clot was longer by a factor of 30% in comparison with that of PPP-clot. When the release and the aggregation of platelets were blocked by prostaglandin E1 (PGE1) and theophylline in this experiment, the lysis time of PRP-clot was essentially the same as that of PPP-clot. We then measured the antigen levels of total PAI-1 and t-PA-PAI-1 complex in the lyzed solutions of PRP-clot and PPP-clot to analyse the possible effect of plasminogen activator inhibitor-1 (PAI-1) present in platelets. Most of PAI-1 in a PPP-clot lyzed sample existed as t-PA-PAI-1 complex. In the lyzed solution of PRP-clot, however, the antigen levels of both total PAI-1 and t-PA-PAI-1 complex were significantly higher than those in PPP-clot, and larger amounts of PAI-1 existed as free PAI-1 which possesses activity. These data suggest that at least certain amounts of PAI-1 in platelets exist as an active form and inhibits t-PA activity resulting in the prolongation of the clot lysis time. Activation of platelets, therefore, seems to play an important role in the platelet rich plasma clot lysis induced by t-PA.
Alprostadil↗
Identification of a regulatory region of integrin beta 1 subunit using activating and inhibiting antibodies.
Members of the beta 1 integrin subfamily recognize multiple ligands such as fibronectin, laminin, and collagen and mediate cell-cell and cell-extracellular matrix interactions. beta 1 subunit may play a central role in regulating beta 1 integrin avidity. Here we have identified a small region of beta 1 subunit (residues 207-218) that is critical for the binding of both activating (8A2, A1A5, and TS2/16) and inhibiting (4B4, 4B5, 13, AIIB2, and P4C10) monoclonal antibodies against human beta 1 using interspecies chimeric beta 1 and site-directed mutagenesis. Chicken beta 1 that has human sequence within residues 207-218 (CH mutant) is recognized by all the human specific antibodies listed above. The region 207-218 is located between the two putative ligand binding sites (residues 120-182 and 220-231), and the amino acid sequence of the region involves a predicted bend structure. The other anti-beta 1 antibodies that do not affect cell attachment to ligands (K20, 102DF5, LM442, and LM534) recognized the carboxyl-terminal regions of extracellular domain of beta 1 (residues 426-587 for K20 and 588-708 for 102DF5, LM442, and LM534, respectively). Our data suggest a potential mechanism for the avidity regulation of beta 1 integrin through conformational changes of beta 1 subunit.
Amino Acid Sequence↗
Particle spectrum in gluon jets produced in e+e- annihilations at sqrt s around 58 GeV.
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Journal Article↗
The function and distinctive regulation of the integrin VLA-3 in cell adhesion, spreading, and homotypic cell aggregation.
To assess directly the functional role of the integrin VLA-3 (alpha 3 beta 1), we transfected human alpha 3 cDNA into erythroleukemia (K562) cells and rhabdomyosarcoma (RD) cells. The resulting transfectants (KA3 and RA3) expressed alpha 3 beta 1 on the cell surface as confirmed using a panel of nine anti-alpha 3 monoclonal antibodies. Neither of the transfected cells exhibited increased adhesion to the extracellular matrix proteins fibronectin, laminin, and collagen. However, the KA3 transfectants did bind strongly to the extracellular matrix deposited by epidermal and carcinoma cell lines, allowing the cells to attach and spread. Binding to this cell-deposited ligand, probably containing epiligrin/kalinin, was specific to VLA-3 and could be inhibited by anti-alpha 3 antibodies and by EDTA, but not by RGD peptides. In marked contrast to other integrins (VLA-2 and VLA-4), VLA-3 showed high constitutive activity in K562 cells, but was minimally active in RD cells. Also contrasting with other beta 1 integrins, VLA-3 was minimally stimulated by the anti-beta 1 monoclonal antibody TS/216 under normal conditions. VLA-3-mediated adhesive function was well supported by either Mg2+ or Mn2+, but was almost completely abolished by the presence of 1 mM Ca2+. Surprisingly, this negative Ca2+ effect was completely overcome by the addition of the stimulatory anti-beta 1 monoclonal antibody TS2/16. Together, these results point to markedly distinct regulation for VLA-3 function compared to other beta 1 integrins. Also, all anti-VLA-3 antibodies were able to induce temperature-dependent homotypic cell aggregation of KA3 cells, but not K562 cells. However, this aggregation did not appear to be directly mediated by VLA-3 since it was not inhibited by EDTA. In addition, no enhancement of heterotypic cell-cell adhesion was observed in alpha 3-transfected cells.
Animals↗
The effect of MCI-9042 on serotonin-induced platelet aggregation in type 2 diabetes mellitus.
MCI-9042, a potent inhibitor of 5HT2 receptor, was used to examine its effects on serotonin induced-aggregation of platelets obtained from patients with type 2 diabetes mellitus (DM). The extent of platelet aggregation induced by serotonin increased in DM patients without retinopathy, but the increase was further significant in DM patients with retinopathy. MCI-9042 as well as ketanserin, inhibited significantly serotonin induced-aggregation of platelets obtained from DM patients with retinopathy. MCI-9042 dose dependently inhibited platelet aggregation induced by serotonin and collagen. These results suggest that serotonin which may be released from platelets of DM patients may activate platelets together with collagen exposed on atherosclerotic endothelium and that MCI-9042 may be inhibitory to enhanced platelet aggregability under these conditions.
Adult↗
Conformational change of plasminogen: effects of N-terminal peptides of Glu-plasminogen.
Seven peptides were synthesized to analyze the mechanism of the intramolecular binding of the N-terminal peptide of Glu-plasminogen (Glu-plg) to its kringles. They were Ala44-Lys50, Ala44-Glu51, Ala44-Ser49, Val17-Gly23, Lys19-Gly23, Lys19-Gln21 and Lys19-Lys20. Ala44-Lys50, Ala44-Glu51 and Lys19-Lys20.enhanced the activation of Glu-plg by tissue plasminogen activator (t-PA) or urinary plasminogen activator (u-PA). The activation of Lys-plg, however, was not influenced by these peptides. Therefore, it is suggested that these three peptides worked on Glu-plg in a similar manner as lysine analogue by making the conformation of Glu-plg looser. These peptides did not have any direct effects on u-PA and t-PA. Concerning the effect on fibrinolysis Ala44-Lys50 and Lys19-Lys20 prolonged euglobulin clot lysis time. These results indicate that Ala44-Glu51 may be a responsible binding site in the N-terminal portion of Glu-plg, and LBS of kringle 1 or 4 is the binding site of N-terminal portion of Glu-plg.
Amino Acid Sequence↗
Impaired fibrinolytic activity induced by ingestion of butter: effect of increased plasma lipids on the fibrinolytic activity.
To investigate the effects of the increased plasma lipid level on fibrinolysis, we measured the levels of fibrinolytic components in serially obtained plasma samples from healthy volunteers after the intake of different amounts of butter. Plasma triglyceride level increased significantly after butter intake compared to the control group. Eight hours after the intake of 100g of butter, plasminogen activator inhibitor 1 (PAI-1) level in plasma was significantly higher and euglobulin clot lysis time was significantly prolonged compared to those of the control group. There was no effect on plasma tissue plasminogen activator level. These results suggest that the temporary increase in plasma triglyceride level induced high PAI-1 level, resulting in impaired fibrinolytic activity. The effect of temporary hyperlipidemia on platelet function was also analyzed and revealed that the response of platelets to ADP and collagen was lower in the butter intake group compared to those of the control.
Adolescent↗
[Radiotherapy for vulvar cancer].
Fifteen patients who had primary vulvar cancer treated with radiotherapy as an initial treatment at Hyogo Medical Center for Adults and Hyogo Cancer Center from January 1971 to December 1990 are presented. Two patients were stage 0, one stage I, three stage II and nine stage III. Nine patients received electron irradiation with or without interstitial irradiation and intracavitary vaginal irradiation. Five patients received megavoltage X-ray irradiation using AP/PA parallel opposed fields including the pelvic nodes and perineum followed by boost irradiation of electrons, interstitial irradiation and intracavitary vaginal irradiation. The total dose delivered to the primary tumor ranged from 50 to 100 Gy (73 Gy on average). The actuarial 5-year survival rate of the patients was 43.6%. Complete regression (CR) was achieved in 60% of the patients. However, CR was not achieved in any of five patients with palpable inguinal nodes. In contrast, all the patients who had tumors of less than 2 cm in diameter achieved CR. Five of nine CR cases relapsed. First sites of failure were vagina, groin and vulvar region. Recurrence occurred more than four years after treatment in three cases. Necrosis occurred in five of nine CR cases.
Adult↗
Dissociation of alpha 2-plasmin-inhibitor-plasmin complex and regeneration of plasmin activity by SDS treatment.
In order to understand the mechanism for the complex between alpha 2-plasmin-inhibitor (alpha 2-PI) and plasmin to express its specific activity on fibrin autography after SDS-PAGE, we analyzed the effects of SDS on alpha 2-PI molecule and alpha 2-PI-plasmin complex. Treatment of alpha 2-PI by SDS at the concentrations of 0.01% and 0.1% abolished the activity of alpha 2-PI to form a stoichiometric complex with plasmin, whereas it did not interfere with plasmin's activity. More interestingly, in the case of 0.01% SDS, alpha 2-PI was further cleaved to a smaller molecule. Treatment of previously formed alpha 2-PI-plasmin complex by SDS at the concentrations of both 0.01% and 0.1% dissociated the complex and expressed specific amidolytic activity against tripeptide substrate (S-2251), which activity was totally quenched by aprotinin. When alpha 2-PI-plasmin complex was treated by higher concentration of SDS for 12 hours, dissociated free plasmin's band could be observed on SDS-PAGE analysis. It is likely, therefore, that the exposure of alpha 2-PI-plasmin complex to SDS during the procedure of SDS-PAGE dissociates the complex and expresses its specific proteolytic activity in fibrin autography. These features of alpha 2-PI and its complex with plasmin are similar to those of plasminogen activator inhibitor type 1 (PAI-1) and its complex with plasminogen activators (PAs), thus they may represent some common features of the SERPINS.
Antifibrinolytic Agents↗