Effects of aniracetam, a nootropic drug, in senile dementia--a preliminary report.
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Biomedical subjects
Publications and source records attributed to I Kato.
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Augmentation of antitumor activity of Lactobacillus casei YIT 9018 (LC 9018), which strongly inhibits the growth of transplantable allogeneic and syngeneic mouse tumors, in combination with antitumor drugs was investigated. Antitumor drugs used in this study were cyclophosphamide (CY), mitomycin C (MMC), 5-fluorouracil (5-FU) and bleomycin (BLM). The antitumor activity of LC 9018 was augmented by combining 5-FU, MMC or BLM against subcutaneously implanted Meth A and BLM, 5-FU or CY against subcutaneously implanted Sarcoma 180 respectively. Furthermore, combinations with BLM, CY, MMC or 5-FU, BLM, CY, MMC significantly inhibited the growth of intraperitoneally inoculated Meth A or Sarcoma 180, respectively. The combination therapy of LC 9018 with CY significantly prolonged the life span of L 1210-inoculated mouse, while the treatment with LC 9018 alone had no inhibitory effect on L 1210. It was suggested that augmentation of antitumor activity of LC 9018 in combination with CY was due to the inhibition of decrease in the number of peritoneal exudate cells caused by CY injection.
Antitumor activity of Lactobacillus casei YIT 9018 ( LC9018 ) was studied in BALB/c mice by using two syngeneic tumors; methylcholanthrene-induced tumor (Meth A fibrosarcoma) and Kirstein murine sarcoma virus-transformed BALB/3T3 ( K234 tumor). Administration of an LC9018 -Meth A cell mixture induced complete suppression of the tumor growth, while simultaneous injections of LC9018 and Meth A cells into different sites had no suppressive effect on the tumor growth. Administration of the mixture subsequently induced specific transplantation immunity to the challenge tumor, which started to be generated on about the 5th day after the administration and continued to at least the 30th day. Administration of an LC9018 - K234 cell mixture also induced suppression of the tumor growth and generated specific antitumor immunity. Neutralization (Winn type) tests showed that T lymphocytes possessed tumor cytotoxicity but humoral immune serum did not, suggesting that the T cells with LC9018 -potentiated antitumor immunity functioned in the suppression of the tumor growth.
Antitumor activity of lactobacilli on Sarcoma 180 was investigated and was shown to be different from strain to strain. In general, Lactobacillus casei had higher antitumor activity compared with other species of lactobacilli. Among these, L. casei YIT 9018 (LC 9018) had significant antitumor activity against Meth A fibrosarcoma when administered into BALB/c mice intravenously, intraperitoneally, subcutaneously, intratumorally or orally. LC 9018 showed antitumor activity against rat ascites hepatoma by intravenous or oral administration, but this activity was lower than that against Meth A in mice.
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The time course experiments of 32Pi-labelling and breakdown of phospholipids in rabbit leukocytes exposed to leukocidin from Pseudomonas aeruginosa suggested that the initial action of this toxin was to stimulate phosphatidic acid production, presumably by causing a rapid metabolic change of phosphatidylinositol (PI response) correlating with phosphatidylinositol-specific phospholipase C and 1,2-diacylglycerol kinase. It appears that a rapid formation of phosphatidic acid and degradation of polyphosphoinositides in leukocytes treated with the toxin might be related a Ca2+-movement from extra- and intracellular spaces, resulting in the activation of Ca2+-dependent enzymes involved in the leukocidic process.
A leukocidin was isolated and purified from autolysates of Pseudomonas aeruginosa strain 158 by a combination of procedures such as column chromatography on DEAE-Sephadex A-50, gel filtration on Sephadex G-100, and zone electrophoresis on pevikon. The purified preparation showed a single band in each experiment using electrophoreses in the presence or absence of sodium dodecyl sulfate (SDS), and the agar-gel Ouchterlony immunodiffusion test. The purified pseudomonal leukocidin was crystallized by salting out with saturated ammonium sulfate at pH 7.0 in a needle-leaf like form. The molecular weight of the leukocidin was estimated to be 42,500 by SDS-polyacrylamide gel electrophoresis, 40,000 by gel filtration, and 44,700 (3.3 S20,W) by sucrose density gradient centrifugation. The isoelectric point of the leukocidin was estimated to be at pH 6.3 by isoelectrofocusing. Morphological studies of a leukocidin-treated leukocyte showed that the formation of vacuoles of cytosolic granules and the swelling of the lobulated nuclei occurred prior to leukocyte enlargement. In a slide adhesion test with rabbit polymorphonuclear leukocytes (1 X 10(6], the minimum cytotoxic dose for the destruction of all leukocytes was 13-20 ng of the crystallized toxin. Rabbit lymphocytes were one-thirtieth as sensitive as rabbit leukocytes. Leukocidin did not act on rabbit erythrocytes or on platelets.
Effects of Lactobacillus casei YIT 9018 (LC 9018), which has antitumor activities against allogeneic and syngeneic murine tumors, on macrophage functions were examined. By intraperitoneal (i.p.) injection of LC 9018, acid phosphatase activity and phagocytic activity of peritoneal macrophages were enhanced significantly compared with those of normal peritoneal macrophages. The phagocytic activities showed peaks 2-3 days after the LC 9018-injection. LC 9018 accelerated the phagocytic function of the reticuloendotherial system in ICR mice tested by the carbon clearance test. The cytostatic activity of peritoneal exudate cells (PEC) induced by i.p. injection of LC 9018 into C57BL/6 mice against EL4 cells was also enhanced. On the other hand, PEC induced by L. fermentum YIT 0159, which has no antitumor activity, did not have cytostatic activity. These observations showed that LC 9018 was able to activate macrophages in mice.
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Peaks corresponding to the C6 protons of the four histidine residues (positions 58, 111, 123, and 182) of chicken ovomucoid have been assigned in 1H NMR spectra (360 or 470 MHz) of the native single-chain protein and of fragments of the protein corresponding to its three homologous structural domains. Comparison of the 1H NMR pH titration behavior of these histidine residues and the deuterium exchange rates of their C6-H positions show the following: (1) The chemical shift properties of histidine residues 58, 123, and 182 differ despite the fact that the three residues are located in homologous positions in the three tandem domains. (2) The properties of three of the four histidine residues (58, 111, and 123) do not change appreciably when the domains in which they are located are isolated, indicating that their environments are similar in both the fragment and the native protein. (3) The properties of the fourth histidine (182) differ in the isolated domain and in the native protein. (4) The observed properties of the histidine residues stem primarily from intradomain interactions that remain constant in isolated domains rather than from interactions with neighboring domains; an interdomain interaction is required to explain the behavior of only histidine-182. (5) The chemical shift of histidine-111 is affected by the titration of the side chain of aspartate-98 with pHmid 2.6 in native ovomucoid but not in isolated second domain; the chemical shift of histidine-182 is perturbed by the titration of the carboxyl group of the C-terminal cysteine-186 with pHmid 2.4 in native ovomucoid and pHmid 2.6 in isolated third domain.
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