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Biomedical subjects

S Hatta

Publications and source records attributed to S Hatta.

At least 73 records · Page 4Linked to original sources
PubMed1989

Melanogenic regulatory factors in coated vesicles from melanoma cells.

Coated vesicles have been found to contain much higher tyrosinase and gamma-glutamyl transpeptidase activities than premelanosomes. This indicates that similar to tyrosinase, gamma-glutamyl transpeptidase, an enzyme responsible for pheomelanogenesis, is highly concentrated in coated vesicles after its maturation in Golgi associated endoplasmic reticulum (GERL). Furthermore, in the pre- and post-dopaquinone melanogenic pathway, coated vesicles convert dopachrome to colorless indole compounds more quickly than in premelanosomes because of their higher dopachrome conversion factor activity. Melanosomes have been found to exhibit indole conversion factor activity, while coated vesicles show indole blocking factor activity. In moderately tyrosinase-rich premelanosomes, the levels of dopachrome conversion factor and indole blocking factor are lower than in coated vesicles or melanosomes. High levels of indole blocking factor in coated vesicles may indicate why melanin polymer formation does not occur there in vivo despite their high tyrosinase activity.

Coated Pits, Cell-Membrane↗
PubMed1989

Treatment of malignant melanoma by selective thermal neutron capture therapy using melanoma-seeking compound.

As pigment cells undergo melanoma genesis, accentuated melanogenesis concurrently occurs in principle. Subsequent to the understanding of intrinsic factors controlling both processes, we found our selective melanoma neutron capture therapy (NCT) using 10B-dopa (melanin substrate) analogue, 10B1-p-boronophenylalanine (10B1-BPA), followed by 10B(n, alpha)7Li reaction, induced by essentially harmless thermal neutrons, which releases energy of 2.33 MeV to 14 mu, the diameter of melanoma cells. In vitro/in vivo radiobiological analysis revealed the highly enhanced melanoma killing effect of 10B1-BPA. Chemical and prompt gamma ray spectrometry assays of 10B accumulated within melanoma cells after 10B1-BPA administration in vitro and in vivo show high affinity, e.g., 10B melanoma/blood ratio of 11.5. After successfully eradicating melanoma transplanted into hamsters with NCT, we advanced to preclinical studies using spontaneously occurring melanoma in Duroc pig skin. We cured three melanoma cases, 4.6 to 12 cm in diameter, by single neutron capture treatment. Complete disappearance of melanoma was obtained without substantial side effects. Acute and subacute toxicity as well as pharmacodynamics of 10B1-BPA have been studied in relation to therapeutic dosage requirements. Clinical radiation dosimetry using human phantom has been carried out. Further preclinical studies using human melanoma transplanted into nude mouse have been a useful model for obtaining optimal results for each melanoma type. We recently treated the first human melanoma patient with our NCT, using essentially the method for Duroc pig melanoma, and obtained similar regression time course leading to cure.

Animals↗
PubMed1988

Melanin monomers within coated vesicles and premelanosomes in melanin synthesizing cells.

We have found substantial amounts (6.6-143 and 0.5-13 micrograms/mg. protein, respectively) of 5,6-dihydroxyindole (5,6-DHI) and 5,6-dihydroxyindole-2-carboxylic acid (5,6-DHI2C), which are key intermediate monomers for the formation of the eumelanin polymer, within coated vesicle fraction of pigment cells. In addition, the amounts of these eumelanin monomers have been found to decrease along with the process of eumelanin polymer formation from coated vesicles to premelanosomes and finally to melanosomes among melanogenic subcellular compartments. Our present findings seem to indicate that coated vesicles transfer not only highly glycosylated T1-tyrosinase but also eumelanin monomers into premelanosomes.

Animals↗
PubMed1988

Induction of melanogenesis suppression: cellular pharmacology and mode of differential action.

Recent elucidation of regulatory mechanisms of eu- and pheomelanogenesis has led us towards an exciting new era of melanogenesis control. I will chiefly address our progress on inhibitory control of melanogenesis from the macromolecular level to human skin colour. In the past, the exploration and search for skin depigmenting agents has been focussed on and initiated from substances which can suppress isolated tyrosinase in vitro. Now, as I have classified below, many new melanogenic inhibitors have been discovered which, in spite of their non-suppressive effect on isolated naked tyrosinase, suppress melanin formation in the living pigment cell in vitro as well as in the natural world. I will also discuss a recently found unique disorder: unilateral suppression of mixed melanogenesis.

Animals↗
PubMed1987

Regulation of neuronal adenylate cyclase.

It appears that several components function in a spirit of integrated cooperation toward the intracellular regulation of neurotransmitter responsiveness. We have demonstrated that cytoskeletal proteins might interact with GNs and that GNs and GNi might interact with one another. At this juncture, it appears that both of these phenomena might occur only in cells of neural origin. Calmodulin and antidepressants may also affect adenylate cyclase in nervous tissue alone. The effects of AAGTP are different in nervous tissue from other tissues, and experiments with that nucleotide have led to the discovery of a new, 32 kDa GTP-binding protein which appears only in neural crest cells. Appreciation of the intricacies of signal transduction through the adenylate cyclase system are developing along with our understanding of that system. When combined with the complexity of neurotransmitter responsiveness, comprehension of the combined systems remains in its infancy, destined to grow as well as to surprise and delight all who are interested.

Adenylyl Cyclases↗
PubMed1986

Exchange of guanine nucleotide between GTP-binding proteins that regulate neuronal adenylate cyclase.

GTP-binding proteins have been demonstrated to stimulate and inhibit rat brain adenylate cyclase without the prior addition of hormone. Exposure of rat cerebral cortex membranes to hydrolysis-resistant GTP analogs results in inhibition (or stimulation) of adenylate cyclase, which persists subsequent to buffer washing. The hydrolysis-resistant GTP photoaffinity probe P3-(4-azidoanilido)-P1-5' GTP (AAGTP) can promote a similar persistent inhibition of adenylate cyclase, and, after removal of unbound AAGTP and subsequent UV photolysis, AAGTP is covalently linked to the 40-kDa inhibitory GTP binding protein, GNi (inhibitory guanine nucleotide binding regulatory subunit of adenylate cyclase). Under conditions where the persistent inhibition of adenylate cyclase is overcome by subsequent incubation with 5'-guanylyl imidodiphosphate or NaF, AAGTP bound to the 40-kDa GNi protein is diminished while that bound to the 42-kDa stimulatory GTP-binding protein (GNs) is increased. Additionally, we have identified a 32-kDa protein that binds AAGTP with an affinity similar to that of GNs. This protein does not appear to be a byproduct of proteolysis as demonstrated by Staphylococcus aureus V8 protease digestion experiments, and it is not a substrate for ADP-ribosylation by bacterial toxins. The sum of the AAGTP bound by the GNi and GNs proteins is constant, and the transfer of nonphotoactivated AAGTP to GNs from GNi is stable to buffer washing. Furthermore, this alteration in the AAGTP-labeling pattern corresponds to the shift in adenylate cyclase from inhibition to stimulation. These data raise the possibility that hydrolysis-resistant GTP analogs might be exchanged directly between the GNi and GNs and that there exists some interaction between those proteins in the regulation of adenylate cyclase activity.

Adenylyl Cyclase Inhibitors↗
PubMed1986

Effects of 8-(2-dimethylaminoethyl)-3-oxo-4-phenyl-1-thia-4,8-diazaspiro [4,5] decane dihydrochloride monohydrate (Y-8845) on carbon tetrachloride-induced liver injury.

The effects of 8-(2-dimethylaminoethyl)-3-oxo-4-phenyl-1-thia-4,8-diazaspiro [4, 5] decane dihydrochloride monohydrate (Y-8845) on carbon tetrachloride (CCl4)-induced liver injury were investigated in rats. CCl4-induced attenuation of the plasma cyclic AMP (cAMP) response to glucagon stimulation was significantly prevented by pretreatment with Y-8845. Y-8845 also effectively suppressed the increases in the activities of serum transaminases as well as the decreases in microsomal glucose-6-phosphatase activity and microsomal cytochrome P-450 concentrations induced by CCl4. In rats at 72 hr after CCl4 administration, the plasma cAMP response to glucagon, microsomal glucose-6-phosphatase activity and P-450 concentration were all below the control level. Y-8845 treatment after CCl4 administration rectified these reductions to nearly normal levels. Furthermore, Y-8845 stimulated DNA synthesis during liver regeneration after CCl4 intoxication. These results demonstrate that Y-8845 has a protective effect against CCl4-induced injury in the liver and a stimulating effect on the recovery of the damaged liver.

Alanine Transaminase↗
PubMed1985

Influence of plasma hormone levels on various stimulant-induced hepatic DNA synthesis in carbon tetrachloride-intoxicated rats.

The effects of insulin, glucagon, isoproterenol and carbachol on the regeneration of injured liver were investigated in rats treated with carbon tetrachloride (CCl4). These agents effectively potentiated hepatic DNA synthesis in rats both at 48 and at 72 hr after CCl4 intoxication. The maximal stimulatory effects of the agents on the synthesis coincided in time with the peak of elevation in basal DNA synthesis following the intoxication. Plasma levels of insulin and triiodothyronine were decreased before the elevation of basal DNA synthesis in CCl4-treated rats. The possible relationship of these changes in plasma hormones to the potentiated effects of the agents on DNA synthesis was examined in rats treated with streptozotocin (STZ) or methylthiouracil (MTU). The agents caused no potentiation in STZ-treated rats. On the other hand, in MTU-treated rats, isoproterenol and carbachol significantly stimulated DNA synthesis, but this was not the case with insulin and glucagon. These results suggest that the pancreatic hormonal, beta-adrenergic and cholinergic stimulations play positive roles in regulating liver regeneration after CCl4 intoxication. Furthermore, the hypothyroid state developed in CCl4-treated rats may provide favorable conditions for the stimulation of DNA synthesis by isoproterenol and carbachol. It is unlikely, however, that insulin deficiency contributes to potentiations in the regenerative responses of the injured liver.

Animals↗
PubMed1983

Increase in potassium release from rat parotid tissue repeatedly exposed to isoproterenol.

The effect of repeated exposure to isoproterenol (ISO) in parotid tissue was investigated with regards to potassium release in response to a successive challenge of alpha- and beta-adrenergic agonists. An increase in potassium release by epinephrine was potentiated in the parotid tissue from rats repeatedly administered ISO (3 mg/kg, three times daily for 3 days). On the other hand, a decrease in the release by ISO disappeared in ISO-pretreated glands. Cycloheximide and actinomycin D, administered with ISO, completely blocked the ISO-induced development of the enhanced response to epinephrine, but not that of the reduced response to ISO. After in vitro pretreatment with ISO, the potassium release induced by a successive dose of ISO was higher than the basal release of the electrolyte. The same treatment showed a tendency to increase the response to norepinephrine. The increased release induced by a challenge dose of ISO disappeared in the tissue from cycloheximide-treated rats. The ISO-induced increase of potassium release which was caused by ISO-pretreatment in vitro was inhibited by prazosin, but not by yohimbin and propranolol. These results suggest the possibility that the alpha-adrenergic response in parotid tissue might be potentiated by exposure to ISO.

Animals↗
PubMed1981

Stimulating effect of alpha-adrenoceptor agonists on isoproterenol-induced amylase release in rat parotid tissue.

Isoproterenol (ISO)-induced amylase release from rat parotid slices was increased by the addition of methoxamine to either a normal or a calcium (Ca)-free medium. The potentiating effect of methoxamine was completely blocked by the addition of phentolamine, irrespective of whether the slices were incubated in the normal or the Ca-free medium; and the effect also disappeared after prolonged preincubation (60 min) of the slices in the Ca-free medium. Both verapamil and procaine reduced methoxamine-induced amylase release, but only verapamil blocked the stimulating effect of methoxamine in the normal medium. ISO-induced accumulation of cyclic AMP in the slices was unaffected by methoxamine or phenylephrine. The results suggest a possibility that the potentiating effect of methoxamine on ISO-induced amylase release may be independent of the presence of extracellular Ca and the increased accumulation of cyclic AMP in the tissue is unnecessary.

Adrenergic alpha-Agonists↗
PubMed1981

Relationship of carbon tetrachloride-induced alterations of ligandin and Z protein to sulfobromophthalein transport in rat liver.

The relationship of the BSP retaining capacity of organic anion binding protein in the liver to the transport of BSP from plasma to bile was examined in CCl4-treated rats. These proteins were separated into ligandin and Z protein by Sephadex G-75 gel chromatography. The BSP retaining capacity of these proteins was significantly decreased by CCl4 administration (2.5 ml/kg, p.o.). At 3 hours after CCl4, this decreased capacity was caused mainly by the decrease in their binding affinity, at 24 hours after CCl4, however, it was accompanied by decreases in both their binding affinity and protein amounts. At 3 hours, the hepatic uptake of BSP evaluated by determination of plasma BSP concentration, the initial disappearance rate (K1), and the hepatic dye content did not differ from those in the controls, and biliary excretion of BSP was unchanged. At 24 hours, hepatic uptake and biliary excretion of BSP as well as bile flow were significantly decreased. From these results, it is suggested that the alteration in the retaining capacity of ligandin and Z protein would not be a determinant factor in the transfer of BSP from plasma to bile.

Animals↗