Search PubMed⌕ Search

Biomedical subjects

M Naoi

Publications and source records attributed to M Naoi.

At least 37 records · Page 2Linked to original sources
PubMed2001

[A case of hepatic metastasis of gastric cancer responding to TS-1, administered for two consecutive weeks and one week rest].

We have treated a case of hepatic metastasis of gastric cancer that has responded well to TS-1. The patient was a 68-year-old male, who underwent distal gastrectomy for gastric cancer. After surgery 5'-deoxy-5-fluorouridine (5'-DFUR) 800 mg/day was administered orally for two months. Grade 4 diarrhea appeared, so administration of 5'-DFUR was discontinued. Afterward the patient was followed with no chemotherapy. Liver metastasis (S6, 3 cm in diameter) was found at twelve months after surgery. 5'-DFUR (800 mg/day) was administered orally everyday. Grade 3 diarrhea appeared and metastasis showed NC after four weeks. 5'-DFUR administration was discontinued. Seventeen days later TS-1 (80 mg/day) was administered orally everyday for 2 weeks, followed by 1 week rest, as one course. Two courses of TS-1 administration resulted in a marked reduction of the liver metastasis, for a PR (75% reduction). After 3 courses, the liver metastasis showed CR. The patient is alive without recurrence after 12 courses. This TS-1 administration regimen was effective and tolerable for a patient with liver metastasis from gastric cancer.

Adenocarcinoma, Scirrhous↗
PubMed2000

Apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, in dopamine neurons.

A dopamine-derived neurotoxin, 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2, 3,4-tetrahydroisoquinoline [N-methyl(R)salsolinol] was found to cause parkinsonian in rats and to deplete selectively dopamine neurons in the substantia nigra after infusion in the striatum. This isoquinoline occurs enantio-specifically in the nigra-striatum of human brains. The biosynthesis from dopamine is catalyzed by two enzymes, (R)salsolinol synthase and (R)salsolinol N-methyltransferase. The isoquinoline increases in the cerebrospinal fluid from parkinsonian patients, and the increase is ascribed to high activity of its synthesizing neutral (R)salsolinol N-methyltransferase, as shown by analyses in lymphocytes. The cell death caused by this neurotoxin in dopaminergic human neuroblastoma SH-SY5Y cells proved to be apoptotic. Apoptosis by this neurotoxin is mediated by intracellular sequential process, loss of mitochondrial membrane potential, activation of caspases and DNA fragmentation. These results are discussed in relation to the role of apoptosis in neurodegenerative diseases and the involvement of the endogenous toxin in the pathogenesis of Parkinson's disease.

Animals↗
PubMed2000

Dopaminergic neurotoxins, 6,7-dihydroxy-1-(3', 4'-dihydroxybenzyl)-isoquinolines, cause different types of cell death in SH-SY5Y cells: apoptosis was induced by oxidized papaverolines and necrosis by reduced tetrahydropapaverolines.

Dopamine-derived 6,7-dihydroxy-1-(3', 4'-dihydroxybenzyl)-isoquinolines, papaverolines and tetrahydropapaverolines, have been proposed to be neurotoxin candidates related to the pathogenesis of Parkinson's disease. In this paper, the cytotoxicity of papaverolines and their N-methyl derivatives was examined using human dopaminergic neuroblastoma SH-SY5Y cells as a model of dopamine neurons. Apoptotic and necrotic cell death were assessed by morphological observation of cells after staining with propidium iodide and Hoechst 33342. Papaveroline and N-methyl-papaveroline induced apoptosis in almost all the cells with typical features of condensed and fragmented nuclei. On the other hand, (R)- and (S)-tetrahydropapaveroline caused necrosis in cells. Tetrahydropapaverolines markedly reduced adenosine triphosphate (ATP) level, whereas papaverolines did not, suggesting that the types of cell death induced by these isoquinolines, necrosis and apoptosis, depend on ATP concentrations in the cells.

Apoptosis↗
PubMed2000

Mechanism underlying anti-apoptotic activity of a (-)deprenyl-related propargylamine, rasagiline.

A potent inhibitor of type B monoamine oxidase, (-)deprenyl, is known to protect or rescue dying neurons, independent of inhibition of the enzyme activity. After long term administration to rodents, a propargylamine structurally related to (-)deprenyl, (R)(+)-N-propargyl-1-aminoindan (rasagiline) increased the activities of anti-oxidative enzymes, superoxide dismutase and catalase. Rasagiline protected in vitro dopamine cells from apoptosis induced by oxidative stress or neurotoxins. The mechanism of the anti-apoptotic effect was studied by in vitro experiments using human dopaminergic neuroblastoma, SH-SY5Y cells. Peroxynitrite-generating N-morpholino sydonimine (SIN-1) induced apoptosis in SH-SY5Y cells via disruption of mitochondrial membrane potential (DeltaPsim), followed by caspase 3 activation. Rasagiline prevented the loss of DeltaPsim, the initial step to apoptosis, and also following caspase 3-activation and DNA fragmentation. The results suggest that rasagiline may interact with the specific molecule in the mitochondria and suppress the death signal transduction. By the anti-apoptotic function, rasagiline may rescue or protect declining neurons in aging and neurodegenerative disorders, such as Parkinson's disease.

Animals↗
PubMed2000

Enhancing effect of rasagiline on superoxide dismutase and catalase activities in the dopaminergic system in the rat.

Rasagiline [N-propargyl-l(R)-aminoindan] is a selective irreversible MAO-B inhibitor as is (-)deprenyl. The effect of the drug on antioxidant enzyme activities on dopaminergic tissue was examined in male F-344 rats (8.5-months-old). Two experimental groups were infused subcutaneously with rasagiline saline solutions by means of osmotic minipumps implanted subcutaneously in the back of the rats. Control animals were also similarly implanted with saline filled mini-pumps. Three-and-one-half weeks later, animals were sacrificed and selected tissue samples removed from brain, kidney and heart. Two doses of rasagiline (0.5 mg/kg/day, 1.0 mg/kg/day, both for 3.5 weeks) significantly increased catalase activities about 2-fold in substantia nigra and striatum but not in hippocampus. Interestingly, in both renal cortex and medulla. catalase (CAT) activities were significantly increased. Both Mn- and Cu,Zn-superoxide dismutase (SOD) activities were increased 2 to 4 fold in substantia nigra, striatum and renal cortex and heart. Several groups, including our own have reported an extension of survival of deprenyl-treated animals of different species. Although the mechanism(s) of the life extension by deprenyl remains unresolved, it would be interesting to investigate the effect of rasagiline on the survival of animals, since deprenyl also was shown to increase antioxidant enzyme activities in brain dopaminergic regions.

Animals↗
PubMed2000

Enantio-selective occurrence of (S)-tetrahydropapaveroline in human brain.

Tetrahydropapaveroline is an endogenous complex alkaloid derived from dopamine through the oxidation by monoamine oxidase. This alkaloid is considered to be involved in the pathogenesis of alcoholism and to act as a false neurotransmitter. Recently the (S) enantiomer was proposed to be a precursor of morphine biosynthesis in the opium poppy. In this paper stereo-chemical characteristic of tetrahydropapaveroline in human brains was examined. In all four control human brains examined, only the (S)-tetrahydropapaveroline was detected. The concentrations were 0.12-0.22 pmol/g wet weight of brain tissue, and the presence of alcohol in blood did not affect the concentration. The results suggest that (S)-tetrahydropapaveroline may be enantio-selectively synthesized in human brain and it may be an intermediate of the de novo synthesis of morphine analogues.

Aged↗
PubMed2000

Involvement of endogenous N-methyl(R)salsolinol in Parkinson's disease: induction of apoptosis and protection by (-)deprenyl.

An endogenous dopamine-derived N-methyl(R)salsolinol has been suggested to be involved in the pathogenesis of Parkinson's disease. In Parkinson's disease, the level of N-methyl(R)salsolinol increased in cerebrospinal fluid and the high activity of a synthesizing enzyme, (R)salsolinol N-methyltransferase, was detected in lymphocytes. This isoquinoline induced apoptotic DNA damage in human dopaminergic neuroblastoma SH-SY5Y cells. Among catechol isoquinolines, only N-methylsalsolinol induced apoptosis in the cells, and the scavengers of hydroxyl radicals and antioxidants suppressed DNA damage, suggesting that reactive oxygen species initiate apoptosis. The isoquinoline activated caspase-3 like proteases and a caspase-3 inhibitor protected the cells from DNA damage. (-)Deprenyl, but neither clorgyline nor pargyline, prevented apoptotic cell death. The mechanism of the protection was due to stabilization of mitochondrial membrane potential reduced by the toxin. In Parkinson's disease apoptosis may be induced in dopamine neurons by this endogenous neurotoxin, and (-)deprenyl may protect them from apoptotic death process.

Apoptosis↗
PubMed2000

Neurotoxins induce apoptosis in dopamine neurons: protection by N-propargylamine-1(R)- and (S)-aminoindan, rasagiline and TV1022.

In Parkinson's disease, apoptosis was proposed to cause cell death in nigral dopamine neurons. An endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, stereo-selectively induced apoptosis in human neuroblastoma SH-SY5Y cells. In this paper the intracellular mechanism of apoptosis was studied using N-methyl(R)salsolinol, 6-hydroxydopamine and peroxynitrite as inducers of apoptosis. Apoptotic cascade was initiated by opening of mitochondrial permeability transition pore, as shown by collapse of mitochondrial membrane potential, deltapsim. Apoptosis was executed by caspase 3 activation, followed by DNA fragmentation, which was antagonized by overexpressed Bcl-2. Propargylamines were found to protect the cells from apoptosis, and rasagiline, a selective irreversible inhibitor of type B monoamine oxidase was the most potent to prevent the cell death. Rasagiline preserved deltapsim, which was proved also in isolated mitochondria, and rasagiline completely suppressed the activation of caspases and DNA fragmentation. These results suggest that mitochondria regulate apoptotic process, which may be a target of neuroprotection by rasagiline.

Apoptosis↗
PubMed2000

[Studies on endogenous toxins as pathogenic factors in idiopathic parkinson's disease].

The etiology of idiopathic Parkinson's disease remains as an enigma. N-Methyl (R)salsolinol [NM (R) Sal] is a candidate of dopaminergic neurotoxins, and is synthesized from dopamine by 2 enzymes: (R) Salsolinol synthase and a neutral (R) Salsolinol N-methyltransferase (nNMT). NM (R) Sal injection in the rat striatum caused selective depletion of dopamine neurons in the substantia nigra without tissue reaction, suggesting NM (R) Sal induced apoptosis in dopamine neurons. NM (R) Sal level was found to increase significantly in the cerebrospinal fluid of parkinsonian patients, and NM (R) Sal accumulated in the nigrostriatum. By the analysis of the human brain, it was suggested nNMT is the rate-limiting step to synthesize dopamine-derived neurotoxins. The activity of nNMT was found to increase in the lymphocytes from parkinsonian patients. The mechanism of toxicity by NM (R) Sal was studied in vitro using human dopaminergic neuroblastoma SH-SY5Y cells. NM (R) Sal induced apoptosis stereo-specifically, suggesting that a molecule in mitochondria can distinguish the stereo-chemical structure of NM (R) Sal and activate intracellular signal of apoptosis. Recently, we found that propargylamines, inhibitors of type B monoamine oxidase, can prevent the apoptosis induced by NM (R) Sal. Further study on the mechanism underlying increase in nNMT activity in parkinsonian patients will clarify the involvement of genetic and environmental factors in the pathogenesis of Parkinson's disease.

Aging↗
PubMed2000

N-methyl(R)salsolinol and a neutral N-methyltransferase as pathogenic factors in Parkinson's disease.

The pathogenesis of Parkinson's disease is still an enigma. As an endogenous MPTP-like neurotoxin, N-methyl(R)salsolinol was proved to induce parkinsonism in rats and apoptosis in dopaminergic neurons. It is synthesized in the human brain by two enzymes; an (R)salsolinol synthase and an N-methyltransferase, and accumulates in the nigro-striatum in human brains. The activity of a neutral N-methyltransferase in the striatum was found to determine the level of MPP+-like 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion, an oxidation product of N-methyl(R)salsolinol in the substantia nigra. The activity of this N-methyltransferase was found to increase significantly in lymphocytes prepared from parkinsonian patients. In cerebrospinal fluid from untreated parkinsonian patients, N-methyl(R)-salsolinol increases significantly. These results suggest that N-methyl(R)salsolinol and a neutral N-methyltransferase may be endogenous factors in the pathogenesis of Parkinson's disease.

Aged↗
PubMed2000

Anti-apoptotic function of L-(-)deprenyl (Selegiline) and related compounds.

(-)Deprenyl has been proposed to be neuroprotective to dopamine neurons in the parkinsonian brains. To clarify the mechanism, the effects of (-)deprenyl and structurally related compounds on apoptosis induced by a neurotoxin, N-methyl(R)-salsolinol, and reactive oxygen species, nitric oxide and peroxynitrite, were examined in dopaminergic SH-SY5Y cells. DNA damage was quantified by the single cell gel electrophoresis (comet) assay. (-)-Deprenyl protected the cells from apoptosis in a dose-dependent way, which required pre-treatment at least for 20 min. The effect was confirmed even after washing out of (-)deprenyl, indicating that (-)-deprenyl initiates the intracellular process to antagonize the apoptotic death program. The studies on the structure-activity relationship reveal that N-propargyl residue with hydrophobic structure is essential for the anti-apoptotic function. These results suggest that (-)deprenyl and related compounds may be applicable as neuroprotective agents in neurodegenerative diseases.

Antioxidants↗
PubMed1999

Mitogen-activated protein kinase pathway mediates peroxynitrite-induced apoptosis in human dopaminergic neuroblastoma SH-SY5Y cells.

Peroxynitrite, a product of nitric oxide and superoxide, is one of the most potent oxidants and it has been suggested to be involved in many neurodegenerative disorders. The mechanism of the cytotoxicity by peroxynitrite was examined using 3-morpholinosydonimine (SIN-1) as a peroxynitrite donor and SH-SY5Y cells as a model of dopamine neurons. SIN-1 was found to induce apoptotic cell death with typical nucleosomal DNA fragmentation with activation of caspase 3-like proteases. The signal transduction of apoptosis was studied in concern to mitogen-activated protein kinases (MAPKs). After SIN-1 treatment, phosphorylation of p38 was detected, followed by that of Erk. SB202190, an inhibitor of p38, suppressed Erk phosphorylation to the basal level and partially reduced the activation of caspase 3-like proteases and also the cell death. These results suggest that peroxynitrite may activate p38 MAPK pathway to induce apoptosis in dopamine cells via activation of caspase 3-like proteases.

Antioxidants↗
PubMed1999

Apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, is mediated by activation of caspase 3.

An endogenous neurotoxin, N-methyl(R)salsolinol, has been proved to be involved in the pathogenesis of Parkinson's disease. Increased level of N-methyl(R)salsolinol in the cerebrospinal fluid and high activity of its synthesizing (R)salsolinol N-methyltransferase in lymphocytes were confirmed in the majority of parkinsonian patients. Recently this neurotoxin was found to induce apoptosis in human dopaminergic neuroblastoma SH-SY5Y cells. In this study, we tried to elucidate the intracellular mechanism of apoptosis induced by N-methyl(R)salsolinol, and proved activation of caspase 3 after incubation with this toxin by Western blot analysis. Further, a caspase 3 inhibitor, acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspartic aldehyde, prevented the nucleosomal DNA fragmentation completely. These results demonstrate that caspase 3 mediates apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, which may cause apoptotic cell death of dopamine neurons in Parkinson's disease.

Apoptosis↗
PubMed1999

An endogenous MPTP-like dopaminergic neurotoxin, N-methyl(R)salsolinol, in the cerebrospinal fluid decreases with progression of Parkinson's disease.

There have been an increasing number of evidences indicating that dopamine-derived N-methyl(R)salsolinol is an endogenous MPTP-like neurotoxin to cause Parkinson's disease. In the cerebrospinal fluid from newly diagnosed untreated patients with Parkinson's disease, the level of this toxin was found to increase significantly, compared to control and a disease control, multiple system atrophy. The effects of the disease duration and the medication on the level of N-methyl(R)salsolinol were studied from the same patients. After about a 2-year period, the level was significantly reduced. The depletion of dopamine neurons by the disease progression may account for the reduction of the neurotoxin level, whereas L-DOPA therapy did not seem to affect the level of this toxin, even though the enhanced dopamine turnover. The results suggest that N-methyl(R)salsolinol level in the cerebrospinal fluid may indicate remaining dopamine neurons in the parkinsonian brain.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Cell death of dopamine neurons in aging and Parkinson's disease.

Dopamine neurons in the substantia nigra of human brain are selectively vulnerable and the number decline by aging at 5-10% per decade. Enzymatic and non-enzymatic oxidation of dopamine generates reactive oxygen species, which induces apoptotic cell death in dopamine neurons. Parkinson's disease (PD) is also caused by selective cell death of dopamine neurons in this brain region. The pathogenesis of Parkinson's disease remains to be an enigma, but it was found that an endogenous MPTP-like neurotoxin, 1(R), 2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [N-methyl(R)salsolinol, NM(R)Sal], may be one of the pathogenic agents of PD. NM(R)Sal increases in cerebrospinal fluid from untreated parkinsonian patients, and two enzymes, a (R)salsolinol synthase and a neutral N-methyltransferase, synthesize this neurotoxin in the nigro-striatum. The activity of a neutral N-methyltransferase is significantly higher in lymphocytes from parkinsonian patients than in control. The mechanism of cell death by this toxin was proved to be by the induction of apoptosis, by use of dopaminergic SH-SY5Y cells. The apoptosis was suppressed by anti-oxidants, suggesting that the generation of reactive oxygen species may initiate cellular death process. These results indicate that in aging and PD oxidative stress induces degeneration of dopamine neurons, and the antioxidant therapy may delay the decline of dopamine neurons in the brain.

Adult↗
PubMed1999

Neuroprotection by (-)-deprenyl and related compounds.

There is an increasing number of data by in vitro and in vivo experiments, indicating that (-)-deprenyl is neuroprotective to dopamine neurons, even though detailed mechanism remains to be clarified. In this paper neuroprotection by (-)-deprenyl and structurally related compounds was examined in concern with the suppression of apoptosis induced by a reactive oxygen species, peroxynitrite generated from SIN-1. The apoptotic DNA damage was quantitatively determined using dopaminergic SH-SYSY cells and by a single cell gel electrophoresis (comet) assay. DNA damage induced by peroxynitrite was proved to be apoptotic by prevention of the damage by cycloheximide or actinomycin-D. (-)-Deprenyl and other propargylamines protected the cells from apoptosis in a dose-dependent way. (-)-Deprenyl protected the cells even after it was washed out, suggesting that it may initiate the intracellular process to repress the apoptotic death program. The study on the structure-activity relationship of (-)-deprenyl analogues revealed that a N-propargyl residue with adequate size of hydrophobic structure is essentially required for the anti-apoptotic activity. These results suggest that (-)-deprenyl and related compounds may protect neurons from apoptosis and be applicable to delay the deterioration of neurons during advancing ageing and in neurodegenerative disorders.

Aging↗
PubMed1998

Immunohistochemical detection of dityrosine in lipofuscin pigments in the aged human brain.

Lipofuscin is a yellowish brown fluorescent pigment which is sequestered within cytoplasmic granules during aging. To examine the contribution of protein oxidation to lipofuscin accumulation, we performed immunohistochemical detection of dityrosine, which is considered one of the specific markers for protein oxidation, in lipofuscin in the aged human brain using an antibody specific to dityrosine. By characterization using competitive enzyme-linked immunosorbent assay, the specificity of the antibody to dityrosine was confirmed. None of the other tyrosine-related compounds such as L-tyrosine, 3-nitrotyrosine, 3-chlorotyrosine, or 3,4-dihydroxyphenylalanine cross-reacted with the antibody. The anti-dityrosine antibody reacted with lipofuscin granules in the pyramidal neurons of the aged human brain. The results suggest that protein oxidation by free radicals and/or peroxidases may play an important role in lipofuscin accumulation.

Aged↗