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Biomedical subjects

M Mihara

Publications and source records attributed to M Mihara.

At least 73 records · Page 4Linked to original sources
PubMed1998

Alterations with aging and ischemia in nicotinic acetylcholine receptor subunits alpha4 and beta2 messenger RNA expression in postmortem human putamen. Implications for susceptibility to parkinsonism.

Nicotine activates the dopaminergic system and acts to alleviate hypokinetic disorders (parkinsonism). The frequency of parkinsonism increases with age and is sometimes associated with multiple small infarcts (status lacunaris) in the putamen. To investigate changes with aging in control cases free from neurological disease and changes in cases with multiple small infarcts (status lacunaris) in the putamen, the present study determined nicotinic acetylcholine receptor (nAChR) subunit alpha4 and beta2 messenger RNA (mRNA) expression in the postmortem human putamen using the reverse transcription-polymerase chain reaction (RT-PCR). In controls, alpha4 subunit mRNA expression was unaltered, but beta2 subunit mRNA expression decreased significantly with age. In cases with status lacunaris, both beta2 and alpha4 subunit mRNA expressions were significantly lower than in the control cases. The reduction in beta2 mRNA expression alone, or in both alpha4 and beta2 mRNA expressions, suggests a reduction in functional nAChRs in the putamen, which may in part explain the susceptibility to hypokinetic disorders of the elderly and subjects with ischemic damage in the striatum.

Adult↗
PubMed1998

Age-related changes in nicotinic acetylcholine receptor subunits alpha4 and beta2 messenger RNA expression in postmortem human frontal cortex and hippocampus.

Age-related changes in nicotinic acetylcholine receptor (nAChR) subunit alpha4 and beta2 messenger RNA (mRNA) expression in the postmortem human frontal cortex and hippocampus was investigated using the reverse transcription-polymerase chain reaction (RT-PCR). In the frontal cortex, both alpha4 and beta2 subunit mRNA expression decreased with age. In the hippocampus, alpha4 subunit mRNA expression was unaltered, while beta2 subunit mRNA expression significantly decreased with age. These findings suggest that nAChR transcription decreases during aging with differing vulnerability between subunits and brain regions, which could in part contribute to the reduction in cognitive functions seen in the elderly.

Adult↗
PubMed1998

Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1.

NF-kappaB is activated by various stimuli including inflammatory cytokines and stresses. A key step in the activation of NF-kappaB is the phosphorylation of its inhibitors, IkappaBs, by an IkappaB kinase (IKK) complex. Recently, two closely related kinases, designated IKKalpha and IKKbeta, have been identified to be the components of the IKK complex that phosphorylate critical serine residues of IkappaBs for degradation. A previously identified NF-kappaB-inducing kinase (NIK), which mediates NF-kappaB activation by TNFalpha and IL-1, has been demonstrated to activate IKKalpha. Previous studies showed that mitogen-activated protein kinase/ERK kinase kinase-1 (MEKK1), which constitutes the c-Jun N-terminal kinase/stress-activated protein kinase pathway, also activates NF-kappaB by an undefined mechanism. Here, we show that overexpression of MEKK1 preferentially stimulates the kinase activity of IKKbeta, which resulted in phosphorylation of IkappaBs. Moreover, a catalytically inactive mutant of IKKbeta blocked the MEKK1-induced NF-kappaB activation. By contrast, overexpression of NIK stimulates kinase activities of both IKKalpha and IKKbeta comparably, suggesting a qualitative difference between NIK- and MEKK1-mediated NF-kappaB activation pathways. Collectively, these results indicate that NIK and MEKK1 independently activate the IKK complex and that the kinase activities of IKKalpha and IKKbeta are differentially regulated by two upstream kinases, NIK and MEKK1, which are responsive to distinct stimuli.

Amino Acid Sequence↗
PubMed1998

cDNA cloning, expression, subcellular localization, and chromosomal assignment of mammalian aurora homologues, aurora-related kinase (ARK) 1 and 2.

Chromosomal segregation during mitosis as well as meiosis is considered to be regulated by multiple kinases, but the precise mechanism remains largely unknown. A mutation in Drosophila, designated aurora, was identified as a responsible gene for a chromosomal segregation defect and encodes a putative serine-threonine kinase. Here we have identified mammalian aurora homologues, designated aurora-related kinase (ARK) 1 and ARK2. Kinase domains of murine ARK1 and ARK2 showed 61 and 62% identity, respectively, to that of aurora at the amino acid levels, respectively. Cell cycle analysis revealed that the expression of ARK1 was correlated with G2/M phase, while ARK2 was expressed during S and G2/M phases. Immunofluorescence analysis demonstrated that ARK2 was mainly localized to the midbody, while ARK1 has been reported to be localized to the spindle pole during mitosis. Collectively, these results suggest that these two kinases may have distinct roles with different expression timing and subcellular localization during the cell cycle progression. Interspecific backcross mapping revealed that Ark1 is located in a distal region of mouse chromosome 2, while Ark2 is located in a central region of mouse chromosome 11.

3T3 Cells↗
PubMed1998

Age-related changes in D1 and D2 receptor mRNA expression in postmortem human putamen with and without multiple small infarcts.

Expression of messenger RNAs (mRNAs) encoding the D1 and D2 dopamine receptors as a function of age was determined in the human putamen using the reverse transcription-polymerase chain reaction (RT-PCR). In cases without multiple small infarcts (status lacunaris) in the putamen, D1 mRNA expression was unaltered, while D2 mRNA expression significantly decreased with age. Both D1 and D2 mRNA expression was lower in cases with status lacunaris. The reduction in D1 receptors primarily located on striatonigral neurons or D2 receptors primarily located on striatopallidal neurons may inhibit thalamocortical neurons. The decreased transcription of D1 and D2 receptor genes may in part account for increased susceptibility to hypokinetic disorders in the elderly.

Actins↗
PubMed1998

Familial amyloid polyneuropathy related to transthyretin mutation Val30 to Leu in a Japanese family.

A rare variant transthyretin that has a leucine-for-valine substitution at position 30 was reported in a sporadic case of type 1 familial amyloid polyneuropathy (FAP). We found the same substitution in members of a Japanese family with FAP. Three individuals in this family had a guanine-to-cytosine mutation at the first base of codon 30 in exon 2. This family shows a direct link between a valine-to-leucine substitution at position 30 and type 1 FAP.

Amino Acid Substitution↗
PubMed1998

Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis.

OBJECTIVE: To clarify the role of interleukin-6 (IL-6) in the pathogenesis of collagen-induced arthritis (CIA). METHODS: CIA was induced by immunizing twice at a 3-week interval with bovine type II collagen (CII) emulsified with complete adjuvant. Rat anti-mouse IL-6 receptor (anti-IL-6R) monoclonal antibody MR16-1 or isotype-matched control antibody KH-5 was then injected once intraperitoneally. Symptoms of arthritis were evaluated with a visual scoring system, and serum anti-CII antibody and IL-6 levels were measured by enzyme-linked immunosorbent assay. In addition, the CII responsiveness of splenic lymphocytes from mice with CIA was examined. RESULTS: In mice with CIA, excess production of IL-6 in sera was observed within 24 hours after the first CII immunization, and then rapidly decreased. Serum IL-6 increased again beginning 14 days after immunization, in conjunction with the onset of arthritis. When MR16-1 was injected immediately after immunization with CII, it inhibited the development of arthritis in a dose-dependent manner. Furthermore, MR16-1-treated mice exhibited lower serum levels of IgG anti-CII antibody and reduced responsiveness of lymphocytes to CII. This suppressive effect was observed when MR16-1 was injected on day 0 or 3, but not when injected on day 7 or 14. CONCLUSION: IL-6 produced after CII immunization appears to play an essential role in the immunity to CII, and anti-IL-6R antibody reduces the development of CIA by suppressing IL-6 signal transduction.

Animals↗
PubMed1998

A novel non-polyglutamable anti-folate, MX-68, inhibits the induction of experimental autoimmune uveitis in rats.

MX-68 is a novel antifolate which is chemically designed not to undergo intracellular polyglutamation thus preventing the development of adverse effects. The present study was carried out to examine both the in vitro and in vivo effects of MX-68 on experimental autoimmune uveitis (EAU) and to compare its effect on collagen-induced arthritis (CIA) in rats. EAU was induced by injecting Lewis rats with retinal S-antigen in complete Freund's adjuvant. Either MX-68 or methotrexate (MTX), which forms several polyglutamates intracellularly, was orally administered five days a week for three weeks beginning on the day of immunization. In vivo, both MX-68 and MTX significantly delayed the onset of EAU and inhibited the antibody response to S-antigen in a dose-dependent manner. High dose MX-68 (2.5 mg kg-1 day-1) completely abrogated the induction of EAU. No adverse effects were observed in either MX-68- or MTX-treated rats. However, the cessation of MX-68 administration after a period of three weeks resulted in the induction of EAU. In contrast, both MX-68 and MTX suppressed the severity of CIA without affecting the onset of the disease and inhibited anti-collagen antibody production in a dose-dependent fashion. Discontinuation of the drugs did not result in the recurrence of CIA. In vitro, both MX-68 and MTX significantly suppressed the proliferation of S-antigen- and Con A-stimulated lymph node cells obtained from immunized rats in a dose-dependent fashion. These data suggest that MX-68 may be useful for the treatment of autoimmune diseases including EAU and that the pathophysiology of EAU could be different from that of CIA.

2-Aminoadipic Acid↗
PubMed1998

Cutaneous nerves in atopic dermatitis. A histological, immunohistochemical and electron microscopic study.

Although pruritus is the cardinal symptom of atopic dermatitis, its mechanism is not well understood. Free nerve endings in the skin are involved in pruritus as itching receptors. We studied the cutaneous nerve fibres in lichenified lesions of 16 patients with adult atopic dermatitis. On immunohistochemistry, fibres immunoreactive for neurofilament, neuron-specific enolase, and protein gene product 9.5 were observed in the papillary dermis and dermoepidermal junctions as well as in the epidermis. In these areas, no fibres stained positively for substance P, neuropeptide Y, vasoactive intestinal peptide, beta endorphin, somatostatin or serotonin. On electron microscopy, the ultrastructure of subepidermal and intraepidermal free nerve endings appeared to be essentially normal. However, the distribution density of the cutaneous nerve fibres was much higher than in normal controls, and the diameter of these fibres was much larger, because of the large number of axons in each nerve fibre. Degranulation of mast cells was not seen. These findings suggest that pruritus in lichenified atopic skin is probably not caused by damage to the cutaneous free nerve endings. In such lesions, the number of the cutaneous free nerve endings is greatly increased, but they may have a normal function.

Adolescent↗
PubMed1998

Nodular localized cutaneous amyloidosis: further demonstration of monoclonality of infiltrating plasma cells in four additional Japanese patients.

Nodular localized cutaneous amyloidosis (NLCA) is a disorder characterized by deposition of amyloid derived from immunoglobulin light chains. We used semi-nested polymerase chain reaction (PCR) to analyse archival paraffin-embedded sections from a previous patient and from four additional, previously reported patients with NLCA to determine whether involvement of monoclonal plasma cells is a universal feature of this condition. The semi-nested PCR analysis revealed one or two amplified bands, around 100-120 bp, for all five cases of NLCA, although the yields varied from case to case. These results suggest that clonal expansion of plasma cells in NLCA may occur locally.

Adult↗
PubMed1998

Cutaneous presentation of nasal/nasal type T/NK cell lymphoma: clinicopathological findings of four cases.

Epstein-Barr virus (EBV)-associated T/natural killer (NK) cell lymphoma mainly shows nasal lesions, and has recently been shown to be associated with cutaneous T-cell lymphoma (CTCL). The detailed features of CTCL nasal metastasis have yet to be elucidated. We report clinicopathological findings for four cases of cutaneous T/NK cell lymphoma with metastasis to the nose. The four patients presented progressive involvement of nasal lesions of CTCL, an aggressive course and poor outcome. Their pathological and immunohistological findings were consistent with peripheral T/NK cell neoplasm and, in three of four cases, EBER-1 were apparently detected in lymphoma cells by in situ hybridization, and two of four cases were also positive for TIA-1. The polymerase chain reaction (PCR) results showed the identical band from the skin and nasal lesions of the two patients. We also reviewed the cases of similar clinical course and attempted to elucidate clinical, pathological, immunological and genotypic features. The 10 reported cutaneous T/NK cell lymphomas with nasal metastasis revealed a poor prognosis (nine of 10 died at 3-108 months). Six cases of nine showed a positive reaction to EBV, and six cases revealed T-cell receptor beta or -gamma rearrangement. These findings suggest that most cutaneous T/NK cell lymphoma with nasal metastasis are similar to nasal T-cell lymphoma associated with EBV infection. This type of cutaneous T/NK cell lymphoma likely to involve nasal lesions and skin cases seemed to have a poor prognosis.

Adult↗
PubMed1998

IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice.

In the present study, we examined the preventive effect of anti-mouse IL-6 receptor (IL-6R) antibody, MR16-1, on the development of autoimmune kidney disease in female NZB/W F1 (BWF1) mice. Immunological tolerance to MR16-1 or isotype-matched control antibody, KH-5, was induced by the simultaneous administration of anti-CD4 MoAb in mice. Thereafter, mice were intraperitoneally given 0.5 mg of MR16-1, 0.5 mg of KH-5 or saline once a week from 13 to 64 weeks of age. MR16-1 treatment dramatically suppressed proteinuria and prolonged the survival time of BWF1 mice. Only one out of 10 mice died with high levels of proteinuria throughout the experiment. MR16-1 almost completely suppressed the production of IgG forms of anti-DNA and anti-TNP antibodies, but not the IgM forms of these antibodies. In particular, all IgG subclasses (IgG1, IgG2a, IgG2b and IgG3) of anti-DNA antibody production were significantly suppressed. Moreover, serum IgG1, IgG2a and IgG3 levels in MR16-1-treated mice were lower than those in saline- and KH-5-treated mice, whereas serum IgM and IgA levels were not influenced. In conclusion, MR16-1 potently suppressed the development of autoimmune disease in BWF1 mice, and this was attributed to its effect of specific suppression of IgG class antibody production.

Animals↗
PubMed1998

Apoptosis and cellular proliferation in human epidermal squamous cell neoplasia.

We examined cell loss (apoptosis) and proliferation in a histopathological spectrum of epidermal squamous cell neoplasia, including 11 cases of solar keratosis (SK), 18 Bowen's diseases (BD) and 19 invasive squamous cell carcinomas (SCC). Apoptotic and proliferative cells were determined by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end labeling (TUNEL) and by the detection of nuclear antigen Ki-67, respectively. Few apoptotic cells were observed in normal epidermis, while TUNEL index (TI; percentage of TUNEL-positive cells) was highest for SCCs, followed by BDs and SKs, in the order given. Although the mean Ki-67 index did not differ between SCCs and BDs, both disease types showed a significantly higher index than the SKs. Of SCCs, both TI and Ki-67 index values were significantly higher in poorly than in well differentiated carcinomas. TI was significantly higher in SCCs without P53 immunohistochemical expression than in SCCs with P53 expression, while TI and Ki-67 indices did not correlate with P53 expression in the SKs and BDs. These results suggest that apoptosis reflects not only cell loss, but also proliferative activity in the epidermal neoplastic lesions.

Apoptosis↗
PubMed1998

Genital Paget's disease with clear cells in the epidermis of the axilla.

We report an 84-year-old man with extramammary Paget's disease (EMPD) involving the genital region. Microscopic examination revealed very few clear cells appearing pagetoid in the lower portion of prickle cell layer of the right axilla epidermis, with no clinically detectable eruption. Their histochemical, immunohistochemical and lectin-binding reactions were almost identical to those in the genital lesion. However, although the axillary lesion was diagnosed as subclinical Paget's condition, the clinical course showed no aggressive or destructive nature. Our case suggests that not all subclinical Paget's conditions become malignant, and that in some cases the clear cells may be precursors of Paget's cells developing multifocally.

Aged↗