Biomedical subjects

I Nakashima

Publications and source records attributed to I Nakashima.

At least 19 recordsLinked to original sources

PubMed2006

Clinical and MRI features of Japanese patients with multiple sclerosis positive for NMO-IgG.

This study investigates the relation between the serological status of NMO (neuromyelitis optica)-IgG and the clinical and MRI features in Japanese patients with multiple sclerosis. Serum NMO-IgG was tested in 35 Japanese patients diagnosed with multiple sclerosis, including 19 with the optic-spinal form of multiple sclerosis (OSMS), three with the spinal form of multiple sclerosis (SMS), and 13 with the conventional form of multiple sclerosis (CMS), which affects the brain. NMO-IgG was detected in 14 patients, 12 with OSMS and 2 with CMS. In these patients, longitudinally extensive (> 3 vertebral segments) spinal cord lesions (93% v 57%) and permanent, complete blindness (no perception of light) in at least one eye (50% v 0%) were the noticeable features as compared with NMO-IgG-negative OSMS. The two patients having CMS with NMO-IgG had unusual brain lesions, but in other respects had features suggesting OSMS. NMO-IgG was detected in more than half the number of patients with OSMS and in some patients with CMS. This newly discovered serum autoantibody was markedly associated with longitudinally extensive spinal cord lesions and with complete blindness, suggesting severe optic-spinal disease.

Adult↗

PubMed2006

Relevance of callosal and periventricular MRI lesions to oligoclonal bands in multiple sclerosis.

OBJECTIVES: To evaluate the association between callosal or periventricular lesions, and the presence of oligoclonal IgG bands (OB) or the IgG index in Japanese patients with multiple sclerosis (MS). MATERIALS AND METHODS: Brain magnetic resonance imaging (MRI) was studied in 34 Japanese clinically definite MS cases. Sagittal 2-mm fast fluid-attenuated inversion-recovery (FLAIR) imaging was added to the routine MRI studies. RESULTS: Among the 34 patients, 20 (59%) were OB positive. Among the 20 patients with OB-positive MS, 17 (85%) had callosal lesions, although only two (14%) of 14 OB-negative MS patients had callosal lesions. The periventricular lesion area was significantly larger in the OB-positive patients compared with the OB-negative patients. CONCLUSIONS: The present study clearly demonstrated a strong association between the periventricular lesions and OB in Japanese MS. Certain OB-related immune mechanisms may contribute to the development of callosal and periventricular lesions in MS. OB may be an important factor to understand the pathomechanisms of MS lesions.

Adult↗

PubMed2005

Intractable hiccup and nausea with periaqueductal lesions in neuromyelitis optica.

Intractable hiccup and nausea (IHN) was found in eight of 47 cases of relapsing neuromyelitis optica (NMO) (17%) but in none of 130 cases of multiple sclerosis (MS). IHN resolved with methylprednisolone. In six cases, MRI detected linear medullary lesions involving the pericanal region, the area postrema, and the nucleus tractus solitarius. Like long and centrally located myelitis, a linear medullary lesion causing IHN may distinguish NMO from MS.

Adult↗

PubMed2005

5-aminolaevulinic acid photodynamic therapy in a transgenic mouse model of skin melanoma.

Photodynamic therapy (PDT) is widely used to treat preneoplastic skin lesions and non-melanoma skin tumours. Studies analyzing the effects of PDT on malignant melanoma have yielded conflicting results. On the one hand, melanoma cell lines in culture as well as cell lines transplanted into experimental animals were sensitive to PDT. On the other hand, spontaneous melanomas of human patients responded poorly to most PDT regimens tested so far. Here, we analyzed effects of 5-aminolaevulinic acid (5-ALA)-based PDT on melanoma cell lines and on experimental melanomas. To mimic the clinical situation as closely as possible, metallothionein-I/ret (MT-ret) mice, a transgenic model of skin melanoma development, were used. Optimal doses of 5-ALA as well as energy doses and power densities were determined in vitro using a cell line (Mel25) established by us from a melanoma of an MT-ret transgenic mouse as well as commercially available human and mouse melanoma cell lines. Treatment with light irradiation alone had no effect. In combination with 5-ALA, however, this illumination readily induced the death of all mouse and human melanoma cell lines examined. Still, 5-ALA PDT caused only minor focal regressive changes including haemorrhages and fibrosis of MT-ret melanomas in vivo and did not significantly delay tumour growth. These results show that, even though MT-ret melanoma cells are vulnerable to 5-ALA PDT in vitro, malignant MT-ret melanomas in vivo are quite resistant to this type of therapy at doses which are highly effective in vitro.

Aminolevulinic Acid↗

PubMed2004

Absence of IgG1 response in the cerebrospinal fluid of relapsing neuromyelitis optica.

The authors studied immunoglobulin (Ig) G subclasses in the CSF and sera of patients with relapsing neuromyelitis optica (RNMO) and typical multiple sclerosis (MS). Although the total IgG concentrations were elevated in the CSF of patients with RNMO and MS, IgG1% and IgG1 index were significantly elevated only in patients with MS. The absence of the CSF IgG1 responses in the patients with RNMO may suggest less Th1 immunity and may also explain the rarity of oligoclonal IgG bands in patients with this disease.

Adult↗

PubMed2004

Epitope analysis of the cerebrospinal fluid IgG in HTLV-I associated myelopathy patients using phage display method.

We, for the first time, analyzed the binding motifs of immunoglobulin G (IgG) in the cerebrospinal fluid (CSF) of human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients with a phage library displaying 12-mer random peptides. As a result, the sequences highly homologous to HTLV-I gp46 192-199, 237-243 and 255-261 were the common linear epitopes of high affinity- IgG exclusively detected in both CSF and sera of the patients. These IgG responses were confirmed with corresponding HTLV-I peptides and serum antibody titers significantly correlated with disease severity or duration. Gp46 237-243 has not been detected in previous enzyme-linked immunosorbent assay (ELISA) studies using bound longer peptides, suggesting the usefulness of the phage display method.

Adult↗

PubMed2003

Protein phosphatase 2A-linked and -unlinked caspase-dependent pathways for downregulation of Akt kinase triggered by 4-hydroxynonenal.

We studied the signal pathways for regulation of serine/threonine protein kinase Akt in Jurkat cells that had been treated with 4-hydroxynonenal (HNE) for caspase-dependent apoptosis induction. Treatment of cells with HNE led to a decrease in the level of Akt activity due to the dephosphorylation at Ser473, a major regulatory phosphorylation site. HNE-mediated dephosphorylation of Akt was prevented by a protein phosphatase 2A (PP2A) inhibitor, okadaic acid, and by a caspase-3 inhibitor, DEVD-CHO. HNE treatment resulted in an increase in the total level of PP2A activity, release of active tyrosine-dephosphorylated PP2A from the cytoskeleton and PP2A-Akt association, which were all dependent on caspase-3 activation. These results suggest that the level of PP2A activity is at least in part determined by its tyrosine phosphorylation, which is dually controlled by okadaic acid-sensitive phosphatases and protein-tyrosine kinases. Possibly underlying the mechanism of caspase-mediated activation of PP2A, HNE treatment resulted in downregulation of the activity of Src kinase, as a representative caspase-sensitive kinase to phosphorylate PP2A at tyrosine. In addition, activated caspase-3 partially cleaved Akt at a late stage of the apoptosis. These results indicate the existence of two distinct caspase-dependent signal pathways for downregulation of Akt that works as a mechanism of positive feedback regulation for HNE-triggered apoptotic signals.

Aldehydes↗

PubMed2003

Sustained activation of c-jun-terminal kinase (JNK) is closely related to arsenic trioxide-induced apoptosis in an acute myeloid leukemia (M2)-derived cell line, NKM-1.

High concentrations (greater than 5 microM) of arsenic trioxide (As(2)O(3)) have been reported to be able to induce apoptosis in several malignant cells. We explored cell lines in which apoptosis was induced with a therapeutic concentration (1-2 microM) of As(2)O(3), and found that 1 microM of As(2)O(3) induced apoptosis in the NKM-1 cell line, which was established from a patient with acute myeloid leukemia (M2). Apoptosis induced by 1 microM of As(2)O(3) in NKM-1 cells was accompanied by an increased cellular content of H(2)O(2), a decreased mitochondrial membrane potential (Deltapsim), and activation of caspase-3. C-Jun-terminal kinase (JNK) was activated only in NKM-1 cells and arsenic-sensitive NB4 cells, but not in arsenic-insensitive HL-60 cells. Activation of JNK in NKM-1 was sustained from 6 to 24 h after As(2)O(3) treatment, and preceded changes in cellular H(2)O(2), Deltapsim, and caspase-3 activation. Moreover, addition of a JNK inhibitor reduced the percentage of apoptotic cells after the As(2)O(3) treatment. Taken together, in the M2 cell line NKM-1, 1 microM of As(2)O(3) induced sustained activation of JNK and apoptosis. This finding may provide a basis to select a subgroup other than acute promyelocytic leukemia, which can benefit from As(2)O(3) treatment.

Acute Disease↗

PubMed2002

Activation of caspase-8 is critical for sensitivity to cytotoxic anti-Fas antibody-induced apoptosis in human ovarian cancer cells.

Two ovarian cancer cell lines named NOS4 and SKOV-3 have been shown to have different sensitivities to a cytotoxic anti-Fas antibody, CH-11. Although both cell lines express Fas molecules on the cell surfaces at the same intensities, apoptosis is induced by CH-11 in NOS4 cells but not in SKOV-3 cells. In this study, the different apoptosis-sensitivities of these cells were assessed. Both cell lines express almost the same levels of FADD, RIP, c-FLIP, FAP-1, Bax, Bcl-2 and Bcl-XL. Evidence of caspase-8, caspase-9 and caspase-3 activation and of cleavage of PARP and Bid was obtained in NOS4 cells but not in SKOV-3 cells. When triggered by FasL protein, DNA fragmentation and caspase-8 activation were observed in SKOV-3 cells, though they were not as clear as in NOS4 cells. All the anti-Fas antibody-mediated signals for apoptosis induction in NOS4 cells were completely blocked by a caspase-8-specific inhibitor, Z-IETD-FMK. These results indicate that the different sensitivities to the anti-Fas antibody are solely dependent on the activation of caspase-8, which could be influenced by yet unknown qualitative or quantitative abnormalities in molecules involved in DISC formation.

Adaptor Proteins, Signal Transducing↗

PubMed2002

A comparative study of Japanese multiple sclerosis patients with and without oligoclonal IgG bands.

The cerebrospinal fluid oligodonal IgG bands (OB) are less frequently observed in Japanese multiple sclerosis (MS) patients compared with Caucasian patients. We studied 40 consecutive Japanese MS patients to investigate the differences in the clinical and magnetic resonance imaging (MRI) features of MS between OB-positive patients and OB-negative ones. Among the 40 patients, 22 (55%) patients were OB-positive by either agarose gel electrophoresis (AGE) or isoelectric focusing (IEF), and 18 (45%) patients were OB-negative by both AGE and IEF. There were differences between the two groups only in the clincal forms of MS, but not in terms of gender, onset age, disease duration, or disease severity. In the OB-negative group, nine (50%) of the patients had the optic-spinal form of MS (OS-MS), but only one patient (4.5%) in the OB-positive group had OS-MS. Although most OB-positive patients showed brain MRI lesions typical of MS, 13 (72%) of the OB-negative patients showed no or few brain MRI lesions and the rest of the OB-negative patients showed atypical MS lesions, such as diffuse white matter lesions or large ring-enhanced lesions. Our results suggest that the majority of OB-negative Japanese MS patents show either no or few brain MRI lesions or atypical brain MRI lesions.

Adult↗

PubMed2001

Glyoxal and methylglyoxal induce lyoxal and methyglyoxal induce aggregation and inactivation of ERK in human endothelial cells.

Increased production of glyoxal (GO) and methylglyoxal (MGO) under oxidative stress is harmful to the cells. In this study, we examined the early signaling effect of GO/MGO on cultured human umbilical vein endothelial cells. Both GO and MGO induced tyrosine phosphorylation and aggregation of a number of cellular proteins. Aggregation occurred mainly for cell surface proteins such as Flk-1 and VE-cadherin, but barely for the majority of intracellular proteins. Interestingly, however, GO/MGO caused both aggregation and dephosphorylation of intracellular phospho-ERK for inactivation. This phospho-ERK dephosphorylation was mediated by orthovanadate-sensitive phosphatase activity accompanying chemical recruitment of MKP-1 to the aggregated phospho-ERK. Evidence was provided that GO/MGO upregulated MKP-1 activity that in turn dephosphorylated possibly co-aggregated phospho-ERK efficiently for inactivation. These results together suggest that GO and MGO trigger a novel pathway for chemical reaction-mediated downregulation of ERK.

Cell Cycle Proteins↗

PubMed2001

RET tyrosine kinase enhances hair growth in association with promotion of melanogenesis.

We first demonstrated that c-Ret protein is transiently expressed mainly in the inner and outer root sheaths of hair follicles soon after birth in the skin of normal C57BL/6 and BALB/c mice. A longer-lasting expression of activated RET protein overlapped the c-Ret expression with some preferential expression in the outer root sheath in close association with increase in the number of S-100 protein-containing cells in the area and excess melanogenesis in and around hair bulbs in the skin of RFP-RET-transgenic mice on a C57BL/6 background (RFP-RET/B6). Hair follicles in the skin of the transgenic mice continuously showed histology of the anagen phase, and the recovery period for the hair of the transgenic mice after shaving was shortened. Such growth promotion was not observed in the case of white hairs of RFP-RET-transgenic mice on a BALB/c background. These results suggest that RET works to extend the anagen phase in association with upregulation of melanin production.

Aged↗

PubMed2001

Synthesis of a set of di- and tri-sulfated galabioses.

Among cell-adhesion molecules, L-selectin recognizes sulfated sLe(x) with relatively low affinity. Here, we aimed at artificial mimics by synthesizing a set of di- and tri-sulfated galabioses, which may surpass the affinity of sulfated sLe(x). As a strategy to obtain 3',6',6-tri-O-sulfogalabioses, regioselective reductive cleavage of 4,6- and 4',6'-di-O-benzylidenegalabioses was employed. Two suitably protected galactose precursors were conjugated to yield alpha and beta anomers (48 and 18%, respectively) by using a pentenyl galactoside donor and iodinium di-sym-collidine perchlorate as the catalyst. For synthesizing the 3',6-di-O-sulfogalabiose, however, a trichloroacetimidate donor was superior (52%) to the pentenyl one (30%).

Acetamides↗

PubMed2001

Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process.

Methylglyoxal (MG) is a physiological metabolite, but it is known to be toxic, inducing stress and causing apoptosis. Our previous studies demonstrated that MG induced apoptosis in Jurkat cells by activating the c-Jun N-terminal kinase (JNK) signal transduction pathway, which induced an obvious decrease in mitochondrial membrane potential, followed by caspase-3 activation. Here, we observed that MG-induced apoptosis was associated with both rapid production of superoxide anion (O(2)(-)) followed by a marked increase in ROS and striking and temporal activation of ASK1. Overexpression of wild-type ASK1 could enhance the rate of apoptosis induced by MG, whereas the expression of the kinase-inactive form of ASK1 notably prevented cells from MG-induced death. NAC and PDTC blocked the activation of ASK1 and MG-induced apoptosis completely. Moreover, nonthiol antioxidants SOD-mimic MnTBAP and catalase together obviously inhibited MG-induced ASK1 activation and apoptosis induction. Correspondingly, MG-mediated ASK1 activation was enhanced by diethyldithiocarbamate (DDC). Addition of antioxidant into the culture of cells at a later stage (4-8 h after the initial MG treatment) failed to prevent their death. These results suggest that activating ASK1 at the early stage linking to production of O(2)(-) is crucial for subsequent progression of apoptosis in MG-treated Jurkat cells.

Acetylcysteine↗

PubMed2001

Glyoxal and methylglyoxal trigger distinct signals for map family kinases and caspase activation in human endothelial cells.

Carbonyl compounds with diverse carbon skeletons may be differentially related to the pathogenesis of vascular diseases. In this study, we compared intracellular signals delivered into cultured human umbilical vein endothelial cells (HUVECs) by glyoxal (GO) and methylglyoxal (MGO), which differ only by a methyl group. Depending on their concentrations, GO and MGO promoted phosphorylations of ERK1 and ERK2, which were blocked by the protein-tyrosine kinase (PTK) inhibitors herbimycin A and staurosporine, thereby being PTK-dependent. GO and MGO also induced phosphorylations of JNK, p38 MAPK, and c-Jun, either PTK-dependently (GO) or -independently (MGO). Next, we found that MGO, but not GO, induced degradation of poly(ADP-ribose) polymerase (PARP) as the intracellular substrate of caspase-3. Curcumin and SB203580, which inhibit JNK and p38 MAPK signaling pathways, but not herbimycin A/staurosporine, prevented the MGO-induced PARP degradation. We then found that MGO, but not GO, reduced the intracellular glutathione level, and that cysteine, but not cystine, inhibited the MGO-mediated activation of ERK, JNK, p38 MAPK, or c-Jun more extensively than did lysine or arginine. In addition, all the signals triggered by GO and MGO were blocked by amino guanidine (AG), which traps carbonyls. These results demonstrated that GO and MGO triggered two distinct signal cascades, one for PTK-dependent control of ERK and another for PTK-independent redox-linked activation of JNK/p38 MAPK and caspases in HUVECs, depending on the structure of the carbon skeleton of the chemicals.

Caspases↗

PubMed2001

Linear pontine trigeminal root lesions in multiple sclerosis: clinical and magnetic resonance imaging studies in 5 cases.

BACKGROUND: Magnetic resonance imaging (MRI) is useful for demonstrating demyelinating lesions in patients with multiple sclerosis (MS). Magnetic resonance imaging studies show that MS lesions are generally not uniform in shape, size, or distribution. Linearly shaped lesions at the trigeminal root entry zone have been occasionally reported in single cases of MS, but, to our knowlege, the frequency and the clinical features of such patients have not been comprehensively characterized. OBJECTIVE: To describe the frequency and the clinical and laboratory features of patients with MS who had linearly shaped lesions at the trigeminal root as seen on MRI. DESIGN AND SETTING: A retrospective review of medical records and MRI films of Japanese patients with MS admitted to a university hospital and its affiliated hospital in Sendai, Japan. PATIENTS AND METHODS: Brain MRI films of 74 consecutive Japanese patients with MS (51 females and 23 males) were studied retrospectively and the clinical and laboratory features of the patients with linearly shaped lesions at the trigeminal root were also investigated retrospectively. RESULTS: Five patients (6.8%) were shown to have T1-weighted-hypointense, T2-weighted-hyperintense, nonenhanced linear lesions in the pons on MRI, and these were uniformly localized in the intramedullary portion of the trigeminal root. All of these patients had clinically definite MS and had various types of facial sensory disturbances, such as neuralgia (1 patient), hypesthesia (2 patients), or paresthesia (3 patients). No other clinical or laboratory feature was characteristic in these 5 patients. CONCLUSIONS: Linear pontine trigeminal root lesions were common in our patients with MS. They were associated with various facial sensory symptoms. Since similar lesions are formed in animal models of herpes simplex virus infection, further study is needed to clarify whether these MS lesions are virally induced.

Adolescent↗

PubMed2001

Acrolein induces activation of the epidermal growth factor receptor of human keratinocytes for cell death.

Acrolein, which is a highly reactive formaldehyde generated by lipid peroxidation, can affect skin and cause various disorders. The effect of exposure of human keratinocytes to acrolein on cell surface-oriented signal transduction into cells was examined. Incubation of human keratinocytes with a relatively low concentration (50 microM) of acrolein caused a prompt and selective induction of tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) as a 180-kDa molecule during the period from 5-30 min after the start of incubation. This early event was followed by an increase in the density and number of phosphotyrosine-containing proteins during the period from 60-120 min after the start of incubation. The catalytic activity of EGFR as measured by the levels of autophorphorylation and phosphorylation of an exogenously added substrate, casein, in in vitro kinase assay, greatly increased as early as 1 min after the start of incubation and then decreased gradually 30 min later. MAP family kinases, including ERK, JNK, and p38 kinase, and the potentially downstream transcription factor c-Jun were all promoted for phosphorylation/activation during a period of 5-30 min. Selective prompt phosphorylation/activation of EGFR followed by phosphorylation of MAP family kinases and c-Jun and their blockade by a specific EGFR inhibitor, AG1478, suggested that activation of EGFR is the major, and possibly single, cell surface element for intracellular signal transduction in acrolein-treated cells. Incubation of human keratinocytes with 50 microM of acrolein induced atypical apoptosis with morphologic apoptotic features with low-grade oligonucleoside-sized DNA fragmentation. Partial inhibition of such a cytopathic effect of acrolein on human keratinocytes by preincubation with AG1478 suggests the involvement of an EGFR-mediated signal pathway for atypical apoptosis. These results provide new information on acrolein-induced cell surface-oriented signal transduction to human keratinocytes, and this information may be useful for understanding the pathogenesis of a number of skin diseases in response to environmental acrolein and acrolein-generating ultraviolet irradiation.

Acrolein↗

PubMed2001

Cepharanthine activates caspases and induces apoptosis in Jurkat and K562 human leukemia cell lines.

Cepharanthine (CEP) is a known membrane stabilizer that has been widely used in Japan for the treatment of several disorders such as anticancer therapy-provoked leukopenia. We here report that apoptosis was induced by low concentrations (1-5 microM) of CEP in a human leukemia T cell line, Jurkat, and by slightly higher concentrations (5-10 microM) in a human chronic myelogenous leukemia (CML) cell line K562, which expresses a p210 antiapoptotic Bcr-Abl fusion protein. Induction of apoptosis was confirmed in both Jurkat and K562 cells by DNA fragmentation and typical apoptotic nuclear change, which were preceded by disruption of mitochondrial membrane potential and were induced through a Fas-independent pathway. CEP treatment induced activation of caspase-9 and -3 accompanied by cleavage of PARP, Bid, lamin B1, and DFF45/ICAD in both Jurkat and K562 cells, whereas caspase-8 activation and Akt cleavage were observed only in Jurkat cells. The CEP-induced apoptosis was completely blocked by zVAD-fmk, a broad caspase inhibitor. Interestingly, CEP treatment induced remarkable degradation of the Bcr-Abl protein in K562 cells, and this degradation was prevented partially by zVAD-fmk. When used in combination with a nontoxic concentration of herbimycin A, lower concentrations (2-5 microM) of CEP induced obvious apoptosis in K562 cells with rapid degradation or decrease in the amount of Bcr-Abl and Akt proteins. Our results suggest that CEP, which does not have bone marrow toxicity, may possess therapeutic potential against human leukemias, including CML, which is resistant to anticancer drugs and radiotherapy.

Alkaloids↗