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N Kumagai

Publications and source records attributed to N Kumagai.

At least 19 recordsLinked to original sources
PubMed2006

Local delivery of angiotensin receptor blocker into the kidney ameliorates progression of experimental glomerulonephritis.

Intrarenally synthesized angiotensin II (Ang II) may be involved in the progression of glomerulonephritis, leading to irreversible glomerulosclerosis. There is increasing evidence that systemic angiotensin receptor blocker (ARB) treatment has beneficial effect on the prognosis of progressive glomerulonephritis and diabetic nephropathy. However, the cellular and molecular mechanisms behind this therapeutic effect of ARB remain unclear. In this study, we used a novel strategy of local ARB delivery via type-1 collagen sponge, to treat progressive glomerulonephritis that would result in irreversible glomerulosclerosis in our previously established rat model. At days 9 and 14 after disease induction, mild proteinuria, 20.7+/-4.7 and 10+/-1.3 mg/day, was found. Local ARB treatment reduced proteinuria significantly to 3.19+/-3.2 and 5.25+/-0.95 mg/day (P < 0.01), respectively. Scoring of glomerular matrix expansion and sclerotic index revealed that local ARB treatment significantly ameliorated glomerular pathology. Ang II type 1 receptor mRNA expression was remarkably enhanced in the Ang II group and ARB treatment reversed this effect at 14 days. Local delivery of ARB significantly improved glomerular blood flow levels, compared to the untreated disease control group, from 710+/-18.25 to 859.44+/-22.86 microm/s, respectively. Local delivery of ARB into the kidney affected local RAS and thus improved the renal injury and function in the potentially progressive glomerulosclerosis of rat model.

Angiotensin II↗
PubMed2006

Differential cross section and photon-beam asymmetry for the gamma n --> K+ Sigma- reaction at E gamma = 1.5-2.4 GeV.

Differential cross sections and photon-beam asymmetries have been measured for the gamma n --> K+ Sigma- and gamma p --> K+Sigma0 reactions separately using liquid deuterium and hydrogen targets with incident linearly polarized photon beams of E gamma = 1.5-2.4 GeV at 0.6 < cos ThetacmK< 1. The cross section ratio of sigma K+ Sigma-/sigma K+ Sigma0, expected to be 2 on the basis of the isospin 1/2 exchange, is found to be close to 1. For the K+ Sigma- reaction, large positive asymmetries are observed, indicating the dominance of K* exchange. The large difference between the asymmetries for the K+ Sigma- and K+ Sigma0 reactions cannot be explained by simple theoretical considerations based on Regge model calculations.

Journal Article↗
PubMed2006

Interleukin 10 and transforming growth factor beta contribute to the development of experimentally induced allergic conjunctivitis in mice during the effector phase.

AIM: To investigate the involvement of interleukin (IL)10 and transforming growth factor (TGF) beta in the development of experimentally induced allergic conjunctivitis in mice. METHODS: Balb/c mice were actively sensitised with ragweed in alum, and then challenged with ragweed in eye drops after 10 days. 24 h later, the conjunctivas, spleens and blood were collected for histological and cytokine expression analyses, proliferation and cytokine production assays and measurement of immunoglobulin (Ig) levels. Mice developing experimentally induced allergic conjunctivitis were injected intraperitoneally with 200 microg of anti-IL10 or anti-TGF beta antibodies at 0, 2, 4, 6 and 8 days (induction phase treatment) or 500 microg of antibodies 2 h before ragweed challenge (effector phase treatment). Normal rat IgG was used for control injections. RESULTS: Treatment with either anti-IL10 or anti-TGF beta antibodies during the induction phase did not affect eosinophil infiltration into the conjunctiva. By contrast, treatment with either antibody during the effector phase suppressed infiltration. During the effector phase, treatment with anti-TGF beta antibody, but not the anti-IL10 antibody, markedly up regulated proliferation and Th2 cytokine production by splenocytes. IL1alpha levels in the conjunctiva were reduced after treatment with either antibody; in addition, eotaxin and tumour necrosis factor alpha levels were reduced after treatment with antibody to TGF beta. CONCLUSIONS: IL10 and TGF beta do not have immunosuppressive roles in the development of experimentally induced allergic conjunctivitis. Rather, they augment the infiltration of eosinophils into the conjunctiva during the effector phase of experimentally induced allergic conjunctivitis.

Adoptive Transfer↗
PubMed2005

Near-threshold diffractive psi-meson photoproduction from the proton.

Photoproduction of a phi meson on protons was studied by means of linearly polarized photons at forward angles in the low-energy region from threshold to Egamma = 2.37 GeV. The differential cross sections at t = -|t|min do not increase smoothly as Egamma increases but show a local maximum at around 2.0 GeV. The angular distributions demonstrate that phi mesons are photoproduced predominantly by helicity-conserving processes, and the local maximum is not likely due to unnatural-parity processes.

Journal Article↗
PubMed2005

Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice.

BACKGROUND: While tumour necrosis factor alpha (TNF-alpha) appears to be associated with the development of non-alcoholic steatohepatitis (NASH), its precise role in the pathogenesis of NASH is not well understood. METHODS: Male mice deficient in both TNF receptors 1 (TNFR1) and 2 (TNFR2) (TNFRDKO mice) and wild-type mice were fed a methionine and choline deficient (MCD) diet or a control diet for eight weeks, maintaining isoenergetic intake. RESULTS: MCD dietary feeding of TNFRDKO mice for eight weeks resulted in attenuated liver steatosis and fibrosis compared with control wild-type mice. In the liver, the number of activated hepatic Kupffer cells recruited was significantly decreased in TNFRDKO mice after MCD dietary feeding. In addition, hepatic induction of TNF-alpha, vascular cell adhesion molecule 1, and intracellular adhesion molecule 1 was significantly suppressed in TNFRDKO mice. While in control animals MCD dietary feeding dramatically increased mRNA expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) in both whole liver and hepatic stellate cells, concomitant with enhanced activation of hepatic stellate cells, both factors were significantly lower in TNFRDKO mice. In primary cultures, TNF-alpha administration enhanced TIMP-1 mRNA expression in activated hepatic stellate cells and suppressed apoptotic induction in activated hepatic stellate cells. Inhibition of TNF induced TIMP-1 upregulation by TIMP-1 specific siRNA reversed the apoptotic suppression seen in hepatic stellate cells. CONCLUSIONS: Enhancement of the TNF-alpha/TNFR mediated signalling pathway via activation of Kupffer cells in an autocrine or paracrine manner may be critically involved in the pathogenesis of liver fibrosis in this NASH animal model.

Animals↗
PubMed2005

Fibulin-5 deposition in human skin: decrease with ageing and ultraviolet B exposure and increase in solar elastosis.

BACKGROUND: Fibulin-5 was recently found as a secreted extracellular matrix protein that functions as a scaffold for elastic fibres. However, the distribution of fibulin-5 in human skin and its changes during the ageing process are not known. OBJECTIVES: To explore the involvement of fibulin-5 in skin ageing, the age-dependent changes in fibulin-5 localization in human skin were examined compared with those of other elastic fibre components including elastin, fibrillin-1 and fibulin-2. Methods The distribution of elastin, fibrillin-1, fibrillin-2, fibulin-2 and fibulin-5 was investigated by means of immunohistochemistry using their specific antibodies. Skin samples were recovered from 12 healthy subjects undergoing plastic surgery. Ultraviolet (UV) B-irradiated or control nonirradiated buttock skin samples were obtained from two healthy volunteers at 2 days after the irradiation at 2 minimal erythemal doses. RESULTS: In the reticular dermis of young sun-protected skin from the upper arm, fibulin-5 colocalized with the other elastic fibre components, while in the papillary dermis fibulin-5 showed candelabra-like structures perpendicular to the epidermis with an unstained area just beneath the epidermis, which was similar to that of elastin but not fibrillin-1. Fibulin-5 in the reticular dermis decreased and disappeared with age even in sun-protected skin from the thigh, abdomen and upper arm. In sun-exposed skin, fibulin-5 was extremely reduced in the dermis of cheek skin even from a 20-year-old man. UVB irradiation reduced fibulin-5, fibulin-2 and elastin markedly, moderately and weakly, respectively, compared with levels in control nontreated skin. Interestingly, the deposition of fibulin-5 was increased in solar elastosis, like that of other elastic fibre components. CONCLUSIONS: These results suggest that fibulin-5 is a good marker of skin ageing and that the earlier loss of fibulin-5 may involve age-dependent changes in other elastic fibre components.

Adolescent↗
PubMed2005

Tyrosinase induction and inactivation in normal cultured human melanocytes by endothelin-1.

Since endothelin was found to be expressed in epithelial cells as well as in vascular endothelial cells, the functional regulation of melanocytes with endothelin has been actively investigated. In particular, it has been suggested that endothelin may influence pigmentation and depigmentation, which are mediated by melanocytes. In the present study, we investigated the regulation of melanocyte function and tyrosinase expression by endothelin from the point of view of tyrosinase protein expression and enzyme activity. The influence of endothelins on melanocyte function was assessed. Melanocytes showed a dose-dependent increase in cell proliferation with the addition of endothelin-1. When the confluence of melanocytes was cultured with endothelin-1 for 72 h, tyrosinase activity in melanocytes was significantly and dose-dependently decreased. In contrast, there was no significant change with endothelin-3. However, tyrosinase protein expression of melanocytes was significantly and dose-dependently increased by endothelin-1, but endothelin-3 had no effect. Both the suppression of enzyme activity and the enhanced protein expression were regulated by the ETA receptor antagonist, BQ123. In view of these observations, we conclude that endothelin-1-induced tyrosinase is mediated by ETA receptors. However, the reason for the decrease in the specific activity of tyrosinase remains unknown, and our results suggest that another mechanism underlying the activation of tyrosinase is present in addition to the inductive action of endothelin-1 on tyrosinase.

Cell Proliferation↗
PubMed2004

Polymorphisms of NS5B protein relates to early clearance of hepatitis C virus by interferon plus ribavirin: a pilot study.

Although randomized trials have shown enhancement of efficacy for combination therapy with interferon (IFN) alpha-2b and ribavirin compared with IFN monotherapy as first-line treatment for chronic hepatitis C, infection with genotype 1b and high viremia are still associated with significantly low response rates compared with non-1 genotypes and low viremia. We analysed amino acid sequences of the viral RNA-dependent RNA polymerase (RdRP) or nonstructural protein 5B (NS5B), responsible for ribavirin misincorporation into RNA products in patients with genotype 1b-related chronic hepatitis C and high viremia, and examined the relationship between such RdRp polymorphisms, and the initial decline in viral load induced by combination therapy with IFN-alpha and ribavirin. Substitution of glutamic acid to lysine at the 124th position (E124K) and of isoleucine to valine at the 85th position (I85V) were found to be closely associated with a potent decline of viral load and viral clearance at 8 weeks of treatment (five of five patients, coincidence rate 100%). In conclusion, our results suggest that the polymorphisms of E124K and I85V identified in NS5B protein are crucial for early viral clearance in patients with genotype 1b and high viremia by combination therapy with IFN and ribavirin, and that detection of amino acid sequence motifs might enable prediction of clinical efficacy.

Aged↗
PubMed2003

Beam-polarization asymmetries for the p(gamma-->, K+)Lambda and p(gamma-->, K+)Sigma(0) reactions for E(gamma)=1.5-2.4 GeV.

Beam polarization asymmetries for the p(gamma-->,K+)Lambda and p(gamma-->,K+)Sigma(0) reactions are measured for the first time for E(gamma)=1.5-2.4 GeV and 0.6<cos((theta(c.m.)(K+))<1.0 by using linearly polarized photons at the Laser-Electron-Photon facility at SPring-8 (LEPS). The observed asymmetries are positive and gradually increase with rising photon energy. The data are not consistent with theoretical predictions based on tree-level effective-Lagrangian approaches. Including the new results in the development of the models is, therefore, crucial for understanding the reaction mechanism and to test the presence of baryon resonances which are predicted in quark models but are thus far undiscovered.

Journal Article↗
PubMed2003

Evidence for a narrow S = +1 baryon resonance in photoproduction from the neutron.

The gamman-->K(+)K(-)n reaction on 12C has been studied by measuring both K+ and K- at forward angles. A sharp baryon resonance peak was observed at 1.54+/-0.01 GeV/c(2) with a width smaller than 25 MeV/c(2) and a Gaussian significance of 4.6sigma. The strangeness quantum number (S) of the baryon resonance is +1. It can be interpreted as a molecular meson-baryon resonance or alternatively as an exotic five-quark state (uuddsmacr;) that decays into a K+ and a neutron. The resonance is consistent with the lowest member of an antidecuplet of baryons predicted by the chiral soliton model.

Journal Article↗
PubMed2003

Evaluation of autologous cultured epithelium as replacement skin after tattoo excision: correlation between skin texture and histological features.

BACKGROUND: Cultured epidermal autographs (CEAs) are currently used as a coverage treatment for burn wounds, for disfiguring burn scars involving depigmentation and in restoring the elasticity of the skin. The advantage of CEAs is that epidermal sheets prepared from small skin pieces can be enlarged sufficiently to cover large burn areas. OBJECTIVES: We examined the correlation between recovery of skin texture, and elastic fibre formation and keratinocyte differentiation (assessed by immunohistochemistry) in CEAs used as replacement skin after tattoo excision in a Japanese patient. METHODS: The tattooed skin was excised down to the deep dermal layer and then CEA was transplanted onto the patient. The skin textures were evaluated by taking replicas of the skin surface, and histological changes of filaggrin, transglutaminase, involucrin, fibrillin and elastin in the autograft skin were examined by immunohistochemistry. RESULTS: The skin texture improved with time after grafting the CEA, and appeared similar to that of normal skin at 39 months. Among keratinocyte differentiation markers, filaggrin recovered to a normal pattern at around 6 months, and transglutaminase did so at 39 months, whereas involucrin expression remained abnormal at 39 months. Fibrillin expression appeared similar to that of normal skin by 39 months, except for sparse candelabra-like structures of short fibres. Elastin expression remained at a low level throughout. CONCLUSIONS: Our results show that the recovery of skin texture after application of CEAs following tattoo excision is associated with the normalization of epidermal differentiation markers, except involucrin, and with the regeneration of elastic fibres in the dermis.

Adult↗
PubMed2001

Enantioselective 1,4-addition of unmodified ketone catalyzed by a bimetallic Zn-Zn-linked-BINOL complex.

1,4-Addition (Michael addition) of 2-hydroxy-2'-methoxyacetophenone (2) to various alpha,beta-unsaturated ketones was efficiently promoted by a bimetallic Zn-Zn-linked-BINOL complex 3 with good yield (up to 90%) and excellent enantiomeric excess (up to 99% ee). The resulting 2-hydroxy-1,5-diketones were successfully converted to synthetically more versatile esters and amides. [reaction: see text]

Journal Article↗
PubMed2001

Direct catalytic enantio- and diastereoselective aldol reaction using a Zn-Zn-linked-BINOL complex: a practical synthesis of syn-1,2-diols.

[reaction: see text] The direct catalytic enantio- and diastereoselective aldol reaction with 2-hydroxy-2'-methoxyacetophenone proceeded smoothly using as little as 1 mol % of a dinuclear zinc catalyst, Zn-Zn-linked-BINOL complex 2, to afford alpha,beta-dihydroxy ketones in a highly syn-selective manner (up to syn/anti 97/3) and in excellent yields (up to 95%) and ees (up to 99%). Efficient transformations of the alpha,beta-dihydroxy ketone into an alpha,beta-dihydroxy ester and an alpha,beta-dihydroxy amide via regioselective rearrangements are also described.

Journal Article↗
PubMed2001

Effects of nitric oxide synthase inhibitors on vascular hyperpermeability with thermal injury in mice.

The role of nitric oxide and related synthase in thermal injury was investigated by using models of experimental burn to evaluate severity from the aspect of vascular permeability. Thermal injuries were produced in the murine right ear by pinching with a pair of preheated tweezers. Immediately thereafter, Evans blue dye was intravenously administered, and the mice injured with burns were sacrificed at various times. The burned ears were collected and hydrolyzed, and the level of extracted dye was measured as an indicator of inflammation. Vascular hyperpermeability was suppressed by the administration of nitric oxide synthase inhibitors. LNAME not only suppressed vascular hyperpermeability in thermal injuries in a dose-dependent manner but was also effective with either prophylactic or therapeutic administration. Although aminoguanidine also suppressed the inflammatory response, it had no effect on the early inflammatory phase. Nitric oxide synthase is well known to have two types of isozymes. Aminoguanidine, an inhibitor specific to inducible nitric oxide synthase, suppressed the late phase 6 h after injury, suggesting that inducible nitric oxide synthase is involved in inflammatory responses of thermal injuries. These results also demonstrated that inducible nitric oxide synthase-like protein stained the burned region immunohistochemically. Therefore, both types of enzymes mediating nitric oxide affect inflammatory responses, i.e., vascular hyperpermeability, and their regulation may lead to the development of new therapy for thermal injuries.

Animals↗
PubMed2001

Th1 and Th2 cytokines differentially regulate the transformation of Kupffer cells into multinucleated giant cells but similarly enhance the Kupffer cell-induced hepatic stellate cell proliferation.

To investigate the effects of T-helper cytokines on Kupffer cells (KCs), the effects of interferon-gamma (IFN-gamma; Th1 cytokine) and interleukin-4 (IL-4; Th2 cytokine) on KC morphology and their role in modulating the growth of hepatic stellate cells (HSCs) were examined. Fluorescence microscopic and electron microscopic data demonstrated that IL-4 transforms rat KCs into multinucleated giant cells (MGCs) in vitro. This transformation was inhibited by the addition of anti-ICAM-1 and anti-CD18 monoclonal antibodies. In addition, IL-4-induced KC transformation was suppressed by the presence of IFN-gamma. The formation of mouse hepatic MGCs was also demonstrated in vivo by the intraperitoneal injection of recombinant mouse IL-4. Although the presence of MGCs was found in all five out of five livers from IL-4-treated Th2-dominant BALB/c mice, but it was in only two out of five livers from IL-4-treated Th1-dominant C57BL/6 mice. In addition, fewer MGCs were found in the liver of C57BL/6 mice. In contrast, IFN-gamma treatment did not form hepatic MGCs in mice at all. The growth of HSCs in vitro was significantly increased by the addition of culture supernatant from lipopolysaccharide-stimulated rat KCs. Pretreatment of the KCs with either IFN-gamma or IL-4 further enhanced the growth stimulation. These results suggest that IFN-gamma and IL-4 affect KC morphology differently, but that both Th1 and Th2 cytokines play a similar role in the modulation of HSC growth by Kupffer cells in the presence of lipopolysaccharide.

Journal Article↗
PubMed2001

Anti-fibrogenic effect of an angiotensin converting enzyme inhibitor on chronic carbon tetrachloride-induced hepatic fibrosis in rats.

The tissue renin-angiotensin system has recently been demonstrated to reduce fibrogenesis in various organs. However, little has been clarified regarding its role in hepatic fibrosis. The purpose of this study was to investigate the effect of angiotensin-converting enzyme inhibitors on liver fibrogenesis induced in rats by low-dose chronic carbon tetrachloride administration. We used lisinopril that is absorbed in its active form and not metabolized in the liver to avoid any influence by the administration of the chemical. Carbon tetrachloride was administered twice a week i.p. Twelve and 24 weeks after the start of treatment, expanded periportal fibrosis or portal-portal bridgings and severe fat deposition were observed in the rats treated with carbon tetrachloride alone, and these findings were significantly reduced with the simultaneous treatment with lisinopril. The hydroxyproline content of the liver was significantly lower in the lisinopril-treated group. Angiotensin II up-regulated mRNA of pro alpha (I) collagen and transforming growth factor-beta in isolated hepatic stellate cells. These results suggest that the local tissue renin-angiotensin system plays a role in rat hepatic fibrogenesis induced by chronic carbon tetrachloride administration and that hepatic fibrogenesis is significantly reduced by ACE inhibitors.

Journal Article↗