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H Tsutsui

Publications and source records attributed to H Tsutsui.

At least 19 recordsLinked to original sources
PubMed2006

Topical suplatast tosilate (IPD) ameliorates Th2 cytokine-mediated dermatitis in caspase-1 transgenic mice by downregulating interleukin-4 and interleukin-5.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by elevated serum levels of IgE. AD is associated with Th2 cytokines including interleukin (IL)-4, IL-5, IL-13 and IL-10. Systemic administration of suplatast tosilate (IPD) is currently used to treat Th2 cytokine-mediated AD. OBJECTIVES: To evaluate the effect of topical IPD on skin lesions of AD using a genetically engineered AD mouse model (K14/caspase-1 transgenic mouse: KCASP1Tg). METHODS: IPD ointment (3%) and white petrolatum (WP) were applied to KCASP1Tg mice every other day from 6 to 14 weeks after birth. Histopathological analysis of skin lesions and measurement of mRNA expression of cytokines in skin lesions and spleen cells were carried out. We also compared changes in serum parameters between IPD-treated and WP-treated KCASP1Tg mice. RESULTS: WP-treated mice developed dermatitis at 8 weeks after birth. However, skin lesions in IPD-treated mice were limited. Histopathologically, skin lesions in WP-treated KCASP1Tg mice showed marked inflammatory changes with increased mast cell infiltration. However, mice treated with IPD showed minimum skin lesions with scarce mast cell infiltration. WP-treated KCASP1Tg mice had significant elevation in the serum levels of histamine, IgE and IL-18 as compared with IPD-treated KCASP1Tg mice. mRNA expression of IL-4 and IL-5 in the skin lesions from WP-treated KCASP1Tg mice was significantly higher than in those from IPD-treated mice. In the spleen, the expression of IL-4, IL-5 and interferon-gamma was significantly increased in WP-treated KCASP1Tg mice as compared with their IPD-treated counterparts. CONCLUSIONS: This study shows that topical therapy with IPD inhibits the expression of IL-4 and IL-5 and ameliorates skin manifestations in an AD mouse model, suggesting the potential usefulness of topical IPD for the treatment of AD.

Administration, Topical↗
PubMed2003

Cytokine-induced inflammatory liver injuries.

IL-18 is a pleiotropic cytokine and is produced by various types of cells including activated macrophages, particularly Kupffer cells. IL-18 has potential to activate inflammatory responses through induction of IFN-gamma production in collaboration with IL-12. Somewhat paradoxically, IL-18 also has the capacity to induce allergic responses via induction of IL-4 production by T helper cells and to activate mast cells and basophils to release atopic effector molecules such as histamine. Indeed, IL-18 is involved in inflammatory tissue injuries, such as Crohn's disease and atherosclerosis, and also in hyper IgE and atopic dermatitis. IL-18 is particularly important for induction of experimental liver diseases. Endotoxin-induced liver injury or Fas ligand-induced hepatitis is caused by endogenous IL-18 in mice. Moreover, patients with liver diseases such as fulminant hepatitis, liver cirrhosis due to hepatitis virus infection and primary biliary cirrhosis show elevation of serum levels of IL-18, that correlates with the corresponding disease severity. Therefore, endogenous IL-18 plays a major role in induction of some types of liver injuries in mice and human. NKT cells that express both T cell receptor and NK cell marker are abundant in the liver of mice and human. Recent studies have revealed that NKT cells participate in some types of liver injuries, such as concanavalin A-induced T cell-mediated hepatitis and malaria hepatitis. In this review article, we focus on IL-18-involving liver damages and NKT-cell-mediated liver injuries.

Animals↗
PubMed2002

Optimisation of illumination for photodynamic therapy with mTHPC on normal colon and a transplantable tumour in rats.

Recent reports suggest that the effect of photodynamic therapy (PDT) can be enhanced by fractionating the light dose or reducing the light fluence rate. We assessed these options on two tissues in rats (normal colon and a transplanted fibrosarcoma) using the photosensitiser meta-tetrahydroxyphenylchlorin (mTHPC). Animals were sensitised with 0.3 mg/kg mTHPC, 3 days prior to illumination with red light (652 nm) using a single fibre touching the target tissue and killed 1-3 days later for quantitative measurement of the extent of PDT necrosis. Results were similar for both tissues, although the differences between illumination regimens were less marked in tumour tissue. Using continuous illumination and a fixed low energy in colon, the extent of necrosis was up to almost three times larger with 5 mW than with 100 mW, although the maximum attainable necrosis was independent of power. The long treatment time using 5 mW could be halved without loss of effect by increasing the power during treatment. Dividing the light into two equal fractions at 100 mW increased the lesion size by up to 20% in colon (independent of the timing of the dark interval), but by only 10% in tumour and had no effect at 20 mW. Previous studies using 5-aminolaevulinic acid (ALA) showed a much larger effect of fractionation that was critically dependent on the timing of the dark interval. We postulate that enhancement of PDT by fractionation is due to improved oxygen supply to the treated area which may be due to reversal of temporary vascular occlusion (more likely with ALA) or less rapid photochemical consumption of oxygen (more likely with mTHPC). At lower fluence rates, the oxygen consumption rate is not fast enough to be improved by fractionation. We conclude that fractionated or low power light delivery can enhance PDT with mTHPC. Although the effects are not large, this may be of value for interstitial treatment of solid tumours when multiple sites are treated simultaneously.

Animals↗
PubMed2001

8-oxo-dGTPase, which prevents oxidative stress-induced DNA damage, increases in the mitochondria from failing hearts.

BACKGROUND: Reactive oxygen species (ROS) can cause an oxidative modification of nucleotides, such as 8-oxo-7,8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP), which can lead to defects in DNA replication. The misincorporation of 8-oxo-dGTP into DNA is prevented by 8-oxo-dGTPase, which hydrolyzes 8-oxo-dGTP into 8-oxo-dGMP. The changes in this defensive system have not yet been examined in failing hearts, in which the generation of ROS increases. METHODS AND RESULTS: Myocardial infarction (MI) was created in mice by ligating the left coronary artery. Four weeks later, the left ventricle was dilated and contractility was diminished on echocardiography. The generation of ROS, as measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, increased in the noninfarcted left ventricle from MI mice. The formation of thiobarbituric acid-reactive substances also increased in the mitochondria from MI mice. 8-Oxo-dGTPase was detected in the mitochondrial fractions isolated from MI mice using a Western blot analysis with an antibody to its human homologue (hMTH1). Immunohistochemistry showed positive staining for hMTH1 was localized in the cardiac myocytes. CONCLUSIONS: The level of 8-oxo-dGTPase increased in the mitochondria isolated from post-MI hearts as oxidative stress increased, thus suggesting that a preventive mechanism is activated against ROS-induced DNA damage. As a result, 8-oxo-dGTPase is considered a useful marker of mitochondrial oxidative stress in heart failure.

Animals↗
PubMed2001

Plasmodium berghei infection in mice induces liver injury by an IL-12- and toll-like receptor/myeloid differentiation factor 88-dependent mechanism.

Malaria, caused by infection with Plasmodium spp., is a life cycle-specific disease that includes liver injury at the erythrocyte stage of the parasite. In this study, we have investigated the mechanisms underlying Plasmodium berghei-induced liver injury, which is characterized by the presence of apoptotic and necrotic hepatocytes and dense infiltration of lymphocytes. Although both IL-12 and IL-18 serum levels were elevated after infection, IL-12-deficient, but not IL-18-deficient, mice were resistant to liver injury induced by P. berghei. Neither elevation of serum IL-12 levels nor liver injury was observed in mice deficient in myeloid differentiation factor 88 (MyD88), an adaptor molecule shared by Toll-like receptors (TLRs). These results demonstrated a requirement of the TLR-MyD88 pathway for induction of IL-12 production during P. berghei infection. Hepatic lymphocytes from P. berghei-infected wild-type mice lysed hepatocytes from both uninfected and infected mice. The hepatocytotoxic action of these cells was blocked by a perforin inhibitor but not by a neutralizing anti-Fas ligand Ab and was up-regulated by IL-12. Surprisingly, these cells killed hepatocytes in an MHC-unrestricted manner. However, CD1d-deficient mice that lack CD1d-restricted NK T cells, were susceptible to liver injury induced by P. berghei. Collectively, our results indicate that the liver injury induced by P. berghei infection of mice induces activation of the TLR-MyD88 signaling pathway which results in IL-12 production and activation of the perforin-dependent cytotoxic activities of MHC-unrestricted hepatic lymphocytes.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Imaging postsynaptic activities of teleost thalamic neurons at single cell resolution using a voltage-sensitive dye.

Optical recording of neuronal activities using voltage-sensitive dyes (VSDs) is a useful method for simultaneous multi-site recording. However, it has been rather difficult to distinguish optical signals from individual, identified cells. We applied the optical recording technique using a high-speed charge coupled device (CCD) imaging system to a teleost thalamic nucleus, corpus glomerulosum (CG) which has a well-defined histological organization and large postsynaptic dendrites. Patch-like dye (di-4-ANEPPS) signals were observed in the dendritic layer of the CG in response to afferent nerve stimulations. These responses were completely blocked by an alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionate (AMPA) receptor antagonist, did not propagate, and the size of the patches were close to that of a single dendritic tip of the 'large cell'. Thus, we found that these patch-like VSD signals most likely represent postsynaptic potentials at individual dendritic tips of the large cells.

Animals↗
PubMed2001

Interaction of Myc-associated zinc finger protein with DCC, the product of a tumor-suppressor gene, during the neural differentiation of P19 EC cells.

Expression of the DCC (deleted in colorectal cancer) protein is strongly induced during the neural differentiation of mouse P19 embryonal carcinoma (EC) cells that occurs when these cells are treated with retinoic acid (RA). Myc-associated zinc finger protein (MAZ) is a DNA-binding protein that is widely expressed and functions in human, mouse and hamster cells as an activator, an initiator or a terminator of transcription. However, the biological functions of MAZ remain elusive. We report here that MAZ associates with the cytoplasmic domain of the DCC protein in vivo and in vitro. Yeast two-hybrid assays confirmed this association. An immunofluorescence study demonstrated that DCC protein is expressed at elevated levels in neuron-like P19 EC cells, in particular in axons, in which the MAZ protein is also expressed. We found that MAZ was translocated from the nucleus to the cytoplasm during the RA-induced terminal differentiation of P19 EC cells with resultant loss of the ability of MAZ to bind to the ME1a1 site of the c-myc promoter. Taken together, our observations imply that the DCC protein might play a critical role as a signaling molecule in the regulation of the transcriptional activity of MAZ during the neural differentiation of P19 EC cells.

Active Transport, Cell Nucleus↗
PubMed2001

Catalytic asymmetric synthesis of 1,1'-spirobi[indan-3,3'-dione] via a double intramolecular C-H insertion process.

A highly efficient one-pot construction of optically active 1,1'-spirobi[indan-3,3'-dione] derivative (up to 80% ee) has been achieved by exploiting the double intramolecular C-H insertion reaction of dimethyl 2,2'-methylenebis(alpha-diazo-beta-oxobenzenepropanoate) under the influence of dirhodium(II) tetrakis[N-phthaloyl-(R or S)-tert-leucinate] as a catalyst.

Journal Article↗
PubMed2001

Mortality and readmission of hospitalized patients with congestive heart failure and preserved versus depressed systolic function.

Patients with congestive heart failure (CHF) and preserved systolic function are very common. Despite the high prevalence of this syndrome, very little information is known regarding its mortality and morbidity (e.g., readmission), or the efficacy of drugs. The purpose of this study was to compare the clinical characteristics and prognosis among consecutively hospitalized patients with CHF and preserved versus depressed left ventricular systolic function. Patients with severe aortic or mitral valve disease were excluded from the study. Patients were categorized based on the values of ejection fraction (EF) as having "preserved" (EF>50%), "intermediate" (EF 40% to 50%), or "depressed" (EF<40%) systolic function. Clinical characteristics as well as mortality and hospital readmission rates during 2.4 years of follow-up were recorded for each patient. Sixty-one patients (35%) had preserved systolic function, 73 (43%) had depressed function, and 38 (22%) had intermediate function. Patients with preserved systolic function were more often women and had a higher prevalence of left ventricular hypertrophy (all p <0.05). At follow-up, cumulative survival probabilities were similar between patients with preserved systolic function and those with systolic dysfunction (p = 0.84). Readmission rates were also comparable between preserved and depressed systolic function (36% vs 48%; p = NS). The prognosis of CHF patients with preserved systolic function was similar to those with systolic dysfunction. In light of these findings, effective therapeutic strategy for this subset of patients is needed.

Aged↗
PubMed2001

Lumen loss in transplant coronary artery disease is a biphasic process involving early intimal thickening and late constrictive remodeling: results from a 5-year serial intravascular ultrasound study.

BACKGROUND: Coronary artery disease is the major cause of late cardiac allograft failure. However, few data exist regarding the natural history of changes in intimal and external elastic membrane (EEM) areas after heart transplantation. METHODS AND RESULTS: In 38 transplant recipients, serial intravascular ultrasound examinations were performed 3.7+/-2.2 weeks after transplantation and annually thereafter for 5 years. In 59 coronary arteries, we compared 135 matched segments among serial studies. In each segment, intravascular ultrasound images were digitized at 1-mm intervals, and mean values of EEM and lumen and intimal areas were analyzed. In the first year after transplantation, the intimal area increased significantly from 1.8+/-1.6 to 3.0+/-2.1 mm(2) (P<0.001). Subsequently, the annual increase in intimal area decreased. EEM area did not change during the first year; however, between years 1 and 3, significant expansion of EEM area occurred (15.4+/-4.6 to 17.2+/-5.4 mm(2), P<0.001). Thereafter, EEM area decreased significantly from 17.2+/-5.4 mm(2) (year 3) to 15.1+/-4.9 mm(2) (year 5, P=0.01). Different mechanisms of lumen loss were observed during 2 phases after transplantation: early lumen loss primarily caused by intimal thickening and late lumen loss caused by EEM area constriction. CONCLUSIONS: This serial ultrasound study revealed that most of the intimal thickening occurred during the first year after heart transplantation. Changes in the EEM area showed a biphasic response, consisting of early expansion and late constriction. Thus, different mechanisms of lumen loss were observed during the early and late phases after transplantation.

Adult↗
PubMed2001

Enhanced generation of reactive oxygen species in the limb skeletal muscles from a murine infarct model of heart failure.

BACKGROUND: The generation of reactive oxygen species (ROS) is enhanced in the failing myocardium. We hypothesized that ROS were also increased in the limb skeletal muscles in heart failure. Methods and Results-- Myocardial infarction (MI) was created in mice by ligating the left coronary artery. After 4 weeks, the left ventricle was dilated and contractility was diminished by echocardiography. Left ventricular end-diastolic pressure was elevated after MI in association with an increase in lung weight/body weight and the presence of pleural effusion. The generation of ROS in the limb muscles, including the soleus and gastrocnemius muscles, which were excised after MI, was measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO). Overall, generation was increased, but it was attenuated in the presence of dimethylthiourea or 4,5-dihydroxy-1,2-benzenedisulfonic disodium salt in the reaction mixture, indicating increased generation of hydroxyl radicals originating from superoxide anion. Thiobarbituric acid-reactive substance formation was also increased in muscles after MI. Mitochondrial complex I and III activities were both decreased after MI, which may have caused the functional uncoupling of the respiratory chain and ROS production. Antioxidant enzyme activities, including superoxide dismutase, catalase, and glutathione peroxidase, were comparable between groups. CONCLUSIONS: Skeletal muscle in post-MI heart failure expressed an increased amount of ROS in association with ROS-mediated lipid peroxidation. This supports the hypothesis that oxidative stress may cause (at least in part) skeletal muscle dysfunction in heart failure.

Animals↗
PubMed2001

Fas ligand-induced caspase-1-dependent accumulation of interleukin-18 in mice with acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD), the fatal side effects of bone marrow transplantation, was shown to be accompanied by elevation of serum levels of interleukin 18 (IL-18). In this study, the mechanism underlying the accumulation of IL-18 in aGVHD in mice was investigated. Lethally irradiated recipients having transplantation with H-2 disparate donor splenocytes demonstrated aGVHD and contained markedly elevated serum levels of IL-18. In contrast, recipients having transplantation with gld/gld spleen cells, which lack functional Fas ligand (FasL), contained only normal ranges of IL-18, indicating FasL-mediated IL-18 release in aGVHD. The wild-type hosts engrafted with caspase-1-deficient cells revealed marked increases of IL-18 similar to those engrafted with wild-type cells, whereas caspase-1-deficient recipients engrafted with wild-type cells showed only a slight elevation of serum IL-18, indicating that IL-18 elevation is derived from host cells in a caspase-1-dependent manner. These results suggest FasL-mediated caspase-1-dependent IL-18 secretion in aGVHD in mice.

Acute Disease↗
PubMed2001

Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction.

Mitochondria are one of the enzymatic sources of reactive oxygen species (ROS) and could also be a major target for ROS-mediated damage. We hypothesized that ROS may induce mitochondrial DNA (mtDNA) damage, which leads to defects of mtDNA-encoded gene expression and respiratory chain complex enzymes and thus may contribute to the progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). In a murine model of MI and remodeling created by the left anterior descending coronary artery ligation for 4 weeks, the LV was dilated and contractility was diminished. Hydroxyl radicals, which originated from the superoxide anion, and lipid peroxide formation in the mitochondria were both increased in the noninfarcted LV from MI mice. The mtDNA copy number relative to the nuclear gene (18S rRNA) preferentially decreased by 44% in MI by a Southern blot analysis, associated with a parallel decrease (30% to 50% of sham) in the mtDNA-encoded gene transcripts, including the subunits of complex I (ND1, 2, 3, 4, 4L, and 5), complex III (cytochrome b), complex IV (cytochrome c oxidase), and rRNA (12S and 16S). Consistent with these molecular changes, the enzymatic activity of complexes I, III, and IV decreased in MI, whereas, in contrast, complex II and citrate synthase, encoded only by nuclear DNA, both remained at normal levels. An intimate link among ROS, mtDNA damage, and defects in the electron transport function, which may lead to an additional generation of ROS, might play an important role in the development and progression of LV remodeling and failure.

Animals↗
PubMed2001

Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1beta.

IL-18, produced as biologically inactive precursor, is secreted from LPS-stimulated macrophages after cleavage by caspase-1. In this study, we investigated the mechanism underlying caspase-1-mediated IL-18 secretion. Kupffer cells constantly stored IL-18 and constitutively expressed caspase-1. Inhibition of new protein synthesis only slightly reduced IL-18 secretion, while it decreased and abrogated their IL-1beta and IL-12 secretion, respectively. Kupffer cells deficient in Toll-like receptor (TLR) 4, an LPS-signaling receptor, did not secrete IL-18, IL-1beta, and IL-12 upon LPS stimulation. In contrast, Kupffer cells lacking myeloid differentiation factor 88 (MyD88), an adaptor molecule for TLR-mediated-signaling, secreted IL-18 without IL-1beta and IL-12 production in a caspase-1-dependent and de novo synthesis-independent manner. These results indicate that MyD88 is essential for IL-12 and IL-1beta production from Kupffer cells while their IL-18 secretion is mediated via activation of endogenous caspase-1 without de novo protein synthesis in a MyD88-independent fashion after stimulation with LPS. In addition, infection with Listeria monocytogenes, products of which have the capacity to activate TLR, increased serum levels of IL-18 in wild-type and MyD88-deficient mice but not in caspase-1-deficient mice, whereas it induced elevation of serum levels of IL-12 in both wild-type and caspase-1-deficient mice but not in MyD88-deficient mice. Taken together, these results suggested caspase-1-dependent, MyD88-independent IL-18 release in bacterial infection.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Unprecedented effects of achiral oxazolidinones on enantioselective radical-mediated conjugate additions using a chiral zinc triflate.

[figure: see text] A role of achiral oxazolidinones to enhance the enantioselectivity in reactions of N-cinnamoyloxazolidinones with alkyl radicals promoted by a chiral Lewis acid is described. Efficient enantioselective radical-mediated conjugate additions of N-cinnamoyloxazolidinone can be realized by use of a chiral zinc triflate generated from a readily prepared chiral bisoxazoline and an achiral oxazolidione. The NH moiety of achiral oxazolidinones is found to be necessary to enhance the enantioselectivity.

Journal Article↗