PubMed Health⌕ Search

Biomedical subjects

Go Hasegawa

Publications and source records attributed to Go Hasegawa.

At least 19 recordsLinked to original sources
PubMed2025

Mitochondrial dysfunction in MED13 variant-associated disease: a case of infantile spasms, cardiomyopathy and hepatomegaly.

Here we report a de novo heterozygous MED13 variant (c.2503C>T, p.Pro835Ser) in an infant presenting with infantile spasms, hypertrophic cardiomyopathy and hepatomegaly. Autopsy revealed mitochondrial abnormalities in cardiac and hepatic tissues, with reduced respiratory chain complex activity. This is the first case report linking a MED13 variant to systemic mitochondrial dysfunction, suggesting a novel pathogenic mechanism.

Journal Article↗
PubMed2006

Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette-Guerin cell wall skeleton stimulation.

PURPOSE: We developed an effective immunotherapy, which could induce antitumor immune responses against shared and unique tumor antigens expressed in autologous tumors. EXPERIMENTAL DESIGN: Intratumoral administration of dendritic cells is one of the individualized immunotherapies; however, the antitumor activity is relatively weak. In this study, we attempted to enhance the antitumor efficacy of the i.t. dendritic cell administration by combining dendritic cells stimulated with Bacillus Calmette-Guerin cell wall skeleton (BCG-CWS) additionally with cryoablative pretreatment of tumors and analyzed the therapeutic mechanisms. RESULTS: These two modifications (cryoablation of tumors and BCG-CWS stimulation of dendritic cells) significantly increases the antitumor effect on both the treated tumor and the untreated tumor, which was distant at the opposite side, in a bilateral s.c. murine CT26 colon cancer model. Further analysis of the augmented antitumor effects revealed that the cryoablative pretreatment enhances the uptake of tumor antigens by the introduced dendritic cells, resulting in the induction of tumor-specific CD8(+) T cells responsible for the in vivo tumor regression of both treated and remote untreated tumors. This novel combination i.t. dendritic cell immunotherapy was effective against well-established large tumors. The antitumor efficacy was further enhanced by depletion of CD4(+)CD25(+)FoxP3(+) regulatory T cells. CONCLUSIONS: This novel dendritic cell immunotherapy with i.t. administration of BCG-CWS-treated dendritic cells following tumor cryoablation could be used for the therapy of cancer patients with multiple metastases.

Adjuvants, Immunologic↗
PubMed2006

Development and maturation of thymic dendritic cells during human ontogeny.

Thymic dendritic cells (TDC) are dendritic cells situated mainly in the cortico-medullary zone and in the medullary region of the thymus. However, the phenotype of TDC during ontogeny is poorly documented. The aim of this study has been to investigate the development and maturation of TDC during human ontogeny. Immunohistochemical analyses and immunoelectron-microscopic investigation of 21 human thymus specimens have been performed to detect the subtypes of TDC by using various DC-related and DC-development-related markers. TDC express a Langerhans-cell-like phenotype during human ontogeny. Cells expressing thymic stromal lymphopoietin receptor have been observed in Hassal's corpuscles of the thymus. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is also expressed in thymic epithelial cells (TEC) localized in Hassal's corpuscles. During human ontogeny, GM-CSF is produced by TEC of Hassal's corpuscles and might play a key role in the differentiation of TDC having Langerhans-cell-like phenotypes.

Antigens, CD↗
PubMed2006

Erythroid cells play essential roles in angiogenesis by bone marrow cell implantation.

Bone marrow cell implantation (BMI) has been utilized to treat patients with limb and heart ischemia. BMI provides angiogenic precursors and angiogenic cytokine-producing cells, especially erythroid cells. In this study, we induced in vitro angiogenesis cultures and in vivo BMI simulation using a murine limb ischemia model to examine the role of erythroid cells and the effect of erythropoietin (EPO). Human erythroid colonies (BFU-e) induced capillary networks around the colonies in vitro. Erythroid cells in human bone marrow produced vascular endothelial growth factor and placental growth factor. The angiogenic effects of erythroid cells were further amplified in the presence of EPO. Limb-ischemic mice were treated with BMI +/- EPO, and limb survival, blood flow recovery, and muscle histology were analyzed. Treatment with whole bone marrow cells + EPO significantly improved limb survival and blood flow. The cumulative effects of EPO on BMI induced and increase in capillary number and artery enlargement. Erythroid cells were essential for the in vivo effects of BMI, and CD14-positive cells supported the biological effects. In addition to the direct effect of EPO on angiogenesis, EPO showed indirect effect on angiogenesis through amplifying the angiogenic effects by erythroid cells supported by CD14-positive cells.

Adult↗
PubMed2006

Multiple extranodal follicular dendritic cell tumors initially presenting in the soft tissue in the chest wall.

A follicular dendritic cell (FDC) tumor that involved the soft tissue of the chest wall, liver and thyroid was reported in a 72-year-old Japanese man. A biopsy specimen from the chest wall showed an uncommon malignant soft-tissue tumor. No distinct immunohistochemical reactions were found. The patient died 1 year after the initial presentation. No definite diagnosis was given until autopsy was performed. Upon autopsy, each tumor was well-circumscribed and a solid tan-gray color on cut section. Microscopically, the tumor cells were composed of oval to spindle cells arranged in a short fascicular growth pattern. The autopsy specimen from the soft tissue of the chest wall had a strong reaction for CD21/CD35 and clusterin, a new FDC marker, whereas the biopsy specimen had an undistinct reaction for CD21/CD35 and a weak reaction for clusterin. FDC makers assisted in this diagnosis, especially with the autopsy specimen. In conclusion, it was difficult to diagnose an FDC tumor because of the particular tumor sites involved, lack of characteristic microscopic features, and because of aggressive tumor behavior.

Aged↗
PubMed2005

SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice.

In obesity-related insulin resistance, pancreatic islets compensate for insulin resistance by increasing secretory capacity. Here, we report the identification of sex-determining region Y-box 6 (SOX6), a member of the high mobility group box superfamily of transcription factors, as a co-repressor for pancreatic-duodenal homeobox factor-1 (PDX1). SOX6 mRNA levels were profoundly reduced by both a long term high fat feeding protocol in normal mice and in genetically obese ob/ob mice on a normal chow diet. Interestingly, we show that SOX6 is expressed in adult pancreatic insulin-producing beta-cells and that overexpression of SOX6 decreased glucose-stimulated insulin secretion, which was accompanied by decreased ATP/ADP ratio, Ca(2+) mobilization, proinsulin content, and insulin gene expression. In a complementary fashion, depletion of SOX6 by small interfering RNAs augmented glucose-stimulated insulin secretion in insulinoma mouse MIN6 and rat INS-1E cells. These effects can be explained by our mechanistic studies that show SOX6 acts to suppress PDX1 stimulation of the insulin II promoter through a direct protein/protein interaction. Furthermore, SOX6 retroviral expression decreased acetylation of histones H3 and H4 in chromatin from the promoter for the insulin II gene, suggesting that SOX6 may decrease PDX1 stimulation through changes in chromatin structure at specific promoters. These results suggest that perturbations in transcriptional regulation that are coordinated through SOX6 and PDX1 in beta-cells may contribute to the beta-cell adaptation in obesity-related insulin resistance.

Acetylation↗
PubMed2005

The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis.

PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePten(flox/+) mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85alpha and p110gamma. In vitro, Tie2CrePten(flox/+) endothelial cells showed enhanced proliferation/migration. Tie2CrePten(flox/flox) mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110gamma rather than on p85alpha and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.

Animals↗
PubMed2005

Synthesis and characterization of a novel reagent containing dansyl group, which specifically alkylates sulfhydryl group: an example of application for protein chemistry.

We have synthesized a novel reagent containing dansyl group, iodoacethyl dansylcadaverine (IADC), which specifically alkylates sulfhydryl groups. The carboxyl group of iodoacetic acid was activated with dicyclohexylcarbodiimide and was condensed with amino group of dansylcadaverine. Purity and chemical structure of IADC was confirmed with mass spectrometry (MS) and NMR. IADC alkylated GSH but not GSSG, which was confirmed by MS. The reactivity of IADC with proteins was also investigated with Western blotting using anti-dansyl antibody. IADC reacted only with sulfhydryl-containing proteins. The specificity of the interaction of IADC with sulfhydryl groups in proteins was confirmed by adding excessive amount of a well-known sulfhydryl-specific reagent, 5, 5'-dithiobis(2-nitrobenzoic acid), which led to a complete inhibition. To show the usefulness of IADC, the cysteines in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from chicken muscle were modified with this reagent, and GAPDH was then digested by lysyl endopeptidase. The peptides generated from digestion of IADC-incorporated GAPDH were applied to an anti-dansyl immunoaffinity column. The peptide fragments bound and eluted from the column were separated by HPLC, and the amino acid sequence of each peptide was analyzed, and peptide was identified as the one containing a Cys residue(s). These data showed that IADC is a useful reagent to specifically identify the positions of a Cys residue(s) in proteins.

Amino Acid Sequence↗
PubMed2005

Humoral hypercalcemia complicating adenocarcinoma of the sigmoid colon: report of a case.

Humoral hypercalcemia can arise from a variety of malignancies, but its association with primary colorectal carcinoma is rare, with only 20 such cases documented in the English-language literature to date. We report an additional case to clarify the clinicopathologic features of colorectal carcinoma with humoral hypercalcemia. A 54-year-old woman was admitted with symptomatic hypercalcemia of 14.2 mg/dl and multiple hepatic metastases, 2 years after resection of sigmoid colon cancer. The hypercalcemia was caused by the circulating parathyroid hormone-related peptide (PTHrP) produced by poorly differentiated adenocarcinoma in the liver. The PTHrP level on admission was 13.5 pmol/l. Despite systemic chemotherapy, the patient died of disease progression 3 weeks after the humoral hypercalcemia was diagnosed. A review of the 21 reported cases, including ours, suggests that colorectal carcinoma associated with humoral hypercalcemia is characterized by a poorly differentiated tumor with or without squamous or neuroendocrine features, distant metastases, and a dismal prognosis.

Adenocarcinoma↗
PubMed2005

Human neuroblastoma GOTO cells express CD44 and localize it into lipid rafts upon differentiation into Schwannian cells.

Neuroblastoma, which is a malignant tumor consisting of dedifferentiated neuroectodermal cells, is known to show spontaneous maturation or regression in its growth. Cultured human neuroblastoma GOTO cells could be induced to differentiate into Schwannian cells and neuronal cells by incubation in the presence of 5-bromo-2'-deoxyuridine (BrdU) and by serum depletion, respectively. Here we report that in association with these differentiations, cells differentiated into Schwannian cells specifically expressed a cell adhesion molecule CD44, of which expression is usually suppressed in GOTO cells. In contrast, it remained suppressed in cells differentiated into neuronal cells. Polymerase-chain reaction revealed that the CD44 species expressed was the hemopoietic form (CD44H) with long cytoplasmic tail. Furthermore, the newly expressed CD44 in the cells was found exclusively in membrane microdomains, called lipid rafts. These data suggest that CD44 might play an important role in GOTO cells differentiated into Schwannian cells.

Amino Acid Sequence↗
PubMed2004

Differentiation and function of Kupffer cells.

Kupffer cells are the largest population of tissue macrophages. They are predominantly distributed in the lumen of hepatic sinusoids and exhibit endocytic activity against blood-borne materials entering the liver. Macrophage colony-stimulating factor and other growth factors regulate Kupffer cell differentiation in the fetal and adult period. Because of the unique attributes of tissue, Kupffer cells play essential roles not only in host defense but also in the homeostatic responses of tissue. Macrophage scavenger receptors and heme oxygenase are expressed in Kupffer cells from an early stage of ontogeny. Scavenger receptors are involved not only in the lipid metabolism but also in the bactericidal mechanism. Heme oxygenase in Kupffer cells is essential to the production of bilirubin. In this review, the developmental mechanism and functional activities of Kupffer cells are described. Evidence suggests that Kupffer cells represent a distinct cell population with unique differentiation mechanisms, metabolic functions, and responsiveness to inflammatory agents.

Aging↗
PubMed2004

Effects of pranidipine, a novel calcium channel antagonist, on the progression of left ventricular dysfunction and remodeling in rats with heart failure.

The cardioprotective properties of pranidipine were studied in a rat model of heart failure after autoimmune myocarditis. Twenty-eight days after immunization the surviving rats were divided into three groups and received oral treatment of 0.03 mg/kg/day (group 0.03) or 0.3 mg/kg/day (group 0.3) of pranidipine or vehicle (group V) for 1 month. High-dose pranidipine (group 0.3) improved the survival rate, and significantly reduced heart weight, heart weight to body weight ratio, myocardial fibrosis, central venous pressure and left ventricular end-diastolic pressure than low-dose pranidipine (group 0.03) and group V. Pranidipine at high dose also decreased the left ventricular systolic and diastolic dimensions, and increased fractional shortening compared with group V. The increase in level of TGF-beta1 and collagen-III mRNA were suppressed by pranidipine in a dose-dependent manner. Our results indicated that pranidipine has cardioprotective effects on heart failure, and that the beneficial effect can be partly explained by attenuation of fibrotic response through suppression of TGF-beta1 and collagen-III mRNA expression, and regression of myocyte hypertrophy.

Animals↗
PubMed2004

Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.

PTEN is a tumor suppressor gene mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP system to generate a hepatocyte-specific null mutation of Pten in mice (AlbCrePten(flox/flox) mice). AlbCrePten(flox/flox) mice showed massive hepatomegaly and steatohepatitis with triglyceride accumulation, a phenotype similar to human nonalcoholic steatohepatitis. Adipocyte-specific genes were induced in mutant hepatocytes, implying adipogenic-like transformation of these cells. Genes involved in lipogenesis and beta-oxidation were also induced, possibly as a result of elevated levels of the transactivating factors PPARgamma and SREBP1c. Importantly, the loss of Pten function in the liver led to tumorigenesis, with 47% of AlbCrePten(flox/flox) livers developing liver cell adenomas by 44 weeks of age. By 74-78 weeks of age, 100% of AlbCrePten(flox/flox) livers showed adenomas and 66% had hepatocellular carcinomas. AlbCrePten(flox/flox) mice also showed insulin hypersensitivity. In vitro, AlbCrePten(flox/flox) hepatocytes were hyperproliferative and showed increased hyperoxidation with abnormal activation of protein kinase B and MAPK. Pten is thus an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver.

Adipocytes↗
PubMed2004

Plasma concentrations of cytokines and neurohumoral factors in a case of fulminant myocarditis successfully treated with intravenous immunoglobulin and percutaneous cardiopulmonary support.

A 53-year-old Japanese man with fulminant myocarditis was referred. Percutaneous cardiopulmonary support (PCPS) was introduced immediately and intravenous immunoglobulin (IVIG) therapy followed for 2 days. Cardiac function showed signs of recovery on the 4th hospital day and the patient was weaned from PCPS on the 7th hospital day. Creatine kinase-MB peaked at 12 h after admission and was 176 ng/ml. Endomyocardial biopsy showed active myocarditis. A marked increase of the neutralizing antibody titer suggested coxsackievirus B3 infection. Plasma concentrations of cytokines and neurohumoral factors were analyzed. Proinflammatory cytokines, such as interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF-alpha), and anti-inflammatory cytokines, such as IL-1 receptor antagonist, soluble TNF receptor-1 and IL-10, were elevated on admission and all had decreased on the 7th hospital day. Brain natriuretic peptide and noradrenaline were already elevated upon admission (1,940 pg/ml and 4.6 ng/ml, respectively) and decreased thereafter. Although IVIG therapy under PCPS is a common treatment for fulminant myocarditis, the immunological response in vivo remains unclear. This case demonstrated suppression of serum cytokines after IVIG and PCPS treatment. Immunological parameters in those who have been treated with IVIG and PCPS and survived without complications are of great value for evaluation of the therapy. Further analysis with more cases in a multicenter study is necessary.

Cardiology↗
PubMed2003

12(S)-Hydroxyeicosatetraenoic acid induces cAMP production via increasing intracellular calcium concentration.

We have found that a 12-lipoxygenase metabolite of arachidonic acid, 12(S)-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-HETE), induces cAMP production in human normal fibroblast TIG-1 cells. This phenomenon was not observed in other cells tested including human embryonic kidney HEK293 cells. We have speculated that this specific response might be influenced by the kinds of isoform of adenylyl cyclase (AC) present in cells. We found that TIG-1 cells specifically expressed type VIII AC. As type VIII AC is known to be activated by an increase of calcium concentration, we determined the change of intracellular Ca2+ concentration after the addition of 12-HETE. It was elevated not only in TIG-1 cells, but also HEK293 cells, which did not respond to 12-HETE to produce cAMP. The addition of a calcium ionophore elevated the concentration of intracellular cAMP in TIG-1 cells, but it was without effect in HEK293 cells. To show that the expression of this particular isoform of AC is responsible for the positive response to 12-HETE, we transfected this AC isoform into HEK293 cells. The type VIII AC-transfected cells, in contrast to the mock-transfected ones, became very responsive to 12-HETE to produce cAMP. Taken all together the data would strongly suggest that 12-HETE specifically activates type VIII AC via increasing intracellular Ca2+ concentration.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed2003

A novel function of tissue-type transglutaminase: protein disulphide isomerase.

We have found that tissue-type transglutaminase (tTG), also called TGc, TGase2 and Galpha(h), has the activity of protein disulphide isomerase (PDI). We have shown that tTG converts completely reduced/denatured inactive RNase A molecule to the native active enzyme. The PDI activity of tTG was strongly inhibited by bacitracin, which is a frequently used inhibitor of conventional PDI activity. It was substantially inhibited by the simultaneous presence of other potential substrate proteins such as completely reduced BSA, but not by native BSA. This activity was especially high in the presence of GSSG, but not GSH. The addition of GSH to the reaction mixture in the presence of GSSG at a fixed concentration up to at least 200-fold excess did not very substantially inhibit the PDI activity. It is possible that tTG can exert PDI activity in a fairly reducing environment like cytosol, where most of tTG is found. It is quite obvious from the following observations that PDI activity of tTG is catalysed by a domain different from that used for the transglutaminase reaction. Although the alkylation of Cys residues in tTG completely abolished the transglutaminase activity, as was expected, it did not affect the PDI activity at all. This PDI activity did not require the presence of Ca(2+). It was not inhibited by nucleotides including GTP at all, unlike the other activity of tTG.

Chromatography, Gel↗