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Biomedical subjects

I Makino

Publications and source records attributed to I Makino.

At least 19 recordsLinked to original sources
PubMed2001

Bile acids regulate RANTES gene expression through its cognate NF-kappaB binding sites.

Regulated upon activation, normal T-cells expressed and secreted (RANTES) mainly migrates memory type CD4+ T-lymphocytes to inflamed tissues. In this study, we examined effects of bile acids on RANTES gene expression in human hepatoma cells. Upon stimulation with hydrophobic bile acids, RANTES proteins were clearly increased. Semiquantitative RT-PCR analysis revealed that chenodeoxycholic acid (CDCA) induced RANTES mRNA expression. Moreover, RANTES was transcriptionally induced in two hepatoma cell lines by CDCA, presumably via its cognate NF-kappaB binding sites in the RANTES promoter. Electrophoretic mobility shift assay revealed that hydrophobic bile acids induced DNA-binding activity of NF-kappaB. Additionally, the magnitude of inducibility was closely associated with the hydrophobicity of bile acids. In conclusion, we might indicate that bile acids induced RANTES gene expression in human hepatoma cells, possibly suggesting that bile acids play an important role in migration of inflammatory cells by RANTES to the liver in patients with primary biliary cirrhosis.

Antibodies↗
PubMed2001

Effect of central urocortin on carbon tetrachloride-induced acute liver injury in rats.

The effect of intracisternal injection of urocortin, an endogenous ligand for corticotropin-releasing factor (CRF) 2 receptor, on carbon tetrachloride (CCl4)-induced acute liver injury was investigated in rats. Intracisternal injection of urocortin dose-dependently enhanced elevation of serum alanine aminotransferase and aspartate aminotransferase levels induced by CCl4. Intracisternal urocortin also aggravated CCl4-induced histological changes of the liver. The aggravating effect of central urocortin on CCl4-induced acute liver injury was abolished by chemical sympathectomy, but not by vagotomy. These data demonstrate that urocortin acts in the brain to exacerbate acute liver injury through the sympathetic nervous system and suggest a possible involvement of the CRF2 receptor in the central CRF-induced exacerbation of acute liver injury in rats.

Acute Disease↗
PubMed2001

Phenotypic changes of adrenomedullin receptor components, RAMP2, and CRLR mRNA expression in cultured rat vascular smooth muscle cells.

Adrenomedullin is known to inhibit cell proliferation in cultured rat vascular smooth muscle cells, through a cAMP-dependent process. The calcitonin receptor-like receptor could function as an adrenomedullin receptor when co-expressed with receptor activity-modifying protein 2. To determine whether vascular adrenomedullin receptor components, the calcitonin receptor-like receptor and the receptor activity-modifying protein 2, phenotypically change during in vitro culture conditions, we examined the expression of adrenomedullin receptor components, adrenomedullin-induced cAMP production, and the inhibition of cell proliferation in culture rat vascular smooth muscle cells during serial passages. The results demonstrated that the receptor activity-modifying protein 2 and calcitonin receptor-like receptor mRNAs increased in a passage-dependent manner in rat vascular smooth muscle cells. Furthermore, the responses of both the elevation of cAMP and the inhibition of cell proliferation became larger in vascular smooth muscle cells with an increasing number of passages. The results suggest that the increase in functional AM receptor during phenotypic change may in part contribute to the development of vascular lesions, such as in atherosclerosis.

Adrenomedullin↗
PubMed2001

Functional modulation of the glucocorticoid receptor and suppression of NF-kappaB-dependent transcription by ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA) is the current mainstay of treatment for various liver diseases including primary biliary cirrhosis. UDCA acts as a bile secretagogue, cytoprotective agent, immunomodulator, and inhibitor of cellular apoptosis. Despite this cumulative evidence of the cytoprotective and immunosuppressive effects of UDCA, both the target molecule and pathway of UDCA action remain unknown. We previously described that, in the absence of glucocorticoid ligand, UDCA activates the glucocorticoid receptor (GR) into DNA binding species but does not elicit its transactivational function in a transient transfection assay. Here we further studied the molecular mechanism of UDCA action and revealed that the ligand binding domain of the GR is responsible for UDCA-dependent nuclear translocation of the GR. Indeed, we demonstrated that UDCA acts on the distinct region of the ligand binding domain when compared with the classical GR agonist dexamethasone, resulting in loss of coactivator recruitment and differential regulation of gene expression by the GR. Our data clearly indicated that UDCA, at least in part via activation of the GR, suppresses NF-kappaB-dependent transcription through the intervention of GR-p65 interaction. Together with the established clinical safety of UDCA, we may propose that UDCA could be a prototypical compound for development of a novel and selective GR modifier.

Active Transport, Cell Nucleus↗
PubMed2001

Changes in the levels of glutathione after cellular and cutaneous damage induced by squalene monohydroperoxide.

Squalene monohydroperoxide (Sq-OOH), the initial product of ultraviolet-peroxidated squalene, was used to investigate the effect of peroxidative challenge upon the glutathione contents in rabbit ear skin and primary-cultured fibroblasts derived from rabbit ear skin. The cellular reduced glutathione (GSH) contents decreased during 30-minute incubations in vitro with Sq-OOH, and oxidized glutathione (GSSG) was formed concomitantly, indicating that Sq-OOH had a potential for GSH-depleting activity in vitro. When Sq-OOH was applied topically to the skin in vivo, only GSSG contents increased significantly within 30 minutes. Moreover, pretreatment with the GSH depletors, DL-buthionine sulfoximine (BSO) and diethyl maleate (DEM), could potentiate the cytotoxicity and comedogenicity induced by Sq-OOH. These findings suggest that the endogenous antioxidant, glutathione, is quite sensitive to Sq-OOH and may be an important material for protecting cells and/or tissues against the oxidative stress induced by Sq-OOH treatment.

Animals↗
PubMed2001

Macrophage inflammatory protein-2 induced by TNF-alpha plays a pivotal role in concanavalin A-induced liver injury in mice.

BACKGROUND/AIMS: Macrophage inflammatory protein-2 (MIP-2), one of the CXC chemokines, is involved in the recruitment of neutrophils in several tissue injuries. In this study, we investigated the role of MIP-2 in concanavalin A (Con A)-induced liver injury in mice. METHODS: Liver injury was induced by intravenous injection of Con A (15 mg/kg) and plasma alanine aminotransferase (ALT), MIP-2 levels were determined and histological assessment of the liver was performed. Anti-mouse MIP-2 antibody was intravenously administered 30 min before Con A injection. RESULTS: The plasma ALT level significantly elevated and reached a maximum at 8 h after Con A injection. The plasma MIP-2 level was also elevated and reached a peak value at 2 h after Con A injection. The elevated ALT level by Con A injection was significantly inhibited by the MIP-2 antibody. The elevated plasma MIP-2 level after Con A injection was significantly reduced by the tumor necrosis factor alpha (TNF-alpha) antibody, and MIP-2 was induced in plasma after recombinant TNF-alpha injection. Hepatic necrosis and infiltration of neutrophils were observed after Con A injection, and these histological changes were attenuated by the MIP-2 antibody. CONCLUSIONS: These findings suggest that Con A induces TNF-alpha release, and this TNF-alpha stimulates MIP-2 induction, at least partially contributing to the liver injury mediated through the recruitment of neutrophils.

Alanine Transaminase↗
PubMed2001

Gastric neuropeptides and gastric motor abnormality in streptozotocin-induced diabetic rats: observation for four weeks after streptozotocin.

Alterations of gastric calcitonin gene-related peptide and substance P content and gastric emptying in early stages of streptozotocin-induced diabetic rats were investigated. Diabetes was induced by intravenous injection of streptozotocin (50 mg/kg) in male Wistar rats. Gastric emptying of phenol red solution and calcitonin gene-related peptide and substance P content of gastric walls, measured by radioimmunoassay, was assessed two and four weeks after streptozotocin injection. Gastric emptying two weeks after streptozotocin was delayed (32+/-9%) and that four weeks after was enhanced (73+/-2%) compared with nondiabetic control rats (50+/-3%). Calcitonin gene-related peptide content of the gastric antrum and corpus was increased two weeks after and decreased four weeks after streptozotocin, while gastric substance P content was not changed at any time in diabetic rats. Insulin treatment reversed alterations of gastric emptying and calcitonin gene-related peptide content. The delayed gastric emptying in two-week diabetic rats was reversed by CGRP antagonist and the enhanced gastric emptying in four-week diabetic rats was reversed by CGRP pretreatment. These results suggest a possible relationship between gastric calcitonin gene-related peptide and abnormal gastric motility in diabetic state.

Animals↗
PubMed2001

Aryl hydrocarbon receptor/dioxin receptor in human monocytes and macrophages.

Aryl hydrocarbon receptor (AhR) belongs to the bHLH/PAS transcription factor family and is activated by various polycyclic or halogenated aromatic hydrocarbons, e.g. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3-methylcholanthrene (3MC). In the present study, we showed that in U937 cells and human macrophages AhR, with its partner cofactor Arnt, is expressed and CYP1A1 mRNA expression is induced in the presence of AhR ligand 3MC. Moreover, we showed that AhR, associating with Arnt, binds to target DNA sequences and activates transcription. Since part of AhR is activated into DNA binding species in the absence of exogenous ligand and competitive AhR antagonist alpha-naphthoflavone inhibits this activation process with reducing CYP1A1 mRNA expression levels, the presence of endogenous ligand is indicated.

Benzoflavones↗
PubMed2001

Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study.

BACKGROUND: Non-alcoholic steatohepatitis is a distinct entity, characterized by fatty change, lobular inflammation and fibrosis of the liver. Some cases of non-alcoholic steatohepatitis progress to cirrhosis, but it is not easy to distinguish this disease from non-alcoholic fatty liver by non-invasive examinations. No proven therapy for non-alcoholic steatohepatitis exists. Transforming growth factor-beta1 is implicated in the development of liver fibrosis, and is inhibited by alpha-tocopherol (vitamin E) in the liver. Therefore, in this study, the significance of the measurement of the level of plasma transforming growth factor-beta1 and the effect of alpha-tocopherol on the clinical course of non-alcoholic steatohepatitis were investigated. METHODS: Twelve patients with non-alcoholic steatohepatitis and 10 patients with non-alcoholic fatty liver, with a diagnosis confirmed by liver biopsy, were studied. None of the patients had a history of alcohol abuse, habitual medicine or malignant or inflammatory diseases. All patients were negative for hepatitis B, C and G virus. Patients were given dietary instruction for 6 months, and then alpha-tocopherol (300 mg/day) was given for 1 year. Blood chemistries, measurement of plasma transforming growth factor-beta1 level and liver biopsies were undertaken before and after the 1-year alpha-tocopherol treatment. RESULTS: The serum alanine transaminase level decreased in non-alcoholic fatty liver patients, but not in non-alcoholic steatohepatitis patients, after 6 months of dietary therapy. Although the serum alanine transaminase level in non-alcoholic steatohepatitis patients was reduced during the 1-year alpha-tocopherol treatment, alpha-tocopherol had no effect on the serum alanine transaminase level in non-alcoholic fatty liver patients. The histological findings, such as steatosis, inflammation and fibrosis, of the non-alcoholic steatohepatitis patients were improved after alpha-tocopherol treatment. The plasma transforming growth factor-beta1 level in non-alcoholic steatohepatitis patients was significantly elevated compared with that in non-alcoholic fatty liver patients and healthy controls, and decreased, accompanied by an improvement in serum alanine transaminase level, with alpha-tocopherol treatment. CONCLUSIONS: Our data suggest that the measurement of the level of plasma transforming growth factor-beta1 represents a possible method of distinguishing between non-alcoholic steatohepatitis and non-alcoholic fatty liver. Long-term alpha-tocopherol treatment may be safe and effective for non-alcoholic steatohepatitis. A randomized, controlled, double-blind trial is needed to confirm the full potential of alpha-tocopherol in the management of non-alcoholic steatohepatitis.

Adult↗
PubMed2001

Alteration of the adrenomedullin receptor components gene expression associated with the blood pressure in pregnancy-induced hypertension.

Adrenomedullin (AM) is a potent vasodilator. Pregnancy-induced hypertension (PIH) is a common cause of maternal or fetal mortality. We measured the changes of adrenomedullin receptor components gene expression, receptor activity-modifying protein 2 (RAMP2) and calcitonin receptor-like receptor (CRLR), at feto-maternal tissues in human normotensive pregnant women and pregnancy-induced hypertensive women by Northern blot analysis. Samples of the placenta, uterine muscle, umbilical artery, and fetal membranes were obtained from each patient under informed consent. RAMP2 mRNA significantly decreased in the umbilical artery (54%, P < 0.01) and uterus (53%, P < 0.01) of the patients with PIH. CRLR mRNA also significantly decreased in both tissues of the patients with PIH. On the other hand, the RAMP2 mRNA was significantly increased in the fetal membrane of the patients with PIH. In addition, there was a significant negative correlation between the RAMP2 mRNA levels in the umbilical artery (systolic; r = -0.623, P < 0.01, diastolic; r = -0.552, P < 0.01) and uterine muscle (systolic; r = -0.563, P < 0.01, diastolic; r = -0.553, P< 0.01) and blood pressure. However, there was no correlation between the mRNA level and blood pressure in fetal membrane and placenta, suggesting that there is no close relationship to the pathogenesis in PIH. These findings suggested that the reduced expression of adrenomedullin receptor component in umbilical artery and uterus may have some role in PIH.

Adult↗
PubMed2000

Increased levels of advanced glycosylation end products in the kidney and liver from spontaneously diabetic Chinese hamsters determined by immunochemical assay.

Increased levels of advanced glycosylation end products (AGEs) have been reported in tissues in association with diabetes mellitus. Thus, we measured tissue AGE levels and detected an accumulation of AGEs in the kidney and liver from spontaneously diabetic Chinese hamsters (CHAD) to determine the relationship between AGEs and diabetes mellitus. Diabetic CHAD aged 12 to 13 months were studied together with age-matched nondiabetic CHAD. We used an AGE-specific noncompetitive enzyme-linked immunosorbent assay (ELISA) with polyclonal anti-AGE-bovine serum albumin (BSA) antibody to measure tissue AGE levels. The samples extracted from the kidney and liver obtained from diabetic and nondiabetic CHAD reacted with anti-AGE-BSA antibody. When the absorbance of standard AGE-BSA (0.1 microg/mL) was expressed as 1 U, AGE levels in the kidney and liver from diabetic CHAD were significantly increased as compared with nondiabetic CHAD (kidney, 0.26 +/- 0.05 v 0.10 +/- 0.03 U/microg protein, P< .01; liver, 0.20 +/- 0.03 v 0.09 +/- 0.02 U/microg protein, P< .01). Positive AGE staining was observed in the renal cortex, especially in the tubules of diabetic CHAD, but little AGE staining was observed in the glomerulus by the immunohistochemical study. AGE staining was diffuse in the hepatocytes. These AGE levels were significantly correlated with fasting plasma glucose and glycated hemoglobin (P < .01, respectively). In conclusion, we have confirmed that AGE structures were expressed in the kidney and liver from CHAD, and these AGE levels were increased in diabetic CHAD. AGE staining was observed in the renal tubules and hepatocytes. Tissue AGE levels were positively correlated with glycemic control in CHAD.

Animals↗
PubMed2000

Detection of the association between a deletion polymorphism in the gene encoding angiotensin I-converting enzyme and advanced diabetic retinopathy.

We investigated the relationship between advanced diabetic retinopathy (ADR) and an angiotensin-converting enzyme (ACE) gene polymorphism in subjects with type 2 diabetes and ADR, pre-proliferative (PrePDR) or proliferative diabetic retinopathy (PDR) without overt nephropathy. Polymerase chain reactions were used to detect insertion/deletion (I/D) polymorphisms of the ACE gene. There was no difference in the frequency of II, ID, or DD genotypes, or of I and D alleles among subjects with type 2 diabetes without diabetic retinopathy (NDR) or with simple diabetic retinopathy (SDR) and non-diabetic controls. There was also no difference in the frequency of ACE genotypes among subjects with type 2 diabetes with NDR, or SDR and ADR. However, the frequency of the ACE DD genotype in ADR was significantly higher than that in controls (chi(2)=6.64, P=0.036). On the other hand, the frequency of the D allele in ADR was significantly higher than that in controls (chi(2)=6.33, P=0.012), NDR (chi(2)=4.18, P=0.041) and SDR (chi(2)=4. 89, P=0.027), respectively. These results indicate a significant relationship between the presence of the D allele polymorphism in the ACE gene and ADR in Japanese subjects with type 2 diabetes and no overt nephropathy.

Albuminuria↗
PubMed2000

Functional modulation of the mineralocorticoid receptor by cis-diamminedichloroplatinum (II).

BACKGROUND: Renal salt wasting and hypotension are some of the frequent complications in patients treated with cis-diamminedichloroplatinum (II) (cDDP), and it is suggested that cDDP produces an abnormality in the renin-angiotensin system. However, not only the underlying mechanism but also prophylactic treatment of this cDDP toxicity remains unknown. In the present study, we investigated the molecular mechanism of this cDDP-induced disturbance of renal sodium handling with focusing on the effect of cDDP on mineralocorticoid receptor (MR) function. METHODS: The effect of cDDP was studied on nuclear translocation, DNA binding activity, and transactivation function of the MR. RESULTS: In a transient transfection assay, cDDP suppressed MR-dependent reporter gene expression. This cDDP-mediated repression of MR function, at least in part, is suggested to be due to the generation of reactive oxygen species and a subsequent decrease in ligand-dependent nuclear translocation and suppression of the interaction with DNA of the MR. This redox-dependent repression of MR function both in vitro and in vivo was reversed by treatment with reducing reagents. Moreover, cDDP, most possibly via formation of DNA adducts, inhibited MR-DNA interaction in a redox-independent fashion. CONCLUSIONS: MR function is impaired by cDDP at multiple levels, via redox-dependent and -independent mechanisms.

Animals↗
PubMed2000

Comedogenicity of squalene monohydroperoxide in the skin after topical application.

The comedogenicity of squalene peroxides was examined on the rabbit ear skin after topical application of squalene-monohydroperoxide (Sq-OOH), the initial product when squalene was irradiated with UV-A. Since comedogenic products from UV-irradiated squalene were extracted with methanol solution, we isolated Sq-OOH by reverse-phased HPLC with a methanol mobile phase solvent. The degree of comedogenic reaction induced by Sq-OOH was higher than that of well-known comedogenic cosmetic ingredients. Unlike two other mono-peroxides, tert-butyl hydroperoxide and cumene-mono-hydroperoxide, Sq-OOH induced comedo-formation in the rabbit ear skin. However, the comedogenicity of reduced Sq-OOH, squalene-hydroxide (Sq-OH) and squalene itself was lower than that of Sq-OOH. These results indicate that Sq-OOH is a potent comedogenic mono-hydroperoxide chemical to rabbit skin.

Acne Vulgaris↗
PubMed1999

Potentiation of the hypotensive effect of adrenomedullin in pregnant rats.

The hypotensive effect of adrenomedullin, a potent vasodilator peptide, was examined in conscious pregnant (6, 13 and 20 days of pregnancy) and non-pregnant rats. The intravenous administration of adrenomedullin (0.01-3.0 nmol/kg) produced a dose-dependent depressor response in pregnant and non-pregnant rats. At low doses (0.01-0.1 nmol/kg), the maximum decrease in blood pressure was significantly higher in pregnant rats (20 days pregnant) than in non-pregnant rats. At high doses, no significant difference was observed between the two groups. Furthermore, the administration of adrenomedullin did not significantly affect the basal mean blood pressure (MBP) at any dose when compared to the non-pregnant group at 6 and 13 days of pregnancy. In the ovariectomized rats, the depressor responses in 17beta-estradiol-treated, progesterone-treated and 17beta-estradiol+progesterone-treated rats were not significantly different from that in the control rats, suggesting that the augmented effect on the depressor response to adrenomedullin in pregnant rats may not be due to hormonal changes during pregnancy. The adrenomedullin receptor mRNA level of the descending thoracic aorta was significantly higher in the late-pregnancy rats (20 days of pregnancy). However, the levels did not show any difference between the early-pregnant rats (6 and 13 days of pregnancy) and the non-pregnant rats. These findings suggested that the changes in the depressor response to adrenomedullin which occur at term in pregnant rats may be mediated by changes of adrenomedullin receptor gene expression rather than by sex hormones.

Adrenomedullin↗