Role of putative phosphorylation sites in down-regulation of histamine H1 receptors.
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Amino Acids↗
Biomedical subjects
H Fukui
Publications and source records attributed to H Fukui.
Characteristics of the antihistamine effect of TAK-427, a novel imidazopyridazine derivative.
OBJECTIVE AND DESIGN: The characteristics of the antihistamine effect of the new antiallergic compound TAK-427 were investigated. MATERIALS AND METHODS: In vitro binding assay of [(3)H] pyrilamine was performed using recombinant human histamine H(1) receptors (rhH(1)R). In vivo studies were performed in male ICR mice or Hartley guinea pigs. Drugs were administered orally 1 h before examinations. Determinations were made of histamine-induced skin reaction, ex vivo measured radioligand binding to brain and lung H(1) receptors, pentobarbital-induced sleeping time, passive cutaneous anaphylaxis (PCA) reaction, and antigen-induced itch-scratch responses (ISRs). RESULTS: TAK-427 inhibited ligand binding to rhH(1)R with an IC(50) value of 17.3 nmol/l. TAK-427 inhibited histamine-induced skin reactions in guinea pigs and mice with an ID(50) value of 0.884 and 0.450 mg/kg, p.o., respectively; significant inhibition associated with 10 mg/kg of TAK-427 was still observed 24 h after dosing in guinea pigs. TAK-427 showed as high selectivity for peripheral H(1) receptors as terfenadine and epinastine did, which was evaluated by ex vivo measured radioligand binding. Even at 300 mg/kg, TAK-427 did not affect pentobarbital-induced sleeping time in mice. TAK-427 significantly inhibited PCA in mice and guinea pigs, and also inhibited antigen-induced ISRs in guinea pigs. CONCLUSIONS: These results suggest that TAK-427 may have a long-lasting antihistamine activity with minimum sedative side effect and suppress acute phase allergic reactions.
Algorithms↗
Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis.
BACKGROUND: It has been shown that expression of the potent angiogenic factor, vascular endothelial growth factor (VEGF), and its receptors, flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2), increased during the development of liver fibrosis. AIMS: To elucidate the in vivo role of interaction between VEGF and its receptors in liver fibrogenesis. METHODS: A model of CCl(4) induced hepatic fibrosis was used to assess the role of VEGFR-1 and VEGFR-2 by means of specific neutralising monoclonal antibodies (R-1mAb and R-2mAb, respectively). R-1mAb and R-2mAb were administered after two weeks of treatment with CCl(4), and indices of fibrosis were assessed at eight weeks. RESULTS: Hepatic VEGF mRNA expression significantly increased during the development of liver fibrosis. Both R-1mAb and R-2mAb treatments significantly attenuated the development of fibrosis associated with suppression of neovascularisation in the liver. Hepatic hydroxyproline and serum fibrosis markers were also suppressed. Furthermore, the number of alpha-smooth muscle actin positive cells and alpha1(I)-procollagen mRNA expression were significantly suppressed by R-1mAb and R-2mAb treatment. The inhibitory effect of R-2mAb was more potent than that of R-1mAb, and combination treatment with both mAbs almost completely attenuated fibrosis development. Our in vitro study showed that VEGF treatment significantly stimulated proliferation of both activated hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC). VEGF also significantly increased alpha1(I)-procollagen mRNA expression in activated HSC. CONCLUSIONS: These results suggest that the interaction of VEGF and its receptor, which reflected the combined effects of both on HSC and SEC, was a prerequisite for liver fibrosis development.
Animals↗
Inhibition of histamine H1 receptor downregulation by KT5823, a protein kinase G inhibitor.
The role of various protein kinases in the downregulation of histamine H(1) receptors was studied by using their inhibitors and activators. Human histamine H(1) receptors (H(1)Rs) expressed in CHO cells were downregulated by histamine in a dose- and time-dependent manner, and this downregulation continued to increase over a 24-h period. KT5823, an inhibitor of protein kinase G, remarkably but not completely reversed the histamine-induced H(1)R downregulation over 24 h. HA1004, another inhibitor of protein kinase G, showed a similar inhibitory effect. However, both 8-Br-cGMP and 8-pCPT-cGMP, membrane-permeable analogues of cGMP, did not show any effects on H(1)R downregulation in the absence or presence of histamine. Ro 31-8220, an inhibitor of protein kinase C (PKC), did not affect histamine-induced downregulation of H(1)R; nor did phorbol 12-myristate 13-acetate, a PKC-activating phorbol ester. Similarly, histamine-induced downregulation of H(1)R was unaffected by either H-89, an inhibitor of protein kinase A, or 8-Br-cAMP, a membrane-permeable analogue of cAMP.
8-Bromo Cyclic Adenosine Monophosphate↗
[Thoracoscopic resection of localized fibrous tumor of the pleura; report of a case and review of the Japanese literature].
A 61-year-old female was admitted with abnormal shadow on chest X-ray. Chest computed tomography (CT) showed a clearly localized flat tumor at the peripheral region of the left lung. We suspected localized fibrous tumor of the pleura (LFTP) and performed video-assisted thoracic surgery (VATS). Under the thoracoscopy, the tumor was connected to the visceral pleura with a short pedicle and completely resected with safety margin. Pathological findings, including immunohistochemical examination, definitely revealed benign LFTP. VATS is a good indication for the diagnosis and treatment of LFTP. This case was reported together with some reviews of the literature.
Female↗
[A resected case of malignant fibrous histiocytoma of the chest wall].
We report a 74-year-old woman with malignant fibrous histiocytoma (MFH), treated successfully by radiation and followed with chest wall resection and reconstruction. The patient suffered from right back pain and her chest X-ray showed a clear round shadow in the middle field of the right lung. Chest computed tomography (CT) showed a 5 x 5 cm tumor in diameter, involving the right 8 rib with destructive changes. After radiation therapy of total 30 Gy to the tumor to obtain the safety surgical margin, we widely resected 10 x 9 cm chest wall with 3 ribs in area under thoracoscopy and performed reconstruction using GORE-TEX Soft Tissue Patch. The pathological and immuno-histochemical diagnosis showed pleomorphic type of MFH. Final result of the tumor negative in surgical margin manifested that our technique of chest wall resection and reconstruction using thoracoscope after the irradiation to the tumor was very safe and useful.
Aged↗
Insulin-induced up-regulation of histamine H1-receptors.
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Astrocytoma↗
A case of aceruloplasminaemia: abnormal serum ceruloplasmin protein without ferroxidase activity.
A 34 year old diabetic man with a complete deficiency of serum ferroxidase activity, regardless of the presence of serum ceruloplasmin (Cp), a multicopper ferroxidase protein, is described. The patient had had diabetes mellitus for 13 years, and was also found to have retinal degeneration accompanied by the development of a hearing disturbance of unknown aetiology. Laboratory examination showed markedly increased serum ferritin and low serum iron. Magnetic resonance imaging showed a pronounced hypointensity in the putamen, caudate, cerebellar dentate, and thalamus on T2 weighted images, and also disclosed a low level signal in the liver, suggesting the accumulation of some magnetic substances in the brain and liver. Liver biopsies histochemically identified iron deposition in the hepatocytes. Most of these findings were consistent with the newly established autosomal recessive disease "aceruloplasminaemia", except for the presence of serum Cp and the lack of apparent neurological symptoms. Interestingly, no ferroxidase activity was detected in the patient's serum, whereas suppressed ferroxidase activity was found in his mother's serum. A nucleotide sequence analysis of the Cp gene showed two mutations; a C to T substitution at nucleotide 2701 in exon 16, resulting in a nonsense mutation at amino acid 882 (Arg882ter), and a T to G substitution at nucleotide 2991 in exon 17, resulting in an amino acid alternation at amino acid 978 (His978Gln). The second mutation was also found in the patient's mother. The absence of serum ferroxidase activity despite the presence of serum Cp protein in this compound heterozygote was considered to be due to the production of a non-functional Cp harbouring no ferroxidase activity.
Adult↗
The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells.
Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy.
Animals↗
Enhanced colonic peristalsis by impairment of nitrergic enteric neurons in spontaneously diabetic rats.
Changes in enteric neurons containing various neurotransmitters in the colon have been described in diabetic rats; however, how these changes are related to colonic motility disorders remains unclear. Nitric oxide (NO) is known to be an important inhibitory neurotransmitter in the enteric nervous system. In the present study, we investigated the peristaltic reflex using our modified Trendelenburg's method to evaluate the differences in enteric nitrergic neurons of the distal colon between spontaneously diabetic rats and their sibling control rats. We measured maximum intraluminal pressure, threshold pressure and propagation distance of the reflex contraction. These diabetic rats showed a greater maximum intraluminal pressure than that in the control rats. NG nitro-L-arginine methyl ester (L-NAME) significantly increased the maximum pressure in the control rats. Although L-arginine did not change the maximum pressure, sodium nitroprusside (SNP) significantly decreased it in these diabetic rats. Nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase reactivities in the myenteric plexus were much weaker in the diabetic rats than those in the control rats. These results indicate that the colonic peristaltic reflex is enhanced by impairment of enteric nitrergic inhibitory neurons in spontaneously diabetic rats.
Animals↗
Specific recognition of cytosolic thymidine kinase in the human lung tumor by monoclonal antibodies raised against recombinant human thymidine kinase.
Anti-TK monoclonal antibodies (mAbs) were raised against recombinant human cytosolic thymidine kinase (rhTK) and characterized by Western immunoblotting, enzyme-linked immunosorbent assay (ELISA) and immunostaining of tumor cells. Twenty-three clones of TK mAbs were characterized to recognize specifically not only rhTK produced by Escherichia coli but also TK subunit of 25 kDa in human lung cancer. The anti-TK mAbs reacted specifically with cytosolic TK but not with mitochondrial TK. Only one clone of the mAbs inhibited the catalytic activity of TK. By solid phase sandwich enzyme immunoassay using these mAbs, we could quantitate the cytosolic TK content in tissues. Immunohistochemical staining analysis using one of the TK mAbs showed that human lung adenocarcinoma and squamous cell carcinoma exhibited much higher staining intensity than stromal cells. These mAbs are useful for biochemical studies on the regulation of human TK in proliferating cells such as tumor cells and for diagnosis of highly proliferating tumors.
Adenocarcinoma↗
Histamine H1 receptor mRNA is expressed in capsaicin-insensitive sensory neurons with neuropeptide Y-immunoreactivity in guinea pigs.
Histamine H1 receptor mRNA-expressing sensory neurons in guinea pigs are unmyelinated and are not immunoreactive to substance P and calcitonin gene-related peptide (CGRP) [Mol. Brain Res. 66 (1999) 24], which are implicated in the nociceptive transmission of the primary sensory system. In this study, we examined whether these H1 receptor mRNA-expressing neurons are sensitive to capsaicin by using in situ hybridization histochemistry. Of lumbar dorsal root ganglion (DRG) neurons in control animals, 17% were positive for CGRP. In guinea pigs neonatally treated with capsaicin (50 mg/kg), few CGRP-immunoreactive neurons were seen in the DRGs. However, the percentages of H1 receptor mRNA-expressing neurons (15-20%) and the intensity of the mRNA signals in these neurons were not affected by neonatal capsaicin treatment. We also revealed the presence of both capsaicin-sensitive and insensitive neuropeptide Y (NPY)-immunoreactive neurons in the DRGs. These neurons were exclusively small. H1 receptor mRNA was expressed in NPY-immunoreactive neurons in naive guinea pig DRGs. These results suggest that H1 receptor mRNA is expressed in capsaicin-insensitive DRG neurons with NPY-immunoreactivity in guinea pigs.
Animals↗
Evaluation of a floating dosage form of nicardipine hydrochloride and hydroxypropylmethylcellulose acetate succinate prepared using a twin-screw extruder.
A floating dosage form composed of nicardipine hydrochloride (NH) and hydroxypropylmethylcellulose acetate succinate (enteric polymer) was prepared using a twin-screw extruder. By adjusting the position of the high-pressure screw elements in the immediate vicinity of die outlet, and by controlling the barrel temperature, we were able to prepare a puffed dosage form with very small and uniform pores. It was found that the porosity and pore diameter could be controlled by the varying amount of calcium phosphate dihydrate. In the shaking test, the puffed dosage form was found to have excellent floating ability and mechanical strength in acid solution (JP First Fluid, pH 1.2). The dissolution profile of NH was controlled by the amount of wheat starch. In the dissolution test using JP Second Fluid (pH 6.8), rapid dissolution of NH and loss of buoyancy were observed. It was shown that the puffed dosage form, consisting of enteric polymer prepared using the twin-screw extruder, was very useful as a floating dosage form that was retained for a long period in the stomach.
Administration, Oral↗
Structural changes of quartz-type crystalline and vitreous GeO2 under pressure.
Using a large volume high pressure apparatus, quartz-type crystalline GeO2 and Li2O-4GeO2 glass have been compressed up to 14 GPa at room temperature and their local structural changes have been investigated by an in-situ XAFS method. In quartz-type crystalline GeO2, the change of the coordination number from 4 to 6 begins above 8 GPa and finishes below 12 GPa. On decompression, reversal transition begins below 8 GPa and there is a large hysteresis. Almost no sixfold coordination of Ge is preserved after releasing pressure. Change of coordination number in vitreous Li2O-4GeO2 begins above 6 GPa and is completed below 10 GPa. Reversal transition begins below 10 GPa and the hysteresis is smaller than that of quartz-type GeO2. Change of coordination number in vitreous Li2O-4GeO2 is also reversal.
Journal Article↗
Genetic analysis of a local recurrent tumor after colonic polypectomy.
After polypectomy, the cut end of the polyp is usually examined by light microscopy to assess the risk of recurrent cancer. Here, we report a recurrent tumor that appeared in the colon 6 years after polypectomy, although cancer cells were not observed in hematoxylin and eosin-stained sections of the cut end of the primary polyp. Retrospectively, the primary polyp and the recurrent tumor were analyzed for mutations of the p53 gene. We detected p53 mutations in the primary polyp, even in the cut end of the polyp. The same set of two p53 mutations was detected in the recurrent tumor. These observations indicate a common origin of the primary tumor and the recurrent tumor. We conclude that it is important to analyze p53 mutations in colonic polyps, especially when the cut end of the polyp is difficult to evaluate histologically, in order to predict recurrence.
Adenocarcinoma↗
Microscopic polyangiitis complicated with massive intestinal bleeding.
Microscopic polyangiitis (MPA) is associated with renal dysfunction, in most cases, and occasionally with pulmonary hemorrhage. However, massive intestinal bleeding is a rare manifestation. We report a case of MPA in a man who developed arterial bleeding in the small intestine. A 74-year-old man was admitted after enduring a fever for 4 weeks. Laboratory examination revealed leucocytosis with neutrophil predominance, and renal dysfunction was noted. He did not respond to treatment with antibiotics, and the worsened renal function soon required hemodialysis. On the seventh hospital day, he suddenly developed massive melena. A colonoscopic examination suggested bleeding in the small intestine, and abdominal angiography demonstrated that the bleeding originated in a branch of the ileal artery. Hemostasis was achieved by transarterial embolization (TAE), but the patient suffered a massive pulmonary hemorrhage 2 days after the TAE. Although he responded well to a combination treatment with corticosteroid and cyclophosphamide, recurrence of pulmonary hemorrhage led to death, on the 87th hospital day. MPA in this patient was associated with three serious complications; deteriorating renal function, massive melena, and pulmonary hemorrhage. Of the various manifestations associated with MPA, arterial bleeding in the gastrointestinal tract, although rare, should be considered as one of the serious complications in MPA.
Aged↗
Hepatic adenomas treated with percutaneous ethanol injection in a patient with glycogen storage disease type Ia.
We report a 20-year-old man with glycogen storage disease type Ia (GSD Ia) who presented multiple hepatocellular adenomas (HCAs) in 1993 and in whom percutaneous ethanol injection (PEI) was conducted as treatment for some enlarging tumors beneath the liver surface. In a 6-year follow-up period, we observed gradual enlargement of some of the HCAs, and the rapid growth of a newly developed tumor. In August 1996, one slow-growth HCA was 52 mm in diameter and was located beneath the surface of the liver. We conducted PEI therapy to prevent its spontaneous rupture. During the following year, another tumor developed beneath the liver surface, but showed extremely rapid growth, reaching 51 mm in diameter, from being undetectable, within 12 months. PEI therapy was again conducted for this newly developed tumor. Although additional PEI therapy was required for each tumor, because of suspected recurrence, no findings of discrete recurrence have been detected by computed tomography and magnetic resonance imaging for more than 2 years, up to the time of this study. We consider PEI to be a useful and effective therapeutic modality for individual HCAs in patients with GSD Ia.
Adenoma↗
Identification of GFAT1-L, a novel splice variant of human glutamine: fructose-6-phosphate amidotransferase (GFAT1) that is expressed abundantly in skeletal muscle.
Glutamine:fructose-6-phosphate amidotransferase (GFAT1) is the rate-limiting enzyme in the hexosamine biosynthetic pathway, which plays an important role in hyperglycemia-induced insulin resistance. To evaluate the role of GFAT1 expression, we analyzed the expression profiles of GFAT1 mRNA in various human tissues using reverse transcriptase-polymerase chain reaction. We report here the identification and cDNA cloning of a novel GFAT1 splice variant expressed abundantly in skeletal muscle and heart. This subtype, designated GFAT1-L, contains a 54-bp insertion within the GFAT1 coding sequence. Recombinant GFAT1-L protein possessed functional GFAT activities and biochemical characteristics similar to GFAT1. Previously, GFAT1 was considered a simplex enzyme. The identification of a novel GFAT1 subtype possessing functional enzymatic activity and tissue-specific expression should provide additional insight into the mechanism of skeletal muscle insulin resistance and diabetes complications.
Alternative Splicing↗