Frameshift mutation, A263fsinsGG, in the hepatocyte nuclear factor-1beta gene associated with diabetes and renal dysfunction.
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Adult↗
Biomedical subjects
H Nishigori
Publications and source records attributed to H Nishigori.
Hepatocyte growth factor in vitreous fluid of patients with proliferative diabetic retinopathy and other retinal disorders.
OBJECTIVE: To determine whether hepatocyte growth factor (HGF) is elevated in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR). RESEARCH DESIGN AND METHODS: Vitreous fluid samples were obtained at the time of vitreoretinal surgery from 73 eyes of PDR patients and from 17 eyes of nondiabetic patients (control subjects) who had macular hole, rhegmatogenous retinal detachment, or epiretinal membrane (9, 4, and 4 eyes, respectively) but no associated proliferative vitreoretinopathy Stages of PDR were classified as active or quiescent. Concentrations of HGF and vascular endothelial growth factor (VEGF) in vitreous fluid were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Intravitreous concentrations of HGF (median [range]) were significantly higher in diabetic patients with PDR (6.00 ng/ml [0.75-22.21) than in control patients (2.86 ng/ml [0.75-5.801). Intravitreous concentrations of VEGF were also higher in diabetic patients with PDR (1.62 ng/ml [0.15-7.91) than in control patients (0.16 ng/ml [0.160.29]). Both VEGF and HGF concentrations were significantly higher in patients with active retinopathy than in those with quiescent retinopathy However, vitreous concentrations of HGF were unrelated to those of VEGE CONCLUSIONS: We found that levels of HGF in vitreous fluid of PDR patients are significantly higher than in nondiabetic patients and that the levels of HGF are elevated in the active PDR stage. This suggests that HGF stimulates or perpetuates neovascularization in PDR.
Diabetic Retinopathy↗
Mutations in the hepatocyte nuclear factor-1alpha gene (MODY3) are not a major cause of late-onset NIDDM in Japanese subjects.
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Age Factors↗
Identification of mutations in the hepatocyte nuclear factor (HNF)-1 alpha gene in Japanese subjects with IDDM.
One form of maturity-onset diabetes of the young, MODY3, is characterized by a severe insulin secretory defect, compared with MODY2, a glucokinase-deficient diabetes. It has recently been shown that mutations of the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1 alpha cause MODY3. Because of the rapid progress to overt diabetes and the high prevalence of required insulin treatment in patients with MODY3, we screened the HNF-1 alpha gene for mutations in Japanese subjects with IDDM. Ten exons and flanking introns of the HNF-1 alpha gene in these subjects were amplified by polymerase chain reaction and direct sequencing of the products. Mutations were identified in three (5.5%) of the 55 unrelated subjects with IDDM. A missense mutation of R272H (replacement of Arg by His in codon 272) in the DNA binding domain of HNF-1 alpha was found in a subject who developed IDDM 1 year after diagnosis of NIDDM at 8 years of age. A frameshift mutation of P291 fsinsC (insertion of a C in a polyC tract around codon 291 for Pro), which would generate a mutant truncated protein of 340 amino acids, was found in a subject who started insulin treatment when hyperglycemia and ketonuria were noticed at 13 years of age. A missense mutation of R583G (replacement of Arg by Gly in codon 583) in the transactivation domain of HNF-1 alpha was found in a subject with sudden-onset IDDM at 20 years of age. None of these mutations were present in 100 nondiabetic subjects (200 normal chromosomes). These results indicate that the HNF-1 alpha gene defects could lead to the development of not only early-onset NIDDM but also IDDM, implicating the importance of subclassification of HNF-1 alpha-deficient IDDM from a classical type of autoimmune-based IDDM in Japanese.
Adolescent↗
Synthesis of monoesters of pyrroloquinoline quinone and imidazopyrroloquinoline, and radical scavenging activities using electron spin resonance in vitro and pharmacological activity in vivo.
Monoesters with the ester groups at C-2 of pyrroloquinoline quinone (PQQ) and C-9 of imidazopyrroloquinoline (IPQ) were synthesized, and radical scavenging activities of coenzyme PQQ, IPQ compounds synthesized from PQQ and various amino acids, and monoesters of PQQ and IPQ were studied in vitro and in vivo. PQQ and PQQ monoesters had strong radical scavenging activity using ESR in in vitro experiments. The IC50 value for superoxide (O2-) was from 1 to 6 x 10(-8) M and that for the hydroxy radical (.OH) was from 4 to 6 x 10(-5) M. IPQ compounds and IPQ monoesters also showed radical scavenging activity. These compounds prevented injury during in vivo experiments, such as hydrocortisone-induced cataracts, endotoxin shock and CCl4-induced liver injury (isolated hepatocytes and rats). Especially, the monoesters of PQQ and IPQ prevented liver injury in rats equally by oral or intraperitoneal administration. These results suggest that PQQ functions as a radical scavenging factor in addition to being a cofactor of quinoprotein enzymes, and monoesters with the ester groups at C-2 of PQQ and C-9 of IPQ are developed as treatment or preventive medicine for disease caused by radical compounds on the basis of strong radical scavenging activities, absorbability into cells, toxicity, safety and chemical stability.
Administration, Oral↗
Rapid diagnostic imaging of cancer using radiolabeled liposomes.
A novel tumor diagnostic imaging method was developed that allows tumor localization soon after administration of radiolabeled liposomes. Although previous studies showed that radiolabeled liposomes can reach various tumors in a short time, their blood clearance is slow, and the high blood background hinders early imaging. Therefore, we attempted to remove actively the liposomes from the circulation using the strong affinity between avidin and biotin. Liposomes that had biotin bound to their surface and were labeled with 111In, 67Ga, or 99mTc were administered to mice bearing sarcoma 180, followed by administration of avidin 2 or 4 h later. Avidin initiated liposomal aggregation, resulting in their rapid removal by the reticuloendothelial system. Consequently, their blood level was markedly reduced without any changes in tumor levels. The tumor-to-blood ratio reached about 13 at only 2.5 h after administration of 99mTc-labeled liposomes, versus 1.0 or less without postadministration of avidin. Increased liver accumulation was also observed, but it decreased gradually with time.
Animals↗
Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3)
The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden. Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder. Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2-5% of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosomes 7, 12 and 20 (refs 5, 7, 8) and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinases which plays a key role in generating the metabolic signal for insulin secretion and in integrating hepatic glucose uptake. Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin-I gene.
Animals↗
Comparison of lens biochemistry and structure between BSO-treated and glucocorticoid-treated developing chick embryos.
In this paper various changes in glutathione level, which were influenced by balance of its synthesis, degradation, transport and utilization, were analysed in chick embryos administered with glucocorticoid (GC) or buthionine sulfoximine (BSO; an inhibitor of glutathione synthesis). When BSO (30 mumol egg-1) was administered twice to chick embryos on day 14 and 15, the GSH in both the lens and the liver decreased to 15-20% and 30-40% of the age-matched control level, respectively, between 24 and 48 hr after the second treatment, then began to recover. Although this decline in the GSH level in these tissues was greater and more prolonged in embryos treated with BSO than with GC, the former embryos maintained lens transparency even up to 144 hr by a visual examination. However, histological changes in the lens occurred after 96 hr and more significantly 144 hr after second administration of BSO. The changes mainly consisted of pale epithelial cells on the anterior peripheral surface of the lens, irregular height of the epithelial cells at the equator, clefts between the epithelium and the cortex and swelling of almost all the cortical fibers. These observations may suggest that BSO treatment could produce the beginning of a cataract. Embryos with GC-cataract revealed the following changes at 48 hr: loss of transparency, elevation of LPO (TBA-reacting substance) in the lens, the blood and the liver. These were not observed in BSO-treated embryos during the experimental period. The GC-cataract may well depend on the generation of LPO. BSO cataract, having a distinct mechanism compared to that caused by GC, develops more slowly in GSH-depleted lenses. The BSO-treated chick embryos will be a useful model to screen the risk factors which accelerate cataract formation.
Animals↗
Optimal radiolabeled liposomes for tumor imaging.
UNLABELLED: We conducted a systematic study of the effects of liposome formulation and encapsulated radionuclides on imaging ability. METHODS: Various types of liposomes were prepared and labeled with 67Ga, 111In or 99mTc. Their tumor-imaging potential was evaluated in terms of tumor accumulation and tumor-to-blood ratios of radioactivity delivered by the liposomes. Mouse sarcoma 180 and Ehrlich solid tumor were the tumor models. RESULTS: Liposomes could be labeled rapidly and with high efficiency, which was sufficient for clinical application. Tumor accumulation of liposome-encapsulated radionuclides that have intrinsic tumor affinity, such as 67Ga-NTA or 111In-NTA, was larger than that of the other nuclides. Liposomes that were fairly small, cholesterol-rich and composed of so-called rigid phospholipids, could deliver large amounts of encapsulated radionuclides to the tumor. We also found that tumor uptake of such liposomes was large and their blood retention was prolonged. Liposomal lipid dose also influenced tumor delivery and blood retention. The results suggest that these factors extended liposomal blood retention and, consequently, increased tumor uptake of the liposomes and tumor delivery of encapsulated radionuclides. Not all liposomes with long blood retention, however, are suitable for tumor imaging. Incorporation of monosialo-ganglioside in the liposomal membrane greatly extended blood retention but increased tumor uptake only slightly and, consequently, made the tumor-to-blood value worse. One of the 67Ga-labeled liposome formulations resulted in high tumor uptake and tumor-to-blood ratios in various tumor models as well as clearly visualized tumors clearly in sarcoma 180-bearing mice. CONCLUSION: For tumor imaging with radiolabeled liposomes, we should choose liposomal formulations and dose to give prolonged blood retention for large tumor delivery. We must then select liposomes that give good tumor-to-blood values. For the best results, the radionuclide should have intrinsic tumor affinity. Labeled liposomes that meet these criteria result in excellent tumor images.
Animals↗
Morphological study of age-related changes in Fischer rat lens.
The authors conducted a morphological investigation of age-related changes in the lens of male Fischer rats at 6, 12, 18 and 24 months of age. At 6 months, there were no abnormalities of particular note other than slight swelling of the subcapsular fibers. Moreover, other than a slight decrease in the density of epithelial cells and slightly more extensive fiber swelling, there were no remarkable changes seen in the lens at 12 months. At 18 months of age, posterior invasion by the processes of the cortical lens fibers toward the lens capsule and slight swelling of the anterior cortical fibers were seen in addition to the above-mentioned changes. By 24 months of age, these changes had become more noticeable, with further reduction in the density of epithelial cells, swelling and degeneration of both anterior and posterior fibers and extension of the thin processes of the equatorial fibers toward the capsule. However, the bow configuration at the equator appeared almost normal. These findings indicate that the age-related changes in the Fischer rat lens occurred in the epithelial cells and superficial layer of the cortical fibers, subsequently leading to the loss of clarity in the lens.
Aging↗
Assessment of antioxidative ability in brain: technetium-99m-meso-HMPAO as an imaging agent for glutathione localization.
UNLABELLED: To visualize the regional localization of glutathione (GSH) in the brain, the relationship between the concentrations of tissue GSH and uptake of [99mTc]meso-hexamethyl propyleneamine oxime ([99mTc] meso-HMPAO) or [99mTc]d,l-hexamethyl propyleneamine oxime ([99mTc]d,l-HMPAO) was studied in mice. METHODS: The uptake of [99mTc]meso-HMPAO in the mouse brain was decreased to 35% of control paralleling the decrease in GSH content by pre-loading of diethyl maleate (DEM), an agent to reduce GSH. In contrast, pre-treatment with DEM scarcely affected the 99mTc-d,l-HMPAO uptake in the brain. RESULTS: The DEM treatment decreased the GSH content in liver, kidney, spleen, fat and lung but did not affect the uptake of [99mTc]meso-HMPAO in those tissues except lung. The images of rat brain acquired with a gamma camera showed a significant reduction of [99mTc]meso-HMPAO uptake by DEM treatment. CONCLUSION: Technetium-99m-meso-HMPAO may be a potential tool to assess GSH content and to estimate antioxidative ability in the brain.
Animals↗
Pyrroloquinoline quinone (PQQ) inhibits the expression of tyrosinase mRNA by alpha-melanocyte stimulating hormone in murine B16 melanoma cells.
The biological functions of pyrroloquinoline quinone (PQQ), a bacterial redox coenzyme and potent radical scavenger, have not been elucidated in mammals. In this paper, we studied the effects of PQQ on tyrosinase activity and subsequent melanogenesis in murine B16-F10 melanoma and found that alpha-Melanocyte stimulating hormone (MSH)-induced melanogenesis was inhibited by 6.3 to 25 microM PQQ in a dose-dependent manner. Moreover, PQQ inhibited MSH-induced tyrosinase activity by suppressing tyrosinase mRNA expressed by MSH. However, PQQ had no effect on MSH-stimulated cyclic adenosine 3', 5'-monophosphate (cAMP) production. These observations suggest that PQQ inhibits the expression of tyrosinase mRNA at a post receptor level and that PQQ may be useful in investigating hormone actions mediated by cAMP.
Animals↗
Glucocorticoid-induced cataract of developing chick embryo as a screening model for anticataract agents.
In order to develop an effective screening model for anticataract agents, we examined the age dependence of cataract induction by glucocorticoid in developing chick embryos. Hydrocortisone sodium succinate (0.25 mumol) was administered to chick embryos on day 15 (15-day-old) and cataract formation was examined 48 hr later. Administration earlier than on day 13 or later than on day 15 was a little or ineffective. These results indicate that the formation of glucocorticoid-induced cataract in developing chick embryos depends on developing stages. The embryos treated with hydrocortisone sodium succinate on day 15 decreased GSH amount in the lens, approximately 50% of the control in 48hr. However, the embryos treated at other ages, in which cataract was not induced, showed little or no decrease of GSH. The cataract formation in chick embryos appeared to depend on structure of steroid and was due to biological activities of glucocorticoids. Since cataract is easily produced in a reproducible manner with high incidence by glucocorticoid, our chick embryo model will be a valuable model system for screening anticataract agents.
Animals↗
Glucocorticoid-induced cataract of the developing chick embryo-prevention by propylene glycol.
When 0.25 mumol of hydrocortisone succinate sodium (HC) was administered to 15-day-old hen's fertile eggs, almost all lenses of the embryos became cataractous with stages IV-V (> 90%) 48 h after the treatment. However, a triple application of propylene glycol (1.5 mmol/egg) at 3, 10 and 20 h after HC treatment effectively prevented the HC-induced cataract formation (I: 84%, II: 12%, III: 4%, IV-V: 0%) and repressed the decline of glutathione and the elevation of lipid peroxide in the lens caused by HC. Propylene glycol is metabolized to lactate and pyruvate producing NADH and is known to possess protective activities against X-ray irradiation. These properties have modified the HC-induced effects and decreased the production of oxidative stress in ovo, protecting the lens from losing its transparency after HC administration. Furthermore, a marked elevation of glucose in cataractous lenses noted after HC administration was not directly involved in opacification of the lenses.
Animals↗
Rapid tumor imaging by active background reduction using biotin-bearing liposomes and avidin.
Tumor imaging with labeled liposomes is slow; although they reach the tumor quickly, their blood clearance is slow, and the high blood background hinders early imaging. We have developed a rapid tumor imaging technique based on the active removal of liposomes from the circulation by using the avidin-biotin system. 67Ga- or 111In-labeled liposomes with biotin molecules bound on the surface were administered to mice bearing sarcoma 180, and avidin was administered 2 h later. The strong affinity between biotin and avidin initiated the aggregation of liposomes, resulting in their rapid removal from the circulation by the reticuloendothelial system, and the blood level of radioactivity was dramatically reduced without any change of the tumor level. Consequently, the tumor:blood ratio reached 14-18 only 2.5 h after liposome injection. Increased accumulation in the liver was also observed. By this method, an acceptable tumor image could be obtained no more than 2 h after administration of labeled liposomes.
Animals↗
Preventive effect of SA3443, a novel cyclic disulfide, on glucocorticoid-induced cataract formation of developing chick embryo.
The preventive effect of SA3443 [(4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid] against glucocorticoid-induced cataract of developing chick embryos was studied. When hydrocortisone succinate sodium (HC: 0.25 mumol per egg) was administered to 15-day-old embryos, almost all lenses became opaque (stage I:O%, II: 2.5 +/- 4.6%, III: 5 +/- 5.4%, IV-V 92.5 +/- 7.1%) at 48 hr after the treatment. However, a double application of SA3443 (10 mumol per egg) at 3 and 10 hr after HC treatment effectively prevented the cataract formation (stage I: 52.8 +/- 13.7%, II: 11.6 +/- 6.3%, III: 22.9 +/- 8.9%, IV-V: 13.9 +/- 11.0%) and diminished the decline in glutathione in the lens at 48 hr and in the liver at 24 hr after HC administration. The cleavage of the cyclic disulfide bond of SA3443 did not occur in the lens homogenate but in the liver homogenate. These results suggest that the appearance of sulfhydryl residue in the liver may contribute to the anticataract effects by representing radical scavenger activities.
Animals↗
Morphological study on glucocorticoid-induced cataract in developing chick embryo.
Nishigori et al. reported a transient cataract model after administering glucocorticoid to a 15-day-old chick. Biochemically, the mechanism of onset of this cataract was though to be related to damage caused by the formation of oxidative stresses and by a protein-water phase separation. There appear to be no reports on changes in the fine structure. After hydrocortisone succinate sodium was administered to 15-day-old chick embryos, the lenses were removed at 12, 24, 30, 48, 72 and 96 h and put in 4% glutaraldehyde. The specimens were examined by light, transmission and scanning electron microscopy. Twelve to 24 h after administration to chick embryos, lens fibers containing electron-dense cytoplasm began to appear in the bow area of the equator and were still present thereafter. Thirty to 48 h after administration, numerous vacuoles of varying sizes began to appear in the lens in sites corresponding to the opaque region. These vacuoles, ranging from 2 to 8 microns in diameter, were distributed in the intercellular spaces between the lens fibers. The vacuoles had disappeared by 96 h after administration, but during that period, the height of the epithelial cells in the equatorial region and the elongation of the equatorial lens fibers had become irregular. Transient opacity was due to the presence of vacuoles of various sizes, occurring in the intercellular space between the lens fibers around the lens nucleus. Moreover, the effect of glucocorticoid administration was noted in the lens epithelium and the lens fibers in the equatorial region.
Animals↗
[Synthetic estrogens--new pharmacological actions and mechanisms].
Many constitutional analogues of estrogen have been reported. In this review, some new synthetic estrogens possessing a different action from natural estrogens are described. Aminoestrogens inhibit platelet aggregation. Estradiol-chlorambucil conjugate (KM2210) decreases the level of estrogen receptor mRNA in the human breast cancer cell MCF-7. The representative synthetic estrogen, diethylstilbestrol, and its derivatives show an inhibitory action against H(+)- and Ca(2+)-ATPase. Moreover, the effect of the diastereometric [1,2-bis(2,6-dihalo-3-hydroxyphenyl)ethylenediamine ] sulfatoplatinum (II) complexes, derivatives of hexesterol-platinum complexes, on estrogenic action and the growth-inhibitory action of hormone dependent breast cancer, are strongly dependent on the halogen atoms and on their position in the aromatic ring. These drugs are expected to be applicable for clinical use.
Animals↗