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H Kaneto

Publications and source records attributed to H Kaneto.

At least 73 records · Page 4Linked to original sources
PubMed1996

A potent mu-opioid receptor agonist, dihydroetorphine, fails to produce the conditioned place preference in mice.

Reinforcing effects of dihydroetorphine (DHE) and morphine were evaluated by the conditioned place preference paradigm. Both DHE and morphine produced an antinociceptive effect in a dose-dependent manner. On the other hand, DHE (0.1, 1, 3 and 10 micrograms/kg, i.p.) failed to induce the conditioned preference, while morphine (0.1, 1, 3 and 10 mg/kg, i.p.) caused a dose-dependent preference for the drug-paired place. Thus, these characteristic properties of DHE make it attractive for development as a novel potent analgesic compound that has less dependence liability.

Analgesics, Opioid↗
PubMed1996

Characterization of protein kinase C expression in human kidney.

Protein kinase C (PKC), the calcium and phospholipid-dependent kinase, is a key enzyme for regulation of growth and differentiation of various cells and tissues. Abnormalities of PKC modulation may cause diseases such as neoplasia. The present study was designed to demonstrate localization of PKC in normal human nephron segments. Surgically extirpated specimens for renal tumor were used. PKC was determined by immunoblotting and immunohistochemical methods using specific antibody against PKC that recognizes alpha and beta subtypes of this enzyme. Immunoblotting study demonstrated PKC in the cytosolic fractions of homogenized cortical tubules and medullary tubules prepared from morphologically normal part of the kidney. PKC was faintly detected in glomerular supernatants. Immunohistochemical study revealed that PKC was present throughout the nephron and especially concentrated in the cytoplasm of the proximal tubules and the medullary collecting ducts. The results indicate that PKC appears to play a role in regulation of normal nephron function in human kidney.

Adult↗
PubMed1996

The human glucokinase gene beta-cell-type promoter: an essential role of insulin promoter factor 1/PDX-1 in its activation in HIT-T15 cells.

The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription. An anti-IPF1 antiserum used in gel-mobility shift analysis supershifted the DNA protein complex formed with the hUPE3 probe and nuclear extracts from HIT-T15 cells, thus supporting the involvement of IPF1 in GK gene activation in HIT-T15 cells. In contrast to the insulin gene, however, neither the synergistic effect of the Pan1 expression on the IPF1-induced promoter activation nor the glucose responsiveness of the activity was observed for the GK gene promoter. These results revealed some conservative but unique features for the transcriptional regulation of the beta-cell-specific genes in humans. Being implicated in insulin and GK gene regulations as a common transcription factor, IPF1/STF-1/PDX-1 is likely to play an essential role in maintaining normal beta-cell functions.

Amino Acid Sequence↗
PubMed1996

Involvement of glycation and oxidative stress in diabetic macroangiopathy.

Under diabetic conditions, the Maillard reaction facilitates the production of reactive oxygen species, and the activity of antioxidant enzymes such as Cu,Zn-superoxide dismutase is decreased, resulting in a remarkable increase of oxidative stress. The oxidative stress attacks DNA, lipids, and proteins and is also thought to be involved in the pathogenesis of diabetic complications, including the progression of macroangiopathy. Proliferation of smooth muscle cells (SMCs) is known to be associated with progression of macroangiopathy and is modulated by several growth factors. At least three mitogens for SMCs, platelet-derived growth factor (PDGF), fibroblast growth factor, and heparin-binding epidermal growth factor-like growth factor (HB-EGF), are known to be produced by SMCs themselves and are considered to be the most potent growth factors in the progression of macroangiopathy as seen in diabetes. HB-EGF, but not PDGF, is regulated at the transcriptional level by 3-deoxyglucosone (3-DG), a major and highly reactive intermediate in the glycation reaction. The induction seems to be triggered by the increase of reactive oxygen species produced by 3-DG. Taken together, glycation reactions under diabetic conditions may be highly associated with the pathogenesis of diabetic macroangiography by enhancing the gene expression of HB-EGF.

Animals↗
PubMed1996

Determining the origin of hematuria by immunocytochemical staining of erythrocytes in urine for Tamm-Horsfall protein.

PURPOSE: We analyzed the feasibility of immunocytochemical staining of urinary erythrocytes for Tamm-Horsfall protein to differentiate renal from nonrenal hematuria. MATERIALS AND METHODS: Urine samples collected from 74 patients with hematuria were evaluated. Erythrocytes in urine were inspected morphologically and the same samples were immunocytochemically stained with antibody against human Tamm-Horsfall protein. RESULTS: Erythrocytes in urine were clearly stained for Tamm-Horsfall protein in renal hematuria. Tamm-Horsfall protein immunocytochemistry was more consistent with clinical diagnosis than morphology. CONCLUSIONS: Immunocytochemical staining of urine erythrocytes for Tamm-Horsfall protein appears to be a reliable tool to differentiate renal from nonrenal hematuria.

Diabetic Nephropathies↗
PubMed1995

Effects of footshock-, psychological- and forced swimming-stress on the learning and memory processes: involvement of opioidergic pathways.

Modulation of learning and memory acquisition, retention and retrieval in the one trial passive avoidance learning task in mice by three inescapable stresses, i.e., footshock (FS), psychological (PSY) and forced swimming (SW) were investigated. Pre-, post-training and pre-test FS-stress (2 mA, 0.2 Hz, 1 sec for 30 min) and pre-training PSY-stress (communication box, 5 min) resulted in enhanced test latencies. On the contrary, SW-stress (20 degrees C, 5 min) immediately or 1 hr after training impaired retention latencies that tended to recover after 2 hr post-training SW-stress, suggesting that at least 2 hr are required to consolidate newly acquired information. In contrast, pre-stress naloxone (Nx), which did not affect FS- and PSY-stress induced facilitatory effects, returned to control levels the impaired retention latencies induced by SW-stress. Taken collectively, these results imply the involvement of an opioid-dependent mechanism in the modulation of memory by SW-stress and non-opioid in the case of FS- and PSY-stress. Furthermore, they suggest that different mechanisms are involved in stress-induced memory modifications and the production of stress-induced analgesia (SIA) since in the latter, FS and PSY but not SW stress produce Nx-sensitive antinociception.

Animals↗
PubMed1995

Role of GABAergic systems in the development of morphine tolerance in formalin-treated mice.

Since the development of tolerance to morphine antinociception in formalin-treated mice was delayed and diazepam normalized the delay, the involvement of GABAergic systems in the process was investigated. Gamma amino-n-butyric acid (GABA) at 10 mg/kg and the GABAA-receptor agonist muscimol at 0.05 mg/kg, i.p., 30 min before daily morphine injection at 10 mg/kg, s.c. completely reversed the delay in the development of morphine tolerance in the formalin-treated mice. The GABAA antagonist bicuculline at 1 mg/kg and the Cl(-)-channel blocker picrotoxin at 1 mg/kg extinguished the reverse effect of muscimol and GABA, respectively. In contrast, the GABAB antagonist CGP 35348 (3-aminopropane-diethoxymethyl-phosphinic acid) up to 100 mg/kg, i.p. failed to abolish the GABA effect; and baclofen, a GABAB-receptor agonist, at 0.5 and 2 mg/kg, i.p., 30 min before morphine was without effect on the delay. On the other hand, bicuculline was incapable of abolishing the reverse effects of diazepam on the delay of tolerance development; and likewise, the reverse effect of muscimol was not affected by flumazenil. No appreciable influence of these GABA-related compounds was seen on morphine antinociception itself nor the development of tolerance in normal mice. These results suggest that the benzodiazepine-GABAA-Cl- channel complex is involved in the mechanism underlying the delay of the development of morphine tolerance in formalin-treated mice; however, it is deduced that benzodiazepine-receptor and GABAergic systems are not always functionally coupled to each other in the mechanisms.

Analgesics, Opioid↗
PubMed1995

Synaptic plasticity: stairway to memory.

Since the idea that memory is associated with alterations in synaptic strength was accepted, studies on the cellular and molecular mechanisms responsible for the plastic changes in neurons have attracted wide interest in the scientific community. Recent studies on memory processes have also pointed out some unifying themes emerging from a wide range of nervous systems, suggesting that regardless of the species or brain regions, a common denominator for memory may exist. Thus, the present review attempted to create a hypothetical and universal synaptic model valid for a variety of nervous systems, ranging from molluscs to mammals. The cellular and molecular events leading to short- and long-term modifications of memory have been described in a sequential order, from the triggering signals to the gene expression, synthesis of new proteins and neuronal growth. These events are thought to represent the late phases of memory consolidation leading to persistent modifications in synaptic plasticity, thereby facilitating the permanent storage of acquired information throughout the individual's life.

Animals↗
PubMed1995

Apoptotic cell death triggered by nitric oxide in pancreatic beta-cells.

Nitric oxide (NO) is believed to be an effector molecule that mediates interleukin (IL)-1 beta-induced destruction and dysfunction of pancreatic beta-cells. We have demonstrated that both exogenous NO and NO generated endogenously by IL-1 beta brought about apoptosis of isolated rat pancreatic islet cells as well as pancreatic beta-cell tumor-derived cell line HIT. This apoptosis was characterized by cleavage of DNA into nucleosomal fragments of 180-200 bp and morphologically by nuclear shrinkage, chromatic condensation, and apoptotic body formation. The IL-1 beta-induced internucleosomal DNA cleavage occurred in a time- and dose-dependent manner. Actinomycin D, cycloheximide, and nitric oxide synthase inhibitors inhibited the DNA cleavage, which was correlated with the amount of NO produced, indicating that NO produced by HIT cells themselves could mediate the apoptosis. Furthermore, in the presence of tumor necrosis factor (TNF)-alpha, large amounts of NO were produced by IL-1 beta and DNA cleavage occurred more noticeably, although TNF-alpha alone did not generate NO. Streptozotocin (STZ), a diabetogenic reagent containing a nitroso moiety, also released NO and induced internucleosomal DNA cleavage in HIT cells. These results suggest that NO-induced internucleosomal DNA cleavage is an important initial step in the destruction and dysfunction of pancreatic beta-cells induced by inflammatory stimulation or treatment with STZ.

Amino Acid Oxidoreductases↗
PubMed1995

[Assessment of anxiolytics (6)--A novel method in mice using psychological stress].

Both antinociception induced by psychological stress (PSY, using the communication box) and the suppression by the stress of the development of antinociceptive tolerance to morphine were completely extinguished by diazepam (DZP, 1-2 mg/kg), suggesting an essential role of emotional factors in the underlying mechanisms. Based on these findings, a simple and selective method for evaluating anxiolytics was designed. Treatment with methysergide (2-20 mg/kg, ip), buspirone (1-10 mg/kg, ip), ritanserin (1-5 mg/kg, ip), Y-25,130 (0.03-0.1 mg/kg, ip) and ICS 205-930 (1-100 micrograms/kg, po), all of which reportedly possess anxiolytic activity, dose-dependently suppressed both the production of PSY stress-induced antinociception (PSY-SIA) and the blockade of the development of morphine tolerance by PSY stress. In contrast to these compounds, (+/-)pindolol (up to 3 mg/kg) and imipramine, even after pretreatment daily with 40 mg/kg, ip, for 5 days, produced no such suppression. In an elevated plus-maze (EPM) method, frequently used as a simple method for detecting anxiolytic drugs, not only DZP, buspirone, Y-25,130 and ICS 205-930 but also imipramine (daily with 40 mg/kg for 5 days) increased the time spent on the open arms, while methysergide or retanserin failed to augment the time, indicating that the EPM method is not selective for this purpose. Since U-50,488H suppresses the development of morphine tolerance, the utility of the compound for PSY stress was also examined; however, the suppressive effect was counteracted by (+/-)pindolol but not by ritanserin. Thus, we proposed a valid new method for screening anxiolytic drugs in mice, by testing the extinguishable effect of drugs on these parameters, i.e., PSY-SIA and suppression by PSY stress of the development of morphine tolerance.

Animals↗
PubMed1994

DNA cleavage induced by glycation of Cu,Zn-superoxide dismutase.

Human Cu,Zn-superoxide dismutase (Cu,Zn-SOD) undergoes site-specific and random fragmentation by non-enzymic glycosylation (glycation). Released Cu2+ from the glycated Cu,Zn-SOD probably facilitates a Fenton reaction to convert H2O2 into hydroxy radical, which then participates in the non-specific fragmentation [Ookawara et al. (1992) J. Biol. Chem. 267, 18505-18510]. In the present study, we investigated the effects of glycated Cu,Zn-SOD on cloned DNA fragments and nuclear DNA and analysed the formation of 8-hydroxydeoxyguanosine (8-OH-dG). Incubation of cloned DNA fragments with Cu,Zn-SOD and reducing sugars resulted in cleavage of the DNA. The extent of the cleavage corresponded to the reducing capacity of the sugar. Metal-chelating reagents, EDTA and bathocuproine, and an H2O2 scavenger, catalase, inhibited the DNA cleavage. Hydroxy radical scavengers and aminoguanidine, an inhibitor of glycation, also inhibited the reaction. Moreover, the glycation of Cu,Zn-SOD caused the substantial formation of 8-OH-dG in DNA. When isolated nuclei were incubated with CuCl2 plus H2O2, nuclear DNA cleavage was observed. Incubation of isolated nuclei with Cu,Zn-SOD that had been pre-incubated with glucose also resulted in nuclear DNA cleavage. These results suggest that hydroxy radical is produced through a Fenton reaction by Cu2+ and H2O2 released from the glycated Cu,Zn-SOD, and participates in nuclear DNA cleavage. This mechanism may partly explain the deterioration of organs under diabetic conditions.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1994

Location of an inducible nitric oxide synthase mRNA in the normal kidney.

An inducible nitric oxide synthase (iNOS) mRNA was found primarily in the outer medulla of normal rat kidney. Identification of the mRNA was based upon the specificity of the oligonucleotide primers used for PCR amplification, PCR-Southern blot analysis and the nucleic acid sequence of the cloned PCR product. In addition to the outer medulla, glomeruli prepared from normal rat kidney contained significant amounts of an iNOS mRNA. These results suggest that there may be tonic influences in the outer medulla of the normal rat kidney resulting in the "steady-state" presence of an iNOS mRNA. Cortical tubules and the inner medulla were found to contain detectable but lesser amounts of the iNOS mRNA. The outer medulla was microdissected into proximal straight tubule (PST), medullary thick ascending limb (MTAL), medullary collecting duct (MCD) and vasa recta bundle (VRB). The iNOS mRNA was found primarily in the MTAL with minor amounts in the MCD and VRB of normal rat kidney. Animals were injected with lipopolysaccharide (LPS) and sacrificed 24 hours later. Treatment with LPS caused at least a 20-fold increase in the amount of iNOS mRNA in the liver or in macrophages isolated from the peritoneum. Endotoxin treatment led to over a 10-fold increase in iNOS mRNA content in glomeruli and the inner medulla. The iNOS mRNA level of the outer medulla was increased two- to threefold due to LPS treatment.

Amino Acid Oxidoreductases↗
PubMed1994

Enalapril reduces collagen type IV synthesis and expansion of the interstitium in the obstructed rat kidney.

Chronic unilateral ureteral obstruction (UUO) results in interstitial fibrosis of the affected kidney. In this study we determined that enalapril ameliorates the increased production of extracellular matrix (ECM) protein in the tubulointerstitium during UUO. The relative volume (Vv) of the tubulointerstitium measured by a point-counting method increased significantly at three or five days of UUO as compared to the contralateral kidney. Enalapril significantly blunted this increase at either three or five days. Immunofluorescence studies revealed that collagen type IV increased remarkably in both the tubular basement membrane (TBM) and the interstitial space at three or five days of UUO. Glomeruli did not show any change. Collagen types I and III were faintly stained in the control kidneys while they were obviously increased in the interstitial space of the obstructed kidney. We examined the expression of collagen type IV (COL IV) because this basement membrane matrix protein appeared to be a major ECM protein deposited in the tubulointerstitium of the obstructed kidney. Semiquantitative analysis of COL IV by immunofluorescence microscopy revealed that enalapril reduced slightly (21%) but significantly (P < 0.01) the deposition of COL IV in the obstructed kidney. Measurement of cyanogen bromide peptides from the obstructed kidney by Western blotting showed an increase of COL IV. This increase was reduced slightly (20%) by enalapril. The level of COL IV mRNA measured by reverse transcription-PCR was very low or undetectable in the control and contralateral kidneys, while it was significantly increased in the obstructed kidney at three or five days of UUO. COL IV mRNA was abundant in glomeruli while it was almost undetectable in renal tubules in the control and contralateral kidneys. However, COL IV mRNA was increased in renal tubules but not in the glomeruli of the obstructed kidney. Enalapril treatment resulted in a 42% decrease (P < 0.01) in COL IV mRNA in the cortex and a remarkable decrease in the renal tubules of the obstructed kidney at five days. Enalapril treatment resulted in an 89% decrease in the number of infiltrating ED-1 positive monocytes/macrophages. These results indicate that enalapril treatment ameliorates the tubulointerstitial fibrosis of the affected kidney in UUO. This effect of enalapril on fibrosis may be due to the severe reduction in monocytes/macrophages capable of secreting the profibrotic factor TGF-beta 1.

Animals↗
PubMed1994

Physical dependence produced by dihydroetorphine in mice.

Using various administration schedules, the physical dependence produced by dihydroetorphine (DHE) was compared with that of morphine in mice. Physical dependence, evaluated by naloxone-precipitated withdrawal signs, did not develop following daily treatment with DHE (10, 20, 100 and 1000 micrograms/kg, i.p. or 30, 100 and 1000 ng/mouse, i.c.v.) for 6 d. However, 5 repeated injections of DHE (10 micrograms/kg, i.p.) at 1 or 2 h intervals did produce physical dependence and the dependent state disappeared after 2 h. Accordingly, it was demonstrated that a sufficient degree of antinociceptive activity needed to be maintained, longer than several hours, for the development of physical dependence on DHE and that the duration of the dependent state was very short. In the single dose suppression test, a single dose of DHE completely suppressed the natural withdrawal signs that appeared following abstinence in morphine-dependent animals without reappearance of significant withdrawal signs, indicating the suitability of DHE as a substitute for morphine. The characteristic properties of DHE, the extremely potent antinociceptive effect and minimal dependence, indicate the separation of the antinociceptive effect from dependence, and suggest that it may be possible to develop a novel drug which may be safely used in clinical situations.

Analgesics↗
PubMed1994

Amino acids and peptides. XXII. Preparation and antinociceptive effect of [D-Ala2]Leu-enkephalin-poly(ethylene glycol) hybrid.

The hybrid of poly(ethylene glycol) and [D-Ala2]Leu-enkephalin was prepared by the solution method and its antinociceptive effect and inhibitory effect on the electrically induced contractions of mouse vas deferens were examined. The hybrid was synthesized by the coupling of Boc-Tyr-D-Ala-Gly-Phe-Leu-OH and amino-poly(ethylene glycol), followed by trifluoroacetic acid treatment. The hybrid showed more potent antinociceptive activity in mice and 120 times higher inhibitory activity in mouse vas deferens preparation than intact [D-Ala2]Leu-enkephalin.

Amino Acid Sequence↗
PubMed1994

Amino acids and peptides. XXIII. Leu-enkephalin analogs containing a fluorinated amino acid at position 2, 4 or 5.

Fluorinated analogs of Leu-enkephalin were synthesized by the solution method and the solid-phase method. The synthetic peptides were examined for opioid activities on mouse vas deferens and guinea pig ileum. Among the synthetic peptides,[D-Ala2,Leu(F3)(2R,4S)5]enkephalin and [D-Ala2,Leu(F3)(2S,4R)5]enkephalin exhibited potent opioid activity, and [Leu(F3)(2S,4R)5]enkephalin exhibited high delta-receptor selectivity.

Amino Acid Sequence↗