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Biomedical subjects

Y Konishi

Publications and source records attributed to Y Konishi.

At least 19 recordsLinked to original sources
PubMed2006

Gamma loop dysfunction in the quadriceps femoris of patients who underwent anterior cruciate ligament reconstruction remains bilaterally.

Purpose of this study was to investigate the effects of anterior cruciate ligament (ACL) repair on the gamma loop of the bilateral quadriceps femoris (QF). Maximal voluntary contraction (MVC) of knee extension and integrated electromyogram (I-EMG) of vastus medialis (VM), vastus lateralis (VL), and rectus femoris (RF) were examined in uninjured and injured limbs of 18 patients and 10 normal subjects, before and after 20-min vibration applied to the QF. Mean percentage changes were calculated as: (pre-vibration value-post-vibration value)/pre-vibration value x 100. Patients were divided into two groups: short-term-group (tested </=12 months after ACL repair, n=8), long-term-group (tested >/=18 months after ACL repair, n=10). Mean percentage changes of the four groups were compared with those of controls. Results indicated that changes of MVC and I-EMG on the uninjured and injured sides in short-term-group in response to vibration were significantly different from those of controls. There were no significant differences between uninjured sides in long-term and control groups. MVC and I-EMG of VM and RF of injured side in patients in the long-term-group in response to vibration were not different from those of controls. From these results, we concluded that this abnormality of the gamma loop in both injured and uninjured sides did not recover despite ACL reconstruction. However, the abnormality in uninjured side might recover >/=18 months after repair.

Adult↗
PubMed2006

Decrease in tetrahydrobiopterin as a possible cause of nephropathy in type II diabetic rats.

A decrease in renal synthesis of nitric oxide (NO) in the progression of diabetic nephropathy has been documented. As (6R)-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor of NO synthase, we investigated whether BH4 deficiency is involved in the pathogenesis of nephropathy. Ten-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were used as a type II diabetic model, and Long-Evans Tokushima Otsuka (LETO) rats as the healthy controls. OLETF rats were orally treated with BH4 (10 mg/kg daily) or with water from 10 to 61 weeks of age. In another experiment, OLETF rats were treated orally with a calcium channel blocker, benidipine (5 mg/kg daily), or with 0.3% carboxymethyl cellulose (nontreated) from 10 to 52 weeks of age. Proteinuria was observed periodically, and at the end of the study, BH4 level and GTP cyclohydrolase I (GTPCH) activity in the kidney were measured. Proteinuria was observed at 13 weeks of age in the OLETF rats, and deteriorated until 61 weeks of age. Supplemental BH4 reduced the proteinuria. At 52 weeks of age, GTPCH activity and the BH4 level were decreased in the plasma and kidneys of OLETF rats, whereas they were significantly higher in the benidipine group than in the nontreated group. Proteinuria was milder in the benidipine group than in the nontreated group, without a concomitant decrease in blood pressure. Histologically observed glomerulosclerosis was mild in the BH4 and benidipine groups. In type II diabetic rats, renal BH4 is considered to play a crucial role in the pathogenesis of diabetic nephropathy. Benidipine was found to preserve BH4 levels, suggesting therapeutic renoprotective effects.

Animals↗
PubMed2006

Secretory IgA, salivary peroxidase, and catalase-mediated microbicidal activity during hydrogen peroxide catabolism in viridans streptococci: pathogen coaggregation.

Viridans streptococci can kill methicillin-resistant Staphylococcus aureus (MRSA) through the production of hydrogen peroxide (H2O2). However, several hundred viridans streptococci cells are necessary to kill 1 cfu of MRSA. We analyzed the potency of bactericidal and fungicidal effector molecules induced by catabolism of H2O2 in the oral cavity. Secretory IgA (SIgA) and an unidentified salivary component bound Streptococcus sanguinis, a viridans streprococcus, and MRSA into coaggregates. In these coaggregates, salivary peroxidase and the MRSA catalase produced singlet molecular oxygen (1O2) from H2O2 produced by viridans streptococci. SIgA converted 1O2 into ozone, which has potent bactericidal and fungicidal activity. We calculated that <10 cfu of Streptococcus sanguinis were necessary to kill 1 cfu of MRSA in the coaggregate. SIgA, Aspergillus niger catalase, and H2O2 in saliva killed Candida albicans, which is highly resistant to reagent H2O2. Together with indigenous bacteria and innate immunity, SIgA potentially constitutes a novel system that may sustain oral homeostasis.

Adult↗
PubMed2006

Drug evolution concept in drug design: 2. Chimera method.

The drug evolution method represents a novel approach towards efficient rational drug design by implementing the drug evolution concept to the creation and development of general chemical libraries with the purpose of allowing the identification of drug candidates with improved odds and lesser costs than the traditional drug design strategies. As another example of successful translation of the biological evolution into chemical evolution, the chimera method comprises the grafting of selected building blocks, identified through a basic search within a drug library, onto the same substitution sites on a rationally chosen scaffold. The method allows the creation of a library containing both drugs and prospective drug candidates without any priorly required knowledge on the pursued disease or molecular target. Two libraries having scaffolds derived from para-aminobenzoic acid and salicylic acid have exemplified the application of the chimera method. The validation of the method has been achieved through the high number of recognized drugs within the library, which exhibit in the same time a wide variety of therapeutic activities and interact with a broad spectrum of molecular targets. The drug-enriched chimera libraries are expected to provide a highly efficient access to novel drug candidates whose unspecified therapeutic effects should be further revealed through high-throughput screening.

4-Aminobenzoic Acid↗
PubMed2003

IGF-I gene transfer by electroporation promotes regeneration in a muscle injury model.

The goal of this study was to determine whether insulin-like growth factor-I (IGF-I) gene delivery by electroporation promotes repair after muscle injury. An injury-repair model was created using mice in which a hamstring muscle was cut and sutured. A total of 50 microg of IGF-I DNA or green fluorescent protein (GFP) DNA (both in pCAGGS) was injected into the lesion and introduced into muscle cells by electrostimulation using an electric pulse generator. The number of regenerating muscle fibers in the IGF-I DNA group was significantly more than that in the GFP DNA group at 2 weeks after injection. The diameter of regenerating muscle fibers from the IGF-I DNA group was larger than that of the GFP DNA group at 4 weeks after injection. There was no significant difference in the serum IGF-I concentration between the IGF-I DNA group and the GFP DNA group at 1, 2, and 4 weeks after injection. However, muscle IGF-I concentration in the IGF-I DNA injection group was significantly greater than that in the GFP DNA injection group at 2 weeks after injection. These results demonstrated that the effects of enhanced IGF-I production were local and limited to the injected area. The ratio (injected/uninjected; intact) of the amplitude of compound muscle action potentials (CMAP) in the IGF-I DNA injection group was greater than that in the GFP DNA injection group at 4 weeks after injection and of the control group. In conclusion, IGF-I gene transfer by electroporation proved to be a simple, safe, inexpensive, and effective method to promote the regeneration of injured muscles in our injury model.

Animals↗
PubMed2002

Low-dose ACTH therapy for West syndrome: initial effects and long-term outcome.

BACKGROUND: Most Japanese pediatric neurologists attempt other treatments before using adrenocorticotropic hormone (ACTH) therapy for West syndrome (WS), and even then, they use only a low-dose synthetic ACTH to avoid serious adverse effects. In this multi-institutional study, the authors analyzed the initial effects, adverse effects, and long-term outcome in patients treated with low-dose synthetic ACTH in Japan. METHODS: The medical records of 138 patients with WS, who were treated with low-dose synthetic ACTH therapy for the first time at the authors' institutions between 1989 and 1998, were analyzed. RESULTS: At the end of ACTH therapy, excellent effect on seizures was noted in 106 of 138 (76%) patients, good effect in 23 (17%), and poor effect in 9 (7%). Initial effects on EEG were excellent in 53 of 138 (38%) patients, good in 76 (55%), and poor in 9 (7%). As for seizure prognosis at the time of follow-up, 51 of 99 (52%) patients were seizure-free, whereas 48 (48%) patients had seizures. Mental outcome was normal in 6 of 98 (6%) patients, mild mental retardation in 16 (16%), moderate mental retardation in 26 (27%), and severe mental retardation in 50 (51%). The initial effects of ACTH on seizures and long-term outcome were not dose dependent (daily dosage 0.005 to 0.032 mg/kg, 0.2 to 1.28 IU/kg; total dosage 0.1 to 0.87 mg/kg, 4 to 34.8 IU/kg). The severity of adverse effects correlated with total dosage of ACTH, and the severity of brain volume loss due to ACTH correlated well with the daily dosage and total dosage of ACTH. CONCLUSION: Low-dose synthetic ACTH therapy is as effective for the treatment of WS as the higher doses used in previous studies. The dosage of synthetic ACTH used in the treatment of WS can be decreased as much as possible to avoid serious adverse effects.

Brain↗
PubMed2002

Mechanism of quadriceps femoris muscle weakness in patients with anterior cruciate ligament reconstruction.

The purpose of this study was to investigate gamma loop function in the quadriceps femoris muscle in patients who with less than 6 month-history of anterior cruciate ligament (ACL) reconstruction. For this purpose, we compared the response to vibration stimulation in 10 patients with ACL repair and 12 normal healthy subjects, by measuring the maximal voluntary isometric contraction (MVC) and integrated electromyograms (I-EMG) of the quadriceps muscles. Pre-vibration data were obtained from each subject by measuring the MVC of the knee extension and the I-EMG from the vastus medialis, vastus lateralis, and rectus femoris muscles. Vibration stimulation was applied to the infrapatellar tendons, followed immediately by repeating the MVC and I-EMG recording. Prolonged vibration resulted in a significant decrease of both MVC and I-EMG in the control group. In contrast, the same stimulus failed to elicit changes in ACL-repair group. Our results suggest the presence of abnormal gamma loop function in the quadriceps femoris muscle of patients with ACL repair, which may explain the muscle weakness often described in such patients.

Adult↗
PubMed2001

Stimulation of gene expression of NeuroD-related factor in the mouse brain following pentylenetetrazol-induced seizures.

Various genes for transcription factors are induced in neurons involving long-lasting synaptic plasticity that is accompanied by de novo protein synthesis. In this study, we analyzed the gene expression of NeuroD-related factor (NDRF/neuroD2), a neural basic helix-loop-helix transcription factor, in the mouse hippocampus following pentylenetetrazol (PTZ)-induced seizures. Both the levels of mRNA and protein of NDRF were elevated by PTZ injection. In contrast to c-fos, a representative neuronal activation-related immediate-early gene that was induced within 1 h after PTZ administration, induction of the NDRF gene expression reached a maximum level at 7-8 h after PTZ injection and was inhibited by pretreatment with cycloheximide and MK801. In situ hybridization of the mouse hippocampus revealed that NDRF mRNA was significantly induced in the dentate gyrus. During hippocampal development, NDRF transcripts were found to be highly expressed in a juvenile period, when extensive synaptogenesis occurs. Our present results demonstrate that NDRF is a new member of the family of activation-induced transcription factors, whose expression is probably regulated by immediate-early transcription factors. NDRF is thought to be involved in long-lasting neuronal activation.

Age Factors↗
PubMed2001

Promoter structure and gene expression of the mouse inositol 1,4,5-trisphosphate receptor type 3 gene.

Inositol 1,4,5-trisphosphate receptor type 3 (IP(3)R3) is a ubiquitously expressed IP(3)R gene in the IP(3)R gene family. We identified an upstream region of the mouse IP(3)R3 genomic DNA. Transcription start points for the IP(3)R3 gene were found to be located mainly at four sites between nucleotide position -325 and -285 relative to the first ATG codon. The major start point was mapped around -325. Transcription promotion ability was detected between -325 and -285 in an IP(3)R3 proximal promoter sequence. The promoter had no TATA-box but was highly GC-rich and contained two putative Sp1-binding sites. There was no sequence similarity between promoter regions of IP(3)R3 and IP(3)R2, another ubiquitous gene, except for GC-boxes. By using a series of 5'-truncation versions and a transient luciferase assay, we detected multiple common and cell-type-dependent regulatory regions within the distal promoter sequence downstream from -4.0 kb that function positively or negatively. The IP(3)R3 gene was highly transcribed in the kidney, spleen, heart, and skeletal muscle, and this tissue distribution pattern was nearly complementary to that of IP(3)R2. We found that IP(3)R3 gene expression was repressed in retinoic acid-treated and neural differentiated P19 mouse embryonic carcinoma cells.

3T3 Cells↗
PubMed2001

A two-process model describes the hydrogen exchange behavior of cytochrome c in the molten globule state with various extents of acetylation.

Acetylation of Lys residues of horse cytochrome c steadily stabilizes the molten globule state in 18 mM HCl as more Lys residues are acetylated [Goto and Nishikiori (1991) J. Mol. Biol. 222, 679-686]. The dynamic features of the molten globule state were characterized by hydrogen/deuterium exchange of amide protons, monitored by mass spectrometry as each deuteration increased the protein mass by 1 Da. Electrospray mass spectrometry enabled us to monitor simultaneously the exchange kinetics of more than seven species with a different number of acetyl groups. One to four Lys residue-acetylated cytochrome c showed almost no protection of the amide protons from rapid exchange. The transition from the unprotected to the protected state occurred between five and eight Lys residue-acetylated species. For species with more than nine acetylated Lys residues, the exchange kinetics were independent of the extent of acetylation, and 26 amide protons were protected at 60 min of exchange, indicating the formation of a rigid hydrophobic core with hydrogen-bonded secondary structures. The apparent transition to the protected state required a higher degree of acetylation than the conformational transition measured by circular dichroism, which had a midpoint at about four acetylated residues. This difference in the transitions suggested a two-process model in which the exchange occurs either from the protected folded state or from the unprotected unfolded state through global unfolding. On the basis of a two-process model and with the reported values of the exchange and stability parameters, we simulated the exchange kinetics of a series of acetylated cytochrome c species. The simulated kinetics reproduced the observed kinetics well, indicating validity of this model for hydrogen exchange of the molten globule state.

Acetylation↗
PubMed2001

Detection and partial structure elucidation of basic taxoids from Taxus wallichiana by electrospray ionization tandem mass spectrometry.

A sensitive method for the detection and characterization of basic taxoids from the ethyl acetate extract of Taxus wallichiana has been described. A combined analysis of the fragmentation spectra of 3 purified standard basic taxoids and the substructure analysis of 139 previously reported taxoids provided information on typical primary and secondary product ions that are generated by CID mass spectrometry of basic taxoids. Precursor-scan analysis of selected product ions allowed for the detection of 57 basic taxoids from the ethyl acetate extract of T. wallichiana, 45 of which have not been reported. The method describe in this paper provides a fast method for the "dereplication" of natural products. The mass spectrometric data derived by this method was sufficient for the partial structure elucidation of novel basic taxoids. The method presented in this paper can be easily adapted into a high-throughput screening protocol for the identification and characterization of bioactive natural products.

Alkaloids↗
PubMed2001

Absence of beta-catenin gene mutations in pancreatic duct lesions induced by N-nitrosobis(2-oxopropyl)amine in hamsters.

The involvement of beta-catenin gene alterations in pancreatic duct carcinogenesis induced by N-nitrosobis(2-oxopropyl)amine (BOP) in hamsters was examined by polymerase chain reaction-single strand conformation polymorphism analysis and the expression of beta-catenin protein was examined by immunohistochemistry. No mutations of the beta-catenin gene were detected in 20 pancreatic duct adenocarcinomas (PDAs). Immunohistochemical staining showed the beta-catenin protein to be ubiquitously localized in the cell membranes. beta-Catenin accumulation was not identified in the cytoplasm and/or nucleus in any of 102 hyperplasias, 35 atypical hyperplasias, and 73 PDAs, as well as normal pancreatic duct cells. These results suggest that the Wnt/beta-catenin signaling pathway may not play an important role in pancreatic duct carcinogenesis induced by BOP in hamsters.

Animals↗
PubMed2001

Dimethylarsinic acid induces 8-hydroxy-2'-deoxyguanosine formation in the kidney of NCI-Black-Reiter rats.

Dirnethylarsenic peroxyl radical [(CH(3))(2)AsOO] has been postulated to be responsible for DNA damage induced by dimethylarsinic acid (DMA). In an effort to elucidate the possible mechanism of tumor-inducing potential of DMA, an experiment was designed to investigate the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a specific marker of oxidative base damage in the kidney tissues of NCI-Black Reiter (NBR) rats. Animals were divided into four groups and administered the vehicle - saline, 5, 10 and 20 mg/kg body weight respectively of DMA by gavage, once a day, 5 days a week, for a period of 4 weeks. DMA induced increase of 8-OHdG levels in the kidney of the rats treated, with the highest level at the dose of 10 mg/kg body weight. Analysis of the kidney for cell proliferation employing PCNA-positive index showed greater proliferation in the tissues of treated rats. However, DMA did not have any influence on apoptosis in this regimen. Histopathological examination of the kidney selections revealed the presence of vacuolated degeneration and dilation of the proximal tubule cells in two groups (10 and 20 mg/kg body weight). This study provides evidence to substantiate the role of DMA in inducing oxidative DNA damage in the kidney.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Increased expression of cyclooxygenase-2 protein in 4-nitroquinoline-1-oxide-induced rat tongue carcinomas and chemopreventive efficacy of a specific inhibitor, nimesulide.

Expression of cyclooxygenase (COX)-2 protein in 4-nitroquinoline-1-oxide (4-NQO)-induced rat tongue lesions and the postinitiation chemopreventive potential of a selective COX-2 inhibitor, nimesulide (NIM), were examined in Fischer 344 male rats. NIM was administered in the diet at doses of 150, 300, and 600 ppm for 14 weeks after treatment with 25-35 ppm 4-NQO in the drinking water for 12 weeks. Western blot analysis revealed COX-2 protein to be barely expressed in the normal tongue epithelia, whereas it was increased approximately 6-fold in squamous cell carcinomas (SCCs). Immunohistochemically, COX-2 protein was diffusely present in SCCs and dysplasia but expressed only in basal cells in hyperplasia and papillomas. In basal cells of normal epithelia, it was also occasionally weakly stained. NIM dose-dependently decreased at doses of 150 and 300 ppm, the incidences of SCCs to 4 of 12 (33.3%) and 1 of 13 (7.7%) and their multiplicity to 0.33+/-0.49 and 0.08+/-0.28 per rat, respectively, as compared with 4-NQO alone group values of 9 of 11 (81.8%) and 1.00+/-0.77. A lesser decrease was observed with 600 ppm, the values being 5 of 12 (41.7%) and 0.50+/-0.67. NIM did not significantly affect the development of hyperplasias, dysplasias, and papillomas. These results clearly indicate chemopreventive potential of a selective COX-2 inhibitor against the postinitiation development of SCCs in rat tongue carcinogenesis.

4-Nitroquinoline-1-oxide↗