Publications by authors named "Toshimasa Jindo"

ASB20123, a C-type natriuretic peptide/ghrelin chimeric peptide, was designed as a novel peptide and demonstrated full agonistic activity for natriuretic-peptide receptor B and a significantly longer half-life in plasma compared with the native peptide. We researched the toxicological profile of ASB20123, the correlation between the morphological change of the epiphyseal plate and bone and cartilage toxicity, and biomarkers to detect the toxicity. ASB20123 was systemically administered to male and female rats at daily dose levels of 0.

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C-type natriuretic peptide (CNP)-knockout (KO) rats exhibit impaired skeletal growth, with long bones shorter than those in wild-type (WT) rats. This study compared craniofacial morphology in the CNP-KO rat with that in the Spontaneous Dwarf Rat (SDR), a growth hormone (GH)-deficient model. The effects of subcutaneous administration of human CNP with 53 amino acids (CNP-53) from 5 weeks of age for 4 weeks on craniofacial morphology in CNP-KO rats were also investigated.

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Article Synopsis
  • - C-type natriuretic peptide (CNP) and its receptor (NPR-B) play a critical role in promoting bone growth, making the CNP/NPR-B signaling pathway a potential target for treating growth disorders like dwarfism.
  • - The study evaluates a new peptide, ASB20123, a combination of CNP and human ghrelin, which shows better stability and cartilage distribution than CNP alone, enhancing its potential as a treatment for short stature.
  • - ASB20123 was effective in promoting skeletal growth in rats and responded better to continuous infusion than single injections; the findings suggest that sustained-release formulations could optimize its therapeutic use.
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Signaling by C-type natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor-B, is a pivotal stimulator of endochondral bone growth. We recently developed CNP knockout (KO) rats that exhibit impaired skeletal growth with early growth plate closure. In the current study, we further characterized the phenotype and growth plate morphology in CNP-KO rats, and the effects of exogenous CNP in rats.

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We have previously investigated the physiological role of C-type natriuretic peptide (CNP) on endochondral bone growth, mainly with mutant mouse models deficient in CNP, and reported that CNP is indispensable for physiological endochondral bone growth in mice. However, the survival rate of CNP knockout (KO) mice fell to as low as about 70% until 10 weeks after birth, and we could not sufficiently analyze the phenotype at the adult stage. Herein, we generated CNP KO rats by using zinc-finger nuclease-mediated genome editing technology.

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A nine-year-old male beagle dog had a white spherical mass in the subcutis of the left lumbar region. Microscopically, spindle to oval cells diffusely proliferated in the fibrous and myxoid stroma. Many neoplastic cells showed rhabdoid features or vacuolated cytoplasm.

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(+)-Usnic acid (UA) has been known to be a strong uncoupler, and mitochondrial and endoplasmic reticulum (ER)-related stresses are suggested to be involved in the mechanism of hepatotoxicity. However, it has not been clarified whether UA causes toxicity in other mitochondria-rich organs such as the heart. We elucidated whether UA induces cardiotoxicity and its mechanism.

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The mechanism of spontaneous islet fibrosis in Sprague-Dawley rats was investigated. Using sections of the pancreas in naive males aged 26 to 102 weeks old and 26-week-old males injected with β-estradiol 3-benzoate (EB), the incidence of lesions and histological scores of fibrosis were examined in conjunction with immunohistochemistry for α-smooth muscle actin (α-SMA), platelet-derived growth factor receptor-α (PDGFRα) and estrogen receptor-α (ERα). The incidence of islet fibrosis increased in 78-week-old animals compared to the 26-week-old animals, and the incidence of atrophy in the fibrotic islet increased in animals over 52 weeks old.

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The effect of body-weight loading onto the articular cartilage on the occurrence of chondrotoxicity was investigated in male juvenile Sprague-Dawley rats given ofloxacin (OFLX) orally once at 900 mg/kg. Just after dosing of OFLX, hindlimb unloading was performed for 0, 2, 4, or 8 h by a tail-suspension method. Animals were sacrificed at 8h post-dose, and then the distal femoral articular cartilage was subjected to a histological examination and an investigation for gene expression of tumor necrosis factor receptor superfamily, member 12a (Tnfrsf12a); prostaglandin-endoperoxide synthase 2 (Ptgs2); plasminogen activator, urokinase receptor (Plaur); and matrix metalloproteinase 3 (Mmp3) by qRT-PCR analysis.

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The effect of hypertension on the occurrence of micro-hemorrhage in the pancreatic islet, known to be observed in Sprague-Dawley (SD) rats spontaneously, and endothelial markers were investigated in male Dahl-Iwai salt-sensitive (DIS, derived from SD rats), salt-resistant (DIR), and SD rats. DIS and DIR rats were fed 8% NaCl-containing diet to induce hypertension, with blood pressure measurement once a week, euthanized at 6, 8, or 12 weeks of age, and subjected to the measurement of plasma nitric oxide (NO) and von Willebrand factor (vWF) concentrations combined with histopathological examinations and immunohistochemical detections of vWF in the pancreas and kidney. As a result, hypertension was observed from 7 through 12 weeks of age in DIS rats.

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A 32-month-old male common marmoset had a firm and white-colored mass in the duodenal wall. The cut surface was smooth and grayish white in color. Histologically, the mass consisted of a proliferation of spindle cells with an oval to spindle-shaped nucleus and scant eosinophilic cytoplasm in a loose myxoid or fibrotic background.

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Quinolone antibacterial agents are extensively utilized in antimicrobial chemotherapy. However, they have been reported to induce arthropathy in juvenile animals, and the mechanism has not been clarified. Recently, we have demonstrated that Dusp1, Tnfrsf12a, Ptgs2, Fos, Mt1a, Plaur, Mmp3, Sstr1 and Has2 genes change in the articular cartilage of juvenile rats with a single oral administration of ofloxacin (OFLX), suggesting that these genes are involved in the induction of OFLX-induced chondrotoxicity.

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Tienilic acid is reported to be converted into electrophilic metabolites by cytochrome P450 (CYP) in vitro. In vivo, however, the metabolites have not been detected and their effect on liver function is unknown. We previously demonstrated that tienilic acid decreased the GSH level and upregulated genes responsive to oxidative/electrophilic stresses, such as heme oxygenase-1 (Ho-1), glutamate-cysteine ligase modifier subunit (Gclm) and NAD(P)H dehydrogenase quinone 1 (Nqo1), in rat liver, as well as inducing hepatotoxicity by co-treatment with the glutathione biosynthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO).

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To investigate the hepatotoxic potential of tienilic acid in vivo, we administered a single oral dose of tienilic acid to Sprague-Dawley rats and performed general clinicopathological examinations and hepatic gene expression analysis using Affymetrix microarrays. No change in the serum transaminases was noted at up to 1000 mg/kg, although slight elevation of the serum bile acid and bilirubin, and very mild hepatotoxic changes in morphology were observed. In contrast to the marginal clinicopathological changes, marked upregulation of the genes involved in glutathione biosynthesis [glutathione synthetase and glutamate-cysteine ligase (Gcl)], oxidative stress response [heme oxygenase-1 and NAD(P)H dehydrogenase quinone 1] and phase II drug metabolism (glutathione S-transferase and UDP glycosyltransferase 1A6) were noted after 3 or 6 h post-dosing.

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Quinolone antibacterial agents are extensively utilized in antimicrobial chemotherapy. However, they have been reported to induce arthropathy in juvenile animals, and the mechanism has not been clarified. In the present study, to investigate the molecular details of the chondrotoxicity of the quinolone ofloxacin (OFLX), it was orally administered by gavage at a dose level of 900 mg/kg once to male juvenile Sprague-Dawley rats, 3 weeks of age.

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To ascertain the early pathophysiological features in canine renal papillary necrosis (RPN) caused by the neurotransmission enhancer nefiracetam, male beagle dogs were orally administered nefiracetam at 300 mg/kg/day for 4 to 7 weeks in comparison with ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), at 50 mg/kg/day for 5 weeks. During the dosing period, the animals were periodically subjected to laboratory tests, light-microscopic, immunohistochemical, and electron-microscopic examinations and/or cyclooxygenase (COX)-2 mRNA analysis. In laboratory tests, a decrease in urinary osmotic pressure and increases in urine volume and urinary lactate dehydrogenase (LDH) level were early biomarkers for detecting RPN.

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The occurrence of renal papillary necrosis (RPN), seen only in dogs after repeated oral administration of nefiracetam, a neurotransmission enhancer, at a relatively high dose, is because of inhibition of renal prostaglandin synthesis by the nefiracetam metabolite M-18. In this study, analyses of urinary proteins and renal mRNA expression were performed to investigate the possible existence of a specific protein expressing the characteristics of RPN evoked by nefiracetam. In the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of urinary proteins from male dogs given nefiracetam at 300 mg kg(-1) day(-1) over weeks 5-11, a protein of approximately 40 kDa, which was not seen in control urine, and protein of approximately 30 kDa emerged as distinct bands.

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We examined the structure-phototoxicity relationship for fluoroquinolone antimicrobial agents (quinolones) using female albino Balb/c mice. First of all, to obtain an optimum dosage level for induction of phototoxicity, the prototype phototoxicant sparfloxacin was intravenously administered once at 10 mg/kg, 30 mg/kg or 100 mg/kg to female mice, followed immediately by ultraviolet-A (UVA) irradiation for 4 h (21.6J/cm2).

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The effects of nefiracetam, a neurotransmission enhancer, on renal biochemistry and morphology with toxicokinetic disposition were investigated in both in vivo and in vitro systems. In the in vivo studies with rats, dogs, and monkeys, only the dog exhibited renal papillary necrosis. Namely, when beagle dogs were orally administered with 300 mg/kg/day of nefiracetam over 11 weeks, decreased urinary osmotic pressure was noted from week 5, followed by increases in urine volume and urinary lactate dehydrogenase from week 8.

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Repeated oral treatment of dogs with a high dose of nefiracetam is reported to induce hemorrhagic lesions in the urinary bladder. To delineate its pathogenesis, we established the primary culture of uroepithelial cells of the canine urinary bladder, and then explored the effect of nefiracetam on the cultured cells. Uroepithelial cells scraped from the connective tissues of the urinary bladder of naive dogs were suspended in the minimum essential medium containing dispase, and then resuspended in the keratinocyte medium to be 6.

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