58 results on '"Fumiaki Shono"'
Search Results
2. An Updated In Silico Prediction Method for Volumes of Systemic Circulation of 323 Disparate Chemicals for Use in Physiologically Based Pharmacokinetic Models to Estimate Plasma and Tissue Concentrations after Oral Doses in Rats
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Yusuke Kamiya, Junya Ohori, Fumiaki Shono, Hiroshi Yamazaki, Kimito Funatsu, Tomonori Miura, Masato Kitajima, Makiko Shimizu, and Kentaro Handa
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Absorption rate ,Chemical descriptors ,Physiologically based pharmacokinetic modelling ,Tissue concentrations ,Correlation coefficient ,Pharmacokinetics ,Chemistry ,In silico ,General Medicine ,Toxicology ,Biological system ,Systemic circulation - Abstract
Updated algorithms for predicting the volumes of systemic circulation (V1), along with absorption rate constants and hepatic intrinsic clearances, as input parameters for physiologically based pharmacokinetic (PBPK) models were established to improve the accuracy of estimated plasma and tissue concentrations of 323 chemicals after virtual oral administrations in rats. Using ridge regression with an enlarged set of chemical descriptors (up to 99), the estimated input V1 values resulted in an improved correlation coefficient (from 246 compounds) with the traditionally determined values. The PBPK model input parameters for rats of diverse compounds can be precisely estimated by increasing the number of descriptors.
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- 2021
3. In Silico Prediction of Input Parameters for Simplified Physiologically Based Pharmacokinetic Models for Estimating Plasma, Liver, and Kidney Exposures in Rats after Oral Doses of 246 Disparate Chemicals
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Tomonori Miura, Hiroshi Yamazaki, Makiko Shimizu, Yusuke Kamiya, Fumiaki Shono, Shiori Hina, Kazuki Shigeta, Kentaro Handa, Kimito Funatsu, Masato Kitajima, and Mayu Yanagi
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0303 health sciences ,Physiologically based pharmacokinetic modelling ,Chromatography ,Chemistry ,Liver and kidney ,In silico ,General Medicine ,010501 environmental sciences ,Toxicology ,01 natural sciences ,Systemic circulation ,03 medical and health sciences ,Pharmacokinetics ,In vivo ,Cheminformatics ,Dosing ,030304 developmental biology ,0105 earth and related environmental sciences - Abstract
Recently developed computational models can estimate plasma, hepatic, and renal concentrations of industrial chemicals in rats. Typically, the input parameter values (i.e., the absorption rate constant, volume of systemic circulation, and hepatic intrinsic clearance) for simplified physiologically based pharmacokinetic (PBPK) model systems are calculated to give the best fit to measured or reported in vivo blood substance concentration values in animals. The purpose of the present study was to estimate in silico these three input pharmacokinetic parameters using a machine learning algorithm applied to a broad range of chemical properties obtained from several cheminformatics software tools. These in silico estimated parameters were then incorporated into PBPK models for predicting internal exposures in rats. Following this approach, simplified PBPK models were set up for 246 drugs, food components, and industrial chemicals with a broad range of chemical structures. We had previously generated PBPK models for 158 of these substances, whereas 88 for which concentration series data were available in the literature were newly modeled. The values for the absorption rate constant, volume of systemic circulation, and hepatic intrinsic clearance could be generated in silico by equations containing between 14 and 26 physicochemical properties. After virtual oral dosing, the output concentration values of the 246 compounds in plasma, liver, and kidney from rat PBPK models using traditionally determined and in silico estimated input parameters were well correlated (r ≥ 0.83). In summary, by using PBPK models consisting of chemical receptor (gut), metabolizing (liver), excreting (kidney), and central (main) compartments with in silico-derived input parameters, the forward dosimetry of new chemicals could provide the plasma/tissue concentrations of drugs and chemicals after oral dosing, thereby facilitating estimates of hematotoxic, hepatotoxic, or nephrotoxic potential as a part of risk assessment.
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- 2021
4. Physiologically Based Pharmacokinetic Models Predicting Renal and Hepatic Concentrations of Industrial Chemicals after Virtual Oral Doses in Rats
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Masato Kitajima, Yusuke Kamiya, Makiko Shimizu, Fumiaki Shono, Tomonori Miura, Yui Kobayashi, Manae Yoshizawa, Kimito Funatsu, Ayane Nakano, Hiroshi Yamazaki, Shohei Otsuka, and Miyu Iwasaki
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Physiologically based pharmacokinetic modelling ,Alternatives to animal testing ,Administration, Oral ,010501 environmental sciences ,Pharmacology ,Kidney ,Toxicology ,Models, Biological ,01 natural sciences ,Nephrotoxicity ,03 medical and health sciences ,Pharmacokinetics ,medicine ,Animals ,Computer Simulation ,Dosing ,Hazard evaluation ,030304 developmental biology ,0105 earth and related environmental sciences ,0303 health sciences ,Chemistry ,In vitro toxicology ,General Medicine ,Rats ,medicine.anatomical_structure ,Liver ,Pharmaceutical Preparations - Abstract
Recently developed high-throughput in vitro assays in combination with computational models could provide alternatives to animal testing. The purpose of the present study was to model the plasma, hepatic, and renal pharmacokinetics of approximately 150 structurally varied types of drugs, food components, and industrial chemicals after virtual external oral dosing in rats and to determine the relationship between the simulated internal concentrations in tissue/plasma and their lowest-observed-effect levels. The model parameters were based on rat plasma data from the literature and empirically determined pharmacokinetics measured after oral administrations to rats carried out to evaluate hepatotoxic or nephrotic potentials. To ensure that the analyzed substances exhibited a broad diversity of chemical structures, their structure-based location in the chemical space underwent projection onto a two-dimensional plane, as reported previously, using generative topographic mapping. A high-throughput in silico one-compartment model and a physiologically based pharmacokinetic (PBPK) model consisting of chemical receptor (gut), metabolizing (liver), central (main), and excreting (kidney) compartments were developed in parallel. For 159 disparate chemicals, the maximum plasma concentrations and the areas under the concentration-time curves obtained by one-compartment models and modified simple PBPK models were closely correlated. However, there were differences between the PBPK modeled and empirically obtained hepatic/renal concentrations and plasma maximal concentrations/areas under the concentration-time curves of the 159 chemicals. For a few compounds, the lowest-observed-effect levels were available for hepatotoxicity and nephrotoxicity in the Hazard Evaluation Support System Integrated Platform in Japan. The areas under the renal or hepatic concentration-time curves estimated using PBPK modeling were inversely associated with these lowest-observed-effect levels. Using PBPK forward dosimetry could provide the plasma/tissue concentrations of drugs and chemicals after oral dosing, thereby facilitating estimates of nephrotoxic or hepatotoxic potential as a part of the risk assessment.
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- 2020
5. Determination and prediction of permeability across intestinal epithelial cell monolayer of a diverse range of industrial chemicals/drugs for estimation of oral absorption as a putative marker of hepatotoxicity
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Yuto Abe, Makiko Shimizu, Masato Kitajima, Hiroka Takaku, Norie Murayama, Chisato Akase, Fumiaki Shono, Hiroshi Yamazaki, Yusuke Kamiya, Kimito Funatsu, Rio Yamada, and Yuko Sekiguchi
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Drug ,Apparent permeability ,Health, Toxicology and Mutagenesis ,media_common.quotation_subject ,Cell ,010501 environmental sciences ,Toxicology ,01 natural sciences ,03 medical and health sciences ,0302 clinical medicine ,lcsh:RA1190-1270 ,Monolayer ,medicine ,Caco-2 cells ,lcsh:Toxicology. Poisons ,0105 earth and related environmental sciences ,media_common ,ComputingMethodologies_COMPUTERGRAPHICS ,Molecular mass ,Chemistry ,Fraction absorbed ,Regular Article ,In vitro ,Epithelium ,No-observed-effect level ,medicine.anatomical_structure ,Biochemistry ,Multivariate prediction equation ,Octanol–water distribution coefficient ,030217 neurology & neurosurgery - Abstract
Graphical abstract, Highlights • Permeability values of 90 industry chemicals were measured by a Caco-2 system. • A multivariate prediction equation for permeability of chemicals was proposed. • Chemical permeability coefficients were inversely associated with hepatic NOELs., Apparent permeability coefficients (Papp) across a human intestinal epithelial Caco-2 cell monolayer were measured for a range of industrial/drug chemicals. A predictive equation for determining in vitro Papp values of fifty-six substances was set up using multivariate regression analysis based on in silico-estimated physicochemical properties (molecular weights and water distribution coefficients for apical and basal pH environments) (r = 0.77, p
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- 2020
6. An Updated
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Yusuke, Kamiya, Kentaro, Handa, Tomonori, Miura, Junya, Ohori, Makiko, Shimizu, Masato, Kitajima, Fumiaki, Shono, Kimito, Funatsu, and Hiroshi, Yamazaki
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Administration, Oral ,Animals ,Tissue Distribution ,Organic Chemicals ,Rats - Abstract
Updated algorithms for predicting the volumes of systemic circulation (
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- 2021
7. Prediction of permeability across intestinal cell monolayers for 219 disparate chemicals using in vitro experimental coefficients in a pH gradient system and in silico analyses by trivariate linear regressions and machine learning
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Riku Hayasaka, Junya Ohori, Hiroshi Yamazaki, Kimito Funatsu, Izumi Sano, Masato Kitajima, Rie Saito, Fumiaki Shono, Yusuke Kamiya, Asuka Omura, and Kentaro Handa
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Pharmacology ,Cell Membrane Permeability ,Membrane permeability ,Chemistry ,In silico ,Biochemistry ,In vitro ,Machine Learning ,Intestinal Absorption ,Caco-2 ,Permeability (electromagnetism) ,Inorganic Chemicals ,Linear regression ,Biophysics ,Linear Models ,Distribution (pharmacology) ,Humans ,Computer Simulation ,Efflux ,Caco-2 Cells ,Forecasting - Abstract
For medicines, the apparent membrane permeability coefficients (Papp) across human colorectal carcinoma cell line (Caco-2) monolayers under a pH gradient generally correlate with the fraction absorbed after oral intake. Furthermore, the in vitro Papp values of 29 industrial chemicals were found to have an inverse association with their reported no-observed effect levels for hepatotoxicity in rats. In the current study, we expanded our influx permeability predictions for the 90 previously investigated chemicals to both influx and efflux permeability predictions for 207 diverse primary compounds, along with those for 23 secondary compounds. Trivariate linear regression analysis found that the observed influx and efflux logPapp values determined by in vitro experiments significantly correlated with molecular weights and the octanol–water distribution coefficients at apical and basal pH levels (pH 6.0 and 7.4, respectively) (apical to basal, r = 0.76, n = 198; and basal to apical, r = 0.77, n = 202); the distribution coefficients were estimated in silico. Further, prediction accuracy was enhanced by applying a light gradient boosting machine learning system (LightGBM) to estimate influx and efflux logPapp values that incorporated 17 and 19 in silico chemical descriptors (r = 0.83–0.84, p
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- 2021
8. Correction to 'An Updated In Silico Prediction Method for Volumes of Systemic Circulation of 323 Disparate Chemicals for Use in Physiologically Based Pharmacokinetic Models to Estimate Plasma and Tissue Concentrations after Oral Doses in Rats'
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Yusuke Kamiya, Kentaro Handa, Tomonori Miura, Junya Ohori, Makiko Shimizu, Masato Kitajima, Fumiaki Shono, Kimito Funatsu, and Hiroshi Yamazaki
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General Medicine ,Toxicology - Published
- 2022
9. Comparison of pro-adipogenic effects between prostaglandin (PG) D2 and its stable, isosteric analogue, 11-deoxy-11-methylene-PGD2, during the maturation phase of cultured adipocytes
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Mohammad Shahidur Rahman, Md. Mazharul Islam Chowdhury, Fumiaki Shono, Mitsuo Jisaka, Hidehisa Shimizu, Pinky Karim Syeda, Michael Nii N. Nartey, Kohji Nishimura, and Kazushige Yokota
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0301 basic medicine ,medicine.medical_specialty ,Physiology ,Prostaglandin ,Peroxisome proliferator-activated receptor ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Cell surface receptor ,Internal medicine ,medicine ,Receptor ,Pharmacology ,chemistry.chemical_classification ,integumentary system ,biology ,Antagonist ,Prostanoid ,Cell Biology ,030104 developmental biology ,Endocrinology ,chemistry ,Adipogenesis ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Cyclooxygenase - Abstract
Prostaglandin (PG) D2 is relatively unstable and dehydrated non-enzymatically into PGJ2 derivatives, which are known to serve as pro-adipogenic factors by activating peroxisome proliferator-activated receptor (PPAR) γ, a master regulator of adipogenesis. 11-Deoxy-11-methylene-PGD2 (11d-11m-PGD2) is a novel, chemically stable, isosteric analogue of PGD2 in which the 11-keto group is replaced by an exocyclic methylene. Here we attempted to investigate pro-adipogenic effects of PGD2 and 11d-11m-PGD2 and to compare the difference in their ways during the maturation phase of cultured adipocytes. The dose-dependent study showed that 11d-11m-PGD2 was significantly more potent than natural PGD2 to stimulate the storage of fats suppressed in the presence of indomethacin, a cyclooxygenase inhibitor. These pro-adipogenic effects were caused by the up-regulation of adipogenesis as evident with higher gene expression levels of adipogenesis markers. Analysis of transcript levels revealed the enhanced gene expression of two subtypes of cell-surface membrane receptors for PGD2, namely the prostanoid DP1 and DP2 (chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2)) receptors together with lipocalin-type PGD synthase during the maturation phase. Specific agonists for DP1, CRTH2, and PPARγ were appreciably effective to rescue adipogenesis attenuated by indomethacin. The action of PGD2 was attenuated by specific antagonists for DP1 and PPARγ. By contrast, the effect of 11d-11m-PGD2 was more potently interfered by a selective antagonist for CRTH2 than that for DP1 while PPARγ antagonist GW9662 had almost no inhibitory effects. These results suggest that PGD2 exerts its pro-adipogenic effect principally through the mediation of DP1 and PPARγ, whereas the stimulatory effect of 11d-11m-PGD2 on adipogenesis occurs preferentially by the interaction with CRTH2.
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- 2018
10. Correction to 'Plasma and Hepatic Concentrations of Chemicals after Virtual Oral Administrations Extrapolated Using Rat Plasma Data and Simple Physiologically Based Pharmacokinetic Models'
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Hiroshi Yamazaki, Rio Yamada, Tomonori Miura, Shohei Otsuka, Hitomi Nakamura, Kimito Funatsu, Sawa Mizuno, Fumiaki Shono, Mayuko Nakazato, Yusuke Kamiya, and Hiroka Takaku
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Chromatography ,Pharmacokinetics ,Chemistry ,Simple (abstract algebra) ,General Medicine ,Plasma ,Toxicology - Published
- 2019
11. Plasma and Hepatic Concentrations of Chemicals after Virtual Oral Administrations Extrapolated Using Rat Plasma Data and Simple Physiologically Based Pharmacokinetic Models
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Yusuke Kamiya, Shohei Otsuka, Hitomi Nakamura, Tomonori Miura, Hiroshi Yamazaki, Kimito Funatsu, Mayuko Nakazato, Hiroka Takaku, Sawa Mizuno, Fumiaki Shono, and Rio Yamada
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Liver chemistry ,0303 health sciences ,Chemistry ,Administration, Oral ,General Medicine ,010501 environmental sciences ,Pharmacology ,Toxicology ,01 natural sciences ,Permeability ,Rats ,03 medical and health sciences ,Liver metabolism ,Pharmacokinetics ,Liver ,In vivo ,Toxicokinetics ,Animals ,Humans ,Tissue Distribution ,Tissue distribution ,Caco-2 Cells ,Organic Chemicals ,030304 developmental biology ,0105 earth and related environmental sciences - Abstract
Only a small fraction of chemicals possesses adequate in vivo toxicokinetic data for assessing potential hazards. The aim of the present study was to model the plasma and hepatic pharmacokinetics of more than 50 disparate types of chemicals and drugs after virtual oral administrations in rats. The models were based on reported pharmacokinetics determined after oral administration to rats. An inverse relationship was observed between no-observed-effect levels after oral administration and chemical absorbance rates evaluated for cell permeability ( r = -0.98, p0.001, n = 17). For a varied selection of more than 30 chemicals, the plasma concentration curves and the maximum concentrations obtained using a simple one-compartment model (recently recommended as a high-throughput toxicokinetic model) and a simple physiologically based pharmacokinetic (PBPK) model (consisting of chemical receptor, metabolizing, and central compartments) were highly consistent. The hepatic and plasma concentrations and the hepatic and plasma areas under the concentration-time curves of more than 50 chemicals were roughly correlated; however, differences were evident between the PBPK-modeled values in livers and empirically obtained values in plasma. Of the compounds selected for analysis, only seven had the lowest observed effect level (LOEL) values for hepatoxicity listed in the Hazard Evaluation Support System Integrated Platform in Japan. For these seven compounds, the LOEL values and the areas under the hepatic concentration-time curves estimated using PBPK modeling were inversely correlated ( r = -0.78, p0.05, n = 7). This study provides important information to help simulate the high hepatic levels of potent hepatotoxic compounds. Using suitable PBPK parameters, the present models could estimate the plasma/hepatic concentrations of chemicals and drugs after oral doses using both PBPK forward and reverse dosimetry, thereby indicating the potential value of this modeling approach in predicting hepatic toxicity as a part of risk assessments of chemicals absorbed in the human body.
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- 2018
12. Endogenous synthesis of prostacyclin was positively regulated during the maturation phase of cultured adipocytes
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Fumiaki Shono, Kohji Nishimura, Pinky Karim Syeda, Tsutomu Nagaya, Ferdous Khan, Kazushige Yokota, Mohammad S Rahman, and Mitsuo Jisaka
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Clinical Biochemistry ,Biomedical Engineering ,Adipose tissue ,Prostaglandin ,Bioengineering ,Endogeny ,Prostacyclin ,Cell Biology ,Biology ,Cyclooxygenase pathway ,chemistry.chemical_compound ,Prostaglandin I-2 ,6-Keto-PGF(1 alpha) ,Enzyme-linked immunosorbent assay ,Adipocyte ,3T3-L1 cells ,Adipogenesis ,chemistry ,Biochemistry ,medicine ,lipids (amino acids, peptides, and proteins) ,Receptor ,Biotechnology ,medicine.drug ,Original Research - Abstract
Prostacyclin alternatively called prostaglandin (PG) I2 is an unstable metabolite synthesized by the arachidonate cyclooxygenase pathway. Earlier studies have suggested that prostacyclin analogues can act as a potent effector of adipose differentiation. However, biosynthesis of PGI2 has not been determined comprehensively at different life stages of adipocytes. PGI2 is rapidly hydrolyzed to the stable product, 6-keto-PGF1α, in biological fluids. Therefore, the generation of PGI2 can be quantified as the amount of 6-keto-PGF1α. In this study, we attempted to develop a solid-phase enzyme-linked immunosorbent assay (ELISA) using a mouse antiserum specific for 6-keto-PGF1α. According to the typical calibration curve of our ELISA, 6-keto-PGF1α can be quantified from 0.8 pg to 7.7 ng in an assay. The evaluation of our ELISA revealed the higher specificity of our antiserum without the cross-reaction with other related prostanoids while it exhibited only the cross-reaction of 1.5 % with PGF2α. The resulting ELISA was applied to the quantification of 6-keto-PGF1α generated endogenously by cultured 3T3-L1 cells at different stages. The cultured cells showed the highest capability to generate 6-keto-PGF1α during the maturation phase of 4–6 days, which was consistent with the coordinated changes in the gene expression of PGI synthase and the IP receptor for PGI2. Following these events, the accumulation of fats was continuously promoted up to 14 days. Thus, our immunological assay specific for 6-keto-PGF1α is useful for monitoring the endogenous levels of the unstable parent PGI2 at different life stages of adipogenesis and for further studies on the potential association with the up-regulation of adipogenesis in cultured adipocytes.
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- 2014
13. Octanol/water partition coefficients estimated using retention times in reverse-phase liquid chromatography and calculated in silico as one of the determinant factors for pharmacokinetic parameter estimations of general chemical substances.
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Koichiro Adachi, Makiko Shimizu, Fumiaki Shono, Kimito Funatsu, and Hiroshi Yamazaki
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LIQUID chromatography , *PARAMETER estimation , *OCTYL alcohol , *PHARMACOKINETICS , *TIME management , *PARTITION coefficient (Chemistry) , *RF values (Chromatography) - Abstract
The octanol/water partition coefficient P (logP) is a hydrophobicity index and is one of the determining factors for the pharmacokinetics of orally administered substances because it influences membrane permeability. To illustrate the wide-ranging variety of compounds in the chemical space, a two-dimensional data plot consisting of 25 blocks was previously proposed based on a substance’s in silico chemical descriptors. The logP values of approximately 200 diverse chemicals (test plus reference compounds covering all 25 blocks of the chemical space) were estimated experimentally using retention times in reverse-phase liquid chromatography; these values were compared with those of authentic reference compounds with established logP values (available for 17 of 60 reference substances in the Organization for Economic Co-operation and Development Test Guideline 117). The logP values of 140 of 165 chemicals successfully estimated using four different mobile phase conditions (pH 2, 4, 7, and 10 for molecular forms) correlated significantly with those calculated using the in silico packages ChemDraw and ACD/Percepta (r > 0.72). Although substances that neighbored authentic compounds in the chemical space had precisely correlated logP values estimated experimentally and in silico, some compounds that were more distant from authentic substances showed lower logP values than those estimated in silico. These results indicate that additional authentic reference materials with wider ranging chemical diversity and their logP values from reverse-phase liquid chromatography should be included in the international test guidance to promote simple and reliable estimation of octanol/water partition coefficients, which are important determinant factors for the pharmacokinetics of general chemicals. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
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14. Consideration of the Visual Resemblance between Original and Generic Drugs
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Takahiro Hiurata, Fumiaki Shono, Koichiro Tsuchiya, Kaori Harada, Kaori Tomita, Eri Maeda, and Sayuri Doi
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Business - Published
- 2013
15. Stimulation of fat storage by prostacyclin and selective agonists of prostanoid IP receptor during the maturation phase of cultured adipocytes
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Pinky Karim Syeda, Fumiaki Shono, Mitsuo Jisaka, Michael Nii N. Nartey, Mohammad Shahidur Rahman, Kohji Nishimura, Ferdous Khan, Mohammad Safiqul Islam, and Kazushige Yokota
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0301 basic medicine ,medicine.medical_specialty ,Clinical Biochemistry ,Biomedical Engineering ,Prostaglandin ,Peroxisome proliferator-activated receptor ,Bioengineering ,Prostacyclin ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Receptor ,chemistry.chemical_classification ,Forskolin ,Troglitazone ,Cell Biology ,Prostaglandin I-2 ,IP receptor ,Adipogenesis ,3T3-L1 cells ,cAMP ,Peroxisome proliferator-activated receptor gamma ,030104 developmental biology ,Endocrinology ,chemistry ,biology.protein ,Original Article ,Cyclooxygenase ,030217 neurology & neurosurgery ,Biotechnology ,medicine.drug - Abstract
We have previously shown that cultured adipocytes have the ability to biosynthesize prostaglandin (PG) I2 called alternatively as prostacyclin during the maturation phase by the positive regulation of gene expression of PGI synthase and the prostanoid IP receptor. To clarify how prostacyclin regulates adipogenesis, we investigated the effects of prostacyclin and the specific agonists or antagonists for the IP receptor on the storage of fats during the maturation phase of cultured adipocytes. Exogenous PGI2 and the related selective agonists for the IP receptor including MRE-269 and treprostinil rescued the storage of fats attenuated by aspirin, a cyclooxygenase inhibitor. On the other hand, selective antagonists for IP such as CAY10441 and CAY10449 were effective to suppress the accumulation of fats as GW9662, a specific antagonist for peroxisome proliferator-activated receptor (PPAR)γ. Thus, pro-adipogenic action of prostacyclin can be explained by the action mediated through the IP receptor expressed at the maturation stage of adipocytes. Cultured adipocytes incubated with each of PGI2 and MRE-269 together with troglitazone, an activator for PPARγ, exhibited additively higher stimulation of fats storage than with either compound alone. The combined effect of MRE-269 and troglitazone was almost abolished by co-incubation with GW9662, but not with CAY10441. Increasing concentrations of troglitazone were found to reverse the inhibitory effect of CAY10441 in a dose-dependent manner while those of MRE-269 failed to rescue adipogenesis suppressed by GW9662, indicating the critical role of the PPARγ activation as a downstream factor for the stimulated adipogenesis through the IP receptor. Treatment of cultured adipocytes with cell permeable stable cAMP analogues or forskolin as a cAMP elevating agent partly restored the inhibitory effect of aspirin. However, excess levels of cAMP stimulated by forskolin attenuated adipogenesis. Supplementation with H-89, a cell permeable inhibitor for protein kinase A (PKA), had no effect on the promoting action of PGI2 or MRE-269 along with aspirin on the storage of fats, suggesting that the promotion of adipogenesis mediated by the IP receptor does not require the PKA activity.
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- 2016
16. Generation of Monoclonal Antibody for 15-deoxy-Δ12,14-Prostaglandin J2 and Development of Enzyme-Linked Immunosorbent Assay for Its Quantification in Culture Medium of Adipocytes
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Mohammad S Rahman, Kohji Nishimura, Fumiaki Shono, Abu Asad Chowdhury, Pinky Karim Syeda, Mohammad Salim Hossain, Kazushige Yokota, Tsutomu Nagaya, and Mitsuo Jisaka
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chemistry.chemical_classification ,medicine.drug_class ,Bioengineering ,Endogeny ,Biological activity ,General Medicine ,Monoclonal antibody ,Applied Microbiology and Biotechnology ,Biochemistry ,Molecular biology ,Enzyme ,chemistry ,Antigen ,medicine ,Secretion ,Molecular Biology ,Incubation ,Biotechnology ,Conjugate - Abstract
15-deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2) is a biologically active molecule serving as a pro-adipogenic factor or an anti-inflammatory regulator. This compound is one of naturally occurring derivatives formed by the non-enzymatic dehydration of PGD2. To determine the endogenous synthesis of 15d-PGJ2, a convenient immunological approach is useful. At first, we established a cloned hybridoma cell line to secrete a monoclonal antibody specific for 15d-PGJ2. For the development of a solid-phase enzyme-linked immunosorbent assay (ELISA), the immobilized antigen using a protein conjugate of 15d-PGJ2 was allowed to react competitively with a monoclonal antibody in the presence of free 15d-PGJ2. Under the optimized conditions, a sensitive calibration curve was generated able to determine the amount of 15d-PGJ2 from 0.5 pg to 9.7 ng with 71 pg of 50% displacement in one assay. Our monoclonal antibody did not recognize other related prostanoids except PGJ2 with cross-reaction of 4%. Our ELISA was demonstrated to be reliable for the quantification of 15d-PGJ2 in the maturation medium of cultured adipocytes by confirming the accuracy and specificity of its determination. The application of our assay revealed that the non-enzymatic formation of 15d-PGJ2 became more evident after several hours of incubation with authentic PGD2 at 37 °C. The results indicate the usefulness of our developed solid-phase ELISA with the monoclonal antibody for further studies on the endogenous synthesis of 15d-PGJ2 and its roles in various cells and tissues.
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- 2012
17. Pretreatment of cultured preadipocytes with arachidonic acid during the differentiation phase without a cAMP-elevating agent enhances fat storage after the maturation phase
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Kohji Nishimura, Fumiaki Shono, Kazushige Yokota, Michael Nii N. Nartey, Pinky Karim Syeda, Ferdous Khan, Mitsuo Jisaka, Mohammad Safiqul Islam, and Mohammad Shahidur Rahman
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0301 basic medicine ,IBMX ,Physiology ,Receptors, Prostaglandin ,Acetates ,Dinoprost ,Biochemistry ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Adipocyte ,1-Methyl-3-isobutylxanthine ,Adipocytes ,Cyclic AMP ,Receptor ,Cells, Cultured ,Prostaglandin-E Synthases ,Adipogenesis ,Arachidonic Acid ,biology ,Cell Differentiation ,Pyrazines ,Hydroxyprostaglandin Dehydrogenases ,lipids (amino acids, peptides, and proteins) ,Arachidonic acid ,Signal Transduction ,medicine.medical_specialty ,Prostaglandin ,6-Ketoprostaglandin F1 alpha ,Dinoprostone ,03 medical and health sciences ,Internal medicine ,3T3-L1 Cells ,medicine ,Animals ,Humans ,Cyclooxygenase Inhibitors ,Triglycerides ,Pharmacology ,Prostanoid ,Membrane Proteins ,Mesenchymal Stem Cells ,Cell Biology ,030104 developmental biology ,Endocrinology ,chemistry ,Gene Expression Regulation ,Cyclooxygenase 2 ,biology.protein ,Cyclooxygenase 1 ,Cyclooxygenase ,Receptors, Prostaglandin E, EP4 Subtype ,030217 neurology & neurosurgery - Abstract
Arachidonic acid (AA) and the related prostanoids exert complex effects on the adipocyte differentiation depending on the culture conditions and life stages. Here, we investigated the effect of the pretreatment of cultured 3T3-L1 preadipocytes with exogenous AA during the differentiation phase without 3-isobutyl-1-methylxanthine (IBMX), a cAMP-elevating agent, on the storage of fats after the maturation phase. This pretreatment with AA stimulated appreciably adipogenesis after the maturation phase as evident with the up-regulated gene expression of adipogenic markers. The stimulatory effect of the pretreatment with AA was attenuated by the co-incubation with each of cyclooxygenase (COX) inhibitors. Among exogenous prostanoids and related compounds, the pretreatment with MRE-269, a selective agonist of the IP receptor for prostaglandin (PG) I2, strikingly stimulated the storage of fats in adipocytes. The gene expression analysis of arachidonate COX pathway revealed that the transcript levels of inducible COX-2, membrane-bound PGE synthase-1, and PGF synthase declined more greatly in cultured preadipocytes treated with AA. By contrast, the expression levels of COX-1, cytosolic PGE synthase, and PGI synthase remained constitutive. The treatment of cultured preadipocytes with AA resulted in the decreased synthesis of PGE2 and PGF2α serving as anti-adipogenic PGs although the biosynthesis of pro-adipogenic PGI2 was up-regulated during the differentiation phase. Moreover, the gene expression levels of EP4 and FP, the respective prostanoid receptors for PGE2 and PGF2α, were gradually suppressed by the supplementation with AA, whereas that of IP for PGI2 remained relatively constant. Collectively, these results suggest the predominant role of endogenous PGI2 in the stimulatory effect of the pretreatment of cultured preadipoccytes with AA during the differentiation phase without IBMX on adipogenesis after the maturation phase.
- Published
- 2015
18. Blood concentrations of acrylonitrile in humans after oral administration extrapolated from in vivo rat pharmacokinetics, in vitro human metabolism, and physiologically based pharmacokinetic modeling
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Fumiaki Shono, Kana Horiuchi, Hiroshi Yamazaki, Ryohji Takano, Masato Kitajima, Norie Murayama, and Masatoshi Kumamoto
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Male ,No-Observed-Adverse-Effect Level ,Physiologically based pharmacokinetic modelling ,Acrylonitrile ,Dose-Response Relationship, Drug ,Chemistry ,Administration, Oral ,General Medicine ,Compartment (chemistry) ,Absorption (skin) ,Pharmacology ,Toxicology ,Models, Biological ,Rats ,chemistry.chemical_compound ,Species Specificity ,Pharmacokinetics ,In vivo ,Oral administration ,Microsomes, Liver ,Microsome ,Animals ,Humans - Abstract
The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for acrylonitrile in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a prior previously developed PBPK model in rats. The model basically consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for acrylonitrile. Evaluation of a previous rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after oral treatment with acrylonitrile (30 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of acrylonitrile in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. Acrylonitrile was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for acrylonitrile is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses.
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- 2010
19. Biomonitoring of Urinary Cotinine Concentrations Associated with Plasma Levels of Nicotine Metabolites after Daily Cigarette Smoking in a Male Japanese Population
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Taku Nagano, Norie Murayama, Hiroshi Yamazaki, Ryohji Takano, Fumiaki Shono, Tetsuya Kamataki, Kazuma Kiyotani, and Makiko Shimizu
- Subjects
Adult ,Male ,CYP2A6 ,Nicotine ,Genotype ,cytochrome P450 ,Health, Toxicology and Mutagenesis ,Metabolite ,Urinary system ,Population ,lcsh:Medicine ,Physiology ,Urine ,Pharmacology ,3′-hydroxycotinine ,genetic polymorphism ,smoking index ,biomarker ,3-Hydroxycotinine ,Article ,Cytochrome P-450 CYP2A6 ,chemistry.chemical_compound ,Asian People ,Medicine ,Humans ,education ,Cotinine ,education.field_of_study ,Polymorphism, Genetic ,business.industry ,lcsh:R ,Smoking ,Public Health, Environmental and Occupational Health ,chemistry ,Linear Models ,Aryl Hydrocarbon Hydroxylases ,business ,Biomarkers ,medicine.drug ,Environmental Monitoring - Abstract
Human biomonitoring of plasma and urinary levels of nicotine, cotinine, and 3′-hydroxycotinine was conducted after daily cigarette smoking in a population of 92 male Japanese smokers with a mean age of 37 years who had smoked an average of 23 cigarettes per day for 16 years. Members of the population were genotyped for the nicotine-metabolizing enzyme cytochrome P450 2A6 (CYP2A6). The mean levels of nicotine, the levels of its metabolites cotinine and 3′-hydroxycotinine, and the sum of these three levels in subjects one hour after smoking the first cigarette on the sampling day were 20.1, 158, 27.7, and 198 ng/mL in plasma and 846, 1,020, 1,010, and 2,870 ng/mL in urine under daily smoking conditions. Plasma levels of 3'-hydroxycotinine and urinary levels of nicotine and 3′-hydroxycotinine were dependent on the CYP2A6 phenotype group, which was estimated from the CYP2A6 genotypes of the subjects, including those with whole gene deletion. Plasma cotinine levels were significantly correlated with the number of cigarettes smoked on the day before sampling (r = 0.71), the average number of cigarettes smoked daily (r = 0.58), and the Brinkman index (daily cigarettes × years, r = 0.48) under the present conditions. The sum of nicotine, cotinine, and 3′-hydroxycotinine concentrations in plasma showed a similar relationship to that of the plasma cotinine levels. Urinary concentrations of cotinine and the sum of nicotine metabolite concentrations also showed significant correlations with the plasma levels and the previous day’s and average cigarette consumption. The numbers of cigarettes smoked per day by two subjects with self-reported light smoking habits were predicted by measuring the urinary cotinine concentrations and using linear regression equations derived from above-mentioned data. These results indicate that biomonitoring of the urinary cotinine concentration is a good, easy-to-use marker for plasma levels of cotinine and the sum of nicotine metabolites in smokers independent of genetic polymorphism of CYP2A6.
- Published
- 2010
20. Up-regulation of adipogenesis in adipocytes expressing stably cyclooxygenase-2 in the antisense direction
- Author
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Fumiaki Shono, Kazushige Yokota, Mitsuo Jisaka, Xiaoqing Chu, Tsutomu Nagaya, and Kohji Nishimura
- Subjects
DNA, Complementary ,Physiology ,Genetic Vectors ,Transfection ,Biochemistry ,Dinoprostone ,Gene Expression Regulation, Enzymologic ,Mice ,chemistry.chemical_compound ,3T3-L1 Cells ,Adipocyte ,Antisense Technology ,Gene expression ,Sense (molecular biology) ,Adipocytes ,Animals ,Humans ,RNA, Antisense ,RNA, Messenger ,Cloning, Molecular ,Cell Proliferation ,Pharmacology ,Adipogenesis ,Cyclooxygenase 2 Inhibitors ,biology ,Cell growth ,Cell Biology ,Lipid Metabolism ,Molecular biology ,Antisense RNA ,chemistry ,Cyclooxygenase 2 ,biology.protein ,Cyclooxygenase ,Biomarkers - Abstract
Adipocytes and the precursor cells express two types of cyclooxygenase (COX) isoforms that are involved in the biosynthesis of different types of prostaglandins (PGs) exerting opposite effects on adipogenesis. To evaluate the role of the inducible COX-2 isoform in the control of the differentiation and maturation of adipocytes, we employed an antisense technology to suppress specifically the expression of COX-2 in adipocytes. Cultured 3T3-L1 preadipocytes were transfected stably with a mammalian expression vector having the full-length cDNA encoding mouse COX-2 oriented in the antisense direction. The cloned transfectants with antisense COX-2 exhibited stable expression of antisense RNA for COX-2, which was accompanied by the suppressed expression of mRNA and protein levels of sense COX-2. However, almost no alteration in the expression of COX-1 was detected. The transfectants with antisense COX-2 showed significant decreases in the delayed synthesis of PGE 2 involving the inducible COX-2 in response to cell stimuli. By contrast, the immediate synthesis of PGE 2 associated with the constitutive COX-1 was not influenced appreciably. The stable expression of antisense mRNA of COX-2 resulted in significant stimulation of fat storage during the maturation phase without affecting the cell proliferation associated with the clonal expansion phase. The gene expression studies revealed higher expression levels of adipocyte-specific markers in the transfectants with antisense COX-2, indicating the mechanism that stimulates adipogenesis program. The up-regulation of fat storage was appreciably prevented by anti-adipogenic prostanoids, such as PGE 2 and PGF 2α , during the maturation phase. These results suggest that COX-2 is more preferentially involved in the generation of endogenous anti-adipogenic prostanoids during the maturation phase of adipocytes.
- Published
- 2010
21. Blood Concentrations of 1,4-Dioxane in Humans after Oral Administration Extrapolated from In Vivo Rat Pharmacokinetics, In Vitro Human Metabolism, and Physiologically Based Pharmacokinetic Modeling
- Author
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Kana Horiuchi, Fumiaki Shono, Hiroshi Yamazaki, Ryohji Takano, Masato Kitajima, and Norie Murayama
- Subjects
Physiologically based pharmacokinetic modelling ,No-observed-adverse-effect level ,Pharmacokinetics ,Oral administration ,In vivo ,Chemistry ,Health, Toxicology and Mutagenesis ,Microsome ,Absorption (skin) ,Pharmacology ,Toxicology ,Compartment (pharmacokinetics) - Abstract
The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for 1,4-dioxane in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a developed PBPK model in rats. The model consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for 1,4-dioxane. Evaluation of the rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after daily oral treatment with 1,4-dioxane (500 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of 1,4-dioxane in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. 1,4-Dioxane was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for 1,4-dioxane is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses.
- Published
- 2010
22. Development of enzyme-linked immunosorbent assay for 8-iso-prostaglandin F2α, a biomarker of oxidative stress in vivo, and its application to the quantification in aged rats
- Author
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Xiaoqing Chu, Mitsuo Jisaka, Kazushige Yokota, Tsutomu Nagaya, Fumiaki Shono, Kohji Nishimura, and Yuji Ageishi
- Subjects
Aging ,medicine.medical_specialty ,Time Factors ,Free Radicals ,Clinical Biochemistry ,Pharmaceutical Science ,Enzyme-Linked Immunosorbent Assay ,Dinoprost ,Kidney ,medicine.disease_cause ,Analytical Chemistry ,Lipid peroxidation ,Mice ,chemistry.chemical_compound ,In vivo ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Rats, Wistar ,Prostaglandin a ,Spectroscopy ,Unsaturated fatty acid ,Mice, Inbred BALB C ,Arachidonic Acid ,Antibodies, Monoclonal ,Rats ,Oxidative Stress ,Endocrinology ,Liver ,chemistry ,Eicosanoid ,Biochemistry ,Biomarker (medicine) ,Female ,Arachidonic acid ,Lipid Peroxidation ,Biomarkers ,Oxidative stress - Abstract
8-iso-Prostaglandin F2alpha (8-iso-PGF2alpha) is one of the isoprostanes that are mainly generated nonenzymatically in vivo from arachidonic acid through free radical-induced lipid peroxidation. To assess oxidative stress in vivo, we developed a quantitative enzyme-linked immunosorbent assay (ELISA) for 8-iso-PGF2alpha. A sensitive calibration curve allowed the quantification of the amounts from 0.23 pg to 98.4 pg with 4.7 pg of 50% displacement in one assay. The ELISA method was applied to the measurement of the plasma levels of 8-iso-PGF2alpha in young rats (4-8 weeks of age) and aged rats (106-123 weeks). The average level of esterified form in the plasma from aged rats was 30.6-fold higher than that in the plasma from young rats, reflecting the enhanced status of oxidative stress in aged animals. In addition, the aged rats exhibited higher levels of this F2-isoprostane esterified to lipids from liver and kidney, suggesting local oxidative injury in specific organs. These results indicate the utility and accuracy of our ELISA for 8-iso-PGF2alpha as a biomarker in vivo to assess systemic oxidative stress in animals or humans as well as oxidative injury at local sites.
- Published
- 2009
23. Surveillance and the Approach for the Proper Use of Antibiotics at Tokushima University Hospital
- Author
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Seiki Tashiro, Fumiaki Shono, Ichiro Shimizu, Kazuo Minakuchi, Keiko Hama, Yasuhiko Nishioka, and Susumu Ito
- Subjects
Pediatrics ,medicine.medical_specialty ,medicine.drug_class ,business.industry ,Antibiotics ,Cephalosporin ,medicine ,Infection control ,Antibiotic use ,business ,University hospital ,Intensive care medicine ,Medical costs - Abstract
The working committee for the proper use of antibiotics was organized at Tokushima University Hospital in March 2002, and the institutional guidelines for the selection and use of antibiotics were established. The infection control team (ICT) also started monitoring the use of particular antibiotics, including third-and fourthgeneration cephalosporins, calbapenems and anti-MRSA antibiotics, and reported on their use in August 2002. To assess these activities, we examined the status of antibiotic use for injections and compared our findings with the previous data.The results were as follows : 1) the reports required were presented in 47% of the total antibiotics used; 2) after starting the surveillance, the use of the third-and fourth-generation cephalosporins and calbapenems shifted to the first-and second-generation drugs, while the use of anti-MRSA drugs clearly decreased; 3) these changes resulted in a savings of more than two million yen in medical expenditures in a month. These results suggest that closely monitoring the use of antibiotics may thus be beneficial not only for promoting the proper use of antibiotics but also for reducing overall medical costs.
- Published
- 2003
24. Stimulatory effect of enkephalins on calcium efflux from bovine adrenal chromaffin cells in culture
- Author
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Masanori Yoshizumi, Fumiaki Shono, Hitoshi Houchi, Kazuo Minakuchi, Toshiaki Tamaki, Takabumi Umeda, Mami Azuma, and Toshitaka Ikehara
- Subjects
endocrine system ,medicine.medical_specialty ,Fura-2 ,Enkephalin ,Chromaffin Cells ,Enkephalin, Methionine ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,Catecholamines ,Internal medicine ,Cyclic AMP ,medicine ,Extracellular ,Animals ,General Pharmacology, Toxicology and Pharmaceutics ,Cyclic GMP ,Cells, Cultured ,Fluorescent Dyes ,Calcium metabolism ,Calcium Radioisotopes ,Enkephalins ,General Medicine ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Adrenal Medulla ,Chromaffin cell ,Catecholamine ,Calcium ,Cattle ,Efflux ,Intracellular ,Enkephalin, Leucine ,medicine.drug - Abstract
The effects of leucine- and methionine-enkephalin, opiate peptides, on Ca2+ efflux from cultured bovine adrenal chromaffin cells were examined. These enkephalins stimulated the efflux of 45Ca2+ from cells in a concentration-dependent manner (10(-8) M-10(-6) M). Leucine-enkephalin did not increase the intracellular free Ca2+ level, 45Ca2+ uptake, catecholamine secretion, cAMP level or cGMP level. The peptide-stimulated 45Ca2+ efflux was not inhibited by incubation in Ca2+-free medium, but was inhibited by incubation in Na+-free medium. These results indicate that enkephalins stimulate extracellular Na+-dependent 45Ca2+ efflux from cultured bovine adrenal chromaffin cells, probably by stimulating membrane Na+/Ca2+ exchange.
- Published
- 1999
25. Cultured preadipocytes undergoing stable transfection with cyclooxygenase-1 in the antisense direction accelerate adipogenesis during the maturation phase of adipocytes
- Author
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Mitsuo Jisaka, Pinky Karim Syeda, Mohammad S Rahman, Kazushige Yokota, Kohji Nishimura, Ferdous Khan, Tsutomu Nagaya, and Fumiaki Shono
- Subjects
Bioengineering ,Endogeny ,Transfection ,Applied Microbiology and Biotechnology ,Biochemistry ,Dinoprostone ,Gene Expression Regulation, Enzymologic ,chemistry.chemical_compound ,Mice ,Adipocyte ,3T3-L1 Cells ,Gene expression ,Adipocytes ,Animals ,RNA, Antisense ,Autocrine signalling ,Molecular Biology ,Triglycerides ,Regulation of gene expression ,Adipogenesis ,biology ,Prostaglandin D2 ,General Medicine ,Molecular biology ,chemistry ,biology.protein ,Cyclooxygenase 1 ,Cyclooxygenase ,Biomarkers ,Biotechnology - Abstract
The arachidonate cyclooxygenase (COX) pathway is involved in the generation of several types of endogenous prostaglandins (PGs) with opposite effects on adipogenesis at different life stages of adipocytes. However, the specific role of COX isoforms, the rate-limiting enzymes for the pathway, remains elusive in the regulation of the endogenous synthesis of PGs. This study was aimed at the selective suppression of the constitutive COX-1 in cultured preadipocytes by the isolation of cloned preadipocytes transfected stably with a mammalian expression vector harboring cDNA encoding mouse COX-1 in the antisense direction. The gene expression analysis revealed that the transcript and protein levels of the constitutive COX-1 were substantially suppressed in the isolated cloned transfectants with antisense COX-1. By contrast, the expression of the inducible COX-2 was not affected in the stable transfectants with antisense COX-1. All of the cloned stable transfectants with antisense COX-1 exhibited a significant reduction in the immediate synthesis of PGE2 serving as an anti-adipogenic factor. The sustained expression of COX-1 in the antisense direction induced the appreciable stimulation of fat storage in adipocytes during the maturation phase, which was associated with the higher expression levels of adipocyte-specific genes, indicating the positive regulation of adipogenesis program. Moreover, the up-regulation of adipogenesis is accompanied by a higher production of J2 series PGs including 15-deoxy-Δ(12,14)-PGJ2 and Δ(12)-PGJ2, known as pro-adipogenic factors by the transfectants with antisense COX-1. The results suggest that the inducible COX-2 can contribute to the endogenous synthesis of PGJ2 derivatives acting as autocrine mediators to simulate adipogenesis during the maturation phase by way of compensation for the suppressed expression of the constitutive COX-1.
- Published
- 2013
26. [Trends of activities in international organization and authorities in each country regarding risk management of nanomaterials]
- Author
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Masatoshi Kumamoto, Fumiaki Shono, and Kozo Inoue
- Subjects
Pharmacology ,International relations ,Economic growth ,Risk Management ,business.industry ,International Cooperation ,Industrial scale ,Pharmaceutical Science ,Chemical Safety ,Nanostructures ,Human health ,Drug Delivery Systems ,Nanomedicine ,Environmental protection ,Agriculture ,Humans ,Health Services Research ,business ,Risk management - Abstract
The Organisation for Economic Co-operation and Development (OECD) estimates that in 2015 the worldwide nanotechnology-related market will reach about US$1 trillion and will create about two million additional jobs. The field began with the general technical industry, including many areas of the pharmaceutical, medical, agricultural, and environmental/energy industries, and recently has expanded to the formulation of nanotechnology. In particular, elements of nanometer-sized research and development (R & D) in the areas of drug delivery systems and nanomedicine are attracting widespread interest. On the other hand, the potential negative effects on human health and the environment of nanomaterials manufactured on the industrial scale have not been investigated in detail. Therefore, although the risks have not been fully clarified, research institutions and international organizations such as the OECD are working in earnest to elucidate them. This paper outlines the status of initiatives in industry and regulatory conditions and trends in individual countries and institutions to determine the safety of nanomaterials from the perspective of international relations.
- Published
- 2013
27. Research to develop a predicting system of mammalian subacute toxicity (3) construction of a predictive toxicokinetics model
- Author
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Hiroshi Nishimura, Shoji Saito, Masashi Yabuki, Fumiaki Shono, Masatoshi Matsuo, Takaaki Yamaguchi, Naohiko Isobe, and Tomoyuki Watanabe
- Subjects
Environmental Engineering ,Health, Toxicology and Mutagenesis ,Metabolite ,Subacute toxicity ,Cmax ,Administration, Oral ,Pharmacology ,Kidney ,Hazardous Substances ,Rats, Sprague-Dawley ,Toxicology ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pharmacokinetics ,Predictive Value of Tests ,Oral administration ,medicine ,Animals ,Environmental Chemistry ,Toxicokinetics ,Computer Simulation ,Tissue Distribution ,Chromosome Aberrations ,Dose-Response Relationship, Drug ,Muscles ,Public Health, Environmental and Occupational Health ,General Medicine ,General Chemistry ,Pollution ,Rats ,medicine.anatomical_structure ,Adipose Tissue ,Liver ,chemistry ,Toxicity ,Algorithms - Abstract
A new predictive toxicokinetics model was developed to estimate subacute toxicity (target organs, severity, etc.) of non-congeneric industrial chemicals, where the chemical structures and physico-chemical properties are only available. Thus, a physiological pharmacokinetics model, which consists of blood, liver, kidney (these were experimentally found as major toxicological targets), muscle and fat compartments, was established to simulate the chemical concentrations in organs/tissues with pharmacokinetic parameters by means of Runge-Kutta-Gill algorithm. The pharmacokinetic parameters, i.e. absorption rate, absorption ratio, hepatic extraction ratio of metabolism and renal clearance were calculated by using separately established Quantitative Structure-Pharmacokinetics Relationship equations. The developed predictive model was then applied to simulations of 43 non-congeneric industrial chemicals. The chemical concentrations in organs/tissues after single oral administration were simulated, and their maximum concentrations (Cmax's) and area under the concentration-time curves (AUC's) were calculated. Fast Inverse Laplace Transform was newly applied for the purpose of simulation of 28-day repeated dose toxicity. Simulated concentrations of 28 days repeated dose were, however, found to be the same as those of simple repetitions of a single administration per day because of the short half-lives of non-congeneric industrial chemicals. A comparison of subacute toxicity data with Cmax's and AUC's in a single dose scenario suggested that the organs/tissues with relatively high concentrations of tested chemical substances were the most sensitive targets within a chemical. Chemical concentrations in liver, for instance, were correlated with the severity of hepatotoxicity among the chemicals. It was also suggested that to improve and widen the present approach, data of metabolite and reactivity of non-congeneric industrial chemicals to organs/tissues, receptors, etc. should be incorporated into the model.
- Published
- 1996
28. A research to develop a predicting system of mammalian subacute toxicity (2) single dose detailed toxicity studies
- Author
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Hiroshi Sako, Shoji Saito, Masatoshi Matsuo, Kunio Shiba, Haruhiko Adachi, Naohiko Isobe, Masashi Yabuki, Hiroshi Nishimura, Fumiaki Shono, Takaaki Yamaguchi, and Tomoyuki Watanabe
- Subjects
Environmental Engineering ,Chemical compound ,Health, Toxicology and Mutagenesis ,Public Health, Environmental and Occupational Health ,Subacute toxicity ,General Medicine ,General Chemistry ,Pharmacology ,Biology ,Pollution ,Toxicology ,chemistry.chemical_compound ,Investigation methods ,chemistry ,Toxicity ,Environmental Chemistry ,Target organ - Abstract
“Single dose detailed toxicity study” in rats was conducted with 6 chemical substances to establish a predicting system of subacute toxicity of non-congeneric industrial chemicals. In the detailed examinations, new and previously reported biological parameters were developed and utilized for the establishment and confirmation of the correlations for both qualitative and quantitative prediction of target organs and effects in repeated dose toxicity studies of non-congeners; the new parameters were concerned with liver, kidneys and blood and the established relating equations for prediction had a correlation coefficient of 0. 83 (liver), 0.49 (kidneys) and 0. 94 (blood), while the old parameters effectively confirmed the previous correlations. The serial changes in the study gave a biological explanation to the established relationships between acute and subacute toxicities in terms of extrapolation.
- Published
- 1996
29. A research to develop a predicting system of mammalian subacute toxicity (1) prediction of subacute toxicity using the biological parameters of acute toxicities
- Author
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Tomoyuki Watanabe, Shoji Saito, Masatoshi Matsuo, Kunio Shiba, Michiko Kumano, Haruhiko Adachi, Naohiko Isobe, Hiroshi Nishimura, Masashi Yabuki, Takaaki Yamaguchi, Fumio Kishida, and Fumiaki Shono
- Subjects
Environmental Engineering ,Chemical compound ,Health, Toxicology and Mutagenesis ,Public Health, Environmental and Occupational Health ,Subacute toxicity ,General Medicine ,General Chemistry ,Pharmacology ,Pollution ,Regression ,Toxicology ,chemistry.chemical_compound ,Investigation methods ,chemistry ,Linear regression ,Toxicity ,Environmental Chemistry - Abstract
Predicting equations of subacute toxicity were developed by analyzing rat acute and subacute toxicity data of 56 chemicals of various structures. Minimum or 10% effect level in acute or subacute toxicity was estimated as a “biological parameter”. Good regression equations were established between the geometrical means (“combined parameters' of any two of the parameters of acute and subacute toxicities and introduction of log P to the equations improved the correlations with a statistically significant multiple regression coefficient. The lowest predicted effect level of the subacute toxicity, which is selected from the data calculated by the above several correlations, can predict the upper limit of the no observed effect level.
- Published
- 1996
30. A monoclonal antibody specific for Δ12-prostaglandin J2 and its utilization in the immunological assay in cell culture system of adipocytes
- Author
-
Fumiaki Shono, Kazushige Yokota, Ferdous Khan, Mohammad S Rahman, Mohammad Salim Hossain, Abu Asad Chowdhury, Tsutomu Nagaya, Kohji Nishimura, Mitsuo Jisaka, and Pinky Karim Syeda
- Subjects
Immunoconjugates ,medicine.drug_class ,Cellular differentiation ,Immunology ,Cell Culture Techniques ,Prostaglandin ,Succinimides ,Enzyme-Linked Immunosorbent Assay ,Monoclonal antibody ,chemistry.chemical_compound ,Mice ,Antigen ,Antibody Specificity ,3T3-L1 Cells ,medicine ,Adipocytes ,Immunology and Allergy ,Animals ,Receptor ,Mice, Inbred BALB C ,Adipogenesis ,Hybridomas ,biology ,Prostaglandin D2 ,Antibodies, Monoclonal ,Reproducibility of Results ,Cell Differentiation ,Molecular biology ,Clone Cells ,Biochemistry ,chemistry ,Cell culture ,Culture Media, Conditioned ,biology.protein ,Female ,Immunization ,gamma-Globulins ,Antibody ,Haptens ,Conjugate - Abstract
Prostaglandin (PG) D(2) can be produced in adipocytes and dehydrated to PGs of J(2) series, including Δ(12)-PGJ(2) and 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)), which serve as pro-adipogenic prostanoids through the activation of peroxisome proliferator-activated receptor γ. To accomplish the quantification of Δ(12)-PGJ(2) in the cell culture system of adipocytes, the present study aimed to develop a sensitive and specific immunological assay for Δ(12)-PGJ(2). Here, we established a cloned hybridoma cell line secreting a monoclonal antibody specifically recognizing Δ(12)-PGJ(2) and utilized for the development of its solid-phase enzyme-linked immunosorbent assay (ELISA). The immobilized antigen using a conjugate of Δ(12)-PGJ(2) and γ-globulin was competitively allowed to react with the monoclonal antibody in the presence of free Δ(12)-PGJ(2). The assay provided a sensitive calibration curve for Δ(12)-PGJ(2), allowing us to determine a range from 0.16 pg to 0.99 ng with a value of 13 pg at 50% displacement in one assay. The monoclonal antibody showed almost no cross-reactivity with other related prostanoids since PGJ(2) and 15d-PGJ(2) were only recognized with much lower values of 0.5% and 0.2%, respectively. The accuracy for determining Δ(12)-PGJ(2) in the culture medium of adipocytes was confirmed by measurement after the culture medium was fortified with known amounts of authentic Δ(12)-PGJ(2) in a range from 10 to 200 pg/mL. The application of our ELISA revealed that the formation of Δ(12)-PGJ(2) became more pronounced after several hours of incubation of PGD(2) at 37°C in fresh maturation medium of cultured adipocytes. Furthermore, we provide evidence for the increased ability of cultured adipocytes to synthesize endogenous Δ(12)-PGJ(2) during the progression of adipogenesis. These results indicate the reliability and usefulness of our solid-phase ELISA for stable Δ(12)-PGJ(2), reflecting the biosynthesis of unstable PGD(2) in the culture system of adipocytes.
- Published
- 2012
31. Pharmacokinetic Studies of L-DOPS (L-threo-3,4-Dihydroxyphenylserine) in Renal Failure Rats
- Author
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Akira Yoshitake, Fumiaki Shono, Iwao Nakatsuka, Masaki Ito, and Yoshiko Mizuno
- Subjects
Excretion ,chemistry.chemical_compound ,Pharmacokinetics ,Chemistry ,Oral administration ,Cmax ,Area under the curve ,Vanillic acid ,Urine ,Metabolism ,Pharmacology - Abstract
The pharmacokinetics of (-)-(2S, 3R) -2-amino-3-hydroxy) -3 (3, 4-dihydoxy-phenyl)propiconic acid (L-DOPS), the precursor of (-)-norepinephrine (NE), were studied, using 14C-L-DOPS labelled at C-3 position (10 mg/kg), in rats with renal failure. After single oral administration of 14C-L-DOPS (10 mg/kg) to 5/6 partially nephrectomized rats, the serum 14C halflife (T1/2) was longer and the maximum concentration (Cmax), the area under the curve (AUC0-48) were 3, 10 times higher than those of the sham-operated rats respectively. Nevertheless, the excretion of radioactivity into urine or feces within 72 hr after administration were not significantly different between nephrectomized and sham-operated normal rats. L-DOPS, (-)-(2S, 3R)-2-amino-3-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-propionic acid (3-OM-DOPS), 3, 4-dihydroxybenzoic acid (Protocatechuicacid, PA), 4-hydroxy-3-methoxybenzoic acid (Vanillic acid, VA), their conjugates and 3, 4-dihydroxytoluene conjugate were identified as the metabolites present in the serum at 24 hr after single oral administration of 14C-L-DOPS (10 mg/kg) to completely nephrectomized rats. VA and PA conjugates were measured as the major metabolites. 14C levels in major tissues were changed in parallel with 14C serum levels and no particular 14C increase in tissue was found in 5/6 partially nephrectomized rats. The radioactivity decreased in tissues rapidly and no tissue with specific 14C accumulation was observed. During the consecutive oral administration of 14C-L-DOPS (10 mg/kg/day) to 5/6 partially nephrectomized rats for 7 days, the 14C serum levels profile on the 4th day and 7th day were similar to those observed on the 1st day. After repeated oral administration of 14C-L-DOPS (10 mg/kg) for 7 days, the elimination rate of 14C in tissues was slower than that observed on the 1st day, however 14C decreased below 1.0 μg eg./g. in all tissues at 72 hr and no particular accumulation in any tissue was found.
- Published
- 1994
32. Generation of monoclonal antibody for 15-deoxy-Δ¹²,¹⁴-prostaglandin J₂ and development of enzyme-linked immunosorbent assay for its quantification in culture medium of adipocytes
- Author
-
Pinky Karim, Syeda, Mohammad Salim, Hossain, Abu Asad, Chowdhury, Mohammad Sharifur, Rahman, Kohji, Nishimura, Mitsuo, Jisaka, Tsutomu, Nagaya, Fumiaki, Shono, and Kazushige, Yokota
- Subjects
Mice ,Mice, Inbred BALB C ,Antibody Specificity ,Prostaglandin D2 ,Adipocytes ,Animals ,Antibodies, Monoclonal ,Humans ,Enzyme-Linked Immunosorbent Assay ,Female ,Immunization ,Cell Line ,Culture Media - Abstract
15-deoxy-Δ¹²,¹⁴-prostaglandin J₂ (15d-PGJ₂) is a biologically active molecule serving as a pro-adipogenic factor or an anti-inflammatory regulator. This compound is one of naturally occurring derivatives formed by the non-enzymatic dehydration of PGD₂. To determine the endogenous synthesis of 15d-PGJ₂, a convenient immunological approach is useful. At first, we established a cloned hybridoma cell line to secrete a monoclonal antibody specific for 15d-PGJ₂. For the development of a solid-phase enzyme-linked immunosorbent assay (ELISA), the immobilized antigen using a protein conjugate of 15d-PGJ₂ was allowed to react competitively with a monoclonal antibody in the presence of free 15d-PGJ₂. Under the optimized conditions, a sensitive calibration curve was generated able to determine the amount of 15d-PGJ₂ from 0.5 pg to 9.7 ng with 71 pg of 50% displacement in one assay. Our monoclonal antibody did not recognize other related prostanoids except PGJ₂ with cross-reaction of 4%. Our ELISA was demonstrated to be reliable for the quantification of 15d-PGJ₂ in the maturation medium of cultured adipocytes by confirming the accuracy and specificity of its determination. The application of our assay revealed that the non-enzymatic formation of 15d-PGJ₂ became more evident after several hours of incubation with authentic PGD₂ at 37 °C. The results indicate the usefulness of our developed solid-phase ELISA with the monoclonal antibody for further studies on the endogenous synthesis of 15d-PGJ₂ and its roles in various cells and tissues.
- Published
- 2011
33. Sustained expression of lipocalin-type prostaglandin D synthase in the antisense direction positively regulates adipogenesis in cloned cultured preadipocytes
- Author
-
Tsutomu Nagaya, Mohammad Salim Hossain, Abu Asad Chowdhury, Kazushige Yokota, Fumiaki Shono, Kohji Nishimura, Mitsuo Jisaka, and Mohammad S Rahman
- Subjects
Biophysics ,Prostaglandin ,Lipocalin ,Biology ,Biochemistry ,Cyclooxygenase pathway ,chemistry.chemical_compound ,Mice ,Adipocyte ,3T3-L1 Cells ,Gene expression ,Adipocytes ,Animals ,RNA, Antisense ,Molecular Biology ,Cells, Cultured ,Mice, Inbred BALB C ,Adipogenesis ,Prostaglandin D2 ,Cell Biology ,Molecular biology ,Lipocalins ,Clone Cells ,Intramolecular Oxidoreductases ,chemistry ,lipids (amino acids, peptides, and proteins) ,Arachidonic acid - Abstract
Adipocytes express preferentially lipocalin-type prostaglandin (PG)D synthase (L-PGDS) that is responsible for the biosynthesis of PGD(2) and other related prostanoids with pro-adipogenic or anti-adipogenic effects. To evaluate the role of L-PGDS in cultured adipocytes and the precursor cells, we attempted to interfere the intracellular expression of L-PGDS in cultured 3T3-L1 preadipocytes by stable transfection with a mammalian expression vector having the full-length cDNA of L-PGDS oriented in the antisense direction. The cloned transfectants with antisense L-PGDS exhibited the reduction in the transcript and protein levels of L-PGDS, resulting in the significant inhibition of the PGD(2) synthesis from exogenous and endogenous arachidonic acid. By contrast, the synthesis of PGE(2) was not influenced appreciably, indicating no interfering effects on cyclooxygenases and PGE synthases. The stable transfection with antisense L-PGDS induced markedly the stimulation of fat storage in cultured adipocytes during the maturation phase. In addition, the spontaneous accumulation of fats occurred in the transfectants with antisense L-PGDS without undergoing the stimulation with inducing factors. The gene expression studies revealed the enhanced expression of adipocyte-specific markers in the transfectants with antisense L-PGDS, indicating the up-regulation of adipogenesis program. The stimulated adipogenesis was significantly reversed by anti-adipogenic prostanoids including PGE(2) and PGF(2α), while the storage of fats was additionally enhanced by pro-adipogenic 15-deoxy- Δ(12,14)-prostaglandin J(2). These results suggest that the stably reduced expression levels of L-PGDS regulates positively adipogenesis program in a cellular mechanism independent of pro-adipogenic action of PGJ(2) series.
- Published
- 2011
34. 15-Deoxy-Δ(12,14)-prostaglandin J(2) interferes inducible synthesis of prostaglandins E(2) and F(2α) that suppress subsequent adipogenesis program in cultured preadipocytes
- Author
-
Kohji Nishimura, Fumiaki Shono, Kazushige Yokota, Mohammad S Rahman, Abu Asad Chowdhury, Tsutomu Nagaya, Takahiro Ishikawa, and Mitsuo Jisaka
- Subjects
medicine.medical_specialty ,Proline ,Physiology ,Prostaglandin ,Gene Expression ,Endogeny ,Dinoprost ,Biochemistry ,Dinoprostone ,chemistry.chemical_compound ,Mice ,Troglitazone ,Thiocarbamates ,Adipocyte ,Internal medicine ,3T3-L1 Cells ,medicine ,Adipocytes ,Animals ,Chromans ,Receptor ,Calcimycin ,Triglycerides ,Cell Proliferation ,Pharmacology ,Adipogenesis ,Arachidonic Acid ,biology ,Ionophores ,Prostaglandin D2 ,NF-kappa B ,Cell Biology ,Lipid Metabolism ,Isoenzymes ,PPAR gamma ,Endocrinology ,chemistry ,Prostaglandin-Endoperoxide Synthases ,Phorbol ,biology.protein ,Tetradecanoylphorbol Acetate ,lipids (amino acids, peptides, and proteins) ,Thiazolidinediones ,Cyclooxygenase ,medicine.drug - Abstract
Cultured preadipocytes enhance the synthesis of prostaglandin (PG) E 2 and PGF 2α involving the induction of cyclooxygenase (COX)-2 during the growth phase upon stimulation with a mixture of phorbol 12-myristate 13-acetate, a mitogenic factor, and calcium ionophore A23187. Here, we studied the interactive effect of 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) on the inducible synthesis of the endogenous PGs in cultured preadipocytes and its implication in adipogenesis program. 15d-PGJ 2 interfered significantly the endogenous synthesis of those PGs in response to cell stimuli by suppressing the induction of COX-2 following the attenuation of NF-κB activation. In contrast, Δ 12 -PGJ 2 and troglitazone had almost no inhibitory effects, indicating a mechanism independent of the activation of peroxisome proliferator-activated receptor γ for the action of 15-PGJ 2 . Pyrrolidinedithiocarbamate (PDTC), an NF-κB inhibitor, effectively inhibited on the inducible synthesis of those PGs in preadipocytes. Endogenous PGs generated by preadipocytes only during the growth phase in response to the cell stimuli autonomously attenuated the subsequent adipogenesis program leading to the differentiation and maturation of adipocytes. These effects were prevented by additional co-incubation of preadipocytes with either 15d-PGJ 2 or PDTC although 15d-PGJ 2 alone has no stimulatory effect. Moreover, 15d-PGJ 2 did not block the inhibitory effects of exogenous PGE 2 and PGF 2α on the adipogenesis program in preadipocytes. Taken together, 15d-PGJ 2 can interfere the COX pathway leading to the induced synthesis of endogenous PGs that contribute to negative regulation of adipogenesis program in preadipocytes.
- Published
- 2011
35. Development of enzyme-linked immunosorbent assay for Δ12-prostaglandin J2 and its application to the measurement of the endogenous product generated by cultured adipocytes during the maturation phase
- Author
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Mohammad S Rahman, Tsutomu Nagaya, Fumiaki Shono, Mitsuo Jisaka, Kohji Nishimura, Kazushige Yokota, Mohammad Salim Hossain, and Abu Asad Chowdhury
- Subjects
medicine.medical_specialty ,Physiology ,Peroxisome proliferator-activated receptor ,Prostaglandin ,Endogeny ,Enzyme-Linked Immunosorbent Assay ,Biochemistry ,chemistry.chemical_compound ,Mice ,Internal medicine ,3T3-L1 Cells ,Gene expression ,medicine ,Adipocytes ,Animals ,Receptor ,Pharmacology ,chemistry.chemical_classification ,Adipogenesis ,biology ,Prostaglandin D2 ,Cell Biology ,PPAR gamma ,Endocrinology ,Enzyme ,chemistry ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Cyclooxygenase - Abstract
Peroxisome proliferator-activated receptor (PPAR)γ is a well-known master regulator for the differentiation and maturation of adipocytes. Prostaglandin (PG) D 2 can be produced in adipocytes and dehydrated to J 2 series of PGs including 15-deoxy-Δ 12,14 -PGJ 2 (15d-PGJ 2 ) and Δ 12 -PGJ 2 , which serve as pro-adipogenic prostanoids through the activation of PPARγ. However, the quantitative determination of Δ 12 -PGJ 2 has not been attempted during the life stage of adipocytes. In this study, we developed an enzyme-linked immunosorbent assay using mouse antiserum specific for Δ 12 -PGJ 2 . According to the standard curve, the amount of Δ 12 -PGJ 2 can be measured from 0.5 pg to 14.4 ng in an assay. Our antiserum did not recognize most other prostanoids including 15d-PGJ 2 , while it only showed the cross-reaction of 28% with unstable PGJ 2 . This immunological assay was applied to the determination of the endogenous formation of Δ 12 -PGJ 2 in cultured 3T3-L1 adipocytes during the maturation phase. The ability of cultured adipocytes to form endogenous Δ 12 -PGJ 2 increased gradually at an earlier stage of the maturation phase and detectable at higher levels than 15d-PGJ 2 . Treatment of cultured cells with either aspirin or indomethacin, a general cyclooxygenase inhibitor, significantly reduced the production of endogenous Δ 12 -PGJ 2 in the maturation medium as expected. Furthermore, we evaluated individually the exogenous effects of PGJ 2 series at various doses on adipogenesis during the maturation phase. Although Δ 12 -PGJ 2 was slightly less potent than 15d-PGJ 2 , each of these PGJ 2 series rescued effectively both the accumulation of fats and the gene expression of typical adipocyte-markers that were attenuated in the presence of aspirin. Taken together, our findings indicate that endogenous Δ 12 -PGJ 2 contributes substantially to the up-regulation of adipogenesis program through the activation of PPARγ together with 15d-PGJ 2 during the maturation phase of cultured adipocytes.
- Published
- 2010
36. Human Blood Concentrations of Cotinine, a Biomonitoring Marker for Tobacco Smoke, Extrapolated from Nicotine Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling
- Author
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Kana Horiuchi, Fumiaki Shono, Norie Murayama, Taku Nagano, Masato Kitajima, Makiko Shimizu, Hiroshi Yamazaki, and Ryohji Takano
- Subjects
Adult ,Male ,Nicotine ,Physiologically based pharmacokinetic modelling ,No-observed-adverse-effect level ,cytochrome P450 ,Health, Toxicology and Mutagenesis ,lcsh:Medicine ,physiologically based biokinetic modeling ,Administration, Oral ,Absorption (skin) ,Pharmacology ,Article ,Tobacco smoke ,human liver microsomes ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Pharmacokinetics ,In vivo ,simulation ,no-observed-adverse-effect level ,biomonitoring ,medicine ,Animals ,Humans ,Cotinine ,Chemistry ,lcsh:R ,Smoking ,Public Health, Environmental and Occupational Health ,Models, Theoretical ,Rats ,Models, Animal ,Microsomes, Liver ,Biomarkers ,medicine.drug - Abstract
The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for nicotine and its primary metabolite cotinine in humans, based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing compartment, and a central compartment for nicotine and three equivalent compartments for cotinine. Evaluation of a rat model was performed by making comparisons with predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after oral treatment with nicotine (1.0 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of nicotine in vitro were established from data from rat liver microsomes and from human pooled liver microsomes. Human biomonitoring data (17 ng nicotine and 150 ng cotinine per mL plasma 1 h after smoking) from pooled five male Japanese smokers (daily intake of 43 mg nicotine by smoking) revealed that these blood concentrations could be calculated using a human PBPK model. These results indicate that a simplified PBPK model for nicotine/cotinine is useful for a forward dosimetry approach in humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses.
- Published
- 2010
- Full Text
- View/download PDF
37. Suppression of adipogenesis program in cultured preadipocytes transfected stably with cyclooxygenase isoforms
- Author
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Fumiaki Shono, Kohji Nishimura, Kazushige Yokota, Tsutomu Nagaya, Mitsuo Jisaka, Li Xu, and Xiaoqing Chu
- Subjects
Gene isoform ,medicine.medical_specialty ,Blotting, Western ,Enzyme-Linked Immunosorbent Assay ,Transfection ,chemistry.chemical_compound ,Mice ,Adipocyte ,Internal medicine ,3T3-L1 Cells ,Gene expression ,medicine ,Adipocytes ,Animals ,RNA, Messenger ,Receptor ,Molecular Biology ,Triglycerides ,Oligonucleotide Array Sequence Analysis ,Adipogenesis ,Arachidonic Acid ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Troglitazone ,Membrane Proteins ,Cell Differentiation ,Cell Biology ,Cell biology ,Isoenzymes ,PPAR gamma ,Endocrinology ,chemistry ,Cyclooxygenase 2 ,biology.protein ,Cyclooxygenase 1 ,Prostaglandins ,Cyclooxygenase ,medicine.drug - Abstract
Prostaglandins (PGs) are known to play a variety of roles in adipocytes and precursor cells, which have the arachidonate cyclooxygenase (COX) pathway to generate several series of PGs at different stages of life cycle of adipocytes. To gain a unique insight into the specific roles of the COX isoforms during the life cycle of adipocytes, 3T3-L1 preadipocytes were stably transfected with a mammalian expression vector harboring either cDNA coding for murine COX-1 or COX-2. The cloned stable transfectants with COX-1 or COX-2 exhibited higher expression levels of their corresponding mRNA and proteins, and greater production of PGE(2) upon stimulation with free arachidonic acid or A23187 than the parent cells and the transfectants with vector only. However, either type of transfectants brought about the marked reduction in the accumulation of triacylglycerols after the standard adipogenesis program. Unexpectedly, aspirin or other COX inhibitors at different phases of life cycle of adipocytes failed to reverse the reduced storage of fats. The transfectants with COX-2 were sensitive to exogenous 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) and troglitazone as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists during the maturation phase for restoring the adipogenesis. By contrast, the transfectants with COX-1 were much less sensitive, which was reflected by much lower gene expression levels of PPARgamma and the related adipocyte-specific markers. Taken together, the results suggest that the sustained overexpression of either COX-1 or COX-2 resulted in the interference of adipogenesis program through a PG-independent mechanism with a different mode of action of COX isoforms.
- Published
- 2008
38. [Evaluation of dissolution behavior for the products containing tegafur and uracil]
- Author
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Mami Azuma, Hitoshi Houchi, Katsuhiko Ichimaru, Kazuo Minakuchi, Takabumi Umeda, Toshihide Kujime, Fumiaki Shono, and Kohei Ishiki
- Subjects
Pharmacology ,Active ingredient ,Drug ,media_common.quotation_subject ,Pharmaceutical Science ,Uracil ,Capsules ,Combinatorial chemistry ,Tegafur ,Dosage form ,Cost savings ,chemistry.chemical_compound ,Drug Combinations ,chemistry ,Pharmaceutical technology ,Solubility ,medicine ,Drugs, Generic ,Dissolution ,medicine.drug ,media_common - Abstract
Generic drugs are widely used with the object of cost saving in many Japanese therapeutic scenes now. The products containing the same active ingredient(s), even if they are innovative drugs or generic ones, must be designed to possess the equivalent quality. In this report, we observed the dissolution behavior patterns of three generic drugs that contain Tegafur and Uracil, drugs A, B, and C, and compared them with that of an innovative product, UFT. Drugs B and C were similar to UFT in the dissolution rate of Tegafur, but drug A was not. On the dissolution rate of Uracil, all the generic products, drugs A, B and C, did not amount to the level equivalent to that of UFT. Therefore, these generic products did not indicate the same dissolution behavior pattern as UFT. It was suggested that the pharmaceutical technology used in the manufacture was not equivalent even if the products of the same dosage form contain the same kind and content of the active ingredient(s).
- Published
- 1999
39. Interactive Pro-Adipogenic Effect of 15-deoxy-Δ-Prostaglandin J to Interfere the Inducible Synthesis of Anti-Adipogenic Prostanoids in Cultured 3T3-L1 Preadipocytes, an Important Molecular Event to Consider for Drug Development
- Author
-
Mitsuo Jisaka, Fumiaki Shono, Kohji Nishimura, Tsutomu Nagaya, Mohammad S Rahman, Abu Asad Chowdhury, Kazushige Yokota, and Mohammad A. Rashid
- Subjects
medicine.medical_specialty ,business.industry ,Pharmacy ,3T3-L1 ,Biology ,Clinical pharmacy ,Endocrinology ,Drug development ,Adipogenesis ,Family medicine ,Internal medicine ,15 deoxy δ12 14 prostaglandin j2 ,medicine ,business - Abstract
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Dhaka-1000, Bangladesh; Center for Integrated Research in Science, Shimane University; United Graduate School of Agricultural Sciences, Tottori University; Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University; Department of Clinical Pharmacy, Faculty of Pharmacy, Tokushima Bunri University
- Published
- 2013
40. Immunoaffinity purification of 11-dehydro-thromboxane B2 from human urine and plasma for quantitative analysis by radioimmunoassay
- Author
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Akihiko Nakagawa, Fumiaki Shono, Wataru Takasaki, Keiko Watanabe, Hiroshi Miyazaki, Shozo Yamamoto, Kouwa Yamashita, and Yoko Hayashi
- Subjects
Adult ,Male ,Thromboxane ,Metabolite ,Biophysics ,Radioimmunoassay ,Cross Reactions ,Biochemistry ,Chromatography, Affinity ,Sepharose ,chemistry.chemical_compound ,Mice ,Affinity chromatography ,Animals ,Humans ,Selected ion monitoring ,Molecular Biology ,Mice, Inbred BALB C ,Chromatography ,Chemistry ,Antibodies, Monoclonal ,Reproducibility of Results ,Cell Biology ,Thromboxane B2 ,Female ,Quantitative analysis (chemistry) - Abstract
11-Dehydro-thromboxane B 2 is now considered to be a reliable parameter of thromboxane A 2 formation in vivo . An immunoaffinity purification method was developed for radioimmunoassay of this compound contained in human urine and plasma. Monoclonal anti-11-dehydro-thromboxane B 2 antibody was prepared and coupled to BrCN-activated Sepharose 4B. Human urine or plasma was applied to a disposable column of the immobilized antibody. After the column was washed with water, 11-dehydro-thromboxane B 2 was eluted with methanol/water ( 95 5 ) with a recovery of more than 90%. The purified extract was subjected to a radioimmunoassay utilizing 11-[ 3 H]dehydro-thromboxane B 2 methyl ester and the monoclonal anti-11-dehydro-thromboxane B 2 antibody. The detection range of the assay was 10–600 fmol (IC 50 = 90 fmol). The cross-reactivities of the antibody with thromboxane B 2 , 2,3-dinor-thromboxane B 2 , and other arachidonate metabolites were less than 0.05%. These compounds were efficiently separated from 11-dehydro-thromboxane B 2 by the immunoaffinity purification. This procedure also allowed the separation of 11-dehydro-thromboxane B 2 from unidentified urinary and plasma substances which interfered with the radioimmunoassay. Validity of the results obtained by the radioimmunoassay was confirmed by GC MS employing selected ion monitoring for quantification.
- Published
- 1990
41. Labelled organophosphorus pesticides. II. Synthesis of carbon-14 labelled N-sec-butyl O-ethyl O-(5-methyl-2-nitrophenyl) phosphoramidothioate (cremart®)
- Author
-
Akira Yoshitake, Fumiaki Shono, Takeshi Kamada, and Iwao Nakatsuka
- Subjects
Chemistry ,Aryl ,Organic Chemistry ,Biochemistry ,Medicinal chemistry ,Analytical Chemistry ,Potassium carbonate ,chemistry.chemical_compound ,Yield (chemistry) ,Drug Discovery ,Organic chemistry ,Radiology, Nuclear Medicine and imaging ,Carbon-14 ,Boron tribromide ,Organophosphorus pesticides ,Spectroscopy ,Methyl group - Abstract
N-sec-Butyl O-ethyl O-(5-methyl–2-nitrophenyl) phosphoramidothioate (Cremart) (I), an organophosphorus herbicide, was labelled with carbon-14 at the aryl methyl group for metabolic studies. The synthetic procedures are shown in Fig. 1. 1-Methoxy-3-methyl-14C-benzene was nitrated with fuming nitric acid-acetic anhydride to give 2-methoxy-4-methyl-14C-1-nitrobenzene which on O-demethylation with boron tribromide gave 5-methyl-14C-2-nitrophenol. Condensation of the latter with N-sec-butyl O-ethyl phosphoramidochloridothioate in the presence of potassium carbonate afforded Cremart-(aryl methyl-14C)(I) in the overall yield of 9.2% from methanol-14C, which had a specifie activity of 5.96 mCi/mmole.
- Published
- 1977
42. A Solid-Phase Enzyme Immunoassay of Thromboxane B21
- Author
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Fumiaki Shono, Kazushige Yokota, and Shozo Yamamoto
- Subjects
chemistry.chemical_classification ,Chromatography ,medicine.diagnostic_test ,biology ,Thromboxane ,Metabolite ,Radioimmunoassay ,General Medicine ,Biochemistry ,High-performance liquid chromatography ,Enzyme assay ,Thromboxane B2 ,chemistry.chemical_compound ,Enzyme ,chemistry ,Immunoassay ,medicine ,biology.protein ,Molecular Biology - Abstract
A solid-phase enzyme immunoassay for thromboxane B2 was developed using a conjugate of thromboxane B2 and beta-galactosidase. Anti-thromboxane B2 IgG was bound to a polystyrene tube, and the enzyme-labeled and unlabeled thromboxane B2 were allowed to react in a competitive manner with the immobilized antibody. Then, the specifically bound beta-galactosidase was assayed fluorimetrically, and the enzyme activity was correlated with the amount of unlabeled thromboxane B2. By using a calibration curve, thromboxane B2 was determined in the range of 20 fmol-14 pmol. 2,3-Dinor- and 2,3,4,5-tetranor-thromboxane B2 cross-reacted with thromboxane B2 to the extents of 18.6% and 0.4%, respectively. Most prostaglandins and their metabolites tested showed cross-reactivities of less than 1%. In application of the method to human blood and urine, an octadecylsilyl silica column was utilized for extraction and concentration of thromboxane B2. The crude extract contained a substance(s) which disturbed the enzyme immunoassay and gave an apparently high value of thromboxane B2, and the interfering substance was separated from thromboxane B2 by reverse-phase HPLC. Various amounts of authentic thromboxane B2 added to the purified material from human plasma could be determined by the enzyme immunoassay with a recovery of about 80% and the results correlated well with the values obtained by radioimmunoassay (r = 0.979). When the extract from human urine was analyzed by reverse-phase HPLC, the 2,3-dinor metabolite rather than thromboxane B2 was the predominant compound detected by the enzyme immunoassay.
- Published
- 1985
43. 14C-labelling of optically active fenvalerate, α-cyano-3-phenoxy-benzyl (S)-2-(4-chlorophenyl)-3-methylbutyrate (I)
- Author
-
Hiroshi Kanamaru, Iwao Nakatsuka, Akira Yoshitake, and Fumiaki Shono
- Subjects
Fenvalerate ,Organic Chemistry ,Alcohol ,Biochemistry ,Medicinal chemistry ,Analytical Chemistry ,Ullmann reaction ,chemistry.chemical_compound ,Hydrolysis ,chemistry ,Bromide ,Bromobenzene ,Drug Discovery ,Organic chemistry ,Radiology, Nuclear Medicine and imaging ,Potassium dichromate ,Spectroscopy ,Sodium cyanide - Abstract
(S)-α-Cyano-3-phenoxybenzyl (S)-2-(4-chlorophenyl)-3-methylbutyrate (fenvalerate Aα), an optically active insecticide, was labelled with carbon-14 individually at the benzyl ring (1a) and the chlorophenyl ring (1b) for use in metabolic studies. Ullmann reaction of 3-methylphenol-14C6 (2) with bromobenzene followed by oxygen oxidation gave 3-phenoxybenzoic-14C6 acid (4). Reduction of 4 followed by potassium dichromate oxidation of the alcohol (5) gave 3-phenoxybenzaldehyde-14C6 (6). Condensation of 6 with (S)-2-(4-chlorophenyl)-3-methylbutanoyl chloride and sodium cyanide afforded fenvalerate A-(benzyl-14C6), which on optical resolution gave 1a in 29% yield from 2. Isopropylation of 4-chlorophenyl-14C6-acetonitrile (9) followed by hydrolysis gave 2-(4-chlorophenyl-14C6)-3-methylbutyric acid which on optical resolution gave the (S)-acid (12). Esterification of the acid with α-cyano-3-phenoxybenzyl bromide yielded fenvalerate A-(phenyl-14C6), which was resolved to give 1b in 9% yield from 9.
- Published
- 1981
44. Pharmaceutical Properties and Purities of Diclofenac Sodium Preparations
- Author
-
Fumiaki Shono, Masumitsu Takasugi, Kazuo Minakuchi, and Kazuyoshi Miyata
- Subjects
chemistry.chemical_classification ,Chromatography ,Chemistry ,Potassium ,Salt (chemistry) ,chemistry.chemical_element ,Diclofenac Sodium ,Bioavailability ,law.invention ,stomatognathic diseases ,Diclofenac ,law ,medicine ,Gas chromatography ,Atomic absorption spectroscopy ,Quantitative analysis (chemistry) ,medicine.drug - Abstract
The relationship between in-vitro pharmaceutical properties and bioavailability of commercially available diclofenac sodium was described in the previous paper showing results of our general pharmaceutical tests and determination of the concentration in human plasma. Further studies were conducted this time to detect residual organic solvents in drugs, to measure the quantity of diclofenac by the ultraviolet absorption method, and to make quantitative analysis of diclofenac by atomic absorption spectrophotometry. The quantitative values of the diclofenac preparations tested were in agreement with one exception where the value was very low. On the other hand, the atomic absorption spectrophotometry study showed that some of the products contained approximately 30% of potassium salt although they were labelled sodium salt. Furthermore, the gas chromatography study showed the presence of 100 ppm or more ethanol and/ or isopropanol residuals in several products.
- Published
- 1983
45. Labelled organophosphorus pesticides. III. Synthesis of carbon-14 labelled o-(2,6-dichloro-4-methylphenyl) O,O-dlmethyl phosphorothioate
- Author
-
Akira Yoshitake, Iwao Nakatsuka, Fumiaki Shono, and Hiroshi Kanamaru
- Subjects
Potassium ,Aryl ,Organic Chemistry ,chemistry.chemical_element ,Ring (chemistry) ,Biochemistry ,Medicinal chemistry ,Analytical Chemistry ,Catalysis ,chemistry.chemical_compound ,chemistry ,Yield (chemistry) ,Drug Discovery ,Chlorine ,Organic chemistry ,Radiology, Nuclear Medicine and imaging ,Carbon-14 ,Organophosphorus pesticides ,Spectroscopy - Abstract
O- (2,6-Dichloro-4-methylphenyl) O,O-dimethyl phosphorothioate (5-3349) (1), a fungicide in soil, was labelled with carbon-14 individually at the aryl methyl and the phenyl ring for use in metabolic studies. The synthetic procedures are illustrated in Fig. 1. 4-Cyano-14C-phenol was quantitatively converted to 4-methyl-14C-Phenol (3a) by catalytic hydrogenation using 10% Pd-C as a catalyst. Dichlorination of 3a with chlorine gave 2,6-di-chloro-4-methyl-14C-phenol (4a). Condensation of 4a with O,O-dimethyl phosphorochloridothioate gave S-3349-(aryl methyl-14C) (1a) in the overall yield of 22% from potassium cyanide-14C. By the similar procedures, 4-methylphenol-14C6 (3b) was converted to S-3349-(Phenyl-14C6) (1b) in 70% yield.
- Published
- 1979
46. Metabolism of 14C-Miloxacin in Rats
- Author
-
Kazuo Kawahara, Akira Yoshitake, and Fumiaki Shono
- Subjects
Radiation ,Chromatography ,medicine.drug_class ,Antibiotics ,Urine ,Metabolism ,Glucuronic acid ,Antimicrobial ,Biological materials ,chemistry.chemical_compound ,chemistry ,Oral administration ,medicine ,Feces - Abstract
Isolation and characterization of metabolites of miloxacin, a new antimicrobial agent, were undertaken with rats. 14C-Miloxacin was orally administered to Sprague-Dawley rats at a dose of 50 mg/kg, and urine, bile and feces were collected. The metabolites extracted from the biological samples were isolated by column and thin-layer chromatographies. Characterization of the isolated metabolites was carried out by comparison with the authentic materials in various physicochemical analyses. Eight metabolites together with intact miloxacin were identified; containing the metabolites of N-demethoxy (M-1), catechol (M-3) and 6-methoxy (M-2 and M-4) types and their conjugates with glucuronic acid.
- Published
- 1979
47. Studies on peptides. CXVII. Solution synthesis of the tetratetracontapeptide amide corresponding to the entire amino acid sequence of growth hormone releasing factor, somatocrinin
- Author
-
Fumiaki Shono, Masafumi Tsuda, Akira Yoshitake, Haruaki Yajima, Masanori Shimokura, Motoyoshi Nomizu, and Nobutaka Fujii
- Subjects
chemistry.chemical_classification ,geography ,geography.geographical_feature_category ,Stereochemistry ,Peptide ,Biological activity ,General Chemistry ,General Medicine ,Peptide hormone ,Islet ,Preprohormone ,chemistry.chemical_compound ,chemistry ,Biochemistry ,In vivo ,Amide ,Drug Discovery ,Peptide sequence - Abstract
The tetratetracontapeptide corresponding to the entire amino acid sequence of growth hormone releasing peptide derived from human pancreas islet tumor was synthesized by assembling eight peptide fragments in a conventional manner, followed by thioanisole-mediated deprotection with 1 M trifluoromethanesulfonic acid in TFA. Our synthetic peptide significantly stimulated the release of immunoreactive growth hormone in vivo.
- Published
- 1984
48. Synthesis of a hentetracontapeptide amide corresponding to the entire amino acid sequence of human corticotropin releasing factor (hCRF)
- Author
-
Haruaki Yajima, Fumiaki Shono, Nobutaka Fujii, Akira Yoshitake, Shinichi Katakura, Masanori Shimokura, Kazuhide Watanabe, Masafumi Tsuda, Motoyoshi Nomizu, and Kenichi Akaji
- Subjects
chemistry.chemical_classification ,endocrine system ,Oligopeptide ,medicine.drug_class ,Carboxamide ,Peptide ,General Chemistry ,General Medicine ,Peptide hormone ,Human corticotropin-releasing factor ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Amide ,Drug Discovery ,Trifluoroacetic acid ,medicine ,Peptide sequence ,hormones, hormone substitutes, and hormone antagonists - Abstract
Human corticotropin releasing factor (hCRF), a hentetracontapeptide amide identical with rat CRF, was synthesized in a conventional manner by assembling nine peptide fragments followed by deprotection with 1 M trifluoromethanesulfonic acid-thioanisole in trifluoroacetic acid.
- Published
- 1984
49. Improved syntheses of carbon-14 labelled 3-phenoxybenzyl [1R,cis]- and [lR,trans]-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylates
- Author
-
Iwao Nakatsuka, Akira Yoshitake, and Fumiaki Shono
- Subjects
Stereochemistry ,Organic Chemistry ,Alcohol ,Biochemistry ,Analytical Chemistry ,Hydrolysis ,chemistry.chemical_compound ,Stereospecificity ,chemistry ,Yield (chemistry) ,Drug Discovery ,Wittig reaction ,Tetrachloride ,Side chain ,Radiology, Nuclear Medicine and imaging ,Carbon-14 ,Spectroscopy - Abstract
3-Phenoxybenzyl [1R,cis]-3–2(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropanecarboxylate (I) and its [1R,trans]-isomer (II) were labelled with carbon-14 at C-2 position of the dichlorovinyl side chain for metabolic studies. The stereospecific syntheses were achieved according to the reaction scheme shown in Fig. 1. Wittig reaction of methyl [1R,cis]-3-formyl-2,2-dimethylcyclo-propanecarboxylate with carbon-14C tetrachloride followed by hydrolysis gave [1R,cis]-3-(2,2-dichlorovinyl-2–14C)-2,2-dimethylcyclopropanecarboxylic acid (VIa). Chlorination of the acid (VIa) and subsequent treatment of the resulting acid chloride with 3-phenoxybenzyl alcohol afforded 3-phenoxybenzyl [1R,cis]-3–(2,2-dichlorovinyl–2-14C)-2,2-dimethylcyclopropane-carboxylate (I) in the overall yield of 33%. Its [1R,trans]-isomer (II) was also prepared in 35% yield by the similar procedures. The specific activities of I and II were 4.30 and 3.80 mCi/mmole respectively.
- Published
- 1977
50. Studies on peptides. CXIX. Synthesis of growth hormone releasing factor (hpGRF-40-OH)
- Author
-
Fumiaki Shono, Nobutaka Fujii, Akira Yoshitake, Masafumi Tsuda, Haruaki Yajima, and Masanori Shimokura
- Subjects
Oligopeptide ,Chemical Phenomena ,Chemistry ,Liquid phase ,Biological activity ,General Chemistry ,General Medicine ,Peptide hormone ,Growth Hormone-Releasing Hormone ,Peptide Fragments ,In vitro ,Rats ,Biochemistry ,In vivo ,Drug Discovery ,Growth Hormone-Releasing Factor ,Animals - Published
- 1984
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