102 results on '"Shiizaki K"'
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2. Direct injection of calcitriol or its analog into hyperplastic parathyroid glands induces apoptosis of parathyroid cells
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Shiizaki, K., Negi, S., Hatamura, I., Tatsuta, K., Shibata, M., Shimada, S., Sakaguchi, T., and Akizawa, T.
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- 2006
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3. Mineral and bone disease - CKD 1-5
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Loh, Z. Y., primary, Yap, C. W., additional, Anantharaman, V., additional, How, P., additional, Hirata, M., additional, Aizawa, K., additional, Yogo, K., additional, Tashiro, Y., additional, Takeda, S., additional, Endo, K., additional, Fukagawa, M., additional, Serizawa, K.-I., additional, Fujii, H., additional, Kono, K., additional, Nakai, K., additional, Goto, S., additional, Shinohara, M., additional, Kitazawa, R., additional, Kitazawa, S., additional, Nishi, S., additional, Oruc, A., additional, Korkmaz, S., additional, Bal, O., additional, Yilmaztepe Oral, A., additional, Ersoy, A., additional, Gullulu, M., additional, Ketteler, M., additional, Martin, K., additional, Amdahl, M., additional, Cozzolino, M., additional, Goldsmith, D., additional, Sharma, A., additional, Khan, S., additional, Chitalia, N., additional, Afzali, B., additional, Edozie, F., additional, Manghat, P., additional, Wierzbicki, A., additional, Hampson, G., additional, Corradini, M., additional, Iannuzzella, F., additional, Manenti, L., additional, Ciarrocchi, A., additional, Albertazzi, L., additional, Somenzi, D., additional, Pasquali, S., additional, Calabria Baxmann, A., additional, Barcellos Menon, V., additional, Froeder, L., additional, Medina-Pestana, J. O., additional, Barbosa Carvalho, A., additional, Pfeferman Heilberg, I., additional, Sola, L., additional, De Souza, N., additional, Flores, J., additional, Perico, N., additional, Yuste, C., additional, Garcia DE Vinuesa, M. S., additional, Luno, J., additional, Goicoechea, M. A., additional, Barraca, D., additional, Panizo, N., additional, Quiroga, B., additional, Kim, S. M., additional, Kwon, S. K., additional, Kim, H.-Y., additional, Cournoyer, S., additional, Bell, R., additional, Berbiche, D., additional, Menard, L., additional, Viaene, L., additional, Evenepoel, P., additional, Meijers, B., additional, Overbergh, L., additional, Mathieu, C., additional, Pasquali, M., additional, Rotondi, S., additional, Conte, C., additional, Pirro, G., additional, Mazzaferro, S., additional, Frasheri, A., additional, Marangella, M., additional, Tartaglione, L., additional, Park, J.-S., additional, Koo, T. Y., additional, Kim, G.-H., additional, Kang, C. M., additional, Lee, C.-H., additional, Hiemstra, T. F., additional, Casian, A., additional, Boraks, P., additional, Jayne, D., additional, Schoenmakers, I., additional, Schmiedeke, B., additional, Niemann, M., additional, Schmiedeke, D., additional, Davydenko, I., additional, Emmert, A., additional, Pilz, S., additional, Obermayer-Pietsch, B., additional, Weidemann, F., additional, Breunig, F., additional, Wanner, C., additional, Drechsler, C., additional, Shiizaki, K., additional, Ito, C., additional, Onishi, A., additional, Nakazawa, E., additional, Ogura, M., additional, Kusano, E., additional, Ermolenko, V., additional, Mikhaylova, N., additional, Vartanjan, K., additional, Levchuk, D., additional, Dobrina, E., additional, Capusa, C., additional, Stancu, S., additional, Maria, D., additional, Vladu, I., additional, Barsan, L., additional, Garneata, L., additional, Mota, E., additional, Mircescu, G., additional, Ilyes, A., additional, Dorobantu, N., additional, Petrescu, L., additional, Martinez-Gallardo, R., additional, Ferreira, F., additional, Garcia-Pino, G., additional, Luna, E., additional, Caravaca, F., additional, De Jager, D. J., additional, Grootendorst, D. C., additional, Postmus, I., additional, De Goeij, M. C. M., additional, Boeschoten, E. W., additional, Sijpkens, Y. W. J., additional, Dekker, F. W., additional, Halbesma, N., additional, Wuthrich, R. P., additional, Covic, A., additional, Gaillard, S., additional, Rakov, V., additional, Louvet, L., additional, Buchel, J., additional, Steppan, S., additional, Passlick-Deetjen, J., additional, Massy, Z. A., additional, Akalin, N., additional, Altiparmak, M. R., additional, Trabulus, S., additional, Yalin, A. S., additional, Seyahi, N., additional, Ataman, R., additional, Serdengecti, K., additional, Donate-Correa, J., additional, Martinez-Sanz, R., additional, Muros-de-Fuentes, M., additional, Garcia, J., additional, Garcia, P., additional, Cazana, V., additional, Mora-Fernandez, C., additional, Navarro-Gonzalez, J. F., additional, Berutti, S., additional, Marranca, D., additional, Soragna, G., additional, Erroi, L., additional, Migliardi, M., additional, Belloni, L., additional, Parmeggiani, M., additional, Camerini, C., additional, Pezzotta, M., additional, Zani, R., additional, Movilli, E., additional, Cancarini, G., additional, Anwar, S., additional, Pruthi, R., additional, Kenchayikoppad, S., additional, Reyes, J., additional, Dasilva, I., additional, Furlano, M., additional, Calero, F., additional, Montanes, R., additional, Ayasreh, N., additional, Del Pozo, M., additional, Estorch, M., additional, Rousaud, F., additional, Ballarin, J. A., additional, Bover, J., additional, Resende, A., additional, Dias, C. B., additional, Dos Reis, L., additional, Jorgetti, V., additional, Woronik, V., additional, Panuccio, V., additional, Enia, G., additional, Tripepi, R., additional, Cutrupi, S., additional, Pizzini, P., additional, Aliotta, R., additional, Zoccali, C., additional, Yildiz, I., additional, Sagliker, Y., additional, Demirhan, O., additional, Tunc, E., additional, Inandiklioglu, N., additional, Tasdemir, D., additional, Acharya, V., additional, Zhang, L., additional, Golea, O., additional, Sabry, A., additional, Ookalkar, D., additional, Radulescu, D., additional, Ben Maiz, H., additional, Chen, C. H., additional, Rome, J. P., additional, Benzegoutta, M., additional, Paylar, N., additional, Eyupoglu, K., additional, Karatepe, E., additional, Esenturk, M., additional, Yavascan, O., additional, Grzegorzevska, A., additional, Shilo, V., additional, M-Mazdeh, M., additional, Francesco, R. C., additional, Gouda, Z., additional, Adam, S. M., additional, Emir, I., additional, Ocal, F., additional, Usta, E., additional, Kiralp, N., additional, Sagliker, C., additional, S Ozkaynak, P., additional, Sagliker, H. S., additional, Bassuoni, M., additional, El-Wakil, H. S., additional, Akar, H., additional, Yenicerioglu, Y., additional, Kose, E., additional, and Sekin, O., additional more...
- Published
- 2012
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4. Cellular changes following direct vitamin D injection into the uraemia-induced hyperplastic parathyroid gland
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Shiizaki, K., primary, Hatamura, I., additional, Negi, S., additional, Nakazawa, E., additional, Tozawa, R., additional, Izawa, S., additional, Akizawa, T., additional, and Kusano, E., additional
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- 2008
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5. Highly concentrated calcitriol and its analogues induce apoptosis of parathyroid cells and regression of the hyperplastic gland--study in rats
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Shiizaki, K., primary, Hatamura, I., additional, Negi, S., additional, Sakaguchi, T., additional, Saji, F., additional, Imazeki, I., additional, Kusano, E., additional, Shigematsu, T., additional, and Akizawa, T., additional more...
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- 2008
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6. Binding of highly concentrated maxacalcitol to the nuclear vitamin D receptors of parathyroid cells
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Shiizaki, K., primary, Hayakawa, N., additional, Imazeki, I., additional, Hatamura, I., additional, Okada, T., additional, Negi, S., additional, Sakaguchi, T., additional, Shigematsu, T., additional, and Akizawa, T., additional more...
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- 2007
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7. Effect of percutaneous calcitriol injection therapy on secondary hyperparathyroidism in uraemic patients
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Shiizaki, K., primary
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- 2003
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8. Bioassay of phytoestrogen in herbal medicine used for postmenopausal disorder using transformed MCF-7 cells.
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Shiizaki, Kazuhiro, Goto, Kazuhiro, Ishige, Atsusi, Komatsu, Yasuhiro, Shiizaki, K, Goto, K, Ishige, A, and Komatsu, Y
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- 1999
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9. Plasma Exchange for the Treatment of Human T-Cell Lymphotropic Virus Type 1 Associated Myelopathy
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Narukawa, N., Shiizaki, K., Kitabata, Y., Abe, T., Kobata, H., and Akizawa, T.
- Abstract
A 55-year-old man was admitted to our hospital because of myelopathy. He had a history of chronic renal failure due to polycystic kidney disease at the age of 39, being treated by hemodialysis for 9 years with several blood transfusions for the treatment of renal anemia. After cadaver renal transplantation at the age of 48, he discontinued hemodialysis. At 50 years of age, he had pulmonary tuberculosis and tuberculous arthritis of the left elbow joint. He has experienced difficulty in walking since he was 48 years old, with mild dysuria. Gait disturbance gradually aggravated after that, and urinary retention was observed. When he was 55 years old, being human T-cell lymphotropic virus type-1 (HTLV-1)-positive in the serum and cerebrospinal fluid, he was diagnosed as having HTLV-1-associated myelopathy (HAM). As active steroid therapy was unapplicable because of the history of pulmonary tuberculosis and immunosuppression for transplanted kidney, a series of plasma exchanges (PE) was performed with fresh frozen plasma as a replacement fluid. After PE, dyskinesia of the left leg and dysuria subjectively and objectively improved. These results suggest that PE seems to be one of the therapeutic tools for the treatment of HAM. more...
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- 2001
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10. Experimental study of multi-user detector with trellis-coding for microcellular radio
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Koike, T., primary, Shiizaki, K., additional, Murata, H., additional, and Yoshida, S., additional
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11. Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease
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Akimoto Tetsu, Yoshizawa Hiromichi, Watanabe Yuko, Numata Akihiko, Yamazaki Tomoyuki, Takeshima Eri, Iwazu Kana, Komada Takanori, Otani Naoko, Morishita Yoshiyuki, Ito Chiharu, Shiizaki Kazuhiro, Ando Yasuhiro, Muto Shigeaki, Kuro-o Makoto, and Kusano Eiji more...
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Klotho ,Chronic kidney disease ,Renal function ,Urinary protein ,Creatinine ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Background Klotho is a single-pass transmembrane protein, which appears to be implicated in aging. The purpose of the present study was to characterize the relationship between the soluble Klotho level and renal function in patients with various degrees of chronic kidney disease (CKD). Methods The levels of soluble Klotho in the serum and urine obtained from one hundred thirty-one CKD patients were determined by a sandwich enzyme-linked immunosorbent assay system. Results The amount of urinary excreted Klotho during the 24 hr period ranged from 1.6 to 5178 ng/day (median 427 ng/day; interquartile range [IR] 56.8-1293.1), and the serum Klotho concentration ranged from 163.9 to 2123.7 pg/ml (median 759.7 pg/ml; IR 579.5-1069.1). The estimated glomerular filtration rate (eGFR) was significantly correlated with the log-transformed values of the amount of 24 hr urinary excreted Klotho (r = 0.407, p Conclusions The amount of urinary Klotho, rather than the serum Klotho levels, should be linked to the magnitude of the functioning nephrons in CKD patients. The use of random urine Klotho/Cr as a surrogate for the amount of 24-hr urinary excreted Klotho needs to be evaluated more carefully. more...
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- 2012
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12. Experimental study of multi-user detector with trellis-coding for microcellular radio.
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Koike, T., Shiizaki, K., Murata, H., and Yoshida, S.
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- 2002
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13. Abortion in AhR-knockout mice and fetomaternal immunity.
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Karube R, Koike M, Ikuta T, and Shiizaki K
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- Animals, Female, Pregnancy, Mice, Male, Abortion, Spontaneous genetics, Abortion, Spontaneous immunology, Forkhead Transcription Factors metabolism, Forkhead Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Mice, Inbred ICR, Receptors, Aryl Hydrocarbon genetics, Receptors, Aryl Hydrocarbon metabolism, Mice, Knockout, Placenta metabolism, Placenta immunology, Indoleamine-Pyrrole 2,3,-Dioxygenase genetics, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism
- Abstract
AhR knockout mice are not completely infertile; however, they do experience decreased litter sizes after repeated pregnancies. This study revealed that the decrease in the number of live births is partly due to fetal deaths leading to miscarriages. Interestingly, fetal mortality was found to be linked only to maternal AhR gene defects and not the fetal genotype. Furthermore, we observed no significant changes in litter sizes in allogenic pregnancy, where AhR-KO female mice were crossed with ICR male mice. The results indicated that the absence of AhR in the dams affected the expression of immune tolerance-related genes in both the placenta and fetus. Specifically, FoxP3 and indoleamine 2,3-dioxygenase-1 (IDO1) mRNA levels were lower in the placentas of AhR-KO dams than in those of wild-type dams. Moreover, there were elevated levels of IL-1β and IFN-γ mRNA in the placentas of the AhR-KO dams, which indicated increased inflammation. However, the mRNA expression levels of IL-6 and IDO1 were low despite the elevated mRNA levels of IL-1β and IFN-γ, which may be because AhR is directly involved in IL-6 and IDO1 transcription. These findings imply that in AhR-KO mice, fetal death may be attributed to the disturbance of fetal-maternal immune tolerance as a result of increased inflammation and reduced IDO1 and FoxP3 mRNA levels., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.) more...
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- 2024
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14. Attenuation of Bone Mineral Density Decline During Anemia Treatment With Methenolone Acetate in Myelodysplastic Syndrome.
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Ushimaru S, Sumi H, Aso M, Fujishima R, Shiizaki K, and Tominaga N
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In an aging society, addressing the risks and management of osteoporotic fractures is critical to reduce mortality. Similarly, the morbidity of chronic kidney disease and myelodysplastic syndrome increases with aging. The association between chronic kidney disease and fractures is well understood; however, recent reports have indicated an increased risk of incident osteoporosis in patients with prevalent myelodysplastic syndrome. In this case report, we present an older man with stage 4 chronic kidney disease complicated by myelodysplastic syndrome and progressive decline in bone mineral density. He was treated with methenolone acetate and darbepoetin for anemia caused by myelodysplastic syndrome. During anemia treatment, the decline in bone mineral density was attenuated overtime. The case findings suggest the potential association between the use of methenolone acetate as a synthetic anabolic steroid and attenuated decline in bone mineral density., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.) more...
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- 2024
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15. Effect of denosumab on bone mineral density in a postmenopausal osteoporotic woman with prolonged chronic mild hyponatremia.
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Fujishima R, Ushimaru S, Sumi H, Aso M, Akaike T, Shiizaki K, and Tominaga N
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- Female, Humans, Denosumab adverse effects, Bone Density, Postmenopause, Hyponatremia chemically induced, Bone Density Conservation Agents adverse effects, Osteoporosis, Postmenopausal complications, Osteoporosis, Postmenopausal drug therapy
- Published
- 2023
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16. Removal of calciprotein particles from the blood using an adsorption column improves prognosis of hemodialysis miniature pigs.
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Miura M, Miura Y, Iwazu Y, Mukai H, Sugiura T, Suzuki Y, Kato M, Kano M, Nagata D, Shiizaki K, Kurosu H, and Kuro-O M
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- Animals, Swine, Swine, Miniature, Adsorption, Prognosis, Renal Dialysis, Hyperphosphatemia, Calcinosis therapy, Choristoma
- Abstract
Hyperphosphatemia is a major risk for poor prognosis in patients with end-stage renal disease. However, the molecular mechanism behind this link remains elusive. We and others have demonstrated that serum phosphorus levels correlate positively with circulating levels of calciprotein particles (CPPs). CPPs are colloidal mineral-protein complexes containing insoluble calcium-phosphate precipitates and have been reported to induce calcification in cultured vascular smooth muscle cells and inflammatory responses in cultured macrophages. Hence, we hypothesize that CPPs may be responsible for disorders associated with hyperphosphatemia. Using hyperphosphatemic miniature pigs receiving hemodialysis, here we show that removal of CPPs from the blood with a newly developed CPP adsorption column improves survival and alleviates complications including coronary artery calcification, vascular endothelial dysfunction, metastatic pulmonary calcification, left ventricular hypertrophy, and chronic inflammation. The present study identifies CPPs as an effective therapeutic target and justifies clinical trials to determine whether the CPP adsorption column may be useful as a medical device for improving clinical outcomes of hemodialysis patients., (© 2023. Springer Nature Limited.) more...
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- 2023
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17. Comment on One-Year Romosozumab Treatment Followed by One-Year Denosumab Treatment for Osteoporosis in Patients on Hemodialysis: An Observational Study.
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Ogata M, Sumi H, Shiizaki K, and Tominaga N
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- Humans, Antibodies, Monoclonal therapeutic use, Renal Dialysis, Denosumab therapeutic use, Osteoporosis drug therapy, Osteoporosis chemically induced
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- 2023
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18. Letter to the Editor From Sumi et al.: "Lower Bone Turnover and Skeletal PTH Responsiveness in Japanese Compared to European Patients Receiving Hemodialysis".
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Sumi H, Shiizaki K, and Tominaga N
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- Humans, Renal Dialysis, Bone Remodeling, East Asian People, Kidney Failure, Chronic
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- 2023
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19. Correlative light and electron microscopic observation of calcium phosphate particles in a mouse kidney formed under a high-phosphate diet.
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Battulga B, Shiizaki K, Miura Y, Osanai Y, Yamazaki R, Shinohara Y, Kubota Y, Hara T, Kuro-O M, and Ohno N
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- Mice, Animals, Microscopy, Electron, Scanning, Phosphates, Kidney, Diet, Electrons, Calcium Phosphates
- Abstract
Calcium phosphate forms particles under excessive urinary excretion of phosphate in the kidney. While the formation of calcium phosphate particles (CaPs) has been implicated in the damage to renal tubular cells and renal dysfunction, clarifying the ultrastructural information and the elemental composition of the small CaPs in the wide areas of kidney tissue has been technically difficult. This study introduces correlative and sequential light as well as electron microscopic CaP observation in the kidney tissue by combining fluorescent staining for CaPs and energy-dispersive X-ray spectroscopy (EDS) in scanning electron microscopy (SEM) on resin sections prepared using high-pressure freezing and freeze substitution. CaPs formed in mouse kidneys under long-term feeding of a high-phosphate diet were clearly visualized on resin sections by fluorescence-conjugated alendronate derivatives and toluidine blue metachromasia. These CaPs were verified by correlative observation with EDS. Furthermore, small CaPs formed in the kidney under short-term feeding were detected using fluorescent probes. The elemental composition of the particles, including calcium and magnesium, was identified following EDS analyses. These results suggest that the correlative microscopy approach is helpful for observing in situ distribution and elemental composition of CaPs in the kidney and contributing to studies regarding CaP formation-associated pathophysiology., (© 2023. The Author(s).) more...
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- 2023
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20. Romosozumab improves low bone mineral density in a postmenopausal woman undergoing chronic hemodialysis and treated with a calcium-sensing receptor agonist.
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Ogata M, Ushimaru S, Fujishima R, Sumi H, Shiizaki K, and Tominaga N
- Abstract
Preventing osteoporotic fractures is an issue requiring urgent attention to reduce mortality. However, unlike chronic kidney disease-mineral and bone disorder (CKD-MBD), osteoporosis is inadequately addressed in patients undergoing chronic dialysis. In fact, little is known about the proper use of anti-osteoporotic drugs for patients with CKD-MBD. A recent study showed that romosozumab, an anti-osteoporotic drug, increased bone mineral density in osteoporotic patients on hemodialysis without clinically significant adverse events. However, the efficacy and safety of coadministering romosozumab with a calcium-sensing receptor (CaSR) agonist, a pivotal drug used in the management of CKD-MBD, remain unclear. Here, we report the case of a postmenopausal woman undergoing chronic hemodialysis and treated with add-on romosozumab for osteoporosis to CaSR agonist for secondary hyperparathyroidism. After 1 year of treatment, her bone mineral density increased; however, hypocalcemia occurred during the treatment. These results suggest that the concomitant use of romosozumab with CaSR agonist may be a possible treatment option for severe osteoporosis in postmenopausal women receiving chronic hemodialysis with a high fracture risk, but serum calcium levels should be monitored closely and those at risk of ectopic calcification might not be ideal candidates for such treatment., Competing Interests: Naoto Tominaga received an honorarium from Astellas Pharmaceutical Inc. for being a speaker on HIF-PhD inhibitors which is not mentioned in this case report. The other authors have no conflicts of interest to declare., (© 2022 The Authors.) more...
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- 2022
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21. Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression.
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Shiizaki K, Tsubouchi A, Miura Y, Seo K, Kuchimaru T, Hayashi H, Iwazu Y, Miura M, Battulga B, Ohno N, Hara T, Kunishige R, Masutani M, Negishi K, Kario K, Kotani K, Yamada T, Nagata D, Komuro I, Itoh H, Kurosu H, Murata M, and Kuro-O M more...
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- Animals, Body Fluids chemistry, Calcium Phosphates chemistry, Cell Line, Crystallization, Diet, Western adverse effects, Disease Progression, Endocytosis, Fibroblast Growth Factor-23, Fibroblast Growth Factors blood, Homeostasis, Humans, Kidney Tubules pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphates administration & dosage, Phosphates adverse effects, Renal Insufficiency, Chronic etiology, Renal Insufficiency, Chronic pathology, Toll-Like Receptor 4 deficiency, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 metabolism, Calcium Phosphates metabolism, Kidney Tubules metabolism, Renal Insufficiency, Chronic metabolism
- Abstract
The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression. more...
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- 2021
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22. Bone responsiveness to parathyroid hormone is negatively associated with parathyroid hormone-lowering drug use in patients undergoing hemodialysis: a cross-sectional study.
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Tominaga N, Yonaha T, Yamanouchi M, Sumi H, Taki Y, Shibagaki Y, Shiizaki K, and Yano S
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- Cross-Sectional Studies, Female, Humans, Japan epidemiology, Male, Middle Aged, Osteoclasts drug effects, Osteoclasts physiology, Peritoneal Dialysis adverse effects, Peritoneal Dialysis methods, Bone Remodeling drug effects, Bone Remodeling physiology, Bone Resorption metabolism, Bone Resorption prevention & control, Kidney Failure, Chronic epidemiology, Kidney Failure, Chronic metabolism, Kidney Failure, Chronic therapy, Parathyroid Hormone blood, Parathyroid Hormone metabolism, Receptors, Calcitriol metabolism, Receptors, Calcium-Sensing agonists, Renal Dialysis adverse effects, Renal Dialysis methods, Tartrate-Resistant Acid Phosphatase blood, Tartrate-Resistant Acid Phosphatase metabolism
- Abstract
Background: Parathyroid hormone (PTH) acts on bone to indirectly increase the number and activity of osteoclasts. Thus, PTH has a stimulatory effect on bone resorption and upregulates bone turnover. However, the responsiveness of bone to PTH varies widely among patients receiving dialysis. In fact, relative to the serum PTH level, the level of serum tartrate-resistant acid phosphatase-5b (TRACP-5b), a bone resorption marker derived from osteoclasts, varies as well. This study aimed to examine factors related to bone responsiveness to PTH in patients undergoing chronic hemodialysis (HD)., Methods: This study included patients receiving chronic HD in Kawasaki Municipal Tama Hospital (Kanagawa, Japan) and Yonaha Medical Clinic (Okinawa, Japan) and excluded patients who received HD for less than 6 months, those who received a combination of HD and peritoneal dialysis, and those who had cancer bone metastases or myeloma. The TRACP-5b/intact PTH (iPTH) ratio was created as an index of bone responsiveness to PTH, categorized into tertiles (low, medium, and high), and a cross-sectional study was conducted. P < 0.05 indicated statistically significant differences., Results: One hundred and six patients were analyzed. Age (P = 0.010), body mass index (BMI) (P = 0.003), use of calcium-sensing receptor (CaSR) agonists (P = 0.008), use of vitamin D receptor activators (VDRAs) (P = 0.012), plasma iPTH level (P < 0.001), serum 1,25(OH)
2 D level (P = 0.003), and serum TRACP-5b level (P < 0.001) were significantly different among the three categories. In the single linear regression analysis, age (P = 0.016), corrected serum calcium level (P = 0.007), and ln [1,25(OH)2 D] (P = 0.044) showed a significant positive correlation with ln [TRACP-5b/iPTH], whereas BMI (P = 0.026), use of CaSR agonists (P = 0.001), use of VDRAs (P = 0.009), and serum phosphorus level (P = 0.018) showed a significant negative correlation. Upon conducting multiple linear regression analysis incorporating significant variables in the single linear regression analysis, a significant negative correlation was observed between the TRACP-5b/iPTH ratio and intravenous administration of a CaSR agonist (etelcalcetide) and/or a VDRA (calcitriol or maxacalcitol) in all the adjusted models., Conclusions: Bone responsiveness to PTH is negatively correlated with the intravenous administration of a CaSR agonist and/or a VDRA in patients undergoing chronic HD., (© 2021. The Author(s).) more...- Published
- 2021
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23. Construction of reporter gene assays using CWP and PDR mutant yeasts for enhanced detection of various sex steroids.
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Ito-Harashima S, Matano M, Onishi K, Nomura T, Nakajima S, Ebata S, Shiizaki K, Kawanishi M, and Yagi T
- Abstract
Background: Sex steroid hormone receptors are classified into three classes of receptors: estrogen receptors (ER) α and β, androgen receptor (AR), and progesterone receptor (PR). They belong to the nuclear receptor superfamily and activate their downstream genes in a ligand-dependent manner. Since sex steroid hormones are involved in a wide variety of physiological processes and cancer development, synthetic chemical substances that exhibit sex steroid hormone activities have been applied as pharmaceuticals and consumed in large amounts worldwide. They are potentially hazardous contaminants as endocrine disruptors in the environment because they may induce inappropriate gene expression mediated by sex steroid hormone receptors in vivo., Results: To develop simple reporter gene assays with enhanced sensitivity for the detection of sex steroid hormones, we newly established mutant yeast strains lacking the CWP and PDR genes encoding cell wall mannoproteins and plasma membrane drug efflux pumps, respectively, and expressing human ERα, ERβ, AR, and PR. Reporter gene assays with mutant yeast strains responded to endogenous and synthetic ligands more strongly than those with wild-type strains. Sex steroid hormone activities in some pharmaceutical oral tablets and human urine were also detectable in these yeast assays., Conclusions: Yeast reporter gene assay systems for all six steroid hormone receptors, including previously established glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) assay yeasts, are now available. Environmental endocrine disrupters with steroid hormone activity will be qualitatively detectable by simple and easy procedures. The yeast-based reporter gene assay will be valuable as a primary screening tool to detect and evaluate steroid hormone activities in various test samples. Our assay system will strongly support the detection of agonists, antagonists, and inverse agonists of steroid hormone receptors in the field of novel drug discovery and assessments of environmental pollutants., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.) more...
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- 2020
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24. Interleukin-36α as a potential biomarker for renal tubular damage induced by dietary phosphate load.
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Hirano Y, Kurosu H, Shiizaki K, Iwazu Y, Tsuruoka S, and Kuro-O M
- Subjects
- Acute Kidney Injury chemically induced, Acute Kidney Injury metabolism, Animals, Biomarkers metabolism, Cytokines metabolism, Dietary Supplements, Gene Expression genetics, Inflammation metabolism, Interleukin-1alpha analysis, Interleukins adverse effects, Interleukins metabolism, Kidney pathology, Kidney Tubules physiopathology, Male, Mice, Mice, Inbred C57BL, Phosphates metabolism, Signal Transduction genetics, Interleukin-1alpha metabolism, Kidney Tubules metabolism, Phosphates adverse effects
- Abstract
Excessive intake of phosphate has been known to induce renal tubular damage and interstitial inflammation, leading to acute kidney injury or chronic kidney disease in rodents and humans. However, sensitive and early biomarkers for phosphate-induced kidney damage remain to be identified. Our previous RNA sequencing analysis of renal gene expression identified interleukin-36α (IL-36α) as a gene significantly upregulated by dietary phosphate load in mice. To determine the time course and dose dependency of renal IL-36α expression induced by dietary phosphate load, we placed mice with or without uninephrectomy on a diet containing either 0.35%, 1.0%, 1.5%, or 2.0% inorganic phosphate for 10 days, 4 weeks, or 8 weeks and evaluated renal expression of IL-36α and other markers of tubular damage and inflammation by quantitative RT-PCR, immunoblot analysis, and immunohistochemistry. We found that IL-36α expression was induced in distal convoluted tubules and correlated with phosphate excretion per nephron. The increase in IL-36α expression was simultaneous with but more robust in amplitude than the increase in tubular damage markers such as Osteopontin and neutrophil gelatinase-associated lipocalin, preceding the increase in expression of other inflammatory cytokines, including transforming growth factor-α, interleukin-1β, and transforming growth factor-β1. We conclude that IL-36α serves as a marker that reflects the degree of phosphate load excreted per nephron and of associated kidney damage., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.) more...
- Published
- 2020
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25. Calciprotein particles regulate fibroblast growth factor-23 expression in osteoblasts.
- Author
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Akiyama KI, Miura Y, Hayashi H, Sakata A, Matsumura Y, Kojima M, Tsuchiya K, Nitta K, Shiizaki K, Kurosu H, and Kuro-O M
- Subjects
- Animals, Bone and Bones, Fibroblast Growth Factor-23, Mice, Osteocytes, Phosphates, Fibroblast Growth Factors, Osteoblasts
- Abstract
Fibroblast growth factor-23 (FGF23) is a hormone indispensable for maintaining phosphate homeostasis. In response to phosphate intake, FGF23 is secreted from osteocytes/osteoblasts and acts on the kidney to increase urinary phosphate excretion. However, the mechanism by which these cells sense phosphate intake remains elusive. Calciprotein particles are nanoparticles of calcium-phosphate precipitates bound to serum protein fetuin-A and are generated spontaneously in solution containing calcium, phosphate, and fetuin-A to be dispersed as colloids. In cultured osteoblastic cells, increase in either calcium or phosphate concentration in the medium induced FGF23 expression, which was dependent on calciprotein particle formation. When transition of calcium-phosphate precipitates from the amorphous phase to the crystalline phase was blocked by bisphosphonate, the calciprotein particle size was reduced and FGF23 expression was augmented, suggesting that small calciprotein particles containing amorphous calcium-phosphate precipitates function as a more potent FGF23 inducer than larger calciprotein particles containing crystalline calcium-phosphate precipitates. In mice, bolus phosphate administration by oral gavage transiently increased circulating calciprotein particle levels followed by a modest increase in FGF23 expression and serum FGF23 levels. However, continuous dietary phosphate load induced robust and persistent increase in circulating calciprotein particles and FGF23 levels. We confirmed by in vivo imaging that calciprotein particles injected intravenously extravasated into the bone marrow and were deposited on the inner surface of the bone, indicating that these particles have direct access to osteoblasts. Thus, we propose that osteoblasts induce FGF23 expression and secretion when they sense an increase in extracellular calciprotein particles following phosphate ingestion., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2020
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26. Comprehensive analysis of DNA adducts (DNA adductome analysis) in the liver of rats treated with 1,4-dioxane.
- Author
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Totsuka Y, Maesako Y, Ono H, Nagai M, Kato M, Gi M, Wanibuchi H, Fukushima S, Shiizaki K, and Nakagama H
- Subjects
- Animals, Rats, DNA Adducts metabolism, Dioxanes toxicity, Liver drug effects, Liver metabolism
- Abstract
1,4-Dioxane is a genotoxic carcinogen, and its mutagenic properties were recently observed in the liver of guanine phosphoribosyl transferase (gpt) delta transgenic rats. However, the mechanisms of its genotoxicity remain unclear. We analyzed DNA adduct formation in rat livers following 1,4-dioxane treatment. After administering 1,4-dioxane in drinking water at doses of 0, 20, 200, and 5,000 ppm, liver adduct formation was analyzed by DNA adductome analysis. Adducts in treated rat livers were dose-dependently increased compared with those in the control group. Principal component analysis-discriminant analysis (PCA-DA) clearly revealed two clusters of DNA adducts, associated with 0 ppm and low-dose (20 ppm) 1,4-dioxane-treatment versus middle- and high-dose (200, 5,000 ppm)-treated rats. After confirming the intensity of each adduct, three adducts were screened as characteristic of 1,4-dioxane treatment. Two of the three candidates contained thymine or cytidine/uracil moieties. Another candidate was identified as 8-oxo-dG based on mass fragmentation together with high-resolution accurate-mass (HRAM) mass spectrometry data. Oxidative stress responses may partly explain the mechanisms of increased mutations in the liver of gpt delta rats following 1,4-dioxane treatment. more...
- Published
- 2020
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27. Postlabeling/PAGE Method for Detection of DNA Adducts.
- Author
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Shiizaki K
- Subjects
- Animals, Cell Line, DNA Adducts chemistry, Humans, DNA Adducts analysis, Electrophoresis, Polyacrylamide Gel, Isotope Labeling, Phosphorus Radioisotopes
- Abstract
In DNA adduct analysis, the
32 P-postlabeling technique is a powerful tool due to its high detection sensitivity. It is performed by enzymatic digestion of DNA samples, enrichment of the adduct nucleotides, and then 5'-labeling with32 P. This method is particularly useful for detection of bulky adducts. An additional advantage is that only a small amount of DNA is required for detecting DNA adducts. This chapter describes the experimental procedure for separation and detection of DNA adducts by polyacrylamide gel electrophoresis, which is an attractive method for visually assessing differences in adduct formation between samples. more...- Published
- 2020
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28. Increased fibroblast growth factor-21 in chronic kidney disease is a trade-off between survival benefit and blood pressure dysregulation.
- Author
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Nakano T, Shiizaki K, Miura Y, Matsui M, Kosaki K, Mori S, Yamagata K, Maeda S, Kishi T, Usui N, Yoshida M, Onaka T, Mizukami H, Kaneda R, Karasawa K, Nitta K, Kurosu H, and Kuro-O M
- Subjects
- Animals, Disease Models, Animal, Fibroblast Growth Factors genetics, Humans, Mice, Mice, Knockout, Renal Insufficiency, Chronic genetics, Renal Insufficiency, Chronic pathology, Renal Insufficiency, Chronic physiopathology, Blood Pressure, Fibroblast Growth Factors metabolism, Pressoreceptors metabolism, Renal Insufficiency, Chronic metabolism
- Abstract
Circulating levels of fibroblast growth factor-21 (FGF21) start increasing in patients with chronic kidney disease (CKD) since early stages during the cause of disease progression. FGF21 is a liver-derived hormone that induces responses to stress through acting on hypothalamus to activate the sympathetic nervous system and the hypothalamus-pituitary-adrenal endocrine axis. However, roles that FGF21 plays in pathophysiology of CKD remains elusive. Here we show in mice that FGF21 is required to survive CKD but responsible for blood pressure dysregulation. When introduced with CKD, Fgf21
-/- mice died earlier than wild-type mice. Paradoxically, these Fgf21-/- CKD mice escaped several complications observed in wild-type mice, including augmentation of blood pressure elevating response and activation of the sympathetic nervous system during physical activity and increase in serum noradrenalin and corticosterone levels. Supplementation of FGF21 by administration of an FGF21-expressing adeno-associated virus vector recapitulated these complications in wild-type mice and restored the survival period in Fgf21-/- CKD mice. In CKD patients, high serum FGF21 levels are independently associated with decreased baroreceptor sensitivity. Thus, increased FGF21 in CKD can be viewed as a survival response at the sacrifice of blood pressure homeostasis. more...- Published
- 2019
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29. Insight into the relationship between aryl-hydrocarbon receptor and β-catenin in human colon cancer cells.
- Author
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Shiizaki K, Kido K, and Mizuta Y
- Subjects
- Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Immunoprecipitation, Reverse Transcriptase Polymerase Chain Reaction, Two-Hybrid System Techniques, Basic Helix-Loop-Helix Transcription Factors metabolism, Colonic Neoplasms metabolism, Receptors, Aryl Hydrocarbon metabolism, beta Catenin metabolism
- Abstract
β-Catenin is a multi-functional protein involved in cell adhesion and signal transduction and has a critical role in colorectal cancer development. β-Catenin positively regulates the aryl-hydrocarbon receptor (AhR) mediated signal by both induction of AhR expression and enhancement of AhR-dependent gene induction. Conversely, it was reported that AhR negatively regulates the β-catenin signal via ubiquitination and subsequent degradation in a ligand dependent manner. However, there have been conflicting data among previous studies regarding the relationship between these two proteins. In this report, we conducted confirmatory studies dissecting the relationship between AhR and β-catenin. We did not observe β-catenin degradation by AhR ligands in several colon cancer cell lines. Reporter assays revealed that the AhR ligand did not alter TcF/β-catenin dependent transcription. Yeast and mammalian two-hybrid assays failed to reconstruct the interaction of β-catenin and AhR even when other factors, Arnt, CUL4B, and DDB1, were co-expressed additionally. Independently to induction of AhR expression, β-catenin enhanced AhR-dependent transcriptional activation via the xenobiotic response element (XRE). Coimmunoprecipitation detected the formation of a β-catenin and ligand-activated AhR complex, which was thought to reflect the β-catenin mediated enhancement of the AhR signaling. Overall, we could only confirm unidirectional interaction, which is positive regulation of the AhR signal by β-catenin. These results suggested that data from previous reports on the degradation of β-catenin via liganded AhR warrants further investigation to yield clarity in the field., Competing Interests: The authors have declared that no competing interests exist. more...
- Published
- 2019
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30. A decreased soluble Klotho level with normal eGFR, FGF23, serum phosphate, and FEP in an ADPKD patient with enlarged kidneys due to multiple cysts.
- Author
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Kanai T, Shiizaki K, Betsui H, Aoyagi J, and Yamagata T
- Subjects
- Angiotensin II Type 1 Receptor Blockers therapeutic use, Benzimidazoles administration & dosage, Benzimidazoles therapeutic use, Biphenyl Compounds administration & dosage, Biphenyl Compounds therapeutic use, Calcium Channel Blockers therapeutic use, Child, Preschool, Cysts diagnostic imaging, Cysts pathology, Dihydropyridines administration & dosage, Dihydropyridines therapeutic use, ErbB Receptors metabolism, Fibroblast Growth Factor-23, Fibroblast Growth Factors metabolism, Glomerular Filtration Rate physiology, Humans, Kidney diagnostic imaging, Kidney metabolism, Kidney pathology, Klotho Proteins, Magnetic Resonance Imaging, Male, Phosphates urine, Polycystic Kidney, Autosomal Dominant diagnosis, Polycystic Kidney, Autosomal Dominant drug therapy, Tetrazoles administration & dosage, Tetrazoles therapeutic use, Glucuronidase metabolism, Phosphates blood, Polycystic Kidney, Autosomal Dominant metabolism, Polycystic Kidney, Autosomal Dominant pathology
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder. ADPKD is characterized clinically by the presence of multiple bilateral renal cysts that lead to chronic renal failure. The cysts evolve from renal tubular epithelial cells that express the Klotho gene. Notably, Klotho acts as a co-receptor for fibroblast growth factor 23 (FGF23); in this context, it induces phosphaturia and maintains serum phosphate at a normal level. Many reports have shown that decreases in the soluble Klotho level and increases in the FGF23 level are associated with glomerular filtration rate (GFR) decline, but a recent study observed these changes in patient with normal eGFR. It remains unclear whether the decrease in the Klotho level precedes the increase in FGF23. Here, we present an ADPKD patient with enlarged kidneys due to multiple cysts who had a decreased soluble Klotho level but a normal eGFR and a normal FGF23 level. The patient's serum phosphate level was normal, as was the fractional excretion of phosphate (FEP). This appears to be the first reported case to show a decreased soluble Klotho level plus normal eGFR, FGF23, and FEP. These results suggest that Klotho decreases before FGF23 increases and further suggest that Klotho is not required to maintain normal serum phosphate levels in ADPKD if the FEP and serum phosphate levels are normal. more...
- Published
- 2018
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31. The impact of preserved Klotho gene expression on antioxidative stress activity in healthy kidney.
- Author
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Kimura T, Shiizaki K, Akimoto T, Shinzato T, Shimizu T, Kurosawa A, Kubo T, Nanmoku K, Kuro-O M, and Yagisawa T
- Subjects
- Aged, Animals, Female, Gene Expression Regulation, Enzymologic, Glucuronidase deficiency, Glucuronidase genetics, Humans, Klotho Proteins, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Tyrosine analogs & derivatives, Tyrosine metabolism, Antioxidants metabolism, Glucuronidase metabolism, Kidney enzymology, Oxidative Stress
- Abstract
Klotho, which was originally identified as an antiaging gene, forms a complex with fibroblast growth factor 23 receptor in the kidney, with subsequent signaling that regulates mineral metabolism. Other biological activities of Klotho, including antiaging effects such as protection from various types of cellular stress, have been shown; however, the precise mechanism of these effects of Klotho gene in the healthy human kidney is not well understood. In this study, we examined the relationships of Klotho and antioxidative stress gene expression levels in zero-hour biopsy specimens from 44 donors in kidney transplantation and verified them in animal models whose Klotho gene expression levels were varied. The nitrotyrosine expression level in the kidney was evaluated in these animal models. Expression levels of Klotho gene were positively correlated with the p53 gene and antioxidant enzyme genes such as catalase, superoxide dismutase 1 (SOD1), SOD2, peroxiredoxin 3 (PRDX3), and glutathione peroxidase 1 (GPX1) but not clinical parameters such as age and renal function or pathological features such as glomerulosclerosis and interstitial fibrosis tubular atrophy. The expression levels of all genes were significantly higher in mice with Klotho overexpression than in wild-type mice, and those except for catalase, PRDX3, and GPX1 were significantly lower in Klotho-deficient mice than in wild-type littermate mice. Nitrotyrosine-positive bands of various sizes were observed in kidney from Klotho-deficient mice only. The preservation of Klotho gene expression might induce the antioxidative stress mechanism for homeostasis of healthy human kidney independently of its general condition, including age, renal function, and histological findings. more...
- Published
- 2018
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32. The Body-wide Transcriptome Landscape of Disease Models.
- Author
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Kozawa S, Ueda R, Urayama K, Sagawa F, Endo S, Shiizaki K, Kurosu H, Maria de Almeida G, Hasan SM, Nakazato K, Ozaki S, Yamashita Y, Kuro-O M, and Sato TN
- Abstract
Virtually all diseases affect multiple organs. However, our knowledge of the body-wide effects remains limited. Here, we report the body-wide transcriptome landscape across 13-23 organs of mouse models of myocardial infarction, diabetes, kidney diseases, cancer, and pre-mature aging. Using such datasets, we find (1) differential gene expression in diverse organs across all models; (2) skin as a disease-sensor organ represented by disease-specific activities of putative gene-expression network; (3) a bone-skin cross talk mediated by a bone-derived hormone, FGF23, in response to dysregulated phosphate homeostasis, a known risk-factor for kidney diseases; (4) candidates for the signature activities of many more putative inter-organ cross talk for diseases; and (5) a cross-species map illustrating organ-to-organ and model-to-disease relationships between human and mouse. These findings demonstrate the usefulness and the potential of such body-wide datasets encompassing mouse models of diverse disease types as a resource in biological and medical sciences. Furthermore, the findings described herein could be exploited for designing disease diagnosis and treatment., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2018
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33. Biological and Clinical Effects of Calciprotein Particles on Chronic Kidney Disease-Mineral and Bone Disorder.
- Author
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Akiyama K, Kimura T, and Shiizaki K
- Abstract
Calciprotein particles (CPPs) are a new biological marker of chronic kidney disease-mineral and bone disorder (CKD-MBD). CPPs consist of phosphate, calcium, and some proteins, with phosphate being the major contributor to the level and biological activity of CPPs. Recent studies have shown the physiological and pathological significance of CPPs, including contributions to bone and mineral metabolism, and to tissue and organ impairments such as cardiovascular damage and inflammatory responses. These actions are well known as important aspects of CKD-MBD. Fibroblast growth factor 23 (FGF23), which is secreted from the bone as the phosphaturic hormone, is markedly elevated in CKD-MBD. Many clinical studies have shown significant relationships between the level of FGF23 and outcomes such as mortality, prevalence of cardiovascular disease, bone fracture, and levels of inflammatory markers. Basic and clinical studies have suggested that CPPs contribute to synthesis and secretion of FGF23. Surgical treatments such as renal transplantation and parathyroidectomy for patients with CKD-MBD suppress excess levels of phosphate, calcium, parathyroid hormone (PTH), and FGF23, which are related to the CPP level. Therefore, suppression of CPPs might also contribute to improved clinical outcomes after these treatments. more...
- Published
- 2018
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34. Identification and quantification of plasma calciprotein particles with distinct physical properties in patients with chronic kidney disease.
- Author
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Miura Y, Iwazu Y, Shiizaki K, Akimoto T, Kotani K, Kurabayashi M, Kurosu H, and Kuro-O M
- Subjects
- Biomarkers blood, Calcium Phosphates analysis, Case-Control Studies, Humans, alpha-2-HS-Glycoprotein metabolism, Calcinosis blood, Renal Insufficiency, Chronic blood, alpha-2-HS-Glycoprotein chemistry
- Abstract
Calciprotein particles (CPP) are solid-phase calcium-phosphate bound to serum protein fetuin-A and dispersed as colloids in the blood. Recent clinical studies indicated that serum CPP levels were increased with decline of renal function and associated with inflammation and vascular calcification. However, CPP assays used in these studies measured only a part of CPP over a certain particle size and density. Here we show that such CPP are mostly artifacts generated during processing of serum samples in vitro. The native CPP in fresh plasma are smaller in size and lower in density than those artifactual CPP, composed of fetuin-A carrying amorphous and/or crystalline calcium-phosphate, and increased primarily with serum phosphate levels. We have identified several physicochemical factors that promote aggregation/dissolution of CPP and transition of the calcium-phosphate from the amorphous phase to the crystalline phase in vitro, including addition of anti-coagulants, composition of buffer for sample dilution, the number of freeze-thaw cycles, the speed for sample freezing, and how many hours the samples were left at what temperature. Therefore, it is of critical importance to standardize these factors during sample preparation in clinical studies on CPP and to investigate the biological activity of the native CPP. more...
- Published
- 2018
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35. Influence of GSH S-transferase on the mutagenicity induced by dichloromethane and 1,2-dichloropropane.
- Author
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Akiba N, Shiizaki K, Matsushima Y, Endo O, Inaba K, and Totsuka Y
- Subjects
- DNA Adducts genetics, DNA Mutational Analysis, DNA, Bacterial genetics, Glutathione Transferase biosynthesis, Humans, Mutagenesis, Mutation, Propane pharmacology, Salmonella typhimurium drug effects, Salmonella typhimurium genetics, Glutathione Transferase genetics, Methylene Chloride pharmacology, Mutagens pharmacology, Propane analogs & derivatives
- Abstract
It has been suggested that dichloromethane (DCM) and 1,2-dichloropropane (DCP) are responsible for occupational cholangiocarcinoma. Dihaloalkanes are metabolically activated by GSH S-transferase theta1 (GSTT1) to yield products such as episulfonium ions. However, whether the GSTT1-mediated step of these dihaloalkanes is related to occupational cholangiocarcinoma is not known. In the present study, we investigated the influence of GSTT1 activation on the mutagenicity of DCM and 1,2-DCP using GSTT1-expressing Salmonella typhimurium TA100 (TA100-GST). Since the mutagenicity of DCM was significantly increased in TA100-GST compared with mock control (TA100-pCTC), GSTT1 is thought to be involved in the mutagenicity of DCM. Mutation spectrum analysis on the hisG gene revealed that C:G to A:T transversions were the predominant form observed in DCM-treated TA100-pCTC. However, C:G to T:A transitions were dramatically increased in TA100-GST. We also analysed the DCM-DNA adduct, N2-GSH-Me-dG, and formation of N2-GSH-Me-dG was increased in TA100-GST compared with TA100-pCTC. On the other hand, 1,2-DCP did not increase the numbers of revertants in TA100-GSTT1. In mutation spectrum analysis, C:G to T:A transitions was predominant in both TA100-pCTC and TA100-GSTT1. These findings suggest that GSTT1 has little involvement in DCP mutagenicity, and other mechanisms might be more important for bioactivation and consequent genotoxicity. Clarification of the mechanisms underlying the development of DCM- and/or 1,2-DCP-related human cholangiocarcinoma may help establish risk assessment and prevention strategies against occupational cancer., (© The Author 2017. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...
- Published
- 2017
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36. Association between circulating fibroblast growth factor 21 and mortality in end-stage renal disease.
- Author
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Kohara M, Masuda T, Shiizaki K, Akimoto T, Watanabe Y, Honma S, Sekiguchi C, Miyazawa Y, Kusano E, Kanda Y, Asano Y, Kuro-O M, and Nagata D
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers blood, Heart Failure blood, Heart Failure etiology, Heart Failure mortality, Humans, Kidney Failure, Chronic mortality, Kidney Failure, Chronic pathology, Kidney Failure, Chronic therapy, Middle Aged, Myocardial Infarction blood, Myocardial Infarction etiology, Myocardial Infarction mortality, Prognosis, Proportional Hazards Models, Renal Dialysis, Retrospective Studies, Fibroblast Growth Factors blood, Heart Failure diagnosis, Kidney Failure, Chronic complications, Myocardial Infarction diagnosis
- Abstract
Fibroblast growth factor 21 (FGF21) is an endocrine factor that regulates glucose and lipid metabolism. Circulating FGF21 predicts cardiovascular events and mortality in type 2 diabetes mellitus, including early-stage chronic kidney disease, but its impact on clinical outcomes in end-stage renal disease (ESRD) patients remains unclear. This study enrolled 90 ESRD patients receiving chronic hemodialysis who were categorized into low- and high-FGF21 groups by the median value. We investigated the association between circulating FGF21 levels and the cardiovascular event and mortality during a median follow-up period of 64 months. A Kaplan-Meier analysis showed that the mortality rate was significantly higher in the high-FGF21 group than in the low-FGF21 group (28.3% vs. 9.1%, log-rank, P = 0.034), while the rate of cardiovascular events did not significantly differ between the two groups (30.4% vs. 22.7%, log-rank, P = 0.312). In multivariable Cox models adjusted a high FGF21 level was an independent predictor of all-cause mortality (hazard ratio: 3.98; 95% confidence interval: 1.39-14.27, P = 0.009). Higher circulating FGF21 levels were associated with a high mortality rate, but not cardiovascular events in patient with ESRD, suggesting that circulating FGF21 levels serve as a predictive marker for mortality in these subjects. more...
- Published
- 2017
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37. Modulation of benzo[a]pyrene-DNA adduct formation by CYP1 inducer and inhibitor.
- Author
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Shiizaki K, Kawanishi M, and Yagi T
- Abstract
Benzo[ a ]pyrene (BaP) is a well-studied pro-carcinogen that is metabolically activated by cytochrome P450 enzymes. Cytochrome P4501A1 (CYP1A1) has been considered to play a central role in the activation step, which is essential for the formation of DNA adducts. This enzyme is strongly induced by many different chemical agents, including 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), which binds to the aryl hydrocarbon receptor (AhR). Therefore, AhR activators are suspected to have the potential to aggravate the toxicity of BaP through the induction of CYP1A1. Besides, CYP1A1 inhibitors, including its substrates, are estimated to have preventive effects against BaP toxicity. However, strangely, increased hepatic BaP-DNA adduct levels have been reported in Cyp1a1 knockout mice. Moreover, numerous reports describe that concomitant treatment of AhR activators reduced BaP-DNA adduct formation. In an experiment using several human cell lines, TCDD had diverse modulatory effects on BaP-DNA adducts, both enhancing and inhibiting their formation. In this review, we focus on the factors that could influence the BaP-DNA adduct formation. To interpret these complicated outcomes, we propose a hypothesis that CYP1A1 is a key enzyme for both generation and reduction of (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), the major carcinogenic intermediate of BaP. Conversely, CYP1B1 is thought to contribute only to the metabolic activation of BaP related to carcinogenesis. more...
- Published
- 2017
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38. Fibroblast growth factor 21, assisted by elevated glucose, activates paraventricular nucleus NUCB2/Nesfatin-1 neurons to produce satiety under fed states.
- Author
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Santoso P, Nakata M, Shiizaki K, Boyang Z, Parmila K, Otgon-Uul Z, Hashimoto K, Satoh T, Mori M, Kuro-O M, and Yada T
- Subjects
- Animals, Calcium-Binding Proteins metabolism, DNA-Binding Proteins metabolism, Eating, Infusions, Intraventricular, Male, Mice, Mice, Knockout, Nerve Tissue Proteins metabolism, Neurons drug effects, Nucleobindins, Paraventricular Hypothalamic Nucleus metabolism, Proto-Oncogene Proteins c-fos, Blood Glucose, Fibroblast Growth Factors pharmacology, Paraventricular Hypothalamic Nucleus drug effects, Satiation physiology
- Abstract
Fibroblast growth factor 21 (FGF21), liver-derived hormone, exerts diverse metabolic effects, being considered for clinical application to treat obesity and diabetes. However, its anorexigenic effect is debatable and whether it involves the central mechanism remains unclarified. Moreover, the neuron mediating FGF21's anorexigenic effect and the systemic energy state supporting it are unclear. We explored the target neuron and fed/fasted state dependence of FGF21's anorexigenic action. Intracerebroventricular (ICV) injection of FGF21 markedly suppressed food intake in fed mice with elevated blood glucose. FGF21 induced c-Fos expression preferentially in hypothalamic paraventricular nucleus (PVN), and increased mRNA expression selectively for nucleobindin 2/nesfatin-1 (NUCB2/Nesf-1). FGF21 at elevated glucose increased [Ca
2+ ]i in PVN NUCB2/Nesf-1 neurons. FGF21 failed to suppress food intake in PVN-preferential Sim1-Nucb2-KO mice. These findings reveal that FGF21, assisted by elevated glucose, activates PVN NUCB2/Nesf-1 neurons to suppress feeding under fed states, serving as the glycemia-monitoring messenger of liver-hypothalamic network for integrative regulation of energy and glucose metabolism. more...- Published
- 2017
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39. Development of yeast reporter assays for the enhanced detection of environmental ligands of thyroid hormone receptors α and β from Xenopus tropicalis.
- Author
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Matsui S, Ito-Harashima S, Sugimoto Y, Takada E, Shiizaki K, Kawanishi M, and Yagi T
- Subjects
- Animals, DNA, Complementary genetics, Feces chemistry, Genes, Reporter, Humans, Ligands, Plasmids, Rivers chemistry, Thyroid Hormones metabolism, Urine chemistry, Nuclear Receptor Coactivator 1 genetics, Nuclear Receptor Coactivator 1 metabolism, Saccharomyces cerevisiae genetics, Thyroid Hormone Receptors alpha genetics, Thyroid Hormone Receptors alpha metabolism, Thyroid Hormone Receptors beta genetics, Thyroid Hormone Receptors beta metabolism, Xenopus genetics
- Abstract
Thyroid hormones (THs) are involved in the regulation of metabolic homeostasis during the development and differentiation of vertebrates, particularly amphibian metamorphosis, which is entirely controlled by internal TH levels. Some artificial chemicals have been shown to exhibit TH-disrupting activities. In order to detect TH disruptors for amphibians, we herein developed a reporter assay using yeast strains expressing the thyroid hormone receptors (TRs) α and β together with the transcriptional coactivator SRC-1, all of which were derived from the frog Xenopus tropicalis (XT). These yeast strains responded to endogenous THs (T
2 , T3 , and T4 ) in a dose-dependent manner. They detected the TR ligand activities of some artificial chemicals suspected to exhibit TH-disrupting activities, as well as TR ligand activity in river water collected downstream of sewage plant discharges, which may have originated from human excrement. Moreover, the responses of XT TR strains to these endogenous and artificial ligands were stronger than those of yeast strains for human TRα and β assays, which had previously been established in our laboratory. These results indicate that the yeast reporter assay system for XT TRα and β is valuable for assessing TR ligand activities in environmental samples that may be particularly potent in amphibians., (Copyright © 2016. Published by Elsevier Ltd.) more...- Published
- 2016
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40. [Role of parathyroid hormone in Klotho-FGF23 system].
- Author
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Kimura T, Shiizaki K, and Kuro-O M
- Subjects
- Animals, Fibroblast Growth Factor-23, Glucuronidase genetics, Humans, Kidney metabolism, Klotho Proteins, Thymus Gland metabolism, Fibroblast Growth Factors metabolism, Glucuronidase metabolism, Parathyroid Hormone metabolism, Signal Transduction
- Abstract
Klotho was originally identified as an anti-aging gene that accelerated aging when disrupted and extended life span when overexpressed in mice. The Klotho gene encodes a single-pass transmembrane protein and is expressed in the kidney and parathyroid gland. Klotho protein functions as an obligate subunit of the receptor for fibroblast growth factor 23 (FGF23). FGF23 is a hormone secreted from osteocytes and osteoblasts and acts on renal tubular cells to promote phosphate excretion into the urine and suppress synthesis of active form of vitamin D (1,25-dihydroxyvitamin D3;1,25(OH)(2)D(3)). Decreased Klotho expression due to the kidney damage including CKD might increase the circulating level of FGF23 and trigger disturbed mineral-bone metabolism, leading to CKD-MBD. Characteristic features of CKD-MBD including hyperphosphatemia, hypocalcemia, and decreased serum 1,25(OH)(2)D(3) can be explained by (mal) adaptation of the Klotho-FGF23 system, which also contributes to the pathophysiology of secondary hyperparathyroidism (SHPT). In addition to its function as a receptor for FGF23, the extracellular domain of Klotho is secreted by ectodomain shedding and functions as a humoral factor that regulates multiple ion channels and transporters. Thus, Klotho has emerged as a key regulator of mineral metabolism in health and disease. more...
- Published
- 2016
- Full Text
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41. Phosphate-Induced Renal Fibrosis Requires the Prolyl Isomerase Pin1.
- Author
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Shen ZJ, Hu J, Shiizaki K, Kuro-o M, and Malter JS
- Subjects
- Animals, Calcium blood, Disease Models, Animal, Disease Progression, Extracellular Matrix pathology, Fibrosis, Kidney Diseases pathology, Macrophage Activation genetics, Macrophage Activation immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, NIMA-Interacting Peptidylprolyl Isomerase, Phosphates administration & dosage, Phosphates blood, Weight Gain genetics, Diet adverse effects, Kidney pathology, Kidney Diseases chemically induced, Kidney Diseases genetics, Peptidylprolyl Isomerase genetics
- Abstract
Tubulo-interstitial fibrosis is a common, destructive endpoint for a variety of kidney diseases. Fibrosis is well correlated with the loss of kidney function in both humans and rodents. The identification of modulators of fibrosis could provide novel therapeutic approaches to reducing disease progression or severity. Here, we show that the peptidyl-prolyl isomerase Pin1 is an important molecular contributor that facilitates renal fibrosis in a well-characterized animal model. While wild-type mice fed a high phosphate diet (HPD) for 8-12 weeks developed calcium deposition, macrophage infiltration and extracellular matrix (ECM) accumulation in the kidney interstitium, Pin1 null mice showed significantly less pathology. The serum Pi in both WT and KO mice were significantly increased by the HPD, but the serum Ca was slightly decreased in KO compared to WT. In addition, both WT and KO HPD mice had less weight gain but exhibited normal organ mass (kidney, lung, spleen, liver and heart). Unexpectedly, renal function was not initially impaired in either genotype irrespective of the HPD. Our results suggest that diet containing high Pi induces rapid renal fibrosis before a significant impact on renal function and that Pin1 plays an important role in the fibrotic process. more...
- Published
- 2016
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42. Construction of sensitive reporter assay yeasts for comprehensive detection of ligand activities of human corticosteroid receptors through inactivation of CWP and PDR genes.
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Ito-Harashima S, Shiizaki K, Kawanishi M, Kakiuchi K, Onishi K, Yamaji R, and Yagi T
- Subjects
- Biological Assay methods, Eplerenone, Humans, Ligands, Mifepristone pharmacology, Spironolactone analogs & derivatives, Spironolactone pharmacology, Yeasts drug effects, Genes, Reporter genetics, Receptors, Glucocorticoid genetics, Receptors, Mineralocorticoid genetics, Receptors, Steroid genetics, Yeasts genetics
- Abstract
Introduction: The glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are members of the nuclear receptor superfamily and ligand-dependent transcription factors, whose major ligands are glucocorticoid and mineralocorticoid, so-called corticosteroids. The corticosteroids are a class of substances that include steroid hormones naturally produced in the adrenal cortex of vertebrates and analogues of these hormones that are synthesized in industry. They are involved in a wide range of physiological processes including stress and immune responses, and the regulation of carbohydrate metabolism, protein catabolism, sodium homeostasis, and inflammation. These substances are potential environmental contaminants because they are clinically consumed in large amounts worldwide. To develop a simple and sensitive bioassay to detect corticosteroids, we newly established reporter assay yeasts expressing human GR and MR., Methods: Ligand responses of the established assay yeasts were improved by forced expression of a human transcription coactivator SRC-1e. Further enhancement of the responses was achieved by inactivating the CWP and PDR genes that encode cell wall mannoproteins and plasma membrane efflux pumps, respectively, which may be attributable to an increased intracellular concentration of ligands., Results: These new assay yeasts were more responsive to both natural and synthetic agonist ligands than the conventional assay yeasts. They detected both agonistic and antagonistic activities of mifepristone, spironolactone, and eplerenone in a receptor-selective manner. They also detected ligand activities contained in oral pharmaceutical tablets and human urine., Discussion: This assay system will be a valuable tool to detect agonists as well as antagonists of corticosteroid receptors, in the fields of drug discovery and the assessment of environmental pollutants., (Copyright © 2015 Elsevier Inc. All rights reserved.) more...
- Published
- 2015
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43. Association between Serum Soluble Klotho Levels and Mortality in Chronic Hemodialysis Patients.
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Otani-Takei N, Masuda T, Akimoto T, Honma S, Watanabe Y, Shiizaki K, Miki T, Kusano E, Asano Y, Kuro-O M, and Nagata D
- Abstract
Klotho is a single-pass transmembrane protein predominantly expressed in the kidney. The extracellular domain of Klotho is subject to ectodomain shedding and is released into the circulation as a soluble form. Soluble Klotho is also generated from alternative splicing of the Klotho gene. In mice, defects in Klotho expression lead to complex phenotypes resembling those observed in dialysis patients. However, the relationship between the level of serum soluble Klotho and overall survival in hemodialysis patients, who exhibit a state of Klotho deficiency, remains to be delineated. Here we prospectively followed a cohort of 63 patients with a mean duration of chronic hemodialysis of 6.7 ± 5.4 years for a median of 65 months. Serum soluble Klotho was detectable in all patients (median 371 pg/mL, interquartile range 309-449). Patients with serum soluble Klotho levels below the lower quartile (<309 pg/mL) had significantly higher cardiovascular and all-cause mortality rates. Furthermore, the higher all-cause mortality persisted even after adjustment for confounders (hazard ratio 4.14, confidence interval 1.29-13.48). We conclude that there may be a threshold for the serum soluble Klotho level associated with a higher risk of mortality. more...
- Published
- 2015
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44. Microbial metabolites of omeprazole activate murine aryl hydrocarbon receptor in vitro and in vivo.
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Shiizaki K, Kawanishi M, and Yagi T
- Subjects
- Animals, Benzoflavones pharmacology, Biotransformation, Cecum drug effects, Cecum metabolism, Cecum microbiology, Cells, Cultured, Culture Media metabolism, Cytochrome P-450 CYP1A1 biosynthesis, Humans, Mice, Omeprazole antagonists & inhibitors, Basic Helix-Loop-Helix Transcription Factors agonists, Omeprazole metabolism, Omeprazole pharmacology, Receptors, Aryl Hydrocarbon agonists, Saccharomyces cerevisiae metabolism
- Abstract
Omeprazole (OME), a proton pump inhibitor used to treat gastritis, is also an aryl hydrocarbon receptor (AhR) activator. OME activates AhR in human hepatocytes and hepatoma cells, but not in mice in vivo or in vitro. We recently discovered that this species-specific difference results from a difference in a few amino acids in the ligand-binding domain of AhR. However, OME activates both mouse and human AhRs in the yeast reporter assay system. Nevertheless, the cause of this discrepancy in OME responses remains unknown. Here, we report that CYP1A1 mRNA expression in mouse cecum was elevated after OME administration, although the mouse is regarded as an OME-unresponsive animal. Using the yeast reporter assay system with human and murine AhRs, we found AhR agonist-like activity in the cecal extracts of OME-treated mice. We speculated that OME metabolites produced by cecal bacteria might activate murine AhRs in vivo. In high-performance liquid chromatography (HPLC) analysis, AhR agonist-like activity of cecal bacterial culture and cecal extracts were detected at the same retention time. AhR agonist-like activity was also detected in the HPLC fractions of yeast culture media containing OME. This unknown substance could induce reporter gene expression via mouse and human AhRs. The agonist-like activity of the OME metabolite was reduced by concomitant α-naphthoflavone exposure. These results indicate that a yeast-generated OME metabolite elicited the response of mouse AhR to OME in the yeast system, and that bacterial OME metabolites may act as AhR ligands in human and mouse intestines., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.) more...
- Published
- 2014
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45. Development of yeast reporter assay for screening specific ligands of retinoic acid and retinoid X receptor subtypes.
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Shiizaki K, Yoshikawa T, Takada E, Hirose S, Ito-Harashima S, Kawanishi M, and Yagi T
- Subjects
- Genes, Reporter genetics, Humans, Ligands, Receptors, Retinoic Acid metabolism, Retinoid X Receptors metabolism, Saccharomyces cerevisiae genetics, Tretinoin metabolism
- Abstract
Introduction: Retinoic acids are essential for embryonic development, tissue organization, and homeostasis and act via retinoic acid receptors (RARs) that form heterodimers with retinoid X receptors (RXRs). Human RARs and RXRs include the three subtypes α, β, and γ, which have varying distributions and physiological functions among human tissues. Recent reports show that subtype-specific binding of several chemicals to RARs or RXRs may lead to endocrine disruption. To evaluate these ligand-like chemicals, convenient assay systems for each receptor subtype are required., Methods: We developed reporter assay yeasts to screen ligands for RXR subtype receptor homodimers. To screen RAR ligands, yeasts were engineered to express RAR subtypes with defective RXRα, which fails to bind to coactivators because of its shortened c-terminus., Results: These assay yeasts were validated using known RXR- and RAR-specific ligands and subtype-specific responses were clearly shown. Subtype-specific ligand activities of the suspected chemical RAR or RXR ligands o-t-butylphenol, triphenyltin chloride, tributyltin chloride, and 4-nonylphenol were determined., Discussion: The present assay yeasts may be valuable tools for subtype-specific assessments of unidentified environmental ligand chemicals and receptor-specific pharmaceuticals., (Copyright © 2014 Elsevier Inc. All rights reserved.) more...
- Published
- 2014
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46. Identification of amino acid residues in the ligand-binding domain of the aryl hydrocarbon receptor causing the species-specific response to omeprazole: possible determinants for binding putative endogenous ligands.
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Shiizaki K, Ohsako S, Kawanishi M, and Yagi T
- Subjects
- Amino Acid Sequence, Animals, Binding Sites, Cells, Cultured, Cytochrome P-450 CYP1A1 antagonists & inhibitors, Cytochrome P-450 CYP1A1 genetics, Cytochrome P-450 CYP1A1 physiology, Guinea Pigs, Humans, Ligands, Mice, Molecular Sequence Data, Polychlorinated Dibenzodioxins pharmacology, Receptors, Aryl Hydrocarbon metabolism, Species Specificity, Omeprazole pharmacology, Proton Pump Inhibitors pharmacology, Receptors, Aryl Hydrocarbon chemistry
- Abstract
Omeprazole (OME) induces the expression of genes encoding drug-metabolizing enzymes, such as CYP1A1, via activation of the aryl hydrocarbon receptor (AhR) both in vivo and in vitro. However, the precise mechanism of OME-mediated AhR activation is still under investigation. While elucidating species-specific susceptibility to dioxin, we found that OME-mediated AhR activation was mammalian species specific. Moreover, we previously reported that OME has inhibitory activity toward CYP1A1 enzymes. From these observations, we speculated that OME-mediated AhR target gene transcription is due to AhR activation by increasing amounts of putative AhR ligands in serum by inhibition of CYP1A1 activity. We compared the amino acid sequences of OME-sensitive rabbit AhR and nonsensitive mouse AhR to identify the residues responsible for the species-specific response. Chimeric AhRs were constructed by exchanging domains between mouse and rabbit AhRs to define the region required for the response to OME. OME-mediated transactivation was observed only with the chimeric AhR that included the ligand-binding domain (LBD) of the rabbit AhR. Site-directed mutagenesis revealed three amino acids (M328, T353, and F367) in the rabbit AhR that were responsible for OME-mediated transactivation. Replacing these residues with those of the mouse AhR abolished the response of the rabbit AhR. In contrast, substitutions of these amino acids with those of the rabbit AhR altered nonsensitive mouse AhR to become sensitive to OME. These results suggest that OME-mediated AhR activation requires a specific structure within LBD that is probably essential for binding with enigmatic endogenous ligands. more...
- Published
- 2014
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47. ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice.
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Ikuta T, Kobayashi Y, Kitazawa M, Shiizaki K, Itano N, Noda T, Pettersson S, Poellinger L, Fujii-Kuriyama Y, Taniguchi S, and Kawajiri K
- Subjects
- Adenomatous Polyposis Coli immunology, Adenomatous Polyposis Coli pathology, Amino Acid Chloromethyl Ketones pharmacology, Animals, Basic Helix-Loop-Helix Transcription Factors genetics, CARD Signaling Adaptor Proteins genetics, Caspase 1 metabolism, Caspase Inhibitors pharmacology, Cecal Neoplasms immunology, Cell Line, Enzyme Activation, Female, Germ-Free Life, Inflammasomes immunology, Inflammation immunology, Inflammation metabolism, Interleukin-1beta immunology, Interleukin-6 immunology, Intestines immunology, Intestines microbiology, Macrophages immunology, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor Cross-Talk, Receptors, Aryl Hydrocarbon genetics, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Signal Transduction drug effects, Tyrphostins pharmacology, beta Catenin immunology, beta Catenin metabolism, Basic Helix-Loop-Helix Transcription Factors metabolism, CARD Signaling Adaptor Proteins metabolism, Cecal Neoplasms pathology, Inflammation pathology, Receptors, Aryl Hydrocarbon metabolism
- Abstract
The aryl hydrocarbon receptor (AhR) plays a suppressive role in cecal carcinogenesis by CUL4B/AhR-mediated ubiquitylation and degradation of β-catenin, which is activated by xenobiotics and natural ligands. AhR-deficient (AhR(-)(/-)) mice develop cecal tumors with severe inflammation. To elucidate whether the tumors develop autonomously in AhR(-/-) mice due to impaired β-catenin degradation or in association with accelerated inflammation, we performed two kinds of experiments using germ-free (GF) AhR(-/-) mice and compound mutant mice lacking genes for AhR and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which plays an essential role in caspase-1 activation in inflammasomes. Both GF AhR(-/-) and AhR(-/-)•ASC(-/-) mice showed considerably reduced tumor development compared with that in AhR(-/-) mice albeit in a 'cancer-prone' state with aberrant β-catenin accumulation. Blocking of the interleukin (IL)-1β signaling pathway by treatment with a caspase-1 inhibitor, YVAD, reduced cecal tumorigenesis in AhR(-/-) mice. Signal transducers and activators of transcription 3 (STAT3) activation was detected in the cecal epithelium of the AhR(-/-) mice due to enhanced IL-6 production. An inhibitor of the STAT3 signaling pathway, AG490 suppressed the tumor formation. ASC-mediated inflammation was also found to play a critical role in tumor development in Apc(Min/+) mice, a mouse model of familial adenomatous polyposis. Collectively, these results revealed an important role of the bacteria-triggered or ASC-mediated inflammation signaling pathway in the intestinal tumorigenesis of mice and suggest a possible chemical therapeutic intervention, including AhR ligands and inhibitors of the inflammation pathway. more...
- Published
- 2013
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48. Pin1 null mice exhibit low bone mass and attenuation of BMP signaling.
- Author
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Shen ZJ, Hu J, Ali A, Pastor J, Shiizaki K, Blank RD, Kuro-o M, and Malter JS
- Subjects
- Animals, Bone Morphogenetic Protein 2 metabolism, Bone and Bones diagnostic imaging, Calcium blood, Cell Differentiation, Cholecalciferol blood, Gene Expression, Mice, Mice, Knockout, NIMA-Interacting Peptidylprolyl Isomerase, Osteoclasts cytology, Osteoclasts metabolism, Peptidylprolyl Isomerase metabolism, Protein Binding, Radiography, Smad5 Protein metabolism, Bone Density genetics, Bone Development genetics, Bone Morphogenetic Proteins metabolism, Bone and Bones metabolism, Peptidylprolyl Isomerase genetics, Signal Transduction
- Abstract
Bone is constantly formed and resorbed throughout life by coordinated actions of osteoblasts and osteoclasts. However, the molecular mechanisms involved in osteoblast function remain incompletely understood. Here we show, for the first time, that the peptidyl-prolyl isomerase PIN1 controls the osteogenic activity of osteoblasts. Pin1 null mice exhibited an age-dependent decrease in bone mineral density and trabecular bone formation without alteration in cortical bone. Further analysis identified a defect in BMP signaling in Pin1 null osteoblasts but normal osteoclast function. PIN1 interacted with SMAD5 and was required for the expression by primary osteoblasts of osteoblast specific transcription factors (CBFA1 and OSX), ECM (collagen I and OCN) and the formation of bone nodules. Our results thus uncover a novel aspect of the molecular underpinning of osteoblast function and identify a new therapeutic target for bone diseases. more...
- Published
- 2013
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49. Dioxin suppresses benzo[a]pyrene-induced mutations and DNA adduct formation through cytochrome P450 1A1 induction and (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide inactivation in human hepatoma cells.
- Author
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Shiizaki K, Kawanishi M, and Yagi T
- Subjects
- Animals, Cell Line, Tumor, Humans, Mice, Mutation drug effects, 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide metabolism, Carcinoma, Hepatocellular genetics, Cytochrome P-450 CYP1A1 biosynthesis, DNA Adducts, Dioxins pharmacology, Polychlorinated Dibenzodioxins pharmacology
- Abstract
Benzo[a]pyrene (BaP) is metabolically activated by cytochrome P450 enzymes, and forms DNA adduct leading to mutations. Cytochrome P450 1A1 plays a central role in this activation step, and this enzyme is strongly induced by chemical agents that bind to the aryl hydrocarbon receptor (AhR), which is also known as a dioxin receptor. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR ligand has not been shown to form any DNA adduct, but has a possibility to aggravate the toxicity of precarcinogenic polycyclic hydrocarbons through the induction of metabolic enzymes. We treated human hepatoma cells (HepG2) with TCDD, and subsequently exposed them to BaP to elucidate the synergistic effects on mutations. Surprisingly, mutant frequency induced by BaP at the hypoxanthine-guanine phosphribosyltransferase (HPRT) locus was decreased by pretreatment with TCDD. In correlation with decrease in the mutant frequencies, BaP-DNA adduct formation was also decreased by TCDD pretreatment. This suppressive effect of TCDD was more potent when the cells were exposed to (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), a reactive metabolic intermediate of BaP. Among the enzymes catalyzing BaP oxidation and conjugation, cytochrome P450 1A1, 1A2, 3A4 and UDP-glucuronosyltransferase 1A1 mRNAs were induced by the exposure to TCDD. In cytochrome P450 1A1-deficient murine cells and cytochrome P450 1A1-uninducible human cells, TCDD could not suppress BPDE-DNA adduct formation. Further experiments using "Tet-On" cytochrome P450 1A1-overexpressing cells and a recombinant cytochrome P450 1A1 enzyme demonstrated that this is the key enzyme involved in the biotransformation of BaP, that is, both production and inactivation of BPDE. We conclude that TCDD-induced cytochrome P450 catalyzes the metabolism of BPDE to as yet-unidentified products that are not apparently DNA-reactive, thereby reducing mutations in hepatoma cells., (Copyright © 2012 Elsevier B.V. All rights reserved.) more...
- Published
- 2013
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50. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.
- Author
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Hu MC, Shiizaki K, Kuro-o M, and Moe OW
- Subjects
- Animals, Bone and Bones physiology, Fibroblast Growth Factor-23, Homeostasis physiology, Humans, Intestines physiology, Kidney physiology, Klotho Proteins, Endocrine System physiology, Fibroblast Growth Factors physiology, Glucuronidase physiology, Minerals metabolism
- Abstract
The metabolically active and perpetually remodeling calcium phosphate-based endoskeleton in terrestrial vertebrates sets the demands on whole-organism calcium and phosphate homeostasis that involves multiple organs in terms of mineral flux and endocrine cross talk. The fibroblast growth factor (FGF)-Klotho endocrine networks epitomize the complexity of systems biology, and specifically, the FGF23-αKlotho axis highlights the concept of the skeleton holding the master switch of homeostasis rather than a passive target organ as hitherto conceived. Other than serving as a coreceptor for FGF23, αKlotho circulates as an endocrine substance with a multitude of effects. This review covers recent data on the physiological regulation and function of the complex FGF23-αKlotho network. Chronic kidney disease is a common pathophysiological state in which FGF23-αKlotho, a multiorgan endocrine network, is deranged in a self-amplifying vortex resulting in organ dysfunction of the utmost severity that contributes to its morbidity and mortality. more...
- Published
- 2013
- Full Text
- View/download PDF
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