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Khairallah P, Cortez NE, McMahon DJ, Sammons S, Agarwal S, Crew RJ, Cohen DJ, Dube GK, Mohan S, Chang JH, Morris HK, Fernandez HE, Aponte MA, Adebayo AO, Aghi A, Zaninotto M, Plebani M, Tripepi G, Gallieni M, Cosma C, Fusaro M, Nickolas TL. Calcitriol supplementation after kidney transplantation: results of a double-blinded, randomized, placebo-controlled trial. J Bone Miner Res 2025; 40:603-616. [PMID: 40089990 PMCID: PMC12103722 DOI: 10.1093/jbmr/zjaf044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 02/12/2025] [Accepted: 02/28/2025] [Indexed: 03/18/2025]
Abstract
A significant number of kidney transplant recipients have low BMD. We hypothesized that calcitriol administration over the first year posttransplantation would protect the cortical skeleton in recipients managed without corticosteroids by suppressing PTH and bone remodeling. In this double-blind, placebo-controlled trial, 67 participants aged ≥18 yr on corticosteroid-sparing immunosuppressive regimen were randomized to daily calcitriol 0.5 μg or placebo for 12 mo after transplantation. The primary endpoint was the percent change in cortical density at the radius and tibia from pre- to postcalcitriol treatment compared to placebo as measured by HR-pQCT. Areal BMD was measured by DXA. Cortical and trabecular volumetric BMD and microarchitecture and total estimated bone strength were measured by HR-pQCT. Blood samples for bone metabolic markers were obtained at baseline, 1- and 12 mo. All primary analyses were intent to treat. Safety was assessed for hypercalcemia and progression of vascular calcifications. Thirty-two participants received calcitriol and 29 received placebo; 27 and 27 participants completed the study, respectively. Most participants were male and Caucasian. Baseline Z-scores at all sites were within 0.5 SD of the general population. At 12 mo posttransplantation, there were no between-group differences in areal BMD, volumetric BMD, microarchitecture or bone strength, or serum levels of bone markers. Participants with versus without bone loss had a blunted anabolic response over 12 mo measured by serum bone markers. Hypercalcemia was higher in the calcitriol group compared to placebo (p < .001). No changes in arterial calcification scores were observed. In this randomized placebo-controlled study of calcitriol administration in kidney transplant recipients on corticosteroid-sparing immunosuppression, calcitriol did not improve bone quality and strength but was associated with higher rates of hypercalcemia.
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Affiliation(s)
- Pascale Khairallah
- Department of Medicine, University of California, San Francisco, CA, 94110, United States
| | - Natalia E Cortez
- Department of Clinical and Biological Sciences, University of Turin, Turin, 10124, Italy
| | - Donald J McMahon
- Department of Medicine, Columbia University, New York, NY, 10032, United States
| | - Stephen Sammons
- Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT, 84112, United States
| | - Sanchita Agarwal
- Department of Medicine, Columbia University, New York, NY, 10032, United States
| | - R John Crew
- Department of Medicine, Columbia University, New York, NY, 10032, United States
| | - David J Cohen
- Department of Medicine, Columbia University, New York, NY, 10032, United States
| | - Geoffrey K Dube
- Department of Medicine, Columbia University, New York, NY, 10032, United States
| | - Sumit Mohan
- Department of Medicine, Columbia University, New York, NY, 10032, United States
| | - Jae-Hyung Chang
- Department of Medicine, Columbia University, New York, NY, 10032, United States
| | - Heather K Morris
- Department of Medicine, Columbia University, New York, NY, 10032, United States
| | - Hilda E Fernandez
- Department of Medicine, Columbia University, New York, NY, 10032, United States
| | | | | | | | - Martina Zaninotto
- QI.LAB.MED, Spin-off of the University of Padova, Padua, 35122, Italy
| | - Mario Plebani
- Department of Medicine, University of Padova, Padua, 35122, Italy
| | - Giovanni Tripepi
- National Research Council (CNR), Institute of Clinical Physiology (IFC), Pisa, 56124, Italy
| | - Maurizio Gallieni
- Department of Biomedical and Clinical Sciences, University of Milano, Milan, 20157, Italy
| | - Chiara Cosma
- Department of Medicine, University of Padova, Padua, 35122, Italy
| | - Maria Fusaro
- Department of Medicine, University of Padova, Padua, 35122, Italy
- National Research Council (CNR), Institute of Clinical Physiology (IFC), Pisa, 56124, Italy
| | - Thomas L Nickolas
- Division of Bone and Mineral Diseases, Washington University, St. Louis, MO 63110, United States
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Luo ZH, Ma JX, Zhang W, Tian AX, Gong SW, Li Y, Lai YX, Ma XL. Alterations in the microenvironment and the effects produced of TRPV5 in osteoporosis. J Transl Med 2023; 21:327. [PMID: 37198647 DOI: 10.1186/s12967-023-04182-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 05/05/2023] [Indexed: 05/19/2023] Open
Abstract
The pathogenesis of osteoporosis involves multiple factors, among which alterations in the bone microenvironment play a crucial role in disrupting normal bone metabolic balance. Transient receptor potential vanilloid 5 (TRPV5), a member of the TRPV family, is an essential determinant of the bone microenvironment, acting at multiple levels to influence its properties. TRPV5 exerts a pivotal influence on bone through the regulation of calcium reabsorption and transportation while also responding to steroid hormones and agonists. Although the metabolic consequences of osteoporosis, such as loss of bone calcium, reduced mineralization capacity, and active osteoclasts, have received significant attention, this review focuses on the changes in the osteoporotic microenvironment and the specific effects of TRPV5 at various levels.
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Affiliation(s)
- Zhi-Heng Luo
- Tianjin Hospital, Tianjin University, Jie Fang Nan Road 406, Tianjin, 300211, People's Republic of China
- Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin Hospital, Tianjin, 300050, People's Republic of China
| | - Jian-Xiong Ma
- Tianjin Hospital, Tianjin University, Jie Fang Nan Road 406, Tianjin, 300211, People's Republic of China
- Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin Hospital, Tianjin, 300050, People's Republic of China
| | - Wei Zhang
- Centre for Translational Medicine Research & Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 1068 Xue Yuan Avenue, Shenzhen University Town, Shenzhen, 518055, Guangdong, People's Republic of China
| | - Ai-Xian Tian
- Tianjin Hospital, Tianjin University, Jie Fang Nan Road 406, Tianjin, 300211, People's Republic of China
- Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin Hospital, Tianjin, 300050, People's Republic of China
| | - Shu-Wei Gong
- Tianjin Hospital, Tianjin University, Jie Fang Nan Road 406, Tianjin, 300211, People's Republic of China
- Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin Hospital, Tianjin, 300050, People's Republic of China
| | - Yan Li
- Tianjin Hospital, Tianjin University, Jie Fang Nan Road 406, Tianjin, 300211, People's Republic of China
- Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin Hospital, Tianjin, 300050, People's Republic of China
| | - Yu-Xiao Lai
- Centre for Translational Medicine Research & Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 1068 Xue Yuan Avenue, Shenzhen University Town, Shenzhen, 518055, Guangdong, People's Republic of China.
| | - Xin-Long Ma
- Tianjin Hospital, Tianjin University, Jie Fang Nan Road 406, Tianjin, 300211, People's Republic of China.
- Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin Hospital, Tianjin, 300050, People's Republic of China.
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Tang J, Li Z, Qiang C, Han Y, Yang L, Zhu L, Dang T, Chen G, Ye Y. A long-wavelength mitochondria-targeted fluorescent probe for imaging of peroxynitrite during dexamethasone treatment. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2023; 292:122429. [PMID: 36750010 DOI: 10.1016/j.saa.2023.122429] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 01/12/2023] [Accepted: 01/30/2023] [Indexed: 06/18/2023]
Abstract
Peroxynitrite (ONOO-), as a strong oxidizing reactive nitrogen substance (RNS), is generated endogenously by cells. Its visualization research is crucial to understand relevant disease processes. Herein, we reported a long-wavelength mitochondria-targeted fluorescence "turn on" probe TL. The probe TL could react with ONOO- by using 4-(Bromomethyl)benzeneboronic as a reactive site, which exhibited outstanding characteristics for detection of ONOO-, thus improving response time (about 50 s), sensitivity (DL, 10.1 nM), and emission wavelength (667 nm). Besides, TL displayed well mitochondria targeting and biological visualizing of exogenous and endogenous ONOO- in biological systems. Finally, TL was used to monitor high concentration of dexamethasone-induced an up-regulation of ONOO-. This indicated that TL has excellent potential to study the fluctuation of ONOO- in the physiological and pathological system.
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Affiliation(s)
- Jun Tang
- School of Chemistry and Materials Engineering, Xinxiang University, Xinxiang, Henan 453003, China.
| | - Ziyi Li
- School of Chemistry and Materials Engineering, Xinxiang University, Xinxiang, Henan 453003, China
| | - Chuchu Qiang
- School of Chemistry and Materials Engineering, Xinxiang University, Xinxiang, Henan 453003, China
| | - Yan Han
- School of Chemistry and Materials Engineering, Xinxiang University, Xinxiang, Henan 453003, China
| | - Lifang Yang
- School of Chemistry and Materials Engineering, Xinxiang University, Xinxiang, Henan 453003, China
| | - Li Zhu
- School of Chemistry and Materials Engineering, Xinxiang University, Xinxiang, Henan 453003, China
| | - Tan Dang
- School of Chemistry and Materials Engineering, Xinxiang University, Xinxiang, Henan 453003, China
| | - Gairong Chen
- School of Chemistry and Materials Engineering, Xinxiang University, Xinxiang, Henan 453003, China
| | - Yong Ye
- Green Catalysis Center, and College of Chemistry, Zhengzhou University, Zhengzhou 450001, China
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Ozdemir K, Saruhan E, Benli TK, Kaya G, Meral O, Yavuz MY, Sen T, Kiziloglu I, Kavak S. Comparison of trace element (selenium, iron), electrolyte (calcium, sodium), and physical activity levels in COVID-19 patients before and after the treatment. J Trace Elem Med Biol 2022; 73:127015. [PMID: 35700624 PMCID: PMC9150912 DOI: 10.1016/j.jtemb.2022.127015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 05/11/2022] [Accepted: 05/28/2022] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), a worldwide health problem, is the cause of 2019 coronavirus disease. This study aimed to compare the trace element (selenium and iron), electrolyte (calcium and sodium), and physical activity levels of COVID-19 patients before and after COVID-19 treatment. METHOD This prospective study was conducted in patients diagnosed with COVID-19 (n = 15). Trace element (selenium and iron), electrolyte (calcium and sodium), and physical activity levels of the patients were compared before and after the treatment. RESULT Most of patients had selenium deficiency (86.7 %), iron deficiency (73.3 %), calcium deficiency (66.7 %) and sodium deficiency (46.7 %) before COVID-19 treatment. The most important improvements were seen in iron deficiency (from 73.3 % to 26.7 %) and sodium deficiency (from 46.7 % to 13.3 %) after the treatment. Selenium, iron, calcium, and sodium levels of the patients were significantly higher after the treatment (p < 0.05). The patients had low physical activity before and after COVID-19 treatment. In addition, no statistically significant difference was found in the comparison of physical activity levels (p > 0.05). CONCLUSION This study indicated that selenium, iron, calcium, and sodium levels and deficiencies might improve after treating patients with COVID-19. However, the results of this study showed that the physical activity levels of COVID-19 patients might remain stable and low throughout the treatment process.
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Affiliation(s)
- Kadirhan Ozdemir
- Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Izmir Bakircay University, Izmir, Turkey.
| | - Ercan Saruhan
- Department of Medical Biochemistry, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey.
| | - Tuba Kaya Benli
- Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Izmir Bakircay University, Izmir, Turkey.
| | - Gozde Kaya
- Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Izmir Bakircay University, Izmir, Turkey.
| | - Orhan Meral
- Department of Forensic Medicine, Faculty of Medicine, Izmir Bakircay University, Izmir, Turkey.
| | - Melike Yuksel Yavuz
- Department of Work and Occupational Diseases, Dokuz Eylul University Research and Application Hospital, Izmir, Turkey.
| | - Teoman Sen
- Department of Pediatric Surgery, Faculty of Medicine, Izmir Bakircay University, Izmir, Turkey.
| | - Ilker Kiziloglu
- Department of General Surgery, Faculty of Medicine, Izmir Bakircay University, Izmir, Turkey.
| | - Servet Kavak
- Department of Biophysics, Faculty of Medicine, Izmir Bakircay University, Izmir, Turkey.
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Khattar V, Wang L, Peng JB. Calcium selective channel TRPV6: Structure, function, and implications in health and disease. Gene 2022; 817:146192. [PMID: 35031425 PMCID: PMC8950124 DOI: 10.1016/j.gene.2022.146192] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 12/20/2021] [Accepted: 01/07/2022] [Indexed: 12/14/2022]
Abstract
Calcium-selective channel TRPV6 (Transient Receptor Potential channel family, Vanilloid subfamily member 6) belongs to the TRP family of cation channels and plays critical roles in transcellular calcium (Ca2+) transport, reuptake of Ca2+ into cells, and maintaining a local low Ca2+ environment for certain biological processes. Recent crystal and cryo-electron microscopy-based structures of TRPV6 have revealed mechanistic insights on how the protein achieves Ca2+ selectivity, permeation, and inactivation by calmodulin. The TRPV6 protein is expressed in a range of epithelial tissues such as the intestine, kidney, placenta, epididymis, and exocrine glands such as the pancreas, prostate and salivary, sweat, and mammary glands. The TRPV6 gene is a direct transcriptional target of the active form of vitamin D and is efficiently regulated to meet the body's need for Ca2+ demand. In addition, TRPV6 is also regulated by the level of dietary Ca2+ and under physiological conditions such as pregnancy and lactation. Genetic models of loss of function in TRPV6 display hypercalciuria, decreased bone marrow density, deficient weight gain, reduced fertility, and in some cases alopecia. The models also reveal that the channel plays an indispensable role in maintaining maternal-fetal Ca2+ transport and low Ca2+ environment in the epididymal lumen that is critical for male fertility. Most recently, loss of function mutations in TRPV6 gene is linked to transient neonatal hyperparathyroidism and early onset chronic pancreatitis. TRPV6 is overexpressed in a wide range of human malignancies and its upregulation is strongly correlated to tumor aggressiveness, metastasis, and poor survival in selected cancers. This review summarizes the current state of knowledge on the expression, structure, biophysical properties, function, polymorphisms, and regulation of TRPV6. The aberrant expression, polymorphisms, and dysfunction of this protein linked to human diseases are also discussed.
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Affiliation(s)
- Vinayak Khattar
- Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, Department of Urology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Lingyun Wang
- Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, Department of Urology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Ji-Bin Peng
- Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, Department of Urology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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Abstract
As the world's population ages, the treatment of osteoporosis is a major problem to be addressed. The cause of osteoporosis remains unclear. Ca2+ is not only an important component of bones but also plays a key role in osteoporosis treatment. Transient receptor potential vanilloid (TRPV) channels are one of the TRP channel families that is widely distributed in various organs, playing an important role in the physiological regulation of the human body. Bone formation and bone absorption may require Ca2+ transport via TRPV channels. It has been proven that the TRPV subtypes 1, 2, 4, 5, 6 (TRPV1, TRPV2, TRPV4, TRPV5, TRPV6) may affect bone metabolism balance through selective regulation of Ca2+. They significantly regulate osteoblast/osteoclast proliferation, differentiation and function. The purpose of this review is to explore the mechanisms of TRPV channels involved in regulation of the differentiation of osteoblasts and osteoclasts, as well as to discuss the latest developments in current researches, which may provide new clues and directions for an in-depth study of osteoporosis and other related bone metabolic diseases.
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Liao F, Zhu Z, Xiao C, Yuan J, Geng B, Hu J. Hydrogen sulfide inhibits calcium and phosphorus loss after fracture by negatively regulating glucocorticoid/glucocorticoid receptor α. Life Sci 2021; 274:119363. [PMID: 33737083 DOI: 10.1016/j.lfs.2021.119363] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/19/2021] [Accepted: 03/11/2021] [Indexed: 11/30/2022]
Abstract
AIMS Post-fracture calcium and phosphorus excretion is greater than influx, which might be caused by stress. Glucocorticoid is known to enhance calcium and phosphorous excretion, and hydrogen sulfide (H2S) has been shown to exert inhibitory effects on glucocorticoid. Therefore, this study explored whether H2S could inhibit calcium and phosphorus loss after fracture by regulating glucocorticoid and/or its receptor. MAIN METHODS The following properties were analyzed in rats with femur fractures: serum and urinary calcium and phosphorus (by colorimetry); bone turnover markers alkaline phosphatase, serum type 1 collagen amino terminal peptide, type 1 procollagen carboxy terminal peptide, and anti-tartaric acid phosphatase (by ELISA); factors related to calcium-phosphorus metabolism including glucocorticoid, parathyroid hormone, calcitonin, fibroblast growth factor 23, and 1,25(OH)2D3 (by ELISA); and sulfhydration of glucocorticoid receptor α in the kidney (by immunoprecipitation linked biotin-switch assay), after supplementing with mifepristone, the H2S donor GYY4137 or H2S generating enzyme inhibitors aminooxyacetic acid and propargylglycine. KEY FINDINGS Serum H2S decreased and glucocorticoid secretion increased in rats post-fracture. The glucocorticoid receptor inhibitor mifepristone partly blunted calcium and phosphorus loss. Furthermore, supplementation with GYY4137 reduced glucocorticoid secretion; inhibited glucocorticoid receptor α activity by sulfhydration; downregulated vitamin D 1α-hydroxylase expression; and upregulated 24-hydroxylase, calbindin-D28k, and sodium phosphate cotransporter 2a expression in the kidney; thereby inhibiting calcium and phosphorus loss induced by fracture. Moreover, inhibiting endogenous H2S generation showed opposite effects. SIGNIFICANCE Our findings suggest that H2S antagonized calcium and phosphorus loss after fracture by reducing glucocorticoid secretion and inhibiting glucocorticoid receptor α activity by sulfhydration.
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Affiliation(s)
- Feng Liao
- Department of Orthopaedics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China
| | - Zongdong Zhu
- Department of Orthopaedics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China
| | - Chengwei Xiao
- Department of Orthopaedics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China
| | - Jiabin Yuan
- Department of Orthopaedics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China
| | - Bin Geng
- Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing 102308, PR China.
| | - Jiang Hu
- Department of Orthopaedics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, PR China.
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Areco VA, Kohan R, Talamoni G, Tolosa de Talamoni NG, Peralta López ME. Intestinal Ca 2+ absorption revisited: A molecular and clinical approach. World J Gastroenterol 2020; 26:3344-3364. [PMID: 32655262 PMCID: PMC7327788 DOI: 10.3748/wjg.v26.i24.3344] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/11/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Ca2+ has an important role in the maintenance of the skeleton and is involved in the main physiological processes. Its homeostasis is controlled by the intestine, kidney, bone and parathyroid glands. The intestinal Ca2+ absorption occurs mainly via the paracellular and the transcellular pathways. The proteins involved in both ways are regulated by calcitriol and other hormones as well as dietary factors. Fibroblast growth factor 23 (FGF-23) is a strong antagonist of vitamin D action. Part of the intestinal Ca2+ movement seems to be vitamin D independent. Intestinal Ca2+ absorption changes according to different physiological conditions. It is promoted under high Ca2+ demands such as growth, pregnancy, lactation, dietary Ca2+ deficiency and high physical activity. In contrast, the intestinal Ca2+ transport decreases with aging. Oxidative stress inhibits the intestinal Ca2+ absorption whereas the antioxidants counteract the effects of prooxidants leading to the normalization of this physiological process. Several pathologies such as celiac disease, inflammatory bowel diseases, Turner syndrome and others occur with inhibition of intestinal Ca2+ absorption, some hypercalciurias show Ca2+ hyperabsorption, most of these alterations are related to the vitamin D endocrine system. Further research work should be accomplished in order not only to know more molecular details but also to detect possible therapeutic targets to ameliorate or avoid the consequences of altered intestinal Ca2+ absorption.
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Affiliation(s)
- Vanessa A Areco
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
| | - Romina Kohan
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
| | - Germán Talamoni
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
| | - Nori G Tolosa de Talamoni
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
| | - María E Peralta López
- Laboratorio “Dr. Fernando Cañas”, Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Córdoba 5000, Argentina
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Povaliaeva AA, Pigarova EA, Dzeranova LK, Rozhinskaya LY, Mel'nichenko GA. [Vitamin D metabolism in hypercorticism and acromegaly]. ACTA ACUST UNITED AC 2020; 65:444-450. [PMID: 33351327 DOI: 10.14341/probl12099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 01/22/2020] [Indexed: 11/06/2022]
Abstract
Due to the high prevalence of low vitamin D levels in the overwhelming majority of regions of the world and discovery of extra-skeletal effects of vitamin D, the issue of maintaining adequate levels of vitamin D in the blood remains extremely relevant, especially in people with high risk of severe deficiency. To date, few studies have been performed on the features of vitamin D metabolism in disorders such as hypercorticism and acromegaly. However, vitamin D deficiency in such patients, according to available literature, may be more widespread and more pronounced than in general population. It is now recommended to use standard prophylactic and therapeutic doses of vitamin D for the treatment of these diseases, which may not satisfy the therapeutic goals specific to each disease. This review provides information on normal vitamin D metabolism, as well as literature data on the possible relationship and mutual influence between these endocrinopathies and vitamin D metabolism.
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Dexamethasone Treatment Increases the Intracellular Calcium Level Through TRPV6 in A549 Cells. Int J Mol Sci 2020; 21:ijms21031050. [PMID: 32033337 PMCID: PMC7037905 DOI: 10.3390/ijms21031050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 02/03/2020] [Accepted: 02/04/2020] [Indexed: 12/04/2022] Open
Abstract
This study investigated the effect of dexamethasone (DEX) on intracellular calcium levels and the expressions of transient receptor potential cation channel subcomponent V member 6 (TRPV6), sodium-calcium exchanger 1 (NCX1), and plasma membrane calcium ATPase 1 (PMCA1) in A549 cells. The intracellular calcium level, by using the calcium indicator pGP-CMV-GCaMP6f, increased following DEX treatment for 6, 12, and 24 h in A549 cells. In addition, Rhod-4 assay after DEX treatment for 24 h showed that DEX increased the level of intracellular calcium. The expression of the calcium influx TRPV6 gene significantly increased, whereas the expressions of the calcium outflow NCX1 and PMCA1 genes significantly decreased with DEX treatment. The mRNA levels of surfactant protein genes SFTPA1, SFTPB, SFTPC, and SFTPD and the secreted airway mucin genes MUC1 and MUC5AC were investigated by treating cells with DEX. The DEX treatment decreased the mRNA levels of SFTPA1 and SFTPB but increased the mRNA levels of SFTPC and SFTPD. The MUC1 mRNA level was increased by DEX treatment, whereas MUC5AC mRNA was significantly decreased. These results indicate that DEX influences the intracellular calcium level through TRPV6, and affects pulmonary surfactant genes and secreted airway mucin genes in A549 cells.
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Evolution of secondary hyperparathyroidism in patients following return to hemodialysis after kidney transplant failure. Nephrol Ther 2019; 16:118-123. [PMID: 31791898 DOI: 10.1016/j.nephro.2019.07.328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 07/15/2019] [Accepted: 07/17/2019] [Indexed: 01/16/2023]
Abstract
INTRODUCTION Severe uncontrolled secondary hyperparathyroidism and kidney transplantation history are both risk factors for fractures in hemodialyzed patients. Moreover, patients who return to dialysis after transplant failure have more severe infections/anemia and higher mortality risk than transplant-naive patients starting dialysis with native kidneys. In this context, our aim was to test the hypothesis that transplant failure patients have more secondary hyperparathyroidism than transplant-naive patients. METHODS We retrospectively compared 29 transplant failure patients to 58 transplant-naive patients matched for age, sex, chronic kidney disease duration and diabetes condition (1 transplant failure/2 transplant-naive ratio), who started dialysis between 2010 and 2014. Clinical and biological data were collected at baseline, 6 and 12 months. FINDINGS At baseline, neither serum parathyroid hormone (transplant-naive: 386±286pg/mL; transplant failure: 547±652pg/mL) nor serum 25-hydroxyvitamin D (transplant-naive: 27.8±17.0μg/L, transplant failure: 31.1±14.9μg/L) differed between groups. However, serum parathyroid hormone at 12 months and the proportion of patients with uncontrolled secondary hyperparathyroidism (parathyroid hormone>540pg/mL, KDIGO criteria) were significantly higher in transplant failure than in transplant-naive (parathyroid hormone: 286±205 vs. 462±449, P<0.01; uncontrolled secondary hyperparathyroidism: 30% vs. 13%, P<0.01, respectively). Within the transplant failure group, patients with uncontrolled secondary hyperparathyroidism at 12 months were younger than patients with normal or low parathyroid hormone. DISCUSSION This retrospective and monocentric study suggests that transplant failure patients are more likely to develop secondary hyperparathyroidism. Thus, finding high serum parathyroid hormone in young transplant failure patients, who are expected to undergo further transplantations, should incite physicians to treat early and more aggressively this complication.
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Park SY, Yoo YM, Jung EM, Jeung EB. Distribution of and steroid hormone effects on calbindin-D 9k in the immature rat brain. Brain Res Bull 2019; 152:225-235. [PMID: 31357009 DOI: 10.1016/j.brainresbull.2019.07.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 07/08/2019] [Accepted: 07/23/2019] [Indexed: 01/06/2023]
Abstract
Calbindin-D9k (CaBP-9k), one of the major calcium-binding and calcium-buffering proteins, is important in the physiological functioning of organs. The neuroanatomical localization of CaBP-9k in the rodent brain has not been reported; thus, this study investigated the neuroanatomical distribution of CaBP-9k and the regulation of CaBP-9k expression on steroid hormones in the immature rat brain. To confirm the influence of steroid hormones on CaBP-9k expression, immature female rats were injected for 5 days with estrogen (E2), progesterone (P4), dexamethasone (DEX), and their antagonists (ICI 182, 780 and RU 486). The localization and expression of the CaBP-9k protein in brain regions were identified by immunofluorescence and western blot assays, respectively. We observed that CaBP-9k expression was especially strong in hypothalamus, cerebellum, and brain stem. In addition, CaBP-9k was colocalized with mature-, GABAergic, dopaminergic, and oxytocinergic neurons. We also observed that the CaBP-9k protein level was significantly increased by P4 and reversed by antagonist RU 486 treatment in immature rat brain. In summary, CaBP-9k positive cells have a wide distribution in the immature rat brain, and CaBP-9k expression is regulated by P4. We suggest that CaBP-9k expression regulated by steroid hormone may serve as an important regulator of cytosolic calcium concentration in the brain.
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Affiliation(s)
- Seon Young Park
- Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 362-763, Republic of Korea
| | - Yeong-Min Yoo
- Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 362-763, Republic of Korea
| | - Eui-Man Jung
- Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 362-763, Republic of Korea.
| | - Eui-Bae Jeung
- Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 362-763, Republic of Korea.
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Prevalence and Risk Factors of Reduced Bone Mineral Density in Systemic Lupus Erythematosus Patients: A Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:3731648. [PMID: 30915352 PMCID: PMC6402203 DOI: 10.1155/2019/3731648] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 01/22/2019] [Indexed: 01/09/2023]
Abstract
Background We aimed to conduct a meta-analysis concerning the frequency and risk factors of reduced bone mineral density (BMD) in systemic lupus erythematosus (SLE) with evidence from published studies. Methods A comprehensive literature search was conducted based on the EMBASE, Web of Science, PubMed, and Cochrane Library databases up to March 5th, 2017. Eligible studies reported any prevalence of reduced BMD in SLE patients. All risk factors with odds ratios or risk ratios associated with reduced BMD were extracted. Results 71 reports with 33527 SLE patients were included. Low BMD, osteopenia, and osteoporosis at any site were presented, respectively, in 45%, 38%, and 13% of the SLE patients. The prevalence of osteoporosis increased with the advancing of age, while U-shaped associations between age and the prevalence of low BMD and osteopenia were found. Lumbar spine was indicated to have higher prevalence of osteoporosis. Age, disease duration, drugs use, and many other factors were identified as predictors of reduced BMD. Conclusion Low BMD, osteoporosis, and osteopenia appeared to be prevalent in patients with SLE. Risk factors of reduced BMD were various.
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Meurer M, Höcherl K. Endotoxaemia differentially regulates the expression of renal Ca 2+ transport proteins in mice. Acta Physiol (Oxf) 2019; 225:e13175. [PMID: 30133162 DOI: 10.1111/apha.13175] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 08/17/2018] [Accepted: 08/18/2018] [Indexed: 12/16/2022]
Abstract
AIM Alterations in parathyroid hormone (PTH) and/or vitamin D signalling are frequently reported in patients with sepsis. The consequences on renal and intestinal Ca2+ and Pi regulatory mechanisms are still unclear. We hypothesized that endotoxaemia alters the expression of important renal and intestinal Ca2+ and Pi transport proteins. METHODS Male C57BL/6 mice were treated with lipopolysaccharide (LPS; 3 mg/kg; i.p.). The mRNA and protein levels of renal and intestinal Ca2+ and Pi transport proteins were measured by RT-qPCR, immunohistochemistry and western blot analysis. RESULTS Lipopolysaccharide-induced hypocalcaemia and hyperphosphataemia was paralleled by a decrease in glomerular filtration rate and urinary excretion of Ca2+ and Pi . Endotoxaemia augmented plasma levels of PTH and affected the fibroblast growth factor 23 (FGF23)-klotho-vitamin D axis by increasing plasma levels of FGF23 and downregulation of renal klotho expression. Renal expression of CYP27b1 and plasma levels of 1,25-dihydroxyvitamin D3 were increased in response to LPS. Endotoxaemia augmented the renal expression of TRPV5, TRPV6 and PiT1, whereas the renal expression of calbindin-D28K , NCX1, NaPi -2a and NaPi -2c were decreased. Incubation of primary distal tubule cells with LPS increased TRPV6 mRNA levels. Furthermore, LPS decreased the intestinal expression of TRPV6, calbindin-D9K and of NaPi -2b. CONCLUSION Our findings indicate that endotoxaemia is associated with hypocalcaemia and hyperphosphataemia and a disturbed FGF23-klotho-vitamin D signaling. Further, LPS-induced acute kidney injury was accompanied by an increased or decreased expression of specific renal and intestinal Ca2+ and Pi transporters respectively. It seems unlikely that LPS-induced hypocalcaemia is due to renal loss of Ca2+ .
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Affiliation(s)
- Manuel Meurer
- Institute of Experimental and Clinical Pharmacology and Toxicology; Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU); Erlangen Germany
| | - Klaus Höcherl
- Institute of Experimental and Clinical Pharmacology and Toxicology; Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU); Erlangen Germany
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Mohn ES, Kern HJ, Saltzman E, Mitmesser SH, McKay DL. Evidence of Drug-Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update. Pharmaceutics 2018; 10:E36. [PMID: 29558445 PMCID: PMC5874849 DOI: 10.3390/pharmaceutics10010036] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 03/13/2018] [Accepted: 03/16/2018] [Indexed: 12/18/2022] Open
Abstract
The long-term use of prescription and over-the-counter drugs can induce subclinical and clinically relevant micronutrient deficiencies, which may develop gradually over months or even years. Given the large number of medications currently available, the number of research studies examining potential drug-nutrient interactions is quite limited. A comprehensive, updated review of the potential drug-nutrient interactions with chronic use of the most often prescribed medications for commonly diagnosed conditions among the general U.S. adult population is presented. For the majority of the interactions described in this paper, more high-quality intervention trials are needed to better understand their clinical importance and potential consequences. A number of these studies have identified potential risk factors that may make certain populations more susceptible, but guidelines on how to best manage and/or prevent drug-induced nutrient inadequacies are lacking. Although widespread supplementation is not currently recommended, it is important to ensure at-risk patients reach their recommended intakes for vitamins and minerals. In conjunction with an overall healthy diet, appropriate dietary supplementation may be a practical and efficacious way to maintain or improve micronutrient status in patients at risk of deficiencies, such as those taking medications known to compromise nutritional status. The summary evidence presented in this review will help inform future research efforts and, ultimately, guide recommendations for patient care.
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Affiliation(s)
- Emily S Mohn
- Jean Mayer USDA Human Nutrition Research Center on Aging, and Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA 02111, USA.
| | - Hua J Kern
- Nutrition & Scientific Affairs, Nature's Bounty Co., Ronkonkoma, NY 11779, USA.
| | - Edward Saltzman
- Jean Mayer USDA Human Nutrition Research Center on Aging, and Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA 02111, USA.
| | - Susan H Mitmesser
- Nutrition & Scientific Affairs, Nature's Bounty Co., Ronkonkoma, NY 11779, USA.
| | - Diane L McKay
- Jean Mayer USDA Human Nutrition Research Center on Aging, and Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA 02111, USA.
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Luo W, Johnson CS, Trump DL. Vitamin D Signaling Modulators in Cancer Therapy. VITAMINS AND HORMONES 2016; 100:433-72. [PMID: 26827962 DOI: 10.1016/bs.vh.2015.11.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The antiproliferative and pro-apoptotic effects of 1α,25-dihydroxycholecalciferol (1,25(OH)2D3, 1,25D3, calcitriol) have been demonstrated in various tumor model systems in vitro and in vivo. However, limited antitumor effects of 1,25D3 have been observed in clinical trials. This may be attributed to a variety of factors including overexpression of the primary 1,25D3 degrading enzyme, CYP24A1, in tumors, which would lead to rapid local inactivation of 1,25D3. An alternative strategy for improving the antitumor activity of 1,25D3 involves the combination with a selective CYP24A1 inhibitor. The validity of this approach is supported by numerous preclinical investigations, which demonstrate that CYP24A1 inhibitors suppress 1,25D3 catabolism in tumor cells and increase the effects of 1,25D3 on gene expression and cell growth. Studies are now required to determine whether selective CYP24A1 inhibitors+1,25D3 can be used safely and effectively in patients. CYP24A1 inhibitors plus 1,25D3 can cause dose-limiting toxicity of vitamin D (hypercalcemia) in some patients. Dexamethasone significantly reduces 1,25D3-mediated hypercalcemia and enhances the antitumor activity of 1,25D3, increases VDR-ligand binding, and increases VDR protein expression. Efforts to dissect the mechanisms responsible for CYP24A1 overexpression and combinational effect of 1,25D3/dexamethasone in tumors are underway. Understanding the cross talk between vitamin D receptor (VDR) and glucocorticoid receptor (GR) signaling axes is of crucial importance to the design of new therapies that include 1,25D3 and dexamethasone. Insights gained from these studies are expected to yield novel strategies to improve the efficacy of 1,25D3 treatment.
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Affiliation(s)
- Wei Luo
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Candace S Johnson
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Donald L Trump
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA; Inova Dwight and Martha Schar Cancer Institute, Falls Church, Virginia, USA.
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Diaz de Barboza G, Guizzardi S, Tolosa de Talamoni N. Molecular aspects of intestinal calcium absorption. World J Gastroenterol 2015; 21:7142-7154. [PMID: 26109800 PMCID: PMC4476875 DOI: 10.3748/wjg.v21.i23.7142] [Citation(s) in RCA: 154] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 03/21/2015] [Accepted: 04/17/2015] [Indexed: 02/06/2023] Open
Abstract
Intestinal Ca2+ absorption is a crucial physiological process for maintaining bone mineralization and Ca2+ homeostasis. It occurs through the transcellular and paracellular pathways. The first route comprises 3 steps: the entrance of Ca2+ across the brush border membranes (BBM) of enterocytes through epithelial Ca2+ channels TRPV6, TRPV5, and Cav1.3; Ca2+ movement from the BBM to the basolateral membranes by binding proteins with high Ca2+ affinity (such as CB9k); and Ca2+ extrusion into the blood. Plasma membrane Ca2+ ATPase (PMCA1b) and sodium calcium exchanger (NCX1) are mainly involved in the exit of Ca2+ from enterocytes. A novel molecule, the 4.1R protein, seems to be a partner of PMCA1b, since both molecules co-localize and interact. The paracellular pathway consists of Ca2+ transport through transmembrane proteins of tight junction structures, such as claudins 2, 12, and 15. There is evidence of crosstalk between the transcellular and paracellular pathways in intestinal Ca2+ transport. When intestinal oxidative stress is triggered, there is a decrease in the expression of several molecules of both pathways that inhibit intestinal Ca2+ absorption. Normalization of redox status in the intestine with drugs such as quercetin, ursodeoxycholic acid, or melatonin return intestinal Ca2+ transport to control values. Calcitriol [1,25(OH)2D3] is the major controlling hormone of intestinal Ca2+ transport. It increases the gene and protein expression of most of the molecules involved in both pathways. PTH, thyroid hormones, estrogens, prolactin, growth hormone, and glucocorticoids apparently also regulate Ca2+ transport by direct action, indirect mechanism mediated by the increase of renal 1,25(OH)2D3 production, or both. Different physiological conditions, such as growth, pregnancy, lactation, and aging, adjust intestinal Ca2+ absorption according to Ca2+ demands. Better knowledge of the molecular details of intestinal Ca2+ absorption could lead to the development of nutritional and medical strategies for optimizing the efficiency of intestinal Ca2+ absorption and preventing osteoporosis and other pathologies related to Ca2+ metabolism.
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Abstract
TRPV5 is one of the two channels in the TRPV family that exhibit high selectivity to Ca(2+) ions. TRPV5 mediates Ca(2+) influx into cells as the first step to transport Ca(2+) across epithelia. The specialized distribution in the distal tubule of the kidney positions TRPV5 as a key player in Ca(2+) reabsorption. The responsiveness in expression and/or activity of TRPV5 to hormones such as 1,25-dihydroxyvitamin D3, parathyroid hormone, estrogen, and testosterone makes TRPV5 suitable for its role in the fine-tuning of Ca(2+) reabsorption. This role is further optimized by the modulation of TRPV5 trafficking and activity via its binding partners; co-expressed proteins; tubular factors such as calbindin-D28k, calmodulin, klotho, uromodulin, and plasmin; extracellular and intracellular factors such as proton, Mg(2+), Ca(2+), and phosphatidylinositol-4,5-bisphosphate; and fluid flow. These regulations allow TRPV5 to adjust its overall activity in response to the body's demand for Ca(2+) and to prevent kidney stone formation. A point mutation in mouse Trpv5 gene leads to hypercalciuria similar to Trpv5 knockout mice, suggesting a possible role of TRPV5 in hypercalciuric disorders in humans. In addition, the single nucleotide polymorphisms in Trpv5 gene prevalently present in African descents may contribute to the efficient renal Ca(2+) reabsorption among African descendants. TRPV5 represents a potential therapeutic target for disorders with altered Ca(2+) homeostasis.
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Affiliation(s)
- Tao Na
- Cell Collection and Research Center, Institute for Biological Product Control, National Institutes for Food and Drug Control, Beijing, China
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19
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Abstract
TRPV6 (former synonyms ECAC2, CaT1, CaT-like) displays several specific features which makes it unique among the members of the mammalian Trp gene family (1) TRPV6 (and its closest relative, TRPV5) are the only highly Ca(2+)-selective channels of the entire TRP superfamily (Peng et al. 1999; Wissenbach et al. 2001; Voets et al. 2004). (2) Translation of Trpv6 initiates at a non-AUG codon, at ACG, located upstream of the annotated AUG, which is not used for initiation (Fecher-Trost et al. 2013). The ACG codon is nevertheless decoded by methionine. Not only a very rare event in eukaryotic biology, the full-length TRPV6 protein existing in vivo comprises an amino terminus extended by 40 amino acid residues compared to the annotated truncated TRPV6 protein which has been used in most studies on TRPV6 channel activity so far. (In the following numbering occurs according to this full-length protein, with the numbers of the so far annotated truncated protein in brackets). (3) Only in humans a coupled polymorphism of Trpv6 exists causing three amino acid exchanges and resulting in an ancestral Trpv6 haplotype and a so-called derived Trpv6 haplotype (Wissenbach et al. 2001). The ancestral allele encodes the amino acid residues C197(157), M418(378) and M721(681) and the derived alleles R197(157), V418(378) and T721(681). The ancestral haplotype is found in all species, the derived Trpv6 haplotype has only been identified in humans, and its frequency increases with the distance to the African continent. Apparently the Trpv6 gene has been a strong target for selection in humans, and its derived variant is one of the few examples showing consistently differences to the orthologues genes of other primates (Akey et al. 2004, 2006; Stajich and Hahn 2005; Hughes et al. 2008). (4) The Trpv6 gene expression is significantly upregulated in several human malignancies including the most common cancers, prostate and breast cancer (Wissenbach et al. 2001; Zhuang et al. 2002; Fixemer et al. 2003; Bolanz et al. 2008). (5) Male mice lacking functional TRPV6 channels are hypo-/infertile making TRPV6 one of the very few channels essential for male fertility (Weissgerber et al. 2011, 2012).
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Affiliation(s)
- Claudia Fecher-Trost
- Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, 66421, Homburg, Germany
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Govindarajan P, Khassawna T, Kampschulte M, Böcker W, Huerter B, Dürselen L, Faulenbach M, Heiss C. Implications of combined ovariectomy and glucocorticoid (dexamethasone) treatment on mineral, microarchitectural, biomechanical and matrix properties of rat bone. Int J Exp Pathol 2013; 94:387-98. [PMID: 23998329 PMCID: PMC3944450 DOI: 10.1111/iep.12038] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2013] [Accepted: 06/12/2013] [Indexed: 12/28/2022] Open
Abstract
Osteoporosis is one of the deleterious side effects of long-term glucocorticoid therapy. Since the condition is particularly aggressive in postmenopausal women who are on steroid therapy, in this study we have attempted to analyse the combined effect of glucocorticoid (dexamethasone) treatment and cessation of oestrogen on rat bone. The dual aim was to generate osteoporotic bone status in a short time scale and to characterise the combination of glucocorticoid-postmenopausal osteoporotic conditions. Sprague Dawley rats (N = 42) were grouped randomly into three groups: untreated control, sham-operated and ovariectomized-steroid (OVX-Steroid) rats. Control animals were euthanized with no treatment [Month 0 (M0)], while sham and OVX-Steroid rats were monitored up to 1 month (M1) and 3 months (M3) post laparotomy/post OVX-Steroid treatment. Histology, dual-energy X-ray absorptiometry (DXA), micro-computed tomography (micro-CT), and biomechanical and mRNA expression analysis of collagenous, non-collagenous matrix proteins and osteoclast markers were examined. The study indicated enhanced osteoclastogenesis and significantly lower bone mineral density (BMD) in the OVX-Steroid rats with Z-scores below -2.5, reduced torsional strength, reduced bone volume (BV/TV%), significantly enhanced trabecular separation (Tb.S), and less trabecular number (Tb.N) compared with sham rats. Osteoclast markers, cathepsin K and MMP 9 were upregulated along with Col1α1 and biglycan with no significant expression variation in fibronectin, MMP 14, LRP-5, Car II and TNC. These results show higher bone turnover with enhanced bone resorption accompanied with reduced torsional strength in OVX-Steroid rats; and these changes were attained within a short timeframe. This could be a useful model which mimics human postmenopausal osteoporosis that is associated with steroid therapy and could prove of value both in disease diagnosis and for testing generating and testing biological agents which could be used in treatment.
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Affiliation(s)
| | - Thaqif Khassawna
- Laboratory of Experimental Trauma Surgery, Justus-Liebig UniversityGiessen, Germany
| | - Marian Kampschulte
- Department of Radiology, University Hospital of Giessen-MarburgGiessen, Germany
| | - Wolfgang Böcker
- Department of Trauma Surgery, University Hospital of Giessen-MarburgGiessen, Germany
| | - Britta Huerter
- Laboratory of Experimental Trauma Surgery, Justus-Liebig UniversityGiessen, Germany
| | - Lutz Dürselen
- Institute of Orthopedic Research and Biomechanics, Centre of Musculoskeletal Research Ulm, University of UlmUlm, Germany
| | - Miriam Faulenbach
- Department of Radiology, University Hospital of Giessen-MarburgGiessen, Germany
| | - Christian Heiss
- Laboratory of Experimental Trauma Surgery, Justus-Liebig UniversityGiessen, Germany
- Department of Trauma Surgery, University Hospital of Giessen-MarburgGiessen, Germany
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21
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Xu H, Kona S, Su LC, Tsai YT, Dong JF, Brilakis ES, Tang L, Banerjee S, Nguyen KT. Multi-ligand poly(L-lactic-co-glycolic acid) nanoparticles inhibit activation of endothelial cells. J Cardiovasc Transl Res 2013; 6:570-8. [PMID: 23640308 DOI: 10.1007/s12265-013-9460-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 03/19/2013] [Indexed: 11/29/2022]
Abstract
Endothelial cell (EC) activation and inflammation is a key step in the initiation and progression of many cardiovascular diseases. Targeted delivery of therapeutic reagents to inflamed EC using nanoparticles is challenging as nanoparticles do not arrest on EC efficiently under high shear stress. In this study, we developed a novel polymeric platelet-mimicking nanoparticle for strong particle adhesion onto ECs and enhanced particle internalization by ECs. This nanoparticle was encapsulated with dexamethasone as the anti-inflammatory drug, and conjugated with polyethylene glycol, glycoprotein 1b, and trans-activating transcriptional peptide. The multi-ligand nanoparticle showed significantly greater adhesion on P-selectin, von Willebrand Factor, than the unmodified particles, and activated EC in vitro under both static and flow conditions. Treatment of injured rat carotid arteries with these multi-ligand nanoparticles suppressed neointimal stenosis more than unconjugated nanoparticles did. These results indicate that this novel multi-ligand nanoparticle is efficient to target inflamed EC and inhibit inflammation and subsequent stenosis.
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Affiliation(s)
- Hao Xu
- Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Duodenal calcium transporter mRNA expression in stressed male rats treated with diazepam, fluoxetine, reboxetine, or venlafaxine. Mol Cell Biochem 2012; 369:87-94. [DOI: 10.1007/s11010-012-1371-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2012] [Accepted: 06/20/2012] [Indexed: 01/22/2023]
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Charoenphandhu N, Teerapornpuntakit J, Lapmanee S, Dorkkam N, Krishnamra N, Charoenphandhu J. Long-term swimming in an inescapable stressful environment attenuates the stimulatory effect of endurance swimming on duodenal calcium absorption in rats. J Physiol Sci 2011; 61:473-86. [PMID: 21858657 PMCID: PMC10717476 DOI: 10.1007/s12576-011-0168-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Accepted: 07/20/2011] [Indexed: 12/14/2022]
Abstract
Endurance swimming is known to increase duodenal calcium absorption in normal rats and bone strength in estrogen-deficient rats. Because the stress resulting from forced training often attenuates the stimulatory effect of exercise, swimming in an inescapable chamber should reveal both the positive effect of the exercise and the negative effect of stress. In the work reported herein, swimming rats showed no signs of stress during 2 weeks of training. However, stress response gradually developed thereafter and peaked at weeks 6 and 7. In rats swimming for 2 weeks, transcellular duodenal calcium transport was enhanced ~2-fold. In contrast, calcium absorption was reduced in rats swimming for 8 weeks, consistent with the absence of swimming-induced upregulation of calcium transporter genes in the 8-week group. In conclusion, prolonged stress hindered the stimulatory effect of swimming on duodenal calcium absorption, and thus endurance exercise should be performed without forced training or stress to retain its beneficial effect on calcium metabolism.
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Affiliation(s)
- Narattaphol Charoenphandhu
- Department of Physiology, Faculty of Science, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand.
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Hidalgo AA, Deeb KK, Pike JW, Johnson CS, Trump DL. Dexamethasone enhances 1alpha,25-dihydroxyvitamin D3 effects by increasing vitamin D receptor transcription. J Biol Chem 2011; 286:36228-37. [PMID: 21868377 DOI: 10.1074/jbc.m111.244061] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Calcitriol, the active form of vitamin D, in combination with the glucocorticoid dexamethasone (Dex) has been shown to increase the antitumor effects of calcitriol in squamous cell carcinoma. In this study we found that pretreatment with Dex potentiates calcitriol effects by inhibiting cell growth and increasing vitamin D receptor (VDR) and VDR-mediated transcription. Treatment with actinomycin D inhibits Vdr mRNA synthesis, indicating that Dex regulates VDR expression at transcriptional level. Real time PCR shows that treatment with Dex increases Vdr transcripts in a time- and a dose-dependent manner, indicating that Dex directly regulates expression of Vdr. RU486, an inhibitor of glucocorticoids, inhibits Dex-induced Vdr expression. In addition, the silencing of glucocorticoid receptor (GR) abolishes the induction of Vdr by Dex, indicating that Dex increases Vdr transcripts in a GR-dependent manner. A fragment located 5.2 kb upstream of Vdr transcription start site containing two putative glucocorticoid response elements (GREs) was evaluated using a luciferase-based reporter assay. Treatment with 100 nm Dex induces transcription of luciferase driven by the fragment. Deletion of the GRE distal to transcription start site was sufficient to abolish Dex induction of luciferase. Also, chromatin immunoprecipitation reveals recruitment of GR to distal GRE with Dex treatment. We conclude that Dex increases VDR and vitamin D effects by increasing Vdr de novo transcription in a GR-dependent manner.
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Affiliation(s)
- Alejandro A Hidalgo
- Department of Biochemistry, State University of New York at Buffalo, Buffalo, New York 14214, USA
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25
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Heise N, Shumilina E, Nurbaeva MK, Schmid E, Szteyn K, Yang W, Xuan NT, Wang K, Zemtsova IM, Duszenko M, Lang F. Effect of dexamethasone on Na+/Ca2+exchanger in dendritic cells. Am J Physiol Cell Physiol 2011; 300:C1306-13. [DOI: 10.1152/ajpcell.00396.2010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Ca+-dependent signaling regulates the function of dendritic cells (DCs), antigen-presenting cells linking innate and adaptive immunity. The activity of DCs is suppressed by glucocorticoids, potent immunosuppressive hormones. The present study explored whether the glucocorticoid dexamethasone influences the cytosolic Ca2+concentration ([Ca2+]i) in DCs. To this end, DCs were isolated from mouse bone marrow. According to fura-2 fluorescence, exposure of DCs to lipopolysaccharide (LPS, 100 ng/ml) increased [Ca2+]i, an effect significantly blunted by overnight incubation with 10 nM dexamethasone before LPS treatment. Dexamethasone did not affect the Ca2+content of intracellular stores, sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 and SERCA3 expression, ryanodine receptor (RyR)1 expression, or Ca2+entry through store-operated Ca2+channels. In contrast, dexamethasone increased the transcript level and the membrane protein abundance of the Na+/Ca2+exchanger NCX3. The activity of Na+/Ca2+exchangers was assessed by removal of extracellular Na+in the presence of external Ca2+, a maneuver triggering the Ca2+influx mode. Indeed, Na+removal resulted in a rapid transient increase of [Ca2+]iand induced an outwardly directed current as measured in whole cell patch-clamp experiments. Dexamethasone significantly augmented the increase of [Ca2+]iand the outward current following removal of extracellular Na+. The NCX blocker KB-R7943 reversed the inhibitory effect of dexamethasone on LPS-induced increase in [Ca2+]i. Dexamethasone blunted LPS-induced stimulation of CD86 expression and TNF-α production, an effect significantly less pronounced in the presence of NCX blocker KB-R7943. In conclusion, our results show that glucocorticoid treatment blunts LPS-induced increase in [Ca2+]iin DCs by increasing expression and activity of Na+/Ca2+exchanger NCX3. The effect contributes to the inhibitory effect of the glucocorticoid on DC maturation.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Michael Duszenko
- Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
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Ritchie MF, Zhou Y, Soboloff J. Transcriptional mechanisms regulating Ca(2+) homeostasis. Cell Calcium 2011; 49:314-21. [PMID: 21074851 PMCID: PMC3225030 DOI: 10.1016/j.ceca.2010.10.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2010] [Revised: 09/29/2010] [Accepted: 10/01/2010] [Indexed: 01/08/2023]
Abstract
Ca(2+) is a dynamic cellular secondary messenger which mediates a vast array of cellular responses. Control over these processes is achieved via an extensive combination of pumps and channels which regulate the concentration of Ca(2+) within not only the cytosol but also all intracellular compartments. Precisely how these pumps and channels are regulated is only partially understood, however, recent investigations have identified members of the Early Growth Response (EGR) family of zinc finger transcription factors as critical players in this process. The roles of several other transcription factors in control of Ca(2+) homeostasis have also been demonstrated, including Wilms Tumor Suppressor 1 (WT1), Nuclear Factor of Activated T cells (NFAT) and c-myc. In this review, we will discuss not only how these transcription factors regulate the expression of the major proteins involved in control of Ca(2+) homeostasis, but also how this transcriptional remodeling of Ca(2+) homeostasis affects Ca(2+) dynamics and cellular responses.
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Affiliation(s)
- Michael F Ritchie
- Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, United States
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Peng JB. TRPV5 and TRPV6 in transcellular Ca(2+) transport: regulation, gene duplication, and polymorphisms in African populations. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2011; 704:239-75. [PMID: 21290300 DOI: 10.1007/978-94-007-0265-3_14] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
TRPV5 and TRPV6 are unique members of the TRP super family. They are highly selective for Ca(2+) ions with multiple layers of Ca(2+)-dependent inactivation mechanisms, expressed at the apical membrane of Ca(2+) transporting epithelia, and robustly responsive to 1,25-dihydroxivitamin D(3). These features are well suited for their roles as Ca(2+) entry channels in the first step of transcellular Ca(2+) transport pathways, which are involved in intestinal absorption, renal reabsorption of Ca(2+), placental transfer of Ca(2+) to fetus, and many other processes. While TRPV6 is more broadly expressed in a variety of tissues such as esophagus, stomach, small intestine, colon, kidney, placenta, pancreas, prostate, uterus, salivary gland, and sweat gland, TRPV5 expression is relatively restricted to the distal convoluted tubule and connecting tubule of the kidney. There is only one TRPV6-like gene in fish and birds in comparison to both TRPV5 and TRPV6 genes in mammals, indicating TRPV5 gene was likely generated from duplication of TRPV6 gene during the evolution of mammals to meet the needs of complex renal function. TRPV5 and TRPV6 are subjected to vigorous regulations under physiological, pathological, and therapeutic conditions. The elevated TRPV6 level in malignant tumors such as prostate and breast cancers makes it a potential therapeutic target. TRPV6, and to a lesser extent TRPV5, exhibit unusually high levels of single nucleotide polymorphisms (SNPs) in African populations as compared to other populations, indicating TRPV6 gene was under selective pressure during or after humans migrated out of Africa. The SNPs of TRPV6 and TRPV5 likely contribute to the Ca(2+) conservation mechanisms in African populations.
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Affiliation(s)
- Ji-Bin Peng
- Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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Hidalgo AA, Trump DL, Johnson CS. Glucocorticoid regulation of the vitamin D receptor. J Steroid Biochem Mol Biol 2010; 121:372-5. [PMID: 20398752 PMCID: PMC2907065 DOI: 10.1016/j.jsbmb.2010.03.081] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Revised: 03/04/2010] [Accepted: 03/26/2010] [Indexed: 10/19/2022]
Abstract
Many studies indicate calcitriol has potent anti-tumor activity in different types of cancers. However, high levels of vitamin D can produce hypercalcemia in some patients. Glucocorticoids are used to ameliorate hypercalcemia and to enhance calcitriol anti-tumor activity. Calcitriol in combination with the glucocorticoid dexamethasone (Dex) increased vitamin D receptor (VDR) protein levels and ligand binding in squamous cell carcinoma VII (SCC). In this study we found that both calcitriol and Dex induce VDR- and glucocorticoid receptor (GR)-mediated transcription respectively, indicating both hormone receptors are active in SCC. Pre-treatment with Dex increases VDR-mediated transcription at the human CYP24A1 promoter. Whereas, pre-treatment with other steroid hormones, including dihydrotestosterone and R1881, has no effect on VDR-mediated transcription. Real-time PCR indicates treatment with Dex increases Vdr transcripts in a time-dependent manner, suggesting Dex may directly regulate expression of Vdr. Numerous putative glucocorticoid response elements (GREs) were found in the Vdr gene. Chromatin immuno-precipitation (ChIP) assay demonstrated GR binding at several putative GREs located within the mouse Vdr gene. However, none of the putative GREs studied increase GR-mediated transcription in luciferase reporter assays. In an attempt to identify the response element responsible for Vdr transcript regulation, future studies will continue to analyze newly identified GREs more distal from the Vdr gene promoter.
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Affiliation(s)
- Alejandro A Hidalgo
- Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY 14214, United States
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