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Wang C, Zhou J, Zhang Q, Chen H, Luo X, Liu Z, Ye Z, Zhang Z, Wei G, Liu X. From cause to relief: Vitamin D plays a crucial role in overactive bladder via the RhoA/ROCK signaling pathway. Biochem Biophys Res Commun 2025; 766:151919. [PMID: 40311294 DOI: 10.1016/j.bbrc.2025.151919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2025] [Revised: 04/27/2025] [Accepted: 04/28/2025] [Indexed: 05/03/2025]
Abstract
Overactive bladder (OAB) is a common urological disorder, characterized by urinary urgency and frequency. However, the etiology and pathogenesis of OAB remain unclear. The objective of this study was to construct a Vitamin D-deficient rat model with the aim of clarifying the relationship between Vitamin D deficiency and the development of OAB, as well as investigating the potential mechanisms involved. The findings revealed that rats with vitamin D deficiency exhibited indications of OAB, including increased urinary frequency and urgency, as evidenced by void spot assay and cystometry. Furthermore, supplementation with vitamin D proved to be an effective intervention in alleviating these symptoms. The activation of RhoA/ROCK pathway was found in the bladder tissues and urine of rats with vitamin D deficiency. Moreover, supplementation with vitamin D led to a significant decrease in the expression levels of RhoA/ROCK pathway in both bladder tissue and urine. In conclusion, our study was the first to demonstrate that vitamin D deficiency is one of the etiological factors of OAB through the activation of the RhoA/ROCK signaling pathway, and that vitamin D supplementation has been shown to effectively alleviate OAB symptoms by inhibiting this pathway. Meanwhile, urinary RhoA may be a biomarker of OAB. Our present work makes a significant contribution to the clarification of the etiology and mechanism of OAB, as well as to the refinement of OAB treatment strategies.
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Affiliation(s)
- Chong Wang
- Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, PR China
| | - Jiaxin Zhou
- Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, PR China
| | - Qiang Zhang
- Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, PR China
| | - Hongsong Chen
- Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, PR China
| | - Xingguo Luo
- Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, PR China
| | - Zhenmin Liu
- Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, PR China
| | - Zihan Ye
- Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, PR China
| | - Zhicheng Zhang
- Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, PR China
| | - Guanghui Wei
- Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, PR China
| | - Xing Liu
- Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, 400014, PR China.
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Zhang Q, Zhang Z, He X, Liu Z, Shen L, Long C, Wei G, Liu X, Guo C. Vitamin D levels and the risk of overactive bladder: a systematic review and meta-analysis. Nutr Rev 2024; 82:166-175. [PMID: 37195440 DOI: 10.1093/nutrit/nuad049] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2023] Open
Abstract
CONTEXT Overactive bladder is treated mainly with behavioral and drug therapy, and symptoms of urinary frequency and incontinence are challenging to eliminate. There is thus a continuous unmet need for new drugs with a substitution effect mechanism. OBJECTIVE It not known whether vitamin D deficiency can lead to overactive bladder or urinary incontinence or whether vitamin D supplementation alleviates bladder symptoms. This comprehensive systematic review with meta-analysis was conducted to determine whether overactive bladder is associated with vitamin D deficiency. DATA SOURCES The PubMed and Cochrane Library databases were searched systematically up to July 3, 2022. DATA EXTRACTION Initially, 706 articles were identified in the literature search, of which 13 were included in the systematic review: 4 randomized controlled trials, 3 cohort studies, 3 cross-sectional studies, and 3 case-control studies. DATA ANALYSIS An increased risk of overactive bladder and urinary incontinence was observed with vitamin D deficiency (odds ratio [OR] = 4.46; 95%CI, 1.03-19.33; P = 0.046 and OR = 1.30; 95%CI, 1.01-1.66; P = 0.036, respectively). Vitamin D levels were relatively low in patients with overactive bladder or urinary incontinence (SMD = -0.33; 95%CI, -0.61 to -0.06, P = 0.019). On the basis of existing data, the risk of urinary incontinence was reduced by 66% after vitamin D supplementation (OR = 0.34; 95%CI, 0.18-0.66; P = 0.001). Egger test was conducted to assess publication bias, and the results were tested for robustness using a sensitivity analysis. CONCLUSIONS Vitamin D deficiency increases the risk of overactive bladder and urinary incontinence, and vitamin D supplementation reduces the risk of urinary incontinence. The development of new strategies to prevent or alleviate bladder symptoms is crucial. Vitamin D supplementation may be gaining recognition as an effective strategy for prevention or alleviation of bladder symptoms such as overactive bladder and incontinence. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration no. CRD42022351443.
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Affiliation(s)
- Qiang Zhang
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Zhicheng Zhang
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Xueyu He
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Zhenmin Liu
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Lianju Shen
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Chunlan Long
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Guanghui Wei
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Xing Liu
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China
- Program for Youth Innovation in Future Medicine, Chongqing Medical University, Chongqing, People's Republic of China
| | - Chunming Guo
- School of Life Sciences, Yunnan University, Kunming, China
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Michel MC, Cardozo L, Chermansky CJ, Cruz F, Igawa Y, Lee KS, Sahai A, Wein AJ, Andersson KE. Current and Emerging Pharmacological Targets and Treatments of Urinary Incontinence and Related Disorders. Pharmacol Rev 2023; 75:554-674. [PMID: 36918261 DOI: 10.1124/pharmrev.121.000523] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 03/16/2023] Open
Abstract
Overactive bladder syndrome with and without urinary incontinence and related conditions, signs, and disorders such as detrusor overactivity, neurogenic lower urinary tract dysfunction, underactive bladder, stress urinary incontinence, and nocturia are common in the general population and have a major impact on the quality of life of the affected patients and their partners. Based on the deliberations of the subcommittee on pharmacological treatments of the 7th International Consultation on Incontinence, we present a comprehensive review of established drug targets in the treatment of overactive bladder syndrome and the aforementioned related conditions and the approved drugs used in its treatment. Investigational drug targets and compounds are also reviewed. We conclude that, despite a range of available medical treatment options, a considerable medical need continues to exist. This is largely because the existing treatments are symptomatic and have limited efficacy and/or tolerability, which leads to poor long-term adherence. SIGNIFICANCE STATEMENT: Urinary incontinence and related disorders are prevalent in the general population. While many treatments have been approved, few patients stay on long-term treatment despite none of them being curative. This paper provides a comprehensive discussion of existing and emerging treatment options for various types of incontinence and related disorders.
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Affiliation(s)
- Martin C Michel
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Linda Cardozo
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Christopher J Chermansky
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Francisco Cruz
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Yasuhiko Igawa
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Kyu-Sung Lee
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Arun Sahai
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Alan J Wein
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
| | - Karl-Erik Andersson
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.C.M.); Department of Urogynaecology, King's College Hospital, London, UK (L.C.); Department of Urology, Magee Women's Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (C.J.C.); Department of Urology, Faculty of Medicine of University of Porto, Hospital São João and i3S Institute for Innovation and Investigation in Health, Porto, Portugal (F.C.); Department of Urology, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan (Y.I.); Department of Urology Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (K-S.L.); Guy's Hospital and King's College London, London, UK (A.S.); Dept. of Urology, Perlman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.J.W.); Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.J.W.); and Institute for Laboratory Medicine, Lund University, Lund, Sweden (K-E.A.)
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Lütke-Dörhoff M, Schulz J, Westendarp H, Visscher C, Wilkens MR. Dietary supplementation of 25-hydroxycholecalciferol as an alternative to cholecalciferol in swine diets: A review. J Anim Physiol Anim Nutr (Berl) 2022; 106:1288-1305. [PMID: 36045590 DOI: 10.1111/jpn.13768] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 07/31/2022] [Accepted: 08/11/2022] [Indexed: 12/01/2022]
Abstract
25-hydroxycholecalciferol (25-OHD3 ) formed via hepatic hydroxylation from vitamin D, cholecalciferol, represents the precursor of the biologically active vitamin D hormone, 1,25-dihydroxyvitamin D. Due to a higher absorption rate and the omission of one hydroxylation, dietary supplementation of 25-OHD3 instead of vitamin D3 is considered to be more efficient as plasma concentrations of 25-OHD3 are increased more pronounced. The present review summarises studies investigating potential beneficial effects on mineral homeostasis, bone metabolism, health status and performance in sows, piglets and fattening pigs. Results are inconsistent. While most studies could not demonstrate any or only a slight impact of partial or total replacement of vitamin D3 by 25-OHD3 , some experiments indicated that 25-OHD3 might alter physiological processes when animals are challenged, for example, by a restricted mineral supply.
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Affiliation(s)
- Michael Lütke-Dörhoff
- Institute for Animal Hygiene, Animal Welfare and Farm Animal Behaviour, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany.,Department of Animal Nutrition, Faculty of Agricultural Sciences and Landscape Architecture, Hochschule Osnabrück, Osnabrück, Germany
| | - Jochen Schulz
- Institute for Animal Hygiene, Animal Welfare and Farm Animal Behaviour, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany
| | - Heiner Westendarp
- Department of Animal Nutrition, Faculty of Agricultural Sciences and Landscape Architecture, Hochschule Osnabrück, Osnabrück, Germany
| | - Christian Visscher
- Institute for Animal Nutrition, University of Veterinary Medicine Hannover, Foundation, Hanover, Germany
| | - Mirja R Wilkens
- Institute of Animal Nutrition, Nutrition Diseases and Dietetics, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany
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Baer R, Tene L, Weintraub AY, Kalichman L. The effect of vitamin D deficiency and supplementation on urinary incontinence: scoping review. Int Urogynecol J 2022; 33:1083-1090. [PMID: 34491371 DOI: 10.1007/s00192-021-04963-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/27/2021] [Indexed: 11/29/2022]
Abstract
INTRODUCTION AND HYPOTHESIS Vitamin D receptors are found in skeletal and smooth muscle cells throughout the body, specifically in the bladder detrusor muscle. We reviewed the current literature on the association between vitamin D deficiency and urinary incontinence (UI), and whether vitamin D supplementation plays a role in the treatment of UI symptoms. METHODS We performed a scoping review of all available studies. PubMed, Google Scholar, and PEDro databases were searched from inception until August 2020 with the keywords "urinary incontinence," "pelvic floor disorders," "lower urinary tract symptoms," "overactive bladder," and various terms for vitamin D. No language restrictions were imposed. The reference lists of all retrieved articles were also searched. RESULTS The search revealed 12 studies of different research methodologies after elimination. In 6 out of the 7 cross-sectional studies reviewed, a significant association between vitamin D deficiency or insufficiency and the onset and severity of UI was found. In 2 out of the 3 prospective studies included, no association between vitamin D intake and UI was found; however, both randomized controlled trials that were reviewed found that vitamin D supplementation is effective for the treatment of UI. CONCLUSIONS The existing literature supports an association between low levels of serum vitamin D and UI. Initial evidence regarding the effect of vitamin D supplementation on UI is accumulating, yet additional, comprehensive research is warranted to establish these findings.
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Affiliation(s)
- Ronnie Baer
- Department of Physical Therapy, Recanati School for Community Health Professions, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, 84105, Beer Sheva, Israel
| | - Lea Tene
- Department of Physical Therapy, Recanati School for Community Health Professions, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, 84105, Beer Sheva, Israel.
| | - Adi Y Weintraub
- Department of Obstetrics and Gynecology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Leonid Kalichman
- Department of Physical Therapy, Recanati School for Community Health Professions, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, 84105, Beer Sheva, Israel
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Markland AD, Vaughan C, Huang A, Kim E, Bubes VY, Tangpricha V, Buring J, Lee IM, Cook N, Manson JE, Grodstein F. Effect of vitamin D supplementation on urinary incontinence in older women: ancillary findings from a randomized trial. Am J Obstet Gynecol 2022; 226:535.e1-535.e12. [PMID: 34678177 PMCID: PMC8983596 DOI: 10.1016/j.ajog.2021.10.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 09/17/2021] [Accepted: 10/13/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Observational studies among older women have associated vitamin D insufficiency with a greater prevalence and incidence of urinary incontinence. However, little is known about the effect of vitamin D supplementation in reducing urinary incontinence. OBJECTIVE This study aimed to evaluate the effects of vitamin D supplementation in reducing the frequency of urinary incontinence in older women. STUDY DESIGN We conducted an ancillary study of women aged ≥55 years in the Vitamin D and Omega-3 Trial, a randomized trial with a 2×2 factorial design. Recruitment of participants started from 2011 to 2014 across 50 US states, and the follow-up of participants ended in January 2018. Randomized treatments in the parent study included (1) vitamin D3 (cholecalciferol) at a dosage of 2000 IU/d, (2) marine omega-3 fatty acids at a dosage of 1 g/d, and (3) matching placebo. Here, we analyzed women according to their randomization to vitamin D supplementation or placebo, regardless of treatment with omega-3 fatty acid supplementation. Validated frequency of urinary incontinence questions were added in year 2 of the study and were used again in year 5 at the end of trial. Prespecified ancillary outcomes included the prevalence of urinary incontinence at years 2 and 5, along with incident incontinence and progression of incontinence (from lower to higher frequency) from year 2 to year 5. Preplanned subgroup analyses examined the following outcomes: prerandomization of low serum levels of vitamin D (serum 25-hydroxyvitamin D<20 ng/mL), incontinence types, weight categories, and African American race. RESULTS Among the randomized women who provided urinary incontinence data, 11,646 women at year 2 and 10,527 women at year 5, the mean age was 70 years at year 2, with 29% racial and ethnic minorities. The prevalence of urinary incontinence that occurred at least weekly was 29% at year 2 and increased to 37% at year 5. Vitamin D supplementation compared to with placebo was not associated with lower odds of urinary incontinence occurring at least weekly at year 2 (odds ratio, 1.08; 95% confidence interval, 0.99-1.19) or year 5 (odds ratio, 1.04; 95% confidence interval, 0.94-1.15). Vitamin D supplementation compared to placebo was not associated with lower incidence or progression of urinary incontinence from year 2 to year 5: incidence (odds ratio, 1.06; 95% confidence interval, 0.83-1.35) or progression (odds ratio, 0.94; 95% confidence interval, 0.82-1.08). Women with prerandomization of low serum levels of vitamin D (n=836) did not have lower odds of the prevalence, incidence, or progression of urinary incontinence. The findings were null in subgroups according to incontinence type, women with obesity, and African American women. Only women with healthy weight randomized to vitamin D had lower odds of progression of urinary incontinence (odds ratio, 0.78; 95% confidence interval, 0.63-0.95; P=.01). CONCLUSION Vitamin D supplementation compared to placebo for 2 to 5 years was not associated with differences in the prevalence, incidence, or progression of urinary incontinence in older women with and without adequate serum vitamin D levels, with inconsistent differences among subgroups. The findings showed that the broad use of moderate doses of vitamin D supplementation did not reduce urinary incontinence in older women.
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Affiliation(s)
- Alayne D Markland
- Department of Veterans Affairs, Birmingham/Atlanta Geriatric Research, Education, and Clinical Center, Birmingham, AL, and Atlanta, GA; Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL.
| | - Camille Vaughan
- Department of Veterans Affairs, Birmingham/Atlanta Geriatric Research, Education, and Clinical Center, Birmingham, AL, and Atlanta, GA; Atlanta Veterans Affairs Medical Center, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Alison Huang
- Department of Medicine, University of California San Francisco, San Francisco, CA
| | - Eunjung Kim
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Vadim Y Bubes
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Vin Tangpricha
- Department of Veterans Affairs, Birmingham/Atlanta Geriatric Research, Education, and Clinical Center, Birmingham, AL, and Atlanta, GA; Atlanta Veterans Affairs Medical Center, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Julie Buring
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - I-Min Lee
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Nancy Cook
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - JoAnn E Manson
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
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da Silva SB. Vitamin D deficiency or insufficiency is associated with lower urinary tract symptoms. Int Braz J Urol 2022; 48:326-327. [PMID: 36165560 PMCID: PMC8932030 DOI: 10.1590/s1677-5538.ibju.2021.0645.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 12/28/2021] [Indexed: 11/22/2022] Open
Affiliation(s)
- Sandra Barbosa da Silva
- Laboratório de Morfometria, Metabolismo e Doenças Cardiovasculares. Universidade do Estado do Rio de Janeiro - UERJ, Rio de Janeiro, RJ, Brasil
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Serum vitamin D levels in females with urinary incontinence: a meta-analysis of observational trials. Int Urogynecol J 2021; 33:1187-1192. [PMID: 34132863 DOI: 10.1007/s00192-021-04886-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 05/26/2021] [Indexed: 10/21/2022]
Abstract
INTRODUCTION AND HYPOTHESIS The association of vitamin D deficiency with female urinary incontinence is unclear. METHODS A systematic review of English and non-English articles was conducted. All observational studies in databases including PubMed, EMBASE, the Cochrane Library Trials Register, and Google Scholar were searched until 5 October 2020. Additional studies were identified by contacting clinical experts and searching the bibliographies and abstracts of the compiled articles. Search terms included urinary incontinence and vitamin D. Article data, including study quality indicators, were independently extracted by two authors using predefined data fields. RESULTS Two cohort studies, four case-control studies and five cross-sectional studies were included in the qualitative synthesis. Two cohort studies and one cross-sectional study, with a total of 2501 females, were included in the meta-analysis. Heterogeneity among the three studies was not observed (I2 = 0.0%, P = 0.69). All pooled analyses were based on fixed-effects models. No difference in vitamin D level was observed between the urinary incontinence group and the control group (mean difference 0.07 ng/ml; 95% confidence interval [CI] -0.57-0.72, P = 0.81, I2 = 0%). CONCLUSIONS Our meta-analysis revealed that adult females with urinary incontinence did not have lower serum vitamin D levels than control females.
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Markland AD, Vaughan C, Huang A, Tangpricha V, Grodstein F. Vitamin D intake and the 10-year risk of urgency urinary incontinence in women. J Steroid Biochem Mol Biol 2020; 199:105601. [PMID: 32001360 PMCID: PMC7166185 DOI: 10.1016/j.jsbmb.2020.105601] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 01/14/2020] [Accepted: 01/16/2020] [Indexed: 11/22/2022]
Abstract
Evidence indicates that higher serum 25-hydroxy vitamin D levels may be associated with decreased prevalence of urgency urinary incontinence (UI), but the impact of vitamin D consumption on development of urgency and mixed UI is unclear. The objective was to assess whether greater vitamin D intake was associated with decreased risk of incident urgency and mixed UI over 10 years using 2 large prospective cohorts of middle-aged and older women. We analyzed 38,101 women from the Nurses' Health Study I (NHS I) and 35,190 women from NHS II who were free of UI at baseline. We followed incident UI, defined as new UI occurring at least monthly, separately by subtype (urgency, mixed, stress UI), from 2002-2012. We categorized vitamin D intake from supplements and diet. We estimated relative risk for developing UI according to vitamin D intake using Cox-proportional hazard models with adjustment for covariates. Median vitamin D intake was 580IU in the older women in NHS I (age range 56-71 at baseline) and 487IU in middle-aged women in NHS II (age range 40-57). Among women taking ≥1000IU of vitamin D, median intake in the older women was 1252IU and 1202IU in the middle-aged women. Among the older women, we found no relation of vitamin D intake to risk of developing UI, across all UI subtypes. In multivariable-adjusted analysis for middle-aged women, the relative risk of developing mixed UI among women taking >1000IU was 0.79 (0.63, 0.99) and for urgency UI was 0.88 (0.71, 1.07), versus <200IU. Risks of developing stress UI were not related to vitamin D intake categories. Overall, we did not find a relationship between vitamin D intake and UI incidence in middle-aged and older women; however, the reported intake was moderate.
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Affiliation(s)
- Alayne D Markland
- Birmingham Geriatric Research, Education, and Clinical Center (GRECC), Department of Veterans Affairs, Birmingham, AL, United States; University of Alabama at Birmingham, Department of Medicine, Birmingham, AL, United States.
| | - Camille Vaughan
- Birmingham Geriatric Research, Education, and Clinical Center (GRECC), Department of Veterans Affairs, Birmingham, AL, United States; Emory University Department of Medicine, Atlanta, GA, United States
| | - Alison Huang
- University of California, San Francisco, Department of Medicine, San Francisco, CA, United States
| | - Vin Tangpricha
- Emory University Department of Medicine, Atlanta, GA, United States
| | - Francine Grodstein
- Channing Division of Network Medicine Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States
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10
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Almasmoum H, Refaat B, Ghaith MM, Almaimani RA, Idris S, Ahmad J, Abdelghany AH, BaSalamah MA, El-Boshy M. Protective effect of Vitamin D3 against lead induced hepatotoxicity, oxidative stress, immunosuppressive and calcium homeostasis disorders in rat. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2019; 72:103246. [PMID: 31465891 DOI: 10.1016/j.etap.2019.103246] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 08/20/2019] [Accepted: 08/22/2019] [Indexed: 06/10/2023]
Abstract
Lead (Pb) is an extremely poisonous, non-essential trace element and toxicity develops in humans following frequent exposure to the heavy metal in polluted environmental and occupational settings. Pb induces hepatic damage through the depletion of the antioxidant system, enhancing cellular oxidative stress and stimulation of proinflammatory cytokines. Although the antioxidant and anti-inflammatory actions of vitamin D3 (VD3) are well-established, a minority of studies measured the protective actions of VD3 against Pb toxicity. Therefore, this work studied the effects of vitamin VD3 therapy on the fundamental molecular basis underlying hepatic injury induced by chronic Pb toxicity. Twenty-four adult male rats were distributed equally into the negative controls (NC), positive controls (PC) and VD3 groups. While both the PC and VD3 groups received Pb-acetate in drinking water (1000 mg/L) for four weeks, the latter group also received intramuscular VD3 injections (1000 IU/kg; 3 days/week) simultaneously with Pb. The liver enzymes together with the serum and hepatic tissue Pb concentrations increased markedly in the PC group compared with the NC group. Pb toxicity also drastically induced hepatocyte apoptosis/necrosis, increased the hepatic tissue concentrations of malondialdehyde and the pro-inflammatory cytokines (TGF-β, IL-4 & TNF-α) as well as reduced the anti-oxidative enzymes (GSH, GPx & CAT) and the anti-inflammatory cytokine, IL-10, compared with the NC group. Pb also significantly decreased the serum concentrations of VD3 and Ca2+. Additionally, the hepatic expressions of VD receptor, Cyp24a1 enzyme, L-type Ca2+-channel, calbindin-D28k & -D29k, calmodulin and calmodulin-dependent protein kinase II were significantly upregulated, whereas the VD binding protein, CYP2R1 enzyme and T-type Ca2+-channel were markedly inhibited at the gene and protein levels following Pb intoxication. VD3 alleviated the hepatic damage, inhibited the oxidative stress and pro-inflammatory molecules as well as upregulated the anti-oxidant and anti-inflammatory markers and restored the expression of the VD/Ca2+ regulatory molecules compared with the PC group. VD3 supplementation discloses promising protective effects against Pb-induced hepatic damage, through its anti-inflammatory and antioxidant actions as well as by modulating the hepatocyte calcium homeostatic molecules.
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Affiliation(s)
- Hussain Almasmoum
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia.
| | - Bassem Refaat
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia.
| | - Mazen M Ghaith
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia.
| | - Riyad A Almaimani
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia.
| | - Shakir Idris
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia.
| | - Jawwad Ahmad
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia.
| | - Abdelghany H Abdelghany
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia; Department of Anatomy, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
| | - Mohammad A BaSalamah
- Pathology Department, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Saudi Arabia.
| | - Mohamed El-Boshy
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia; Department of Clinical Pathology, Fac. Vet. Med, Mansoura University, Mansoura, Egypt.
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11
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Almaimani RA, Almasmoum H, Ghaith MM, El-Boshy M, Idris S, Ahmad J, Abdelghany AH, BaSalamah MA, Mahbub A, Refaat B. Enhanced remedial effects for vitamin D3 and calcium co-supplementation against pre-existing lead nephrotoxicity in mice: The roles of renal calcium homeostatic molecules. Biochim Biophys Acta Mol Basis Dis 2019; 1865:512-524. [DOI: 10.1016/j.bbadis.2018.11.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 11/09/2018] [Accepted: 11/24/2018] [Indexed: 12/31/2022]
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Ikeda Y, Zabbarova IV, Birder LA, Wipf P, Getchell SE, Tyagi P, Fry CH, Drake MJ, Kanai AJ. Relaxin-2 therapy reverses radiation-induced fibrosis and restores bladder function in mice. Neurourol Urodyn 2018; 37:2441-2451. [PMID: 29806709 PMCID: PMC6202145 DOI: 10.1002/nau.23721] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 05/09/2018] [Indexed: 12/27/2022]
Abstract
AIM To determine the efficacy of human relaxin-2 (hRLX2) in reversing radiation-induced bladder fibrosis and lower urinary tract dysfunction (LUTD). Radiation cystitis is a consequence of radiotherapy for pelvic malignancies. Acutely, irradiation leads to reactive oxygen/nitrogen species in urothelial cells, apoptosis, barrier disruption, and inflammation. Chronically, this results in collagen deposition, bladder fibrosis, and attenuated storage and voiding functions. In severe cases, cystectomies are performed as current therapies do not reverse fibrosis. METHODS We developed a mouse model for selective bladder irradiation (10 Gray; 1 Gy = 100 rads) resulting in chronic fibrosis within 6 weeks, with decreased bladder compliance, contractility, and overflow incontinence. Seven weeks post-irradiation, female C57Bl/6 mice were continuously infused with hRLX2 (400 μg/kg/day/14 days) or vehicle (saline) via subcutaneous osmotic pumps. Mice were evaluated in vivo using urine spot analysis, cystometrograms and external urethral sphincter electromyograms; and in vitro using length-tension measurements, Western blots, histology, and immunohistochemistry. RESULTS hRLX2 reversed fibrosis, decreased collagen content, improved bladder wall architecture, and increased bladder compliance, detrusor smooth muscle Cav1.2 expression and detrusor contractility in mice with chronic radiation cystitis. hRLX2 treatment outcomes were likely caused by the activation of RXFP1/2 receptors which are expressed on the detrusor. CONCLUSION hRLX2 may be a new therapeutic option for rescuing bladders with chronic radiation cystitis.
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Affiliation(s)
- Youko Ikeda
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Irina V. Zabbarova
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Lori A. Birder
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania,Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Peter Wipf
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Samuel E. Getchell
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Pradeep Tyagi
- Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Christopher H. Fry
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Marcus J. Drake
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Anthony J. Kanai
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania,Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Snekalatha S, Kanthakumar P. Ascorbic acid does not modulate potassium currents in cultured human lymphocytes. J Basic Clin Physiol Pharmacol 2017; 28:371-375. [PMID: 28306530 DOI: 10.1515/jbcpp-2016-0182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 01/13/2017] [Indexed: 11/15/2022]
Abstract
BACKGROUND Ascorbic acid (AA) is known to modulate lymphocyte function, but the mechanism of action is not clearly understood. As voltage-gated potassium currents play an important role in lymphocyte function, the effect of AA on voltage-gated potassium currents was studied. METHODS Peripheral blood mononuclear cells were cultured in the presence of increasing concentrations of AA (0, 0.125, 0.25, 0.5, and 1 mM). Potassium currents in resting lymphocytes were studied by whole cell patch clamp technique using a depolarizing protocol. Lymphocyte function was assessed by measuring interleukin-2 (IL-2) secretion after mitogenic stimulation by ELISA. RESULTS The mean current density of potassium currents recorded from cells cultured for 48 h in the presence of 0.125 mM AA was not significantly different from that of cells cultured in the absence of AA. There was about 50% inhibition of IL-2 secretion in cell cultures with 0.125 mM AA when compared to controls without AA. At higher concentrations of AA, the IL-2 secretion decreased further. CONCLUSIONS The results of the study indicate that the inhibition of lymphocyte function by AA in vitro may not be due to inhibition of potassium currents in the concentration tested.
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Expected Next-Generation Drugs Under Development in Relation to Voiding Symptoms. Int Neurourol J 2017; 21:97-101. [PMID: 28673067 PMCID: PMC5497200 DOI: 10.5213/inj.1734928.464] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 06/19/2017] [Indexed: 11/12/2022] Open
Abstract
New drug development is a high-risk venture, but if successful, will bring great revenues to those willing to accept the risk. In the field of urology, in particular for lower urinary tract symptoms (LUTS), the recent successful landing of drugs (e.g., mirabegron, botulinum toxin A, and tadalafil) has resulted in increased interest in new drug development. Benign prostatic hyperplasia and overactive bladder syndrome, representative LUTS diseases, are attractive targets because of their prevalence and market size in the field of urology. Additionally, the awareness about new stream of research is very important not only because of the market size and economic factors, but also because to keep steady attention to these research for the researcher’s. We have reviewed a selection of new drugs currently under development for the treatment of the two aforementioned diseases and hope to offer urologists an overview of the current situation and future directions in the field of urology.
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Association of Circulating 25(OH)D and Lower Urinary Tract Symptoms: A Four-Year Prospective Study among Elderly Chinese Men. Nutrients 2016; 8:nu8050273. [PMID: 27164139 PMCID: PMC4882686 DOI: 10.3390/nu8050273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 04/29/2016] [Accepted: 05/04/2016] [Indexed: 01/23/2023] Open
Abstract
The role of vitamin D in relation to lower urinary tract symptoms (LUTS) remains inconclusive. This four-year longitudinal study aims to explore the association of circulating 25(OH)D and LUTS in elderly Chinese men. Two thousand Chinese men aged 65 and older were recruited from a local community, of which 1998 (99.9%) at baseline and 1564 (78.2%) at four-year follow-up reported data on LUTS, and 988 of the randomly chosen subpopulation were assayed for serum 25(OH)D by radioimmunoassay at baseline. LUTS were evaluated by a validated International Prostate Symptoms Scale (IPSS). Data on demographic characteristics, lifestyle factors, health, and medications were collected. Serum parathyroid and sex steroid hormones and genotypes of vitamin D receptors were assayed. The association of serum 25(OH)D and LUTS was examined by using multivariable regression models. Serum 25(OH)D was not significantly associated with the changes of IPSS or the risk of LUTS in overall participants. However, among men with 25(OH)D ≤ 60 nmol/L, each 10 nmol/L increase of 25(OH)D over 0 nmol/L was significantly associated with 1.3 lower points of IPSS or a 51.6% decreased risk for moderate/severe LUTS four years later. Adjustment for serum androstenedione (p = 0.019) and dehydropiandrosterone (p = 0.037) attenuated the associations. Our study suggested that among individuals with low vitamin D status, the increase of the 25(OH)D level may be associated with a lowered risk of LUTS.
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Sacco E, Recupero S, Bientinesi R, Palermo G, D’Agostino D, Currò D, Bassi P. Pioneering drugs for overactive bladder and detrusor overactivity: Ongoing research and future directions. World J Obstet Gynecol 2015; 4:24-39. [DOI: 10.5317/wjog.v4.i2.24] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Revised: 01/31/2015] [Accepted: 04/14/2015] [Indexed: 02/05/2023] Open
Abstract
The ongoing research on pioneering drug candidates for the overactive bladder (OAB) aimed to overcome the limitations of currently licensed pharmacotherapies, such as antimuscarinics, β3-adrenergic agents, and botulinum neurotoxin, has been reviewed performing a systematic literature review and web search. The review covers the exploratory agents alternative to available medications for OAB and that may ultimately prove to be therapeutically useful in the future management of OAB patients based on preclinical and early clinical data. It emerges that many alternative pharmacological strategies have been discovered or are under investigation in disease-oriented studies. Several potential therapeutics are known for years but still find obstacles to pass the clinical stages of development, while other completely novel compounds, targeting new pharmacological targets, have been recently discovered and show potential to translate into clinical therapeutic agents for idiopathic and neurogenic OAB syndrome. The global scenario of investigational drugs for OAB gives promise for the development of innovative therapeutics that may ultimately prove effective as first, combined or second-line treatments within a realistic timescale of ten years.
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Gacci M, Carini M, Salvi M, Sebastianelli A, Vignozzi L, Corona G, Maggi M, McVary KT, Kaplan SA, Oelke M, Serni S. Management of benign prostatic hyperplasia: role of phosphodiesterase-5 inhibitors. Drugs Aging 2015; 31:425-39. [PMID: 24811735 DOI: 10.1007/s40266-014-0177-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Several studies have highlighted a strong association between benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) and erectile dysfunction (ED), particularly in elderly men. Many epidemiological trials, such as in vitro and in vivo studies, have reported the emerging role of metabolic syndrome, including abdominal obesity, impaired glucose metabolism, hypertriglyceridemia, low high-density lipoprotein cholesterol, and hypertension, in the development and progression of urinary and sexual symptoms. Moreover, many authors have focused their studies on the identification of all the shared pathogenetic mechanisms of LUTS/BPH and ED, including alteration of cyclic guanosine monophosphate and RhoA-ROCK pathways or vascular and neurogenic dysfunction. All these are potential targets for proposed phosphodiesterase type 5 inhibitors (PDE5-Is). Therefore, several trials have recently been designed to evaluate the role of PDE5-Is alone or in combination with conventional treatment for BPH, such as α-adrenergic blockers, in men affected by LUTS/BPH, with or without ED. Different PDE5-Is are in clinical use worldwide and currently six of them are licensed for the oral treatment of ED. All these compounds differ in pharmacokinetic factors, with influence on drug action, and subsequently in the overall safety and efficacy profile.
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Affiliation(s)
- M Gacci
- Department of Urology, University of Florence, Careggi Hospital, Viale Pieraccini 18, 50139, Florence, Italy,
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Sacco E, Bientinesi R. Innovative pharmacotherapies for women with overactive bladder: where are we now and what is in the pipeline? Int Urogynecol J 2014; 26:629-40. [PMID: 25377296 DOI: 10.1007/s00192-014-2557-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 10/18/2014] [Indexed: 12/12/2022]
Abstract
INTRODUCTION AND HYPOTHESIS The impressive prevalence of overactive bladder (OAB) and the relevant limitations of current treatments urge the need for novel therapeutic approaches. METHODS A systematic literature and web search was performed to identify investigational drugs that entered the early and late phases of clinical development for women with OAB symptoms. RESULTS Approved pharmacological therapies for OAB (antimuscarinics, beta-3 agonists, and botulinum toxin) are evolving with the development of alternative administration methods, combination strategies, and novel compounds, expected to improve effectiveness, bladder selectivity, and dose flexibility. A wealth of investigational compounds, developed with both public and companies' indoor nonclinical disease-oriented studies, entered the early and late stages of clinical development in the last decade. Most non-anticholinergic compounds in ongoing clinical trials target central and peripheral neurotransmitter receptors involved in neurological modulation of micturition, nonadrenergic-noncholinergic mechanisms, cyclic nucleotide metabolism, different subtypes of ion channels or peripheral receptors of prostaglandins, vanilloids, vitamin D3, and opioids. Fascinating advances are ongoing also in the field of genetic therapy. CONCLUSIONS New pharmaceutical formulations and drug combinations are expected to be available in the next decade in order to overcome the limitations of current drugs for OAB. Although proof-of-concept, patient-oriented studies yielded disappointing results for several tentative drugs, a lot of clinical research is ongoing that is expected to provide clinicians with novel therapeutic agents in the near future.
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Affiliation(s)
- Emilio Sacco
- Department of Urology, "Agostino Gemelli" Hospital, Catholic University Medical School, Rome, Italy,
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You are what you eat: The impact of diet on overactive bladder and lower urinary tract symptoms. Maturitas 2014; 79:8-13. [DOI: 10.1016/j.maturitas.2014.06.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 06/11/2014] [Indexed: 11/21/2022]
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Foti D, Greco M, Cantiello F, Damiano R, Gulletta E, Pujia A, Montalcini T. Hypovitaminosis D and Low Urinary Tract Symptoms in a Female Population. EUR J INFLAMM 2014. [DOI: 10.1177/1721727x1401200215] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
An increasing number of studies have suggested a key role for low levels of vitamin D in the development of several chronic diseases and bacterial infections. In particular, its role in acute respiratory infection has been clarified, while the potential role of vitamin D for susceptibility to urinary tract infections still remains unexplored. Since the typical symptoms associated with urinary infections or with other conditions, like overactive bladder, include dysuria, urgency and frequency, the aim of this study was to investigate the association between these symptoms and vitamin D status. We conducted a retrospective study on 233 women who, in the previous year, had their serum levels of vitamin D measured. The subjects were queried about the presence of urinary symptoms and their frequency over the previous year. Women with low serum levels of vitamin D had a higher prevalence of symptoms than those with normal levels of vitamin D (p<0.001). In particular, women who reported high frequency of symptoms had a mean vitamin D level of ∼ 27 ng/mL, those with low frequency had a mean vitamin D level of ∼ 24 ng/mL, while asymptomatic women had mean levels of ∼ 37 ng/mL (p=0.004 among group). In this study hypovitaminosis D is associated with urinary symptoms in a population of women, and it may suggest a key role of this vitamin in the development of infections or other conditions affecting the urinary tract.
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Affiliation(s)
- D. Foti
- Laboratory Unit, Clinical Pathology, Department of Health Sciences, University Magna Grecia, Catanzaro, Italy
| | - M. Greco
- Laboratory Unit, Clinical Pathology, Department of Health Sciences, University Magna Grecia, Catanzaro, Italy
| | - F. Cantiello
- Urology Unit, Department of Clinical and Experimental Medicine, University Magna Grecia, Catanzaro, Italy
| | - R. Damiano
- Urology Unit, Department of Clinical and Experimental Medicine, University Magna Grecia, Catanzaro, Italy
| | - E. Gulletta
- Laboratory Unit, Clinical Pathology, Department of Health Sciences, University Magna Grecia, Catanzaro, Italy
| | - A. Pujia
- Clinical Nutrition Unit, Department of Medical and Surgical Science, University Magna Grecia, Catanzaro, Italy
| | - T. Montalcini
- Clinical Nutrition Unit, Department of Medical and Surgical Science, University Magna Grecia, Catanzaro, Italy
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Kedar A, Nikitina Y, Henry OR, Abell KB, Vedanarayanan V, Griswold ME, Subramony C, Abell TL. Gastric dysmotility and low serum vitamin D levels in patients with gastroparesis. Horm Metab Res 2013; 45:47-53. [PMID: 22956309 PMCID: PMC5089061 DOI: 10.1055/s-0032-1323689] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Nutritional abnormalities are common in patients with gastroparesis (Gp), a disorder that may affect gastric motility and may delay emptying. The aim of this work was to identify relationships between serum nutrition markers including 25-OH vitamin D and gastric motility measures in Gp patients. We enrolled 59 consecutive gastric motility clinic patients (48 females, 11 males; mean age 44 years; 42 idiopathic; 17 diabetes mellitus) with Gp symptoms. The 25-OH vitamin D levels, for most patients slightly above the lower limit of normal (96.98 nmol/l ± 60.99), were lowest in diabetic range (DM) (75.68 nmol/l ± 34.22) vs. idiopathic (ID) (105.03 nmol/l ± 67.08) gastroparesis patients. First hour GET: one unit increase in 25-OH vitamin D level was associated 0.11% improvement (95% CI -0.22, 0.01 p=0.056) in gastric motility in all patients; this association, although marked in ID Gp patients, (-0.13, CI -0.25, -0.01 p=0.034), was not seen in DM Gp, (0.2, CI -0.45, 0.87, p=0.525). Fourth hour GET: Every unit increase of 25-OH vitamin D was associated with significant improvement in all patients, ( 0.11% CI -0.23, 0.01, p=0.053), and some weak improvement in ID group, (0.11% -0.24, 0.01, p=0.076) and absent in patients with DM (0.03, CI -0.66, 0.72, p=0.932). It is concluded that 25-OH vitamin D levels may influence gastric emptying. Underlying mechanisms for this observation might include the impact of 25-OH vitamin D on the health of the enteric nervous system. 25-OH vitamin D contributions to enteric nerve functions should be explored, particularly where autonomic nervous system comorbidities exist.
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Affiliation(s)
- A Kedar
- Division of Digestive Diseases, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
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Dicken CL, Israel DD, Davis JB, Sun Y, Shu J, Hardin J, Neal-Perry G. Peripubertal vitamin D(3) deficiency delays puberty and disrupts the estrous cycle in adult female mice. Biol Reprod 2012; 87:51. [PMID: 22572998 DOI: 10.1095/biolreprod.111.096511] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
The mechanism(s) by which vitamin D(3) regulates female reproduction is minimally understood. We tested the hypothesis that peripubertal vitamin D(3) deficiency disrupts hypothalamic-pituitary-ovarian physiology. To test this hypothesis, we used wild-type mice and Cyp27b1 (the rate-limiting enzyme in the synthesis of 1,25-dihydroxyvitamin D(3)) null mice to study the effect of vitamin D(3) deficiency on puberty and reproductive physiology. At the time of weaning, mice were randomized to a vitamin D(3)-replete or -deficient diet supplemented with calcium. We assessed the age of vaginal opening and first estrus (puberty markers), gonadotropin levels, ovarian histology, ovarian responsiveness to exogenous gonadotropins, and estrous cyclicity. Peripubertal vitamin D(3) deficiency significantly delayed vaginal opening without affecting the number of GnRH-immunopositive neurons or estradiol-negative feedback on gonadotropin levels during diestrus. Young adult females maintained on a vitamin D(3)-deficient diet after puberty had arrested follicular development and prolonged estrous cycles characterized by extended periods of diestrus. Ovaries of vitamin D(3)-deficient Cyp27b1 null mice responded to exogenous gonadotropins and deposited significantly more oocytes into the oviducts than mice maintained on a vitamin D(3)-replete diet. Estrous cycles were restored when vitamin D(3)-deficient Cyp27b1 null young adult females were transferred to a vitamin D(3)-replete diet. This study is the first to demonstrate that peripubertal vitamin D(3) sufficiency is important for an appropriately timed pubertal transition and maintenance of normal female reproductive physiology. These data suggest vitamin D(3) is a key regulator of neuroendocrine and ovarian physiology.
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Affiliation(s)
- Cary L Dicken
- Department of Obstetrics and Gynecology and Women's Health, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, USA
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23
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Streng T, Andersson KE, Hedlund P, Gratzke C, Baroni E, D'Ambrosio D, Benigni F. Effects on bladder function of combining elocalcitol and tolterodine in rats with outflow obstruction. BJU Int 2012; 110:E125-31. [DOI: 10.1111/j.1464-410x.2011.10838.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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Vaughan CP, Johnson TM, Goode PS, Redden DT, Burgio KL, Markland AD. Vitamin D and lower urinary tract symptoms among US men: results from the 2005-2006 National Health and Nutrition Examination Survey. Urology 2011; 78:1292-7. [PMID: 22014969 DOI: 10.1016/j.urology.2011.07.1415] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2011] [Revised: 07/27/2011] [Accepted: 07/29/2011] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To evaluate the association of vitamin D levels and lower urinary tract symptoms (LUTS) among US men. MATERIAL AND METHODS Data were analyzed for 2387 men (≥20 years) who participated in the 2005-2006 cycle of the National Health and Nutrition Examination Survey, a cross-sectional survey of the US noninstitutionalized population. LUTS included nocturia, incomplete emptying, hesitancy, and urinary incontinence (UI). Plasma 25-hydroxyvitamin D was categorized as ≥30 ng/mL (normal), 20-30 ng/mL (insufficiency), and <20 ng/mL (deficiency). Other factors included age, race/ethnicity, education, body mass index, self-reported health status, chronic diseases, and prior diagnosis of benign prostatic enlargement and/or prostate cancer (men ≥40 years of age). Prevalence and prevalence odds ratios (POR) were estimated from a multivariable logistic regression analysis using appropriate sampling weights. RESULTS A majority (89%, n = 1241) had vitamin D levels <30 ng/mL, of whom 55% (n = 684) had vitamin D levels <20 ng/mL. Vitamin D levels ranged from 2-56 ng/mL (median 19 ng/mL, mean ± SD 19.9 ± 8.0). Among the 1388 (58%) men with LUTS data and vitamin D levels, 48% (n = 666) had at least 1 LUTS. In multivariable analyses adjusting for age and race norms, vitamin D deficiency was associated with the presence of moderate-severe UI (POR 1.8, 95% CI 1.1, 3.0) and at least 1 LUTS (POR 1.4, 95% CI 1.0, 2.0). CONCLUSION Vitamin D insufficiency and deficiency are highly prevalent among adult men in the US, and vitamin D deficiency is associated with moderate-severe UI and the presence of at least 1 LUTS.
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Affiliation(s)
- Camille P Vaughan
- Department of Veterans Affairs Medical Center, Birmingham, AL 35233, USA
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Squecco R, Garella R, Luciani G, Francini F, Baccari MC. Muscular effects of orexin A on the mouse duodenum: mechanical and electrophysiological studies. J Physiol 2011; 589:5231-46. [PMID: 21911618 DOI: 10.1113/jphysiol.2011.214940] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Orexin A (OXA) has been reported to influence gastrointestinal motility, acting at both central and peripheral neural levels. The aim of the present study was to evaluate whether OXA also exerts direct effects on the duodenal smooth muscle. The possible mechanism of action involved was investigated by employing a combined mechanical and electrophysiological approach. Duodenal segments were mounted in organ baths for isometric recording of the mechanical activity. Ionic channel activity was recorded in current- and voltage-clamp conditions by a single microelectrode inserted in a duodenal longitudinal muscle cell. In the duodenal preparations, OXA (0.3 μM) caused a TTX-insensitive transient contraction. Nifedipine (1 μM), as well as 2-aminoethyl diphenyl borate (10 μM), reduced the amplitude and shortened the duration of the response to OXA, which was abolished by Ni(2+) (50 μM) or TEA (1 mM). Electrophysiological studies in current-clamp conditions showed that OXA caused an early depolarization, which paralleled in time the contractile response, followed by a long-lasting depolarization. Such a depolarization was triggered by activation of receptor-operated Ca(2+) channels and enhanced by activation of T- and L-type Ca(2+) channels and store-operated Ca(2+) channels and by inhibition of K(+) channels. Experiments in voltage-clamp conditions demonstrated that OXA affects not only receptor-operated Ca(2+) channels, but also the maximal conductance and kinetics of activation and inactivation of Na(+), T- and L-type Ca(2+) voltage-gated channels. The results demonstrate, for the first time, that OXA exerts direct excitatory effects on the mouse duodenal smooth muscle. Finally, this work demonstrates new findings related to the expression and kinetics of the voltage-gated channel types, as well as store-operated Ca(2+) channels.
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Affiliation(s)
- Roberta Squecco
- Dipartimento di Scienze Fisiologiche, Università di Firenze, Firenze, Italy
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26
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Adorini L, Penna G, Fibbi B, Maggi M. Vitamin D receptor agonists target static, dynamic, and inflammatory components of benign prostatic hyperplasia. Ann N Y Acad Sci 2010; 1193:146-52. [PMID: 20398021 DOI: 10.1111/j.1749-6632.2009.05299.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The bioactive form of vitamin D, 1,25-dihydroxyvitamin D(3), is a secosteroid hormone that binds to the vitamin D receptor (VDR), a member of the nuclear receptor superfamily, and modulates a variety of biological functions. The VDR is expressed by most cell types, including cells of the urogenital system, such as prostate and bladder cells. In particular, the prostate is a target organ of VDR agonists and represents an extrarenal synthesis site of 1,25-dihydroxyvitamin D(3). We have analyzed the capacity of VDR agonists to treat benign prostatic hyperplasia (BPH), a complex syndrome characterized by a static component related to prostate overgrowth, a dynamic component responsible for urinary irritative symptoms, and an inflammatory component. Data reviewed here demonstrate that VDR agonists, and notably elocalcitol, reduce the static component of BPH by inhibiting the activity of intraprostatic growth factors downstream of the androgen receptor, the dynamic component by targeting the RhoA/ROCK pathway in prostate and bladder cells, and the inflammatory component by targeting the NF-kappaB pathway.
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Mizwicki MT, Norman AW. The vitamin D sterol-vitamin D receptor ensemble model offers unique insights into both genomic and rapid-response signaling. Sci Signal 2009; 2:re4. [PMID: 19531804 DOI: 10.1126/scisignal.275re4] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Steroid hormones serve as chemical messengers in a wide number of species and target tissues by transmitting signals that result in both genomic and nongenomic responses. Genomic responses are mediated by the formation of a ligand-receptor complex with its cognate steroid hormone nuclear receptor (NR). Nongenomic responses can be mediated at the plasma membrane by a membrane-localized NR. The focus of this Review is on the structural attributes and molecular mechanisms underlying vitamin D sterol (VDS)-vitamin D receptor (VDR) selective and stereospecific regulation of nongenomic and genomic signaling. The VDS-VDR conformational ensemble model describes how VDSs can selectively initiate or block either nongenomic or genomic biological responses by interacting with two VDR ligand-binding pockets, one kinetically favored by 1alpha,25(OH)(2)D(3) (1,25D) and the other thermodynamically favored. We describe the variables that affect the three major elements of the model: the conformational flexibility of the unliganded (apo) protein, the flexibility of the VDS, and the physicochemical selectivity of the VDR genomic pocket (VDR-GP) and alternative pocket (VDR-AP). We also discuss how these three factors collectively provide a rational explanation for the complexities of VDS regulation of cell biology and highlight the current limitations of the model.
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Affiliation(s)
- Mathew T Mizwicki
- Department of Biochemistry, University of California, Riverside, CA 92521, USA.
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Cross HS, Kallay E. Regulation of the colonic vitamin D system for prevention of tumor progression: an update. Future Oncol 2009; 5:493-507. [DOI: 10.2217/fon.09.22] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
A compromised vitamin D status and nutritional calcium deficit are linked with sporadic colorectal cancer incidence. 25(OH)D3 serum concentration is a major determinant of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) synthesis in colonic mucosa, which expresses the vitamin D receptor and both the synthesizing (CYP27B1) and catabolic (CYP24A1) hydroxylases. Receptor-bound, 1,25(OH)2D3 regulates proliferation, differentiation and apoptosis in an autocrine/paracrine manner. During early malignancy 1,25(OH)2D3 synthesis is often enhanced to counteract hyperproliferation. In many advanced tumors, vitamin D catabolism surpasses synthesis. In vivo, expression and activity of CYP27B1 and vitamin D receptor are stimulated by (phyto)estrogens. Conversely, low nutritional calcium and folate enhance vitamin D catabolism. These insights could explain the lower colorectal cancer incidence in females, the chemopreventive potency of vitamin D and calcium against colorectal cancer, and the benefit of nutritional folate as a methyl donor for epigenetic regulation of the vitamin D system.
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Affiliation(s)
- Heide S Cross
- Department of Pathophysiology, Medical University of Vienna, Waehringerguertel 18–20, A-1090 Vienna, Austria
| | - Enikoe Kallay
- Department of Pathophysiology, Medical University of Vienna, Waehringerguertel 18–20, A-1090 Vienna, Austria
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29
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Penna G, Fibbi B, Amuchastegui S, Corsiero E, Laverny G, Silvestrini E, Chavalmane A, Morelli A, Sarchielli E, Vannelli GB, Gacci M, Colli E, Maggi M, Adorini L. The vitamin D receptor agonist elocalcitol inhibits IL-8-dependent benign prostatic hyperplasia stromal cell proliferation and inflammatory response by targeting the RhoA/Rho kinase and NF-kappaB pathways. Prostate 2009; 69:480-93. [PMID: 19107880 DOI: 10.1002/pros.20896] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Benign prostatic hyperplasia (BPH) is characterized by an important inflammatory component. Stimulation of human prostate stromal cells from BPH tissues with proinflammatory cytokines leads to secretion of IL-8, a chemokine involved in BPH pathogenesis. The vitamin D receptor (VDR) agonist elocalcitol can arrest prostate growth in BPH patients, but its mechanism of action in this pathology is still incompletely understood. METHODS IL-8 levels were measured by real-time RT-PCR and ELISA. NF-kappaB translocation and COX-2 expression were evaluated by confocal microscopy. RhoA and Rho-kinase (ROCK) gene expression and functional activity were studied by real-time RT-PCR, immuno-kinase assays, Western blot analysis, confocal microscopy, and cell invasion. RESULTS Stimulation of BPH cells with IL-8 activates the calcium-sensitizing RhoA/ROCK pathway, as demonstrated by the increased membrane translocation of RhoA and by phosphorylation of the ROCK substrate myosin phosphatase target subunit 1 (MYPT-1). In agreement with these data, C3 exoenzyme, a selective RhoA inhibitor, inhibits IL-8-induced invasion of BPH cells. The VDR agonist elocalcitol significantly inhibits IL-8 production by BPH cells stimulated with inflammatory cytokines, and IL-8-induced proliferation of BPH cells. In addition, elocalcitol inhibits IL-8-induced membrane translocation of RhoA and MYPT-1 phosphorylation in BPH cells, and inhibits dose-dependently their IL-8-dependent invasion. The inhibition induced by elocalcitol of IL-8 production by BPH cells is accompanied by decreased COX-2 expression and PGE(2) production and by arrest of NF-kappaB p65 nuclear translocation, associated with inhibition of the RhoA/ROCK pathway. CONCLUSIONS These data provide a mechanistic explanation for the anti-proliferative and anti-inflammatory properties of elocalcitol in BPH cells.
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Ordóñez-Morán P, Larriba MJ, Pálmer HG, Valero RA, Barbáchano A, Duñach M, de Herreros AG, Villalobos C, Berciano MT, Lafarga M, Muñoz A. RhoA-ROCK and p38MAPK-MSK1 mediate vitamin D effects on gene expression, phenotype, and Wnt pathway in colon cancer cells. ACTA ACUST UNITED AC 2008; 183:697-710. [PMID: 19015318 PMCID: PMC2582889 DOI: 10.1083/jcb.200803020] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The active vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits proliferation and promotes differentiation of colon cancer cells through the activation of vitamin D receptor (VDR), a transcription factor of the nuclear receptor superfamily. Additionally, 1,25(OH)2D3 has several nongenomic effects of uncertain relevance. We show that 1,25(OH)2D3 induces a transcription-independent Ca2+ influx and activation of RhoA–Rho-associated coiled kinase (ROCK). This requires VDR and is followed by activation of the p38 mitogen-activated protein kinase (p38MAPK) and mitogen- and stress-activated kinase 1 (MSK1). As shown by the use of chemical inhibitors, dominant-negative mutants and small interfering RNA, RhoA–ROCK, and p38MAPK-MSK1 activation is necessary for the induction of CDH1/E-cadherin, CYP24, and other genes and of an adhesive phenotype by 1,25(OH)2D3. RhoA–ROCK and MSK1 are also required for the inhibition of Wnt–β-catenin pathway and cell proliferation. Thus, the action of 1,25(OH)2D3 on colon carcinoma cells depends on the dual action of VDR as a transcription factor and a nongenomic activator of RhoA–ROCK and p38MAPK-MSK1.
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Affiliation(s)
- Paloma Ordóñez-Morán
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
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